WO2020212898A1 - Pharmaceutical oral liquid solution of ivacaftor - Google Patents

Pharmaceutical oral liquid solution of ivacaftor Download PDF

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Publication number
WO2020212898A1
WO2020212898A1 PCT/IB2020/053602 IB2020053602W WO2020212898A1 WO 2020212898 A1 WO2020212898 A1 WO 2020212898A1 IB 2020053602 W IB2020053602 W IB 2020053602W WO 2020212898 A1 WO2020212898 A1 WO 2020212898A1
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Prior art keywords
ivacaftor
oral liquid
liquid solution
oil
group
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PCT/IB2020/053602
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French (fr)
Inventor
Vardhaman Chandrakant Bafna
Mahesh Mohanrao Bhadgale
Mokshada Milind VABLE
Sweety Rajbahadur SINGH
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Callidus Research Laboratories Pvt Ltd
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Callidus Research Laboratories Pvt Ltd
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Priority to EP20790975.5A priority Critical patent/EP3968955B1/en
Priority to US17/593,430 priority patent/US12303502B2/en
Publication of WO2020212898A1 publication Critical patent/WO2020212898A1/en
Anticipated expiration legal-status Critical
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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
    • A61K9/0087—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
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
    • 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
    • A61K9/08—Solutions
    • 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
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C07D215/54—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3
    • C07D215/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3 with oxygen atoms in position 4

Definitions

  • the present invention relates to stable oral liquid solution comprising ivacaftor or a pharmaceutically acceptable salt or solvate thereof and solvent system selected from the group essentially of polyethylene glycols or hydrogenated vegetable oil or mixture thereof.
  • Ivacaftor is classified as a cystic fibrosis transmembrane conductance regulator (CFTR) potentiator and is indicated for the treatment of cystic fibrosis (CF) in patients who have a G55 ID mutation in the CFTR gene.
  • Ivacaftor is a white powder with a low aqueous solubility and the bioavailability of Ivacaftor is significantly enhanced when co-administered with food.
  • Ivacaftor is chemically known as N-(2,4-di-tert-butyl-5-hydroxyphenyl)-l,4-dihydro-4- oxoquinoline-3-carboxamide and is represented by compound of structural formula I.
  • Ivacaftor is having an empirical formula of C H N O and a molecular weight of 392.499 g/mol.
  • Cystic fibrosis is a recessive genetic disease that affects approximately 30,000 children and adults in the United States, approximately 30,000 children and adults in Europe, and more than 70,000 people worldwide. Despite progress in the treatment of CF, there is no cure. Approximately 1000 new cases of CF are diagnosed each year, more than 75 percent of people with CF are diagnosed by age of 2, and more than half of the CF population is age 18 or older. CF is caused by mutations in the cystic fibrosis transmembrane conductance regulator gene (CFTR) that encodes an epithelial chloride ion channel responsible for aiding in the regulation of salt and water absorption and secretion in various tissues. Small molecule drugs, known as potentiator that increase the probability of CFTR channel opening, represent one potential therapeutic strategy to treat CF.
  • cystic fibrosis transmembrane conductance regulator gene CFTR
  • Small molecule drugs known as potentiator that increase the probability of CFTR channel opening, represent one potential therapeutic strategy to treat CF.
  • U.S. Patent No. 7,495,103 discloses modulators of ATP-binding cassette transporters such as ivacaftor and also discloses methods of treating CFTR transporter mediated diseases using such modulators.
  • U.S. Patent No. 8,324,242 describes a method of treating or lessening the severity of cystic fibrosis in a patient, said method comprising the step of administering to said patient an effective amount of ivacaftor, wherein the patient possesses a cystic fibrosis transmembrane receptor with a G55 ID mutation.
  • U.S. Patent No. 8,354,427 describes a method of treating or lessening the severity of cystic fibrosis in a patient, wherein said patient possess a cystic fibrosis transmembrane receptor (CFTR) with a R117H mutation, said method comprising the step of administering to said patient an effective amount of ivacaftor.
  • CFTR cystic fibrosis transmembrane receptor
  • U.S. Patent No. 8,629, 162 describes a method of treating or lessening the severity of a moderate to mild clinical phenotype of cystic fibrosis in a patient, said method comprising the step of administering to said patient a pharmaceutical composition comprising ivacaftor.
  • U.S. Patent No. 8,754,224 describes a solid dispersion comprising amorphous ivacaftor and a polymer, wherein the polymer is polyvinylpyrrolidone (PVP), polyvinyl alcohols (PVA), polymethacrylate, b-cyclodextin, or vinylpyrrolidone/vinyl acetate copolymer (PVP/VA). It also describes crystal form A, crystal form B and amorphous form of ivacaftor.
  • PVP polyvinylpyrrolidone
  • PVA polyvinyl alcohols
  • PV/VA vinylpyrrolidone/vinyl acetate copolymer
  • U.S. Patent No. 8,471,029 discloses crystalline form C of ivacaftor, pharmaceutical compositions thereof and methods therewith.
  • U.S. Patent No. 8,674,108 discloses crystalline solvate forms of ivacaftor, which are designated as Form D, Form E, Form F, Form G, Form H, Form I, Form J, Form K, Form L, Form M, Form N, Form O, Form P, Form Q, Form R, Form S, Form T, Form W and hydrate B and methods for their preparation. It further discloses pharmaceutical compositions comprising the crystalline solvate forms of ivacaftor, as well as methods of treatment therewith.
  • U.S. Patent No. 8,163,772 discloses solid forms of ivacaftor which are co-forms, for example, salts, solvates, co-crystals and hydrates of ivacaftor. It describes Ivacaftor co-forms with 2- methylbutyric acid, propylene glycol, PEG400.KOAc, lactic acid, isobutyric acid, propionic acid, ethanol, 2-propanol, water, besylate, hemibesylate, and besylate monohydrate.
  • U.S. Patent No. 8883206 describes pharmaceutical compositions containing a solid dispersion of ivacaftor with HPMCAS and one or more of the excipients selected from one or more fillers, a sweetener, a disintegrant, a wetting agent, a glidant, and a lubricant.
  • the said pharmaceutical composition of the solid dispersions formulated into powders, granules and mini-tablets. It also describes methods for manufacturing and processing the powders, granules and mini-tablets, and methods for treating cystic fibrosis employing the pharmaceutical composition.
  • U.S. Publication No. 2014/0221424 describes pharmaceutical composition of ivacaftor use in the treatment of cystic fibrosis, wherein said composition is in the form of tablets obtain by spray dried dispersion technique.
  • U.S. Patent No. 7,553,855 discloses a pharmaceutical composition comprising ivacaftor, PEG 400, and PVP K30.
  • U.S. Publication No. 2015/0010628 discloses a pharmaceutical composition comprising a solid dispersion of amorphous or substantially amorphous ivacaftor, a filler, a sweetener, a disintegrant, a glidant and a lubricant, and optionally a wetting agent.
  • compositions of ivacaftor or a pharmaceutically acceptable salt thereof discloses nanoparticulate compositions of ivacaftor or a pharmaceutically acceptable salt thereof, and methods of making and using such compositions.
  • the said compositions comprise ivacaftor particles having an effective average particle size of less than about 2000 nm, at least one surface stabilizer and optionally one or more pharmaceutically acceptable excipients.
  • Ivacaftor is marketed as Tablets in strength of 75 mg and 150 mg and Oral granules in strength of 25mg, 50 mg and 75 mg per packet under the trade name KALYDECO ® which is a cystic fibrosis transmembrane conductance regulator (CFTR) potentiator indicated for the treatment of cystic fibrosis (CF) in patients age 12 months and older who have one mutation in the CFTR gene.
  • CFTR cystic fibrosis transmembrane conductance regulator
  • the solid dosage forms are difficult to swallow, especially for paediatric and geriatric patients. Further, the fear of swallowing or choking on such solid shaped forms is still a concern in certain populations. However, administration of oral granules may be associated with an issue of incomplete dosing. The patient compliance is often a problem with oral solid dosage forms, especially with young paediatrics and geriatrics patients.
  • the drug administered in oral liquid solution dosage form is immediately available for absorption from the gastrointestinal tract and can be absorbed faster than the same amount of drug administered in a tablet or capsule. Therefore, the inventors of present application developed a stable oral liquid solution of ivacaftor which can obviate the problems associated with prior art and increases patient compliance.
  • the object of the invention is to develop a stable oral liquid solution of ivacaftor for the treatment of cystic fibrosis, providing flexibility in dosage regimes for patients who need special doses of the drug, specifically in paediatrics, geriatrics along with institutionalized patients and patients with complications for swallowing.
  • a first aspect of the present invention is to provide a stable oral liquid solution comprising a therapeutically effective amount of ivacaftor, and a pharmaceutically acceptable combination of excipients in an amount sufficient for oral liquid solution dosage form.
  • Another aspect of the present invention is to provide a stable oral liquid solution of ivacaftor, wherein the composition comprises:
  • a solvent system selected from group consisting of Polyethylene Glycols 400 and or Hydrogenated Vegetable Oil used individually or in combination thereof.
  • Another aspect of the present invention is to provide a stable oral liquid solution of ivacaftor, wherein the composition comprises:
  • a solvent system selected from group consisting of Polyethylene Glycols 400 and or Hydrogenated Vegetable Oil used individually or in combination thereof;
  • a solvent or cosolvent system selected from group consisting of either Glycerol, polyols like sorbitol, maltitol, lactitol etc. or Polyoxylglycerides or Hydrogenated Vegetable Oil and or combination thereof;
  • Another aspect of the present invention is to provide a stable oral liquid solution of ivacaftor, wherein the composition comprises:
  • a solvent system selected from group consisting of Polyethylene Glycols 400 and or Hydrogenated Vegetable Oil used individually or in combination thereof;
  • a solvent or cosolvent system selected from group consisting of either Glycerol, polyols like sorbitol, maltitol, lactitol etc. or Polyoxylglycerides or Hydrogenated Vegetable Oil and or combination thereof;
  • solubilizing agent d) solubilizing agent; and e) other pharmaceutically acceptable excipients selected from group consisting of antioxidants, antimicrobial preservatives, sweetening agents, flavoring agents, coloring agents, buffering agents and the like.
  • Another aspect of the present invention is to provide a process for the preparation of a stable oral liquid solution comprising of ivacaftor and pharmaceutically acceptable excipients.
  • Another aspect of the present invention is to provide a method for treating or lessening the severity of cystic fibrosis in a patient who has difficulty in swallowing, comprising administering a pharmaceutically effective dose of an oral liquid solution of Ivacaftor.
  • the present invention provides a stable oral liquid solution comprising a therapeutically effective amount of ivacaftor, and a pharmaceutically acceptable combination of excipients in an amount sufficient for oral liquid solution dosage form.
  • the present invention provides a stable oral liquid solution of ivacaftor, wherein the composition comprises:
  • a solvent system selected from group consisting of Polyethylene Glycols 400 and or Hydrogenated Vegetable Oil used individually or in combination thereof.
  • the present invention provides a stable oral liquid solution of ivacaftor, wherein the composition comprises:
  • a solvent system selected from group consisting of Polyethylene Glycols 400 and or Hydrogenated Vegetable Oil used individually or in combination thereof;
  • a solvent or cosolvent system selected from group consisting of either Glycerol, polyols like sorbitol, maltitol, lactitol etc. or Polyoxylglycerides or Hydrogenated Vegetable Oil and or combination thereof;
  • the present invention provides a stable oral liquid solution of ivacaftor, wherein the composition comprises:
  • a solvent system selected from group consisting of Polyethylene Glycols 400 and or Hydrogenated Vegetable Oil used individually or in combination thereof;
  • a solvent or cosolvent system selected from group consisting of either Glycerol, polyols like sorbitol, maltitol, lactitol etc. or Polyoxylglycerides or Hydrogenated Vegetable Oil and or combination thereof;
  • Ivacaftor refers to N-(2,4-di-tert-butyl-5-hydroxyphenyl)-l,4-dihydro-4- oxoquinoline-3 -carboxamide, as well as a pharmaceutically acceptable salt or solvate thereof.
  • a “therapeutically effective amount” of Ivacaftor is an amount of Ivacaftor or its pharmaceutically acceptable salts or solvate thereof which eliminates, alleviates, or provides relief of the symptoms for which it is administered.
  • oral liquid solution refers to a liquid preparation in which the therapeutic agent i.e. ivacaftor and or various excipients are dissolved in the chosen solvent system.
  • Hydrogenated Vegetable Oil is selected from partially or fully hydrogenated oil such as Castor Oil, Peanut Oil, Com Oil, Coconut Oil or Cottonseed Oil.
  • solubilizing agent may include but not limited to ammonium lauryl sulfate (ALS), sodium lauryl sulfate (SLS) , sodium laureth sulfate, sodium myreth sulfate, quaternary ammonium salts: cetrimonium bromide (CTAB) , cetylpyridiniumchloride (CPC), benzalkonium chloride (BAC), benzethonium chloride (BZT), phospholipids phosphatidylserine, phosphatidylethanolamine, phosphatidylcholine and sphingomyelins, Poloxamer, Tweens, Spans and the like with or without water.
  • ALS ammonium lauryl sulfate
  • SLS sodium lauryl sulfate
  • CPC cet
  • antioxidants may include but not limited to Sodium sulphate, sodium metabisulphite, sodium formaldehyde, sulphoxylate, ascorbic acid, butylated hydroxytoluene (BHT), Butylated hydroxy anisole, propyl gallate, sodium citrate, citric acid, and the like.
  • antimicrobial preservatives may include but not limited to Sorbic acid and its salts, potassium sorbate, methyl parahydroxybenzoate (Methylparaben), propyl parahydroxybenzoate, sodium benzoate, propionic acid used individually or in combination thereof.
  • sweetening agents may include but not limited to Sucrose, acesulfame potassium, sucralose, sodium saccharin, aspartame, sorbitol, xylitol, Neotame, Ammoniated Glycyrrhizin, Monoammonium Glycyrrhizinate or a combination thereof.
  • flavoring agents may include but not limited to peppermint, grape, orange, lime oil, lemon, pineapple, berries, lavender, dill, spearmint, eucalyptus, ethyl vanillin, fruit Flavor, caramel Flavor or combination thereof.
  • coloring agents may include but not limited to Titanium dioxide, brilliant Blue, indigo tine, erythrosine, allura red, sunset yellow, tartrazine, aluminum blue lake or combination thereof.
  • buffering agents may include but not limited to citric acid, sodium citrate, trometamol and the like used individually or in combination thereof.
  • the present invention provides a process for the preparation of a stable oral liquid solution comprising of ivacaftor and pharmaceutically acceptable excipients.
  • the present invention provides a method for treating or lessening the severity of cystic fibrosis in a patient who has difficulty in swallowing, comprising administering a pharmaceutically effective dose of an oral liquid solution of Ivacaftor.
  • the present invention provides a stable oral liquid solution of ivacaftor having higher bioavailability under fasted and fed condition against existing marketed tablet formulation i.e. KALYDECO tablets.
  • compositions described herein are stored in a glass bottle.
  • the enclosed, glass bottle has a volume of 150ml or 300ml.
  • the following is an exemplary method of preparing oral liquid solution of Ivacaftor.
  • Table No. 1 General composition for oral liquid solution of Ivacaftor
  • the following is an exemplary method of preparing oral liquid solution of Ivacaftor.
  • the following is an exemplary method of preparing oral liquid solution of Ivacaftor.
  • Hydrogenated Vegetable Oil is dispensed into a mixing tank, to it accurately weighed quantity of Ivacaftor API is added under continuous stirring. Weighed quantity of sodium lauryl sulfate is added and stirred to form clear mixture. All other excipients are added in a sequential manner to this mixture and mixed until complete dissolution is achieved.
  • the following is an exemplary method of preparing oral liquid solution of Ivacaftor.
  • the following is an exemplary method of preparing oral liquid solution of Ivacaftor.
  • the following is an exemplary method of preparing oral liquid solution of Ivacaftor.
  • the following is an exemplary method of preparing oral liquid solution of Ivacaftor.
  • the following is an exemplary method of preparing oral liquid solution of Ivacaftor.
  • the following is an exemplary method of preparing oral liquid solution of Ivacaftor.

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Abstract

The present invention provides a stable oral liquid solution composition comprising ivacaftor or a pharmaceutically acceptable salt or solvate thereof and a solvent system selected from the group consisting of Polyethylene Glycols 400 and / or Hydrogenated Vegetable Oil used individually or in combination thereof. The invention also provides a method for treating or lessening the severity of cystic fibrosis is provided.

Description

PHARMACEUTICAL ORAL LIQUID SOLUTION OF IVACAFTOR
PRIORITY:
This application claims the benefit of Indian complete application number 201921015579 dated 18th April 2019 entitled, ‘Pharmaceutical Oral Liquid Solution of Ivacaftor’, the contents of which are incorporated herein by reference.
TECHNICAL FIELD OF THE INVENTION:
The present invention relates to stable oral liquid solution comprising ivacaftor or a pharmaceutically acceptable salt or solvate thereof and solvent system selected from the group essentially of polyethylene glycols or hydrogenated vegetable oil or mixture thereof.
BACKGROUND OF THE INVENTION:
Ivacaftor is classified as a cystic fibrosis transmembrane conductance regulator (CFTR) potentiator and is indicated for the treatment of cystic fibrosis (CF) in patients who have a G55 ID mutation in the CFTR gene. Ivacaftor is a white powder with a low aqueous solubility and the bioavailability of Ivacaftor is significantly enhanced when co-administered with food. Ivacaftor is chemically known as N-(2,4-di-tert-butyl-5-hydroxyphenyl)-l,4-dihydro-4- oxoquinoline-3-carboxamide and is represented by compound of structural formula I. Ivacaftor is having an empirical formula of C H N O and a molecular weight of 392.499 g/mol.
Figure imgf000002_0001
Formula I
Cystic fibrosis (CF) is a recessive genetic disease that affects approximately 30,000 children and adults in the United States, approximately 30,000 children and adults in Europe, and more than 70,000 people worldwide. Despite progress in the treatment of CF, there is no cure. Approximately 1000 new cases of CF are diagnosed each year, more than 75 percent of people with CF are diagnosed by age of 2, and more than half of the CF population is age 18 or older. CF is caused by mutations in the cystic fibrosis transmembrane conductance regulator gene (CFTR) that encodes an epithelial chloride ion channel responsible for aiding in the regulation of salt and water absorption and secretion in various tissues. Small molecule drugs, known as potentiator that increase the probability of CFTR channel opening, represent one potential therapeutic strategy to treat CF.
U.S. Patent No. 7,495,103 discloses modulators of ATP-binding cassette transporters such as ivacaftor and also discloses methods of treating CFTR transporter mediated diseases using such modulators.
U.S. Patent No. 8,324,242 describes a method of treating or lessening the severity of cystic fibrosis in a patient, said method comprising the step of administering to said patient an effective amount of ivacaftor, wherein the patient possesses a cystic fibrosis transmembrane receptor with a G55 ID mutation.
U.S. Patent No. 8,354,427 describes a method of treating or lessening the severity of cystic fibrosis in a patient, wherein said patient possess a cystic fibrosis transmembrane receptor (CFTR) with a R117H mutation, said method comprising the step of administering to said patient an effective amount of ivacaftor.
U.S. Patent No. 8,629, 162 describes a method of treating or lessening the severity of a moderate to mild clinical phenotype of cystic fibrosis in a patient, said method comprising the step of administering to said patient a pharmaceutical composition comprising ivacaftor.
U.S. Patent No. 8,754,224 describes a solid dispersion comprising amorphous ivacaftor and a polymer, wherein the polymer is polyvinylpyrrolidone (PVP), polyvinyl alcohols (PVA), polymethacrylate, b-cyclodextin, or vinylpyrrolidone/vinyl acetate copolymer (PVP/VA). It also describes crystal form A, crystal form B and amorphous form of ivacaftor.
U.S. Patent No. 8,471,029 discloses crystalline form C of ivacaftor, pharmaceutical compositions thereof and methods therewith. U.S. Patent No. 8,674,108 discloses crystalline solvate forms of ivacaftor, which are designated as Form D, Form E, Form F, Form G, Form H, Form I, Form J, Form K, Form L, Form M, Form N, Form O, Form P, Form Q, Form R, Form S, Form T, Form W and hydrate B and methods for their preparation. It further discloses pharmaceutical compositions comprising the crystalline solvate forms of ivacaftor, as well as methods of treatment therewith.
U.S. Patent No. 8,163,772 discloses solid forms of ivacaftor which are co-forms, for example, salts, solvates, co-crystals and hydrates of ivacaftor. It describes Ivacaftor co-forms with 2- methylbutyric acid, propylene glycol, PEG400.KOAc, lactic acid, isobutyric acid, propionic acid, ethanol, 2-propanol, water, besylate, hemibesylate, and besylate monohydrate.
U.S. Patent No. 8883206 describes pharmaceutical compositions containing a solid dispersion of ivacaftor with HPMCAS and one or more of the excipients selected from one or more fillers, a sweetener, a disintegrant, a wetting agent, a glidant, and a lubricant. The said pharmaceutical composition of the solid dispersions formulated into powders, granules and mini-tablets. It also describes methods for manufacturing and processing the powders, granules and mini-tablets, and methods for treating cystic fibrosis employing the pharmaceutical composition.
U.S. Publication No. 2014/0221424 describes pharmaceutical composition of ivacaftor use in the treatment of cystic fibrosis, wherein said composition is in the form of tablets obtain by spray dried dispersion technique.
U.S. Patent No. 7,553,855 discloses a pharmaceutical composition comprising ivacaftor, PEG 400, and PVP K30.
U.S. Publication No. 2015/0010628 discloses a pharmaceutical composition comprising a solid dispersion of amorphous or substantially amorphous ivacaftor, a filler, a sweetener, a disintegrant, a glidant and a lubricant, and optionally a wetting agent.
PCT Publication No. 2016/199085 discloses nanoparticulate compositions of ivacaftor or a pharmaceutically acceptable salt thereof, and methods of making and using such compositions. The said compositions comprise ivacaftor particles having an effective average particle size of less than about 2000 nm, at least one surface stabilizer and optionally one or more pharmaceutically acceptable excipients.
Currently, Ivacaftor is marketed as Tablets in strength of 75 mg and 150 mg and Oral granules in strength of 25mg, 50 mg and 75 mg per packet under the trade name KALYDECO® which is a cystic fibrosis transmembrane conductance regulator (CFTR) potentiator indicated for the treatment of cystic fibrosis (CF) in patients age 12 months and older who have one mutation in the CFTR gene.
The solid dosage forms are difficult to swallow, especially for paediatric and geriatric patients. Further, the fear of swallowing or choking on such solid shaped forms is still a concern in certain populations. However, administration of oral granules may be associated with an issue of incomplete dosing. The patient compliance is often a problem with oral solid dosage forms, especially with young paediatrics and geriatrics patients.
Therefore, there is need in the art to develop stable oral liquid solution of ivacaftor for the treatment of cystic fibrosis (CF) in patients age 12 months and older who have one mutation in the CFTR gene. The oral liquid solution is beneficial for administration specifically in paediatrics, geriatrics along with institutionalized patients and patients with physical disabilities or incapacitated, nausea, vomiting and motion sickness complications.
The drug administered in oral liquid solution dosage form is immediately available for absorption from the gastrointestinal tract and can be absorbed faster than the same amount of drug administered in a tablet or capsule. Therefore, the inventors of present application developed a stable oral liquid solution of ivacaftor which can obviate the problems associated with prior art and increases patient compliance.
OBJECT OF THE INVENTION:
The object of the invention is to develop a stable oral liquid solution of ivacaftor for the treatment of cystic fibrosis, providing flexibility in dosage regimes for patients who need special doses of the drug, specifically in paediatrics, geriatrics along with institutionalized patients and patients with complications for swallowing.
SUMMARY OF THE INVENTION: A first aspect of the present invention is to provide a stable oral liquid solution comprising a therapeutically effective amount of ivacaftor, and a pharmaceutically acceptable combination of excipients in an amount sufficient for oral liquid solution dosage form.
Another aspect of the present invention is to provide a stable oral liquid solution of ivacaftor, wherein the composition comprises:
a) a therapeutically effective amount of ivacaftor or a pharmaceutically acceptable salt or solvate thereof, and
b) a solvent system selected from group consisting of Polyethylene Glycols 400 and or Hydrogenated Vegetable Oil used individually or in combination thereof.
Another aspect of the present invention is to provide a stable oral liquid solution of ivacaftor, wherein the composition comprises:
a) a therapeutically effective amount of ivacaftor or a pharmaceutically acceptable salt or solvate thereof;
b) a solvent system selected from group consisting of Polyethylene Glycols 400 and or Hydrogenated Vegetable Oil used individually or in combination thereof;
c) a solvent or cosolvent system selected from group consisting of either Glycerol, polyols like sorbitol, maltitol, lactitol etc. or Polyoxylglycerides or Hydrogenated Vegetable Oil and or combination thereof;
d) solubilizing agent; and
e) other pharmaceutically acceptable excipients.
Another aspect of the present invention is to provide a stable oral liquid solution of ivacaftor, wherein the composition comprises:
a) a therapeutically effective amount of ivacaftor or a pharmaceutically acceptable salt or solvate thereof;
b) a solvent system selected from group consisting of Polyethylene Glycols 400 and or Hydrogenated Vegetable Oil used individually or in combination thereof;
c) a solvent or cosolvent system selected from group consisting of either Glycerol, polyols like sorbitol, maltitol, lactitol etc. or Polyoxylglycerides or Hydrogenated Vegetable Oil and or combination thereof;
d) solubilizing agent; and e) other pharmaceutically acceptable excipients selected from group consisting of antioxidants, antimicrobial preservatives, sweetening agents, flavoring agents, coloring agents, buffering agents and the like.
Another aspect of the present invention is to provide a process for the preparation of a stable oral liquid solution comprising of ivacaftor and pharmaceutically acceptable excipients.
Another aspect of the present invention is to provide a method for treating or lessening the severity of cystic fibrosis in a patient who has difficulty in swallowing, comprising administering a pharmaceutically effective dose of an oral liquid solution of Ivacaftor.
DETAIL DESCRIPTION OF THE INVENTION:
In one embodiment the present invention provides a stable oral liquid solution comprising a therapeutically effective amount of ivacaftor, and a pharmaceutically acceptable combination of excipients in an amount sufficient for oral liquid solution dosage form.
In another embodiment the present invention provides a stable oral liquid solution of ivacaftor, wherein the composition comprises:
a) a therapeutically effective amount of ivacaftor or a pharmaceutically acceptable salt or solvate thereof, and
b) a solvent system selected from group consisting of Polyethylene Glycols 400 and or Hydrogenated Vegetable Oil used individually or in combination thereof.
In another embodiment the present invention provides a stable oral liquid solution of ivacaftor, wherein the composition comprises:
a) a therapeutically effective amount of ivacaftor or a pharmaceutically acceptable salt or solvate thereof;
b) a solvent system selected from group consisting of Polyethylene Glycols 400 and or Hydrogenated Vegetable Oil used individually or in combination thereof;
c) a solvent or cosolvent system selected from group consisting of either Glycerol, polyols like sorbitol, maltitol, lactitol etc. or Polyoxylglycerides or Hydrogenated Vegetable Oil and or combination thereof;
d) solubilizing agent; and
e) other pharmaceutically acceptable excipients. In another embodiment the present invention provides a stable oral liquid solution of ivacaftor, wherein the composition comprises:
a) a therapeutically effective amount of ivacaftor or a pharmaceutically acceptable salt or solvate thereof;
b) a solvent system selected from group consisting of Polyethylene Glycols 400 and or Hydrogenated Vegetable Oil used individually or in combination thereof;
c) a solvent or cosolvent system selected from group consisting of either Glycerol, polyols like sorbitol, maltitol, lactitol etc. or Polyoxylglycerides or Hydrogenated Vegetable Oil and or combination thereof;
d) solubilizing agent; and
e) other pharmaceutically acceptable excipients selected from group consisting of antioxidants, antimicrobial preservatives, sweetening agents, flavoring agents, coloring agents, buffering agents and the like.
“Ivacaftor” as used herein refers to N-(2,4-di-tert-butyl-5-hydroxyphenyl)-l,4-dihydro-4- oxoquinoline-3 -carboxamide, as well as a pharmaceutically acceptable salt or solvate thereof.
A “therapeutically effective amount” of Ivacaftor is an amount of Ivacaftor or its pharmaceutically acceptable salts or solvate thereof which eliminates, alleviates, or provides relief of the symptoms for which it is administered.
As used in this specification, the singular forms "a", "an", and "the" include plural references unless the context clearly dictates otherwise. Thus, for example, a reference to "a method"“a process” includes one or more methods or processes, and/or steps of the type described herein and/or which will become apparent to those persons skilled in the art upon reading this disclosure and so forth.
As used in this specification, the term“oral liquid solution”, refers to a liquid preparation in which the therapeutic agent i.e. ivacaftor and or various excipients are dissolved in the chosen solvent system.
The example of Hydrogenated Vegetable Oil is selected from partially or fully hydrogenated oil such as Castor Oil, Peanut Oil, Com Oil, Coconut Oil or Cottonseed Oil. The examples of solubilizing agent may include but not limited to ammonium lauryl sulfate (ALS), sodium lauryl sulfate (SLS) , sodium laureth sulfate, sodium myreth sulfate, quaternary ammonium salts: cetrimonium bromide (CTAB) , cetylpyridiniumchloride (CPC), benzalkonium chloride (BAC), benzethonium chloride (BZT), phospholipids phosphatidylserine, phosphatidylethanolamine, phosphatidylcholine and sphingomyelins, Poloxamer, Tweens, Spans and the like with or without water.
The examples of antioxidants may include but not limited to Sodium sulphate, sodium metabisulphite, sodium formaldehyde, sulphoxylate, ascorbic acid, butylated hydroxytoluene (BHT), Butylated hydroxy anisole, propyl gallate, sodium citrate, citric acid, and the like.
The examples of antimicrobial preservatives may include but not limited to Sorbic acid and its salts, potassium sorbate, methyl parahydroxybenzoate (Methylparaben), propyl parahydroxybenzoate, sodium benzoate, propionic acid used individually or in combination thereof.
The examples of sweetening agents may include but not limited to Sucrose, acesulfame potassium, sucralose, sodium saccharin, aspartame, sorbitol, xylitol, Neotame, Ammoniated Glycyrrhizin, Monoammonium Glycyrrhizinate or a combination thereof.
The examples of flavoring agents may include but not limited to peppermint, grape, orange, lime oil, lemon, pineapple, berries, lavender, dill, spearmint, eucalyptus, ethyl vanillin, fruit Flavor, caramel Flavor or combination thereof.
The examples of coloring agents may include but not limited to Titanium dioxide, brilliant Blue, indigo tine, erythrosine, allura red, sunset yellow, tartrazine, aluminum blue lake or combination thereof.
The examples of buffering agents may include but not limited to citric acid, sodium citrate, trometamol and the like used individually or in combination thereof. In another embodiment the present invention provides a process for the preparation of a stable oral liquid solution comprising of ivacaftor and pharmaceutically acceptable excipients.
In another embodiment the present invention provides a method for treating or lessening the severity of cystic fibrosis in a patient who has difficulty in swallowing, comprising administering a pharmaceutically effective dose of an oral liquid solution of Ivacaftor.
In another embodiment the present invention provides a stable oral liquid solution of ivacaftor having higher bioavailability under fasted and fed condition against existing marketed tablet formulation i.e. KALYDECO tablets.
It is contemplated that the pharmaceutical compositions described herein are stored in a glass bottle. In yet another embodiment, the enclosed, glass bottle has a volume of 150ml or 300ml.
EXAMPLES:
The invention is further illustrated by the following examples which are provided merely to be exemplary of the invention and do not limit the scope of the present invention. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the invention. However, these are not intended to limit the scope of the present invention in any way.
Example 1:
The following is an exemplary method of preparing oral liquid solution of Ivacaftor.
Table No. 1: General composition for oral liquid solution of Ivacaftor
Figure imgf000010_0001
Figure imgf000011_0001
Procedure: Polyethylene glycol is dispensed into a mixing tank, to it accurately weighed quantity of Ivacaftor API is added under continuous stirring. Weighed quantity of sodium lauryl sulfate is added and stirred to form a clear liquid. All other excipients are added in a sequential manner to this mixture and mixed until complete dissolution is achieved.
Example 2:
The following is an exemplary method of preparing oral liquid solution of Ivacaftor.
Table No. 2: General composition for oral liquid solution of Ivacaftor
Figure imgf000012_0001
Procedure: Polyethylene glycol is dispensed into a mixing tank, to it accurately weighed quantity of Ivacaftor API is added under continuous stirring. Weighed quantity of sodium lauryl sulfate is added and stirred to form clear mixture. All other excipients are added in a sequential manner to this mixture and mixed until complete dissolution is achieved.
Example 3:
The following is an exemplary method of preparing oral liquid solution of Ivacaftor.
Table No. 3: General composition for oral liquid solution of Ivacaftor
Figure imgf000012_0002
Procedure: Hydrogenated Vegetable Oil is dispensed into a mixing tank, to it accurately weighed quantity of Ivacaftor API is added under continuous stirring. Weighed quantity of sodium lauryl sulfate is added and stirred to form clear mixture. All other excipients are added in a sequential manner to this mixture and mixed until complete dissolution is achieved.
Example 4:
The following is an exemplary method of preparing oral liquid solution of Ivacaftor.
Table No. 4: General composition for oral liquid solution of Ivacaftor
Figure imgf000013_0001
Procedure: Polyethylene glycol is dispensed into a mixing tank, to it accurately weighed quantity of Ivacaftor API is added under continuous stirring. All other excipients are added in a sequential manner to this mixture and mixed until complete dissolution is achieved.
Example 5:
The following is an exemplary method of preparing oral liquid solution of Ivacaftor.
Table No. 5: General composition for oral liquid solution of Ivacaftor
Figure imgf000014_0001
Procedure: Polyethylene glycol is dispensed into a mixing tank, to it accurately weighed quantity of Ivacaftor API is added under continuous stirring. Weighed quantity of sodium lauryl sulfate is added and stirred to form clear mixture. All other excipients are added in a sequential manner to this mixture and mixed until complete dissolution is achieved.
Example 6:
The following is an exemplary method of preparing oral liquid solution of Ivacaftor.
Table No. 6: General composition for oral liquid solution of Ivacaftor
Figure imgf000015_0001
Procedure: Polyethylene glycol is dispensed into a mixing tank, to it accurately weighed quantity of Ivacaftor API is added under continuous stirring. Weighed quantity of sodium lauryl sulfate is added and stirred to form clear mixture. All other excipients are added in a sequential manner to this mixture and mixed until complete dissolution is achieved.
Example 7:
The following is an exemplary method of preparing oral liquid solution of Ivacaftor.
Table No. 7: General composition for oral liquid solution of Ivacaftor
Figure imgf000016_0001
Procedure: Polyethylene glycol is dispensed into a mixing tank, to it accurately weighed quantity of Ivacaftor API is added under continuous stirring. Weighed quantity of sodium lauryl sulfate is added and stirred to form clear mixture. All other excipients are added in a sequential manner to this mixture and mixed until complete dissolution is achieved.
Example 8:
The following is an exemplary method of preparing oral liquid solution of Ivacaftor.
Table No. 8: Specific composition for oral liquid solution of Ivacaftor
Figure imgf000016_0002
Figure imgf000017_0001
Procedure: Polyethylene glycol is dispensed into a mixing tank, to it accurately weighed quantity of Ivacaftor API is added under continuous stirring. Weighed quantity of sodium lauryl sulfate is added and stirred to form clear mixture. All other excipients are added in a sequential manner to this mixture and mixed until complete dissolution is achieved.
Example 9:
The following is an exemplary method of preparing oral liquid solution of Ivacaftor.
Table No. 9: Specific composition for oral liquid solution of Ivacaftor
Figure imgf000017_0002
Procedure: Polyethylene glycol is dispensed into a mixing tank, to it accurately weighed quantity of Ivacaftor API is added under continuous stirring. Weighed quantity of other ingredients were added and stirred to form clear mixture. All other excipients are added in a sequential manner to this mixture and mixed until complete dissolution is achieved.
Observed stability data for the Example 8 composition packed in glass bottle, under accelerated and long-term storage are reported in Tables 10.
Figure imgf000017_0003
Figure imgf000018_0001
* ND: Not detected
*NMT: Not More Than
Bioavailability study:
Bioavailability Study was performed for oral liquid solution of Ivacaftor and the observed pharmacokinetic parameters are summarized below:
1. Randomized, Open Label, Balanced, Single-Dose, Two-Treatment, Two-Period, Two-Sequence, Two-Way Crossover bioavailability study under fed condition:
Ivacaftor Oral Solution 150mg/5ml (Tl) vs Kalydeco® tabletl50mg
Figure imgf000018_0002
2. Randomized, Open Label, Balanced, Single-Dose, Two-Treatment, Two-Period, Two-Sequence, Two-Way Crossover bioavailability study under fasted condition:
Ivacaftor Oral Solution 150mg/5ml (Tl) vs Kalydeco® tabletl50mg
Figure imgf000019_0001
From above bioavailability study, it is observed that oral liquid solution of Ivacaftor has significantly higher bioavailability under fasted and fed condition.

Claims

WE CLAIM:
1. A stable oral liquid solution of ivacaftor, wherein the composition comprises:
a) a therapeutically effective amount of ivacaftor or a pharmaceutically acceptable salt or solvate thereof, and
b) a solvent system selected from group consisting of Polyethylene Glycols 400 and or Hydrogenated Vegetable Oil used individually or in combination thereof.
2. The stable oral liquid solution of ivacaftor as claimed in claim no. 1, wherein the composition further comprises:
a) a solvent or cosolvent system selected from group consisting of either Glycerol, polyols like sorbitol, maltitol, lactitol etc. or Polyoxylglycerides or Hydrogenated Vegetable Oil and or combination thereof;
b) solubilizing agent; and
c) other pharmaceutically acceptable excipients selected from group consisting of antioxidants, antimicrobial preservatives, sweetening agents, flavoring agents, coloring agents, buffering agents and the like.
3. The stable oral liquid solution of ivacaftor as claimed in claim nos. 1 and 2, wherein the Hydrogenated Vegetable Oil is selected from group but not limited to partially or fully hydrogenated oil such as Castor Oil, Peanut Oil, Com Oil, Coconut Oil or Cottonseed Oil.
4. The stable oral liquid solution of ivacaftor as claimed in claim no. 2, wherein the examples of solubilizing agent is selected from the group consisting but not limited to ammonium lauryl sulfate (ALS), sodium lauryl sulfate (SLS) , sodium laureth sulfate, sodium myreth sulfate, quaternary ammonium salts: cetrimonium bromide (CTAB) , cetylpyridiniumchloride (CPC), benzalkonium chloride (BAC), benzethonium chloride (BZT), phospholipids phosphatidylserine, phosphatidylethanolamine, phosphatidylcholine and sphingomyelins, Poloxamer, Tweens or Spans.
5. The stable oral liquid solution of ivacaftor as claimed in claim no. 2, wherein the examples of antioxidants is selected from the group consisting but not limited to Sodium sulphate, sodium metabisulphite, sodium formaldehyde, sulphoxylate, ascorbic acid, butylated hydroxytoluene (BHT), Butylated hydroxy anisole, propyl gallate, sodium citrate or citric acid.
6. The stable oral liquid solution of ivacaftor as claimed in claim no. 2, wherein the examples of antimicrobial preservatives is selected from the group consisting but not limited to Sorbic acid and its salts, potassium sorbate, methyl parahydroxybenzoate (Methylparaben), propyl parahydroxybenzoate, sodium benzoate, propionic acid used individually or in combination thereof.
7. The stable oral liquid solution of ivacaftor as claimed in claim no. 2, wherein the examples of sweetening agents is selected from the group consisting but not limited to sucrose, acesulfame potassium, sucralose, sodium saccharin, aspartame, sorbitol, xylitol, Neotame, Ammoniated Glycyrrhizin, Monoammonium Glycyrrhizinate or a combination thereof.
8. The stable oral liquid solution of ivacaftor as claimed in claim no. 2, wherein the examples of flavoring agents is selected from the group consisting but not limited to peppermint oil, grape oil, orange oil, lime oil, lemon oil, pineapple oil, berries, lavender, dill oil, spearmint oil, eucalyptus oil, ethyl vanillin, fruit flavor, caramel flavor and pharmaceutically acceptable flavors or combination thereof.
9. The stable oral liquid solution of ivacaftor as claimed in claim no. 2, wherein the examples of coloring agents is selected from the group consisting but not limited to Titanium dioxide, brilliant Blue, indigo tine, erythrosine, allura red, sunset yellow, tartrazine, aluminum blue lake or combination thereof.
10. The stable oral liquid solution of ivacaftor as claimed in claim no. 2, wherein the examples of buffering agents may include but not limited to citric acid, sodium citrate, trometamol or combination thereof.
11. The stable oral solution of Ivacaftor as per claim no. 1, where the finished product is packed in glass bottle.
12. A method for treating or lessening the severity of cystic fibrosis in a patient who has difficulty in swallowing, comprising administering a pharmaceutically effective dose of an oral liquid solution of Ivacaftor as claimed in claim no. 1.
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