RU2814927C1 - Antiviral pharmaceutical composition containing favipiravir and amino acid, drug containing it, as well as their use for treating and/or preventing viral infections - Google Patents

Abstract

FIELD: chemical-pharmaceutical industry; medicine.

SUBSTANCE: group of inventions relates to a pharmaceutical composition and a medicinal agent exhibiting preventive and/or therapeutic antiviral activity, and use thereof. Pharmaceutical composition contains in therapeutically effective amounts favipiravir and at least one aliphatic mono- or diaminomonocarboxylic non-proteinogenic amino acid with weight ratio of favipiravir to amino acid 1.0:0.1–1.0:1.20 respectively. Medicinal agent contains the above pharmaceutical composition and at least one pharmaceutically acceptable excipient. Also disclosed is use of said pharmaceutical composition for preparing a drug exhibiting preventive and/or therapeutic antiviral activity.

EFFECT: group of inventions provides a wider range of antiviral agents, pharmaceutical composition and medicinal agent described above have improved processing characteristics, stability and bioavailability.

52 cl, 2 tbl, 4 ex

Description

The invention relates to the field of chemical-pharmaceutical industry and medicine, and is a new pharmaceutical composition of favipiravir with one or more amino acids, as well as a medicinal product containing the said pharmaceutical composition.

The worldwide outbreak of SARS-CoV-2 and its associated consequences pose a threat to the public health and economies of many countries. The lack of specific therapy against the new virus and its high variability requires the creation of new drugs.

As part of the fight against the new infection, a number of preventive vaccines, as well as nonspecific therapies that alleviate the course of the disease, have been developed. However, in addition to existing therapies, specific drugs are needed that have a direct effect on the virus, leading to alleviation of the symptoms of the disease, accelerated resolution of the disease, blocking the transmission of infection and reducing the risk of developing clinical complications.

Nucleoside analogue drugs directly target the activity of RNA-dependent RNA polymerase and block viral RNA synthesis for a wide range of RNA viruses, including the human coronavirus family. Favipiravir (6-fluoro-3-hydroxy-2-pyrazinecarboxamide), a guanine analogue clinically approved for the treatment of influenza, has been shown to effectively block the RNA-dependent RNA polymerase of influenza viruses (various types), Ebola virus, yellow fever, and chikungunya. , noroviruses, enteroviruses [De Clercq, E. New nucleoside analogues for the treatment of hemorrhagic fever virus infections. Chem. Asian J. 14, 3962-3968, 2019].

A recent study showed the effectiveness of favipiravir against SARS-CoV-2 (EC50=61.88 μM in Vero E6 cell culture) [Wang, M. et al. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Res. - 2020.-30, p.269-271]. The study tested the combination of favipiravir with interferon-a (ChiCTR2000029600) and favipiravir with baloquavir marboxil (an approved cap-dependent endonuclease inhibitor for influenza) (ChiCTR2000029544) in patients with SARS-CoV-2.

The universal mechanism of action of favipiravir, specifically acting on the fundamental enzyme of the viral replication apparatus, suggests a wide range of antiviral activity of this substance, which has been demonstrated in many studies listed below.

Antiviral activity of favipiravir.

According to the Global Pharmaceutical Substances Report, favipiravir has now entered clinical trials against COVID-19 disease based on its proven mechanism of action against viral RCP. In a clinical trial at the National Center for Clinical Research of Infectious Diseases in Shenzhen, favipiravir was administered to 340 patients (age groups and comorbidities not specified) in two doses (2 doses) of 1600 mg on the first day and two doses of 600 mg for the next 13 days in addition to interferon-alpha inhalation aerosol (5 million units* 2/day). This dosage led to a more rapid disappearance of the virus to undetectable values in the blood) than in the group of patients taking the combination of anti-HIV proteases - lopinavir / ritonavir, with a median clearance of viral particles of 4 days, versus 11, respectively, and was assessed by CT control thoracic region. According to the current study, the use of favipiravir reduces the number of detectable viral particles in the blood, which means it demonstrably inhibits viral replication, delays the development of an aggressive scenario for COVID-19, or even prevents it.

The effect of favipiravir against the influenza virus

An influenza epidemic occurs throughout the world every year. The disease is caused by strains of influenza virus of varying virulence. The highly pathogenic avian influenza A(H5N1) virus caused the first outbreak in Hong Kong in 1997 and continues to cause local outbreaks of this type of influenza each year. The avian influenza A(H7N9) epidemic in China in 2013 and the influenza A(H1N1) pandemic in 2009 resulted in 17,700 deaths, and influenza is still a major health problem worldwide, not only in terms of incidence but and on the critical health complications it causes [Writing Committee of the WHO Consultation on Clinical Aspects of Pandemic (H1N1) 2009 Influenza. Clinical aspects of pandemic 2009 influenza A (H1N1) virus infection.- 2010.- N. Engl. J. Med.]. The A(H1N1) epidemic showed that this strain is resistant to ocetalmivir (Tamiflu), a neuramidase inhibitor, and amantadine, an inhibitor of the non-structural protein M2. In this regard, in medical practice there is an urgent need for a medicine with a different mechanism of action.

Favipiravir (T-705; 6-fluoro-3-hydroxy-2-pyrazinecarboxamide) is effective against a wide range of influenza virus strains, including A(H1N1) (2009 pandemic), A(H5N1) and A(H7N9), due to that the viral PsRp mistakes the favipirovir-RTF metabolite for a purine nucleotide. Favipiravir has undergone phase III studies in Japan and Poi in the United States for the treatment of influenza.

In addition to its antiviral activity against influenza, favipiravir inhibits the replication of arenaviruses, phleboviruses (Rift Valley fever, phlebotomy fever virus and Punta Toro fever virus), hantaviruses (Maporal, Dobrava and Prospect Hill); flaviviruses (yellow fever and West Nile fever); enteroviruses (complete and rhinoviruses); respiratory syncytium paramyxovirus and norovirus [Yousuke Furuta, Brian B.Gowen, KazumiTakahashi, KimiyasuShiraki, Donald F.Smee, Dale L.Barnard. Favipiravir (T-705), a novel viral RNA polymerase inhibitor. Antiviral Research. - 2013. - Volume 100, Issue 2].

Use of favipiravir in in vitro models of influenza

In in vitro studies, favipiravir showed high antiviral activity against all strains of influenza virus, A, B and C. Based on plaque-forming units (PFU) counts in MDCK cell culture, the effective concentration (EC50) ranged from 0.014 to 0.55 iG /ml [Furuta Y., Takahashi K., Fukuda Y., Kuno M., Kamiyama T., Kozaki K., Nomura N., Egawa H., Minami S., Watanabe Y., Narita H., Shiraki K. In vitro and in vivo activities of anti-influenza virus compound T-705.-2002.-Antimicrob Agents Chemother; 46(4), p.977-981].

Favipiravir is known to be active against 53 strains of influenza virus, including seasonal strains A(H1N1), A(H3N2), and type B influenza virus strains; A(HlNl)pdm09 pandemic virus, highly pathogenic avian influenza A(H5N1), isolated from humans, strains A(НШ1) and A(НШ2), isolated from pigs, and A(H2N2), A(H4N2), A(H7N2) .

Use of favipiravir in in vivo models of influenza

In vivo, in mouse models of viral infection with lethal doses of strains H3N2 (A/Victoria/3/75), H3N2 (A/Osaka/5/70) or H5N1 (A/Duck/MN/1525/81), favipiravir was administered one hour after infection . Survival of mice at doses of 30 mg/kg/day 2 or 4 times daily was significant, whereas all infected control mice died.

When administered at 60 to 300 mg/kg/day, favipiravir has been shown to be effective in reducing viral load in the lungs of H1N1-infected mice (A/California/04/09), as well as when administered delayed up to 96 hours postinfection [Takahashi K ., Furuta Y., Fukuda Y., Kuno M., Kamiyama T., Kozaki K., Nomura N., Egawa H., Minami S., Shiraki K. In vitro and in vivo activities of T-705 and oseltamivir against influenza virus. Antivir. Chem. Chemother.- 2003; Sidwell R.W., Barnard D.L., Day C.W., Smee D.F., Bailey K.W., Wong M.H., Morrey J.D., Furuta Y. Efficacy of orally administered T-705 on lethal avian influenza A (H5N1) virus infections in mice.- 2007.-Antimicrob Agents Chemother]. Favipiravir showed a significant therapeutic effect compared with ocetalmivir in mice that were given a 100-fold higher dose of the virus, and the treatment itself was delayed for 96 hours post-infection [Takahashi K, Furuta Y, Fukuda Y, Kuno M, Kamiyama T, Kozaki K, Nomura N, Egawa H, Minami S, Shiraki K. Antivir Chem Chemother. In vitro and in vivo activities of T-705 and oseltamivir against influenza virus. 2003].

Efficacy of favipiravir against other families of RNA viruses in in vitro and in vivo studies.

Arena viridae

Arenaviruses cause fatal human diseases [Moraz M.L., Kunz S. Pathogenesis of arenavirus hemorrhagic fevers. - 2011.- Expert Rev. Anti Infect. Ther. - 9(1), p. 49-59], for which there are no antiviral drugs, except for ribavirin, which has a pronounced toxic effect.

Use of favipiravir in in vivo models of arenaviruses

In vitro, favipiravir showed greater selectivity than ribavirin. When measuring the cytopathic effect in cell culture, the EC50 values for the drug were 0.79-0.94 ig/ml for the Yunin, Pichinde and Takaribe viruses. Also, the viral load when using favipiravir decreased significantly by the third day. When studying the method of counting foci of hemolysis 3K90s against the highly pathogenic Romero strain of Guanarito virus JUNV (Romero) and Machupo virus was 3.3-8.4 mg/ml (21-53 mM) [Mendenhall M, Russell A, Juelich T, Messina EL, Smee DF, Freiberg AN, Holbrook MR, Furuta Y, de la Torre JC, Nunberg JH, Gowen BB. Antimicrob Agents Chemother. T-705 (favipiravir) inhibition of arenavirus replication in cell culture.- 2011.- Antimicrob Agents Chemother. - 55(2), p. 782-787].

When administered orally, favipiravir in a model line of hamsters infected with the Pichinde virus, the drug prevented death, reduced the number of viral titers in the blood and tissues, and at dosages of 60 mg/kg/day, it twice prevented liver destruction when used for 7 days, starting at 4 hours postinfection [Gowen V.V., Wong M.N., Jung K.N., Sanders A.V., Mendenhall M., Bailey K.W., Furuta Y., Sidwell R.W. In vitro and in vivo activities of T-705 against arenavirus and bunyavirus infections. Antimicrob. Agents Chemother.- 2007.- 51(9), p.3168-3176]. The viral load also decreased significantly when treatment began on days 4, 5, and 6 post-infection. When used in dosages of 100 mg/kg/day, animal survival significantly increased [Gowen V.V., Smee D.F., Wong M.N., Hall J.O., Jung K.H., Bailey K.W., Stevens J.R., Furuta Y., Morrey J.D. Treatment of late stage disease in a model of arenaviral hemorrhagic fever: T-705 efficacy and reduced toxicity suggests an alternative to ribavirin.- 2008.- PLoS One 3, e3725].

In a guinea pig infection model, favipiravir demonstrated its effectiveness even after the onset of acute symptoms of the disease [Mendenhall M., Russell A., Smee D.F., Hall J.O., Skirpstunas R., Furuta Y., Gowen B.B. Effective oral favipiravir (T-705) therapy initiated after the onset of clinical disease in a model of arenavirus hemorrhagic fever.-2011.- PLoS Negl. Trop.Dis. 5, e1342].

When favpiravir was used at a dose of 300 mg/kg/day, it showed significant effects on survival: 100% of the animals participating in the experiment survived, at a dose of 150 mg/kg/day the rates decreased to 50 and 25%, the animals maintained their body weight, their temperature dropped to normal and all indicators were generally better than those for ribavirin at a dosage of 50 mg/kg/day. The concentration of a prognostic marker of Lassa fever disease severity in the blood, aspartate aminotransferase (AST), decreased significantly in a dose-dependent manner by the tenth day of the disease when treated with favipiravir. Mean infectious dose viremia per ml of eluate decreased to an average of 2.1, 1.3, and 1.6 log10 CCID50/ml in the high- and medium-dose favipiravir and ribavirin groups, respectively.

The effectiveness of oral favipiravir has also been shown in guinea pig and mouse models infected with the lethal Lassa virus [Safronetz D., et al. The broad-spectrum antiviral favipiravir protects guinea pigs from lethal Lassa virus infection post-disease onset.- 2015.- Sci. Rep.5, 14775]. The therapeutic effect was observed on the 2nd day after infection. Subcutaneous administration of favipiravir at dosages of 300 mg/kg/day once daily reduced fever, prevented weight loss, and increased animal survival. The effects of favipiravir were many times greater than the therapeutic results of ribavirin at a dosage of 50 mg/kg/day. A significant improvement in the survival of Lassa virus-infected guinea pigs was observed even on days 5, 7 and 9 post-infection [Safronetz D., et al. The broad-spectrum antiviral favipiravir protects guinea pigs from lethal Lassa virus infection post-disease onset.- 2015.- Sci. Rep.5, 14775].

Bunyaviridae

Viruses of the Bunyavirida family, including La Croce virus (LACV), Rift Valley fever virus (RVFV), Crimean-Congo hemorrhagic fever virus (CCHFV), acute fever with thrombocytopenia syndrome virus (SFTSV), and hantavirus, cause severe hemorrhagic fevers with associated pulmonary and renal complications.

In vitro studies have shown the superiority of favipiravir over other drugs in targeting, efficiency and speed of action against a number of similar viruses [Yousuke Furuta, et al. Favipiravir (T-705), a novel viral RNA polymerase inhibitor.- 2013.- Antiviral Research. Volume 100; Gowen B.B., et al. Efficacy of favipiravir (T-705) and T-1106 pyrazine derivatives in phlebovirus disease models. - 2010. - Antiviral Res., Volume 86, Issue 2, p.121-12]. EC50 values in plaque-forming unit (PFU) cell culture studies ranged from 0.9 to 30 μg/ml drug for Lassa, Punta Toro, Rifa Valle, acute fever virus (SFTSV), phlebotomy fever, and Dobrava, Maporal, and Prospect Hill hantaviruses [ Tani N., et al. Efficacy of T-705 (Favipiravir) in the treatment of infections with lethal severe fever with thrombocytopenia syndrome virus.- 2016.- mSphere 1, e00061 15].

Use of favipiravir in in vitro and in vivo models of bunyaviruses Acute fever with thrombocytopenia virus (SFTSV) emerged several years ago as a seasonal disease in China, Korea and Japan [Yu X., Liang M., et al. Fever with thrombocytopenia associated with a novel bunyavirus in China.- 2011.- N. Engl. J. Med, 364. P. 523-1532]. Favipiravir inhibited SFTSV replication in cell culture with EC50 values of 0.71-1.3 μg/ml.

The therapeutic effect of favipiravir has been demonstrated in interferon-a receptor knockout (IFNAR-/-) mouse models, which do not develop an immediate immune response.

When administered orally with favipiravir at a dose of 300 mg/kg/day for 5 days, starting from day 3 post-infection, all experimental mice survived (P < 0.001), and starting from days 4 and 5 post-infection, performance improved significantly survival in the group. Based on data from in vivo studies in Japan, the drug entered clinical trials and has successfully completed them to date. Studies have shown the effectiveness of favipiravir even after the onset of the disease and the onset of clinical symptoms (Yousuke Furuta, et al.. Favipiravir (T-705), a novel viral RNA polymerase inhibitor. - 2013. - Antiviral Research. Volume 100, Issue 2].

Flaviviridae

Favipiravir blocks the replication of viruses of the flaviviride family, including yellow fever virus (YFV) and West Nile virus (WNV) [Julander J.G., et al. Activity of T-705 in a hamster model of yellow fever virus infection in comparison with a chemically related compound T-1106. - 2009. - Antimicrob. Agents Chemother, 53(1), p.- 202-209; Morrey J.D., et al. Efficacy of orally administered T-705 pyrazine analog on lethal West Nile virus infection in rodents. - 2008. - Antiviral Res., 80(3), p.377-379], however, in higher concentrations than necessary to block the activity of the influenza virus.

The EC of favipiravir against YFV is 51.8 μg/ml in in vitro studies to determine the release of active viral particles in Vero cell culture.

Use of favipiravir in in vivo models of flaviviruses

YFV-infected hamsters were treated orally with favipiravir at doses of 200 to 400 mg/kg/day for 8 days, starting 4 hours before infection. This therapy significantly reduced the mortality rate of animals when treatment was initiated [Julander J.G., et al. Activity of T-705 in a hamster model of yellow fever virus infection in comparison with a chemically related compound T-1106.- 2009.- Antimicrob. Agents Chemother, 53(1), p.202-209].

Complete recovery was achieved with 400 mg/kg/day, starting on day 2 post-infection.

In vitro and in vivo antiviral efficacy of favipiravir against West Nile virus was achieved at EC50 concentrations of 53 μg/ml in Vero cell culture.

Oral administration of favipiravir in doses of 400 mg/kg/day 2 times a day, 4 hours after infection, saved 90% of mice from death, and also significantly reduced the expression of viral proteins and viral RNA in brain tissue. The same effectiveness was shown in WNV-infected hamster lines at the same doses. WNV envelope proteins were not detected in the brains of treated animals.

Togaviridae

Favipiravir exhibits antiviral activity against Western equine encephalitis virus (WEEV) in Vero cell culture, reaching EC90 at 49 μg/ml [Julander J.G., et al. Effect of T-705 treatment on western equine encephalitis in a mouse model. Antiviral Res, 82(3), p.169-171].

In mice infected with WEEV, oral administration of favipiravir significantly increased survival and lifespan of infected animals when administered twice at a dose of 400 mg/kg/day for 7 days, starting at 4 hours postinfection. Viral titers in brain tissue were reduced on the 4th day of postinfection.

Favipiravir showed antiviral activity against Chikungunya virus (CHIKV) in Vero cell culture, reaching an EC50 of 0.3-9.4 μg/ml. In CHIKV-infected mice, oral favipiravir improved survival at two doses of 300 mg/kg/day starting 24 hours before or 4 hours after infection [Delang L., et al. Mutations in the chikungunya virus non-structural proteins cause resistance to favipiravir (T-705), a broad-spectrum antiviral. - 2014. - J. Antimicrob. Chemother, 69(10), p. 2770-2784].

Picornaviridae

Use of favipiravir in in vitro models of picornaviruses Replication of vesicular stomatitis enterovirus was inhibited by favipirovir in in vitro studies with an EC50 of 14 μg/ml [Sakamoto K., et al. The inhibition of FMD virus excretion from the infected pigs by an antiviral agent, T-1105. FAO report of the research group of the standing technical committee of the European commission for the control of Foot-and-Mouth Disease. - 2006.- Paphos, Cyprus. FAO Appendix 64; Furuta Y., et al. T-705 (favipiravir) and related compounds: Novel broad-spectrum inhibitors of RNA viral infections. - 2009. - Antiviral Res, 82(3), p. 95-102].

Favipiravir also blocked the replication of polio virus in Vero cell culture and rhinovirus in HeLa cell culture at 3K50s of 4.8 and 23 μg/ml, and with a selectivity index of 29 and >43, respectively [Furuta Y., et al. In vitro and in vivo activities of anti-influenza virus compound T-705. Antimicrob. 2002.- Agents Chemother, 46(4), p. 977-981]. Favipiravir inhibited Enterovirus replication with an EC50 of 23 μg/ml [Wang Y., et al. In vitro assessment of combinations of enterovirus inhibitors against enterovirus 71. - 2016. - Antimicrob. Agents Chemother, 60(9), p. 5357-5367].

Caliciviridae

Favipiravir is active against murine noravirus with EC50 values of 39 μg/ml in viral plaque counting studies in the murine macrophage cell line RAW 264.7. Real-time PCR revealed blocking of RNA synthesis by favipiravir with an EC50 of 19 fir/ml [Rocha-Pereira J., et al. Favipiravir (T-705) inhibits in vitro norovirus replication. - 2012. - Biochem. Biophys. Res. Commun, 424(4), p. 777-780].

Use of favipiravir in in vivo models of the noravirus genus from the Calicivirus family

In a murine model of persistent infection, oral favpiravir 600 mg/kg/day administered twice for 8 weeks, 4 weeks post-infection, resulted in a significant reduction in viral titers in mouse feces and the number of norovirus-positive mice. Scientific evidence also confirms that favipiravir-RTF inhibits the RNA polymerase activity of human Noraviruses [Jin Z., et al. Biochemical evaluation of the inhibition properties of Favipiravir and 2'-C-methyl-cytidine triphosphates against human and mouse norovirus RNA polymerases.- 2015 Antimicrob. Agents Chemother].

Filoviridae

Favipiravir showed antiviral activity against the Zaire Ebola virus (strain Mayinga 1976) in Vero E6 cell culture with an EC50 of 10.5 μg/ml. In a strain of mice infected with the interferon-alpha receptor-deficient strain Mayinga 1976 (IFNAR/C57BL/6), oral favipiravir avoided death and reduced viral titers in the blood when administered twice from 300 mg/kg/day for 8 days. from day 6 post-infection, whereas in the placebo group all mice died [Oestereich L., et al. Successful treatment of advanced Ebola virus infection with T-705 (favipiravir) in a small animal model.- 2014.- Antiviral Res, 105, p.17-21]. Similarly, in the IFNAR/ interferon receptor knockout line A129 infected with Ebola E718, treatment with oral favipiravir completely rescued all infected mice from death when given twice the drug at a dose of 300 mg/kg/day for 14 days, starting from day 1. hours after infection [Smither S.J., et al.- Post-exposure efficacy of oral T-705 (Favipiravir) against inhalational Ebola virus infection in a mouse model.- 2014.- Antiviral Res, Volume 104, Pages 153-155].

During the Ebola outbreak in West Africa in 2014, the French Institute of Health and Medical Research (INSERM) and the government of Guinea conducted a clinical trial of favipiravir in patients [Mentre F., Taburet A.M. Dose regimen of favipiravir for Ebola virus disease. 2015.- Lancet Infect. Dis, VOLUME 15, ISSUE 2, P.150-151]. Favipiravir was well tolerated and reduced deaths in patients with low viral titers. A group of Chinese researchers also noted an increase in the survival rate of Ebola patients when using favipiravir in Sierra Leone [Bai C.Q., Clinical and virological characteristics of Ebola virus disease patients treated with favipiravir (T-705) - Sierra Leone, 2016. Clin. Infect. Dis, 63(10), p. 1288-1294].

Rhabdoviridae

The activity of favipiravir against rabies virus (RABV) was detected on the mouse neuroblastoma cell line Neuro-2a with 3K50s at 5.1-7.0 μg/ml [Yamada K., et al. Efficacy of Favipiravir (T-705) in rabies postexposure prophylaxis.- 2016.- J. Infect. Dis, 213(8), p.1253-1261]. Favipiravir significantly reduced morbidity and mortality in RABV-infected mice when administered orally at doses of 300 mg/kg/day twice for 7 days, starting 1 hour postinfection.

All the generalized data described above on the undeniable effectiveness of favipiravir against a very wide range of RNA viruses show that this medicine perfectly “closes” the hitherto effectively unreached niche of incurable, acute and fatal viral diseases, including a wide range of tropical fevers. Before studies on favipiravir, ribavirin and/or alpha-interferon were used against the above-mentioned RNA infections, but the former has significantly less antiviral activity and effectiveness against RNA viruses, and both drugs lead to debilitating side effects with long-term use.

Favipiravir, based on its wide spectrum and proven mechanism of action, can also alleviate the course of viral diseases, if taken in a timely manner, and also significantly reduce the viral load during diseases with complications.

In view of the versatility and high effectiveness demonstrated by favipiravir preparations, it seems necessary to use them during periods of epidemics.

However, such use is associated with a number of difficulties. Thus, in order to provide quick and high-quality assistance to the population, it is necessary to create a reserve of stable medications, which in turn involves the possibility of their long-term storage.

Currently, the only form of favipiravir available for medical use is oral tablets containing favipiravir 200 mg/tablet, which have a shelf life of 2 years.

At the same time, oral forms cause difficulties in taking medications in children, elderly patients and patients with dysphagia of various natures, as well as seriously ill patients in intensive care, connected to a ventilator or in a coma, which can significantly complicate the necessary therapy. In addition, taking a large number of tablets, especially over a long period of time, can have a negative effect on the human digestive system.

In addition, the entry of SARS-CoV into the host body is mediated by the interaction between the needle glycoprotein attached to the virus envelope and the angiotensin-converting enzyme type 2 (ACE-2) receptor of human cells. At its highest concentration, the ACE-2 receptor, which serves as the entry gate for SARS-CoV-2, is expressed in lung cells, epithelium of the upper esophagus, as well as in enterocytes of the ileum and colon [She J, Liu L, Liu W. COVID-19 epidemic : disease characteristics in children. Journal of Medical Virology.- 2020; 92, p.747-754]. SARS-CoV-2, acting on ACE-2 receptors in the gastrointestinal tract, is able to increase the permeability of the intestinal mucosa, which leads to disruption of the absorption of fluid and electrolytes by enterocytes. In addition to SARS-CoV-2 itself, the gastrointestinal tract is also seriously affected by the treatment of COVID-19 with antibiotics, antiviral and hormonal drugs, which place a large burden on the gastrointestinal tract. Thus, people with COVID-19 experience disruption of the gastrointestinal tract, including nausea, vomiting, diarrhea, impaired motility, dysbacteriosis, etc., thereby changing the rate of absorption of the drug and its bioavailability.

Based on the above, it seems necessary to create new dosage forms of favipiravir that have antiviral activity, with improved pharmacotherapeutic, technological, physicochemical characteristics, as well as increased bioavailability, including dosage forms that allow the drug to be administered in therapeutically effective concentrations without negative effects on the digestive system inherent in oral forms.

The objective of the present invention was to develop a new, industrially marketable formulation of favipiravir with improved technological characteristics, stability and bioavailability.

The technical results of the present invention are:

- improving the bioavailability of favipiravir;

- improving the uniformity of dosing of the active agent in medicines;

increasing the stability of the favipiravir composition (including photostability, stability in different climatic zones and long-term stability);

- synergistic antiviral activity;

- improvement of the electrical properties of the drug favipiravir in powder form;

- reducing the time for obtaining the favipiravir drug reconstituted from the lyophilisate;

- reducing the local irritant effect when injecting the composition of favipiravir with an amino acid.

- expansion of the arsenal of antiviral drugs.

The following are terms that are used in the description of the present invention. Unless otherwise specified, all technical and technical terms used in the specification have their common meaning in the art.

The term "pharmaceutical composition" means a composition comprising favipiravir and at least one amino acid in an effective amount, and the pharmaceutical composition in the context of the present invention may further contain one of the components selected from the group consisting of pharmaceutically acceptable and pharmacologically compatible excipients, such as , but not limited to, excipients, solubilizers, solvents, co-solvents, antioxidants, buffering agents, cryoprotectants, diluents, preservatives, stabilizers, humectants, emulsifiers, lubricants, lubricants, suspending agents, thickeners, sweeteners, fragrances, flavoring agents, antibacterial agents , fungicides, prolonged delivery regulators, isotonic agents, pH-regulating agents, the choice and ratio of which depends on the nature, purpose and dosage.

Non-limiting (illustrative) examples of suspending agents include ethoxylated isostearyl alcohol, polyoxyethylene, sorbitol and sorbitol ether, and mixtures thereof.

Protection of the pharmaceutical composition from the action of microorganisms can be achieved using a variety of antibacterial and antifungal agents, for example, sorbic acid, parabens (methylparaben, propylparaben, ethylparaben, butylparaben, isobutylparaben, isopropylparaben, benzylparaben, heptylparaben and mixtures thereof), chlorobutanol and the like connections.

As isotonic agents, the pharmaceutical composition may include, but is not limited to, sugars, sodium chloride, sodium bicarbonate, etc. Prolonged action of the pharmaceutical composition can be achieved, without limitation, by using agents that slow down the absorption of the active agent (for example, hydrophilic and hydrophobic polymer release retardants).

Non-limiting (illustrative) examples of suitable fillers include lactose, various types of starch, microcrystalline cellulose, calcium carbonate and phosphate, etc.

As solvents and diluents, water, organic esters suitable for parenteral forms, ethanol, polyalcohols, and mixtures thereof can be used, without limitation. Examples of lubricants can be magnesium or calcium stearate, talc, sodium lauryl sulfate, sodium stearyl fumarate, etc. Silicon dioxide, talc, kaolin, bentonites, etc. can be used as lubricants. Various organic and inorganic acids or alkalis can be used to regulate the pH, such as, but not limited to, hydrochloric acid, malic, ascorbic, citric, acetic, succinic, tartaric, fumaric, lactic, aspartic, glutaric, glutamic, sorbic acid, sodium hydroxide, etc. Examples of dispersing agents and distributing agents are starch, alginic acid and its salts, and silicates.

The pharmaceutical composition can be administered to animals and humans orally, parenterally (intradermally, subcutaneously, intramuscularly, intravenously, intraarterially, in the cavity), sublingually, locally, including but not limited to, ophthalmic, nasal administration, etc., rectally in a standard form of administration , in the form of a mixture with traditional pharmaceutical carriers. Suitable unit dosage forms include (but are not limited to) oral forms: tablets, capsules, pellets, granules, powders, solutions, oral and nasal spray solutions, syrups, suspensions, etc., oral: solutions, suspensions, emulsions, concentrates for preparation of injection and infusion dosage forms, aerosols and powders for inhalation administration, sprays, pulmonary powders (powders for spraying with an inhaler directly into the lungs), powders and lyophilisates for the preparation of injection and infusion dosage forms; rectal: suppositories, capsules, etc.; eye drops.

The term “excipient” in the context of the present invention characterizes substances of inorganic or organic origin used in the production process of medicinal products to give them the necessary physicochemical properties.

"Pharmaceutically acceptable salt" means the relatively non-toxic organic and inorganic salts of the acids and bases claimed in the present invention.

The term "pharmaceutically acceptable" in the context of the present invention means that the substance or composition to which this term is applied must be compatible from a chemical and/or toxicological point of view with the other ingredients included in the preparation, and safe for those for whom treated with this substance or composition.

The term “proteinogenic amino acids” in the context of the present invention characterizes amino acids that are included in proteins during biosynthesis in ribosomes under the genetic control of messenger RNA. Proteinogenic non-standard amino acids arise from standard ones through the process of post-translational modifications.

The term “non-proteinogenic amino acids” in the context of the present invention describes amino acids that do not participate in the formation of proteins. In some cases, there is a close structural relationship between non-proteinogenic and proteinogenic amino acids, since non-proteinogenic amino acids also include derivatives of proteinogenic amino acids.

The term "isoelectric point of amino acids" in the context of the present invention means the pH value at which the charge of an amino acid is zero.

The term "racemate" in the context of the present invention means a mixture of two enantiomers. An amino acid in the form of a racemate characterizes a mixture of L- and D-isomers of an amino acid in any proportions.

The term “drug” in the context of the present invention characterizes substances or combinations thereof that come into contact with the human or animal body, penetrate the organs, tissues of the human or animal body, used for the prevention, treatment of diseases, obtained by synthesis methods. Medicines include pharmaceutical substances and drugs. The drug may be presented in various finished forms intended for administration into the animal or human body in various ways, for example, but not limited to, orally, sublingually, topically, rectally, parenterally, inhalation, directly into the lungs, for example, in the form of an aerosol or Pulmonary powder using an inhaler.

The term “lyophilisate” in the context of the present invention characterizes a solid drug in the form of a powder or porous mass obtained by lyophilization of drugs with a liquid or soft consistency. Lyophilisates can be in the form of: powder; amorphous porous mass; porous mass compacted into a tablet, and other shapes. Before use, lyophilisates are dissolved (dispersed) to obtain drugs in various dosage forms: solutions; suspensions; emulsions.

The term "concentrate" in the context of the present invention characterizes a liquid dosage form intended for use after dilution (dilution). The concentrate may be prepared, without limitation, by dissolving the lyophilisate in a pharmaceutically acceptable solvent. If the conversion of the original dosage form to the use form is a two-step process, the term "concentrate" is used to designate the intermediate form. For example, if the lyophilisate must first be dissolved in a small amount of diluent to obtain a concentrate, then the resulting solution must be further diluted in a larger amount of diluent before infusion. In such a case, the solvent and diluent may be the same or different pharmaceutically acceptable excipients.

Also for the purposes of the present invention, the terms “comprising”, “contains”, “including” mean that the specified combinations, compositions and concentrate include the listed components, but do not exclude the inclusion of other components.

The term "therapeutically effective amount" in the context of the present invention means an amount of a substance (as well as a combination of substances) that, when administered to a subject for the treatment or prevention of a disease, or at least one of the clinical symptoms of a disease or disorder, is sufficient to effect such treatment (prevention). for a disease, disorder or symptom. The “therapeutically effective amount” may vary depending on the form of the substance (e.g., polymorph, salt, solvate, hydrate, etc.), 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 , as well as the age and/or weight of the subject requiring such treatment (prophylaxis).

The terms “about”, “approximately”, “about” characterize plus or minus ten percent of the specified value.

The stated problem is solved, and the stated technical result is achieved by obtaining a new pharmaceutical composition exhibiting preventive and/or therapeutic antiviral activity, containing favipiravir and at least one amino acid and/or its pharmaceutically acceptable salt in therapeutically effective quantities.

One embodiment of the invention is a pharmaceutical composition, where the mass ratio of favipiravir to amino acid is 1.0:0.1-1.0:1.2, respectively.

More preferably, the weight ratio of favipiravir to amino acid is 1.0:0.1, respectively.

More preferably, the weight ratio of favipiravir to amino acid is 1.0:0.15, respectively.

More preferably, the weight ratio of favipiravir to amino acid is 1.0:0.20, respectively.

More preferably, the weight ratio of favipiravir to amino acid is 1.0:0.25, respectively.

More preferably, the weight ratio of favipiravir to amino acid is 1.0:0.30, respectively.

More preferably, the weight ratio of favipiravir to amino acid is 1.0:0.35, respectively.

More preferably, the weight ratio of favipiravir to amino acid is 1.0:0.40, respectively.

More preferably, the weight ratio of favipiravir to amino acid is 1.0:0.45, respectively.

More preferably, the weight ratio of favipiravir to amino acid is 1.0:0.50, respectively.

More preferably, the weight ratio of favipiravir to amino acid is 1.0:0.55, respectively.

More preferably, the weight ratio of favipiravir to amino acid is 1.0:0.60, respectively.

More preferably, the weight ratio of favipiravir to amino acid is 1.0:0.65, respectively.

More preferably, the weight ratio of favipiravir to amino acid is 1.0:0.70, respectively.

More preferably, the weight ratio of favipiravir to amino acid is 1.0:0.75, respectively.

More preferably, the weight ratio of favipiravir to amino acid is 1.0:0.80, respectively.

More preferably, the weight ratio of favipiravir to amino acid is 1.0:0.85, respectively.

More preferably, the weight ratio of favipiravir to amino acid is 1.0:0.90, respectively.

More preferably, the weight ratio of favipiravir to amino acid is 1.0:0.95, respectively.

More preferably, the weight ratio of favipiravir to amino acid is 1.0:1.00, respectively.

More preferably, the weight ratio of favipiravir to amino acid is 1.0:1.05, respectively.

More preferably, the weight ratio of favipiravir to amino acid is 1.0:1.10, respectively.

More preferably, the weight ratio of favipiravir to amino acid is 1.0:1.15, respectively.

More preferably, the weight ratio of favipiravir to amino acid is 1.0:1.20, respectively.

One embodiment of the present invention is a pharmaceutical composition in which favipiravir is in free base form.

All amino acids are isomeristic. The bulk of natural amino acids are represented by a-isomers, but p- and y-amino acids are also found. All α-amino acids, except glycine, have an asymmetric (chiral) α-carbon atom and exist in the form of two enantiomers (L- and D-amino acids).

One embodiment of the invention is a pharmaceutical composition in which at least one pharmaceutically acceptable amino acid and/or a pharmaceutically acceptable salt thereof is an α-amino acid.

More preferably, the α-amino acid is glycine, alanine, valine, leucine, glutamine, lysine, arginine, histidine, aspartic acid, glutamic acid, isoleucine, proline, phenylalanine, tryptophan, methionine, serine, threonine, asparagine, cysteine, tyrosine.

One embodiment of the invention is a pharmaceutical composition in which at least one pharmaceutically acceptable amino acid and/or a pharmaceutically acceptable salt thereof has an isoelectric point from 2 to 11.

More preferably, the pharmaceutically acceptable amino acid and/or its pharmaceutically acceptable salt has an isoelectric point of 2.5 to 11.

More preferably, the pharmaceutically acceptable amino acid and/or its pharmaceutically acceptable salt has an isoelectric point of from 3.0 to 11.

More preferably, the pharmaceutically acceptable amino acid and/or its pharmaceutically acceptable salt has an isoelectric point of from 3.5 to 11.

More preferably, the pharmaceutically acceptable amino acid and/or its pharmaceutically acceptable salt has an isoelectric point of from 4.0 to 11.

More preferably, the pharmaceutically acceptable amino acid and/or its pharmaceutically acceptable salt has an isoelectric point of from 4.5 to 11.

More preferably, the pharmaceutically acceptable amino acid and/or its pharmaceutically acceptable salt has an isoelectric point of from 5.0 to 11.

More preferably, the pharmaceutically acceptable amino acid and/or its pharmaceutically acceptable salt has an isoelectric point of 5.5 to 11.

More preferably, the pharmaceutically acceptable amino acid and/or its pharmaceutically acceptable salt has an isoelectric point of 6.0 to 11.

More preferably, the pharmaceutically acceptable amino acid and/or its pharmaceutically acceptable salt has an isoelectric point of 6.5 to 11.

More preferably, the pharmaceutically acceptable amino acid and/or its pharmaceutically acceptable salt has an isoelectric point of 7.0 to 11.

More preferably, the pharmaceutically acceptable amino acid and/or its pharmaceutically acceptable salt has an isoelectric point of 7.5 to 11.

More preferably, the pharmaceutically acceptable amino acid and/or its pharmaceutically acceptable salt has an isoelectric point of 8.0 to 11.

More preferably, the pharmaceutically acceptable amino acid and/or its pharmaceutically acceptable salt has an isoelectric point of 8.5 to 11.

More preferably, the pharmaceutically acceptable amino acid and/or its pharmaceutically acceptable salt has an isoelectric point of 9.0 to 11.

More preferably, the pharmaceutically acceptable amino acid and/or its pharmaceutically acceptable salt has an isoelectric point of 9.5 to 11.

More preferably, the pharmaceutically acceptable amino acid and/or its pharmaceutically acceptable salt has an isoelectric point of 9.0 to 10.

One embodiment of the invention is a pharmaceutical composition in which at least one pharmaceutically acceptable amino acid and/or a pharmaceutically acceptable salt thereof is an amino acid in the L or D configuration, or in the form of a racemate.

One embodiment of the invention is a pharmaceutical composition in which at least one amino acid is a proteinogenic amino acid.

More preferably, the proteinogenic amino acid is a nonessential or essential amino acid.

More preferably, the proteinogenic amino acid is a standard or non-standard amino acid.

More preferably, the proteinogenic standard amino acid is L-lysine.

More preferably, the proteinogenic standard amino acid is L-histidine.

More preferably, the proteinogenic standard amino acid is L-methionine.

More preferably, the proteinogenic standard amino acid is L-ornithine.

More preferably, the proteinogenic standard amino acid is L-isoleucine.

More preferably, the proteinogenic standard amino acid is L-leucine.

More preferably, the proteinogenic standard amino acid is L-alanine.

More preferably, the proteinogenic standard amino acid is glycine.

More preferably, the proteinogenic standard amino acid is L-threonine.

More preferably, the proteinogenic standard amino acid is L-tryptophan.

More preferably, the proteinogenic standard amino acid is L-proline.

More preferably, the proteinogenic standard amino acid is L-valine.

More preferably, the proteinogenic standard amino acid is L-cysteine.

More preferably, the proteinogenic standard amino acid is L-phenylalanine.

More preferably, the proteinogenic standard amino acid is L-asparagine.

More preferably, the proteinogenic standard amino acid is L-serine.

More preferably, the proteinogenic standard amino acid is L-tyrosine.

More preferably, the proteinogenic standard amino acid is L-glutamic acid.

More preferably, the proteinogenic standard amino acid is L-aspartic acid.

More preferably, the proteinogenic standard amino acid is L-arginine.

More preferably, the proteinogenic non-standard amino acid is L-selenocysteine.

More preferably, the proteinogenic non-standard amino acid is L-pyrrolysine.

In addition to proteinogenic amino acids, other non-proteinogenic pharmaceutically acceptable amino acids that are not involved in protein synthesis may be used in the present invention. Such amino acids are often formed as metabolic intermediates for standard amino acids.

One embodiment of the invention is a pharmaceutical composition in which at least one amino acid and/or a pharmaceutically acceptable salt thereof is a non-proteinogenic amino acid selected from, but not limited to, M-acetyl-O-alanine, N-acetylglycine, hydroxylysine, hydroxyproline , norarginine, homoarginine, homolysine, 2,7-diaminoheptanoic acid, 2,4-diaminobutyric acid, 3-aminoalanine, dehydroalanine, hydroxyproline, cystine, sarcosine, acetylcysteine and/or pharmaceutically acceptable salts thereof.

In preferred non-limiting embodiments of the present invention, the pharmaceutical composition contains an amino acid selected from imino acid, aliphatic, aromatic or heterocyclic amino acids.

More preferably, the aliphatic amino acids are monoaminodicarboxylic amino acid amides, monoaminomonocarboxylic,

oxymonoaminocarboxylic, monoaminodicarboxylic, diaminomonocarboxylic or sulfur-containing amino acids.

More preferably, the monoaminomonocarboxylic amino acids are selected from, but are not limited to, glycine, alanine, valine, isoleucine, or leucine.

More preferably, the oxymonoaminocarboxylic amino acids are selected from, but are not limited to, serine or threonine.

More preferably, the monoaminodicarboxylic amino acids are selected from, but are not limited to, aspartate or glutamate.

More preferably, the monoaminodicarboxylic amino acid amides are selected from, but are not limited to, asparagine or glutamine.

More preferably, the diaminomonocarboxylic amino acids are selected from, but are not limited to, lysine or arginine.

More preferably, the sulfur-containing amino acids are selected from, but are not limited to, cysteine or methionine.

More preferably, the aromatic amino acids are selected from, but are not limited to, phenylalanine, tyrosine or tryptophan.

More preferably, the heterocyclic amino acids are selected from, but are not limited to, tryptophan, histidine, or proline.

In preferred non-limiting embodiments of the present invention, the pharmaceutical composition contains an amino acid selected from polar uncharged, polar negatively charged, polar positively charged or non-polar amino acids.

More preferably, the polar uncharged amino acids are selected from, but are not limited to, serine, threonine, cysteine, asparagine, glutamine or tyrosine.

More preferably, the polar negatively charged amino acids are selected from, but are not limited to, aspartate or glutamate.

More preferably, the polar, positively charged amino acids are selected from, but are not limited to, lysine, arginine or histidine.

More preferably, the non-polar amino acids are selected from, but are not limited to, glycine, alanine, valine, isoleucine, leucine, proline, methionine, phenylalanine or tryptophan.

In preferred non-limiting embodiments of the present invention, the pharmaceutical composition contains an amino acid selected from, but not limited to, glucogenic, ketogenic or gluco-ketogenic amino acids.

More preferably, the glucogenic amino acids are selected from, but are not limited to, glycine, alanine, valine, proline, serine, threonine, cysteine, methionine, aspartate, asparagine, glutamate, glutamine, arginine or histidine.

More preferably, the ketogenic amino acids are selected from, but are not limited to, leucine or lysine.

More preferably, the gluco-ketogenic amino acids are selected from, but are not limited to, isoleucine, phenylalanine, tyrosine or tryptophan.

One embodiment of the invention is a pharmaceutical composition in which the amount of favipiravir is from 100 to 4000 mg.

More preferably, the amount of favipiravir in the pharmaceutical composition is from 100 to 3700 mg.

More preferably, the amount of favipiravir in the pharmaceutical composition is from 110 to 3300 mg.

More preferably, the amount of favipiravir in the pharmaceutical composition is from 120 to 3000 mg.

More preferably, the amount of favipiravir in the pharmaceutical composition is from 130 to 2700 mg.

More preferably, the amount of favipiravir in the pharmaceutical composition is from 140 to 2400 mg.

More preferably, the amount of favipiravir in the pharmaceutical composition is from 150 to 2100 mg.

More preferably, the amount of favipiravir in the pharmaceutical composition is from 160 to 1800 mg.

More preferably, the amount of favipiravir in the pharmaceutical composition is from 170 to 1500 mg.

More preferably, the amount of favipiravir in the pharmaceutical composition is from 180 to 1200 mg.

More preferably, the amount of favipiravir in the pharmaceutical composition is from 190 to 900 mg.

More preferably, the amount of favipiravir in the pharmaceutical composition is from 200 to 600 mg.

More preferably, the amount of favipiravir in the pharmaceutical composition is from 200 mg.

More preferably, the amount of favipiravir in the pharmaceutical composition is from 300 mg.

More preferably, the amount of favipiravir in the pharmaceutical composition is from 400 mg.

More preferably, the amount of favipiravir in the pharmaceutical composition is from 600 mg.

More preferably, the amount of favipiravir in the pharmaceutical composition is from 800 mg.

One embodiment of the invention is a pharmaceutical composition in which the amount of favipiravir ranges from 5 to 95 wt. % by weight of the entire pharmaceutical composition.

More preferably, the amount of favipiravir in the pharmaceutical composition is from 10 to 90 wt. % by weight of the entire pharmaceutical composition.

More preferably, the amount of favipiravir in the pharmaceutical composition is from 15 to 85 wt. % by weight of the entire pharmaceutical composition.

More preferably, the amount of favipiravir in the pharmaceutical composition is from 20 to 80 wt. % by weight of the entire pharmaceutical composition.

More preferably, the amount of favipiravir in the pharmaceutical composition is from 25 to 75 wt. % by weight of the entire pharmaceutical composition.

More preferably, the amount of favipiravir in the pharmaceutical composition is from 30 to 70 wt. % by weight of the entire pharmaceutical composition.

More preferably, the amount of favipiravir in the pharmaceutical composition is from 35 to 70 wt. % by weight of the entire pharmaceutical composition.

More preferably, the amount of favipiravir in the pharmaceutical composition is from 40 to 70 wt. % by weight of the entire pharmaceutical composition.

More preferably, the amount of favipiravir in the pharmaceutical composition is from 45 to 70 wt. % by weight of the entire pharmaceutical composition.

More preferably, the amount of favipiravir in the pharmaceutical composition is from 50 to 70 wt. % by weight of the entire pharmaceutical composition.

More preferably, the amount of favipiravir in the pharmaceutical composition is from 55 to 65 wt. % by weight of the entire pharmaceutical composition.

One embodiment of the invention is a pharmaceutical composition in which the amount of an amino acid or a pharmaceutically acceptable salt thereof is from 10 to 750 mg. More preferably, the amount of an amino acid or a pharmaceutically acceptable salt thereof is from 20 to 730 mg.

More preferably, the amount of the amino acid or a pharmaceutically acceptable salt thereof is from 30 to 710 mg.

More preferably, the amount of the amino acid or a pharmaceutically acceptable salt thereof is from 40 to 690 mg.

More preferably, the amount of the amino acid or a pharmaceutically acceptable salt thereof is from 50 to 670 mg.

More preferably, the amount of the amino acid or a pharmaceutically acceptable salt thereof is from 60 to 650 mg.

More preferably, the amount of the amino acid or a pharmaceutically acceptable salt thereof is from 70 to 630 mg.

More preferably, the amount of the amino acid or a pharmaceutically acceptable salt thereof is from 80 to 610 mg.

More preferably, the amount of the amino acid or a pharmaceutically acceptable salt thereof is from 90 to 590 mg.

More preferably, the amount of the amino acid or a pharmaceutically acceptable salt thereof is from 100 to 570 mg.

More preferably, the amount of the amino acid or a pharmaceutically acceptable salt thereof is from 110 to 550 mg.

More preferably, the amount of the amino acid or a pharmaceutically acceptable salt thereof is from 120 to 530 mg.

More preferably, the amount of the amino acid or a pharmaceutically acceptable salt thereof is from 130 to 510 mg.

More preferably, the amount of the amino acid or a pharmaceutically acceptable salt thereof is from 140 to 490 mg.

More preferably, the amount of the amino acid or a pharmaceutically acceptable salt thereof is from 150 to 470 mg.

More preferably, the amount of the amino acid or a pharmaceutically acceptable salt thereof is from 160 to 450 mg.

More preferably, the amount of the amino acid or a pharmaceutically acceptable salt thereof is from 170 to 430 mg.

More preferably, the amount of the amino acid or a pharmaceutically acceptable salt thereof is from 180 to 410 mg.

More preferably, the amount of the amino acid or a pharmaceutically acceptable salt thereof is from 190 to 390 mg.

More preferably, the amount of the amino acid or a pharmaceutically acceptable salt thereof is from 200 to 370 mg.

More preferably, the amount of the amino acid or a pharmaceutically acceptable salt thereof is from 210 to 350 mg.

More preferably, the amount of the amino acid or a pharmaceutically acceptable salt thereof is from 220 to 330 mg.

More preferably, the amount of the amino acid or a pharmaceutically acceptable salt thereof is from 230 to 310 mg.

More preferably, the amount of amino acid or pharmaceutically acceptable salt thereof is from 240 to 290 mg.

One embodiment of the invention is a pharmaceutical composition in which the amount of an amino acid or a pharmaceutically acceptable salt thereof is from 5 to 95 wt. % by weight of the entire pharmaceutical composition.

More preferably, the amount of amino acid or pharmaceutically acceptable salt thereof is from 10 to 85 wt. % by weight of the entire pharmaceutical composition.

More preferably, the amount of amino acid or pharmaceutically acceptable salt thereof is from 15 to 75 wt. % by weight of the entire pharmaceutical composition.

More preferably, the amount of amino acid or pharmaceutically acceptable salt thereof is from 20 to 65 wt. % by weight of the entire pharmaceutical composition.

More preferably, the amount of amino acid or pharmaceutically acceptable salt thereof is from 25 to 55 wt. % by weight of the entire pharmaceutical composition.

More preferably, the amount of amino acid or pharmaceutically acceptable salt thereof is from 25 to 45 wt. % by weight of the entire pharmaceutical composition.

More preferably, the amount of amino acid or pharmaceutically acceptable salt thereof is from 25 to 35 wt. % by weight of the entire pharmaceutical composition.

One embodiment of the invention is that the pharmaceutical composition further contains at least one pharmaceutically acceptable excipient.

More preferably, the pharmaceutically acceptable excipient is selected from the group consisting of, but not limited to, a stabilizer, a buffering agent, or a pH adjusting agent.

The pharmaceutically acceptable excipient of the present invention may be present in the pharmaceutical composition in an amount of from 0 to 90 wt. % by weight of the entire pharmaceutical composition.

More preferably, the pharmaceutically acceptable excipient of the present invention may be present in the pharmaceutical composition in an amount of from 1 to 50 wt. % by weight of the entire pharmaceutical composition.

More preferably, the pharmaceutically acceptable excipient of the present invention may be present in the pharmaceutical composition in an amount of from 1 to 25 wt. % by weight of the entire pharmaceutical composition.

More preferably, the pharmaceutically acceptable excipient of the present invention may be present in the pharmaceutical composition in an amount of from 1 to 15 wt. % by weight of the entire pharmaceutical composition.

More preferably, the pharmaceutically acceptable excipient in the pharmaceutical composition of the present invention is sodium hydroxide or hydrochloric acid.

More preferably, the sodium hydroxide of the present invention may be present in the pharmaceutical composition in an amount of 10 to 200 mg.

More preferably, the sodium hydroxide of the present invention may be present in the pharmaceutical composition in an amount of from 10 to 190 mg.

More preferably, the sodium hydroxide of the present invention may be present in the pharmaceutical composition in an amount of 15 to 180 mg.

More preferably, the sodium hydroxide of the present invention may be present in the pharmaceutical composition in an amount of from 20 to 170 mg.

More preferably, the sodium hydroxide of the present invention may be present in the pharmaceutical composition in an amount of 25 to 160 mg.

More preferably, the sodium hydroxide of the present invention may be present in the pharmaceutical composition in an amount of 30 to 150 mg.

More preferably, the sodium hydroxide of the present invention may be present in the pharmaceutical composition in an amount of 35 to 140 mg.

More preferably, the sodium hydroxide of the present invention may be present in the pharmaceutical composition in an amount of 40 to 130 mg.

More preferably, the sodium hydroxide of the present invention may be present in the pharmaceutical composition in an amount of 45 to 120 mg.

More preferably, the sodium hydroxide of the present invention may be present in the pharmaceutical composition in an amount of 50 to 110 mg.

More preferably, the sodium hydroxide of the present invention may be present in the pharmaceutical composition in an amount of 55 to 100 mg.

More preferably, the sodium hydroxide of the present invention may be present in the pharmaceutical composition in an amount of 60 to 90 mg.

More preferably, the sodium hydroxide of the present invention may be present in the pharmaceutical composition in an amount of 65 to 80 mg.

More preferably, the sodium hydroxide of the present invention may be present in the pharmaceutical composition in an amount of 50 to 150 mg.

One embodiment of the invention is a pharmaceutical composition exhibiting preventive and/or therapeutic antiviral activity, where the virus is a virus whose genome is encoded by a single-stranded sense (+) strand as well as an antisense (-) strand of RNA and which uses viral RNA dependent RNA polymerase for its replication.

More preferably, the virus of the present invention is an influenza virus, coronavirus, picornavirus, arenavirus, flavivirus, bunyavirus, filovirus, phlebovirus, hantavirus, enterovirus, togavirus, calicivirus, respiratory syncytial virus, parainfluenza virus, rhinoviruses, metapneumoviruses, rotavirus or noravirus.

More preferably, the virus of the present invention is a highly virulent or low virulent virus.

More preferably, the virus of the present invention is SARS-CoV-2, MERS-CoV or Influenza A, B, C.

More preferably, the influenza virus of the present invention is, but is not limited to, influenza A virus, including strains A(H1N1), A(H1N1)pdm09, A(H1N2), A(H3N2), A(H2N2), A(H4N2) , A (H7N2), swine influenza type A, avian influenza type A, including highly pathogenic strains (including H5N1 and H7N9).

The stated problem is solved, and the stated technical result is achieved by obtaining a medicinal product exhibiting preventive and/or therapeutic antiviral activity, containing a pharmaceutical composition according to the present invention and at least one pharmaceutically acceptable excipient.

One embodiment of the invention is a medicinal product that is a solid medicinal product.

More preferably, the solid drug of the present invention is, but is not limited to, a tablet, capsule, pellet, sachet, dragee, powder or lyophilisate.

Lyophilization (lyophilic drying) is the process of removing solvent from frozen material by sublimation (sublimation) of solvent crystals under vacuum conditions, i.e. turning it into steam, bypassing the liquid phase. The drug in the form of a lyophilisate completely retains its pharmacological activity.

Solvent removal during freeze-drying is carried out mainly by sublimation. Sublimation is the removal of solvent from a frozen object without the formation of a liquid phase; it is carried out under vacuum or, much less often, in an inert gas. The freezing stage is one of the determining stages for obtaining a high-quality drug in the form of a lyophilisate.

Auxiliary excipients used in freeze-dried medicinal preparations according to the present invention include: solvents, solubilizers (EDTA, α-cyclodextrin, etc.), fillers (mannitol, glycine, glucose, sucrose, lactose, milk, etc. ), preservatives (benzyl alcohol, ethyl and methyl parahydroxybenzoate, etc.), pH regulators (buffer solutions, sodium hydroxide, hydrochloric acid), stabilizers, cryoprotectants (dextran, gelatin, hydroxyethyl starch, etc.).

In the form of lyophilisates according to the present invention, both individual medicinal substances and their mixtures with excipients can be presented.

The lyophilisate may be presented in the form of two or more components in which favipiravir is packaged separately from the other components. For example, the first component, for example, in a unit dosage form, such as a sachet, vial or container, may contain favipiravir. The second component, for example, is a unit dosage form, such as a sachet (packaged form) or bottle, containing the amino acid.

Currently, there are known problems with the occurrence of static electricity upon contact or impact of particles of dry components of lyophilized substances. A charge of static electricity occurs during any movement of the powder during the manufacture of compositions, during grinding, pouring, shaking. In addition, during the production and storage of solid dosage forms, sticking of particles of drug components is often observed, which in turn negatively affects its therapeutic activity. When developing a drug in powder form, it is also a challenge to obtain a powder with relatively high flowability and low hygroscopicity.

The inventors have surprisingly discovered that by using at least one amino acid in a solid dosage form containing favipiravir, all of the above disadvantages can be avoided.

One embodiment of the invention is a medicinal product that is a concentrate.

One embodiment of the invention is a medicinal product that is a concentrate in which the concentration of favipiravir is from 10 to 150 mg/ml.

More preferably, the concentration of favipiravir in the concentrate of the present invention is from 10 to 140 mg.

More preferably, the concentration of favipiravir in the concentrate of the present invention is from 10 to 130 mg.

More preferably, the concentration of favipiravir in the concentrate of the present invention is from 10 to 120 mg.

More preferably, the concentration of favipiravir in the concentrate of the present invention is from 10 to 110 mg.

More preferably, the concentration of favipiravir in the concentrate of the present invention is from 10 to 100 mg.

More preferably, the concentration of favipiravir in the concentrate of the present invention is from 10 to 90 mg.

More preferably, the concentration of favipiravir in the concentrate of the present invention is from 10 to 80 mg.

More preferably, the concentration of favipiravir in the concentrate of the present invention is from 10 to 70 mg.

More preferably, the concentration of favipiravir in the concentrate of the present invention is from 10 to 60 mg.

More preferably, the concentration of favipiravir in the concentrate of the present invention is from 10 to 50 mg.

More preferably, the concentration of favipiravir in the concentrate of the present invention is from 10 to 40 mg.

More preferably, the concentration of favipiravir in the concentrate of the present invention is from 10 to 30 mg.

More preferably, the concentrate of the present invention has a pH between 6.5 and

8.5.

More preferably, the concentrate of the present invention has a pH between 7.0 and

7.5.

The concentrate of the present invention, obtained including reconstitution of the lyophilisate, is in turn diluted to a solution that is suitable for injection or infusion into the patient. The volume of aqueous material used for reconstitution is dictated by the concentration of favipiravir in the final pharmaceutical composition. Reconstitution using a smaller volume of reducing agent than the pre-lyophilization volume results in a composition that is more concentrated than before lyophilization.

One embodiment of the invention is a medicinal product that is a parenteral medicinal product.

Parenteral administration of drugs is a route of administration of drugs into the body in which they bypass the gastrointestinal tract, in contrast to the oral route of drug administration. Parenteral drugs are sterile preparations intended for administration by injection, infusion, inhalation or implantation into the human or animal body. These include solutions, emulsions, suspensions, aerosols, powders and tablets for the preparation of solutions and implantation, powders for inhalation, lyophilized preparations for the preparation of dosage forms introduced into the body parenterally (subcutaneously, intramuscularly, intravenously, intraarterially, into various cavities).

Parenteral routes of administration include administration into tissues (intradermal, subcutaneous, intramuscular, intraosseous), into vessels (intravenous, intraarterial, lymphatic vessels), into cavities (pleural, abdominal, cardiac and articular cavities), into the subarachnoid space, as well as inhalation , intranasal and subconjunctival administration.

More preferably, the parenteral drug of the present invention is, but is not limited to, an infusion solution, an injection solution, an inhalation drug, including an aerosol, a spray or a powder.

More preferably, the parenteral drug of the present invention is an infusion solution.

More preferably, the parenteral drug of the present invention is an injection solution.

More preferably, the parenteral drug of the present invention is an inhalation drug.

One embodiment of the invention is a drug that is a drug for topical administration.

Local administration of drugs means the application of a drug to the mucous membranes (including ocular, nasal, rectal, vaginal application, application to the gums, oral mucosa, etc.), as well as introduction into the external auditory canal.

More preferably, the topical drug of the present invention is a drug for ophthalmic, nasal and rectal administration.

One embodiment of the invention is a medicament that is a medicament for rectal administration.

More preferably, the rectal medicament of the present invention is, but is not limited to, suppositories or capsules.

One embodiment of the invention is a medicinal product in which the pharmaceutically acceptable excipients are selected from the group including, but not limited to, excipients, stabilizers, solubilizers, solvents, humectants, lubricants, lubricants, thickeners, sweeteners, flavoring agents, flavoring agents, fungicides, Extended delivery regulators, cosolvents, diluents, fillers, emulsifiers, preservatives, antioxidants, buffering agents, cryoprotectants, pH adjusting agents, isotonicity agents or corrective agents.

More preferably, the solvent of the present invention is, but is not limited to, saline solution, water injection, pyrogen-free water, distilled water, Ringer's solution or glucose solution.

The stated problem is solved, and the stated technical result is achieved through the use of the pharmaceutical composition of the present invention to obtain a medicinal product exhibiting preventive and/or therapeutic antiviral activity.

The stated problem is solved, and the stated technical result is achieved through the use of a pharmaceutical composition or drug for the treatment and/or prevention of viral infections.

More preferably, the viral infection to be treated and/or prevented by the pharmaceutical composition or drug of the present invention is COVID-19.

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

A person skilled in the art will understand that other particular embodiments of the invention are possible, including other dosage forms of favipiravir and amino acids in accordance with the present invention, not described in these examples, for example, tablets, suppositories, inhalation formulations, and so on.

Examples

Example 1. Preparation of a pharmaceutical composition of favipiravir with an amino acid in the form of a solution.

Previously, 50% of the calculated amount of favipiravir powder was mixed with the calculated amount of lysine powder in a separate container. Water for injection was placed in a container for preparing solutions and heated to 60-70°C, then it was alkalized and pre-mixed favipiravir powders with lysine were added to the resulting solution with stirring. Stirring was continued until the components were completely dissolved. The remaining amount of favipiravir was added to the resulting solution and stirring was continued at a temperature of 60-70°C until a clear pharmaceutical composition was obtained in the form of a solution. Next, the pH of the solution was measured and, if necessary, its value was adjusted by adding a solution of sodium hydroxide or hydrochloric acid. When the required pH value was reached, the solution was adjusted with water for injection to the specified volume and filtered through a membrane filter, the filtrate was poured into containers and hermetically sealed.

In a similar manner, pharmaceutical compositions of favipiravir were prepared with other amino acids, such as, but not limited to, tyrosine series.

Example 2. Preparation of favipiravir medicines with amino acids in the form of lyophilisate and concentrate.

Solutions of favipiravir with amino acids prepared according to the described method in example 1 were subjected to freeze-drying after filtration. The output was a solid drug of favipiravir with amino acids in the form of a lyophilisate.

Recovery of the solution. The calculated amount of physiological solution was slowly added to the vial of the resulting lyophilisate with the calculated amount of favipiravir along the inner wall. The bottle was shaken vigorously for approximately 30 seconds until the drug was completely dissolved. In case of incomplete dissolution of the drug, stirring was repeated. A clear liquid formulation of favipiravir with amino acids was obtained as a yellow to greenish-yellow solution.

In a similar way, lyophilisates and concentrates of favipiravir with other amino acids, such as, in particular, tyrosine and serine, were prepared.

Example 3. Study of the antiviral activity of the composition of favipiravir with amino acids against the SARS-CoV-2 virus.

The antiviral activity of favipiravir compositions with amino acids of the compositions indicated in Table 1 against the SARS-CoV-2 virus was carried out on a permanent culture of African green monkey kidney cells. Hanks' saline solution containing fetal calf serum was used as growth and support medium.

The study used nine formulations of favipiravir with amino acids with different qualitative and quantitative characteristics (compositions 1-3, 5-7, 9-11) and three formulations containing an amount of favipiravir identical to its group (composition 4: an amount of favipiravir identical to compositions 1-3; composition 8: the amount of favipiravir is identical to compositions 5-7; composition 12: the amount of favipiravir is identical to compositions 9-11) (Table 1). Saline solution (composition 13) was used as a control.

To infect 13 samples of African green monkey kidney cells with the SARS-CoV-2 virus, the growth medium was removed from the cell monolayer and the SARS-CoV-2 virus was added, incubated for 60 minutes at a temperature of 37±0.5°C, then the inoculum was removed and washed , fresh medium containing the studied samples of compositions 1-13 was added to the cell samples, respectively. The samples were incubated at a temperature of 37±0.5°C for 48 hours. Biological activity was assessed by titrating the resulting cell suspension according to the cytopathic effect of the virus 24 and 48 hours after infection. The research results are presented in Table 1.

The main criterion for assessing the effectiveness of compositions 1-12 in vitro was the coefficient of inhibition of the cytopathogenic effect of the virus (CI, %).

The inhibition coefficient (CI, %) was calculated using the formula:

Where:

Acont - biological activity of the virus, determined in cells without adding the drug (using a control composition);

AOP is the biological activity of the virus, determined in cells with the addition of the drug.

Thus, the presented experimental results clearly demonstrate the antiviral activity of pharmaceutical compositions of favipiravir with various amino acids in ratios of 1.0:0.1-1.0:1.2. Moreover, these compositions exhibit a synergistic effect in relation to antiviral activity compared to favipiravir monotherapy in identical quantities.

Example 4. Study of the stability of a solid drug in the form of favipiravir lyophilisate with amino acids during storage.

The stability of favipiravir drugs with amino acids in the form of lyophilisates obtained by the method described in example 2 was assessed by the “accelerated aging” method based on the content of favipiravir and compared with the stability of lyophilisates containing only favipiravir.

Quantitative characteristics of drugs in the form of lyophilisates are presented in Table 1.

In accordance with GPM.1.1.0009.15, the “accelerated aging” method (storage at elevated temperatures) is based on the dependence of the rate of a chemical reaction on temperature in accordance with the van’t Hoff rule: with an increase in temperature by 10°C, the rate of a chemical reaction increases by 2-4 times. The stability of lyophilisates was tested using the accelerated aging method at 40±2°C for 457 days, which corresponds to 5 years of storage under standard conditions (no more than 25°C). The experiment was carried out on 3 batches of each drug. The quantitative content of favipiravir was expressed in average values.

The content of favipiravir was determined by HPLC using standards.

Table 2 shows that after 457 days of storage under the accelerated aging method, the favipiravir amino acid formulations in the form of lyophilisates of the present invention (formulations 1-3; 5-7; 9-11) had increased stability and remained chemically pure. Medicines of compositions 4, 8, 12 remained chemically pure for less than 150 days; by the end of the experiment, the content of the active substance decreased by more than 3.5-5%.

Thus, favipiravir amino acid formulations in the form of lyophilisates of the present invention (formulations 1-3; 5-7; 9-11) have statistically significant improved storage stability compared to compositions (4; 8; 12).

Claims (52)

1. A pharmaceutical composition exhibiting preventive and/or therapeutic antiviral activity, containing in therapeutically effective amounts favipiravir and at least one aliphatic mono- or diaminomonocarboxylic non-proteinogenic amino acid and/or its pharmaceutically acceptable salt, where the mass ratio of favipiravir to amino acid is 1.0 :0.1-1.0:1.2 respectively. 2. The pharmaceutical composition according to claim 1, in which the mass ratio of favipiravir to amino acid is 1.0:0.15; 1.0:0.2; 1.0:0.25; 1.0:0.3; 1.0:0.35; 1.0:0.4; 1.0:0.45; 1.0:0.5; 1.0:0.55; 1.0:0.6; 1.0:0.65; 1.0:0.7; 1.0:0.75; 1.0:0.8; 1.0:0.85; 1.0:0.9; 1.0:0.95; 1.0:1.00; 1.0:1.05; 1.0:1.10; 1.0:1.15. 3. The pharmaceutical composition according to claim 1, in which at least one amino acid and/or a pharmaceutically acceptable salt thereof is an amino acid in the L- or D-configuration, or in the form of a racemate. 4. The pharmaceutical composition according to claim 1, wherein at least one amino acid and/or a pharmaceutically acceptable salt thereof is an α-amino acid. 5. The pharmaceutical composition according to claim 1, in which at least one amino acid and/or its pharmaceutically acceptable salt has an isoelectric point from 2 to 11. 6. The pharmaceutical composition according to claim 5, in which at least one amino acid and/or its pharmaceutically acceptable salt has an isoelectric point from 5 to 11. 7. The pharmaceutical composition according to claim 6, in which at least one amino acid and/or its pharmaceutically acceptable salt has an isoelectric point from 7 to 10. 8. The pharmaceutical composition according to claim 1, in which the amino acid is a polar uncharged, polar negatively charged, polar positively charged or non-polar amino acid. 9. The pharmaceutical composition according to claim 1, wherein the amino acid is a glucogenic, ketogenic or gluco-ketogenic amino acid. 10. Pharmaceutical composition according to claim 1, in which the non-proteinogenic amino acid is N-acetyl-D-alanine, N-acetylglycine, hydroxylysine, homolysine, 2,7-diaminoheptanoic acid, 2,4-diaminobutyric acid, 3-aminoalanine, dehydroalanine , sarcosine, acetylcysteine and/or pharmaceutically acceptable salts thereof. 11. The pharmaceutical composition according to claim 1, in which the amount of favipiravir is from 5 to 90 wt.% by weight of the entire pharmaceutical composition. 12. Pharmaceutical composition according to claim 11, in which the amount of favipiravir is from 10 to 90 wt.%, from 15 to 85 wt.%, from 20 to 80 wt.%, from 25 to 75 wt.%, from 30 to 70 wt.%, from 35 to 70 wt.%, from 40 to 70 wt.%, from 45 to 70 wt.%, from 50 to 70 wt.% or from 55 to 65 wt.% by weight of the total pharmaceutical composition. 13. The pharmaceutical composition according to claim 1, in which the amount of the amino acid or its pharmaceutically acceptable salt is from 5 to 55 wt.% by weight of the entire pharmaceutical composition. 14. The pharmaceutical composition according to claim 13, in which the amount of amino acid is from 10 to 55 wt.%, from 15 to 55 wt. %, from 20 to 55 wt.%, from 25 to 55 wt.%, from 25 to 45 wt.% or from 25 to 35 wt.% by weight of the entire pharmaceutical composition. 15. The pharmaceutical composition according to claim 1, characterized in that it additionally contains at least one pharmaceutically acceptable excipient. 16. The pharmaceutical composition according to claim 15, characterized in that the pharmaceutically acceptable excipient is selected from the group consisting of a stabilizer, a buffering agent or a pH-regulating agent. 17. The pharmaceutical composition according to claim 15, in which the amount of pharmaceutically acceptable excipients is from 1 to 90 wt.% by weight of the entire pharmaceutical composition. 18. The pharmaceutical composition according to claim 17, in which the amount of pharmaceutically acceptable excipients is from 1 to 50 wt.% by weight of the entire pharmaceutical composition. 19. The pharmaceutical composition according to claim 18, in which the amount of pharmaceutically acceptable excipients is from 1 to 25 wt.% by weight of the total pharmaceutical composition. 20. The pharmaceutical composition according to claim 19, in which the amount of pharmaceutically acceptable excipients is from 1 to 15 wt.% by weight of the total pharmaceutical composition. 21. The pharmaceutical composition according to claim 1, consisting of favipiravir and a non-proteinogenic amino acid in therapeutically effective quantities, where the mass ratio of favipiravir to amino acid is 1.0:0.1-1.0:1.20, respectively. 22. The pharmaceutical composition according to claim 15, consisting of favipiravir, a non-proteinogenic amino acid in therapeutically effective quantities and sodium hydroxide, where the mass ratio of favipiravir to amino acid is 1.0:0.1-1.0:1.20, respectively. 23. The pharmaceutical composition according to claim 15, consisting of favipiravir, a non-proteinogenic amino acid in therapeutically effective amounts, sodium hydroxide and injection water, where the mass ratio of favipiravir to amino acid is 1.0:0.1-1.0:1.20, respectively. 24. A medicinal product exhibiting preventive and/or therapeutic antiviral activity, containing a pharmaceutical composition according to claims. 1-23 and at least one pharmaceutically acceptable excipient. 25. The medicinal product according to claim 24, in which the amount of favipiravir is from 100 to 4000 mg. 26. The medicinal product according to claim 25, in which the amount of favipiravir is from 100 to 3700 mg, from 110 to 3300 mg, from 120 to 3000 mg, from 130 to 2700 mg, from 140 to 2400 mg, from 150 to 2100 mg, 160 to 1800 mg, 170 to 1500 mg, 180 to 1200 mg, 190 to 900 mg, or 200 to 600 mg. 27. The medicinal product according to claim 25, in which the amount of favipiravir is 200 mg. 28. The medicinal product according to claim 25, in which the amount of favipiravir is 300 mg. 29. The medicinal product according to claim 25, in which the amount of favipiravir is 400 mg. 30. The medicinal product according to claim 25, in which the amount of favipiravir is 600 mg. 31. The medicinal product according to claim 25, in which the amount of favipiravir is 800 mg. 32. The drug according to claim 24, in which the amount of non-proteinogenic amino acid is from 10 to 750 mg. 33. The medicinal product according to claim 32, in which the amount of non-proteinogenic amino acid is from 20 to 730 mg, from 30 to 710 mg, from 40 to 690 mg, from 50 to 670 mg, from 60 to 650 mg, 70 to 630 mg, from 80 to 610 mg, 90 to 590 mg, from 100 to 570 mg, from 110 to 550 mg, from 120 to 530 mg, from 130 to 510 mg, from 140 to 490 mg, from 150 to 470 mg, from 160 to 450 mg, 170 to 430 mg, 180 to 410 mg, 190 to 390 mg, 200 to 370 mg, 210 to 350 mg, 220 to 330 mg, 230 to 310 mg, or 240 to 290 mg . 34. The medicinal product according to claim 24, characterized in that it is a solid medicinal product. 35. The medicinal product according to claim 34, characterized in that it is a lyophilisate. 36. The medicinal product according to claim 24, characterized in that it is a concentrate. 37. The medicinal product according to claim 36, characterized in that the concentrate has a pH from 6.5 to 8.5. 38. The medicinal product according to claim 37, characterized in that the concentrate has a pH from 7.0 to 7.5. 39. The medicinal product according to claim 36, in which the concentration of favipiravir in concentrate is from 10 to 150 mg/ml. 40. The medicinal product according to claim 39, in which the concentration of favipiravir in concentrate is from 10 to 140 mg/ml, from 10 to 130 mg/ml, from 10 to 120 mg/ml, from 10 to 110 mg/ml, from 10 up to 100 mg/ml, 10 to 90 mg/ml, from 10 to 80 mg/ml, from 10 to 70 mg/ml, from 10 to 60 mg/ml, from 10 to 50 mg/ml, from 10 to 40 mg /ml or from 10 to 30 mg/ml. 41. The medicinal product according to claim 24, characterized in that it is a parenteral medicinal product. 42. The medicinal product according to claim 41, characterized in that it is an infusion solution. 43. The medicinal product according to claim 41, characterized in that it is an injection solution. 44. The medicinal product according to claim 24, characterized in that the pharmaceutically acceptable excipients are selected from the group including formative substances, stabilizers, solubilizers, solvents, humectants, lubricants, lubricants, thickeners, sweeteners, flavors, flavors, fungicides, prolonged delivery regulators , co-solvents, diluents, fillers, emulsifiers, preservatives, antioxidants, buffering agents, cryoprotectants, pH-regulating agents, isotonicity agents or corrective agents. 45. The medicinal product according to claim 44, wherein the pharmaceutically acceptable excipient is sodium hydroxide or hydrochloric acid. 46. The medicinal product according to claim 45, in which the amount of sodium hydroxide or hydrochloric acid is from 10 to 200 mg. 47. The medicinal product according to claim 46, in which the amount of sodium hydroxide or hydrochloric acid is from 10 to 190 mg, from 15 to 180 mg, from 20 to 170 mg, from 25 to 160 mg, from 30 to 150 mg, from 35 up to 140 mg, from 40 to 130 mg, from 45 to 120 mg, from 50 to 110 mg, from 55 to 100 mg, from 60 to 90 mg or from 65 to 80 mg. 48. The medicinal product according to claim 44, characterized in that the solvent is saline solution, injection water, pyrogen-free water, distilled water, Ringer's solution or glucose solution. 49. The medicinal product according to claim 45, consisting of favipiravir, a non-proteinogenic amino acid in therapeutically effective amounts and sodium hydroxide, where the mass ratio of favipiravir to amino acid is 1.0:0.1-1.0:1.20, respectively. 50. Medicine according to claims. 45, 48, consisting of favipiravir, a non-proteinogenic amino acid in therapeutically effective quantities, sodium hydroxide and water for injection, where the mass ratio of favipiravir to amino acid is 1.0:0.1-1.0:1.20, respectively. 51. Use of a pharmaceutical composition according to claims. 1-23 to obtain a medicinal product exhibiting prophylactic and/or therapeutic antiviral activity. 52. Use according to claim 51, wherein the viral infection is SARS-CoV-2.