WO2023170712A1 - Composition pharmaceutique antivirale - Google Patents

Composition pharmaceutique antivirale Download PDF

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Publication number
WO2023170712A1
WO2023170712A1 PCT/IN2023/050230 IN2023050230W WO2023170712A1 WO 2023170712 A1 WO2023170712 A1 WO 2023170712A1 IN 2023050230 W IN2023050230 W IN 2023050230W WO 2023170712 A1 WO2023170712 A1 WO 2023170712A1
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WIPO (PCT)
Prior art keywords
pharmaceutical composition
ritonavir
nirmatrelvir
pharmaceutically acceptable
present
Prior art date
Application number
PCT/IN2023/050230
Other languages
English (en)
Inventor
Pradeep Bhadauria
Preeti Prashant RAUT
Atul Daroi
Nidhi BAGREE
Original Assignee
Cipla Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
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Publication date
Application filed by Cipla Limited filed Critical Cipla Limited
Publication of WO2023170712A1 publication Critical patent/WO2023170712A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
    • A61K9/209—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat containing drug in at least two layers or in the core and in at least one outer layer
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
    • A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
    • A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4866—Organic macromolecular compounds

Definitions

  • 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.
  • 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.
  • 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 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.
  • 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.
  • 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.
  • 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 .
  • 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.
  • favipiravir 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 1 st 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.
  • 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.
  • PaxlovidTM may decrease hospitalization and mortality rates and prevent virus transmission, and has good oral bioavailability.
  • the Food and Drug Administration 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.
  • EUA Emergency Use Authorization
  • 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.
  • 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 .
  • 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.
  • oral administration of bitter drugs with an acceptable degree of palatability is a key issue for health care providers, especially for paediatric patients.
  • unpleasant taste should be avoided, since it leads to noncompliance resulting in decreased therapeutic efficacy.
  • 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.
  • An object of the present invention is to provide a pharmaceutical composition 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 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.
  • 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 .
  • nirmatrelvir 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.
  • 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
  • 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.
  • the pharmaceutical composition of the present invention comprises nirmatrelvir from about 150 mg to 300 mg per unit dosage form.
  • the pharmaceutical composition of present invention for pediatric patients comprises nirmatrelvir in an amount from about 5mg to about 200mg per unit dosage form.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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, ⁇ -lactose, ⁇ -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, Meth
  • 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.
  • stearic acid and pharmaceutically acceptable salts or esters thereof for example, magnesium stearate, calcium stea
  • 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.
  • polyvinyl pyrrolidone also known as povidone
  • polyethylene glycol also known as povidone
  • acacia alginic acid
  • agar calcium carragenan
  • cellulose derivative such as ethyl cellulose, methyl cellulose, hydroxypropyl cellulose, hydroxypropyl
  • 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.
  • 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.
  • HPC hydroxylpropyl cellulose
  • HPC low substituted hydroxylpropyl cellulose
  • CMC carboxymethylcellulose
  • sodium CMC sodium CMC
  • calcium CMC calcium CMC
  • crospovidone croscarmellose sodium
  • starches exemplified under examples of fillers and also carboxymethyl starch, hydroxylpropyl starch, modified starch
  • 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.
  • 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 (herein
  • 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.
  • 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, micro
  • 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.
  • 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.
  • aldehyde flavorings 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); aldeh
  • the taste-masking agents may include combination of acesulfame potassium and flavors.
  • the pharmaceutical composition may also optionally be coated, i.e. seal coated, enteric coated or film coated.
  • the pharmaceutical composition may be seal coated and then film coated. More preferably, the pharmaceutical composition may be film coated.
  • 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 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 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.
  • a process for preparing the pharmaceutical composition which process comprises mixing nirmatrelvir and ritonavir with intragranular excipients, granulating/compacting, lubricating and drying the granules.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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
  • 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.
  • 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.
  • 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.
  • nucleoside reverse transcriptase inhibitor such as Zidovudine, Didanosine, Zalcitabine, Stavudine, Lamivudine, Abacavir, Tenofovir, Emtricitabine non-nucle
  • 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.
  • the present invention provides a method of treating diseases caused by viruses such as covid, which method comprises administering the pharmaceutical composition of present invention
  • 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 Nirmatrelvir and Ritonavir Tablets – Bilayer FDC Tablet Total 1915.00 Manufacturing process: 1. Sifted all materials through specified sieves. Layer I 2.
  • Example 2 Nirmatrelvir and Ritonavir Tablets –FDC Tablet 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.
  • 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.
  • 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.
  • Nirmatrelvir and Ritonavir Tablets 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.
  • Step 5 and 8 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
  • 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 Manufacturing process: 1. Sifted all materials through specified sieves. 2. Loaded Copovidone in Rapid Mixer Granulator and add Sorbitan monolaurate over Copovidone. 3.
  • step 2 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.
  • Example 8 Nirmatrelvir and Ritonavir Sprinkle Capsules 10 mg/ 25 mg, 25 mg/ 50 mg and 100 mg/ 50 mg 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.

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Abstract

: La présente invention concerne des formulations pharmaceutiques à dose fixe de nirmatrelvir, de ritonavir et d'excipients pharmaceutiquement acceptables, leur utilisation et un procédé de préparation desdites formulations.
PCT/IN2023/050230 2022-03-10 2023-03-10 Composition pharmaceutique antivirale WO2023170712A1 (fr)

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IN202221013096 2022-03-10

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021242760A1 (fr) * 2020-05-26 2021-12-02 Lowell Therapeutics, Inc. Procédés de traitement d'une infection virale à l'aide d'inhibiteurs de protéase
CN114085181A (zh) * 2022-01-18 2022-02-25 南京桦冠生物技术有限公司 一种6,6-二甲基-3-氮杂双环[3.1.0]己烷的合成方法及其应用

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021242760A1 (fr) * 2020-05-26 2021-12-02 Lowell Therapeutics, Inc. Procédés de traitement d'une infection virale à l'aide d'inhibiteurs de protéase
CN114085181A (zh) * 2022-01-18 2022-02-25 南京桦冠生物技术有限公司 一种6,6-二甲基-3-氮杂双环[3.1.0]己烷的合成方法及其应用

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