Composition, its preparation method and its use

Abstract

The present invention relates to a composition, its preparation method and its use, which belongs to the field of drug formulation. The composition includes ATV014 compound and pharma- ceutical acceptable auxiliary agents, and the composition has good stability, high dissolution rate and high bioavailability, and can be used for preventing, alleviating or treating coronavirus infection or its homologous mutant virus replication or reproduction and its cytopathic effects. [Formula 1] TIFF2025511264000026.tif48170

Description

[Technical field]

[0001] The present invention relates to the field of drug formulations, specifically to a composition and its preparation method and use. [Background technology]

[0002] SARS-CoV-2 is an enveloped, single-stranded RNA virus that belongs to the βcoronavirus genus. Similar to SARS and MERS, the SARS-CoV-2 genome encodes nonstructural proteins, such as 3C-like protease (3CLpro), papain-like protease (PLpro), helicase, and RNA-dependent RNA polymerase (RdRp). Structural proteins include spike glycoproteins and accessory proteins. SARS-CoV-2 infects human respiratory epithelial cells by binding to the angiotensin-converting enzyme (ACE2) receptor on the surface of human cells through the surface spike glycoproteins. After the virus enters the host cell, it disassembles and releases the nucleocapsid and viral RNA into the cytoplasm. The open reading frame (ORF1a / b) at the 5' end of the viral RNA encodes polyproteins (pp1a and pp1ab), which play an important role in the processing and maturation of enzymes required for viral replication. pp1a and pp1ab are cleaved by papain-like protease (PLpro) and 3C-like protease (3CLpro) to produce nonstructural proteins, including RNA-dependent RNA polymerase and helicase, which play a crucial role in the transcription and replication of the new coronavirus. At present, the surface spike glycoproteins for identifying coronavirus receptors, and the key proteins 3CLpro, PLpro and RdRp involved in the replication and transcription process, are very attractive targets for the research and development of antiviral drugs.

[0003] Regarding the research and development of a new coronavirus vaccine, on December 2nd, the UK first approved emergency use rights for the Pfizer and BioNTech new coronavirus vaccine. On the one hand, the universal effectiveness of the vaccine is still unknown, and on the other hand, the strict low-temperature storage requirements have caused great inconvenience to its widespread use.

[0004] Regarding drug research and development for corona, remdesivir is currently the only corona drug approved by the US FDA. Remdesivir is an adenosine analogue monophosphate carbamate prodrug, originally developed as an anti-Ebola virus drug by Gilead Sciences. As an RdRp inhibitor, remdesivir has shown anti-coronavirus activity at the cellular level, but clinical trials have shown that remdesivir did not significantly reduce the mortality rate in humans. Moreover, the doses used in clinical trials are already approaching safe doses, so some obvious side effects must be taken into consideration.

[0005] Therefore, there is still a need for a novel coronavirus treatment drug with good safety, stability and bioavailability. Summary of the Invention [Problem to be solved by the invention]

[0006] To solve said problem, in a first aspect, the present invention provides a composition, said composition comprising an ATV014 compound and a pharma- ceutically acceptable adjuvant. [ka] In some embodiments, the pharma- ceutical acceptable auxiliary agent comprises at least one selected from diluents, disintegrants, binders, lubricants, 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. It is advantageous to employ microcrystalline cellulose or mannitol as a diluent to improve the compatibility of raw materials and auxiliary materials. As the diluent, microcrystalline cellulose or mannitol is preferred. As the diluent, microcrystalline cellulose PH102 or mannitol 50C is more preferred. As the diluent, mannitol 50C is most preferred.

[0007] In a second aspect, the present invention provides the use of said composition in the preparation of a product for the prevention, mitigation or treatment of coronavirus infection or the replication or propagation of a homologous mutant virus thereof and the cytopathic effects it produces.

[0008] In a third aspect, the present invention provides a method for preparing the composition, the method employing grinding or pulverizing ATV014 to reduce the particle size of ATV014 is advantageous for improving the dissolution rate of the product and for making the granule hardness appropriate during the dry granulation process. The method employs ground ATV014 for dry granulation, which is advantageous for obtaining granules with relatively good hardness. The method employs dry granulation, which is advantageous for improving the disintegration rate of the product. [Means for solving the problem]

[0009] To solve the above problems, the present invention provides a composition, its pharmaceutical formulation, use and preparation method. In a first aspect, a composition is provided. The composition comprises an ATV014 compound and a pharma- ceutically acceptable adjuvant. [ka]

[0010] In some embodiments, the pharma- ceutically acceptable excipients include at least one selected from diluents, disintegrants, binders, lubricants, and other excipients, In some embodiments, the pharma-ceutically acceptable excipients include diluents, disintegrants, binders, and lubricants.

[0011] In some embodiments, the diluent comprises at least one selected from microcrystalline cellulose, mannitol, calcium hydrogen phosphate, and pregelatinized starch. 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. The use of microcrystalline cellulose or mannitol as a diluent is advantageous for improving compatibility between the raw materials and auxiliary materials. In some more preferred embodiments, the diluent is microcrystalline cellulose PH102 or mannitol 50C, which is more advantageous for improving compatibility between the raw materials and auxiliary materials. In some most preferred embodiments, the diluent is mannitol 50C, which is most advantageous for improving compatibility between the raw materials and auxiliary materials.

[0012] In some embodiments, the disintegrant can comprise at least one selected from croscarmellose sodium, crospovidone, sodium carboxymethyl starch, and hydroxypropyl cellulose, hi some embodiments, the disintegrant is croscarmellose sodium.

[0013] In some embodiments, the binder can include at least one selected from hydroxypropyl cellulose, povidone, and starch. In some embodiments, the binder is hydroxypropyl cellulose.

[0014] In some embodiments, the lubricant may include at least one selected from the group consisting of magnesium stearate, stearic acid, and sodium stearate fumarate, hi some embodiments, the lubricant is magnesium stearate.

[0015] In some embodiments, the other adjuvants may include flow aids.

[0016] In some embodiments, the flow aid may be selected from colloidal silica or talc.

[0017] In some embodiments, the amount of the ATV014 compound is 15 wt%-70 wt%, calculated based on the total weight of the composition. In some embodiments, the amount of the ATV014 compound is 50 wt%-60 wt%, calculated based on the total weight of the composition. In some embodiments, the amount of the ATV014 compound is 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%, calculated based on the total weight of the composition.

[0018] In some embodiments, the diluent content may be 20 wt%-70 wt% calculated based on the total weight of the composition. In some embodiments, the diluent content is 30 wt%-40 wt% calculated based on the total weight of the composition. In some embodiments, the diluent content is 20 wt%, 25 wt%, 30 wt%, 35 wt%, 36 wt%, 37 wt%, 40 wt%, 45 wt%, 50 wt%, 55 wt%, 60 wt%, 65 wt%, or 70 wt% calculated based on the total weight of the composition.

[0019] In some embodiments, the content of the disintegrant may be 1 wt%-10 wt%, calculated based on the total weight of the composition. In some embodiments, the content of the disintegrant is 2 wt%-5 wt%, calculated 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%, calculated based on the total weight of the composition.

[0020] In some embodiments, the binder content may be 1 wt%-10 wt% calculated based on the total weight of the composition. In some embodiments, the binder content is 2 wt%-5 wt% calculated based on the total weight of the composition. In some embodiments, the binder content is 1 wt%, 2 wt%, 3 wt%, 4 wt%, 5 wt%, 6 wt%, 7 wt%, 8 wt%, 9 wt%, or 10 wt% calculated based on the total weight of the composition.

[0021] In some embodiments, the lubricant may be present in an amount of 0.5 wt%-5 wt% based on the total weight of the composition. In some embodiments, the lubricant is present in an amount of 1.5 wt%-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.

[0022] In some embodiments, the composition may be free of a surfactant, hi some embodiments, the composition may be free of sodium dodecyl sulfate.

[0023] In some embodiments, the composition may also include an external lubricant.

[0024] In some embodiments, the external lubricant comprises at least one selected from magnesium stearate, sodium stearate, and sodium stearate fumarate, hi some embodiments, the external lubricant is magnesium stearate.

[0025] In some embodiments, the amount of the external lubricant is 0.5 wt%-5 wt% calculated based on the total mass of the composition. In some embodiments, the amount of the external lubricant is 1.5 wt%-5 wt% calculated based on the total mass of the composition. In some embodiments, the amount of the external lubricant is 0.5 wt%, 1 wt%, 1.5 wt%, 2 wt%, 3 wt%, 4 wt%, or 5 wt% calculated based on the total mass of the composition.

[0026] In some embodiments of the present invention, the composition comprises an ATV014 compound and a pharma- ceutically acceptable excipient. The pharma- ceutically acceptable excipient comprises at least one selected from diluents, disintegrants, binders, lubricants and other excipients. The diluents comprise at least one selected from microcrystalline cellulose, mannitol, calcium hydrogen phosphate and pregelatinized starch. The disintegrants comprise at least one selected from croscarmellose sodium, crospovidone, sodium carboxymethyl starch and hydroxypropyl cellulose. The binders comprise at least one selected from hydroxypropyl cellulose, povidone and starch. The lubricants comprise at least one selected from magnesium stearate, stearic acid and sodium stearate fumarate. Calculated based on the total mass of the composition, the content of the ATV014 compound may be 15wt%-70wt%, the content of the diluent may be 20wt%-70wt%, the content of the disintegrant may be 1wt%-10wt%, the content of the binder may be 1wt%-10wt%, and the content of the lubricant may be 0.5wt%-5wt%.

[0027] In some embodiments of the present invention, the composition comprises an ATV014 compound and a pharma- ceutically acceptable excipient. The pharma- ceutically acceptable excipient comprises at least one selected from diluents, disintegrants, binders, lubricants and other excipients. The diluents comprise at least one selected from microcrystalline cellulose, mannitol, calcium hydrogen phosphate and pregelatinized starch. The disintegrants comprise at least one selected from croscarmellose sodium, crospovidone, sodium carboxymethyl starch and hydroxypropyl cellulose. The binders comprise at least one selected from hydroxypropyl cellulose, povidone and starch. The lubricants comprise at least one selected from magnesium stearate, stearic acid and sodium stearate fumarate. Calculated based on the total mass of the composition, the content of the ATV014 compound may be 50wt%-60wt%, the content of the diluent may be 30wt%-40wt%, the content of the disintegrant may be 2wt%-5wt%, the content of the binder may be 2wt%-5wt%, and the content of the lubricant may be 1.5%-5wt%.

[0028] In some embodiments of the present invention, the composition comprises an ATV014 compound and a pharma- ceutically acceptable auxiliary. The pharma- ceutically acceptable auxiliary comprises at least one selected from diluents, disintegrants, binders, lubricants and other auxiliary agents. The diluents comprise at least one selected from microcrystalline cellulose and mannitol. The disintegrants are selected from croscarmellose sodium. The binders are selected from hydroxypropyl cellulose. The lubricants comprise at least one selected from magnesium stearate, stearic acid and sodium stearate fumarate. Calculated based on the total mass of the composition, the content of the ATV014 compound may be 50wt%-60wt%, the content of the diluents may be 30wt%-40wt%, the content of the disintegrants may be 2wt%-5wt%, the content of the binders may be 2wt%-5wt%, and the content of the lubricants may be 1.5%-5wt%.

[0029] In some embodiments of the present invention, the composition comprises an ATV014 compound and a pharma- ceutically acceptable auxiliary. The pharma- ceutically acceptable auxiliary comprises at least one selected from a diluent, a disintegrant, a binder, a lubricant and other auxiliary. The diluent is microcrystalline cellulose PH102 or mannitol 50C. The disintegrant is selected from croscarmellose sodium. The binder is selected from hydroxypropyl cellulose. The lubricant comprises at least one selected from magnesium stearate, stearic acid and sodium stearate fumarate. Calculated based on the total mass of the composition, the content of the ATV014 compound may be 50wt%-60wt%, the content of the diluent may be 30wt%-40wt%, the content of the disintegrant may be 2wt%-5wt%, the content of the binder may be 2wt%-5wt%, and the content of the lubricant may be 1.5%-5wt%.

[0030] In some embodiments of the present invention, the composition comprises an ATV014 compound and a pharma- ceutically acceptable auxiliary. The pharma- ceutically acceptable auxiliary comprises at least one selected from diluents, disintegrants, binders, lubricants and other auxiliary agents. The diluents are microcrystalline cellulose PH102 and mannitol 50C. The disintegrants are selected from croscarmellose sodium. The binders are selected from hydroxypropyl cellulose. The lubricants comprise at least one selected from magnesium stearate, stearic acid and sodium stearate fumarate. Calculated based on the total mass of the composition, the content of the ATV014 compound may be 50wt%-60wt%, the content of the diluents may be 30wt%-40wt%, the content of the disintegrants may be 2wt%-5wt%, the content of the binders may be 2wt%-5wt%, and the content of the lubricants may be 1.5%-5wt%.

[0031] In some embodiments of the present invention, the composition comprises an ATV014 compound and a pharma- ceutically acceptable auxiliary. The pharma- ceutically acceptable auxiliary comprises at least one selected from a diluent, a disintegrant, a binder, a lubricant, and other auxiliary. The diluent is mannitol 50C. The disintegrant is selected from croscarmellose sodium. The binder is selected from hydroxypropyl cellulose. The lubricant comprises at least one selected from magnesium stearate, stearic acid, and sodium stearate fumarate. Calculated based on the total mass of the composition, the content of the ATV014 compound may be 50wt%-60wt%, the content of the diluent may be 30wt%-40wt%, the content of the disintegrant may be 2wt%-5wt%, the content of the binder may be 2wt%-5wt%, and the content of the lubricant may be 1.5%-5wt%.

[0032] In some embodiments, the composition is in the form of an oral solid formulation or an injectable formulation, hi some embodiments, the composition is in the form of a tablet, granule, or capsule.

[0033] In some embodiments, the dosage form has a size of 10 mg-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 has a size of 15 mg-300 mg. In some embodiments, the dosage form has a size of 20 mg-200 mg. In some embodiments, the dosage form has a size of 50 mg-200 mg. In some embodiments, the dosage form has a size of 50 mg.

[0034] In a third aspect, a use is provided. 2. Use of the composition according to the first aspect in the manufacture of a medicament.

[0035] In some embodiments, the composition of the first aspect is used in the preparation of a product for the prevention, mitigation or treatment of coronavirus infection or the replication or propagation of a homologous mutant virus thereof and the cytopathic effects it produces.

[0036] In some embodiments, the infection comprises fever, cough, sore throat, pneumonia, acute respiratory infection, severe acute respiratory infection, hypoxemic respiratory failure and acute respiratory distress syndrome, sepsis or septic shock.

[0037] In some embodiments, the composition of the first aspect is used in the manufacture of a product for use in detecting coronavirus or a homologous variant thereof.

[0038] In some embodiments, 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 comprises a mutated or unmutated strain of SARS-CoV-2. More preferably, the variant of SARS-CoV-2 comprises SARS-CoV-2 variant B.1, SARS-CoV-2 variant B.1.351, SARS-CoV-2 variant B.1.617.2, SARS-CoV-2 variant C.37, SARS-CoV-2 variant P.1 lineage, SARS-CoV-2 variant B.1.525, SARS-CoV-2 variant B.1.427 or SARS-CoV-2 variant B.1.429.

[0039] In some embodiments, the composition is applied to a human or animal, hi some embodiments, the animal includes a bovine, equine, ovine, porcine, canine, feline, rodent, primate, avian, or piscine animal.

[0040] In a fourth aspect, there is provided a method for preparing the composition of the first aspect. A method for producing the composition of the first aspect includes mixing the ATV014 compound with a pharma- ceutically acceptable auxiliary, dry granulating, adding an external lubricant, mixing, and compressing into tablets or capsules or packing into bags to obtain the composition.

[0041] In some embodiments of the present invention, there is provided a method for preparing the composition of the first aspect, comprising mixing ATV014 compound with a pharma- ceutically acceptable excipient, wet granulating, grinding, drying, dry grinding, adding an external lubricant, mixing, tableting or encapsulating or bagging to obtain the composition.

[0042] In some embodiments of the present invention, there is provided a process for preparing the composition of the first aspect, comprising grinding or milling ATV014 compound, mixing with a pharma- ceutically acceptable excipient, dry granulating, adding an external lubricant, blending, tableting or encapsulating or bagging to obtain the composition.

[0043] In some embodiments of the present invention, there is provided a method for preparing the composition of the first aspect, comprising grinding or milling ATV014 compound, mixing with a pharma- ceutically acceptable excipient, wet granulating, grinding, drying, dry grinding, adding an external lubricant, mixing, tableting or encapsulating or bagging to obtain the composition.

[0044] In some embodiments, the ATV014 has a particle size D90 of ≦500 μm. In some embodiments, the ATV014 has a particle size D90 of ≦300 μm. In some embodiments, the ATV014 has a particle size D90 of ≦200 μm. In some embodiments, the ATV014 has a particle size D90 of ≦100 μm. In some embodiments, the ATV014 has a particle size D90 of ≦50 μm. In some preferred embodiments, the ATV014 has a particle size D90 of ≦25 μm. In some preferred embodiments, the ATV014 has a particle size D90 of ≦20 μm. In some more preferred embodiments, the ATV014 has a particle size D90 of ≦10 μm. Effect of the Invention

[0045] Compared with the prior art, certain embodiments of the present invention include at least one of the following beneficial technical advantages: (1) The formulation and formulation ratio adopted in the present invention are advantageous in improving dissolution rate and bioavailability. (2) The formulation and formulation ratio adopted in the present invention are advantageous in effectively improving the stability of the drug under conditions such as high temperature, high humidity and light exposure. (3) The formulations and formulation ratios adopted by the present invention can be used to prevent, alleviate or treat coronavirus infection or its homologous mutant virus replication or reproduction and the cytopathic effects it produces. (4) A method that does not require the addition of surfactants is adopted, which is advantageous in improving the dissolution rate of the product. (5) The content of lubricant (e.g. magnesium stearate) is preferably 1.5% or more, which is advantageous for particle hardness and smoothness in dry granulation. (6) The content of binder (e.g., hydroxypropyl cellulose) is preferably 3% or more, which is advantageous for particle hardness and smoothness in dry granulation. (7) The content of binder (e.g. hydroxypropyl cellulose) is preferably about 3%, which is favorable for the dissolution degree of the product. (8) ATV014 is ground or pulverized to reduce the particle size of ATV014, which is advantageous for improving the dissolution rate of the product and for making the granules have an appropriate hardness during the dry granulation process. (9) Using ATV014 after grinding to perform dry granulation is advantageous in obtaining granules with relatively good hardness. (10) Dry granulation is adopted, which is advantageous in improving the disintegration rate of the product. (11) Compared with other diluents, the use of microcrystalline cellulose or mannitol as a diluent is more advantageous in improving the compatibility between raw materials and auxiliary materials. As the diluent, microcrystalline cellulose or mannitol is preferred, microcrystalline cellulose PH102 or mannitol 50C is more preferred, and mannitol 50C is most preferred.

[0046] (Definition of terms) In the present invention, "room temperature" refers to the environmental temperature, which may be 20°C to 30°C. In some embodiments, it is 22°C to 28°C. In some embodiments, it is 24°C to 26°C. In some embodiments, it is 25°C.

[0047] In the present invention, all numerical values ​​disclosed herein are approximate values, regardless of whether the term "approximately" or "about" is used. Based on the numerical values ​​disclosed, the numerical values ​​of each number may vary by ±10% or less, or by ±1%, ±2%, ±3%, ±4% or ±5%, which is considered reasonable by a person skilled in the art.

[0048] The terms "optional," "optional," or "optionally" mean that the event or circumstance described below may occur, but does not necessarily occur. For example, "optional surfactant" means that a surfactant may or may not be present.

[0049] The term "external lubricant" means a substance added after granulation to reduce the friction between the particles obtained by granulation, to prevent the adhesion of raw materials and auxiliary materials to the punch surfaces, or to reduce the friction between the tablet and the die hole walls.

[0050] The term "specification" refers to the weight of active ingredient in one unit of formulation (one tablet or one capsule).

[0051] The term "weight percent" or "percent by weight" or "wt%" is defined as the weight of an individual component in a composition divided by the total weight of all components of the composition, then multiplied by 100.

[0052] The term "and / or" should be understood to mean any one of any alternatives or a combination of any two or more.

[0053] The term "wt%" stands for weight percent.

[0054] The term "treatment" as used herein refers to a clinical intervention intended to alter the natural course of a disease in the individual being treated. The intended therapeutic effects include, but are not limited to, prevention of the onset or recurrence of a disease, alleviation of symptoms, reduction of any direct or indirect pathological consequences of a disease, prevention of metastasis, slowing the rate of progression of a disease condition, amelioration or remission of the disease state, and alleviation or improvement of prognosis.

[0055] In the description of this specification, a statement referring to the terms "one embodiment", "some embodiments", "examples", "specific examples", or "some examples" means that the particular feature, structure, material, or characteristic described in connection with that embodiment or example is included in at least one embodiment or example of the present invention. In the description of this specification, the exemplary expressions of the above terms do not necessarily refer to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described can be combined in an appropriate manner in one or more embodiments or examples. Furthermore, a person skilled in the art can combine and combine different embodiments or examples described herein and features of different embodiments or examples without mutual contradiction.

[0056] In this specification, "composition" can be conveniently expressed in the form of unit dose and can be prepared by any method well known in the pharmaceutical field. All methods herein include the step of combining active ingredient with carrier that constitutes one or more accessory ingredients. In this specification, composition is usually prepared by combining active compound uniformly and thoroughly with liquid carrier, finely divided solid carrier, or both.

[0057] Compound structures represented by abbreviations of some compounds herein [Table 1] DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0058] In order to allow those skilled in the art to better understand the technical solutions of the present invention, the following further discloses some non-limiting embodiments to describe the present invention in more detail. All of the reagents used in the present invention can be purchased commercially or prepared by the methods described in this invention. "#0" refers to capsule shell number 0. "#4" refers to capsule shell number 4. "API" refers to API, and in the specific examples below, refers to compound ATV014. "rpm" refers to rotational speed units "revolutions per minute." "SDS" refers to sodium dodecyl sulfate. "h" refers to hours. "min" refers to minutes. "μM" refers to micromoles per liter, or μmol / L. "mL" or "ml" refers to milliliters. "Compound RDV" or "RDV" refers to Remdesivir.

[0059] Example 1: Preparation of ATV014 [ka] 1.50g of compound 5 was dissolved in 15ml of dichloromethane, and 0.42mL of cyclohexane carboxylic acid and 55.40mg of 4-dimethylaminopyridine were added. After stirring for 10 minutes, 1.02g of dicyclohexylcarbodiimide was added and stirred at room temperature for 24 hours. Compound 7 was obtained by column chromatography separation (eluent: petroleum ether / ethyl acetate (V / V(V / V))=1 / 1). 1.50 g of compound 7 was dissolved in 3 mL of 37% hydrochloric acid aqueous solution and 15 mL of tetrahydrofuran, and stirred for 6 hours. Sodium carbonate was added to adjust the pH to 8, and the organic solvent was removed by rotary evaporation. 0.28 g of compound ATV014 (white solid, yield 45.8%) was obtained by column chromatography separation (eluent: petroleum ether / ethyl acetate (V / V(V / V))=1 / 3). The hydrogen spectrum and carbon spectrum of the obtained compound ATV014 were measured, and the results are as follows. Hydrogen spectrum :1H NMR (600 MHz, DMSO-d6) δ (ppm): 7.92 (s, 1H), 7.86 (br, 1H), 6.92 (d, J=4.5 Hz,1H), 6.81 (d, J=4.5 Hz, 1H), 6.33 (d, J=5.9 Hz, 1H), 5.38 (d, J=5.9 Hz, 1H), 4.70 (t, J=5.3 Hz, 1H), 4.32-4.29 (dd, J=12.2 Hz, 2.6 Hz, 1H), 4.24-4.21 (m, 1H), 4.16-4.13 (dd, J=12.3 Hz, 4.8 Hz, 1H), 3.98-3.95 (q, J=5.9 Hz, 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). Carbon Spectrum :13 C NMR (150 MHz, DMSO-d6) δ (ppm): 175.34, 156.06, 148.4, 124.0, 117.4, 117.0, 110.7, 101.2, 81.7, 79.4, 74.5, 70.6, 63.0, 42.6, 29.0, 28.9, 25.7, 25.2, 25.1.

[0060] Example 2: Inhibitory effect of compounds on SARS-CoV-2 replicon in HEK293T cells Compounds GS-441524, ATV014, and ATV014 intermediate 5 are the compounds to be measured, and are operated as follows. HEK293T cells were inoculated into 24-well plates, and when the cells grew to a density of 40-50%, 250ng of SARS-CoV-2 replicon plasmid was transfected by LIPO2000 (liposome 2000). After 6-8 hours of transfection, the cell supernatant was discarded, fresh DMEM medium was replaced, and the compounds to be tested were added to the final concentrations of 50μM, 10μM, 5μM, 2μM, 1μM, 0.1μM or 0.01μM, respectively. After 60 hours of transfection, the cell supernatant was discarded, and the cell RNA was taken up in TRIZOL, total RNA was extracted, and cDNA was obtained by reverse transcriptase. Finally, the internal gene Gapdh and the subgenome of SARS-CoV-2 N gene in the cDNA were examined and measured by fluorescent quantitative PCR to detect the viral replication situation in the SARS-CoV-2 replicon, and the inhibitory effects of different concentrations of drugs on the virus were calculated, and the IC 50 was calculated and the results are shown in Table 2. Table 2: Inhibitory effect of compounds on SARS-CoV-2 replicon expression in HEK293T cells [Table 2] Conclusion: The tested compounds inhibited the replication of SARS-CoV-2 to some extent in HEK293T cells. Here, the activity of ATV014 was 3.65 times that of compound GS-441524, which significantly improved the activity. The inhibitory effect of different compounds on the SARS-CoV-2 replicon in HEK293T cells is shown in Table 2.

[0061] Example 3: Inhibitory effect of compounds on SARS-CoV-2 in Vero-E6 cells The compounds RDV, GS-441524, and ATV014 are used as test compounds, and the procedures are as follows. 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, and each compound was 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. The virus copy numbers in the supernatant after 48 h of infection were analyzed by quantitative real-time polymerase chain reaction (qRT-PCR) to evaluate the antiviral activity. The inhibitory effects of different concentrations of the test drugs on virus replication were calculated, and their IC50 values ​​were calculated. The IC50 of different compounds against SARS-CoV-2 in Vero-E6 cells are shown in Table 3. Table 3: Inhibitory effect of different compounds against SARS-CoV-2 in Vero-E6 cells [Table 3]

[0062] Example 4: Consideration of surfactant (production method is wet granulation) Capsules are manufactured according to the formulation in Table 4. Table 4: Prescription ratios [Table 4] Manufacturing method: ATV014 (formula 37181-037-B unpolished) is polished, and ATV014 and other ingredients are sieved. According to the formulation ratio, the internal additive ingredients are mixed, water is added and the mixture is granulated by a wet method, polished, dried, dry polished, the external additive ingredients are added, mixed, and filled into capsules to obtain capsules. Dissolution detection: Take the obtained capsules, and use 900mL of 0.1N hydrochloric acid as a medium to detect the dissolution at 5, 15, 30, 45, 60, and 75 minutes using the slurry method at a rotation speed of 75 rpm. The results are shown in Table 5. Table 5: Dissolution detection results [Table 5] Result analysis: (1) The use of a formulation that does not contain a surfactant (e.g., sodium dodecyl sulfate (SDS)) is advantageous in improving the dissolution rate. (2) After polishing the API, it is advantageous to improve the dissolution rate. (3) By adopting a method in which the API is polished without adding a surfactant (e.g., sodium dodecyl sulfate (SDS)), the two methods work synergistically to significantly improve the dissolution rate.

[0063] Example 5: Manufacturing method of air-milled API (wet granulation) Capsules are manufactured according to the formulation in Table 6. Table 6: Prescription ratios [Table 6] Manufacturing method: ATV014 is polished, and ATV014 and other ingredients are sieved. According to the prescription ratio, the internal additive ingredients are mixed, water is added for wet granulation, polishing, drying, dry polishing, the external additive ingredients are added, mixed, and filled into capsules to obtain capsules. Dissolution detection: Take the obtained capsules, and use 900mL of 0.1N hydrochloric acid as a medium to detect the dissolution at 5, 15, 30, 45, 60, and 75 minutes using the slurry method at a rotation speed of 75 rpm. The results are shown in Table 7. Table 7: Elution test results [Table 7] Result analysis: Formulations containing air-milled API and no SDS have faster dissolution rates and higher dissolution platforms.

[0064] Example 6: Effect of ATV014 polishing on dissolution rate (manufacturing method is dry granulation) Capsules are prepared according to the formulation set forth in Table 8. Table 8: Prescription ratios [Table 8] Manufacturing method: ATV014 (formulation 37181-027B no grinding) is ground, and ATV014 and other ingredients are sieved. According to the formula ratio, the internal additive ingredients are mixed, dry granulated, the external additive ingredients are added, mixed, and then filled into capsules to obtain capsules. Dissolution detection: Take the obtained capsules, and use 900mL of 0.1N hydrochloric acid as a medium to detect the dissolution at 5, 15, 30, 45, 60, and 75 minutes using the slurry method at a rotation speed of 75 rpm. The results are shown in Table 9. Table 9: Dissolution results [Table 9] Result analysis: (1) Dry granulation is more advantageous than wet granulation in improving the dissolution rate of the product. (2) After the API is polished, it is advantageous to improve the dissolution rate of the product.

[0065] Example 7: Effect of ATV014 grinding on the particles and disintegration time of dry granulation (the manufacturing method is dry granulation or direct filling) Capsules are manufactured according to the formulation in Table 10. Table 10: Prescription ratios [Table 10] The manufacturing method of the formula 37181-020-B: ATV014 is polished, and ATV014 and other ingredients are sieved. According to the prescription ratio, the internal additive ingredients are mixed, dry granulated, the external additive ingredients are added, mixed, and the mixture is filled into capsules to obtain capsules. Manufacturing method of formula 37181-019-B: After sieving unpolished ATV014 and other ingredients, mix the internal additive ingredients according to the prescription ratio, add the external additive ingredients, mix, and fill into capsules to obtain capsules. The manufacturing method of the formula 37181-021-B: ATV014 is polished, and ATV014 and other ingredients are sieved. According to the formula ratio, the internal additive ingredients are mixed, and the external additive ingredients are added, mixed, and then filled into capsules to obtain capsules. 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. Table 11: Observation results of dry granulation phenomenon [Table 11] Summary: Dry granulation using ATV014 after grinding is advantageous for obtaining particles with relatively good hardness. Disintegration time observation: The capsules obtained in this example were taken and the disintegration time of the capsules was tested and measured according to Part 4 General Rule 0921 of the 2020 edition of the Chinese Pharmacopoeia. The results are shown in Table 12. Table 12: Collapse time limit observation results [Table 12] Conclusion: The capsules obtained by using the grinding API and the preparation method of dry granulation followed by filling have a fast disintegration time, and dry granulation is favorable for improving the disintegration rate of the product.

[0066] Example 8: Considerations of binder and lubricant content Capsules are manufactured according to the formulation in Table 13. Table 13: Prescription ratios [Table 13] Manufacturing method: ATV014 is polished, and ATV014 and other ingredients are sieved. According to the prescription ratio, the internal additive ingredients are mixed, dry granulated, the external additive ingredients are added, mixed, and then filled into capsules to obtain capsules. Observation of dry granulation phenomenon: Granulation was performed using the dry granulation process parameters shown in Table 14, and the results of observing the properties of the materials during the granulation process are shown in Table 14. Table 14: Observations of dry granulation phenomena [Table 14] summary: 1. The content of magnesium stearate is preferably 1.5 wt% or more, which is advantageous for the particle hardness and smoothness during dry granulation. 2. The content of hydroxypropyl cellulose is preferably 3 wt% or more, which is advantageous for particle hardness and smoothness during dry granulation. Dissolution detection: Roll pressure is 6-12kg / cm 2 The capsules obtained in step 1 are taken, and the dissolution rate is detected at 5, 15, 30, 45, 60, and 75 minutes, respectively, using 900 mL of 0.1N hydrochloric acid as a medium and adopting the slurry method at a rotation speed of 75 rpm. The results are shown in Table 15. Table 15: Dissolution results [Table 15] Conclusion: The capsules obtained from formulations 37181-047-B and 37181-051-B could both dissolve rapidly and completely, and the release rate of formulation 37181-051-B here was faster.

[0067] Example 9: Capsules of different specifications Capsules are prepared according to the formulation set forth in Table 16. Table 16: Prescription ratios [Table 16] Manufacturing method: ATV014 is polished, and ATV014 and other ingredients are sieved. According to the prescription ratio, the internal additive ingredients are mixed, dry granulated, the external additive ingredients are added, mixed, and then filled into capsules to obtain capsules. Dissolution detection: Take the obtained capsules, use 900mL of 0.1N hydrochloric acid as a medium, adopt the slurry method, rotate at 75 rpm, and detect the dissolution at 5 minutes, 15 minutes, 30 minutes, 45 minutes, 60 minutes, and 75 minutes, respectively. The results are shown in Table 17. Table 17: Dissolution results [Table 17] Conclusion: The capsules of different sizes all have good dissolution rates, among which the dissolution rate of the 50 mg capsule is faster.

[0068] Example 10: Stability Considerations The capsules provided by the present invention were examined for stability under the conditions shown in Table 18, and it was found that the related substances in the capsules provided by the present invention have good stability. Table 18: Stability considerations for related substances [Table 18]

[0069] Example 11: Considerations regarding compatibility of raw materials and auxiliary materials Excipient Compatibility Study The raw materials and auxiliary materials shown in Table 19 were mixed in the proportions shown in Table 19 and left 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 irradiation conditions (4500lx±500lx) for 10 and 30 days respectively, then removed and the changes in content and related substances were measured. The results are shown in Table 20. Table 19: Tests on compatibility of raw materials and auxiliary materials [Table 19] Table 20: Content detection results (results in %) [Table 20] N / A: Substitute auxiliary material according to EC policy, not detected. Conclusion: Detection of related substances: The auxiliary materials selected by the present invention and ATV014 are left under accelerated (40°C / 75%±5%RH), high humidity (25°C / 90%±5%RH) or high temperature (60°C) conditions for 30 days, and left under light irradiation conditions (visible light not lower than 1.2×106 Lux·hr, near ultraviolet not lower than 200w·hr / m2) for 10 days, after which there is no obvious change in impurities, and all the auxiliary materials and raw materials have relatively good compatibility.

[0070] This can be seen from the results in Table 20. In the diluent considerations (numbers 2-6), the use of microcrystalline cellulose PH102 was favorable for the stability of ATV014 under high temperature (60°C) and light irradiation conditions (visible light not lower than 1.2×106 Lux·hr, near-ultraviolet not lower than 200w·hr / m2). Compared with other diluents, the use of mannitol 50C was more favorable for the stability of ATV014 under high temperature (60°C), high humidity conditions (25°C, 92.5%RH), accelerated conditions (40°C±2°C, 75%RH±5%) and light irradiation conditions (4500lx±500lx), and has unpredictable technical effects.

[0071] In considering the disintegrants (numbers 7-8), the use of croscarmellose sodium VIVASOL® or crospovidone XL-10 was advantageous for 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 irradiation conditions (4500 lx±500 lx).

[0072] In terms of the binders (numbers 9-10), the use of hydroxypropylcellulose-EXF or povidone K30 was advantageous for 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 irradiation conditions (4500 lx ± 500 lx).

[0073] In considering the surfactant (number 11), the use of sodium dodecyl sulfate was advantageous in terms of 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 irradiation conditions (4500 lx ± 500 lx).

[0074] In the lubricant considerations (numbers 12-13), the use of magnesium stearate LIGAMED MF-2-V or sodium stearyl fumarate PRUV was advantageous for 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 irradiation conditions (4500lx±500lx).

[0075] In the consideration of flow aids (number 14), the use of Silica 200Pharma was advantageous for 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 irradiation conditions (4500 lx ± 500 lx).

[0076] In considering the capsule materials and coating materials (numbers 15-16), the use of hollow capsules, 0#rich yellow opaque, or Opadry® II complete coating system 85F620077-CN, US was advantageous for 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 irradiation conditions (4500 lx±500 lx).

[0077] Although the method of the present invention has been described by a preferred embodiment, it is obvious to those skilled in the art that, within the content, spirit and scope of the present invention, modifications or suitable modifications and combinations may be made to the methods and applications described in the present invention in order to realize and apply the technology of the present invention. Those skilled in the art can refer to the content of this document and appropriately improve the realization of the process parameters. In particular, it should be noted that all similar replacements and modifications are obvious to those skilled in the art and are considered to be included in the present invention.

Claims

1. A composition comprising an ATV014 compound and a pharma- ceutically acceptable adjuvant. 【Chemistry 1】

2. The composition of claim 1, wherein the pharma- ceutically acceptable excipient comprises at least one selected from diluents, disintegrants, binders, lubricants and other auxiliary materials.

3. 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 croscarmellose sodium, crospovidone, 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 stearate fumarate; and / or said other aids being selected from flow aids; and / or the flow aid is selected from colloidal silica or talc; and / or The composition further comprises an external lubricant; and / or 3. The composition according to claim 2, wherein the external lubricant comprises at least one selected from the group consisting of magnesium stearate, sodium stearate, and sodium stearate fumarate.

4. The content of the ATV014 compound is 15 wt %-70 wt %, calculated based on the total mass of the composition; and / or The content of the diluent is 20 wt %-70 wt % calculated on the total weight of the composition; and / or The content of the disintegrant is 1 wt %-10 wt %, calculated based on the total weight of the composition; and / or The binder content is 1 wt %-10 wt %, calculated on the total weight of the composition; and / or The content of the lubricant is 0.5 wt % to 5 wt %, calculated on the total mass of the composition; and / or The content of the external lubricant is 0.5 wt % to 5 wt % calculated based on the total mass of the composition, and / or The composition according to any one of claims 2 to 3, characterized in that the composition does not contain a surfactant or the composition does not contain sodium dodecyl sulfate.

5. The pharmaceutical composition includes an ATV014 compound and a pharma- ceutically acceptable excipient, the pharma- ceutically acceptable excipient being at least one selected from a diluent, a disintegrant, a binder, a lubricant, and other excipients, the diluent being at least one selected from microcrystalline cellulose, mannitol, calcium hydrogen phosphate, and pregelatinized starch, the disintegrant being at least one selected from croscarmellose sodium, crospovidone, sodium carboxymethyl starch, and hydroxypropyl cellulose, and the binder being hydroxypropyl cellulose. The composition comprises at least one selected from the group consisting of cellulose, povidone, and starch, and the lubricant comprises at least one selected from the group consisting of magnesium stearate, stearic acid, and sodium stearate fumarate, and 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%, calculated based on the total mass of the composition; or The composition comprises an ATV014 compound and a pharma- ceutically acceptable excipient, the pharma- ceutically acceptable excipient comprising at least one selected from a diluent, a disintegrant, a binder, a lubricant and other excipients, the diluent comprising at least one selected from microcrystalline cellulose, mannitol, calcium hydrogen phosphate and pregelatinized starch, the disintegrant comprising at least one selected from croscarmellose sodium, crospovidone, sodium carboxymethyl starch and hydroxypropyl cellulose, the binder comprising at least one selected from hydroxypropyl cellulose, ... The composition comprises at least one selected from the group consisting of pyrulose, povidone and starch, and the lubricant comprises at least one selected from the group consisting of magnesium stearate, stearic acid and sodium stearate 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 2wt%-5wt%, the content of the binder is 2wt%-5wt%, and the content of the lubricant is 1.5%-5wt%, calculated based on the total mass of the composition; or a pharmaceutical composition comprising an ATV014 compound and a pharma- ceutically acceptable excipient, the pharmaceutical composition comprising at least one selected from a diluent, a disintegrant, a binder, a lubricant and other excipients, the diluent comprising at least one selected from microcrystalline cellulose and mannitol, the disintegrant comprising croscarmellose sodium, the binder comprising hydroxypropylcellulose, the lubricant comprising at least one selected from magnesium stearate, stearic acid and sodium stearate fumarate, the content of the ATV014 compound being 50 wt%-60 wt%, the content of the diluent being 30 wt%-40 wt%, the content of the disintegrant being 2 wt%-5 wt%, the content of the binder being 2 wt%-5 wt%, and the content of the lubricant being 1.5%-5 wt%, calculated based on the total weight of the composition; or A composition comprising an ATV014 compound and a pharma- ceutically acceptable excipient, the pharma-ceutically acceptable excipient comprising at least one selected from a diluent, a disintegrant, a binder, a lubricant and other excipients, the diluent being microcrystalline cellulose PH102 or mannitol 50C, the disintegrant being selected from croscarmellose sodium, the binder being selected from hydroxypropylcellulose, the lubricant being at least one selected from magnesium stearate, stearic acid and sodium stearate fumarate, the content of the ATV014 compound being 50wt%-60wt%, the content of the diluent being 30wt%-40wt%, the content of the disintegrant being 2wt%-5wt%, the content of the binder being 2wt%-5wt%, and the content of the lubricant being 1.5%-5wt%, calculated based on the total weight of the composition; or A composition comprising an ATV014 compound and a pharma- ceutically acceptable excipient, the pharma-ceutically acceptable excipient comprising at least one selected from a diluent, a disintegrant, a binder, a lubricant and other excipients, the diluent being microcrystalline cellulose PH102 and mannitol 50C, the disintegrant being selected from croscarmellose sodium, the binder being selected from hydroxypropylcellulose, the lubricant being at least one selected from magnesium stearate, stearic acid and sodium stearate fumarate, the content of the ATV014 compound being 50wt%-60wt%, the content of the diluent being 30wt%-40wt%, the content of the disintegrant being 2wt%-5wt%, the content of the binder being 2wt%-5wt%, and the content of the lubricant being 1.5%-5wt%, calculated based on the total weight of the composition; or The composition according to any one of claims 2 to 3, comprising an ATV014 compound and a pharma- ceutically acceptable auxiliary, the pharma-ceutically acceptable auxiliary comprising at least one selected from a diluent, a disintegrant, a binder, a lubricant and other auxiliary, the diluent being mannitol 50C, the disintegrant being selected from croscarmellose sodium, the binder being selected from hydroxypropylcellulose, the lubricant being at least one selected from magnesium stearate, stearic acid and sodium stearate 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 2wt%-5wt%, the content of the binder is 2wt%-5wt%, and the content of the lubricant is 1.5%-5wt%, calculated based on the total mass of the composition.

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

7. Use of the composition according to any one of claims 1 to 6 in the manufacture of a product for preventing, alleviating or treating infection with coronavirus or the replication or proliferation of its homologous mutant virus and the resulting cytopathic effects, or for detecting coronavirus or its homologous mutant virus.

8. 8. The use according to claim 7, characterized in that the infection comprises fever, cough, sore throat, pneumonia, acute respiratory tract infection, severe acute respiratory tract infection, hypoxemic respiratory failure and acute respiratory distress syndrome, pyemia or pyototoxic shock.

9. 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 non-mutant strain of SARS-CoV-2, more preferably, the mutant strain of SARS-CoV-2 includes SARS-CoV-2 mutant B.1, SARS-CoV-2 mutant B.1.351, SARS-CoV-2 mutant B.1.617.2, SARS-CoV-2 mutant C.1.2, SARS-CoV-2 mutant D.1.1, SARS-CoV-2 mutant D.1.2, SARS-CoV-2 mutant D.1.3, SARS-CoV-2 mutant D.1.4, SARS-CoV-2 mutant D.1.5, SARS-CoV-2 mutant D.1.6, SARS-CoV-2 mutant D.1.7, SARS-CoV-2 mutant D.1.8, SARS-CoV-2 mutant D.1.9, SARS-CoV-2 mutant D.1.11, SARS-CoV-2 mutant D.1.12, SARS-CoV-2 mutant D.1.13, SARS-CoV-2 mutant D.1.14, SARS-CoV-2 mutant D.1.15, SARS-CoV-2 mutant D.1.16, SARS-CoV-2 mutant D.1.17, SARS-CoV-2 mutant D.1.18, SARS-CoV-2 mutant D.1.19, SARS-CoV-2 mutant D.1.21, SARS-CoV-2 mutant D.1.22, SARS-CoV-2 mutant D.1.2 The use according to any one of claims 7 to 8, characterized in that the use comprises SARS-CoV-2 variant P.37, SARS-CoV-2 variant P.1 pedigree, SARS-CoV-2 variant B.1.525, SARS-CoV-2 variant B.1.427 or SARS-CoV-2 variant B.1.

429.

10. The composition may be applied to a human or animal, and / or The use according to any one of claims 7 to 8, characterized in that the animal comprises a bovine, equine, ovine, porcine, canine, feline, rodent, primate, avian or piscine animal.

11. Mixing the ATV014 compound with a pharma- ceutically acceptable auxiliary, dry granulating, adding an external lubricant, mixing, tableting, filling into capsules or sachets to obtain the composition; or Mixing the ATV014 compound with a pharma- ceutically acceptable auxiliary, wet granulating, grinding, drying, dry grinding, adding an external lubricant, mixing, tableting, filling into capsules or sacking to obtain the composition; or Grinding or pulverizing the ATV014 compound, mixing it with a pharma- ceutically acceptable auxiliary, dry granulating it, adding an external lubricant, mixing it, tableting it, filling it into capsules or packing it into bags to obtain the composition; or The method for preparing the composition according to any one of claims 1 to 6, characterized in that the ATV014 compound is ground or pulverized, mixed with a pharma- ceutically acceptable auxiliary, wet granulated, ground, dried, dry ground, added with an external lubricant, mixed, tableted, encapsulated or bagged to obtain the composition.

Images