SARS-CoV-2 Antiviral Pharmaceutical Composition and Application Thereof

Abstract

This invention relates to a novel anti-RNA, including anti-SARS-CoV-2, viral pharmaceutical composition of Avipiravir in tablets or capsules containing 40-48 wt % of micronized favipiravir, the other ingredients being excipients.

The drug Antiprovir for the prevention and treatment of coronavirus disease COVID-19 is a pharmaceutical composition in the form of coated tablets containing 200 mg, 300 mg, 400 mg, or 600 mg of micronized favipiravir (44.1% by weight-45.6% by weight) with a particle size of 40-211 microns, the other ingredients being excipients.

Claims

1. An anti-SARS-CoV-2 viral pharmaceutical composition containing 40-48 wt % of micronized favipiravir with a particle size of 40-211 μm, the other ingredients being excipients.

2. The composition according to claim 1 containing 44.1-45.6 wt % of micronized favipiravir.

3. The composition according to any one of claims 1-2 containing excipients selected from a range of fillers, disintegrants, binders, glidants, and lubricants.

4. The composition according to any one of claims 1-3 for the prevention and treatment of COVID-19.

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

Description

BEST EMBODIMENT OF INVENTION

[0027] This invention is illustrated by, but not limited to, the following examples.

[0028] Example 1. Preparation of an Avifavir pharmaceutical composition in capsules, each containing 200 mg (45%) of FPV. Two hundred grams of micronized FPV with a microcrystal size of 40-50 μm and 250 grams of lactose powder are thoroughly mixed. The resulting powdered mixture is packed in 450 mg portions into suitably sized gelatin capsules, each containing 200 mg (44.4%) of FPV.

[0029] Example 2. Preparation of an Avifavir pharmaceutical composition in coated tablets, each containing 200 mg, 300 mg, 400 mg, or 600 mg FPV (formulation 3 in Table 1). All raw materials are weighed, and magnesium stearate is sifted for dusting. Micronized FPV with a microcrystalline size of 40-50 μm (200 g), microcrystalline cellulose MCC 102 (194.65 g), croscarmellose sodium (27.0 g), and 2.7 g of colloidal silicon dioxide (USP/NF, Ph.Eur.) are sequentially loaded into a granulator mixer, and the components are mixed until the mixture is homogeneous. With constant stirring of the mixture, a previously prepared 6% solution of povidone K30 (22.5 g) is loaded into the granulator mixer, 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 the specified residual humidity. The dried granulate is calibrated through a 0.5 mm sieve with setting the optimal fractional composition. The resulting granulate is powdered in a mixer with pre-sifted magnesium stearate (3.15 g). 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, or ≈1350 mg containing 200 mg, 300 mg, 400 mg, or 600 mg of FPV, respectively, each having a hardness of 60 N, an abrasion of no more than 5%, and a disintegration of no more than 3 min are transferred to the coating stage. The process of film coating (Opadry 85F38183 yellow) is carried out in a tablet coater until the target weight of an Avifavir tablet weighing 462 mg, 693 mg, or 1386 mg, respectively, is reached.

[0030] Similarly, pharmaceutical compositions of Avifavir in coated tablets are obtained according to formulations 1 and 2 (Table 1).

[0031] Example 3. The kinetics of dissolution of coated Avifavir tablets containing 200 mg FPV in three buffers.

[0032] The study of the kinetics of dissolution of Avipiravir in coated tablets containing 200 mg FPV was carried out in accordance with the guidelines for the examination of medicines [Guidelines for the Examination of Medicines. Volume 1. Moscow: Grif and K., 2013, 328 pp., Chapter 7.5; Guidelines for the Examination of Medicines. Volume 3, Moscow: POLYGRAPHPLUS, 2014, 344 pp., Chapter 11.] in three buffer media with pH=1.2, 4.5, and 6.8 to model the main areas of the gastrointestinal tract wherein the release and absorption of the active ingredient occurs. The following media were used in the study: 0.2% sodium chloride solution in 0.1 M hydrochloric acid with pH 1.2, sodium acetate buffer solution with pH 4.5 (quality control medium), and phosphate buffer solution with pH 6.8 all prepared in accordance with the EP.7.0.5.17.1 «Recommendations on Dissolution Testings». Time sampling points were selected to provide a reliable description of the dissolution profile with a gradual increase and subsequent attainment of complete release (at least 85% of the active ingredient) or plateau. To study dissolution kinetics, the following time sampling 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 carried out on 12 dosage form units. 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.

[0033] Dissolution kinetics was studied using a DT828 Tablet/Capsule Dissolution Tester (Erweka, Germany). Quantification was performed using liquid chromatographs: Agilent 1260 (Agilent Technologies, USA) with OpenLab ChemStation software and LC-20A Prominence (Shimadzu, Japan) with LabSolutions software. The laboratory scales MV210A (SartoGosm, Russia), Acculab VIC-210d2 (Acculab, Sartorius Group, USA), and Quintix 64-1ORU (Sartorius Group, Germany) as well as the pH-meter SEVEN MULTI (Mettler Toledo, Switzerland) were used as supporting equipment. Statistical processing of the experimental results was performed using Microsoft Office Excel 2007. We used volumetric glassware of classes “A” (volumetric flasks of 50, 500, 1000 ml), “AS” (1- and 5-ml analytical pipettes), and “B” (100-, 250- and 1000-ml volumetric cylinders).

[0034] The test was conducted in accordance with the requirements of SPRF XIV, GPM 1.4.2.0014.15 “Dissolution for Solid Dosage Forms”. [SPRF XIV, Vol. 2, 2018, 2164 pp., GPM.1.4.2.0014.15 Dissolution for Solid Dosage Forms], “Guidelines for the examination of medicinal products”. [Guidelines for the Examination of Medicinal Products. Vol. 1. Moscow: Grif & K., 2013, 328 pp., Chapter 7.5. Guidelines for the Examination of Medicinal Products. Volume 3. Moscow: POLIGRAFPLUS, 2014, 344 pp., Chapter 11.] as well as in accordance with the recommendations of the scientific and practical guidelines for the pharmaceutical industry “Dissolution Test in the Development and Registration of Medical Products” edited by I. E. Shokhin [Test in the Development and Registration of Medical Products. Scientific and Practical Guidlines for the Pharmaceutical Industry, Ed. by Shokhin I. E. Moscow: Pero Publ., 2015, 320 pp.]

[0035] Test conditions: apparatus type—paddle stirrer; temperature −37±0.5° C.; medium volume −900 ml; rotation speed −75 rpm; time sampling points −5, 10, 15, 20, and 30 min. The results of the evaluation of FPV release from three formulations of Avipiravir tablets as a function of FPV particle size, solution acidity, and stirring time are presented in Table 1.

INDUSTRIAL APPLICABILITY

[0036] The invention can be used in medicine and veterinary medicine.