RU2751108C1 - Antiviral composition - Google Patents

Abstract

FIELD: pharmacy and medicine.SUBSTANCE: group of inventions relates to the field of pharmacy and medicine, more specifically to the oral dosage form of favipiravir and its use. The proposed dosage form of favipiravir, which exhibits preventive and/or therapeutic antiviral activity, is a film-coated tablet, including a core and a film shell. At the same time, the core of the tablet has the following composition: favipiravir 200 mg, microcrystalline cellulose 100.00-140.00 mg, low-substituted hydroxypropyl cellulose 50.00-80.00 mg, crospovidone 14.00-25.00 mg, povidone 15.00 mg, colloidal silicon dioxide 8.00 mg, stearic acid 3.00 mg. It is also proposed to use the dosage form described above for the treatment and/or prevention of viral diseases.EFFECT: invention ensures improved technological characteristics and increased stability of the product relative to the known analogue, in particular, the composition retains its properties during transportation and long-term storage, including long-term storage within the 4 main climatic zones without deterioration of the main quality indicators.8 cl, 5 tbl, 4 ex

Description

The present invention relates to the field of pharmaceuticals and medicine, namely, to a drug containing favipiravir as an active component, exhibiting antiviral activity with high stability.

Known from the patent RU 2224520, the compound favipiravir, which is an analogue of adenosine, has good clinical potential against various viruses, in particular, using RNA-dependent RNA polymerase in replication, in particular against 2019-nCoV.

Drugs - nucleoside analogs are directly aimed at blocking the activity of RNA-dependent-RNA-polymerase and block the synthesis of the viral RNA chain for a wide range of RNA viruses, including the family of human coronaviruses [De Clercq, E. New nucleoside analogues for the treatment of hemorrhagic fever virus infections ... Chem. Asian. J. 14, 3962-3968, 2019]. Favipiravir (T-705), a guanine analogue approved in clinical practice 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, chikungunya, noroviruses, enteroviruses [De Clercq, E. New nucleoside analogues for the treatment of hemorrhagic fever virus infections. Chem. Asian.]. 14, 3962-3968, 2019].

A recent study has shown its efficacy against 2019-nCoV (EC ₅₀ = 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. https://doi.org/10.1038/s41422-020-0282-0, 2020, Rebecca Sheets History and Characterization of the Vero Cell Line. A Report for the Vaccines and Related Biological Products Advisory Committee Meeting]. The study tested the combined use of favipiravir with interferon-α (ChiCTR2000029600) and favipiravir with balokvavir marboxil (an approved cap-dependent endonuclease inhibitor for influenza) (ChiCTR2000029544) in patients with SARS-CoV-2.

Favipiravir has a proven targeting effect against SARS-CoV-2. This is easily explained by its properties as an inhibitor of RNA-dependent-RNA polymerase, proven in many studies of RNA viruses of different families, all using this enzyme, listed below.

The mechanism of action of Favipiravir

Favipiravir (Compound 1) was originally discovered as a potent inhibitor of viral replication in influenza virus studies [Furuta Y., Takahashi K., Kuno-Maekawa M., Sangawa N., Uehara S., Kozaki K., Nomura N., Egawa H., Shiraki K. 2005. Mechanism of action of T-705 against influenza virus. Antimicrob. Agents Chemother]. In vitro studies using a model of Madin Darby Canine Kidney cell lines infected with the influenza virus, the effect of favipiravir was weakened in the presence of purine nucleosides or purine bases, indicating a selective competition of the substance with purine bases in the synthesis of new RNA strands during replication. Favipiravir was added to MDCK cells, and the cell metabolites were then analyzed by high pressure liquid chromatography. As a result, favipiravir ribofuranosyl 5'-triphosphate (favipiravir RTF), favipiravir-ribofuranose (favipiravir - P) and favipiravir ribofuranosyl-5'-monophosphate (favipiravir - PMF) were identified, indicating that ... Chemically synthesized favipiravir - RTF inhibits viral RNA-dependent-RNA polymerase at nano- and micromolar concentrations [Furuta Y., Takahashi K., Kuno-Maekawa M., Sangawa N., Uehara S., Kozaki K., Nomura N. , Egawa H., Shiraki K. 2005. Mechanism of action of T-705 against influenza virus. Antimicrob. Agents Chemother]. These data showed that favipiravir as a substance is a pro-drug and, being phospho-ribosylated in the cell to favipiravir-RTF, inhibits viral RNA-dependent RNA polymerase.

A.I., Gallego I., Soria M.E., Gregori J., Quer J., Esteban J.I., Rice С.М., Domingo E., Perales C. (2016) Lethal mutagenesis of Hepatitis С virus induced by Favipiravir. PLoS One 11, e0164691; Arias A., Thorne L., Goodfellow I. (2014) Favipiravir elicits antiviral mutagenesis during virus replication in vivo. eLife 3, e03679].Currently, it is believed that favipiravir integrates into the growing viral RNA chain, interrupting it, and also simultaneously structurally interacts with the viral RgRp domains, thus inhibiting both transcription and translation of the viral genome [Yousuke Furuta, Brian B. Gowen, Kazumi Takahashi , Kimiyasu Shiraki, Donald F. Smee, Dale L. Barnard. Favipiravir (T-705), a novel viral RNA polymerase inhibitor. Antiviral Research. Volume 100, Issue 2, November 2013]. Also in studies on the influenza virus, it was shown that favipiravir leads to lethal mutagenesis of the viral genome, dramatically reducing viral titers in cell culture [Baranovich T., Wong SS, Armstrong J., Marjuki H., Webby RJ, Webster RG, Govorkova EA ( 2013) T-705 (favipiravir) induces lethal mutagenesis in influenza A H1N1 viruses in vitro. J. Virol. 87]. It is significant that for the entire time of many years of research on this substance, it was not possible to identify a single viral strain resistant to favipiravir. Based on the described mechanism of action, mutagenesis caused by favipiravir can also occur in other RNA viruses, as well as inhibition of PgRp, which makes it a powerful, effective and universal inhibitor of a whole group of epidemiologically significant viruses of various families that cause serious, often fatal diseases. [Vanderlinden E., Vrancken B., Van Houdt J., Rajwanshi VK, Gillemot S., Andrei G., Lemey P., Naesens L. (2016) Distinct effects of T-705 (favipiravir) and ribavirin on influenza virus replication and viral RNA synthesis. Antimicrob. Agents Chemother; e

AI, Gallego I., Soria ME, Gregori J., Quer J., Esteban JI, Rice CM, Domingo E., Perales C. (2016) Lethal mutagenesis of Hepatitis C virus induced by Favipiravir. PLoS One 11, e0164691; Arias A., Thorne L., Goodfellow I. (2014) Favipiravir elicits antiviral mutagenesis during virus replication in vivo. eLife 3, e03679].

RNA synthesis is an integral part of human cell life. Unlike viruses, humans do not have RgRp, but there is a DNA-dependent RNA polymerase (DsRp), as well as a DNA-dependent DNA polymerase. Favipiravir-RTF is able to inhibit these two human enzymes at different concentrations of the active drug. It was shown that favipiravir-RTF blocks influenza PgRp at an IC _{50 of} 0.341 μmol / liter, but did not have any inhibitory effect on DNA polymerase α, β, γ at concentrations up to 1000 μmol / liter. Favipiravir insignificantly inhibited human RNA polymerase II related to DsRp, but at high concentrations - IC ₅₀ 905 μmol / liter [Kiso M., Takahashi K., Sakai-Tagawa Y., Shinya K., Sakabe S., Le QM, Ozawa M., Furuta Y., Kawaoka Y. (2010) T-705 (favipiravir) activity against lethal H5N1 influenza A viruses. Proc. Natl. Acad. Sci. USA]. At concentrations of 637 μmol / liter in vitro in MDCK cells, favipiravir blocked neither the synthesis of cellular DNA nor the synthesis of cellular RNA.

This universal mechanism of action of favipiravir is specific to the underlying enzyme of the replicative apparatus of the virus, suggesting a wide spectrum of antiviral activity of this substance, which has been demonstrated in many of the studies listed below.

Antiviral activity of favipiravir

According to the global report on pharmaceutical substances, favipiravir is currently included in clinical trials against COVID-19 disease, based on the proven mechanism of its action against viral RhRp (https://www.clinicaltrialsarena.com/comment/influenza-favipiravir-covid- nineteen/). In a clinical study by the National Center for Clinical Research on Infectious Diseases in Shenzhen, favipiravir was administered to 340 patients (age groups and comorbidity 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 inhalation aerosol of interferon-alpha (5 million units * 2 / day). This dosage led to a more rapid disappearance of the virus to values undetectable in the blood) than in the group of patients taking a combination of anti-HIV proteases - lopinavir / ritonavir, with a median elimination of viral particles at 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 that it demonstrably inhibits viral replication, delays the development of an aggressive course of COVID-19, or prevents it altogether.

Effect of using favipiravir against influenza virus

An influenza epidemic occurs around the world every year. The disease is caused by strains of the 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 every year. The 2013 avian influenza A (H7N9) epidemic in China and the 2009 influenza A (H1N1) pandemic resulted in 17,700 deaths, and influenza is still a major public health problem worldwide, not only in terms of morbidity, but also on critical health complications that it causes [Writing Committee of the WHO Consultation on Clinical Aspects of Pandemic (H1N1) 2009 Influenza (2010) Clinical aspects of pandemic 2009 influenza A (H1N1) virus infection. N. Engl. J. Med.]. Epidemic A (H1N1) showed that this strain is resistant to ocetalmivir (Tamiflu), a neuramidase inhibitor, and to amantadine, an inhibitor of the non-structural protein M2. In this regard, in medical practice, a drug with a different mechanism of action is urgently needed.

Favipiravir (T-705; 6-fluoro-3-hydroxy-2-pyrazinecarboxamide) is effective against a wide range of influenza strains, including A (H1N1) (pandemic 2009), A (H5N1) and A (H7N9), due to the fact that that the viral PgRp mistakenly takes the metabolite favipyrovir-RTF for a purine nucleotide. Favipiravir has undergone Phase III studies in Japan and Phase II studies in the United States to treat influenza.

In addition to antiviral activity against influenza, favipiravir inhibits the replication of arenaviruses (Yunin, Machupo and Pichinde), phleboviruses (Rift-Valle fever, phlebotoma fever and Punta Toro virus), hantaviruses (Maporal, Dobillrava) and Prospectus flaviviruses (yellow fever and West Nile fever); enteroviruses (polio- and rhinofiruses); Western encephalitis alphavirus, respiratory syncytia paramyxovirus and norovirus [Yousuke Furuta, Brian B. Gowen, Kazumi Takahashi, Kimiyasu Shiraki, Donald F. Smee, Dale L. Barnard. Favipiravir (T-705), a novel viral RNA polymerase inhibitor. Antiviral Research. Volume 100, Issue 2, November 2013].

Use of favipiravir in in vitro influenza models

In in vitro studies, favipiravir showed high antiviral activity against all strains of influenza virus, A, B and C. Based on the calculation of plaque-forming units (PFU) in the MDCK cell culture, the effective concentration indicator (hereinafter EC ₅₀ ) ranged from 0.014 to 0.55 μg / 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 . (2002) In vitro and in vivo activities of anti-influenza virus compound T-705. Antimicrob. Agents Chemother]. The drug is not cytotoxic to MDCK cell culture. Table 1 shows the measured activities of favipiravir against 53 strains of influenza virus, including seasonal strains A (H1N1), A (H3N2), and strains of influenza type B; A (H1N1) pdm09 pandemic virus, highly pathogenic avian influenza A (H5N1) isolated from humans, A (H1N1) and A (H1N2) strains isolated from pigs, and A (H2N2), A (H4N2), A (H7N2) [78]. This study included a large number of strains resistant to existing influenza drugs such as amantadine, rimantadine, ocetalmivir, zanamivir [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. Antimicrob Agents Chemother. 2002 Apr].

Use of favipiravir in in vivo models of influenza

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

At 60 to 300 mg / kg / day, favipiravir has been shown to be effective in lowering viral load in the lungs of H1N1-infected mice (A / California / 04/09), as well as delayed use, up to 96 hours after infection [Takahashi K ., Furuta Y., Fukuda Y., Kuno M., Kamiyama T., Kozaki K., Nomura N., Egawa H., Minami S., Shiraki K. (2003) In vitro and in vivo activities of T-705 and oseltamivir against influenza virus. Antivir. Chem. Chemother; Sidwell R.W., Barnard D.L., Day C.W., Smee D.F., Bailey K.W., Wong M.H., Morrey J.D., Furuta Y. (2007) Efficacy of orally administered T-705 on lethal avian influenza A (H5N1) virus infections in mice. Antimicrob. Agents Chemother].

Favipiravir showed a significant therapeutic effect in comparison with ocetalmivir in mice, which were injected with a 100-fold higher dose of the virus, and the treatment itself was delayed by 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 for other families of RNA viruses in in vitro and in vivo studies.

Arenaviridae

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

Use of favipiravir in in vivo arenavirus models

In vitro, favipiravir has shown greater selectivity than ribavirin. When measuring the cytopathic effect in cell culture, the EC ₅₀ values for the drug were 0.79-0.94 μg / ml for the Junin, Pichinde and Takaribe viruses. Also, the viral load when using favipiravir significantly decreased by the third day. In the study by counting the foci of hemolysis EC ₉₀ s against the highly pathogenic Romero strain of the Guanarito virus JUNV (Romero) and the Machupo virus was 3.3-8.4 μg / ml (21-53 μM) (Table 2) [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].

When favipiravir was taken orally in a model line of hamsters infected with the Pichinda virus, the drug prevented death, reduced the number of viral titers in the blood and tissues, at a dosage of 60 mg / kg / day, it twice prevented liver destruction when used for 7 days, starting from 4 hours post-infection [Gowen V.V., Wong M.N., Jung K.N., Sanders A.V., Mendenhall M., Bailey KW, Furuta Y., Sidwell RW (2007) In vitro and in vivo activities of T-705 against arenavirus and bunyavirus infections. Antimicrob. Agents Chemother] The viral load was also significantly reduced at the start of treatment from 4, 5 and 6 days post-infection. When used in dosages of 100 mg / kg / day, the survival rate of animals was 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. (2008) Treatment of late stage disease in a model of arenaviral hemorrhagic fever: T-705 efficacy and reduced toxicity suggests an alternative to ribavirin. PLoS One 3, e3725].

On the model of infection of guinea pigs, 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. (2011) Effective oral favipiravir (T-705) therapy initiated after the onset of clinical disease in a model of arenavirus hemorrhagic fever. PLoS Negl. Trop. Dis. 5, el342].

When using favpiravir 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 indicators decreased to 50 and 25%, the animals retained their body weight, in 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 aspartate aminotransferase (AST), a prognostic marker of the severity of Lassa fever in the blood, decreased significantly in a dose-dependent manner by the tenth day of illness during treatment with favipiravir. The viremia of the mean infectious dose per ml of eluate decreased on average to 2.1, 1.3 and 1.6 log ₁₀ CCID ₅₀ / ml in the groups treated with high and medium doses of favipiravir and ribavirin, respectively.

The efficacy of oral administration of favipiravir has also been shown in models infected with the lethal Lassa virus in guinea pigs and mice [Safronetz D., Rosenke K., Westover JB, Martellaro C., Okumura A., Furuta Y., Geisbert J., Saturday G., Komeno T., Geisbert TW, Feldmann H., Gowen BB (2015) The broad-spectrum antiviral favipiravir protects guinea pigs from lethal Lassa virus infection post-disease onset. Sci. Rep. 5, 14775]. The therapeutic effect was observed on the 2nd day after infection. Subcutaneous administration of favipiravir at a dosage of 300 mg / kg / day once a day reduced temperature, prevented weight loss, and increased animal survival. The effects of favipiravir were many times greater than the therapeutic effects of ribavirin at a dosage of 50 mg / kg / day. A significant improvement in the survival rate of guinea pigs infected with Lassa virus was observed even on days 5.7 and 9 post-infection [Safronetz D., Rosenke K., Westover J. B., Martellaro C., Okumura A., Furuta Y., Geisbert J., Saturday G., Komeno T., Geisbert TW, Feldmann H., Gowen BB (2015) The broad-spectrum antiviral favipiravir protects guinea pigs from lethal Lassa virus infection post-disease onset. Sci. Rep. 5, 14775].

Bunyaviridae

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

In vitro studies have shown the superiority of favipiravir over other drugs in targeting, efficacy and rapidity of action against a number of similar viruses (Table 3 [Yousuke Furuta, Brian B. Gowen, Kazumi Takahashi, Kimiyasu Shiraki, Donald F. Smee, Dale L. Barnard. Favipiravir (T-705), a novel viral RNA polymerase inhibitor. Antiviral Research. Volume 100, Issue 2, November 2013, Gowen BB, Wong MH, Jung KH, Smee DF, Morrey JD, Furuta Y. (2010) Efficacy of favipiravir (T-705) and T-1106 pyrazine derivatives in phlebovirus disease models. Antiviral Res.]). EC ₅₀ values in studies of plaque-forming units (PFU) in cell culture started at 0.9-30 μg / ml of the drug for Lassa, Punta Toro, Rifa-Valle viruses, acute fever (SFTSV), phlebotomic fever, and Hantaviruses Dobrava, Maporal and Prospekt Hill [Tani N., Fukuma A., Fukushi S., Taniguchi S., Yoshikawa T., Iwata-Yoshikawa N., Sato Y., Suzuki T., Nagata N., Hasegawa H., Kawai Y., Uda A ., Morikawa S., Shimojima M., Watanabe H., Saijo M. (2016) Efficacy of T-705 (Favipiravir) in the treatment of infections with lethal severe fever with thrombocytopenia syndrome virus. 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., Zhang S., Liu Y., Li J., Sun Y., Zhang L., Zhang Q., Popov VL, Li C., Qu J., Li Q., Zhang Y., Hai R., Wu W., Wang Q., Zhan F., Wang X., Kan B., Wang S. , Wan KL, Jing HQ, Lu JX, Yin WW, Zhou H., Guan XH, Liu JF, Bi ZQ, Liu GH, Ren J., Wang H., Zhao Z., Song JD, He JR, Wan T. , Zhang JS, Fu XP, Sun LN, Dong XP, Feng ZJ, Yang WZ, Hong T., Zhang Y., Walker DH, Wang Y., Li DX (2011) Fever with thrombocytopenia associated with a novel bunyavirus in China. N. Engl. J. Med; Kim K., Yi J., Kim G., Choi SJ, Jun KI, Kim N., Choe PG, Kim N., Lee J., Oh M. (2013) Severe fever with thrombocytopenia syndrome, South Korea, 2012. Emerg. Infect. Dis]. Favipiravir inhibited SFTSV replication in cell culture with EC ₅₀ values of 0.71-1.3 μg / ml.

(IFNAR^-/-), которые не развивают немедленный иммунный ответ.The therapeutic effect of favipiravir has been demonstrated in mouse models with K receptor knockout.

(IFNAR ^{- / -} ) that do not develop an immediate immune response.

After oral administration of 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 from 4 and 5 days post-infection, survival rates improved significantly in a group. Based on the data of in vivo studies in Japan, the drug entered clinical trials and successfully completed them to date [30]. It showed the efficacy of favipiravir even after the onset of the disease and the onset of clinical symptoms (Table 4) [Yousuke Furuta, Brian B. Gowen, Kazumi Takahashi, Kimiyasu Shiraki, Donald F. Smee, Dale L. Barnard. Favipiravir (T-705), a novel viral RNA polymerase inhibitor. Antiviral Research. Volume 100, Issue 2, November 2013].

Flaviviridae

Favipiravir blocks the replication of viruses of the flaviviride family, including yellow fever virus (YFV) and West Nile virus (WNV) [Julander JG, Shafer K., Smee DF, Morrey JD, Furuta Y. (2009) Activity of T-705 in a hamster model of yellow fever virus infection in comparison with a chemically related compound T-1106. Antimicrob. Agents Chemother; Morrey J.D., Taro B.S., Siddharthan V., Wang H., Smee D.F., Christensen A.J., Furuta Y. (2008) Efficacy of orally administered T-705 pyrazine analog on lethal West Nile virus infection in rodents. Antiviral Res.], However, at higher concentrations than needed to block influenza virus activity.

EC _{90 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 flavivirus models

YFV-infected hamsters were treated orally with favipiravir at doses ranging from 200 to 400 mg / kg / day for 8 days, starting 4 hours prior to infection. This therapy significantly reduced the mortality rate of animals at the start of treatment [Julander JG, Shafer K., Smee DF, Morrey JD, Furuta Y. (2009) Activity of T-705 in a hamster model of yellow fever virus infection in comparison with a chemically related compound T-1106. Antimicrob. Agents Chemother].

Complete recovery was achieved with an injection of 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 EC ₅₀ concentrations of 53 μg / ml in Vero cell culture.

Oral administration of favipiravir at 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 tissues. The same efficacy was shown in lines infected with WNV, hamsters at the same doses. The envelope proteins of the WNV virus were not detected in the brains of the treated animals.

Zika virus (ZIKV) is a newly emerging arbovirus of the Flaviviridae family, transmitted mainly by mosquito bites. The data indicate a link between infection in the developing fetus and microcephaly. Favipiravir blocked ZIKV replication in Vero cell culture at EC ₅₀ from 3.5-3.8 μg / ml [Zmurko J., Marques RE, Schols D., Verbeken E., Kaptein SJ, Neyts J. (2016) The viral polymerase inhibitor 7-deaza -2'-C-methyladenosine is a potent inhibitor of in vitro Zika virus replication and delays disease progression in a robust mouse infection model. PLoS Negl. Trop. Dis. 10, e0004695].

Togaviridae

Favipiravir exhibits antiviral activity against Western Equine Encephalitis Virus (WEEV) in Vero cell culture, reaching EC ₉₀ at 49 μg / ml [Julander JG, Smee DF, Morrey JD, Furuta Y. (2009) Effect of T-705 treatment on western equine encephalitis in a mouse model. Antiviral Res].

In WEEV-infected mice, oral administration of favipiravir significantly increased the survival and lifespan of the infected animals when twice administered at a dose of 400 mg / kg / day for 7 days, starting at the 4th hour post-infection. Viral titers in the brain tissues were reduced on the 4th day of post-infection, however, a complete cure from infection with the use of favipiravir did not occur.

G., Pastorino В., Froeyen M., Dallmeier K., Jochmans D., Herdewijn P., Bello F., Snijder E.J., de Lamballerie X., Martina В., Neyts J., van Hemert M.J., Leyssen P. (2014) Mutations in the chikungunya virus non-structural proteins cause resistance to favipiravir (T-705), a broad-spectrum antiviral. J. Antimicrob. Chemother].Favipiravir showed antiviral activity against Chikungunya virus (CHIKV) in Vero cell culture, reaching EC ₅₀ at 0.3-9.4 μg / ml. In CHIKV-infected mice, oral administration of favipiravir improved survival rates at two-fold doses from 300 mg / kg / day, starting one day before or 4 hours after infection [Delang L., Segura Guerrero N., Tas A.,

G., Pastorino B., Froeyen M., Dallmeier K., Jochmans D., Herdewijn P., Bello F., Snijder EJ, de Lamballerie X., Martina B., Neyts J., van Hemert MJ, Leyssen P. (2014) Mutations in the chikungunya virus non-structural proteins cause resistance to favipiravir (T-705), a broad-spectrum antiviral. J. Antimicrob. Chemother].

Picornaviridae

Use of favipiravir in in vitro picornavirus models

Replication of vesicular stomatitis enterovirus was inhibited by favipirovir in in vitro studies with EC ₅₀ at 14 μg / ml [Sakamoto K., Ohashi S., Yamazoe R., Takahashi K., Furuta Y. (2006) 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 european commission for the control of Foot-and-Mouth Disease, Paphos, Cyprus. FAO Appendix 64; Furuta Y., Takahashi K., Shiraki K., Sakamoto K., Smee DF, Barnard DL, Gowen BB, Julander JG, Morrey JD (2009) T-705 (favipiravir) and related compounds: Novel broad-spectrum inhibitors of RNA viral infections. Antiviral Res].

Favipiravir also blocked the replication of poliomyelitis virus in Vero cell culture and rhinovirus in HeLa cell culture at EC ₅₀ s at 4.8 and 23 μg / ml, and with a selectivity index of 29 and> 43, respectively [Furuta Y., Takahashi K., Fukuda Y., Kuno M., Kamiyama T., Kozaki K., Nomura N., Egawa H., Minami S., Watanabe Y., Narita H., Shiraki K. (2002) In vitro and in vivo activities of anti- influenza virus compound T-705. Antimicrob. Agents Chemother]. Favipiravir inhibited the replication of Enterovirus with an EC ₅₀ of 23 μg / ml [Wang Y., Li G., Yuan S., Gao Q., Lan K., Altmeyer R., Zou G. (2016) In vitro assessment of combinations of enterovirus inhibitors against enterovirus 71. Antimicrob. Agents Chemother].

Caliciviridae

Favipiravir is active against murine noravirus with EC ₅₀ values from 39 μg / ml in studies of viral plaque counting in the RAW 264.7 murine macrophage cell line. Real-time PCR revealed blocking of RNA synthesis using favipiravir with EC ₅₀ from 19 μg / ml [Rocha-Pereira J., Jochmans D., Dallmeier K., Leyssen P., Nascimento MS, Neyts J. (2012) Favipiravir (T- 705) inhibits in vitro norovirus replication. Biochem. Biophys. Res. Commun].

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

In a mouse model of persistent infection, oral administration of favpiravir at a dose of 600 mg / kg / day twice for 8 weeks, after 4 weeks post-infection, resulted in a significant decrease in viral titers in the feces of mice and in the number of norovirus-positive mice. Scientific evidence also confirms that favipiravir-RTF inhibits the RNA polymerase activity of human Noraviruses [Jin Z., Tucker K., Lin X., Kao C.C, Shaw K., Tan N., Symons J., Behera I., Rajwanshi VK, Dyatkina N., Wang G., Beigelman L., Deval J. (2015) Biochemical evaluation of the inhibition properties of Favipiravir and 2'-C-methyl-cytidine triphosphates against human and mouse norovirus RNA polymerases. Antimicrob. Agents Chemother].

Filoviridae

А., Wurr S., Rieger Т.,

С.,

S. (2014) Successful treatment of advanced Ebola virus infection with T-705 (favipiravir) in a small animal model. Antiviral Res]. Сходным образом, в линии А129, нокаутной по рецептору интерферона IFNAR^-/-, зараженной шитаммом Эбола Е718, лечение фавипиравиром орально полностью спасло всех зараженных мышей от смерти при двукратном применении лекарства в дозе от 300 мг/кг/день в течение 14 дней, начиная с 1ого часа после заражения [Smither S.J., Eastaugh L.S., Steward J.A., Nelson M., Lenk R.P., Lever M.S. (2014) Post-exposure efficacy of oral T-705 (Favipiravir) against inhalational Ebola virus infection in a mouse model. Antiviral Res].Favipiravir showed antiviral activity against Zaire Ebola virus (Mayinga 1976 strain) in Vero E6 cell culture with EC ₅₀ at 10.5 μg / ml. In a strain of mice infected with the Mayinga 1976 strain lacking the interferon-alpha receptor (IFNAR ^{- / -} C57BL / 6), oral administration of favipiravir avoided death and reduced viral titers in the blood when twice administered from 300 mg / kg / day for 8 days from the 6th day of post-infection, while in the placebo group all mice died [Oestereich L.,

A., Wurr S., Rieger T.,

FROM.,

S. (2014) Successful treatment of advanced Ebola virus infection with T-705 (favipiravir) in a small animal model. Antiviral Res]. Similarly, in the IFNAR ^{- / -} IFNAR - / - interferon receptor knockout A129 strain infected with Ebola E718 shitamm, oral favipiravir treatment completely saved all infected mice from death with two doses of 300 mg / kg / day for 14 days starting from 1 hour after infection [Smither SJ, Eastaugh LS, Steward JA, Nelson M., Lenk RP, Lever MS (2014) Post-exposure efficacy of oral T-705 (Favipiravir) against inhalational Ebola virus infection in a mouse model. Antiviral Res].

F., Taburet A.M., Guedj J., Anglaret X.,

S., de Lamballerie X., Malvy D. (2015) Dose regimen of favipiravir for Ebola virus disease. Lancet Infect. Dis]. Фавипиравир хорошо переносился пациентами и снижал количество смертельных исходов у пациентов с низкими вирусными титрами [Sissoko D., Laouenan С, Folkesson Е., M'Lebing А.В., Beavogui А.Н., Baize S., Camara A.M., Maes P., Shepherd S., Danel C., Carazo S., Conde M.N., Gala J.L., Colin G., Savini H., Bore J.A., Le Marcis F., Koundouno F.R., Petitjean F., Lamah M.C., Diederich S., Tounkara A., Poelart G., Berbain E., Dindart J.M., Duraffour S., Lefevre A., Leno Т., Peyrouset O., Irenge L., Bangoura N., Palich R., Hinzmann J., Kraus A., Barry T.S., Berette S., Bongono A., Camara M.S., Munoz V.C., Doumbouya L., Harouna S., Kighoma P.M., Koundouno F.R., Lolamou R., Loua С.М., Massala V., Moumouni K., Provost C., Samake N., Sekou C., Soumah A., Arnould I., Komano M.S., Gustin L., Berutto C., Camara D., Camara F.S., Colpaert J., Delamou L., Jansson L., Kourouma E., Loua M., Malme K., Manfrin E., Maomou A., Milinouno A., Ombelet S., Sidiboun A.Y., Verreckt I., Yombouno P., Bocquin A., Carbonnelle C., Carmoi Т., Frange P., Mely S., Nguyen V.K., Pannetier D., Taburet A.M., Treluyer J.M., Kolie J., Moh R., Gonzalez M.C., Kuisma E., Liedigk В., Ngabo D., Rudolf M., Thom R., Kerber R., Gabriel M., Di Caro A.,

R., Badir J., Bentahir M., Deccache Y., Dumont C., Durant J.F., El Bakkouri K., Uwamahoro M.G., Smits В., Toufik N., Van Cauwenberghe S., Ezzedine K., Dortenzio E., Pizarro L., Etienne A., Guedj J., Fizet A., de Sainte Fare E.B., Murgue В., Tran-Minh Т., Rapp C., Piguet P., Poncin M., Draguez В., Allaford Duverger Т., Barbe S., Baret G., Defourny I., Carroll M., Raoul H., Augier A., Eholie S.P., Yazdanpanah Y., Levy-Marchal C., Antierrens A., Van Herp M.,

S., de, Lamballerie X.,

S., Mentre F., Anglaret X., Malvy D., JIKI Study Group (2016) Experimental treatment with Favipiravir for Ebola virus disease (the JIKI Trial): A historically controlled, single-arm proof-of-concept trial in Guinea. PLoS Med. 13, e1001967]. Группа китайских исследователей также отметила увеличение выживаемости пациентов с Эбола при применении фавипиравира в Сьерра Леоне [Bai C.Q., Mu J.S., Kargbo D., Song Y.B., Niu W.K., Nie W.M., Kanu A., Liu W.W., Wang Y.P., Dafae F., Yan Т., Hu Y., Deng Y.Q., Lu H.J., Yang F., Zhang X.G., Sun Y., Cao Y.X., Su H.X., Sun Y., Liu W.S., Wang C.Y., Qian J., Liu L., Wang H., Tong Y.G., Liu Z.Y., Chen Y.S., Wang H.Q., Kargbo В., Gao G.F., Jiang J.F. (2016) Clinical and virological characteristics of Ebola virus disease patients treated with favipiravir (T-705)-Sierra Leone, 2014. Clin. Infect. Dis].In the 2014 Ebola outbreak in West Africa, the French Institute for Health and Medical Research (INSERM) and the Government of Guinea conducted a clinical trial of favipiravir in patients [

F., Taburet AM, Guedj J., Anglaret X.,

S., de Lamballerie X., Malvy D. (2015) Dose regimen of favipiravir for Ebola virus disease. Lancet Infect. Dis]. Favipiravir was well tolerated by patients and reduced the number of deaths in patients with low viral titers [Sissoko D., Laouenan C, Folkesson E., M'Lebing AV, Beavogui AN, Baize S., Camara AM, Maes P ., Shepherd S., Danel C., Carazo S., Conde MN, Gala JL, Colin G., Savini H., Bore JA, Le Marcis F., Koundouno FR, Petitjean F., Lamah MC, Diederich S., Tounkara A., Poelart G., Berbain E., Dindart JM, Duraffour S., Lefevre A., Leno T., Peyrouset O., Irenge L., Bangoura N., Palich R., Hinzmann J., Kraus A. , Barry TS, Berette S., Bongono A., Camara MS, Munoz VC, Doumbouya L., Harouna S., Kighoma PM, Koundouno FR, Lolamou R., Loua C.M., Massala V., Moumouni K., Provost C., Samake N., Sekou C., Soumah A., Arnould I., Komano MS, Gustin L., Berutto C., Camara D., Camara FS, Colpaert J., Delamou L., Jansson L., Kourouma E., Loua M., Malme K., Manfrin E., Maomou A., Milinouno A., Ombelet S., Sidiboun AY, Verreckt I., Yombouno P., Bocquin A., Carbonnelle C., Carmoi T. , Frange P., Mely S., Nguyen VK, Pannetier D., Taburet AM, Treluyer JM, Kolie J., Moh R., Gonzalez MC, Kuisma E., Liedigk B., Ngabo D., Rudolf M., Thom R., Kerber R ., Gabriel M., Di Caro A.,

R., Badir J., Bentahir M., Deccache Y., Dumont C., Durant JF, El Bakkouri K., Uwamahoro MG, Smits B., Toufik N., Van Cauwenberghe S., Ezzedine K., Dortenzio E. , Pizarro L., Etienne A., Guedj J., Fizet A., de Sainte Fare EB, Murgue B., Tran-Minh T., Rapp C., Piguet P., Poncin M., Draguez B., Allaford Duverger T., Barbe S., Baret G., Defourny I., Carroll M., Raoul H., Augier A., Eholie SP, Yazdanpanah Y., Levy-Marchal C., Antierrens A., Van Herp M.,

S., de, Lamballerie X.,

S., Mentre F., Anglaret X., Malvy D., JIKI Study Group (2016) Experimental treatment with Favipiravir for Ebola virus disease (the JIKI Trial): A historically controlled, single-arm proof-of-concept trial in Guinea ... PLoS Med. 13, e1001967]. A group of Chinese researchers also noted an increase in the survival of Ebola patients with favipiravir in Sierra Leone [Bai CQ, Mu JS, Kargbo D., Song YB, Niu WK, Nie WM, Kanu A., Liu WW, Wang YP, Dafae F., Yan T., Hu Y., Deng YQ, Lu HJ, Yang F., Zhang XG, Sun Y., Cao YX, Su HX, Sun Y., Liu WS, Wang CY, Qian J., Liu L., Wang H., Tong YG, Liu ZY, Chen YS, Wang HQ, Kargbo B., Gao GF, Jiang JF (2016) Clinical and virological characteristics of Ebola virus disease patients treated with favipiravir (T-705) -Sierra Leone, 2014. Clin. Infect. Dis].

Rhabdoviridae

The activity of favipiravir against rabies virus (RABV) was detected on the Neuro-2a murine neuroblastoma cell line with EC ₅₀ s at 5.1-7.0 μg / ml [Yamada K., Noguchi K., Komeno T., Furuta Y., Nishizono A. ( 2016) Efficacy of Favipiravir (T-705) in rabies postexposure prophylaxis. J. Infect. Dis]. Favipiravir significantly reduced morbidity and mortality in RABV-infected mice when taken orally at doses of 300 mg / kg / day, twice for 7 days, starting at 1 hour post-infection.

All the generalized data described above on the indisputable efficacy of favipiravir against a very wide range of RNA viruses show that this drug perfectly "closes" the still effectively uncovered niche of incurable, acute and fatal viral ailments, including a wide range of tropical fevers. Prior to studies on favipiravir, ribavirin and / or alpha-interferon were used against the aforementioned RNA infections, but the former has significantly less antiviral activity and efficacy against RNA viruses, and both drugs, with prolonged use, lead to debilitating side effects. Favipiravir, unlike other antiviral drugs, is well tolerated in clinical trials and deserves widespread use due to the knowledge and versatility of the mechanism.

Favipiravir, relying on a wide spectrum and a proven mechanism of its action, can also alleviate the course of viral diseases, with a timely start of admission, and also significantly reduce the viral load during the course of diseases with complications.

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

However, this use is fraught with a number of difficulties. So, in order to provide quick and high-quality assistance to the population, it is necessary to create a reserve of medicines, which in turn is associated with the possibility of their long-term storage. Those. preparations must be highly stable for a long time in various climatic conditions, especially in conditions of high temperatures and high humidity, even in violation of storage conditions, in particular, packaging.

Known methods for improving the quality of drugs, including storage stability, often require a more complex manufacturing process (higher purity, substances, additional expensive stabilizing components); however, the use of these approaches in the manufacture of antiviral drugs is not always justified for economic reasons.

Often, epidemics of viral diseases occur in areas of hot and hot-humid climates, while in such countries traditionally experiencing a shortage in the supply and availability of medicines due to the difficult economic situation of the population.

In this regard, there is a need for a dosage form of an antiviral drug that would be quite economical in production, but at the same time retaining maximum stability during long-term storage, including under conditions of violation of the recommended storage regimes (conditions of hot and hot-humid climates), especially there is such a need for oral drugs, the circulation and storage of which, after their distribution to the population (often by humanitarian organizations), is practically not controlled.

Thus, outbreaks of the Ebola and Lassa viruses in West Africa in 2014 caused a great wave of social concern about possible subsequent outbreaks of deadly viruses in Asia and Africa with insufficient effective containment [WHO Ebola Response Team (2014) Ebola virus disease in West Africa - the first 9 months of the epidemic and forward projections. N. Engl. J. Med; Mylne A.Q., Pigott D.M., Longbottom J., Shearer F., Duda K.A., Messina J.P., Weiss D.J., Moyes C.L., Golding N., Hay S.I. (2015) Mapping the zoonotic niche of Lassa fever in Africa. Trans. R. Soc. Trop. Med. Hyg.].

Favipiravir is known to have poor water solubility, which results in low bioavailability of preparations containing it.

Many authors are trying to solve this problem by creating highly soluble forms of favipiravir.

For example, CN 104288154 discloses an increased solubility favipiravir tablet containing 200 parts by weight favipiravir, 0-400 parts by weight of excipient, 10-90 parts by weight of disintegrant, 5-10 parts by weight. lubricating agent. The particle size distribution of favipiravir corresponds to D10 = 0.1 ~ 8 microns, D50 = 10 ~ 30 microns and D90 <50 microns.

However, powders with such a particle size distribution have poor compressibility and low stability associated with a developed active surface.

The currently produced preparation of favipiravir "Avigan" is represented by a film-coated tablet containing favipiravir, povidone, colloidal silicon dioxide, hydroxypropyl cellulose, crospovidone, sodium stearyl fumarate, hypromellose, titanium dioxide, talc, iron oxide yellow.

The authors of the patent RU 2527766 investigate the stability of the drug "Avigan", selected as a prototype, in terms of packaging and transportation, linking it with the hardness of the tablet. However, other characteristics of the tablet affecting its stability, as well as the stability of the tablet itself over time, are not studied in the patent.

Known from application CN 107737128 compositions of favipiravir in the form of a tablet in general form, characterized by a content of 200 mg of favipiravir in the form of particles D90 less than 40 μm and D50 26-33 μm, 24-45 mg of microcrystalline cellulose, 10-18 mg of lactose, 8-16 mg of polyethylene glycol 6000, 0.8-1.3 mg sodium lauryl sulfate, 2-5 mg colloidal silicon dioxide, 1-2.5 mg magnesium stearate.

Particular compositions according to this invention, after storage at a constant temperature of 30 ° C and a relative humidity of 65% for 6 months, showed a stability of about 86-87%.

However, in modern realities, such parameters may be insufficient. In addition, the document does not contain information on the stability of the composition in hot and humid climates.

The objective of the present invention is to provide an agent exhibiting prophylactic and / or therapeutic antiviral activity, having improved technological characteristics, more stable during long-term storage than the known analogue, stable during such long-term storage in a wide range of temperatures and humidity, and also quite economical in production as in view of the technological methods used, and in view of the economic availability of the means used.

The authors of the invention solve the problem posed by creating a drug in the form of a tablet, film-coated, showing prophylactic and / or therapeutic antiviral activity, including the core of the following composition:

The technical result, manifested in the implementation of the claimed invention, is to create a tool with improved technological characteristics.

The technical result, manifested in the implementation of the claimed invention, also lies in the increased stability of the agent relative to the known analogue and the preservation of its properties by the composition during transportation and long-term storage, in particular, during long-term storage within 4 main climatic zones without deterioration of the main quality indicators, as well as that the proposed tool is quite economical in production in comparison with the analogue.

Implementation of the invention

The invention relates to a dosage form of favipiravir exhibiting prophylactic and / or therapeutic activity, which is a film-coated tablet comprising a core and a film coating, wherein the tablet core has the following composition (in mg):

The dosage form of favipiravir according to the invention may preferably have the following tablet core composition (mg):

The dosage form of favipiravir according to the invention may also preferably have the following tablet core composition

The dosage form of favipiravir according to the invention may also have the following tablet core composition

The dosage form is preferably film-coated. The film casing can be made of a ready-made coating Opadray 03F220114 yellow, including hypromellose, titanium dioxide, macrogol 4000, iron oxide yellow E172.

Medicines according to the present invention are directed to the prevention and / or therapy of viral diseases.

In a private embodiment, drugs are aimed at preventing and / or treating viral diseases caused by exposure to viruses whose genome is encoded by a single-stranded RNA strand and which use viral RNA-dependent RNA polymerase for their replication.

The drugs of the present invention are aimed at significantly alleviating the clinical symptoms, course and cure of a wide range of diseases caused by exposure to viruses, the genome of which is encoded by a single-stranded sense (+) - strand, as well as an antisense (-) - RNA strand and which use viral RNA-dependent -RNA polymerase for its replication.

Viruses against which the compositions of the present invention are active are influenza viruses of both high and low virulence strains, viruses of the families Coronaviridae, Picornaviridae, Arenaviridae, Flaviviridae, Bunyaviridae, Togaviridae, Orthomyxoviridae.

The administration of the drugs according to the invention, namely, the relief of symptoms, up to recovery, in a patient in need of treatment may be associated with infection of the patient with a virus, which is a calicivirus or noravirus.

The medicaments of the present invention are used in treatment or prophylaxis by a course.

The duration of the course and the daily dose is determined by the task, the complexity of the disease and the individual characteristics of the patient and can be adjusted during therapy and / or prophylaxis.

The duration of the prophylactic course can be from one to four weeks and include taking from one to thirty dosage forms per day.

The duration of a therapeutic course can be from one to four weeks and include taking from one to thirty dosage forms per day.

The course for the treatment of diseases may include taking from 3 doses of dosage forms per day in the first 2 days, then 2 doses.

The course for the treatment of diseases may include taking from 2 doses per day.

Examples of

The present invention and methods for its implementation will be clear to the specialist from the following non-limiting examples of its implementation.

These examples, related to drugs favipiravir, relate only to its particular implementation options, possible and other specific options for implementation.

Example 1.

Obtaining a medicinal product of the following composition:

The technology for obtaining the product was based on two options for wet granulation - in a mixer-granulator with subsequent drying, and in a fluidized bed granulator with a classical spray of a humidifier from above.

Preparation in a mixer granulator.

A 10% humidifier solution was prepared. The mixer-granulator was loaded in sequence with low-substituted hyprolose, favipiravir, and half of microcrystalline cellulose. The mixture was stirred with a stirrer at 100 rpm for 5 minutes. The humidifier was fed at a rate of 5 ml / min and humidified at a stirrer speed of 150 rpm and a chopper of 900 rpm until the humidifier was fully applied. The mixture was granulated at a stirrer speed of 200 rpm, chopper speed of 1500 rpm for 10 minutes. The resulting granules were dried in a fluidized bed unit at a product temperature of 45 ° C and a flow of 35 m ³ / h to a residual moisture content of no more than 2%. The granules were calibrated through a sieve with a mesh size of 1 mm.

To obtain a ready mixture for tabletting, the resulting granulate was mixed with the remaining half of microcrystalline cellulose, crospovidone and colloidal silicon dioxide in a gravimetric mixer for 10 minutes. The resulting mixture was dusted with stearic acid for 2 minutes.

Preparation in a fluidized bed granulator.

A 5% humidifier solution was prepared. The mixer basket was loaded with half of microcrystalline cellulose, favipiravir, low-substituted hyprolose, and the mixture was heated to 35 ° C with an air flow of 20 m ³ / h. A humidifier was applied at a rate of 7 ml / min. Moistened until complete consumption of the humidifier at a product temperature of 39 ° C and a flow of 30 m ³ . Dried at a temperature of 45 ° C and a flow of 35 m ³ to a residual moisture content of not more than 2%. Calibrated through a 1 mm sieve.

To obtain a ready mixture for tabletting, the resulting granulate was mixed with the remaining half of microcrystalline cellulose, crospovidone and colloidal silicon dioxide in a gravimetric mixer for 10 minutes. The resulting mixture was dusted with stearic acid for 2 minutes.

The resulting mixtures were tableted on a rotary tablet press with 8 stations, and a rotor speed of 50 rpm.

The resulting cores were coated in a perforated drum coater. Air flow rate 140 m ³ / h, bed temperature 35 ° C, casing feed 3 ml / min, drum speed 8 rpm.

Table 1 shows the technical characteristics of example 1 for two technologies. Table 1.1. presents the technical characteristics of example 1 for two technologies after a day of storage.

Example 2.

Obtaining a medicinal product of the following composition:

In the proposed technology, two variants of wet granulation were used - in a mixer-granulator with subsequent drying, and in a fluidized bed granulator with a classical spray of a humidifier from above.

Preparation in a mixer granulator.

A 10% humidifier solution was prepared. The mixer-granulator was loaded in sequence with low-substituted hyprolose, favipiravir, and half of microcrystalline cellulose. The mixture was stirred with a stirrer at 100 rpm for 5 minutes. The humidifier was fed at a rate of 5 ml / min and humidified at a stirrer speed of 150 rpm and a chopper of 900 rpm until the humidifier was fully applied. The mixture was granulated at a stirrer speed of 200 rpm, chopper speed of 1500 rpm for 10 minutes. The resulting granules were dried in a fluidized bed unit at a product temperature of 45 ° C and a flow of 35 m ³ / h to a residual moisture content of no more than 2%. The granules were calibrated through a sieve with a mesh size of 1 mm.

To obtain a ready mixture for tabletting, the resulting granulate was mixed with the remaining half of microcrystalline cellulose, crospovidone and colloidal silicon dioxide in a gravimetric mixer for 10 minutes. The resulting mixture was dusted with stearic acid for 2 minutes.

Preparation in a fluidized bed granulator.

A 5% humidifier solution was prepared. The mixer basket was loaded with half of microcrystalline cellulose, favipiravir, low-substituted hyprolose, and the mixture was heated to 35 ° C with an air flow of 20 m ³ / h. A humidifier was applied at a rate of 7 ml / min. Moistened until complete consumption of the humidifier at a product temperature of 39 ° C and a flow of 30 m ³ . Dried at a temperature of 45 ° C and a flow of 35 m ³ to a residual moisture content of not more than 2%. Calibrated through a 1 mm sieve.

To obtain a ready mixture for tabletting, the resulting granulate was mixed with the remaining half of microcrystalline cellulose, crospovidone and colloidal silicon dioxide in a gravimetric mixer for 10 minutes. The resulting mixture was dusted with stearic acid for 2 minutes.

The resulting mixtures were tableted on a rotary tablet press with 8 stations, and a rotor speed of 50 rpm.

The resulting cores were coated in a perforated drum coater. Air flow rate 140 m ³ / h, bed temperature 35 ° C, casing feed 3 ml / min, drum speed 8 rpm.

Table 2 shows the technical characteristics of example 2 for two technologies

Example 3.

Obtaining a medicinal product of the following composition:

In this technology, two variants of wet granulation were used - in a mixer-granulator with subsequent drying, and in a fluidized bed granulator with a classical spray of a humidifier from above.

Preparation in a mixer granulator.

A 10% humidifier solution was prepared. The mixer-granulator was loaded in sequence with low-substituted hyprolose, favipiravir, and half of microcrystalline cellulose. The mixture was stirred with a stirrer at 100 rpm for 5 minutes. The humidifier was fed at a rate of 5 ml / min and humidified at a stirrer speed of 150 rpm and a chopper of 900 rpm until the humidifier was fully applied. The mixture was granulated at a stirrer speed of 200 rpm, chopper speed of 1500 rpm for 10 minutes. The resulting granules were dried in a fluidized bed unit at a product temperature of 45 ° C and a flow of 35 m ³ / h to a residual moisture content of no more than 2%. The granules were calibrated through a 1 mm sieve.

To obtain a ready mixture for tabletting, the resulting granulate was mixed with the remaining half of microcrystalline cellulose, crospovidone and colloidal silicon dioxide in a gravimetric mixer for 10 minutes. The resulting mixture was dusted with stearic acid for 2 minutes.

Cooking in a fluidized bed granulator

A 5% humidifier solution was prepared. The mixer basket was loaded with half of microcrystalline cellulose, favipiravir, low-substituted hyprolose, and the mixture was heated to 35 ° C with an air flow of 20 m ³ / h. A humidifier was applied at a rate of 7 ml / min. Moistened until complete consumption of the humidifier at a product temperature of 39 ° C and a flow of 30 m ³ . Dried at a temperature of 45 ° C and a flow of 35 m ³ to a residual moisture content of not more than 2%. Calibrated through a 1 mm sieve.

To obtain a ready mixture for tabletting, the resulting granulate was mixed with the remaining half of microcrystalline cellulose, crospovidone and colloidal silicon dioxide in a gravimetric mixer for 10 minutes. The resulting mixture was dusted with stearic acid for 2 minutes.

The resulting mixtures were tableted on a rotary tablet press with 8 stations, and a rotor speed of 50 rpm.

The resulting cores were coated in a perforated drum coater. Air flow rate 140 m ³ / h, bed temperature 35 ° C, casing feed 3 ml / min, drum speed 8 rpm.

Table 3 shows the technical characteristics of example 3 for two technologies

Example 4. Determination of the stability of a medicinal product, namely tablets of favipiravir, obtained according to the invention.

Determined by the accelerated aging method at a temperature of 40 ± 2 ° C and a relative humidity of 75 ± 5% for 15 months. Dissolution and impurities determined by UV spectrometry and HPLC were chosen as criteria for assessing stability; the test conditions are given below.

Dissolution test. Dissolution is carried out using a paddle mixer. Dissolution medium - hydrochloric acid solution 0.1 M; the volume of the dissolution medium is 900 ml, the rotation speed is 50 rpm, the dissolution time is 45 min, the temperature of the dissolution medium is (37 ± 0.5) ° С. The amount passed into the solution of favipiravir is determined by UV spectrophotometry at a wavelength of 320 nm in a cuvette with a layer thickness of 10 mm. A known tablet (Avigan) is used as a standard for calculations.

Impurities. Determination is carried out by HPLC.

Chromatography conditions:

- device - high pressure liquid chromatograph equipped with a UV detector;

- column - stainless steel "Kromasil C18" 250 × 4.6 mm, particle size 5 microns or similar, meeting the requirements of the test "Check the suitability of the chromatographic system";

- wavelength - 210 nm;

- flow rate - 1.0 ml / min;

- temperature of the column thermostating - 30 ° С;

- volume of injected sample - 10 μl;

- chromatography time - 55 min;

- gradient chromatography mode in accordance with the program:

Mobile phase A. 1.4 g of potassium dihydrogen phosphate is placed in a volumetric flask with a capacity of 1000 ml, dissolved in 950 ml of water, the pH is adjusted to (4.00 ± 0.05) potentiometrically with concentrated phosphoric acid, the volume of the solution is brought to the mark with water and mix. The resulting solution is filtered through a Millipore membrane filter with a pore size of 0.45 μm and degassed in any convenient way.

Mobile phase B: Acetonitrile.

To dissolve the sample, use a mixture of mobile phases A and B in a ratio of 60 to 40.

Tablets obtained in accordance with examples 1 to 3 were considered suitable, in which the percentage released under dissolution conditions was not lower than 75, while the sum of impurities did not exceed 1.5%, provided that a single impurity did not exceed 0.1%. The tests were carried out every three months. The obtained results of the study of stability are shown in tables 4, 5.

The data given in tables 4, 5 allow us to state that the composition of favipiravir tablets declared in the patent makes it possible to obtain a preparation with excellent technological characteristics, such as exceptionally high stability under accelerated aging, which, in turn, allows us to conclude that it is possible to use it in a wide range of applications. spectrum of climatic zones without loss of effectiveness and quality of the drug.

Claims (12)

1. A dosage form of favipiravir exhibiting prophylactic and / or therapeutic antiviral activity, which is a film-coated tablet comprising a core and a film-coated tablet, characterized in that the tablet core has the following composition, mg: Favipiravir 200,00 Microcrystalline cellulose 100.00 - 140.00 Low substituted hydroxypropyl cellulose 50.00 - 80.00 Crospovidone 14.00 - 25.00 Povidone 15.00 Colloidal silicon dioxide 8.00 Stearic acid 3.00 2. Dosage form of favipiravir according to claim 1, where the tablet core has the following composition, mg: Favipiravir 200.00 Microcrystalline cellulose 135.00 Low substituted hydroxypropyl cellulose 60,00 Crospovidone 14.00 Povidone 15.00 Colloidal silicon dioxide 8.00 Stearic acid 3.00 3. Dosage form of favipiravir according to claim 1, where the tablet core has the following composition, mg: Favipiravir 200.00 Microcrystalline cellulose 100,00 Low substituted hydroxypropyl cellulose 80,00 Crospovidone 21.00 Povidone 15.00 Colloidal silicon dioxide 8.00 Stearic acid 3.00 4. Dosage form of favipiravir according to claim 1, where the tablet core has the following composition, mg: Favipiravir 200.00 Microcrystalline cellulose 120,00 Low substituted hydroxypropyl cellulose 50,00 Crospovidone 21.00 Povidone 15.00 Colloidal silicon dioxide 8.00 Stearic acid 3.00 5. A dosage form of favipiravir according to claim 1, wherein the virus is a virus whose genome is encoded by a single-stranded RNA strand and which uses viral RNA-dependent RNA polymerase for its replication. 6. A dosage form of favipiravir according to claim 5, wherein the virus is an influenza virus, coronavirus, picornavirus, arenavirus, flavivirus, bunyavirus, togavirus, calicivirus, or noravirus. 7. A dosage form of favipiravir according to claim 6, wherein the influenza virus is a highly virulent virus or a low virulent virus. 8. The use of a dosage form according to any one of paragraphs. 1-7 for the treatment and / or prevention of viral diseases.