DESC:CROSS-REFERENCE TO RELATED APPLICATIONS
This application claims priority to Indian Application No. 202221013096, filed on10 March 2022 and entitled “Antiviral Pharmaceutical Composition” which is incorporated herein in its entirety.

FIELD OF INVENTION:
The present invention relates to a pharmaceutical composition comprising nirmatrelvir and one or more antiviral agent, 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 coronavirus disease 2019 (COVID-19) is an infectious disease caused by SARS-CoV-2 that mainly affects the respiratory system, as interstitial pneumonia and acute respiratory distress syndrome (ARDS). Clinical presentations of COVID-19 range from no, or mild, symptoms, to severe hypoxia, respiratory or multiorgan failure, and even death. The SARS-CoV-2 pandemic has resulted in 5.5 million deaths out of 272 million confirmed cases reported worldwide by the end of December 2021. SARS-CoV-2 is expected to remain a persistent global threat in 2022 and so on due to the mutations in virus and emergence of variants of virus. Coronavirus disease 2019 (COVID-19) represents an unmet clinical need, due to a high mortality rate, rapid mutation rate in the virus, increased chances of reinfection, lack of effectiveness of repurposed drugs and economic damage. COVID-19 pandemic has created an urgent need for effective molecules.
COVID-19 management is divided into two directions: prevention and treatment. Regarding the preventive methods, several vaccines have been developed and are used worldwide in order to maximize the immune response and to minimize the pathogenic effects of coronavirus disease infections. From a therapeutic point of view, several antiviral molecules have been authorized in various countries: Remdesivir (RDV), Favipiravir (FVP), umifenovir, molnupiravir, nirmatrelvir-ritonavir combination. In addition, the present approaches include the introduction of monoclonal antibodies into therapy (e.g., bamlanivimab, etesevimab, casirivimab, imdevimab, sotrovimab). Remdesivir (RDV; GS-5734) is currently the only FDA approved antiviral drug for the treatment of SARS-CoV-2 infection. However, RDV must be administered intravenously, restricting its clinical use to patients with relatively advanced disease requiring hospitalization. Molnupiravir, an inhibitor of RNA-dependent RNA polymerase, provided a 30% reduction in hospitalization or death compared with the placebo group in a phase III study enrolling non-hospitalized adults with mild to moderate COVID-19, and at least one risk factor for severe disease, within five days of symptom onset . However, molnupiravir is associated with the alarming possibilities of inducing mutations in human DNA and accelerating the development of new viral variants . Favipiravir is administered by oral route, however the recommended dosage of favipiravir for adults is 1800 mg orally twice daily on 1st day followed by 800 mg orally twice daily, up to maximum of 14 days. Since favipiravir is available as 200mg tablet, to achieve the recommended dose of favipiravir per day, the patient has to take 9 tablets twice for 1st day and 4 tablets twice daily which is not patient compliance. It is also possible that patient may miss the dose and thus therapeutic effect may not be achieved. With monoclonal antibody therapy, common adverse events are injection site reactions and infusion-related reactions. Also , Monoclonal antibody therapy is not indicated in severe cases requiring hospitalization

Further, nirmatrelvir has shown excellent anti-SARS-CoV-2 activity in vitro. According to the study results, the insignificant in vitro cytotoxicity of nirmatrelvir indicates that it is a safe drug. As per the studies and literature, CYP3A4 played a primary role in the metabolism of nirmatrelvir, which suggested the possibility of boosting serum concentrations of nirmatrelvir by co-treatment with the potent CYP3A4 inactivator, ritonavir. The combination drug of nirmatrelvir/ritonavir which is administered orally provides the most promising therapeutic effect as 89% reduction in the risk of hospitalization or death is observed after administration. Nirmatrelvir/ritonavir have been expected to change the course of the COVID-19 pandemic. Paxlovid™ (nirmatrelvir/ritonavir) may decrease hospitalization and mortality rates and prevent virus transmission, and has good oral bioavailability. The Food and Drug Administration (FDA) issued an Emergency Use Authorization (EUA) for nirmatrelvir/ritonavir for the treatment of patients: (1) with mild to moderate COVID-19 within five days of symptom onset, and (2) at a high risk of progression to severe disease, on 22 December 2021. The nirmatrelvir tablets and ritonavir tablets are co-packaged for oral use. The recommended dose for patients with normal renal function is nirmatrelvir 300 mg (two 150 mg tablets) plus ritonavir 100 mg (one 100 mg tablet) orally, twice daily, with all three tablets taken together twice daily for 5 days. Following such recommended dose which require 3 tablets of two different drugs to be taken together twice a day is quite cumbersome as in addition to paxlovid , the patient may has to take other medications as well for other ongoing complications.

Patient compliance is an important aspect of anti-viral treatment. If patient compliance decreases, the therapeutic efficiency of the treatment decreases, which in turn may increase resistance to the said treatment. Dosage forms which lead to improved patient compliance therefore improve the overall long term therapeutic efficacy of the treatment. Issues surrounding patient compliance are particularly important for long-term treatments involving chronic infections . The geriatric and paediatric patients often experience difficulty in swallowing larger sized tablets, since large size tablets may result in oesophageal damage due to their physical characteristics, if they are not swallowed properly, which may lead to poor patient compliance.

Also, oral administration of bitter drugs with an acceptable degree of palatability is a key issue for health care providers, especially for paediatric patients. In the case of paediatric and geriatric patients, unpleasant taste should be avoided, since it leads to noncompliance resulting in decreased therapeutic efficacy. Patients particularly prefer oral dosage forms that are easy to swallow and have a pleasant taste or no taste at all. Objectionable taste is one of the most important formulation problems that are found with certain drugs. This is a distinct problem for drugs which are required to be formulated in an oral dosage form. Thus oral administration of bitter drugs is a major concern for patient compliance.

Further, there has been an enhanced demand for dosage forms that are more patient- friendly and compliant. Since the development cost of a new drug molecule is very high, efforts are now being made to focus on the development of new drug dosage forms for existing drugs with improved safety and efficacy together with reduced dosing frequency as well as which are cost-effective.

Several taste masking techniques are available, such as sensory masking by adding correctives, and . chemical masking by chemical modification, such as preparation of inclusion compounds and prodrugs, masking by using a matrix, and physical masking by use of additives. Many techniques have been developed, not only to improve the taste of the molecule but also the formulation and performance of the molecule. These include inclusion complex formation with cyclodextrin, use of ion exchange resin, solubility limiting1 methods, liposome and multiple emulsions, etc. However all such techniques involve use of complex methods or systems and moreover are expensive.

Hence, to fulfil these medical needs, and to overcome the issues of patient compliance, there remains a need to produce suitable dosage forms which meet the aforementioned requirements.

The inventors of present invention have provided a fixed dose combination formulations of nirmatrelvir and ritonavir with an intention to reduce the number of individual medications that patients must remember to take, which may enhance compliance with the prescribed drug regimen and offers reduced costs to the patients and insurers. The fixed dose combination formulations of nirmatrelvir and ritonavir of present invention provide synergistic effect, lesser side effects because of lower doses or counteractive actions, elongated product life - cycle management , cost savings, and improved patient compliance with reduced pill burden. The formulations of present invention are safe and effective 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 nirmatrelvir, ritonavir and one or more pharmaceutically acceptable excipients. Another object of the present invention is to provide a fixed dose pharmaceutical formulation comprising nirmatrelvir, ritonavir and one or more pharmaceutically acceptable excipients. Yet another object of the present invention is to provide a stable fixed dose pharmaceutical formulation comprising nirmatrelvir, ritonavir and one or more pharmaceutically acceptable excipients. One object of present invention is to provide a fixed dose pharmaceutical formulation comprising nirmatrelvir, ritonavir and one or more pharmaceutically acceptable excipients which can be administered as a whole to patients in need thereof. Another object of the present invention is to provide a fixed dose pharmaceutical formulation comprising nirmatrelvir, ritonavir and one or more pharmaceutically acceptable excipients in a form such that it is suitable to administer to pediatric patients, geriatric patients and patients suffering from dysphagia. Another object of the present invention is to provide a process for preparing a pharmaceutical composition comprising nirmatrelvir, ritonavir and one or more pharmaceutically acceptable excipients. 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 of present invention.

SUMMARY OF THE INVENTION
According to an aspect of present invention is to provide a pharmaceutical composition comprising nirmatrelvir, ritonavir and one or more pharmaceutically acceptable excipients and process of preparation of the formulation. Another aspect of the present invention is to provide a stable fixed dose pharmaceutical formulation comprising nirmatrelvir, ritonavir and one or more pharmaceutically acceptable excipients which can be administered as a whole to the patient in need thereof or can be administered to pediatric , geriatric and patients suffering from dysphagia. Yet one another aspect of the present invention is to provide a method for treatment or prophylaxis of diseases caused by viruses which comprises administering a pharmaceutical composition of present invention.

DETAILED DESCRIPTION OF THE INVENTION
The inventors of the present invention have developed fixed dose pharmaceutical formulation comprising of nirmatrelvir, ritonavir and one or more pharmaceutically acceptable excipients.

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.

Nirmatrelvir (or PF-07321332)/ritonavir, developed by Pfizer, Inc., and is known as Paxlovid is an orally bioavailable SARS-CoV-2 main protease inhibitor with extensive coronavirus antiviral activity, good off-target selectivity, and thus fewer adverse drug reactions.

Ritonavir is chemically designated as l,3-thiazol-5-ylmethyl N-[(2S,3S,5S)-3-hydroxy-5- [(2S)-3-methyl-2-{[methyl({[2-(propan-2-yl)-l,3-thiazol-4yl]methyl})carbamoyl]amino}butanamido]-l,6-diphenylhexan-2-yl]carbamate and has the following structure.

Ritonavir has been used as a pharmacokinetic enhancer of several marketed protease inhibitors of HIV (e.g., darunavir and lopinavir) that are metabolized through CYP3A4 . Ritonavir is thus combined with nirmatrelvir to enhance its therapeutic concentration
The term “nirmatrelvir”, “ritonavir” is used in a broad sense to include not only “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 formulation" or “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 formulation, according to the present invention is presented in a solid dosage form, conveniently in unit dosage form, and include dosage form suitable for oral and buccal administration.
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 nirmatrelvir in an amount from about 10 mg to 500 mg per unit dosage form. Preferably, the pharmaceutical composition of the present invention comprises nirmatrelvir from about 150 mg to 300 mg per unit dosage form.
In an embodiment, the pharmaceutical composition of present invention for pediatric patients, comprises nirmatrelvir in an amount from about 5mg to about 200mg per unit dosage form. Preferably, the pharmaceutical composition of present invention for pediatric patients, comprises nirmatrelvir in an amount from about 10mg to about 150mg per unit dosage form.
The pharmaceutical composition, according to the present invention, comprises fixed dose combination of nirmatrelvir with ritonavir present in an amount from about 25 mg to about 100 mg per unit dosage form.
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 another aspect, the pharmaceutical composition, according to the present invention, is administered as a fixed dose combination tablet, multilayer tablet, preferably a bilayer tablet. The formulation of present invention can be taken by swallowing as a whole with water by patients who do not have difficulty in swallowing.
For specific patient populations such as geriatrics and pediatrics, the dosage form as suggested may be of concern as these patient populations may experience difficulty in swallowing larger sized tablets or capsules, leading to poor patient compliance. In an embodiment, the pharmaceutical composition, according to the present invention, is intended for pediatric use. The preferred dosage form for administration to pediatric patients is fixed dose formulation of suitable dose such as tablets, sachets, capsules, sprinkle formulations and the like.
The present invention further relates to a pharmaceutical solid oral sprinkle composition comprising nirmatrelvir, ritonavir and one or more pharmaceutically acceptable excipients, for use in geriatrics and paediatrics. Thus, the present invention provides a pharmaceutical solid oral sprinkle composition comprising one or more antiretroviral drugs and one or more pharmaceutically acceptable excipients, for use in geriatrics and paediatrics. The term "sprinkle formulation" as used throughout the specification is a formulation comprising a plurality of particles. The pharmaceutical solid oral composition according to the present invention is a sprinkle formulation comprising particles in the form of mini-tablets or granules. The term "particle " in context of the of the composition of the present invention would be defined as the smallest unit of the composition. Such particles may be incorporated in capsules or sachets that may be incorporated in a hard gelatin capsule, sachet or packet. Such capsules or sachets, according to the present invention may 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.
Further, the pharmaceutical solid oral sprinkle composition of the present invention may also be provided in the form of kit compositions which has an advantage since the patient always has access to the set of instructions for administration contained in the kit. The inclusion of a set of instructions for administration has been shown to improve patient compliance.
It will be understood that the administration of the pharmaceutical solid oral sprinkle composition of the present invention by means of a kit, with a set of instructions for administration diverting the patient to the correct use of the invention is a desirable, additional feature of this invention.
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, dicalcium phosphate anhydrous , 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 solid oral formulation of the present invention may further comprise a solubility enhancer or also known as a surfactant Surfactant used in the oral dosage forms according to the present invention enhances the permeability of water to powder and improves solubility of the drug. Examples of the surfactants useful in the present invention include, but are not limited to, sodium lauryl sulfate (SLS) and its derivatives, poloxamer and its derivatives, medium chain triglyceride (MCT) , labrasol, transcutol, labrafil, labrafac, various polysorbate[which are exemplified as polyoxyethylene sorbitan monolaurate( hereinafter, abbreviated to "Tween 20"), polyoxyethylene sorbitan monopalmitate( hereinafter, abbreviated to "Tween 40"), polyoxyethylene sorbitan monostearate (hereinafter, abbreviated to "Tween 60") and polyoxyethylene sorbitan monooleate (hereinafter, abbreviated to "Tween 80")], Sorbitan Esters [which are exemplified as sorbitan monolaurate (hereinafter, abbreviated to "Span 20"), sorbitan monopaImitate (hereinafter, abbreviated to "Span 40"), sorbitan monostearate (hereinafter, abbreviated to "Span 60"), sorbitan monooleate (hereinafter, "Span 80"), sorbitan trilaurate (hereinafter, abbreviated to "Span 25"), sorbitan trioleate (hereinafter, abbreviated to "Span 85"), sorbitan tristearate (hereinafter, abbreviated to "Span 65")], Cremophor, PEG-60 hydrogenated castor oil, PEG-40 hydrogenated castor oil, sodium lauryl glutamate, disodium cocoamphodiacetate, Polyoxyl 23 lauryl ester (hereinafter, Brij 35) or their mixtures.
Preferred surfactants are anionic surfactants such as sodium lauryl sulfate (SLS) and its derivatives, nonionic surfactants such as Tween 20, Tween 40, Tween 60 or Tween 80 and sorbitan esters such as Span 20, Span 40, Span 60, Span 80, Span 25, Span 85 or Span 65. SLS and Tween 80 are most preferable surfactants

The pharmaceutical solid oral composition of the present invention may further comprise a lubricant, glidant and/or an anti- adherent. The glidant, anti-adherents and/or lubricant may comprise: 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, silicon dioxide, colloidal silicon dioxide and polymers thereof, crospovidone, magnesium stearate, magnesium aluminosilicate and/ or magnesium alumino metasilicate); sucrose ester of fatty acids; hydrogenated vegetable oils (for example, hydrogenated castor oil); or any mixture thereof.
In the pharmaceutical formulation of present invention, the bitter taste of actives have been masked so that the patient has pleasant taste after administration of formulation of present invention. The taste masking can be carried out by using various techniques like addition of flavors, film coating, complexation with cyclodextrins, melting and liquid extrusion, encapsulation, pH modification of active pharmaceutical ingredient (API), and ion-exchange resins. Preferably, the technique used for taste masking is use of polymers. Polymer layer ensures a protective environment around the drug thus avoiding its contact with the tongue. Polymers used for taste masking are cellulose ethers (hydroxypropylmethyl cellulose and methyl cellulose) and synthetic vinyl polymers, Copolymers of acrylic and methacrylic acid, copolymers of methyl methacrylate, ethyl acrylate and ethyl cellulose, commercially available polymers such as Eudragit® E PO ReadyMix [29], Kollicoat SmartSeal® 30 D [30], Aquacoat® ECD [31], Sepifilm® TMLP [32], Opadry® AMB [33], and Surelease.
Suitable taste-masking agents that may be included in formulations of present invention include, but are not limited to, essential oils, water soluble extracts, sugar, monosaccharides, oligosaccharides, aldose, ketose, dextrose, maltose, lactose, glucose, fructose, sucrose, mannitol xylitol, D-sorbitol, erythritol, pentitol, hexitol, malitol, acesulfame potassium, talin, glycyrrhizin, sucralose, aspartame, saccharin, sodium saccharin, sodium cyclamate, eugenyl formate aldehyde flavorings and combinations thereof. Exemplary aldehyde flavorings that may be used include, but are not limited to acetaldehyde (apple); benzaldehyde (cherry, almond); cinnamic aldehyde (cinnamon); citral, i.e., alpha citral (lemon, lime); neral, i.e., beta citral (lemon, lime); decanal (orange, lemon); ethyl vanillin (vanilla, cream); heliotropine, i.e., piperonal (vanilla, cream); vanillin (vanilla, cream); alpha-amyl cinnamaldehyde (spicy fruity flavors); butyraldehyde (butter, cheese); valeraldehyde (butter, cheese); citronellal (modifies, many types); decanal (citrus fruits); aldehyde C-8 (citrus fruits); aldehyde C-9 (citrus fruits); aldehyde C-12 (citrus fruits); 2-ethyl butyraldehyde (berry fruits); hexenal, i.e., trans-2 (berry fruits); tolyl aldehyde (cherry, almond); veratraldehyde (vanilla); 2,6-dimethyl-5-heptenal, i.e., melonal (melon); 2-6-dimethyloctanal (green fruit); and 2-dodecenal (citrus, mandarin). In some embodiments, the taste-masking agents may include combination of acesulfame potassium and flavors.
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 nirmatrelvir and 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. The formulation of present invention may also be prepared by hot melt extrusion technique wherein the granules are prepared by hot melt extrusion of excipients after sieving and the prepared granules are either compressed to tablets, mini-tablets or alternatively filled in capsules or sachets.
In an embodiment, the formulation of present invention comprises mixture of two or more types of granules, minitablets comprising ritonavir and /or nirmatrelvir and pharmaceutically acceptable excipients. One or both of the granule or minitablet is prepared by hot melt extrusion process, atleast one type of granule or minitablet by direct compression or roller compaction process and thereby filing the granules or minitablets in sachet or capsules and the like.
In an embodiment, the capsules or sachets may be filled with first minitablets of ritonavir and second minitablets of nirmatrelvir, minitablets of ritonavir and granules of nirmatrelvir, granules of ritonavir and minitablets of nirmatrelvir, first granules of granules of nirmatrelvir and second granules of ritonavir formulation. In another embodiment, the capsules or sachets are filled with plurality of minitablets wherein each minitablet comprises of fixed dose combination of ritonavir and nirmatrelvir and pharmaceutically acceptable excipients. In yet another embodiment, the capsules or sachets are filled with plurality of granules wherein each granule comprises of fixed dose combination of ritonavir and nirmatrelvir and pharmaceutically acceptable excipients
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 comprising of , but not limited to, nucleoside reverse transcriptase inhibitor such as Zidovudine, Didanosine, Zalcitabine, Stavudine, Lamivudine, Abacavir, Tenofovir, Emtricitabine non-nucleoside reverse transcriptase inhibitor such as Nevirapine, Delavirdine, Efavirenz, Etravirine, rlipivirine, integrase strand transfer inhibitor such as Raltegravir, Elvitegarvir, Dolutegravir and protease inhibitor such as Saquinavir
Indinavir, Ritonavir, Nelfinavir, Amprenavir, Lopinavir, Fosamprenavir, Atazanavir, Tipranavir
Darunavir. 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 of present invention. In an embodiment, the present invention provides a method of treating diseases caused by viruses such as covid, which method comprises administering the pharmaceutical composition of present inventionThe 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: Nirmatrelvir and Ritonavir Tablets – Bilayer FDC Tablet
Ingredients Mg/unit
Layer 1
Ritonavir 100.00
Dibasic calcium phosphate anhydrous 45.00
Colloidal silicon dioxide 6.90
Copovidone 490.00
Sorbitan Monolaurate 61.00
Colloidal silicon dioxide 10.00
Dibasic calcium phosphate anhydrous 45.00
Sodium Stearyl Fumarate 4.10
Layer II
Nirmatrelvir 300.00
Microcrystalline cellulose 500.00
Lactose monohydrate 200.00
Colloidal silicon dioxide 50.00
Croscarmellose sodium 25.00
Sodium Stearyl Fumarate 18.00
Seal coating
Hydroxypropyl methyl cellulose 30.00
Isopropyl alcohol q. s.
Purified water q. s.
Film coating
Opadry white 30.00
Purified water q. s.
Total 1915.00

Manufacturing process:
1. Sifted all materials through specified sieves.
Layer I
2. Loaded Copovidone in Rapid Mixer Granulator and added Sorbitan monolaurate over Copovidone.
3. Added co-sifted Ritonavir, Colloidal silicon dioxide and Dicalcium phosphate anhydrous to step 2 and mix.
4. Performed Hot melt extrusion of step 3 material to get uniform extrudes.
5. Milled the hot extrudes through desired mill.
6. Blended and lubricated milled extrudes with extra-granular material to get lubricated blend.
Layer II
7. Blended Intra-granular material using blender.
8. Dry granulate the intra-granular material using suitable process parameters.
9. Blended and lubricated sized granules with extra-granular material to get lubricated blend.
10. Compressed bilayer tablets using blend of Layer I and II.
11. Seal coated the tablet using Hypromellose solution.
12. Film coated the seal coated tablets using Opadry.

Example 2: Nirmatrelvir and Ritonavir Tablets –FDC Tablet
Sr. No. Ingredients Mg/unit
1 Ritonavir 100.00
2 Dibasic calcium phosphate anhydrous 50.00
3 Colloidal silicon dioxide 7.50
4 Copovidone 500.00
5 Sorbitan Monolaurate 65.00
6 Colloidal silicon dioxide 10.00
7 Dibasic calcium phosphate anhydrous 45.00
8 Sodium Stearyl Fumarate 4.50
9 Nirmatrelvir 300.00
10 Microcrystalline cellulose 650.00
11 Lactose monohydrate 250.00
12 Colloidal silicon dioxide 50.00
13 Croscarmellose sodium 25.00
14 Sodium Stearyl Fumarate 18.00
Seal coating
15 Hydroxypropyl methyl cellulose 35.00
16 Isopropyl alcohol q. s.
17 Purified water q. s.
Film coating
18 Opadry white 35.00
19 Purified water q. s.
2145.00

Manufacturing process:
1. Sifted all materials through specified sieves.
Ritonavir part
2. Loaded Copovidone in Rapid Mixer Granulator and add Sorbitan monolaurate over Copovidone.
3. Added co-sifted Ritonavir, Colloidal silicon dioxide and Dicalcium phosphate anhydrous to step 2 and mixed.
4. Performed Hot melt extrusion of step 3 material to get uniform extrudes.
5. Milled the hot extrudes through desired mill.
6. Blended and lubricated milled extrudes with extra-granular material to get lubricated blend.
Nirmatrelvir part
7. Blended Intra-granular material using blender.
8. Dry granulated the intra-granular material using suitable process parameters.
9. Blended and lubricated sized granules with extra-granular material to get lubricated blend.
10. Blended the Ritonavir granules and Nirmatrelvir granules.
11. Compressed into tablets.
12. Seal coated the tablet using Hypromellose solution.
13. Film coated the seal coated tablets using Opadry.

Example 3: Nirmatrelvir and Ritonavir Tablets – Bilayer FDC Tablet (Peadiatric)
Sr. No. Ingredients Mg/unit
Strength 10 mg/ 25 mg 25 mg/ 50 mg 100 mg/ 50 mg
Layer I
1 Ritonavir 25.00 50.00 50.00
2 Dibasic calcium phosphate anhydrous 5.00 10.00 10.00
3 Colloidal silicon dioxide 5.00 10.00 10.00
4 Copovidone 125.00 250.00 250.00
5 Sorbitan Monolaurate 10.00 20.00 20.00
Layer II
6 Nirmatrelvir 10.00 25.00 100.00
7 Microcrystalline cellulose 30.00 75.00 300.00
8 Lactose monohydrate 10.00 30.00 100.00
9 Croscarmellose sodium 3.00 15.00 30.00
10 Sodium Stearyl Fumarate 2.00 10.00 20.00
Seal coating
11 Hydroxypropyl methyl cellulose 1.50 7.50 15.00
12 Isopropyl alcohol q. s. q. s. q. s.
13 Purified water q. s. q. s. q. s.
Film coating
14 Opadry white 1.50 7.50 15.00
15 Purified water q. s. q. s. q. s.
Total 228.00 510.00 920.00

Manufacturing process:
1. Sifted all materials through specified sieves.
Layer I
2. Loaded Copovidone in Rapid Mixer Granulator and add Sorbitan monolaurate over Copovidone.
3. Added co-sifted Ritonavir, Colloidal silicon dioxide and Dicalcium phosphate anhydrous to step 2 and mixed.
4. Performed Hot melt extrusion of step 3 material to get uniform extrudes.
5. Milled the hot extrudes through desired mill.
6. Blended and lubricated milled extrudes with extra-granular material to get lubricated blend.
Layer II
7. Blended Intra-granular material using blender.
8. Dry granulated the intra-granular material using suitable process parameters.
9. Blended and lubricated sized granules with extra-granular material to get lubricated blend.
10. Compressed bilayer tablets using blend of Layer I and II.
11. Seal coated the tablet using Hypromellose solution.
12. Film coated the seal coated tablets using Opadry.
Example 4: Nirmatrelvir and Ritonavir Tablets
Sr. No. Ingredients Mg/unit
Strength 10 mg/ 25 mg 25 mg/ 50 mg 100 mg/ 50 mg
1 Ritonavir 25.00 50.00 50.00
2 Dibasic calcium phosphate anhydrous 10.00 20.00 20.00
3 Colloidal silicon dioxide 8.00 16.00 16.00
4 Copovidone 130.00 260.00 260.00
5 Sorbitan Monolaurate 15.00 30.00 30.00
6 Nirmatrelvir 10.00 25.00 100.00
7 Microcrystalline cellulose 40.00 100.00 400.00
8 Lactose monohydrate 15.00 37.50 150.00
9 Croscarmellose sodium 5.00 12.50 50.00
10 Sodium Stearyl Fumarate 4.00 10.00 40.00
Seal coating
11 Hydroxypropyl methyl cellulose 2.00 5.00 20.00
12 Isopropyl alcohol q. s. q. s. q. s.
13 Purified water q. s. q. s. q. s.
Film coating
14 Opadry white 2.00 5.00 20.00
15 Purified water q. s. q. s. q. s.
266.00 571.00 1156.00

Manufacturing process:
1. Sifted all materials through specified sieves.
2. Loaded Copovidone in Rapid Mixer Granulator and add Sorbitan monolaurate over Copovidone.
3. Added co-sifted Ritonavir, Colloidal silicon dioxide and Dicalcium phosphate anhydrous to step 2 and mix.
4. Performed Hot melt extrusion of step 3 material to get uniform extrudes.
5. Milled the hot extrudes through desired mill.
6. Blended and lubricated milled extrudes with extra-granular material to get lubricated blend.
7. Blended Intra-granular material using blender.
8. Dried the granulate the intra-granular material using suitable process parameters.
9. Blended and lubricated sized granules with extra-granular material to get lubricated blend.
10. Blended Ritonavir and Nirmatrelvir granules.
11. Compressed into tablets.
12. Seal coated the tablet using Hypromellose solution.
13. Film coated the seal coated tablets using Opadry.

Example 5:Nirmatrelvir and Ritonavir Sachets
Sr. No. Ingredients Mg/unit
Strength 10 mg/ 25 mg 25 mg/ 50 mg 100 mg/ 50 mg
1 Ritonavir 25.00 50.00 50.00
2 Dibasic calcium phosphate anhydrous 15.00 30.00 30.00
3 Colloidal silicon dioxide 8.00 16.00 16.00
4 Copovidone 125.00 250.00 250.00
5 Sorbitan Monolaurate 20.00 40.00 40.00
6 Nirmatrelvir 10.00 25.00 100.00
7 Microcrystalline cellulose 35.00 175.00 350.00
8 Lactose monohydrate 16.00 40.00 160.00
9 Croscarmellose sodium 6.00 15.00 60.00
10 Sodium Stearyl Fumarate 4.00 10.00 40.00
11 Sodium saccharin 6 10 20
12 Strawberry flavour 10 15 30
280 676 1146

Manufacturing process:
1. Sifted all materials through specified sieves.
2. Loaded Copovidone in Rapid Mixer Granulator and add Sorbitan monolaurate over Copovidone.
3. Added co-sifted Ritonavir, Colloidal silicon dioxide and Dicalcium phosphate anhydrous to step 2 and mix.
4. Performed Hot melt extrusion of step 3 material to get uniform extrudes.
5. Milled the hot extrudes through desired mill.
6. Blended and lubricated milled extrudes with extra-granular material to get lubricated blend.
7. Blended Intra-granular material using blender.
8. Dry granulated the intra-granular material using suitable process parameters.
9. Blended and lubricated sized granules with extra-granular material to get lubricated blend.
10. Filled blend of step 5 and 8 into sachets

Example 6: Nirmatrelvir and Ritonavir Sachets 10 mg/ 25 mg, 25 mg/ 50 mg and 100 mg/ 50 mg
Sr. No. Ingredients Mg/unit
Strength 10 mg/ 25 mg 25 mg/ 50 mg 100 mg/ 50 mg
1 Ritonavir 25.00 50.00 50.00
2 Dibasic calcium phosphate anhydrous 15.00 30.00 30.00
3 Colloidal silicon dioxide 8.00 16.00 16.00
4 Amino methacrylate copolymer 150.00 300.00 300.00
5 Sorbitan Monolaurate 25.00 50.00 50.00
6 Nirmatrelvir 10.00 25.00 100.00
7 Microcrystalline cellulose 40.00 100.00 400.00
8 Lactose monohydrate 16.00 40.00 160.00
9 Croscarmellose sodium 6.00 15.00 60.00
10 Sodium Stearyl Fumarate 4.00 10.00 40.00
11 Sodium saccharin 6 10 20
12 Strawberry flavour 10 15 30
315 661 1256

Manufacturing process:
1. Sifted all materials through specified sieves.
2. Loaded Amino methacrylate copolymer in Rapid Mixer Granulator and add Sorbitan monolaurate over Amino methacrylate copolymer.
3. Added co-sifted Ritonavir, Colloidal silicon dioxide and Dicalcium phosphate anhydrous to step 2 and mix.
4. Performed Hot melt extrusion of step 3 material to get uniform extrudes.
5. Milled the hot extrudes through desired mill.
6. Blended and lubricated milled extrudes with extra-granular material to get lubricated blend.
7. Blended Intra-granular material using blender.
8. Dry granulated the intra-granular material using suitable process parameters.
9. Blended and lubricated sized granules with extra-granular material to get lubricated blend.
10. Filled blend of step 5 and 8 into sachets.
Example 7: Nirmatrelvir and Ritonavir Sprinkle Capsules 10 mg/ 25 mg, 25 mg/ 50 mg and 100 mg/ 50 mg
Sr. No. Ingredients Mg/unit
Strength 10 mg/ 25 mg 25 mg/ 50 mg 100 mg/ 50 mg
1 Ritonavir 25.00 50.00 50.00
2 Dibasic calcium phosphate anhydrous 15.00 30.00 30.00
3 Colloidal silicon dioxide 8.00 16.00 16.00
4 Copovidone 125.00 250.00 250.00
5 Sorbitan Monolaurate 15.00 30.00 30.00
6 Nirmatrelvir 10.00 25.00 100.00
7 Microcrystalline cellulose 10.00 25.00 100.00
8 Lactose monohydrate 10.00 25.00 100.00
9 Croscarmellose sodium 2.00 5.00 20.00
10 Sodium Stearyl Fumarate 2.00 5.00 20.00
11 Capsule shell 63.00 104.00 130.00
285.00 565.00 846.00

Manufacturing process:
1. Sifted all materials through specified sieves.
2. Loaded Copovidone in Rapid Mixer Granulator and add Sorbitan monolaurate over Copovidone.
3. Added co-sifted Ritonavir, Colloidal silicon dioxide and Dicalcium phosphate anhydrous to step 2 and mixed.
4. Performed Hot melt extrusion of step 3 material to get uniform extrudes.
5. Milled the hot extrudes through desired mill.
6. Blended and lubricated milled extrudes with extra-granular material to get lubricated blend.
7. Compressed the minitablets using blend of step 6.
8. Blended Intra-granular material using blender.
9. Dry granulated the intra-granular material using suitable process parameters.
10. Blended and lubricated sized granules with extra-granular material to get lubricated blend.
11. Compressed the minitablets using blend of step 10.
12. Filled the minitablets of step 7 and 11 in capsule shells using Capsule filling machine.

Example 8: Nirmatrelvir and Ritonavir Sprinkle Capsules 10 mg/ 25 mg, 25 mg/ 50 mg and 100 mg/ 50 mg
Sr. No. Ingredients Mg/unit
Strength 10 mg/ 25 mg 25 mg/ 50 mg 100 mg/ 50 mg
1 Ritonavir 25.00 50.00 50.00
2 Dibasic calcium phosphate anhydrous 10.00 20.00 20.00
3 Colloidal silicon dioxide 7.00 14.00 14.00
4 Copovidone 120.00 240.00 240.00
5 Sorbitan Monolaurate 10.00 20.00 20.00
6 Nirmatrelvir 10.00 25.00 100.00
7 Microcrystalline cellulose 10.00 25.00 100.00
8 Lactose monohydrate 12.00 30.00 120.00
9 Croscarmellose sodium 2.00 5.00 20.00
10 Sodium Stearyl Fumarate 2.00 5.00 20.00
11 Capsule shell 63.00 104.00 130.00
271.00 538.00 834.00

Manufacturing process:
1. Sifted all materials through specified sieves.
2. Loaded Copovidone in Rapid Mixer Granulator and add Sorbitan monolaurate over Copovidone.
3. Added co-sifted Ritonavir, Colloidal silicon dioxide and Dicalcium phosphate anhydrous to step 2 and mix.
4. Performed Hot melt extrusion of step 3 material to get uniform extrudes.
5. Milled the hot extrudes through desired mill.
6. Blended and lubricated milled extrudes with extra-granular material to get lubricated blend.
7. Compressed the minitablets using blend of step 6.
8. Blended Intra-granular material using blender.
9. Dry granulated the intra-granular material using suitable process parameters.
10. Blended and lubricated sized granules with extra-granular material to get lubricated blend.
11. Filled the minitablets of step 7 and blend of step 10 in capsule shells using Capsule filling machine.
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 nirmatrelvir or its pharmaceutically acceptable derivative thereof, ritonavir or its pharmaceutically acceptable derivative thereof and one or more pharmaceutically acceptable excipients
2. 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.
3. The pharmaceutical composition according to any preceding claim wherein the dose of nirmatrelvir is from about 10 mg to 500 mg per unit dosage form and ritonavir is from about 25 mg to 100 mg per unit dosage form.
4. The pharmaceutical composition according to any preceding claim wherein the pharmaceutically acceptable excipient is selected from diluents, fillers , glidants, anti-adherents, lubricants ,solvents, disintegrants , taste masking agents, release modifying agents and the combination thereof.
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 5, for prevention, treatment and prophylaxis of diseases to a human patient caused by viruses.
8. The pharmaceutical composition as claimed in claim 7 , wherein the human patient is adult, pediatric, geriatric and patients suffering from dysphagia
9. A pharmaceutical composition substantially as herein described with reference to the examples.

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