AU2021276914A1

AU2021276914A1 - Novel composition for the treatment of viral infections

Info

Publication number: AU2021276914A1
Application number: AU2021276914A
Authority: AU
Inventors: Chitra AJITHAN VARMA; Chandanmal pukhraj BOTHRA; Hemanth Kumar BOTHRA; Elayaraja NATARAJAN
Original assignee: Nokha Trading LLP; Lyrus Life Sciences Pvt Ltd
Current assignee: Nokha Trading LLP; Lyrus Life Sciences Pvt Ltd
Priority date: 2020-05-20
Filing date: 2021-05-18
Publication date: 2022-12-01
Also published as: CA3176914A1; WO2021234554A2; WO2021234554A3

Abstract

The present invention relates to the combination of primary active agent and a mucolytic agent as an adjuvant for the treatment of Viral infections. The present invention relates to the combination of primary active agent and a mucolytic agent as an adjuvant specifically for the treatment of COVID-19. The present invention relates to the co-pack of primary active agent and a mucolytic agent as an adjuvant specifically for the treatment of COVID-19. The present invention specifically relates to composition comprising combination of anti-viral agent as primary active agent and a mucolytic agent as an adjuvant for the treatment of COVID-19. The present invention specifically relates composition comprising combination of anti-gout agent as primary active agent and a mucolytic agent as an adjuvant for the treatment of COVID-19. The present invention more specifically relates to the composition comprising Favipiravir as primary active agent and Carbocisteine as adjuvant, Colchicine as primary active agent and Carbocisteine as adjuvant for the treatment of COVID-19.

Description

NOVEL COMPOSITION FOR THE TREATMENT OF VIRAL

INFECTIONS

FIELD OF INVENTION

The present invention relates to the combination of primary active agent and a mucolytic agent as an adjuvant for the treatment of Viral infections.

The present invention relates to the combination of primary active agent and a mucolytic agent as an adjuvant specifically for the treatment of COVID-19.

The present invention relates to the co-pack of primary active agent and a mucolytic agent as an adjuvant specifically for the treatment of COVID-19.

The present invention specifically relates to composition comprising combination of anti-viral agent as primary active agent and a mucolytic agent as an adjuvant for the treatment of COVID-19.

The present invention specifically relates composition comprising combination of anti-gout agent as primary active agent and a mucolytic agent as an adjuvant for the treatment of COVID-19.

The present invention more specifically relates to the composition comprising Favipiravir as primary active agent and Carbocisteine as adjuvant, Colchicine as primary active agent and Carbocisteine as adjuvant for the treatment of COVID-19.

BACKGROUND OF THE INVENTION

Coronavirus disease (COVID-19) is an infectious disease caused by a newly discovered coronavirus. Most people infected with the COVID-19 virus will experience mild to moderate respiratory illness and recover without requiring special treatment. Older people and those with underlying medical problems like cardiovascular disease, diabetes, chronic respiratory disease, and cancer are more likely to develop serious illness.

The best way to prevent and slow down transmission is be well informed about the COVID-19 virus, the disease it causes and how it spreads. Protect yourself and others from infection by washing your hands or using an alcohol based rub frequently and not touching your face. The COVID-19 virus spreads primarily through droplets of saliva or discharge from the nose when an infected person coughs or sneezes, so it’s important that you also practice respiratory etiquette (for example, by coughing into a flexed elbow).

Acute respiratory disease caused by a novel coronavirus (SARS-CoV-2), the coronavirus disease 2019 (COVID-19). The emergence of SARS-CoV-2, since the severe acute respiratory syndrome coronavirus (SARS-CoV) in 2002 and Middle East respiratory syndrome coronavirus (MERS-CoV) in 2012, marked the third introduction of a highly pathogenic and large-scale epidemic coronavirus into the human population in the twenty-first century. Several independent research groups have identified that SARS-CoV-2 belongs to b-coronavirus, with highly identical genome to bat coronavirus, pointing to bat as the natural host.

The novel coronavirus uses the same receptor, angiotensin-converting enzyme 2 (ACE2) as that for SARS-CoV, and mainly spreads through the respiratory tract. Importantly, increasingly evidence showed sustained human-to-human transmission, along with many exported cases across the globe.

Carbocisteine, also called carbocysteine, is a mucolytic agent that reduces the viscosity of sputum and so can be used to help relieve the symptoms of chronic obstructive pulmonary disorder (COPD) and bronchiectasis by allowing the sufferer to bring up sputum more easily. The chemical name of Carbocisteine is S- carboxymethyl-L-cysteine. Carbocisteine has a chemical formula of C₅H₉NO₄S and a molecular mass of 179.19 g/mol. It has a structural formula of: Favipiravir is an antiviral medication used to treat influenza. The chemical name of Favipiravir is 6-Fluoro-3-hydroxypyrazine-2-carboxamide. Favipiravir has a chemical formula of C5H4FN3O2 and a molecular mass of 157.1 g/mol. It has a structural formula of:

Colchicine is a medication used to treat gout and Behcet's disease. In gout, it is less preferred to NSAIDs or steroids. Other uses include the prevention of pericarditis and familial Mediterranean fever. Colchicine is an alkaloid chemically described as (S) N-(5,6,7,9-tetrahydro-l,2,3,10-tetramethoxy-9-oxobenzo[alpha]heptalen-7-yl) acetamide. Colchicine has a chemical formula of C22H25NO6 and a molecular mass of 399.4 g/mol. It has a structural formula of:

WO Publication No. 2005/020885 A2 discloses composition and methods for treating a coronavirus infection, especially a SARS CoV infection. This application discloses the composition and methods for treating viral infections, such as coronavirus infections, by pulmonary or nasal administration of antiviral compounds and composition comprising the same. WO Publication No. 2006/030221 A1 discloses treatment of respiratory diseases which include Chronic Obstructive Pulmonary Disorder, pneumonia, bronchitis, cystic fibrosis, allergic disorders, asthma and several such disorders, which are characterized by bronchoconstriction accompanied by excessive mucus secretion. The formulations include a mucolytic agent along with an-antibacterial or an anti- viral agent. However, no specific antiviral agents are mentioned.

Rheumatology, 2017, 56(10), e24-e48 discloses mucolytic agent (i.e. Carbocisteine) reduced the viscosity of sputum, improved the ability to cough up bronchial secretions and reduced cough frequency and shortness of breath in a double blind controlled study of patients with chronic bronchitis. It also discloses improvements in ocular and oral dryness, lowering of ESR and immunoglobulin levels, together with reductions in fatigue levels and joint pain in patients treated with HCQ (Hydroxychloroquine).

British Medical Journal, 2020, 368, m627, 1-2, it discloses that Carbocisteine has been proven to reduce sputum viscosity, and has also been shown to modulate airway inflammation by reducing the cytokine storm and subsequent respiratory tract tissue damage and believes it might possibly also be able to reduce the quantity of COVID-19 viral particles. Since Carbocisteine is readily available, cost-effective and has few serious side-effects in capsule form, it is suggested that consideration be given to empirically add Carbocisteine to the current treatment regimen in patients infected with COVID-19 or those at high risk of infection since urgent clinical necessity and ethical considerations may not currently allow for the conduct of randomised trials with Carbocisteine in COVID-19 patients.

There are several vaccines approved to combat coronavirus (COVID-19) like The Oxford-AstraZeneca COVID-19 vaccine, sold under the brand names Vaxzevria and Covishield, The Pfizer-BioNTech COVID-19 vaccine, also known as Comirnaty, The Sputnik V COVID-19 vaccine, BBIBP-CorV, The Johnson & Johnson COVID- 19 vaccine, The Moderna COVID-19 vaccine, CoronaVac, Covaxin, Convidecia, EpiVacCorona, RBD-Dimer, WIBP-CorV and CoviVac.

There are many ongoing clinical trials evaluating potential treatments. There is a need to overcome the worldwide emergency situation caused by the novel coronavirus (CO VID- 19).

All the prior art references related to the composition and methods for treating a coronavirus infection, especially a SARS CoV infection using antiviral compounds. However, none of the patents/patent applications disclose use of composition comprising combination of the anti-viral agent as primary active agent and a mucolytic agent as an adjuvant, anti-gout agent as primary active agent and a mucolytic agent as an adjuvant.

The inventors of present invention provide novel composition comprising combinations of anti- viral agent as primary active agent and a mucolytic agent as an adjuvant, anti-gout agent as primary active agent and a mucolytic agent as an adjuvant for the treatment of COVID-19.

OBJECTIVE OF THE INVENTION

The main objective of the present invention is to provide combination of primary active agent and a mucolytic agent as an adjuvant for the treatment of Viral Infections.

Another objective of the present invention is to provide combination of primary active agent and a mucolytic agent as an adjuvant for the treatment of COVID-19.

Another objective of the present invention is to provide co-pack of primary active agent and a mucolytic agent as an adjuvant for the treatment of COVID-19. Another objective of the present invention is to provide composition comprising combination of anti-viral agent as primary active agent and a mucolytic agent as an adjuvant for the treatment of COVID-19.

Another objective of the present invention is to provide composition comprising combination of anti-gout agent as primary active agent and a mucolytic agent as an adjuvant for the treatment of COVID-19.

Another objective of the present invention is to provide composition comprising combination of Favipiravir as primary active agent and Carbocisteine as adjuvant for the treatment of COVID-19.

Another objective of the present invention is to provide composition comprising combination of Colchicine as primary active agent and Carbocisteine as adjuvant for the treatment of COVID-19.

SUMMARY OF THE INVENTION

Accordingly, the present invention provides a combination of primary active agent and a mucolytic agent as an adjuvant for the treatment of Viral Infections.

In one embodiment, the present invention provides combination of primary active agent and a mucolytic agent as an adjuvant for the treatment of COVID-19.

In one embodiment, the present invention provides co-pack of primary active agent and a mucolytic agent as an adjuvant for the treatment of COVID-19.

In one embodiment, the present invention provides co-pack of Favipiravir and Carbocisteine for the treatment of COVID-19. In one embodiment, the present invention provides co-pack of Colchicine and Carbocisteine for the treatment of COVID-19.

In another embodiment, present invention provides composition comprising combination of primary active agent and a mucolytic agent as an adjuvant, wherein said composition further comprises one or more of other excipients selected from diluents, binders, disintegrating agents, surfactants, glidants and lubricants.

In another embodiment, present invention provides composition comprising combination of primary active agent and a mucolytic agent as an adjuvant, wherein said composition further comprises one or more of other excipients selected from 5% to 90% w/w of diluents, 1% to 20% w/w of binders, 1% to 15% w/w of disintegrating agents, 0.01% to 2% w/w of surfactants, 0.1% to 10% w/w of glidants and 0.1% to 10% w/w of lubricants.

In another embodiment, present invention provides a bilayer tablet composition comprising; a) primary active agent layer comprising diluent, binder, surfactant and lubricant, and b) mucolytic agent layer comprising diluents, binders, disintegrating agents, surfactants, glidants and lubricants.

In one embodiment, the present invention provides composition comprising combination of primary active agent and a mucolytic agent as an adjuvant for the treatment of COVID-19, wherein the primary active agent is selected from anti- viral agent and anti-gout agent.

In one embodiment, the present invention provides composition comprising combination of primary active agent and a mucolytic agent as an adjuvant for the treatment of COVID-19, wherein the primary active agent is selected from anti- viral agent or anti-gout agent and a mucolytic agent is Carbocisteine.

In one embodiment, the present invention provides composition comprising combination of primary active agent and a mucolytic agent as an adjuvant for the treatment of COVID-19, wherein the primary active agent is Favipiravir.

In one embodiment, the present invention provides composition comprising combination of primary active agent and a mucolytic agent as an adjuvant for the treatment of COVID-19, wherein the primary active agent is Colchicine.

In another embodiment, the present invention provides composition comprising combination of Favipiravir as primary active agent and Carbocisteine as adjuvant for the treatment of COVID-19.

In another embodiment, present invention provides composition comprising combination of Favipiravir and Carbocisteine, wherein said composition further comprises one or more of other excipients selected from diluents, binders, disintegrating agents, surfactants, glidants and lubricants.

In another embodiment, present invention provides composition comprising combination of Favipiravir and Carbocisteine, wherein the composition further comprises lactose monohydrate, povidone, sodium lauryl sulphate and magnesium Stearate.

In another embodiment, present invention provides a bilayer tablet composition comprising; a) Carbocisteine layer comprising lactose monohydrate, povidone, sodium lauryl sulphate, magnesium Stearate, and b) Favipiravir layer comprising microcrystalline cellulose, colloidal silicon dioxide, low substituted hydroxypropyl cellulose, crospovidone, sodium stearyl fumarate.

In another embodiment, present invention provides a process for the preparation of composition comprising combination of Favipiravir and Carbocisteine, wherein the process comprises; a) mixing the Favipiravir, Carbocisteine and lactose monohydrate for 10 minutes in a rapid mixer granulator, b) preparing the binder solution of povidone in purified water under stirring, c) preparing solution of sodium lauryl sulphate in purified water under stirring, d) granulating the dry mixed materials of step (a) with binder solution and sodium lauryl sulphate solution, e) drying and lubricating granules with magnesium stearate and filled into capsules or compressed into tablets.

In another embodiment, present invention provides a process for the preparation of bilayer tablet of Favipiravir and Carbocisteine, wherein the process comprises;

1) preparation of Carbocisteine layer comprising; a) mixing Carbocisteine and lactose monohydrate for 10 minutes in a rapid mixer granulator, b) preparing the binder solution of povidone in purified water under stirring, c) preparing solution of sodium lauryl sulphate in purified water under stirring, d) granulating the dry mixed materials of step (a) with binder solution and sodium lauryl sulphate solution, e) drying and lubricating granules with magnesium stearate and

2) preparation of Favipiravir layer a) blending Favipiravir, colloidal silicon dioxide, microcrystalline cellulose and low substituted hydroxypropyl cellulose using suitable blender, b) granulating the blend using a roller compactor, c) sifting granules and lubricating the granules by adding crospovidone and sodium stearyl fumarate, wherein the granules obtained in step 1 and 2 are compressed into bilayer tablet.

In another embodiment, the present invention provides composition comprising combination of Colchicine as primary active agent and Carbocisteine as adjuvant for the treatment of COVID-19. In another embodiment, present invention provides composition comprising combination of Colchicine and Carbocisteine, wherein said composition further comprises one or more of other excipients selected from diluents, binders, disintegrating agents, surfactants, glidants and lubricants. In another embodiment, present invention provides composition comprising combination of Colchicine and Carbocisteine, wherein the composition further comprises lactose monohydrate, povidone, sodium lauryl sulphate and magnesium Stearate. In another embodiment, present invention provides a bilayer tablet composition comprising; a) Carbocisteine layer comprising lactose monohydrate, povidone, sodium lauryl sulphate, magnesium stearate, and b) Colchicine layer comprising lactose monohydrate, silica colloidal anhydrous and stearic acid.

In another embodiment, present invention provides a process for the preparation of composition comprising combination of Colchicine and Carbocisteine, wherein the process comprises; a) mixing the Colchicine, Carbocisteine and lactose monohydrate for 10 minutes in a rapid mixer granulator, b) preparing the binder solution of povidone in purified water under stirring, c) preparing solution of sodium lauryl sulphate in purified water under stirring, d) granulating the dry mixed materials of step (a) with binder solution and sodium lauryl sulphate solution, e) drying and lubricating granules with magnesium stearate and filled into capsules or compressed into tablets. In another embodiment, present invention provides a process for the preparation of bilayer tablet of Colchicine and Carbocisteine, wherein the process comprises;

2) preparation of Colchicine layer a) preparing solution of Colchicine in ethanol and purified water, b) granulating the lactose in rapid mixer granulator using the solution (a). c) drying the granules and adding silica colloidal anhydrous, wherein the granules obtained in step 1 and 2 are compressed into bilayer tablet.

DETAILED DESCRIPTION OF THE INVENTION

The term "comprising", which is synonymous with "including", "containing", or "characterized by" here is defined as being inclusive or open-ended, and does not exclude additional, unrecited elements or method steps, unless the context clearly requires otherwise.

The term “primary active agent” would be one which can inhibit viral replication. The term “adjuvant” would be the one which would be used along with the primary active agent in order to relive the respiratory conditions that occur during the later phase of COVID-19 infection.

The formulations comprising the primary active agent and adjuvant may be devised such that both the drugs are uniformly distributed within one dosage unit. Examples are bilayer tablet, tablet in tablet, single syrup etc. which can be proposed for the treatment.

Viral infections as used herein include and not limited to infections caused by common cold, influenza, human immunodeficiency virus (HIV), severe acute respiratory syndrome coronavirus (SARS-CoV) in 2002, Middle East respiratory syndrome coronavirus (MERS-CoV), Hepatitis B virus (HBV), Hepatitis C virus (HCV), Herpes Simplex 1 (HSV-1), Herpes Simplex 2 (HSV-2), cytomegalovirus (CMV), Varicella Zoster virus (VZV), Epstein Barr virus (EBV) and hence may be useful in the treatment of respiratory diseases which include Chronic Obstructive Pulmonary Disorder, pneumonia, bronchitis, cystic fibrosis, allergic disorders, asthma and several such disorders.

Coronaviruses are a large group of viruses that are common among animals. In rare cases, they can be transmitted from animals to humans. The spikes protruding from the virus's membrane look like the sun's corona. It is from this that the virus gets the name 'coronavirus'. It causes illnesses of the respiratory tract, ranging from the common cold to severe conditions like SARS. COVID-19 affects different people in different ways. Most infected people will develop mild to moderate illness and recover without hospitalization. Most common symptoms include fever, dry cough and tiredness. Less common symptoms include aches, pains, sore throat, diarrhoea, conjunctivitis, headache, loss of taste or smell, a rash on skin, or discolouration of fingers or toes.

The term “active ingredient” of the present invention is used to treat a person in need from COVID-19. Preferably used active ingredient is selected from anti-viral agent and anti-gout agent in combination with a mucolytic agent as adjuvant.

The term “mucolyte agent” of the present invention includes but is not limited to acetylcysteine, carbocisteine, erdosteine, letosteine, stepronin, bromhexine and ambroxol. Preferably used mucolyte agent is Carbocisteine.

Carbocisteine exhibits a wide range of in vitro and in vivo anti-inflammatory and anti-oxidant activities in both human and animal models. In certain circumstances, it may diminish inflammatory cell recruitment to the airways, attenuate endothelial injury and associated cough sensitivity, and act as a potent, free- radical scavenger. These actions, in parallel with its mucoregulatory function, have theoretical relevance to pathogenic processes in COPD and other inflammatory airways disease. Carbocisteine has also been shown in in-vitro studies to be able to modulate airway inflammation and reduce the quantity of viral particles in studies with Rhinovirus, Influenza virus, and Respiratory syncytial virus.

COVID-19 acts on angiotensin receptors for gaining entry into the host cell. Carbocisteine blocks the entry of organism via intercellular protein receptors and these receptors which are controlled by angiotensin receptors. Further, Carbocisteine may have potential to modulate airway inflammation by reducing the cytokine storm and subsequent respiratory tract tissue damage. Thus, the use of carbocisteine may help as an adjuvant to the primary active agent. The term “anti-viral agent” of the present invention includes but is not limited to abacavir, acyclovir, adefovir, amprenavir, atazanavir, cidofovir, didanosine, dideoxyadenosine, edoxudine, emtricitabine, entecavir, floxuridine, ganciclovir, idoxuridine, indinavir, kethoxal, lamivudine, lopinavir, 5-(methylamino)-2- deoxyuridine (madu), nelfinavir, nevirapine, penciclovir, podophyllotoxin, resiquimod, Favipiravir, ribavirin, ritonavir, saquinavir, sorivudine, stavudine, tenofovir, tipranavir, trifluridine, tromantadine, valganciclovir, vidarabine, zalcitabine, zanamivir or zidovudine. Preferably used anti-viral agent is Favipiravir.

Favipiravir, also known as Avigan, was approved for use in Japan in 2014 and is active against a range of illnesses, including influenza strains, yellow fever, Ebola and foot-and-mouth disease. Favipiravir was approved as an experimental treatment for COVID-19 infections.

The term “anti-gout agent” of the present invention includes but is not limited to allopurinol, carprofen, colchicine or orotic acid, benzbromarone, probenecid. Preferably used anti-gout agent is Colchicine.

Colchicine is used for treatment of acute gout. It is also used for prophylaxis of recurrent gout. Colchicine is indicated in Familial Mediterranean Fever for prophylaxis of attacks and prevention of amyloidosis. Colchicine has capacity to bind to tubulins, thereby blocking the assembly and polymerization of microtubules. Microtubules are involved in various cellular processes including maintenance of cell shape, intracellular trafficking, cytokine and chemokine secretion, cell migration, and regulation of ion channels and cell division. As pathogenic cargos, viruses require microtubules to transport to and from their intracellular sites of replication.

Colchicine binds to tubulin to form tubulin-colchicine complexes, which then binds to the ends of microtubules to prevent the elongation of the microtubule polymer. At low concentrations, colchicine arrests microtubule growth and, at higher concentrations, colchicine promotes microtubule depolymerisation. This may inhibit the intracellular transportation of the virus. Colchicine also has anti-inflammatory effects, mainly related to disruption of microtubules and downstream cellular functions of leucocytes. This may be further beneficial to counteract the cytokine storm which develops in the later phase of the viral infection.

Anti- viral agent, anti-gout agent acting as primary active agents and mucolytic agent as adjuvant are the novel potential combination therapies for the treatment of COVID-19.

Favipiravir, Colchicine acting as primary active agents and Carbocisteine as adjuvant are the novel potential combination therapies for the treatment of COVID- 19.

The composition of the present invention further comprising diluents, binders, disintegrating agents, surfactants, glidants and lubricants.

The diluents used in the composition of the present invention are selected from and not limited to, microcrystalline cellulose, powdered cellulose, lactose (anhydrous or monohydrate), compressible sugar, fructose, dextranes, other sugars such as mannitol, sorbitol, lactitol, saccharose or a mixture thereof, siliconised microcrystalline cellulose, calcium hydrogen phosphate, calcium carbonate, calcium lactate or mixtures thereof.

The concentration diluents present in the composition of the present invention is from 5% to 90% w/w of total weight of the composition.

The binders used in the composition of the present invention are selected from and not limited to, polyvinyl pyrollidone, polyvinylpyrrolidone/vinyl acetate copolymer, polyvinyl alcohol, polymers of acrylic acid and its salts, starch, celluloses and celluloses derivatives like methylcellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxyl propyl cellulose, ethylhydroxyethylcellulose, hydroxypropyl methylcellulose, carboxymethyl cellulose etc., maltrin, sucrose solution, dextrose solution, acacia, tragacanth, locust bean gum, gelatine, guar gum, starch, pregelatinised starch, partially hydrolysed starch, alginates, xanthan or polymethacrylate, or mixtures thereof.

The concentration binders present in the composition of the present invention is from 1% to 20% w/w of total weight of the composition.

The disintegrating agents used in the composition of the present invention are selected from and not limited to, carboxymethylcellulose, carboxymethylcellulosecalcium (CMC-Ca), carboxymethylcellulose sodium (CMC- Na), crosslinked sodium carboxymethyl cellulose as e.g. Ac-Di-Sol®, Primellose®, Pharmacelt® XL, Explocel®, and Nymcel® ZSX having a molecular weight of 90 000-700 000, sodium starch glycolate e.g. Explosol®, Explotab®, Glycolys®, Primojel®, Tablo®, Vivastar® P, in particular having molecular weight is 500000- 11000000, crosslinked polyvinylpolypyrrolidone (Plasone-XL®, Polyplasdone® XL and Kollidon® CL) in particular having a molecular weight in excess of 1000000, more particularly having a particle size distribution of less than 400 microns or less than 74 microns, microcrystalline cellulose, L-HPC (low-substituted hydroxypropylcellulose), sodium carboxymethyl starch, sodium glycolate of potato starch, partially hydrolysed starch, wheat starch, maize starch, rice starch or potato starch, cornstarch, pregelatinized starch, crospovidone, for example, POLYPLASDONE XL® (International Specialty Products), magnesium aluminium silicate or mixtures thereof.

The concentration disintegrating agents present in the composition of the present invention is from 1% to 15% w/w of total weight of the composition. The surfactants used in the composition of the present invention are selected from and not limited to, sodium salts of fatty alcohol sulphates such as sodium lauryl sulphate; or sulphosuccinates such as sodium dioctyl sulpho succinate; or partial fatty acid esters of polyhydric alcohols such as glycerol monostearate, glyceryl monooleate, glyceryl monobutyrate; or block copolymers of ethylene oxide and propylene oxide, also known as polyoxyethylene polyoxypropylene block copolymers or polyoxyethylene polypropyleneglycol, such as Poloxamer 124, Poloxamer 188, Poloxamer 237, Poloxamer 388, Poloxamer 407 (BASF Wyandotte Corp.); or fatty acid esters of sorbitan such as sorbitan mono laurate, sorbitan monopalmitate, sorbitan monooleate, sorbitan stearate, sorbitan monolaurate etc. such as Span or Arlacel , Emsorb®, Capmul®, or Sorbester®, Triton X-200 etc.; or a fatty acid esters of polyhydroxyethylene sorbitan such as polyoxyethylene (20) sorbitan, e.g. polyoxyethylene (20) sorbitan monooleate (Tween® 80), polyoxyethylene (20) sorbitan monostearate (Tween®60), polyoxyethylene (20) sorbitan monopalmitate (Tween® 40), polyoxyethylene (20) sorbitan monolaurate (Tween® 20); or polyethylene glycol fatty acid esters, e.g. PEG-200 monolaurate, PEG-200 dilaurate, PEG-300 dilaurate, PEG-400 dilaurate, PEG-300 distearate, PEG-300 dioleate; alkylene glycol fatty acid mono esters, e.g. propylene glycol monolaurate (Lauroglycol®); or hydrogenated castor oil and polyoxyethylene castor oil derivates, e.g. polyoxyethyleneglycerol triricinoleate or polyoxyl 35 castor oil (Cremophor® EL; BASF Corp.); or polyoxyethyleneglycerol oxystearate such as polyethylenglycol 40 hydrogenated castor oil (Cremophor RH® 40) or polyethylenglycol 60 hydrogenated castor oil (Cremophor RH® 60); or sucrose fatty acid esters, such as sucrose stearate, sucrose oleate, sucrose palmitate, sucrose laurate, and sucrose acetate butyrate; or vitamin E and its derivatives such as Vitamin E-TPGS® (d-alpha- tocopheryl polyethylene glycol 1000 succinate); or phospholipids, glycerophospholipids (lecithins, kephalins, phosphatidyl serine), glyceroglycolipids (galactopyransoide), sphingophospholipids (sphingomyelin), and sphingoglycolipids (ceramides, gangliosides), DSS (docusate sodium), docusate calcium, docusate potassium, SDS (sodium dodecyl sulfate or sodium lauryl sulfate), dipalmitoyl phosphatidic acid, sodium caprylate; or bile acids and salts thereof; or ethoxylated triglycerides; or quaternary ammonium salts such as cetyl-trimethylammonium bromide, cetylpyridinium chloride; or glycerol acetates such as acetin, diacetin and triacetin; or triethanolamine, lecithin, monohydric alcohol esters such as trialkyl citrates, lactones and lower alcohol fatty acid esters, nitrogen-containing solvents, glycerol fatty acid esters such as mono-, di- and triglycerides and a cetylated mono- and di-glycerides; propylene glycol esters, ethylene glycol esters, glycerol, cholic acid or derivatives thereof, lecithins, alcohols and glycine or taurine conjugates, ursodeoxycholic acid, sodium cholate, sodium deoxycholate, sodium taurocholate, sodium glycocholate, N-Hexadecyl-N, N-dimethyl-3-ammonio-l-propanesulfonate, anionic (alkyl- arylsulphonates) monovalent surfactants, palmitoyl lysophosphatidyl- L-serine, lysophospholipids (e.g. l-acyl-sn-glycero-3-phosphate esters of ethanolamine, choline, serine or threonine), alkyl, alkoxyl (alkyl ester), alkoxy (alkyl ether)- derivatives of lysophosphatidyl and phosphatidylcholines, e.g. lauroyl and myristoyl derivatives of lysophosphatidylcholine, dipalmitoylphosphatidylcholine, and modifications of the polar head group, that is cholines, ethanolamines, phosphatidic acid, serines, threonines, glycerol, inositol, and the postively charged DODAC, DOTMA, DCP, BISHOP, lysophosphatidylserine and lysophosphatidylthreonine, zwitterionic surfactants (e.g. N-alkyl-N, N- dimethylammonio- 1 -propanesulfonates, 3-cholamido-l-propyldimethylammonio-l - propanesulfonate, dodecylphosphocholine, myristoyl lysophosphatidylcholine, hen egg lysolecithin), cationic surfactants (quarternary ammonium bases), fusidic acid derivatives-(e.g. sodium tauro-dihydrofusidate etc.), long-chain falty acids and salts thereof C6-C2 (eg. oleic acid and caprylic acid), acylcarnitines and derivatives, N-a- acylated derivatives of lysine, arginine or histidine, or side-chain acylated derivatives of lysine or arginine, N-a-acylated derivatives of dipeptides comprising any combination of lysine, arginine or histidine and a neutral or acidic amino acid, N-a- acylated derivative of a tripeptide comprising any combination of a neutral amino acid and two charged amino acids, or the surfactant may be selected from the group of imidazoline derivatives, or mixtures thereof. The concentration surfactants present in the composition of the present invention is from 0.01% to 2% w/w of total weight of the composition.

The glidants used in the composition of the present invention are selected from and not limited to, talc, Silica colloidal anhydrous, fumed silica, magnesium stearate, stearic acid, kaolin, magnesium trisilicate either alone or in combination thereof.

The concentration glidants present in the composition of the present invention is from 0.1% to 10% w/w of total weight of the composition.

The lubricants used in the composition of the present invention are selected from and not limited to, stearic acid, magnesium stearate, calcium stearate, sodium lauryl sulphate, hydrogenated vegetable oil, hydrogenated castor oil, sodium stearyl fumarate, macrogols, or mixtures thereof.

The concentration lubricants present in the composition of the present invention is from 0.1% to 10% w/w of total weight of the composition.

The solvents used in the composition of the present invention are selected from and not limited to, methylene chloride, isopropyl alcohol, acetone, methanol, ethanol, water and the like and mixtures thereof.

The present invention is illustrated in detail but not limiting to, the following examples. It will be apparent to those skilled in the art that many modifications, both to materials and methods, may be practiced without departing from the scope of the invention. Example 1:

Formula: Carbocisteine 375 mg capsules

Manufacturing procedure: Sift the ingredients using a suitable mesh. Carry out dry mixing of Carbocisteine and Lactose monohydrate for 10 minutes in a rapid mixer granulator using suitable mixer speed. Prepare binder solution of Povidone in purified water under stirring conditions to get clear solution. Prepare solution of Sodium lauryl sulphate in purified water under stirring conditions to get clear solution. Granulate the dry mixed materials in rapid mixer granulator using suitable mixer speed. Transfer the wet mass into the FBD (Fluidized Bed Dryer) and dry the wet granules for 5 minutes at room temperature. After completion of 5 minutes of drying, continue drying the granules with an inlet air temperature of 55° C to 65°C (Target 60° C) till Loss on Drying (LOD) reaches not more than 2.00 % w/w. Sift the dried granules through #20 mesh, collect the retains of 20# and mill through multi-mill using 2.0 mm screen at OPTIMUM speed. Load the sized granules into the blender and add Magnesium Stearate. Mix for 3 minutes at optimum speed of Blender. Unload the lubricated granules into double polyethylene bag lined container and carry out capsule filling into size ‘O’ capsules.

Example 2:

Formula: Carbocisteine 375 mg capsules

Manufacturing procedure:

Sift the ingredients using a suitable mesh. Carry out dry mixing of Carbocisteine and Starch for 10 minutes in a rapid mixer granulator using suitable mixer speed. Prepare binder solution of Povidone in purified water under stirring conditions to get clear solution. Prepare solution of Sodium lauryl sulphate in purified water under stirring conditions to get clear solution. Granulate the dry mixed materials in rapid mixer granulator using suitable mixer speed. Transfer the wet mass into the FBD (Fluidized Bed Dryer) and dry the wet granules for 5 minutes at room temperature. After completion of 5 minutes of drying, continue drying the granules with an inlet air temperature of 55° C to 65°C (Target 60° C) till Loss on Drying (LOD) reaches not more than 2.00 % w/w. Sift the dried granules through #20 mesh, collect the retains of 20# and mill through multi-mill using 2.0 mm screen at OPTIMUM speed. Load the sized granules into the blender and add Magnesium Stearate. Mix for 3 minutes at optimum speed of Blender. Unload the lubricated granules into double polyethylene bag lined container and carry out capsule filling into size ‘O’ capsules.

Example 3:

Formula: Carbocisteine 375 mg capsules

Manufacturing procedure:

Sift the ingredients using a suitable mesh. Carry out dry mixing of Carbocisteine and Lactose monohydrate for 10 minutes in a rapid mixer granulator using suitable mixer speed. Prepare binder solution of Hypromellose in purified water under stirring conditions to get clear solution. Prepare solution of Sodium lauryl sulphate in purified water under stirring conditions to get clear solution. Granulate the dry mixed materials in rapid mixer granulator using suitable mixer speed. Transfer the wet mass into the FBD (Fluidized Bed Dryer) and dry the wet granules for 5 minutes at room temperature. After completion of 5 minutes of drying, continue drying the granules with an inlet air temperature of 55° C to 65°C (Target 60° C) till Loss on Drying (LOD) reaches not more than 2.00 % w/w. Sift the dried granules through #20 mesh, collect the retains of 20# and mill through multi-mill using 2.0 mm screen at OPTIMUM speed. Load the sized granules into the blender and add Magnesium Stearate. Mix for 3 minutes at optimum speed of Blender. Unload the lubricated granules into double polyethylene bag lined container and carry out capsule filling into size ‘O’ capsules.

Example 4: Formula: Favipiravir 200 mg Tablets

Manufacturing procedure:

Sift the ingredients using a suitable mesh. Blend Favipiravir, Colloidal silicon dioxide, Microcrystalline cellulose and Low substituted Hydroxy propyl cellulose using suitable blender. Dry granulate the materials using a roller compactor. Sift the granules through #20 mesh, collect the retains of 20# and mill through multi-mill using 2.0 mm screen at OPTIMUM speed. Load the sized granules into the blender and add Crosspovidone and mix for 10 minutes at optimum speed of Blender. Add Sodium stearyl fumarate and mix for 5 minutes at optimum speed of Blender. Unload the lubricated granules into double polyethylene bag lined container and carry out compression. Coat the tablets using the film coating system.

Example 5:

Formula: Colchicine 0.5 mg Tablets

Manufacturing procedure: Sift the ingredients using a suitable mesh. Carry out dry mixing of Lactose monohydrate (200M), Starch pregelatinized and Sodium starch glycolate (Type A) for 5 minutes in a rapid mixer granulator using suitable mixer speed. Prepare solution of Colchicine in Ethanol and purified water mixture under stirring conditions to get clear solution. Granulate the dry mixed materials in rapid mixer granulator using suitable mixer speed. Transfer the wet mass into the FBD (Fluidized Bed Dryer) and dry the wet granules for 5 minutes at room temperature. After completion of 5 minutes of drying, continue drying the granules with an inlet air temperature of 55° C to 65°C (Target 60° C) till Foss on Drying (FOD) reaches not more than 2.50 % w/w. Sift the dried granules through #20 mesh, collect the retains of 20# and mill through multi-mill using 2.0 mm screen at OPTIMUM speed. Foad the sized granules into the blender and add Silica colloidal anhydrous and Sodium starch glycolate (Type A). Mix for 10 minutes at optimum speed of Blender. Add Stearic acid and mix for 3 minutes at optimum speed of Blender. Unload the lubricated granules into double polyethylene bag lined container and carry out compression.

Example 6:

Formula: Carbocisteine 375 mg and Colchicine 0.5 mg Capsules Manufacturing procedure: Sift the ingredients using a suitable mesh. Carry out dry mixing of Colchicine, Carbocisteine and Lactose monohydrate for 10 minutes in a rapid mixer granulator using suitable mixer speed. Prepare binder solution of Povidone in purified water under stirring conditions to get clear solution. Prepare solution of Sodium lauryl sulphate in purified water under stirring conditions to get clear solution. Granulate the dry mixed materials in rapid mixer granulator using suitable mixer speed. Transfer the wet mass into the FBD (Fluidized Bed Dryer) and dry the wet granules for 5 minutes at room temperature. After completion of 5 minutes of drying, continue drying the granules with an inlet air temperature of 55° C to 65°C (Target 60° C) till Loss on Drying (LOD) reaches not more than 2.00 % w/w. Sift the dried granules through #20 mesh, collect the retains of 20# and mill through multi-mill using 2.0 mm screen at OPTIMUM speed. Load the sized granules into the blender and add Magnesium Stearate. Mix for 3 minutes at optimum speed of Blender. Unload the lubricated granules into double polyethylene bag lined container and carry out capsule filling into size ‘O’ capsules. For Tablets, compress the blend using suitable tooling.

Example 7:

Formula: Carbocisteine 375 mg and Colchicine 0.5 mg Bilayer Tablets

Manufacturing procedure:

For Layer 1 :

Sift the ingredients using a suitable mesh. Carry out dry mixing of Carbocisteine and Lactose monohydrate for 10 minutes in a rapid mixer granulator using suitable mixer speed. Prepare binder solution of Povidone in purified water under stirring conditions to get clear solution. Prepare solution of Sodium lauryl sulphate in purified water under stirring conditions to get clear solution. Granulate the dry mixed materials in rapid mixer granulator using suitable mixer speed. Transfer the wet mass into the FBD (Fluidized Bed Dryer) and dry the wet granules for 5 minutes at room temperature. After completion of 5 minutes of drying, continue drying the granules with an inlet air temperature of 55° C to 65°C (Target 60° C) till Loss on Drying (LOD) reaches not more than 2.00 % w/w. Sift the dried granules through #20 mesh, collect the retains of 20# and mill through multi-mill using 2.0 mm screen at OPTIMUM speed. Load the sized granules into the blender and add Magnesium Stearate. Mix for 3 minutes at optimum speed of Blender. Unload the lubricated granules into double polyethylene bag lined container.

For Layer 2:

Sift the ingredients using a suitable mesh. Prepare solution of Colchicine in Ethanol and purified water mixture under stirring conditions to get clear solution. Granulate the Lactose in rapid mixer granulator using the above solution using suitable mixer speed. Transfer the wet mass into the FBD (Fluidized Bed Dryer) and dry the wet granules for 5 minutes at room temperature. After completion of 5 minutes of drying, continue drying the granules with an inlet air temperature of 55° C to 65°C (Target 60° C) till Loss on Drying (LOD) reaches not more than 2.50 % w/w. Sift the dried granules through #20 mesh, collect the retains of 20# and mill through multi-mill using 2.0 mm screen at OPTIMUM speed. Load the sized granules into the blender and add Silica colloidal anhydrous. Mix for 10 minutes at optimum speed of Blender. Add Stearic acid and mix for 3 minutes at optimum speed of Blender. Unload the lubricated granules into double polyethylene bag lined container. Carry out the compression of layer 1 and layer 2 into bilayer tablets using a bilayer compression machine.

Example 8:

Formula: Carbocisteine 375 mg and Favipiravir 200 mg Bilayer Tablets

Manufacturing procedure:

For Layer 1 : Sift the ingredients using a suitable mesh. Carry out dry mixing of Carbocisteine and Lactose monohydrate for 10 minutes in a rapid mixer granulator using suitable mixer speed. Prepare binder solution of Povidone in purified water under stirring conditions to get clear solution. Prepare solution of Sodium lauryl sulphate in purified water under stirring conditions to get clear solution. Granulate the dry mixed materials in rapid mixer granulator using suitable mixer speed. Transfer the wet mass into the FBD (Fluidized Bed Dryer) and dry the wet granules for 5 minutes at room temperature. After completion of 5 minutes of drying, continue drying the granules with an inlet air temperature of 55° C to 65°C (Target 60° C) till Loss on Drying (LOD) reaches not more than 2.00 % w/w. Sift the dried granules through #20 mesh, collect the retains of 20# and mill through multi-mill using 2.0 mm screen at OPTIMUM speed. Load the sized granules into the blender and add Magnesium Stearate. Mix for 3 minutes at optimum speed of Blender. Unload the lubricated granules into double polyethylene bag lined container. For Layer 2:

Sift the ingredients using a suitable mesh. Blend Favipiravir, Colloidal silicon dioxide, Microcrystalline cellulose and Low substituted Hydroxypropyl cellulose using suitable blender. Dry granulate the materials using a roller compactor. Sift the granules through #20 mesh, collect the retains of 20# and mill through multi-mill using 2.0 mm screen at OPTIMUM speed. Load the sized granules into the blender and add Crosspovidone and mix for 10 minutes at optimum speed of Blender. Add Sodium stearyl fumarate and mix for 5 minutes at optimum speed of Blender. Unload the lubricated granules into double polyethylene bag lined container.

Carry out the compression of layer 1 and layer 2 into bilayer tablets using a bilayer compression machine.

Carbocisteine capsules from Example 1, 2 or 3 can be administered concomitantly together with Favipiravir (example 4) or Colchicine (example 5) acting as primary active agents. Carbocisteine can be supplied along with Favipiravir or Colchicine in COMBO packs i.e. in a single pack for treatment of COVID-19.

Stability Study

The above formulations were found to be stable at accelerated stability conditions for a period of 6 months. The data is shown below in different tables:

Example 1 in 40° C/75 % RH condition, Blister packs Example 4 in 40° C/75 % RH condition, Blister packs

Example 5 in 40° C/75 % RH condition, Blister packs

Example 6 Capsules in 40° C/75 % RH condition, Blister packs

Example 8 in 40° C/75 % RH condition, Blister packs

Claims

WE CLAIM:

1. A combination of primary active agent and a mucolytic agent as an adjuvant for the treatment of Viral Infections.

2. The combination as claimed in claim 1, wherein the combination of primary active agent and a mucolytic agent as an adjuvant for the treatment of COVID-19.

3. A composition comprising combination of primary active agent and a mucolytic agent as an adjuvant, wherein said composition further comprises one or more of other excipients selected from diluents, binders, disintegrating agents, surfactants, glidants and lubricants.

4. The composition as claimed in claim 3, wherein composition comprising combination of primary active agent and a mucolytic agent as an adjuvant, wherein said composition further comprises one or more of other excipients selected from 5% to 90% w/w of diluents, 1% to 20% w/w of binders, 1% to 15% w/w of disintegrating agents, 0.01% to 2% w/w of surfactants, 0.1% to 10% w/w of glidants and 0.1% to 10% w/w of lubricants.

5. A bilayer tablet composition comprising; a) primary active agent layer comprising diluent, binder, surfactant and lubricant, and b) mucolytic agent layer comprising diluents, binders, disintegrating agents, surfactants, glidants and lubricants and c) optional other pharmaceutically acceptable excipients.

6. A composition comprising combination of primary active agent and a mucolytic agent as an adjuvant for the treatment of COVID-19, wherein the primary active agent is selected from anti-viral agent or anti-gout agent and a mucolytic agent is Carbocisteine.

7. The composition as claimed in claim 6, wherein the anti- viral agent is Favipiravir.

8. The composition as claimed in claim 6, wherein the anti-gout agent is Colchicine.

9. A composition comprising combination of Favipiravir and Carbocisteine, wherein said composition further comprises one or more of other excipients selected from diluents, binders, disintegrating agents, surfactants, glidants and lubricants.

10. The composition as claimed in claim 9, wherein the composition comprising combination of Favipiravir, Carbocisteine, lactose monohydrate, povidone, sodium lauryl sulphate and magnesium Stearate.

11. A bilayer tablet composition comprising; a) Carbocisteine layer comprising lactose monohydrate, povidone, sodium lauryl sulphate, magnesium Stearate, and b) Favipiravir layer comprising microcrystalline cellulose, colloidal silicon dioxide, low substituted hydroxypropyl cellulose, crospovidone, sodium stearyl fumarate and c) optional other pharmaceutically acceptable excipients.

12. A process for the preparation of composition comprising combination of Favipiravir and Carbocisteine, wherein the process comprises; a) mixing the Favipiravir, Carbocisteine and lactose monohydrate for 10 minutes in a rapid mixer granulator, b) preparing the binder solution of povidone in purified water under stirring, c) preparing solution of sodium lauryl sulphate in purified water under stirring, d) granulating the dry mixed materials of step (a) with binder solution and sodium lauryl sulphate solution, e) drying and lubricating granules with magnesium stearate and filled into capsules or compressed into tablets.

13. A process for the preparation of bilayer tablet of Favipiravir and Carbocisteine, wherein the process comprises;

1) preparation of Carbocisteine layer comprising; a) mixing Carbocisteine and lactose monohydrate for 10 minutes in a rapid mixer granulator, b) preparing the binder solution of povidone in purified water under stirring, c) preparing solution of sodium lauryl sulphate in purified water under stirring, d) granulating the dry mixed materials of step (a) with binder solution and sodium lauryl sulphate solution, e) drying and lubricating granules with magnesium stearate and 2) preparation of Favipiravir layer a) blending Favipiravir, colloidal silicon dioxide, microcrystalline cellulose and low substituted hydroxypropyl cellulose using suitable blender, b) granulating the blend using a roller compactor, c) sifting granules and lubricating the granules by adding crospovidone and sodium stearyl fumarate, wherein the granules obtained in step 1 and 2 are compressed into bilayer tablet.

14. A composition comprising combination of Colchicine and Carbocisteine, wherein said composition further comprises one or more of other excipients selected from diluents, binders, disintegrating agents, surfactants, glidants and lubricants.

15. The composition as claimed in claim 14, wherein the composition comprising combination of Colchicine, Carbocisteine, lactose monohydrate, povidone, sodium lauryl sulphate and magnesium Stearate.

16. A bilayer tablet composition comprising; a) Carbocisteine layer comprising lactose monohydrate, povidone, sodium lauryl sulphate, magnesium stearate, and b) Colchicine layer comprising lactose monohydrate, silica colloidal anhydrous and stearic acid and c) optional other pharmaceutically acceptable excipients.

17. A process for the preparation of composition comprising combination of

Colchicine and Carbocisteine, wherein the process comprises; a) mixing the Colchicine, Carbocisteine and lactose monohydrate for 10 minutes in a rapid mixer granulator, b) preparing the binder solution of povidone in purified water under stirring, c) preparing solution of sodium lauryl sulphate in purified water under stirring, d) granulating the dry mixed materials of step (a) with binder solution and sodium lauryl sulphate solution, e) drying and lubricating granules with magnesium stearate and filled into capsules or compressed into tablets.

18. A process for the preparation of bilayer tablet of Colchicine and Carbocisteine, wherein the process comprises;

19. The composition as claimed in claim 3, wherein diluents are selected from and not limited to, microcrystalline cellulose, powdered cellulose, lactose (anhydrous or monohydrate), compressible sugar, fructose, dextranes, other sugars such as mannitol, sorbitol, lactitol, saccharose or a mixture thereof, siliconised microcrystalline cellulose, calcium hydrogen phosphate, calcium carbonate, calcium lactate or mixtures thereof.

20. The composition as claimed in claim 3, wherein binders are selected from and not limited to, polyvinyl pyrollidone, polyvinylpyrrolidone/vinyl acetate copolymer, polyvinyl alcohol, polymers of acrylic acid and its salts, starch, celluloses and celluloses derivatives like methylcellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxyl propyl cellulose, ethylhydroxyethylcellulose, hydroxypropyl methylcellulose, carboxymethyl cellulose etc., maltrin, sucrose solution, dextrose solution, acacia, tragacanth, locust bean gum, gelatine, guar gum, starch, pregelatinised starch, partially hydrolysed starch, alginates, xanthan or polymethacrylate, or mixtures thereof.

21. The composition as claimed in claim 3, wherein disintegrating agents are selected from and not limited to, carboxymethylcellulose, carboxymethylcellulosecalcium, arboxymethylcellulose sodium (CMC-Na), crosslinked sodium carboxymethyl cellulose, sodium starch glycolate, crosslinked polyvinylpolypyrrolidone, microcrystalline cellulose, low -substituted hydroxypropylcellulose, sodium carboxymethyl starch, sodium glycolate of potato starch, partially hydrolysed starch, wheat starch, maize starch, rice starch or potato starch, cornstarch, pregelatinized starch, crospovidone, for example, magnesium aluminium silicate or mixtures thereof.

22. The composition as claimed in claim 3, wherein surfactants used in the composition of the present invention are selected from and not limited to, sodium salts of fatty alcohol sulphates such as sodium lauryl sulphate; or sulphosuccinates such as sodium dioctyl sulpho succinate or mixtures thereof.

23. The composition as claimed in claim 3, wherein glidants are selected from and not limited to, talc, Silica colloidal anhydrous, fumed silica, magnesium stearate, stearic acid, kaolin, magnesium trisilicate either alone or in combination thereof.

24. The composition as claimed in claim 3, wherein lubricants are selected from and not limited to, stearic acid, magnesium stearate, calcium stearate, sodium lauryl sulphate, hydrogenated vegetable oil, hydrogenated castor oil, sodium stearyl fumarate, macrogols, or mixtures thereof.

25. A co-pack of primary active agent and a mucolytic agent as an adjuvant for the treatment of COVID-19.

26. A co-pack of Favipiravir and Carbocisteine for the treatment of COVID-19.

27. A co-pack of Colchicine and Carbocisteine for the treatment of COVID-19.