DESC:FIELD OF INVENTION:
The present invention relates to a pharmaceutical composition comprising molnupiravir, nirmatrelvir and optionally ritonavir, a process for preparing such pharmaceutical composition, and use of the said pharmaceutical composition for the prevention, treatment and prophylaxis of diseases caused by viruses.
BACKGROUND AND PRIOR ART
The SARS-CoV-2 coronavirus, and its associated disease, COVID-19, has led to an unprecedented series of steps to mitigate its spread throughout the world. SARS-CoV-2 infects primarily lung tissue and leads to a wide variety of symptoms, including: fever or chills, cough, shortness of breath or difficulty breathing, fatigue, muscle or body aches, blood clots, headache, new loss of taste or smell, sore throat, congestion or runny nose, nausea or vomiting, diarrhea and/or death.
COVID19, caused by the betacoronavirus (CoV) Glade SARS-CoV-2, ranges from asymptomatic disease to fatal multi-organ failure. COVID-19 disease severity may be influenced by adverse environmental exposures such as to air pollution and underlying comorbidities such as obesity, hypertension and diabetes
The worldwide mobilization of medical resources to prevent, treat, or reduce the symptoms of COVID-19 is following many different tracks, including vaccine development, newer anti-viral medications, and the use of existing agents to reduce the level the need for hospitalization and the use of ventilators.
Molnupiravir is one such antiviral drug which is commercially available as 200 mg capsules under the trade name Lagevrio® for the treatment of mild to moderate coronavirus disease 2019 (COVID-19) in adults. The recommended adult dosage of molnupiravir is 800 mg orally i.e. four 200 mg capsules taken orally every 12 hours for 5 days.
Molnupiravir is chemically known as N-Hydroxy-5'-O-isobutyryl-3,4-dihydrocytidine [(2R,3S,4R,5R)-3,4-Dihydroxy-5-[4-(hydroxyamino)-2-oxopyrimidin-1-yl]oxolan-2-yl]methyl 2-methylpropanoate and has the following structural formula.

Molnupiravir is a prodrug that is metabolised to the ribonucleoside analogue N-hydroxycytidine (NHC) which distributes into cells where it is phosphorylated to form the pharmacologically active ribonucleoside triphosphate (NHC-TP). NHC-TP acts by a mechanism known as viral error catastrophe. NHC-TP incorporation into viral RNA by the viral RNA polymerase, results in an accumulation of errors in the viral genome leading to inhibition of replication.
Nirmatrelvir is an antiviral drug which acts as an orally active 3CL protease inhibitor.
Nirmatrelvir is chemically known as (1R,2S,5S)-N-[(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl]-3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-azabicyclo[3.1.0]hexane-2-carboxamideand has the following structural formula.

The combination of nirmatrelvir with ritonavir is currently in phase III trials for the treatment of COVID-19. Further, the combination of nirmatrelvir with ritonavir, when given within three days of symptom onset, reduced the risk of hospitalization or death by 89% compared with placebo in 2,246 high-risk participants studied.
Based on hospitalized patient data, the majority of COVID-19 cases (about 80%) present with asymptomatic or mild symptoms, while the remainder are severe or critical (Huang et al. , Lancet 395:497 (2020); Chan et al., Lancet 395:514 (2020)). Although the vast majority of patients experience only a mild form of the illness, approximately 15% of the patients experience a severe form of the illness that often requires assisted ventilation and oxygenation.
Hence, there is an urgent need for safe and effective therapeutic and prophylactic agents or combination of such therapeutic and prophylactic agents against coronavirus infections, such SARS-CoV-2 and related viruses.
OBJECT OF THE INVENTION:
An object of the present invention is to provide a pharmaceutical composition comprising molnupiravir, nirmatrelvir.
Another object of the present invention is to provide a pharmaceutical composition comprising molnupiravir, nirmatrelvir and ritonavir.
Yet another object of the present invention is to provide a stable pharmaceutical composition comprising molnupiravir, nirmatrelvir and optionally ritonavir.
Another object of the present invention is to provide a process for preparing a pharmaceutical composition comprising molnupiravir, nirmatrelvir and optionally ritonavir.
One another object of the present invention is to provide a method for treatment or prophylaxis of diseases caused by viruses which comprises administering a pharmaceutical composition comprising molnupiravir, nirmatrelvir and optionally ritonavir.
Another object of the present invention is to provide a pharmaceutical composition comprising molnupiravir, nirmatrelvir and optionally ritonavir for use in treating diseases caused by viruses.

SUMMARY OF THE INVENTION
According to another aspect of the present invention there is provided a process of manufacturing a pharmaceutical composition comprising molnupiravir, nirmatrelvir and optionally ritonavir and one or more pharmaceutically acceptable excipients.
According to yet another aspect of the present invention, there is provided a stable pharmaceutical composition comprising molnupiravir, nirmatrelvir and optionally ritonavir.
According to another aspect of the present invention there is provided a method of preventing, treating or prophylaxis of diseases caused by viruses, which method comprises administering pharmaceutical composition comprising molnupiravir, nirmatrelvir and optionally ritonavir.
According to another aspect of the present invention there is provided a pharmaceutical composition comprising molnupiravir, nirmatrelvir and optionally ritonavir for use in treating diseases caused by viruses.
DETAILED DESCRIPTION OF THE INVENTION
The inventors of the present invention have developed pharmaceutical composition comprising of molnupiravir, nirmatrelvir and optionally ritonavir.
The term “molnupiravir, “nirmatrelvir”, “ritonavir” is used in a broad sense to include not only “molnupiravir, “nirmatrelvir”, “ritonavir” per se but also their pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable hydrates, pharmaceutically acceptable enantiomers, pharmaceutically acceptable esters, pharmaceutically acceptable derivatives, pharmaceutically acceptable polymorphs, pharmaceutically acceptable prodrugs, pharmaceutically acceptable complexes etc.
The term "pharmaceutical composition" includes tablets, powders, powders for reconstitution, pellets, beads, mini-tablets, film coated tablets, bilayered tablets, tablet in tablet, pills, micro-pellets, small tablet units, MUPS, disintegrating tablets, dispersible tablets, granules, and microspheres, multiparticulates, capsules (filled with powders, powders for reconstitution, pellets, beads, mini-tablets, pills, micro-pellets, small tablet units, MUPS, orally disintegrating MUPS, disintegrating tablets, dispersible tablets, granules, and microspheres, multiparticulates), sachets (filled with powders, pellets, beads, mini-tablets, pills, micro-pellets, small tablet units, MUPS, disintegrating tablets, dispersible tablets, modified release tablets or capsules, effervescent granules, granules, and microspheres, multiparticulates) and sprinkles and the like, however, other dosage forms such as liquid dosage forms (liquids, liquid dispersions, suspensions, solutions, emulsions, sprays, spot-ons), liposomal formulations, injection preparations, implants, depots, gels, aerosols, ointments, creams, controlled release formulations, lyophilized formulations, delayed release formulations, extended release formulations, pulsatile release formulations, and mixed immediate release and controlled release formulations etc. may also be envisaged under the ambit of the invention.
Suitably, the pharmaceutical composition, according to the present invention are presented in a solid dosage form, conveniently in unit dosage form, and include dosage form suitable for oral and buccal administration.
Preferably, the pharmaceutical composition is a solid oral dosage form. More preferably, the solid dosage form is in the form of tablets, powders, powders for reconstitution, pellets, beads, mini-tablets, film coated tablets, tablet in tablet, bilayered tablets, pills, micro-pellets, small tablet units, MUPS, orally disintegrating MUPS, disintegrating tablets, dispersible tablets, granules, modified release tablets or capsules, microspheres, multiparticulates, capsules (filled with powders, powders for reconstitution, pellets, beads, mini-tablets, pills, micro-pellets, small tablet units, MUPS, disintegrating tablets, dispersible tablets, granules, effervescent granules, microspheres, multiparticulates), sachets (filled with powders, pellets, beads, mini-tablets, pills, micro-pellets, small tablet units, MUPS, disintegrating tablets, dispersible tablets, granules, and microspheres, multiparticulates) and sprinkles and the like. A tablet formulation is the preferred solid dosage form due to its greater stability, less risk of chemical interaction between different medicaments, smaller bulk, accurate dosage, and ease of production.
According to one embodiment, the present invention also relates to a pharmaceutical composition comprising molnupiravir, nirmatrelvir and optionally ritonavir.
It will be understood, however, that specific dose level and frequency of dosage according to the invention for any particular patient may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, the severity of the particular condition, and the host undergoing therapy.
According to the preferred embodiment, the pharmaceutical composition of the present invention comprises molnupiravir from about 200 mg to 800 mg, nirmatrelvir from about 100 mg to 500 mg. Preferably, the pharmaceutical composition of the present invention comprises nirmatrelvir from about 150 mg to 300 mg.
In one aspect, the pharmaceutical composition, according to the present invention, is administered in combination with ritonavir in dosages of ritonavir from about 25 mg to 100 mg.
In another aspect, the pharmaceutical composition, according to the present invention, is administered once or twice a day for 3 days, once or twice a day for 5 days, once or twice a day for 7 days.
In yet another aspect, the pharmaceutical composition, according to the present invention, is intended for pediatric use.
In another aspect, the pharmaceutical composition, according to the present invention, is administered as a fixed dose combination tablet, multilayer tablet, preferably a bilayer tablet.
In yet another aspect, the pharmaceutical composition, according to the present invention, is administered as a kit dosage form.
In another aspect, the pharmaceutical composition, according to the present invention, is administered as powders, powders for reconstitution, pellets, beads, mini-tablets, film coated tablets, tablet in tablet, bilayered tablet, pills, micro-pellets, small tablet units, MUPS, orally disintegrating MUPS, modified release tablets or capsules, disintegrating tablets, dispersible tablets, granules, and microspheres, multiparticulates directly or the powders, powders for reconstitution, pellets, beads, mini-tablets, pills, micro-pellets, small tablet units, MUPS, disintegrating tablets, dispersible tablets, granules, effervescent granules, sprinkles and microspheres, multiparticulates which may be filled into capsules or sachets and administered in the respective dosage form thus formulated.
Such capsules or sachets, according to the present invention may also be administered by sprinkling the formulation onto a regular meal, or administered with a liquid or semi-solid beverage, such as fruit juices, water, milk, baby formulas, soft foods, apple sauce, yogurt, and the like.
Suitable excipients are used for formulating the various dosage forms according to the present invention.
According to the present invention, pharmaceutically acceptable carriers, diluents or fillers for use in the pharmaceutical composition of the present invention may comprise one or more, but are not limited to lactose (for example, spray-dried lactose, a-lactose, ß-lactose), lactose available under the trade mark Tablettose, various grades of lactose available under the trade mark Pharmatose or other commercially available forms of lactose, lactitol, saccharose, sorbitol, mannitol, dextrates, dextrins, dextrose, maltodextrin, croscarmellose sodium, microcrystalline cellulose (for example, microcrystalline cellulose available under the trade mark Avicel), hydroxypropylcellulose, L-hydroxypropylcellulose (low substituted), hydroxypropyl methylcellulose (HPMC), methylcellulose polymers (such as, for example Methocel A, Methocel A4C, Methocel A15C, Methocel A4M), hydroxyethylcellulose, sodium carboxymethylcellulose, carboxymethylene, carboxymethyl hydroxyethylcellulose and other cellulose derivatives, starches or modified starches (including potato starch, corn starch, maize starch and rice starch) and the like or mixtures thereof.
According to the present invention, glidants, anti-adherents and lubricants may also be incorporated in the pharmaceutical composition of the present invention, which may comprise one or more, but not limited to stearic acid and pharmaceutically acceptable salts or esters thereof (for example, magnesium stearate, calcium stearate, sodium stearyl fumarate or other metallic stearate), talc, waxes (for example, microcrystalline waxes) and glycerides, light mineral oil, PEG, silica acid or a derivative or salt thereof (for example, silicates, light anhydrous silicic acid, hydrated silicon dioxide, silicon dioxide, colloidal silicon dioxide and polymers thereof, crospovidone, magnesium aluminosilicate and/or magnesium alumino metasilicate), sucrose ester of fatty acids, hydrogenated vegetable oils (for example, hydrogenated castor oil), and the like or mixtures thereof.
According to the present invention, suitable binders may also present in the pharmaceutical composition, which may comprise one or more, but not limited to polyvinyl pyrrolidone (also known as povidone), polyethylene glycol, acacia, alginic acid, agar, calcium carragenan, cellulose derivative such as ethyl cellulose, methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose or sodium carboxymethylcellulose, microcrystalline cellulose, dextrin, gelatin, gum arabic, guar gum, tragacanth, sodium alginate, copovidone, starches, and the like or any other pharmaceutically acceptable substances with cohesive properties, or any combination thereof.
Suitable solvents used in the processes of preparing the pharmaceutical composition of the present invention, include, but are not limited to, water, methanol, ethanol, acidified ethanol, acetone, diacetone, polyols, polyethers, oils, esters, alkyl ketones, methylene chloride, isopropyl alcohol, butyl alcohol, methyl acetate, ethyl acetate, isopropyl acetate, castor oil, ethylene glycol monoethyl ether, diethylene glycol monobutyl ether, diethylene glycol monoethyl ether, dimethylsulphoxide, N,N-dimethylformamide, tetrahydrofuran and the likeor mixtures thereof.
According to the present invention, suitable disintegrants may also be present in the pharmaceutical composition, which may comprise one or more, but not limited to hydroxylpropyl cellulose (HPC), low substituted hydroxylpropyl cellulose (HPC), carboxymethylcellulose (CMC), sodium CMC, calcium CMC, crospovidone, croscarmellose sodium; starches exemplified under examples of fillers and also carboxymethyl starch, hydroxylpropyl starch, modified starch; crystalline cellulose, sodium starch glycolate; alginic acid or a salt thereof, such as sodium alginate or their equivalents and the like or mixtures thereof.
Additional ingredients, such as dissolving agents/ solubilisers, buffer agents, taste masking agents, release modifying agents and the like may also be added to the pharmaceutical composition of the present invention as required. The pharmaceutical composition of the present invention may also comprise additional active agents to achieve the desired therapeutic results.
The pharmaceutical composition, according to the present invention, may also optionally be coated, i.e. seal coated, enteric coated or film coated. Preferably, the pharmaceutical composition may be seal coated and then film coated. More preferably, the pharmaceutical composition may be film coated.
According to the present invention, the seal coat comprises film forming polymeric materials, such as but not limited to, hydroxypropylmethylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, methylcellulose, carboxymethylcellulose, hypromellose, acacia, gelatin to increase adherence and coherence of the seal coat.
The HPMC component of the seal coating, if present, may be mixed with a solvent, wherein said solvent may comprise acetone, methylene chloride, isopropyl alcohol, or any combination thereof. The seal coating may also comprise talc.
Suitable film-forming agents include, but are not limited to, cellulose derivatives, such as, soluble alkyl- or hydroalkyl-cellulose derivatives such as methylcelluloses, hydroxymethyl celluloses, hydroxyethyl celluloses, hydroxypropyl celluloses, hydroxymethylethyl celluloses, hydroxypropyl methylcelluloses, sodium carboxymethyl celluloses, insoluble cellulose derivatives such as ethylcelluloses and the like, dextrins, starches and starch derivatives, Suitable opacifiers include, but are not limited to, titanium dioxide.
Suitable anti-adhesives include, but are not limited to, talc.
Suitable polishing agents include, but are not limited to, polyethylene glycols of various molecular weights or mixtures thereof, talc, surfactants (glycerol monostearate and poloxamers), fatty alcohols (stearyl alcohol, cetyl alcohol, lauryl alcohol and myristyl alcohol) and waxes (carnauba wax, candelilla wax and white wax) and the like, or any mixtures thereof.
The pharmaceutical composition, according to the present invention, may be prepared through various techniques or processes known in the art which includes, but are not limited to direct compression, wet granulation, dry granulation, slugging or compaction, melt granulation, melt extrusion, spray drying, solution evaporation, freeze drying, direct blending, hot melt extrusion, extrusion-spheronization and the like, or combinations thereof.
According to one aspect the present invention, there is provided a process for preparing the pharmaceutical composition, which process comprises mixing molnupiravir, nirmatrelvir and optionally ritonavir with intragranular excipients, granulating/compacting, lubricating and drying the granules. Alternatively, the dried granules are compressed into tablets or processed further to the desired dosage form.
Optionally when coated, the tablet may be coated with at least one of the coats such as, but not limited to, seal coat, enteric coat, film coat or combinations thereof. The uncoated or coated tablets may also be further filled into capsules or sachets as required.
According to a preferred embodiment, the granules as obtained above may be further mixed, sieved, sifted and /or coated and filled into capsules or sachets and are administered directly.
Such capsules or sachets, according to the present invention are administered by sprinkling the formulation onto a regular meal, or to be administered with a liquid or semi-solid beverage, such as fruit juices, water, milk, baby formulas, soft foods, apple sauce, yogurt, and the like.
The pharmaceutical composition, according to the present invention can be administered in combination with other antiviral compounds.
In one embodiment, the pharmaceutical composition, according to the present invention, in combination with other antiviral compounds, are administered simultaneously, separately, or sequentially.
The present invention also provides a method of treating diseases caused by viruses, which method comprises administering the pharmaceutical composition.
The present invention also provides a pharmaceutical composition for use in treating diseases caused by viruses.
The following examples are for the purpose of illustration of the invention only and are not intended in any way to limit the scope of the present invention.
Example 1
Ingredient Quantity (mg/tab)
Molnupiravir 800 400
Microcrystalline cellulose 355 177.5
Croscarmellose Sodium (Ac-di-sol) 70 35
Colloidal silicon dioxide 20 10
Low Substituted hydroxypropylcellulose 25 12.5
Magnesium Stearate (Veg. grade) 30 15
Nirmatrelvir 300 150
Total 1600 800
Coating
Opadry White 50 25
Total 1650 825

Process:
1) Molnupiravir, Nirmatrelvir, microcrystalline cellulose, croscarmellose sodium, colloidal silicon dioxide, low substituted hydroxypropylcellulose were mixed and sifted to form a dry mix.
2) The dry mix so obtained in step (1) was roll compacted and sized to produce free flowing granules
3) The granules obtained in step (2) were lubricated with magnesium stearate and compressed to produce tablets.

4) The tablets obtained in step (3) are film coated.

Example 2

Ingredient Quantity (mg/tab)
Molnupiravir 800 400
Microcrystalline cellulose 355 177.5
Croscarmellose Sodium (Ac-di-sol) 70 35
Colloidal silicon dioxide 20 10
Low Substituted hydroxypropylcellulose 25 12.5
Magnesium Stearate (Veg. grade) 30 15
Nirmatrelvir 300 150
Microcrystalline cellulose 190 95
Croscarmellose Sodium (Ac-di-sol) 30 15
Colloidal silicon dioxide 20 10
Magnesium Stearate (Veg. grade) 10 5
Total 1850 925
Coating
Opadry White 50 25
Total 1900 950
Process
1) Molnupiravir, microcrystalline cellulose, croscarmellose sodium, colloidal silicon dioxide, low substituted hydroxypropylcellulose were mixed and sifted to form a dry mix.
2) The dry mix so obtained in step (1) was roll compacted and sized to produce free flowing granules
3) The granules obtained in step (2) were lubricated with magnesium stearate to produce molnupiravir granules.

4) Nirmatrelvir, microcrystalline cellulose, croscarmellose sodium, colloidal silicon dioxide, were mixed and sifted to form a dry mix.
5) The dry mix so obtained in step (4) was roll compacted and sized to produce free flowing granules
6) The granules obtained in step (5) were lubricated with magnesium stearate to produce nirmatrelvir granules.

7) The granules obtained in step (3) and step (6) were compressed to form bilayer tablets.

8) The tablets obtained in step (7) are film coated.

Example 3

Ingredient Quantity (mg/tab)
Molnupiravir 800 400
Microcrystalline cellulose 355 177.5
Croscarmellose Sodium (Ac-di-sol) 70 35
Hydroxypropyl cellulose 30 15
Colloidal silicon dioxide 20 10
Low Substituted hydroxypropylcellulose 25 12.5
Magnesium Stearate (Veg. grade) 30 15
Nirmatrelvir 300 150
Microcrystalline cellulose 190 95
Croscarmellose Sodium (Ac-di-sol) 30 15
Hydroxypropyl cellulose 20 10
Colloidal silicon dioxide 20 10
Magnesium Stearate (Veg. grade) 10 5
Purified Water q.s. q.s.
Total 1900 950
Coating
Opadry White 50 25
Total 1950 975
Process
1) Molnupiravir, microcrystalline cellulose, croscarmellose sodium, hydroxypropyl cellulose, colloidal silicon dioxide, low substituted hydroxypropylcellulose were mixed and sifted to form a dry mix.
2) The dry mix so obtained in step (1) was roll compacted and sized to produce free flowing granules
3) The granules obtained in step (2) were lubricated with magnesium stearate to produce molnupiravir granules.

4) Nirmatrelvir, microcrystalline cellulose, croscarmellose sodium, hydroxypropyl cellulose, colloidal silicon dioxide, were mixed and sifted to form a dry mix.
5) The dry mix so obtained in step (4) was roll compacted and sized to produce free flowing granules
6) The granules obtained in step (5) were lubricated with magnesium stearate to produce nirmatrelvir granules.

7) The granules obtained in step (3) and step (6) were compressed to form bilayer tablets.

8) The tablets obtained in step (7) are film coated.

It will be readily apparent to one skilled in the art that varying substitutions and modifications may be made to the invention disclosed herein without departing from the spirit of the invention. Thus, it should be understood that although the present invention has been specifically disclosed by the preferred embodiments and optional features, modification and variation of the concepts herein disclosed may be resorted to by those skilled in the art, and such modifications and variations are considered to fall within the scope of the invention.
It is to be understood that the phraseology and terminology used herein is for the purpose of description and should not be regarded as limiting. The use of “including,” “comprising,” or “having” and variations thereof herein is meant to encompass the items listed thereafter and equivalents thereof as well as additional items.
It must be noted that, as used in this specification and the appended claims, the singular forms "a," "an" and "the" include plural references unless the context clearly dictates otherwise. Thus, for example, reference to "an excipient" includes a single excipient as well as two or more different excipients, and the like.
,CLAIMS:1. A pharmaceutical composition comprising molnupiravir, nirmatrelvir and optionally ritonavir along with one or more pharmaceutically acceptable excipients.

2. The pharmaceutical composition according to claim 1, comprising molnupiravir, nirmatrelvir and ritonavir in the form of a pharmaceutically acceptable derivative thereof.

3. The pharmaceutical composition according to claim 2, wherein the pharmaceutically acceptable derivative thereof is a salt, solvate, complex, hydrate, isomer, ester, tautomer, anhydrate, enantiomer, polymorph or prodrug.

4. The pharmaceutical composition according to any preceding claim wherein molnupiravir is from about 200 mg to 800 mg, nirmatrelvir is from about 100 mg to 500 mg and ritonavir is from about 25 mg to 100 mg.

5. The pharmaceutical composition according to any preceding claim wherein the composition is administered as a fixed dose combination tablet, multilayer tablet, preferably a bilayer tablet or administered as a kit.

6. The pharmaceutical composition according to any preceding claim wherein the composition is administered once or twice a day for 3 days, once or twice a day for 5 days, once or twice a day for 7 days.

7. A pharmaceutical composition according to any one of claims 1 to 7, for prevention, treatment and prophylaxis of diseases caused by viruses.

8. A pharmaceutical composition substantially as herein described with reference to the examples.

9. A process for preparing a pharmaceutical composition as substantially described herein, with reference to any one of the examples.