Pharmaceutical composition and medicine for treating coronavirus infection

Abstract

The present invention relates to the field of medical and chemical and pharmaceutical industry, and more particularly, to a novel pharmaceutical composition for treating and / or preventing viral diseases by inhibiting the activity of a viral 3CL protease, in particular a coronavirus 3CL protease, and a drug comprising the same, the pharmaceutical composition comprises ritonavir in an amount of 10.0 to 70.0% by weight and nemategravir in an amount of 30.0 to 90.0% by weight. The present invention can improve the physicochemical properties and processability of pharmaceutical compositions and drugs.

Description

Technical Field

[0001] The present invention relates to the fields of medicine, chemistry and the pharmaceutical industry. Specifically, the present invention relates to a new pharmaceutical composition of ritonavir or a pharmaceutically acceptable salt or solvate thereof and nirmatrelvir or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutical product comprising the said pharmaceutical composition. Background Art

[0002] According to the data of the World Health Organization (WHO), new infectious viral diseases have emerged at an alarming rate. Since the 1970s, approximately 40 new infectious viral diseases have been discovered. Some of the most dangerous newly emerging viruses include: Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV) in 2002-2003, Swine Influenza Virus (A / H1N1) in 2009, Middle East Respiratory Syndrome (MERS) Coronavirus in 2012, the Ebola virus epidemic in 2013-2015, the Zika virus pandemic in 2016-2017, and now SARS-CoV2 which has caused the COVID-19 pandemic. In addition to these newly discovered pathogens, previously recognized viral infections, including pandemic influenza, yellow fever, measles, etc., continue to pose threats through the occurrence of new epidemics (David A. Schwartz. Prioritizing the Continuing Global Challenges to Emerging and Reemerging Viral Infections / / Front. Virol.-2021).

[0003] Phylogenetic analysis indicates that some single-stranded (+)RNA viruses can be classified into the picornavirus-like supercluster, including viruses belonging to the Picornaviridae, Caliciviridae, and Coronaviridae families. A common feature of picornavirus-like supercluster viruses is that they utilize 3C or 3C-like proteases (3Cpro or 3CLpro, respectively) in metabolism. The conserved 3Cpro or 3CLpro sites may be attractive targets for the development of broad-spectrum antiviral drugs against picornavirus-like supercluster viruses (Yunjeong Kim et al. Broad-Spectrum Antivirals against 3C or 3C-Like Proteases of Picornaviruses, Noroviruses, and Coronaviruses / / J Virol.-2012.-86(21), p. 11754–11762).

[0004] The SARS-CoV2 virus has been identified as the pathogen of COVID-19, a severe viral infectious disease accompanied by acute respiratory illness. The coronavirus pandemic began globally in December 2019. Statistically, there are hundreds of thousands of cases and thousands of deaths every day. As of October 11, 2021, the number of cases was 251 million, and the death toll had exceeded 5 million. Since the outbreak of the global pandemic, both global human health and the global economy have been severely damaged. The pandemic poses challenges to modern medicine, and there is an urgent need to develop effective strategies for preventing and treating viral diseases and to establish a government reserve of targeted drugs. Due to the lack of specific treatments for new viruses and their highly variable viruses, there is an urgent need to develop new drugs. In addition to existing therapies, specific drugs that act directly on the virus are needed to relieve disease symptoms, accelerate the resolution of the disease, block the transmission of infection, and reduce the risk of developing clinical complications.

[0005] A promising method for inhibiting the SARS-CoV2 virus is to inhibit the SARS-CoV2 protease, which is also known as 3C-like protease (3CL or 3CLpro). Inhibiting the 3CL protease prevents virus replication. Nirmatrelvir, characterized by formula (I), inhibits the activity of the cysteine residue in the protease during the proteolysis stage. 3CLpro is responsible for the cleavage process of viral lipoproteins, including 3CLpro itself, PLpro (papain-like protease), and 14 other proteins. In preclinical studies in a mouse-adapted SARS-CoV-2 model, this molecule showed high antiviral activity. In addition, it is known from the prior art that nirmatrelvir exhibits inhibitory ability against various 3C-like proteases and not just SARS-CoV-2, which highlights the possibility of using it for other human viruses.

[0006]

[0007] The compound of formula (I)

[0008] There is an urgent search worldwide for drugs that can effectively combat the SARS-CoV-2 virus. One effective way to search for drugs to treat novel coronavirus infections (in particular) is to analyze existing antiviral drugs. For example, various drugs such as ribavirin, interferon, favipiravir, and ritonavir, lopinavir / ritonavir, etc. have been used to treat previous human coronavirus infections, and many of these drugs are currently used to treat COVID-19.

[0009] Ritonavir, the compound of formula (II), is a peptidomimetic inhibitor of HIV protease.

[0010]

[0011] The compound of formula (II)

[0012] Ritonavir plays an important role in restricting the cellular transport of other protease inhibitors. Therefore, ritonavir is often used in combination with other active agents. Using a low dose of ritonavir as a pharmacokinetic enhancer can extend the dosing interval of the main protease inhibitor (once or twice a day), while improving the pill burden, and in the treatment of HIV, compared with unboosted drugs, the efficacy is improved and the possibility of developing drug resistance is reduced (Mark W.H., et al., Ritonavir-boosted protease inhibitors in HIV therapy. / / Annals of Medicine.-2011.-43:5.-p.375-388).

[0013] Ritonavir can also be used to treat hepatitis C virus. Therefore, the use of narlaprevir in combination with ritonavir and sofosbuvir to treat chronic hepatitis C has been proven to be highly effective (Klimova E.A., et al., Narlaprevir, ritonavir and sofosbuvir in patients with chronic hepatitis C infected with genotype 1 of the virus, without liver cirrhosis / / Infectious diseases: news, opinions, training.-2020.-Vol.9, No.1.-P.50-56). The direct-acting antiviral drugs paritaprevir, ritonavir, ombitasvir and dasabuvir have been proven to be highly effective and well-tolerated in patients with HCV-related compensated cirrhosis (Ambalov Yu.M., et al., Combined use of direct antiviral drugs - paritaprevir, ritonavir, ombitasvir and dasabuvir in the treatment of patients with HCV-deterministic compensated cirrhosis in real clinical practice. Medical Bulletin of the South of Russia.-2018.-9(2).-P.88-91).

[0014] It has been reported that lonafarnib in combination with low-dose ritonavir, with the addition of peginterferon alpha, can effectively treat patients with chronic hepatitis D (Cihan Yurdaydin et al., A Phase ii dose finding study of lonafarnib and ritonavir with or without interferon alpha for chronic delta hepatitis\\Hepatology.-2022.-75(6).-p.1551-1565).

[0015] Ritonavir is currently used to increase the plasma concentration of nirmatrelvir. Ritonavir itself is inactive against SARS-CoV-2 (Nirmatrelvir and ritonavir for COVID-19. Aust Prescr. - 2022. - 45(2):61). As a CYP3A inhibitor, ritonavir can downregulate the metabolism of nirmatrelvir, so nirmatrelvir combined with ritonavir has the greatest therapeutic effect. In non-hospitalized adults at high risk of progressing to severe COVID-19, the combination of nirmatrelvir and ritonavir can effectively reduce the risk of progressing to severe COVID-19 (Lamb YN. Nirmatrelvir Plus Ritonavir: First Approval. Drugs. - 2022. - 82(5). - p.585 - 591).

[0016] Currently, Pfizer has developed a combined antiviral drug Paxlovid, which is manufactured in the form of a combination of nirmatrelvir tablets and ritonavir tablets for the treatment of COVID-19. Ritonavir is added to this combination to enhance the effect of the main ingredient nirmatrelvir. Although this drug is effective, the process and physicochemical properties of this drug have not been fully studied.

[0017] Currently, there is an urgent need to develop alternative formulations and processes to produce a drug that contains both nirmatrelvir and ritonavir and to improve its process and physicochemical properties.

[0018] When developing a drug, it is important that the ingredients of the drug have certain satisfactory physicochemical and process characteristics while demonstrating their pharmacological activity. Such compositions must be able to be effectively stored for a relatively long time under various conditions, and the physicochemical properties of the active ingredient or mixture of active ingredients do not change significantly.

[0019] In order to provide rapid and high-quality assistance to the public, it is necessary to establish a reserve of antiviral drugs, which depends on whether the drugs can be stored for a long time. That is to say, such drugs must have optimal process and physicochemical properties, including high stability for a long time under various climate conditions (including stress conditions such as high temperature, high humidity, light, etc.). Summary of the Invention

[0020] Controlling the physicochemical and process characteristics of materials has a global impact on the development of rational and economically advantageous modern drug production processes. Crucial parameters in the production of solid dosage forms (tablets, dragees, granules, powders, capsules, etc.) are the process and physicochemical properties of each individual substance and their mixtures.

[0021] The physicochemical properties of the pharmaceutical preparation and the bulk material of the medicament containing said preparation include solubility, reactivity, hygroscopicity, stability, hydrophilicity, density, shape, size, properties of the particle surface, specific surface area of the particles, coefficient of contact friction, wettability, adhesiveness, cohesiveness, static electricity, and surface activity. For an appropriate combination of substances in a pharmaceutical composition, it is crucial to consider their physicochemical properties, which can both avoid the generation of impurities due to the interaction of substances during the production and storage of medicaments and minimize the risk of degradation of substances during the production of medicaments.

[0022] Even in small amounts, pharmaceutical impurities can have serious adverse effects on the health of patients, affecting the action and efficacy of medicaments. Degradation impurities of medicaments can have various negative impacts on the quality of medicaments. For example, impurities may cause incompatibility and / or negative interactions with other active agents and / or pharmaceutical excipients, and shorten the shelf life of medicaments. Impurities in medicaments (including related impurities of the active agent in the medicament) sometimes change the physicochemical properties of the components of the medicament, making it difficult to predict the efficacy of the medicament. In addition, the presence of impurities changes the pharmacological properties of the medicament, including pharmacokinetics. In some cases, impurities significantly reduce the therapeutic effect of the medicament while having toxic effects, which may manifest unpredictably. The effects of impurities on the medicament pose a threat to the safety of patients and reduce the tolerance of the medicament.

[0023] The process / process performance of the bulk material in the pharmaceutical preparation and the medicament containing said preparation includes plasticity, strength, bulk density, elasticity, viscosity, degree of compaction, flowability, humidity, disintegrability, dispersibility, porosity, compressibility, force of extrusion from the matrix, uniformity of composition, distribution of the active agent in the medicament, etc. The structural and mechanical properties of a set of materials selected in a balanced manner directly ensure the quality of the finished medicament.

[0024] Controlling the coefficient of friction of the bulk material in the production of medicaments can estimate the degree of wear of tablets. The selection of the pressing tool of the tablet press depends on the coefficient of friction of the bulk material. The higher the value of the coefficient of contact friction, the more wear-resistant the equipment should be.

[0025] The wettability of the components and their mixtures in solid pharmaceutical preparations characterizes their ability to interact with various liquids (mainly water). Controlling the wettability of the preparation can reasonably formulate the process strategy to avoid unnecessary absorption of liquid by the composition and avoid water accumulation due to contact with steam in the air. Based on this property, the granulation technology is selected. Bulk materials that are not easily wetted are dry granulated, and bulk materials with good wettability can be dry and wet granulated. Pharmaceuticals with good disintegrability can be manufactured from bulk materials with good wettability (the most important property of tablets, and the release kinetics of pharmaceutical active ingredients in the human digestive tract depends on this). It is also worth noting that due to the uncontrolled absorption of moisture by tablets, negative effects such as swelling, loss of necessary technological properties of the structure and composition, deterioration of the quality of the components in the mixture (including hydrolysis of substances, resulting in the formation of impurities) can be observed.

[0026] The phenomenon of excessive charging of bulk materials during the pharmaceutical production process may have a negative impact on the process. Among the adverse phenomena, equipment contamination, disruption of the uniformity of the composition and distribution of the active ingredient, and unsatisfactory technological properties of the finished pharmaceutical may be observed. During the pressing process of pharmaceutical preparations, not only surface friction and spatial orientation compression occur, but also polarization occurs with the appearance of surface charges. When the particles contact the wall of the tablet press die or the particles contact each other, a contact potential difference is generated. The greater the contact potential difference, the stronger the cohesion. The coagulation ability of hydrophobic substances is lower than that of hydrophilic substances because their surface conductivity is lower.

[0027] During the development of the process, it is very important to control the fractional (particle size) composition because this characteristic is related to the fluidity of pharmaceutical preparations and thus directly affects the regular operation of the tablet press, the stability of the quality of the obtained tablets, the accuracy of active ingredient administration, and the quality characteristics of the tablets (including appearance, physicochemical and technological properties).

[0028] The basic characteristic of all bulk materials is density. Knowing the bulk density of the bulk materials used in pharmaceutical preparations, their volume can be calculated, and accordingly, when designing containers or dispensers, as well as capsules and tablets, the filling height can be calculated. By controlling this parameter, the mass of a dose, a portion, or a package can be easily calculated, thereby determining the dose of the encapsulator or tablet press and any other packaging equipment, which is necessary for the effective development of the process.

[0029] In pharmaceutical production, in addition to density, it is also important to control the porosity and compactibility of materials, because the ability of bulk materials to be compressed under pressure and the formation of finished pharmaceuticals with specified properties depend on these parameters. In turn, the compressibility of bulk materials depends on the shape of the particles and their ability to move and deform under pressure. In particular, the higher the compressibility, the more time it takes to press the tablet mass, and the force required to push the tablet out of the die channel depth also increases. As the bulk density increases, the flowability of the powder improves, but this is not the case for the finest particle fraction, and the relationship between bulk density and flowability may be disrupted due to a sharp increase in internal friction.

[0030] Flowability characterizes the ability of bulk materials to pour out of a container under their own gravity and uniformly fill the die channel space. The flowability of a pharmaceutical composition in powder form depends on its humidity, the shape and size of the particles, and the particle size composition. Powders with good flowability are easy to dose and mix. If the flowability characteristics of the material are unsatisfactory, adhesion to the container walls, disruption of the regular flow of the material, and non-uniform distribution will occur, ultimately leading to fluctuations in the specified quality and density of the tablets.

[0031] The possibility of forming stable, durable, compact, and uniform pharmaceuticals depends on the compressibility of the bulk materials. In turn, compressibility depends on the strength and elasticity of the raw material particles: the higher these properties, the greater the likelihood that the pharmaceutical will retain its properties after the compression process. In addition, the compressibility of bulk materials is affected by the ability of the particles to be attracted under the action of static electricity. This effect is exhibited if the structure of the bulk material contains polar compounds, because non-polar compounds are not prone to forming surface charges. Therefore, the better the compressibility of the bulk materials, the higher the strength of solid pharmaceuticals, including tablets. At the same time, when ejected from the die, the low strength of the tablets can lead to fragility or complete destruction, resulting in manufacturing defects.

[0032] Therefore, it can be concluded that many of the above properties are interrelated and directly affect the quality of pharmaceuticals, including those in solid form. Conducting multidisciplinary research on the properties of solid pharmaceuticals and their production materials (components) can achieve an appropriate level of mechanization in the production stage and operations, the accuracy of active substance administration, the portability of the pharmaceutical production process, the overall preservation of the active agent and the pharmaceutical, the combination (union) of poorly compatible pharmaceuticals, and the regulation of active agent release.

[0033] Currently, there is a continuous need to develop improved solid dosage forms. In particular, compositions for forming solid pharmaceuticals have received much attention, which will have a higher and more uniform active agent release profile while improving the physicochemical properties, including the stability of the pharmaceutical during storage.

[0034] The technical problem of the present invention is to develop and study a drug for treating and / or preventing viral diseases by inhibiting the activity of viral 3CL protease, which has improved technological and physicochemical properties.

[0035] The inventors solved the above technical problem by combining ritonavir or its pharmaceutically acceptable salt or solvate and nirmatrelvir or its pharmaceutically acceptable salt or solvate in a single drug, and making the components evenly distributed in the drug.

[0036] As a result of long-term experiments, the inventors obtained and studied a new combination drug, which contains ritonavir or its pharmaceutically acceptable salt or solvate and nirmatrelvir or its pharmaceutically acceptable salt or solvate, and the combination drug has improved technological, physicochemical and pharmacokinetic properties.

[0037] Therefore, the technical achievements of the present invention are:

[0038] - improving the stability of the combination preparation containing ritonavir or its pharmaceutically acceptable salt or solvate and nirmatrelvir or its pharmaceutically acceptable salt or solvate (including during storage at a wide range of temperatures and humidities, and photo-stability);

[0039] - reducing the impurities formed in the combination preparation containing ritonavir or its pharmaceutically acceptable salt or solvate and nirmatrelvir or its pharmaceutically acceptable salt or solvate during the storage of the preparation or the manufacturing process of the drug;

[0040] - improving the pharmacokinetic properties of the combination preparation containing ritonavir or its pharmaceutically acceptable salt or solvate and nirmatrelvir or its pharmaceutically acceptable salt or solvate;

[0041] - expanding the drug library of antiviral agents with new pharmacological, physicochemical and technological properties without reducing the therapeutic activity.

[0042] The inventors also studied the properties of the solid - form formulations according to the present invention, which formulations comprise ritonavir or a pharmaceutically acceptable salt or solvate thereof and nirmatrelvir or a pharmaceutically acceptable salt or solvate thereof. As a result of extensive experiments, it was unexpectedly found that a formulation comprising ritonavir or a pharmaceutically acceptable salt or solvate thereof and nirmatrelvir or a pharmaceutically acceptable salt or solvate thereof, in the case of adding at least one water - insoluble polymer selected from cellulose derivatives with a content of about 5.0 to 40.0% by weight of the formulation, at least one water - soluble polymer selected from vinylpyrrolidone derivatives with a content of about 5.0 to 35.0% by weight of the formulation, and at least one disaccharide with a content of about 9.0 to 25.0% by weight of the formulation, exhibits improved compression properties while maintaining good flowability, without significant electrostatic phenomena, and the compression tablets obtained from these compositions have most preferably disintegration characteristics.

[0043] The definitions of the terms used in the description of the present invention are given below.

[0044] Unless otherwise specified, all technical and professional terms used in this context have their generally accepted meanings in the art.

[0045] In the context of the present invention, the term "excipient" refers to a substance of inorganic or organic origin that confers the necessary physicochemical properties to a drug during the production and preparation of the drug.

[0046] In the context of the present invention, the term "pharmaceutical composition" refers to a composition comprising a therapeutic active ingredient or a combination of active ingredients, and if necessary, further comprising at least one pharmaceutically acceptable and pharmacologically compatible excipient.

[0047] In the context of the present invention, the term "pharmaceutically acceptable" means that the substance or composition to which this term applies must be chemically and / or toxicologically compatible with the other components of the composition or drug, and is safe for the person being treated with the substance or composition.

[0048] In the context of the present invention, "pharmaceutically acceptable salts" refer to relatively safe and non - toxic organic and inorganic salts of the acids and bases claimed in the present invention.

[0049] In the context of the present invention, the term "drug" refers to a synthetic or natural - source substance or mixture of substances that comes into contact with the human or animal organism, penetrates into the organs and tissues of the human or animal organism, and is used for the prevention or treatment of diseases. Drugs include finished - dosage - form drugs, including active ingredients and at least one excipient, and are intended to be administered to animals or humans by various methods (such as but not limited to oral, sublingual administration). Suitable unit dosage forms include (but are not limited to) oral forms: tablets, capsules, pills, granules.

[0050] In the context of the present invention, the expression "in solid form" refers to pharmaceutical compositions and medicaments having a solid, dense or viscous consistency, in which the particles interact so that the substance retains its size and shape.

[0051] In the context of the present invention, the term "impurity" is any component in a pharmaceutical composition and / or medicament that is not an active ingredient or an excipient. The quality indicators of a pharmaceutical composition and / or medicament characterize the content of impurities in the pharmaceutical composition and / or medicament, including residual impurities that enter the pharmaceutical composition and / or medicament during the synthesis of the active ingredient (including related impurities), impurities during the production of the substance, pharmaceutical composition / medicament (process impurities), and impurities formed during the degradation of the substance, pharmaceutical composition components and / or medicament components during storage, and are expressed as a percentage. The sources of impurities may be residues of reagents, catalysts, process equipment, filter materials, and raw materials with insufficient purification used for synthesizing pharmaceutical composition and / or medicament components and producing pharmaceutical compositions / medicaments.

[0052] In the context of the present invention, the terms "include", "comprising", "comprises" mean that the said pharmaceutical composition and / or medicament includes the listed components, but do not exclude the inclusion of other components.

[0053] In the context of the present invention, the term "effective amount" means that when administered to a subject for treating and / or preventing a disease, or at least one clinical symptom of a disease or disorder, this amount of the substance (and combinations of substances) is sufficient to make such treatment and / or prevention effective against the disease, disorder or symptom. The "effective amount" depends on the disease, disorder, and / or symptoms of the disease or disorder; the severity of the disease, disorder, and / or symptoms of the disease or disorder; the clinical manifestations and general health status of the patient, and the age and / or weight of the subject in need of such treatment and / or prevention.

[0054] The terms "about" and "approximately" used in the description mean approximately plus or minus 10% of the specific value.

[0055] In the context of the present invention, "stability" refers to the ability of an active ingredient, pharmaceutical composition or medicament to maintain its performance and quality characteristics within a specified range under established storage conditions throughout the shelf life (storage time) and period of use. The stability of an active ingredient, pharmaceutical composition or medicament is a necessary condition to ensure the therapeutic effect or the absence of new side effects.

[0056] Depending on the nature of preservation and quality characteristics, the following types of stability of active ingredients, substances, pharmaceutical compositions or medicaments are distinguished:

[0057] - Chemical stability, in which the chemical integrity and activity of the active ingredient are maintained within the ranges specified by the specifications;

[0058] - Physical stability, in which the main physical properties of the active ingredient, pharmaceutical composition or drug product are retained, including appearance, taste, homogeneity, solubility, suspension, etc.;

[0059] - Microbiological stability, maintaining the sterility or microbiological purity of the active ingredient, pharmaceutical composition or drug product according to the specified requirements, or the effectiveness of the antibacterial preservatives contained in the composition within the specified range;

[0060] - Toxicological stability, in which the toxicity of the drug product does not increase significantly;

[0061] - Therapeutic stability, in which the therapeutic effect of the active ingredient, pharmaceutical composition or drug product remains unchanged.

[0062] In the context of the present invention, the term "vinylpyrrolidone derivative" refers to water-soluble polymers including N-vinylpyrrolidone (the molecular composition of these polymers includes N-vinylpyrrolidone monomers).

[0063] In the context of the present invention, the term "cellulose derivative" refers to compounds having one or more different atoms from cellulose, for example, including isotopes of atoms, functional groups such as alkyl (saturated or unsaturated), cycloalkyl, heterocyclic, aryl (substituted or unsubstituted), alcohol, alkoxy, carbonyl (aldehyde or ketone), carboxyl, ester, amino (including substituted), nitro, nitroso, nitrile, hydrazine, amide, mercaptan, sulfide, disulfide, sulfoxide, sulfonyl, halogen atoms; any of which functional groups may be replaced by another functional group or atom; isomers of a given compound, including structural and spatial isomers (i.e., geometric isomers (such as cis / trans isomers), optical isomers (such as R / S isomers, D / L isomers), enantiomers, diastereomers, anomers, dynamic isomers (such as tautomers), conformational isomers); various solid forms of a given compound, i.e., salts, solvates, including hydrates. Description of the Drawings

[0064] The present invention is further illustrated by Figure 1 which

[0065] Figure 1 shows the viral titers in the lungs of hamsters treated with the formulation containing nirmatrelvir and ritonavir (1) and microcrystalline cellulose - placebo (2). Detailed Description

[0066] By preparing a pharmaceutical composition for treating and / or preventing viral diseases by inhibiting the activity of viral 3CL protease, the above technical problems are solved and the claimed technical results are achieved. The pharmaceutical composition comprises ritonavir or a pharmaceutically acceptable salt or solvate thereof in an amount of 10.0 to 70.0% by weight of the pharmaceutical composition, and nirmatrelvir or a pharmaceutically acceptable salt or solvate thereof in an amount of 30.0 to 90.0% by weight of the pharmaceutical composition, wherein ritonavir and nirmatrelvir are uniformly distributed in the pharmaceutical composition.

[0067] By preparing a pharmaceutical composition for treating and / or preventing viral diseases by inhibiting the activity of viral 3C-like protease, the above technical problems are solved and the claimed technical results are achieved. The pharmaceutical composition comprises an effective amount of ritonavir or a pharmaceutically acceptable salt or solvate thereof in an amount of 10.0 to 70.0% by weight of the pharmaceutical composition, and nirmatrelvir or a pharmaceutically acceptable salt or solvate thereof in an amount of 30.0 to 90.0% by weight of the pharmaceutical composition, wherein ritonavir and nirmatrelvir are uniformly distributed in the pharmaceutical composition.

[0068] By preparing a pharmaceutical composition for treating and / or preventing viral diseases by inhibiting the activity of viral 3C-like protease, the above technical problems are solved and the claimed technical results are achieved. The pharmaceutical composition comprises ritonavir or a pharmaceutically acceptable salt or solvate thereof in an amount of 15.0 to 25.0% by weight of the pharmaceutical composition, and nirmatrelvir or a pharmaceutically acceptable salt or solvate thereof in an amount of 75.0 to 85.0% by weight of the pharmaceutical composition, wherein ritonavir and nirmatrelvir are uniformly distributed in the pharmaceutical composition.

[0069] By preparing a pharmaceutical composition for treating and / or preventing viral diseases by inhibiting the activity of viral 3C-like protease, the above technical problems are solved and the claimed technical results are achieved. The pharmaceutical composition comprises ritonavir or a pharmaceutically acceptable salt or solvate thereof in an amount of 5.0 to 50.0% by weight of the pharmaceutical composition, nirmatrelvir or a pharmaceutically acceptable salt or solvate thereof in an amount of 10.0 to 60.0% by weight of the pharmaceutical composition, and additional pharmaceutically acceptable excipients, wherein the components of the pharmaceutical composition are uniformly distributed in the pharmaceutical composition.

[0070] By preparing a pharmaceutical composition for treating and / or preventing viral diseases, the above technical problems are solved and the claimed technical results are achieved. The pharmaceutical composition contains ritonavir or a pharmaceutically acceptable salt or solvate thereof in an amount of 5.0 to 50.0% by weight of the pharmaceutical composition, and nirmatrelvir or a pharmaceutically acceptable salt or solvate thereof in an amount of 10.0 to 60.0% by weight of the pharmaceutical composition, wherein ritonavir and nirmatrelvir are uniformly distributed in the pharmaceutical composition.

[0071] By preparing a pharmaceutical composition for treating and / or preventing viral diseases by inhibiting the activity of viral 3C-like protease, the above technical problems are solved and the claimed technical results are achieved. The pharmaceutical composition contains ritonavir or a pharmaceutically acceptable salt thereof in an amount of 5.0 to 50.0% by weight of the pharmaceutical composition, nirmatrelvir or a pharmaceutically acceptable solvate thereof in an amount of 10.0 to 60.0% by weight of the pharmaceutical composition, and additional pharmaceutically acceptable excipients, wherein each component is uniformly distributed by weight of the pharmaceutical composition.

[0072] By preparing a pharmaceutical composition for treating and / or preventing viral diseases by inhibiting the activity of viral 3C-like protease, the above technical problems are solved and the claimed technical results are achieved. The pharmaceutical composition contains ritonavir or a pharmaceutically acceptable salt or solvate thereof in an amount of 5.0 to 50.0% by weight of the pharmaceutical composition, nirmatrelvir or a pharmaceutically acceptable salt or solvate thereof in an amount of 10.0 to 60.0% by weight of the pharmaceutical composition, and additional pharmaceutically acceptable excipients, wherein ritonavir and nirmatrelvir are not separated from each other but are uniformly distributed in the pharmaceutical composition.

[0073] In one embodiment of the present invention, there is provided a pharmaceutical composition according to the present invention, characterized in that it contains ritonavir or a pharmaceutically acceptable salt or solvate thereof in an amount of 10.0 to 15.0% by weight of the pharmaceutical composition, nirmatrelvir or a pharmaceutically acceptable salt or solvate thereof in an amount of 30.0 to 40.0% by weight of the pharmaceutical composition, and additional pharmaceutically acceptable excipients.

[0074] In one embodiment of the present invention, there is provided a pharmaceutical composition according to the present invention, characterized in that it contains ritonavir or a pharmaceutically acceptable salt thereof in an amount of 10.0 to 15.0% by weight of the pharmaceutical composition, nirmatrelvir or a pharmaceutically acceptable solvate thereof in an amount of 30.0 to 40.0% by weight of the pharmaceutical composition, and additional pharmaceutically acceptable excipients.

[0075] In one embodiment of the present invention, a pharmaceutical composition is provided, wherein ritonavir or a pharmaceutically acceptable salt or solvate thereof and nirmatrelvir or a pharmaceutically acceptable salt or solvate thereof are the active agents in the pharmaceutical composition.

[0076] In one embodiment of the present invention, a pharmaceutical composition is provided, wherein ritonavir or a pharmaceutically acceptable salt or solvate thereof and nirmatrelvir or a pharmaceutically acceptable salt or solvate thereof are uniformly distributed in the pharmaceutical composition.

[0077] In one embodiment of the present invention, a pharmaceutical composition is provided, wherein ritonavir or a pharmaceutically acceptable salt or solvate thereof and nirmatrelvir or a pharmaceutically acceptable salt or solvate thereof are not separated from each other, but are uniformly distributed in the pharmaceutical composition.

[0078] In one embodiment of the present invention, a pharmaceutical composition is provided, which is characterized in that it is a solid pharmaceutical composition.

[0079] In one embodiment of the present invention, a pharmaceutical composition is provided, which is characterized in that it is a solid pharmaceutical composition in powder form.

[0080] In one embodiment of the present invention, a pharmaceutical composition is provided, which is characterized in that it contains a pharmaceutically acceptable excipient.

[0081] In one embodiment of the present invention, a pharmaceutical composition is provided, which is characterized in that it further contains a pharmaceutically acceptable excipient.

[0082] In one embodiment of the present invention, a pharmaceutical composition is provided, which is characterized in that it contains a pharmaceutically acceptable excipient selected from fillers, disintegrants, binders, detergents (surfactants) and lubricants.

[0083] In one embodiment of the present invention, a pharmaceutical composition is provided, which may contain, but is not limited to, lactose, lactose monohydrate, microcrystalline cellulose, sucrose, starch, corn starch, trehalose, trehalose dihydrate, calcium carbonate or a mixture thereof as a filler.

[0084] In one embodiment of the present invention, a pharmaceutical composition is provided, which may contain, but is not limited to, sodium carboxymethylcellulose cross-linked, starch, maltose, carboxymethylcellulose cross-linked, methylcellulose, hydroxypropylcellulose low-substituted, crospovidone or a mixture thereof as a disintegrant.

[0085] In one embodiment of the present invention, there is provided a pharmaceutical composition, characterized in that it may comprise, but is not limited to, povidone, copovidone, polyethylene glycol (Macrogol), sodium alginate, ethyl cellulose, sucrose or a mixture thereof as a binder.

[0086] In one embodiment of the present invention, there is provided a pharmaceutical composition, characterized in that it may comprise, but is not limited to, sodium lauryl sulfate, polysorbate, sorbitan laurate or a mixture thereof as a detergent (surfactant).

[0087] In one embodiment of the present invention, there is provided a pharmaceutical composition, characterized in that it may comprise, but is not limited to, sodium stearyl fumarate, stearic acid, magnesium stearate, calcium stearate or a mixture thereof as a lubricant.

[0088] In one embodiment of the present invention, there is provided a pharmaceutical composition, characterized in that it comprises at least one filler in an amount of 10.0 to 55.0% by weight of the pharmaceutical composition, at least one disintegrant in an amount of 5.0 to 15.0% by weight of the pharmaceutical composition, at least one binder in an amount of 4.0 to 15.0% by weight of the pharmaceutical composition, at least one detergent (surfactant) in an amount of 1.5 to 5.0% by weight of the pharmaceutical composition, and at least one lubricant in an amount of 0.5 to 5.0% by weight of the pharmaceutical composition.

[0089] In one embodiment of the present invention, there is provided a pharmaceutical composition, characterized in that it comprises at least one filler in an amount of 12.0 to 32.0% by weight of the pharmaceutical composition, at least one disintegrant in an amount of 5.0 to 7.0% by weight of the pharmaceutical composition, at least one binder in an amount of 4.0 to 7.0% by weight of the pharmaceutical composition, at least one detergent (surfactant) in an amount of 1.5 to 3.0% by weight of the pharmaceutical composition, and at least one lubricant in an amount of 0.5 to 1.5% by weight of the pharmaceutical composition.

[0090] In one embodiment of the present invention, there is provided a pharmaceutical composition, characterized in that it comprises at least one water-soluble polymer selected from vinyl pyrrolidone derivatives as a pharmaceutically acceptable excipient.

[0091] In one embodiment of the present invention, there is provided a pharmaceutical composition, characterized in that the vinyl pyrrolidone derivatives are selected from the group consisting of povidone and copovidone.

[0092] In one embodiment of the present invention, there is provided a pharmaceutical composition, characterized in that it comprises at least one vinyl pyrrolidone derivative in an amount of 5.0 to 35.0% by weight of the pharmaceutical composition.

[0093] In one embodiment of the present invention, there is provided a pharmaceutical composition, which is characterized in that it contains at least one vinylpyrrolidone derivative in an amount of 5.0 to 15.0% by weight of the pharmaceutical composition.

[0094] In one embodiment of the present invention, there is provided a pharmaceutical composition, which is characterized in that it contains at least one water-insoluble polymer selected from cellulose derivatives as a pharmaceutically acceptable excipient.

[0095] In one embodiment of the present invention, there is provided a pharmaceutical composition, which is characterized in that the cellulose derivatives are selected from the group consisting of microcrystalline cellulose, sodium carboxymethylcellulose cross-linked, ethylcellulose, low-substituted hydroxypropylcellulose, and hypromellose acetate succinate.

[0096] In one embodiment of the present invention, there is provided a pharmaceutical composition, which is characterized in that it contains at least one cellulose derivative in an amount of 5.0 to 40.0% by weight of the pharmaceutical composition.

[0097] In one embodiment of the present invention, there is provided a pharmaceutical composition, which is characterized in that it contains at least one cellulose derivative in an amount of 5.0 to 20.0% by weight of the pharmaceutical composition.

[0098] In one embodiment of the present invention, there is provided a pharmaceutical composition, which is characterized in that it contains at least one disaccharide or its hydrate as a pharmaceutically acceptable excipient.

[0099] In one embodiment of the present invention, there is provided a pharmaceutical composition, which is characterized in that the disaccharide or its hydrate is selected from the group consisting of lactose monohydrate, lactose, sucrose, trehalose, trehalose dihydrate, and maltose.

[0100] In one embodiment of the present invention, there is provided a pharmaceutical composition, which is characterized in that it contains at least one disaccharide or its hydrate in an amount of 9.0 to 25.0% by weight of the pharmaceutical composition as a pharmaceutically acceptable excipient.

[0101] In one embodiment of the present invention, there is provided a pharmaceutical composition, which is characterized in that it contains at least one disaccharide or hydrate in an amount of 9.0 to 19.0% by weight of the pharmaceutical composition as a pharmaceutically acceptable excipient.

[0102] In one embodiment of the present invention, there is provided a pharmaceutical composition, characterized in that it comprises at least one water-soluble polymer selected from vinyl pyrrolidone derivatives as a pharmaceutically acceptable excipient in an amount of 5.0 to 35.0% by weight of the pharmaceutical composition, at least one water-insoluble polymer selected from cellulose derivatives in an amount of 5.0 to 40.0% by weight of the pharmaceutical composition, and a disaccharide or hydrate in an amount of 9.0 to 25.0% by weight of the pharmaceutical composition.

[0103] In one embodiment of the present invention, there is provided a pharmaceutical composition, characterized in that it comprises at least one water-soluble polymer selected from vinyl pyrrolidone derivatives as a pharmaceutically acceptable excipient in an amount of 5.0 to 15.0% by weight of the pharmaceutical composition, at least one water-insoluble polymer selected from cellulose derivatives in an amount of 5.0 to 20.0% by weight of the pharmaceutical composition, and a disaccharide or hydrate in an amount of 9.0 to 19.0% by weight of the pharmaceutical composition.

[0104] In one embodiment of the present invention, there is provided a pharmaceutical composition, characterized in that it consists of ritonavir or a pharmaceutically acceptable salt or solvate thereof in an amount of 5.0 to 50.0% by weight of the pharmaceutical composition, nirmatrelvir or a pharmaceutically acceptable salt or solvate thereof in an amount of 10.0 to 60.0% by weight of the pharmaceutical composition, at least one water-soluble polymer selected from vinyl pyrrolidone derivatives in an amount of 5.0 to 35.0% by weight of the pharmaceutical composition, at least one water-insoluble polymer selected from cellulose derivatives in an amount of 5.0 to 40.0% by weight of the pharmaceutical composition, at least one disaccharide or its hydrate in an amount of 9.0 to 25.0% by weight of the pharmaceutical composition, at least one surfactant (detergent) in an amount of 1.0 to 3.0% by weight of the pharmaceutical composition, and at least one lubricant in an amount of 0.5 to 1.5% by weight of the pharmaceutical composition.

[0105] In one embodiment of the present invention, there is provided a pharmaceutical composition, characterized in that it consists of ritonavir or a pharmaceutically acceptable salt or solvate thereof in an amount of 5.0 to 50.0% by weight of the pharmaceutical composition, nirmatrelvir or a pharmaceutically acceptable salt or solvate thereof in an amount of 10.0 to 60.0% by weight of the pharmaceutical composition, at least one water-soluble polymer selected from vinyl pyrrolidone derivatives in an amount of 5.0 to 15.0% by weight of the pharmaceutical composition, at least one water-insoluble polymer selected from cellulose derivatives in an amount of 5.0 to 20.0% by weight of the pharmaceutical composition, at least one disaccharide or its hydrate in an amount of 9.0 to 19.0% by weight of the pharmaceutical composition, at least one surfactant (detergent) in an amount of 1.0 to 3.0% by weight of the pharmaceutical composition, and at least one lubricant in an amount of 0.5 to 1.5% by weight of the pharmaceutical composition.

[0106] In one embodiment of the present invention, a pharmaceutical composition is provided, which is characterized in that it consists of ritonavir or a pharmaceutically acceptable salt or solvate thereof in an amount of 10.0 to 25.0% by weight of the pharmaceutical composition, nirmatrelvir or a pharmaceutically acceptable salt or solvate thereof in an amount of 25.0 to 45.0% by weight of the pharmaceutical composition, at least one water-soluble polymer selected from vinyl pyrrolidone derivatives in an amount of 5.0 to 12.0% by weight of the pharmaceutical composition, at least one water-insoluble polymer selected from cellulose derivatives in an amount of 10.0 to 20.0% by weight of the pharmaceutical composition, at least one disaccharide or its hydrate in an amount of 12.0 to 19.0% by weight of the pharmaceutical composition, at least one surfactant (detergent) in an amount of 1.5 to 3.0% by weight of the pharmaceutical composition, and at least one lubricant in an amount of 0.5 to 1.5% by weight of the pharmaceutical composition.

[0107] In one embodiment of the present invention, a pharmaceutical composition is provided, which is characterized in that it consists of ritonavir or a pharmaceutically acceptable salt or solvate thereof in an amount of 10.0 to 15.0% by weight of the pharmaceutical composition, nirmatrelvir or a pharmaceutically acceptable salt or solvate thereof in an amount of 30.0 to 40.0% by weight of the pharmaceutical composition, at least one water-soluble polymer selected from vinyl pyrrolidone derivatives in an amount of 5.0 to 10.0% by weight of the pharmaceutical composition, at least one water-insoluble polymer selected from cellulose derivatives in an amount of 15.0 to 20.0% by weight of the pharmaceutical composition, at least one disaccharide or its hydrate in an amount of 15.0 to 19.0% by weight of the pharmaceutical composition, at least one surfactant (detergent) in an amount of 1.5 to 2.5% by weight of the pharmaceutical composition, and at least one lubricant in an amount of 0.5 to 1.5% by weight of the pharmaceutical composition.

[0108] By preparing a medicament for treating and / or preventing viral diseases by inhibiting the activity of viral 3C-like protease, the above technical problems are solved and the required technical results are achieved. The medicament contains the pharmaceutical composition according to the present invention and at least one pharmaceutically acceptable excipient.

[0109] By preparing a medicament for treating and / or preventing viral diseases by inhibiting the activity of viral 3C-like protease, the above technical problems are solved and the required technical results are achieved. The medicament contains the pharmaceutical composition according to the present invention.

[0110] By preparing a medicament for treating and / or preventing viral diseases by inhibiting the activity of viral 3C-like protease, the above technical problems are solved and the required technical results are achieved. The medicament comprises a pharmaceutical composition, which contains ritonavir or a pharmaceutically acceptable salt or solvate thereof at a content of 5.0 to 50.0% by weight of the pharmaceutical composition, nirmatrelvir or a pharmaceutically acceptable salt or solvate thereof at a content of 10.0 to 60.0% by weight of the pharmaceutical composition, and at least one pharmaceutically acceptable excipient.

[0111] By preparing a medicament for treating and / or preventing viral diseases by inhibiting the activity of viral 3C-like protease, the above technical problems are solved and the required technical results are achieved. The medicament comprises a pharmaceutical composition, which contains an effective amount of ritonavir or a pharmaceutically acceptable salt or solvate thereof at a content of 5.0 to 50.0% by weight of the pharmaceutical composition, nirmatrelvir or a pharmaceutically acceptable salt or solvate thereof at a content of 10.0 to 60.0% by weight of the pharmaceutical composition, and at least one pharmaceutically acceptable excipient.

[0112] By preparing a medicament for treating and / or preventing viral diseases by inhibiting the activity of viral 3C-like protease, the above technical problems are solved and the required technical results are achieved. The medicament comprises a pharmaceutical composition, which contains ritonavir or a pharmaceutically acceptable salt or solvate thereof at a content of 5.0 to 50.0% by weight of the pharmaceutical composition, nirmatrelvir or a pharmaceutically acceptable salt or solvate thereof at a content of 10.0 to 60.0% by weight of the pharmaceutical composition, and at least one pharmaceutically acceptable excipient, wherein all components in the medicament are evenly distributed according to the weight of the medicament.

[0113] By preparing a medicament for treating and / or preventing viral diseases by inhibiting the activity of viral 3C-like protease, the above technical problems are solved and the required technical results are achieved. The medicament contains ritonavir or a pharmaceutically acceptable salt or solvate thereof at a content of 5.0 to 50.0% by weight of the medicament, nirmatrelvir or a pharmaceutically acceptable drug thereof, and at least one pharmaceutically acceptable excipient, wherein all components in the medicament are evenly distributed according to the weight of the medicament.

[0114] By preparing a medicament for treating and / or preventing viral diseases by inhibiting the activity of viral 3C-like protease, the above technical problems are solved and the required technical results are achieved. The medicament contains an effective amount of ritonavir or a pharmaceutically acceptable salt or solvate thereof at a content of 5.0 to 50.0% by weight of the medicament, nirmatrelvir or a pharmaceutically acceptable drug thereof, and at least one pharmaceutically acceptable excipient, wherein all components in the medicament are evenly distributed according to the weight of the medicament.

[0115] By preparing a medicament for treating and / or preventing viral diseases by inhibiting the activity of viral 3C-like protease, the above technical problems are solved and the required technical results are achieved. The medicament contains ritonavir or a pharmaceutically acceptable salt or solvate thereof in an amount of 5.0 to 50.0% by weight of the medicament, nirmatrelvir or a pharmaceutically acceptable salt or solvate thereof in an amount of 10.0 to 60.0% by weight of the medicament, and at least one pharmaceutically acceptable excipient, wherein ritonavir and nirmatrelvir are not separated from each other, but are in the same medicament and are uniformly distributed in the medicament.

[0116] By preparing a medicament for treating and / or preventing viral diseases by inhibiting the activity of viral 3C-like protease, the above technical problems are solved and the required technical results are achieved. The medicament contains ritonavir or a pharmaceutically acceptable salt or solvate thereof in an amount of 5.0 to 50.0% by weight of the medicament, nirmatrelvir or a pharmaceutically acceptable salt or solvate thereof in an amount of 10.0 to 60.0% by weight of the medicament, and at least one pharmaceutically acceptable excipient, wherein ritonavir and nirmatrelvir are not separated from each other, but are in the same medicament and are uniformly distributed according to the weight of the medicament.

[0117] In one embodiment of the present invention, a medicament is provided, which is characterized in that it contains ritonavir or a pharmaceutically acceptable salt or solvate thereof and nirmatrelvir or a pharmaceutically acceptable salt or solvate thereof as active ingredients, and they are uniformly distributed in the medicament.

[0118] In one embodiment of the present invention, a medicament is provided, which is characterized in that it contains ritonavir or a pharmaceutically acceptable salt or solvate thereof and nirmatrelvir or a pharmaceutically acceptable salt or solvate thereof as active ingredients, and they are uniformly distributed according to the weight of the medicament.

[0119] In one embodiment of the present invention, a medicament is provided, which is characterized in that it contains ritonavir or a pharmaceutically acceptable salt or solvate thereof and nirmatrelvir or a pharmaceutically acceptable salt or solvate thereof as active ingredients, wherein ritonavir and nirmatrelvir are not separated from each other, but are uniformly distributed according to the weight of the medicament.

[0120] In one embodiment of the present invention, a medicament is provided, which is characterized in that it contains ritonavir or a pharmaceutically acceptable salt or solvate thereof, nirmatrelvir or a pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient, wherein the components of the medicament are uniformly distributed according to the total weight of the medicament.

[0121] In one embodiment of the present invention, there is provided a pharmaceutical product, which is characterized in that it contains at least one water-soluble polymer selected from vinyl pyrrolidone derivatives as a pharmaceutically acceptable excipient.

[0122] In one embodiment of the present invention, there is provided a pharmaceutical product, which is characterized in that the vinyl pyrrolidone derivative is selected from the group consisting of povidone and copovidone.

[0123] In one embodiment of the present invention, there is provided a pharmaceutical product, which is characterized in that it contains at least one vinyl pyrrolidone derivative in an amount of 5.0 to 35.0% by weight of the pharmaceutical product.

[0124] In one embodiment of the present invention, there is provided a pharmaceutical product, which is characterized in that it contains at least one vinyl pyrrolidone derivative in an amount of 5.0 to 15.0% by weight of the pharmaceutical product.

[0125] In one embodiment of the present invention, there is provided a pharmaceutical product, which is characterized in that it contains at least one water-insoluble polymer selected from cellulose derivatives as a pharmaceutically acceptable excipient.

[0126] In one embodiment of the present invention, there is provided a pharmaceutical product, which is characterized in that the cellulose derivative is selected from the group consisting of microcrystalline cellulose, sodium carboxymethylcellulose cross-linked, ethylcellulose, and low-substituted hydroxypropyl cellulose.

[0127] In one embodiment of the present invention, there is provided a pharmaceutical product, which is characterized in that it contains at least one cellulose derivative in an amount of 5.0 to 40.0% by weight of the pharmaceutical product.

[0128] In one embodiment of the present invention, there is provided a pharmaceutical product, which is characterized in that it contains at least one cellulose derivative in an amount of 5.0 to 20.0% by weight of the pharmaceutical product.

[0129] In one embodiment of the present invention, there is provided a pharmaceutical product, which is characterized in that it contains at least one disaccharide or its hydrate as a pharmaceutically acceptable excipient.

[0130] In one embodiment of the present invention, there is provided a pharmaceutical product, which is characterized in that the disaccharide or its hydrate is selected from the group consisting of lactose monohydrate, lactose, sucrose, trehalose, trehalose dihydrate, and maltose.

[0131] In one embodiment of the present invention, there is provided a pharmaceutical product, which is characterized in that it contains at least one disaccharide or its hydrate in an amount of 9.0 to 25.0% by weight of the pharmaceutical product as a pharmaceutically acceptable excipient.

[0132] In one embodiment of the present invention, there is provided a pharmaceutical product, which is characterized in that it contains at least one disaccharide or hydrate in an amount of 9.0 to 19.0% by weight of the pharmaceutical product as a pharmaceutically acceptable excipient.

[0133] In one embodiment of the present invention, there is provided a pharmaceutical product, which is characterized in that it contains at least one water-soluble polymer selected from vinyl pyrrolidone derivatives in an amount of 5.0 to 35.0% by weight of the pharmaceutical product, at least one water-insoluble polymer selected from cellulose derivatives in an amount of 5.0 to 40.0% by weight of the pharmaceutical product, and a disaccharide or hydrate in an amount of 9.0 to 25.0% by weight of the pharmaceutical product as pharmaceutically acceptable excipients.

[0134] In one embodiment of the present invention, there is provided a pharmaceutical product, which is characterized in that it consists of ritonavir or a pharmaceutically acceptable salt or solvate thereof in an amount of 5.0 to 50.0% by weight of the pharmaceutical product, nirmatrelvir or a pharmaceutically acceptable salt or solvate thereof in an amount of 10.0 to 60.0% by weight of the pharmaceutical product, at least one water-soluble polymer selected from vinyl pyrrolidone derivatives in an amount of 5.0 to 35.0% by weight of the pharmaceutical product, at least one water-insoluble polymer selected from cellulose derivatives in an amount of 5.0 to 40.0% by weight of the pharmaceutical product, at least one disaccharide or its hydrate in an amount of 9.0 to 25.0% by weight of the pharmaceutical product, at least one surfactant (detergent) in an amount of 1.0 to 3.0% by weight of the pharmaceutical product, and at least one lubricant in an amount of 0.5 to 1.5% by weight of the pharmaceutical product.

[0135] In one embodiment of the present invention, there is provided a pharmaceutical product, which is characterized in that it consists of ritonavir or a pharmaceutically acceptable salt or solvate thereof in an amount of 5.0 to 50.0% by weight of the pharmaceutical product, nirmatrelvir or a pharmaceutically acceptable salt or solvate thereof in an amount of 10.0 to 60.0% by weight of the pharmaceutical product, at least one water-soluble polymer selected from vinyl pyrrolidone derivatives in an amount of 5.0 to 15.0% by weight of the pharmaceutical product, at least one water-insoluble polymer selected from cellulose derivatives in an amount of 5.0 to 20.0% by weight of the pharmaceutical product, at least one disaccharide or its hydrate in an amount of 9.0 to 19.0% by weight of the pharmaceutical product, at least one surfactant (detergent) in an amount of 1.0 to 3.0% by weight of the pharmaceutical product, and at least one lubricant in an amount of 0.5 to 1.5% by weight of the pharmaceutical product.

[0136] In one embodiment of the present invention, a pharmaceutical product is provided, which is characterized in that it consists of ritonavir or a pharmaceutically acceptable salt or solvate thereof in an amount of 10.0 to 25.0% by weight of the pharmaceutical product, nirmatrelvir or a pharmaceutically acceptable salt or solvate thereof in an amount of 25.0 to 45.0% by weight of the pharmaceutical product, at least one water-soluble polymer selected from vinyl pyrrolidone derivatives in an amount of 5.0 to 12.0% by weight of the pharmaceutical product, at least one water-insoluble polymer selected from cellulose derivatives in an amount of 10.0 to 20.0% by weight of the pharmaceutical product, at least one disaccharide or its hydrate in an amount of 12.0 to 19.0% by weight of the pharmaceutical product, at least one surfactant (detergent) in an amount of 1.5 to 3.0% by weight of the pharmaceutical product, and at least one lubricant in an amount of 0.5 to 1.5% by weight of the pharmaceutical product.

[0137] In one embodiment of the present invention, a pharmaceutical product is provided, which is characterized in that it consists of ritonavir or a pharmaceutically acceptable salt or solvate thereof in an amount of 10.0 to 15.0% by weight of the pharmaceutical product, nirmatrelvir or a pharmaceutically acceptable salt or solvate thereof in an amount of 30.0 to 40.0% by weight of the pharmaceutical product, at least one water-soluble polymer selected from vinyl pyrrolidone derivatives in an amount of 5.0 to 10.0% by weight of the pharmaceutical product, at least one water-insoluble polymer selected from cellulose derivatives in an amount of 15.0 to 20.0% by weight of the pharmaceutical product, at least one disaccharide or its hydrate in an amount of 15.0 to 19.0% by weight of the pharmaceutical product, at least one surfactant (detergent) in an amount of 1.5 to 2.5% by weight of the pharmaceutical product, and at least one lubricant in an amount of 0.5 to 1.5% by weight of the pharmaceutical product.

[0138] In one embodiment of the present invention, a pharmaceutical product is provided, which is characterized in that it contains at least one water-soluble polymer selected from vinyl pyrrolidone derivatives in an amount of 5.0 to 15.0% by weight of the pharmaceutical product, at least one water-insoluble polymer selected from cellulose derivatives in an amount of 5.0 to 20.0% by weight of the pharmaceutical product, and a disaccharide or hydrate in an amount of 9.0 to 19.0% by weight of the pharmaceutical product as pharmaceutically acceptable excipients.

[0139] In one embodiment of the present invention, there is provided a pharmaceutical product, which is characterized in that it is a film-coated tablet, comprising a core (center) and a film coating, wherein the core is composed of ritonavir or a pharmaceutically acceptable salt or solvate thereof in an amount of 5.0 to 50.0% by weight of the pharmaceutical product, nirmatrelvir or a pharmaceutically acceptable salt or solvate thereof in an amount of 10.0 to 60.0% by weight of the pharmaceutical product, at least one water-soluble polymer selected from vinyl pyrrolidone derivatives in an amount of 5.0 to 35.0% by weight of the pharmaceutical product, at least one water-insoluble polymer selected from cellulose derivatives in an amount of 5.0 to 40.0% by weight of the pharmaceutical product, at least one disaccharide or its hydrate in an amount of 9.0 to 25.0% by weight of the pharmaceutical product, at least one surfactant (detergent) in an amount of 1.0 to 3.0% by weight of the pharmaceutical product, and at least one lubricant in an amount of 0.5 to 1.5% by weight of the pharmaceutical product.

[0140] In one embodiment of the present invention, there is provided a pharmaceutical product, which is characterized in that it is a film-coated tablet, comprising a core (center) and a film coating, wherein the core is composed of ritonavir or a pharmaceutically acceptable salt or solvate thereof in an amount of 5.0 to 50.0% by weight of the pharmaceutical product, nirmatrelvir or a pharmaceutically acceptable salt or solvate thereof in an amount of 10.0 to 60.0% by weight of the pharmaceutical product, at least one water-soluble polymer selected from vinyl pyrrolidone derivatives in an amount of 5.0 to 35.0% by weight of the pharmaceutical product, at least one water-insoluble polymer selected from cellulose derivatives in an amount of 5.0 to 40.0% by weight of the pharmaceutical product, at least one disaccharide or its hydrate in an amount of 9.0 to 25.0% by weight of the pharmaceutical product, at least one surfactant (detergent) in an amount of 1.0 to 3.0% by weight of the pharmaceutical product, and at least one lubricant in an amount of 0.5 to 1.5% by weight of the pharmaceutical product, wherein the components of the core are uniformly distributed by weight of the core.

[0141] In one embodiment of the present invention, there is provided a pharmaceutical product, which is characterized in that it is a film-coated tablet, comprising a core (center) and a film coating, wherein the core is composed of ritonavir or a pharmaceutically acceptable salt or solvate thereof in an amount of 5.0 to 50.0% by weight of the pharmaceutical product, nirmatrelvir or a pharmaceutically acceptable salt or solvate thereof in an amount of 10.0 to 60.0% by weight of the pharmaceutical product, at least one water-soluble polymer selected from vinyl pyrrolidone derivatives in an amount of 5.0 to 35.0% by weight of the pharmaceutical product, at least one water-insoluble polymer selected from cellulose derivatives in an amount of 5.0 to 40.0% by weight of the pharmaceutical product, at least one disaccharide or its hydrate in an amount of 9.0 to 25.0% by weight of the pharmaceutical product, at least one surfactant (detergent) in an amount of 1.0 to 3.0% by weight of the pharmaceutical product, and at least one lubricant in an amount of 0.5 to 1.5% by weight of the pharmaceutical product, wherein the components of the core are uniformly distributed by weight of the core, and wherein ritonavir and nirmatrelvir are not separated from each other.

[0142] In one embodiment of the present invention, there is provided a pharmaceutical product, which is characterized in that it is a film-coated tablet, comprising a core (center) and a film coating, wherein the core is composed of ritonavir or a pharmaceutically acceptable salt or solvate thereof in an amount of 10.0 to 15.0% by weight of the pharmaceutical product, nirmatrelvir or a pharmaceutically acceptable salt or solvate thereof in an amount of 30.0 to 40.0% by weight of the pharmaceutical product, at least one water-soluble polymer selected from vinyl pyrrolidone derivatives in an amount of 5.0 to 10.0% by weight of the pharmaceutical product, at least one water-insoluble polymer selected from cellulose derivatives in an amount of 15.0 to 20.0% by weight of the pharmaceutical product, at least one disaccharide or its hydrate in an amount of 15.0 to 19.0% by weight of the pharmaceutical product, at least one surfactant (detergent) in an amount of 1.5 to 2.5% by weight of the pharmaceutical product, and at least one lubricant in an amount of 0.5 to 1.5% by weight of the pharmaceutical product.

[0143] In one embodiment of the present invention, there is provided a pharmaceutical product, which is characterized in that it is a film-coated tablet, comprising a core (center) and a film coating, wherein the core consists of ritonavir or a pharmaceutically acceptable salt or solvate thereof at a content of 10.0 to 15.0% by weight of the pharmaceutical product, nirmatrelvir or a pharmaceutically acceptable salt or solvate thereof at a content of 30.0 to 40.0% by weight of the pharmaceutical product, at least one water-soluble polymer selected from vinyl pyrrolidone derivatives at a content of 5.0 to 10.0% by weight of the pharmaceutical product, at least one water-insoluble polymer selected from cellulose derivatives at a content of 15.0 to 20.0% by weight of the pharmaceutical product, at least one disaccharide or its hydrate at a content of 15.0 to 19.0% by weight of the pharmaceutical product, at least one surfactant (detergent) at a content of 1.5 to 2.5% by weight of the pharmaceutical product, and at least one lubricant at a content of 0.5 to 1.5% by weight of the pharmaceutical product, and the components of the core are uniformly distributed by weight of the core.

[0144] In one embodiment of the present invention, there is provided a pharmaceutical product, which is characterized in that it is a film-coated tablet, comprising a core (center) and a film coating, wherein the core consists of ritonavir or a pharmaceutically acceptable salt or solvate thereof at a content of 10.0 to 15.0% by weight of the pharmaceutical product, nirmatrelvir or a pharmaceutically acceptable salt or solvate thereof at a content of 30.0 to 40.0% by weight of the pharmaceutical product, at least one water-soluble polymer selected from vinyl pyrrolidone derivatives at a content of 5.0 to 10.0% by weight of the pharmaceutical product, at least one water-insoluble polymer selected from cellulose derivatives at a content of 15.0 to 20.0% by weight of the pharmaceutical product, at least one disaccharide or its hydrate at a content of 15.0 to 19.0% by weight of the pharmaceutical product, at least one surfactant (detergent) at a content of 1.5 to 2.5% by weight of the pharmaceutical product, and at least one lubricant at a content of 0.5 to 1.5% by weight of the pharmaceutical product, and the components of the core are uniformly distributed by weight of the core, wherein ritonavir and nirmatrelvir are not separated from each other.

[0145] In one embodiment of the present invention, there is provided a pharmaceutical product, which is characterized in that it is a film-coated tablet, wherein the film coating accounts for 2.5 to 4.0% by weight of the total pharmaceutical product.

[0146] In one embodiment of the present invention, a pharmaceutical product is provided, which is characterized in that it is a film-coated tablet, comprising a core (center) and a film coating, wherein the core consists of ritonavir in an amount of 10.0 to 15.0% by weight of the pharmaceutical product, nirmatrelvir in an amount of 30.0 to 40.0% by weight of the pharmaceutical product, at least one water-soluble polymer selected from povidone and copovidone in an amount of 5.0 to 10.0% by weight of the pharmaceutical product, at least one water-insoluble polymer selected from microcrystalline cellulose and croscarmellose sodium in an amount of 15.0 to 20.0% by weight of the pharmaceutical product, lactose monohydrate in an amount of 15.0 to 19.0% by weight of the pharmaceutical product, sodium lauryl sulfate in an amount of 1.5 to 2.5% by weight of the pharmaceutical product, and sodium stearyl fumarate in an amount of 0.5 to 1.5% by weight of the pharmaceutical product, wherein the components of the core are uniformly distributed by weight of the core, and wherein the film coating accounts for 1.5 to 4.0% by weight of the pharmaceutical product.

[0147] In one embodiment of the present invention, a pharmaceutical product is provided, which is characterized in that it is a film-coated tablet, comprising a core (center) and a film coating, wherein the core consists of ritonavir in an amount of 10.0 to 15.0% by weight of the pharmaceutical product, nirmatrelvir in an amount of 30.0 to 40.0% by weight of the pharmaceutical product, at least one water-soluble polymer selected from povidone and copovidone in an amount of 5.0 to 10.0% by weight of the pharmaceutical product, at least one water-insoluble polymer selected from microcrystalline cellulose and croscarmellose sodium in an amount of 15.0 to 20.0% by weight of the pharmaceutical product, lactose monohydrate in an amount of 15.0 to 19.0% by weight of the pharmaceutical product, sodium lauryl sulfate in an amount of 1.5 to 2.5% by weight of the pharmaceutical product, and sodium stearyl fumarate in an amount of 0.5 to 1.5% by weight of the pharmaceutical product, wherein the components of the core are uniformly distributed by weight of the core, wherein ritonavir and nirmatrelvir are not separated from each other, and wherein the film coating accounts for 1.5 to 4.0% by weight of the pharmaceutical product.

[0148] In one embodiment of the present invention, a pharmaceutical product is provided, which is characterized in that it is a film-coated tablet, comprising a core (center) and a film coating, wherein the core consists of a combination of povidone and copovidone as a water-soluble polymer in an amount of 5.0 to 10.0% by weight of the pharmaceutical product, a combination of microcrystalline cellulose and croscarmellose sodium as a water-insoluble polymer in an amount of 15.0 to 20.0% by weight of the pharmaceutical product, lactose monohydrate in an amount of 15.0 to 19.0% by weight of the pharmaceutical product, sodium lauryl sulfate in an amount of 1.5 to 2.5% by weight of the pharmaceutical product, and sodium stearyl fumarate in an amount of 0.5 to 1.5% by weight of the pharmaceutical product, wherein the components of the core are uniformly distributed by weight of the core, wherein ritonavir and nirmatrelvir are not separated from each other, and wherein the film coating accounts for 1.5 to 4.0% by weight of the pharmaceutical product.

[0149] In one embodiment of the present invention, a pharmaceutical product is provided, which is characterized in that it contains pharmaceutically acceptable excipients selected from, but not limited to, fillers, disintegrants, binders, detergents (surfactants), and lubricants.

[0150] In one embodiment of the present invention, the pharmaceutical product is provided, which is characterized in that it may include, but not limited to, lactose, lactose monohydrate, microcrystalline cellulose, sucrose, starch, corn starch, trehalose, trehalose dihydrate, calcium carbonate, or a mixture thereof as fillers.

[0151] In one embodiment of the present invention, a pharmaceutical product is provided, which is characterized in that it may contain, but not limited to, sodium carboxymethylcellulose cross-linked, starch, maltose, carboxymethylcellulose cross-linked, methylcellulose, hydroxypropylcellulose low-substituted, crospovidone, or a mixture thereof as disintegrants.

[0152] In one embodiment of the present invention, a pharmaceutical product is provided, which is characterized in that it may include, but not limited to, povidone, copovidone, polyethylene glycol, sodium alginate, ethylcellulose, sucrose, or a mixture thereof as binders.

[0153] In one embodiment of the present invention, a pharmaceutical product is provided, which is characterized in that it may include, but not limited to, sodium lauryl sulfate, polysorbate, sorbitan laurate, or a mixture thereof as detergents (surfactants).

[0154] In one embodiment of the present invention, a pharmaceutical product is provided, which is characterized in that it may include, but not limited to, sodium stearyl fumarate, stearic acid, magnesium stearate, calcium stearate, or a mixture thereof as lubricants.

[0155] In one embodiment of the present invention, a pharmaceutical product is provided, which is characterized in that it contains, but not limited to, at least one filler in an amount of 10.0% to 55.0% by weight of the pharmaceutical product, at least one disintegrant in an amount of 5.0% to 15.0% by weight of the pharmaceutical product, at least one binder in an amount of 4.0% to 15.0% by weight of the pharmaceutical product, at least one detergent (surfactant) in an amount of 1.5% to 5.0% by weight of the pharmaceutical product, and at least one lubricant in an amount of 0.5% to 5.0% by weight of the pharmaceutical product.

[0156] In one embodiment of the present invention, there is provided a pharmaceutical product, which is characterized in that it comprises, but is not limited to, at least one filler in an amount of 12.0 to 32.0% by weight of the pharmaceutical product, at least one disintegrant in an amount of 5.0 to 7.0% by weight of the pharmaceutical product, at least one binder in an amount of 4.0 to 7.0% by weight of the pharmaceutical product, at least one cleaning agent (surfactant) in an amount of 1.5 to 3.0% by weight of the pharmaceutical product, and at least one lubricant in an amount of 0.5 to 1.5% by weight of the pharmaceutical product.

[0157] In one embodiment of the present invention, there is provided a pharmaceutical product, which is characterized in that it is an oral pharmaceutical product.

[0158] In one embodiment of the present invention, there is provided a pharmaceutical product, which is characterized in that it is a solid pharmaceutical product.

[0159] In one embodiment of the present invention, there is provided a pharmaceutical product, which is characterized in that it is a tablet.

[0160] In one embodiment of the present invention, there is provided a pharmaceutical product, which is characterized in that it is a film-coated tablet.

[0161] In one embodiment of the present invention, solid pharmaceutical products (including tablets and film-coated tablets) can be prepared by various processes or methods known in the art, including but not limited to direct compression, granulation, melt extrusion, spray drying, and evaporation of solutions.

[0162] The hot melt extrusion method is carried out in a conventional extruder known to those skilled in the art.

[0163] According to the present invention, the components of the pharmaceutical product can be first mixed and then melt-extruded, or the components can be mixed simultaneously and extruded from the melt. Generally, the melt is homogenized to effectively disperse the active ingredient. It may also be convenient to first melt a suitable polymer and then mix and homogenize the active ingredient.

[0164] According to the present invention, the method of softening the preparation can include the steps of wetting, grinding, extruding from the melt, spray drying, and dissolution.

[0165] By using the pharmaceutical composition according to the present invention to prepare a pharmaceutical product for treating and / or preventing viral diseases by inhibiting the activity of viral protease 3C, the above technical problems are solved and the claimed technical results are achieved.

[0166] By using the pharmaceutical composition according to the present invention to treat and / or prevent viral diseases by inhibiting the activity of viral protease 3C, the above technical problems are solved and the claimed technical results are achieved.

[0167] By using the medicament according to the present invention to treat and / or prevent viral diseases by inhibiting the activity of viral protease 3C, the above technical problems are solved and the claimed technical results are achieved.

[0168] In one embodiment of the present invention, there is provided the use of a pharmaceutical composition according to the present invention for the preparation of a medicament for treating and / or preventing viral diseases by inhibiting the activity of a viral 3C-like protease, wherein the viral disease is caused by a coronavirus.

[0169] In one embodiment of the present invention, there is provided the use of a pharmaceutical composition of the present invention for the preparation of a medicament for treating and / or preventing viral diseases by inhibiting the activity of viral protease 3C, wherein the viral disease is caused by the SARS-CoV-2 virus.

[0170] More preferably, the viral infection of the present invention is the SARS-CoV-2 virus.

[0171] The following are examples of the present invention, which illustrate the present invention but do not cover all possible embodiments and do not limit the present invention.

[0172] Those skilled in the art will understand that other specific embodiments of the present invention are also possible.

[0173] Example 1. Preparation of a medicament comprising ritonavir or a pharmaceutically acceptable salt or solvate thereof and nirmatrelvir or a pharmaceutically acceptable salt or solvate thereof.

[0174] Film-coated tablets

[0175] To obtain a solid medicament in the form of film-coated tablets comprising ritonavir or a pharmaceutically acceptable salt or solvate thereof and nirmatrelvir or a pharmaceutically acceptable salt or solvate thereof as active ingredients, the pre-ground and weighed ritonavir and nirmatrelvir materials, as well as pharmaceutically acceptable excipients, are sequentially loaded into a mixer and mixed for 5 minutes. For example, in a specific embodiment of the present invention, the pharmaceutically acceptable excipients are microcrystalline cellulose, lactose monohydrate, copovidone, and sodium lauryl sulfate. According to the present invention, the process of mixing each active ingredient with auxiliary excipients can also be carried out in different mixers. For example, the ritonavir material is mixed with pharmaceutically acceptable excipients in one mixer, while the nirmatrelvir material is mixed with auxiliary excipients in another mixer.

[0176] The resulting mixture is softened by methods known in the prior art. In certain embodiments, a povidone solution is used as a wetting agent to moisten the mixture. The wetting process is carried out by spraying in a fluidized bed of the wetting agent in a granulator dryer. Then drying is carried out at a temperature of 50 - 55 °C. Croscarmellose sodium and sodium stearyl fumarate are added to the dry mixture and ground for 3 minutes. The granules are passed through a conical ball mill (sieve hole diameter - 1.0 mm).

[0177] Then, the resulting substance for tableting is tabletted using a pressing method on a rotary tablet press.

[0178] After the tablet cores come out of the tablet press, they enter a dust removal area where the tablet cores are dusted. During operation, the quality of the tablet cores is systematically monitored. The tablet cores are poured from the tablet press tray into a stainless - steel container and weighed. If there is dust on the tablet cores, additional dust removal and tumbling treatments are carried out on the dust removal device.

[0179] Then, the tablet cores are loaded into the preparation tank of a drum - type film - coating device, and a calculated amount of film - forming solution is loaded into the preparation solution tank. Then, the fan and the electric heater are turned on in sequence. The temperature of the heated air at the inlet is 58 - 60 °C, at the outlet is 40 - 43 °C, the pre - heating time of the tablet layer is 10 minutes. The coating time of the tablet cores is 60 minutes. The solution feeding rate is 70 - 80 ml / min. The cooling time of the coated tablets is 30 minutes. The pressure drop inside the drum is (- 80) Pa. The drum rotation speed is 10 - 11 rpm. This process is carried out with continuous stirring of the solution until the solution is completely used up.

[0180] The finished film - coated tablets are placed in a pre - weighed container.

[0181] Table 1 shows specific embodiments of the film - coated tablets according to the present invention.

[0182] Table 1. Composition of film - coated tablets containing ritonavir and nirmatrelvir.

[0183]

[0184] Example 2. Stability study of nirmatrelvir and ritonavir preparations during storage.

[0185] The inventors investigated the stability of the nirmatrelvir and / or ritonavir formulations under accelerated test conditions and under stress test conditions. Table 2 lists the qualitative and quantitative characteristics of the formulations studied. In the experiment, Formulations 2 and 5 containing only nirmatrelvir as the active ingredient, and Formulations 3 and 6 containing only ritonavir as the active ingredient were used as comparative samples. The qualitative and quantitative compositions of the auxiliary excipients in the studied Formulations 2 and 3 were similar to those of Formulation 1, and the qualitative and quantitative compositions of the auxiliary excipients in Formulations 5 and 6 were similar to those of Formulation 4.

[0186] Table 2. Formulations Studied

[0187]

[0188]

[0189]

[0190] Accelerated stability testing was carried out for 148 days at a temperature of 50 ± 2 °C and a relative humidity of 75 ± 5%, which is equivalent to storing for 4 years under standard storage conditions. Three experiments were carried out for each formulation. The quantitative content of the active ingredient is expressed as an average value. Table 3 shows the stability data of the studied formulations under accelerated test conditions.

[0191] Stress testing was carried out under the following stress test conditions: temperature 40 ± 2 °C, relative humidity W = 75 ± 5%, cold white fluorescent lamp radiation 1.2 million lx - hours, near - ultraviolet lamp 200 W·h / m 2 , and the study time was 576 hours (24 days). Table 4 shows the data on the stability of the formulations under stress test conditions. Additional photostability studies of the studied formulations were also carried out by placing the samples separately in the following packages: blister packs made of PVC film, PVC / PVDC film, OPA / AL / PVC film, and printed lacquered aluminum foil; and pharmaceutical polymer cans made of low - density polyethylene, which were sealed with a low - density polyethylene screw cap with first - opening control and equipped with a desiccant pack (silica gel); or cans with a barrier neck made of low - density polyethylene, which were sealed with a press - in opening cap (with first - opening control) made of low - density polyethylene and high - density polyethylene and equipped with a desiccant pack (silica gel). The empty space in the cans was filled with medical absorbent cotton.

[0192] The content of the active ingredients nirmatrelvir and / or ritonavir was determined by HPLC using a reference standard.

[0193] Table 3. Results of the Stability Study of Nirmatrelvir and / or Ritonavir Formulations under Accelerated Test Conditions.

[0194]

[0195]

[0196] Table 3 shows that after 148 days of storage under the conditions of the "accelerated aging" method, Formulations 1 and 4 studied according to the present invention have higher stability and the chemical purity remains unchanged. The chemical purity of Comparative Formulations 2, 3, 5, and 6 remained less than 111 days, and by the end of the experiment, the content of the active substance in Formulations 2, 3, 5, and 6 decreased by more than 3.5%.

[0197] Table 4. Results of the stability study of nirmatrelvir and / or ritonavir formulations in the stress study.

[0198]

[0199]

[0200] Table 4 shows that after 24 days of storage under the stress study conditions, Formulations 1 and 4 studied according to the present invention have higher stability and the chemical purity remains unchanged. The chemical purity of Comparative Formulations 2, 3, 5, and 6 remained less than 12 days, and by the end of the experiment, the content of the active substance in Formulations 2, 3, 5, and 6 decreased by more than 4.0%.

[0201] Compared with the formulations containing only nirmatrelvir and the formulations containing only ritonavir, the studies conducted confirmed that the formulations containing nirmatrelvir and ritonavir according to the present invention have improved stability. Among the decomposition products of the active substance in the studied formulations, impurities known in the prior art and individual unidentified impurities were found. It is important to note that as a result of the stability study of the nirmatrelvir and ritonavir combination drug formulation according to the present invention, by the end of the experiment, among the related impurities formed during the storage of the formulation, compared with the formulation containing only ritonavir, no ritonavir impurities (compounds of formula III) formed during the degradation of ritonavir were recorded.

[0202]

[0203] Compound of formula (III). Structural formula of ritonavir impurity.

[0204] In addition, stability studies were also conducted under accelerated and stress test conditions for cases where the qualitative and / or quantitative characteristics of the excipients and active ingredients in the nirmatrelvir and / or ritonavir preparations were different from those of the compositions described above. As a result of a large number of stability studies on the preparations under various conditions, the inventors unexpectedly found that, compared with preparations having other qualitative and quantitative characteristics, the preparations of the present invention showed improved and most preferably stable results. The preparations contain at least one water-insoluble polymer selected from cellulose derivatives in an amount of about 5.0 to 40.0% by weight of the preparation, at least one water-soluble polymer selected from vinyl pyrrolidone derivatives in an amount of about 5.0 to 35.0% by weight of the preparation (in particular, a mixture of povidone and copovidone in a preferred embodiment), and at least one disaccharide in an amount of about 9.0 to 25.0% by weight of the preparation.

[0205] Example 3. Study on the therapeutic effect of the preparation containing nirmatrelvir and ritonavir against coronavirus infection.

[0206] Using an experimental infection model of Syrian hamsters caused by the SARS-CoV-2 coronavirus Delta strain, the antiviral activity of the preparation containing nirmatrelvir and ritonavir against the SARS-CoV-2 virus was studied.

[0207] Viral infection was modeled in 30 Syrian hamster subjects, which were randomly divided into 2 groups of 15 subjects each. This experiment involved Syrian female hamsters (8 - 9 weeks old) weighing up to 85 g. The hamsters had free access to water and food and were housed in a standard animal rearing system in an animal farm. Before the study, all animals were weighed and examined to determine the presence of external injuries, hair damage, signs of poisoning, and oropharyngeal swabs were collected from all animals for PCR to detect the presence of SARS-CoV-2 coronavirus RNA (negative control during infection). Under anesthesia of the subjects, SARS-CoV-2 infection was performed intranasally at a dose of 50 μl of 10 4 TCID 50 dose.

[0208] The first group received a preparation containing 300 mg of nirmatrelvir and 100 mg of ritonavir (the dose is expressed in human equivalent dose); the second group received microcrystalline cellulose in suspension form.

[0209] These drugs were administered by tube in suspension form twice a day. The first administration was 1.5 hours before infection. The experiment was conducted for 5 days.

[0210] On the second day of the experiment, the content of SARS-CoV-2 virus RNA in the oropharyngeal swabs of the subjects was analyzed. According to the manufacturer's instructions, the analysis was performed using the POLIVIR SARS-CoV-2 kit (Litech, Russia), and the Ct was determined. In the hamsters of Group 1 and Group 2, viral RNA was detected in the oropharyngeal swabs on the second day. These results confirmed that the animals in Group 1 and Group 2 were infected with the Delta strain of SARS-CoV-2.

[0211] On the fifth day, the animals were sacrificed by one-stage decapitation according to the requirements of the Ethics Committee, the lungs were collected and the viral titer in the lung tissue was evaluated. For this purpose, the lung tissue was homogenized. To disrupt the cells and increase the yield of the virus, the homogenate was frozen and thawed once and centrifuged. The supernatant was collected, filtered and used for introducing plasma samples. In Vero E6 cells, the viral load in the collected samples was quantitatively determined by endpoint indicator titration.

[0212] The measured values of the average lg TCID 50 / ml for each group are as Figure 1 shown. In Group 1, there was a significant difference in the viral titer in the lungs compared to Group 2 (p<0.05).

[0213] Based on the experimental results, it can be concluded that the preparation containing nirmatrelvir and ritonavir according to the present invention exhibits antiviral activity against the SARS-CoV-2 virus.

[0214] Histopathological studies were also performed on the lung tissues of the hamsters participating in the experiment.

[0215] In the group of subjects receiving the placebo, histopathological analysis of the animals' lungs recorded petechiae and ecchymoses diffusely distributed over the entire surface of one lung, as well as partial damage to the second lung. In some subjects, only the distribution of petechiae and ecchymoses on the surface of one lung was recorded. The color of the organ changed to a rich pink / red (in some cases, dark red). A significant reduction in air circulation in the lungs was also observed, and in some subjects, the sharpness of the organ edges decreased while the lung surface was convex (in some subjects, mainly smooth).

[0216] In the group of subjects receiving the preparation containing nirmatrelvir and ritonavir according to the present invention, histopathological analysis of the lungs of some subjects showed isolated petechiae (mainly on one lobe of the lung). Morphologically, there was no disruption from the outside. The color of the organ was pink (in some subjects, dark pink was recorded). The dorsal surface of the lung was moderately convex, and most of the air circulation in the organ was retained (when immersed in water, the lung mainly remained on the surface).

[0217] Thus, according to the present invention, histopathological analysis of the lungs of the subjects participating in the experiment showed that during treatment with the preparation containing nirmatrelvir and ritonavir, there was a significant protective effect on the lung tissue from the negative impact of the virus.

[0218] In addition, during the entire experiment, clinical observations were carried out on the animals during treatment, including recording the body weights of the animals. Each animal within the group was marked. According to the markings, a subject number was assigned to each animal selected for the study. The animals were observed daily, and any deviations in the general condition of each animal were recorded. Before the experiment, there were no differences in the average body weights among the groups of animals. The animals were observed daily, and any deviations in the general condition of each animal were recorded. The body weights of the animals were measured daily. Data on the changes in body weight relative to the initial body weight on the day of infection were recorded.

[0219] According to the observations, on the 1st day after infection, the body weight of the subjects in Group 1 and Group 2 decreased by within 3%, on the 2nd day of the experiment, the body weight of the subjects in Group 1 decreased by no more than 4% of the initial value, while that in Group 2 was as high as 7%. In addition, during the experiment, the decrease in the body weight of the animals in Group 1 tended to stabilize on the 3rd day, and afterwards, a steady increase in the body weight of some subjects was observed, reaching the initial value or exceeding the initial value by 5%. In Group 2, the decrease in the body weight of the subjects was observed to continue until the end of the experiment.

[0220] During repeated oral administration to adult male and female Wistar rats (3 months old, average body weight 210.2 ± 1.1 g), the toxicological properties of the preparation containing nirmatrelvir and ritonavir were also studied. Before the experiment, the animals were isolated (for 14 days) to monitor the manifestation of health deviations.

[0221] A two-week toxicity study was conducted with repeated administration of nirmatrelvir at 60, 200, and 1000 mg / kg / day. No clinical manifestations of toxicity were observed in this study, no death events were observed, and there were no changes in body weight and food intake. In terms of hematological parameters, when nirmatrelvir was used at a dose of 1000 mg / kg / day, parameters such as prothrombin time, APTT level, platelet level, red blood cells, fibrinogen, etc. deviated slightly from the normal values. Blood biochemistry showed a moderate increase in the activities of alkaline phosphatase and cholesterol in the blood of the subjects. Even after administration of a high dose of nirmatrelvir, no significant changes were recorded in the general condition of the animals and the overall indicators of the vital functions of the organs and body systems of the subjects. The above changes were reversible, as determined at the end of the two-week recovery period.

[0222] Ritonavir has long been used as a pharmacokinetic enhancer and has shown good safety in preclinical and clinical studies. No additional toxicity was observed when nirmatrelvir at a dose of up to 1000 mg / kg / day and ritonavir at a dose of up to 250 mg / kg / day were administered orally in combination.

Claims

1. A pharmaceutical composition for treating and / or preventing viral diseases by inhibiting the activity of viral 3C-like protease, comprising ritonavir or a pharmaceutically acceptable salt or solvate thereof in an amount of 10.0 to 70.0% by weight of the pharmaceutical composition, and nirmatrelvir or a pharmaceutically acceptable salt or solvate thereof in an amount of 30.0 to 90.0% by weight of the pharmaceutical composition, wherein ritonavir and nirmatrelvir are uniformly distributed in the pharmaceutical composition.

2. The pharmaceutical composition according to claim 1, characterized in that, it comprises ritonavir or a pharmaceutically acceptable salt or solvate thereof in an amount of 15.0 to 25.0% by weight of the pharmaceutical composition, and nirmatrelvir or a pharmaceutically acceptable salt or solvate thereof in an amount of 75.0 to 85.0% by weight of the pharmaceutical composition.

3. The pharmaceutical composition according to claim 1, characterized in that, it is a solid pharmaceutical composition.

4. A medicament for treating and / or preventing viral diseases by inhibiting the activity of viral 3C-like protease, comprising the pharmaceutical composition according to claims 1 to 3 and at least one pharmaceutically acceptable excipient.

5. The medicament according to claim 4, characterized in that, it comprises at least one water-soluble polymer selected from vinyl pyrrolidone derivatives as a pharmaceutically acceptable excipient.

6. The medicament according to claim 5, characterized in that, the vinyl pyrrolidone derivatives are selected from the group comprising povidone and copovidone.

7. The medicament according to claim 5, characterized in that, it comprises at least one vinyl pyrrolidone derivative in an amount of 5.0 to 35.0% by weight of the medicament.

8. The medicament according to claim 7, characterized in that, it comprises at least one vinyl pyrrolidone derivative in an amount of 5.0 to 15.0% by weight of the medicament.

9. The medicament according to claim 4, characterized in that, it comprises at least one water-insoluble polymer selected from cellulose derivatives as a pharmaceutically acceptable excipient.

10. The medicament according to claim 9, characterized in that, the cellulose derivatives are selected from the group comprising microcrystalline cellulose, croscarmellose sodium, ethyl cellulose, and low-substituted hydroxypropyl cellulose.

11. The medicament according to claim 9, characterized in that, it comprises at least one cellulose derivative in an amount of 5.0 to 40.0% by weight of the medicament.

12. The medicament according to claim 11, characterized in that, it comprises at least one cellulose derivative in an amount of 5.0 to 20.0% by weight of the medicament.

13. The medicament according to claim 4, characterized in that, it comprises at least one disaccharide or its hydrate as a pharmaceutically acceptable excipient.

14. The medicament according to claim 13, characterized in that, the disaccharide or its hydrate is selected from the group comprising lactose monohydrate, lactose, sucrose, trehalose, trehalose dihydrate, and maltose.

15. The medicament according to claim 13, characterized in that, It contains at least one disaccharide or its hydrate in an amount of 9.0 to 25.0% by weight of the drug as a pharmaceutically acceptable excipient.

16. The drug according to claim 15, characterized in that it contains at least one disaccharide or hydrate in an amount of 9.0 to 19.0% by weight of the drug as a pharmaceutically acceptable excipient.

17. The drug according to claim 4, characterized in that it contains at least one water-soluble polymer selected from vinyl pyrrolidone derivatives in an amount of 5.0 to 35.0% by weight of the drug, at least one water-insoluble polymer selected from cellulose derivatives in an amount of 5.0 to 40.0% by weight of the drug, and a disaccharide or its hydrate in an amount of 9.0 to 25.0% by weight of the drug as pharmaceutically acceptable excipients.

18. The drug according to claim 17, characterized in that it contains at least one water-soluble polymer selected from vinyl pyrrolidone derivatives in an amount of 5.0 to 15.0% by weight of the drug, at least one water-insoluble polymer selected from cellulose derivatives in an amount of 5.0 to 20.0% by weight of the drug, and a disaccharide or its hydrate in an amount of 9.0 to 19.0% by weight of the drug as pharmaceutically acceptable excipients.

19. The drug according to claim 4, characterized in that it is a solid drug.

20. The drug according to claim 19, characterized in that it is a tablet.

21. The drug according to claim 20, characterized in that it is a film-coated tablet.

22. Use of the pharmaceutical composition according to claims 1 to 3 for the preparation of a drug for treating and / or preventing a viral disease by inhibiting the activity of a viral 3C-like protease.

23. The use according to claim 22, characterized in that the viral disease is caused by a coronavirus.

24. The use according to claim 23, characterized in that the viral disease is caused by the SARS-CoV-2 virus.

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