RU2764444C1 - ANTI-SARS-CoV-2-VIRAL PHARMACEUTICAL COMPOSITION AND APPLICATION THEREOF - Google Patents

Abstract

FIELD: pharmaceuticals.SUBSTANCE: invention relates to an application of a pharmaceutical composition containing micronised favipiravir and excipients, wherein the composition comprises 42.1 wt.% microcrystalline cellulose as a filler, 5.8 wt.% sodium croscarmellose as a disintegrant, 4.9 wt.% povidone as a binder, 0.7 wt.% magnesium stearate as a lubricant, 0.6 wt.% colloidal silicon dioxide, and 2.6 wt.% of a film shell, 43.3 wt.% of micronised favipiravir, with the following size distribution of micronised particles: D(90)=40.6 mcm at Std. Dev. 1.71 mcm, D(50)=10.7 mcm at Std. Dev. 0.459 mcm, and D(10)=2.5 mcm at Std. Dev. 0.0979 mcm, to produce an anti-SARS-CoV-2-viral dosage form in the form of film-coated tablets.EFFECT: application of the composition of the above composition ensures rapid release of favipiravir from the dosage form (tablets).1 cl, 4 dwg, 1 tbl, 5 ex

Description

This invention relates to a new anti-SARS-CoV-2 viral pharmaceutical composition intended for the treatment of RNA viral diseases, including the prevention and treatment of COVID-19 mediated by SARS-CoV-2 viral infection. The sudden outbreak of the novel coronavirus in 2019, later named SARS-CoV-2, in Wuhan, China, which quickly turned into a global pandemic, marked the third introduction of a 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.

As of April 30, 2020, COVID-19 has affected 210 countries and territories, with a total of 3,308,233 cases of SARS-CoV-2 infected people, 1,042,819 recoveries and 234,105 deaths [https://www.worldometers.info/coronavirus/ ?utm_campaign=homeAdvegasl?].

In this regard, an intensive search is underway around the world for vaccines and therapeutic agents 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 intended for other viral infections, as 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 H5N1 strain of 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 been successfully tested in 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 an encouraging drug candidate, but has not yet been approved by the WHO.

Ebola virus (EVD), also known as Ebola hemorrhagic fever (EHF) or simply Ebola, is a viral hemorrhagic fever in humans and other primates caused by ebolaviruses. The disease has a high risk of death, killing between 25% and 90% of those infected, with an average of about 50%. Outbreaks of EVD occur intermittently in tropical regions of sub-Saharan Africa. Between 1976 and 2013, WHO reports 24 outbreaks with 2387 cases and 1590 deaths. The largest outbreak to date was 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, PEF was successfully trialled in an initial randomized trial in China as an antiviral therapy for the SARS-CoV-2 coronavirus (COVID-19). FVP received short-term approval in China on February 16, 2020 as an effective antiviral agent against COVID-19 for five years. It is currently manufactured in China under the name Favilavir [https://de.wikipedia.org/wiki/Favipiravir].

FVP, sold 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 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 a generic.

In 2010, the international application PCT JP 2010/054191 (12.03.2010) [WO 2010/104170 (16.09.2010)] was published, according to which 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 treatment of viral diseases. Known 200 mg Avigan coated tablets from Toyama Chemical Co., LTV Toyama, protected by patent RU 2527766, contain 50-95% FVP per tablet. In all presented 19 examples, the content of FVP in tablets varies in the range of 70-80%.

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

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

The compositions described in the above CN documents are for the treatment 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 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 was even used in China for treatment of COVID-19 [https://de.wikipedia.org/wiki/Favipiravir].

However, there is no data in the scientific and patent literature on the composition and clinical efficacy of the “Anti-SARS-CoV-2 viral pharmaceutical composition in the form of a tablet or capsule containing favipiravir.

Considering that SARS-CoV-2 poses a serious threat to public health and the economy around the world, it seems appropriate 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 the treatment of RNA viral diseases, including the prevention and treatment of COVID-19 mediated by SARS-CoV-2.

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

Mostly the composition contains 44.0 wt%. - 47.6% wt. micronized favipiravir. At the same time, 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 µm.

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

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

The subject of the present invention is also the use of a new anti-SARS-CoV-2 viral pharmaceutical composition containing 40-48% by weight. micronized favipiravir, including the fraction D(90) of micronized particles with a size of ≤40.6 to ≤211 μm, and the rest of the excipients for obtaining a dosage form in the form of tablets or capsules.

The pharmaceutical composition of the present invention, named as Avifavir, in the form of coated tablets or capsules, containing a fraction of micronized particles D(90) with a particle size in the range ≤40.6 - ≤211 μm, and comprising 200 mg, 300 mg, 400 mg or 600mg of micronized FVP, has improved solubility.

As can be seen from Table 1, reducing the particle size of the FPV in the pharmaceutical composition in the form of a coated tablet leads to a significant improvement in its main parameter - the release time of the FPV from the tablet in various media. Indeed, the release time of PPV from tablet 3 containing the minimum particle size of PPV significantly exceeds the release time of PPV from tablets 1 and 2, in which the particle size exceeds 60 μm.

It should be noted that a reduced content of PVP also leads to a decrease in the release time of PVP from a pharmaceutical composition in the form of a coated tablet. Thus, the percentage of FPV release 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% of FPV, respectively, is 93.5% and 86.7% in 15 minutes . At the same time, tablet 3 according to this invention, containing 43.3% FVP, releases a higher percentage of FVP (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) of the FPV from coated tablets in solution with pH 4.5 according to examples 4÷10 (Table 2) from patent RU 2527766, containing 77, 5% FPV. At the same time, tablet 3 according to this invention containing 43.3% FVP releases 100% (Table 1) of FVP in 10 minutes.

Note that tablets 3 according to this invention also rapidly and almost quantitatively release PVP in solutions with pH 1.2 and pH 6.8 (Table 1). Below are table 1, additional figures 1-3.

Due to the reduced content of FPV in the Avifavir pharmaceutical composition 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 dosing of the active substance in each dosage form unit.

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

The technology and composition of Avifavir tablets can reduce the time spent on the production process. The high productivity of the Tableting stage and the Film coating stage are 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 solids content of up to 20%. As tests have shown, the use of the proposed Avifavir composition is more effective and significantly reduces 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. Distribution of micronized crystalline particles of FVP used in the formulation of 1 tablets according to example 2, with 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 FVP 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.

Fig. 4. Shown is the dissolution curve of capsules in an aqueous solution of pH 4.5.

The present invention is illustrated but not limited by the following examples.

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

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 gelatin capsules of suitable size, each containing 200 mg (44.4%) of FVP.

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

All raw materials are weighed and magnesium stearate is sieved for dusting. 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 is added to the mixer-granulator, in full, 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-sifted 3.15 g of magnesium stearate. The powdered mixture is divided into three parts and tableted on a rotary tablet press. The obtained core tablets with a mass of ≈450 mg, ≈675 mg and ≈1350 mg, each containing 200 mg, 300 mg, 400 mg or 600 mg of FVP, respectively, with a hardness of 60 N, abrasion of not more than 5% and disintegration of not more than 3 minutes are passed to the coating stage. The film coating process (Opadry 85F38183 yellow) is carried out in a coater until the desired weight of the Avifavir coated tablet weighing 462 mg, 693 mg or 1386 mg, respectively, is reached.

Similarly, pharmaceutical compositions of Avifavir are obtained in the form of coated tablets corresponding to formulations 1 and 2 (Table 1).

Example 3 Dissolution kinetics of Avifavir coated tablets containing 200 mg 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 medicinal products” [Guidelines for the examination of medicinal products. Volume 1. - M.: Grif and K., 2013. - 328 p., chapter 7. 5. Guidelines for the examination of medicines. Volume 3. - M.: POLYGRAPHPLUS, 2014. - 344 p., chapter 11.] in three buffer media with a pH value of 1.2, 4.5 and 6.8, simulating the main sections 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 pH 4.5 (quality control medium), phosphate buffer pH 6.8, prepared in in accordance with the requirements of the European Pharmacopoeia 7.0, GPM 5.17.1 "Recommendations for the dissolution test" [EP.7.0. 5.17.1 "Recommendations on dissolution testings".]. 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 (at least 85% of the active substance) or a plateau. When conducting a dissolution kinetics study, the following sampling time points were chosen: 5 min, 10 min, 15 min, 20 min and 30 min. To obtain statistically significant results for each drug, the test was performed on 12 units of the dosage form. The quantitative content of PPV released into the dissolution medium was determined by HPLC. When performing calculations, the change in the volume of the dissolution medium was taken into account.

The study of the kinetics of dissolution was carried out on the device Tester for determining the dissolution of tablets / capsules DT828 (Erweka, Germany). Quantification 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 auxiliary equipment was used: laboratory scales МВ210А (SartoGosm, Russia), Acculab VIC-210d2 (Acculab, Sartorius Group, USA) and Quintix 64-1ORU (Sartorius Group, Germany); SEVEN MULTI pH meter (Mettler Toledo, Switzerland). Statistical processing of the results of the experiment was carried out using the Microsoft Office Excel 2007 package. In the work, 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 pp., OFS.1.4.2.0014.15 Dissolution for solid dosage forms.], "Guidelines for the examination of medicinal products" [Guidelines for the examination of medicinal products. Volume 1. - M.: Grif and K., 2013. - 328 p., chapter 7. 5. Guidelines for the examination of medicines. Volume 3. - M.: POLYGRAPHPLUS, 2014. - 344 p., Chapter 11.], as well as in accordance with the recommendations of the scientific and practical guide for the pharmaceutical industry "Dissolution test in the development and registration of medicines" ed. I.E. Shokhina [Test "Dissolution" in the development and registration of medicines. Scientific and practical guide for the pharmaceutical industry / Ed. Shokhina I.E. - M. Izdvo Pero, 2015. - 320 s]. Testing conditions: Apparatus type - "Paddle stirrer"; Temperature -37±0.5°С; Medium volume - 900 ml; Rotation speed - 75 rpm; Time sampling points - 5, 10, 15, 20 and 30 min. The results of the study of the release of PVP from three formulations of Avipiravir tablets, depending on the particle size of PVP, the acidity of the solutions and the mixing time are presented in table 1.

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

All raw materials are weighed and magnesium stearate is sieved for dusting. 100 g of micronized FVP with grain size 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 is added to the mixer-granulator, in full, 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-sifted 1.55 g of magnesium stearate. The powdered mixture is packaged in 445 mg No. 0 gelatin capsules, each containing 200 mg (44.9%) of FVP. Figure 4 shows the dissolution curve of capsules in an aqueous solution of pH 4.5, from which it follows that the release of PVP from the pharmaceutical composition in the form of a capsule corresponds to ~90% within 15 minutes, which is in accordance with the methodological recommendations. In particular, for medicinal products with a pharmaceutical substance of class II, 2 points are recommended - 15 minutes and further (30, 45 or 60 minutes) to ensure that 85% of the pharmaceutical substance is dissolved [100] [I.E. Smekhova et al. Dissolution Test and Modern Approaches to Assessing the Equivalence of Medicinal Products (Review). Development and registration of medicines 2013, 1(2), p. 56. http://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 dosing regimen for Avifavir (tablets containing FVP, according to example 2, formulation 3). The design of the study was based on the WHO R&D guidelines for clinical trials of COVID-19 drugs.

After signing an 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 FVP twice daily on Day 1 and thereafter. 600 mg PEF twice a day on days 2-14 (group 1: 1600/600 mg) and 1800 mg PEF twice a day on day 1 and then 800 mg PEF twice a day on days 2-14 (group 2: 1800/800 mg), and SOC - 20 patients per treatment group 3. All randomized patients completed safety and ITT assays.

Avifavir was administered for a median of 11 days with antibiotics (30%) and anticoagulants (35%) in 35% of patients as concomitant medications for COVID-19. SOC was prescribed in the control group in accordance with the recommended treatment regimens presented in the interim guidelines of the Ministry of Health of Russia for the treatment of COVID-19. Patients received hydroxychloroquine (65%), chloroquine (10%), lopinavir/ritonavir (5%), or etiological treatment (20%) with antibiotics (40%) and anticoagulants (20%) as concomitant medications for COVID-19.

The treatment groups were broadly comparable in demographic and baseline characteristics. 37% of patients had risk factors for severe disease (age 60 and/or chronic comorbidities). At baseline, 73% of patients were outdoors (WHO Clinical Improvement Scale score 3), and 27% of patients required supplemental oxygen via a mask or nasal cannula (score 4). The average duration of the disease 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 evaluations included daily vital signs, SpO2, and the WHO Ordinal Scale for Clinical Improvement; PCR for SARS-CoV-2 RNA at baseline and days 5, 10, and 15; Chest CT at baseline and day 15; physical examination, SVS with differential, biochemistry, CRP, urinalysis and ECG at baseline, days 5 and 15. If patients were not previously discharged from the hospital, patients attended follow-up visits on days 22 and 29, followed by days 29.

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

On day 5 (i.e. 4 days after the start of treatment), SARS-CoV-2 clearance was achieved in 26/40 (65%) patients with Avifavir (similar proportions for both dose levels) and in 6/20 (30% ) patients on SOC (p=0.011). By day 10 (i.e. 9 days after the start of treatment), elimination of SARS-CoV-2 was achieved in 36/40 (90%) patients 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%) of patients, including diarrhea, nausea, vomiting, chest pain, and ALT/AST elevation. Adverse reactions were mild to moderate and led to early discontinuation of study drug in 2/40 (5%) of patients.

Conclusion. On May 29, 2020, following a successful phase 2/3 randomized clinical trial, the Russian Ministry of Health granted Avifavir approval for accelerated promotion of a drug for the treatment of COVID-19. Interim results of the study showed that 65% of patients treated with Avifavir achieved viral clearance within 4 days after treatment, and the median time to normal body temperature was 2 days. The safety profile of Avifavir was consistent with known data.

Claims (1)

The use of a pharmaceutical composition containing micronized favipiravir and excipients, where the composition contains 42.1 wt.% microcrystalline cellulose as a filler, 5.8 wt.% croscarmellose sodium as a disintegrant, 4.9 wt.% povidone as a binder, 0 .7 wt.% magnesium stearate as a lubricant, 0.6 wt.% colloidal silicon dioxide and 2.6 wt.% film coat, 43.3 wt.% micronized favipiravir with the following micronized particle size distribution: D(90) =40.6 µm at Std Dev 1.71 µm, D(50)=10.7 µm at Std Dev 0.459 µm and D(10)=2.5 µm at Std Dev 0.0979 µm, to obtain anti-SARS -CoV-2 viral dosage form in the form of film-coated tablets.

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