Pharmaceutical composition for novel coronavirus and method for preparing the same

Abstract

The present invention provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, and an auxiliary agent comprising one or more fillers, binders, flow promoters, disintegrants, and lubricants, wherein the pharmaceutical composition is prepared for formulation processes, has excellent formulation properties, stability and dissolution, and meets pharmaceutical standards. TIFF2026516804000057.tif46170

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical preparations, and particularly to a pharmaceutical composition for novel coronavirus and a method for preparing the same.

Background Art

[0002] Coronavirus is a single-stranded positive-strand RNA virus family belonging to the order Nidovirales and having a viral envelope. The Coronaviridae family includes pathogens of many animal species such as humans, horses, cows, pigs, chickens, cats, monkeys, etc., and has been known for more than 60 years. For example, the isolation of the prototype strain JHM of mouse coronavirus was reported in 1949. Coronaviruses often cause mild to moderate upper respiratory tract diseases in humans and are common viruses whose name is derived from the crown-like protrusions present on the surface of the envelope. The 2003 SARS epidemic led to the emergence of SARS-CoV-1, a pathogen causing severe respiratory infections. Subsequently, with the rapid increase in coronavirus studies, two other human coronaviruses showing mild pathogenicity, such as HCoV-NL63 and HCoV-HKU1, were discovered. MERS-CoV, which emerged in 2012, is one member belonging to the group of pathogens causing severe respiratory infections. Although SARS-CoV-1 and MERS-CoV are very lethal pathogens, the public health, social, and economic losses they caused are negligible compared to SARS-CoV-2. SARS-CoV-2 is a newly emerged human CoV pathogen that causes COVID-19. This has caused the COVID-19 pandemic, which is second only to the 1918 influenza pandemic, and has had a devastating impact worldwide. As of April 2023, the number of COVID-19 cases worldwide has exceeded 680 million, and the number of deaths has reached more than 6.85 million. In order to reduce the devastating damage caused by COVID-19 to public health, society, and the economy, the early discovery of appropriate treatment methods is extremely important.

[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, containing at least six open reading frames (ORFs). The first ORF (ORF1a / b) is directly translated into two polyproteins, pp1a and pp1ab. These polyproteins are processed into 16 non-structural proteins by 3C-like proteases (3CLpro) (also known as major proteases (Mpro)). These non-structural proteins are involved in the production of subgenomic RNAs encoding four structural proteins: envelope proteins, membrane proteins, spike proteins, and nucleocapsid proteins, as well as other accessory proteins. Therefore, 3C-like proteases are known to play a crucial role in the life cycle of coronaviruses.

[0004] 3C-like proteases are cysteine ​​proteases involved in most of the cleavage of precursor polyproteins. The active 3C-like protease is a homodimer of two protomers, each possessing a Cys-His dimer located between domains I and II. 3C-like proteases are conserved among coronaviruses, and their substrates share several common characteristics across different coronaviruses. Because 3C-like proteases lack human homologs, they are ideal targets for antiviral drugs.

[0005] Paxlovid is an oral anti-COVID-19 drug developed by Pfizer, consisting of 300 mg of nilmatrelvir (two 150 mg tablets) and one 100 mg tablet of ritonavir. The Paxlovid package insert states that the nilmatrelvir tablets are composed of nilmatrelvir, microcrystalline cellulose, lactose monohydrate, cross-linked carboxymethylcellulose sodium, colloidal silica, stearyl fumarate sodium, hydroxypropyl methylcellulose, etc.

[0006] Lelitrelvir tablets (trade name: Le Rui Ling) are an oral anti-COVID-19 drug developed by Guangdong Raynovent Biotech Co., Ltd. It is a 3C-like protease inhibitor that does not require concomitant use with ritonavir and is currently sold in China.

[0007] Chinese patent ZL202211095326.8 discloses a series of ketoamide derivatives, including the compound of formula (I), that have excellent activity against the anti-coronavirus Mpro protease. [ka]

[0008] Chinese patent ZL202211095326.8 discloses in vitro studies of this series of ketoamide compounds, demonstrating potent anti-COVID-19 activity and favorable pharmacokinetics. However, currently, only activity studies of these compounds and their pharmaceutically acceptable salts have been conducted, and there are no reports on pharmaceutical compositions or formulations containing these compounds as active ingredients. Therefore, further investigation and application of these compounds are urgently needed. [Overview of the Initiative] [Problems that the invention aims to solve]

[0009] The technical problem that this invention aims to solve is to overcome the shortcomings of the prior art and provide a pharmaceutical composition for the novel coronavirus and a method for preparing the same. [Means for solving the problem]

[0010] To achieve the above objectives, the present invention proposes a pharmaceutical composition comprising the compound of formula (I) or a pharmaceutically acceptable salt thereof, which has good feasibility in the formulation process, high stability, can treat COVID-19 by oral administration, is easy to prepare, and is suitable for industrial production, through numerous experimental studies and improvements on the formulations and processes of existing formulations.

[0011] A specific technical means of the present invention is a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and an auxiliary agent, wherein the auxiliary agent comprises one or more of a filler, a binder, a flow promoter, a disintegrant, and a lubricant, the filler being one or more of lactose, anhydrous lactose, microcrystalline cellulose, mannitol, or starch, the binder being one or more of hydroxypropyl methylcellulose, hydroxypropyl cellulose, povidone, hydroxyethyl cellulose, sodium carboxymethylcellulose, or polyvinyl alcohol, the flow promoter being one or more of colloidal silica, talc, or micronized silica gel, and the disintegrant being low-substituted hydroxypropyl The pharmaceutical composition comprises one or more of propyl cellulose, cross-linked carboxymethylcellulose sodium, carboxymethyl starch sodium, or cross-linked povidone, and one or more of magnesium stearate, calcium stearate, or stearyl fumarate sodium as a lubricant, with a mass ratio of the compound of formula (I) to the filler being 1:1.0 to 2.5, a mass ratio of the compound of formula (I) to the binder being 1:0.01 to 0.05, a mass ratio of the compound of formula (I) to the flow promoter being 1:0.01 to 0.03, a mass ratio of the compound of formula (I) to the disintegrant being 1:0.10 to 0.30, and a mass ratio of the compound of formula (I) to the lubricant being 1:0.01 to 0.10.

[0012] Unless otherwise specified, throughout the context of this invention, the mass of the compound of formula (I) above refers to the mass of the compound of formula (I) itself, or the mass of the compound of formula (I) in a pharmaceutical composition of the compound of formula (I). [ka]

[0013] Alternatively, the present invention relates to a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and an auxiliary agent, wherein the auxiliary agent comprises one or more of a filler, a binder, a flow promoter, a disintegrant, and a lubricant, the filler being one or more of lactose, anhydrous lactose, microcrystalline cellulose, mannitol, or starch, the binder being one or more of hydroxypropyl methylcellulose, hydroxypropyl cellulose, povidone, hydroxyethyl cellulose, sodium carboxymethylcellulose, or polyvinyl alcohol, the flow promoter being one or more of colloidal silica, talc, or micronized silica gel, and the disintegrant being low-substituted hydroxypropyl cellulose, cross-linked carboxymethylcellulose. The present invention provides a pharmaceutical composition comprising one or more of sodium methylcellulose, sodium carboxymethyl starch, or cross-linked povidone, one or more of magnesium stearate, calcium stearate, or sodium stearyl fumarate as a lubricant, a mass ratio of the compound of formula (I) to the filler being 1:1.0 to 2.5, a mass ratio of the compound of formula (I) to the binder being 1:0.01 to 0.05, a mass ratio of the compound of formula (I) to the flow promoter being 1:0.01 to 0.03, a mass ratio of the compound of formula (I) to the disintegrant being 1:0.10 to 0.30, a mass ratio of the compound of formula (I) to the lubricant being 1:0.01 to 0.10, and a water content of the pharmaceutical composition being less than 5.0%. [ka]

[0014] Alternatively, the present invention provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and an auxiliary agent, wherein the auxiliary agent comprises one or more of a filler, a binder, a flow promoter, a disintegrant, and a lubricant, the filler being one or more of lactose, anhydrous lactose, microcrystalline cellulose, mannitol, or starch, the binder being one or more of hydroxypropyl methylcellulose, hydroxypropyl cellulose, povidone, hydroxyethyl cellulose, sodium carboxymethylcellulose, or polyvinyl alcohol, the flow promoter being one or more of colloidal silica, talc, or micronized silica gel, the disintegrant being one or more of low-substituted hydroxypropyl cellulose, cross-linked sodium carboxymethylcellulose, sodium carboxymethyl starch, or cross-linked povidone, and the lubricant being one or more of magnesium stearate, calcium stearate, or sodium stearyl fumarate, characterized in that the pharmaceutical composition exhibits an elution rate of 70.0% or more in 60 mins when a pH 6.8 phosphate buffer is used as the elution medium. [ka]

[0015] The present invention provides a pharmaceutical composition for the novel coronavirus and a method for preparing the same, in which the effect is achieved by selecting an appropriate adjuvant for the formulation by combining the physicochemical properties of the raw materials and the results of suitability tests of the adjuvant. The type of formulation and / or the amount of formulation greatly affects the formulation process and formulation quality. Adjuvant used in the present invention includes fillers, wetting agents, binders, disintegrants, lubricants, etc. According to the present invention, a pharmaceutical composition containing the compound of formula (I) is introduced with a filler containing one or more of lactose, anhydrous lactose, microcrystalline cellulose, mannitol, or starch, preferably a mixture of lactose and microcrystalline cellulose, thereby ensuring that the oral formulation of the compound of formula (I) meets the quality or volume criteria for solid formulations. According to the present invention, a pharmaceutical composition containing the compound of formula (I) is introduced with a binder containing one or more of hydroxypropyl methylcellulose, hydroxypropyl cellulose, povidone, hydroxyethylcellulose, carboxymethylcellulose sodium, or polyvinyl alcohol, preferably hydroxypropyl methylcellulose, thereby enabling the binding of the active pharmaceutical ingredient and the adjuvant, and in the case of hydroxypropyl methylcellulose, its surface activity helps to promote the dissolution of the pharmaceutical. According to the present invention, a flow promoter containing one or more of colloidal silica, talc, or micronized silica gel, preferably colloidal silica, is introduced into a pharmaceutical composition containing a compound of formula (I). This reduces adhesion and friction between granules and between tablets and mold cavity walls, thereby improving the fluidity of the granules and making the tablet surface smooth and beautiful.According to the present invention, a pharmaceutical composition containing the compound of formula (I) is introduced with a disintegrant comprising one or more of low-substituted hydroxypropylcellulose, cross-linked carboxymethylcellulose sodium, carboxymethyl starch sodium, or cross-linked povidone, preferably cross-linked carboxymethylcellulose sodium. This allows the tablet to rapidly disintegrate into fine granules in the digestive fluid, enabling the functional component to dissolve and be absorbed quickly and exert its effects. When the disintegrant is cross-linked carboxymethylcellulose sodium, adding either an intragranular or extragranular disintegrant does not affect the brittleness of the tablet. According to the present invention, a pharmaceutical composition containing the compound of formula (I) is introduced with a lubricant comprising one or more of magnesium stearate, calcium stearate, or stearyl fumarate sodium, preferably magnesium stearate. This makes it possible to make the pressure distribution applied during tableting and the density of the tablet uniform.

[0016] The present invention also provides a pharmaceutical composition against the novel coronavirus and a method for preparing the same, the effect of which can be achieved by controlling the amount of formulation adjuvants. Specifically, increasing the amount of adjuvants contributes to improved compressibility and reduced adhesion, but it also increases the weight of the tablets, which is undesirable for administration to patients. Furthermore, it negatively affects the performance of the formulation, for example, too much disintegrant can cause the tablets to become excessively lubricated, delaying dissolution. Unless otherwise specified, the amounts of active ingredients in the formulations of the present invention are all calculated based on the compound of formula (I) (on a dry basis / purified basis). When a corresponding auxiliary agent is selected, the amounts of this auxiliary agent are as follows: the mass ratio of the compound of formula (I) to the filler is 1:1.0 to 2.5, the mass ratio of the compound of formula (I) to the binder is 1:0.01 to 0.05, the mass ratio of the compound of formula (I) to the flow promoter is 1:0.01 to 0.03, the mass ratio of the compound of formula (I) to the disintegrant is 1:0.10 to 0.30, and the mass ratio of the compound of formula (I) to the lubricant is 1:0.01 to 0.10. Preferably, when a corresponding auxiliary agent is selected, the amount of the auxiliary agent is such that the mass ratio of the compound of formula (I) to the filler is 1:1.5 to 2.0, the mass ratio of the compound of formula (I) to the binder is 1:0.02 to 0.04, the mass ratio of the compound of formula (I) to the flow promoter is 1:0.012 to 0.020, the mass ratio of the compound of formula (I) to the disintegrant is 1:0.15 to 0.25, and the mass ratio of the compound of formula (I) to the lubricant is 1:0.02 to 0.06. Within the range of preferred ratios described above, any one small range can achieve similar technical effects. For example, as described above, one preferred range of lubricant ratios may be 1:0.02 to 0.05. More preferably, if a corresponding auxiliary agent is selected, the amount of this auxiliary agent is such that 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 flow promoter 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.

[0017] Oral formulations are absorbed into the body only if the active drug component is dissolved in vivo; therefore, after preparation, dissolution rate tests in vivo and in vitro are necessary. There is a certain correlation between the in vivo and in vitro dissolution characteristics of a drug, and the in vitro dissolution characteristics of a drug can reflect the dissolution behavior of the formulation in vivo. By using a highly discriminative dissolution rate measurement method, the preparation quality of the formulation can be objectively evaluated, and differences in the quality of pharmaceutical formulations can be distinguished from aspects such as the physicochemical properties of the active pharmaceutical ingredient, the preparation formula, and the preparation process, thereby improving the safety and clinical efficacy of the drug. In oral pharmaceutical compositions such as tablets, the dissolution rate of the active ingredient greatly affects its efficacy and safety, so dissolution standards have been established in various countries. For example, dissolution test methods are included in the pharmacopoeias of China, Japan, the United States, and European countries, and various dissolution test solutions (hereinafter also referred to as test solutions or dissolution solutions) are used in dissolution tests. These dissolution test solutions are adjusted to a pH range of 1 to 8. For example, the Chinese Pharmacopoeia (2020 edition, Part IV, 0931) specifies the amount of buffer solution to be eluted, using 250 ml of 0.2 mol / L sodium phosphate solution (adjusting the pH to 6.8 with 2 mol / L hydrochloric acid solution or 2 mol / L sodium hydroxide solution as needed). The Japanese Pharmacopoeia's measurement method specifies strongly acidic elution solutions (e.g., Solution 1 described in the Japanese Pharmacopoeia, 0.1N hydrochloric acid aqueous solution), pH 3-5 elution solutions (e.g., acetate-sodium acetate buffer, McIlvaine buffer), pH 6.8 elution solutions (e.g., Solution 2 described in the Japanese Pharmacopoeia, pH 6.8 phosphate buffer), and water. When performing dissolution tests using these elution solutions for oral formulations, good dissolution properties are required. Currently, similar elution media are disclosed in various national pharmacopoeias, but the dissolution time and corresponding dissolution rate are not disclosed for specific compositions.

[0018] When using a phosphate buffer solution with a pH of 6.8 as the elution medium, it shows an elution rate of 70.0% or more in 60 minutes. Further, when using a phosphate buffer solution with a pH of 6.8 as the elution medium, it shows an elution rate of 43.0% or more in 15 minutes. Further, when using a phosphate buffer solution with a pH of 6.8 as the elution medium, it shows an elution rate of 60.0% or more in 30 minutes. A pharmaceutical composition against the novel coronavirus is provided. Further, in the case of the phosphate buffer solution with a pH of 6.8, it has a certain quality discrimination ability for the final preparation.

[0019] These elution test solutions can be prepared by the methods described in the pharmacopoeias of various countries, etc. When the elution test solution is a buffer solution, the pH of these elution test solutions is preferably within ±0.05 of the pH specified for each elution test solution.

[0020] In this specification, the measurement in the elution test can be carried out in accordance with the elution rate and release rate measurement method (Chinese Pharmacopoeia 2020 Edition, Fourth Part, General Rule 0931, Method 2). In this case, 900 ml of a phosphate buffer solution with a pH of 6.8 (prepared by mixing 250 ml of a 0.2 mol / L potassium dihydrogen phosphate solution with 112 ml of a 0.2 mol / L sodium hydroxide solution and then diluting to 1000 ml with water and uniformly mixing) is used as the elution medium, the rotation speed is 75 rpm, and the operation is carried out according to the specified method. Sampling is carried out after a predetermined time has elapsed.

[0021] The present invention also provides a pharmaceutical composition for the novel coronavirus, the effect of which is further achieved by controlling the water content, and a method for preparing the same. Here, the inventors have surprisingly discovered that water not only affects the quality of the formulation such as tablet forming in the formulation process, but also affects the performance of the formulation such as dissolution. Specifically, due to the inherent properties of the compound of formula (I), when the water content is too high, the "caking" phenomenon gradually occurs inside during storage, which further affects the dissolution of the formulation and the stability of long-term storage. However, the pharmacopoeias of China, the United States, Japan and the United Kingdom do not provide regulations regarding the water content of tablets. Therefore, the composition of the present invention is subject to stricter control of the water content than general formulations. Specifically, its water content is less than 5.0%, preferably 1.0% - 5.0%, more preferably 3.0% - 5.0%. Under such conditions, the composition containing the compound of formula (I) of the present invention is very stable under long-term storage conditions or accelerated storage conditions of 40°C / 75% relative humidity. For example, when the composition according to the present invention is stored under the conditions of 40°C ± 2°C and 75%RH ± 5%RH for 3 months, the dissolution change of this composition is small.

[0022] As used herein, the "water content" refers to the total amount of water present in the composition. The water here includes, in addition to the unbound water or "water" of any auxiliary agent that may be present as a raw material and / or any coating that may be present, a part of the bound water in the crystal structure of any auxiliary agent that may be present as a raw material and / or any coating that may be present. The percentage of the water content can be easily determined by those skilled in the art using the Karl Fischer technique. For the composition according to the present invention, when calculating its water content, its water content will never exceed 5.0%.

[0023] In the present invention, the moisture content of the composition of the present invention can be measured using a moisture measurement method (Chinese Pharmacopoeia 2020 Edition, Part IV, General Rule 0832, Method 1 (Karl Fischer method)). The present invention provides a pharmaceutical composition for novel coronavirus and a method for preparing the same, the effect of which is further achieved by specific preparation techniques. By selecting specific preparation techniques considering the inherent properties of the active pharmaceutical ingredient and auxiliaries, a formulation of superior quality and further superior stability can be obtained. The non-wet granulation preparation techniques employed in the present invention refer to formulation methods that do not use a wet granulation process and include dry granulation, fluidized bed one-step granulation, and direct compaction. Since the compound of formula (I) is sensitive to moisture and heat, a non-wet granulation preparation technique, preferably dry granulation, is employed, thereby avoiding the destabilization of the active pharmaceutical ingredient and the increase of impurities caused by the addition of granulation liquid and the drying process after granulation in the wet granulation process.

[0024] This invention provides a pharmaceutical composition against the novel coronavirus and a method for preparing the same, the effect of which is further achieved by controlling the particle size of the compound active pharmaceutical ingredient of formula (I). The particle size of the active pharmaceutical ingredient affects the feasibility of the formulation process and the dissolution of the product, and ultimately may affect in vivo dissolution; therefore, it is necessary to consider and control the particle size distribution of the active pharmaceutical ingredient. Generally, as the particle size decreases, the particle size becomes finer and more uniform, the specific surface area increases, the porosity increases, the adsorption is enhanced, the solubility improves, the affinity increases, the chemical reaction rate increases, and the dissolution rate of the drug improves. If the particle size is too large, mixing with the adjuvants becomes difficult, the uniformity of the formulation mixture deteriorates, and subsequent release is affected. Therefore, if the particle size of the active pharmaceutical ingredient is of an appropriate size, uniform mixing of the active pharmaceutical ingredient and the adjuvants is ensured, which not only contributes to the formation of the formulation but also improves its dissolution. When the particle size of the compound of formula (I) simultaneously satisfies D10 ≤ 8 μm, D50 ≤ 25 μm, and D90 ≤ 160 μm, there is no significant effect on the particle size distribution of the dried granules after dry granulation, and there is no significant effect on the elution curves of the obtained formulation in each elution medium (pH 1.0, pH 4.5, pH 6.8, purified water). Preferably, the particle size of the compound of formula (I) is D10 ≤ 5 μm, D50 ≤ 20 μm, D90 ≤ 150 μm, more preferably D10 ≤ 3 μm, D50 ≤ 15 μm, and D90 ≤ 140 μm.

[0025] The present invention provides a pharmaceutical composition against the novel coronavirus and a method for preparing the same, in which the effect is further achieved by a specific crystalline form, namely the crystalline form of the compound of formula (I). Furthermore, the crystalline form of the compound of formula (I) can optimize the dissolution properties of the resulting formulation, thereby exhibiting superior therapeutic effects in clinical treatment. The quality and therapeutic effect of solid oral formulations depend on the selection of the active pharmaceutical ingredient, the formulation design, and the manufacturing process of the pharmaceutical formulation. However, processing-induced phase transitions in the manufacturing process of pharmaceutical formulations are difficult to predict and control. Many pharmaceuticals exhibit polymorphism, and different crystalline forms can have different crystal habits, physicochemical properties such as melting point, density, stability, solubility, and dissolution rate, as well as powder properties such as bulk density, flowability, and compressibility. Therefore, the crystalline form of a pharmaceutical can affect the manufacturing process of the formulation and the pharmaceutical effect of the formulation in vivo and in vitro. Preferably, the crystalline form of the compound of formula (I) used in the present invention is the amorphous form of this compound, which has stable properties, good solubility, and a high dissolution rate, making it suitable for formulation development. Specifically, the X-ray powder diffraction pattern of this amorphous form lacks sharp diffraction peaks and has two characteristic peaks between 2θ angles of 5° to 15° and 15° to 25°, as shown in Figure 1.

[0026] This invention provides a pharmaceutical composition for the novel coronavirus and a method for preparing it, in which the effect is achieved by controlling the mass ratio of lactose and microcrystalline cellulose as fillers, and furthermore, by controlling the mass ratio of lactose and microcrystalline cellulose as fillers, the dissolution properties of the resulting formulation can be optimized, making it possible to exhibit a better therapeutic effect in clinical treatment. Based on the physicochemical properties of the raw materials and the results of compatibility tests of the auxiliary agents, a mixture of lactose and microcrystalline cellulose is selected as the filler. If the amount of microcrystalline cellulose is too large, a "bottom deposition" phenomenon may occur in the dissolution process, that is, microcrystals may be deposited at the bottom of the dissolution tank in the later stages of dissolution, resulting in incomplete release of the drug and adversely affecting the dissolution of the drug. To ensure the prepareability and performance of the resulting formulation, the mass ratio of lactose to microcrystalline cellulose is 1:0.5 to 5, preferably 1:0.6 to 3. Within the range of the preferred ratios described above, similar technical effects can be achieved in any small range. For example, the ratio range of the filler is preferably 1:1 to 3, and more preferably 1:0.69, 1:0.98, or 1:2.

[0027] This invention provides a pharmaceutical composition against the novel coronavirus in which the tableting performance of the formulation is basically achieved based on the above formulation composition. Although a very small number of tablets may crumble or break, this is within a reasonable range of manufacturing tolerance. To further reduce errors, this invention is achieved by further controlling the method and amount of addition of disintegrants and lubricants in the preparation process. Furthermore, by optimizing the method and amount of addition of disintegrants and lubricants in the preparation process, the dissolution properties of the resulting formulation can be optimized, resulting in a better therapeutic effect in clinical treatment. When a disintegrant is added inside the granules, the disintegration process starts from inside the granules, causing complete disintegration. Also, because the disintegrant is sealed inside the granules, contact with water is delayed, and furthermore, because it has already been exposed to slight heat during the granulation process, the disintegration effect is weak. When a disintegrant is added outside the granules, the disintegration rate is faster, but the disintegration process mainly occurs between the granules, and after disintegration, it often becomes a granular state rather than a fine powder. By adding a lubricant inside and outside the granules, fluidity between separated granules is ensured, while simultaneously improving friction between the polymer and the high-temperature metal surface of the processing equipment, thereby ensuring the quality of the tablet compression.

[0028] In the pharmaceutical composition of this technology, the disintegrant is added both inside and outside the granules during the preparation process, and the lubricant is added both inside and outside the granules during the preparation process. When the disintegrant is added both inside and outside the granules during the preparation process, the mass ratio of the internal disintegrant to the external disintegrant is 1:0.5 to 3, the dissolution of the pharmaceutical is good, there are no significant differences in the quality characteristics (granule size, angle of repose, bulk density, tap density) between the granules (tablets) of the formulation, and there are no significant differences in the dissolution rate. Preferably, the mass ratio of the internal disintegrant to the external disintegrant is 1:0.8 to 2, and more preferably, the mass ratio of the internal disintegrant to the external disintegrant is 1:1. When lubricants are added to the inside and outside of granules during the preparation process, the mass ratio of lubricants inside the granules to lubricants outside the granules is 1:0.5 to 3, and similarly, the dissolution of the pharmaceutical product is good, there are no significant differences in quality characteristics between the granules (tablets) of the formulation (granule size, angle of repose, bulk density, tap density), and there are no significant differences in dissolution rate. Preferably, the mass ratio of lubricants inside the granules to lubricants outside the granules is 1:0.8 to 2, and more preferably, the mass ratio of lubricants inside the granules to lubricants outside the granules is 1:1.

[0029] It is well known to those skilled in the art that a predetermined error range is permissible in the mass ratio between adjuvants depending on the actual manufacturing conditions of the formulation, and the error range of the mass ratio described in the present invention may be ±0.5%.

[0030] The present invention also provides the following composition comprising the following components, the formulation being a preferred technical means of the present invention, which simultaneously solves formulation stability, formulation process (adhesion, etc.), and dissolution-related problems of the compound of formula (I), and the resulting formulation is of excellent quality, free from conditions such as adhesion, crumbling, and cracking, has good dissolution properties, good stability, and satisfies the effects of pharmaceutical applications.

[0031] The pharmaceutical composition contains the following ingredients: [Table 1]

[0032] The compound of formula (I) above has particle sizes D10 ≤ 3 μm, D50 ≤ 15 μm, and D90 ≤ 140 μm, and the compound of formula (I) above is in an amorphous form.

[0033] The pharmaceutical composition contains the following ingredients: [Table 2] The compound of formula (I) above has particle sizes D10 ≤ 3 μm, D50 ≤ 15 μm, and D90 ≤ 140 μm, and the compound of formula (I) above is in an amorphous form.

[0034] The pharmaceutical composition contains the following ingredients: [Table 3] The compound of formula (I) above has particle sizes D10 ≤ 3 μm, D50 ≤ 15 μm, and D90 ≤ 140 μm, and the compound of formula (I) above is in an amorphous form.

[0035] Furthermore, the pharmaceutical composition contains the following ingredients: [Table 4]

[0036] The compound of formula (I) above has particle sizes D10 ≤ 3 μm, D50 ≤ 15 μm, and D90 ≤ 140 μm, the compound of formula (I) above is in amorphous form, and the water content of the above pharmaceutical composition is 3.0% to 5.0%.

[0037] Furthermore, the pharmaceutical composition contains the following ingredients: [Table 5] The compound of formula (I) above has particle sizes D10 ≤ 3 μm, D50 ≤ 15 μm, and D90 ≤ 140 μm, the compound of formula (I) above is in amorphous form, and the water content of the above pharmaceutical composition is 3.0% to 5.0%.

[0038] Furthermore, the pharmaceutical composition contains the following ingredients: [Table 6] The compound of formula (I) above has particle sizes D10 ≤ 3 μm, D50 ≤ 15 μm, and D90 ≤ 140 μm, the compound of formula (I) above is in amorphous form, and the water content of the above pharmaceutical composition is 3.0% to 5.0%.

[0039] Furthermore, the pharmaceutical composition contains the following ingredients: [Table 7] The compound of formula (I) above has particle sizes D10 ≤ 3 μm, D50 ≤ 15 μm, and D90 ≤ 140 μm, and the compound of formula (I) above is in amorphous form. The pharmaceutical composition above shows an elution rate of 70.0% or more in 60 mins when pH 6.8 phosphate buffer is used as the elution medium.

[0040] Furthermore, the pharmaceutical composition contains the following ingredients: [Table 8] The compound of formula (I) above has particle sizes D10 ≤ 3 μm, D50 ≤ 15 μm, and D90 ≤ 140 μm, and the compound of formula (I) above is in amorphous form. The pharmaceutical composition above shows an elution rate of 70.0% or more in 60 mins when pH 6.8 phosphate buffer is used as the elution medium.

[0041] Furthermore, the pharmaceutical composition contains the following ingredients: [Table 9] The compound of formula (I) above has particle sizes D10 ≤ 3 μm, D50 ≤ 15 μm, and D90 ≤ 140 μm, and the compound of formula (I) above is in amorphous form. The pharmaceutical composition above shows an elution rate of 70.0% or more in 60 mins when pH 6.8 phosphate buffer is used as the elution medium.

[0042] Furthermore, the pharmaceutical composition contains the following ingredients: [Table 10] The compound of formula (I) above has particle sizes D10 ≤ 3 μm, D50 ≤ 15 μm, and D90 ≤ 140 μm, and the compound of formula (I) above is in amorphous form. The pharmaceutical composition above shows an elution rate of 70.0% or more in 60 mins when pH 6.8 phosphate buffer is used as the elution medium.

[0043] Furthermore, the pharmaceutical composition contains the following ingredients: [Table 11] The compound of formula (I) above has particle sizes D10 ≤ 3 μm, D50 ≤ 15 μm, and D90 ≤ 140 μm, and the compound of formula (I) above is in amorphous form. The pharmaceutical composition above shows an elution rate of 70.0% or more in 60 mins when pH 6.8 phosphate buffer is used as the elution medium.

[0044] Furthermore, the pharmaceutical composition contains the following ingredients: [Table 12] The compound of formula (I) above has particle sizes D10 ≤ 3 μm, D50 ≤ 15 μm, and D90 ≤ 140 μm, and the compound of formula (I) above is in amorphous form. The pharmaceutical composition above shows an elution rate of 70.0% or more in 60 mins when pH 6.8 phosphate buffer is used as the elution medium.

[0045] A second object of the present invention is to provide a method for preparing a pharmaceutical composition using a non-wet granulation preparation technique.

[0046] A third object of the present invention is to provide a pharmaceutical tablet comprising a tablet core and a coating applied to the outside of the tablet core, wherein the tablet core is composed of the pharmaceutical composition of the present invention.

[0047] Depending on the type of coating material, coated tablets can be mainly classified into sugar-coated tablets, film-coated tablets, and enteric-coated tablets. In the present invention, the above coating is a suitable coating known not to adversely affect the dissolution rate of the final formulation, and is preferably a gastric-soluble film coating. By applying a sealing coating to the tablet core with a film coating, patients and clinical personnel are protected, and the tablet core is prevented from coming into contact with air and moisture, thereby reducing the possibility of drug degradation.

[0048] A suitable film coating material includes a film-forming agent such as a film-forming polymer. Preferably, the film coating material also includes additional components such as plasticizers, colorants, dispersants, and light-shielding agents. Plasticizers can be used to improve the flexibility, durability, and adhesion of the film coating. Preferred film-forming polymers are selected from one or more such as film-forming vinyl polymers (e.g., polyvinyl alcohol), film-forming acrylic polymers (e.g., methacrylate-methyl methacrylate copolymers), and water-soluble cellulose ethers (e.g., hydroxypropyl methylcellulose). Preferred plasticizers are selected from glycerol, acetylated monoglycerides, citrate esters, propylene glycol, polyethylene glycol, triglycerides, or phthalates. Suitable light-shielding and colorants include, for example, titanium dioxide, yellow iron oxide, black iron oxide, and Alura red aluminum lake. Suitable dispersants include, for example, talc.

[0049] The appropriate film coating material may be a concentrate and is prepared as a coating solution with water or an organic solvent before being sprayed onto the tablet core. The coating material used in this invention is a pharmaceutical film coating premix (gastric type) (Opadry 85F64732-CN pink), which is prepared as a coating solution with a solid content of 15% and sprayed onto the tablet core. Here, the mass of the coating is 0.5% to 10%, preferably 1% to 6%, and more preferably 3%, of the mass of the tablet core.

[0050] In the present invention, the specifications for the compound tablets of formula (I) are 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, and so on, ranging from 100 mg to 300 mg, preferably 150 mg to 250 mg, and more preferably 200 mg.

[0051] According to the present invention, a method for preparing the above-mentioned pharmaceutical tablets is also provided, which specifically includes the following steps. 1) The compound of formula (I) and lactose in the prescribed amount are sieved and granulated, then the prescribed amount of hydroxypropyl methylcellulose, cross-linked carboxymethylcellulose sodium (inside the granules), and colloidal silica are mixed and sieved, and finally the prescribed amount of microcrystalline cellulose is sieved, with a sieve size of Φ1.0 mm and a granulation frequency of 8 Hz. Premix 1 is performed on the sieved material, with a premixing rotation speed of 10 rpm and a premixing time of 15 min to obtain premix 1. After premixing 1 is complete, magnesium stearate (in the granules) is added and premixing 2 is performed, with a premixing rotation speed of 10 rpm and a premixing time of 5 min to obtain premix 2.

[0052] 2) Premix 2 is fed into a dry granulator and dry granulation is performed, with the hopper feed rotation speed 5-10 rpm, screw feed rotation speed 10-20 rpm, pressure roller rotation speed 13-23 rpm, hydraulic pressure 60-80 bar, pressure roller gap 1.0 mm, sieve size specification for granule 1 10 mesh, rotation speed for granule 1 30-80 rpm, sieve size specification for granule 2 24 mesh, rotation speed for granule 2 80-180 rpm. After granulation, dry granules are obtained, and after the completion of dry granulation, a sample is taken to measure the weight loss rate, and the weight loss rate shall not exceed 5.0%.

[0053] 3) Transfer the dried granules together with the converted cross-linked sodium carboxymethylcellulose (outside the granules) to a mixer and perform a complete premix at a mixing speed of 10 rpm for 5 minutes to obtain a complete premix. Then, add the converted magnesium stearate (outside the granules) and mix with the complete premix in the mixer at a mixing speed of 10 rpm for 3 minutes to obtain a complete mixture. After the complete mixing is complete, take a sample for intermediate product inspection.

[0054] 4) After the granule content of the complete mixture passes inspection, the tablets are compressed using a 17mm*8.5mm shallow concave punch tool, with a compression speed of 100-180 tablets / hour, a main pressure of 8-11kN, and a hardness controlled to 100-180N. After the compression is complete, samples are taken for intermediate product inspection.

[0055] 5) Weigh the film coating premix and purified water to prepare the coating solution. Using a high-efficiency coating machine, coat the material with the following settings: coating air temperature 40-66°C, exhaust temperature 35-55°C, material temperature 35-55°C, spray speed 0.1-0.5 kg / min, atomization pressure 1.0-5.0 bar, and coating weight increase range 2.0-4.0%. After coating is complete, samples are taken to measure the appearance, coating weight increase, and dry weight decrease rate, none of which should exceed 5.0%.

[0056] A fourth object of the present invention is to provide the use of the above-mentioned pharmaceutical tablets in the preparation of a product for preventing, alleviating or treating an infection or disease caused by the novel coronavirus, wherein the above-mentioned novel coronavirus includes non-mutant or mutant novel coronavirus, and the mutant novel coronavirus is selected from the Alpha mutant, Beta mutant, Gamma mutant, Delta mutant, Lambda mutant, and / or Omicron mutant of the novel coronavirus. 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. Preferably, diseases include novel coronavirus pneumonia.

[0057] The pharmaceutical composition containing the compound of formula (I) according to the present invention and the tablets containing the same are easy to prepare, have adaptability in the formulation process, have excellent formulation characteristics (no sticking, cracking, etc.), have excellent stability and dissolution, exhibit a dissolution rate of 70.0% or more in 60 mins, and furthermore, have similarly excellent stability and dissolution properties under long-term storage conditions or accelerated storage conditions, and the dissolution properties meet the standards for pharmaceuticals. [Brief explanation of the drawing]

[0058] [Figure 1] This is the XRPD spectrogram of the Cu-Kα line in the amorphous form of the compound of formula (I). [Figure 2]This is the XRPD spectrogram of the Cu-Kα line of crystalline form I of the compound of formula (I). [Figure 3] These are elution curve graphs for Example 2 and Comparative Example 6 under phosphate buffer conditions at pH 6.8. [Figure 4] These are the elution curve graphs for Examples 2, 6, and 7, and Comparative Example 5. [Modes for carrying out the invention]

[0059] The present invention will be described in detail below with reference to examples.

[0060] The following embodiments represent preferred embodiments of the present invention, but embodiments of the present invention are not limited to the above embodiments. Any other changes, modifications, substitutions, combinations, and simplifications made without departing from the spirit and principles of the present invention are all included within the scope of protection of the present invention as equivalent alternatives.

[0061] Dissolution rate test

[0062] The elution and release rates were measured according to the method for determining elution and release rates (Chinese Pharmacopoeia 2020 Edition, Part IV, General Rule 0931, Method 2).

[0063] Elution conditions: 900 ml of pH 6.8 phosphate buffer (250 ml of 0.2 mol / L potassium dihydrogen phosphate solution mixed with 112 ml of 0.2 mol / L sodium hydroxide solution, then diluted with water to 1000 ml and homogeneously mixed) was used as the elution medium. The procedure was carried out at a rotation speed of 75 rpm according to the prescribed method, and sampling was performed after the predetermined time had elapsed.

[0064] Dissolution testing device: Raytor RT-612-AT

[0065] Test solution: An appropriate amount of eluate was collected and filtered. The first 2 ml of filtrate was discarded, and the next filtrate was collected.

[0066] Control solution: A suitable amount of commercially available lelitrelvir tablets was taken as a control, precisely weighed, dissolved in a solvent [anhydrous ethanol-water (80:20)], and quantitatively diluted to prepare a solution containing approximately 0.22 mg (0.2 g specification) or 0.11 mg (0.1 g specification) per 1 ml.

[0067] Chromatography conditions and system compatibility requirements

[0068] The measurements were performed using high-performance liquid chromatography (Chinese Pharmacopoeia 2020 Edition, Part IV, General Rule 0512).

[0069] Solvent: Anhydrous ethanol - water (80:20).

[0070] Test solution: Ten tablets of this product were taken and precisely weighed, then ground into a fine powder. An appropriate amount of the fine powder (equivalent to approximately 200 mg of lelitrevir) was precisely weighed and placed in a 100 ml volumetric flask. An appropriate amount of solvent was added, and the mixture was dissolved by sonication. After standing at room temperature, the solution was diluted with solvent up to the marked level, shaken well, and then centrifuged at 8000 rpm for 10 minutes. An appropriate amount of the supernatant was precisely weighed and quantitatively diluted with solvent to prepare a solution containing approximately 0.2 mg per 1 ml.

[0071] Control solution: A suitable amount of commercially available lelitrelvir tablets was taken as a control, precisely weighed, dissolved in a solvent, and quantitatively diluted to prepare a solution containing approximately 0.2 mg per 1 ml.

[0072] Equipment: Agilent 1260 Infinity II VWD / DAD

[0073] Chromatography conditions: Octadecylsilane-bound silica gel was used as the packing material (Waters Xbridge C18, 4.6 mm × 150 mm, 3.5 μm or equivalent chromatography column), 0.005 mol / L dipotassium hydrogen phosphate solution (pH adjusted to 8.4 with 1% phosphoric acid solution) - methanol (30:70) was used as the mobile phase, the flow rate was 1.0 ml / min, the detection wavelength was 210 nm, the column temperature was 55 °C, and the injection volume was 10 μl.

[0074] System conformance requirement: In the chromatogram of the control solution, the theoretical plate number calculated based on the relitrelvir peak must not be less than 2000.

[0075] Measurement method: The test solution and control solution were precisely weighed, injected into a liquid chromatograph, and the chromatograms were recorded. The peak area was used to calculate the chromatogram according to the external standard method. Calculation formula: [Formula 1] TIFF2026516804000018.tif18170

[0076] Method for measuring moisture content:

[0077] 1. Equipment and Devices (1) Moisture meter: Metrohm 915KF Ti-Touch (2) Electronic analytical balance: Sartorius BCE224I-1CCN

[0078] 2. Reagents and control samples (1) Ultrapure water / purified water: Homemade (2) Anhydrous methanol: Purchased from Chengdu Kelong Chemicals Co., Ltd. (3) Pyridine-free Karl Fischer reagent: Purchased from Tianjin Kemiu Chemical Reagents Co., Ltd.

[0079] 3. Operating Procedure

[0080] The procedure was carried out in accordance with the Chinese Pharmacopoeia 2020 Edition, Part IV, General Rule 0832, Method 1 for Moisture Measurement (Karl Fischer Method). Karl Fischer reagent calibration: Approximately 10 mg of purified water was accurately weighed and directly calibrated three times using a moisture meter. Measurement of the test product: The product was ground into a fine powder, approximately 200 mg of the powder was weighed, and measured at least twice using a moisture meter.

[0081] Measurement results can be expressed as a range value or the average of multiple measurements, but in either case, the average of multiple measurements must all fall within the range of this test.

[0082] The amorphous form of the compound of formula (I) can be prepared and measured by referring to PCT / CN2023 / 120437. Crystalline form I of the compound of formula (I) can be prepared and measured by referring to PCT / CN2023 / 120726. All compounds of formula (I) above were obtained from Guangdong Raynovent Biotech Co., Ltd.

[0083] The particle size of the active pharmaceutical ingredient was obtained by controlling the size of the grinding screen.

[0084] The test conditions for the active pharmaceutical ingredient particle size of the compound of formula (I) are as follows: Instrument name: Malvern laser particle size analyzer Model: Mastersizer 3000 Sample injector: Dry type Injection rate: 35% Dispersed air pressure: 2 bar Measurement time: 5 seconds.

[0085] Example 1: Compatibility experiment between the active pharmaceutical ingredient and the adjuvant.

[0086] The selected adjuvants were lactose, microcrystalline cellulose, mannitol, cross-linked sodium carboxymethylcellulose, sodium stearyl fumarate, poloxamer, hydroxypropyl methylcellulose, glyceryl behenate, colloidal silica, sodium dodecyl sulfate, magnesium stearate, and film coating premix. Each was mixed with the main ingredient in the proportions shown in Table 1, left to stand under the conditions in Table 1, and samples were taken and measured at the specified time points to examine changes in properties, content, and related substances (total impurities). HPLC was used as the analytical method.

[0087] [Table 13] TIFF2026516804000020.tif253170

[0088] From the above results, it was found that, regarding the properties, when the compound drug substance of formula (I) was placed with poloxamer 188 for 5 and 10 days under high temperature conditions, the properties of the binary mixture changed, and the appearance changed from a white powder to a brown semi-solid. When the compound drug substance of formula (I) was placed with poloxamer 188 for 5 and 10 days under high humidity conditions, the properties of the binary mixture changed, and the appearance changed from a white powder to white crystals. When the compound drug substance of formula (I) was placed with sodium dodecyl sulfate for 10 days under high humidity conditions, the appearance changed from a white powder to a white liquid. When the other compound drug substances of formula (I) were placed with auxiliaries for 5 and 10 days, there was no apparent change in appearance, and all remained as white powders.

[0089] Regarding the content, the content of the compound active ingredient of formula (I) and the binary mixture of poloxamer 188 and glyceryl behenate all decreased significantly after being left under high temperature conditions for 5 and 10 days. The content of the compound active ingredient of formula (I) and the binary mixture of sodium dodecyl sulfate all decreased significantly under high humidity conditions. The content of the compound active ingredient of formula (I) and all auxiliary agents all decreased significantly under light irradiation conditions. However, no significant change in content was observed in the other binary mixtures under high temperature and high humidity conditions compared to day 0.

[0090] Regarding the related substances, it was found that the total impurities of compound API of formula (I) and poloxamer 188 increased significantly under high-temperature conditions, the total impurities of compound API of formula (I), poloxamer 188, and sodium dodecyl sulfate increased significantly under high-humidity conditions, and the total impurities of each binary mixture increased under light irradiation conditions for compound API of formula (I) and all auxiliary agents, and this increasing trend was basically consistent with that of compound API of formula (I).

[0091] As described above, the compound active pharmaceutical ingredient of formula (I) showed good compatibility with lactose, microcrystalline cellulose, mannitol, cross-linked sodium carboxymethylcellulose, sodium stearyl fumarate, hydroxypropyl methylcellulose, colloidal silica, and magnesium stearate, and these are applicable to formulation studies. However, it showed poor compatibility with poloxamer 188, sodium dodecyl sulfate, and glyceryl behenate.

[0092] Example 2 Preparation of tablets of compound (I)

[0093] Formulation composition of compound tablets of formula (I) for 1000 tablets [Table 14]

[0094] Preparation method:

[0095] 1) The compound of formula (I) and lactose in the prescribed amount are sieved and granulated, then the prescribed amount of hydroxypropyl methylcellulose, cross-linked carboxymethylcellulose sodium (inside the granules), and colloidal silica are mixed and sieved, and finally the prescribed amount of microcrystalline cellulose is sieved, with a sieve size of Φ1.0 mm and a granulation frequency of 8 Hz. The sieved materials were pre-mixed in a mixer, with a pre-mixing speed of 10 rpm and a pre-mixing time of 15 min, to obtain premix 1. After premixing 1 was completed, magnesium stearate (in the granules) was added and premixing 2 was performed, with a premixing rotation speed of 10 rpm and a premixing time of 5 min to obtain premix 2.

[0096] 2) Premix 2 is fed into a dry granulator and dry granulation is performed, with the hopper feed rotation speed 5-10 rpm, screw feed rotation speed 10-20 rpm, pressure roller rotation speed 13-23 rpm, hydraulic pressure 60-80 bar, pressure roller gap 1.0 mm, sieve size specification for granule 1 10 mesh, rotation speed for granule 1 30-80 rpm, sieve size specification for granule 2 24 mesh, rotation speed for granule 2 80-180 rpm. After granulation, dry granules are obtained, and after the completion of dry granulation, a sample is taken to measure the weight loss rate, and the weight loss rate shall not exceed 5.0%.

[0097] 3) The dried granules were transferred to a mixer along with the converted cross-linked sodium carboxymethylcellulose (outside the granules), and a complete premix was performed at a mixing speed of 10 rpm for 5 minutes to obtain a complete premix. Then, the converted magnesium stearate (outside the granules) was added and the complete premix was mixed with the mixer at a mixing speed of 10 rpm for 3 minutes to obtain a complete mixture. After the complete mixing was completed, a sample was taken for intermediate product inspection.

[0098] 4) After the granule content of the complete mixture passed inspection, the tablets were compressed using a 17mm*8.5mm shallow concave punch tool, with a compression speed of 100-180 tablets / hour, a main pressure of 8-11kN, and a hardness controlled to 100-180N. After the compression was complete, samples were taken for intermediate product inspection.

[0099] 5) The film coating premix and purified water were weighed and prepared as a coating solution. Using a high-efficiency coating machine, the coating was performed with a coating air temperature of 40-66°C, exhaust temperature of 35-55°C, material temperature of 35-55°C, spray speed of 0.1-0.5 kg / min, atomization pressure of 1.0-5.0 bar, and a coating weight increase range of 2.0-4.0%. After coating was completed, samples were taken to measure the appearance, coating weight increase, and dry weight decrease rate. None of these should exceed 5.0%, and the moisture content was controlled to 3.0%-5.0% depending on the drying time.

[0100] Example 3 Preparation of tablets of compound (I)

[0101] Formulation composition of compound tablets of formula (I) for 1000 tablets [Table 15]

[0102] The preparation method was as described in Example 2, with the moisture content further controlled to 3.0% to 5.0%.

[0103] Example 4 Preparation of tablets of compound (I)

[0104] Formulation composition of compound tablets of formula (I) for 1000 tablets [Table 16]

[0105] The preparation method was as described in Example 2, with the moisture content further controlled to 3.0% to 5.0%.

[0106] Example 5 Preparation of tablets of compound (I)

[0107] Formulation composition of compound tablets of formula (I) for 1000 tablets [Table 17]

[0108] The preparation method was as described in Example 2, with the moisture content further controlled to 3.0% to 5.0%.

[0109] Example 6 Preparation of tablets of compound (I)

[0110] Formulation composition of compound tablets of formula (I) for 1000 tablets [Table 18]

[0111] The preparation method was as described in Example 2, with the moisture content further controlled to 3.0% to 5.0%.

[0112] Example 7 Preparation of tablets of compound (I)

[0113] Formulation composition of compound tablets of formula (I) for 1000 tablets [Table 19]

[0114] The preparation method was as described in Example 2, with the moisture content further controlled to 3.0% to 5.0%.

[0115] Example 8 Preparation of tablets of compound (I)

[0116] Formulation composition of compound tablets of formula (I) for 1000 tablets [Table 20]

[0117] Preparation method:

[0118] 1) The compound of formula (I) and lactose in the prescribed amount are sieved and granulated, and then the prescribed amount of povidone, hydroxypropylcellulose (low substitution) (inside the granules) and talc are mixed and sieved, with a sieve size of Φ1.0 mm and a granulation frequency of 8 Hz. The sieved materials were pre-mixed in a mixer, with a pre-mixing speed of 10 rpm and a pre-mixing time of 15 min, to obtain premix 1. After premixing 1 was completed, sodium stearyl fumarate (in the granules) was added and premixing 2 was performed at a premixing rotation speed of 10 rpm and a premixing time of 5 min to obtain premix 2.

[0119] 2) Premix 2 is fed into a dry granulator and dry granulation is performed, with the hopper feed rotation speed 5-10 rpm, screw feed rotation speed 10-20 rpm, pressure roller rotation speed 13-23 rpm, hydraulic pressure 60-80 bar, pressure roller gap 1.0 mm, sieve size specification for granule 1 10 mesh, rotation speed for granule 1 30-80 rpm, sieve size specification for granule 2 24 mesh, rotation speed for granule 2 80-180 rpm. After granulation, dry granules are obtained, and after the completion of dry granulation, a sample is taken to measure the weight loss rate, and the weight loss rate shall not exceed 5.0%.

[0120] 3) The dried granules were transferred to a mixer along with the converted hydroxypropyl cellulose (low substitution) (external granules), and the mixture was pre-mixed at a mixing speed of 10 rpm for 5 minutes to obtain a complete premix. Then, the converted stearyl sodium fumarate (external granules) was added and the mixture was thoroughly mixed with the complete premix in the mixer at a mixing speed of 10 rpm for 3 minutes to obtain a complete mixture. After the complete mixing was finished, a sample was taken for intermediate product inspection.

[0121] 4) After the granule content of the complete mixture passed inspection, the tablets were compressed using a 17mm*8.5mm shallow concave punch tool, with a compression speed of 100-180 tablets / hour, a main pressure of 8-11kN, and a hardness controlled to 100-180N. After the compression was complete, samples were taken for intermediate product inspection.

[0122] 5) The film coating premix and purified water were weighed and prepared as a coating solution. Using a high-efficiency coating machine, the coating was performed with a coating air temperature of 40-66°C, exhaust temperature of 35-55°C, material temperature of 35-55°C, spray speed of 0.1-0.5 kg / min, atomization pressure of 1.0-5.0 bar, and a coating weight increase range of 2.0-4.0%. After coating was completed, samples were taken to measure the appearance, coating weight increase, and dry weight decrease rate. None of these should exceed 5.0%, and the moisture content was controlled to 3.0%-5.0% depending on the drying time.

[0123] Example 9 Preparation of tablets of compound (I)

[0124] Formulation composition of compound tablets of formula (I) for 1000 tablets [Table 21]

[0125] The preparation method was as described in Example 2, with the moisture content further controlled to 2.0% to 3.0%.

[0126] Example 10 Preparation of tablets of compound (I)

[0127] Formulation composition of compound tablets of formula (I) for 1000 tablets [Table 22]

[0128] The preparation method was as described in Example 2, with the moisture content further controlled to 1.0% to 2.0%.

[0129] Comparative Example 1: Preparation of tablets of compound (I)

[0130] Formulation composition of compound tablets of formula (I) for 1000 tablets [Table 23]

[0131] 1) The compound of formula (I) and lactose in the prescribed quantities are sieved to granules, then the prescribed quantities of hydroxypropyl methylcellulose, cross-linked carboxymethylcellulose sodium and colloidal silica are mixed and sieved, and finally the prescribed quantities of microcrystalline cellulose are sieved, with sieve size specifications of Φ1.0 mm and granulation frequency of 8 Hz. The sieved materials were pre-mixed in a mixer, with a pre-mixing speed of 10 rpm and a pre-mixing time of 15 min, to obtain premix 1. After premixing 1 was completed, magnesium stearate was added and premixing 2 was performed. The premixing speed was set to 10 rpm and the premixing time to 5 min to obtain premix 2.

[0132] 2) Premix 2 is fed into a dry granulator and dry granulation is performed, with the hopper feed rotation speed 5-10 rpm, screw feed rotation speed 10-20 rpm, pressure roller rotation speed 13-23 rpm, hydraulic pressure 60-80 bar, pressure roller gap 1.0 mm, sieve size specification for granule 1 10 mesh, rotation speed for granule 1 30-80 rpm, sieve size specification for granule 2 24 mesh, rotation speed for granule 2 80-180 rpm. After granulation, dry granules are obtained, and after the completion of dry granulation, a sample is taken to measure the weight loss rate, and the weight loss rate shall not exceed 5.0%.

[0133] 3) After the granule content passed inspection, tablets were compressed using a 17mm*8.5mm shallow concave punch tool, at a compression speed of 100-180 tablets / hour, with a main press pressure of 8-11kN and a hardness controlled to 100-180N. After the compression was complete, samples were taken for intermediate product inspection.

[0134] 4) The film coating premix and purified water were weighed and prepared as a coating solution. Using a high-efficiency coating machine, the coating was performed with a coating air supply temperature of 40-66°C, exhaust temperature of 35-55°C, material temperature of 35-55°C, spray speed of 0.1-0.5 kg / min, atomization pressure of 1.0-5.0 bar, and a coating weight increase range of 2.0-4.0%. After the coating was completed, samples were taken to measure the appearance, coating weight increase, and dry weight decrease rate. None of these should exceed 5.0%, and the moisture content was controlled to 3.0%-5.0% depending on the drying time.

[0135] Comparative Example 1 contains less binder and more lubricant compared to Example 2. In the preparation process, the disintegrant and lubricant were not added either inside or outside the granules.

[0136] Comparative Example 2: Preparation of tablets of compound (I)

[0137] Formulation composition of compound tablets of formula (I) for 1000 tablets [Table 24]

[0138] The preparation method was as described in Example 2, with the moisture content further controlled to 3.0% to 5.0%. In the formulation of Comparative Example 2, the amount of filler was higher than usual, the proportion of microcrystalline cellulose mixed in the filler was higher than usual, while the amounts of disintegrant and lubricant were higher than usual.

[0139] Comparative Example 3: Preparation of tablets of compound (I)

[0140] Formulation composition of compound tablets of formula (I) for 1000 tablets [Table 25]

[0141] Comparative Example 3 uses wet granulation, and the preparation method is as follows.

[0142] 1) Pretreatment: The material was passed through a 35-mesh sieve into colloidal silica and stored until use.

[0143] 2) Preparation of granulation solution: Hydroxypropyl methylcellulose and Tween 80 were dissolved in purified water and stored until use.

[0144] 3) Premixing: The compound of formula (I) in prescribed quantities, along with prescribed quantities of lactose, microcrystalline cellulose, and granular cross-linked carboxymethylcellulose sodium, were weighed and mixed by passing them through a 60-mesh sieve to obtain a premix.

[0145] 4) Wet granulation: The prepared granulation solution was dropped onto the premix, and wet granules that "roll up when lightly squeezed and scatter when lightly pressed" were obtained by manual wet granulation.

[0146] 5) Wet granulation: The wet granules obtained by wet granulation were wet-sieved using an 18-mesh sieve.

[0147] 6) Drying: The wet-sizing granules were dried in a precise hot-air drying oven to control the drying weight loss rate to 3.0% or less.

[0148] 7) Dry sizing: The dried granules were dry-sized using an 18-mesh sieve.

[0149] 8) Complete mixing: Based on the amount of dry granules, the amounts of extra-crosslinked carboxymethylcellulose sodium and colloidal silica were calculated. The extra-crosslinked carboxymethylcellulose sodium and colloidal silica were then passed through a 60-mesh sieve together with three times the amount of dry granules, and mixed with the total dry granules. The calculated amount of magnesium stearate was then added and the mixture was completely mixed to obtain a complete mixture of granules.

[0150] 9) Tableting: The complete mixture granules were compressed into tablets to further control the moisture content to 3.0% to 5.0%.

[0151] Comparative Example 4: Preparation of tablets of compound (I)

[0152] Formulation composition of compound tablets of formula (I) for 1000 tablets [Table 26]

[0153] The preparation method was as described in Example 2, with the moisture content further controlled to 3.0% to 5.0%. The formulation of Comparative Example 4 had larger-than-usual particle sizes of the compound of formula (I) compared to the formulation of Example 2.

[0154] Comparative Example 5: Preparation of tablets of compound (I)

[0155] Formulation composition of compound tablets of formula (I) for 1000 tablets [Table 27]

[0156] The preparation method was as described in Example 2, and the moisture content was controlled to 6.0% to 8.0%. The formulation of Comparative Example 5 was controlled to have a moisture content exceeding 5.0% compared to the formulation of Example 2.

[0157] Comparative Example 6: Preparation of tablets of compound (I)

[0158] Formulation composition of compound tablets of formula (I) for 1000 tablets [Table 28]

[0159] The preparation method is as described in Example 2, and the moisture content is controlled to 3.0% to 5.0%. The formulation of Comparative Example 6, compared to the formulation of Example 2, contains a predetermined ratio of crystalline form I of the compound of formula (I) in the active pharmaceutical ingredient of the compound of formula (I).

[0160] Example 11

[0161] The following are the results of quality tests conducted on the compound tablets of formula (I) prepared in Examples 2-10 and Comparative Examples 1-6.

[0162] [Table 29]

[0163] [Table 30]

[0164] From the above results, the tablets of the compound of formula (I) prepared in Examples 2-10 and Comparative Examples 1-6 all exhibited a white or off-white shape after the coating was removed. However, it became clear that the tablets obtained with the formulation of Comparative Example 1 crumbled and cracked during the preparation process. Analysis revealed that this formulation had a low amount of binder and a high amount of lubricant, resulting in improper mixing, uneven pressure distribution, and subsequent crumbling and cracking. The tablets obtained with the formulation of Comparative Example 2 exceeded the standard for content uniformity. Analysis revealed that this formulation had higher-than-usual amounts of filler, disintegrant, and lubricant, resulting in uneven mixing of the active pharmaceutical ingredient and auxiliary agents, and thus failing to achieve optimal uniformity. Examples 2 to 10 represent preferred technical methods of the present technical means, all of which have been optimized, including the type and ratio of auxiliary agents. For example, by using lactose and microcrystalline cellulose in more appropriate ratios as mixed fillers and adding disintegrants and lubricants inside and outside the granules, excessive lubrication and the occurrence of crumbling and cracking during mixing are suppressed, the compressibility of the resulting tablets is further improved, and the compound tablets of formula (I) as a whole combination of the above conditions can achieve optimal results in the preparation process.

[0165] Example 12 Investigation of relevant substances in different formulations

[0166] [Table 31]

[0167] From the above results, it was found that tablets obtained with the formulations of Examples 2, 6, 7, 9, 10 and Comparative Examples 4, 5, and 6 did not show a significant increase in the relevant substance (RRT0.82, RRT0.95 / 0.96), whereas tablets obtained with the formulation of Comparative Example 3 showed a significant increase in the relevant substance (RRT0.82, RRT0.95 / 0.96). This is because the compound active pharmaceutical ingredient of formula (I) is sensitive to moisture and heat, and the addition of the granulation solution in the wet granulation process and the drying process after granulation destabilize the compound active pharmaceutical ingredient of formula (I), leading to an increase in impurities. The inventors subsequently investigated the relevant substance in tablets obtained with the formulations of Examples 3-5 and 8, and similarly did not find a significant increase in the relevant substance (RRT0.82, RRT0.95 / 0.96). Examples 2 to 10 represent preferred technical methods within this technical framework, and by employing dry granulation, the influence of related substances in the formulation process can be sufficiently reduced.

[0168] Example 13 Investigation of the discriminative ability of eluting media

[0169] The ability of a pH 6.8 medium to distinguish between different final formulations was investigated by comparing the differences in dissolution behavior between a final formulation containing a predetermined ratio of crystalline active pharmaceutical ingredient in a pH 6.8 medium and a final formulation containing an amorphous active pharmaceutical ingredient.

[0170] Dissolution Experiment: Dissolution experiments were conducted on the compound composition of formula (I) of the present invention using the paddle method at a rotation speed of 75 rpm in 900 ml of pH 6.8 phosphate buffer. The results are shown in Table 5.

[0171] [Table 32]

[0172] From the above results and Figure 3, it can be seen that the tablets obtained with the formulation of Example 2 showed good dissolution properties, with an dissolution rate of 43.0% or more in 15 min, 60.0% or more in 30 min, 70.0% or more in 60 min, and almost complete dissolution within 120 min in pH 6.8 phosphate buffer. On the other hand, the formulation of Comparative Example 6 contained a predetermined ratio of crystalline form I, so it was clear that 70.0% dissolution was not achieved in 60 min and dissolution was incomplete even within 120 min. From this, it was found that there is a significant difference in dissolution rate when measuring the final formulation containing a predetermined ratio of crystalline form I and the final formulation containing amorphous material in a pH 6.8 medium, i.e., pH 6.8 phosphate buffer. Furthermore, it was revealed that pH 6.8 phosphate buffer has a predetermined discriminative ability for the final formulation.

[0173] Example 14 Investigation of elution of multiple media

[0174] Dissolution rate tests were performed on compound tablets of formula (I) prepared in Examples 2, 6, 7, 9, 10, Comparative Example 2, Comparative Example 4, and Comparative Example 5. Sampling was performed at 5 min, 10 min, 15 min, 20 min, 30 min, 45 min, 60 min, 90 min, and 120 min, and the average cumulative dissolution percentage was calculated. The results of the dissolution rate investigation are shown in Tables 6 and 7.

[0175] [Table 33]

[0176] [Table 34]

[0177] From the above results, it was revealed that the tablets obtained using the formulations of Examples 2, 6, 7, 9, and 10 exhibited good dissolution properties, showing an dissolution rate of 43.0% or more in 15 min, 60.0% or more in 30 min, and 70.0% or more in 60 min in pH 6.8 phosphate buffer. Furthermore, they showed excellent dissolution properties, almost completely dissolving within 120 min in multiple media (pH 1.0, pH 4.5, pH 6.8, and purified water).

[0178] When tablets obtained using the formulation of Comparative Example 2 were dissolved in multiple media (pH 1.0, pH 4.5, pH 6.8, and purified water), they maintained normal dissolution for up to 30 minutes, but after 30 minutes the dissolution time was prolonged, and they could not be completely dissolved within 120 minutes. Analysis revealed that in this formulation, the amount of microcrystalline cellulose was too high, causing a gradual "bottom deposition" phenomenon in the later stages of dissolution. Microcrystals deposited at the bottom of the dissolution tank, resulting in incomplete drug release and adversely affecting drug dissolution.

[0179] The tablets obtained using the formulation of Comparative Example 4 had long dissolution times, failing to completely dissolve within 120 minutes in multiple media (pH 1.0, pH 4.5, pH 6.8, and purified water). Analysis revealed that in the formulation of Comparative Example 4, the particle size of the compound raw material of formula (I) was larger than usual, resulting in poor mixing uniformity of the formulation and affecting subsequent release.

[0180] In the formulations of Examples 2, 6, 7, 9, and 10, the particle size of the compound raw material of formula (I) was appropriate, and the type and amount of formulation were within a favorable range, resulting in good elution in multiple media (pH 1.0, pH 4.5, pH 6.8, and purified water).

[0181] Example 15: Stability study

[0182] For stability testing, the samples (compound tablets of formula (I) prepared in Examples 2, 6, 7, 9, 10, and Comparative Example 5) were enclosed in a "polyvinyl chloride / polypyridene chloride solid pharmaceutical composite hard tablet + pharmaceutical aluminum foil (plain aluminum)" and enclosed in a "polyester / aluminum / polyethylene pharmaceutical packaging composite film".

[0183] Under the planned packaging conditions, accelerated stability testing was investigated. The samples were stored for 3 months at 40°C ± 2°C and 75% ± 5% RH, and no significant changes were observed in any of the measured parameters.

[0184] [Table 35] TIFF2026516804000043.tif91170

[0185] As is clear from the results above, when tablets obtained using the formulations of Examples 2, 6, 7, 9, and 10 were investigated for 3 months under accelerated testing conditions (40°C ± 2°C, 75% ± 5% RH), no significant changes were observed in any of the measured items such as properties, content, isomers, dissolution rate, impurities, moisture content, and crystal form. The moisture content of the tablets obtained using the formulations of Examples 2, 6, 7, 9, and 10 was controlled to 5.0% or less, and no effect was observed on dissolution. At the same time, it was found that in long-term storage, the lower the moisture content, the higher the dissolution rate (moisture content: Example 2 > Example 9 > Example 10, dissolution rate: Example 2 < Example 9 < Example 10).

[0186] As shown in Figure 4, the tablets obtained with the formulation of Comparative Example 5 showed a gradual decrease in dissolution rate over time. Analysis revealed that when the water content is too high, a "caking" phenomenon gradually occurs inside the tablet during storage, further affecting the dissolution of the formulation and leading to a decrease in the dissolution rate.

[0187] As described above, the compound composition of formula (I) prepared by this technical means has excellent formulation quality, is free from problems such as adhesion, crumbling, and cracking, has good dissolution properties, exhibits suitable stability, maintains good dissolution and stability even after long-term storage, satisfies the efficacy requirements for pharmaceutical applications, and the preparation process is simple and suitable for industrial production.

[0188] Example 16

[0189] The tablets used in this embodiment are prepared according to the formulation and preparation method of Example 2.

[0190] To verify the therapeutic effect of the pharmaceutical composition of the present invention, a clinical study was conducted using tablets of the compound of formula (I) obtained in Example 2 of the present invention as a test drug. The study process and results are as follows.

[0191] I. Related Standards 1.1 Diagnostic Criteria 1.1.1 Diagnosis of diseases in Western medicine

[0192] According to the "COVID-19 Diagnostic and Treatment Protocol (Trial Version 10)," if an epidemiological history and clinical symptoms are present, the etiological evidence (positive nucleic acid test or antigen test for COVID-19 pneumonia) is considered to be met.

[0193] According to the "COVID-19 Diagnostic and Treatment Protocol (Trial Version 10)," pathological classifications are categorized into mild, general, severe, and critical.

[0194] 1.2 Eligibility Criteria (1) Persons who have tested positive for COVID-19 nucleic acid or antigen, (2) Based on the classification criteria of the "COVID-19 Diagnosis and Treatment Protocol (Trial Version 10)", persons who are considered to have mild symptoms, (3) Persons aged 18 to 65 years (including the borderline age), (4) The person who signed the informed consent form.

[0195] Exclusion criteria: (1) Individuals with serious underlying conditions such as acute heart failure, or those exhibiting acute exacerbations of chronic diseases, (2) Female subjects who are pregnant, breastfeeding, or lactating, (3) Individuals suffering from diseases that affect the duration of symptoms, such as bronchopneumonia, chronic lung abscess, chronic cough lasting more than 8 weeks, or chronic pharyngitis accompanied by cough.

[0196] 1.3 Case withdrawals and dropouts

[0197] Case withdrawal or dropout refers to cases where a patient, after enrollment, does not wish to continue participating in the clinical trial during the review process, or is unable to complete the entire treatment course as prescribed.

[0198] Handling of withdrawal / dropout cases: Reviewers should contact subjects via home visits, telephone, or letter, record the date and time of the last treatment, perform all possible evaluation items, understand the reason for withdrawal, and accurately record it in the case report form. Observational data for all withdrawal / dropout cases must be retained.

[0199] II. Case origins: Numerous clinical review centers nationwide, including the First Affiliated Hospital of Guangzhou Medical University.

[0200] III. Intervention and grouping:

[0201] All patients included in the group of compounds of formula (I) took tablets of the compound of formula (I) obtained in Example 2, two tablets three times a day, with each tablet containing 200 mg.

[0202] After registration, all patients underwent diagnosis and treatment in accordance with the "COVID-19 Pneumonia Diagnostic and Treatment Protocol (Trial Version 9)," ensuring that patients received basic medical care, but antiviral therapy was not administered.

[0203] IV. Statistical methods:

[0204] Normality tests were performed on the quantitative data. Data following a normal distribution were expressed as mean ± standard deviation, while data not following a normal distribution were described using the median and quartiles. Treatment effects were compared sequentially, with paired t-tests used for normally distributed data and nonparametric tests used for non-normally distributed data. Quantitative data were analyzed using chi-squared tests.

[0205] V. Test Results

[0206] [Table 36]

[0207] Table 9 shows that, based on ITT analysis, 1107 out of 1359 subjects (81.5%) achieved clinical recovery, including 538 (79.2%) in the placebo group and 569 (83.7%) in the compound group (I). The median time to sustained clinical recovery for the 11 symptoms in the compound group (I) and the placebo group was 251.02 hours (95% CI: 246.48, 268.13) and 271.33 hours (95% CI: 264.72, 294.20), respectively. After adjusting for the subjects' actual baseline clinical classification and whether or not they belonged to the high-risk group for severe / critical cases, a stratified log-rank test was used to compare the difference in median time to sustained clinical recovery between the two groups, revealing a statistically significant difference (P=0.002). The group of compounds of formula (I) showed a 20.31h reduction in the time to sustained clinical recovery for the 11 symptoms compared to the placebo group. Therefore, the group of compounds of formula (I) is considered superior to the placebo group in that it shortens the time to sustained clinical recovery for the 11 symptoms. From this, it has become clear that the compositions prepared in this invention can achieve ideal clinical therapeutic effects when the dissolution behavior conditions of the present invention are met.

[0208] As described above, the composition of compound (I) prepared by this technical means has excellent formulation quality, is free from adhesion, crumbling, and cracking, has good dissolution properties, is stable, and satisfies the efficacy requirements for pharmaceutical applications. Furthermore, the preparation process is simple and suitable for industrial production.

[0209] While the above embodiments represent preferred embodiments of the present invention, the embodiments of the present invention are not limited to those embodiments, and any other changes, modifications, substitutions, combinations, or simplifications made without departing from the spirit and principles of the present invention are all included within the scope of protection of the present invention as equivalent substitution methods.

Claims

1. A pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and an auxiliary agent, wherein the auxiliary agent comprises one or more of a filler, a binder, a flow promoter, a disintegrant, and a lubricant, the filler being one or more of lactose, anhydrous lactose, microcrystalline cellulose, mannitol, or starch, the binder being one or more of hydroxypropyl methylcellulose, hydroxypropyl cellulose, povidone, hydroxyethyl cellulose, carboxymethylcellulose sodium, or polyvinyl alcohol, the flow promoter being one or more of colloidal silica, talc, or micronized silica gel, and the disintegrant being low-substituted hydroxypropyl cellulose, A pharmaceutical composition characterized by comprising one or more of bridged carboxymethylcellulose sodium, carboxymethyl starch sodium, or cross-linked povidone, one or more of magnesium stearate, calcium stearate, or stearyl fumarate sodium as a lubricant, a mass ratio of the compound of formula (I) to the filler being 1:1.0 to 2.5, a mass ratio of the compound of formula (I) to the binder being 1:0.01 to 0.05, a mass ratio of the compound of formula (I) to the flow promoter being 1:0.01 to 0.03, a mass ratio of the compound of formula (I) to the disintegrant being 1:0.10 to 0.30, and a mass ratio of the compound of formula (I) to the lubricant being 1:0.01 to 0.

10. 【Chemistry 1】

2. A pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and an auxiliary agent, wherein the auxiliary agent comprises one or more of a filler, a binder, a flow promoter, a disintegrant, and a lubricant, the filler being one or more of lactose, anhydrous lactose, microcrystalline cellulose, mannitol, or starch, the binder being one or more of hydroxypropyl methylcellulose, hydroxypropyl cellulose, povidone, hydroxyethyl cellulose, sodium carboxymethylcellulose, or polyvinyl alcohol, the flow promoter being one or more of colloidal silica, talc, or micronized silica gel, and the disintegrant being low-substituted hydroxypropyl cellulose, cross-linked carboxymethyl cellulose A pharmaceutical composition characterized in that it comprises one or more of sodium carboxymethyl starch, sodium carboxymethyl starch, or cross-linked povidone, 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 to 2.5, the mass ratio of the compound of formula (I) to the binder is 1:0.01 to 0.05, the mass ratio of the compound of formula (I) to the flow promoter is 1:0.01 to 0.03, the mass ratio of the compound of formula (I) to the disintegrant is 1:0.10 to 0.30, the mass ratio of the compound of formula (I) to the lubricant is 1:0.01 to 0.10, and the water content of the pharmaceutical composition is less than 5.0%. 【Chemistry 2】

3. A pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and an auxiliary agent, wherein the auxiliary agent comprises one or more of a filler, a binder, a flow promoter, a disintegrant, and a lubricant, the filler being one or more of lactose, anhydrous lactose, microcrystalline cellulose, mannitol, or starch, the binder being one or more of hydroxypropyl methylcellulose, hydroxypropyl cellulose, povidone, hydroxyethyl cellulose, sodium carboxymethylcellulose, or polyvinyl alcohol, the flow promoter being one or more of colloidal silica, talc, or micronized silica gel, the disintegrant being one or more of low-substituted hydroxypropyl cellulose, crosslinked sodium carboxymethylcellulose, sodium carboxymethyl starch, or crosslinked povidone, and the lubricant being one or more of magnesium stearate, calcium stearate, or sodium stearyl fumarate, the pharmaceutical composition characterized by exhibiting an elution rate of 70.0% or more in 60 min when a pH 6.8 phosphate buffer is used as the elution medium. 【Transformation 3】

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 hydroxypropyl methylcellulose, the flow promoter is colloidal silica, the disintegrant is cross-linked carboxymethylcellulose sodium, 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 to 2.5, the mass ratio of the compound of formula (I) to the binder is 1:0.01 to 0.05, the mass ratio of the compound of formula (I) to the flow promoter is 1:0.01 to 0.03, the mass ratio of the compound of formula (I) to the disintegrant is 1:0.10 to 0.30, and the mass ratio of the compound of formula (I) to the lubricant is 1:0.01 to 0.

10.

6. The mass ratio of the compound of formula (I) to the filler is 1:1.5 to 2.0, the mass ratio of the compound of formula (I) to the binder is 1:0.02 to 0.04, the mass ratio of the compound of formula (I) to the flow promoter is 1:0.012 to 0.020, the mass ratio of the compound of formula (I) to the disintegrant is 1:0.15 to 0.25, and the mass ratio of the compound of formula (I) to the lubricant is 1:0.02 to 0.06, preferably 1:0.02 to 0.

05. The pharmaceutical composition according to any one of claims 1 to 3, wherein 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 flow promoter 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 water 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 it exhibits an elution rate of 43.0% or more in 15 minutes when a phosphate buffer with a pH of 6.8 is used as the elution medium.

9. The pharmaceutical composition according to claim 3, characterized in that it exhibits an elution rate of 60.0% or more in 30 minutes when a phosphate buffer with a pH of 6.8 is used as the elution medium.

10. The pharmaceutical composition according to any one of claims 1 to 3, characterized in that the disintegrant is added inside and outside the granules during the preparation process, and the lubricant is added inside and outside the granules during the preparation process.

11. The pharmaceutical composition according to claim 10, characterized in that, when the disintegrant is added inside or outside the granules during the preparation process, the mass ratio of the disintegrant inside the granules to the disintegrant outside the granules is 1:0.5 to 3, preferably 1:0.8 to 2, and more preferably 1:

1.

12. The pharmaceutical composition according to claim 10, characterized in that when the lubricant is added inside or outside the granules during the preparation process, the mass ratio of the lubricant inside the granules to the lubricant outside the granules is 1:0.5 to 3, preferably 1:0.8 to 2, and more preferably 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 to 5, preferably 1:0.6 to 3, more preferably 1:1 to 3, and most preferably 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 ≤ 8 μm, D50 ≤ 25 μm, and D90 ≤ 160 μm, preferably D10 ≤ 5 μm, D50 ≤ 20 μm, and D90 ≤ 150 μm, and more preferably D10 ≤ 3 μm, D50 ≤ 15 μm, and D90 ≤ 140 μm.

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

16. A pharmaceutical composition comprising the following components, wherein 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. Table 1

17. A pharmaceutical composition comprising the following components, wherein 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. Table 2

18. A pharmaceutical composition comprising the following components, wherein 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. Table 3

19. A pharmaceutical composition comprising the following components, wherein the particle size of the compound of formula (I) is D10 ≤ 3 μm, D50 ≤ 15 μm, and D90 ≤ 140 μm, the compound of formula (I) is in an amorphous form, and the water content of the pharmaceutical composition is 3.0% to 5.0%. Table 4

20. A pharmaceutical composition comprising the following components, wherein the particle size of the compound of formula (I) is D10 ≤ 3 μm, D50 ≤ 15 μm, and D90 ≤ 140 μm, the compound of formula (I) is in an amorphous form, and the water content of the pharmaceutical composition is 3.0% to 5.0%. Table 5

21. A pharmaceutical composition comprising the following components, wherein the particle size of the compound of formula (I) is D10 ≤ 3 μm, D50 ≤ 15 μm, and D90 ≤ 140 μm, the compound of formula (I) is in an amorphous form, and the water content of the pharmaceutical composition is 3.0% to 5.0%. Table 6

22. A pharmaceutical composition comprising the following components, wherein the particle size of the compound of formula (I) is D10 ≤ 3 μm, D50 ≤ 15 μm, and D90 ≤ 140 μm, the compound of formula (I) is in an amorphous form, and the pharmaceutical composition exhibits an elution rate of 70.0% or more in 60 mins when pH 6.8 phosphate buffer is used as the elution medium. Table 7

23. A pharmaceutical composition comprising the following components, wherein the particle size of the compound of formula (I) is D10 ≤ 3 μm, D50 ≤ 15 μm, and D90 ≤ 140 μm, the compound of formula (I) is in an amorphous form, and the pharmaceutical composition exhibits an elution rate of 70.0% or more in 60 mins when pH 6.8 phosphate buffer is used as the elution medium. Table 8

24. A pharmaceutical composition comprising the following components, wherein the particle size of the compound of formula (I) is D10 ≤ 3 μm, D50 ≤ 15 μm, and D90 ≤ 140 μm, the compound of formula (I) is in an amorphous form, and the pharmaceutical composition exhibits an elution rate of 70.0% or more in 60 mins when pH 6.8 phosphate buffer is used as the elution medium. Table 9

25. A method for preparing a pharmaceutical composition according to any one of claims 1 to 24, wherein the preparation method is a non-wet granulation preparation technique.

26. A pharmaceutical tablet comprising a tablet core and a coating applied to the outside of the tablet core, wherein the tablet core is composed of a 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% to 10% of the tablet core mass, preferably 1% to 6%, and more preferably 3%.

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

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