Composition, method for preparing same, and use thereof

Abstract

The present invention relates to the field of pharmaceutical formulations, and particularly, to a composition, a method for preparing same, and use thereof. The composition comprises ATV014 compound and a pharmaceutically acceptable excipient. The composition features good stability, high dissolution rate and high bioavailability, and can be used for preventing, ameliorating or treating a coronavirus infection or the replication or reproduction of homologous virus variants thereof and the cytopathic effect caused by same.

Description

A composition and its preparation method and use Technical Field

[0001] The present invention relates to the field of pharmaceutical preparations, and in particular to a composition, a preparation method and use thereof. Background Art

[0002] The novel coronavirus (COVID-19) is an enveloped, single-stranded RNA virus belonging to the genus Betacoronavirus. Similar to SARS and MERS, the SARS-CoV-2 genome encodes nonstructural proteins: 3-chymotrypsin-like protease (3CLpro), papain-like protease (PLpro), helicase, and RNA-dependent RNA polymerase (RdRp); and structural proteins: spike glycoprotein and accessory proteins. The novel coronavirus's surface spike glycoprotein binds to the angiotensin-converting enzyme (ACE2) receptor on human cells, enabling infection of human respiratory epithelial cells. After entering the host cell, the virus disassembles, releasing the nucleocapsid and viral RNA into the cytoplasm. The open reading frames at the 5′ ends of the viral RNA (ORF1a / b) encode polyproteins (pp1a and pp1ab), which play important roles in the processing and maturation of enzymes required for viral replication. Pp1a and pp1ab can be cleaved by papain-like proteases (PLpro) and 3C-like proteases (3CLpro), producing nonstructural proteins, including RNA-dependent RNA polymerase and helicase, which play a key role in the transcription and replication of the novel coronavirus. Currently, the coronavirus's surface spike glycoprotein, which recognizes the receptor, and 3CLpro, PLpro, and RdRp, important proteins involved in replication and transcription, are four very attractive targets for antiviral drug development.

[0003] Regarding the development of COVID-19 vaccines, the UK first approved the emergency use of the Pfizer and BioNTech COVID-19 vaccine on December 2. While the effectiveness of this vaccine in widespread use remains unknown, its strict cryogenic storage requirements pose significant challenges to widespread use.

[0004] Regarding COVID-19 drug development, remdesivir is currently the only FDA-approved COVID-19 drug. Remdesivir, a prodrug of an adenosine analogue (aminomethyl monophosphate), was originally developed by Gilead Sciences for the Ebola virus. As an RdRp inhibitor, remdesivir has demonstrated activity against COVID-19 at the cellular level. However, clinical trials have shown that remdesivir does not significantly reduce mortality in humans. Furthermore, since the clinically used dose is close to the safe dose, some significant side effects warrant attention.

[0005] Therefore, there is still a need for a drug with good safety, stability and bioavailability to treat the new coronavirus.

[0006] Summary of the Invention

[0007] SUMMARY OF THE INVENTION

[0008] To solve the above problems, in a first aspect, the present invention provides a composition comprising an ATV014 compound and a pharmaceutically acceptable excipient.

[0009] In some embodiments, the pharmaceutically acceptable excipients may include at least one selected from: a diluent, a disintegrant, a binder, a lubricant, and other excipients. In some embodiments, the diluent is at least one of microcrystalline cellulose, mannitol, and pregelatinized starch. In some embodiments, the diluent is microcrystalline cellulose and mannitol. In some embodiments, the diluent is microcrystalline cellulose or mannitol. Using microcrystalline cellulose or mannitol as a diluent is more conducive to improving the compatibility of raw materials and excipients, preferably microcrystalline cellulose or mannitol as a diluent; more preferably microcrystalline cellulose PH102 or mannitol 50C as a diluent; most preferably mannitol 50C as a diluent.

[0010] In a second aspect, the present invention provides a use of the aforementioned composition in the preparation of a product for preventing, alleviating or treating coronavirus infection or the replication or reproduction of its homologous variant viruses and the resulting cytopathic effects.

[0011] In a third aspect, the present invention provides a method for preparing the aforementioned composition. This method utilizes grinding or pulverizing ATV014 to reduce the particle size of the ATV014, thereby improving the dissolution rate of the product and achieving a moderate granule hardness during dry granulation. Dry granulation using the ground ATV014 facilitates obtaining granules of superior hardness. The dry granulation method also facilitates improving the disintegration rate of the product.

[0012] Detailed Description of the Invention

[0013] To solve the above problems, the present invention provides a composition and its pharmaceutical preparation, use and preparation method.

[0014] In a first aspect, a composition is provided.

[0015] A composition comprising: an ATV014 compound and a pharmaceutically acceptable excipient,

[0016] In some embodiments, the pharmaceutically acceptable excipients may include at least one selected from the group consisting of: diluents, disintegrants, binders, lubricants, and other excipients. In some embodiments, the pharmaceutically acceptable excipients include diluents, disintegrants, binders, and lubricants.

[0017] In certain embodiments, the diluent may include at least one selected from microcrystalline cellulose, mannitol, calcium hydrogen phosphate and pregelatinized starch. In certain embodiments, the diluent is at least one of microcrystalline cellulose, mannitol and pregelatinized starch. In certain embodiments, the diluent is microcrystalline cellulose and mannitol. In certain embodiments, the diluent is microcrystalline cellulose or mannitol. Using microcrystalline cellulose or mannitol as a diluent is conducive to improving the compatibility of raw materials and supplementary materials. In some more selected embodiments, the diluent is microcrystalline cellulose PH102 or mannitol 50C, which is more conducive to improving the compatibility of raw materials and supplementary materials. In some most preferred embodiments, the diluent is mannitol 50C, which is most conducive to the compatibility of raw materials and supplementary materials.

[0018] In some embodiments, the disintegrant may include at least one selected from the group consisting of cross-linked carboxymethyl cellulose sodium, cross-linked polyvinylpyrrolidone, sodium carboxymethyl starch, and hydroxypropyl cellulose. In some embodiments, the disintegrant is cross-linked carboxymethyl cellulose sodium.

[0019] In some embodiments, the binder may include at least one selected from hydroxypropyl cellulose, povidone, and starch. In some embodiments, the binder is hydroxypropyl cellulose.

[0020] In some embodiments, the lubricant may include at least one selected from magnesium stearate, stearic acid, and sodium stearyl fumarate. In some embodiments, the lubricant is magnesium stearate.

[0021] In some embodiments, the other excipients may include glidants.

[0022] In some embodiments, the glidant may include colloidal silicon dioxide or talc.

[0023] In some embodiments, the amount of the ATV014 compound may be 15 wt% to 70 wt% based on the total weight of the composition. In some embodiments, the amount of the ATV014 compound may be 50 wt% to 60 wt% based on the total weight of the composition. In some embodiments, the amount of the ATV014 compound may be 15 wt%, 20 wt%, 25 wt%, 30 wt%, 35 wt%, 40 wt%, 45 wt%, 50 wt%, 55 wt%, 56 wt%, 60 wt%, 65 wt%, or 70 wt% based on the total weight of the composition.

[0024] In some embodiments, the content of the diluent is 20wt%-70wt% based on the total mass of the composition. In some embodiments, the content of the diluent is 30wt%-40wt% based on the total mass of the composition. In some embodiments, the content of the diluent is 20wt%, 25wt%, 30wt%, 35wt%, 36wt%, 37wt%, 40wt%, 45wt%, 50wt%, 55wt%, 60wt%, 65wt% or 70wt% based on the total mass of the composition.

[0025] In some embodiments, the content of the disintegrant is 1 wt% to 10 wt% based on the total weight of the composition. In some embodiments, the content of the disintegrant is 2 wt% to 5 wt% based on the total weight of the composition. In some embodiments, the content of the disintegrant is 1 wt%, 2 wt%, 3 wt%, 4 wt%, 5 wt%, 6 wt%, 7 wt%, 8 wt%, 9 wt% or 10 wt% based on the total weight of the composition.

[0026] In some embodiments, the binder may be present in an amount of 1 wt% to 10 wt% based on the total weight of the composition. In some embodiments, the binder is present in an amount of 2 wt% to 5 wt% based on the total weight of the composition. In some embodiments, the binder is present in an amount of 1 wt%, 2 wt%, 3 wt%, 4 wt%, 5 wt%, 6 wt%, 7 wt%, 8 wt%, 9 wt%, or 10 wt% based on the total weight of the composition.

[0027] In some embodiments, the lubricant may be present in an amount of 0.5 wt % to 5 wt % based on the total weight of the composition. In some embodiments, the lubricant is present in an amount of 1.5 wt % to 5 wt % based on the total weight of the composition. In some embodiments, the lubricant is present in an amount of 0.5 wt %, 1 wt %, 1.5 wt %, 2 wt %, 3 wt %, 4 wt %, or 5 wt % based on the total weight of the composition.

[0028] In some embodiments, the composition may not include a surfactant. In some embodiments, the composition may not include sodium lauryl sulfate.

[0029] In some embodiments, the composition may further include an external lubricant.

[0030] In some embodiments, the external lubricant comprises at least one selected from magnesium stearate, sodium stearate and sodium stearyl fumarate. In some embodiments, the external lubricant is magnesium stearate.

[0031] In some embodiments, the content of the added lubricant is 0.5 wt % to 5 wt % based on the total mass of the composition. In some embodiments, the content of the added lubricant is 1.5 wt % to 5 wt % based on the total mass of the composition. In some embodiments, the content of the added lubricant is 0.5 wt %, 1 wt %, 1.5 wt %, 2 wt %, 3 wt %, 4 wt % or 5 wt % based on the total mass of the composition.

[0032] In some embodiments of the present invention, a composition comprises: an ATV014 compound and a pharmaceutically acceptable excipient, wherein the pharmaceutically acceptable excipient comprises at least one selected from: a diluent, a disintegrant, a binder, a lubricant and other excipients, the diluent comprises at least one selected from microcrystalline cellulose, mannitol, calcium hydrogen phosphate and pregelatinized starch, the disintegrant comprises at least one selected from cross-linked sodium carboxymethyl cellulose, cross-linked polyvinylpyrrolidone, sodium carboxymethyl starch and hydroxypropyl cellulose, the binder comprises at least one selected from hydroxypropyl cellulose, polyvinylpyrrolidone and starch, and the lubricant comprises at least one selected from magnesium stearate, stearic acid and sodium stearyl fumarate. Calculated based on the total mass of the composition, the content of the ATV014 compound is 15 wt%-70 wt%, the content of the diluent is 20 wt%-70 wt%, the content of the disintegrant is 1 wt%-10 wt%, the content of the binder is 1 wt%-10 wt%, and the content of the lubricant may be 0.5 wt%-5 wt%.

[0033] In some embodiments of the present invention, a composition comprises: an ATV014 compound and a pharmaceutically acceptable excipient, wherein the pharmaceutically acceptable excipient comprises at least one selected from: a diluent, a disintegrant, a binder, a lubricant and other excipients, the diluent comprises at least one selected from microcrystalline cellulose, mannitol, calcium hydrogen phosphate and pregelatinized starch, the disintegrant comprises at least one selected from cross-linked sodium carboxymethyl cellulose, cross-linked polyvinylpyrrolidone, sodium carboxymethyl starch and hydroxypropyl cellulose, the binder comprises at least one selected from hydroxypropyl cellulose, polyvinylpyrrolidone and starch, and the lubricant comprises at least one selected from magnesium stearate, stearic acid and sodium stearyl fumarate. Calculated based on the total mass of the composition, the content of the ATV014 compound is 50 wt%-60 wt%, the content of the diluent is 30 wt%-40 wt%, the content of the disintegrant is 2 wt%-5 wt%, the content of the binder is 2 wt%-5 wt%, and the content of the lubricant may be 1.5%-5 wt%.

[0034] In some embodiments of the present invention, a composition comprises: an ATV014 compound and a pharmaceutically acceptable excipient, wherein the pharmaceutically acceptable excipient comprises at least one selected from: a diluent, a disintegrant, a binder, a lubricant and other excipients, the diluent comprises at least one selected from microcrystalline cellulose and mannitol, the disintegrant comprises cross-linked sodium carboxymethyl cellulose, the binder comprises hydroxypropyl cellulose, and the lubricant comprises at least one selected from magnesium stearate, stearic acid and sodium stearyl fumarate. Calculated based on the total mass of the composition, the content of the ATV014 compound is 50 wt%-60 wt%, the content of the diluent is 30 wt%-40 wt%, the content of the disintegrant is 2 wt%-5 wt%, the content of the binder is 2 wt%-5 wt%, and the content of the lubricant can be 1.5%-5 wt%.

[0035] In some embodiments of the present invention, a composition comprises: an ATV014 compound and a pharmaceutically acceptable excipient, wherein the pharmaceutically acceptable excipient comprises at least one selected from: a diluent, a disintegrant, a binder, a lubricant and other excipients, the diluent is microcrystalline cellulose PH102 or mannitol 50C, the disintegrant comprises cross-linked sodium carboxymethyl cellulose, the binder comprises hydroxypropyl cellulose, and the lubricant comprises at least one selected from magnesium stearate, stearic acid and sodium stearyl fumarate. Calculated based on the total mass of the composition, the content of the ATV014 compound is 50 wt%-60 wt%, the content of the diluent is 30 wt%-40 wt%, the content of the disintegrant is 2 wt%-5 wt%, the content of the binder is 2 wt%-5 wt%, and the content of the lubricant can be 1.5%-5 wt%.

[0036] In some embodiments of the present invention, a composition comprises: an ATV014 compound and a pharmaceutically acceptable excipient, wherein the pharmaceutically acceptable excipient comprises at least one selected from: a diluent, a disintegrant, a binder, a lubricant and other excipients, the diluent is microcrystalline cellulose PH102 and mannitol 50C, the disintegrant comprises cross-linked sodium carboxymethyl cellulose, the binder comprises hydroxypropyl cellulose, and the lubricant comprises at least one selected from magnesium stearate, stearic acid and sodium stearyl fumarate. Calculated based on the total mass of the composition, the content of the ATV014 compound is 50 wt%-60 wt%, the content of the diluent is 30 wt%-40 wt%, the content of the disintegrant is 2 wt%-5 wt%, the content of the binder is 2 wt%-5 wt%, and the content of the lubricant can be 1.5%-5 wt%.

[0037] In some embodiments of the present invention, a composition comprises: an ATV014 compound and a pharmaceutically acceptable excipient, wherein the pharmaceutically acceptable excipient comprises at least one selected from: a diluent, a disintegrant, a binder, a lubricant and other excipients, the diluent is mannitol 50C, the disintegrant comprises cross-linked sodium carboxymethyl cellulose, the binder comprises hydroxypropyl cellulose, and the lubricant comprises at least one selected from magnesium stearate, stearic acid and sodium stearyl fumarate. Calculated based on the total mass of the composition, the content of the ATV014 compound is 50wt%-60wt%, the content of the diluent is 30wt%-40wt%, the content of the disintegrant is 2wt%-5wt%, the content of the binder is 2wt%-5wt%, and the content of the lubricant can be 1.5%-5wt%.

[0038] In some embodiments, the dosage form of the composition can be an oral solid preparation or an injection. In some embodiments, the dosage form of the composition is a tablet, granule or capsule.

[0039] In some embodiments, the dosage form may be in a dosage form of 10 mg to 500 mg (e.g., 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, or 500 mg). In some embodiments, the dosage form is in a dosage form of 15 mg to 300 mg. In some embodiments, the dosage form is in a dosage form of 20 mg to 200 mg. In some embodiments, the dosage form is in a dosage form of 50 mg to 200 mg. In some embodiments, the dosage form is in a dosage form of 50 mg.

[0040] Thirdly, a use is provided.

[0041] A use of the composition of the first aspect in preparing a medicament.

[0042] In some embodiments, a composition according to the first aspect is used in the preparation of a product for preventing, alleviating or treating coronavirus infection or the replication or reproduction of its homologous variant virus and the resulting cytopathic effect.

[0043] In some embodiments, the infection comprises fever, cough, sore throat, pneumonia, acute respiratory infection, severe acute respiratory infection, hypoxic respiratory failure and acute respiratory distress syndrome, sepsis or septic shock.

[0044] In some embodiments, a composition according to the first aspect is used in the preparation of a product for detecting a coronavirus or a homologous variant virus thereof.

[0045] In some embodiments, the coronavirus includes: MHV-A59, HCoV-229E, HCoV-OC43, HCoV-NL63, HCoV-HKU1, SARS-CoV, MERS-CoV, SARS-CoV-2, mouse hepatitis virus, feline infectious peritonitis virus, canine coronavirus, bovine coronavirus, avian infectious bronchitis virus or porcine coronavirus. Preferably, the SARS-CoV-2 includes a mutant or unmutated strain of SARS-CoV-2; more preferably, the mutant strain of SARS-CoV-2 includes SARS-CoV-2 mutant strain B.1, SARS-CoV-2 mutant strain B.1.351, SARS-CoV-2 mutant strain B.1.617.2, SARS-CoV-2 mutant strain C.37, SARS-CoV-2 mutant strain P.1 family tree, SARS-CoV-2 mutant strain B.1.525, SARS-CoV-2 mutant strain B.1.427 or SARS-CoV-2 mutant strain B.1.429.

[0046] In some embodiments, the composition is suitable for use in humans or animals. In some embodiments, the animal comprises bovine, equine, ovine, porcine, canine, feline, rodent, primate, avian, or piscine.

[0047] In a fourth aspect, a method for preparing the composition described in the first aspect is provided.

[0048] A method for preparing the composition of the first aspect comprises: mixing the ATV014 compound and pharmaceutically acceptable excipients, dry granulating, adding an external lubricant, mixing, tableting or capsule filling or bagging to obtain the composition.

[0049] In some embodiments of the present invention, a method for preparing the composition of the first aspect comprises: mixing the ATV014 compound and a pharmaceutically acceptable excipient, wet granulating, grinding, drying, dry grinding, adding an external lubricant, mixing, tableting or capsule filling or bagging to obtain the composition.

[0050] In some embodiments of the present invention, a method for preparing the composition of the first aspect comprises: grinding or crushing the ATV014 compound, mixing with pharmaceutically acceptable excipients, dry granulating, adding an external lubricant, mixing, tableting or capsule filling or bagging to obtain the composition.

[0051] In some embodiments of the present invention, a method for preparing the composition of the first aspect comprises: grinding or pulverizing the ATV014 compound, mixing with a pharmaceutically acceptable excipient, wet granulating, grinding, drying, dry milling, adding an external lubricant, mixing, tableting or capsule filling or bagging to obtain the composition.

[0052] In some embodiments, the particle size D90 of the ATV014 may be ≤500 μm. In some embodiments, the particle size D90 of the ATV014 is ≤300 μm. In some embodiments, the particle size D90 of the ATV014 is ≤200 μm. In some embodiments, the particle size D90 of the ATV014 is ≤100 μm. In some embodiments, the particle size D90 of the ATV014 is ≤50 μm. In some preferred embodiments, the particle size D90 of the ATV014 is ≤25 μm. In some preferred embodiments, the particle size D90 of the ATV014 is ≤20 μm. In some more preferred embodiments, the particle size D90 of the ATV014 is ≤10 μm. Beneficial effects

[0053] Compared with the prior art, an embodiment of the present invention has at least one of the following beneficial technical effects:

[0054] (1) The formulation and formulation ratio adopted in the present invention are beneficial to improving dissolution and bioavailability.

[0055] (2) The prescription and prescription ratio adopted in the present invention are beneficial to improving the stability of the drug under conditions such as high temperature, high humidity, and light.

[0056] (3) The prescription and prescription ratio adopted by the present invention can be used to prevent, alleviate or treat coronavirus infection or the replication or reproduction of its homologous variant virus and the resulting cytopathic effect.

[0057] (4) Using a method without adding surfactant is beneficial to increasing the dissolution rate of the product.

[0058] (5) The content of lubricant (e.g., magnesium stearate) is preferably 1.5% or more, which is beneficial to the hardness and smoothness of the granules produced by dry granulation.

[0059] (6) The content of the binder (e.g., hydroxypropyl cellulose) is preferably 3% or more, which is beneficial to the hardness and smoothness of the granules produced by dry granulation.

[0060] (7) The content of the binder (e.g., hydroxypropyl cellulose) is preferably about 3%, which is beneficial to the dissolution rate of the product.

[0061] (8) Grinding or crushing ATV014 to reduce the particle size of ATV014 is beneficial to increasing the dissolution rate of the product and also helps to make the particle hardness moderate during the dry granulation process.

[0062] (9) Using ground ATV014 for dry granulation is beneficial for obtaining particles with better hardness.

[0063] (10) Dry granulation is beneficial to improving the disintegration rate of the product.

[0064] (11) Compared with other diluents, using microcrystalline cellulose or mannitol as a diluent is more conducive to improving the compatibility of raw materials and excipients. Microcrystalline cellulose or mannitol is preferably used as a diluent, more preferably microcrystalline cellulose PH102 or mannitol 50C, and most preferably mannitol 50C.

[0065] Definition of terms:

[0066] In the present invention, "room temperature" refers to ambient temperature, which may be 20°C-30°C; in some embodiments, 22°C-28°C; in some embodiments, 24°C-26°C; in some embodiments, 25°C.

[0067] In the foregoing text of the present invention, all numerical values ​​disclosed herein are approximate, regardless of whether the word "about" or "approximately" is used. Based on the disclosed numbers, the value of each numerical value may vary by less than ±10% or by a reasonable difference deemed by a person skilled in the art, such as ±1%, ±2%, ±3%, ±4%, or ±5%.

[0068] The terms "optional", "optional" or "optionally" mean that the subsequently described event or circumstance may but need not occur. For example, "optional surfactant" means that a surfactant may or may not be present.

[0069] The term "external lubricant" refers to a substance added after granulation to reduce the friction between the granules obtained by granulation, prevent the raw materials and excipients from sticking to the punch surface, or reduce the friction between the tablet and the wall of the die hole.

[0070] The term "strength" refers to the weight of active ingredient in one unit of dosage form (a single tablet or capsule).

[0071] The term "weight percent" or "percent by weight" or "wt%" is defined as the weight of a single component in a composition divided by the total weight of all components of the composition multiplied by 100.

[0072] The term "and / or" should be understood to mean any one of the options or a combination of any two or more of the options.

[0073] The term "wt%" means percentage by mass.

[0074] As used herein, the term "treatment" refers to clinical intervention intended to alter the natural course of a disease in the individual being treated. Desired therapeutic effects include, but are not limited to, preventing the appearance or recurrence of the disease, alleviating symptoms, reducing any direct or indirect pathological consequences of the disease, preventing metastasis, reducing the rate of disease progression, ameliorating or palliating the disease state, and alleviating or improving prognosis.

[0075] In the description of this specification, the reference terms "one embodiment", "some embodiments", "example", "specific example", or "some examples" mean that the specific features, structures, materials or characteristics described in conjunction with the embodiment or example are included in at least one embodiment or example of the present invention. In this specification, the schematic representations of the above terms do not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials or characteristics described can be combined in any one or more embodiments or examples in a suitable manner. In addition, those skilled in the art can combine and combine different embodiments or examples described in this specification and features of different embodiments or examples without contradiction.

[0076] As used herein, a "composition" may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the pharmaceutical art. All methods include the step of bringing the active ingredient into association with the carrier which constitutes one or more accessory ingredients. Generally, the compositions are prepared by uniformly and thoroughly combining the active compound with a liquid carrier, a finely divided solid carrier, or both.

[0077] In the present invention, the abbreviations of some compounds represent the compound structures: DETAILED DESCRIPTION

[0078] In order to enable those skilled in the art to better understand the technical solutions of the present invention, some non-limiting embodiments are further disclosed below to further illustrate the present invention in detail.

[0079] The reagents used in the present invention can be purchased from the market or prepared by the method described in the present invention.

[0080] "#0" indicates capsule shell size 0. "#4" indicates capsule shell size 4. "API" indicates the active pharmaceutical ingredient, which in the following examples refers to compound ATV014. "rpm" indicates revolutions per minute. "SDS" indicates sodium dodecyl sulfate. "h" indicates hour. "min" indicates minute. "μM" indicates micromoles per liter, i.e., μmol / L. "mL" or "ml" indicates milliliters. "Compound RDV" or "RDV" indicates remdesivir.

[0081] Example 1: Preparation of ATV014

[0082] Dissolve 1.50 g of compound 5 in 15 ml of dichloromethane, add 0.42 mL of cyclohexanecarboxylic acid and 55.40 mg of 4-dimethylaminopyridine, stir for 10 min, then add 1.02 g of dicyclohexylcarbodiimide, and stir at room temperature for 24 h. Separate by column chromatography (eluent: petroleum ether / ethyl acetate (v / v) = 1 / 1) to obtain compound 7.

[0083] 1.50 g of compound 7 was dissolved in 3 mL of 37% aqueous hydrochloric acid and 15 mL of tetrahydrofuran. After stirring for 6 hours, sodium carbonate was added to adjust the pH to 8. The organic solvent was removed by rotary evaporation. Column chromatography (eluent: petroleum ether / ethyl acetate (v / v) = 1 / 3) was performed to obtain 0.28 g of compound ATV014 (white solid, 45.8% yield). The obtained compound ATV014 was subjected to proton and carbon spectroscopy, and the results were as follows:

[0084] Proton spectrum: 1 H NMR (600MHz, DMSO-d6) δ (ppm): 7.92 (s, 1H), 7.86 (br, 1H), 6.92 (d, J = 4.5Hz, 1H), 6.81 (d, J = 4 .5Hz,1H),6.33(d,J=5.9Hz,1H),5.38(d,J=5.9Hz,1H),4.70(t,J=5.3Hz,1H),4.32-4.29(dd ,J=12.2Hz,2.6Hz,1H),4.24-4.21(m,1H),4.16-4.13(dd,J=12.3Hz,4.8Hz,1H),3.98-3.95( q,J=5.9Hz,1H),2.26-2.22(m,1H),1.75-1.72(m,2H),1.64-1.56(m,3H),1.30-1.12(m,5H).

[0085] Carbon spectrum: 13 C NMR(150MHz,DMSO-d6)δ(ppm):175.34,156.06,148.4,124.0,117.4,117.0,1 10.7,101.2,81.7,79.4,74.5,70.6,63.0,42.6,29.0,28.9,25.7,25.2,25.1.

[0086] Example 2: Inhibitory effect of compounds on SARS-CoV-2 replicon in HEK293T cells

[0087] Compound GS-441524, ATV014 or ATV014 intermediate 5 was used as the test compound, and the following steps were performed:

[0088] HEK293T cells were seeded in 24-well plates. When the cells grew to a density of 40-50%, 250 ng of SARS-CoV-2 replicon plasmid was transfected using LIPO2000 (lipofectamine 2000). After 6-8 hours of transfection, the cell supernatant was discarded and replaced with fresh DMEM medium. The test compound was added to a final concentration of 50 μM, 10 μM, 5 μM, 2 μM, 1 μM, 0.1 μM or 0.01 μM, respectively. After 60 hours of transfection, the cell supernatant was discarded and TRIZOL was used to collect cell RNA. Total RNA was extracted and cDNA was obtained by reverse transcriptase. Finally, the internal reference gene Gapdh and the SARS-CoV-2N gene subgenome in the cDNA were detected by fluorescent quantitative PCR to reflect the viral replication in the SARS-CoV-2 replicon. The inhibitory effect of different concentrations of drugs on the virus was calculated, and the IC value of the drug was calculated. 50 , the results are shown in Table 2.

[0089] Table 2: Inhibitory effects of compounds on SARS-CoV-2 replicon in HEK293T cells

[0090] Conclusion: All test compounds inhibited SARS-CoV-2 replication in HEK293T cells to varying degrees. ATV014 exhibited a significantly higher activity, 3.65-fold greater than that of GS-441524. The inhibitory effects of different compounds on SARS-CoV-2 replicon replication in HEK293T cells are shown in Table 2.

[0091] Example 3: Inhibitory effect of compounds on SARS-CoV-2 in Vero-E6 cells

[0092] Take compounds RDV, GS-441524, and ATV014 as test compounds, and perform the following steps:

[0093] Vero-E6 cells were seeded in 48-well plates. When the cell density reached approximately 70-80%, the supernatant was discarded and replaced with fresh DMEM medium. Each compound was then added to the medium to a final concentration of 50 μM, 10 μM, 5 μM, 2 μM, 1 μM, 0.5 μM, 0.25 μM, 0.1 μM, or 0.01 μM. The cells were infected with three SARS-CoV-2 mutants (B.1, B.1.351, and B.1.617.2) at a multiplicity of infection (MOI) of 0.05. Antiviral activity was assessed by quantitative real-time polymerase chain reaction (qRT-PCR) to quantify viral copy number in the supernatant 48 hours after infection. The inhibitory effects of different concentrations of the test drugs on viral replication were calculated, and their IC50 values ​​were calculated. The IC50 values ​​of different compounds against SARS-CoV-2 in Vero-E6 cells are shown in Table 3.

[0094] Table 3: Inhibitory effects of different compounds on SARS-CoV-2 in Vero-E6 cells

[0095] Example 4: Investigation of surfactants (preparation method: wet granulation)

[0096] Capsules were prepared according to the formulation described in Table 4.

[0097] Table 4: Prescription ratio

[0098] Preparation method: Grind ATV014 (prescription 37181-037-B is not ground), and sieve ATV014 and other components, mix the internal components according to the prescription ratio, add water and wet granulate, grind, dry, dry grind, add external components, mix, and fill with capsules to obtain capsules.

[0099] Dissolution testing: The resulting capsules were tested for dissolution in 900 mL of 0.1N hydrochloric acid using a paddle method at 75 rpm for 5, 15, 30, 45, 60, and 75 minutes. The results are shown in Table 5.

[0100] Table 5: Dissolution test results

[0101] Result analysis:

[0102] (1) Using a formulation without adding surfactants (such as sodium dodecyl sulfate (SDS)) is more conducive to improving the dissolution rate.

[0103] (2) Grinding the API helps to increase the dissolution rate.

[0104] (3) By grinding the API and not adding surfactants (such as sodium dodecyl sulfate (SDS)), the two can synergize and greatly improve the dissolution rate.

[0105] Example 5: Preparation of API by airflow milling (wet granulation)

[0106] Capsules were prepared according to the formulation described in Table 6.

[0107] Table 6: Prescription ratio

[0108] Preparation method: grind ATV014, and sieve ATV014 and other components, mix the internal components according to the prescription ratio, add water and wet granulate, grind, dry, dry grind, add external components, mix, and fill with capsules to obtain capsules.

[0109] Dissolution testing: The resulting capsules were tested for dissolution in 900 mL of 0.1N hydrochloric acid using a paddle method at 75 rpm for 5, 15, 30, 45, 60, and 75 minutes. The results are shown in Table 7.

[0110] Table 7: Dissolution test results

[0111] Result analysis:

[0112] 1. The formulation containing jet-milled API and no SDS showed a fast dissolution rate and a high dissolution plateau.

[0113] Example 6: Effect of ATV014 Grinding on Dissolution (Preparation Method: Dry Granulation)

[0114] Capsules were prepared according to the formulation described in Table 8.

[0115] Table 8: Prescription ratio

[0116] Preparation method: Grind ATV014 (prescription 37181-027B is not ground), and sieve ATV014 and other components, mix the internal components according to the prescription ratio, dry granulate, add the external components, mix, and fill with capsules to obtain capsules.

[0117] Dissolution testing: The resulting capsules were tested for dissolution in 900 mL of 0.1N hydrochloric acid using a paddle method at 75 rpm for 5, 15, 30, 45, 60, and 75 minutes. The results are shown in Table 9.

[0118] Table 9: Dissolution results

[0119] Result analysis:

[0120] (1) Compared with wet granulation, dry granulation is more conducive to improving product dissolution.

[0121] (2) Grinding of API helps improve the dissolution rate of the product.

[0122] Example 7: Effect of ATV014 Grinding on Dry Granulation Particles and Disintegration Time (Preparation Method: Dry Granulation or Direct Filling)

[0123] Capsules were prepared according to the formulation described in Table 10.

[0124] Table 10: Prescription ratio

[0125] Preparation method of prescription 37181-020-B: grind ATV014, and sieve ATV014 and other components, mix the internal components according to the prescription ratio, dry granulate, add the external components, mix, and fill with capsules to obtain capsules.

[0126] Preparation method of prescription 37181-019-B: After sieving unground ATV014 and other components separately, the internal components are mixed according to the prescription ratio, and then the external components are added, mixed, and filled with capsules to obtain capsules.

[0127] Preparation method of prescription 37181-021-B: Grind ATV014, and sieve ATV014 and other components, mix the internal components according to the prescription ratio, and then add the external components, mix, and fill them with capsules to obtain capsules.

[0128] Observation of dry granulation phenomenon: Granulation was carried out using the dry granulation process parameters shown in Table 11. During the granulation process, the material properties were observed. The results are shown in Table 11.

[0129] Table 11: Observation results of dry granulation phenomena

[0130] Summary: Using ground ATV014 for dry granulation is beneficial to obtaining granules with better hardness.

[0131] Disintegration time investigation: The capsules obtained in this example were taken and the disintegration time of the capsules was tested according to the 2020 edition of the Chinese Pharmacopoeia, Part IV, General Chapter 0921. The results are shown in Table 12.

[0132] Table 12: Disintegration time test results

[0133] Conclusion: The capsules prepared by grinding API and dry granulating followed by filling have a fast disintegration time, and dry granulation is beneficial to improving the disintegration rate of the product.

[0134] Example 8: Investigation of binder and lubricant content

[0135] Capsules were prepared according to the formulation described in Table 13.

[0136] Table 13: Prescription ratio

[0137] Preparation method: grind ATV014, and sieve ATV014 and other components, mix the internal components according to the prescription ratio, dry granulate, add the external components, mix, and fill with capsules to obtain capsules.

[0138] Observation of dry granulation phenomenon: Granulation was carried out using the dry granulation process parameters shown in Table 14. During the granulation process, the material properties were observed. The results are shown in Table 14.

[0139] Table 14: Observation of dry granulation phenomena

[0140] summary:

[0141] 1. The magnesium stearate content is preferably 1.5 wt% or more, which is beneficial to the hardness and smoothness of the granules produced by dry granulation.

[0142] 2. The hydroxypropyl cellulose content is preferably 3 wt% or more, which is beneficial to the hardness and smoothness of the granules produced by dry granulation.

[0143] Dissolution test: roller pressure is 6-12kg / cm 2 The resulting capsules were tested for dissolution at 5, 15, 30, 45, 60, and 75 minutes using a paddle method at 75 rpm in 900 mL of 0.1N hydrochloric acid. The results are shown in Table 15.

[0144] Table 15: Dissolution Results

[0145] Conclusion: The capsules obtained from prescriptions 37181-047-B and 37181-051-B can dissolve rapidly and completely, among which the release rate of prescription 37181-051-B is faster.

[0146] Example 9: Capsules of different specifications

[0147] Capsules were prepared according to the formulation described in Table 16.

[0148] Table 16: Prescription ratio

[0149] Preparation method: grind ATV014, and sieve ATV014 and other components, mix the internal components according to the prescription ratio, dry granulate, add the external components, mix, and fill with capsules to obtain capsules.

[0150] Dissolution testing: The resulting capsules were tested for dissolution in 900 mL of 0.1N hydrochloric acid using a paddle method at 75 rpm for 5, 15, 30, 45, 60, and 75 minutes. The results are shown in Table 17.

[0151] Table 17: Dissolution Results

[0152] Conclusion: Capsules of different strengths all have good dissolution rates, and the 50 mg capsule has a faster dissolution rate.

[0153] Example 10: Stability Study

[0154] The capsules provided by the present invention were taken and the stability was examined under the conditions shown in Table 18. The results showed that the relevant substances in the capsules provided by the present invention had good stability.

[0155] Table 18: Results of stability study on relevant substances

[0156] Example 11: Compatibility study of raw materials and auxiliary materials

[0157] Excipient Compatibility Study

[0158] The raw and auxiliary materials were mixed in the proportions shown in Table 19, and placed under high temperature conditions (60°C), high humidity conditions (25°C, 92.5% RH), accelerated conditions (40°C ± 2°C, 75% RH ± 5%), and light conditions (4500lx ± 500lx) for 10 days and 30 days, respectively. The mixture was taken out and the changes in its content and related substances were detected. The results are shown in Table 20.

[0159] Table 19: Compatibility test of raw materials and auxiliary materials

[0160] Table 20: Content test results (results in %) N / A: According to the EC plan, this is an alternative excipient and has not been tested.

[0161] in conclusion:

[0162] Detection of related substances: The excipients selected in the present invention and ATV014 were placed under accelerated (40°C / 75%±5%RH), high humidity (25°C / 90%±5%RH) or high temperature (60°C) conditions for 30 days and under light (visible light not less than 1.2×106Lux·hr, near ultraviolet not less than 200w·hr / m2) conditions for 10 days, and there was no significant change in impurities. All excipients and raw materials have good compatibility.

[0163] From the results in Table 20, we can see that:

[0164] Among the diluents examined (numbers 2-6), microcrystalline cellulose PH102 was found to be beneficial for the stability of ATV014 under high temperature (60°C) and light conditions (visible light intensity not less than 1.2×106 Lux·hr, near-ultraviolet light intensity not less than 200w·hr / m2). Compared to other diluents, mannitol 50C was found to be more beneficial for the stability of ATV014 under high temperature (60°C), high humidity (25°C, 92.5% RH), accelerated conditions (40°C±2°C, 75% RH±5%), and light conditions (4500lx±500lx), demonstrating unexpected technical benefits.

[0165] In the investigation of disintegrants (No. 7-8), cross-linked carboxymethyl cellulose sodium was used. or crospovidone XL-10 are beneficial to the stability of ATV014 under high temperature conditions (60°C), high humidity conditions (25°C, 92.5% RH), accelerated conditions (40°C ± 2°C, 75% RH ± 5%) and light conditions (4500lx ± 500lx).

[0166] In the investigation of adhesives (No. 9-10), the use of hydroxypropyl cellulose-EXF or povidone K30 was beneficial to the stability of ATV014 under high temperature conditions (60°C), high humidity conditions (25°C, 92.5% RH), accelerated conditions (40°C ± 2°C, 75% RH ± 5%) and light conditions (4500lx ± 500 lx).

[0167] In the investigation of surfactants (No. 11), the use of sodium lauryl sulfate is beneficial to the stability under high temperature conditions (60°C), high humidity conditions (25°C, 92.5% RH), accelerated conditions (40°C ± 2°C, 75% RH ± 5%) and light conditions (4500lx ± 500lx).

[0168] In the investigation of lubricants (No. 12 to 13), the use of magnesium stearate LIGAMED MF-2-V or sodium stearyl fumarate PRUV is beneficial to the stability of ATV014 under high temperature conditions (60°C), high humidity conditions (25°C, 92.5% RH), accelerated conditions (40°C ± 2°C, 75% RH ± 5%) and light conditions (4500lx ± 500lx).

[0169] In the investigation of the flow aid (No. 14), the use of silicon dioxide 200Pharma is beneficial to the stability of ATV014 under high temperature conditions (60°C), high humidity conditions (25°C, 92.5% RH), accelerated conditions (40°C ± 2°C, 75% RH ± 5%) and light conditions (4500lx ± 500lx).

[0170] In the investigation of capsule materials and coating materials (No. 15-16), hollow capsules, 0# rich yellow opaque or II Complete coating system 85F620077-CN, US is beneficial to the stability of ATV014 under high temperature conditions (60℃), high humidity conditions (25℃, 92.5%RH), accelerated conditions (40℃±2℃, 75%RH±5%) and light conditions (4500lx±500lx).

[0171] The methods of the present invention have been described through preferred embodiments. It is apparent that those skilled in the art will be able to modify or appropriately alter and combine the methods and applications described herein within the scope, spirit, and spirit of the present invention to implement and apply the technology of the present invention. Those skilled in the art may refer to the disclosure herein and appropriately modify the process parameters to achieve the desired effect. It is particularly important to note that all similar substitutions and modifications apparent to those skilled in the art are considered encompassed by the present invention.

Claims

1. A composition comprising: ATV014 compound and pharmaceutically acceptable excipients, 2. The composition according to claim 1, wherein the pharmaceutically acceptable excipient comprises at least one selected from the group consisting of a diluent, a disintegrant, a binder, a lubricant and other excipients.

3. The composition according to claim 2, wherein the diluent comprises at least one selected from microcrystalline cellulose, mannitol and pregelatinized starch; preferably, the diluent is microcrystalline cellulose or mannitol; more preferably, the diluent is microcrystalline cellulose PH102 or mannitol 50C; most preferably, the diluent is mannitol 50C; and / or The disintegrant comprises at least one selected from the group consisting of cross-linked carboxymethyl cellulose sodium, cross-linked polyvinylpyrrolidone, sodium carboxymethyl starch and hydroxypropyl cellulose; and / or The binder comprises at least one selected from hydroxypropyl cellulose, povidone and starch; and / or The lubricant comprises at least one selected from magnesium stearate, stearic acid and sodium stearyl fumarate; and / or The other excipients include glidants; and / or The glidant comprises colloidal silicon dioxide or talc; and / or The composition further comprises an external lubricant; and / or The external lubricant includes at least one selected from magnesium stearate, sodium stearate and sodium stearyl fumarate.

4. The composition according to any one of claims 2 to 3, wherein the content of the ATV014 compound is 15 wt% to 70 wt% based on the total mass of the composition; and / or The content of the diluent is 20wt%-70wt% based on the total mass of the composition; and / or The content of the disintegrant is 1 wt% to 10 wt% based on the total mass of the composition; and / or The content of the binder is 1 wt% to 10 wt% based on the total mass of the composition; and / or The content of the lubricant is 0.5wt%-5wt% based on the total mass of the composition; and / or The content of the added lubricant is 0.5wt%-5wt% based on the total mass of the composition; and / or The composition does not include a surfactant; or the composition does not include sodium lauryl sulfate.

5. The composition according to any one of claims 2 to 3, characterized in that include: An ATV014 compound and a pharmaceutically acceptable excipient, wherein the pharmaceutically acceptable excipient comprises at least one selected from the group consisting of a diluent, a disintegrant, a binder, a lubricant and other excipients, the diluent comprises at least one selected from the group consisting of microcrystalline cellulose, mannitol, calcium hydrogen phosphate and pregelatinized starch, the disintegrant comprises at least one selected from the group consisting of cross-linked sodium carboxymethyl cellulose, cross-linked polyvinylpyrrolidone, sodium carboxymethyl starch and hydroxypropyl cellulose, the binder comprises at least one selected from the group consisting of hydroxypropyl cellulose, polyvinylpyrrolidone and starch, and the lubricant comprises at least one selected from the group consisting of magnesium stearate, stearic acid and sodium stearyl fumarate, and based on the total mass of the composition, the content of the ATV014 compound is 15 wt%-70 wt%, the content of the diluent is 20 wt%-70 wt%, the content of the disintegrant is 1 wt%-10 wt%, the content of the binder is 1 wt%-10 wt%, and the content of the lubricant is 0.5 wt%-5 wt%; or comprising: an ATV014 compound and a pharmaceutically acceptable excipient, wherein the pharmaceutically acceptable excipient comprises at least one selected from the group consisting of a diluent, a disintegrant, a binder, a lubricant and other excipients, the diluent comprises at least one selected from the group consisting of microcrystalline cellulose, mannitol, calcium hydrogen phosphate and pregelatinized starch, the disintegrant comprises at least one selected from the group consisting of cross-linked sodium carboxymethyl cellulose, cross-linked polyvinylpyrrolidone, sodium carboxymethyl starch and hydroxypropyl cellulose, the binder comprises at least one selected from the group consisting of hydroxypropyl cellulose, polyvinylpyrrolidone and starch, the lubricant comprises at least one selected from the group consisting of magnesium stearate, stearic acid and sodium stearyl fumarate, and, based on the total mass of the composition, the content of the ATV014 compound is 50 wt%-60 wt%, the content of the diluent is 30 wt%-40 wt%, the content of the disintegrant is 2 wt%-5 wt%, the content of the binder is 2 wt%-5 wt%, and the content of the lubricant is 1.5%-5 wt%; or Comprising: an ATV014 compound and a pharmaceutically acceptable excipient, wherein the pharmaceutically acceptable excipient comprises at least one selected from the group consisting of a diluent, a disintegrant, a binder, a lubricant and other excipients, the diluent comprises at least one selected from the group consisting of microcrystalline cellulose and mannitol, the disintegrant comprises cross-linked sodium carboxymethyl cellulose, the binder comprises hydroxypropyl cellulose, and the lubricant comprises at least one selected from the group consisting of magnesium stearate, stearic acid and sodium stearyl fumarate, and based on the total mass of the composition, the content of the ATV014 compound is 50 wt%-60 wt%, the content of the diluent is 30 wt%-40 wt%, the content of the disintegrant is 2 wt%-5 wt%, the content of the binder is 2 wt%-5 wt%, and the content of the lubricant is 1.5%-5 wt%; or Comprising: an ATV014 compound and a pharmaceutically acceptable excipient, wherein the pharmaceutically acceptable excipient comprises at least one selected from: a diluent, a disintegrant, a binder, a lubricant and other excipients, the diluent is microcrystalline cellulose PH102 or mannitol 50C, the disintegrant comprises cross-linked carboxymethyl cellulose sodium, the binder comprises hydroxypropyl cellulose, and the lubricant comprises at least one selected from magnesium stearate, stearic acid and sodium stearyl fumarate. Calculated based on the total mass of the composition, the content of the ATV014 compound is 50 wt%-60 wt%, the content of the diluent is 30 wt%-40 wt%, the content of the disintegrant is 2 wt%-5 wt%, the content of the binder is 2 wt%-5 wt%, and the content of the lubricant may be 1.5%-5 wt%; or The invention comprises: an ATV014 compound and a pharmaceutically acceptable excipient, wherein the pharmaceutically acceptable excipient comprises at least one selected from: a diluent, a disintegrant, a binder, a lubricant and other excipients, the diluent is microcrystalline cellulose PH102 and mannitol 50C, the disintegrant comprises cross-linked carboxymethyl cellulose sodium, the binder comprises hydroxypropyl cellulose, the lubricant comprises at least one selected from magnesium stearate, stearic acid and sodium stearyl fumarate, and the content of the ATV014 compound is 50wt%-60wt%, the content of the diluent is 30wt%-40wt%, the content of the disintegrant is 100wt%-200wt%, and the content of the disintegrant is 100wt%-200wt%. The content of the agent is 2wt%-5wt%, the content of the adhesive is 2wt%-5wt%, and the content of the lubricant is 1.5%-5wt%; or The invention comprises: an ATV014 compound and a pharmaceutically acceptable excipient, wherein the pharmaceutically acceptable excipient comprises at least one selected from: a diluent, a disintegrant, a binder, a lubricant and other excipients, the diluent is mannitol 50C, the disintegrant comprises cross-linked carboxymethyl cellulose sodium, the binder comprises hydroxypropyl cellulose, and the lubricant comprises at least one selected from magnesium stearate, stearic acid and sodium stearyl fumarate. Calculated based on the total mass of the composition, the content of the ATV014 compound is 50wt%-60wt%, the content of the diluent is 30wt%-40wt%, the content of the disintegrant is 2wt%-5wt%, the content of the binder is 2wt%-5wt%, and the content of the lubricant is 1.5%-5wt%.

6. The composition according to any one of claims 1 to 3, wherein the composition is in the form of an oral solid preparation or an injection; Optionally, the dosage form is a tablet, granule or capsule.

7. Use of the composition according to any one of claims 1 to 6 in the preparation of a product for preventing, alleviating or treating coronavirus infection or the replication or reproduction of its homologous variant virus and the resulting cytopathic effect, or for detecting coronavirus or its homologous variant virus.

8. The use according to claim 7, wherein the infection comprises fever, cough, sore throat, pneumonia, acute respiratory tract infection, severe acute respiratory tract infection, hypoxic respiratory failure and acute respiratory distress syndrome, sepsis or septic shock.

9. The use according to any one of claims 7-8, wherein the coronavirus comprises: MHV-A59, HCoV-229E, HCoV-OC43, HCoV-NL63, HCoV-HKU1, SARS-CoV, MERS-CoV, SARS-CoV-2, mouse hepatitis virus, feline infectious peritonitis virus, canine coronavirus, bovine coronavirus, avian infectious bronchitis virus or porcine coronavirus, preferably, the SARS-CoV-2 includes mutants or unmutated strains of SARS-CoV-2; more preferably, the mutants of SARS-CoV-2 include SARS-CoV-2 mutant strain B.1, SARS-CoV-2 mutant strain B.1.351, SARS-CoV-2 mutant strain B.1.617.2, SARS-CoV-2 mutant strain C.37, SARS-CoV-2 mutant strain P.1 family tree, SARS-CoV-2 mutant strain B.1.525, SARS-CoV-2 mutant strain B.1.427 or SARS-CoV-2 mutant strain B.1.

429.

10. The use according to any one of claims 7-8, characterized in that The composition is suitable for use in humans or animals; and / or The animals include bovines, equines, ovines, porcines, canines, felines, rodents, primates, birds or fish.

11. A method for preparing the composition according to any one of claims 1 to 6, comprising: The ATV014 compound and pharmaceutically acceptable excipients are mixed, dry granulated, an external lubricant is added, mixed, tableted or capsule filled or bagged to obtain the composition; or The ATV014 compound and pharmaceutically acceptable excipients are mixed, wet granulated, ground, dried, dry-milled, an external lubricant is added, mixed, tableted or capsule-filled or bagged to obtain the composition; or Grinding or crushing the ATV014 compound, mixing with pharmaceutically acceptable excipients, dry granulating, adding an external lubricant, mixing, tableting or capsule filling or bagging to obtain the composition; or The ATV014 compound is ground or pulverized, mixed with pharmaceutically acceptable excipients, wet granulated, ground, dried, dry-milled, an external lubricant added, mixed, tableted or capsule-filled or bagged to obtain the composition.