CN117247375A

CN117247375A - Bulk drug of crystalline form of compound and fumaric acid, pharmaceutical composition and application thereof

Info

Publication number: CN117247375A
Application number: CN202211071032.1A
Authority: CN
Inventors: 何红燕; 黄旺; 吴小涛; 王松笛; 鲍标贵; 李超; 曲蕾
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: 2022-06-09
Filing date: 2022-06-09
Publication date: 2023-12-19
Also published as: CN114716417A; CN114716417B

Abstract

The invention provides a bulk drug which comprises a compound of a formula (I) and a crystal form of fumaric acid, and is characterized in that the particle size D of the bulk drug ₉₀ 5-60 μm;a pharmaceutical composition comprising the drug substance and a physiologically acceptable/pharmaceutically acceptable excipient, wherein the physiologically acceptable/pharmaceutically acceptable excipient comprises one or more of a filler, a disintegrant, a lubricant, a binder, a solubilizing agent, a glidant; a process for the preparation of the pharmaceutical composition; and/or, the crude drug or the pharmaceutical composition is preparedUse in the preparation of a medicament for treating a disease caused by a coronavirus in a subject, including children, adults or elderly. The bulk drug of the invention can lead the pharmaceutical composition containing the bulk drug to have faster dissolution rate and higher dissolution rate.

Description

Bulk drug of crystalline form of compound and fumaric acid, pharmaceutical composition and application thereof

Technical Field

The present invention relates to bulk drugs of crystalline forms of a compound and fumaric acid, pharmaceutical compositions comprising the same and their use in the manufacture of a medicament for the treatment of a coronavirus-induced disease in a subject.

Background

Coronaviruses are becoming a research hotspot in the virology field due to severe acute respiratory syndrome, middle eastern respiratory syndrome, and new coronavirus pneumonia.

The prior art discloses compounds having therapeutic potential against diseases caused by coronaviruses, in particular novel coronaviruses, but there is still a need for a pharmaceutical composition for treating diseases caused by coronaviruses, in particular novel coronaviruses, to meet the urgent need of clinical treatment.

Disclosure of Invention

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

In a first aspect of the present invention there is provided a pharmaceutical formulation comprising a crystalline form of a compound of formula (I) with fumaric acid,

characterized in that it has a particle diameter D ₉₀ 5-60 μm.

In a second aspect of the present invention, there is provided a pharmaceutical composition comprising a drug substance of the present invention, and a physiologically acceptable/pharmaceutically acceptable excipient; wherein the physiologically acceptable/pharmaceutically acceptable excipient comprises one or more of filler, disintegrant, lubricant, glidant.

In a third 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 the bulk drug of the invention and physiologically acceptable/pharmaceutically acceptable excipients;

(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 fourth aspect of the invention there is provided the use of a drug substance of the invention or a pharmaceutical composition of the invention in the manufacture of a medicament for the treatment of a disease caused by coronavirus in a subject.

The inventive research shows that the bulk drug can enable the pharmaceutical composition containing the bulk drug to have higher dissolution rate and higher dissolution rate.

Drawings

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

FIG. 2 is a Differential Scanning Calorimeter (DSC) profile and thermogravimetric analysis (TGA) profile of a compound of formula (I) with crystalline form A of fumaric acid.

FIG. 3 is an X-ray powder diffraction pattern of crystalline form B of the compound of formula (I) with fumaric acid. Wherein the abscissa is 2θ (°), and the ordinate is intensity (count).

Fig. 4 is a Differential Scanning Calorimeter (DSC) profile of crystalline form B of the compound of formula (I) and fumaric acid.

FIG. 5 is a thermogravimetric analysis (TGA) spectrum of crystalline form B of the compound of formula (I) with fumaric acid.

Fig. 6 is a Polarized Light Microscope (PLM) image of drug substance 6 comprising crystalline form a of the compound of formula (I) and fumaric acid, prepared in the example of the present invention.

FIG. 7 is a particle size distribution diagram of a drug substance 5 comprising a crystalline form A of a compound of formula (I) and fumaric acid, wherein D, prepared in accordance with the examples of the present invention ₅₀ 18.6 μm, D ₉₀ 34.2 μm.

Detailed Description

The term "drug substance" refers to a drug substance used for producing various preparations, which is an active ingredient (also referred to as an active ingredient) in the preparation, is prepared by a chemical synthesis or biotechnology method and is used as a medicinal powder, crystal or the like, but cannot be directly taken by a subject.

In one specific embodiment, the bulk drug of the invention is characterized in that the particle size D ₅₀ Less than or equal to 30 μm, preferably D ₅₀ ≤20μm。

In one specific embodiment, the bulk drug of the invention is characterized in that the particle size D ₉₀ 10-40 μm.

In still another embodiment, the drug substance of the present invention is characterized by a particle size D ₅₀ Less than or equal to 30 mu m (preferably D) ₅₀ Less than or equal to 20 mu m) and the particle diameter D thereof ₉₀ 5-60 μm (preferably 10-40 μm).

The crystalline forms of the compound of formula (I) and fumaric acid were characterized by X-ray powder diffractometer PANalytical Empyrean (PANalytical, NL) with a 2θ scan angle from 3 ° to 45 °, a scan step size of 0.013 °, a test time of 5 minutes 8 seconds, a light pipe voltage and current of 45kV and 40mA, respectively, and a zero background sample pan.

In a specific embodiment, using Cu-ka radiation, 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 9.5, 13.81, 18.61, 22.59, 23.8, preferably further comprise any one or more of 7.81, 10.14, 11.50, 11.93, 12.31, more preferably still further comprise any one or more of 14.73, 20.87, 21.49, 21.97, 25.39.

In a specific embodiment, the crystalline form of the compound of formula (I) and fumaric acid uses Cu-ka radiation, the characteristic diffraction peaks of the X-ray powder diffraction pattern expressed in terms of 2θ 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 characteristic peaks of the X-ray powder diffraction pattern expressed in terms of 2θ value ± 0.2 ° are shown in the following table.

XRPD diffraction peak data for crystalline form a of compound of formula (I) and fumaric acid

Specifically, the XRPD patterns of the crystalline form a of the compound of formula (I) and fumaric acid are shown in figure 1.

In a specific embodiment, the differential scanning calorimetry pattern of the crystalline form of the compound of formula (I) with fumaric acid has an endothermic peak in the range 274 ℃ ± 2 ℃; preferably, the differential scanning calorimetric profile is as shown in fig. 2.

In a specific embodiment, the thermogravimetric profile of the crystalline form of the compound of formula (I) with fumaric acid is substantially free of weight loss or less than 0.5% weight loss in the range of 150 ℃ and undergoes decomposition at 240 ℃ ± 2 ℃; more preferably, the thermogravimetric analysis is as shown in figure 2.

In a specific embodiment, the ratio of the compound of formula (I) to fumaric acid is 1:1 in crystalline form of the compound of formula (I) to fumaric acid.

In the present application, the crystalline form of the compound of formula (I) and fumaric acid in the present invention is sometimes also referred to as crystalline form a of the compound of formula (I) and fumaric acid, which is distinguished from other crystalline forms of the compound of formula (I) and fumaric acid, as referred to herein as crystalline form B of the compound of formula (I) and fumaric acid.

Specifically, the compound of formula (I) and crystalline form B of fumaric acid use Cu-ka radiation and the characteristic diffraction peaks of the X-ray powder diffraction pattern expressed in terms of 2θ values ± 0.2 ° comprise any three of 14.74, 22.80, 28.80 and 29.42 or 14.74, 22.80, 28.80 and 29.42. Specifically, the characteristic diffraction peaks of the X-ray powder diffraction pattern expressed in terms of 2θ values ± 0.2 ° using Cu-ka radiation for the crystalline form B of the compound of formula (I) and fumaric acid further include any one or more of 7.37, 10.68, 12.13, 19.26, 19.68, 25.03, 31.80, 37.30 and 37.85. Preferably, the crystalline form B of the compound of formula (I) and fumaric acid is irradiated with Cu-ka, and the characteristic peaks of the X-ray powder diffraction pattern expressed in terms of 2θ value ± 0.2 ° are shown in the following table.

XRPD diffraction peak data for crystalline form B of compound of formula (I) and fumaric acid

Diffraction angle 2 theta (°)	d value	Relative intensity (%)
			7.37	12.00	28.8
10.68	8.28	14.5
			12.13	7.29	10.2
14.74	6.01	33.9
			19.26	4.61	28.9
19.68	4.51	24.7
			22.80	3.90	54.9
25.03	3.55	25.4
			28.80	3.10	100.0
29.42	3.03	39.8
			31.80	2.81	19.8
37.30	2.41	9.5
			37.85	2.38	9.7

Specifically, the XRPD patterns of the crystalline form a of the compound of formula (I) and fumaric acid are shown in figure 3.

Specifically, the differential scanning calorimetry pattern of the crystalline form B of the compound of formula (I) and fumaric acid starts phase transition at 132 ℃ and has a melting endotherm at about 266.4 ℃; more preferably, the thermogravimetric analysis is as shown in fig. 4.

Specifically, the thermogravimetric profile of the crystalline form B of the compound of formula (I) and fumaric acid begins to lose a small amount of adsorbed water or solvent when heated to 110 ℃, to 140 ℃, a weight loss of 0.737%; more preferably, the thermogravimetric analysis is as shown in fig. 5.

The inventors have also found that under accelerated stability test conditions (40 ℃ C., 75% Relative Humidity (RH)), the crystalline form A of the compound of formula (I) and fumaric acid is stable, maintains stable appearance and purity over 2 months, and does not dissociate or transcrystalline; in contrast, the crystalline form B of the compound of formula (I) and fumaric acid is unstable and undergoes dissociation or seeding.

The term "physiologically acceptable/pharmaceutically acceptable excipient" refers to an excipient that does not cause significant irritation to an organism and does not interfere with the biological activity and properties of the active ingredient(s) being administered, such as the drug substance(s) described herein.

The physiologically acceptable/pharmaceutically acceptable excipients that are mixed with the bulk drug described herein to form the pharmaceutical composition of the present invention may depend on the intended method of administration of the pharmaceutical composition.

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

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

The pharmaceutical composition of the present invention may be administered orally. Oral administration involves swallowing, whereby the active ingredient (the drug substance according to the invention) is absorbed from the intestine and delivered via the portal circulation to the liver (hepatic first pass metabolism), ultimately into the Gastrointestinal (GI) tract.

The pharmaceutical composition of the present invention is preferably prepared in the form of an oral formulation. The shape of the oral preparation is not particularly limited, and may be any 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 dispersions or suspensions 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 a unit dosage 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 has the same meaning as 2019-nCoV-2, and also includes all variants thereof, such as all variants of 2019 novel coronavirus, e.g., NCBI or GISAID (global shared influenza data initiative organization) listing, particularly including strong important variants such as transmissibility, pathogenicity, or immune evasion, e.g., WHO specified Alpha, beta, gamma, delta, eta, iota, kappa, or Lambda variants, and subsequently 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 a branched polymer with alpha-1-6 glycosidic linkages at the branching site and thousands of glucose units with alpha-1-4 linkages in the linear region. 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.

In a specific embodiment, the pharmaceutical composition of the present invention consists of the drug substance of the present invention and physiologically acceptable/pharmaceutically acceptable excipients.

In a specific embodiment, the weight percentage of the drug substance in the pharmaceutical composition is 15% -60%, preferably 25% -45%.

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

In a specific embodiment, the weight ratio of drug substance to filler is in the range of 1:5 to 1:1, preferably in the range of 1:2 to 1:1.

In a specific embodiment, the weight ratio of disintegrant to lubricant is in the range of 1:0.5 to 1:1, preferably in the range of 1:0.7 to 1:0.8.

In a specific embodiment, the weight ratio of glidant to lubricant is in the range of 1:0.5 to 1:1, preferably in the range of 1:0.7 to 1:0.8.

In a specific embodiment, the weight ratio of glidant to lubricant is in the range of 1:2 to 2:1, preferably in the range of 1:1.5 to 1.5:1.

In a specific embodiment, the filler is present in the pharmaceutical composition in a weight percentage of 10% to 80%, preferably 40% to 60%.

In a specific embodiment, the weight percentage of disintegrant in the pharmaceutical composition is 1% to 10%, preferably 2% to 3%.

In a specific embodiment, the weight percentage of lubricant in the pharmaceutical composition is 0.5% -5%, preferably 1-2%.

In a specific embodiment, the glidant is present in the pharmaceutical composition in an amount of 0.5% to 5%, preferably 2-3% by weight.

In a specific embodiment, the physiologically acceptable/pharmaceutically acceptable excipient further comprises a binder and/or a solubilizing agent.

In particular, the weight ratio of solubilizer, if present, to lubricant is in the range of 1:3 to 3:1, preferably in the range of 1:1 to 1:1.

In particular, the weight ratio of binder, if present, to lubricant is in the range of 1:3 to 3:1, preferably in the range of 1:1 to 1:1.

Specifically, the weight percentage of the binder in the pharmaceutical composition is 0% -10%, preferably 1-2%.

Specifically, the solubilizer is present in the pharmaceutical composition in an amount of 0% to 5%, preferably 0.5% to 2% by weight.

Specifically, the binder includes one or more of hypromellose, methylcellulose, hydroxyethyl cellulose, carboxymethyl cellulose, copovidone, and polyvinylpyrrolidone. More specifically, the binder is selected from one or more of hypromellose, methylcellulose, hydroxyethyl cellulose, carboxymethyl cellulose, copovidone, and polyvinylpyrrolidone, preferably hypromellose, and/or copovidone.

Specifically, the solubilizing agent comprises one or more of sodium dodecyl sulfate, polysorbate 80, polyoxyethylene hydrogenated castor oil, and poloxamer. More specifically, the solubilizing agent 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 filler comprises one or more of lactose, 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 lactose, 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.

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 glidant comprises colloidal silicon dioxide and/or talc. In particular, the glidant is selected from colloidal silicon dioxide and/or talc.

In a specific embodiment, the pharmaceutical composition is an oral formulation, preferably an oral solid formulation (e.g. a 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).

The inventors have also found through inventive studies that, in a specific particle size (e.g., D ₅₀ And/or D ₉₀ ) The bulk drug in the range can enable the pharmaceutical composition containing the bulk drug to have a faster dissolution rate and a higher dissolution rate. Furthermore, when the pharmaceutical composition of the present invention is a tablet, the excipient is the same, the excipient is used in the composition having a specific particle diameter (e.g., D ₅₀ And/or D ₉₀ ) The bulk drug in the range can enable the tablets to have acceptable friability, and has no obvious sticky or astringent impact in the process of preparing the tablets (such as tabletting process).

In a specific embodiment, when the pharmaceutical composition of the present invention is a solid preparation 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 active ingredient (i.e., the drug substance of the present invention) is contained in the pharmaceutical composition per unit dose; for example, the pharmaceutical composition comprises 50mg, 60mg, 70mg, 80mg, 90mg, 100mg, 110mg, 120mg, 125mg, 130mg, 140mg, 150mg, 160mg, 170mg, 180mg, 190mg 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.

The inventors also examined formulation parameters (e.g. in vitro dissolution) of pharmaceutical compositions (e.g. tablets) comprising the compound of formula (I) and crystalline form a of fumaric acid and pharmaceutical compositions (e.g. tablets) comprising the crystalline form B of fumaric acid of the compound of formula (I). Specifically, the pharmaceutical composition comprising the crystalline form a of the compound of formula (I) and fumaric acid differs from the pharmaceutical composition comprising the crystalline form B of the compound of formula (I) only in the crystalline form (i.e. the difference between crystalline form a and crystalline form B), the other components and the content are the same, and the preparation process is also the same. The results show that the pharmaceutical composition (in particular a tablet) comprising crystalline form a dissolves faster and has higher in vitro dissolution in the same dissolution medium, enabling the dissolution requirements to be met. The pharmaceutical composition (particularly a tablet) containing the crystalline form B has lower dissolution rate and can not meet the dissolution requirement that the dissolution rate is more than or equal to 75% in 60 minutes, and is not suitable for subsequent preparation development.

In a specific embodiment, in the process for the preparation of a pharmaceutical composition according to the invention, step (i) is carried out by: the bulk drugs, the filling agent, the disintegrating agent, the optional adhesive, the optional solubilizer and the glidant are mixed in sequence. Specifically, step (i) is achieved by: the bulk drugs and the filling agent are firstly mixed, and then the disintegrating agent, the optional adhesive, the optional solubilizer and the glidant are added for mixing. Preferably, step (i) is achieved by: the bulk drug of the invention and the first filler are mixed first, and then the second filler, the disintegrating agent, the optional binder, the optional solubilizer and the glidant are added for mixing. Wherein the first filler and the second filler may be the same or different, preferably, the first filler is a cellulose filler as described herein, and the second filler is a starch filler as described herein. 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 depending on the 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 performed by granulating the mixture obtained in step (i) by means of a dry granulator. 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 the particles from 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 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 invention 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 invention 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 invention 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 one aspect, the invention also provides a preparation method of the bulk drug, which comprises the following steps:

adding fumaric acid in solid form to an organic solvent (e.g. C) ₁ -C ₆ And (3) heating (for example, heating to 55-70 ℃) and stirring, then cooling (for example, cooling to 20-30 ℃) and stirring, and filtering to obtain the bulk drug containing the compound of formula (I) and the crystal form of fumaric acid (for example, the compound of formula (I) and the crystal form A of fumaric acid).

Specifically, the preparation method of the bulk drug of the invention further comprises the step of drying (such as vacuum drying) the solid obtained by filtration.

Specifically, C ₁ -C ₆ Alkyl ketones mean straight-chain or branched alkyl alcohols having 1 to 6 carbon atoms, i.e. C with keto groups (c=o) ₁ -C ₆ An alkyl group. Examples include, but are not limited to, acetone, methyl isobutyl ketone.

In another aspect, the present invention also provides the use of the drug substance of the present invention in the preparation of a pharmaceutical composition comprising the drug substance of the present invention and a physiologically acceptable/pharmaceutically acceptable excipient. In particular, the physiologically acceptable/pharmaceutically acceptable excipients are as defined above. In particular, the pharmaceutical composition is for use in treating a coronavirus-caused disease (preferably a novel coronavirus-caused disease) in a subject.

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 the bulk drug of the invention and physiologically acceptable/pharmaceutically acceptable excipients; (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 may be 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 double-ingredient seaweed Limited, microcrystalline cellulose was purchased from Sian Tianzheng pharmaceutical auxiliary material Limited, croscarmellose sodium was purchased from Jiangxi alpha high-tech pharmaceutical auxiliary material Co., ltd, colloidal silicon dioxide was purchased from Shanghai Feng pharmaceutical auxiliary material technology Co., ltd, magnesium stearate was purchased from Hebei Pengyo biosciences Co., ltd, pregelatinized starch was purchased from Hebei Innova source biosciences Co., hydroxypropyl cellulose was purchased from Mishilan chemical industry (Nanjing) Co., lactose was purchased from Shanghai Katsu Tao Co., ltd, and copovidone was purchased from Hai Ling pharmaceutical Co., ltd.

Examples

I. Preparation example

Example 1

(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-triazin-E-2, 4-dione fumaric acid solid form (45 g) was taken and added to 450mL of acetone to prepare a suspension, and the suspension was stirred by heating to 55-70 ℃ and then cooling to 20-30 ℃ according to the following table, and the suspension was separated and dried in vacuo to give a white solid as a crude drug (42.8 g-43.7 g) containing crystalline form A of the compound and fumaric acid having particle diameters as shown in the following table.

Specific reaction temperature and stirring conditions, and particle diameter (D) ₅₀ And/or D ₉₀ )

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The morphology of the bulk drug prepared by the embodiment of the invention is observed by taking a small amount of the bulk drug (such as bulk drug 6) prepared by the embodiment of the invention and placing the bulk drug on a glass slide through a polarizing microscope (model is Nikon Ci-POL, nikon, JP). The results are shown in FIG. 6.

The particle size distribution of the drug substance prepared in the examples of the present invention was determined by using a laser particle size analyzer model number Mastersizer 3000 (Malvern Panalytical, UK). Specifically, about 20mg of the crude drug (e.g., crude drug 5) prepared in the example of the present invention was taken, dispersed in 8mL of n-heptane, and after 10 seconds of sonication, the sample dispersion unit was added until the masking degree was 10-20% and the stirring speed in the dispersion chamber was 2000rpm for 10 seconds. The results are shown in FIG. 7.

Comparative example 1

A mixture of (6E) -6- [ (6-chloro-2-methyl-2H-indazol-5-yl) imino ] -3- [ (1-methyl-1H-1, 4-triazol-3-yl) methyl ] -1- (2, 4, 5-trifluorobenzyl) -1,3, 5-triazin-E-2, 4-dione (1.17 g,2.2 mmol) and fumaric acid (278 mg,2.4 mmol) in EtOAc (5.9 mL) was stirred at room temperature for 45min. The suspension was filtered to give a white solid 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-triazin-E-2, 4-dione fumaric acid co-crystals, referred to herein as crystalline form B (1.37 g) of the compound of formula (I) with fumaric acid.

The solid samples obtained in example 1 and comparative example 1 were characterized by an X-ray powder diffractometer PANalytical Empyrean (pamalytical, 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.

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

Furthermore, the inventors have found that: the stability of the crystalline form a of the compound of formula (I) with fumaric acid is better than the stability of the crystalline form B of the compound of formula (I) with fumaric acid; moreover, the in vitro dissolution of the pharmaceutical composition (in particular, a tablet) comprising the compound of formula (I) and crystalline form B of fumaric acid does not meet the dissolution requirement of 60min dissolution of greater than or equal to 75%, and is not suitable for subsequent formulation development.

Accordingly, the present inventors continued to study the preparation of a drug substance comprising the compound of formula (I) and crystalline form a of fumaric acid and the effects thereof.

Formulation examples

Example 1

The preparation method comprises the following steps:

(1) Uniformly mixing the compound of the formula (I) and the bulk drugs 1-3 or 16 of the fumaric acid in the crystal form A with microcrystalline cellulose;

(2) Adding lactose, 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, performing cyclic granulation, sieving with a 40-60 mesh sieve, and drying at 60 ℃ for 2 hours;

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

(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 2

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The preparation method comprises the following steps:

(1) Uniformly mixing bulk drug 4-6 or bulk drug 17 containing a compound of formula (I) and a crystalline form A of fumaric acid with microcrystalline cellulose;

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

(3) Granulating the mixture obtained in the step (2) by using a dry granulator, performing cyclic granulation, and sieving with a 40-60 mesh sieve;

Example 3

The preparation method comprises the following steps:

(1) Uniformly mixing a bulk drug 7-9 containing a compound of formula (I) and a crystalline form A of fumaric acid with lactose;

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

(3) Grinding the mixture obtained in the step (2) into fine powder;

(4) Sieving the fine powder obtained in the step (3) with a 100-120 mesh sieve, and filling into packaging materials (such as small bags) to obtain powder or dry suspension with a weight of 375mg per package.

Example 4

The preparation method comprises the following steps:

(1) Uniformly mixing a bulk drug 10-12 containing a compound of formula (I) and a crystalline form A of fumaric acid with lactose;

(3) Grinding the mixture obtained in the step (2) into fine powder;

Example 5

The preparation method comprises the following steps:

(1) Uniformly mixing 13-15 of bulk drug containing a compound of formula (I) and a crystalline form A of fumaric acid with mannitol;

(3) Grinding the mixture obtained in the step (2) into fine powder;

Effect examples

1. In vitro dissolution experiments

The experimental method is as follows: the paddle method was used at a speed of 75 revolutions per minute, 900ml of dissolution medium. The dissolution profiles of formulations 1-6 and 16-17 of the present invention in dissolution medium, i.e., purified water, pH1.2+0.2% Tween 80, were determined, respectively. And respectively taking a proper amount of dissolution liquid at 5min, 10min, 15min, 30min, 45min and 60min, filtering, taking the subsequent filtrate as a sample solution, and measuring the in-vitro dissolution rate.

The specific measurement results are shown in the following table:

conclusion: in the dissolution medium of purified water pH1.2+0.2% Tween 80, the formulations 1-6 of the present invention had faster dissolution rates and higher in vitro dissolution rates, while formulations 16-17 had slower dissolution rates and relatively lower in vitro dissolution rates.

2. Investigation of main parameters of tablets

The present study focused on whether sticking or astringent impact occurred during tablet compression in formulations 1-6 and 16-17 of the present invention, as well as the friability of the tablets. Specifically, in the case where the tabletting conditions (including conditions of temperature, humidity, etc. at the time of tabletting) were the same, whether or not sticking or astringent impact occurred during tabletting was observed by naked eyes, and according to the chinese pharmacopoeia of 2020 edition (fourth tablet friability check method), it was prescribed that 18 tablets prepared according to formulation examples 1 and 2 were taken for each formulation, and the tablet friability parameter (i.e., weight reduction percentage) was counted by measurement with a tablet friability tester (CS-3 friability tester, available from the tuo instrument limited of Tianjin city).

The specific results are shown in the following table:

sticking and punching phenomenon:

-represents substantially free of sticking or powder adhesion;

+ represents that trace powder is attached, and no obvious sticking or astringent impact exists;

++ represents that the impact surface has obvious adhesion;

++ represents has obvious effects of sticking or astringent.

Conclusion: in the aspect of sticking and punching of tablets, the preparation 1-6 of the invention basically has no sticking and punching or no obvious sticking and punching or no astringent punching in the tabletting process. In terms of tablet friability, the tablet friability parameters of formulations 1-6 of the present invention met pharmacopoeia specifications (weight percent reduction no more than 1%), whereas the tablets of formulations 16-17 did not meet pharmacopoeia specifications (weight percent reduction much more than 1%). The inventors have found that in a particular particle size range (e.g., D ₅₀ Less than or equal to 30 mu m and/or D ₉₀ A pharmaceutical composition comprising a crystalline form a of the compound of formula (I) and fumaric acid in the range of 5 μm to 60 μm) is suitable for the preparation of tablets.

The foregoing embodiments have been provided for the purpose of illustrating the general principles of the present invention, and are not meant to limit the scope of the invention, but to limit the scope of the invention.

Claims

1. (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-triazin-2, 4-dione fumaric acid solid form bulk drug, characterized in that the bulk drug has a particle size D ₉₀ 5-60 μm.

2. The drug substance of claim 1, wherein the drug substance has a particle size D ₅₀ ≤30μm。

3. A method of preparing the drug substance of any one of claims 1-2, characterized in that: suspending a 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-triazin-E-2, 4-dione fumaric acid in an organic solvent, adjusting the temperature, controlling stirring, separating the suspension, and drying to obtain a crude drug in solid form, wherein the crude drug in solid form is crushed or not crushed.

4. A process according to claim 3, characterized in that: the crushing treatment is micronization treatment.

5. The preparation method according to claim 3 or 4, characterized in that: the temperature is regulated by heating and then cooling.

6. A pharmaceutical composition comprising the drug substance of any one of claims 1-2, characterized in that: the weight percentage of the raw material medicine or the API in the pharmaceutical composition is 15-60%, and the content of the raw material medicine is 50-200 mg.

7. The pharmaceutical composition according to claim 6, wherein: also included are physiologically acceptable/pharmaceutically acceptable excipients including one or more of fillers, binders, disintegrants, lubricants, glidants.

8. The pharmaceutical composition according to claim 7, wherein: the filler is selected from one or more of microcrystalline cellulose, pregelatinized starch, and mannitol.

9. The pharmaceutical composition according to claims 7-8, characterized in that: the adhesive is hydroxypropyl cellulose.

10. The pharmaceutical composition according to claims 7-9, characterized in that: the disintegrating agent is croscarmellose sodium.

11. The pharmaceutical composition according to claims 7-10, characterized in that: the glidant is colloidal silicon dioxide.

12. The pharmaceutical composition according to claims 7-11, characterized in that: the lubricant is magnesium stearate.

13. Use of a bulk drug of any one of claims 1-2 or a pharmaceutical composition of claims 6-12 in the manufacture of a medicament for treating a disease caused by coronavirus in a subject.

14. A pharmaceutical composition comprising one or two (6E) -6- [ (6-chloro-2-methyl-2H-indazol-5-yl) imino groups]-3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl]Crystalline form of solid (i) 1- (2, 4, 5-trifluorobenzyl) -1,3, 5-triazin-E-2, 4-dione fumaric acid, characterized by (6E) -6- [ (6-chloro-2-methyl-2H-indazol-5-yl) imino]-3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl]The crystalline form of the solid 1- (2, 4, 5-trifluorobenzyl) -1,3, 5-triazin-2, 4-dione 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 °, comprise any three of 10.94, 19.06, 23.50, 24.66; another (6E) -6- [ (6-chloro-2-methyl-2H-indazol-5-yl) imino group]-3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl ]Crystalline forms of (E) -1- (2, 4, 5-trifluorobenzyl) -1,3, 5-triazin-2, 4-dione fumaric acid solid the characteristic diffraction peaks of the X-ray powder diffraction pattern, expressed in terms of 2 theta values + -0.2 DEG, using Cu-K alpha radiation, comprise any three of 14.74, 22.80, 28.80 and 29.42, one or two of (6E) -6- [ (6-chloro-2-methyl-2H-indazol-5-yl) imino groups]-3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl]Particle size D of crystalline form of solid of (E) -1- (2, 4, 5-trifluorobenzyl) -1,3, 5-triazin-2, 4-dione fumaric acid ₉₀ 5-60 μm.

15. The pharmaceutical composition of claim 14, wherein one or two (6E) -6- [ (6-chloro-2-methyl-2H-indazol-5-yl) imino groups]-3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl]Particle size D of crystalline form of solid of (E) -1- (2, 4, 5-trifluorobenzyl) -1,3, 5-triazin-2, 4-dione fumaric acid ₅₀ ≤30μm。

16. A pharmaceutical composition comprising the crystalline form of one or two (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-triazin-E-2, 4-dione fumaric acid solids of any one of claims 14-15, and a physiologically acceptable/pharmaceutically acceptable excipient, characterized in that: the physiologically acceptable/pharmaceutically acceptable excipients include one or more of fillers, binders, disintegrants, lubricants, glidants.

17. The pharmaceutical composition according to claim 16, wherein: the crystalline form of one or both (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-triazin-E-2, 4-dione fumaric acid solids is present in the pharmaceutical composition in a weight percentage of 15% -60%.

18. The pharmaceutical composition according to claim 17, wherein: the crystalline form of one or both (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-triazin-E-2, 4-dione fumaric acid solids is present in the pharmaceutical composition in a weight percentage of 25% -45%.

19. The pharmaceutical composition according to any one of claims 16-18, wherein: the weight percentage of the adhesive in the medicine composition is 1% -10%.

20. The pharmaceutical composition according to any one of claims 16-19, wherein: the weight percentage of the disintegrating agent in the pharmaceutical composition is 1% -10%.

21. The pharmaceutical composition according to any one of claims 16-20, wherein: the weight percentage of the lubricant in the pharmaceutical composition is 0.5% -5%.

22. The pharmaceutical composition according to any one of claims 16-21, wherein: the glidant accounts for 0.5 to 5 percent of the weight of the pharmaceutical composition.

23. The pharmaceutical composition according to any one of claims 16-22, wherein: the crystalline form to filler weight ratio of the one or two (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-triazin-E-2, 4-dione fumaric acid solids is in the range of 1:5 to 1:1;

the weight ratio of the disintegrant to lubricant is in the range of 1:0.5 to 1:1;

and/or

The weight ratio of glidant to lubricant is in the range of 1:0.5 to 1:1.

24. The pharmaceutical composition according to any one of claims 16-23, wherein: the filler comprises one or more of lactose, anhydrous calcium bicarbonate, sugar alcohols, celluloses and starches;

the adhesive comprises one or more of hydroxypropyl cellulose and copovidone;

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

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

and/or

The glidant includes colloidal silicon dioxide and/or talc.

25. A pharmaceutical composition according to any one of claims 16-24, characterized in that: the pharmaceutical composition is an oral preparation; and/or wherein the pharmaceutical composition is in unit dosage form.

26. A pharmaceutical composition according to any one of claims 16-25, characterized in that: the pharmaceutical composition comprises one or two 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-trifluorobenzyl) -1,3, 5-triazin-E-2, 4-dione fumaric acid solids in an amount of 50mg to 200mg.

27. A process for the preparation of a pharmaceutical composition according to any one of claims 16-26, comprising the steps of:

(i) Mixing the crystalline form of one or two (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-triazin-E-2, 4-dione fumaric acid solids of any one of claims 7-8 with or without comminution treatment and with physiologically acceptable/pharmaceutically acceptable excipients;

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

28. The method of preparing according to claim 27, characterized in that: the crushing treatment is micronization treatment.

29. Use of a pharmaceutical composition according to any one of claims 16-26 for the manufacture of a medicament for treating a coronavirus-caused disease in a subject.