A liquid formulation containing nirmatrelvir and ritonavir, and a preparation method and application thereof

Abstract

The application belongs to the technical field of pharmaceutical preparations, and discloses a liquid preparation containing nirmatrelvir and ritonavir as well as a preparation method and application thereof. The liquid preparation is prepared by combining nirmatrelvir, ritonavir and other excipients, has high absorption and high bioavailability, is accurate in dosing, and can accurately give a reasonable dose according to different symptoms. The application solves the problems of the existing Paxlovid tablet, such as large dose, inconvenience in taking, low dissolution, low bioavailability and the need to take multiple tablets, improves the medication compliance of patients, and reduces the drug toxicity. The preparation process of the liquid preparation containing nirmatrelvir and ritonavir is simple, and large equipment is not needed. The liquid preparation containing nirmatrelvir and ritonavir retains the medicinal properties of nirmatrelvir and ritonavir, and can be used for preparing a drug for novel coronavirus.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of pharmaceutical preparations, in particular to a liquid preparation containing nirmatrelvir and ritonavir, and a preparation method and application thereof. BACKGROUND

[0002] In oral administration dosage form drugs, various factors can affect its bioavailability. These factors include water solubility, drug absorption throughout the gastrointestinal tract, dosage strength and first-pass effect. Water solubility is one of the most important factors among these factors. When a drug has poor water solubility, different excipients or preparations are usually added to improve the water solubility of the drug, thereby improving its bioavailability.

[0003] Nirmatrelvir (PF-07321332) chemical name: (1R, 2S, 5S)-N-{(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}-3-[(2S)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide, nirmatrelvir is soluble in 1-butanol, methyl isobutyl ketone (MIBK) and isopropyl acetate. Nirmatrelvir is a white to light powder, slightly soluble in n-propyl acetate, n-butyl acetate and anisole, very slightly soluble in n-heptane and water. Nirmatrelvir is an orally bioavailable severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) 3CL protease (3CLpro) inhibitor with potential antiviral activity against SARS-CoV-2 and other coronaviruses.

[0004] Ritonavir (Ritonavir), chemical name: N-[(2S, 3S, 5R)-3-hydroxy-5-[[(2S)-3-methyl-2-[[methyl-[(2-isopropyl-1, 3-thiazol-4-yl) methyl] aminocarbonyl] amino] butanoyl] amino]-1, 6-diphenyl-hexan-2-yl] aminocarbonyl. Ritonavir is a white to light yellow brown powder, easily soluble in methanol and ethanol, slightly soluble in acetonitrile, and difficultly soluble in water. Ritonavir is an antiretroviral protease inhibitor, widely used in combination with other protease inhibitors for the treatment and prevention of human immunodeficiency virus (HIV) infection and acquired immune deficiency syndrome (AIDS).

[0005] Paxlovid is a combined preparation, which is a combination package of nirmatrelvir (300mg) / ritonavir (100mg) tablets. Pfizer has announced the amazing effect of Paxlovid in preventing severe COVID-19 and reducing the risk of death: the previous EPIC-HR clinical study showed that taking it within 3-5 days after the onset of COVID-19 symptoms and taking it for 5 days can reduce the hospitalization and mortality rate of high-risk groups by nearly 90%.

[0006] The existing preparation Paxlovid is inconvenient to take, especially for the elderly, and the compliance is not good. Oral solution is a dosage form that is convenient to take, absorbs quickly, takes effect quickly, and has high bioavailability, which is particularly suitable for elderly patients. So far, no oral solution of nirmatrelvir and ritonavir has been developed for clinical use. In addition, compared with uncoated tablets, the C max and AUC last of the suspension are increased by 44% and 19%, respectively. Therefore, it is necessary to develop a liquid dosage form of the combined preparation of nirmatrelvir and ritonavir. SUMMARY

[0007] Therefore, the present application provides a liquid preparation containing nirmatrelvir and ritonavir, and a preparation method and application thereof, to solve the problem that the existing preparation Paxlovid is a combined preparation, which is a combination package, and is inconvenient to take, especially for the elderly, and the compliance is not good.

[0008] To achieve the above-mentioned purpose, the present application adopts the following technical solutions:

[0009] The present application provides a liquid preparation containing nirmatrelvir and ritonavir, which comprises the following components: ritonavir, nirmatrelvir, a latent solvent, a solubilizer, a pH regulator, a flavoring agent, and a solvent.

[0010] As a preferred, the liquid preparation further comprises a stabilizer and a suspending agent.

[0011] As a preferred, the latent solvent is one or more of glycerol, ethanol, propylene glycol, and polyethylene glycol; the solubilizer is one or more of polyoxyethylene hydrogenated castor oil, sodium dodecyl sulfate, polysorbate, and poloxamer; the volume concentration of the latent solvent in the liquid preparation is 10-80%; and the mass concentration of the solubilizer in the liquid preparation is 0.01-15%.

[0012] As preferred, the pH regulator is one or more of phosphoric acid and its phosphate, citric acid and its citrate, and lactic acid and its lactate; the flavoring agent is one or more of sucrose, aspartame, acesulfame potassium, sodium saccharin, cyclamate, xylitol, sucralose, erythritol, and essence; the pH regulator is used in an amount to make the pH value of the liquid preparation 3-7; in the liquid preparation, the mass concentration of the flavoring agent is 0.01-10%.

[0013] As preferred, the solvent is water; the mass ratio of ritonavir and nirmatrelvir is 1:1-10; in the liquid preparation, the mass concentration of ritonavir and nirmatrelvir is 0.05-60%.

[0014] As preferred, the suspending agent is one or more of xanthan gum, colloidal silicon dioxide, hypromellose, and colloidal silicon dioxide; the stabilizer is povidone and / or hypromellose; in the liquid preparation, the mass concentration of the suspending agent is 0.1-10%, and the mass concentration of the stabilizer is 0.25-5%.

[0015] The application also provides a preparation method of the liquid preparation containing nirmatrelvir and ritonavir, comprising the following steps:

[0016] The components are mixed, and the liquid preparation containing nirmatrelvir and ritonavir is obtained through post-processing.

[0017] As preferred, the post-processing is filtration and sterilization.

[0018] The application also provides use of the liquid preparation containing nirmatrelvir and ritonavir in preparation of a new coronavirus drug.

[0019] Through the technical solution described above, compared with the prior art, the application has the following beneficial effects:

[0020] (1) The liquid preparation containing nirmatrelvir and ritonavir provided by the application has good safety performance and good taste, and solves the problem of inconvenient use of large-dose Paxlovid tablets. The in-vitro dissolution rate of nirmatrelvir and ritonavir is greatly improved, the bioavailability is improved, the phenomenon of low dissolution rate, short action time, and the need to take multiple tablets in the prior art is solved, and the medication compliance of patients is improved. Moreover, the liquid preparation obtained by the application has rapid onset, stable quality, and does not appear crystallization and precipitation after long-term storage, has good taste, and has good patient compliance.

[0021] (2) The liquid preparation containing nirmatrelvir and ritonavir has a simple preparation process and is accurate in dosage. Due to the characteristics of the dosage form, a reasonable dose can be given according to the volume of the measuring cup according to different symptoms. BRIEF DESCRIPTION OF DRAWINGS

[0022] In order to more clearly illustrate the technical solutions in the embodiments of the present application or the prior art, the following will briefly introduce the drawings needed to be used in the embodiments or prior art description. Obviously, the drawings in the following description are only the embodiments of the present application, and for those skilled in the art, other drawings can also be obtained without creative effort based on the provided drawings.

[0023] Figure 1 The blood concentration-time curve of nirmatrelvir (NRV) in the liquid preparation containing nirmatrelvir and ritonavir obtained in Example 1, wherein S-NRV is nirmatrelvir in the experimental group, and R-NRV is nirmatrelvir in the control group;

[0024] Figure 2 The blood concentration-time curve of ritonavir (RTV) in the liquid preparation containing nirmatrelvir and ritonavir obtained in Example 1, wherein S-RTV is ritonavir in the experimental group, and R-RTV is ritonavir in the control group. DETAILED DESCRIPTION

[0025] The present application provides a liquid preparation containing nirmatrelvir and ritonavir, which comprises the following components: ritonavir, nirmatrelvir, a latent solvent, a solubilizer, a pH regulator, a flavoring agent and a solvent.

[0026] In the present application, the liquid preparation further comprises a stabilizer and a suspending agent.

[0027] In the present application, the latent solvent is preferably one or more of glycerol, ethanol, propylene glycol and polyethylene glycol, and is further preferably one or more of ethanol, propylene glycol and polyethylene glycol; the polyethylene glycol is preferably one or more of polyethylene glycol 300, polyethylene glycol 400 and polyethylene glycol 600, and is further preferably polyethylene glycol 300 and / or polyethylene glycol 400; in the liquid preparation, the volume concentration of the latent solvent is preferably 10-80%, and is further preferably 20-50%.

[0028] In the present application, the solubilizer is preferably one or more of polyoxyethylene hydrogenated castor oil, sodium dodecyl sulfate, polysorbate and poloxamer, and is further preferably polyoxyethylene hydrogenated castor oil; the polyoxyethylene hydrogenated castor oil is preferably polyoxyethylene 35 hydrogenated castor oil and / or polyoxyethylene 40 hydrogenated castor oil, and is further preferably polyoxyethylene 35 hydrogenated castor oil or polyoxyethylene 40 hydrogenated castor oil; the polysorbate is preferably polysorbate 80; the poloxamer is preferably poloxamer 188; in the liquid preparation, the mass concentration of the solubilizer is preferably 0.01-15%, and is further preferably 0.05-7%.

[0029] In the present application, the pH adjusting agent is preferably one or more of phosphoric acid and its phosphate, citric acid and its citrate, and lactic acid and its lactate, further preferably phosphoric acid and its phosphate; the pH adjusting agent is preferably used in an amount to make the pH value of the liquid preparation 3-7, further preferably 4-6.5; the mass concentration of the pH adjusting agent is 0.05-3%.

[0030] In the present application, the flavoring agent is preferably one or more of sucrose, aspartame, acesulfame, sodium saccharin, cyclamate, xylitol, chloro sucrose, erythritol, and essence, further preferably one or more of sucrose, sodium saccharin, xylitol, chloro sucrose, and essence; in the liquid preparation, the mass concentration of the flavoring agent is preferably 0.01-10%, further preferably 0.02-5%.

[0031] In the present application, the solvent is preferably water; the mass ratio of ritonavir and nirmatrelvir is preferably 1:1-10, further preferably 1:2-5; in the liquid preparation, the mass concentration of ritonavir and nirmatrelvir is preferably 0.05-60%, further preferably 0.08-40%.

[0032] In the present application, the suspending agent is preferably one or more of xanthan gum, colloidal silicon dioxide, and hypromellose, further preferably xanthan gum and / or colloidal silicon dioxide; in the liquid preparation, the mass concentration of the suspending agent is preferably 0.1-10%, further preferably 1-8%.

[0033] In the present application, the stabilizer is preferably povidone and / or hypromellose, further preferably hypromellose; in the liquid preparation, the mass concentration of the stabilizer is preferably 0.25-5%, further preferably 0.25-3%.

[0034] In the present application, the liquid preparation is an oral solution, a syrup, or a suspension; when the liquid preparation is an oral solution or a syrup, the liquid preparation does not contain a suspending agent.

[0035] The present application also provides a preparation method of the liquid preparation containing nirmatrelvir and ritonavir, comprising the following steps:

[0036] The components are mixed, and the liquid preparation containing nirmatrelvir and ritonavir is obtained after post-treatment.

[0037] In this invention, the specific steps for mixing the components are as follows: (1) mixing ritonavir, nematriberi and a co-solvent to obtain a first mixture; diluting the solubilizer and flavoring agent in a solvent to obtain a second mixture; (2) adding a solvent to the mixture of the first mixture and the second mixture to make up the volume, adding a pH adjuster to adjust the pH value after mixing, and finally post-processing to obtain a liquid preparation containing nematriberi and ritonavir.

[0038] In the first mixture of the present invention, the mixing is ultrasonic mixing; when the liquid preparation is an oral solution or syrup, the mixing time is preferably until the liquid preparation becomes a transparent solution; when the liquid preparation is a suspension, the mixing time is preferably until uniform suspension is achieved; the frequency of the ultrasound is preferably 30-50 kHz, more preferably 35-40 kHz.

[0039] In the second mixture of the present invention, the amount of water used is preferably such that the total mass concentration of the solubilizer and flavoring agent in the second mixture is 55-80%, and more preferably such that the total mass concentration of the solubilizer and flavoring agent in the second mixture is 56-75%.

[0040] In step (2) of the present invention, the mixing is a stirring mixing, and the mixing speed is preferably 100-200 r / min, more preferably 110-150 r / min.

[0041] In this invention, the post-processing is filtration and sterilization; the filtration is carried out using a filter; sterilization is performed using a filter membrane with a pore size of 0.22 μm, and the filter membrane material is preferably polytetrafluoroethylene (PTFE), polyethersulfone (PES), polypropylene (PP) or nylon, and more preferably polytetrafluoroethylene (PTFE), polyethersulfone (PES) or polypropylene (PP).

[0042] In this invention, when the liquid formulation is a suspension, the second mixture includes a suspending agent.

[0043] The present invention also provides the use of the liquid formulation containing nematvir and ritonavir in the preparation of drugs for the novel coronavirus.

[0044] The technical solutions provided by the present invention will be described in detail below with reference to the embodiments, but they should not be construed as limiting the scope of protection of the present invention.

[0045] Example 1

[0046] The components and dosages of the liquid formulation described in this embodiment are as follows:

[0047]

[0048]

[0049] The preparation process is as follows:

[0050] Ethanol and propylene glycol were placed in a container, and ritonavir and nelmatevir were added. The mixture was sonicated at 40 kHz to dissolve them, obtaining a first mixture. Polyoxyethylene 40 hydrogenated castor oil, sucralose, flavoring, and water were then mixed (to achieve a mass concentration of 72% for these components), and added to the first mixture. Water was added to a final volume of 1000 mL, and the mixture was stirred at 100 rpm until homogeneous. The pH was then adjusted to 3.5 with 0.3% citric acid. The mixture was then filtered, dispensed, and sterilized by filtration through a 0.22 μm PTFE membrane to obtain a liquid formulation containing nelmatevir and ritonavir.

[0051] Example 2

[0052] The components and dosages of the liquid formulation described in this embodiment are as follows:

[0053]

[0054]

[0055] The preparation process is as follows:

[0056] Ethanol and propylene glycol were measured and placed in a container. Ritonavir and nelmatevir were added and sonicated at 45 kHz to dissolve them, obtaining a first mixture. Polyoxyethylene 35% hydrogenated castor oil, sodium saccharin, flavoring, and water were then mixed (to achieve a mass concentration of 70% for these components). This mixture was added to the first mixture, and water was added to bring the volume of the liquid preparation to 1000 mL. The mixture was stirred at 110 rpm until homogeneous, and the pH was adjusted to 4.5 with 0.1% citric acid. The mixture was then filtered, dispensed, and sterilized by filtration through a 0.22 μm pore size polypropylene membrane to obtain a liquid preparation containing nelmatevir and ritonavir.

[0057] Example 3

[0058] The components and dosages of the liquid formulation described in this embodiment are as follows:

[0059]

[0060] The preparation process is as follows:

[0061] Ethanol and propylene glycol were measured and placed in a container. Ritonavir and nelmatevir were added and sonicated at 35 kHz to dissolve them, obtaining a first mixture. Sodium dodecyl sulfate, xylitol, flavoring, and water were then mixed (to achieve a mass concentration of 70% for polyoxyethylene 35-hydrogenated castor oil, sodium saccharin, and flavoring in the mixture), and added to the first mixture. Water was added to bring the liquid preparation volume to 1000 mL, and the mixture was stirred at 120 rpm until homogeneous. The pH was then adjusted to 5.5 with 0.2% citric acid. The mixture was then filtered, dispensed, and sterilized by filtration through a 0.22 μm pore size polyethersulfone membrane to obtain a liquid preparation containing nelmatevir and ritonavir.

[0062] Example 4

[0063] The components and dosages of the liquid formulation described in this embodiment are as follows:

[0064]

[0065] Preparation process:

[0066] Ethanol and propylene glycol were measured and placed in a container. Ritonavir and nelmatevir were added and sonicated at 45 kHz to dissolve them, obtaining a first mixture. Then, 35% hydrogenated castor oil, sodium saccharin, flavoring, xanthan gum, and water were mixed (to achieve a mass concentration of 70% for these components). This mixture was added to the first mixture, and water was added to a final volume of 1000 mL. The mixture was stirred at 115 rpm until homogeneous, and the pH was adjusted to 4.5 with 0.1% citric acid. The solution was then filtered, dispensed, and sterilized by filtration through a 0.22 μm polypropylene membrane to obtain a liquid formulation containing nelmatevir and ritonavir.

[0067] Example 5

[0068] The components and dosages of the liquid formulation described in this embodiment are as follows:

[0069]

[0070]

[0071] The preparation process is as follows:

[0072] Ethanol and propylene glycol were measured and placed in a container. Ritonavir and nelmatevir were added and sonicated at 35 kHz to dissolve them, obtaining the first mixture. Sodium dodecyl sulfate, xylitol, flavoring, colloidal silica, povidone, and water were then mixed (to achieve a mass concentration of 70% for polyoxyethylene 35-hydrogenated castor oil, sodium saccharin, and flavoring in the mixture), and added to the first mixture. Water was added to a final volume of 1000 mL, and the mixture was stirred at 115 rpm until homogeneous. The pH was then adjusted to 7 with 0.8% citric acid. The mixture was then filtered, dispensed, and sterilized by filtration through a 0.22 μm polyethersulfone membrane to obtain the liquid formulation containing nelmatevir and ritonavir.

[0073] The performance of the liquid formulation containing nematvir and ritonavir obtained in Example 1 was tested. The test methods and results are as follows.

[0074] 1. Bioavailability test:

[0075] (1) Equipment and conditions:

[0076] a. Equipment: LC-MS / MS (Waters, TQ-S), column: Agela Venusil MP-C18 column, 3.0×50mm, 3μm; centrifuge: 8040R centrifuge (Eppendorf Instruments); pre-column: Agilent ZORBAX SB-C18;

[0077] b. Conditions:

[0078] Chromatographic conditions: Agela Venusil MP-C18 column, 3.0×50mm, 3μm; column temperature: 40℃; injection volume: 1μL; flow rate: 0.4mL / min; analysis time: 4min; sample pan temperature: 10℃; program settings are shown in Table 1.

[0079] Table 1. Chromatographic analysis procedure settings

[0080] Time (min) Flow rate (mL / min) Channel A (%) Channel B (%) 0.00 0.4 5.0 95.0 0.50 0.4 5.0 95.0 1.20 0.4 95.0 5.0 2.0 0.4 95.0 5.0 2.10 0.4 5.0 95.0 3.00 0.4 5.0 95.0

[0081] Mass spectrometry conditions: LC-MS, triple quadrupole, ESI ionization source, positive ion monitoring, MRM mode. Nematovevir (NRV): Progenitor ion m / z = 500.2473, daughter particle m / z = 319.1625, daughter particle m / z = 291.1813, daughter particle m / z = 110.0964. Ritonavir (RTV): Progenitor ion m / z = 721.4, daughter particle m / z = 296.2. Internal standard Telmisartan: Progenitor ion m / z = 515.3, daughter particle m / z = 276.2.

[0082] (2) Test Methods: Eighteen male Sprague-Dawley rats (6-8 weeks old, 180±20g) provided by Jinan Pengyue Experimental Animal Breeding Co., Ltd. (Jinan, China) were selected. The 18 rats were randomly divided into three groups of six each: experimental group, control group, and standard group. Before the experiment, the rats were acclimatized for 7 days at 25±0.5℃ and 60±5% relative humidity, while being provided with a standard diet. The experimental procedures were strictly conducted in accordance with the "Animal Experiment Ethics and Regulations" guidelines approved by the Institutional Ethics Committee of Liaocheng University (Approval No.: 2020-08-003).

[0083] After the adaptation period, nelmatvir was administered via gavage at a dose of 60 mg / kg. The experimental group received the liquid formulation containing nelmatvir and ritonavir obtained in Example 1, while the control group received the same dose of physically mixed and homogeneous nelmatvir and ritonavir raw materials (uniformly dispersed in physiological saline). The standard group did not receive any administration.

[0084] Blood samples of 500 μL were drawn from the orbital venous plexus of rats at preset time intervals (15 min, 30 min, 1 h, 1.5 h, 2 h, 4 h, 6 h, 8 h, 12 h, 24 h), and heparin was used to prevent clotting. The blood samples were centrifuged at 5000 r / min for 5 min to immediately separate the plasma, which was then stored at -80 °C. Standards were prepared in the same manner using blank mouse plasma as the sample matrix, with nematidine ranging from 0.001 to 30 μg / mL and ritonavir ranging from 0.0003 to 1.7 μg / mL. 2 >0.99. Detection was performed using liquid chromatography-mass spectrometry. Pharmacokinetic parameters were calculated using WinNonlin 6.1 software (Pharsight, Inc., Mountain View, CA, USA). The results are as follows. Figures 1-2 As shown in Table 2.

[0085] Table 2 Pharmacokinetic parameters of the experimental and control groups

[0086]

[0087] Depend on Figures 1-2 Figure 1 Figure 2 Time (min) Flow rate (mL / min) Channel A (%) Channel B (%) Figures 1-2 Fig As shown in Table 2, the peak time differed between the liquid formulation group and the physical mixture group. In the liquid formulation group, nelmatvir (S-NRV) peaked at approximately 1.5 hours, while in the physical mixture group, nelmatvir (R-NRV) peaked at approximately 1.6 hours. Furthermore, it can be observed that the liquid formulation group exhibited higher blood drug concentrations. max and AUC (0-t)The concentrations were 160.44±72.55 μg / mL and 940.37±259.16 μg-hr / mL, respectively, representing increases of 90-fold and 150-fold compared to the physical mixture group.

[0088] 2. Drug stability testing:

[0089] Three equal amounts of the liquid formulation containing nelmatevir and ritonavir obtained in Example 1 were taken and stored at 4°C, 25°C, and 40°C for 3 months, respectively. The contents of nelmatevir and ritonavir were determined at preset time intervals (5 days, 1 month, and 3 months). The results are shown in Table 3.

[0090] Table 3. Stability test results of liquid formulations containing nematvir and ritonavir

[0091]

[0092] As shown in Table 3, the liquid preparation containing nematriberi and ritonavir obtained by the present invention has high stability. Even after being stored for 3 months, the drug content of nematriberi and ritonavir is still above 99%, and the properties of the liquid preparation remain unchanged, being a colorless and transparent solution.

[0093] The liquid formulation containing nelmatvir and ritonavir provided by this invention is a clear and transparent solution, solving the problem of inconvenient administration due to the large dosage of Paxlovid tablets. Furthermore, compared to tablets, this liquid formulation significantly improves the in vitro dissolution rate of nelmatvir and ritonavir, increasing bioavailability and addressing the issues of low dissolution rates, short duration of action, and the need to take multiple tablets in existing technologies, thus improving patient medication adherence.

[0094] The above description is only a preferred embodiment of the present invention. It should be noted that for those skilled in the art, several improvements and modifications can be made without departing from the principle of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. A liquid formulation containing nematvir and ritonavir, characterized in that, The liquid formulation comprises the following components: ritonavir, nematvir, cosolvent, solubilizer, pH adjuster, flavoring agent, and solvent; The method for preparing the liquid formulation containing nematriberi and ritonavir includes the following steps: mixing the components and then performing post-processing to obtain the liquid formulation containing nematriberi and ritonavir. The co-solvent is ethanol and / or propylene glycol; the solubilizer is polyoxyethylene hydrogenated castor oil and / or sodium dodecyl sulfate. The solvent is water; In liquid formulations, the combined mass concentration of ritonavir and nematvir is 0.05% to 0.5%.

2. The liquid formulation containing nematvir and ritonavir according to claim 1, characterized in that, The liquid formulation also includes stabilizers and suspending agents.

3. The liquid formulation containing nematvir and ritonavir according to claim 1 or 2, characterized in that, In liquid formulations, the volume concentration of the cosolvent is 10–80%; in liquid formulations, the mass concentration of the solubilizer is 0.01–15%.

4. The liquid formulation containing nematamide and ritonavir according to claim 3, characterized in that, The pH adjuster is one or more of phosphoric acid and its phosphates, citric acid and its citrates, and lactic acid and its lactates; the flavoring agent is one or more of sucrose, aspartame, acesulfame potassium, sodium saccharin, cyclamate, xylitol, sucralose, erythritol, and flavoring; the amount of pH adjuster used is to make the pH of the liquid preparation 3 to 7; in the liquid preparation, the mass concentration of the flavoring agent is 0.01 to 10%.

5. The liquid formulation containing nematvir and ritonavir according to claim 1 or 4, characterized in that, The mass ratio of ritonavir to nematovir is 1:1 to 10.

6. The liquid formulation containing nematvir and ritonavir according to claim 2, characterized in that, The suspending agent is one or more of xanthan gum, hydroxypropyl methylcellulose, and colloidal silica; the stabilizer is povidone and / or hydroxypropyl methylcellulose; in the liquid formulation, the mass concentration of the suspending agent is 0.1-10%, and the mass concentration of the stabilizer is 0.25-5%.

7. The method for preparing the liquid formulation containing nematvir and ritonavir as described in any one of claims 1 to 6, characterized in that, The process includes the following steps: mixing the components and then post-processing them to obtain a liquid formulation containing nematvir and ritonavir.

8. The method for preparing the liquid formulation containing nematvir and ritonavir according to claim 7, characterized in that, The post-processing consists of filtration and sterilization.

9. The use of the liquid formulation containing nematvir and ritonavir as described in any one of claims 1 to 6 in the preparation of a drug for the novel coronavirus.

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