Anti-new crown pharmaceutical composition and preparation method thereof

Abstract

The invention provides a pharmaceutical composition which comprises a compound shown as a formula I or pharmaceutically acceptable salt and auxiliary materials, the auxiliary materials comprise one or more of a filling agent, an adhesive, a flow aid, a disintegrating agent and a lubricating agent, and the pharmaceutical composition has the advantages of preparation process preparation feasibility, excellent preparation properties, good stability and good dissolution performance and meets the medicinal standard.

Description

An anti-COVID-19 drug composition and preparation method thereof Technical Field

[0001] The present invention belongs to the field of pharmaceutical preparations, and specifically relates to an anti-COVID-19 pharmaceutical composition and a preparation method thereof. Background Art

[0002] Coronaviruses are a family of enveloped, single-stranded, positive-sense RNA viruses belonging to the order Nidovirales. The coronavirus family encompasses pathogens of many animal species, including humans, horses, cattle, pigs, birds, cats, and monkeys, and has been known for over six decades. For example, the isolation of the prototype murine coronavirus strain, JHM, was reported in 1949. Coronaviruses are common viruses that typically cause mild to moderate upper respiratory tract illnesses in humans and are named for the crown-like spikes on their envelope. The 2003 SARS pandemic led to the emergence of SARS-CoV-1, a pathogen that causes severe respiratory infections. The subsequent surge in coronavirus research led to the discovery of two additional mildly pathogenic human coronaviruses, HCoV-NL63 and HCoV-HKU1. MERS-CoV, a member of this group that emerged in 2012, is a pathogen that causes severe respiratory infections. Although SARS-CoV-1 and MERS-CoV are highly lethal pathogens, the public health, social, and economic costs they have caused have been minimal compared to those of SARS-CoV-2. SARS-CoV-2 is a newly emerged human coronavirus pathogen that causes COVID-19. The COVID-19 pandemic, second only to the 1918 influenza pandemic, has had a devastating impact worldwide. As of April 2023, the total number of COVID-19 cases worldwide has exceeded 680 million, with over 6.85 million deaths. Finding timely treatment options is crucial to mitigate the catastrophic public health, social, and economic damage caused by COVID-19.

[0003] Coronaviruses are enveloped, positive-sense, single-stranded RNA viruses. The genomic RNA of CoV has a 5'-cap structure and a 3'-poly-A tail and contains at least six open reading frames (ORFs). The first ORF (ORF 1a / b) directly translates two polyproteins: pp1a and pp1ab. These polyproteins are processed into 16 non-structural proteins by the 3C-like protease (3CLpro), also known as the major protease (Mpro). These non-structural proteins are involved in the production of subgenomic RNAs that encode the four structural proteins, namely the envelope protein, membrane protein, spike protein, and nucleocapsid protein, as well as other accessory proteins. Therefore, it is understood that the 3C-like protease plays a key role in the coronavirus life cycle.

[0004] The 3C-like protease is a cysteine ​​protease involved in most cleavages within the precursor polyprotein. The active 3C-like protease is a homodimer consisting of two protomers with a Cys-His dyad located between domains I and II. The 3C-like protease is conserved among coronaviruses, and its substrates share several common features across different coronaviruses. Because the 3C-like protease has no human homolog, it is an ideal antiviral target.

[0005] Paxlovid is an oral anti-COVID-19 drug developed by Pfizer. It consists of 300mg (two 150mg tablets) of nematevir and one 100mg tablet of ritonavir. The Paxlovid marketing insert discloses that nematevir tablets are composed of nematevir, microcrystalline cellulose, lactose monohydrate, croscarmellose sodium, colloidal silicon dioxide, sodium stearyl fumarate, and hypromellose.

[0006] Lerestatvir tablets (trade name: Leruiling) are an oral anti-new coronavirus drug developed by Guangdong Zhongsheng Ruichuang Biotechnology Co., Ltd. It is a 3C-like protease inhibitor that does not require concomitant use with ritonavir and is currently available in China.

[0007] Chinese patent ZL202211095326.8 discloses a series of ketoamide derivatives, such as compounds of formula I, which have good anti-novel coronavirus Mpro protease activity.

[0008] Although Chinese patent ZL202211095326.8 discloses in vitro tests of this series of ketoamide compounds, demonstrating their strong anti-COVID-19 effects and good pharmacokinetics, there are currently only related activity studies on the compounds and their pharmaceutically acceptable salts, and there are no reports of pharmaceutical compositions or pharmaceutical preparations with the above compounds as active ingredients. Therefore, further research and application of the above compounds are imminent.

[0009] Summary of the Invention

[0010] The technical problem to be solved by the present invention is to overcome the deficiencies in the prior art and provide an anti-COVID-19 pharmaceutical composition and a preparation method thereof.

[0011] To achieve the above-mentioned purpose, the present invention has conducted a large number of experimental studies and improvements on existing formulation prescriptions and processes, thereby proposing a pharmaceutical composition of the present invention comprising a compound of formula I or a pharmaceutically acceptable salt thereof, which has good formulation process preparation feasibility and high stability, can be orally administered to treat the new coronavirus, and its preparation method is simple to operate and suitable for industrial production.

[0012] The specific technical scheme of the present invention is as follows: A pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof and excipients, wherein the excipients include one or more of a filler, a binder, a glidant, a disintegrant and a lubricant, wherein the filler is one or more of lactose, anhydrous lactose, microcrystalline cellulose, mannitol or starch, the binder is one or more of hydroxypropyl methylcellulose, hydroxypropyl cellulose, povidone, hydroxyethyl cellulose, sodium carboxymethyl cellulose or polyvinyl alcohol, the glidant is one or more of colloidal silicon dioxide, talc or micropowdered silica, and the disintegrant is low-substituted hydroxypropyl The invention relates to a novel composition comprising: a first step of preparing the composition of the present invention and a second step of preparing the composition; a second step of preparing the composition of the present invention and a second step of preparing the composition; a first ...

[0013] Unless otherwise specified, in the full description of the present invention, the mass of the compound of formula I refers to the mass of the compound of formula I itself or the mass of the compound of formula I in the pharmaceutical composition of the compound of formula I.

[0014] Alternatively, the present invention provides a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof and excipients, wherein the excipients include one or more of a filler, a binder, a glidant, a disintegrant, and a lubricant; the filler is one or more of lactose, anhydrous lactose, microcrystalline cellulose, mannitol, or starch; the binder is one or more of hydroxypropyl methylcellulose, hydroxypropyl cellulose, povidone, hydroxyethyl cellulose, sodium carboxymethyl cellulose, or polyvinyl alcohol; the glidant is one or more of colloidal silicon dioxide, talc, or micropowdered silica; the disintegrant is low-substituted hydroxypropyl cellulose, cross-linked carboxymethyl cellulose, or polyvinyl alcohol; The pharmaceutical composition comprises one or more of sodium stearate, sodium carboxymethyl starch or cross-linked polyvinylpyrrolidone, the lubricant is one or more of magnesium stearate, calcium stearate or sodium stearyl fumarate, the mass ratio of the compound of formula I to the filler is 1:1.0-2.5, the mass ratio of the compound of formula I to the binder is 1:0.01-0.05, the mass ratio of the compound of formula I to the glidant is 1:0.01-0.03, the mass ratio of the compound of formula I to the disintegrant is 1:0.10-0.30, the mass ratio of the compound of formula I to the lubricant is 1:0.01-0.10, and the moisture content of the pharmaceutical composition does not exceed 5.0%.

[0015] Alternatively, the present invention provides a pharmaceutical composition, characterized in that it comprises a compound of formula I or a pharmaceutically acceptable salt thereof and excipients, wherein the excipients include one or more of a filler, a binder, a glidant, a disintegrant and a lubricant, the filler is one or more of lactose, anhydrous lactose, microcrystalline cellulose, mannitol or starch, the binder is one or more of hydroxypropyl methylcellulose, hydroxypropyl cellulose, povidone, hydroxyethyl cellulose, sodium carboxymethyl cellulose or polyvinyl alcohol, the glidant is one or more of colloidal silicon dioxide, talc or micropowdered silica, the disintegrant is one or more of low-substituted hydroxypropyl cellulose, cross-linked sodium carboxymethyl cellulose, sodium carboxymethyl starch or cross-linked povidone, and the lubricant is one or more of magnesium stearate, calcium stearate or sodium stearyl fumarate, and the pharmaceutical composition has a solubility of 70.0% or more in 60 minutes using a phosphate buffer having a pH of 6.8 as a dissolution medium.

[0016] The present invention provides an anti-COVID-19 pharmaceutical composition and a preparation method thereof. The effect is achieved by selecting appropriate formulation excipients based on the physicochemical properties of the raw materials and the results of the excipient compatibility test. The type and / or dosage of the prescription have a significant impact on the formulation process and the quality of the formulation. The excipients used in the present invention include fillers, wetting agents, binders, disintegrants, lubricants, etc. According to the present invention, a filler is introduced into a pharmaceutical composition containing a compound of formula I. The filler includes one or more of lactose, anhydrous lactose, microcrystalline cellulose, mannitol or starch, preferably a mixture of lactose and microcrystalline cellulose, which can ensure that the oral formulation of the compound of formula I meets the mass or volume standards for making solid dosage forms. According to the present invention, a binder is introduced into a pharmaceutical composition containing a compound of formula I. The binder includes one or more of hypromellose, hydroxypropyl cellulose, povidone, hydroxyethyl cellulose, sodium carboxymethyl cellulose or polyvinyl alcohol, preferably hypromellose; it can bind the raw materials and excipients; and when the binder is hypromellose, since hypromellose has surface activity, it helps to improve the dissolution of the drug. According to the present invention, a glidant is introduced into a pharmaceutical composition containing a compound of Formula I. The glidant includes one or more of colloidal silicon dioxide, talc, or micropowdered silica, preferably colloidal silicon dioxide; it can reduce sticking and reduce friction between particles and between tablets and the wall of the die hole, improve the fluidity of the particles, and make the tablet surface smooth and beautiful. According to the present invention, a disintegrant is introduced into a pharmaceutical composition containing a compound of Formula I. The disintegrant includes one or more of low-substituted hydroxypropyl cellulose, cross-linked sodium carboxymethyl cellulose, sodium carboxymethyl starch, or cross-linked polyvinylpyrrolidone, preferably cross-linked sodium carboxymethyl cellulose; it can cause the tablet to quickly break into fine particles in the gastrointestinal fluid, thereby allowing the functional ingredients to be quickly dissolved and absorbed and exert their effect. When the disintegrant is cross-linked sodium carboxymethyl cellulose, the brittleness of the tablet is not affected regardless of whether the internal or external addition method is used. According to the present invention, a lubricant is introduced into a pharmaceutical composition containing a compound of Formula I. The lubricant includes one or more of magnesium stearate, calcium stearate, or sodium stearyl fumarate, preferably magnesium stearate, which can uniformly distribute pressure during tableting and make the tablet density uniform.

[0017] The present invention also provides an anti-new crown pharmaceutical composition and a preparation method thereof, the effect of which can be achieved by controlling the amount of formulation excipients. Specifically, the increase in the amount of excipients is conducive to increasing compressibility and reducing the possibility of sticking, but the increase in the amount of excipients will cause the weight of the tablets to be too large, which is not conducive to patients taking it, and will cause additional negative effects on the performance of the preparation, such as excessive disintegrants. It will cause excessive lubrication of the tablets and delay dissolution. Unless otherwise specified, the amount of active ingredient in the formulation of the present invention is calculated in terms of the compound of formula I (dry and pure). When the corresponding excipient is selected, the amount of the excipient is: the mass ratio of the compound of formula I to the filler is 1:1.0-2.5, the mass ratio of the compound of formula I to the binder is 1:0.01-0.05, the mass ratio of the compound of formula I to the glidant is 1:0.01-0.03, the mass ratio of the compound of formula I to the disintegrant is 1:0.10-0.30, and the mass ratio of the compound of formula I to the lubricant is 1:0.01-0.10. Preferably, when the corresponding excipients are selected, the amount of the excipients is: the mass ratio of the compound of formula I to the filler is 1:1.5-2.0, the mass ratio of the compound of formula I to the binder is 1:0.02-0.04, the mass ratio of the compound of formula I to the glidant is 1:0.012-0.020, the mass ratio of the compound of formula I to the disintegrant is 1:0.15-0.25, and the mass ratio of the compound of formula I to the lubricant is 1:0.02-0.06. Within the aforementioned preferred ratio range, any small range can also achieve the same technical effect. For example, the aforementioned preferred lubricant ratio range can be 1:0.02-0.05. More preferably, when the corresponding excipients are selected, the amount of the excipient is: the mass ratio of the compound of formula I to the filler is 1:1.75, the mass ratio of the compound of formula I to the binder is 1:0.03, the mass ratio of the compound of formula I to the glidant is 1:0.015, the mass ratio of the compound of formula I to the disintegrant is 1:0.18 or 1:0.24, and the mass ratio of the compound of formula I to the lubricant is 1:0.03 or 1:0.06.

[0018] Since oral preparations can only be absorbed by the body when the active pharmaceutical ingredient is dissolved in the body, an oral preparation needs to be subjected to in vitro and in vivo dissolution tests after being prepared. There is a certain correlation between the in vitro and in vivo dissolution characteristics of the drug. The dissolution behavior of the preparation in the body can be reflected from the in vitro dissolution characteristics of the drug. Therefore, the preparation quality of the preparation can be objectively evaluated by a dissolution detection method with strong discrimination power, and the quality difference of the drug preparation can be distinguished from the aspects of the physicochemical properties of the raw material, the preparation prescription and the preparation process, thereby improving the safety and clinical effectiveness of the drug. In oral pharmaceutical compositions such as tablets, the dissolution of the active ingredient has a significant impact on its effectiveness and safety, and standards for dissolution have been formulated in various countries. For example, the method for dissolution test is recorded in the pharmacopoeias of China, Japan, the U.S. and European countries. In this dissolution test, various dissolution test solutions (hereinafter also referred to as test solution or dissolution solution) are used. These dissolution test solutions are adjusted to a pH range of 1-8. For example, as a dissolution test solution recorded in the pharmacopoeias of various countries, the Chinese Pharmacopoeia (2020 edition, Part 4, 0931) shows the dissolution amount in the buffer solution, 250 ml of 0.2 mol / L sodium phosphate solution (adjust the pH to 6.8 with 2 mol / L hydrochloric acid solution or 2 mol / L sodium hydroxide solution if necessary), and the Japanese Pharmacopoeia determination method shows a strongly acidic dissolution test solution (for example, the first solution recorded in the Japanese Pharmacopoeia, 0.1N hydrochloric acid aqueous solution, etc.), a dissolution test solution of pH 3-5 (for example, acetic acid-sodium acetate buffer, McIlvaine buffer, etc.) and a dissolution test solution of pH 6.8 (for example, the second solution recorded in the Japanese Pharmacopoeia, pH 6.8 phosphate buffer, etc.) and water, etc. The following requirements are imposed on oral preparations: when these dissolution test solutions are used for dissolution tests, their solubility is good. Although the pharmacopoeias of various countries currently disclose similar dissolution media, their dissolution time and corresponding dissolution rate are not disclosed for specific compositions.

[0019] The present invention provides an anti-COVID-19 pharmaceutical composition, which, when using a pH 6.8 phosphate buffer as a dissolution medium, achieves a solubility of 70.0% or more within 60 minutes; further, when using a pH 6.8 phosphate buffer as a dissolution medium, achieves a solubility of 43.0% or more within 15 minutes; and further, when using a pH 6.8 phosphate buffer as a dissolution medium, achieves a solubility of 60.0% or more within 30 minutes. Furthermore, under this condition of a pH 6.8 phosphate buffer, the finished preparation has a certain quality differentiation ability.

[0020] These dissolution test solutions can be prepared by methods described in various national pharmacopoeias, etc. When the dissolution test solution is a buffer solution, the pH of these dissolution test solutions is preferably within ±0.05 of the pH specified for each dissolution test solution.

[0021] In this specification, the dissolution test can be carried out in accordance with the dissolution and release test method (Chinese Pharmacopoeia 2020 Edition Part IV General Rules 0931 Second Method). 900 ml of pH 6.8 phosphate buffer (mix 250 ml of 0.2 mol / L potassium dihydrogen phosphate solution with 112 ml of 0.2 mol / L sodium hydroxide solution, dilute to 1000 ml with water, and mix well) is used as the dissolution medium. The rotation speed is 75 revolutions per minute. The operation is carried out in accordance with the method and samples are taken after a certain period of time.

[0022] The present invention also provides an anti-COVID-19 pharmaceutical composition and its preparation method, the effects of which can be further achieved by controlling the moisture content. The inventors surprisingly discovered that moisture not only affects the quality of the formulation during the formulation process, such as affecting tablet molding, but also further affects the performance of the formulation, such as dissolution. Specifically, due to the properties of the compound of Formula I, when the moisture content is too high, it gradually develops a "hardening" phenomenon inside during storage, which in turn affects the dissolution of the formulation and the stability of long-term storage. However, the Chinese, US, Japanese, and British Pharmacopoeias do not have any requirements for the moisture content of tablets. Therefore, the composition of the present invention has more stringent requirements for moisture content than conventional formulations. Specifically, the moisture content does not exceed 5.0%. Preferably, the moisture content of the composition is between 1.0% and 5.0%, and more preferably between 3.0% and 5.0%. Under these conditions, the composition of the present invention containing the compound of Formula I is very stable under long-term storage conditions or under accelerated storage conditions of 40°C / 75% relative humidity. For example, when the composition according to the present invention is stored at 40°C ± 2°C and 75% RH ± 5% RH for 3 months, the dissolution of the composition changes little.

[0023] As used herein, "moisture content" refers to the total amount of water present in a composition. This includes not only unbound water or "water" as a raw material, any excipients that may be present, and / or any coatings that may be present, but also water that is bound as part of the crystalline structure of the raw material, any excipients that may be present, and / or any coatings that may be present. One skilled in the art can readily determine the percentage of water content using the Karl Fischer technique. Additionally, when calculating the water content of a composition according to the present invention, for a composition according to the present invention, the water content will always be no more than 5.0%.

[0024] The present invention can use the moisture determination method (Chinese Pharmacopoeia 2020 edition, Part Four, General Rules 0832, First Method (Fischer method)) to determine the water content of the composition of the present invention. The present invention provides an anti-new crown pharmaceutical composition and a preparation method thereof, and this effect can be further achieved through a specific formulation technology. According to the properties of the raw and auxiliary materials themselves, selecting a specific formulation technology can be beneficial to obtaining a preparation with excellent formulation quality and further obtaining a preparation with good stability. The present invention adopts a non-wet granulation formulation technology, which refers to a formulation method that does not adopt a wet granulation process, including dry granulation, fluidized bed one-step granulation and powder direct compression. Due to the moisture and heat sensitivity of the compound of formula I, a non-wet granulation formulation technology is adopted, preferably dry granulation, which can avoid the addition of granulation liquid during the wet granulation process and the drying process after granulation, resulting in instability of the raw material and increased impurities.

[0025] The present invention provides an anti-new crown pharmaceutical composition and a preparation method thereof, the effect of which can be further achieved by controlling the particle size of the raw material drug of the compound of formula I. The particle size of the raw material drug may affect the feasibility of the formulation process and the dissolution of the product, and ultimately affect the dissolution in vivo, so it is necessary to study and control the particle size distribution of the raw material drug. In general, as the particle size decreases, the particle size becomes finer and more uniform, the specific surface area increases, the porosity increases, the adsorption increases, the solubility increases, the affinity becomes larger, the chemical reaction rate increases, and the dissolution rate of the drug is improved. If the particle size is too large, it is not conducive to mixing with the excipients, the preparation mixing uniformity is poor, and it affects the subsequent release. Therefore, the appropriate particle size of the raw material drug can not only make the raw materials and excipients mix evenly, which is beneficial to the formation of the preparation, but also improve its dissolution performance. When the particle size of the compound of formula I satisfies D10≤8μm, D50≤25μm, and D90≤160μm simultaneously, the particle size distribution of the dry granules after dry granulation is not significantly affected, and the dissolution curve of the resulting preparation in various dissolution media (pH 1.0, pH 4.5, pH 6.8, and purified water) is not significantly affected. Preferably, the particle size of the compound of formula I is D10≤5μm, D50≤20μm, and D90≤150μm. More preferably, the particle size of the compound of formula I is D10≤3μm, D50≤15μm, and D90≤140μm.

[0026] The present invention provides an anti-COVID-19 pharmaceutical composition and a preparation method thereof, the effects of which can be further achieved through a specific crystal form, i.e., a crystal form of a compound of formula I. Furthermore, the crystal form of the compound of formula I can optimize the dissolution properties of the resulting preparation, so that it can exert a better therapeutic effect in clinical treatment. The quality and efficacy of solid oral preparations depend on the selection of active pharmaceutical ingredients, prescription design, and pharmaceutical preparation production process. However, processing-induced phase changes in the production process of pharmaceutical preparations are difficult to predict and control. Many drugs have polymorphic forms, and different crystal forms may have different physical and chemical properties such as crystal habit, melting point, density, stability, solubility, dissolution rate, and different powder properties such as bulk density, fluidity, and compressibility. Therefore, the crystal form of the drug may affect the production process of the preparation and the in vitro and in vivo drug effects of the preparation. Preferably, the crystal form of the compound of formula I used in the present invention is an amorphous form of the compound, which has stable properties, good solubility, high solubility, and is suitable for the development of preparations. Specifically, the X-ray powder diffraction pattern of the amorphous form does not have sharp diffraction peaks. Furthermore, the X-ray powder diffraction pattern of the amorphous form has two characteristic peaks at 2θ angles of 5°-15° and 15°-25°. Furthermore, the X-ray powder diffraction pattern of the amorphous form is shown in Figure 1.

[0027] The present invention provides an anti-COVID-19 pharmaceutical composition and a method for preparing the same. This effect can be achieved by controlling the mass ratio of the filler lactose and microcrystalline cellulose. Furthermore, controlling the mass ratio of the filler lactose and microcrystalline cellulose can optimize the dissolution performance of the resulting preparation, enabling it to achieve better therapeutic effects in clinical treatment. Based on the physicochemical properties of the raw materials and the results of the excipient compatibility test, a mixture of lactose and microcrystalline cellulose was selected as the filler. If the amount of microcrystalline cellulose is too large, a "bottoming out" phenomenon will occur during the dissolution process, that is, microcrystals accumulate at the bottom of the dissolution cup in the later stage of dissolution, resulting in incomplete drug release and adversely affecting drug dissolution. To ensure the feasibility and performance of the resulting preparation, the mass ratio of lactose to microcrystalline cellulose is 1:0.5-5. Preferably, the mass ratio of lactose to microcrystalline cellulose is 1:0.6-3. Within the aforementioned preferred ratio range, any smaller range can also achieve the same technical effect. For example, a preferred filler ratio range can be 1:1-3. More preferably, the mass ratio of lactose to microcrystalline cellulose is 1:0.69, 1:0.98, or 1:2.

[0028] The present invention provides an anti-COVID-19 pharmaceutical composition, the tableting performance of which can be basically achieved according to the above-mentioned prescription composition. Although a very small number of tablets occasionally show loose tablets and cracking phenomena, this is also within the reasonable production error range. In order to further reduce the error, the present invention can further achieve this by controlling the addition method and dosage of disintegrants and lubricants during the preparation process. Furthermore, the addition method and dosage of disintegrants and lubricants during the preparation process can optimize the dissolution performance of the resulting preparation, so that it can play a better therapeutic effect in clinical treatment. When the disintegrant is added internally, the disintegration effect starts from the inside of the particles, causing all the particles to disintegrate. Since the disintegrant is enclosed in the particles, it comes into contact with water more slowly, and the disintegrant has been exposed to mild heat during the granulation process, so the disintegration effect is weak. When the disintegrant is added externally, the disintegration speed is faster, but its disintegration effect mainly occurs between particles, and after disintegration, it is often in a granular state rather than a fine powder. The use of the internal and external addition method of lubricants can ensure the fluidity between the separated particles while improving the friction between the polymer and the hot metal surface of the processing equipment, thereby ensuring the tableting quality of the tablets.

[0029] For the pharmaceutical composition of the present technology, the disintegrant is prepared by the internal and external addition method, and the lubricant is prepared by the internal and external addition method. When the disintegrant is prepared by the internal and external addition method, the mass ratio of the internal disintegrant to the external disintegrant is 1:0.5-3, the drug dissolution performance is good, and there is no significant difference in the various quality attributes (particle size, angle of repose, bulk density, tap density) between the particles (tablets) of the preparation, and there is no significant difference in the dissolution rate. Preferably, the mass ratio of the internal disintegrant to the external disintegrant is 1:0.8-2, and more preferably, the mass ratio of the internal disintegrant to the external disintegrant is 1:1. When the lubricant is added internally and externally during the preparation process, the mass ratio of the internal lubricant to the external lubricant is 1:0.5-3. Similarly, the drug dissolution performance is good, and there is no significant difference in the various quality attributes (particle size, angle of repose, bulk density, tap density) between the particles (tablets) of the preparation, and there is no significant difference in the dissolution rate. Preferably, the mass ratio of the internal lubricant to the external lubricant is 1:0.8-2, and more preferably, the mass ratio of the internal lubricant to the external lubricant is 1:1.

[0030] According to the actual production conditions of the preparation, it is well known to those skilled in the art that the mass ratio of the excipients is allowed to have a certain error range. The error range of the mass ratio in the present invention may be ±0.5%.

[0031] The present invention also provides the following composition, comprising the following components. This formulation is the preferred technical solution of the present invention, and simultaneously solves the problems related to the stability of the preparation of the compound of formula I, the preparation process (sticking, etc.) and dissolution. The obtained preparation has excellent quality, no sticking, loosening, or cracking of the tablets, good dissolution performance, good stability, and meets the medicinal effect.

[0032] A pharmaceutical composition comprising the following components,

[0033] The particle size of the compound of formula I is D10≤3 μm, D50≤15 μm, and D90≤140 μm, and the compound of formula I is in an amorphous form.

[0034] A pharmaceutical composition comprising the following components,

[0035] The particle size of the compound of formula I is D10≤3μm, D50≤15μm, and D90≤140μm, and the compound of formula I is in an amorphous form.

[0036] A pharmaceutical composition comprising the following components,

[0037] The particle size of the compound of formula I is D10≤3μm, D50≤15μm, and D90≤140μm, and the compound of formula I is in an amorphous form.

[0038] Furthermore, a pharmaceutical composition comprises the following components:

[0039] The particle size of the compound of formula I is D10≤3μm, D50≤15μm, and D90≤140μm. The compound of formula I is in an amorphous form. The moisture content of the pharmaceutical composition is 3.0% to 5.0%.

[0040] Furthermore, a pharmaceutical composition comprises the following components:

[0041] The particle size of the compound of formula I is D10≤3μm, D50≤15μm, and D90≤140μm. The compound of formula I is in an amorphous form. The moisture content of the pharmaceutical composition is 3.0% to 5.0%.

[0042] Furthermore, a pharmaceutical composition comprises the following components:

[0043] The particle size of the compound of formula I is D10≤3μm, D50≤15μm, and D90≤140μm. The compound of formula I is in an amorphous form. The moisture content of the pharmaceutical composition is 3.0% to 5.0%.

[0044] Furthermore, a pharmaceutical composition comprises the following components:

[0045] The particle size of the compound of formula I is D10≤3μm, D50≤15μm, and D90≤140μm. The compound of formula I is in an amorphous form. The dissolution rate of the pharmaceutical composition reaches more than 70.0% in 60 minutes when using a phosphate buffer solution with a pH of 6.8 as a dissolution medium.

[0046] Furthermore, a pharmaceutical composition comprises the following components:

[0047] The particle size of the compound of formula I is D10≤3μm, D50≤15μm, and D90≤140μm. The compound of formula I is in an amorphous form. The dissolution rate of the pharmaceutical composition reaches more than 70.0% in 60 minutes when using a phosphate buffer solution with a pH of 6.8 as a dissolution medium.

[0048] Furthermore, a pharmaceutical composition comprises the following components:

[0049] The particle size of the compound of formula I is D10≤3μm, D50≤15μm, and D90≤140μm. The compound of formula I is in an amorphous form. The dissolution rate of the pharmaceutical composition reaches more than 70.0% in 60 minutes when using a phosphate buffer solution with a pH of 6.8 as a dissolution medium.

[0050] Furthermore, a pharmaceutical composition comprises the following components:

[0051] The particle size of the compound of formula I is D10≤3μm, D50≤15μm, and D90≤140μm. The compound of formula I is in an amorphous form. The dissolution rate of the pharmaceutical composition reaches more than 70.0% in 60 minutes when using a phosphate buffer solution with a pH of 6.8 as a dissolution medium.

[0052] Furthermore, a pharmaceutical composition comprises the following components:

[0053] The particle size of the compound of formula I is D10≤3μm, D50≤15μm, and D90≤140μm. The compound of formula I is in an amorphous form. The dissolution rate of the pharmaceutical composition reaches more than 70.0% in 60 minutes when using a phosphate buffer solution with a pH of 6.8 as a dissolution medium.

[0054] Furthermore, a pharmaceutical composition comprises the following components:

[0055] The particle size of the compound of formula I is D10≤3μm, D50≤15μm, and D90≤140μm. The compound of formula I is in an amorphous form. The dissolution rate of the pharmaceutical composition reaches more than 70.0% in 60 minutes when using a phosphate buffer solution with a pH of 6.8 as a dissolution medium.

[0056] The second object of the present invention is to provide a method for preparing a pharmaceutical composition, which is a non-wet granulation preparation technology.

[0057] The third object of the present invention is to provide a pharmaceutical tablet comprising a tablet core and a coating coated on the outside of the tablet core, wherein the tablet core is composed of the pharmaceutical composition of the present invention.

[0058] Depending on the coating material, coated tablets can be primarily categorized as sugar-coated tablets, film-coated tablets, and enteric-coated tablets. In the present invention, the coating is a suitable coating known not to negatively affect the dissolution rate of the final formulation, preferably a gastric-soluble film coating. Film coating provides a sealant coating on the tablet core to protect patients and clinical staff, as well as to block contact between the tablet core and air and moisture, thereby reducing the risk of drug degradation.

[0059] Suitable film coating materials include film formers, such as film-forming polymers. Preferably, the film coating material also includes other components, such as plasticizers, colorants, dispersants and sunscreens. Plasticizers can be used to improve the film flexibility and durability and adhesion properties of the film coating. Preferred film-forming polymers are selected from one or more of film-forming vinyl polymers (such as polyvinyl alcohol), film-forming acrylic polymers (such as methacrylic acid-methyl methacrylate copolymers), water-soluble cellulose ethers (such as hypromellose) and the like. Preferred plasticizers are selected from glycerol, acetylated monoglycerides, citrates, propylene glycol, polyethylene glycol, triglycerides or phthalates. Suitable sunscreens and colorants include, for example, titanium dioxide, yellow iron oxide, black iron oxide and allure red aluminum lake. Suitable dispersants include, for example, talc.

[0060] Suitable film coating materials can be prepared as concentrates, with water or an organic solvent used to prepare a coating solution before spraying onto the tablet cores. In the present invention, the coating material used is a pharmaceutical film coating premix (gastric soluble) (Opadry 85F64732-CN, pink), prepared into a coating solution with a solids content of 15% and sprayed onto the tablet cores. The coating weight is 0.5% to 10% of the tablet core weight, preferably 1% to 6%, and more preferably 3%.

[0061] In the present invention, the specification of the tablet of the compound of formula I is 100 mg-300 mg, for example, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, preferably 150 mg-250 mg, more preferably 200 mg.

[0062] According to the present invention, a method for preparing the above-mentioned pharmaceutical tablet is also provided, specifically comprising the following steps:

[0063] 1) The prescribed amount of the compound of formula I and lactose are sieved, and then the prescribed amount of hypromellose, croscarmellose sodium (added internally) and colloidal silicon dioxide are mixed and sieved. Finally, the prescribed amount of microcrystalline cellulose is sieved. The sieve size is Ø1.0 mm and the granulation frequency is 8 Hz.

[0064] The sieved materials were pre-mixed 1 at a pre-mixing speed of 10 rpm and a pre-mixing time of 15 min to obtain pre-mix 1.

[0065] After premixing 1 was completed, magnesium stearate (internal addition) was added to perform premixing 2 at a premixing speed of 10 rpm for 5 minutes to obtain premix 2.

[0066] 2) The premix 2 is placed in a dry granulator for dry granulation. The hopper feed speed is 5-10 rpm, the screw feed speed is 10-20 rpm, the roller speed is 13-23 rpm, the hydraulic pressure is 60-80 bar, the roller gap is 1.0 mm, the granulation screen size is 10 mesh, the granulation speed is 30-80 rpm, the granulation screen size is 24 mesh, and the granulation speed is 80-180 rpm. After granulation, dry granules are obtained. At the end of the dry granulation, samples are taken to test the loss on drying, which shall not exceed 5.0%.

[0067] 3) The dry granules and the converted croscarmellose sodium (externally added) were transferred to a mixer and pre-mixed at a mixing speed of 10 rpm for 5 minutes to obtain a pre-mix. The converted magnesium stearate (externally added) was added to the pre-mix in the mixer and mixed at a mixing speed of 10 rpm for 3 minutes to obtain a total mixture. After the total mixing was completed, samples were taken for intermediate product inspection.

[0068] 4) After the total mixed particle content is tested, the die specifications are 17mm*8.5mm shallow concave punches, the tableting speed is 100-180 thousand tablets / hour, the main pressure of the tablet press is 8-11kN, and the hardness is controlled at 100-180N for tableting. After tableting, samples are taken for intermediate product inspection.

[0069] 5) Weigh the film coating premix and purified water to prepare the coating solution, and use a high-efficiency coating machine for coating. The coating air inlet temperature is 40-66°C, the air outlet temperature is 35-55°C, the material temperature is 35-55°C, the spray rate is 0.1-0.5kg / min, the atomization pressure is 1.0-5.0bar, and the coating weight gain range is 2.0-4.0%. After coating, take samples to test the appearance, coating weight gain and drying loss, which shall not exceed 5.0%.

[0070] A fourth object of the present invention is to provide the use of the pharmaceutical tablet in the preparation of a product for preventing, alleviating or treating an infection or disease caused by a novel coronavirus, wherein the novel coronavirus includes an unmutated novel coronavirus or a mutant novel coronavirus, wherein the mutant novel coronavirus includes a novel coronavirus Alpha variant, a novel coronavirus Beta variant, a novel coronavirus Gamma variant, a novel coronavirus Delta variant, a novel coronavirus Lambda variant and / or a novel coronavirus Omicron variant. Infections include fever, cough, sore throat, pneumonia, acute respiratory infection, severe acute respiratory infection, hypoxic respiratory failure and acute respiratory distress syndrome, sepsis or septic shock, and preferably, the disease includes novel coronavirus pneumonia.

[0071] The pharmaceutical composition containing the compound of formula I and the tablet containing the same provided by the present invention have a simple preparation method, a feasible preparation process, excellent preparation properties (no sticking, cracking, etc.), good stability, and good dissolution performance. The dissolution rate reaches more than 70.0% in 60 minutes. Furthermore, under long-term storage conditions or under accelerated storage conditions, the composition also has excellent stability and dissolution performance, and the dissolution performance meets pharmaceutical standards. BRIEF DESCRIPTION OF THE DRAWINGS

[0072] FIG1 is an XRPD spectrum of an amorphous compound of Formula I under Cu-Kα radiation;

[0073] FIG2 is an XRPD spectrum of Form I of the compound of Formula I using Cu-Kα radiation;

[0074] FIG3 is a dissolution curve diagram of Example 2 and Comparative Example 6 under phosphate buffer conditions of pH 6.8;

[0075] FIG4 is a dissolution curve diagram of Examples 2, 6, 7 and Comparative Example 5. DETAILED DESCRIPTION

[0076] The present invention will be further described in detail below with reference to the embodiments.

[0077] The following examples are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the above examples. Any other changes, modifications, substitutions, combinations, and simplifications that do not deviate from the spirit and principles of the present invention should be considered as equivalent replacement methods and are included in the scope of protection of the present invention.

[0078] Dissolution testing

[0079] The dissolution and release rate was determined according to the dissolution and release rate determination method (Method 0931, General Rules of Part IV, Chinese Pharmacopoeia 2020 Edition).

[0080] Dissolution conditions: Use 900 ml of pH 6.8 phosphate buffer (mix 250 ml of 0.2 mol / L potassium dihydrogen phosphate solution with 112 ml of 0.2 mol / L sodium hydroxide solution, dilute to 1000 ml with water, and mix thoroughly) as the dissolution medium. Set the rotation speed at 75 rpm. Operate according to the method and take samples after a certain period of time.

[0081] Dissolution apparatus: Ruituo RT-612-AT

[0082] Test solution: Take an appropriate amount of the eluate, filter, discard 2 ml of the initial filtrate, and take the subsequent filtrate.

[0083] Reference solution: Take an appropriate amount of commercially available Lerestatvir tablets reference substance, accurately weigh it, dissolve it in solvent [anhydrous ethanol-water (80:20)] and quantitatively dilute it to make a solution containing approximately 0.22 mg (0.2 g specification) or 0.11 mg (0.1 g specification) per 1 ml.

[0084] The chromatographic conditions and system suitability requirements are determined in accordance with the high performance liquid chromatography method (General Chapter 0512 of Part IV of the Chinese Pharmacopoeia 2020 Edition).

[0085] Solvent: anhydrous ethanol-water (80:20).

[0086] Test solution: Take 10 tablets of this product, accurately weigh them, grind them into powder, accurately weigh an appropriate amount of fine powder (equivalent to 200 mg of leretinvir), place it in a 100 ml volumetric flask, add an appropriate amount of solvent, sonicate to dissolve, bring to room temperature, dilute to the scale with solvent, shake well, centrifuge at 8000 rpm for 10 minutes, accurately measure an appropriate amount of supernatant, and quantitatively dilute with solvent to make a solution containing approximately 0.2 mg per 1 ml.

[0087] Reference solution: Take an appropriate amount of commercially available Lerestatvir tablets reference substance, accurately weigh it, dissolve it in a solvent, and quantitatively dilute it to make a solution containing approximately 0.2 mg per 1 ml.

[0088] Instrument: Agilent 1260 Infinity II VWD / DAD

[0089] Chromatographic conditions: Octadecylsilane bonded silica gel as the packing material (Waters Xbridge C18, 4.6 mm × 150 mm, 3.5 μm or equivalent performance column); 0.005 mol / L dipotassium hydrogen phosphate solution (pH adjusted to 8.4 with 1% phosphoric acid solution)-methanol (30:70) as the mobile phase, flow rate: 1.0 ml / min; detection wavelength: 210 nm; column temperature: 55°C; injection volume: 10 μl.

[0090] System suitability requirements: In the chromatogram of the reference solution, the number of theoretical plates based on the Leretovir peak should be no less than 2000.

[0091] Determination method: Accurately measure the test solution and reference solution, inject them into the liquid chromatograph respectively, record the chromatogram, and calculate the peak area according to the external standard method. Calculation formula:

[0092] Moisture determination method:

[0093] 1. Instruments and Equipment

[0094] (1) Moisture meter: Metrohm 915KF Ti-Touch

[0095] (2) Electronic analytical balance: Sartorius BCE224I-1CCN

[0096] 2. Reagents and Reference Materials

[0097] (1) Ultrapure water / purified water: homemade

[0098] (2) Anhydrous methanol, purchased from Chengdu Kelong Chemicals Co., Ltd.

[0099] (3) Pyridine-free Karl Fischer reagent, purchased from Tianjin Kemeiou Chemical Reagent Co., Ltd.

[0100] 3. Operation steps

[0101] Follow the Fischer method, Part IV, General Chapter 0832, Determination of Water, Method 1 (Fischer method), in the 2020 edition of the Chinese Pharmacopoeia. For Fischer solution calibration, accurately weigh approximately 10 mg of purified water and measure directly with a moisture meter three times. For sample determination, grind the product into a fine powder, weigh approximately 200 mg, and measure twice or more with a moisture meter.

[0102] The test results can be expressed as a range value or as the average of several times, but in any case, the average of several times should be within the range of the test.

[0103] The amorphous form of the compound of formula I can be prepared and tested with reference to PCT / CN2023 / 120437;

[0104] The crystalline form I of the compound of formula I can be prepared and tested with reference to PCT / CN2023 / 120726;

[0105] The above compounds of formula I are all sourced from Guangdong Zhongsheng Ruichuang Biotechnology Co., Ltd.

[0106] By controlling the size of the crushing screen, the required particle size of the raw material can be obtained.

[0107] The particle size test conditions for the raw material of the compound of formula I are as follows:

[0108] Instrument name: Malvern laser particle size analyzer;

[0109] Instrument model: Mastersizer 3000;

[0110] Injector: dry method;

[0111] Injection rate: 35%;

[0112] Dispersion air pressure: 2 bar;

[0113] Measuring time: 5s.

[0114] Example 1 Compatibility test of raw materials and auxiliary materials

[0115] The excipients selected were lactose, microcrystalline cellulose, mannitol, croscarmellose sodium, sodium stearyl fumarate, poloxamer, hypromellose, glyceryl behenate, colloidal silicon dioxide, sodium lauryl sulfate, magnesium stearate, and a film coating premix. These were mixed with the main drug in the proportions listed in Table 1 and then allowed to stand according to the conditions listed in Table 1. Samples were taken at specified time points to examine changes in properties, content, and related substances (total impurities). HPLC was used for analysis.

[0116] Table 1 Excipient compatibility test results

[0117] From the above results, it can be seen that with respect to the properties, after the raw material of the compound of Formula I and poloxamer 188 were placed for 5 days and 10 days under high temperature conditions, the properties of the binary mixture changed, and the appearance changed from white powder to brown semisolid; after the raw material of the compound of Formula I and poloxamer 188 were placed for 5 days and 10 days under high humidity conditions, the properties of the binary mixture changed, and the appearance changed from white powder to white crystals; after the raw material of the compound of Formula I and sodium lauryl sulfate were placed for 10 days under high humidity conditions, the appearance changed from white powder to white liquid. After the remaining raw materials of the compound of Formula I and excipients were placed for 5 days and 10 days, the appearance did not change significantly, and they were all white powders.

[0118] Regarding content, the content of the binary mixture of the raw material of the compound of formula I, poloxamer 188, and glyceryl behenate decreased significantly after being placed under high temperature conditions for 5 days and 10 days. The content of the binary mixture of the raw material of the compound of formula I and sodium lauryl sulfate decreased significantly under high humidity conditions. The content of the raw material of the compound of formula I and all excipients decreased significantly under light conditions. The content of other binary mixtures did not change significantly at high temperature and high humidity compared with 0 day.

[0119] Regarding related substances, the total impurities of the raw material of the compound of formula I and poloxamer 188 increased significantly under high temperature conditions, and the total impurities of the raw material of the compound of formula I, poloxamer 188, and sodium lauryl sulfate increased significantly under high humidity conditions. The total impurities of each binary mixture of the raw material of the compound of formula I and all excipients increased under light conditions, and the growth trend was basically consistent with that of the raw material of the compound of formula I.

[0120] In summary, the drug substance of Formula I has good compatibility with lactose, microcrystalline cellulose, mannitol, croscarmellose sodium, sodium stearyl fumarate, hypromellose, colloidal silicon dioxide, and magnesium stearate, and can be used in formulation research. However, it has poor compatibility with poloxamer 188, sodium lauryl sulfate, and glyceryl behenate.

[0121] Example 2 Preparation of Formula I Compound Tablets

[0122] Formula composition of 1000 tablets of Formula I compound

[0123] Preparation method:

[0124] 1) The prescribed amount of the compound of formula I and lactose are sieved, and then the prescribed amount of hypromellose, croscarmellose sodium (added internally) and colloidal silicon dioxide are mixed and sieved. Finally, the prescribed amount of microcrystalline cellulose is sieved. The sieve size is Ø1.0 mm and the granulation frequency is 8 Hz.

[0125] The sieved materials were pre-mixed with a mixer at a speed of 10 rpm for 15 min to obtain a pre-mix 1.

[0126] After premixing 1 was completed, magnesium stearate (internal addition) was added to perform premixing 2 at a premixing speed of 10 rpm for 5 minutes to obtain premix 2.

[0127] 2) The premix 2 is placed in a dry granulator for dry granulation. The hopper feeding speed is 5-10 rpm, the screw feeding speed is 10-20 rpm, the pressing wheel speed is 13-23 rpm, the hydraulic pressure is 60-80 bar, the pressing wheel gap is 1.0 mm, the granulation screen size is 10 mesh, the granulation speed is 30-80 rpm, the granulation screen size is 24 mesh, and the granulation speed is 80-180 rpm. After granulation, dry granules are obtained. At the end of the dry granulation, samples are taken to test the loss on drying, which shall not exceed 5.0%.

[0128] 3) The dry granules and the converted croscarmellose sodium (externally added) were transferred to a mixer and pre-mixed at a mixing speed of 10 rpm for 5 minutes to obtain a pre-mix. The converted magnesium stearate (externally added) was added to the pre-mix in the mixer and mixed at a mixing speed of 10 rpm for 3 minutes to obtain a total mixture. After the total mixing was completed, samples were taken for intermediate product inspection.

[0129] 4) After the total mixed particle content is tested, the die specifications are 17mm*8.5mm shallow concave punches, the tableting speed is 100-180 thousand tablets / hour, the main pressure of the tablet press is 8-11kN, and the hardness is controlled at 100-180N for tableting. After tableting, samples are taken for intermediate product inspection.

[0130] 5) Weigh the film coating premix and purified water to prepare the coating solution, and use a high-efficiency coating machine for coating. The coating air inlet temperature is 40-66°C, the air outlet temperature is 35-55°C, the material temperature is 35-55°C, the spray rate is 0.1-0.5 kg / min, the atomization pressure is 1.0-5.0 bar, and the coating weight gain range is 2.0-4.0%. After coating, samples are taken to test the appearance, coating weight gain and drying loss, which shall not exceed 5.0%. The moisture content is controlled between 3.0% and 5.0% by the drying time.

[0131] Example 3 Preparation of Formula I Compound Tablets

[0132] Formula composition of 1000 tablets of Formula I compound

[0133] The preparation method is the same as in Example 2, and the moisture content is further controlled to be 3.0% to 5.0%.

[0134] Example 4 Preparation of Formula I Compound Tablets

[0135] Formula composition of 1000 tablets of Formula I compound

[0136] The preparation method is the same as in Example 2, and the moisture content is further controlled to be 3.0% to 5.0%.

[0137] Example 5 Preparation of Formula I Compound Tablets

[0138] Formula composition of 1000 tablets of Formula I compound

[0139] The preparation method is the same as in Example 2, and the moisture content is further controlled to be 3.0% to 5.0%.

[0140] Example 6 Preparation of Formula I Compound Tablets

[0141] Formula composition of 1000 tablets of Formula I compound

[0142] The preparation method is the same as in Example 2, and the moisture content is further controlled to be 3.0% to 5.0%.

[0143] Example 7 Preparation of Formula I Compound Tablets

[0144] Formula composition of 1000 tablets of Formula I compound

[0145] The preparation method is the same as in Example 2, and the moisture content is further controlled to be 3.0% to 5.0%.

[0146] Example 8 Preparation of Formula I Compound Tablets

[0147] Formula composition of 1000 tablets of Formula I compound

[0148] Preparation method:

[0149] 1) The prescribed amount of the compound of formula I and lactose are sieved, and then the prescribed amount of povidone, hydroxypropyl cellulose (low-substituted) (internally added) and talc are mixed and sieved. The sieve size is Ø1.0 mm and the granulation frequency is 8 Hz.

[0150] The sieved materials were pre-mixed with a mixer at a speed of 10 rpm for 15 min to obtain a pre-mix 1.

[0151] After premixing 1 is completed, sodium stearyl fumarate (internal addition) is added to perform premixing 2 at a premixing speed of 10 rpm for 5 minutes to obtain premix 2.

[0152] 2) The premix 2 is placed in a dry granulator for dry granulation. The hopper feed speed is 5-10 rpm, the screw feed speed is 10-20 rpm, the roller speed is 13-23 rpm, the hydraulic pressure is 60-80 bar, the roller gap is 1.0 mm, the granulation screen size is 10 mesh, the granulation speed is 30-80 rpm, the granulation screen size is 24 mesh, and the granulation speed is 80-180 rpm. After granulation, dry granules are obtained. At the end of the dry granulation, samples are taken to test the loss on drying, which shall not exceed 5.0%.

[0153] 3) The dry granules and the converted hydroxypropyl cellulose (low-substituted) (externally added) were transferred to a mixer and pre-mixed at a mixing speed of 10 rpm for 5 minutes to obtain a pre-mix. The converted sodium stearyl fumarate (externally added) was added to the pre-mix in the mixer and mixed at a mixing speed of 10 rpm for 3 minutes to obtain a total mixture. After the mixing was completed, samples were taken for intermediate product inspection.

[0154] 4) After the total mixed particle content is tested, the die specifications are 17mm*8.5mm shallow concave punches, the tableting speed is 100-180 thousand tablets / hour, the main pressure of the tablet press is 8-11kN, and the hardness is controlled at 100-180N for tableting. After tableting, samples are taken for intermediate product inspection.

[0155] 5) Weigh the film coating premix and purified water to prepare the coating solution, and use a high-efficiency coating machine for coating. The coating air inlet temperature is 40-66°C, the air outlet temperature is 35-55°C, the material temperature is 35-55°C, the spray rate is 0.1-0.5 kg / min, the atomization pressure is 1.0-5.0 bar, and the coating weight gain range is 2.0-4.0%. After coating, samples are taken to test the appearance, coating weight gain and drying loss, which shall not exceed 5.0%. The moisture content is controlled between 3.0% and 5.0% by the drying time.

[0156] Example 9 Preparation of Formula I Compound Tablets

[0157] Formula composition of 1000 tablets of Formula I compound

[0158] The preparation method is the same as in Example 2, and the moisture content is further controlled to be 2.0% to 3.0%.

[0159] Example 10 Preparation of Formula I Compound Tablets

[0160] Formula composition of 1000 tablets of Formula I compound

[0161] The preparation method is the same as in Example 2, and the moisture content is further controlled to be 1.0% to 2.0%.

[0162] Comparative Example 1 Preparation of Formula I Compound Tablets

[0163] Formula composition of 1000 tablets of Formula I compound

[0164] 1) The prescribed amount of the compound of formula I and lactose are sieved, and then the prescribed amount of hypromellose, croscarmellose sodium and colloidal silicon dioxide are mixed and sieved. Finally, the prescribed amount of microcrystalline cellulose is sieved. The sieve size is Ø1.0 mm and the granulation frequency is 8 Hz.

[0165] The sieved materials were pre-mixed with a mixer at a speed of 10 rpm for 15 min to obtain a pre-mix 1.

[0166] After premixing 1 was completed, magnesium stearate was added to perform premixing 2 at a premixing speed of 10 rpm for 5 minutes to obtain premix 2.

[0167] 2) The premix 2 is placed in a dry granulator for dry granulation. The hopper feeding speed is 5-10 rpm, the screw feeding speed is 10-20 rpm, the pressing wheel speed is 13-23 rpm, the hydraulic pressure is 60-80 bar, the pressing wheel gap is 1.0 mm, the granulation screen size is 10 mesh, the granulation speed is 30-80 rpm, the granulation screen size is 24 mesh, and the granulation speed is 80-180 rpm. After granulation, dry granules are obtained. At the end of the dry granulation, samples are taken to test the loss on drying, which shall not exceed 5.0%.

[0168] 3) After the particle content test is qualified, the die specification is 17mm*8.5mm shallow concave punch, the tablet pressing speed is 100-180 thousand tablets / hour, the main pressure of the tablet press is 8-11kN, and the hardness is controlled at 100-180N for tableting. After the tableting is completed, samples are taken for intermediate product inspection.

[0169] 4) Weigh the film coating premix and purified water to prepare the coating solution, and use a high-efficiency coating machine for coating. The coating air inlet temperature is 40-66°C, the air outlet temperature is 35-55°C, the material temperature is 35-55°C, the spray rate is 0.1-0.5 kg / min, the atomization pressure is 1.0-5.0 bar, and the coating weight gain range is 2.0-4.0%. After coating, samples are taken to test the appearance, coating weight gain and drying loss, which shall not exceed 5.0%. The moisture content is controlled between 3.0% and 5.0% by the drying time.

[0170] Compared with Example 2, in Comparative Example 1, the amount of binder used is less, the amount of lubricant used is too much, and during the preparation process, the disintegrant and lubricant are not added internally or externally.

[0171] Comparative Example 2 Preparation of Formula I Compound Tablets

[0172] Formula composition of 1000 tablets of Formula I compound

[0173] The preparation method is the same as Example 2, and the moisture content is further controlled to be 3.0% to 5.0%. In the formulation of Comparative Example 2, the amount of filler used is too high, and the proportion of microcrystalline cellulose in the mixed filler is too high. At the same time, the amount of disintegrant and lubricant used is too high.

[0174] Comparative Example 3 Preparation of Formula I Compound Tablets

[0175] Formula composition of 1000 tablets of Formula I compound

[0176] Comparative Example 3 adopts wet granulation, and the preparation method is as follows:

[0177] 1) Pretreatment: Pass colloidal silica through a 35-mesh sieve and set aside.

[0178] 2) Preparation of granulation solution: Dissolve HPMC and Tween 80 in purified water and set aside.

[0179] 3) Premixing: Weigh the prescribed amount of the compound of formula I, the prescribed amount of lactose, microcrystalline cellulose, and croscarmellose sodium, and mix them through a 60-mesh sieve to obtain a premix.

[0180] 4) Wet granulation: Add the prepared granulation liquid droplets into the premix and prepare wet granules by manual wet granulation that "form into a ball when lightly squeezed and fall apart when lightly pressed".

[0181] 5) Wet granulation: The wet granules obtained by wet granulation were wet granulated using an 18-mesh sieve.

[0182] 6) Drying: Dry the wet granules after wet granulation in a precision blast drying oven, and control the drying loss to be ≤3.0%.

[0183] 7) Dry granulation: The dried granules are sieved through an 18-mesh sieve for dry granulation.

[0184] 8) Total Blending: Convert the amount of croscarmellose sodium and colloidal silicon dioxide according to the amount of dry particles, and mix the added croscarmellose sodium and colloidal silicon dioxide with three times the amount of dry particles of the added croscarmellose sodium and colloidal silicon dioxide through a 60-mesh sieve with the total dry particles; then add the converted magnesium stearate and mix together to obtain mixed particles.

[0185] 9) Tableting: The mixed granules are tableted, and the moisture content is further controlled to be 3.0% to 5.0%.

[0186] Comparative Example 4 Preparation of Formula I Compound Tablets

[0187] Formula composition of 1000 tablets of Formula I compound

[0188] The preparation method is the same as that of Example 2, and the moisture content is further controlled to be 3.0% to 5.0%. Compared with the formulation of Example 2, the particle size of the compound of Formula I in the formulation of Comparative Example 4 is larger.

[0189] Comparative Example 5 Preparation of Formula I Compound Tablets

[0190] Formula composition of 1000 tablets of Formula I compound

[0191] The preparation method is the same as that of Example 2, and the moisture content is controlled to be 6.0% to 8.0%. Compared with the prescription of Example 2, the moisture content of the prescription of Comparative Example 5 is controlled to be greater than 5.0%.

[0192] Comparative Example 6 Preparation of Formula I Compound Tablets

[0193] Formula composition of 1000 tablets of Formula I compound

[0194] The preparation method is the same as that of Example 2, and the moisture content is controlled to be 3.0% to 5.0%. Compared with the formulation of Example 2, the formulation of Comparative Example 6 contains a certain proportion of the crystalline form I compound of Formula I in the raw material compound of Formula I.

[0195] Example 11

[0196] The tablets of the compound of formula I prepared in Examples 2-10 and Comparative Examples 1-6 were subjected to quality inspection, and the results were as follows:

[0197] Table 2 Quality inspection of the tablets of compound of formula I in Example 2-10

[0198] Table 3 Quality inspection of the tablets of the compound of formula I in comparative examples 1-6

[0199] As can be seen from the above results, Examples 2-10 and Comparative Examples 1-6 prepare tablets of the compound of Formula I, all of which are white or off-white tablets after removing the coating. However, the tablets prepared by the prescription of Comparative Example 1 have loose tablets and cracks during the preparation process. Analysis shows that the amount of binder used in this prescription is small, the amount of lubricant used is large, and the mixing is not appropriate, resulting in uneven pressure distribution, resulting in loose tablets and cracks. The tablets prepared by the prescription of Comparative Example 2 have a content uniformity that exceeds the standard. Analysis shows that the amount of filler, disintegrant, and lubricant used in this prescription is too large, and the raw materials and auxiliary materials cannot be well mixed, so the best uniform effect cannot be achieved. Examples 2-10 are preferred embodiments of this scheme, including the types and proportions of auxiliary materials, all of which are most preferred. For example, a more suitable ratio of lactose and microcrystalline cellulose is used as a mixed filler, and a disintegrant and lubricant are added by internal and external addition, so that over-lubrication and loose tablet cracking are not easily occurred during mixing. The resulting tablets have better compressibility. The overall combination of the above conditions allows the tablets of the compound of Formula I to achieve optimal results during the preparation process.

[0200] Example 12 Investigation of Related Substances in Different Prescriptions

[0201] Table 4 Investigation of related substances in the tablets of compound of formula I

[0202] As can be seen from the above results, the tablets obtained from Examples 2, 6, 7, 9 and 10 and Comparative Examples 4, 5 and 6, the related substances (RRT0.82, RRT0.95 / 0.96) did not increase significantly, while the tablets obtained from the Comparative Example 3 prescription, the related substances (RRT0.82, RRT0.95 / 0.96) increased significantly. The reason may be that the raw material of the compound of formula I has a heat-sensitive characteristic, and the addition of granulation liquid during the wet granulation process and the drying process after granulation cause the raw material of the compound of formula I to be unstable and increase impurities. The inventor subsequently investigated the related substances of the tablets obtained from Examples 3-5 and 8 prescriptions, and also found that the related substances (RRT0.82, RRT0.95 / 0.96) did not increase significantly. Example 2-10 is a preferred embodiment in this scheme, and dry granulation is used to fully reduce the impact of related substances in the preparation process.

[0203] Example 13 Investigation of the Dissolution Medium's Discrimination Ability

[0204] The dissolution behaviors of finished drug products containing a certain proportion of crystalline API and amorphous API in pH 6.8 medium were compared to investigate the discriminatory power of pH 6.8 medium on different finished drug products.

[0205] Dissolution test: The compound of Formula I of the present invention was subjected to a dissolution test in 900 ml of phosphate buffer at pH 6.8 using the paddle method (2020 edition, Part IV, 0931, Method 2) at a speed of 75 rpm. The results are shown in Table 5.

[0206] Table 5 Investigation of the discrimination ability of dissolution media

[0207] As can be seen from the above results and Figure 3, the tablets obtained from the prescription of Example 2 dissolve well in a phosphate buffer of pH 6.8, with a dissolution rate of more than 43.0% within 15 minutes, more than 60.0% within 30 minutes, more than 70.0% within 60 minutes, and substantially complete dissolution within 120 minutes. However, the prescription of Comparative Example 6 contains a certain proportion of Form I, and therefore, the dissolution rate within 60 minutes fails to reach 70.0%, and the dissolution within 120 minutes is incomplete. It can be seen that the dissolution rate of the finished preparation containing a certain proportion of Form I and the finished preparation of the amorphous raw material in a pH 6.8 medium, i.e., a pH 6.8 phosphate buffer, is significantly different. This further demonstrates that the use of a pH 6.8 phosphate buffer has a certain ability to distinguish finished preparations.

[0208] Example 14 Multi-media Dissolution Investigation

[0209] Tablets of the compound of Formula I prepared in Examples 2, 6, 7, 9, 10, Comparative Example 2, 4, and 5 were subjected to dissolution testing. Samples were taken at 5, 10, 15, 20, 30, 45, 60, 90, and 120 minutes, and the average cumulative percentage of dissolution was calculated. The dissolution test results are shown in Tables 6 and 7.

[0210] Table 6 Dissolution test of the compound of formula I tablets (pH 6.8, pH 1.0)

[0211] Table 7 Dissolution of Formula I Compound Tablets (pH 4.5, Water)

[0212] From the above results, it can be seen that the tablets obtained by the prescriptions of Examples 2, 6, 7, 9 and 10 dissolve well in phosphate buffer at pH 6.8, with more than 43.0% dissolved within 15 minutes, more than 60.0% dissolved within 30 minutes, and more than 70.0% dissolved within 60 minutes. Furthermore, the tablets dissolve well in multiple media (pH 1.0, pH 4.5, pH 6.8 and purified water), and are basically completely dissolved within 120 minutes, showing excellent solubility.

[0213] The tablets obtained from the prescription of Comparative Example 2 were dissolved in multiple media (pH 1.0, pH 4.5, pH 6.8 and purified water). Normal dissolution was maintained before 30 minutes, the dissolution time was prolonged after 30 minutes, and it could not be completely dissolved within 120 minutes. Analysis showed that in this prescription, the amount of microcrystalline cellulose was too large, and the "bottoming" phenomenon gradually appeared in the later stage of dissolution. The microcrystals accumulated at the bottom of the dissolution cup, resulting in incomplete drug release, which had an adverse effect on drug dissolution.

[0214] The tablets obtained from the formulation in Comparative Example 4 took a long time to dissolve in multiple media (pH 1.0, pH 4.5, pH 6.8, and purified water), failing to dissolve completely within 120 minutes. Analysis revealed that the raw material particle size of the compound of Formula I in the formulation in Comparative Example 4 was relatively large, resulting in poor mixing uniformity of the formulation, which affected subsequent release.

[0215] In the formulations of Examples 2, 6, 7, 9, and 10, the raw material particle size of the compound of Formula I is appropriate, and the formulation type and dosage are within the preferred range. Therefore, the dissolution in multiple media (pH 1.0, pH 4.5, pH 6.8, and purified water) is good.

[0216] Example 15 Stability Study

[0217] The samples used in the stability test (tablets of the compound of formula I prepared in Examples 2, 6, 7, 9, 10 and Comparative Example 5) used "polyvinyl chloride / polyvinylidene chloride solid pharmaceutical composite hard tablet + pharmaceutical aluminum foil (plain aluminum)" as the inner packaging and "polyester / aluminum / polyethylene pharmaceutical packaging composite film" as the outer packaging.

[0218] An accelerated stability test was conducted under the proposed packaging conditions. The samples were placed at 40℃±2℃, 75%±5%RH for 3 months, and no significant changes were found in the test items.

[0219] Table 8 Accelerated test stability data

[0220] As can be seen from the above results, the tablets obtained by the prescriptions of Examples 2, 6, 7, 9 and 10 were observed under accelerated test conditions (40°C ± 2°C, 75% ± 5% RH) for 3 months, and the properties, content, isomers, dissolution, impurities, moisture and crystal form test items did not change significantly. In addition, the moisture content of the tablets obtained by the prescriptions of Examples 2, 6, 7, 9 and 10 was controlled to be no more than 5.0%, and the dissolution performance was not affected. At the same time, it can be seen that under long-term storage, the lower the moisture content, the higher the dissolution performance (moisture content: Example 2> Example 9> Example 10, dissolution performance: Example 2< Example 9< Example 10).

[0221] As shown in FIG4 , the dissolution rate of the tablets obtained from the prescription of Comparative Example 5 gradually decreased with the passage of time. Analysis showed that when the moisture content of the tablets was too high, the tablets gradually became "hardened" during storage, which in turn affected the dissolution of the preparation and caused a decrease in dissolution rate.

[0222] In summary, the composition of the compound of formula I prepared in this scheme has excellent preparation quality, no sticking, loosening, or cracking, good dissolution performance, good stability, and good dissolution performance and stability even after long-term storage, which meets the medicinal effect. The preparation process is simple to operate and is suitable for industrial production.

[0223] Example 16

[0224] The tablets used in this example were prepared according to the prescription and preparation method of Example 2.

[0225] In order to verify the therapeutic effect of the Chinese medicine composition of the present invention, the present invention carried out a clinical study using the compound of formula I tablets prepared in Example 2 of the present invention as the test drug. The research process and results are as follows:

[0226] 1. Relevant standards

[0227] 1.1 Diagnostic criteria

[0228] 1.1.1 Western medicine disease diagnosis

[0229] Refer to the "Diagnosis and Treatment Plan for New Coronavirus Infection (Trial Tenth Edition)", there is epidemiological history and clinical manifestations, and it meets the etiological evidence (positive nucleic acid test for new coronavirus pneumonia or positive antigen test).

[0230] Disease classification refers to the "Diagnosis and Treatment Plan for Novel Coronavirus Infection (Trial Tenth Edition)" and is divided into mild, common, severe and critical types.

[0231] 1.2 Inclusion criteria

[0232] (1) Those who test positive for COVID-19 nucleic acid or antigen;

[0233] (2) According to the classification standards of the "Diagnosis and Treatment Plan for Novel Coronavirus Infection (Trial Tenth Edition)", it is classified as mild.

[0234] (3) age 18–65 years (inclusive);

[0235] (4) Those who have signed the informed consent form.

[0236] Exclusion criteria:

[0237] (1) Patients with severe underlying diseases or acute exacerbation of chronic diseases, such as acute heart failure.

[0238] (2) Female subjects who are pregnant, breastfeeding or lactating;

[0239] (3) Suffering from diseases that affect the duration of symptoms, such as bronchopneumonia, chronic lung abscess, chronic cough for more than 8 weeks, chronic pharyngitis with cough, etc.

[0240] 1.3 Withdrawal and Dropout of Cases

[0241] Case withdrawal or dropout refers to cases in which patients are unwilling to continue participating in the clinical trial or are unable to complete the full course of treatment as required after enrollment.

[0242] Handling of withdrawals and dropouts: Investigators should contact subjects through home visits, phone calls, letters, and other methods, record the last treatment date, and complete all assessment items that can be completed. They should also understand the reason for withdrawal and record it truthfully in the case report form. Observational data on all withdrawals and dropouts should be retained.

[0243] 2. Case sources: The First Affiliated Hospital of Guangzhou Medical University and several other clinical research centers nationwide.

[0244] 3. Intervention and grouping:

[0245] All patients in the compound of formula I group took the compound of formula I tablets prepared in Example 2, with each tablet having a strength of 200 mg, 3 times a day, 2 tablets each time.

[0246] After enrollment, all patients were diagnosed and treated in accordance with the "Diagnosis and Treatment Plan for Pneumonia Caused by New Coronavirus Infection (Trial Ninth Edition)" to ensure basic treatment for patients, but no antiviral treatment was performed.

[0247] 4. Statistical methods

[0248] Measurement data were tested for normality. Data that conformed to a normal distribution were described using the mean ± standard deviation, while those that did not conform to a normal distribution were described using the median and quartiles. Efficacy comparisons were performed using paired t-tests for normally distributed data and nonparametric tests for nonnormally distributed data. Enumeration data were tested using the chi-square test.

[0249] 5. Test results

[0250] Table 9 Main statistical analysis and sensitivity analysis (ITT) of time to clinical recovery (11 symptoms)

[0251] *Sensitivity analysis using study stratification factors.

[0252] As shown in Table 9, based on the ITT analysis, 1,107 of the 1,359 subjects (81.5%) achieved clinical recovery, including 538 (79.2%) in the placebo group and 569 (83.7%) in the compound of Formula I group. The median time to sustained clinical recovery from all 11 symptoms was 251.02 hours (95% CI: 246.48, 268.13) in the compound of Formula I group and 271.33 hours (95% CI: 264.72, 294.20) in the placebo group, respectively. Using the subjects' actual baseline clinical classification and whether they were in the severe / critical high-risk population as stratification factors, a stratified log-rank test was used to compare the difference in median time to sustained clinical recovery between the two groups. The difference was statistically significant (P = 0.002). The time from 11 symptoms to sustained clinical recovery in the Formula I group was 20.31 hours shorter than that in the placebo group. It can be concluded that the Formula I group was superior to the placebo group in shortening the time from 11 symptoms to sustained clinical recovery. It can be seen that the composition prepared by the present invention can achieve ideal clinical therapeutic effects when it meets the dissolution behavior conditions of the present invention.

[0253] In summary, the compound composition of formula I prepared in this scheme has excellent preparation quality, no sticking, loosening, or cracking, good dissolution performance, good stability, and meets the medicinal effect. The preparation process is simple to operate and is suitable for industrial production.

[0254] The above embodiments are preferred implementation modes of the present invention, but the implementation modes of the present invention are not limited to the above embodiments. Any other changes, modifications, substitutions, combinations, and simplifications that do not deviate from the spirit and principles of the present invention should be considered as equivalent replacement methods and are included in the scope of protection of the present invention.

Claims

1. A pharmaceutical composition, characterized in that The invention comprises a compound of formula I or a pharmaceutically acceptable salt thereof and excipients; the excipients include one or more of a filler, a binder, a glidant, a disintegrant and a lubricant; the filler is one or more of lactose, anhydrous lactose, microcrystalline cellulose, mannitol or starch; the binder is one or more of hydroxypropyl methylcellulose, hydroxypropyl cellulose, povidone, hydroxyethyl cellulose, sodium carboxymethyl cellulose or polyvinyl alcohol; the glidant is one or more of colloidal silicon dioxide, talc or micro-powdered silica gel; the disintegrant is low-substituted hydroxypropyl cellulose, cross-linked carboxymethyl cellulose, One or more of sodium cellulose, sodium carboxymethyl starch or cross-linked polyvinylpyrrolidone; the lubricant is one or more of magnesium stearate, calcium stearate or sodium stearyl fumarate; the mass ratio of the compound of formula I to the filler is 1:1.0-2.5, the mass ratio of the compound of formula I to the binder is 1:0.01-0.05, the mass ratio of the compound of formula I to the glidant is 1:0.01-0.03, the mass ratio of the compound of formula I to the disintegrant is 1:0.10-0.30, and the mass ratio of the compound of formula I to the lubricant is 1:0.01-0.10; 2. A pharmaceutical composition, characterized in that The invention comprises a compound of formula I or a pharmaceutically acceptable salt thereof and excipients; the excipients include one or more of a filler, a binder, a glidant, a disintegrant and a lubricant; the filler is one or more of lactose, anhydrous lactose, microcrystalline cellulose, mannitol or starch; the binder is one or more of hydroxypropyl methylcellulose, hydroxypropyl cellulose, povidone, hydroxyethyl cellulose, sodium carboxymethyl cellulose or polyvinyl alcohol; the glidant is one or more of colloidal silicon dioxide, talc or micro-powdered silica gel; the disintegrant is low-substituted hydroxypropyl cellulose, cross-linked sodium carboxymethyl cellulose, carboxymethyl starch The lubricant is one or more of magnesium stearate, calcium stearate or sodium stearyl fumarate; the mass ratio of the compound of formula I to the filler is 1:1.0-2.5, the mass ratio of the compound of formula I to the binder is 1:0.01-0.05, the mass ratio of the compound of formula I to the glidant is 1:0.01-0.03, the mass ratio of the compound of formula I to the disintegrant is 1:0.10-0.30, and the mass ratio of the compound of formula I to the lubricant is 1:0.01-0.10; the moisture content of the pharmaceutical composition does not exceed 5.0%; 3. A pharmaceutical composition, characterized in that The invention comprises a compound of formula I or a pharmaceutically acceptable salt thereof and excipients; the excipients include one or more of a filler, a binder, a glidant, a disintegrant and a lubricant; the filler is one or more of lactose, anhydrous lactose, microcrystalline cellulose, mannitol or starch; the binder is one or more of hydroxypropyl methylcellulose, hydroxypropyl cellulose, povidone, hydroxyethyl cellulose, sodium carboxymethyl cellulose or polyvinyl alcohol; the glidant is one or more of colloidal silicon dioxide, talc or micro-powdered silica gel; the disintegrant is one or more of low-substituted hydroxypropyl cellulose, cross-linked sodium carboxymethyl cellulose, sodium carboxymethyl starch or cross-linked povidone; the lubricant is one or more of magnesium stearate, calcium stearate or sodium stearyl fumarate; the pharmaceutical composition has a solubility of 70.0% or more at 60 minutes under the condition that a phosphate buffer with a pH of 6.8 is used as a dissolution medium; 4. The pharmaceutical composition according to any one of claims 1 to 3, characterized in that The filler is a mixture of lactose and microcrystalline cellulose, the binder is hypromellose, the glidant is colloidal silicon dioxide, the disintegrant is cross-linked sodium carboxymethyl cellulose, and the lubricant is magnesium stearate.

5. The pharmaceutical composition according to claim 3, characterized in that The mass ratio of the compound of formula I to the filler is 1:1.0-2.5, the mass ratio of the compound of formula I to the binder is 1:0.01-0.05, the mass ratio of the compound of formula I to the glidant is 1:0.01-0.03, the mass ratio of the compound of formula I to the disintegrant is 1:0.10-0.30, and the mass ratio of the compound of formula I to the lubricant is 1:0.01-0.

10.

6. The pharmaceutical composition according to any one of claims 1 to 3, characterized in that The mass ratio of the compound of formula I to the filler is 1:1.5-2.0, the mass ratio of the compound of formula I to the binder is 1:0.02-0.04, the mass ratio of the compound of formula I to the glidant is 1:0.012-0.020, the mass ratio of the compound of formula I to the disintegrant is 1:0.15-0.25, and the mass ratio of the compound of formula I to the lubricant is 1:0.02-0.06; preferably, the mass ratio of the compound of formula I to the lubricant is 1:0.02-0.05; preferably, the mass ratio of the compound of formula I to the filler is 1:1.75, the mass ratio of the compound of formula I to the binder is 1:0.03, the mass ratio of the compound of formula I to the glidant is 1:0.015, the mass ratio of the compound of formula I to the disintegrant is 1:0.18 or 1:0.24, and the mass ratio of the compound of formula I to the lubricant is 1:0.03 or 1:0.

06.

7. The pharmaceutical composition according to claim 2, characterized in that The moisture content of the pharmaceutical composition is 1.0% to 5.0%, preferably 3.0% to 5.0%.

8. The pharmaceutical composition according to claim 3, characterized in that The dissolution rate of the pharmaceutical composition reaches more than 43.0% in 15 minutes when a phosphate buffer solution with a pH of 6.8 is used as a dissolution medium.

9. The pharmaceutical composition according to claim 3, characterized in that The dissolution rate of the pharmaceutical composition reaches more than 60.0% in 30 minutes under the condition that the phosphate buffer with pH 6.8 is used as the dissolution medium.

10. The pharmaceutical composition according to any one of claims 1 to 3, characterized in that The disintegrant is prepared by internal and external addition, and the lubricant is prepared by internal and external addition.

11. The pharmaceutical composition according to claim 10, characterized in that When the disintegrant is prepared by the internal and external addition method, the mass ratio of the internal and external disintegrant is 1:0.5-3; preferably, the mass ratio of the internal and external disintegrant is 1:0.8-2; more preferably, the mass ratio of the internal and external disintegrant is 1:

1.

12. The pharmaceutical composition according to claim 10, characterized in that When the lubricant is prepared by the internal and external addition method, the mass ratio of the internal lubricant to the external lubricant is 1:0.5-3; preferably, the mass ratio of the internal lubricant to the external lubricant is 1:0.8-2; more preferably, the mass ratio of the internal lubricant to the external lubricant is 1:

1.

13. The pharmaceutical composition according to claim 4, characterized in that The mass ratio of lactose to microcrystalline cellulose is 1:0.5-5; preferably, the mass ratio of lactose to microcrystalline cellulose is 1:0.6-3; more preferably, the mass ratio of lactose to microcrystalline cellulose is 1:1-3; most preferably, the mass ratio of lactose to microcrystalline cellulose is 1:0.69, 1:0.98 or 1:

2.

14. The pharmaceutical composition according to any one of claims 1 to 3, characterized in that The particle size of the compound of formula I is D10≤8μm, D50≤25μm, and D90≤160μm; preferably, the particle size of the compound of formula I is D10≤5μm, D50≤20μm, and D90≤150μm; more preferably, the particle size of the compound of formula I is D10≤3μm, D50≤15μm, and D90≤140μm.

15. The pharmaceutical composition according to any one of claims 1 to 3, characterized in that The compound of formula I is in amorphous form.

16. A pharmaceutical composition, characterized in that Contains the following ingredients: ; The particle size of the compound of formula I is D10≤3μm, D50≤15μm, D90≤140μm; the compound of formula I is in an amorphous form.

17. A pharmaceutical composition, characterized in that Contains the following ingredients: ; The particle size of the compound of formula I is D10≤3μm, D50≤15μm, D90≤140μm; the compound of formula I is in an amorphous form.

18. A pharmaceutical composition, characterized in that Contains the following ingredients: ; The particle size of the compound of formula I is D10≤3μm, D50≤15μm, D90≤140μm, and the compound of formula I is in an amorphous form.

19. A pharmaceutical composition, characterized in that Contains the following ingredients: ; The particle size of the compound of formula I is D10≤3μm, D50≤15μm, D90≤140μm; the compound of formula I is in an amorphous form; the moisture content of the pharmaceutical composition is 3.0% to 5.0%.

20. A pharmaceutical composition, characterized in that Contains the following ingredients: ; The particle size of the compound of formula I is D10≤3μm, D50≤15μm, D90≤140μm; the compound of formula I is in an amorphous form; the moisture content of the pharmaceutical composition is 3.0% to 5.0%.

21. A pharmaceutical composition, characterized in that Contains the following ingredients: ; The particle size of the compound of formula I is D10≤3μm, D50≤15μm, D90≤140μm; the compound of formula I is in an amorphous form; the moisture content of the pharmaceutical composition is 3.0% to 5.0%.

22. A pharmaceutical composition, characterized in that Contains the following ingredients: ; The particle size of the compound of formula I is D10≤3μm, D50≤15μm, D90≤140μm; the compound of formula I is in an amorphous form; the solubility of the pharmaceutical composition reaches more than 70.0% at 60 minutes under the condition of pH 6.8 phosphate buffer as the dissolution medium.

23. A pharmaceutical composition, characterized in that Contains the following ingredients: ; The particle size of the compound of formula I is D10≤3μm, D50≤15μm, D90≤140μm; the compound of formula I is in an amorphous form; the solubility of the pharmaceutical composition reaches more than 70.0% at 60 minutes under the condition of pH 6.8 phosphate buffer as the dissolution medium.

24. A pharmaceutical composition, characterized in that Contains the following ingredients: ; The particle size of the compound of formula I is D10≤3μm, D50≤15μm, D90≤140μm; the compound of formula I is in an amorphous form; the solubility of the pharmaceutical composition reaches more than 70.0% at 60 minutes under the condition of pH 6.8 phosphate buffer as the dissolution medium.

25. The method for preparing the pharmaceutical composition according to any one of claims 1 to 24, characterized in that: The preparation method is a non-wet granulation preparation technology.

26. A pharmaceutical tablet, characterized in that The pharmaceutical tablet comprises a tablet core and a coating coated on the outside of the tablet core, and the tablet core is composed of the pharmaceutical composition according to any one of claims 1 to 24.

27. The pharmaceutical tablet according to claim 26, characterized in that The coating is a gastric soluble film coating.

28. The pharmaceutical tablet according to claim 27, characterized in that The mass of the coating is 0.5%-10% of the mass of the tablet core, preferably 1%-6%, more preferably 3%.

29. Use of the pharmaceutical composition according to any one of claims 1 to 24 or the pharmaceutical tablet according to any one of claims 26 to 28 in the preparation of a product for preventing, alleviating or treating infection or disease caused by the new coronavirus.

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