Anti-RNA virus, including anti-SARS-CoV-2 virus, pharmaceutical composition Avifavir

Abstract

This invention relates to a novel anti-RNA virus, including anti-SARS-CoV-2 virus, pharmaceutical composition Avifavir in tablets or capsules containing less than 50 wt % of micronized favipiravir, with the remainder being excipients.

Medicinal product Avifavir for the prevention and treatment of COVID-19 coronaviral disease, said medicinal product being a pharmaceutical composition in coated tablets containing 200 mg, 300 mg, 400 mg, or 600 mg of micronized favipiravir (less than 40-45%) with a particle size of less than 60 μm, with the remainder being excipients.

Claims

1. An anti-SARS-CoV-2 virus pharmaceutical composition in tablets or capsules containing less than 50 wt % of micronized favipiravir, with the remainder being excipients.

2. Composition according to claim 1 in tablets or capsules containing less than 40-45% of micronized favipiravir with a particle size less than 211 μm.

3. Composition according to claims 1, 2 containing fillers, disintegrants, binders, glidants, lubricants and coatings as excipients.

4. Composition according to claims 1÷3 in coated tablets containing 43÷44% favipiravir, 5.5÷6.0% croscarmellose sodium, 4.8÷5.0% povidone, 0.6÷0.8% magnesium stearate, 0.5÷0.7% silicon dioxide colloidal, 2.5÷2.7% film coating, the remainder being microcrystalline cellulose, containing 200 mg, 300 mg, 400 mg, or 600 mg of FVP.

Description

[0026] This invention is illustrated by, but not limited to, the following examples.

[0027] Example 1. Preparation of an Avifavir pharmaceutical composition in capsules containing 200 mg (45%) of FVP. Micronized FVP with a microcrystal size of 40-50 μm (200 g) and lactose powder (250 g) are carefully mixed. The resulting powder mixture is packed in 450 mg gelatin capsules of suitable size, each containing 200 mg (44.4%) of FVP.

[0028] Example 2. Preparation of an Avifavir pharmaceutical composition in coated tablets containing 200 mg, 300 mg, 400 mg, or 600 mg of FVP (formulation 3 in Table 1).

[0029] All starting materials are weighed, and magnesium stearate for dusting is sieved. Micronized FVP with a microcrystal size of 40-50 μm (200 g), MCC 102 microcrystalline cellulose (194.65 g), croscarmellose sodium (27.0 g), and 2.7 g of colloidal silicon dioxide (USP/NF, Ph.Eur.) are sequentially loaded in a granulating mixer, and the components are stirred until a homogeneous mixture is obtained. A previously prepared 6% solution of povidone K30 (22.5 g) is added to the granulator mixer in full at constant stirring, until the final granulation point is reached. Wet granulate is calibrated through a 2.0 mm sieve. The calibrated wet granulate is dried to the specified residual humidity. The dried granulate is calibrated through a 0.5 mm sieve to set 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 resulting core tablets with a mass of ≈450 mg, ≈675 mg, and ≈1350 mg, containing 200 mg, 300 mg, 400 mg, or 600 mg FVP, respectively, each with a hardness of 60 N, an abrasion of max 5% and a disintegration of max 3 min are passed to the coating stage. The film coat (Opadry 85F38183 yellow) is applied in a coater to attain the specified weight of the Avifavir coated tablet weighing 462 mg, 693 mg, or 1386 mg, respectively.

[0030] Avifavir pharmaceutical compositions in coated tablets as per formulations 1 and 2 are obtained similarly (Table 1).

[0031] Example 3. Kinetics of dissolution of Avifavir coated tablets containing 200 mg FVP in three buffer media.

[0032] The study of the kinetics of dissolution of Avipiravir in coated tablets containing 200 mg FVP was carried out in accordance with the “Guidelines for the Examination of Medicinal Products [Volume 1. Moscow: Grif and K., 2013, 328 pp., Chapter 7. 5. Guide to the examination of medicines. Volume 3. Moscow: POLYGRAPHPLUS Publ., 2014, 344 pp., Chapter 11.] in three buffer media with pH values of 1.2, 4.5 and 6.8 modeling the main areas of the gastrointestinal tract, in which the release and absorption of the active ingredient occurs. The following media were used: 0.2% sodium chloride solution in 0.1 M hydrochloric acid solution with pH 1.2; sodium acetate buffer solution with pH 4.5 (quality control medium); and phosphate buffer solution with pH 6.8; all the solutions were prepared in accordance with the requirements of 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 full release (at least 85% of the active ingredient) or a plateau. In studying dissolution kinetics, the following time points were selected: 5 min, 10 min, 15 min, 20 min, and 30 min. To obtain statistically reliable results for each drug, the test was performed on 12 dosage form units. The quantitative content of FVP released into the solution medium was determined by HPLC. The calculations took into account the change in the volume of the dissolution medium.

[0033] The study of the dissolution kinetics was performed on a DT 828 Dissolution Tester (Erweka, Germany) intended to evaluate the dissolution of tablets/capsules. Quantitative determination was performed using liquid chromatographs: Agilent 1260 (Agilent Technologies, USA) using OpenLab ChemStation software and LC-20A Prominence (Shimadzu, Japan) using LabSolutions software. Auxiliary equipment included: laboratory scales MV210A (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 experiment results was performed using the Microsoft Office Excel 2007 package. We used measuring laboratory utensils of classes “A” (measuring 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).

[0034] The test was performed in accordance with the requirements of State Pharmacopoeia XIV, GPM 1.4.2.0014.15 “Dissolution for solid dosage forms” [SPh XIV. Volume 2, 2018.-2164 p., GPM.1.4.2.0014.15 Dissolution for solid dosage forms.], “Guide to the examination of medicines” [Guide to the examination of medicines. Volume 1. Moscow: Grif and K., 2013.-328 p., Chapter 7. 5. Guide to the examination of medicines. Volume 3. Moscow: POLIGRAFPLUS Publ., 2014, 344 pp., 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” edited by I. E. Shokhin [“Dissolution Test” in the Development and Registration of Medicines. Scientific and Practical Guide for the Pharmaceutical Industry/Ed. I. E. Shokhin. Moscow, Pero Publ., 2015, 320 pp]. The test conditions were as follows. Instrument type: paddle apparatus; temperature: 37±0.5° C.; medium volume: 900 ml; rotation speed: 75 rpm; sampling time points: 5, 10, 15, 20, and 30 min. The results obtained from the study of FVP release from three Avipiravir tablet formulations depending on the size of the FVP particle size, the acidity of the solutions and the mixing time are presented in Table 1.