Pharmaceutical composition, preparation method therefor, and use thereof

Abstract

A pharmaceutical composition, a preparation method therefor, and use thereof. The pharmaceutical composition comprises an active pharmaceutical ingredient and a pharmaceutical excipient, wherein the active pharmaceutical ingredient comprises compound (I) or a pharmaceutically acceptable salt thereof, and the excipient comprises 3-20 wt% of a disintegrating agent. The pharmaceutical composition can meet the requirements of formulations and has high bioavailability, good efficacy, and good drug developability.

Description

A pharmaceutical composition and its preparation method and application

[0001] This application claims the benefit of Chinese patent application No. 2024104035821, filed on April 3, 2024. This application incorporates the entirety of the aforementioned Chinese patent application. Technical Field

[0002] The present invention relates to the field of pharmaceutical technology, and in particular to a pharmaceutical composition, a preparation method and an application thereof. Background Art

[0003] The 2019 novel coronavirus (COVID-19) is an enveloped, single-stranded, positive-stranded RNA virus. Viral replication and transcription are encoded by the so-called "replicase" gene, which consists of two overlapping polyproteins. These polyproteins require processing by the viral 3CL protease and PL protease to form functional structural proteins. During this process, the 3CL protease processes the C-proximal region at the junctions between the polyprotein's 11 interdomains to produce structural proteins critical for viral survival and reproduction. Therefore, the 3CL protease is also known as the main protease. The 3CL protease is relatively conserved among coronaviruses, and substrates shared by different coronavirus 3CL proteases share common characteristics. Since no protease homologous to the 3CL protease exists in the human body, the 3CL protease is an ideal target for anti-coronavirus treatment. 3CL protease inhibitors can inhibit 3CL protease activity, thereby interfering with viral replication and achieving antiviral effects.

[0004] Due to the rapid spread of the 2019-nCoV and the resulting heavy casualties, as well as the uncertainty surrounding its subsequent spread and prevalence, drugs to prevent and treat 2019-nCoV infection, particularly orally available small-molecule 3CL protease inhibitors, hold significant practical significance and development potential. Discovering compounds with promising activity is a crucial step in drug development, while preparing them into safe, stable, effective, and uniform formulations to facilitate clinical administration and patient treatment is another crucial step.

[0005] WO2022218442A1 discloses a 3CL protease inhibitor compound shown in the following formula:

[0006] Therefore, it is necessary to prepare it into a safe, stable, effective and uniform pharmaceutical preparation composition to provide clinical therapeutic drugs with safety and efficacy advantages. Summary of the Invention

[0007] To overcome the limitations of existing pharmaceutical compositions containing 3CL protease inhibitors, the present invention provides a pharmaceutical composition, preparation method, and application thereof. The pharmaceutical composition of the present invention exhibits excellent dissolution and release properties, stability, bioavailability, and achieves excellent therapeutic efficacy at extremely low doses.

[0008] The present invention adopts the following technical solutions to solve the above technical problems.

[0009] The present invention provides a pharmaceutical composition comprising a pharmaceutical active ingredient and a pharmaceutical excipient, wherein the pharmaceutical active ingredient comprises compound (I) or a pharmaceutically acceptable salt thereof, and the excipient comprises 3-20 wt% of a disintegrant;

[0010] In the pharmaceutical composition, the type and content of the disintegrant are conventional in the art. The disintegrant is preferably selected from one or more of croscarmellose sodium, cross-linked polyvinylpyrrolidone, sodium starch glycolate, starch, hydroxypropyl starch, and low-substituted hydroxypropyl cellulose; more preferably, croscarmellose sodium. The content of the disintegrant can be 3-20wt%, or 4-15wt% (e.g., 5wt%, 6wt%, 10wt%), where the content of the disintegrant is the weight percentage of the mass of the component relative to the total mass of the active pharmaceutical ingredient and the pharmaceutical excipients.

[0011] In the pharmaceutical composition, the amount of the active pharmaceutical ingredient is conventional in the art. The active pharmaceutical ingredient content can be 15-30wt%, or even 20-25wt%, where the content is the weight percentage of the component relative to the total weight of the active pharmaceutical ingredient and the pharmaceutical excipients.

[0012] The compound (I) may be in an amorphous form and / or a crystalline form, preferably a crystalline form. When the compound (I) is in a crystalline form, the crystalline form of the compound (I) may be Form A; wherein the X-ray powder diffraction pattern of Form A has characteristic diffraction peaks at the following 2θ angles: 10.655±0.200°, 11.988±0.200°, 16.055±0.200°, 18.356±0.200°, and 20.083±0.200°.

[0013] Furthermore, the X-ray powder diffraction pattern of the crystalline form A has characteristic diffraction peaks at the following 2θ angles: 6.917±0.200°, 10.655±0.200°, 11.988±0.200°, 14.481±0.200°, 16.055±0.200°, 17.653±0.200°, 18.356±0.200° and 20.083±0.200°.

[0014] Furthermore, the X-ray powder diffraction pattern of the crystalline form A is substantially as shown in Figure 1.

[0015] The particle size of the compound (I) is preferably D90≤210 μm; more preferably, the particle size is D90≤130 μm.

[0016] The pharmaceutical excipients may further comprise one, two or three of a diluent, a glidant and a lubricant.

[0017] The types and contents of the diluents, glidants, and lubricants are conventional in the art. The present invention particularly prefers the following types and contents, where the contents are expressed as the weight percentage of the component to the total weight of the pharmaceutical composition:

[0018] The diluent is preferably selected from one or more (e.g., two or three) of lactose, microcrystalline cellulose, mannitol, cyclodextrin, starch, pregelatinized starch, anhydrous calcium hydrogen phosphate, and silicified microcrystalline cellulose; preferably lactose (e.g., lactose monohydrate FlowLac100) and / or microcrystalline cellulose. The diluent content may be 50-80 wt%, or 63-71 wt%, for example, 67 wt%.

[0019] The glidant is preferably selected from one, two or three of silicon dioxide, magnesium trisilicate and talc, preferably silicon dioxide (colloidal silicon dioxide). The content of the glidant can be 0.5-10wt%, or 1-5wt%, for example 1.25wt%.

[0020] The lubricant is preferably selected from one or more (e.g., two or three) of the group consisting of stearic acid, sodium stearyl fumarate, magnesium stearate, calcium stearate, sodium lauryl sulfate, polyethylene glycol, glyceryl behenate, talc, and hydrogenated vegetable oil; more preferably, sodium stearyl fumarate. The lubricant content may be 1-10 wt%, or even 2-2.5 wt%.

[0021] The pharmaceutical composition may further comprise coating powder. The type and coating weight of the coating powder are commonly used in the art, for example, the coating powder is a film coating premix (gastric soluble).

[0022] In some embodiments, the pharmaceutical composition is composed of the pharmaceutical active ingredient, the pharmaceutical excipient and the coating powder.

[0023] In some embodiments, in the pharmaceutical composition, the pharmaceutically active ingredient is the aforementioned compound (I) or a pharmaceutically acceptable salt thereof, such as the aforementioned crystalline form A.

[0024] In some embodiments, in the pharmaceutical composition, the pharmaceutical excipients are composed of the above-mentioned disintegrant, the above-mentioned diluent, the above-mentioned glidant and lubricant, for example, cross-linked sodium carboxymethyl cellulose, lactose, microcrystalline cellulose, silicon dioxide and sodium stearyl fumarate.

[0025] In some embodiments, the pharmaceutical composition may comprise the following components in weight percentage: 20-25 wt % of the above-mentioned active pharmaceutical ingredient, 4-15 wt % of the above-mentioned disintegrant, and 1-5 wt % of the above-mentioned glidant.

[0026] Preferably, the pharmaceutical composition comprises 18-22 wt% of the crystalline form A of compound (I) according to claim 2, 4-7 wt% of croscarmellose sodium, 68-75 wt% of a diluent, 0.5-1.5 wt% of silicon dioxide and 1.5-3 wt% of sodium stearyl fumarate;

[0027] The diluent is lactose and / or microcrystalline cellulose.

[0028] More preferably, the pharmaceutical composition comprises 20 wt% of the crystalline form A of the above-mentioned compound (I), 6 wt% of croscarmellose sodium, 71 wt% of a diluent, 1 wt% of silicon dioxide (colloidal silicon dioxide) and 2 wt% of sodium stearyl fumarate;

[0029] The diluent is lactose and / or microcrystalline cellulose.

[0030] In some embodiments, the pharmaceutical composition comprises an intragranular component and an extragranular component; the intragranular component comprises the above-mentioned active pharmaceutical ingredient and a disintegrant; and the extragranular component comprises a disintegrant.

[0031] Among the intragranular components, the disintegrant is preferably selected from one or more (e.g., two or three) of croscarmellose sodium, cross-linked polyvinylpyrrolidone, sodium starch glycolate, starch, hydroxypropyl starch, and low-substituted hydroxypropyl cellulose; more preferably, croscarmellose sodium. The disintegrant content may be 1.5-10 wt%, or 3-7.5 wt% (e.g., 3.75 wt%), where the disintegrant content is the weight percentage of the component relative to the total weight of the pharmaceutical composition.

[0032] Among the intragranular components, the disintegrant is preferably selected from one or more of croscarmellose sodium, cross-linked povidone, sodium starch glycolate, starch, hydroxypropyl starch, and low-substituted hydroxypropyl cellulose; more preferably, croscarmellose sodium. The disintegrant content may be 1.5-10 wt%, or 3-7.5 wt% (e.g., 3.75 wt%), where the disintegrant content is the weight percentage of the component relative to the total weight of the pharmaceutical composition.

[0033] The intragranular components may further include one or more of the aforementioned diluents, glidants, and lubricants. The lubricant is preferably selected from one or more of stearic acid, sodium stearyl fumarate, magnesium stearate, calcium stearate, sodium lauryl sulfate, polyethylene glycol, glyceryl behenate, talc, and hydrogenated vegetable oil; more preferably, sodium stearyl fumarate. The lubricant content may be 0.5-5 wt%, or 1-2.5 wt%, for example, 1.25 wt%.

[0034] The components in the granules include the above-mentioned active pharmaceutical ingredient, the above-mentioned disintegrant, the above-mentioned diluent, the above-mentioned glidant and the above-mentioned lubricant.

[0035] The intragranular components may include the above-mentioned compound (I), croscarmellose sodium, a diluent, colloidal silicon dioxide and sodium stearyl fumarate;

[0036] The diluent is lactose and / or microcrystalline cellulose.

[0037] In the extragranular component, the disintegrant is preferably selected from one or more of croscarmellose sodium, cross-linked polyvinylpyrrolidone, sodium starch glycolate, starch, hydroxypropyl starch, and low-substituted hydroxypropyl cellulose; more preferably, croscarmellose sodium. The disintegrant content may be 1.5-10 wt%, or 3-7.5 wt% (e.g., 3.75 wt%), where the disintegrant content is the weight percentage of the component relative to the total weight of the pharmaceutical composition.

[0038] The extragranular component may further include a lubricant. The lubricant is preferably selected from one or more of stearic acid, sodium stearyl fumarate, magnesium stearate, calcium stearate, sodium lauryl sulfate, polyethylene glycol, glyceryl behenate, talc, and hydrogenated vegetable oil; more preferably, sodium stearyl fumarate. The lubricant content may be 0.5-5 wt%, or 1-2.5 wt%, for example, 1.25 wt%.

[0039] The extragranular component may also consist of a disintegrant and a lubricant.

[0040] The extragranular component may also consist of croscarmellose sodium and sodium stearyl fumarate.

[0041] Preferably,

[0042] The pharmaceutical composition comprises an intragranular component and an extragranular component; the intragranular component comprises the pharmaceutical active ingredient and a disintegrant; the extragranular component comprises a disintegrant;

[0043] The components in the granules are composed of the above-mentioned active pharmaceutical ingredient, the above-mentioned disintegrant, the above-mentioned diluent, the above-mentioned glidant and the above-mentioned lubricant;

[0044] The extragranular component is composed of the above-mentioned disintegrant and the above-mentioned lubricant;

[0045] Better:

[0046] The pharmaceutical composition comprises an intragranular component and an extragranular component; the intragranular component comprises the pharmaceutical active ingredient and a disintegrant; the extragranular component comprises a disintegrant;

[0047] The intragranular components are composed of 20-25 wt% of the above-mentioned crystalline form A, 3-7.5 wt% of croscarmellose sodium, 63-71 wt% of a diluent, 1-5 wt% of colloidal silicon dioxide, and 1-2.5 wt% of sodium stearyl fumarate;

[0048] The diluent is lactose and / or microcrystalline cellulose

[0049] The extragranular component consists of 3-7.5 wt% of cross-linked sodium carboxymethyl cellulose and 1-2.5 wt% of sodium stearyl fumarate.

[0050] The dosage form of the pharmaceutical composition can be various dosage forms in the prior art, such as tablets or capsules.

[0051] When the pharmaceutical composition is a pharmaceutical preparation, the unit dosage form of the pharmaceutical preparation may contain 50-200 mg of the above-mentioned active ingredient (calculated as the amount of free compound (I)); more specifically, it may contain 50 mg of the above-mentioned active ingredient or 150 mg of the above-mentioned active ingredient.

[0052] In a second aspect, the present invention further provides a method for preparing the above-mentioned pharmaceutical composition, comprising the following steps:

[0053] The pharmaceutical composition can be obtained by mixing the above-mentioned active pharmaceutical ingredients and pharmaceutical excipients.

[0054] Optionally, when the dosage form of the pharmaceutical composition is a tablet, the preparation method comprises the following steps: directly compressing the above-mentioned active pharmaceutical ingredients and the above-mentioned pharmaceutical excipients through powder tableting, wet granulation tableting or dry granulation tableting to obtain the pharmaceutical composition.

[0055] Optionally, when the preparation method is wet granulation tableting or dry granulation tableting, the preparation method further comprises the following steps: Step 1: preparing inner granules and outer granules;

[0056] The inner granule preparation method comprises mixing the above-mentioned inner granule components (for example, mixing at a speed of 10 rpm for 10 minutes) and granulating to form the inner granule;

[0057] The method for preparing the external granules comprises mixing and granulating the above-mentioned external granules to form the external granules;

[0058] Step 2: The inner granules and the outer granules are compressed into tablets.

[0059] The above-mentioned granulation conditions are, for example, during the granulation process, a granulation feed speed of 90 rpm, a pressing wheel speed of 30 rpm, a pressing wheel spacing of 2 mm, a crushing speed of 50 rpm, a hydraulic pressure of 6-12 MPa, and a granulation speed of 100 rpm.

[0060] Optionally, the plain tablets prepared above may be subjected to a coating step, for example, coating with coating powder (film coating premix (gastric soluble)).

[0061] In a third aspect, the present invention further provides an oral formulation comprising Form A of Compound (I); the Form A has an X-ray powder diffraction pattern having characteristic diffraction peaks at the following 2θ angles: 10.655±0.200°, 11.988±0.200°, 16.055±0.200°, 18.356±0.200° and 20.083±0.200°;

[0062] In some embodiments, the oral formulation may further contain 1, 2, 3 or 4 of a diluent, a disintegrant, a glidant and a lubricant.

[0063] The types and contents of the diluent, the disintegrant, the glidant and the lubricant are the same as those in the above-mentioned pharmaceutical composition.

[0064] In some embodiments, the oral preparation can be a solid preparation (tablet or capsule). The oral preparation can include an intragranular component and an extragranular component; the types and contents of the intragranular component and the extragranular component are the same as those of the intragranular component and the extragranular component in the above-mentioned pharmaceutical composition.

[0065] In a fourth aspect, the present invention further provides a combination kit comprising a pharmaceutical composition and ritonavir;

[0066] The pharmaceutical composition is the above-mentioned pharmaceutical composition or the above-mentioned oral preparation.

[0067] In a fifth aspect, the present invention provides a substance for use in the preparation of a drug for preventing or treating novel coronavirus infection (COVID-19 infection), wherein the substance is the above-mentioned pharmaceutical composition, the above-mentioned oral preparation or the above-mentioned combination kit.

[0068] Novel coronavirus infection can be mild novel coronavirus infection or moderate novel coronavirus infection (for example, in adult patients).

[0069] In a sixth aspect, the present invention provides a method for preventing or treating novel coronavirus infection (e.g., mild novel coronavirus infection or moderate novel coronavirus infection), which comprises administering an effective amount of the above-mentioned pharmaceutical composition, the above-mentioned oral preparation or the above-mentioned combination kit to a patient (e.g., an adult patient).

[0070] In addition to improving drug solubility and absorption in the body, the preparation of the present invention can also significantly improve stability and bioavailability, so that a lower dose can be used to exert good drug efficacy and therapeutic effects.

[0071] In the present invention, "a plurality of kinds" refers to a selectable number within the range thereof, for example, "two, three, four or five kinds".

[0072] On the basis of conforming to the common sense in this field, the above-mentioned preferred conditions can be arbitrarily combined to obtain the preferred embodiments of the present invention.

[0073] The reagents and raw materials used in the present invention are commercially available.

[0074] Positive effects of the present invention: The pharmaceutical composition of the present invention has any of the following advantages:

[0075] (1) The pharmaceutical composition of the present invention can meet the requirements of pharmaceutical preparations; the prepared tablets have good uniformity, good disintegration, and good dissolution effect;

[0076] (2) The pharmaceutical composition of the present invention has good stability; in an accelerated test (under high humidity and high temperature conditions), the maximum increase in the content of single and total impurities was only 0.01%, the isomer content was ≤0.04%, and no crystal transformation of the active pharmaceutical ingredient was observed;

[0077] (3) The pharmaceutical composition of the present invention has the advantages of good pharmacokinetic properties and high bioavailability;

[0078] (4) The pharmaceutical composition of the present invention can achieve an effective blood concentration at a lower dose (150 mg) similar to that of other existing marketed oral 3CL drugs at higher doses, effectively reducing viral load and achieving effective antiviral therapeutic effects while ensuring safety;

[0079] (5) Form A of the present invention has good stability; no crystal transformation was observed in the accelerated test (under high humidity and high temperature conditions);

[0080] (6) The crystalline form A of the present invention has the advantages of good pharmacokinetic properties and high bioavailability. BRIEF DESCRIPTION OF THE DRAWINGS

[0081] FIG1 is a Cu-Kα radiation XRPD spectrum of Compound (I) A crystal form.

[0082] Figure 2 is a DSC spectrum of Compound (I) A crystal form.

[0083] Figure 3 is a TGA spectrum of Compound (I) A crystal form. DETAILED DESCRIPTION

[0084] The present invention is further illustrated by way of examples below, but the present invention is not limited to the scope of the examples. Experimental methods in the following examples where specific conditions are not specified were performed according to conventional methods and conditions, or selected according to the product specifications.

[0085] Example 1: Preparation of Compound (I) A Crystalline Form

[0086] Step 1: Synthesis of compound 1-2

[0087] Compound 1-1 (5 g, 54.32 mmol) was dissolved in methanol (50 mL) and refluxed at 70°C for 48 h. The reaction system was concentrated under reduced pressure to obtain the crude target product. The crude product was of high purity and was used directly in the next reaction to obtain compound 1-2.

[0088] 1 H NMR (400MHz, CDCl3) δ = 4.81 (s, 1H), 3.77 (s, 3H), 3.43 (s, 3H).

[0089] Step 2: Synthesis of Compounds 1-3

[0090] Dissolve compound 1-2 in toluene (3 mL), cool to 0°C, and slowly add (R)-(+)-phenylethylamine (1.5 g, 12.38 mmol, 1.60 mL) dropwise. Stir at 20°C for 1 h. Add ethyl acetate (60 mL) and saturated brine (30 mL) to the reaction system, extract the organic phase, dry over anhydrous sodium sulfate, and spin-dry to obtain the crude product. Purify the product by silica gel column chromatography (petroleum ether:ethyl acetate = 1:0 to 5:1) to obtain the target compound 1-3.

[0091] 1 H NMR (400MHz, CDCl3) δ=7.95-7.56(m,1H),7.31-7.17(m,5H),4.71-4.40(m,1H),3.95-3.71(m,3H),1.67-1.51(m,3H).

[0092] Step 3: Synthesis of Compounds 1-4

[0093] Compound 1-3 (0.5 g, 2.61 mmol) was dissolved in 2,2,2-trifluoroethanol (5 mL), and trifluoroacetic acid (313.04 mg, 2.75 mmol, 203.28 μL) was added. The temperature was cooled to -10°C and stirred for 1 hour. Cyclopentadiene (207.40 mg, 3.14 mmol) was slowly added dropwise at -10°C, and stirring was continued for 0.5 hour. The reaction system was concentrated under reduced pressure, and methyl tert-butyl ether (60 mL) and saturated sodium bicarbonate solution (30 mL x 2) were added and stirred for 10 minutes. The organic phase was extracted, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Purification by silica gel column chromatography (petroleum ether:ethyl acetate = 1:0 to 5:1) afforded compound 1-4, the configuration of which was confirmed by two-dimensional NMR.

[0094] 1 H NMR (400MHz, CDCl3) δ = 7.34-7.18 (m, 5H), 6.59-6.41 (m, 1H), 6.31 (dd, J = 1.6, 5.6Hz, 1H), 4.35 (br d,J=1.3Hz,1H),3.39(s,3H),3.18-3.03(m,1H),2.95(br s,1H),2.33-2.22(m,1H),2.14(br d,J=8.4Hz,1H),1.54-1.41(m,4H).

[0095] MS m / z(ESI):[M+H] + =258.2.

[0096] Step 4: Synthesis of Compounds 1-5

[0097] Compound 1-4 (100.00 mg, 388.61 μmol) was dissolved in tetrahydrofuran (1.25 mL), cooled to -70°C, and borane tetrahydrofuran complex (1 M, 427.47 μL) was slowly added dropwise. The temperature was slowly raised to 20°C and stirred for 1 h. The temperature was then lowered to 0°C, and a 10% aqueous sodium hydroxide solution (0.55 mL) and a 30% hydrogen peroxide solution (220.28 mg, 1.94 mmol, 186.68 μL) were added. The temperature was slowly raised to 20°C and stirred for 1 h. Saturated sodium thiosulfate solution (10 mL) was added to the reaction system and stirred for 10 min to quench the reaction. The mixture was then extracted with saturated brine (20 mL) and ethyl acetate (60 mL x 2). The organic phase was separated. A small amount of the sample solution was adjusted to a pH below 8 with 3% citric acid. After testing negative with potassium iodide paper, the solution was dried over anhydrous sodium sulfate and concentrated under reduced pressure at 30°C. Compound 1-5 was obtained by purification through silica gel column chromatography (petroleum ether:ethyl acetate=1:0-5:1).

[0098] 1H NMR (400MHz, CDCl3) δ = 7.30-7.13 (m, 5H), 3.93 (br d, J = 6.5Hz, 1H), 3.78 (br s,1H),3.70-3.54(m,1H),3.39-3.32(m,1H),3.31-3.24(m,3H),2.49-2.40(m,1H),2.26(s,1H),2.09-2.00(m,1H),1.72(br d,J=10.1Hz,1H),1.46(br d,J=6.5Hz,1H),1.41-1.33(m,3H).

[0099] MS m / z(ESI):[M+H] + =276.1.

[0100] Step 5: Synthesis of the hydrochloride salt of compound 1-6

[0101] Dissolve compound 1-5 (3 g, 10.90 mmol) in ethanol (80 mL), add hydrochloric acid (1.19 g, 32.69 mmol) and wet palladium on carbon (15 g, 10.68 mmol). Stir the reaction at 20°C for 16 h. Filter the reaction mixture through celite and spin dry to obtain the crude hydrochloride salt of compound 1-6.

[0102] 1H NMR(400MHz, DMSO-d6)δ=10.32-9.78(m,1H),8.94-8.43(m,1H),5.51-5.12(m,1H),4.05-3.98(m,1H),3.96 -3.86(m,2H),3.83-3.71(m,3H),2.70-2.60(m,1H),2.36-2.20(m,1H),1.92-1.81(m,1H),1.51-1.31(m,2H)

[0103] MS m / z(ESI):[M+H] + =172.0.

[0104] Step 6: Synthesis of Compounds 1-8

[0105] Compound 1-7 (1.87 g, 10.90 mmol) was dissolved in N,N-dimethylformamide (20 mL). O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (4.78 g, 12.58 mmol) and diisopropylethylamine (4.34 g, 33.55 mmol) were added. After stirring for 30 minutes, the hydrochloride salt of compound 1-6 (190 mg, 1.12 mmol) was added. The reaction was stirred at 20°C for 16 hours. Water (15 mL) was added to the reaction solution, and the mixture was extracted twice with ethyl acetate (60 mL). The organic phases were combined and washed twice with 5% citric acid (30 mL) and four times with brine (20 mL). The organic phases were dried over anhydrous sodium sulfate, filtered, and dried. Compound 1-8 was purified by column chromatography (petroleum ether:ethyl acetate = 3:1) to obtain compound 1-8.

[0106] 1 H NMR (400MHz, CDCl3) δ=5.28-5.16(m,1H),4.50(br s,1H),4.28(d,J=9.8Hz,1H),3.92(s,1H),3.74(s,3H),2.81(s,1H),2.67(s,1H),2.17(br dd,J=6.1,12.7Hz,1H),1.99-1.93(m,1H),1.90-1.84(m,1H),1.59(br d,J=13.3Hz,2H),1.43(s,9H),1.04(s,9H).

[0107] MS m / z(ESI):[M+H] + =385.2.

[0108] Step 7: Synthesis of Compound 1-9

[0109] Compound 1-8 (500 mg, 1.30 mmol) was dissolved in acetonitrile (7.5 mL), and 2-iodoacylbenzoic acid (976.31 mg, 3.49 mmol) was added. The mixture was stirred at 60°C for 16 h. The reaction mixture was directly filtered through celite and dried by spin drying. Compound 1-9 was obtained without further purification.

[0110] MS m / z(ESI):[M-55] + =327.1.

[0111] Step 8: Synthesis of Compounds 1-10

[0112] Compound 1-9 (0.7 g, 1.83 mmol) was dissolved in tetrahydrofuran (14 mL). TEBBE (μ-chloro-μ-methylene[bis(cyclopentadienyl)titanium]-dimethylaluminum) reagent (0.5 M, 14.64 mL) was added at 0°C. Stirring was performed at 0°C for 1 hour, then the temperature was raised to 15°C and stirring was continued for 3 hours. The reaction mixture was slowly poured into saturated sodium bicarbonate solution (50 mL), filtered through celite, extracted with ethyl acetate (30 mL x 3), and washed with saturated brine (30 mL x 2). Compound 1-10 was purified by column chromatography (petroleum ether:ethyl acetate = 5:1) to afford compound 1-10.

[0113] 1H NMR (400MHz, DMSO-d6)δ=6.63-6.54(m,1H),5.21-5.15(m,1H),4.88-4.82(m,1H),4.76-4.68(m,1H),4.25-4.19(m,1H),3.90-3.85(m ,1H),3.66-3.61(m,3H),3.19-3.11(m,1H),2.42-2.28(m,2H),1.98-1.92(m,1H),1.61-1.53(m,1H),1.38(s,9H),1.00-0.93(m,9H).

[0114] MS m / z(ESI):[M+H] + =381.1.

[0115] Step 9: Synthesis of Compound 1-11

[0116] Under nitrogen, diethylzinc (1 M, 13.14 mL) was slowly added to 1,2-dichloroethane (80 mL) at 0°C. Stir for 0.25 h. Diiodomethane (7.04 g, 26.28 mmol, 2.12 mL) was slowly added to the reaction mixture at 0°C and stirred for 0.25 h. Trifluoroacetic acid (149.84 mg, 1.31 mmol, 97.30 μL) was slowly added to the reaction system and stirring continued for 0.5 h. Compound 1-10 (0.5 g, 1.31 mmol) in 1,2-dichloroethane (5 mL) was added to the reaction system, and the temperature was raised to 20°C and stirring continued for 12 h. The reaction was quenched with saturated sodium bicarbonate solution (200 mL), extracted with dichloromethane (100 mL), dried over anhydrous sodium sulfate, and filtered. Concentrated. The crude product was purified by preparative HPLC (column type: Phenomenex luna C18 80*40mm*3μm; mobile phase: [H2O(HCl)-acetonitrile]; acetonitrile%: 1%-30%, 7min) to obtain compound 1-11.

[0117] MS m / z(ESI):[M+H] + =295.2.

[0118] Step 10: Synthesis of Compounds 1-12

[0119] Compound 1-11 (0.1 g, 339.69 μmol) was dissolved in 1,4-dioxane (3 mL). Potassium carbonate (187.79 mg, 1.36 mmol) and di-tert-butyl dicarbonate (111.20 mg, 509.53 μmol, 117.06 μL) in water (1 mL) were then added. The reaction was stirred at 15°C for 12 h. The reaction mixture was poured into water (30 mL), extracted with ethyl acetate (20 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated. Compound 1-12 was purified by column chromatography (petroleum ether:ethyl acetate = 5:1) to afford compound 1-12.

[0120] 1H NMR(400MHz, DMSO-d6)δ=12.52-12.16(m,1H),6.56-6.31(m,1H),4.66-4.58(m,1H),4.24-4.18(m,1H),4.02(s,1H),3.36-3.28(m,1H),1.97 -1.91(m,2H),1.81-1.73(m,2H),1.66-1.59(m,1H),1.36(s,9H),0.99 -0.93(m,9H),0.80-0.70(m,1H),0.64-0.53(m,1H),0.49-0.33(m,2H)

[0121] MS m / z(ESI):[M+H] + =395.2.

[0122] Step 11: Synthesis of Compounds 1-13

[0123] Compound 1-12 (88.13 mg, 223.40 μmol) was dissolved in tetrahydrofuran (2 mL) and methanol (0.6 mL). Lithium hydroxide monohydrate (28.12 mg, 670.21 μmol) was dissolved in water (0.6 mL) and added. The reaction was stirred at 15°C for 2 h. The pH was adjusted to approximately 5 with 3% citric acid. The mixture was extracted with ethyl acetate (20 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated to yield compound 1-13.

[0124] MS m / z(ESI):[M+H] + =381.3.

[0125] Step 12: Synthesis of Compound 1-15

[0126] Compound 1-13 (0.056 g, 148.79 μmol) was dissolved in N,N-dimethylformamide (2 mL), and O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (84.86 mg, 223.18 μmol) was added to the reaction system, and the reaction was stirred at 15°C for 0.5 h. Diisopropylethylamine (76.92 mg, 595.16 μmol, 103.67 μL) was then added to the reaction solution, and a solution of the hydrochloride of compound 1-14 (43.26 mg, 208.31 μmol) dissolved in N,N-dimethylformamide (0.5 mL) was added to the reaction system, and the reaction was stirred at 15°C for 12 h. The reaction mixture was diluted with water (20 mL), extracted with ethyl acetate (20 mL×3), and the organic phase was washed with 3% citric acid (20 mL), washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 1-15.

[0127] 1H NMR (400MHz, DMSO-d6)δ=8.22-8.08(m,1H),7.56(s,1H),7.32-7.16(m,1H),7.01(s,1H),6.51(br d,J=9.4Hz,1H),4.60-4.49(m,1H),4.28-4.17(m,2H),4.14(s,1H),3.18-2. 98(m,2H),2.47-2.35(m,1H),2.17-2.09(m,2H),1.96-1.84(m,2H),1.76(br d,J=11.0Hz,1H),1.71-1.42(m,4H),1.39-1.34(m,9H),0.95(s,8H),0.84-0.77(m,1H),0.73-0.65(m,1H),0.39(br s,2H)

[0128] MS m / z(ESI):[M+H] + =534.4.

[0129] Step 13: Synthesis of Compound 1-16

[0130] Compound 1-15 (0.02 g, 37.48 μmol) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (141.02 mg, 1.24 mmol, 91.57 μL) was added to the reaction system. Stir at 15°C for 1 h. The reaction was quenched directly with sodium bicarbonate solution (10 mL) and extracted with dichloromethane (5 mL x 5). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to yield compound 1-16.

[0131] 1H NMR (400MHz, DMSO-d6)δ=8.37-8.26(m,1H),8.14(br d,J=3.6Hz,3H),7.59-7.53(m,1H),7.40-7.32(m,1H),7.05-6.92(m,1H),4.33-4.21(m,2H),3.93(br d,J=5.0Hz,1H),3.17-3.08(m,1H),3.06-2.97(m,1H),2.44-2.32(m,1H),2.18-2.08(m,2H),1.96-1.86(m,2H ),1.82-1.57(m,4H),1.51-1.40(m,1H),1.04(s,9H),0.95-0.85(m,1H),0.76-0.67(m,1H),0.54-0.34(m,2H)

[0132] MS m / z(ESI):[M+H] + =434.2.

[0133] Step 14: Synthesis of Compound 1

[0134] Compound 1-16 (0.03 g, 69.20 μmol) was dissolved in dichloromethane (1 mL), and trifluoroacetic anhydride (58.13 mg, 276.79 μmol, 38.50 μL) was added to the reaction system. Stir at 15°C for 1 h. The reaction was quenched directly with sodium bicarbonate solution (10 mL) and extracted with dichloromethane (5 mL x 5). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated by preparative HPLC (column: Waters Xbridge BEH C18 100*30 mm*10 μm; mobile phase: [H2O(NH4HCO3)-acetonitrile]; acetonitrile percentage: 10%-50%, 8 min) to yield compound 1, the compound of formula (I).

[0135] 1H NMR(400MHz,DMSO-d6)δ=9.31(br d,J=8.0Hz,1H),8.87(d,J=8.6Hz,1H),7.66(s,1H),5.01-4.87(m,1H),4.72-4.59(m,2H),4.07(s,1H), 3.17-3.10(m,1H),3.09-2.98(m,1H),2.45-2.33(m,1H),2.19-2.05(m,3H),1.85-1.64(m,5H),1.56(br d,J=12.0Hz,1H),1.20-1.13(m,1H),1.01(s,8H),0.82-0.67(m,2H),0.54-0.46(m,1H),0.45-0.34(m,1H)

[0136] MS m / z(ESI):[M+H] + =512.2.

[0137] Step 15: Preparation of Compound (I) A Crystalline Form

[0138] The compound of formula (I) (9.4 g, 18.38 mmol) was dissolved in H₂O (235 mL) and stirred at 50°C for 48 hours. Filtration afforded a white solid, which was then concentrated under reduced pressure to remove water to afford Form A. XRPD analysis revealed that its X-ray powder diffraction pattern (see Figure 1) exhibited characteristic diffraction peaks at the following 2θ angles: 6.917±0.200°, 10.655±0.200°, 11.988±0.200°, 14.481±0.200°, 16.055±0.200°, 17.653±0.200°, 18.356±0.200°, and 20.083±0.200°.

[0139] In the DSC test, Compound (I) Form A has an endothermic peak at 173.5°C ± 3°C, absorbing 45.1 J / g (see Figure 2). The TGA test shows that Compound (I) Form A loses less than 0.5% of its weight at 150.0°C ± 3°C (see Figure 3). 1 H NMR analysis of Form A revealed no residual organic solvent, indicating that Form A is an anhydrous form.

[0140] Example 2

[0141] Preparation composition

[0142] Preparation method:

[0143] 1) Granulation: Cross-linked sodium carboxymethyl cellulose, colloidal silicon dioxide, and sodium stearyl fumarate were passed through a 1.5 mm sieve, and the sieved cross-linked sodium carboxymethyl cellulose, colloidal silicon dioxide, sodium stearyl fumarate, compound (I) (particle size D90: 128 μm), lactose monohydrate (FlowLac100), and microcrystalline cellulose 112 were uniformly mixed at a mixing speed of 10 rpm for 10 min. After mixing, dry granulation and granulation were performed using a dry granulator at a feed speed of 90 rpm, a roller speed of 30 rpm, a roller spacing of 2 mm, a crushing speed of 50 rpm, a hydraulic pressure of 6-12 MPa, and a granulation speed of 100 rpm.

[0144] 2) Blending: Blend the prepared granules with some of the additional excipients, croscarmellose sodium and sodium stearyl fumarate, at a mixing speed of 10 rpm for 10 min;

[0145] 3) tableting: adjusting tablet weight and pressure, and tableting to obtain the pharmaceutical preparation in the form of tablets;

[0146] 4) Coating: Coating the tablets prepared in step 3).

[0147] Example 3

[0148] Preparation composition:

[0149] Preparation method: same as Example 2

[0150] Example 4 Preparation composition

[0151] Preparation method: same as Example 2

[0152] Example 5

[0153] Preparation method:

[0154] 1) Mixing: Cross-linked sodium carboxymethyl cellulose, colloidal silicon dioxide, and sodium stearyl fumarate were passed through a 1.5 mm sieve, and then the sieved cross-linked sodium carboxymethyl cellulose, colloidal silicon dioxide, sodium stearyl fumarate, compound (I), lactose monohydrate (FlowLac100), and microcrystalline cellulose 112 were mixed uniformly at a mixing speed of 10 rpm for 10 min.

[0155] 2) tableting: adjusting tablet weight and pressure, and tableting to obtain the pharmaceutical preparation in the form of tablets;

[0156] 3) Coating: coating the tablets prepared in step 2).

[0157] Example 6

[0158] Preparation composition:

[0159] Preparation method:

[0160] 1) Granulation: Cross-linked sodium carboxymethyl cellulose, colloidal silicon dioxide, and sodium stearyl fumarate were sieved through a 1.5 mm sieve, and then the sieved cross-linked sodium carboxymethyl cellulose, colloidal silicon dioxide, compound (I), lactose monohydrate 200 mesh, and microcrystalline cellulose 101 were dry-mixed at a stirring speed of 100 rpm for 10 minutes. After dry-mixing, the hydroxypropyl cellulose solution was added to granulate at a stirring speed of 100 rpm and a fly cutter speed of 2000 rpm. After granulation, the wet granules were dried in a fluidized bed at a drying temperature of 60° C. with a drying loss of less than 3.0%. After drying, the granules were sieved through a 1.5 mm pore size sieve.

[0161] 2) Blending: Blend the prepared granules with some of the additional excipients, croscarmellose sodium and sodium stearyl fumarate, at a mixing speed of 10 rpm for 10 min;

[0162] 3) tableting: adjusting tablet weight and pressure, and tableting to obtain the pharmaceutical preparation in the form of tablets;

[0163] 4) Coating: Coating the tablets prepared in step 3).

[0164] Example 7:

[0165] Preparation composition:

[0166] Preparation method: same as Example 2

[0167] Example 8:

[0168] Preparation composition

[0169] Preparation method:

[0170] 1) Granulation: Cross-linked sodium carboxymethyl cellulose, colloidal silicon dioxide, and sodium stearyl fumarate were passed through a 1.5 mm sieve, and the sieved cross-linked sodium carboxymethyl cellulose, colloidal silicon dioxide, sodium stearyl fumarate, compound (I) (particle size D90: 202 μm), lactose monohydrate (FlowLac100), and microcrystalline cellulose 112 were uniformly mixed at a mixing speed of 10 rpm for 10 min. After mixing, dry granulation and granulation were performed using a dry granulator at a feed speed of 90 rpm, a roller speed of 30 rpm, a roller spacing of 2 mm, a crushing speed of 50 rpm, a hydraulic pressure of 6-12 MPa, and a granulation speed of 100 rpm.

[0171] 2) Blending: Blend the prepared granules with some of the additional excipients, croscarmellose sodium and sodium stearyl fumarate, at a mixing speed of 10 rpm for 10 min;

[0172] 3) tableting: adjusting tablet weight and pressure, and tableting to obtain the pharmaceutical preparation in the form of tablets;

[0173] 4) Coating: Coating the tablets prepared in step 3).

[0174] Test Example 1: Content Uniformity Test

[0175] Conclusion: The samples prepared in the examples of the present invention have good content uniformity.

[0176] Test Example 2: Dissolution Test

[0177] The pharmaceutical composition of the embodiment of the present invention was subjected to a dissolution test. The dissolution curve experimental method and conditions were as follows: 12 tablets of the product were taken and the dissolution and release rate determination method (Chinese Pharmacopoeia 2020 Edition, Part IV, General Rules 0931, Method 2) was used, with 900 ml of pH 1.0 hydrochloric acid solution as the dissolution medium, the speed was 65 revolutions per minute, and the operation was carried out in accordance with the law. After 5, 10, 15, and 30 minutes, an appropriate amount of solution was taken (no rehydration was performed during this period), filtered, and used as the test solution.

[0178] Determination was performed according to high-performance liquid chromatography (Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0512). The column was packed with octadecylsilane bonded silica gel (recommended column: YMC-Triart C18 ExRS, 4.6 mm × 150 mm, 3 μm); mobile phase A was 0.1% aqueous phosphoric acid; mobile phase B was acetonitrile; gradient elution was used; detection wavelength was 220 nm; column temperature was 60°C; flow rate was 1.0 ml / min.

[0179] Conclusion: The pharmaceutical preparation of the present invention has good dissolution and release properties.

[0180] Test Example 3: Stability Test

[0181] 3-1 Accelerated stability test

[0182] The stability was examined under accelerated test conditions (40°C ± 2°C, relative humidity 75% ± 5% RH), and the results shown in the following table were obtained.

[0183] The dissolution test method and conditions are as follows: take 6 tablets of this product, follow the dissolution and release determination method (Chinese Pharmacopoeia 2020 Edition Part IV General Rules 0931 Second Method), use 900ml of pH 1.0 hydrochloric acid solution as the dissolution medium, and operate at a speed of 75 revolutions per minute. After 30 minutes, take a sample, filter the dissolution solution, and take the filtrate as the test solution.

[0184] Determination was performed according to high-performance liquid chromatography (Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0512). The column was packed with octadecylsilane bonded silica gel (recommended column: YMC-Triart C18 ExRS, 4.6 mm × 150 mm, 3 μm); mobile phase A was 0.1% aqueous phosphoric acid; mobile phase B was acetonitrile; gradient elution was used; detection wavelength was 220 nm; column temperature was 60°C; flow rate was 1.0 ml / min.

[0185] 3-2 Long-term stability test

[0186] Stability was investigated under long-term test conditions (25°C ± 2°C, relative humidity 60% ± 5% RH), yielding the results shown in the table below. The dissolution test method and conditions used a pH 1.0 hydrochloric acid medium, a rotation speed of 75 rpm, and a sampling interval of 30 minutes. The specific determination method is the same as in 3-1.

[0187] Conclusion: The pharmaceutical preparation of the present invention remained stable under accelerated conditions and long-term conditions in all investigated items and had good stability.

[0188] Test Example 4: Human Pharmacokinetic Test of the Preparation of Example 4

[0189] A single fasting dose study was conducted in healthy subjects strictly according to the clinical trial protocol. The doses were 150 mg of the sample in Example 4 and 150 mg of the sample in Example 4 + 100 mg of ritonavir tablets. Each group consisted of 8 subjects, 6 of whom received the test drug and 2 received a placebo. Pharmacokinetic biospecimens were collected from subjects who received the test drug for pharmacokinetic calculations and statistics. The pharmacokinetic properties of the test sample in healthy subjects were studied. The results are shown in the table below.

[0190] Pharmacokinetic parameters after single administration in humans

[0191] Conclusion: The preparation of the present invention is rapidly absorbed after administration, with a median time to peak absorption (Tmax) ranging from 0.5 to 0.75 hours. The area under the curve (AUC) and peak concentration (Cmax) show an increasing trend within the dosage range. It has good drugability. The preparation of the present invention achieves high concentrations and exposures in vivo at a relatively low dosage (150 mg). Furthermore, when this product is used in combination with ritonavir, Tmax is prolonged and plasma exposure is increased, indicating that ritonavir can significantly enhance the in vivo exposure of this product.

[0192] In addition, healthy subjects were orally administered 150 mg of this product + 100 mg of ritonavir tablets, or 300 mg of this product + 100 mg of ritonavir tablets on an empty stomach twice a day for 5 consecutive days (D5). The test results showed that this product could basically reach a steady state on D2, and there was no obvious accumulation after continuous administration.

[0193] Test Example 5: The effective dosage of the preparation of the present invention is significantly lower than that of similar drugs

[0194] This product (sample in Example 4) was studied in a randomized, double-blind, placebo-controlled Phase II / III clinical study in patients with mild / moderate COVID-19. The study included subjects aged ≥18 years, who tested positive for severe acute respiratory syndrome coronavirus (COVID-19) within 5 days before randomization, and who had at least 2 target symptoms of COVID-19 and at least 1 specified symptom for the first time within 72 hours before randomization. Patients who received COVID-19 antiviral drugs, COVID-19 monoclonal antibodies, intravenous COVID-19 human immunoglobulin, or plasma from recovered COVID-19 patients were excluded.

[0195] The subjects were randomly assigned (1:1) to receive either levofloxacin or placebo, administered orally every 12 hours for 5 consecutive days. Efficacy indicators were analyzed based on a modified intention-to-treat (mITT) analysis, with 1,213 subjects enrolled in the mITT (610 in the levofloxacin group and 603 in the placebo group).

[0196] Based on mITT, the median time to sustained recovery of all target clinical symptoms of COVID-19 in the experimental group and the placebo group and the 95% CI were 13.0 (12.0, 15.0) days and 15.0 (14.0, 15.0) days, respectively. The difference (95.45% CI) in the change in viral load from baseline on day 4 between the experimental group and the placebo group was -1.10Log 10 The difference between the two groups in viral load change compared with the baseline on the fifth day after treatment was the largest, with a difference (95.45% CI) of -1.75Log 10 copies / mL.

[0197] Within 28 days after treatment, the median time for COVID-19 nucleic acid to turn negative was 12 days in the trial group and 14 days in the placebo group, respectively.

[0198] Test Example 6: Study on hygroscopicity and stability of compound (I) A crystal form

[0199] 6-1 Study on the Hygroscopicity of Compound (I) A Crystal Form

[0200] Experimental Materials:

[0201] SMSDVS Advantage Dynamic Vapor Sorption Tester

[0202] Experimental methods:

[0203] 10-30 mg of Compound (I) Form A was placed in a DVS sample tray for testing.

[0204] Experimental conclusion:

[0205] The weight gain of Compound (I) A crystal form at 25° C. and 80% RH is 0.114%, indicating no or almost no hygroscopicity.

[0206] 6-2 Stability test of compound (I) crystal form A under different conditions

[0207] The results are shown in the table below:

[0208] Conclusion: Compound (I) of the present invention, Form A, has good stability under conditions of light, high temperature and high humidity.

[0209] 6-3 Accelerated and long-term stability tests of Compound (I) A

[0210] Two batches of Compound (I) Form A were tested for six months each under accelerated stability conditions (40°C ± 2°C / 75 ± 5% RH) and long-term stability conditions (25°C ± 2°C / 60 ± 5% RH). The results are as follows:

[0211] Accelerated test (40℃±2℃ / 75±5%RH) results

[0212] Long-term test (25℃±2℃ / 60±5%RH) research results

[0213] Experimental conclusion: Compound (I) Form A of the present invention was placed under accelerated and long-term conditions for 6 months, and all test items including impurity content, isomers, and crystal form remained unchanged, indicating good stability.

[0214] Test Example 7: Pharmacokinetics test in rats

[0215] In this study, male and female SD rats were used as test animals. The LC / MS / MS method was used to quantitatively determine the plasma drug concentrations of the test compound at different time points after a single intravenous injection of 2 mg / kg and a single oral gavage of 30 mg / kg of Form A of Compound (I). The pharmacokinetic characteristics of the test drug in rats were evaluated.

[0216] Animals were divided into groups of 3 per sex and administered with Compound (I) Form A. Plasma samples were collected at 0.083 (intravenous injection group only), 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours after administration, and blood drug concentrations were determined using LC-MS / MS. The experimental results are shown in the table below.

[0217] Pharmacokinetic parameters of Compound (I) A crystal form in rats

[0218] a: Bioavailability is determined by AUC 0-las t and theoretical dose calculation. ND: Not determined. --: Not applicable.

[0219] Experimental conclusion: The exposure amount of the crystal form A of the compound (I) of the present invention in plasma is higher and the bioavailability is higher.

[0220] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit it. Although the present invention has been described in detail with reference to the above embodiments, those skilled in the art should understand that they can still modify the technical solutions described in the above embodiments, or replace some or all of the technical features therein with equivalents. However, these modifications or replacements do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of the present invention.

Claims

1. A pharmaceutical composition, characterized in that It comprises a pharmaceutical active ingredient and a pharmaceutical excipient, wherein the pharmaceutical active ingredient comprises compound (I) or a pharmaceutically acceptable salt thereof, and the excipient comprises 3-20 wt% of a disintegrant; 2. The pharmaceutical composition according to claim 1, wherein It meets one or more of the following conditions: (1) The disintegrant is selected from one or more of croscarmellose sodium, cross-linked polyvinylpyrrolidone, sodium carboxymethyl starch, starch, hydroxypropyl starch and low-substituted hydroxypropyl cellulose; preferably croscarmellose sodium; (2) The content of the disintegrant is 4-15 wt%, for example 5 wt%, 6 wt% or 10 wt%; (3) The compound (I) is in an amorphous form and / or a crystalline form, preferably a crystalline form; The crystalline form of the compound (I) is crystalline form A, and its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 10.655±0.200°, 11.988±0.200°, 16.055±0.200°, 18.356±0.200° and 20.083±0.200°; Furthermore, the X-ray powder diffraction pattern of the crystalline form A has characteristic diffraction peaks at the following 2θ angles: 6.917±0.200°, 10.655±0.200°, 11.988±0.200°, 14.481±0.200°, 16.055±0.200°, 17.653±0.200°, 18.356±0.200° and 20.083±0.200°; Furthermore, the X-ray powder diffraction pattern of the crystalline form A is shown in Figure 1; (4) The content of the active ingredient of the medicine is 15-30wt%, and can be 20-25wt%; (5) The pharmaceutical composition is in the form of a tablet or capsule preparation; (6) The pharmaceutical excipient further comprises one, two or three of a diluent, a glidant and a lubricant; The pharmaceutical composition described in (7) further comprises coating powder.

3. The pharmaceutical composition according to claim 1 or 2, wherein It meets one or more of the following conditions: (1) When the pharmaceutical excipient contains a diluent, the diluent is selected from one or more of lactose, microcrystalline cellulose, mannitol, cyclodextrin, starch, pregelatinized starch, anhydrous calcium hydrogen phosphate and silicified microcrystalline cellulose; preferably lactose and / or microcrystalline cellulose; (2) When the pharmaceutical excipient contains a diluent, the content of the diluent is 50-80 wt%, or 63-71 wt%, for example 67 wt%; (3) When the pharmaceutical excipient contains a glidant, the glidant is selected from one, two or three of silicon dioxide, magnesium trisilicate and talc; preferably silicon dioxide; (4) When the pharmaceutical excipient contains a glidant, the content of the glidant is 0.5-10 wt%, and can be 1-5 wt%, for example, 1.25 wt%; (5) When the pharmaceutical excipient contains a lubricant, the lubricant is selected from one or more of stearic acid, sodium stearyl fumarate, magnesium stearate, calcium stearate, sodium lauryl sulfate, polyethylene glycol, glyceryl behenate, talc and hydrogenated vegetable oil; preferably sodium stearyl fumarate; (6) When the pharmaceutical excipient contains a lubricant, the content of the lubricant is 1-10 wt%, and may be 2-2.5 wt%; (7) When the pharmaceutical composition is a pharmaceutical preparation, the unit dosage form of the pharmaceutical preparation contains 50-200 mg of the pharmaceutical active ingredient, for example, 50 mg or 150 mg of the pharmaceutical active ingredient; When the pharmaceutical composition described in (8) further comprises coating powder, the coating powder is a film coating premix.

4. The pharmaceutical composition according to claim 1, wherein It satisfies the following (1) and / or (2): (1) In the pharmaceutical composition, the active pharmaceutical ingredient is the compound (I) or a pharmaceutically acceptable salt thereof, such as the crystalline form A described in claim 2; (2) In the pharmaceutical composition, the pharmaceutical excipients are composed of the disintegrant according to claim 2, the diluent according to claim 3, the glidant according to claim 3 and the lubricant according to claim 3, for example, cross-linked sodium carboxymethyl cellulose, lactose, microcrystalline cellulose, silicon dioxide, and sodium stearyl fumarate.

5. The pharmaceutical composition according to claim 1 or 2, wherein The pharmaceutical composition comprises an intragranular component and an extragranular component; the intragranular component comprises the pharmaceutical active ingredient and a disintegrant; and the extragranular component comprises a disintegrant.

6. The pharmaceutical composition according to claim 5, wherein It meets one or more of the following conditions: (1) In the granular components, the disintegrant is selected from one or more of croscarmellose sodium, cross-linked polyvinylpyrrolidone, sodium carboxymethyl starch, starch, hydroxypropyl starch and low-substituted hydroxypropyl cellulose; preferably croscarmellose sodium; (2) The content of the disintegrant in the granular component may be 1.5-10 wt%, or 2-7.5 wt%, for example 3.75 wt%; (3) The intragranular component further comprises one, two or three of the diluent according to claim 3, the glidant according to claim 3 and the lubricant; The lubricant is preferably selected from one or more of stearic acid, sodium stearyl fumarate, magnesium stearate, calcium stearate, sodium lauryl sulfate, polyethylene glycol, glyceryl behenate, talc and hydrogenated vegetable oil; more preferably sodium stearyl fumarate; The content of the lubricant may be 0.5-5wt%, or 1-2.5wt%, for example 1.25wt%; (4) In the extragranular component, the disintegrant is selected from one or more of croscarmellose sodium, cross-linked polyvinylpyrrolidone, sodium carboxymethyl starch, starch, hydroxypropyl starch, and low-substituted hydroxypropyl cellulose; preferably croscarmellose sodium; (5) The content of the disintegrant in the extragranular component may be 1.5-10 wt%, or 2-7.5 wt%, for example, 3.75 wt%; and the extragranular component of (6) further comprising a lubricant; The lubricant is preferably selected from one or more of stearic acid, sodium stearyl fumarate, magnesium stearate, calcium stearate, sodium lauryl sulfate, polyethylene glycol, glyceryl behenate, talc and hydrogenated vegetable oil; more preferably sodium stearyl fumarate; The content of the lubricant may be 0.5-5 wt%, or 1-2.5 wt%, for example 1.25 wt%.

7. The pharmaceutical composition according to claim 1 or 2, wherein It is any one of options 1 to 6: Option 1: The pharmaceutical composition comprises the following components in weight percentage: 20-25 wt% of the active pharmaceutical ingredient according to claim 2, 4-15 wt% of the disintegrant according to claim 2, and 1-5 wt% of the glidant according to claim 3; Option 2: The pharmaceutical composition comprises 18-22 wt% of the crystalline form A of compound (I) according to claim 2, 4-7 wt% of croscarmellose sodium, 68-75 wt% of a diluent, 0.5-1.5 wt% of silicon dioxide, and 1.5-3 wt% of sodium stearyl fumarate; The diluent is lactose and / or microcrystalline cellulose; Option 3: The pharmaceutical composition comprises 20 wt% of the crystalline form A of compound (I) according to claim 2, 6 wt% of croscarmellose sodium, 71 wt% of a diluent, 1 wt% of silicon dioxide and 2 wt% of sodium stearyl fumarate; The diluent is lactose and / or microcrystalline cellulose; Option 4: The pharmaceutical composition comprises an intragranular component and an extragranular component; the intragranular component comprises the pharmaceutical active ingredient and a disintegrant; the extragranular component comprises a disintegrant; The intragranular components are composed of the active pharmaceutical ingredient, the disintegrant according to claim 6, the diluent according to claim 6, the glidant according to claim 6 and the lubricant according to claim 6; The extragranular component consists of the disintegrant according to claim 6 and the lubricant according to claim 6; Option 5: The pharmaceutical composition comprises an intragranular component and an extragranular component; the intragranular component comprises the pharmaceutical active ingredient and a disintegrant; the extragranular component comprises a disintegrant; The intragranular components are composed of 20-25 wt% of the crystalline form A according to claim 2, 3-7.5 wt% of croscarmellose sodium, 63-71 wt% of a diluent, 1-5 wt% of silicon dioxide, and 1-2.5 wt% of sodium stearyl fumarate; The diluent is lactose and / or microcrystalline cellulose The extragranular component consists of 3-7.5 wt% croscarmellose sodium and 1-2.5 wt% sodium stearyl fumarate; Option 6: The pharmaceutical composition is composed of the pharmaceutical active ingredient according to any one of claims 1 to 6, the pharmaceutical excipient according to any one of claims 1 to 6, and a coating powder.

8. A method for preparing the pharmaceutical composition according to any one of claims 1 to 7, characterized in that: It includes the following steps: The pharmaceutical composition is obtained by mixing the pharmaceutical active ingredient and the pharmaceutical excipient.

9. An oral preparation, characterized in that It contains a crystalline form A of compound (I); the crystalline form A has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2θ angles: 10.655±0.200°, 11.988±0.200°, 16.055±0.200°, 18.356±0.200° and 20.083±0.200°; 10. The oral preparation according to claim 9, wherein It satisfies the following (1) and / or (2): (1) The oral preparation further contains one, two, three or four of a diluent, a disintegrant, a glidant and a lubricant; The types and contents of the diluent, the disintegrant, the glidant and the lubricant are the same as those of the diluent described in any one of claims 2 to 4, the disintegrant described in any one of claims 2 to 4, the glidant described in any one of claims 2 to 4 and the lubricant described in any one of claims 2 to 4; (2) The oral preparation is a solid preparation; The oral formulation may comprise an intragranular component and an extragranular component; both the intragranular component and the extragranular component are as described in claim 5 or 6.

11. A combination medicine kit, characterized in that: It includes a pharmaceutical composition and ritonavir; The pharmaceutical composition is the pharmaceutical composition according to any one of claims 1 to 7 or the oral preparation according to claim 9 or 10.

12. Use of a substance in the preparation of a drug for preventing or treating novel coronavirus infection, characterized in that: The substance is the pharmaceutical composition according to any one of claims 1 to 7, the oral preparation according to claim 9 or 10, or the combination kit according to claim 11.

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