COMBINED PREVENTION AND TREATMENT OF PATIENTS WITH RESPIRATORY DISEASES CAUSED BY RNA VIRAL INFECTIONS

CROSS-REFERENCE TO RELATED PATENT APPLICATIONS

[0001] This application is based upon and claims priority under 35 U.S.C. § 120 to U.S. Application Nos. 17/709,608, filed March 31, 2022, 17/709,609, filed March 31, 2022, 17/709,727, filed March 31, 2022, and 17/709,731, filed March 31, 2022, the entire contents of all of which are incorporated herein by reference in their entirety.

FIELD OF INVENTION

[0002] The present invention is directed to a new combinatorial prevention and treatment of with, a pharmaceutical kit and a pharmaceutical composition for respiratory illnesses caused by RNA virus infection with a combination of aprotinin + anti-RNA vims drug, a pharmaceutical kit, and a pharmaceutical composition for the combinatorial prevention and treatment of diseases due to RNA virus infection.

BACKGROUND OF THE INVENTION

[0003] Influenza (Flu) and COVID- 19 are contagious respiratory illnesses, but different RNA viruses cause them. COVID-19 is caused by infection with a coronavirus named SARS- CoV-2, and flu is caused by infection with influenza viruses [CDC. Clinical Signs and Symptoms of Influenza. https://www. cdc.gov/flu/professionals/aci p/clinical.htm#:~:text=Influenza%20(Flu)%20and %20COVID-,are%20caused%20by%20different%20viruse.]. The RNA viruses, including of influenza viruses and SARS-CoV-2 viruses have a tropism for the epithelium of the mucous membranes of the respiratory system. They are characterized by catarrhal damage to the mucous membranes of the larynx, trachea, and bronchi with the involvement of the lungs in the process. The infections are transmitted mainly by aerosol transmission.

[0004] SARS-CoV-2 is an RNA viral respiratory illness that causes a 2019 Coronavirus Disease (COVID-19). SARS-CoV-2 is responsible for the ongoing COVID-19 pandemic. SARS-CoV-2 is a virus that belongs to a type of coronavirus associated with SARS-CoV

SUBSTITUTE SHEET ( RULE 26) (Coronaviridae Study Group of the International Committee on Taxonomy of Viruses (April 2020). "The species Severe acute respiratory syndrome-related coronavirus: classifying 2019- nCoV and naming it SARS-CoV-2". Nat. Microbiol. 2020, 5(4), 536-544. doi: 10.1038/s41564-020-0695-z). This virus was first identified in December 2019 in Wuhan city, Hubei province, China. On March 11, 2020, WHO declared the outbreak a public health emergency of international concern. SARS-CoV-2 is the successor to the SARS-CoV-1 virus that caused the SARS outbreak in 2002-2004 (“New coronavirus stable for hours on surfaces.” National Institutes of Health (NIH). NIH.gov. 17 March 2020. Archived from the original on 23 March 2020. Retrieved 4 May 2020). SARS-CoV-2 has undergone many changes in two years, and each new mutation has been more perfect than the previous one. First discovered in India in December 2020, the Delta mutation is spreading across continents at an alarming rate. Delta penetrates lung cells more easily than the original virus (the virus that circulated in the early stages of the pandemic). In addition, the Delta strain is more effective in combining infected lung cells with uninfected ones. This could contribute to the more severe course of COVID- 19. It is currently the predominant variant of SARS-CoV-2 worldwide. Delta is a highly contagious SARS-CoV-2 virus strain believed to be more than twice as infectious as previous SARS-CoV-2 variants (K. Katella. 5 Things to Know About the Delta Variant. Yale Medicine NOVEMBER 19, 2021. https://www.yalemedicine.org/nMws/5-things-to-know-delta-var iant-covid).

[0005] A new variant of the SARS-CoV-2 virus is the Omicron strain. It was detected in laboratories in Botswana and South Africa on 22 November 2021. The variant has an unusually large number of mutations, several of which are novel and a significant number of which affect the spike protein targeted by most COVID-19 vaccines at the time of discovering the Omicron variant. This level of variation has led to concerns regarding its transmissibility, immune system evasion, and vaccine resistance. Omicron spreads faster than any previously known variant.

[0006] As of December 17, 2021, 77 countries reported cases of Omicron, and "the reality is that Omicron is probably in most countries, even if it hasn't been detected yet (L. Smith- Spark, What can the world learn from countries where Omicron is surging? CNN Fri December 17, 2021. https://www.cnn.com/2021/12/17/health/covid-omicron-what-can -the-world-leam- cmd-intl/index. html) .

[0007] COVID-19 has variable clinical manifestations ranging from asymptomatic acute infection to mild-to-moderate flu-like illness. However, a substantial minority (5%-10%) of

SUBSTITUTE SHEET ( RULE 26) patients go on to acquire severe infections with systemic symptoms of myalgias, pneumonia, and weakness. Hospitalized subjects with SARS-CoV-2 are considered to have mild-to- moderate disease, whereas those who require supplemental oxygen, pressers, or intensive care unit (ICU) care are considered to have severe disease. Progression to acute respiratory distress syndrome (ARDS) is believed to be mediated, in part, by an overly exuberant host immune response (i. e. , high serum ferritin, C-reactive protein [CRP], interleukin-6 [IL-6] levels) and may also be exacerbated by endothelitis from a viral infection of the vascular endothelium [S.K. Berry, R.J. Fontana. Potential Treatments for SARS-CoV-2 Infection. CLD, 15 (5), 181- 186 (2020). https://doi.org/10.1002/cld.969]

[0008] As of February 11, 2022, 404,910,528 confirmed cases of people infected with coronavirus were registered in the world, of which 5,783,776 died (https://www.who.int/emergencies/diseases/novel-coronavirus- 2019).

[0009] Vaccination remains one of the main public health interventions to combat SARS- CoV-2. However, vaccine development times of at least six months limit their applicability during outbreaks of new strains of SARS-CoV-2, like the Omicron strain. Therefore, the new development of new, highly effective anti-coronavirus drugs is an urgent task.

[0010] Currently, the most advanced anti-RNA virus drugs for SARS-CoV-2 therapies are remdesivir (RDV), molnupiravir (MPV), and nirmatrelvir + ritonavir (NMV + RTV; Paxlovid), and aprotinin (APR) (Figure 1.).

Remdesivir (RDV, Veklury®) Molnupiravir (MPV, Lagevrio®)

SUBSTITUTE SHEET ( RULE 26)

Nirmatrelvir + Ritonavir (NMV + RTV, Paxlovid)

Aprotinin (APR) MW 6511.51; C284H432N84O79S

Figure 1. The inhibitors of SARS-CoV-2.

[0011] RDV, MPV, NMV + RTV have been approved or authorized for emergency use in SARS-CoV-2 1 COVID-19 infection in numerous countries, including Australia, Bangladesh, Canada, China, Egypt, India, Israel, Mexico, Pakistan, Russia, Singapore, South Korea, the European Union, the United Kingdom, the United States, Vietnam, and other countries [https://en.wikipedia.Org/wiki/Remdesivir#Name. https ://en. wikipedia. org/wiki/T alk: Molnupiravir. https ://en. wikipedia. org/wiki/Nirmatrelvir/ritonavir] .

SUBSTITUTE SHEET ( RULE 26) [0012] APR is not currently approved in any country for the prevention and treatment of SARS-CoV-2/COVID-19 infection.

[0013] Remdesivir (RDV, GS-5734, brand name Veklury) received its first approval on May 1, 2020; the FDA issued an Emergency Use Authorization (EUA) for the emergency use of Veklury® intravenous drug for the treatment of hospitalized patients with severe COVID- 19. Veklury is a SARS-CoV-2 RNA polymerase inhibitor. Previously Veklury was an investigational drug and was not FDA-approved for any indication [https ://www. fda. go v/medi a/ 137564/ do wnl oad] .

[0014] Veklury is indicated in adult and pediatric patients (aged 12 years and older and weighing at least 40 kg) for the treatment of COVID-19. Veklury should only be administered intravenously in a hospital or in a healthcare setting [https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/2 147870rigls0001bl.pdf].

[0015] On January 21, 2022, the FDA expanded the approved indication for Veklury to include its use in adults and pediatric patients (12 years of age and older who weigh at least 40 kilograms, which is about 88 pounds) with positive results of direct SARS-CoV-2 viral testing, and who are not hospitalized and have mild-to-moderate COVID-19, and are at high risk for progression to severe COVID-19, including hospitalization or death. [https://www.fda.gov/news-events/press-announcements/fda-tak es-actions-expand-use- treatment-outpatients-mild-moderate-covid-19].

[0016] Dosage of Veklury for patients: for adults and pediatric patients weighing >40 kg: 200 mg on Day 1, followed by once-daily maintenance doses of 100 mg from Day 2, administered only via intravenous infusion; for pediatric patients >28 days old and weighing >3 kg to <40 kg: 5 mg/kg on Day 1, followed by once-daily maintenance doses of 2.5 mg/kg from Day 2, administered only via intravenous infusion [https://www.vekluryhcp.com/dosing- and-admin/; https://www.accessdata.fda.gOv/drugsatfda_docs/label/2020/21 47870rigls0001bl.pdf.].

[0017] Duration of Veklury treatment: for patients who are hospitalized and require invasive mechanical ventilation and/or ECMO, the recommended total treatment duration is ten days. Veklury should be initiated as soon as possible after a diagnosis of symptomatic COVID- 19; for patients who are hospitalized and do not require invasive mechanical ventilation and/or ECMO, the recommended treatment duration is five days. If a patient does not demonstrate clinical improvement, treatment may be extended up to 5 additional days, for a total treatment duration of up to 10 days; for patients who are not hospitalized, diagnosed

SUBSTITUTE SHEET ( RULE 26) with mild-to-moderate COVID-19, and are at high risk for progression to severe COVID-19, including hospitalization or death, the recommended total treatment duration is three days. Veklury should be initiated as soon as possible after a diagnosis of symptomatic COVID-19 and within seven days of symptom onset [https://www.vekluryhcp.com/dosing-and-admin/; https://www.accessdata.fda.gOv/drugsatfda_docs/label/2020/21 47870rigls0001bl.pdf.].

[0018] It should be noted that the largest clinical study on the efficacy and safety of remdisivir is the WHO Solidarity Trial, which was conducted between March 22, 2020, and January 29, 2021. The first results of this study were published, and included data on 11,330 adults who underwent randomization from 405 hospitals in 30 countries, including 2750 patients who were assigned to receive RDV. The study found that in total, 1253 deaths were reported (median day of death, day 8; interquartile range, 4 to 14). The Kaplan-Meier 28-day mortality was 11.8% (39.0% if the patient was already receiving ventilation at randomization and 9.5% otherwise); in the RDV group, death occurred in 301 of 2743 patients and in 303 of 2708 receiving its control (rate ratio, 0.95; 95% confidence interval [CI], 0.81 to 1. 11; p=0.50); no drug (RDV, hydroxychloroquine, lopinavir, and interferon) definitely reduced mortality, overall or in any subgroup, or reduced initiation of ventilation or hospitalization duration. Based on these results [WHO Solidarity Trial Consortium. Repurposed Antiviral Drugs for Covid-19 — Interim WHO Solidarity Trial Results. V. Engl. J. Med. 2021, 384 (6), 497-511. doi: 10.1056/NEJMoa2023184.], on November 19, 2020, the WHO Guideline Development Group did not recommend the use of WFD for the treatment of COVID-19 because there was no evidence of a significant effect on mortality, need for mechanical ventilation, time to clinical improvement, and other important outcomes for the patient [WHO Guideline Development Group advises against the use of remdesivir for covid-19. https://www.bmj.com/company/newsroom/who-guideline-developme nt-group-advises- against-use-of-remdesivir-for-covid- 19/] .

[0019] In this regard, on November 20, 2020, WHO issued a conditional recommendation against the use of remdesivir in hospitalized patients, regardless of the severity of the disease. WHO supported the continued participation of RDV in the WHO “Solidarity” trial [WHO recommends against the use of remdesivir in COVID-19 patients https://www.who.int/news- room/feature-stories/detail/who-recommends-against-the-use-o f-remdesivir-in-covid-19- patients],

[0020] Known the combined methods for the treatment of hospitalized adult patients with COVID-19, using RDV and baricitini (Olumiant®) [Kahl A.C. et al. Baricitinib plus

SUBSTITUTE SHEET ( RULE 26) Remdesivir for Hospitalized Adults with Covid-19. N. Engl. J. Med. 2021, 384, 795-807. DOI: 10.1056/NEJMoa2031994.].

[0021] On November 19, 2020, the FDA issued an EUA for the emergency use of the combination of Olumiant with RDV to treat certain hospitalized patients requiring supplemental oxygen, invasive mechanical ventilation, or extracorporeal membrane oxygenation. Olumiant is an inhibitor of the Janus kinases, which are intracellular enzymes that transmit signals arising from cytokine or growth factor receptor interactions on the cellular membrane to influence cellular processes of hematopoiesis and immune cell [Coronavirus (COVID-19) Update: FDA Authorizes Drug Combination for Treatment of COVID-19. Press release 19 November 2020. https://www.fda.gov/news-events/press- announcements/coronavims-covid-19-update-fda-authorizes-drug -combination-treatment- covid- 19#:~:text=Today%2C%20the%20U.S.%20Food%20and,or%20older%20r equiring%20supp lemental%20oxygen%2C.] .

[0022] However, serious side effects may occur in patients treated with Olumiant: cardiovascular events, thrombosis, malignancy, and serious bacterial, fungal, and viral infections, including tuberculosis, leading to hospitalization or death, (https : //www. olumiant. com/hcp/ co vid- 19/ safety . ) .

[0023] Also known is the combined method for the treatment of hospitalized adult patients with severe COVID-19, using RDV and Tocilizumab [Rosas, I O. et al. Tocilizumab and remdesivir in hospitalized patients with severe COVID-19: A randomized clinical trial. Intensive Care Med. 47 (11), 1258-1270 (2021). doi: 10.1007/s00134-021-06507-x.].

[0024] Tocilizumab is a novel monoclonal antibody that competitively inhibits the binding of interleukin-6 (IL-6) to its receptor (IL-6R). Inhibiting the entire receptor complex prevents IL-6 signal transduction to inflammatory mediators that summon B and T cells [Sebba A. Tocilizumab: the first interleukin -6 receptor inhibitor, Am J Health Syst Pharm. 65 (15) 1413— 1418 (2008), https://doi.org/10.2146/ajhp070449.].

[0025] However, patients with active infections should not be treated with Tocilizumab. Side effects can be categorized into 1) common side effects (respiratory tract infections, headache, hypertension, elevation in liver test), 2) reactions of injection site (rash, redness, swelling, itching), 3) associated serious infection (tuberculosis, sepsis, fungal infection), 4) side effects reported in studies (hypersensitivity reactions, developed cancer, reactivation of herpes zoster, gastrointestinal perforation in patients with diverticulitis) [Samaee H., et al.

SUBSTITUTE SHEET ( RULE 26) Tocilizumab for treatment patients with COVID-19: Recommended medication for novel disease. Int. Immunopharmacol., 89 (2020) 107018; doi:10.1016/j.intimp.2020. 107018.].

[0026] Also known is the combined method for the treatment of hospitalized adult patients with severe COVID-19, using RDV and the monoclonal antibody LY-CoV555. How ever, LY- CoV555, when coadministered with RDV, did not demonstrate efficacy among hospitalized patients who had Covid- 19 [Group A.-T. et al. A neutralizing monoclonal antibody for hospitalized patients with covid-19. N. Engl. J. Med. 384 (10), 905-914 (2021). doi:10.1056/NEJMoa2033130],

[0027] It was also found interferon beta- la plus RDV was not superior in efficacy to RDV alone in hospitalized patients with COVID- 19 pneumonia [Kalil A.C. et al. Efficacy of interferon beta-la plus remdesivir compared with remdesivir alone in hospitalized adults with COVID-19: A double-blind, randomized, placebo-controlled, phase 3 trial. Lancet. Respir. Med. 9 (12), 1365-1376 (2021). doi: 10. 1016/S2213 -2600(21)00384-2.].

[0028] The efficacy of combined therapy of the patient with RDV and dexamethasone was also not confirmed in terms of mortality rate, mechanical ventilation requirement, length of the hospital and intensive care unit stay, as well as radiologic changes were not affected either. [Fakharian, A. et al. Evaluation of adalimumab effects in managing severe cases of COVID- 19: A randomized controlled trial. Int. Immunopharmacol. 99, 107961 (2021). doi:10.1016/j.intimp.2021.107961.].

[0029] Molnupiravir (MPV, MK-4482, EIDD-2801, brand name Lagevrio) received its first approval on 4 November 2021 in the UK for the treatment of mild-to-moderate COVID- 19 in adults with a positive SARS-CoV-2 diagnostic test and who have at least one risk factor for developing severe illness [Merck Sharp & Dohme (UK) Limited. Lagevrio 200 mg hard capsules: UK prescribing information. 2021. https://products.mhra.gov.uk/. UK Medicines and Healthcare products Regulatory Agency. First oral antiviral for COVID- 19, Lagevrio (molnupiravir), approved by MHRA. 4 Nov 2021. https://www.gov.uk.].

[0030] MPV has been FDA-authorized for emergency use to treat mild-to-moderate COVID-19 since December 2021 [Fact sheet for healthcare providers: emergency use authorization for Lagevrio™ (molnupiravir) capsules. https://ww ⁷ w.fda.gov/media/155054/download]. It is a readily bioavailable prodrug of a ribonucleoside analog that interferes with multiple SARS-CoV-2 viral processes, including replication. It also acts potently against several other RNA viruses, including Ebola, influenza, MERS-CoV, and Venezuelan equine encephalitis vims.

SUBSTITUTE SHEET ( RULE 26) [0031] Dosage for Emergency Use of Lagevrio in Adult Patients. Lagevrio is not authorized for use in patients who are less than 18 years of age. The dosage in adult patients is 800 mg (four 200 mg capsules) taken orally every 12 hours for five days, with or without food. Initiate as soon as possible after COVID- 19 diagnosis and within five days of symptom onset [https://www.fda.gov/media/155054/dowTiloa].

[0032] In human airway epithelial cells, MPV has a potent effect against SARS-CoV-2, reducing viral production with an in vitro IC50 of 0.024 pM without observed cytotoxicity [Sheahan T.P. et al. An orally bioavailable broad-spectrum antiviral inhibits SARS-CoV-2 in human airway epithelial cell cultures and multiple coronaviruses in mice. Sci Tr ansi Med. 2020 Apr 6: eabb5883. doi: 10.1126/scitranslmed.abb5883], In mice and ferret models of SARS- CoV-2, MPV has shown efficacy in the prevention and treatment of infection, laying a strong foundation and rationale for clinical studies [Cox R.M. et al. Therapeutically administered ribonucleoside analogue MK-4482/EIDD-2801 blocks SARS-CoV-2 transmission in ferrets. Nat Microbiol. 2021 Jan;6(l): 11-18. doi: 10. 1038/s41564-020-00835-2. Wahl A. et al. SARS- CoV-2 infection is effectively treated and prevented by EIDD-2801. Nature. 2021 Mar;591(7850):451-457. doi: 10.1038/s41586-021-03312-w. Masyem S. et al. Molnupiravir: A lethal mutagenic drug against rapidly mutating severe acute respiratory syndrome coronavirus 2 - A narrative review. J Med Virol. 2022 Jul; 94(7): 3006-3016. Published online 2022 Apr 2. doi: 10.1002/jmv.27730.].

[0033] Results from clinical trials confirmed good bioavailability, safety, and tolerability of the drug. The efficacy of molnupiravir was found to be significant in patients with mild or moderate COVID- 19. It could reduce the risk of hospital admission or death in nonhospitalized adults with mild-to-moderate COVID- 19 [Masyeni S. et al. Molnupiravir: A lethal mutagenic drug against rapidly mutating severe acute respiratory syndrome coronavirus 2 — A narrative review. J Med Virol. 2022 Jul; 94(7): 3006-3016. Published online 2022 Apr 2. doi: 10.1002/jmv.27730.].

[0034] Early treatment of MPV has been shown to reduce the risk of hospitalization or death in nonhospitalized and unvaccinated adult patients with Covid- 19 at risk. In the study, a total of 1433 participants underwent randomization; 716 were assigned to receive MPV and 717 to receive placebo. With the exception of an imbalance in sex, baseline characteristics were similar in the two groups. The superiority of MPV was demonstrated at the interim analysis; the risk of hospitalization for any cause or death through day 29 was lower with MPV (28 of 385 participants [7.3%]) than with placebo (53 of 377 [14.1%]) (difference, -6.8

SUBSTITUTE SHEET ( RULE 26) percentage points; 95% confidence interval [CI], -11.3 to -2.4; P=0.001). In the analysis of all participants who had undergone randomization, the percentage of participants who were hospitalized or died through day 29 was lower in the MPV group than in the placebo group (6.8% [48 of 709] vs. 9.7% [68 of 699]; difference, -3.0 percentage points; 95% CI, -5.9 to -0. 1). One death was reported in the MPV group, and nine were reported in the placebo group through day 29. Adverse events were reported in 216 of 710 participants (30.4%) in the MPV group and 231 of 701 (33.0%) in the placebo group. [Bernal A. J. et al. Molnupiravir for Oral Treatment of Covid-19 in Nonhospitalized Patients. N Engl J Med 2022; 386, 509-520 (2022). doi: 10. 1056/NEJMoa2116044. Editor’s Note: This article was published on December 16, 2021, at NEJM. https://evidence.nejm.org/doi/10.1056/EVIDoa2100044],

[0035] The prophylactic efficacy of MPV in the treatment of Covid- 19 in non-hospitalized patients was also confirmed in a phase 2a clinical trial [Fischer WA, Eron JJ, Jr, Holman W, et al. A phase 2a clinical trial of molnupiravir in patients with COVID- 19 shows accelerated SARS-CoV-2 RNA clearance and elimination of infectious virus. Sci Transl Med. 2022 doi: 10.1126/scitranslmed.abl7430.] and in a phase 2/3 clinical trial [Caraco Y, Crofoot GE, Moncada PA, et al. Phase 2/3 trial of molnupiravir for treatment of Covid-19 in nonhospitalized adults. NEJM Evid. 2021 doi: 10.1056/EVIDoa2100043.].

[0036] In hospitalized adults with COVID-19, MPV showed no clinical benefit in a randomized, double-blind, placebo-controlled phase II trial. [Arribas JR et al. Randomized trial of molnupiravir or placebo in patients hospitalized with Covid-19. NEJM Evid. 1 (2), 1-13 (2021). doi: 10.1056/EVIDoa2100044.].

[0037] Patients aged > 18 years requiring in-hospital treatment for laboratory-confirmed COVID- 19 with symptom onset within ten days were randomized to MPV 200, 400, or 800 mg or placebo twice daily for five days (n = 304). The primary effectiveness endpoint was sustained recovery rate, defined as the proportion of patients being alive and either not hospitalized or medically ready for hospital discharge. The sustained recovery rate was similar between MPV and placebo groups (81.5-85.2% vs. 84.7%), and the median time to sustained recovery' was nine days in all groups. All-cause mortality rates were also similar between the retreatment groups. The lack of clinical benefit with MPV in the hospitalized population was thought to be related to delayed treatment initiation in relation to the temporal pattern of COVID- 19 symptom onset and illness severity [Arribas JR et al. Randomized trial of molnupiravir or placebo in patients hospitalized with Covid-19. NEJM Evid. 1 (2), 1-13 (2021). doi: 10.1056/EVIDoa2100044.].

SUBSTITUTE SHEET ( RULE 26) [0038] On 3 March 2022, WHO updated its living guidelines on COVID-19 therapeutics to include a conditional recommendation on MPV, a new antiviral medicine. MPV should be provided only to non-severe COVID-19 patients with the highest risk of hospitalization. These are typically people who have not received a COVID- 19 vaccination, older people, people with immunodeficiencies, and people living with chronic diseases [WHO updates its treatment guidelines to include molnupiravir. https://reliefweb.int/report/world/who-updates-its- treatment-guidelines-include- molnupiravir?gclid=CjOKCQjwwfiaBhC7ARIsAGvcPe5EAG7zvtT7RuwaH nYm2w GPNqKitVhZ7x 1 AAEj ehV 1 s_D3UxAk8kZcaA16cEALw_wcB] .

The combination of IFN-a and MOV synergistically attenuated the replication of SARS-CoV- 2 in Calu-3 cells [lanevski A, et al. Synergistic interferon-alpha-based combinations for treatment of SARS-CoV-2 and other viral infections. Viruses. 2021, 13, 2489. Doi: 10.3390/vl3122489.].

[0039] Synergism was also observed in the hamster model where MOV was combined with another nucleoside analog, favipiravir [Abdelnabi R , et al. The combined treatment of MOV and FVP results in a potentiation of antiviral efficacy in a SARS-CoV-2 hamster infection model. EBloMedlclne. 2021;72: 103595; Doi: 10.1016/j.ebiom.2021.103595. Eloy P, et al. Combined treatment of molnupiravir and favipiravir against SARS-CoV-2 infection: one + zero equals two? EBioMedicine. 2021 ;74: 103663. Doi: 10. 1016/j.ebiom.202E 103663.].

[0040] The combined treatment of Molnupiravir and Favipiravir has also been shown to result in a potentiation of antiviral efficacy in a SARS-CoV-2 hamster infection model [Abdelnabi R , et al. The combined treatment of Molnupiravir and Favipiravir results in a potentiation of antiviral efficacy in a SARS-CoV-2 hamster infection model. EBioMedicine. 2021, 72, 103595. doi: 10. 1016/j.ebiom.2021.103595.].

[0041] The method of combination therapy discussed above (EBioMedicine. 2021;72: 103595) is only intended to treat a SARS-CoV-2 infection and does not provide the treatment of COVID- 19 patients with moderate and severe disease.

[0042] Nirmatrelvir + Ritonavir (NMV + RTV, brand name Paxlovid) December 16, 2021 , received the first EUA approval from European Medicines Agency (EMA) [EMA issues advice on use of Paxlovid (PF-07321332 and RTV treatment of COVID-19. https://ww ^f w.ema.europa.eu/en/news/ema-issues-advice-use-paxlovid -pf-07321332-ritonavir- treatment-covid- 19.].

SUBSTITUTE SHEET ( RULE 26) [0043] On December 22, 2021, the FDA approved the emergency use of Paxlovid (NMV tablets and ritonavir tablets, co-packaged for oral use) for the treatment of mild-to-moderate COVID-19 in adults and pediatric patients (12 years of age and older weighing at least 40 kg) with positive results of direct SARS-CoV-2 viral testing, and who are at high risk for progression to severe COVID-19, including hospitalization or death. Paxlovid is available by prescription only and should be initiated as soon as possible after a diagnosis of COVID-19 and within five days of symptom onset. [Coronavirus (COVID-19) Update: FDA Authorizes First Oral Antiviral for Treatment of COVID- 19. https://www.fda.gov/news-events/press- announcements/coronavirus-covid- 19-update-fda-authorizes-first-oral-anti viral -treatment- covid-19],

[0044] The dosage for Paxlovid is 300 mg nirmatrelvir (two 150-mg tablets) with 100 mg ritonavir (one 100-mg tablet), with all three tablets taken together orally twice daily for five days. For each dose, all three tablets should be taken at the same time [https://www.paxlovidhcp.com/dosin].

[0045] NMV is an inhibitor of Mpro: also referred to as 3CLpro or nsp5 protease, which is responsible for the cleavage of SARS-CoV-2 polyproteins la and lab. Without SARS-CoV- 2 3CLpro activity, nonstructural proteins (including proteases) cannot be released to perform their functions by inhibiting virus replication [B. Ahmad et al. Exploring the Binding Mechanism of PF-07321332 SARS-CoV-2 Protease Inhibitor through Molecular Dynamics and Binding Free Energy Simulations. IntJMol Sci. 2021 Sep; 22(17): 9124. Published online August 24, 2021. doi: 10.3390/ijms22179124. ].

[0046] RTV is an HIV-1 protease inhibitor and CYP3A inhibitor [Fact sheet for healthcare providers: emergency use authorization for Paxlovid™. https://www.fda.gov/media/155050/download.]. Low-dose ritonavir is included in Paxlovid to slow the breakdown of nirmatrelvir, allowing it to stay in your body longer to fight COVID- 19 [Paxlovid (nirmatrelvir I ritonavir). GoodRx, 2021; https ://www.goodrx. com/paxlovid/what-is] .

[0047] RTV is an antiretroviral protease inhibitor that is widely used in combination with other protease inhibitors in the therapy and prevention of human immunodeficiency virus (HIV) infection and acquired immunodeficiency syndrome (AIDS). RTV can cause transient and usually asymptomatic elevations in serum aminotransferase levels and, rarely, can lead to clinically apparent acute liver injury. In HBV or HCV-coinfected patients, highly active antiretroviral therapy with RTV may result in an exacerbation of the underlying chronic

SUBSTITUTE SHEET ( RULE 26) hepatitis B or C [NIH. Ritonavir. PubChem. https : //pubchem. ncbi . nlmnih. gov/ compound/Ritonavir. ] .

[0048] Paxlovid was approved for use in Canada on January 17, 2022, for the treatment of adult patients with mild to moderate COVID- 19, and later received a conditional marketing authorization from the European Commission on January 27, 2022,9

[https://go.drugbank.com/drugs/DB16691.].

[0049] Combinatorial treatment of nonhospitalized adult patients with symptomatic Covid- 19 with Paxlovid resulted in a risk of progression to severe Covid-19 that was 89% lower than the risk with placebo, without evident safety concerns. The clinical study involved a total of 2246 patients who underwent randomization; 1120 patients received Paxlovid (Paxlovid group), and 1126 received placebo (placebo group).

[0050] The incidence of Covid- 19-related hospitalization or death by day 28 was lower in the Paxlovid group than in the placebo group by 6.32 percentage points (95% confidence interval [CI], -9.04 to -3.59; P<0.001; relative risk reduction, 89.1%); the incidence was 0.77% (3 of 389 patients) in the Paxlovid group, with 0 deaths, as compared with 7.01% (27 of 385 patients) in the placebo group, with seven deaths.

[0051] The incidence of adverse events that emerged during the treatment period was similar in the two groups (any adverse event, 22.6% with Paxlovid group vs. 23.9% with placebo; serious adverse events, 1.6% vs. 6.6%; and adverse events leading to discontinuation of the drugs or placebo, 2.1% vs. 4.2%). Dysgeusia (5.6% vs. 0.3%) and diarrhea (3.1% vs. 1.6%) occurred more frequently with nirmatrelvir plus ritonavir than with placebo [J. Hammond et al. Oral Nirmatrelvir for High-Risk, Nonhospitalized Adults with Covid-19. N Engl J Med, 386, 1397-1408 (2022); Editor’s Note: This article was published on February 16, 2022, at NEJM.org. doi: 10. 1056/NEJMoa2118542.].

[0052] Aprotinin (APR) was discovered in 1930 as an inhibitor of kallikrein in the lymph nodes of cattle [Kraut, H., Frey, E. K., Werle, E., DerNachweis eines Kreislaufhormons in der Pankreasdruse. Hoppe-Seyler's Z. Physiol. Chem. 1930, 192, 1-21.], and in 1936 as a trypsin inhibitor in the pancreas of cattle [Kunitz, M., Northrop, J. H. Isolation from beef pancreas of crystalline trypsinogen, trypsin, a trypsin inhibitor, and an inhibitor - trypsin compound., J. Gen. Physiol. 1936, 19, 991- 1007. doi: 10.1085/jgp.l9.6.991.].

[0053] On December 29, 1993, the FDA approved APR (Trasylol) for prophylactic use to reduce perioperative blood loss and the homologous blood transfusion requirement in patients undergoing cardiopulmonary bypass surgery in the course of repeat coronary artery bypass

SUBSTITUTE SHEET ( RULE 26) graft surgery and in selected cases of primary coronary artery bypass grafting [FDA. Search Orphan Drug Designations and Approvals, https ://www. accessdata. fda. gov/ scripts/op dli sting/ oopd/ detailedlndex. cfm? cfgridkey=66992]

[0054] Owing to the risk of allergic/anaphylactic reactions, an appropriate test for IgG antibodies to an APR-containing drug may be considered prior to the IV administration of an APR drug (Trasylol, Gordox, or another drug containing APR). A 1ml (10,000 KIU) test dose should be administered to all patients at least 10 minutes prior to the remainder of the dose. After the uneventful administration of the 1ml test dose, the therapeutic dose may be given. Standard emergency treatments for anaphylactic and allergic reactions should be readily available [https://pillintrip.com/medicine/gordox] .

[0055] A loading dose of 1 - 2 million KIU is administered to an adult patient as a slow intravenous injection or infusion over 20 - 30 minutes after induction of anesthesia and prior to sternotomy. A further 1 - 2 million KIU should be added to the pump prime of the heartlung machine. To avoid physical incompatibility of Gordox and heparin when adding to the pump prime solution, each agent must be added during recirculation of the pump prime to ensure adequate dilution prior to admixture with the other component. The initial bolus infusion is followed by the administration of a continuous infusion of 250,000 - 500,000 KIU per hour until the end of the operation. In general, the total amount of Gordox administered per treatment course should not exceed 7 million KIU. The safety and efficacy in children below 18 years of age have not been established, [https://pillintrip.com/medicine/gordox. https://www.accessdata.fda.gov/drugsatfda_docs/label/2006/02 0304s0091bl.pdf],

[0056] Inhalation prevention and treatment of infectious and inflammatory diseases of viral etiology (influenza and other acute respiratory viral infections) is carried out using the Aerus device. To do this, one inhalation dose (1 dose of 85 KIU) is administered into each nasal passage every 2-4 hours (800-2000 KlU/day). The maximum daily dose is 50-65 KlU/day per 1 kg of body weight. The main recommended course of inhalation: inhalation through the nose and exhalation through the mouth. The duration of the course is from 3 to 8 days, depending on the severity of the disease [https://lekarstwo.ru/2017/en/01_a/07/page64.html.].

[0057] APR is a competitive inhibitor of several serine proteases, specifically trypsin, chymotrypsin, and plasmin at a concentration of about 125,000 lU/ml and kallikrein at 300,000 lU/ml [ Mahdy A.M., Webster N.R. Perioperative systemic haemostatic agents. British

SUBSTITUTE SHEET ( RULE 26) Journal of Anaesthesia. 93 (6): 842-858 (2004). doi. l 0.1093/bja/aeh227], Its action on kallikrein leads to the inhibition of the formation of factor Xlla. As a result, both the intrinsic pathway of coagulation and fibrinolysis are inhibited. Its action on plasmin independently slows fibrinolysis [ Mannucci P.M. Hemostatic drugs. The New England Journal of Medicine. 339 (4), 245-253 (1998). doi:10.1056/NEJM199807233390407],

[0058] APR is indicated in high-risk surgery to prevent blood loss and reduce inflammatory reactions during surgical interventions in patients undergoing cardiopulmonary- bypass in the course of coronary artery bypass graft surgery [Sedrakyan A., et al. Effect of aprotinin on clinical outcomes in coronary artery bypass graft surgery: a systematic review and meta-analysis of randomized clinical trials. The Journal of Thoracic and Cardiovascular Surgery. 128 (3): 442-448 (2004). doi: 10.1016/j.jtcvs.2004.03.041], orthotopic liver transplantation [Shiga T., et al. Aprotinin in major orthopedic surgery: a systematic review of randomized controlled trials. Anesthesia and Analgesia. 101 (6): 1602-7 (2005). doi: 10. 1213/01. ANE.0000180767.50529.45], total hip replacement, colorectal surgery, peripheral vascular surgery, and heart and heart-lung transplantation [Mahdy A.M., Webster N.R. Perioperative systemic haemostatic agents. British Journal of Anaesthesia. 93 (6): 842- 58 (2004). doi: 10.1093/bja/aeh227], and other surgical operations.

[0059] In 1960 Aprotinin was introduced for the treatment of acute pancreatitis because of its proteinase-inhibiting property [Anderer, F. A., Homie, S., J. The disulfide linkages in kallikrein inactivator of bovine lung. Biol. Chem. 241 (7), 1568-1572 (1966)]. However, most studies have failed to show any benefit from this use [Aprotinin. PubChem,' https : //pubchem. ncbi . nlm. nih. gov/ compound/ A prot i n i nSsecti on=Th erapeut i c- U se ] .

[0060] APR is an inhibitor of transmembrane serine protease 2 (TMPRSS2) of the host cell and an inhibitor of SARS-CoV-2 entry into the host cell [Hoffmann M., et al. SARS-CoV- 2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor. Cell 2020; 181(2), 271-280. e8. Bojkova D., et al. Aprotinin Inhibitors SARS-CoV- 2 Replication. Cells 2020; 9(11), 2377],

[0061] The present invention is also directed to a new combinatorial prevention and treatment of influenza illnesses with a combination of aprotinin + anti-RNA vims drug, a pharmaceutical kit, and a pharmaceutical composition for the combinatorial prevention and treatment of influenza illnesses.

[0062] According to the National Center for Biotechnology Information (NCBI) taxonomy database, -70,000 influenza viruses have been identified, differing in their antigenic spectrum,

SUBSTITUTE SHEET ( RULE 26) including -53,000 influenza A virus (120 subtypes), -16,200 - influenza B virus, -320 influenza C virus, and -90 influenza D virus (Taxonomic Browser (Orthomyxoviridae) - NCBI. htps://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi7id = 11308).

[0063] Influenza is an ARVI that affects all age groups and is associated with high mortality rates during pandemics, epidemics, and sporadic outbreaks. Influenza affects about 10% of the world's population every year. The most common complications of influenza include viral or bacterial pneumonia, which mostly kill about half a million people each year. [0064] Influenza vaccination is the most effective method for preventing influenza infection and its complications. The influenza vaccine’s efficacy varies each season based on the circulating influenza strains and vaccine uptake rates based on the circulating influenza strains and vaccine uptake rates [M. Javanian et al. A brief review of influenza virus infection (J. Med. Virol. 2021, 93(8), 4638-4646. doi: 10.1002/jmv.26990. Epub 2021 Apr 14).

[0065] The influenza virus has several targets for antiviral drugs. The first classes of influenza drugs approved for use were adamantanes, which block the M2 ion channel on the surface of the virion. While these drugs were effective, the relatively rapid emergence of resistant strains ultimately rendered them ineffective. Oseltamivir (Tamiflu), the most common neuraminidase drug, has a similar disadvantage. Also known are polymerase and nucleoprotein inhibitors that target the replication apparatus of influenza viruses. Two of these drugs, Xofluza (baloxavir marboxil, BXM) and Avigan (favipiravir, FVP), have appeared on the market but are currently not widely used. Since 2018, the Xofluza drug has been approved for the treatment of influenza in Japan, the USA, Hong Kong, Australia, Russia, and Europe (Y. Bai et al. Antivirals Targeting the Surface Glycoproteins of Influenza Virus: Mechanisms of Action and Resistance. Viruses 2021, 13 (4), 624, 1-16. doi: 10.3390 I vl3040624). Examples of parenteral influenza drugs are inhaled Relenza (zanamivir) and intravenous Rapivab (peramivir).

[0066] The current medical treatment of influenza patients is based on the administration of neuraminidase (NA) inhibitors [P. Laborda et al. Influenza neuraminidase inhibitors: synthetic approaches, derivatives, and biological activity. Molecules 2016, 21(11), 1513-1553. htps://doi.org/10.3390/molecules21111513].

[0067] Currently, four NA inhibitors are used in clinical practice: inhaled zanamivir (Relenza™; GlaxoSmithKline, 1999), oral oseltamivir phosphate salt (Tamiflu™; Hoffmann- La Roche, 1999), inhaled laninamivir octanoate (Inavir™; Biota/Daiichi-Sankyo, 2010), intravenous peramivir (Rapivab™; BioCryst Pharm, 2014) [J.-J. Shie, J.-M. Fang.

SUBSTITUTE SHEET ( RULE 26) Development of effective anti-influenza drugs: congeners and conjugates - a review. J Biomed Sci 2019 26:84. https://doi.org/10.1186/sl2929-019-0567-0], and oral (3R,4R,5S)-5- guanidino-3-(pentan-3-yloxy)-4-(2-fluoroacetamido)-cyclohexe ne-l-carboxylic acids (AV5080; ASAVI LLC, 2012) [A.V. Ivachtchenko. Fluoro-substituted (3r, 4r, 5s)-5- guanidino-4-acylamino-3-(pentan-3-yloxy) cyclohexene- 1 -carboxylic acids, esters thereof, and a method for the use thereof. US 8895613 (2014)].

[0068] AV5080 is an NA inhibitor of the influenza viruses A/Califomia/07/09 (H1N1),

A/Aichi/2/69 (H3N2), A/Chiken/Rostov on Don/35/07/(H5Nl), A/Pert/265/2009 (H1N1 pdm09; 275Y), A/Duck/MN/1525/81 H5N1, B/Brisbane/60/2008, B/Perth/211/2001 (197D), and B/Perth/211/2001 (197E). The activity of AV5080 against other influenza strains is unknown [A.V. Ivachtchenko. US 8895613 (2014). A.V. Ivachtchenko, et al. Novel oral antiinfluenza drug candidate AV5080. J. Antimicrob. Chemother. 2014, 69(7), 1892-1902. https ://doi. org/ 10.1093/j ac/ dku074] .

[0069] The rapid emergence of resistant strains to known drugs and new resistant strains of influenza remains an ongoing threat and serious problem. Therefore, the development of new anti-influenza drugs remains an urgent task.

[0070] Closest to this invention is the combined prevention and treatment of patients with moderate COVID-19 using intravenous aprotinin (APR) and oral Favipiravir FVP, which is included in Avifavir (AVF). This therapy is more effective because primary and secondary efficacy endpoints of therapy by the APR + FPV combination are significantly better than the efficacy endpoints of therapy by the individual components (Table 1). [Ivashchenko A. A. et al. Effect of Aprotinin and Avifavir® Combination Therapy for Moderate COVID- 19 Patients. Viruses 2021, 13, 1253. https://doi.org/10.3390/vl3071253.]

[0071] This can lead to serious side effects such as hyperuricemia and elevated alanine aminotransferase levels [Hase R, et al., Acute gouty arthritis during treatment with favipiravir for the treatment of coronavirus disease, 2019. Intern Med., 59, 2327-2329 (2020). doi: 10.2169/intemalmedicine.5377-20.], increased liver enzymes [Yilmaz H., et al. Results of Favipiravir Combined Treatment in Intensive Care Patients with COVID-19. Bagcilar Med Bull, 6(3), 339-345 (2021). DOI: 10.4274/BMB.galenos.202L 07.084], increased platelet and lymphocyte count, decreased neutrophil and red blood cell count [Yaylaci S., et al., The effects of favipiravir on hematological parameters of covid-19 patients. Rev. Assoc. Med. Bras., 66 (Suppl 2), 65-70 (2020). https://doi.org/10.1590/1806-9282.66.S2.65], and significant retinol depletions [Sarohan A.R, et al., A novel hypothesis for COVID-19 pathogenesis: Retinol

SUBSTITUTE SHEET ( RULE 26) depletion and retinoid signaling disorder. Cell Signal., 87, 110121 (2021). https ://doi. org/ 10.1016/j . cellsig.2021.110121.]

[0072] The latest data reported by the ClinicalTrials.gov directory shows the existence of 4,371 studies based on multiple antivirals against SARS-CoV-2 [Baig M.H., et al. Is PF- 00835231 a pan-SARS-CoV-2 Mpro inhibitor? A comparative study. Molecules 2021;

26: 1678. doi: 10.3390/molecules26061678.]. Despite this, only a few of them, including the RDV, FVP, MPV, NMV discussed above, and some combinations of the latter, have already reached the final clinical phase.

[0073] However, anti-SARS-CoV-2 virus preparations are an important preventive tool in the fight against the COVID-19 pandemic caused by SARS-CoV-2 infection [Ghahremanpour M.M., et al. Identification of 14 known drugs as inhibitors of the main protease of SARS-CoV- 2. ACS Ned Chem Lett 2020; 11:2526-33; doi:10.1021/acsmedchemlett.0c00521. Chen J., et al. Recent progress in the development of potential drugs against SARS-CoV-2. Curr Res Pharmacol Drug Discov 2021, 1000077; doi: 10.1016/j.crphar.2021.100057.]. [0074] Table 1. Primary and secondary efficacy endpoints of therapy by the intravenous

APR, oral FPV, and their combination.

SUBSTITUTE SHEET ( RULE 26)

TERMS USED IN THE DESCRIPTION OF THIS INVENTION

[0075] The term "drug" (also called medicine, medicament, pharmaceutical composition, or medicinal drug) refers to a drug used to diagnose, cure, treat, or prevent disease and means a substance (or a mixture of substances in the form of a pharmaceutical composition).

[0076] The term "oral drug" refers to solutions, powders, tablets, capsules, and pills that are taken by mouth and swallowed.

[0077] The term "parenteral drug" refers to drugs that are injected into the body, bypassing the gastrointestinal tract. Parenteral drugs are solutions for injection, inhalation, sprays, including for nasal or drip application, and other finished dosage forms, in this case, intended for the treatment and prevention of viral infections and diseases caused by them.

[0078] The term "parenteral therapies” refers to the administration of drugs primarily via injection (intravenously, into the muscles, under the skin), inhalations, and nasally (spray, drops).

[0079] The term "pharmaceutical composition," as used herein, means a composition comprising at least two active ingredients (substances), namely APR and RDV, and at least one excipient.

SUBSTITUTE SHEET ( RULE 26) [0080] The term "parenteral pharmaceutical composition (PPC)" is intended for the parenteral administration of drugs into the body of a patient. These are primarily intravenous, inhalation, and nasal routes of drug administration.

[0081] The term "excipient," as used herein, refers to a compound that is used to prepare a pharmaceutical composition and is generally safe, non-toxic, and neither biologically nor otherwise undesirable, and includes excipients that are acceptable to humans and animals. This invention uses primarily excipients selected from the series: water, sodium chloride, L-lysine monohydrate, sodium hydroxide, hydrochloric acid, benzyl alcohol, ethanol, glycerin, dimethyl sulfoxide, peppermint oil, 1,1,1,2-tetrafluoroethane, and some others.

[0082] The term "pharmaceutical kit" as used herein means a kit including at least two drags: Bexovid® or NMV saline solution, or its lyophilisate and the parenteral drug Trasylol®, or Gordox®, or Aprotex®, or Antagosan®, or Contrycal®, or Traskolan®, or others parenteral drugs including aprotinin, or aqueous or saline solution containing aprotinin.

[0083] The term "pharmaceutical combination therapy" is a therapy that uses more than one pharmaceutical medication (drug). "Pharmaceutical combination therapy" may be achieved by prescribing/administering separate drugs or dosage forms that contain more than one active ingredient (such as fixed-dose combinations).

[0084] The term “combination therapy” is a therapy that uses more than one medication or modality. Typically, the term refers to using multiple therapies to treat a single disease, and often all the therapies are pharmaceutical. "Pharmaceutical" combination therapy may be achieved by prescribing/administering separate drugs or, where available, dosage forms that contain more than one active ingredient (such as fixed-dose combinations).

[0085] The term "therapeutically effective amount" or "dose" as used herein means the amount of medicine needed to reduce the symptoms of a disease in a patient. The dose of medicine will be tailored to the individual requirements in each case. This dose can vary widely depending on numerous factors, such as the severity of the patient's illness, the age and general health of the patient, other drugs with which the patient is being treated, the method and form of administration of medicine, and the experience of the attending physician. Typically, treatment is started with a large initial “loading dose” to rapidly reduce or eliminate the virus and followed by tapering the dose to a level sufficient to prevent an outbreak of infection.

[0086] The term "patient" means a mammal, including but not limited to humans, cattle, pigs, sheep, chickens, turkeys, buffaloes, llamas, ostriches, dogs, cats, hamsters, and mice; preferably, the patient is a human.

SUBSTITUTE SHEET ( RULE 26) [0087] The term "active ingredient (substance)" as used herein means aprotinin and an inhibitor of SARS-CoV-2 virus used in a pharmaceutical composition or drug.

SUMMARY OF THE INVENTION

[0088] In one aspect, the present application relates to the prevention and treatment of respiratory illnesses caused by an RNA virus infection using a combination of aprotinin (APR) or an APR-containing drug and a second component which is an anti-RNA virus ingredient or a drug containing such ingredient, in a patient in need thereof. The present application also relates to a pharmaceutical kit and a pharmaceutical composition for the combined prevention and treatment of respiratory illnesses.

[0089] Another aspect of the invention relates to the combined prevention and treatment of patients with SARS-CoV-2 or with SARS-CoV-2 and COVID-19 disease, comprising the use of a therapeutically effective amount of APR or an APR-containing drug and an anti- SARS-CoV-2 ingredient. In a preferred embodiment, the anti-SARS-CoV-2 ingredient is selected from the group consisting of RDV, MPV, NMV, and FVP or an anti-SARS-CoV-2 ingredient-containing drug.

[0090] Another aspect of the invention relates to the combined prevention and treatment of patients with an influenza virus infection, influenza illness, or influenza pneumonia, comprising the use of a therapeutically effective amount of APR or a drug containing APR and an anti-influenza ingredient. In a preferred embodiment, the anti-influenza ingredient is selected from the group consisting of FVP (T-705), (3R,4R,5S)-5-guanidino-3-(pentan-3- yloxy)-4-(2-fluoroacetamido)cyclohexene-l -carboxylic acids (AV5080), oseltamivir (OS), peramivir (PRV) and zanamivir (ZA) or drug containing an anti -influenza ingredient.

[0091] Another aspect of the invention is directed to a method for the prevention and treatment by intravenous, inhalation, or nasal administration to the patient in a therapeutically effective amount of APR (aprotinin) or a drug containing APR and anti-RNA virus ingredient. [0092] The protocol for the prevention and treatment of respiratory illnesses due to RNA virus infection is determined and prescribed by the physician, depending on the condition of the patient and the specific combination of APR and anti-RNA virus ingredient or depending on the pharmaceutical composition used. The protocol includes the duration of therapy, the number of doses per day, and daily doses.

SUBSTITUTE SHEET ( RULE 26) [0093] Another aspect of the invention is a pharmaceutical composition in the form of its aqueous solution (APC) or its lyophilizate (LPC) for the combined prevention and treatment of respiratory illnesses due to RNA virus infection, comprising a therapeutically effective amount and ratio of aprotinin, an anti-RNA virus ingredient, and at least one excipient.

[0094] In some embodiments, the APR-containing drug is selected from a number of drugs, including Trasylol®, Gordox®, Aprotex®, Antagosan®, Contrycal®, Traskolan®, and other parenteral drugs that include APR, or an aqueous or saline solution containing APR.

[0095] Some embodiments include an RDV (remdesivir)-containing drug. In some embodiments, the RDV-containing drug is Veklury or another drug containing RDV.

[0096] Some embodiments include an MPV (Molnupiravir)-containing drug. In some embodiments, the MPV-containing drug is Lagevrio or another drug containing MPV.

[0097] Some embodiments include an NMV (Nirmatrelvir)-containing drug.

[0098] Some embodiments include a T-705 (Favipiravir)-containing drug. In some embodiments, the T-705-containing drug is Avigan.

[0099] Some embodiments include an AV5080-containing drug.

[0100] Some embodiments include an OS (oseltamivir)-containing drug. In some embodiments, the OS-containing drug is Tamiflu™ or another drug containing OS.

[0101] Some embodiments include a PRV (peramivir)-containing drug. In some embodiments, the PRV-containing drug is Rapivab™ or another drug containing PRV.

[0102] Some embodiments include a ZA (zanamivir)-containing drug. In some embodiments, the ZA drug is Relenza™ or another drug containing ZA.

[0103] In some embodiments, pharmaceutical combinations or formulations according to the present application include excipients. In some embodiments, the excipients are selected from the group consisting of water, sodium chloride, L-lysine monohydrate, 2-hydroxy-beta- cyclodextrin, betadex sulfobutyl ether sodium, sodium hydroxide, hydrochloric acid, benzyl alcohol, ethanol, glycerin, dimethyl sulfoxide, peppermint oil, 1,1,1,2-tetrafluoroethane, and others.

[0104] Another aspect of the invention is also a pharmaceutical kit for the combined prevention and treatment of respiratory illnesses due to RNA virus infection, which includes, in a therapeutically effective ratio and quantity, an aprotinin component (component 1), an anti-RNA virus component (component 2) and a document that contains information about the drugs included in the kit and instructions for the simultaneous administration of the components of this pharmaceutical kit.

SUBSTITUTE SHEET ( RULE 26) [0105] In one embodiment, component 1 is Gordox® or Trasylol® or their analogs - vials containing a solution of aprotinin for injection and solution for infusion (500,000 KIU/50 ml) for intravenous use or 50 mL vials containing lyophilisate of aprotinin (500,000 KIU), which is dissolved in 50 mL of saline before use [https://www.sdrugs.com/?c=drug&s =gordox. https://www.rxlist.com/trasylol-drug.htm (Last updated on RxList: 8/3/2022), https ://ec. europa. eu/health/documents/ community - register/2008/2008021537590/anx_37590_en.pdf]. In preferred embodiments, the dose of component 1 is as prescribed by the doctor.

[0106] In one embodiment, component 2 is Veklury (remdesivir) for injection, for intravenous use (Supplied as 100 mg/20 mL [5 mg/mL] solution in a vial or as 100 mg lyophilized powder in a single-dose Vial) [https://www.gilead.com/- /media/files/pdfs/medicines/covid-19/veklury/veklury _pi.pdf. https://covid- vaccine.canada.ca/info/pdf/veklury-pml-en.pdf|. In preferred embodiments, the dose of component 2 is as prescribed by the doctor.

[0107] An aspect of the invention is also a pharmaceutical kit that includes a PPC containing aprotinin and an anti-SARS-CoV-2 drug. In some embodiments, the kit contains an LPC containing RDV. In preferred embodiments, the dose is as prescribed by the doctor.

[0108] In one embodiment, component 2 is Lagevrio™ (MPV) 200 mg capsules of MPV for oral use. Dosage and administration - 800 mg (four 200 mg capsules) taken orally every 12 hours for five days, with or without food. Lagevrio is supplied in a bottle containing 40 capsules [https://www.fda.gov/media/155054/downloa (Revised EUA Authorized Date: 08/2022). https://www.medsafe.govt.nz/consumers/cmi/l/lageviro.pdf. https://www.news- medical.net/drugs/Lagevrio.aspx]. In preferred embodiments, the dose is as prescribed by the doctor.

[0109] In one embodiment, component 2 is a drug that includes NMV. Dosage: 300 mg NMV (two 150 mg tablets) twice daily for five days [https://www.fda.gov/media/155050/dowTiload]. In preferred embodiments, the dose is as prescribed by the doctor.

[0110] In one embodiment, component 2 is an Avigan-containmg drug, or pills containing 200 mg T-705. In preferred embodiments, the dose administered is as prescribed by the doctor. 10111] In one embodiment, the combination includes an OS drug which is Tamiflu™, optionally in capsules containing 75 mg OS. Some embodiments include another drug containing OS. In preferred embodiments, the dose administered is as prescribed by the doctor.

SUBSTITUTE SHEET ( RULE 26) [0112] In some embodiments, the combination includes a PRV drug which is Rapivab™, optionally in the form of a 20 mL vial of concentrate for infusion. In some embodiments, the combination contains 200 mg of peramivir or another drug containing PRV. In preferred embodiments, the dose administered is as prescribed by the doctor.

[0113] In some embodiments, ZA is provided as a white to off-white powder for oral inhalation with a solubility of approximately 18 mg per mL in water at 20°C. In some embodiments, a ZA-containing drug is Relenza™. Relenza™ is a powder mixture of 5 mg of zanamivir and 20 mg of lactose for administration to the respiratory tract by oral inhalation only. In preferred embodiments, the dose administered is as prescribed by the doctor.

[0114] In some embodiments, the combination includes a drug containing AV5080, optionally in capsules containing 80 mg of AV5080. In preferred embodiments, the dose administered is as prescribed by the doctor.

[0115] Some embodiments of the present application include pharmaceutical kits, including any of the foregoing. In some embodiments, the kit includes the drugs in the amount necessary for a 5- or 10-day course of treatment.

An aspect of the invention is also a pharmaceutical kit that includes a PPC containing aprotinin and an anti-RNA virus component.

[0116] Another aspect of the present application is directed to a method of obtaining the PPC or the parenteral drug of the present invention by dissolving APR and an anti-RNA virus component of the present invention and excipients in saline (0.9% aqueous sodium chloride solution).

[0117] Another aspect of the invention is directed to a method of obtaining PPC or the new parenteral drug of the present invention by dissolving a lyophilizate containing APR and an anti-RNA virus component of the present invention and of the excipients in saline.

[0118] In some embodiments, the active ingredients and PPC of the present invention retain their activity in a lyophilized form suitable for storage and use.

[0119] Another aspect of the invention is directed to the use of an APR in the form of a powder, a lyophilisate, a concentrate, or a drug containing APR, for the preparation of the PPC or the parenteral drug of the present invention.

[0120] Another aspect of the invention is directed to the use of the anti-SARS-CoV-2 drugs of the present invention in the form of a powder, or lyophilizate, or concentrate for preparing the APC or the parenteral drug of the present invention.

SUBSTITUTE SHEET ( RULE 26) [0121] Another aspect of the invention is directed to the use of an anti-RNA virus drug of the present invention in the form of a powder, a lyophilisate, or a concentrate, and an APR drug containing APR, for the preparation of PPC or parenteral drug of the present invention.

[0122] Another aspect of the invention is a method for preparing the PPC by dissolving APR, an anti-RNA virus drug of the present invention, in the form of a powder, or a lyophilizate, or the water solution, and excipients in water or saline followed by lyophilization of the resulting mixture.

[0123] Another aspect of the invention is a process for the preparation of a dosage form bydissolving anti-RNA virus drug or drugs of the present invention in the form of a powder, a lyophilisate, or an aqueous solution, and excipients in Trasylol®, or Gordox®, or Aprox®, or Antagosan®, or Kontrykal®, or Traskolan®, or in other preparations containing APR, followed by lyophilization of the resulting mixture.

[0124] In some embodiments, the PPC can be obtained, including immediately before use, by sequential dissolution in physiological solution (e.g., saline solution) of the crystalline APR or its lyophilizate, a crystalline anti-RNA virus drug or drugs of the present invention or their lyophilizate and, if necessary, excipients.

[0125] In some embodiments, the new PPC can be obtained, including immediately before use, by sequential dissolution in saline of crystalline APR or its lyophilizate, for example, Contrykal®, the crystalline anti-RNA virus ingredients of the present invention, or its lyophilizate and, if necessary, excipients.

[0126] Thus, in the combined treatment of the transgenic mice infected with mouse- adapted SARS-CoV-2 with combinations of APR + RDV, APR + MOV, APR + FVP, and APR + NMV, compared with the control (infected but untreated transgenic mice), a decrease in virus titer (A logTCID50/ml) was observed at 1.74, 4.61 and 3.2 orders of magnitude, respectively.

The above data convincingly demonstrate the high efficiency of the SARS-CoV-2/COVID-19 combination treatment claimed in this invention and a high efficiency (positive effect) compared with the control (infected but untreated transgenic mice).

[0127] The efficiency of the SARS-CoV-2/COVID-19 combination treatment in Syrian hamsters infected with SARS-CoV-2 also has been confirmed in their intravenous treatment with PPC. As a result of animal treatment, a statistically significant decrease in virus titer was obtained in the lungs of infected animals compared to the control group of infected but untreated animals.

SUBSTITUTE SHEET ( RULE 26) [0128] The use of the new pharmaceutical kit and PPC and the new parenteral drug of the present invention in the prevention and treatment of SARS-CoV-2 virus and COVID-19 disease was more effective than monotherapy with the single components of PPC or than monotherapy the single anti-SARS-CoV-2 drugs.

[0129] The use of PPCs or separate saline solutions of APR and anti-SARS-CoV-2 drugs according to the present invention further greatly simplifies the process of preventing and treating patients compared to separate combination therapy of an oral drug + parenteral drug and allows the treatment of patients who cannot take oral drugs.

[0130] The use of the new method of combined prevention and treatment of patients according to the present invention is more effective for the treatment of SARS-CoV-2 vims and COVID-19 disease since it uses fairly safe drugs with different mechanisms of action and excludes drug-drug interaction.

[0131] The following examples further describe and demonstrate embodiments within the scope of the present invention. The examples are given solely for the purpose of illustration and are not to be construed as limitations of the present invention, as many variations thereof are possible without departing from the spirit and scope of the invention.

[0132] Example 1. Preparation of the anti-SARS-CoV-2/COVID-19 pharmaceutical composition (PPC-1 -PPC7) comprising APR and RDV.

[0133] Preparation of PPC-1. RDV from Zenji Pharmaceuticals (Suzhou) Ltd, China (22.0 mg), and APR from Wanhua Biochem, China (185. 19 mg, 1,000,000 KIU) with an activity of 5400 KlU/mg were dissolved in 40 ml of a 20% aqueous solution of 2-hydroxy-beta- cyclodextrin under ultrasonic stirring for 5 minutes. To the resulting solution, ~ 60 ml of saline was added to a total volume of 100 ml. The resulting mixture was stirred with ultrasound for 5 minutes to yield 100 ml PPC-1 containing RDV (0.224 mg/ml) and APR (10,000 KlU/ml).

[0134] Preparation of PPC-2. 19 ml saline was added to 1 ml PPC-1 under ultrasonic stirring to yield 20 ml PPC-2 containing RDV (11.2 ptg/ml) and APR (500 KlU/ml).

[0135] Preparation of PPC-3, Saline (40 ml) was slowly added along the inner wall of a bottle containing a lyophilisate of RDV from Zenji Pharmaceuticals (Suzhou) Ltd, China (100 mg). The vial was vigorously shaken until the drug was completely dissolved. The resulting RDV solution was added with stirring to a mixture of Trasylol®, Gordox®, Aprotex®, or Traskolan (50 ml) containing 500,000 KIU APR and 10 ml of saline to yield 100 ml of PPC-3 containing RDV (1.0 mg/ml) and APR (5000 KlU/ml).

SUBSTITUTE SHEET ( RULE 26) [0136] Preparation of PPC-4, RDV from Zenji Pharmaceuticals (Suzhou) Ltd, China (50.0 mg) and APR from Wanhua Biochem, China (92.6 mg, 500,000 KIU), with an activity of 5400 KlU/mg were dissolved in a 20% aqueous solution of 2-hydroxy-beta-cyclodextrin (50 ml) under ultrasonic stirring for 5 minutes to yield 50 ml of PPC-4 containing RDV (1.0 mg/ml) and APR (10,000 KlU/ml).

[0137] Preparation of PPC-5, 40 mg RDV and SBECD 2.4 g sulfobutylether-p- cyclodextrin (SBECD) were added, with vigorous stirring, to Gordox (20 ml) containing 10000 KlU/ml of APR. Received 20 ml of PPC-5, including 2.0 mg/ml RDV and 10000 KlU/ml APR.

[0138] Preparation of PPC-6, RDV (50 mg) and 3 g SBECD were added with vigorous stirring to Gordox (10 ml) containing 100000 KlU/ml of APR. Received 10 ml of PPC-6, including 5.0 mg/ml RDV and 10000 KlU/ml APR.

[0139] Preparation of PPC-7. The resulting PPC-4 was lyophilized to give PPC-7 containing 50 mg RDV and 500,000 KIU APR.

[0140] Example 2, Stability ofPPS-2,

[0141] The stability of PPC-2 and its APR and RDV components was studied by UV spectroscopy on an Agilent 8453 spectrophotometer after storage under normal conditions and under stress tests. The UV spectra of APC-2 containing 11.2 pg/ml RDV and 500 KlU/ml APR as well as the UV spectra of RDV (11.2 pg/ml) in a 0.9% aqueous sodium chloride solution, were obtained under identical conditions (Table 2).

[0142] UV spectroscopic data indicate the stability of APR solutions since the optical densities of the maxima of the initial spectrum practically coincide with those under stress test conditions.

[0143] In contrast to APR, the optical densities of the maxima of the initial spectra (Conditions 1) of RDV and APC-2 differ greatly from those in the stress test. The percentage of change in optical density under Conditions 4 — 9 compared to optical density under Conditions 1 is A> 2% (Table 2).

[0144] This indicates that RDV and PPC-2 are limitedly stable under rapid test conditions. [0145] The results obtained indicate that anti-RNA viral pharmaceutical compositions PPC-1 - PPC-6 must be used immediately after preparation.

[0146] Table 2. Optical density at the maxima of absorption bands in the UV spectra of PPC-2 and its RDV component immediately after solution preparation (1) and after exposure for 24 hours in the light at 25°C (2), after exposure for 24 hours in the light at 60°C (3), after

SUBSTITUTE SHEET ( RULE 26) exposure for 96 hours in the dark at 25°C (4), after exposure for 96 hours in the light at 25°C (5), after exposure for 96 hours in the dark at 3-5°C (6), after exposure for 96 hours in the dark at 30°C (7), after exposure for 96 hours in the dark at 40°C (8), and after exposure for 96 hours in the dark at 60°C (9). A,% is the percentage of change in optical density under Conditions 2 — 9 compared to optical density under Conditions 1.

SUBSTITUTE SHEET ( RULE 26) [0147] Example 3. Preparation of the anti-SARS-CoV-2/COVID-19 pharmaceutical composition (PPC-8 - PPC-17 ) comprising APR and MOV.

[0148] Preparation of PPC-8, MOV from Jiangsu Zenji Pharmaceuticals Ltd., China (800.0 mg), and APR from Wanhua Biochem, China (92.4 mg, ~ 500,000 KIU), with an activity of 5400 KIU mg were dissolved in saline (50 ml) under ultrasonic stirring for 5 minutes to yield PPC-8 containing MOV (16 mg/ml) and APR (10000 KlU/ml).

[0149] Preparation of PPC-9. Saline (9 ml) was added under ultrasonic stirring to PPC-8 (1 ml) to yield 10 ml of PPC-9 containing MOV (1.6 mg/ml) and APR (1000 KlU/ml).

[0150] Preparation of PPC-10. Saline (999 ml) was added under ultrasonic stirring to PPC- 8 (1 ml) to yield 1000 ml of composition PPC-10 containing MOV (16.0 pg/ml) and APR (10 KlU/ml).

[0151] Preparation of PCT-11, Dissolve 800.0 mg MOV from Jiangsu Zenji Pharmaceuticals Ltd. (China) and 92.4 mg (~ 500,000 KIU) APR from Wanhua Biochem (China) with an activity of 5400 KlU/mg in 50 ml of saline under ultrasonic stirring for 5 minutes to yield pharmaceutical PCT-11 containing 16 mg/ml MOV and 10000 KlU/ml APR. [0152] Preparation of PPC-12, MOV from Jiangsu Zenji Pharmaceuticals Ltd, China (30.0 mg) and APR from Wanhua Biochem, China (37.0 mg, 200,000 KIU), with an activity of 5400 KlU/mg were dissolved in saline (20 ml) under ultrasonic stirring for 5 minutes to yield PPC-

12 containing MOV (1.0 mg/ml) and APR (10,000 KlU/ml).

[0153] Preparation of PPT-13, 50.0 mg of MOV from Jiangsu Zenji Pharmaceuticals Ltd, China, were dissolved in 10 ml Gordox® under ultrasonic stirring for 5 minutes to yield PPT-

13 containing 5.0 mg/ml of MOV and 10000 KlU/ml of APR.

[0154] Preparation of PPC-14 and PPC-15. 100.0 mg of MOV from Jiangsu Zenji Pharmaceuticals Ltd, China, were dissolved in 10 ml Gordox® under ultrasonic stirring for 5 minutes to yield PPC-14 containing 10.0 mg/ml of MOV and 10000 KlU/ml of APR. PPC-14 obtained as an aqueous solution was frozen and lyophilized. Received PPC-15 in the form of a lyophilizate containing 50 mg of MOV and 100,000 KIU of APR.

[0155] Preparation of PPC- 16, 400.0 mg of MOV from Jiangsu Zenji Pharmaceuticals Ltd, China, were dissolved in 20 ml Gordox® under ultrasonic stirring for 5 minutes to yield PPC-

16 containing 20.0 mg/ml of MOV and 10000 KlU/ml of APR.

[0156] PPT-13 obtained as an aqueous solution was frozen and lyophilized. Received PPC-

17 in the form of a lyophilizate containing 50 mg of MOV and 100,000 KIU of APR.

SUBSTITUTE SHEET ( RULE 26) [0157] Example 4. Stability of PPC-10. The stability of PPC-10 was studied by UV spectroscopy on an Agilent 8453 spectrophotometer after storage under normal conditions and under stress tests (Table. 3).

[0158] The optical densities of the maxima of the initial spectra (condition 1 ) PPC- 10 differ greatly from those in the stress test. The percentage of change in optical density (A) under conditions 3-5 compared to optical density under Conditions 1 is > 2% (Table 3). This indicates that PPC-10 and other PPC from Example 2 are limitedly stable under rapid test conditions and must be used within a few hours after preparation.

[0159] Table 3. Optical density at the maxima of absorption bands in the UV spectra of PC-10 immediately after solution preparation (Condition 1) and after exposure for 24 hours in the light at 25°C (2), after exposure for 48 hours in the dark at 3-5°C (3). after exposure for 48 hours in the dark at 25°C (4), and after exposure for 48 hours in the dark at 60°C (5). A, % is the percentage of change in optical density under conditions 2-5 compared to optical density under Conditions 1.

[0160] Example 5. Preparation of the anti-SARS-CoV-2/COVID-19 pharmaceutical composition (PPC-18 - PPC-21 ) comprising APR and NMV.

[0161] Preparation of PPC-18. NMV from Shanghai XingMo Biotechnology Co., Ltd., China (20.0 mg), and APR from Wanhua Biochem, China (37.0 mg, 200,000 KIU), with an activity of 5400 KIU mg were dissolved in saline (20 ml) under ultrasonic stirring for 5 minutes to yield 20 ml PPC-18 containing NMV (1.0 mg/ml) and APR (10,000) KJU/ml.

[0162] Preparation of PPC-19 and PPC-20, 200.0 mg of NMV from Shanghai XingMo Biotechnology Co., Ltd., China, were dissolved in 10 ml Gordox under ultrasonic stirring for

SUBSTITUTE SHEET ( RULE 26) 5 minutes to yield 10 ml PPC-19 containing 20.0 mg/ml of NMV and 10,000 KlU/ml of APR. The resulting PPC-19 was lyophilized to give PPC-20 containing 200 mg NMV and 100,000 KI U APR

[0163] Preparation of PPC-21. 100.0 mg of NMV from Shanghai XingMo Biotechnology Co., Ltd., China, were dissolved in 10 ml Gordox + 90 ml saline under ultrasonic stirring for 5 minutes to yield 100 ml PPC-21 containing 1.0 mg/ml of NMV and 1,000 KlU/ml of APR.

[0164] Example 6. Stability of PPC-18 and PPC-19. The stability of PPC-18 and PPC-19 was studied by UV spectroscopy on an Agilent 8453 spectrophotometer after storage under normal conditions (1) and under stress tests (after exposure for 24 hours in the light at 25°C (conditions 2); after exposure for 48 hours in the dark at 3-5°C (conditions 3); after exposure for 48 hours in the dark at 25°C (conditions 4); and after exposure for 48 hours in the dark at 60°C (conditions 5). The optical densities of the maxima of the initial spectra (condition 1) PPC-18 differ greatly from those in the stress test. The percentage of change in optical density under conditions 3-5 compared to optical density under Conditions 1 is > 2%. This indicates that PPC-18 and PPC-19 are limitedly stable under rapid test conditions and must be used within a few hours after preparation.

[0165] Example 7. A device for inhalation therapy and prevention of SARS-CoV-2 I COVID-19. 5 - 10 ml of PPC-4 containing RDV (1.0 mg/ml) and APR (10,000 KlU/ml) according to Example 1 or PPC-9 containing MOV (1.6 mg/ml) and APR (1000 KlU/ml) according to Example 3 or PPC-21 containing NMV (1 mg/ml) and APR (1,000 KlU/ml) according to Example 5 is placed into a compression nebulizer Omron NE-C300 Complete or in a portable ultrasonic Feellife Aerogo mesh nebulizer and is receive the device for inhalation therapy and prevention of SARS-CoV-2 1 COVID-19.

[0166] Example 8. Devices for nasal spray therapy and prevention of SARS-CoV-2 I COVID-19. 5 - 10 ml of PPC-4 containing RDV (1.0 mg/ml) and APR (10,000 KlU/ml) according to Example 1 or PPC-9 containing MOV (1.6 mg/ml) and APR (1000 KlU/ml) according to Example 3 or PPC-21 containing NMV (1 mg/ml) and APR (1000 KlU/ml) according to Example 5 is placed into a plastic can for nasal administration and comprises a device for nasal therapy and prevention of SARS-CoV-2 / COVID-19.

[0167] Example 9. The compositions of the kit of drugs for a 5-day course of treatment of SARS-CoV-2 / COVID-19.

SUBSTITUTE SHEET ( RULE 26) [0168] When assembling the kit for the treatment of SARS-CoV-2 / COVID-19, the Recommended dosage of drugs of APR and RDV, MPV, and NMV presented above were taken into account. Based on this, the kit for a 5-day course of treatment included:

[0169] Component 1 - ten vials containing Gordox® or Trasylol®, each containing 50 ml of a solution, which include 500,000 KIU of APR each, for intravenous administration or ten vials containing 500,000 KIU lyophilisate of APR each, which are each dissolved in 50 ml of saline before use.

[0170] Component 2 - 5 vials containing a solution of RDV for injection and solution for infusion (Veklury, supplied as 100 mg/20 mL [5 mg/mL]) for intravenous use or 50 mL vials containing lyophilized powder of RDV (100 KIU) in a single-dose vial, which is dissolved in 20 mL of saline before use or a bottle containing 40 capsules Lagevrio™, which include 200 mg each of MPV for oral use or a bottle containing 20 tablets of the drug, which include 150 mg each of NMV for oral use.

[0171] Instructions for the simultaneous administration of the components of this pharmaceutical kit, which are each dissolved in 50 ml of saline before use.

[0172] Example 10. Combined treatment of transgenic mice infected with mouse-adapted SARS-CoV-2 with PPC-6 (APR+RDV). PPC-9 (APR+MOV) and PPC-19 (APR+ NMV). and FVP + Gordox®.

[0173] In the experiment, 11 groups of transgenic mice (B6.Cg-Tg(K18- ACE2)2Prlmn/HEMI Hemizygous for Tg(K18-CE2)2Prlmn from Jackson Immunoresearch, West Grove, PA, USA), females, age - 6-8 weeks, weighing 19-24 g, were formed, four animals per group.

[0174] Group 1 - untreated mice: on day 1, in the morning, the mice were infected with SARS-CoV-2, and then 5 ml/kg of water for injection was intragastrically administered immediately after infection and in the evening of the same day.

[0175] Group 2 treatment with FVP Dose: 250 mg/kg.

[0176] Group 3 treatment with FVP + Gordox® - 10000 KlU/ml of APR. Dose: 250 mg/kg + 50 000 KlU/kg.

[0177] Group 4 - treatment with Gordox® - 10 000 KlU/ml of APR. Dose: 250 KlU/kg APR.

[0178] Group 5 - treatment with saline solution of RDV - 5 mg/ml (5 Mr RDV + 300 Mr SBECD in 1 ml saline). Dose: 25.0 mg/kg of RDV.

SUBSTITUTE SHEET ( RULE 26) [0179] Group 6 - combined treatment with the PPC-6. Dose: 50 000 KlU/kg of APR + 25 mg/kg of RDV.

[0180] Group 7 - treatment with saline solution of MOV - 5 mg/ml. Dose: 25.0 mg/kg of MOV.

[0181] Group 8 - combined treatment with the PPC-9. Dose: 50 000 KlU/kg of APR + 25 mg/kg of MOV.

[0182] Group 9 - combined treatment with the PPC-9. Dose: 50 000 KlU/kg of APR + 50 mg/kg of MOV.

[0183] Group 10 - treatment with saline solution of NMV - 20 mg/ml. Dose: 100.0 mg/kg of RDV.

[0184] Group 11 - combined treatment with the PPC-19. Dose: 50 000 KlU/kg of APR + 100 mg/kg of NMV.

[0185] Treatment regimen for transgenic mice: parenteral (intraperitoneal) administration of drugs two times a day; day 0 - 1 hour before infected with mouse-adapted SARS-CoV-2 (“Dubrovka” strain, identification number GenBank: MW161041.1) and 6-8 hours after infection; days 1, 2, 3 - 2 times a day, for a total of 4 days (days 0, 1, 2, 3); Day 4 - lung sampling from all animals to assess the virus titer in the lungs, visual assessment of the lungs and transfer of the lungs for histology; days 0 - 4 - daily assessment of body weight and condition of mice.

[0186] On day 0, animals from all groups were infected with the SARS-CoV-2 “Dubrovka” virus (10 ^{3 5} TCIDso/ml). All mice were infected intranasally under light ether anesthesia in a volume of 30 pl for both nostrils.

[0187] Euthanasia (painless killing of the animal) was carried out by the responsible person in accordance with the existing ethical requirements by dislocation of the cervical vertebrae with preliminary anesthesia with ether. Euthanasia was performed promptly after the end of the experiments.

[0188] On day four post-infection with the virus, the animals in each group were sacrificed, and the lungs were removed under sterile conditions. One lung was fixed in formalin for further histology; the second lung was prepared to measure the virus titer. To do this, after washing three times in a solution of 0.01 M phosphate-buffered saline (PBS), the lungs were homogenized and resuspended in 1 ml of cold, sterile PBS. The suspension was cleared from cell debris by centrifugation at 2000 g for 10 min, and the supernatant was used to determine

SUBSTITUTE SHEET ( RULE 26) the infectious titer of the virus in cell culture and to perform PCR. The obtained samples were stored at -80°C until the experiments were carried out.

[0189] To determine the infectious titer of the virus from the lungs of mice, Vero CCL81 cells were seeded in 96-well Costar plates with an average density of 20,000 cells per well and grown in DMEM medium in the presence of 5% fetal calf serum, 10 mM glutamine and antibiotics (penicillin 100 lU/well). ml and streptomycin 100 pg/ml) until a complete monolayer is formed (within three days). Before infection with the virus, the cell culture was washed twice with DMEM medium without serum. 10-fold dilutions of each lung virus sample were prepared from 10-1 to 10-7. The prepared dilutions in a volume of 200 pL were added to cell culture plates and incubated in 5% CO2 at 37°C for five days until a cytopathic effect (CPE) appeared in virus control cells. Accounting for the result of the manifestation of CPP in cells was carried out using a quantitative MTT test. The virus titer was calculated using the Ramakrishnan M. A formula in the Excel program [M. A. Ramaknshnan. Determination of 50% endpoint titer using a simple formula. World J. Virol. 2016, 5, 85-86. doi: 10.5501/wjv.v5.i2.85] and expressed as IgTCIDso/ml (TCIDso - The median tissue culture infectious dose is defined as the dilution of a virus required to infect 50% of a given cell culture.) [I. Leneva et al. Antiviral Activity of Umifenovir In Vitro against a Broad Spectrum of Coronaviruses, Including the Novel SARS-CoV-2 Virus. Viruses 2021, 13(8): 1665. doi: 10.3390/vl3081665] . Next, the average titer value for samples from mice of the same group was calculated.

[0190] The efficacy of combined treatment of transgenic mice infected with mouse- adapted SARS-CoV-2 was assessed by the reduction in virus titer in the lungs of the animals after four days.

[0191] The obtained digital data were subjected to statistical processing in the “Statistica 8.0” software. The results are shown in Table 4.

[0192] Table 4. Efficiency of combined treatment of transgenic mice infected with SARS- CoV-2 with the combination of APR+RDV, APR+MOV, APR+NMV, and APR+FVP in comparison with control.

SUBSTITUTE SHEET ( RULE 26)

[0193] Thus, in the combined treatment of animals with combinations of APR + FVP (group No. 3), APR + RDV (group No. 6), APR + MOV (group No. 9), and APR + NMV (group No. 11), compared with the control (group No. 1), a decrease in virus titer (A logTCID50/ml) was observed at 1.34, 1.74, 4.61, and 3.2 orders of magnitude, respectively.

[0194] The above data convincingly demonstrate the high efficiency of the SARS-CoV- 2/COVID-19 combination treatment claimed in this invention and a high efficiency (positive effect) compared with the control.

SUBSTITUTE SHEET ( RULE 26) [0195] Example 11. Combined treatment of Syrian hamsters infected with SARS-CoV-2 with PPC-4 (APR+RDV) and PPC-16 (APR+MOV).

[0196] The efficacy of PPC-4 (APR+RDV) and PPC-16 (APR+MOV) of the present invention was evaluated using a model of SARS-CoV-2 infection in Syrian hamsters [R. Boudewijns et al. STAT2 signaling as double-edged sword restricting viral dissemination but driving severe pneumonia in SARS-CoV-2 infected hamsters. BioRxiv preprint, doi: https://doi.org/10.1101/2020.04.23.056838; this version posted April 24, 2020. https://www.biorxiv.org/content/10.1101/2020.04.23.056838vl] ,

[0197] The strain SARS-CoV-2 hCoV-19/Australia/VIC01/2020 was obtained from the State Research Center of Virology and Biotechnology VECTOR (Russia). The infectious virus was isolated by sequential passage in Vero E6 cells. The titer of the viral suspension was determined by endpoint dilution on Vero E6 cells using the Reed-Muench method. The work related to the live virus was carried out under isolated laboratory conditions that meet the international BSL-3 + VECTOR requirements.

[0198] Vero E6 cells from VECTOR’S Collection of Cell Cultures were cultured in Minimum Essential Medium (MEM) (Gibco) supplemented with 10% fetal bovine serum (Integro), 1% L-glutamine (Gibco), and 1% Bicarbonate (Gibco). Endpoint titrations were performed with a medium containing 2% fetal bovine serum.

[0199] Wild-type Syrian hamsters at the age of 6-10 months weighing 100-120 g from the State Scientific Center for Virology and Biotechnology "Vector" of Rospotrebnadzor (Russia) were kept with unlimited access to food and water. Hamsters were randomized into six cohorts, with eight animals in each cohort (four males and four females).

[0200] Hamsters were anesthetized with zoletil-xyla and inoculated into each nostril with 50 pl anesthetic combination containing I O’TCIDso.

[0201] Group 1 - control group, untreated hamsters. Dose: 5 ml/kg saline.

[0202] Group 2 - treatment with Gordox® - 10 000 KlU/ml of APR. Dose: 10000 KlU/kg

APR.

[0203] Group 3 - treatment with saline solution of RDV - 1 mg/ml. Dose: 5 mg/kg of RDV.

[0204] Group 4 - combined treatment with the PPC-4 (RDV - 1 mg/ml + 10000 KlU/ml of APR). Dose: 50 000 KlU/kg of APR + 5 mg/kg of RDV.

[0205] Group 5 - treatment with saline solution of MOV - 20 mg/ml. Dose: 100 mg/kg of MOV.

SUBSTITUTE SHEET ( RULE 26) [0206] Group 6 - combined treatment with the PPC-16 (MOV - 20 mg/ml + 10000 KlU/ml of APR). Dose: 50 000 KlU/kg of APR + 100 mg/kg of MOV.

[0207] The drugs were injected under light isoflurane anesthesia intravenously, two times a day for four days, starting the first injection one hour before infection, 6 hours after infection, then for three days after 12 hours.

[0208] Hamsters were checked daily for appearance, behavior, and weight. On the 4th day after infection, the hamsters were euthanized by intravenous injection of 500 pl doletai (200 mg/ml sodium pentobarbital, Vetoquinol SA). Hamster lung tissues were harvested after sacrifice and homogenized using a Precellys homogenizer in a 350 pl RNeasy lysis buffer (RNeasy Mini kit, Qiagen) and centrifuged (10,000 rpm, 5 mm) to remove cell debris. RNA was extracted according to the manufacturer's instructions. Real-time PCR was performed on the LightCycler96 platform (Roche) using the iTaq Universal Probes One-Step RT-qPCR kit (BioRad) [R. Boudewijns et al. STAT2 signaling as double-edged sword restricting viral dissemination but driving severe pneumonia in SARS-CoV-2 infected hamsters. BioRxiv preprint, doi: htps://doi.org/10.1101/2020.04.23.056838; this version posted April 24, 2020. htps://www.biorxiv.org/content/10.1101/2020.04.23.056838vl].

[0209] For histological analysis, lung tissue was fixed in 4% formaldehyde, embedded in paraffin, and stained with hematoxylin-eosin. Damage was assessed on a scale from 1 to 3: stagnation, interalveolar bleeding, apoptotic bodies in the bronchial epithelium, necrotic bronchiolitis, perivascular edema, bronchopneumonia, perivascular inflammation, peribronchial inflammation, and vascular inflammation.

[0210] Statistical analysis was performed using the GraphPed Prism software from

GraphPed Software, Inc. Statistical significance was determined using the Mann-Whitney nonparametric U-test. The values of P < 0.05 were considered significant.

[0211] The analysis of the obtained results showed that the combined treatment of SARS- CoV-2 infection in Syrian hamsters with the combinations of RDV + APR and MOV + APR demonstrated high efficiency against SARS-CoV-2. Compared with the control group, after intravenous administration of PPC-4 and PPC-16 to SARS-CoV-2 infected Syrian hamsters, the SARS-CoV-2 titer in the lung tissues of animals decreased by more than an order of magnitude compared to the control group.

[0212] Example 12. Preparation of the APCs comprising APR and FVP (PPC-22. 1 - PPC- 22.12 ).

SUBSTITUTE SHEET ( RULE 26) [0213] PPC-22.1. FVP (175 g) from Zenji Pharmaceuticals (Suzhou) Ltd, China, and APR

(92.6 mg, -500,000 KIU) with an activity of 5400 KJU/mg from Wanhua Biochem, China, were dissolved with stirring in saline (50 ml) to yield PPC-22.1 containing 3.5 mg/ml FVP and 10,000 KlU/ml APR.

[0214] PPC-22.2. 1 ml APC 1.1 was added with stirring to 159 ml of saline to yield PPC-

22.2 containing 21.9 pg/ml FVP and 62.5 KlU/ml APR.

[0215] PPC-22.3. 1 ml PPC 1. 1 was added with stirring to 399 ml of saline to yield PPC-

22.3 containing 8.75 pg/ml FVP and 25 KlU/ml APR.

[0216] PPC-22.4. 925.9 mg APR (powder) from Wanhua Biochem, China, with an activity of 5400 KlU/mg (total 5,000,000 KIU of APR), 3000 mg lysine, and 6000 mg FVP (powder) were dissolved with stirring in 500 ml of saline. A 10M aqueous NaOH solution was added to pH 7.08 7.6 to yield 500 ml of PPC-22.4 containing 10,000 KlU/ml APR and 12 mg/ml FVP for intravenous, nasal (spray), and inhalation treatment and prevention of RNA viral infections.

[0217] PPC-22.5. 40 ml saline was slowly added along the inner wall of a bottle containing

600 mg FVP lyophilisate and 300 mg L-lysine monohydrate. The bottle was shaken vigorously until the drug was completely dissolved. The resulting FVP solution was added with stirring to a mixture of 50 ml Trasylol®, Gordox®, Aprotex®, or Traskolan® containing 500,000 KIU of APR and 110 ml saline to yield 200 ml of PPC-22.5 containing FVP (3.0 mg/ml) and APR (2500 KlU/ml).

[0218] PPC-22.6. A mixture of a lyophilisate containing 350 mg FVP, 46.3 mg (250,000

KIU) APR, and 180 mg L-lysine monohydrate was dissolved with vigorous stirring in 250 ml of saline to yield 250 ml of PPC-22.6 containing FVP (1.4 mg/ml) and APR (1000 KlU/ml).

[0219] PPC-22.7. A mixture of 148.1 mg APR powder from Wanhua Biochem, China, with an activity of 5400 KlU/mg (total 800000 KIU of APR), 300 mg L-lysine, and 600 mg FVP (powder) was dissolved by stirring in 100 ml of saline. A 10M aqueous NaOH solution was added to pH 7.08 7.6 to yield ~100 ml of PPC-22.7 containing APR (8000 KlU/ml) and FVP (6 mg/ml).

[0220] PPC-22.8. 650 mg lyophilisate of FVP, 88 mg (475,000 KIE) APR, and 360 mg L- lysine monohydrate was dissolved with vigorous stirring in 250 ml of saline to yield 500 ml of PPC-22.8 containing FVP (1.3 mg/ml) and APR (950 KlU/ml).

SUBSTITUTE SHEET ( RULE 26) [0221] PPC-22.9. 50 mg lyophilisate of FVP, 92.6 mg (500,000 KIU) APR, and of 36 mg

L-lysine monohydrate was dissolved with vigorous stirring in 50 ml of saline to yield 50 ml of PPC-22.9 containing FVP (1.0 mg/ml) and APR (10000 KlU/ml).

[0222] PPC-22.10. 400 mg FVP and 192 mg L-lysine monohydrate were added with vigorous stirring to a mixture of 20 ml Gordox containing 10000 KlU/ml of APR. A 10M aqueous NaOH solution (260 pl) was added to pH 7.08 7.6 with vigorous stirring until complete dissolution of FVP to yield 20 ml of PPC-22.10 containing FVP (20.0 mg/ml) and APR (10000 KlU/ml).

[0223] PPC-22.11. 20 mg FVP and 10 mg L-lysine monohydrate was added with vigorous stirring to a mixture of 20 ml Gordox containing 10000 KlU/ml of APR. A 10M aqueous NaOH solution was added to pH 7.08 7.6 with vigorous stirring until complete dissolution of FVP to yield 20 ml of PPC-22.11 containing FVP (1.0 mg/ml) and APR (10000 KlU/ml).

[0224] PPC-22.12. 1000 mg FVP and 500 mg L-lysine monohydrate were added with vigorous stirring to a mixture of 20 ml Gordox containing 10000 KlU/ml of APR. A 10M aqueous NaOH solution was added to pH 7.08 7 6 with vigorous stirring until complete dissolution of FVP to yield 20 ml of PPC-22.12 containing FVP (50 mg/ml) and APR (10000 KlU/ml).

[0225] Example 13. The stability of PPC-1.3 from Example 1.

[0226] The stability of PPC-1.3 from Example 12 was studied by UV spectroscopy on an Agilent 8453 spectrophotometer after storage under normal conditions and under stress tests. The optical densities of UV absorption band maxima of PPC-1.3 after stress test conditions strongly differ from the original spectrum of PPC-1.3. (Table 2).

[0227] The percentage of change in optical density' (A) under conditions 2-5 compared to optical density' under Conditions 1 is 9-90% (Table 5 ). This indicates that PPC-1.3 and other PPCs from Example 1 are limitedly stable under rapid test conditions and be used within a few hours after preparation.

[0228] Table 5. Optical density at the maxima of absorption bands in the UV spectra of PPC-1.3 immediately after preparation of their solutions and after their exposure for 48 hours: in the light at 25°C (2), in the dark at 30°C and 65% humidity' (3), in the dark at 40°C and 75% humidity (4), and in the dark at 60°C and 60% humidity (5). A,% is the percentage of change in optical density under Conditions 2 — 5 compared to optical density under Conditions 1.

SUBSTITUTE SHEET ( RULE 26)

[0229] Example 14. Preparation of the PPC comprising aprotinin and AV5080 (PPC 3.1-

3.4).

[0230] PPC-3.1. 50 mg AV5080 and 90.19 mg (487,000 KIU)APR from Wanhua

Biochem, China, with an activity of 5400 KlU/mg, were dissolved in a mixture of 35 ml of a 20% solution of 2-hydroxy-beta-cyclodextrin and 15 ml saline under ultrasonic stirring for 25 minutes to yield 50 ml of PPC-3. 1 containing 1.0 mg/ml AV5080 and 9740 KlU/ml APR.

[0231] PPC-3.1. 50 mg AV5080 and 90.19 mg (487,000 KIU) APR from Wanhua

Biochem, China, with an activity of 5400 KlU/mg were dissolved in a mixture of 350 ml 20% solution of 2-hydroxy-beta-cyclodextrin and a 150 ml saline under ultrasonic stirring for 25 minutes to yield 500 ml of PPC-3.2 containing AV5080 (0. 1 mg/ml) and APR (9974 KlU/ml). [0232] PPC-3.3. 99 ml Saline was added under ultrasonic stirring to 1 ml APC 3. 1 to yield

100 ml of PPC-3.3 containing AV5080 (10 pg/ml) and APR (97.4 KlU/ml).

[0233] PPC-3.4. 2.5 mg AV5080 and 92.6 mg (500,000 KIU) APR from Wanhua

Biochem China with an activity of 5400 KlU/mg were dissolved in 50 ml saline under ultrasonic stirring for 15 minutes to yield 50 ml of PPC-3.4 containing AV5080 (0.05 mg/ml) and APR (10,000 KlU/ml).

[0234] Example 15. Preparation of APC 4. 1 containing APR and PRV.

[0235] PPC-4.1. 7.2 mg PRV from Ambeed, USA, and 2.22 mg (12,000 KIU) APR from Wanhua Biochem, China, with an activity of 5400 KlU/mg were dissolved in 200 ml saline to yield 200 ml of PPC-4. 1 containing PRV (0.36 mg/ml) and APR (11.05 pg/ml, 60 KlU/ml).

[0236] The assessment of optical density changes in the UV spectra of PPC-4.1 (Table 6 ) when stored for 48 hours under selected conditions indicates moderate stability of PPC-4. 1. The percentage of change in optical density (A) under conditions 4 and 5 compared to optical

SUBSTITUTE SHEET ( RULE 26) density under Conditions 1 is >2%. This indicates that PPC 4. 1 is limitedly stable under rapid test conditions and PPC-4. 1 must be used within a few hours after preparation.

[0237] Table 6. Optical density at the maxima of absorption bands in the UV spectra of PPC-4.1 component immediately after solution preparation composition 1 and after exposure for 48 hours in the light at 25°C (2), in the dark at 25°C (3), in the dark at 3-5°C (4), and in the dark at 60°C (5). A,% is the percentage of change in optical density under Conditions 2 — 5 compared to optical density under Conditions 1.

[0238] Example 16. Preparation of PPC-5. 1 comprising APR and ZA.

[0239] PPC-5.1. 7.0 mg of ZA from Ambeed (USA) and 7,41 mg (40000 KIU) of APR from Wanhua Biochem (China) with an activity of 5400 KlU/mg were dissolved in 50 ml of saline to yield 50 ml PPC-5. 1 containing 0.14 mg/ml ZA and 800 KlU/ml APR.

[0240] The results of evaluating the change in optical density in the UV spectra of PPC- 5.1 (Table 7 ), when stored for 48 hours under the selected conditions, indicate moderate stability of PPC-5.1. The results obtained show that anti-RNA viral PPC 5.1 must be used within a few hours after preparation.

[0241] Table 7. Optical density at the maxima of absorption bands in the UV spectra of PPC-5. 1 immediately after preparation of their solutions (composition 1) and after for 48 hours in the light at 25°C (2), in the dark at 25°C (3), in the dark at 3-5°C (4), and in the dark at 60°C (5). A, % is the percentage of change in optical density under Conditions 2-5 compared to optical density under Conditions 1.

SUBSTITUTE SHEET ( RULE 26)

[0242] Example 17. A device for inhalation therapy and prevention of RNA viral infections.

[0243] To prepare a device for inhalation therapy and prevention of RNA viral infections, 5-10 ml PPC-1.2 from Example 12 containing FVP (21.9 pg/ml) and APR (62.5 KlU/ml) is placed into a compression nebulizer Omron NE-C300 Complete or in a portable ultrasonic mesh nebulizer, for example, Feellife Aerogo mesh nebulizer.

[0244] Example 18. Devices for nasal spray therapy and prevention of RNA viral infections.

[0245] To prepare a device for nasal spray therapy and prevention of RNA viral infections, 5 — 10 ml PPC-1.6 from Example 12 containing FVP (1.4 mg/ml) and APR (1000 KlU/ml) or PPC-3.2 from Example 14 containing AV5080 (0.1 mg/ml) and APR (974 KlU/ml) is placed into a plastic can for nasal.

[0246] Example 19. Prevention and treatment of mice infected with influenza A/Califomia/2009 (H1N1) pdm09 virus by inhalation with an anti-RNA viral pharmaceutical composition in a model of influenza pneumonia.

[0247] In the experiment, three groups of BALB/c female mice (from Andreevka nursery, Russia) weighing 12-14 g were formed, 13 animals per group, of which ten mice were tested for survival and three mice were tested for the titer of the virus in the lungs.

[0248] Group 1 - prophylaxis of mice according to Scheme 1 : - on day 0, the mice received 3 (morning, afternoon, and evening) inhalations of PPC-1.6 from Example 12;

- in the morning of day 1, the mice received drug inhalation, then after 1 hour, they were infected with the influenza A/Califomia/2009(H1N1) pdm09 vims, and in the afternoon and evening, they received inhalations again;

SUBSTITUTE SHEET ( RULE 26) - on days 2-10, the mice received 3 (morning, afternoon, and evening) drug inhalations a day.

[0249] Group 2 - treatment of mice according to Scheme 2: - in the morning of day 1, the mice received drug inhalation, then after 1 hour, they were infected with the influenza A/Califomia/2009(H1N1) pdm09 virus, and in the afternoon and evening they received two more inhalations;

- on days 2-10, the mice received 3 (morning, afternoon, and evening) drug inhalations a day.

[0250] Group 3 - untreated mice: in the morning of day 1, the mice were infected with the influenza virus, and then water for injection was intragastrically administered immediately after infection and in the evening of the same day.

[0251] Mice randomized into groups were infected intranasally with the influenza A/Califomia/2009 (H1N1) pdm09 virus sourced from WHO and adapted for mice under light anesthesia at a dose of 5 MLDso/ml (25 pl in each nostril, 10 ^{4 5} TCIDso/O.l ml).

[0252] For treatment, PPC-1.6 containing FVP (1.4 mg/ml) and APR (1000 KlU/ml).

[0253] PPC-1.6 was administered by inhalation using a nebulizer. For this purpose, a group of 5 animals was placed in a chamber and given inhalation of 2 ml of the test drug for 10 minutes.

[0254] The treated and control animals were monitored daily for 16 full days (from the moment the animals were infected with the influenza virus). Mortality was recorded daily in both groups.

[0255] Euthanasia (painless killing of the animal) was carried out by the responsible person in accordance with the existing ethical requirements by dislocation of the cervical vertebrae with preliminary anesthesia with ether. Euthanasia was performed promptly after the end of the experiments.

[0256] The activity of the compounds in the mouse model of influenza pneumonia was assessed according to the following criteria: animal survival, increase in average life expectancy, dynamics of weight loss, and a decrease in the lung virus titers after 24 and 96 hours.

[0257] The mortality rate was determined as the ratio of dead to infected in the group.

[0258] The average life span of animals was calculated from the total number of observation days (after infection) according to the formula: MSD = f * (d-1) / n, where f is the number of mice that died on day d; surviving mice, for which day d is the last day of

SUBSTITUTE SHEET ( RULE 26) observation, are also taken into account; and n is the number of mice in the group. For example, there were ten mice in a group, of which one mouse died on the 8th day, three mice died on the 10th day, one mouse died on the 12th day, and five mice survived. The experiment lasted 14 days. In this case, the average life expectancy of animals calculated according to the above formula will be: MSD = f * (d-1) / n = [1 *(8-1) + 3*(10-l) + 1*(12-1) + 5*(14-1)] / 10 = 11 days.

[0259] A statistically significant increase in the survival rate of animals (p<0.05), an increase in their lifespan, and a statistically significant decrease in the viral titer in the lungs of infected animals (on average, >1.751ogTCID5o) after the introduction of drugs were compared with a control group of infected untreated animals.

[0260] The digital data obtained were statistically processed using the Statistica 8.0 software. Comparison of survival in the groups of mice was performed by means of one-way analysis of variance (ANOVA) using the Statistica 8.0 software.

[0261] The results obtained are presented in Table 8, from which it can be seen that the prevention of group 1 and the treatment of group 2 with PPC-1.6 from Example 8 provide high efficacy in infected mice:

- survival rate (70-80%),

- life expectancy (12.6 - 13.4 days),

- life elongation compared to the control group 1 (46.5 - 55.8%), and

- the maximum decrease in the virus titer in the lungs for four days after infection (IgTCIDso/O. lml = (2.08±0.14) - (3,1±2,84) compared to control group 3.

[0262] Inhalation prophylaxis and treatment of mice by anti-RNA viral APC1.6 from Example 1 effectively protected animals from death, increasing their average lifespan and reliably inhibiting virus multiplication in the lungs, as compared to the viral control group, by an average of 3 IgTCIDso/O.lml (Table 8).

[0263] Thus it was shown the inhalation prophylaxis and treatment of mice by PPC-1.6 from Example 12 effectively protected animals from death, increasing their average lifespan and reliably inhibiting virus multiplication in the lungs, as compared to the control group, by an average of 3 IgTCIDso/O.lml (Table 8).

[0264] Table 8. Efficacy of the prevention and treatment of influenza pneumonia in mice infected with the influenza A/Califomia/2009(H1N1) pdm09 virus adapted to mice with PPC- 1.6 from Example 12 containing APR and the RNA polymerase inhibitor FVP (group 1 - prevention, group 2 - treatment, group 3 - placebo).

SUBSTITUTE SHEET ( RULE 26)

[0265] Example 20. Treatment of mice infected with influenza A/Califomia/04/2009 (H1N1) virus adapted to mice by intraperitoneal injection of PPC in an influenza pneumonia model.

[0266] In the experiment, six groups of BALB/c female mice (Stezar nursery, Russia) weighing 12-14 g were formed, 13 animals per group, of which ten mice were tested for survival and three mice were tested for the titer of the virus in the lungs.

[0267] Group 1 - control group, untreated mice: in the morning of day 1, the mice were infected with the influenza virus, and then water for injection was intragastrically administered immediately after infection and in the evening of the same day.

[0268] Group 2 - treatment with a saline APR solution (10 000 KlU/ml). APR dose: 50 000 KJU/kg, (600 700) KlU/mouse, (0.06 0.07) ml/mouse of saline APR solution (10 000 KlU/ml).

[0269] Group 3 - treatment with a saline AV5080 0.05 mg/ml solution.

[0270] AV5080 dose: 0.25 mg/kg, (0.003 0.0035) mg/mouse, (0.06 0.07) ml/mouse of saline solution.

[0271] Group 4 - treatment with APC 3.4 from Example 3 containing AV5080 (0.05 mg/ml) and APR (10 000 KlU/ml). AV5080 + APR dose: 0.25 mg/kg + 50000 KJU/kg, (0.003 0.0035) mg/mouse + (600 700) KlU/mouse, (0.06 0.07) ml/mouse of pharmaceutical composition 1-9.

[0272] Group 5 - treatment with a saline FVP solution (1.0 mg/ml). FVP dose: 5.0 mg/kg, (0.06 0.07) mg/mouse, (0.06 0.07) ml/mouse of saline FVP solution.

SUBSTITUTE SHEET ( RULE 26) [0273] Group 6 - treatment with PPC-1. 12 from Example 12 containing FVP (1.0 mg/ml) and APR (10 000 KlU/ml). FVP + APR dose: 5.0 mg/kg + 50 000 KJU/kg, (0.06 = 0.07) mg/mouse + (600 = 700) KlU/mouse, (0.06 0.07) ml/mouse of PPC-1.12.

[0274] Groups 2-6 were treated according to Scheme 1 :

- in the morning of day 1, the drug was administered to mice intraperitoneally immediately after infection with the influenza A/Califomia/2009 (H1N1) virus and in the evening (~ 8-12 hours after infection);=

- days 2 — 5: treatment two times a day. Monitoring the survival of mice: 15 days. Measuring the titer of the virus in the lungs (3 mice per group): on day 6 after the last administration of the drug;

- monitoring the survival of mice: 16 days.

[0275] Mice randomized into groups were infected intranasally with influenza A/Califomia/04/2009 (H1N1) virus sourced from WHO and adapted for mice under light anesthesia at a dose of SMLDso/ml (25 pl in each nostril - 10 ^{4 5} TCIDso/O. l ml).

[0276] Euthanasia (painless killing of the animal) was carried out by the responsible person in accordance with the existing ethical requirements by dislocation of the cervical vertebrae with preliminary ether anesthesia. Euthanasia was performed promptly after the end of the experiments.

[0277] The activity of the compounds in the mouse model of influenza pneumonia was assessed according to the following criteria: animal survival, increase in average life expectancy, dynamics of weight loss, and decrease in the titer of the virus in the lungs after five days.

[0278] The mortality rate was determined as the ratio of dead to infected in the group.

[0279] The average life span of animals was calculated from the total number of observation days (after infection) according to the formula: MSD = f * (d-1) / n, where f is the number of mice that died on day d; surviving mice, for which day d is the last day of observation, are also taken into account; and n is the number of mice in the group. For example, there were ten mice in a group, of which one mouse died on the 8th day, three mice died on the 10th day, one mouse died on the 12th day, and five mice survived. The expenment lasted 14 days. In this case, the average life expectancy of animals calculated according to the above formula will be: MSD = f * (d-1) / n = [1 *(8-1) + 3*(10-l) + 1*(12-1 ) + 5*(14-1)] I 10 = 11 days.

SUBSTITUTE SHEET ( RULE 26) [0280] After administration of the drugs, a statistically significant increase in the survival rate of animals (p<0.05), an increase in their life expectancy, and a statistically significant decrease in the titer of the virus in the lungs of infected animals (on average > 1.751ogTCID5o) were observed compared with the control group of infected untreated animals.

[0281] The digital data obtained were statistically processed using the Statistica 8.0 software. Comparison of survival in the groups of mice was performed by means of one-way analysis of variance (ANOVA) using the Statistica 8.0 software. The results are shown in Tables 9 and 10.

[0282] As can be seen from Table 9, the treatment of group 4 with PPC-3.4 provides high efficacy in infected mice:

- survival rate (80%),

- life expectancy (14 days),

- life elongation compared to the control group 1 (94.2%),

- the maximum decrease in the virus titer in the lungs (IgTCIDso 10.1ml = 2.5 ± 0.87) compared to control group 1 and groups 2 and 3 treated with PPC-3.4 containing AV5080 and APR.

[0283] An even higher efficacy is observed in the treatment of group 6 with PPC-1.11 containing APR and FVP compared to control (untreated mice, group 1) and with groups 2 and 5 (APR and FVP).

[0284] As can be seen from Table 10, the treatment of group 6 with PPC-1. 11 also provides high efficacy in infected mice:

- survival rate (100%),

- life expectancy (16 days),

- life elongation compared to the control group 1 (110.5%),

- the maximum decrease in the virus titer in the lungs (IgTCIDso / 0.1ml = 2.08±0.14) compared to control group 1 and groups 2 and 5 treated with APC 1.11 containing FVP and APR.

[0285] The results obtained showed that the treatment of mice infected with influenza A/Califomia/04/2009 (H1N1) virus adapted to mice in an influenza pneumonia model by intraperitoneal injection of PPC-3.4 (Table 97) and PPC-1.11 (Table 10) provides higher efficacy than the active ingredients contained in these compositions.

[0286] Table 9. Effectiveness of PPC-3.4, its active ingredients (AV5080, APR), and the control (untreated mice) in an influenza pneumonia model upon infection of mice with the influenza A/Califomia/04/2009 (H1N1) virus adapted to mice.

SUBSTITUTE SHEET ( RULE 26)

[0287] Table 10. Effectiveness of PPC-1.11, its active ingredients (APR and FVP), and the control (untreated mice) in an influenza pneumonia model upon infection of mice with the influenza A/Califomia/04/2009 (H1N1) virus adapted to mice.

SUBSTITUTE SHEET ( RULE 26)