WO2021225468A1

WO2021225468A1 - Sars-cov-2 antiviral pharmaceutical composition and use thereof

Info

Publication number: WO2021225468A1
Application number: PCT/RU2021/000047
Authority: WO
Inventors: Андрей Александрович ИВАЩЕНКО; Николай Филиппович САВЧУК; Алена Александровна ИВАЩЕНКО; Александр Васильевич ИВАЩЕНКО; Алексей Петрович ИЛЬИН; Дмитрий Владимирович КРАВЧЕНКО; Наталья Александровна ПАПАЗОВА; Тагир Алиевич СИТДЕKОВ
Original assignee: Общество с ограниченной ответственностью "Кромис" (ООО "Кромис")
Priority date: 2020-05-07
Filing date: 2021-02-04
Publication date: 2021-11-11

Abstract

The invention relates to a novel SARS-CoV-2 antiviral pharmaceutical composition and the use thereof to produce a dosage form in the form of tablets or capsules. The composition is intended for treating RNA viral diseases and, inter alia, for the prevention and treatment of SARS-CoV-2-mediated COVID-19. The present SARS-CoV-2 antiviral pharmaceutical composition contains 40-48 wt% micronized favipiravir, comprising a D90 fraction of micronized particles having a size within the range of ≤40.6 - ≤211 μm, the remainder being excipients. The composition preferably contains 44.0-47.6 wt% micronized favipiravir, comprising the aforesaid D90 fraction. The excipients are selected from among fillers, disintegrants, binders, glidants and lubricants. The dosage form in the form of tablets or capsules of the composition is called Avifavir. Using the given D90 fraction of micronized FVP renders the process of manufacturing the claimed SARS-CoV-2 antiviral pharmaceutical composition significantly easier and less expensive since it does not necessitate separation of the micronized particles. In addition, the composition Avifavir is more effective since it significantly reduces COVID-19 treatment time in comparison to known drugs.

Description

IlpoTHBo-SARS-CoV-2 viral pharmaceutical composition and its use

Technology area

This invention relates to a new npOTHBO-SARS-CoV-2 viral pharmaceutical composition intended for the treatment of RNA viral diseases, including for the prevention and treatment of COVID-19 mediated by SARS-CoV-2 viral infection. The sudden outbreak of the new coronavirus in 2019, later named SARS-CoV-2, in Wuhan, China, which quickly turned into a global pandemic, heralded the third introduction of the virulent Coronavirus into human society, affecting not only the healthcare system but also the global economy. ... Effective approaches to vaccination, prevention and treatment of SARS-CoV-2 (COVID-19) and epidemiological control are still lacking.

Prior art

As of April 30, 2020, the COVID-19 coronavirus affected 210 countries and territories, in total there were 3,308,233 cases of SARS-CoV-infected 2 people, 1,042,819 people recovered and 234,105 people died

[htps: //www.worldometers.info/coronavirus/7utm_campai gn = homeAdvegas 1?].

In this regard, there is an intensive search for vaccines and therapeutic agents around the world for the prevention and treatment of SARS-CoV-2 (COVID-19). One practical approach as a rapid response to an emerging pandemic is to repurpose existing therapeutic agents previously targeted for other viral infections, since most of these agents have already been tested for their safety.

In 1999, the Japanese company Toyama Chemical Co. patented the anti-influenza drug Favipiravir (FVP) (Favipiravir, T-705, Avigan), (corresponds to patent RU 2224520]. FVP is used in Japan to treat influenza, including a new highly pathogenic A H5N 1 strain avian influenza [RW Sidwell at al. Antimicrob. Agents Chemother. 2007, 51 (3): 845-851].

FVP exhibits antiviral activity against many other RNA viruses, such as arenaviruses, bunyaviruses, and filoviruses, which are known to cause fatal hemorrhagic fever. [Y. Furuta et al. Review Favipiravir (T-705), a broad spectrum inhibitor of viral RNA polymerase. Proc. Jpn. Acad. Ser. B 93, 2017, 449-463].

FVP has successfully tested the treatment of progressive Ebola virus infection in mice [L. Oestereich et al. Ebola virus infection with T-705 (favipiravir) in a small animal model. Antiviral Research 2014, 105, 17-21] and is a promising drug candidate, but has not yet been approved by WHO.

Viral Ebola (EVD), also known as Ebola haemorrhagic fever (EHF) or simply Ebola, is a viral haemorrhagic fever in humans and other primates caused by ebolaviruses. The disease has a high risk of death, killing 25% to 90% of those infected, with an average of about 50%. EVD outbreaks occur intermittently in tropical regions of sub-Saharan Africa. Between 1976 and 2013, WHO reports 24 outbreaks, with 2,387 cases with 1,590 deaths. The largest outbreak to date was the epidemic in West Africa, which occurred from December 2013 to January 2016, with 28,646 cases and 11,323 deaths. The Ebola vaccine was approved in the US in December 2019. As of 2019, there was no approved treatment for Ebola [https://en.wikipedia.org/wiki/Ebola_virus_disease].

In February 2020, FVP was successfully tested in an initial randomized trial in China as an antiviral therapy for the SARS-CoV-2 (COVID-19) coronavirus. FVP received short-term approval in China on February 16, 2020 as an effective antiviral against COVID-19 for five years. It is currently produced in China under the name Favipiravir [https://de.wikipedia.org/wiki/Favipiravir].

FVP, marketed in Japan under the brand name Avigan (Avigan Tablet 200 mg, Toyama Chemical Co.) and in China under the brand name Favilavir (Favilavir Tablet 200 mg, Zhejiang Hisun Pharm.), Is an antiviral drug used in Japan to treat influenza. It is developed and manufactured by Toyama Chemical Co. (Fujifilm Group) and was approved for medical use in Japan in 2014 [Shiraki K., Daikoku T. Favipiravir, an anti-influenza drug against life-threatening RNA virus infections. Pharmacology & Therapeutics 2020, 107512. doi: 10.1016 / J.pharmthera.2020.107512].

In 2016, Fujifilm licensed the FVP to the Chinese pharmaceutical company Zhejiang Hisun. [E.J. Lane (June 22, 2016). "Fujifilm in Avigan API license with Zhejiang Hisun Pharmaceuticals". Retrieved April 20, 2020.].

In 2019, FVP became generic.

In 2010, the international PCT application JP 2010/054191 (03/12/2010) [WO 2010/104170 (09/16/2010)] was published, under which the patent RU 2527766 C2 was issued for "Tablets and granular powders containing 6-fluoro-3-hydroxy-2-pyrazinecarboxamide."

Patent RU 2527766 C2 describes tablets and granular powders containing favipiravir and excipients for the prevention or therapy of viral diseases. Known 200 mg coated tablets Avigan from Toyama Chemical Co., NTV Toyama, protected by patent RU 2527766, contain 50-95% of FVP in the tablet. In all presented 19 examples, the content of FPP in the tablets varies in the range of 70-80%.

In document CN 105687152 a pharmaceutical composition is protected containing FVP in an amount of less than 50% (in example 42.5%) in the form of micronized particles with a particle size of 120 μm or less, in the form of tablets with immediate release or capsules.

Document CN 104288154 describes a pharmaceutical composition containing less than 50% FVP in the form of particles, which contain fractions D (10) = 0.1-8 microns, D (50) = 1-30 microns and D (90) less than 50 microns.

The compositions described in the above CN documents are intended for the therapy of influenza viruses.

On March 15, 2020, FVP was approved in China for the treatment of coronavirus [Yangfei Z. "Potential coronavirus drug approved for marketing". Chinadaily.com.cn. Retrieved 2020-03-21]

At the time of filing this application, favipiravir was known to have some activity against SARS-CoV-

2 [https://ascpt.onlinelibrary.wiley.com/doi/full/10.1002/cpt.1877] and has even been used in China to treat COVID-19 [https://de.wikipedia.org/wiki/Favipiravir].

However, in the scientific and patent literature there is no data on the composition and clinical efficacy of "Anti-SARS-CoV-

2 viral pharmaceutical composition in the form of a tablet or capsule, comprising favipiravir.

Disclosure of invention

Considering that SARS-CoV-2 poses a serious threat to public health and the economy around the world, it seems advisable to search for new effective anti-coronavirus drugs.

The objective of the present invention is to develop and obtain a new anti-SARS-CoV-2 viral pharmaceutical composition intended for RNA therapy viral diseases, including for the prevention and treatment of COVID-19 mediated by SARS-CoV-2.

The subject of the present invention is a new npoTHBo-SARS-CoV-2 viral pharmaceutical composition containing 40-48 wt%. micronized favipiravir, including fraction D (90) micronized particles with a size of <40.6 to <211 microns, and the rest of the excipients.

Mainly the composition contains 44.0% by weight. - 47.6% by weight. micronized favipiravir. In this case, micronized crystalline particles can have fractions with a distribution of micronized particles with parameters D (90): within <40, 6 - <211 μm, D (50): within <10.7 - <105 μm, D (10) : within <2.5 - <43.8 microns.

The composition can be used in therapy for the prevention and treatment of COVID-19.

As auxiliary substances, the composition may contain substances selected from fillers, disintegrants, binders, glidants and lubricants, and coatings. Such auxiliary substances can be, for example, microcrystalline cellulose, croscarmellose sodium, povidone, magnesium stearate, colloidal silicon dioxide and other substances. The composition can include a film shell.

The subject of the present invention is also the use of a novel anti-SARS-CoV-2 viral pharmaceutical composition containing 40-48 wt%. micronized favipiravir, including fraction D (90) of micronized particles with a size of <40.6 to <211 microns, and the rest are auxiliary substances for obtaining a dosage form in the form of tablets or capsules.

The pharmaceutical composition of the present invention, named Avifavir, in the form of coated tablets or capsules, containing a fraction of micronized particles D (90) with a particle size in the range of <40, 6 - <211 μm, and comprising 200 mg, 300 mg, 400 mg or 600 mg of micronized FVP, has improved solubility.

As can be seen from Table 1, a decrease in the particle size of FPV in a pharmaceutical composition in the form of a coated tablet leads to a significant improvement in its main parameter - the time of FPV release from the tablet in various media. Indeed, the release time of FPV from tablet 3 containing the minimum particle size of FPV is significantly greater than the release time of FPV from tablets 1 and 2, in which the particle size exceeds 60 μm. It should be noted that the reduced content of FPV also leads to a decrease in the release time of FPV from the pharmaceutical composition in the form of a coated tablet. So the percentage of release of FPV from coated tablets in a solution with pH 4.5 according to examples 2 and 3 (Table 1) from patent RU 2527766, containing 79% and 86% FPV, respectively, is 93.5% and 86.7% in 15 minutes ... At the same time, tablet 3 according to the present invention, containing 43.3% of FPV, releases a higher percentage of FPV (98.1%, Table 1) three times faster (in 5 minutes).

A similar picture is observed when comparing the release time (95.1% -99.7% in 15 minutes) FPV from coated tablets in solution with pH 4.5 according to examples 4 10 (Table 2) from patent RU 2527766, containing 77.5 % PDF. At the same time, tablet 3 according to the present invention, containing 43.3% of FPV, releases 100% (Table 1) FPV in 10 minutes.

Note that tablets 3 according to this invention also quickly and practically quantitatively release FVP in solutions with pH 1.2 and pH 6.8 (Table 1).

Below is Table 1, Supplementary Figures 1-3.

Due to the reduced FPV content in the pharmaceutical composition Avifavir compared to the composition according to patent RU 2527766, it was possible to significantly improve the technological properties of the granulate (pharmaceutical composition): flowability, compressibility, which ensures high productivity of the pressing process and high uniformity of dosage of the active substance in each unit of the dosage form.

The use of a certain fraction D (90) of micronized FVP greatly simplifies and reduces the cost of the preparation process of the claimed anti-SARS-COV-2 viral pharmaceutical composition, since separation of particles is not required.

The technology and composition of Avivavir tablets can reduce the time spent on the production process. The high productivity of the Tabletting stage and the Film coating stage is ensured by the excellent technological properties of the granulate and the use of a film coating based on Polyvinyl alcohol (allows the use of a more concentrated suspension with a solid content of up to 20%. the duration of treatment for COVID-19 (see example 5 below) compared to previously known drugs.

The invention is illustrated by the following drawings:

Fig. 1 The distribution of micronized crystalline particles of FVP used in the formulation 1 of the tablets according to example 2, with the parameters D (90) <67.1 μm, D (50) <27.8 μm and D (10) <6.2 μm.

Fig. 2 Distribution of micronized crystalline particles of FVP used in the formulation of 2 tablets according to example 2, with parameters D (90) <211.0 μm, D (50) <105.0 μm and D (10) <43.8 μm.

Fig. 3 Distribution of micronized crystalline particles of FP used in the formulation of 3 tablets according to example 2, with parameters D (90) <40.6 μm, D (50) <10.7 μm and D (10) <2.5 μm.

Figure 4 shows the dissolution curve of the capsules in an aqueous solution of pH 4.5. Disclosure of invention

This invention is illustrated but not limited by the following examples.

Example 1. Obtaining a pharmaceutical composition Avifavir in the form of capsules containing 200 mg (45%) FPV.

Thoroughly mix 200 g of micronized FVP with a microcrystal size of 40-50 μm and 250 g of lactose powder. The resulting powder mixture is packaged in 450 mg of gelatin capsules of a suitable size, each containing 200 mg (44.4%) of FPP.

Example 2. Obtaining a pharmaceutical composition of Avifavir in the form of coated tablets containing 200 mg, 300 mg, 400 mg or 600 mg FPV (formulation 3 in Table 1).

Weigh all raw materials and sift magnesium stearate for dusting. In a mixer-granulator, 200 g of FVP (micronized with a microcrystal size of 40-50 μm), 194.65 g of microcrystalline cellulose MCC 102, 27.0 g of croscarmellose sodium, 2.7 g of colloidal silicon dioxide (USP / NF, Ph.Eur. ) and mix the components until the mixture is homogeneous. With constant stirring of the mixture, the previously prepared 6% solution of 22.5 g of povidone K30, in full volume, is introduced into the mixer-granulator until the end point of granulation is reached. The wet granulate is calibrated through a 2.0 mm sieve. The calibrated wet granulate is dried to a predetermined residual moisture content. The dried granulate is calibrated through a 0.5 mm sieve, setting the optimal fractional composition. The resulting granulate is powdered in a mixer with pre-sieved 3.15 g of magnesium stearate. The powdered mixture is divided into three parts and tableted on a rotary tablet press. The resulting core tablets with a mass of = 450 mg, ~ 675 mg and ~ 1350 mg, containing respectively 200 mg, 300 mg, 400 mg or 600 mg of FPP, each, with a hardness of 60 N, abrasion no more than 5% and no disintegration more than 3 minutes are transferred to the coating stage. The film coating process (Opadry 85F38183 yellow) is carried out in a coater until the target weight of the Avivavir coated tablet weighing 462 mg, 693 mg or 1386 mg, respectively, is achieved.

The pharmaceutical compositions of Avifavir in the form of a coated tablet corresponding to formulations 1 and 2 are obtained in a similar way (Table 1).

Example 3. Kinetics of dissolution of Avifavir in the form of coated tablets containing 200 mg of FPV in three buffers. The study of the dissolution kinetics of Avipiravir in the form of coated tablets containing 200 mg FPV is carried out in accordance with the guidelines for the examination of medicines ”[Guidelines for the examination of medicines. Volume 1. - M .: Grif and K., 2013. - 328 p., Chapter 7. 5. Guidelines for the examination of medicines. Volume 3. - M .: POLYGRAFPLUS, 2014. - 344 p., Chapter 11.] in three buffer media with a pH value of 1.2, 4.5 and 6.8, simulating the main areas of the gastrointestinal tract in which release and absorption of the active ingredient. The following media were used in the study: 0.2% sodium chloride solution in 0.1 M hydrochloric acid pH 1.2, sodium acetate buffer solution pH 4.5 (quality control medium), phosphate buffer solution pH 6.8, prepared in in accordance with the requirements of the European Pharmacopoeia 7.0, OFS 5.17.1 "Recommendations for the dissolution test" [EP.7.0. 5.17.1 Recommendations on dissolution testings.]. The sampling time points were selected in such a way as to provide a reliable description of the dissolution profile with a gradual increase and subsequent reaching the level of complete release (not less than 85% of the active substance) or a plateau. During the study of the kinetics of dissolution, the following sampling time points were selected: 5 min, 10 min, 15 min, 20 min and 30 min. To obtain statistically significant results for each drug, the test was carried out on 12 units of the dosage form. The quantitative content of FPV released into the dissolution medium was determined by HPLC. The calculations took into account the change in the volume of the dissolution medium.

The study of the kinetics of dissolution was carried out on a DT828 tablet / capsule dissolution tester (Erweka, Germany). Quantitative determination was carried out using liquid chromatographs: - Agilent 1260 (Agilent Technologies, USA) with OpenLab ChemStation software and LC-20A Prominence (Shimadzu, Japan) with LabSolutions software. The following accessories were used: laboratory scales MV210A (SartoGosm, Russia), Acculab VIC-210d2 (Acculab, Sartorius Group, USA) and Quintix 64-10RU (Sartorius Group, Germany); pH meter SEVEN MULTI (Mettler Toledo, Switzerland). Statistical processing of the experimental results was carried out using the Microsoft Office Excel 2007 package. We used volumetric laboratory glassware of classes "A" (volumetric flasks with a capacity of 50, 500, 1000 ml), "AS" (analytical pipettes 1 and 5 ml) and "B" (measuring cylinders 100, 250 and 1000 ml). The test was carried out in accordance with the requirements of GF XIV, OFS 1.4.2.0014.15 "Dissolution for solid dosage forms" [GF XIV. Volume 2, 2018. - 2164 p., OFS.1.4.2.0014.15 Dissolution for solid dosage forms.], "Guidelines for the examination of medicines" [Guidelines for the examination of medicines. Volume 1. - M .: Grif and K., 2013. - 328 p., Chapter 7. 5. Guidelines for the examination of medicines. Volume 3. - M .: POLYGRAFPLUS, 2014. - 344 p., Chapter 11.], as well as in accordance with the recommendations of the scientific and practical guide for the pharmaceutical industry "Test" Dissolution "in the development and registration of medicines" ed. I.E. Shokhin [Test "Dissolution" in the development and registration of medicines. Scientific and practical guidance for the pharmaceutical industry / Ed. Shokhina I.E. - M. Publishing house Pero, 2015. - 320 s]. Test conditions: Apparatus type - "Paddle stirrer"; Temperature - 37 ± 0.5 ° С; The volume of the medium is 900 ml; Rotation speed - 75 rpm; Sampling time points - 5, 10, 15, 20 and 30 minutes. The obtained results of the study of the release of FVP from three formulations of Avipiravir tablets depending on the particle size of the FVP, the acidity of the solutions and the mixing time are presented in Table 1.

Example 4. Obtaining a pharmaceutical composition of Avifavir in the form of capsules containing 200 mg (44.9%) FPP.

Weigh all raw materials and sift magnesium stearate for dusting. The mixer-granulator is sequentially loaded with 100 g of micronized FVP with a grain size of D90 <40.6 μm, 95 g of microcrystalline cellulose MCC 102, 13.5 g of croscarmellose sodium, 1.3 g of colloidal silicon dioxide (USP / NF, Ph.Eur. ) and mix the components until the mixture is homogeneous. With constant stirring of the mixture, the previously prepared 6% solution of 11.15 g of povidone K30, in full volume, is introduced into the mixer-granulator until the end point of granulation is reached. The wet granulate is calibrated through a 2.0 mm sieve. The calibrated wet granulate is dried to a predetermined residual moisture content. The dried granulate is calibrated through a 0.5 mm sieve, setting the optimal fractional composition. The resulting granulate is powdered in a mixer with pre-sieved 1.55 g of magnesium stearate. The powdered mixture is packaged at 445 mg in gelatin capsules No. 0, each of which contains 200 mg (44.9%) of FPP. Figure 4 shows the curve of dissolution of capsules in an aqueous solution of pH 4.5, from which it follows that the release of FPP from the pharmaceutical composition in the form of a capsule corresponds to ~ 90% within 15 minutes, which corresponds to the methodological recommendations. In particular, for medicinal products with a class II pharmaceutical substance 2 points are recommended - 15 minutes and then (30, 45 or 60 minutes) to make sure that 85% of the pharmaceutical substance is dissolved [100] [I. E. Smekhova et al. Dissolution test and modern approaches to assessing the equivalence of drugs (review). Drug Development and Registration 2013, 1 (2), p. 56. htp: //fptl.ru/biblioteka/stkr/smehova_test-rastvorenie_2013-1.pdf].

Example 5. An adaptive, multicenter, open-label, randomized clinical trial of Avifavir versus standard of care (SOC) in hospitalized COVID-19 patients with moderate to severe pneumonia.

Study design and participants.

The clinical study was conducted in the second quarter of 2020 at 6 Russian clinical bases in infectious diseases hospitals in Moscow, Smolensk and Nizhny Novgorod.

The aim of the study was to evaluate the efficacy and safety and select the optimal dosage regimen for Avivavir (tablets containing FPV, according to example 2, formulation 3). The study design was based on the WHO R&D guidelines for clinical trials of COVID-19 drugs.

After signing the informed consent form and screening, 60 eligible patients with PCR-confirmed COVID-19 pneumonia were randomized into three groups in a 1: 1: 1 ratio to receive Avifavir containing 1600 mg of FPV twice daily on day 1 and beyond. 600 mg FPV twice daily on days 2-14 (group 1: 1600/600 mg) and 1800 mg FPV twice daily on day 1 and then 800 mg FPV twice daily on days 2-14 ( group 2: 1800/800 mg), and SOC - 20 patients per treatment group 3. All randomized patients were assigned safety and ITT assay kits.

Avifavir was administered for an average of 11 days with antibiotics (30%) and anticoagulants (35%) in 35% of patients as concomitant medications for COVID-19. SOC was assigned to the control group in accordance with the recommended treatment regimens outlined in Russia's M3 interim COVID-19 treatment guidelines. Patients received hydroxychloroquine (65%), chloroquine (10%), lopinavir / ritonavir (5%), or etiologic treatment (20%) with antibiotics (40%) and anticoagulants (20%) as concomitant medications for COVID-19.

The treatment groups were generally comparable in demographic and baseline characteristics. 37% of patients had risk factors for severe illness (age 60 years and / or concomitant chronic diseases). At the beginning of the study, 73% of patients were in the open air (grade 3 on the clinical scale). improvements), and 27% of patients required supplemental oxygen through mask or nasal cannula (score 4). The average duration of illness was 7 days from the onset of the first symptoms. The most common symptoms were body temperature above 37.5 ° C (95%), cough (83%), weakness (70%), anosmia (35%), chest tightness (30%) and shortness of breath (28%).

Study scores included daily vital signs, Sp02, and the WHO Ranking Scale for Clinical Improvement; PCR for SARS-CoV-2 RNA at the beginning of the study and on days 5, 10 and 15; Chest CT at baseline and day 15; physical examination, SHS with differential, biochemistry, SRV, general urinalysis and ECG at the beginning of the study, on the 5th and 15th days. If patients were not previously discharged from the hospital, patients attended follow-up visits on days 22 and 29 followed by day 29.

Results of the efficacy and safety and use of Avifavir in the therapy of COVID-19.

On day 5 (i.e. 4 days after starting treatment), SARS-CoV-2 elimination was achieved in 26/40 (65%) patients treated with Avifavir (similar proportions for both dose levels) and 6/20 (30% ) patients on SOC (p = 0.011). By day 10 (i.e., 9 days after initiation of treatment), SARS-CoV-2 elimination was achieved in 36/40 (90%) of patients treated with Avifavir (similar proportions at both dose levels) and in 16/20 (80% ) patients.

The mean time to normalization of body temperature (<37 ° C) was 2 days (IQR 2-3) in the Avifavir group and 5.5 days (IQR 1.5-8) in the SOC group (p = 0.005). By day 15, chest CT improved in 85% of patients with Avifavir and in 75% of patients with SOC (p = 0.345).

Adverse reactions to Avifavir were reported in 6/40 (15%) patients, including diarrhea, nausea, vomiting, chest pain, and elevated ALT / ACT. Adverse reactions were mild to moderate and caused early discontinuation of study drug in 2/40 (5%) patients.

Conclusion. On May 29, 2020, following a successful phase 2/3 randomized clinical trial, M3 Russia granted Avivavir permission to accelerate the promotion of the drug for the treatment of COVID-19. Interim results of the study showed that 65% of patients receiving Avivavir achieved viral clearance within 4 days after treatment, and the mean time to normal body temperature was 2 days. Avfavir's safety profile was consistent with known data.

Industrial applicability

The invention can be used in medicine and veterinary medicine.

Claims

Claim

1. npoTHBO-SARS-CoV-2 viral pharmaceutical composition containing 40-48% weight. micronized favipiravir, including the fraction of micronized particles D (90) with a size in the range of <40.6 - <211 microns, and the rest are auxiliary substances.

2. The composition according to paragraph 1, containing 44.0% by weight. - 47.6% by weight. micronized favipiravir.

3. Composition according to paragraph 1 or 2, containing excipients selected from a number of fillers, disintegrants, binders, glidants and lubricants.

4. A composition according to any one of claims 1 to 3 for use in therapy for the prevention and treatment of COVED-19.

5. The use of the npoTHBO-SARS-CoV-2 viral pharmaceutical composition according to any one of claims 1 to 4 for preparing a dosage form in the form of tablets or capsules.