US20140163068A1 - Pharmaceutical Compositions for the Treatment of CFTR Mediated Diseases - Google Patents

Pharmaceutical Compositions for the Treatment of CFTR Mediated Diseases Download PDF

Info

Publication number
US20140163068A1
US20140163068A1 US14/069,571 US201314069571A US2014163068A1 US 20140163068 A1 US20140163068 A1 US 20140163068A1 US 201314069571 A US201314069571 A US 201314069571A US 2014163068 A1 US2014163068 A1 US 2014163068A1
Authority
US
United States
Prior art keywords
compound
substantially amorphous
tablet
pharmaceutical composition
solid dispersion
Prior art date
Legal status (The legal status 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 status listed.)
Abandoned
Application number
US14/069,571
Other languages
English (en)
Inventor
Marinus Jacobus Verwijs
Radhika Karkare
Michael Douglas Moore
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Vertex Pharmaceuticals Inc
Original Assignee
Vertex Pharmaceuticals Inc
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.)
Filing date
Publication date
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=50628072&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=US20140163068(A1) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Application filed by Vertex Pharmaceuticals Inc filed Critical Vertex Pharmaceuticals Inc
Priority to US14/069,571 priority Critical patent/US20140163068A1/en
Assigned to VERTEX PHARMACEUTICALS INCORPORATED reassignment VERTEX PHARMACEUTICALS INCORPORATED ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: VERWIJS, MARINUS JACOBUS, MOORE, MICHAEL DOUGLAS, KARKARE, Radhika
Publication of US20140163068A1 publication Critical patent/US20140163068A1/en
Assigned to MACQUARIE US TRADING LLC reassignment MACQUARIE US TRADING LLC SECURITY INTEREST Assignors: VERTEX PHARMACEUTICALS (SAN DIEGO) LLC, VERTEX PHARMACEUTICALS INCORPORATED
Assigned to VERTEX PHARMACEUTICALS INCORPORATED reassignment VERTEX PHARMACEUTICALS INCORPORATED ASSIGNEE CHANGE OF ADDRESS Assignors: VERTEX PHARMACEUTICALS INCORPORATED
Priority to US15/152,092 priority patent/US20160324846A1/en
Assigned to VERTEX PHARMACEUTICALS INCORPORATED, VERTEX PHARMACEUTICALS (SAN DIEGO) LLC reassignment VERTEX PHARMACEUTICALS INCORPORATED RELEASE BY SECURED PARTY (SEE DOCUMENT FOR DETAILS). Assignors: MACQUARIE US TRADING LLC
Priority to US16/722,290 priority patent/US20200338063A1/en
Priority to US18/091,472 priority patent/US20230364073A1/en
Abandoned legal-status Critical Current

Links

Images

Classifications

    • 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
    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/443—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with oxygen as a ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61K9/10—Dispersions; Emulsions
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • 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
    • 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
    • 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
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • 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
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • 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
    • A61K9/2072—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
    • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
    • 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
    • A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/18—Drugs for disorders of the alimentary tract or the digestive system for pancreatic disorders, e.g. pancreatic enzymes
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/12—Drugs for disorders of the metabolism for electrolyte homeostasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the invention relates to pharmaceutical compositions comprising 3-(6-(1-(2,2-difluorobenzo[d][1,3] dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid (Compound 1) Form I and a solid dispersion comprising substantially amorphous N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide (Compound 2), methods of treatment, methods of manufacturing, methods of administering, and kits thereof.
  • Compound 1 3-(6-(1-(2,2-difluorobenzo[d][1,3] dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid
  • Compound 2 a solid dispersion comprising substantially amorphous N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-
  • Cystic fibrosis is a recessive genetic disease that affects approximately 30,000 children and adults in the United States and approximately 30,000 children and adults in Europe. Despite progress in the treatment of CF, there is no cure.
  • CFTR endogenously expressed in respiratory epithelia leads to reduced apical anion secretion causing an imbalance in ion and fluid transport.
  • anion transport contributes to enhanced mucus accumulation in the lung and the accompanying microbial infections that ultimately cause death in CF patients.
  • CF patients In addition to respiratory disease, CF patients typically suffer from gastrointestinal problems and pancreatic insufficiency that, if left untreated, results in death.
  • the majority of males with cystic fibrosis are infertile and fertility is decreased among females with cystic fibrosis.
  • individuals with a single copy of the CF associated gene exhibit increased resistance to cholera and to dehydration resulting from diarrhea—perhaps explaining the relatively high frequency of the CF gene within the population.
  • the most prevalent mutation is a deletion of phenylalanine at position 508 of the CFTR amino acid sequence, and is commonly referred to as ⁇ F508-CFTR. This mutation occurs in approximately 70% of the cases of cystic fibrosis and is associated with a severe disease.
  • deletion of residue 508 in ⁇ F508-CFTR prevents the nascent protein from folding correctly. This results in the inability of the mutant protein to exit the ER, and traffic to the plasma membrane. As a result, the number of channels present in the membrane is far less than observed in cells expressing wild-type CFTR. In addition to impaired trafficking, the mutation results in defective channel gating. Together, the reduced number of channels in the membrane and the defective gating lead to reduced anion transport across epithelia leading to defective ion and fluid transport. (Quinton, P. M. (1990), FASEB J. 4: 2709-2727).
  • Compound 1 in salt form is disclosed in International PCT Publication WO2007056341 and U.S. Pat. No. 7,741,321 as an inducer of CFTR activity and thus as a useful treatment for CFTR-mediated diseases such as cystic fibrosis.
  • Compound 1 Form I which is a substantially crystalline and salt-free form, is disclosed in International PCT Publication WO2009073757 and U.S. Pat. No. 8,507,534.
  • Compound 2 is disclosed in International PCT Publication WO2006002421 and U.S. Pat. No. 7,495,103 as an inducer of CFTR activity and thus as useful treatment for CFTR-mediated diseases such as cystic fibrosis.
  • a solid dispersion comprising substantially amorphous Compound 2 is disclosed in International PCT Publication WO2010019239 and United States Published Patent Application No. US20100074949. All above applications and patents are incorporated in their entirety by reference herein.
  • Compounds which are CFTR potentiators, such as Compound 2, and compounds which are CFTR correctors, such as Compound 1, have been shown independently to have utility in the treatment of CFTR related diseases, such as cystic fibrosis.
  • CFTR mediated diseases such as cystic fibrosis
  • CFTR potentiator and corrector compounds include CFTR potentiator and corrector compounds.
  • CFTR mediated diseases such as cystic fibrosis
  • CFTR potentiator compounds such as substantially amorphous Compound 2
  • CFTR corrector compounds such as Compound 1 Form I.
  • Compound 1 as part of a combination with Compound 2 has been granted a Breakthrough Therapy Designation from the Food and Drug Administration (FDA) for the treatment of cystic fibrosis, one of only two such grants at the time of the filing of this application (the other being for Compound 2).
  • FDA Food and Drug Administration
  • a common challenge for drugs approved by the FDA is the occasional lack of drug availability for patients in need thereof. Accordingly, a significant unmet need exists for the presently disclosed Compound 1 and Compound 2 formulations and processes for preparing them in a continuous and controlled manner.
  • a pharmaceutical composition comprising fixed dosage amounts of a CFTR corrector and CFTR potentiator, wherein the solid forms of said corrector and potentiator are stable, is a significant breakthrough for the treatment of CFTR mediated diseases such as cystic fibrosis.
  • the invention features a pharmaceutical compositions comprising 3-(6-(1-(2,2-difluorobenzo[d][1,3] dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, Compound 1 Form I, which has the structure below:
  • the present invention features a pharmaceutical composition
  • a pharmaceutical composition comprising:
  • PC-I referred to as PC-I.
  • the pharmaceutical compositions of the present invention comprise 30 to 55 percent by weight Compound 1 Form I, and 10 to 45 percent by weight solid dispersion comprising substantially amorphous Compound 2.
  • the filler is selected from cellulose, modified cellulose, sodium carboxymethyl cellulose, ethyl cellulose hydroxymethyl cellulose, hydroxypropylcellulose, cellulose acetate, microcrystalline cellulose, dibasic calcium phosphate, sucrose, lactose, corn starch, potato starch, or any combination thereof.
  • the filler is microcrystalline cellulose, and is present in an amount ranging from 10 to 20 percent by weight.
  • the disintegrant is selected from agar-agar, algins, calcium carbonate, carboxmethylcellulose, cellulose, hydroxypropylcellulose, low substituted hydroxypropylcellulose, clays, croscarmellose sodium, crospovidone, gums, magnesium aluminum silicate, methylcellulose, polacrilin potassium, sodium alginate, sodium starch glycolate, maize starch, potato starch, tapioca starch, or any combination thereof.
  • the disintegrant is croscarmellose sodium, and is present in an amount ranging from 1 to 3 percent by weight.
  • the binder is selected from polyvinylpyrrolidone, dibasic calcium phosphate, sucrose, corn starch, modified cellulose, or any combination thereof. In another embodiment, the binder is polyvinylpyrrolidone, and is present in an amount ranging from 0 to 5 percent by weight.
  • the present invention features a pharmaceutical composition having the following formulation:
  • Compound 1 Form I 35-50 Solid dispersion comprising 25-40 substantially amorphous Compound 2 Microcrystalline cellulose 10-20 Croscarmellose sodium 1-3 Sodium lauryl sulfate 0.5-2 Polyvinylpyrrolidone 0-5 referred to as PC-II.
  • PC-III referred to as PC-III.
  • the pharmaceutical compositions of present invention comprise about 100 to 250 mg of Compound 1 Form I, and about 100 to 150 mg of substantially amorphous Compound 2. In another embodiment, the pharmaceutical compositions of the present invention comprise about 200 mg of Compound 1 Form I, and about 125 mg of substantially amorphous Compound 2. In another embodiment, the pharmaceutical compositions of the present invention comprise about 150 mg of Compound 1 Form I, and about 125 mg of substantially amorphous Compound 2.
  • the filler is selected from cellulose, modified cellulose, sodium carboxymethyl cellulose, ethyl cellulose hydroxymethyl cellulose, hydroxypropylcellulose, cellulose acetate, microcrystalline cellulose, dibasic calcium phosphate, sucrose, lactose, corn starch, potato starch, or any combination thereof.
  • the filler is microcrystalline cellulose, and is present in an amount ranging from 20 to 30 percent by weight.
  • the surfactant is selected from sodium lauryl sulfate, sodium stearyl fumerate, polyoxyethylene 20 sorbitan mono-oleate, or any combination thereof. In another embodiment, the surfactant is sodium lauryl sulfate, and is present in an amount ranging from 0.5 to 2 percent by weight.
  • the lubricant is selected from magnesium stearate, calcium stearate, zinc stearate, sodium stearate, stearic acid, aluminum stearate, leucine, glyceryl behenate, hydrogenated vegetable oil or any combination thereof.
  • the lubricant is magnesium stearate, and is present in an amount ranging from 0.5 to 2 percent by weight.
  • Compound 1 Form I 25-50 A solid dispersion comprising 15-35 substantially amorphous Compound 2 Microcrystalline cellulose 20-30 Croscarmellose sodium 3-10 Sodium lauryl sulfate 0.5-2 Polyvinylpyrrolidone 0-5 Magnesium stearate 0.5-2 referred to as PC-IV.
  • the pharmaceutical compositions of the present invention are solid oral pharmaceutical compositions.
  • the solid oral pharmaceutical compositions are a granular pharmaceutical composition or tablet.
  • the granular pharmaceutical compositions of the present invention have the following formulation:
  • Compound 1 Form I 38 Solid dispersion comprising 40 substantially amorphous Compound 2 Microcrystalline cellulose 16 Croscarmellose sodium 2 Sodium lauryl sulfate 1 Polyvinylpyrrolidone 3 referred to as PC-VI.
  • the granular pharmaceutical compositions of the present invention have the following formulation:
  • Compound 1 Form I 51 Solid dispersion comprising 27 substantially amorphous Compound 2 Microcrystalline cellulose 16 Croscarmellose sodium 2 Sodium lauryl sulfate 1 Polyvinylpyrrolidone 3 referred to as PC-VH.
  • the tablets of the present invention have the following formulation:
  • Compound 1 Form I 31 Solid dispersion comprising 32 substantially amorphous Compound 2 Microcrystalline cellulose 26 Croscarmellose sodium 6 Sodium lauryl sulfate 1 Polyvinylpyrrolidone 3 Magnesium stearate 1 referred to as PC-IX.
  • the tablets of the present invention have the following formulation:
  • the tablets of the present invention have the following formulation:
  • Compound 1 Form I 200 Solid dispersion comprising 156 substantially amorphous Compound 2 Microcrystalline cellulose 150 Croscarmellose sodium 34 Sodium lauryl sulfate 4 Polyvinylpyrrolidone 15 Magnesium stearate 6 referred to as PC-XI.
  • the tablets of the present invention have the following formulation:
  • the tablets of the present invention have the following formulation:
  • Compound 1 Form I 200 Solid dispersion comprising 104 substantially amorphous Compound 2 Microcrystalline cellulose 128 Croscarmellose sodium 29 Sodium lauryl sulfate 4 Polyvinylpyrrolidone 13 Magnesium stearate 5 referred to as PC-XIII.
  • the tablets of the present invention have the following formulation:
  • Compound 1 Form I 34 Solid dispersion comprising 27 substantially amorphous Compound 2 Microcrystalline cellulose 25 Croscarmellose sodium 6 Sodium lauryl sulfate 1 Polyvinylpyrrolidone 3 Magnesium stearate 1 Colorant 3 referred to as PC-XIV.
  • the tablets of the present invention have the following formulation:
  • Compound 1 Form I 30 Solid dispersion comprising 31 substantially amorphous Compound 2 Microcrystalline cellulose 25 Croscarmellose sodium 6 Sodium lauryl sulfate 1 Polyvinylpyrrolidone 3 Magnesium stearate 1 Colorant 3 referred to as PC-XV.
  • the tablets of the present invention have the following formulation:
  • Compound 1 Form I 40 Solid dispersion comprising 21 substantially amorphous Compound 2 Microcrystalline cellulose 25 Croscarmellose sodium 6 Sodium lauryl sulfate 1 Polyvinylpyrrolidone 3 Magnesium stearate 1 Colorant 3 referred to as PC-XVI.
  • the tablets of the present invention have the following formulation:
  • Compound 1 Form I 200 Solid dispersion comprising 156 substantially amorphous Compound 2 Micro crystalline cellulose 150 Croscarmellose sodium 34 Sodium lauryl sulfate 4 Polyvinylpyrrolidone 15 Magnesium stearate 6 Colorant 17 referred to as PC-XVII.
  • the tablets of the present invention have the following formulation:
  • the tablets of the present invention have the following formulation:
  • Compound 1 Form I 150 Solid dispersion comprising 156 substantially amorphous Compound 2 Microcrystalline cellulose 129 Croscarmellose sodium 29 Sodium lauryl sulfate 4 Polyvinylpyrrolidone 13 Magnesium stearate 5 Colorant 15 referred to as PC-XIX.
  • Compound 1 Form I 200 Solid dispersion comprising 104 substantially amorphous Compound 2 Microcrystalline cellulose 128 Croscarmellose sodium 29 Sodium lauryl sulfate 4 Polyvinylpyrrolidone 13 Magnesium stearate 5 Colorant 14 referred to as PC-XX.
  • Compound 1 Form I 200 Solid dispersion comprising 83 substantially amorphous Compound 2 Microcrystalline cellulose 128 Croscarmellose sodium 29 Sodium lauryl sulfate 4 Polyvinylpyrrolidone 13 Magnesium stearate 5 Colorant 14 referred to as PC-XXI.
  • the tablets of the present invention have the following formulation:
  • Component % by wgt. Compound 1 Form I 20-40 Solid dispersion comprising 30-40 substantially amorphous Compound 2 Microcrystalline cellulose 20-30 Croscarmellose sodium 1-10 Polyvinylpyrrolidone 1-5 Sodium lauryl sulfate 0.1-1 Magnesium stearate 0.5-1.5 referred to as PC-XXII.
  • the tablets of the present invention have the following formulation:
  • Compound 1/Compound 2 100 mg/125 mg Component % in Granule % in Tablet mg/Tablet Compound 1 Form I 30 25 100 Solid dispersion 47 38 156 comprising substantially amorphous Compound 2 Microcrystalline 17 13 55 cellulose Croscarmellose 2 2 7 sodium Polyvinylpyrrolidone 3 3 11 Sodium lauryl sulfate 1 1 3 Total Granules 100 82 332 Croscarmellose 4 18 sodium Microcrystalline 13 53 cellulose Magnesium stearate 1 4 Total Tablet 100 407 referred to as PC-XXIII.
  • the tablets of the present invention have the following formulation:
  • the tablets of the present invention have the following formulation:
  • Compound 1/Compound 2 75 mg/125 mg Component % in Granule % in Tablet mg/Tablet Compound 1 Form I 25 20 75 Solid dispersion 52 43 156 comprising substantially amorphous Compound 2 Microcrystalline 17 13 49 cellulose Croscarmellose 2 2 6 sodium Polyvinylpyrrolidone 3 3 10 Sodium lauryl sulfate 1 1 3 Total Granules 100 82 299 Croscarmellose 4 17 sodium Microcrystalline 13 48 cellulose Magnesium stearate 1 4 Core Tablet 100 368 Pink Opadry 3 11 Film Coated Tablet 379
  • the present invention features a method of treating, lessening the severity of, or symptomatically treating cystic fibrosis in a patient comprising administering to the patient an effective amount of the pharmaceutical composition, granular pharmaceutical composition, or tablet of the present invention.
  • the present invention features a method of treating, lessening the severity of, or symptomatically treating cystic fibrosis in a patient comprising administering to the patient an effective amount of the pharmaceutical composition, granular pharmaceutical composition, or tablet of any one of formulations PC-I through PC-XXV.
  • the patient has a ⁇ F508 CFTR mutation. In another embodiment, the patient is homozygous in ⁇ F508. In another embodiment, the patient is heterozygous in ⁇ F508. In another embodiment, two tablets are administered to the patient per day.
  • the present invention features a method of preparing a granular pharmaceutical composition comprising wet granulating the following components:
  • the present invention features a method of preparing a tablet comprising compressing:
  • compositions comprising the following components:
  • the present invention features a kit comprising pharmaceutical compositions, granular pharmaceutical compositions, or tablets of the present invention, and a separate therapeutic agent or pharmaceutical composition thereof.
  • the pharmaceutical compositions, granular pharmaceutical compositions, or tablets of the present invention, and the separate therapeutic agent or pharmaceutical composition thereof are in separate containers.
  • the separate containers are bottles.
  • the separate containers are vials.
  • the separate containers are blister packs.
  • the invention provides a continuous or semi-continuous process for making the pharmaceutical compositions described herein by a twin screw wet granulation process comprising the steps of screening and weighing Compound 1, Compound 2, and excipients; mixing Compound 1, Compound 2, and excipients in a blender and feeding the blend into a continuous granulator while adding a granulation fluid comprising surfactant and a binder at a suitable rate for a suitable amount of time and chopping the mixture into granules; drying the granules; blending the granules with extra-granular excipients for a suitable amount of time; compressing the blend into tablets; coating the tablets; and, optionally, printing a monogram on one or both tablet faces.
  • a twin screw wet granulation process comprising the steps of screening and weighing Compound 1, Compound 2, and excipients; mixing Compound 1, Compound 2, and excipients in a blender and feeding the blend into a continuous granulator while adding a granulation fluid
  • FIG. 1 is an X-ray diffraction pattern calculated from a single crystal structure of Compound 1 Form I.
  • FIG. 2 is an actual X-ray powder diffraction pattern of Compound 1 Form I.
  • FIG. 4 is a graph depicting the stability of the substantially amorphous form of Compound 2 in tablet formulation PC-XVII at 50° C. after pre-equilibrating at 60% relative humidity by showing only a small amount of crystallinity over time.
  • FIG. 5 is a graph depicting the stability of the substantially amorphous form of Compound 2 in tablet formulation PC-XVII at 60° C. after pre-equilibrating at 60% relative humidity by showing only a small amount of crystallinity over time.
  • FIG. 6 is a graph depicting the stability of the substantially amorphous form of Compound 2 in tablet formulation PC-XX at 60° C. after pre-equilibrating at 60% relative humidity by showing only a small amount of crystallinity over time.
  • FIG. 7 is a graph depicting the stability of the substantially amorphous form of Compound 2 in tablet formulation PC-XX at 50° C. after pre-equilibrating at 60% relative humidity by showing only a small amount of crystallinity over time.
  • FIG. 8 is an 1 HNMR spectrum of Compound 1.
  • FIG. 9 is an 1 HNMR spectrum of Compound 1 HCl salt.
  • FIG. 11 is a conformational picture of Compound 1 Form I based on single crystal X-ray analysis.
  • FIG. 12 is a flow chart describing the preparation of a tablet of Compound 1 and Compound 2 by continuous methods.
  • CTR cystic fibrosis transmembrane conductance regulator
  • a “ ⁇ F508 mutation” or “F508-del mutation” is a specific mutation within the CFTR protein.
  • the mutation is a deletion of the three nucleotides that comprise the codon for amino acid phenylalanine at position 508, resulting in CFTR protein that lacks this phenylalanine residue.
  • a patient who is “homozygous” for a particular mutation e.g. ⁇ F508, has the same mutation on each allele.
  • a patient who is “heterozygous” for a particular mutation e.g. ⁇ F508, has this mutation on one allele, and a different mutation on the other allele.
  • CFTR corrector refers to a compound that increases the amount of functional CFTR protein to the cell surface, resulting in enhanced ion transport.
  • CFTR potentiator refers to a compound that increases the channel activity of CFTR protein located at the cell surface, resulting in enhanced ion transport.
  • active pharmaceutical ingredient or “API” refers to a biologically active compound.
  • solid form refers to Compound 1 or Compound 2, in a particular solid form e.g. crystals, amorphous states, and the like.
  • substantially amorphous refers to a solid material having little or no long range order in the position of its molecules.
  • substantially amorphous materials have less than about 15% crystallinity (e.g., less than about 10% crystallinity or less than about 5% crystallinity).
  • substantially amorphous includes the descriptor, ‘amorphous’, which refers to materials having no (0%) crystallinity.
  • substantially crystalline refers to a solid material having predominantly long range order in the position of its molecules.
  • substantially crystalline materials have more than about 85% crystallinity (e.g., more than about 90% crystallinity or more than about 95% crystallinity).
  • substantially crystalline includes the descriptor, ‘crystalline’, which refers to materials having 100% crystallinity.
  • crystalline and related terms used herein, when used to describe a substance, component, product, or form, means that the substance, component or product is substantially crystalline as determined by X-ray diffraction. (See, e.g., Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott Williams & Wilkins, Baltimore, Md. (2003); The United States Pharmacopeia, 23 rd ed., 1843-1844 (1995)).
  • an “excipient” includes functional and non-functional ingredients in a pharmaceutical composition.
  • a “surfactant” is an excipient that imparts pharmaceutical compositions with enhanced solubility and/or wetability.
  • a “binder” is an excipient that imparts a pharmaceutical composition with enhanced cohesion or tensile strength (e.g., hardness).
  • a “glidant” is an excipient that imparts a pharmaceutical compositions with enhanced flow properties.
  • a “colorant” is an excipient that imparts a pharmaceutical composition, e.g. a tablet, with a desired color.
  • colorants include commercially available pigments such as FD&C Blue #1 Aluminum Lake, FD&C Blue #2, other FD&C Blue colors, titanium dioxide, iron oxide, and/or combinations thereof.
  • the tablet provided by the invention is pink.
  • a “lubricant” is an excipient that is added to pharmaceutical compositions that are pressed into tablets.
  • the lubricant aids in compaction of granules into tablets and ejection of a tablet of a pharmaceutical composition from a die press.
  • Friability refers to the property of a tablet to remain intact and hold its form despite an external force of pressure. Friability can be quantified using the mathematical expression presented in equation 1:
  • Friability is measured using a standard USP testing apparatus that tumbles experimental tablets for 100 or 400 revolutions. Some tablets of the invention have a friability of less than 5.0%. In another embodiment, the friability is less than 2.0%. In another embodiment, the target friability is less than 1.0% after 400 revolutions.
  • mean particle diameter is the average particle diameter as measured using techniques such as laser light scattering, image analysis, or sieve analysis.
  • the granules used to prepare the pharmaceutical compositions provided by the invention have a mean particle diameter of less than 1.0 mm.
  • the granules used to prepare the pharmaceutical compositions provided by the invention have a bulk density of about 0.5-0.7 g/cc.
  • an “effective amount” or “therapeutically effective amount” of a compound of the invention may vary according to factors such as the disease state, age, and weight of the subject, and the ability of the compound of the invention to elicit a desired response in the subject. Dosage regimens may be adjusted to provide the optimum therapeutic response. An effective amount is also one in which any toxic or detrimental effects (e.g., side effects) of the compound of the invention are outweighed by the therapeutically beneficial effects.
  • the terms “therapeutically effective amount” and “effective amount” of a compound mean an amount sufficient to provide a therapeutic benefit in the treatment or management of a disease or disorder, or to delay or minimize one or more symptoms associated with the disease or disorder.
  • a “therapeutically effective amount” and “effective amount” of a compound mean an amount of therapeutic agent, alone or in combination with one or more other agent(s), which provides a therapeutic benefit in the treatment or management of the disease or disorder.
  • the terms “therapeutically effective amount” and “effective amount” can encompass an amount that improves overall therapy, reduces or avoids symptoms or causes of disease or disorder, or enhances the therapeutic efficacy of another therapeutic agent.
  • substantially pure as used in the phrase “substantially pure Compound 1 Form I” means greater than about 90% purity. In another embodiment, substantially pure refers to greater than about 95% purity. In another embodiment, substantially pure refers to greater than about 98% purity. In another embodiment, substantially pure refers to greater than about 99% purity.
  • the term “about” or “approximately” means an acceptable error for a particular value as determined by one of ordinary skill in the art, which depends in part on how the value is measured or determined.
  • the term “about” or “approximately” means within 1, 2, 3, or 4 standard deviations.
  • the term “about” or “approximately” means within 30%, 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, or 0.05% of a given value or range.
  • the invention provides pharmaceutical compositions comprising Compound 1 Form I and a solid dispersion comprising substantially amorphous Compound 2.
  • the amount of Compound 1 Form I that is present in the pharmaceutical composition is 100 mg, 125 mg, 150 mg, 200 mg, 250 mg, 300 mg, or 400 mg.
  • wgt. percent of Compound 1 Form I present in the pharmaceutical composition is from 10 to 75 percent.
  • Compound 1 Form I is present as substantially pure Compound 1 Form I.
  • the amount of substantially amorphous Compound 2 that is present in the pharmaceutical composition is 100 mg, 125 mg, 150 mg, 200 mg, or 250 mg. In some embodiments of this aspect, wgt.
  • substantially amorphous Compound 2 percent of substantially amorphous Compound 2 that is present in the pharmaceutical composition is from 10 to 75 percent. In these and other embodiments, substantially amorphous Compound 2 is present as substantially pure and amorphous Compound 2. “Substantially pure” means greater than ninety percent pure; preferably greater than 95 percent pure; more preferably greater than 99.5 percent pure.
  • the invention provides a pharmaceutical composition comprising:
  • the pharmaceutical composition comprises 25 mg of Compound 1 Form I. In another embodiment of this aspect, the pharmaceutical composition comprises 50 mg of Compound 1 Form I. In another embodiment of this aspect, the pharmaceutical composition comprises 100 mg of Compound 1 Form I. In another embodiment of this aspect, the pharmaceutical composition comprises 125 mg of Compound 1 Form I. In another embodiment of this aspect, the pharmaceutical composition comprises 150 mg of Compound 1 Form I. In another embodiment of this aspect, the pharmaceutical composition comprises 200 mg of Compound 1 Form I. In another embodiment of this aspect, the pharmaceutical composition comprises 250 mg of Compound 1 Form I. In another embodiment of this aspect, the pharmaceutical composition comprises 400 mg of Compound 1 Form I.
  • the pharmaceutical composition comprises 25 mg of substantially amorphous Compound 2. In another embodiment of this aspect, the pharmaceutical composition comprises 50 mg of substantially amorphous Compound 2. In another embodiment of this aspect, the pharmaceutical composition comprises 100 mg of substantially amorphous Compound 2. In another embodiment of this aspect, the pharmaceutical composition comprises 125 mg of substantially amorphous Compound 2. In another embodiment of this aspect, the pharmaceutical composition comprises 150 mg of substantially amorphous Compound 2. In another embodiment of this aspect, the pharmaceutical composition comprises 200 mg of substantially amorphous Compound 2. In another embodiment of this aspect, the pharmaceutical composition comprises 250 mg of substantially amorphous Compound 2.
  • the pharmaceutical compositions comprises Compound 1 Form I, wherein Compound 1 Form I is present in an amount of at least 15 wt % (e.g., at least 20 wt %, at least 30 wt %, at least 40 wt %, at least 50 wt %, or at least 60 wt %) by weight of the composition.
  • Compound 1 Form I is present in an amount of at least 15 wt % (e.g., at least 20 wt %, at least 30 wt %, at least 40 wt %, at least 50 wt %, or at least 60 wt %) by weight of the composition.
  • the pharmaceutical compositions comprises substantially amorphous Compound 2, wherein the substantially amorphous Compound 2 is present in an amount of at least 15 wt % (e.g., at least 20 wt %, at least 30 wt %, at least 40 wt %, at least 50 wt %, or at least 60 wt %) by weight of the composition.
  • the pharmaceutical composition comprises Compound 1 Form I, a solid dispersion comprising substantially amorphous Compound 2, a filler, a disintegrant, a surfactant, and a binder.
  • the composition comprises from about 25 wt % to about 55 wt % (e.g., about 30-50 wt %) of Compound 1 Form I by weight of the composition, and more typically, from 40 wt % to about 45 wt % of Compound 1 Form I by weight of the composition.
  • the composition comprises from about 15 wt % to about 40 wt % (e.g., about 20-35 wt %) of substantially amorphous Compound 2 by weight of the composition, and more typically, from 25 wt % to about 30 wt % of substantially amorphous Compound 2 by weight of the composition.
  • the concentration of Compound 1 Form I and substantially amorphous Compound 2 in the composition depends on several factors such as the amount of pharmaceutical composition needed to provide a desired amount of Compound 1 Form I and substantially amorphous Compound 2 and the desired dissolution profile of the pharmaceutical composition.
  • the pharmaceutical composition comprises Compound 1 Form I, in which Compound 1 Form I in its solid form has a mean particle diameter, measured by light scattering (e.g., using a Malvern Mastersizer available from Malvern Instruments in England) of 0.1 microns to 10 microns.
  • the particle size of Compound 1 Form I is 1 micron to 5 microns.
  • Compound 1 Form I has a particle size D50 of 2.0 microns.
  • the pharmaceutical compositions which are oral formulations also comprise one or more excipients such as fillers, disintegrants, surfactants, diluents, binders, glidants, lubricants, colorants, or fragrances and any combination thereof.
  • Fillers suitable for the invention are compatible with the ingredients of the pharmaceutical composition, i.e., they do not substantially reduce the solubility, the hardness, the chemical stability, the physical stability, or the biological activity of the pharmaceutical composition.
  • Exemplary fillers include: celluloses, modified celluloses, (e.g. sodium carboxymethyl cellulose, ethyl cellulose hydroxymethyl cellulose, hydroxypropylcellulose), cellulose acetate, microcrystalline cellulose, calcium phosphates, dibasic calcium phosphate, starches (e.g. corn starch, potato starch), sugars (e.g., sorbitol) lactose, sucrose, or the like), or any combination thereof.
  • the pharmaceutical composition comprises at least one filler in an amount of at least 5 wt % (e.g., at least about 20 wt %, at least about 30 wt %, or at least about 40 wt %) by weight of the composition.
  • the pharmaceutical composition comprises from about 10 wt % to about 60 wt % (e.g., from about 20 wt % to about 55 wt %, from about 25 wt % to about 50 wt %, or from about 27 wt % to about 45 wt %) of filler, by weight of the composition.
  • the pharmaceutical composition comprises at least about 20 wt % (e.g., at least 30 wt % or at least 40 wt %) of microcrystalline cellulose, for example MCC Avicel PH102, by weight of the composition.
  • the pharmaceutical composition comprises from about 10 wt % to about 60 wt % (e.g., from about 20 wt % to about 55 wt % or from about 25 wt % to about 45 wt %) of microcellulose, by weight of the composition.
  • Disintegrants suitable for the invention enhance the dispersal of the pharmaceutical composition and are compatible with the ingredients of the pharmaceutical composition, i.e., they do not substantially reduce the chemical stability, the physical stability, the hardness, or the biological activity of the pharmaceutical composition.
  • Exemplary disintegrants include croscarmellose sodium, sodium starch glycolate, or a combination thereof.
  • the pharmaceutical composition comprises disintegrant in an amount of about 10 wt % or less (e.g., about 7 wt % or less, about 6 wt % or less, or about 5 wt % or less) by weight of the composition.
  • the pharmaceutical composition comprises from about 1 wt % to about 10 wt % (e.g., from about 1.5 wt % to about 7.5 wt % or from about 2.5 wt % to about 6 wt %) of disintegrant, by weight of the composition.
  • the pharmaceutical composition comprises about 10 wt % or less (e.g., 7 wt % or less, 6 wt % or less, or 5 wt % or less) of croscarmellose sodium, by weight of the composition.
  • the pharmaceutical composition comprises from about 1 wt % to about 10 wt % (e.g., from about 1.5 wt % to about 7.5 wt % or from about 2.5 wt % to about 6 wt %) of croscarmellose sodium, by weight of the composition.
  • the pharmaceutical composition comprises from about 0.1% to about 10 wt % (e.g., from about 0.5 wt % to about 7.5 wt % or from about 1.5 wt % to about 6 wt %) of disintegrant, by weight of the composition. In still other examples, the pharmaceutical composition comprises from about 0.5% to about 10 wt % (e.g., from about 1.5 wt % to about 7.5 wt % or from about 2.5 wt % to about 6 wt %) of disintegrant, by weight of the composition.
  • Surfactants suitable for the invention enhance the wettability of the pharmaceutical composition and are compatible with the ingredients of the pharmaceutical composition, i.e., they do not substantially reduce the chemical stability, the physical stability, the hardness, or the biological activity of the pharmaceutical composition.
  • exemplary surfactants include sodium lauryl sulfate (SLS), sodium stearyl fumarate (SSF), polyoxyethylene 20 sorbitan mono-oleate (e.g., TweenTM), any combination thereof, or the like.
  • the pharmaceutical composition comprises a surfactant in an amount of about 10 wt % or less (e.g., about 5 wt % or less, about 2 wt % or less, about 1 wt % or less, about 0.8 wt % or less, or about 0.6 wt % or less) by weight of the composition.
  • the pharmaceutical composition includes from about 10 wt % to about 0.1 wt % (e.g., from about 5 wt % to about 0.2 wt % or from about 2 wt % to about 0.3 wt %) of surfactant, by weight of the composition.
  • the pharmaceutical composition comprises 10 wt % or less (e.g., about 5 wt % or less, about 2 wt % or less, about 1 wt % or less, about 0.8 wt % or less, or about 0.6 wt % or less) of sodium lauryl sulfate, by weight of the composition.
  • the pharmaceutical composition comprises from about 10 wt % to about 0.1 wt % (e.g., from about 5 wt % to about 0.2 wt % or from about 2 wt % to about 0.3 wt %) of sodium lauryl sulfate, by weight of the composition.
  • Binders suitable for the invention enhance the tablet strength of the pharmaceutical composition and are compatible with the ingredients of the pharmaceutical composition, i.e., they do not substantially reduce the chemical stability, the physical stability, or the biological activity of the pharmaceutical composition.
  • exemplary binders include polyvinylpyrrolidone, dibasic calcium phosphate, sucrose, corn (maize) starch, modified cellulose (e.g., hydroxymethyl cellulose), or any combination thereof.
  • the pharmaceutical composition comprises a binder in an amount of at least about 0.1 wt % (e.g., at least about 1 wt %, at least about 3 wt %, at least about 4 wt %, or at least about 5 wt %) by weight of the composition.
  • the pharmaceutical composition comprises from about 0.1 wt % to about 10 wt % (e.g., from about 1 wt % to about 10 wt % or from about 2 wt % to about 7 wt %) of binder, by weight of the composition.
  • the pharmaceutical composition comprises at least about 0.1 wt % (e.g., at least about 1 wt %, at least about 2 wt %, at least about 3 wt %, or at least about 4 wt %) of polyvinylpyrrolidone, by weight of the composition.
  • the pharmaceutical composition comprises a glidant in an amount ranging from about 0.1 wt % to about 10 wt % (e.g., from about 1 wt % to about 8 wt % or from about 2 wt % to about 5 wt %) of polyvinylpyrrolidone, by weight of the composition.
  • Diluents suitable for the invention may add necessary bulk to a formulation to prepare tablets of the desired size and are generally compatible with the ingredients of the pharmaceutical composition, i.e., they do not substantially reduce the solubility, the hardness, the chemical stability, the physical stability, or the biological activity of the pharmaceutical composition.
  • Exemplary diluents include: sugars, for example, confectioner's sugar, compressible sugar, dextrates, dextrin, dextrose, lactose, mannitol, sorbitol, cellulose, and modified celluloses, for example, powdered cellulose, talc, calcium phosphate, starch, or any combination thereof.
  • the pharmaceutical composition comprises a diluent in an amount of 40 wt % or less (e.g., 35 wt % or less, 30 wt % or less, or 25 wt % or less, or 20 wt % or less, or 15 wt % or less, or 10 wt % or less) by weight of the composition.
  • a diluent in an amount of 40 wt % or less (e.g., 35 wt % or less, 30 wt % or less, or 25 wt % or less, or 20 wt % or less, or 15 wt % or less, or 10 wt % or less) by weight of the composition.
  • the pharmaceutical composition comprises from about 40 wt % to about 1 wt % (e.g., from about 35 wt % to about 5 wt % or from about 30 wt % to about 7 wt %, from about 25 wt % to about 10 wt %, from about 20 wt % to about 15 wt %) of diluent, by weight of the composition.
  • the pharmaceutical composition comprises 40 wt % or less (e.g., 35 wt % or less, 25 wt % or less, or 15 wt % or less) of mannitol, by weight of the composition.
  • the pharmaceutical composition comprises from about 35 wt % to about 1 wt % (e.g., from about 30 wt % to about 5 wt % or from about 25 wt % to about 10 wt %) of mannitol, by weight of the composition.
  • Glidants suitable for the invention enhance the flow properties of the pharmaceutical composition and are compatible with the ingredients of the pharmaceutical composition, i.e., they do not substantially reduce the solubility, the hardness, the chemical stability, the physical stability, or the biological activity of the pharmaceutical composition.
  • exemplary glidants include colloidal silicon dioxide, talc, or a combination thereof.
  • the pharmaceutical composition comprises a glidant in an amount of 2 wt % or less (e.g., 1.75 wt %, 1.25 wt % or less, or 1.00 wt % or less) by weight of the composition.
  • the pharmaceutical composition comprises from about 2 wt % to about 0.05 wt % (e.g., from about 1.5 wt % to about 0.07 wt % or from about 1.0 wt % to about 0.09 wt %) of glidant, by weight of the composition.
  • the pharmaceutical composition comprises 2 wt % or less (e.g., 1.75 wt %, 1.25 wt % or less, or 1.00 wt % or less) of colloidal silicon dioxide, by weight of the composition.
  • the pharmaceutical composition comprises from about 2 wt % to about 0.05 wt % (e.g., from about 1.5 wt % to about 0.07 wt % or from about 1.0 wt % to about 0.09 wt %) of colloidal silicon dioxide, by weight of the composition.
  • the pharmaceutical composition can include an oral solid pharmaceutical dosage form which can comprise a lubricant that can prevent adhesion of a granulate-bead admixture to a surface (e.g., a surface of a mixing bowl, a compression die and/or punch).
  • a lubricant can also reduce interparticle friction within the granulate and improve the compression and ejection of compressed pharmaceutical compositions from a die press.
  • the lubricant is also compatible with the ingredients of the pharmaceutical composition, i.e., they do not substantially reduce the solubility, the hardness, or the biological activity of the pharmaceutical composition.
  • Exemplary lubricants include magnesium stearate, calcium stearate, zinc stearate, sodium stearate, stearic acid, aluminum stearate, leucine, glyceryl behenate, hydrogenated vegetable oil or any combination thereof.
  • the pharmaceutical composition comprises a lubricant in an amount of 5 wt % or less (e.g., 4.75 wt %, 4.0 wt % or less, or 3.00 wt % or less, or 2.0 wt % or less) by weight of the composition.
  • the pharmaceutical composition comprises from about 5 wt % to about 0.10 wt % (e.g., from about 4.5 wt % to about 0.5 wt % or from about 3 wt % to about 1 wt %) of lubricant, by weight of the composition.
  • the pharmaceutical composition comprises 5 wt % or less (e.g., 4.0 wt % or less, 3.0 wt % or less, or 2.0 wt % or less, or 1.0 wt % or less) of magnesium stearate, by weight of the composition.
  • the pharmaceutical composition comprises from about 5 wt % to about 0.10 wt % (e.g., from about 4.5 wt % to about 0.15 wt % or from about 3.0 wt % to about 0.50 wt %) of magnesium stearate, by weight of the composition.
  • compositions of the invention can optionally comprise one or more colorants, flavors, and/or fragrances to enhance the visual appeal, taste, and/or scent of the composition.
  • Suitable colorants, flavors, or fragrances are compatible with the ingredients of the pharmaceutical composition, i.e., they do not substantially reduce the solubility, the chemical stability, the physical stability, the hardness, or the biological activity of the pharmaceutical composition.
  • the pharmaceutical composition comprises a colorant, a flavor, and/or a fragrance.
  • the pharmaceutical compositions provided by the invention are purple.
  • the pharmaceutical composition includes or can be made into tablets and the tablets can be coated with a colorant and optionally labeled with a logo, other image and/or text using a suitable ink.
  • the pharmaceutical composition includes or can be made into tablets and the tablets can be coated with a colorant, waxed, and optionally labeled with a logo, other image and/or text using a suitable ink.
  • Suitable colorants and inks are compatible with the ingredients of the pharmaceutical composition, i.e., they do not substantially reduce the solubility, the chemical stability, the physical stability, the hardness, or the biological activity of the pharmaceutical composition.
  • the suitable colorants and inks can be any color and are water based or solvent based.
  • tablets made from the pharmaceutical composition are coated with a colorant and then labeled with a logo, other image, and/or text using a suitable ink.
  • tablets comprising pharmaceutical composition as described herein can be coated with about 3 wt % (e.g., less than about 6 wt % or less than about 4 wt %) of film coating comprising a colorant.
  • the colored tablets can be labeled with a logo and text indicating the strength of the active ingredient in the tablet using a suitable ink.
  • tablets comprising pharmaceutical composition as described herein can be coated with about 3 wt % (e.g., less than about 6 wt % or less than about 4 wt %) of a film coating comprising a colorant.
  • tablets made from the pharmaceutical composition are coated with a colorant, waxed, and then labeled with a logo, other image, and/or text using a suitable ink.
  • tablets comprising pharmaceutical composition as described herein can be coated with about 3 wt % (e.g., less than about 6 wt % or less than about 4 wt %) of film coating comprising a colorant.
  • the colored tablets can be waxed with Carnauba wax powder weighed out in the amount of about 0.01% w/w of the starting tablet core weight.
  • the waxed tablets can be labeled with a logo and text indicating the strength of the active ingredient in the tablet using a suitable ink.
  • tablets comprising pharmaceutical composition as described herein can be coated with about 3 wt % (e.g., less than about 6 wt % or less than about 4 wt %) of a film coating comprising a colorant
  • the colored tablets can be waxed with Carnauba wax powder weighed out in the amount of about 0.01% w/w of the starting tablet core weight.
  • the waxed tablets can be labeled with a logo and text indicating the strength of the active ingredient in the tablet using a pharmaceutical grade ink such as a black ink (e.g., Opacode® S-1-17823, a solvent based ink, commercially available from Colorcon, Inc. of West Point, Pa.).
  • a black ink e.g., Opacode® S-1-17823, a solvent based ink, commercially available from Colorcon, Inc. of West Point, Pa.
  • One exemplary pharmaceutical composition comprises from about 15 wt % to about 70 wt % (e.g., from about 15 wt % to about 60 wt %, from about 15 wt % to about 50 wt %, or from about 20 wt % to about 70 wt %, or from about 30 wt % to about 70 wt %) of Compound 1 Form I, by weight of the composition; and from about 15 wt % to about 40 wt % (e.g., about 20-35 wt %) of substantially amorphous Compound 2 by weight of the composition, and more typically, from 25 wt % to about 30 wt % of substantially amorphous Compound 2 by weight of the composition.
  • compositions can also include one or more pharmaceutically acceptable excipients, for example, from about 20 wt % to about 50 wt % of a filler; from about 1 wt % to about 5 wt % of a disintegrant; from about 2 wt % to about 0.3 wt % of a surfactant; and from about 0.1 wt % to about 5 wt % of a binder.
  • pharmaceutically acceptable excipients for example, from about 20 wt % to about 50 wt % of a filler; from about 1 wt % to about 5 wt % of a disintegrant; from about 2 wt % to about 0.3 wt % of a surfactant; and from about 0.1 wt % to about 5 wt % of a binder.
  • Another exemplary pharmaceutical composition comprises from about 15 wt % to about 70 wt % (e.g., from about 15 wt % to about 60 wt %, from about 15 wt % to about 50 wt %, or from about 15 wt % to about 40 wt % or from about 20 wt % to about 70 wt %, or from about 30 wt % to about 70 wt %, or from about 40 wt % to about 70 wt %, or from about 50 wt % to about 70 wt %) of Compound 1 Form I by weight of the composition, from about 15 wt % to about 40 wt % (e.g., about 20-35 wt %) of substantially amorphous Compound 2 by weight of the composition, and more typically, from 25 wt % to about 30 wt % of substantially amorphous Compound 2 by weight of the composition, and one or more excipients, for example,
  • Another exemplary pharmaceutical composition comprises from about 15 wt % to about 70 wt % (e.g., from about 15 wt % to about 60 wt %, from about 15 wt % to about 50 wt %, or from about 15 wt % to about 40 wt % or from about 20 wt % to about 70 wt %, or from about 30 wt % to about 70 wt %, or from about 40 wt % to about 70 wt %, or from about 50 wt % to about 70 wt %) of Compound 1 Form I by weight of the composition, from about 15 wt % to about 40 wt % (e.g., about 20-35 wt %) of substantially amorphous Compound 2 by weight of the composition, and more typically, from 25 wt % to about 30 wt % of substantially amorphous Compound 2 by weight of the composition, and one or more excipients, for example,
  • the invention is a granular pharmaceutical composition comprising:
  • the invention is a tablet comprising:
  • the invention is a tablet comprising:
  • Another tablet of the invention comprises:
  • microcrystalline cellulose c. about 125 to 175 mg of microcrystalline cellulose
  • magnesium stearate g. about 3 to 7 mg of magnesium stearate.
  • Another tablet of the invention comprises:
  • Another tablet of the invention comprises:
  • magnesium stearate g. about 6 mg of magnesium stearate
  • the invention is a granular pharmaceutical composition comprising:
  • the invention is a tablet comprising:
  • Another tablet of the invention comprises:
  • magnesium stearate g. about 3 to 7 mg of magnesium stearate.
  • Another tablet of the invention comprises:
  • compositions of the invention can be processed into a tablet form, capsule form, pouch form, lozenge form, or other solid form that is suited for oral administration.
  • the pharmaceutical compositions are in tablet form.
  • Another aspect of the invention provides a pharmaceutical formulation consisting of a tablet that includes Compound 1 Form I, a solid dispersion comprising substantially amorphous Compound 2, and excipients (e.g., a filler, a disintegrant, a surfactant, a binder, a colorant, a lubricant, or any combination thereof), each of which is described above and in the Examples below, wherein the tablet has a dissolution of at least about 50% (e.g., at least about 60%, at least about 70%, at least about 80%, at least about 90%, or at least about 99%) in about 30 minutes.
  • excipients e.g., a filler, a disintegrant, a surfactant, a binder, a colorant, a lubricant, or any combination thereof
  • the pharmaceutical composition consists of a tablet that includes Compound 1 Form I in an amount ranging from 25 mg to 400 mg, for example, 25 mg, or 50 mg, or 75 mg, or 100 mg, or 150 mg, 200 mg, 250 mg, 300 mg, or 400 mg, substantially amorphous Compound 2 in an amount ranging from 25 mg to 250 mg, for example, 25 mg, or 50 mg, or 75 mg, or 100 mg, or 150 mg, 200 mg, 250 mg, and one or more excipients (e.g., a filler, a disintegrant, a surfactant, a binder, a colorant, a lubricant, or any combination thereof) each of which is described above and in the Examples below, wherein the tablet has a dissolution of from about 50% to about 100% (e.g., from about 55% to about 95% or from about 60% to about 90%) in about 30 minutes.
  • excipients e.g., a filler, a disintegrant, a surfactant, a binder,
  • Dissolution can be measured with a standard USP Type II apparatus that employs a dissolution media of 0.1% CTAB dissolved in 900 mL of DI water, buffered at pH 6.8 with 50 mM potassium phosphate monoasic, stirring at about 50-75 rpm at a temperature of about 37° C. A single experimental tablet is tested in each test vessel of the apparatus. Dissolution can also be measured with a standard USP Type II apparatus that employs a dissolution media of 0.7% sodium lauryl sulfate dissolved in 900 mL of 50 mM sodium phosphate buffer (pH 6.8), stirring at about 65 rpm at a temperature of about 37° C. A single experimental tablet is tested in each test vessel of the apparatus.
  • Dissolution can also be measured with a standard USP Type II apparatus that employs a dissolution media of 0.5% sodium lauryl sulfate dissolved in 900 mL of 50 mM sodium phosphate buffer (pH 6.8), stirring at about 65 rpm at a temperature of about 37° C. A single experimental tablet is tested in each test vessel of the apparatus.
  • Compound 1 is used as the starting point for Compound 1 Form I and can be prepared by coupling an acid chloride moiety with an amine moiety according to Schemes 1-4.
  • Scheme 1 depicts the preparation of 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarbonyl chloride, which is used in Scheme 3 to make the amide linkage of Compound 1.
  • 2,2-difluorobenzo[d][1,3]dioxole-5-carboxylic acid is commercially available from Saltigo (an affiliate of the Lanxess Corporation). Reduction of the carboxylc acid moiety in 2,2-difluorobenzo[d][1,3]dioxole-5-carboxylic acid to the primary alcohol, followed by conversion to the corresponding chloride using thionyl chloride (SOCl 2 ), provides 5-(chloromethyl)-2,2-difluorobenzo[d][1,3]dioxole, which is subsequently converted to 2-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)acetonitrile using sodium cyanide.
  • SOCl 2 thionyl chloride
  • Scheme 2 depicts an alternative synthesis of the requisite acid chloride.
  • 5-bromomethyl-2,2-difluoro-1,3-benzodioxole is coupled with ethyl cyanoacetate in the presence of a palladium catalyst to form the corresponding alpha cyano ethyl ester.
  • Saponification of the ester moiety to the carboxylic acid gives the cyanoethyl compound.
  • Alkylation of the cyanoethyl compound with 1-bromo-2-chloro ethane in the presence of base gives the cyanocyclopropyl compound.
  • Treatment of the cyanocyclopropyl compound with base gives the carboxylate salt, which is converted to the carboxylic acid by treatment with acid. Conversion of the carboxylic acid to the acid chloride is then accomplished using a chlorinating agent such as thionyl chloride or the like.
  • Scheme 3 depicts the preparation of the requisite tert-butyl 3-(6-amino-3-methylpyridin-2-yl)benzoate, which is coupled with 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarbonyl chloride in Scheme 3 to give Compound 1.
  • Palladium-catalyzed coupling of 2-bromo-3-methylpyridine with 3-(tert-butoxycarbonyl)phenylboronic acid gives tert-butyl 3-(3-methylpyridin-2-yl)benzoate, which is subsequently converted to the desired compound.
  • Compound 1 Form I is prepared by dispersing or dissolving a salt form, such as the HCl salt, of Compound 1 in an appropriate solvent for an effective amount of time. Treatment of the tert-butyl ester with an acid such as HCl, gives the HCL salt of Compound 1, which is typically a crystalline solid. Compound 1 Form I may also be prepared directly from the t-butyl ester precursor by treatment with an appropriate acid, such as formic acid.
  • the HCl salt of 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid can be used to make Form I by dispersing or dissolving the HCl salt of 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid in an appropriate solvent for an effective amount of time.
  • salts of 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid may be used, such as, for example, salts derived from other mineral or organic acids.
  • the other salts result from acid-mediated hydrolysis of the t-butyl ester moiety.
  • Salts derived from other acids may include, for example, nitric, sulfuric, phosphoric, boric, acetic, benzoic and malonic.
  • the effective amount of time for formation of Compound 1 Form I from the salt of 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid can be any time between 2 to 24 hours or greater. It is recognized that the amount of time needed is inversely proportional to the temperature. That is, the higher the temperature the less time needed to affect dissociation of acid to form Compound 1 Form I. When the solvent is water, stirring the dispersion for approximately 24 hours at room temperature provides Compound 1 Form I in an approximately 98% yield.
  • substantially pure refers to greater than about 90% purity. In another embodiment, substantially pure refers to greater than about 95% purity. In another embodiment, substantially pure refers to greater than about 98% purity. In another embodiment, substantially pure refers to greater than about 99% purity.
  • Compound 1 Form I may be further purified by recrystallization from an organic solvent.
  • organic solvents include, but are not limited to, toluene, cumene, anisol, 1-butanol, isopropyl acetate, butyl acetate, isobutyl acetate, methyl t-butyl ether, methyl isobutyl ketone and 1-propanol-water mixtures.
  • the temperature may be as described above.
  • Compound 1 Form I is dissolved in 1-butanol at 75° C. until it is completely dissolved. Cooling down the solution to 10° C. at a rate of 0.2° C./min yields crystals of Compound 1 Form I which may be isolated by filtration.
  • Compound 1 Form I is characterized by one or more peaks at 15.2 to 15.6 degrees, 16.1 to 16.5 degrees, and 14.3 to 14.7 degrees in an X-ray powder diffraction obtained using Cu K alpha radiation. In another embodiment, Compound 1 Form I is characterized by one or more peaks at 15.4, 16.3, and 14.5 degrees. In another embodiment, Compound 1 Form I is further characterized by a peak at 14.6 to 15.0 degrees. In another embodiment, Compound 1 Form I is further characterized by a peak at 14.8 degrees. In another embodiment, Compound 1 Form I is further characterized by a peak at 17.6 to 18.0 degrees. In another embodiment, Compound 1 Form I is further characterized by a peak at 17.8 degrees.
  • Compound 1 Form I is further characterized by a peak at 16.4 to 16.8 degrees. In another embodiment, Compound 1 Form I is further characterized by a peak at 16.4 to 16.8 degrees. In another embodiment, Compound 1 Form I is further characterized by a peak at 16.6 degrees. In another embodiment, Compound 1 Form I is further characterized by a peak at 7.6 to 8.0 degrees. In another embodiment, Compound 1 Form I is further characterized by a peak at 7.8 degrees. In another embodiment, Compound 1 Form I is further characterized by a peak at 25.8 to 26.2 degrees. In another embodiment, Compound 1 Form I is further characterized by a peak at 26.0 degrees. In another embodiment, Compound 1 Form I is further characterized by a peak at 21.4 to 21.8 degrees.
  • the particle size distribution of D90 is about 82 ⁇ m or less for Compound 1 Form I. In some embodiments, the particle size distribution of D50 is about 30 ⁇ m or less for Compound 1 Form I.
  • Compound 2 is the starting point for the solid dispersion comprising substantially amorphous Compound 2 and can be prepared by coupling a 4-oxo-dihydroquinoline carboxylic acid moiety with an amine moiety according to Schemes 5-7.
  • the amorphous form of Compound 2 may be prepared by spray dried methods.
  • Spray drying is a process that converts a liquid feed to a dried particulate form.
  • a secondary drying process such as fluidized bed drying or vacuum drying, may be used to reduce residual solvents to pharmaceutically acceptable levels.
  • spray drying involves contacting a highly dispersed liquid suspension or solution, and a sufficient volume of hot air to produce evaporation and drying of the liquid droplets.
  • the preparation to be spray dried can be any solution, coarse suspension, slurry, colloidal dispersion, or paste that may be atomized using the selected spray drying apparatus.
  • the preparation is sprayed into a current of warm filtered air that evaporates the solvent and conveys the dried product to a collector (e.g. a cyclone).
  • a collector e.g. a cyclone
  • the spent air is then exhausted with the solvent, or alternatively the spent air is sent to a condenser to capture and potentially recycle the solvent.
  • Commercially available types of apparatus may be used to conduct the spray drying.
  • commercial spray dryers are manufactured by Buchi Ltd.
  • Niro e.g., the PSD line of spray driers manufactured by Niro
  • Spray drying typically employs solid loads of material from about 3% to about 30% by weight, (i.e., drug and excipients), for example about 4% to about 20% by weight, preferably at least about 10%.
  • the upper limit of solid loads is governed by the viscosity of (e.g., the ability to pump) the resulting solution and the solubility of the components in the solution.
  • the viscosity of the solution can determine the size of the particle in the resulting powder product.
  • the spray drying is conducted with an inlet temperature of from about 60° C. to about 200° C., for example, from about 95° C. to about 185° C., from about 110° C. to about 182° C., from about 96° C. to about 180° C., e.g., about 145° C.
  • the spray drying is generally conducted with an outlet temperature of from about 30° C. to about 90° C., for example from about 40° C. to about 80° C., about 45° C. to about 80° C. e.g., about 75° C.
  • the atomization flow rate is generally from about 4 kg/h to about 12 kg/h, for example, from about 4.3 kg/h to about 10.5 kg/h, e.g., about 6 kg/h or about 10.5 kg/h.
  • the feed flow rate is generally from about 3 kg/h to about 10 kg/h, for example, from about 3.5 kg/h to about 9.0 kg/h, e.g., about 8 kg/h or about 7.1 kg/h.
  • the atomization ratio is generally from about 0.3 to 1.7, e.g., from about 0.5 to 1.5, e.g., about 0.8 or about 1.5.
  • Removal of the solvent may require a subsequent drying step, such as tray drying, fluid bed drying (e.g., from about room temperature to about 100° C.), vacuum drying, microwave drying, rotary drum drying or biconical vacuum drying (e.g., from about room temperature to about 200° C.).
  • a subsequent drying step such as tray drying, fluid bed drying (e.g., from about room temperature to about 100° C.), vacuum drying, microwave drying, rotary drum drying or biconical vacuum drying (e.g., from about room temperature to about 200° C.).
  • the spray dried dispersion is fluid bed dried.
  • the solvent includes a volatile solvent, for example a solvent having a boiling point of less than about 100° C.
  • the solvent includes a mixture of solvents, for example a mixture of volatile solvents or a mixture of volatile and non-volatile solvents.
  • the mixture can include one or more non-volatile solvents, for example, where the non-volatile solvent is present in the mixture at less than about 15%, e.g., less than about 12%, less than about 10%, less than about 8%, less than about 5%, less than about 3%, or less than about 2%.
  • Preferred solvents are those solvents where Compound 2 has a solubility of at least about 10 mg/ml, (e.g., at least about 15 mg/ml, 20 mg/ml, 25 mg/ml, 30 mg/ml, 35 mg/ml, 40 mg/ml, 45 mg/ml, 50 mg/ml, or greater). More preferred solvents include those where Compound 2 has a solubility of at least about 20 mg/ml.
  • Exemplary solvents that could be tested include acetone, cyclohexane, dichloromethane, N,N-dimethylacetamide (DMA), N,N-dimethylformamide (DMF), 1,3-dimethyl-2-imidazolidinone (DMI), dimethyl sulfoxide (DMSO), dioxane, ethyl acetate, ethyl ether, glacial acetic acid (HAc), methyl ethyl ketone (MEK), N-methyl-2-pyrrolidinone (NMP), methyl tert-butyl ether (MTBE), tetrahydrofuran (THF), pentane, acetonitrile, methanol, ethanol, isopropyl alcohol, isopropyl acetate, and toluene.
  • DMA N,N-dimethylacetamide
  • DMF N,N-dimethylformamide
  • DI 1,3-dimethyl-2-imid
  • acetone and water can be mixed with a third solvent such as DMA, DMF, DMI, DMSO, or HAc.
  • a third solvent such as DMA, DMF, DMI, DMSO, or HAc.
  • preferred solvents dissolve both Compound 2 and the polymer. Suitable solvents include those described above, for example, MEK, acetone, water, methanol, and mixtures thereof.
  • the particle size and the temperature drying range may be modified to prepare an optimal spray dry dispersion.
  • a small particle size would lead to improved solvent removal.
  • Applicants have found however, that smaller particles can lead to fluffy particles that, under some circumstances do not provide optimal spray dry dispersions for downstream processing such as tableting.
  • crystallization or chemical degradation of substantially amorphous Compound 2 may occur.
  • a sufficient amount of the solvent may not be removed.
  • the methods herein provide an optimal particle size and an optimal drying temperature.
  • particle size is such that D10 ( ⁇ m) is less than about 5, e.g., less than about 4.5, less than about 4.0, or less than about 3.5, D50 ( ⁇ m) is generally less than about 17, e.g., less than about 16, less than about 15, less than about 14, less than about 13, and D90 ( ⁇ m) is generally less than about 175, e.g., less than about 170, less than about 170, less than about 150, less than about 125, less than about 100, less than about 90, less than about 80, less than about 70, less than about 60, or less than about less than about 50.
  • bulk density of the spray dried particles is from about 0.08 g/cc to about 0.20 g/cc, e.g., from about 0.10 to about 0.15 g/cc, e.g., about 0.11 g/cc or about 0.14 g/cc.
  • Tap density of the spray dried particles generally ranges from about 0.08 g/cc to about 0.20 g/cc, e.g., from about 0.10 to about 0.15 g/cc, e.g., about 0.11 g/cc or about 0.14 g/cc, for 10 taps; 0.10 g/cc to about 0.25 g/cc, e.g., from about 0.11 to about 0.21 g/cc, e.g., about 0.15 g/cc, about 0.19 g/cc, or about 0.21 g/cc for 500 taps; 0.15 g/cc to about 0.27 g/cc, e.g., from about 0.18 to about 0.24 g/cc, e.g., about 0.18 g/cc, about 0.19 g/cc, about 0.20 g/cc, or about 0.24 g/cc for 1250 taps; and 0.15 g/cc to about 0.27 g/c
  • Spray dried dispersions including amorphous Compound 2 and a polymer (or solid state carrier) also are included herein.
  • Compound 2 is present as an amorphous compound as a component of a solid amorphous dispersion.
  • the solid amorphous dispersion generally includes substantially amorphous Compound 2 and a polymer.
  • Exemplary polymers include cellulosic polymers such as HPMC or HPMCAS and pyrrolidone containing polymers such as PVP/VA.
  • the solid amporphous dispersion includes one or more additional exipients, such as a surfactant.
  • a polymer is able to dissolve in aqueous media.
  • the solubility of the polymers may be pH-independent or pH-dependent.
  • the latter include one or more enteric polymers.
  • enteric polymer refers to a polymer that is preferentially soluble in the less acidic environment of the intestine relative to the more acid environment of the stomach, for example, a polymer that is insoluble in acidic aqueous media but soluble when the pH is above 5-6.
  • An appropriate polymer should be chemically and biologically inert.
  • the glass transition temperature (T g ) of the polymer should be as high as possible.
  • suitable glass transition temperatures of the polymers include at least about 90° C., at least about 95° C., at least about 100° C., at least about 105° C., at least about 110° C., at least about 115° C., at least about 120° C., at least about 125° C., at least about 130° C., at least about 135° C., at least about 140° C., at least about 145° C., at least about 150° C., at least about 155° C., at least about 160° C., at least about 165° C., at least about 170° C., or at least about 175° C. (as measured under dry conditions).
  • a polymer with a higher T g generally has lower molecular mobility at room temperature, which can be a crucial factor in stabilizing the physical stability of the amorphous spray dry dispersion.
  • the hygroscopicity of the polymers should be as low, e.g., less than about 10%.
  • the hygroscopicity of a polymer or composition is characterized at about 60% relative humidity.
  • the polymer has less than about 10% water absorption, for example less than about 9%, less than about 8%, less than about 7%, less than about 6%, less than about 5%, less than about 4%, less than about 3%, or less than about 2% water absorption.
  • the hygroscopicity can also affect the physical stability of the spray dry dispersions. Generally, moisture adsorbed in the polymers can greatly reduce the T g of the polymers as well as the resulting spray dry dispersions, which will further reduce the physical stability of the spray dry dispersions as described above.
  • the polymer is one or more water-soluble polymer(s) or partially water-soluble polymer(s).
  • Water-soluble or partially water-soluble polymers include but are not limited to, cellulose derivatives (e.g., hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC)) or ethylcellulose; polyvinylpyrrolidones (PVP); polyethylene glycols (PEG); polyvinyl alcohols (PVA); acrylates, such as polymethacrylate (e.g., Eudragit® E); cyclodextrins (e.g., ⁇ -cyclodextin) and copolymers and derivatives thereof, including for example PVP-VA (polyvinylpyrollidone-vinyl acetate).
  • HPMC hydroxypropylmethylcellulose
  • HPC hydroxypropylcellulose
  • PVP polyvinylpyrrolidones
  • PEG polyethylene glycols
  • PVA polyvinyl alcohols
  • the polymer is hydroxypropylmethylcellulose (HPMC), such as HPMCAS, HPMC E50, HPMCE15, or HPMC60SHSO).
  • HPMC hydroxypropylmethylcellulose
  • the polymer can be a pH-dependent enteric polymer.
  • pH-dependent enteric polymers include, but are not limited to, cellulose derivatives (e.g., cellulose acetate phthalate (CAP)), hydroxypropyl methyl cellulose phthalates (HPMCP), hydroxypropyl methyl cellulose acetate succinate (HPMCAS), carboxymethylcellulose (CMC) or a salt thereof (e.g., a sodium salt such as (CMC-Na)); cellulose acetate trimellitate (CAT), hydroxypropylcellulose acetate phthalate (HPCAP), hydroxypropylmethyl-cellulose acetate phthalate (HPMCAP), and methylcellulose acetate phthalate (MCAP), or polymethacrylates (e.g., Eudragit® S).
  • the polymer is hydroxypropyl methyl cellulose acetate succinate (HPMCAS).
  • the polymer is hydroxypropyl methyl cellulose acetate succinate (HPMCAS).
  • the polymer is a polyvinylpyrrolidone co-polymer, for example, avinylpyrrolidone/vinyl acetate co-polymer (PVP/VA).
  • PVP/VA avinylpyrrolidone/vinyl acetate co-polymer
  • the amount of polymer relative to the total weight of the spray dry dispersion ranges from about 0.1% to 99% by weight. Unless otherwise specified, percentages of drug, polymer and other excitpients as described within a dispersion are given in weight percentages.
  • the amount of polymer is typically at least about 20%, and preferably at least about 30%, for example, at least about 35%, at least about 40%, at least about 45%, or about 50% (e.g., 49.5%).
  • the amount is typically about 99% or less, and preferably about 80% or less, for example about 75% or less, about 70% or less, about 65% or less, about 60% or less, or about 55% or less.
  • the polymer is in an amount of up to about 50% of the total weight of the dispersion (and even more specifically, between about 40% and 50%, such as about 49%, about 49.5%, or about 50%).
  • HPMC and HPMCAS are available in a variety of grades from ShinEtsu, for example, HPMCAS is available in a number of varieties, including AS-LF, AS-MF, AS-HF, AS-LG, AS-MG, AS-HG. Each of these grades vary with the percent substitution of acetate and succinate.
  • substantially amorphous Compound 2 and polymer are present in roughly equal amounts, for example each of the polymer and the drug make up about half of the percentage weight of the dispersion.
  • the polymer is present in about 49.5% and the drug is present in about 50%.
  • substantially amorphous Compound 2 and the polymer combined represent 1% to 20% w/w total solid content of the non-spray dry dispersion prior to spray drying. In some embodiments, substantially amorphous Compound 2 and the polymer combined represent 5% to 15% w/w total solid content of the non-spray dry dispersion prior to spray drying. In some embodiments, substantially amorphous Compound 2 and the polymer combined represent about 11% w/w total solid content of the non-spray dry dispersion prior to spray drying.
  • the dispersion further includes other minor ingredients, such as a surfactant (e.g., SLS).
  • a surfactant e.g., SLS
  • the surfactant is present in less than about 10% of the dispersion, for example less than about 9%, less than about 8%, less than about 7%, less than about 6%, less than about 5%, less than about 4%, less than about 3%, less than about 2%, about 1%, or about 0.5%.
  • the polymer should be present in an amount effective for stabilizing the spray dry dispersion.
  • Stabilizing includes inhibiting or preventing, the crystallization of substantially amorphous Compound 2. Such stabilizing would inhibit the conversion Compound 2 from amorphous to crystalline form.
  • the polymer would prevent at least a portion (e.g., about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, or greater) of Compound 2 from converting from an amorphous to a crystalline form.
  • Stabilization can be measured, for example, by measuring the glass transition temperature of the spray dry dispersion, measuring the rate of relaxation of the amorphous material, or by measuring the solubility or bioavailability of Compound 2.
  • Suitable polymers for use in combination with Compound 2, for example to form a spray dry dispersion such as an amorphous spray dry dispersion should have one or more of the following properties:
  • the polymer should be relatively non-hygroscopic.
  • the polymer should, when stored under standard conditions, absorb less than about 10% water, for example, less than about 9%, less than about 8%, less than about 7%, less than about 6%, or less than about 5%, less than about 4%, or less than about 3% water.
  • the polymer will, when stored under standard conditions, be substantially free of absorbed water.
  • the polymer should have similar or better solubility in solvents suitable for spray drying processes relative to that of Compound 2.
  • the polymer will dissolve in one or more of the same solvents or solvent systems as Compound 2. It is preferred that the polymer is soluble in at least one non-hydroxy containing solvent such as methylene chloride, acetone, or a combination thereof.
  • the polymer when combined with substantially amorphous Compound 2, for example in a spray dry dispersion or in a liquid suspension, should increase the solubility of Compound 2 in aqueous and physiologically relative media either relative to the solubility of Compound 2 in the absence of polymer or relative to the solubility of Compound 2 when combined with a reference polymer.
  • the polymer could increase the solubility of amorphous Compound 2 by reducing the amount of amorphous Compound 2 that converts to crystalline Compound 2, either from a solid amorphous dispersion or from a liquid suspension.
  • the polymer should decrease the relaxation rate of the amorphous substance.
  • the polymer should increase the physical and/or chemical stability of substantially amorphous Compound 2.
  • the polymer should improve one or more of the handling, administration or storage properties of substantially amorphous Compound 2.
  • the polymer should not interact unfavorably with other pharmaceutical components, for example excipients.
  • the suitability of a candidate polymer (or other component) can be tested using the spray drying methods (or other methods) described herein to form an amorphous composition.
  • the candidate composition can be compared in terms of stability, resistance to the formation of crystals, or other properties, and compared to a reference preparation, e.g., a preparation of neat amorphous Compound 2 or crystalline Compound 2.
  • a reference preparation e.g., a preparation of neat amorphous Compound 2 or crystalline Compound 2.
  • a candidate composition could be tested to determine whether it inhibits the time to onset of solvent mediated crystallization, or the percent conversion at a given time under controlled conditions, by at least 50%, 75%, 100%, or 110% as well as the reference preparation, or a candidate composition could be tested to determine if it has improved bioavailability or solubility relative to crystalline Compound 2.
  • the spray dry dispersion may include a surfactant.
  • a surfactant or surfactant mixture would generally decrease the interfacial tension between the spray dry dispersion and an aqueous medium.
  • An appropriate surfactant or surfactant mixture may also enhance aqueous solubility and bioavailability of Compound 2 from a spray dry dispersion.
  • the surfactants for use in connection with the present invention include, but are not limited to, sorbitan fatty acid esters (e.g., Spans®), polyoxyethylene sorbitan fatty acid esters (e.g., Tweens®), sodium lauryl sulfate (SLS), sodium dodecylbenzene sulfonate (SDBS) dioctyl sodium sulfosuccinate (Docusate), dioxycholic acid sodium salt (DOSS), Sorbitan Monostearate, Sorbitan Tristearate, hexadecyltrimethyl ammonium bromide (HTAB), Sodium N-lauroylsarcosine, Sodium Oleate, Sodium Myristate, Sodium Stearate, Sodium Palmitate, Gelucire 44/14, ethylenediamine tetraacetic acid (EDTA), Vitamin E d-alpha tocopheryl polyethylene glycol 1000 succinate (TPGS), Lecithin,
  • the amount of the surfactant (e.g., SLS) relative to the total weight of the spray dry dispersion may be between 0.1-15%. Preferably, it is from about 0.5% to about 10%, more preferably from about 0.5 to about 5%, e.g., about 0.5 to 4%, about 0.5 to 3%, about 0.5 to 2%, about 0.5 to 1%, or about 0.5%.
  • the amount of the surfactant relative to the total weight of the spray dry dispersion is at least about 0.1%, preferably about 0.5%.
  • the surfactant would be present in an amount of no more than about 15%, and preferably no more than about 12%, about 11%, about 10%, about 9%, about 8%, about 7%, about 6%, about 5%, about 4%, about 3%, about 2% or about 1%.
  • An embodiment wherein the surfactant is in an amount of about 0.5% by weight is preferred.
  • Candidate surfactants can be tested for suitability for use in the invention in a manner similar to that described for testing polymers.
  • compositions of the invention can be produced by, wet granulation, compacting or compressing an admixture or composition, for example, a powder or granules, under pressure to form a stable three-dimensional shape (e.g., a tablet).
  • tablette includes compressed pharmaceutical dosage unit forms of all shapes and sizes, whether coated or uncoated.
  • tablette refers to a physically discrete unit of agent appropriate for the patient to be treated.
  • a compacted mixture has a density greater than that of the mixture prior to compaction.
  • a dosage tablet of the invention can have almost any shape including concave and/or convex faces, rounded or angled corners, and a rounded to rectilinear shape.
  • the compressed tablets of the invention comprise a rounded tablet having flat faces.
  • the tablets of the invention can be prepared by any compaction and compression method known by persons of ordinary skill in the art of forming compressed solid pharmaceutical dosage forms.
  • the formulations provided herein may be prepared using conventional methods known to those skilled in the field of pharmaceutical formulation, as described, e.g., in pertinent textbooks.
  • the ingredients are weighed according to the formula set herein.
  • all of the intragranular ingredients are sifted and mixed well.
  • the ingredients can be lubricated with a suitable lubricant, for example, magnesium stearate.
  • the next step can comprise compaction/slugging of the powder admixture and sized ingredients.
  • the compacted or slugged blends are milled into granules and sifted to obtain the desired size.
  • the granules can be further lubricated with, for example, magnesium stearate.
  • the granular composition of the invention can be compressed on suitable punches into various pharmaceutical formulations in accordance with the invention.
  • the tablets can be coated with a film, colorant or other coating.
  • Another aspect of the invention provides a method for producing a pharmaceutical composition
  • a method for producing a pharmaceutical composition comprising providing an admixture of a composition comprising Compound 1 Form I, a solid dispersion comprising substantially amorphous Compound 2 and one or more excipients selected from: a filler, a diluent, a binder, a surfactant, a lubricant, a disintegrant, and compressing the composition into a tablet having a dissolution of at least about 50% in about 30 minutes.
  • a wet granulation process is performed to yield the pharmaceutical formulation of the invention from an admixture of powdered and liquid ingredients.
  • a pharmaceutical composition comprising an admixture of a composition comprising Compound 1 Form I, a solid dispersion comprising substantially amorphous Compound 2, and one or more excipients selected from: a filler, a binder, a surfactant, or a disintegrant, are weighed as per the formula set herein.
  • all of the intragranular ingredients are sifted and mixed in a high shear or low shear granulator using water or water with a surfactant or water with a binder or water with a surfactant and a binder to granulate the powder blend.
  • a fluid other than water can also be used with or without surfactant and/or binder to granulate the powder blend.
  • the wet granules can optionally be milled using a suitable mill.
  • water may optionally be removed from the admixture by drying the ingredients in any suitable manner.
  • the dried granules can optionally be milled to the required size.
  • extra granular excipients can be added by blending (for example a filler, a diluent, and a disintegrant).
  • the sized granules can be further lubricated with magnesium stearate and a disintegrant, for example, croscarmellose sodium.
  • the granular composition of the invention can be sifted for sufficient time to obtain the correct size and then compressed on suitable punches into various pharmaceutical formulations in accordance with the invention.
  • the tablets can be coated with a film, colorant or other coating.
  • wet granulation can be carried out without substantial loss of the solid state forms of Compound 1 Form I or substantially amorphous Compound 2.
  • the pharmaceutical compositions of the present invention are prepared by a continuous twin screw wet granulation (TSWG) process.
  • TSWG continuous twin screw wet granulation
  • Continuous manufacturing delivers high quality and highly consistent product with on-line monitoring and control. Continuous manufacturing also facilitates quality by design development with a “data rich” design space and an easier to understand impact of upstream variables on the downstream process and final product quality.
  • the pharmaceutical compositions of the present invention can be finalized early on commercial scale equipment which avoids scale-up risks and formulation changes late in development.
  • continuous manufacturing has commercial manufacturing advantages such as improved process control, reduced product handling, and real time release efficiencies. The overall result is a more robust, controllable, and scalable process that has fewer process checks resulting in increased product quality and therefore greater patient safety.
  • HSG high shear granulation
  • TSWG granulation
  • a common granulation technique is well known for the risk of over-granulation and poor process control.
  • Scale-up of this process is very challenging and involves significant risk.
  • Changing from a HSG process to a continuous TSWG process allows scale-up using the same equipment to produce different batch sizes, by running for a longer time. This eliminates the scale-up risk commonly encountered with other granulation processes.
  • the TSWG process is more robust, being less sensitive to over-granulation.
  • FIG. 3 for a Compound 1 tablet the HSG process showed significant dissolution slow-down with increasing water content, while the TSWG process did not show a change for a similar range of water addition.
  • the continuous process starts with feeding individual excipients, Compound 1, and Compound 2 into a continuous in-line blender through loss-in-weight feeding. From this blender, the material is continuously conveyed and processed through twin screw wet granulation, drying, milling, extra-granular excipient addition, blending, compression and film coating.
  • a tablet comprising Compound 1 and Compound 2 may be prepared continuously according to FIG. 12 .
  • the admixture can comprise optional additives, such as, one or more colorants, one or more flavors, and/or one or more fragrances as described above and in the Examples below.
  • the relative concentrations (e.g., wt %) of each of these ingredients (and any optional additives) in the admixture are also presented above and in the Examples below.
  • the ingredients constituting the admixture can be provided sequentially or in any combination of additions; and, the ingredients or combination of ingredients can be provided in any order.
  • the lubricant is the last component added to the admixture.
  • the admixture comprises a composition of Compound 1 Form I, a solid dispersion of substantially amorphous Compound 2, and any one or more of the excipients; a binder, a surfactant, a diluent, a lubricant, a disintegrant, and a filler, wherein each of these ingredients is provided in a powder form (e.g., provided as particles having a mean or average diameter, measured by light scattering, of 250 ⁇ m or less (e.g., 150 ⁇ m or less, 100 ⁇ m or less, 50 ⁇ m or less, 45 ⁇ m or less, 40 ⁇ m or less, or 35 ⁇ m or less)).
  • a powder form e.g., provided as particles having a mean or average diameter, measured by light scattering, of 250 ⁇ m or less (e.g., 150 ⁇ m or less, 100 ⁇ m or less, 50 ⁇ m or less, 45 ⁇ m or less, 40 ⁇ m or less, or 35
  • compressing the admixture into a tablet is accomplished by filling a form (e.g., a mold) with the admixture and applying pressure to admixture. This can be accomplished using a die press or other similar apparatus.
  • a form e.g., a mold
  • the admixture of Compound 1 Form I, a solid dispersion comprising substantially amorphous Compound 2, and excipients can be first processed into granular form. The granules can then be sized and compressed into tablets or formulated for encapsulation according to known methods in the pharmaceutical art. It is also noted that the application of pressure to the admixture in the form can be repeated using the same pressure during each compression or using different pressures during the compressions.
  • the admixture of powdered ingredients or granules can be compressed using a die press that applies sufficient pressure to form a tablet having a dissolution of about 50% or more at about 30 minutes (e.g., about 55% or more at about 30 minutes or about 60% or more at about 30 minutes).
  • the admixture is compressed using a die press to produce a tablet hardness of at least about 5 kP (at least about 5.5 kP, at least about 6 kP, at least about 7 kP, at least about 10 kP, or at least 15 kP).
  • the admixture is compressed to produce a tablet hardness of between about 5 and 20 kP.
  • tablets comprising a pharmaceutical composition as described herein can be coated with about 3.0 wt % of a film coating comprising a colorant by weight of the tablet.
  • the colorant suspension or solution used to coat the tablets comprises about 20% w/w of solids by weight of the colorant suspension or solution.
  • the coated tablets can be labeled with a logo, other image or text.
  • the method for producing a pharmaceutical composition comprises providing an admixture of a solid forms, e.g. an admixture of powdered and/or liquid ingredients, the admixture comprising Compound 1 Form I, a solid dispersion comprising substantially amorphous Compound 2, and one or more excipients selected from: a binder, a diluent, a surfactant, a lubricant, a disintegrant, and a filler; mixing the admixture until the admixture is substantially homogenous, and compressing or compacting the admixture into a granular form.
  • a solid forms e.g. an admixture of powdered and/or liquid ingredients
  • the admixture comprising Compound 1 Form I, a solid dispersion comprising substantially amorphous Compound 2
  • one or more excipients selected from: a binder, a diluent, a surfactant, a lubricant, a disintegr
  • compositions comprising Compound 1 Form I and a solid dispersion comprising substantially amorphous Compound 2 can be compressed into tablets or formulated into capsules as described above or in the Examples below.
  • methods for producing a pharmaceutical composition comprises providing an admixture of Compound 1 Form I, a solid dispersion comprising substantially amorphous Compound 2, and one or more excipients, e.g.
  • a binder a diluent, a surfactant, a lubricant, a disintegrant, and a filler; mixing the admixture until the admixture is substantially homogenous, and compressing/compacting the admixture into a granular form using a high shear wet granule compaction process as set forth in the Examples below.
  • Pharmaceutical formulations for example a tablet as described herein, can be made using the granules prepared incorporating Compound 1 Form I and a solid dispersion comprising substantially amorphous Compound 2 in addition to the selected excipients described herein.
  • the present invention comprises jet milling a pharmaceutical composition comprising Compound 1 Form I and a solid dispersion comprising substantially amorphous Compound 2 in a suitable, conventional milling apparatus using air pressure suitable to produce particles having a significant particle size fraction between 0.1 microns and 50 microns.
  • the particle size is between 0.1 microns and 20 microns.
  • the particles size is between 0.1 microns and 10 microns.
  • the particle size is between 1.0 microns and 5 microns.
  • the pharmaceutical composition has a particle size D50 of 2.0 microns.
  • FIGS. 6 and 7 show similar results for PC-XIX.
  • the present formulations therefore, provide the convenience of a fixed dosage of two breakthrough API's in a surprisingly stable pharmaceutical composition. Such formulations increase patient compliance which directly relates to the effective treatment of diseases.
  • Dosage forms prepared as above can be subjected to in vitro dissolution evaluations according to Test 711 “Dissolution” in United States Pharmacopoeia 29, United States Pharmacopeial Convention, Inc., Rockville, Md., 2005 (“USP”), to determine the rate at which the active substance is released from the dosage forms.
  • the content of active substance and the impurity levels are conveniently measured by techniques such as high performance liquid chromatography (HPLC).
  • the invention includes use of packaging materials such as containers and closures of high-density polyethylene (HDPE), low-density polyethylene (LDPE) and or polypropylene and/or glass, glassine foil, aluminum pouches, and blisters or strips composed of aluminum or high-density polyvinyl chloride (PVC), optionally including a desiccant, polyethylene (PE), polyvinylidene dichloride (PVDC), PVC/PE/PVDC, and the like.
  • packaging materials such as containers and closures of high-density polyethylene (HDPE), low-density polyethylene (LDPE) and or polypropylene and/or glass, glassine foil, aluminum pouches, and blisters or strips composed of aluminum or high-density polyvinyl chloride (PVC), optionally including a desiccant, polyethylene (PE), polyvinylidene dichloride (PVDC), PVC/PE/PVDC, and the like.
  • PVDC polyvinylidene dichloride
  • the pharmaceutical compositions of the invention can be administered to a patient once daily or about every twenty four hours. Alternatively, the pharmaceutical compositions of the invention can be administered to a patient twice daily. Alternatively, the pharmaceutical composition of the invention can be administered about every twelve hours. These pharmaceutical compositions are administered as oral formulations containing about 25 mg, 50 mg, 100 mg, 125 mg, 150 mg, 200 mg, 250 mg, 300 mg, or 400 mg of Compound 1 Form I; and about 25 mg, 50 mg, 100 mg, 125 mg, 150 mg, 200 mg, or 250 mg of substantially amorphous Compound 2.
  • the pharmaceutical compositions comprise a filler; a disintegrant; a surfactant; a binder; and a lubricant (depending on whether the pharmaceutical composition is a granule or a tablet).
  • a dose of 400 mg of Compound 1 Form I may comprise two tablets of the invention each containing 200 mg of Compound 1 Form I.
  • a dose of 250 mg of substantially amorphous Compound 2 may comprise two tablets of the invention each containing 125 mg of substantially amorphous Compound 2.
  • the additional therapeutic agent is selected from a mucolytic agent, bronchodialator, an antibiotic, an anti-infective agent, an anti-inflammatory agent, a compound that induces CFTR activity other than Compound 1 Form I and substantially amorphous Compound 2, or a nutritional agent.
  • the additional agent is (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide.
  • the additional agent is 4-(3-(1(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido) isoquinolin-1-yl)benzoic acid.
  • the additional agent is selected from Table 1:
  • the additional agent is any combination of the above agents.
  • the combination may comprise a pharmaceutical composition or tablet of the present invention comprising Compound 1 Form I and a solid dispersion of substantially amorphous Compound 2, and the additional therapeutic agent is (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide.
  • the additional agent is selected from Table 1:
  • the additional agent is selected from Table 2:
  • the additional therapeutic agent is an antibiotic.
  • antibiotics useful herein include tobramycin, including tobramycin inhaled powder (TIP), azithromycin, cayston, aztreonam, including the aerosolized form of aztreonam, amikacin, including liposomal formulations thereof, ciprofloxacin, including formulations thereof suitable for administration by inhalation, levoflaxacin, including aerosolized formulations thereof, and combinations of two antibiotics, e.g., fosfomycin and tobramycin.
  • the additional agent is a mucolyte.
  • exemplary mucolytes useful herein includes Pulmozyme®.
  • the additional agent is a bronchodialator.
  • exemplary bronchodialtors include albuterol, metaprotenerol sulfate, pirbuterol acetate, salmeterol, or tetrabuline sulfate.
  • the additional agent is effective in restoring lung airway surface liquid.
  • Such agents improve the movement of salt in and out of cells, allowing mucus in the lung airway to be more hydrated and, therefore, cleared more easily.
  • Exemplary such agents include hypertonic saline, denufosol tetrasodium ([[(3S,5R)-5-(4-amino-2-oxopyrimidin-1-yl)-3-hydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl][[[(2R,3S,4R,5R)-5-(2,4-dioxopyrimidin-1-yl)-3,4-dihydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-hydroxyphosphoryl]hydrogen phosphate), or bronchitol (inhaled formulation of mannitol).
  • the additional agent is an anti-inflammatory agent, i.e., an agent that can reduce the inflammation in the lungs.
  • agents useful herein include ibuprofen, docosahexanoic acid (DHA), sildenafil, inhaled glutathione, pioglitazone, hydroxychloroquine, or simavastatin.
  • the additional agent is a compound that augments or induces CFTR activity other than Compound 1 Form I or a solid dispersion comprising substantially amorphous Compound 2, i.e., an agent that has the effect of inducing or augmenting CFTR activity.
  • Exemplary such agents include ataluren (“PTC124®”; 3-[5-(2-fluorophenyl)-1,2,4-oxadiazol-3-yl]benzoic acid), sinapultide, lancovutide, depelestat (a human recombinant neutrophil elastase inhibitor), and cobiprostone (7- ⁇ (2R,4aR,5R,7aR)-2-[(3S)-1,1-difluoro-3-methylpentyl]-2-hydroxy-6-oxooctahydrocyclopenta[b]pyran-5-yl ⁇ heptanoic acid).
  • PTC124® 3-[5-(2-fluorophenyl)-1,2,4-oxadiazol-3-yl]benzoic acid
  • sinapultide lancovutide
  • depelestat a human recombinant neutrophil elastase inhibitor
  • cobiprostone 7- ⁇ (2R,4
  • the additional agent is a nutritional agent.
  • exemplary nutritional agents include pancrelipase (pancreating enzyme replacement), including Pancrease®, Pancreacarb®, Ultrase®, or Creon®, Liprotomase® (formerly Trizytek®), Aquadeks®, or glutathione inhalation.
  • the additional nutritional agent is pancrelipase.
  • the additional agent is a compound selected from gentamicin, curcumin, cyclophosphamide, 4-phenylbutyrate, miglustat, felodipine, nimodipine, Philoxin B, geniestein, Apigenin, cAMP/cGMP augmenters or inducers such as rolipram, sildenafil, milrinone, tadalafil, aminone, isoproterenol, albuterol, and almeterol, deoxyspergualin, HSP 90 inhibitors, HSP 70 inhibitors, proteosome inhibitors such as epoxomicin, lactacystin, etc.
  • inducers such as rolipram, sildenafil, milrinone, tadalafil, aminone, isoproterenol, albuterol, and almeterol, deoxyspergualin, HSP 90 inhibitors, HSP 70 inhibitors, proteosome inhibitors such as
  • the additional agent is a compound selected from 3-amino-6-(4-fluoro-phenyl)-5-trifluoromethyl-pyridine-2-carboxylic acid (3,3,3-trifluoro-2-hydroxy-2-methyl-propyl)-amide; 5-amino-6′-methyl-3-trifluoromethyl-[2,3]bipyridinyl-6-carboxylic acid (3,3,3-trifluoro-2-hydroxy-2-methyl-propyl)-amide; 3-amino-6-cyclopropyl-N-(3,3,3-trifluoro-2-hydroxy-2-methylpropyl)-5-(trifluoromethyl)picolinamide; 3-amino-6-methoxy-N-(3,3,3-trifluoro-2-hydroxy-2-(trifluoromethyl)propyl)-5-(trifluoro methyl)picolinamide; 3-amino-6-(4-fluoro-phenyl)-5-trifluoromethyl-pyridine-2-carboxylic acid
  • the additional agent may be an epithelial sodium channel (ENac) modulator disclosed in PCT publications WO2012035158, WO2009074575, WO2011028740, WO2009150137, WO2011079087, or WO2008135557, incorporated herein in their entirety by reference.
  • ENac epithelial sodium channel
  • the additional agent is a compound disclosed in WO 2004028480, WO 2004110352, WO 2005094374, WO 2005120497, or WO 2006101740, incorporated herein in their entirety by reference.
  • the additional agent is a benzo[c]quinolizinium derivative that exhibits CFTR inducing or augmenting activity or a benzopyran derivative that exhibits CFTR inducing or augmenting activity.
  • the additional agent is a compound disclosed in U.S. Pat. No. 7,202,262, U.S. Pat. No.
  • the additional agent is a compound disclosed in WO2004080972, WO2004111014, WO2005035514, WO2005049018, WO2006099256, WO2006127588, or WO2007044560, incorporated herein in their entirety by reference.
  • 400 mg of Compound 1 Form I and 250 mg of substantially amorphous Compound 2 may be administered to a subject in need thereof.
  • the dosage amounts may be achieved by administration of one or more tablets of the invention.
  • administration of 400 mg of Compound 1 Form I and 250 mg of substantially amorphous Compound 2 may be achieved by administering two tablets each containing 200 mg of Compound 1 Form I, and 125 mg of substantially amorphous Compound 2.
  • the duration of administration may continue until amelioration of the disease is achieved or until a subject's physician advises, e.g. duration of administration may be less than a week, 1 week, 2 weeks, 3 weeks, four weeks (28 days), or a month or longer.
  • two tablets each comprising 200 mg of Compound 1 Form I, and 125 mg of substantially amorphous Compound 2 may be administered to the patient per day.
  • the two tablets may be administered at the same time or at different times during the day.
  • one tablet is administered every 12 hours.
  • 400 mg of Compound 1 Form I and 500 mg of substantially amorphous Compound 2 may be administered to a subject in need thereof.
  • the dosage amounts may be achieved by administration of two tablets each containing 200 mg of Compound 1 Form I, and 250 mg of substantially amorphous Compound 2.
  • a tablet is administered once every 12 hours.
  • the dosage amount may also be achieved by administering two tablets, each containing 100 mg of Compound 1 Form I and 125 mg of substantially amorphous Compound 2, every 12 hours.
  • the dosage amounts may also be achieved by administering Compound 1 Form I and substantially amorphous Compound 2 in separate tablets.
  • the dosage amounts may be achieved by administering two tablets containing 200 mg of Compound 1 Form I, and four tablets containing 125 mg of substantially amorphous Compound 2 or two tablets containing 150 mg of substantially amorphous Compound 2 and two tablets containing 100 mg of substantially amorphous Compound 2.
  • the duration of administration may continue until amelioration of the disease is achieved or until a subject's physician advises, e.g. duration of administration may be less than a week, 1 week, 2 weeks, 3 weeks, four weeks (28 days), or a month or longer.
  • two tablets comprising 200 mg of Compound 1 Form I, and four tablets comprising 125 mg of substantially amorphous Compound 2 may be administered to the patient per day.
  • two tablets comprising 200 mg of Compound 1 Form I may be administered to the patient per day, and two tablets comprising 150 mg and 100 mg of substantially amorphous Compound 2 may be administered to the patient twice per day.
  • the two tablets may be administered at the same time or at different times during the day.
  • one tablet comprising 200 mg of Compound 1 is administered every 12 hours, and two tablets comprising 150 mg and 100 mg of substantially amorphous Compound 2 are administered every 12 hours.
  • 300 mg of Compound 1 Form 1 and 250 mg of substantially amorphous Compound 2 may be administered to a subject in need thereof.
  • the dosage amounts may be achieved by administration of one or more tablets of the invention.
  • administration of 300 mg of Compound 1 Form I and 250 mg of substantially amorphous Compound 2 may be achieved by administering two tablets each containing 150 mg of Compound 1 Form I, and 125 mg of substantially amorphous Compound 2.
  • the duration of administration may continue until amelioration of the disease is achieved or until a subject's physician advises, e.g. duration of administration may be less than a week, 1 week, 2 weeks, 3 weeks, four weeks (28 days), or a month or longer.
  • two tablets each comprising 150 mg of Compound 1 Form I, and 125 mg of substantially amorphous Compound 2 may be administered to the patient per day.
  • the two tablets may be administered at the same time or at different times during the day.
  • one tablet is administered every 12 hours.
  • 600 mg of Compound 1 Form I and 500 mg of substantially amorphous Compound 2 may be administered to a subject in need thereof.
  • the dosage amounts may be achieved by administration of one or more tablets of the invention.
  • administration of 600 mg of Compound 1 Form I and 500 mg of substantially amorphous Compound 2 may be achieved by administering two tablets, each containing 150 mg of Compound 1 Form I, and 125 mg of substantially amorphous Compound 2, every 12 hours.
  • the duration of administration may continue until amelioration of the disease is achieved or until a subject's physician advises, e.g. duration of administration may be less than a week, 1 week, 2 weeks, 3 weeks, four weeks (28 days), or a month or longer.
  • four tablets each comprising 150 mg of Compound 1 Form I, and 125 mg of substantially amorphous Compound 2 may be administered to the patient per day.
  • the four tablets may be administered at the same time or at different times during the day.
  • two tablet is administered every 12 hours.
  • 800 mg of Compound 1 Form I and 500 mg of substantially amorphous Compound 2 may be administered to a subject in need thereof.
  • the dosage amounts may be achieved by administration of one or more tablets of the invention.
  • administration of 800 mg of Compound 1 Form I and 500 mg of substantially amorphous Compound 2 may be achieved by administering four tablets each containing 200 mg of Compound 1 Form I, and 125 mg of substantially amorphous Compound 2.
  • the duration of administration may continue until amelioration of the disease is achieved or until a subject's physician advises, e.g. duration of administration may be less than a week, 1 week, 2 weeks, 3 weeks, four weeks (28 days), or a month or longer.
  • four tablets each comprising 200 mg of Compound 1 Form I, and 125 mg of substantially amorphous Compound 2 may be administered to the patient per day. In a further embodiment, the four tablets may be administered at the same time or at different times during the day. In a further embodiment, two tablets are administered per dosing occasion, and there are two dosing occasions per day. In a further embodiment, 800 mg of Compound 1 and 500 mg of Compound 2 are administered to the patient by administering two tablets each comprising 200 mg of Compound 1 and 125 mg of Compound 2 twice a day (BID). In a further embodiment, 800 mg of Compound 1 and 500 mg of Compound 2 are administered to the patient by administering two tablets each comprising 200 mg of Compound 1 and 125 mg of Compound 2 every 12 hours (q12h).
  • 600 mg of Compound 1 Form I and 250 mg of substantially amorphous Compound 2 may be administered to a subject in need thereof.
  • the dosage amounts may be achieved by administration of one or more tablets of the invention.
  • administration of 600 mg of Compound 1 Form I and 250 mg of substantially amorphous Compound 2 may be achieved by administering three tablets each containing 200 mg of Compound 1 Form I, and 83.3 mg of substantially amorphous Compound 2.
  • the duration of administration may continue until amelioration of the disease is achieved or until a subject's physician advises, e.g. duration of administration may be less than a week, 1 week, 2 weeks, 3 weeks, four weeks (28 days), or a month or longer.
  • three tablets each comprising 200 mg of Compound 1 Form I, and 83.3 mg of substantially amorphous Compound 2 may be administered to the patient per day.
  • the three tablets may be administered at the same time or at different times during the day.
  • three tablets are administered at the same time.
  • 600 mg of Compound 1 Form I and 500 mg of substantially amorphous Compound 2 may be administered to a subject in need thereof.
  • the dosage amounts may be achieved by administration of one or more tablets of the invention.
  • administration of 600 mg of Compound 1 Form I and 500 mg of substantially amorphous Compound 2 may be achieved by administering three tablets each containing 200 mg of Compound 1 Form I, and 83.3 mg of substantially amorphous Compound 2, followed by two additional tablets each comprising 125 mg of Compound 2.
  • the duration of administration may continue until amelioration of the disease is achieved or until a subject's physician advises, e.g.
  • duration of administration may be less than a week, 1 week, 2 weeks, 3 weeks, four weeks (28 days), or a month or longer.
  • 600 mg of Compound 1 may be administered daily (qd) and 250 mg of Compound 2 administered twice a day (bid) by administering three tablets each comprising 200 mg of Compound 1 Form I, and 83.3 mg of substantially amorphous Compound 2 daily (qd) and two tablets each comprising 125 mg of Compound 2 every 12 hours (q12h).
  • 600 mg of Compound 1 may be administered daily (qd) and 250 mg of Compound 2 administered every 12 hours (q12h) by administering three tablets each comprising 200 mg of Compound 1 Form I, and 83.3 mg of substantially amorphous Compound 2 daily (qd) and two tablets each comprising 125 mg of Compound 2 every 12 hours (q12h).
  • the present invention features a kit comprising a pharmaceutical composition or tablet of the present invention comprising Compound 1 Form I and a solid dispersion comprising substantially amorphous Compound 2, and a separate additional therapeutic agent or pharmaceutical composition thereof.
  • the pharmaceutical composition or tablet of the present invention, separate additional therapeutic agent or pharmaceutical composition thereof are in separate containers.
  • the separate containers are bottles.
  • the separate containers are vials.
  • the separate containers are blister packs.
  • the amount of additional therapeutic agent present in the compositions of this invention will be no more than the amount that would normally be administered in a composition comprising that therapeutic agent as the only active agent.
  • the amount of additional therapeutic agent in the presently disclosed compositions will range from about 50% to 100% of the amount normally present in a composition comprising that agent as the only therapeutically active agent.
  • the invention also provides a method of treating, lessening the severity of, or symptomatically treating a disease in a patient, the method comprising administering an effective amount of the pharmaceutical composition or tablet of the invention to the patient, preferably a mammal, wherein the disease is selected from cystic fibrosis, asthma, smoke induced COPD, chronic bronchitis, rhinosinusitis, constipation, pancreatitis, pancreatic insufficiency, male infertility caused by congenital bilateral absence of the vas deferens (CBAVD), mild pulmonary disease, idiopathic pancreatitis, allergic bronchopulmonary aspergillosis (ABPA), liver disease, hereditary emphysema, hereditary hemochromatosis, coagulation-fibrinolysis deficiencies, such as protein C deficiency, Type 1 hereditary angioedema, lipid processing deficiencies, such as familial hypercholesterolemia, Type 1 chylomicronemia
  • the invention also provides a method of treating, lessening the severity of, or symptomatically treating a disease in a patient comprising administering an effective amount of the pharmaceutical composition or tablet of the invention to the patient, preferably a mammal, wherein the disease is selected from generalized epilepsy with ferbrile seizures plus (GEFS+), general epilepsy with ferbile and aferbrile seizures, myotonia, paramyotonia congenital, potassium-aggravated myotonia, hyperkalemic periodic paralysis, LQTS, LQTS/Brugada syndrome, autosomal-dominant LQTS with deafness, autosomal-recessive LQTS, LQTS with dysmorphic features, congenital and acquired LQTS, Timothy syndrome, persistent hyperinsulinemic hypolglycemia of infancy, dilated cardiomyopathy, autosomal-dominant LQTS, Dent disease, Osteopetrosis, Bartter syndrome type III, central core disease,
  • the present invention is directed to a method of treating, lessening the severity of, or symptomatically treating cystic fibrosis in a patient comprising administering an effective amount of the pharmaceutical composition or tablet of the invention to the patient, preferably a mammal, wherein the patient possesses the CFTR genetic mutation N1303K, ⁇ I507, or R560T.
  • the present invention is directed to a method of treating, lessening the severity of, or symptomatically treating cystic fibrosis in a patient comprising administering an effective amount of the pharmaceutical composition or tablet of the invention to the patient, preferably a mammal, wherein the patient possesses the CFTR genetic mutation G551D.
  • the patient is homozygous in G551D.
  • the patient is heterozygous in G551D wherein the other CFTR genetic mutation is any one of ⁇ F508, G542X, N1303K, W1282X, R117H, R553X, 1717-1G->A, 621+1G->T, 2789+5G->A, 3849+10 kbC->T, R1162X, G85E, 3120+1G->A, ⁇ I507, 1898+1G->A, 3659delC, R347P, R560T, R334W, A455E, 2184delA, or 711+1G->T.
  • the other CFTR genetic mutation is any one of ⁇ F508, G542X, N1303K, W1282X, R117H, R553X, 1717-1G->A, 621+1G->T, 2789+5G->A, 3849+10 kbC->T, R1162X, G85E, 3120+1G->A, ⁇ I507, 18
  • the present invention is directed to a method of treating, lessening the severity of, or symptomatically treating cystic fibrosis in a patient comprising administering an effective amount of the pharmaceutical composition or tablet of the invention to the patient, preferably a mammal, wherein the patient possesses the CFTR genetic mutation ⁇ F508.
  • the patient is homozygous in ⁇ F508.
  • the patient is heterozygous in ⁇ F508 wherein the other CFTR genetic mutation is any one of G551D, G542X, N1303K, W1282X, R117H, R553X, 1717-1G->A, 621+1G->T, 2789+5G->A, 3849+10 kbC->T, R1162X, G85E, 3120+1G->A, ⁇ I507, 1898+1G->A, 3659delC, R347P, R560T, R334W, A455E, 2184delA, or 711+1G->T.
  • the other CFTR genetic mutation is any one of G551D, G542X, N1303K, W1282X, R117H, R553X, 1717-1G->A, 621+1G->T, 2789+5G->A, 3849+10 kbC->T, R1162X, G85E, 3120+1G->A, ⁇ I507,
  • the present invention is directed to a method of treating, lessening the severity of, or symptomatically treating cystic fibrosis in a patient comprising administering an effective amount of the pharmaceutical composition or tablet of the invention to the patient, preferably a mammal, wherein the patient possesses the CFTR genetic mutation is selected from G178R, G551S, G970R, G1244E, S1255P, G1349D, S549N, S549R, S1251N, E193K, F1052V, G1069R, R117C, D110H, R347H, R352Q, E56K, P67L, L206W, A455E, D579G, S1235R, S945L, R1070W, F1074L, D110E, D1270N, D1152H, 1717-1G->A, 621+1G->T, 3120+1G->A, 1898+1G->A, 711+1G->T, 2622+1G->
  • the present invention is directed to a method of treating, lessening the severity of, or symptomatically treating cystic fibrosis in a patient comprising administering an effective amount of the pharmaceutical composition or tablet of the invention to the patient, preferably a mammal, wherein the patient possesses the CFTR genetic mutation is selected from G178R, G551S, G970R, G1244E, S1255P, G1349D, S549N, S549R, S1251N, E193K, F1052V and G1069R.
  • the invention provides a method of treating CFTR comprising administering Compound 1 to a patient possessing a human CFTR mutation selected from G178R, G551S, G970R, G1244E, S1255P, G1349D, S549N, S549R and S1251N.
  • the present invention is directed to a method of treating, lessening the severity of, or symptomatically treating cystic fibrosis in a patient comprising administering an effective amount of the pharmaceutical composition or tablet of the invention to the patient, preferably a mammal, wherein the patient possesses the CFTR genetic mutation is selected from E193K, F1052V and G1069R.
  • the method produces a greater than 10-fold increase in chloride transport relative to baseline chloride transport.
  • the present invention is directed to a method of treating, lessening the severity of, or symptomatically treating cystic fibrosis in a patient comprising administering an effective amount of the pharmaceutical composition or tablet of the invention to the patient, preferably a mammal, wherein the patient possesses the CFTR genetic mutation is selected from R117C, D110H, R347H, R352Q, E56K, P67L, L206W, A455E, D579G, S1235R, S945L, R1070W, F1074L, D110E, D1270N and D1152H.
  • the method produces an increase in chloride transport which is greater or equal to 10% above the baseline chloride transport.
  • the present invention is directed to a method of treating, lessening the severity of, or symptomatically treating cystic fibrosis in a patient comprising administering an effective amount of the pharmaceutical composition or tablet of the invention to the patient, preferably a mammal, wherein the patient possesses the CFTR genetic mutation is selected from 1717-1G->A, 621+1G->T, 3120+1G->A, 1898+1G->A, 711+1G->T, 2622+1G->A, 405+1G->A, 406-1G->A, 4005+1G->A, 1812-1G->A, 1525-1G->A, 712-1G->T, 1248+1G->A, 1341+1G->A, 3121-1G->A, 4374+1G->T, 3850-1G->A, 2789+5G->A, 3849+10 kbC->T, 3272-26A->G, 711+5G->A, 3120G->A, 1811+1.6 kbA->G, 711
  • the present invention is directed to a method of treating, lessening the severity of, or symptomatically treating cystic fibrosis in a patient comprising administering an effective amount of the pharmaceutical composition or tablet of the invention to the patient, preferably a mammal, wherein the patient possesses the CFTR genetic mutation is selected from 1717-1G->A, 1811+1.6 kbA->G, 2789+5G->A, 3272-26A->G and 3849+10 kbC->T.
  • the present invention is directed to a method of treating, lessening the severity of, or symptomatically treating cystic fibrosis in a patient comprising administering an effective amount of the pharmaceutical composition or tablet of the invention to the patient, preferably a mammal, wherein the patient possesses the CFTR genetic mutation is selected from 2789+5G->A and 3272-26A->G.
  • the present invention is directed to a method of treating, lessening the severity of, or symptomatically treating cystic fibrosis in a patient comprising administering an effective amount of the pharmaceutical composition or tablet of the invention to the patient, preferably a mammal, wherein the patient possesses the CFTR genetic mutation is selected from G178R, G551S, G970R, G1244E, S1255P, G1349D, S549N, S549R, S1251N, E193K, F1052V, G1069R, R117C, D110H, R347H, R352Q, E56K, P67L, L206W, A455E, D579G, S1235R, S945L, R1070W, F1074L, D110E, D1270N, D1152H, 1717-1G->A, 621+1G->T, 3120+1G->A, 1898+1G->A, 711+1G->T, 2622+1G->
  • the present invention is directed to a method of treating, lessening the severity of, or symptomatically treating cystic fibrosis in a patient comprising administering an effective amount of the pharmaceutical composition or tablet of the invention to the patient, preferably a mammal, wherein the patient possesses the CFTR genetic mutation is selected from G178R, G551S, G970R, G1244E, S1255P, G1349D, S549N, S549R, S1251N, E193K, F1052V and G1069R, and a human CFTR mutation selected from ⁇ F508, R117H, and G551D.
  • the present invention is directed to a method of treating, lessening the severity of, or symptomatically treating cystic fibrosis in a patient comprising administering an effective amount of the pharmaceutical composition or tablet of the invention to the patient, preferably a mammal, wherein the patient possesses the CFTR genetic mutation is selected from G178R, G551S, G970R, G1244E, S1255P, G1349D, S549N, S549R and S1251N, and a human CFTR mutation selected from ⁇ F508, R117H, and G551D.
  • the present invention is directed to a method of treating, lessening the severity of, or symptomatically treating cystic fibrosis in a patient comprising administering an effective amount of the pharmaceutical composition or tablet of the invention to the patient, preferably a mammal, wherein the patient possesses the CFTR genetic mutation is selected from E193K, F1052V and G1069R, and a human CFTR mutation selected from ⁇ F508, R117H, and G551D.
  • the method produces a greater than 10-fold increase in chloride transport relative to baseline chloride transport.
  • the present invention is directed to a method of treating, lessening the severity of, or symptomatically treating cystic fibrosis in a patient comprising administering an effective amount of the pharmaceutical composition or tablet of the invention to the patient, preferably a mammal, wherein the patient possesses the CFTR genetic mutation is selected from R117C, D110H, R347H, R352Q, E56K, P67L, L206W, A455E, D579G, S1235R, S945L, R1070W, F1074L, D110E, D1270N and D1152H, and a human CFTR mutation selected from ⁇ F508, R117H, and G551D.
  • the method produces an increase in chloride transport which is greater or equal to 10% above the baseline chloride transport.
  • the present invention is directed to a method of treating, lessening the severity of, or symptomatically treating cystic fibrosis in a patient comprising administering an effective amount of the pharmaceutical composition or tablet of the invention to the patient, preferably a mammal, wherein the patient possesses the CFTR genetic mutation is selected from 1717-1G->A, 621+1G->T, 3120+1G->A, 1898+1G->A, 711+1G->T, 2622+1G->A, 405+1G->A, 406-1G->A, 4005+1G->A, 1812-1G->A, 1525-1G->A, 712-1G->T, 1248+1G->A, 1341+1G->A, 3121-1G->A, 4374+1G->T, 3850-1G->A, 2789+5G->A, 3849+10 kbC->T, 3272-26A->G, 711+5G->A, 3120G->A, 1811+1.6 kbA->G, 711
  • the present invention is directed to a method of treating, lessening the severity of, or symptomatically treating cystic fibrosis in a patient comprising administering an effective amount of the pharmaceutical composition or tablet of the invention to the patient, preferably a mammal, wherein the patient possesses the CFTR genetic mutation is selected from 1717-1G->A, 1811+1.6 kbA->G, 2789+5G->A, 3272-26A->G and 3849+10 kbC->T, and a human CFTR mutation selected from ⁇ F508, R117H, and G551D.
  • the present invention is directed to a method of treating, lessening the severity of, or symptomatically treating cystic fibrosis in a patient comprising administering an effective amount of the pharmaceutical composition or tablet of the invention to the patient, preferably a mammal, wherein the patient possesses the CFTR genetic mutation is selected from 2789+5G->A and 3272-26A->G, and a human CFTR mutation selected from ⁇ F508, R117H.
  • the present invention is directed to a method of treating, lessening the severity of, or symptomatically treating cystic fibrosis in a patient comprising administering an effective amount of the pharmaceutical composition or tablet of the invention to the patient, preferably a mammal, wherein the patient possesses the CFTR genetic mutation is selected from G178R, G551S, G970R, G1244E, S1255P, G1349D, S549N, S549R, S1251N, E193K, F1052V, G1069R, R117C, D110H, R347H, R352Q, E56K, P67L, L206W, A455E, D579G, S1235R, S945L, R1070W, F1074L, D110E, D1270N, D1152H, 1717-1G->A, 621+1G->T, 3120+1G->A, 1898+1G->A, 711+1G->T, 2622+1G->
  • the present invention is directed to a method of treating, lessening the severity of, or symptomatically treating cystic fibrosis in a patient comprising administering an effective amount of the pharmaceutical composition or tablet of the invention to the patient, preferably a mammal, wherein the patient possesses the CFTR genetic mutation is selected from G178R, G551S, G970R, G1244E, S1255P, G1349D, S549N, S549R, S1251N, E193K, F1052V and G1069R.
  • the present invention is directed to a method of treating, lessening the severity of, or symptomatically treating cystic fibrosis in a patient comprising administering an effective amount of the pharmaceutical composition or tablet of the invention to the patient, preferably a mammal, wherein the patient possesses the CFTR genetic mutation is selected from G178R, G551S, G970R, G1244E, S1255P, G1349D, S549N, S549R and S1251N.
  • the present invention is directed to a method of treating, lessening the severity of, or symptomatically treating cystic fibrosis in a patient comprising administering an effective amount of the pharmaceutical composition or tablet of the invention to the patient, preferably a mammal, wherein the patient possesses the CFTR genetic mutation is selected from E193K, F1052V and G1069R.
  • the method produces a greater than 10-fold increase in chloride transport relative to baseline chloride transport.
  • the present invention is directed to a method of treating, lessening the severity of, or symptomatically treating cystic fibrosis in a patient comprising administering an effective amount of the pharmaceutical composition or tablet of the invention to the patient, preferably a mammal, wherein the patient possesses the CFTR genetic mutation is selected from R117C, D110H, R347H, R352Q, E56K, P67L, L206W, A455E, D579G, S1235R, S945L, R1070W, F1074L, D110E, D1270N and D1152H.
  • the method produces an increase in chloride transport which is greater or equal to 10% above the baseline chloride transport.
  • the present invention is directed to a method of treating, lessening the severity of, or symptomatically treating cystic fibrosis in a patient comprising administering an effective amount of the pharmaceutical composition or tablet of the invention to the patient, preferably a mammal, wherein the patient possesses the CFTR genetic mutation is selected from 1717-1G->A, 621+1G->T, 3120+1G->A, 1898+1G->A, 711+1G->T, 2622+1G->A, 405+1G->A, 406-1G->A, 4005+1G->A, 1812-1G->A, 1525-1G->A, 712-1G->T, 1248+1G->A, 1341+1G->A, 3121-1G->A, 4374+1G->T, 3850-1G->A, 2789+5G->A, 3849+10 kbC->T, 3272-26A->G, 711+5G->A, 3120G->A, 1811+1.6 kbA->G, 711
  • the present invention is directed to a method of treating, lessening the severity of, or symptomatically treating cystic fibrosis in a patient comprising administering an effective amount of the pharmaceutical composition or tablet of the invention to the patient, preferably a mammal, wherein the patient possesses the CFTR genetic mutation is selected from 1717-1G->A, 1811+1.6 kbA->G, 2789+5G->A, 3272-26A->G and 3849+10 kbC->T.
  • the present invention is directed to a method of treating, lessening the severity of, or symptomatically treating cystic fibrosis in a patient comprising administering an effective amount of the pharmaceutical composition or tablet of the invention to the patient, preferably a mammal, wherein the patient possesses the CFTR genetic mutation is selected from 2789+5G->A and 3272-26A->G.
  • the present invention is directed to a method of treating, lessening the severity of, or symptomatically treating cystic fibrosis in a patient comprising administering an effective amount of the pharmaceutical composition or tablet of the invention to the patient, preferably a mammal, wherein the patient possesses the CFTR genetic mutation is selected from G178R, G551S, G970R, G1244E, S1255P, G1349D, S549N, S549R, S1251N, E193K, F1052V, G1069R, R117C, D110H, R347H, R352Q, E56K, P67L, L206W, A455E, D579G, S1235R, S945L, R1070W, F1074L, D110E, D1270N, D1152H, 1717-1G->A, 621+1G->T, 3120+1G->A, 1898+1G->A, 711+1G->T, 2622+1G->
  • the present invention is directed to a method of treating, lessening the severity of, or symptomatically treating cystic fibrosis in a patient comprising administering an effective amount of the pharmaceutical composition or tablet of the invention to the patient, preferably a mammal, wherein the patient possesses the CFTR genetic mutation is selected from G178R, G551S, G970R, G1244E, S1255P, G1349D, S549N, S549R, S1251N, E193K, F1052V and G1069R, and one or more human CFTR mutations selected from ⁇ F508, R117H, and G551D.
  • the present invention is directed to a method of treating, lessening the severity of, or symptomatically treating cystic fibrosis in a patient comprising administering an effective amount of the pharmaceutical composition or tablet of the invention to the patient, preferably a mammal, wherein the patient possesses the CFTR genetic mutation is selected from G178R, G551S, G970R, G1244E, S1255P, G1349D, S549N, S549R and S1251N, and one or more human CFTR mutations selected from ⁇ F508, R117H, and G551D.
  • the present invention is directed to a method of treating, lessening the severity of, or symptomatically treating cystic fibrosis in a patient comprising administering an effective amount of the pharmaceutical composition or tablet of the invention to the patient, preferably a mammal, wherein the patient possesses the CFTR genetic mutation is selected from E193K, F1052V and G1069R, and one or more human CFTR mutations selected from ⁇ F508, R117H, and G551D.
  • the method produces a greater than 10-fold increase in chloride transport relative to baseline chloride transport.
  • the present invention is directed to a method of treating, lessening the severity of, or symptomatically treating cystic fibrosis in a patient comprising administering an effective amount of the pharmaceutical composition or tablet of the invention to the patient, preferably a mammal, wherein the patient possesses the CFTR genetic mutation is selected from R117C, D110H, R347H, R352Q, E56K, P67L, L206W, A455E, D579G, S1235R, S945L, R1070W, F1074L, D110E, D1270N and D1152H, and one or more human CFTR mutations selected from ⁇ F508, R117H, and G551D.
  • the method produces an increase in chloride transport which is greater or equal to 10% above the baseline chloride transport.
  • the present invention is directed to a method of treating, lessening the severity of, or symptomatically treating cystic fibrosis in a patient comprising administering an effective amount of the pharmaceutical composition or tablet of the invention to the patient, preferably a mammal, wherein the patient possesses the CFTR genetic mutation is selected from 1717-1G->A, 621+1G->T, 3120+1G->A, 1898+1G->A, 711+1G->T, 2622+1G->A, 405+1G->A, 406-1G->A, 4005+1G->A, 1812-1G->A, 1525-1G->A, 712-1G->T, 1248+1G->A, 1341+1G->A, 3121-1G->A, 4374+1G->T, 3850-1G->A, 2789+5G->A, 3849+10 kbC->T, 3272-26A->G, 711+5G->A, 3120G->A, 1811+1.6 kbA->G, 711
  • the present invention is directed to a method of treating, lessening the severity of, or symptomatically treating cystic fibrosis in a patient comprising administering an effective amount of the pharmaceutical composition or tablet of the invention to the patient, preferably a mammal, wherein the patient possesses the CFTR genetic mutation is selected from 1717-1G->A, 1811+1.6 kbA->G, 2789+5G->A, 3272-26A->G and 3849+10 kbC->T, and one or more human CFTR mutations selected from ⁇ F508, R117H, and G551D.
  • the present invention is directed to a method of treating, lessening the severity of, or symptomatically treating cystic fibrosis in a patient comprising administering an effective amount of the pharmaceutical composition or tablet of the invention to the patient, preferably a mammal, wherein the patient possesses the CFTR genetic mutation is selected from 2789+5G->A and 3272-26A->G, and one or more human CFTR mutations selected from ⁇ F508, R117H, and G551D.
  • the pharmaceutically acceptable composition or tablet of the present invention comprising Compound 1 Form I and a solid dispersion of substantially amorphous Compound 2 are useful for treating, lessening the severity of, or symptomatically treating cystic fibrosis in patients who exhibit residual CFTR activity in the apical membrane of respiratory and non-respiratory epithelia.
  • the presence of residual CFTR activity at the epithelial surface can be readily detected using methods known in the art, e.g., standard electrophysiological, biochemical, or histochemical techniques. Such methods identify CFTR activity using in vivo or ex vivo electrophysiological techniques, measurement of sweat or salivary Cl ⁇ concentrations, or ex vivo biochemical or histochemical techniques to monitor cell surface density.
  • the pharmaceutically acceptable compositions or tablets comprising Compound 1 Form I and a solid dispersion comprising substantially amorphous Compound 2 are useful for treating, lessening the severity of, or symptomatically treating cystic fibrosis in patients who exhibit little to no residual CFTR activity.
  • compositions or tablets comprising Compound 1 Form I and a solid dispersion comprising substantially amorphous Compound 2 are useful for treating, lessening the severity of, or symptomatically treating cystic fibrosis in patients who exhibit little to no residual CFTR activity in the apical membrane of respiratory epithelia.
  • the compounds and compositions of the present invention are useful for treating or lessening the severity of cystic fibrosis in patients who have residual CFTR activity induced or augmented using pharmacological methods.
  • the compounds and compositions of the present invention are useful for treating or lessening the severity of cystic fibrosis in patients who have residual CFTR activity induced or augmented using or gene therapy. Such methods increase the amount of CFTR present at the cell surface, thereby inducing a hitherto absent CFTR activity in a patient or augmenting the existing level of residual CFTR activity in a patient.
  • compositions and tablets of the present invention comprising Compound 1 Form I and a solid dispersion comprising substantially amorphous Compound 2, as described herein, are useful for treating or lessening the severity of cystic fibrosis in patients within certain genotypes exhibiting residual CFTR activity, e.g., Class I mutations (not synthesized), class II mutation (misfolding), class III mutations (impaired regulation or gating), class IV mutations (altered conductance), or class V mutations (reduced synthesis).
  • compositions and tablets of the present invention comprising Compound 1 Form I and a solid dispersion comprising substantially amorphous Compound 2, as described herein, are useful for treating, lessening the severity of, or symptomatically treating cystic fibrosis in patients within certain clinical phenotypes, e.g., a moderate to mild clinical phenotype that typically correlates with the amount of residual CFTR activity in the apical membrane of epithelia.
  • phenotypes include patients exhibiting pancreatic sufficiency.
  • compositions and tablets of the present invention comprising Compound 1 Form I and a solid dispersion comprising substantially amorphous Compound 2, as described herein, are useful for treating, lessening the severity of, or symptomatically treating patients diagnosed with pancreatic sufficiency, idiopathic pancreatitis and congenital bilateral absence of the vas deferens, or mild lung disease wherein the patient exhibits residual CFTR activity.
  • compositions and tablets of the present invention comprising Compound 1 Form I and a solid dispersion comprising substantially amorphous Compound 2, as described herein, are useful for treating, lessening the severity of, or symptomatically treating patients diagnosed with pancreatic sufficiency, idiopathic pancreatitis and congenital bilateral absence of the vas deferens, or mild lung disease wherein the patient has wild type CFTR.
  • COPD chronic obstructive pulmonary disease
  • COPD dry eye disease
  • Sjogren's Syndrome a chronic obstructive pulmonary disease
  • COPD is characterized by airflow limitation that is progressive and not fully reversible. The airflow limitation is due to mucus hypersecretion, emphysema, and bronchiolitis.
  • Activators of mutant or wild-type CFTR offer a potential treatment of mucus hypersecretion and impaired mucociliary clearance that is common in COPD.
  • CFTR Dry eye disease
  • tear aqueous production and abnormal tear film lipid, protein and mucin profiles There are many causes of dry eye, some of which include age, Lasik eye surgery, arthritis, medications, chemical/thermal burns, allergies, and diseases, such as cystic fibrosis and Sjogrens's syndrome.
  • Increasing anion secretion via CFTR would enhance fluid transport from the corneal endothelial cells and secretory glands surrounding the eye to increase corneal hydration.
  • Sjogrens's syndrome is an autoimmune disease in which the immune system attacks moisture-producing glands throughout the body, including the eye, mouth, skin, respiratory tissue, liver, vagina, and gut. Symptoms, include, dry eye, mouth, and vagina, as well as lung disease. The disease is also associated with rheumatoid arthritis, systemic lupus, systemic sclerosis, and polymypositis/dermatomyositis. Defective protein trafficking is believed to cause the disease, for which treatment options are limited. Augmenters or inducers of CFTR activity may hydrate the various organs afflicted by the disease and help to elevate the associated symptoms.
  • the invention relates to a method of augmenting or inducing anion channel activity in vitro or in vivo, comprising contacting the channel with any one of pharmaceutical compositions PC-I to PC-XXV.
  • the anion channel is a chloride channel or a bicarbonate channel. In another embodiment, the anion channel is a chloride channel.
  • the exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the infection, the particular agent, its mode of administration, and the like.
  • the compounds of the invention are preferably formulated in dosage unit form for ease of administration and uniformity of dosage.
  • dosage unit form refers to a physically discrete unit of agent appropriate for the patient to be treated. It will be understood, however, that the total daily usage of the compounds and compositions of the invention will be decided by the attending physician within the scope of sound medical judgment.
  • the specific effective dose level for any particular patient or organism will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed, and like factors well known in the medical arts.
  • patient means an animal, preferably a mammal, and most preferably a human.
  • X-Ray diffraction (XRD) data of Compound 1 Form I were collected on a Bruker D8 DISCOVER powder diffractometer with HI-STAR 2-dimensional detector and a flat graphite monochromator. Cu sealed tube with K ⁇ radiation was used at 40 kV, 35 mA. The samples were placed on zero-background silicon wafers at 25° C. For each sample, two data frames were collected at 120 seconds each at 2 different ⁇ 2 angles: 8° and 26°. The data were integrated with GADDS software and merged with DIFFRACTP plus EVA software. Uncertainties for the reported peak positions are ⁇ 0.2 degrees.
  • DSC Differential Scanning calorimetry
  • DSC Differential scanning calorimetry
  • Vitride® sodium bis(2-methoxyethoxy)aluminum hydride [or NaAlH 2 (OCH 2 CH 2 OCH 3 ) 2 ], 65 wgt % solution in toluene was purchased from Aldrich Chemicals.
  • 2,2-Difluoro-1,3-benzodioxole-5-carboxylic acid was purchased from Saltigo (an affiliate of the Lanxess Corporation).
  • a reactor was purged with nitrogen and charged with 900 mL of toluene.
  • the solvent was degassed via nitrogen sparge for no less than 16 h.
  • To the reactor was then charged Na 3 PO 4 (155.7 g, 949.5 mmol), followed by bis(dibenzylideneacetone) palladium (0) (7.28 g, 12.66 mmol).
  • a 10% w/w solution of tert-butylphosphine in hexanes (51.23 g, 25.32 mmol) was charged over 10 min at 23° C. from a nitrogen purged addition funnel.
  • 1-(2,2-difluoro-1,3-benzodioxol-5-yl)-cyclopropanecarboxylic acid (1.2 eq) is slurried in toluene (2.5 vol) and the mixture was heated to 60° C. SOCl 2 (1.4 eq) was added via addition funnel. The toluene and SOCl 2 were distilled from the reaction mixture after 30 minutes. Additional toluene (2.5 vol) was added and the resulting mixture was distilled again, leaving the product acid chloride as an oil, which was used without further purification.
  • tent-Butyl-3-(3-methylpyridin-2-yl)benzoate (1.0 eq) was dissolved in EtOAc (6 vol). Water (0.3 vol) was added, followed by urea-hydrogen peroxide (3 eq). Phthalic anhydride (3 eq) was then added portionwise to the mixture as a solid at a rate to maintain the temperature in the reactor below 45° C. After completion of the phthalic anhydride addition, the mixture was heated to 45° C. After stirring for an additional 4 hours, the heat was turned off. 10% w/w aqueous Na 2 SO 3 (1.5 eq) was added via addition funnel. After completion of Na 2 SO 3 addition, the mixture was stirred for an additional 30 min and the layers separated.
  • FIG. 8 An 1 HNMR spectrum of Compound 1 is shown in FIG. 8 and FIG. 9 depicts an 1 HNMR spectrum of Compound 1 as an HCl salt.
  • the DSC trace of Compound 1 Form I is shown in FIG. 10 . Melting for Compound 1 Form I occurs at about 204° C.
  • FIG. 2 An actual X-ray powder diffraction pattern of Compound 1 Form I is shown in FIG. 2 .
  • Table 4 lists the actual peaks for FIG. 2 .
  • Colorless crystals of Compound 1 Form I were obtained by cooling a concentrated 1-butanol solution from 75° C. to 10° C. at a rate of 0.2° C./min. A crystal with dimensions of 0.50 ⁇ 0.08 ⁇ 0.03 mm was selected, cleaned with mineral oil, mounted on a MicroMount and centered on a Bruker APEX II system. Three batches of 40 frames separated in reciprocal space were obtained to provide an orientation matrix and initial cell parameters. Final cell parameters were obtained and refined based on the full data set.
  • a diffraction data set of reciprocal space was obtained to a resolution of 0.82 ⁇ using 0.5° steps using 30 s exposure for each frame. Data were collected at 100 (2) K. Integration of intensities and refinement of cell parameters were accomplished using APEXII software. Observation of the crystal after data collection showed no signs of decomposition.
  • FIG. 11 A conformational picture of Compound 1 Form I based on single crystal X-ray analysis is shown in FIG. 11 .
  • Density of Compound 1 Form I calculated from structural data is 1.492 g/cm 3 at 100 K.
  • Compound 25 (1.0 eq) was suspended in a solution of HCl (10.0 eq) and H 2 O (11.6 vol). The slurry was heated to 85-90° C., although alternative temperatures are also suitable for this hydrolysis step.
  • the hydrolysis can alternatively be performed at a temperature of from about 75 to about 100° C. In some instances, the hydrolysis is performed at a temperature of from about 80 to about 95° C. In others, the hydrolysis step is performed at a temperature of from about 82 to about 93° C. (e.g., from about 82.5 to about 92.5° C. or from about 86 to about 89° C.). After stirring at 85-90° C. for approximately 6.5 hours, the reaction was sampled for reaction completion.
  • Stirring may be performed under any of the temperatures suited for the hydrolysis.
  • the solution was then cooled to 20-25° C. and filtered.
  • the reactor/cake was rinsed with H 2 O (2 vol ⁇ 2).
  • the cake was then washed with 2 vol H 2 O until the pH>3.0.
  • the cake was then dried under vacuum at 60° C. to give compound 26.
  • reaction was then filtered, the filtrate was cooled to 0° C., and an additional 5 mL triethylamine and 3.7 mL methyl chloroformate was then added and the reaction was allowed to warm to room temperature and then stir for an addition 1 hours. At this stage, the reaction was almost complete and was worked up by filtering, then washing with water (2 ⁇ ), followed by brine. The solution was then concentrated to produce a yellow oil and purified using column chromatography to give compound 30.
  • the reaction was then cooled to 10-15° C. and charged with 150 mL water. The mixture was stirred at 15-20° C. for 35-45 minutes and the aqueous layer was then separated and extracted with 150 mL methylene chloride. The organic layers were combined and neutralized with 2.5% HCl (aq) at a temperature of 5-20° C. to give a final pH of 5-6. The organic layer was then washed with water and concentrated in vacuo at a temperature below 20° C. to 150 mL to give compound 30 in methylene chloride.
  • the resulting mixture was diluted with from about 5 to 10 volumes of MeOH (e.g., from about 6 to about 9 volumes of MeOH, from about 7 to about 8.5 volumes of MeOH, from about 7.5 to about 8 volumes of MeOH, or about 7.7 volumes of MeOH), heated to a temperature of about 35 ⁇ 5° C., filtered, washed, and dried, as described above.
  • MeOH e.g., from about 6 to about 9 volumes of MeOH, from about 7 to about 8.5 volumes of MeOH, from about 7.5 to about 8 volumes of MeOH, or about 7.7 volumes of MeOH
  • the filtered solution was concentrated at no more than 35° C. (jacket temperature) and no less than 8.0° C. (internal reaction temperature) under reduced pressure to 20 vol.
  • CH 3 CN was added to 40 vol and the solution concentrated at no more than 35° C. (jacket temperature) and no less than 8.0° C. (internal reaction temperature) to 20 vol.
  • the addition of CH 3 CN and concentration cycle was repeated 2 more times for a total of 3 additions of CH 3 CN and 4 concentrations to 20 vol. After the final concentration to 20 vol, 16.0 vol of CH 3 CN was added followed by 4.0 vol of H 2 O to make a final concentration of 40 vol of 10% H 2 O/CH 3 CN relative to the starting acid.
  • This slurry was heated to 78.0° C.+/ ⁇ 5.0° C. (reflux). The slurry was then stirred for no less than 5 hours. The slurry was cooled to 0.0° C.+/ ⁇ 5° C. over 5 hours, and filtered. The cake was washed with 0.0° C.+/ ⁇ 5.0° C. CH 3 CN (5 vol) 4 times. The resulting solid (Compound 2) was dried in a vacuum oven at 50.0° C.+/ ⁇ 5.0° C.
  • the mixture temperature was adjusted to a range of 20-45° C. and mixed until it was substantially homogenous and all components were substantially dissolved.
  • a high efficiency cyclone separated the wet product from the spray gas and solvent vapors.
  • the wet product contained 8.5-9.7% MEK and 0.56-0.83% Water and had a mean particle size of 17-19 um and a bulk density of 0.27-0.33 g/cc.
  • the wet product was transferred to a 4000L stainless steel double cone vacuum dryer for drying to reduce residual solvents to a level of less than about 5000 ppm and to generate dry spray dry dispersion of amorphous Compound 2, containing ⁇ 0.03% MEK and 0.3% Water.
  • Compound 1 Form I the solid dispersion comprising substantially amorphous Compound 2, and excipients may be dispensed in separate intermediate bin containers (IBCs). These materials may be screened using a “bin-to-bin” screening operation. Appropriate screen sizes are mesh 20, mesh 40, or mesh 60.
  • the IBCs containing the screened Compound 1 Form I, the solid dispersion comprising substantially amorphous Compound 2, and excipients may be docked to the a feeder system, which can feed the materials in a controlled manner, e.g. using volumetric or gravimetric loss in weight feeders, into a continuous blender.
  • the feed rates of the individual components is defined by the formulation composition and the overall line rate.
  • the line rate may be 8 kg/hr to 30 kg/hr.
  • the continuous blender can have different blade configurations to allow appropriate blending and the rotational speed of these blades may be between 80 RPM and 300 RPM.
  • the blend may be added to the twin screw granulator using a Loss in Weight feeder, such as the K-Tron feeder on the DLR, with a feed rate of 8 kg/hr to 24 kg/hr.
  • the twin screw granulator may be operated with a barrel temperature of 25 degrees Celsius and a screw speed of 200 to 950 RPM.
  • the granulation process may be performed for three minutes for small batch sizes or several hours for large batch sizes.
  • the granules may be blended with extra-granular excipients such as fillers and lubricant using loss in weight feeders and a continuous blender.
  • the blending speed may be 80-300 RPM.
  • the compression blend may be compressed into tablets using a single station or rotary tablet press, such as the Courtoy Modul P press, which is part of the DLR system, using appropriately sized tooling.
  • the weight of the tablets for a dose of 200 mg of Compound 1 Form 1 and 125 mg of substantially amorphous Compound 2 may be about 500 or 600 mg.
  • Tablets may be film coated using the innovative Omega film coater, which is part of the DLR system. This coater enables fast film coating of sub-batches of 1 to 4 kg to allow continuous manufacturing.
  • Film coated tablets may be printed with a monogram on one or both tablet faces with, for example, an Ackley ramp printer.
  • Compound 1 Form I the solid dispersion comprising substantially amorphous Compound 2, and excipients may be added to the blender in different order.
  • the blending may be performed in a Turbula blender, a v-shell blender, or a bin blender.
  • the components may be blended for 10 minutes.
  • a granulation solution may be prepared by dissolving 48 g sodium lauryl sulfate and 159 g polyvinylpyrrolidone in 1,626 g water in a stainless steel container, using an overhead stirrer with a stirring speed of 700 RPM.
  • the blend may be granulated using a twin screw granulator such as the ConsiGma-1.
  • the granulation solution may be added to the twin screw granulator using a peristaltic pump, such as the pump on the ConsiGma-1, with a feed rate of 67 g/min.
  • the blend may be added to the twin screw granulator using a Loss in Weight feeder, such as the Brabender feeder on the ConsiGma-1, with a feed rate of 10 kg/hr.
  • the twin screw granulator may be operated with a barrel temperature of 25 degrees Celsius and a screw speed of 400 RPM.
  • the granulation process may be performed for four minutes.
  • the granulation process may be performed for a shorter or longer duration of time to produce a smaller or larger amount of wet granules.
  • the wet granules may be fed directly into a fluid bed dryer, such as the drying chamber on the ConsiGma-1 or the segmented fluid bed dryer on the CTL-25.
  • the drying end-point may be chosen at a product temperature of 43 degrees Celsius at which point the water content of the granules may be 1.6% w/w (“Loss on Drying, LOD”).
  • the drying time may be 12 minutes, or shorter or longer, to reach the desired drying endpoint.
  • the drying may be performed with an air flow of 59 m 3 /min and inlet temperature of 60 degrees Celsius.
  • the wet granules coming from the twin screw granulator may be collected into a bin or container for a certain period of time after which the wet granules are transferred to a separate stand-alone fluid bed dryer, such as the Vector Multi 15.
  • a separate stand-alone fluid bed dryer such as the Vector Multi 15.
  • the dried granules may be milled to reduce the size of the granules.
  • a cone mill such as the Quadro 194 CoMil may be used for this.
  • the granules may be blended with extra-granular excipients such as fillers and lubricant using a V-shell blender or a bin blender.
  • the blending time may be 5, 3 or 1 minute(s).
  • the compression blend may be compressed into tablets using a single station or rotary tablet press, such as the Courtoy Modul P press, using 0.55° ⁇ 0.33° oval shaped tooling.
  • the weight of the tablets for a dose of 200 mg of Compound 1 Form I and 125 mg of substantially amorphous Compound 2 may be about 500 or 600 mg.
  • Tablets may be film coated using a pan coater, such as, for example a Thomas Engineering Compu-Lab coater.
  • a pan coater such as, for example a Thomas Engineering Compu-Lab coater.
  • a trace amount of Carnauba wax may be added to improve tablet appearance and process ability.
  • Film coated tablets may be printed with a monogram on one or both tablet faces with, for example, a Hartnett Delta printer.
  • Granulator ConsiGma or Leistritz or Thermo Fisher twin screw granulator.
  • Compound 1 and excipients may be screened prior to or after weigh-out. Possible screen sizes are mesh 20, mesh 40, or mesh 60. Compound 1 may be pre-blended with one or more of the excipients to simplify screening.
  • Compound 1 and excipients may be added to the blender in different order.
  • the blending may be performed in a Turbula blender, a v-shell blender, a bin blender, or a continuous blender.
  • the components may be blended for 10 minutes for batch blenders or continuously for a continuous blender.
  • Granulation Fluid SLS and binder are added to purified water and mixed until dissolved.
  • a suitable ratio is 2.5% w/w SLS and 10.0% w/w PVP K30 in water.
  • the blend containing Compound 1 and excipients may be dosed into the twin screw granulator using a Loss in Weight feeder at a rate of 10 kg/hr.
  • the granulation fluid may be added using a peristaltic pump at a rate of 3.5 kg/hr.
  • the granulator may be run at a speed of 400 RPM.
  • a notable advantage of the present twin screw wet granulation process is using a granulation fluid that comprises both a surfactant and the binder for better granulation through increased wettability.
  • the surfactant is SLS.
  • Another notable advantage is that because the process is continuous and at any moment in time only a limited amount of material is processed, the process can be well controlled and results in a high quality product.
  • the granules may be dried using a vacuum oven, tray dryer, bi-conical dryer, or fluid bed drier.
  • the granules may be blended with extra-granular excipients.
  • the granules have been blended using a 300 liter bin blender for 60 revolutions.
  • the compression blend has been compressed into tablets using a Courtoy Modul P rotary press
  • Tablets may be film coated using a pan coater, such as, for example an O'Hara Labcoat.
  • a pan coater such as, for example an O'Hara Labcoat.
  • Film coated tablets may be printed with a monogram on one or both tablet faces with, for example, a Hartnett Delta printer.
  • the assay utilizes fluorescent voltage sensing dyes to measure changes in membrane potential using a fluorescent plate reader (e.g., FLIPR III, Molecular Devices, Inc.) as a readout for increase in functional ⁇ F508-CFTR in NIH 3T3 cells.
  • a fluorescent plate reader e.g., FLIPR III, Molecular Devices, Inc.
  • the driving force for the response is the creation of a chloride ion gradient in conjunction with channel activation by a single liquid addition step after the cells have previously been treated with compounds and subsequently loaded with a voltage sensing dye.
  • HTS assay utilizes fluorescent voltage sensing dyes to measure changes in membrane potential on the FLIPR III as a measurement for increase in gating (conductance) of ⁇ F508 CFTR in temperature-corrected ⁇ F508 CFTR NIH 3T3 cells.
  • the driving force for the response is a Cl ⁇ ion gradient in conjunction with channel activation with forskolin in a single liquid addition step using a fluorescent plate reader such as FLIPR III after the cells have previously been treated with potentiator compounds (or DMSO vehicle control) and subsequently loaded with a redistribution dye.
  • Bath Solution #1 (in mM) NaCl 160, KCl 4.5, CaCl 2 2, MgCl 2 1, HEPES 10, pH 7.4 with NaOH.
  • Chloride-free bath solution Chloride salts in Bath Solution #1 (above) are substituted with gluconate salts.
  • NIH3T3 mouse fibroblasts stably expressing ⁇ F508-CFTR are used for optical measurements of membrane potential.
  • the cells are maintained at 37° C. in 5% CO 2 and 90% humidity in Dulbecco's modified Eagle's medium supplemented with 2 mM glutamine, 10% fetal bovine serum, 1 ⁇ NEAA, ⁇ -ME, 1 ⁇ pen/strep, and 25 mM HEPES in 175 cm 2 culture flasks.
  • the cells were seeded at ⁇ 20,000/well in 384-well matrigel-coated plates and cultured for 2 hrs at 37° C. before culturing at 27° C. for 24 hrs. for the potentiator assay.
  • the cells are cultured at 27° C. or 37° C. with and without compounds for 16-24 hours.
  • Electrophysiological Assays for assaying ⁇ F508-CFTR modulation properties of compounds are Electrophysiological Assays for assaying ⁇ F508-CFTR modulation properties of compounds.
  • Non-CF and CF airway epithelia were isolated from bronchial tissue, cultured as previously described (Galietta, L. J. V., Lantero, S., Gazzolo, A., Sacco, O., Romano, L., Rossi, G. A., & Zegarra-Moran, O. (1998) In Vitro Cell. Dev. Biol. 34, 478-481), and plated onto Costar® SnapwellTM filters that were precoated with NIH3T3-conditioned media.
  • Non-CF HBE were isolated from non-smokers that did not have any known lung disease.
  • CF-HBE were isolated from patients homozygous for ⁇ F508.
  • the basolateral solution contained (in mM) 145 NaCl, 0.83 K 2 HPO 4 , 3.3 KH 2 PO 4 , 1.2 MgCl 2 , 1.2 CaCl 2 , 10 Glucose, 10 HEPES (pH adjusted to 7.35 with NaOH) and the apical solution contained (in mM) 145 NaGluconate, 1.2 MgCl 2 , 1.2 CaCl 2 , 10 glucose, 10 HEPES (pH adjusted to 7.35 with NaOH).
  • Typical protocol utilized a basolateral to apical membrane Cl ⁇ concentration gradient. To set up this gradient, normal ringers was used on the basolateral membrane, whereas apical NaCl was replaced by equimolar sodium gluconate (titrated to pH 7.4 with NaOH) to give a large Cl ⁇ concentration gradient across the epithelium. Forskolin (10 ⁇ M) and all test compounds were added to the apical side of the cell culture inserts. The efficacy of the putative ⁇ F508-CFTR potentiators was compared to that of the known potentiator, genistein.
  • the pipette solution contained (in mM) 150 N-methyl-D-glucamine (NMDG)-Cl, 2 MgCl 2 , 2 CaCl 2 , EGTA, 10 HEPES, and 240 ⁇ g/mL amphotericin-B (pH adjusted to 7.35 with HCl).
  • the extracellular medium contained (in mM) 150 NMDG-Cl, 2 MgCl 2 , 2 CaCl 2 , 10 HEPES (pH adjusted to 7.35 with HCl).
  • Pulse generation, data acquisition, and analysis were performed using a PC equipped with a Digidata 1320 A/D interface in conjunction with Clampex 8 (Axon Instruments Inc.). To activate ⁇ F508-CFTR, 10 ⁇ M forskolin and 20 ⁇ M genistein were added to the bath and the current-voltage relation was monitored every 30 sec.
  • ⁇ F508-CFTR potentiators to increase the macroscopic ⁇ F508-CFTR Cl ⁇ current (I ⁇ F508 ) in NIH3T3 cells stably expressing ⁇ F508-CFTR was also investigated using perforated-patch-recording techniques.
  • the potentiators identified from the optical assays evoked a dose-dependent increase in I ⁇ F508 with similar potency and efficacy observed in the optical assays.
  • the reversal potential before and during potentiator application was around ⁇ 30 mV, which is the calculated E Cl ( ⁇ 28 mV).
  • NIH3T3 mouse fibroblasts stably expressing ⁇ F508-CFTR are used for whole-cell recordings.
  • the cells are maintained at 37° C. in 5% CO 2 and 90% humidity in Dulbecco's modified Eagle's medium supplemented with 2 mM glutamine, 10% fetal bovine serum, 1 ⁇ NEAA, ⁇ -ME, 1 ⁇ pen/strep, and 25 mM HEPES in 175 cm 2 culture flasks.
  • 2,500-5,000 cells were seeded on poly-L-lysine-coated glass coverslips and cultured for 24-48 hrs at 27° C. before use to test the activity of potentiators; and incubated with or without the correction compound at 37° C. for measuring the activity of correctors.
  • the pipette contained (in mM): 150 NMDG, 150 aspartic acid, 5 CaCl 2 , 2 MgCl 2 , and 10 HEPES (pH adjusted to 7.35 with Tris base).
  • the bath contained (in mM): 150 NMDG-Cl, 2 MgCl 2 , 5 EGTA, 10 TES, and 14 Tris base (pH adjusted to 7.35 with HCl).
  • both wt- and ⁇ F508-CFTR were activated by adding 1 mM Mg-ATP, 75 nM of the catalytic subunit of cAMP-dependent protein kinase (PKA; Promega Corp.
  • PKA cAMP-dependent protein kinase
  • NIH3T3 mouse fibroblasts stably expressing ⁇ F508-CFTR are used for excised-membrane patch-clamp recordings.
  • the cells are maintained at 37° C. in 5% CO 2 and 90% humidity in Dulbecco's modified Eagle's medium supplemented with 2 mM glutamine, 10% fetal bovine serum, 1 ⁇ NEAA, ⁇ -ME, 1 ⁇ pen/strep, and 25 mM HEPES in 175 cm 2 culture flasks.
  • 2,500-5,000 cells were seeded on poly-L-lysine-coated glass coverslips and cultured for 24-48 hrs at 27° C. before use.
  • the optical membrane potential assay utilized voltage-sensitive FRET sensors described by Gonzalez and Tsien (See Gonzalez, J. E. and R. Y. Tsien (1995) “Voltage sensing by fluorescence resonance energy transfer in single cells” Biophys J 69(4): 1272-80, and Gonzalez, J. E. and R. Y. Tsien (1997) “Improved indicators of cell membrane potential that use fluorescence resonance energy transfer” Chem Biol 4(4): 269-77) in combination with instrumentation for measuring fluorescence changes such as the Voltage/Ion Probe Reader (VIPR) (See, Gonzalez, J. E., K. Oades, et al. (1999) “Cell-based assays and instrumentation for screening ion-channel targets” Drug Discov Today 4(9): 431-439).
  • VIPR Voltage/Ion Probe Reader
  • These voltage sensitive assays are based on the change in fluorescence resonant energy transfer (FRET) between the membrane-soluble, voltage-sensitive dye, DiSBAC 2 (3), and a fluorescent phospholipid, CC2-DMPE, which is attached to the outer leaflet of the plasma membrane and acts as a FRET donor.
  • FRET fluorescence resonant energy transfer
  • V m fluorescent phospholipid
  • the changes in fluorescence emission were monitored using VIPRTM II, which is an integrated liquid handler and fluorescent detector designed to conduct cell-based screens in 96- or 384-well microtiter plates.
  • NIH3T3 mouse fibroblasts stably expressing ⁇ F508-CFTR are used for optical measurements of membrane potential.
  • the cells are maintained at 37° C. in 5% CO 2 and 90% humidity in Dulbecco's modified Eagle's medium supplemented with 2 mM glutamine, 10% fetal bovine serum, 1 ⁇ NEAA, ⁇ -ME, 1 ⁇ pen/strep, and 25 mM HEPES in 175 cm 2 culture flasks.
  • the cells were seeded at 30,000/well in 384-well matrigel-coated plates and cultured for 2 hrs at 37° C. before culturing at 27° C. for 24 hrs for the potentiator assay.
  • the cells are cultured at 27° C. or 37° C. with and without compounds for 16-24 hours.
  • FRT ⁇ F508-CFTR epithelial cells grown on Costar Snapwell cell culture inserts were mounted in an Using chamber (Physiologic Instruments, Inc., San Diego, Calif.), and the monolayers were continuously short-circuited using a Voltage-clamp System (Department of Bioengineering, University of Iowa, Iowa, and, Physiologic Instruments, Inc., San Diego, Calif.). Transepithelial resistance was measured by applying a 2-mV pulse.
  • the FRT epithelia demonstrated resistances of 4 KS ⁇ 2/cm 2 or more.
  • the solutions were maintained at 27° C. and bubbled with air.
  • the electrode offset potential and fluid resistance were corrected using a cell-free insert.
  • the current reflects the flow of Cl ⁇ through ⁇ F508-CFTR expressed in the apical membrane.
  • the I SC was digitally acquired using an MP100A-CE interface and AcqKnowledge software (v3.2.6; BIOPAC Systems, Santa Barbara, Calif.).
  • Typical protocol utilized a basolateral to apical membrane Cl ⁇ concentration gradient. To set up this gradient, normal ringer was used on the basolateral membrane, whereas apical NaCl was replaced by equimolar sodium gluconate (titrated to pH 7.4 with NaOH) to give a large Cl ⁇ concentration gradient across the epithelium. All experiments were performed with intact monolayers. To fully activate ⁇ F508-CFTR, forskolin (10 ⁇ M) and the PDE inhibitor, IBMX (100 ⁇ M), were applied followed by the addition of the CFTR potentiator, genistein (50 ⁇ M).
  • Typical protocol utilized a basolateral to apical membrane Cl ⁇ concentration gradient.
  • normal ringers was used on the basolateral membrane and was permeabilized with nystatin (360 ⁇ g/ml), whereas apical NaCl was replaced by equimolar sodium gluconate (titrated to pH 7.4 with NaOH) to give a large Cl ⁇ concentration gradient across the epithelium. All experiments were performed 30 min after nystatin permeabilization. Forskolin (10 ⁇ M) and all test compounds were added to both sides of the cell culture inserts. The efficacy of the putative ⁇ F508-CFTR potentiators was compared to that of the known potentiator, genistein.
  • FRT Fisher rat epithelial cells expressing ⁇ F508-CFTR
  • FRT ⁇ F508-CFTR Fisher rat epithelial cells expressing ⁇ F508-CFTR
  • the cells were cultured on Costar Snapwell cell culture inserts and cultured for five days at 37° C. and 5% CO 2 in Coon's modified Ham's F-12 medium supplemented with 5% fetal calf serum, 100 U/ml penicillin, and 100 ⁇ g/ml streptomycin.
  • the cells Prior to use for characterizing the potentiator activity of compounds, the cells were incubated at 27° C. for 16-48 hrs to correct for the ⁇ F508-CFTR. To determine the activity of corrections compounds, the cells were incubated at 27° C. or 37° C. with and without the compounds for 24 hours.
  • the macroscopic ⁇ F508-CFTR current (I ⁇ F508 ) in temperature- and test compound-corrected NIH3T3 cells stably expressing ⁇ F508-CFTR were monitored using the perforated-patch, whole-cell recording. Briefly, voltage-clamp recordings of I ⁇ F508 were performed at room temperature using an Axopatch 200B patch-clamp amplifier (Axon Instruments Inc., Foster City, Calif.). All recordings were acquired at a sampling frequency of 10 kHz and low-pass filtered at 1 kHz. Pipettes had a resistance of 5-6 M ⁇ when filled with the intracellular solution.
  • the cells were incubated with 10 ⁇ M of the test compound for 24 hours at 37° C. and the current density was compared to the 27° C. and 37° C. controls (% activity). Prior to recording, the cells were washed 3 ⁇ with extracellular recording medium to remove any remaining test compound. Preincubation with 10 ⁇ M of correction compounds significantly increased the cAMP- and genistein-dependent current compared to the 37° C. controls.
  • ⁇ F508-CFTR potentiators to increase the macroscopic ⁇ F508-CFTR Cl ⁇ current (I ⁇ F508 ) in NIH3T3 cells stably expressing ⁇ F508-CFTR was also investigated using perforated-patch-recording techniques.
  • the potentiators identified from the optical assays evoked a dose-dependent increase in I ⁇ F508 with similar potency and efficacy observed in the optical assays.
  • the reversal potential before and during potentiator application was around ⁇ 30 mV, which is the calculated E Cl ( ⁇ 28 mV).
  • NIH3T3 mouse fibroblasts stably expressing ⁇ F508-CFTR are used for whole-cell recordings.
  • the cells are maintained at 37° C. in 5% CO 2 and 90% humidity in Dulbecco's modified Eagle's medium supplemented with 2 mM glutamine, 10% fetal bovine serum, 1 ⁇ NEAA, ⁇ -ME, 1 ⁇ pen/strep, and 25 mM HEPES in 175 cm 2 culture flasks.
  • 2,500-5,000 cells were seeded on poly-L-lysine-coated glass coverslips and cultured for 24-48 hrs at 27° C. before use to test the activity of potentiators; and incubated with or without the correction compound at 37° C. for measuring the activity of correctors.
  • the single-channel activities of temperature-corrected ⁇ F508-CFTR stably expressed in NIH3T3 cells and activities of potentiator compounds were observed using excised inside-out membrane patch.
  • voltage-clamp recordings of single-channel activity were performed at room temperature with an Axopatch 200B patch-clamp amplifier (Axon Instruments Inc.). All recordings were acquired at a sampling frequency of 10 kHz and low-pass filtered at 400 Hz.
  • Patch pipettes were fabricated from Corning Kovar Sealing #7052 glass (World Precision Instruments, Inc., Sarasota, Fla.) and had a resistance of 5-8 M ⁇ when filled with the extracellular solution.
  • the ⁇ F508-CFTR was activated after excision, by adding 1 mM Mg-ATP, and 75 nM of the cAMP-dependent protein kinase, catalytic subunit (PKA; Promega Corp. Madison, Wis.). After channel activity stabilized, the patch was perifused using a gravity-driven microperfusion system. The inflow was placed adjacent to the patch, resulting in complete solution exchange within 1-2 sec. To maintain ⁇ F508-CFTR activity during the rapid perifusion, the nonspecific phosphatase inhibitor F (10 mM NaF) was added to the bath solution. Under these recording conditions, channel activity remained constant throughout the duration of the patch recording (up to 60 min). Currents produced by positive charge moving from the intra- to extracellular solutions (anions moving in the opposite direction) are shown as positive currents. The pipette potential (V p ) was maintained at 80 mV.
  • V p The pipette potential
  • Channel activity was analyzed from membrane patches containing 2 active channels. The maximum number of simultaneous openings determined the number of active channels during the course of an experiment.
  • the data recorded from 120 sec of ⁇ F508-CFTR activity was filtered “off-line” at 100 Hz and then used to construct all-point amplitude histograms that were fitted with multigaussian functions using Bio-Patch Analysis software (Bio-Logic Comp. France).
  • NIH3T3 mouse fibroblasts stably expressing ⁇ F508-CFTR are used for excised-membrane patch-clamp recordings.
  • the cells are maintained at 37° C. in 5% CO 2 and 90% humidity in Dulbecco's modified Eagle's medium supplemented with 2 mM glutamine, 10% fetal bovine serum, 1 ⁇ NEAA, ⁇ -ME, 1 ⁇ pen/strep, and 25 mM HEPES in 175 cm 2 culture flasks.
  • 2,500-5,000 cells were seeded on poly-L-lysine-coated glass coverslips and cultured for 24-48 hrs at 27° C. before use.
  • Compound 1 and Compound 2 of the invention are useful as augmenters or inducers of CFTR activity.
  • Table 5 below illustrates the EC50 and relative efficacy of Compound 1 and Compound 2. In Table 5 below, the following meanings apply.
  • EC50 “+++” means ⁇ 10 uM; “++” means between 10 uM to 25 uM; “+” means between 25 uM to 60 uM.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Physiology (AREA)
  • Biophysics (AREA)
  • Molecular Biology (AREA)
  • Dispersion Chemistry (AREA)
  • Nutrition Science (AREA)
  • Hematology (AREA)
  • Pulmonology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Diabetes (AREA)
  • Obesity (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
US14/069,571 2012-11-02 2013-11-01 Pharmaceutical Compositions for the Treatment of CFTR Mediated Diseases Abandoned US20140163068A1 (en)

Priority Applications (4)

Application Number Priority Date Filing Date Title
US14/069,571 US20140163068A1 (en) 2012-11-02 2013-11-01 Pharmaceutical Compositions for the Treatment of CFTR Mediated Diseases
US15/152,092 US20160324846A1 (en) 2012-11-02 2016-05-11 Pharmaceutical Compositions for the Treatment of CFTR Mediated Diseases
US16/722,290 US20200338063A1 (en) 2012-11-02 2019-12-20 Pharmaceutical compositions for the treatment of cftr mediated diseases
US18/091,472 US20230364073A1 (en) 2012-11-02 2022-12-30 Pharmaceutical compositions for the treatment of cftr mediated diseases

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
US201261721622P 2012-11-02 2012-11-02
US201261728328P 2012-11-20 2012-11-20
US201361770668P 2013-02-28 2013-02-28
US201361824005P 2013-05-16 2013-05-16
US201361840668P 2013-06-28 2013-06-28
US14/069,571 US20140163068A1 (en) 2012-11-02 2013-11-01 Pharmaceutical Compositions for the Treatment of CFTR Mediated Diseases

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US15/152,092 Continuation US20160324846A1 (en) 2012-11-02 2016-05-11 Pharmaceutical Compositions for the Treatment of CFTR Mediated Diseases

Publications (1)

Publication Number Publication Date
US20140163068A1 true US20140163068A1 (en) 2014-06-12

Family

ID=50628072

Family Applications (4)

Application Number Title Priority Date Filing Date
US14/069,571 Abandoned US20140163068A1 (en) 2012-11-02 2013-11-01 Pharmaceutical Compositions for the Treatment of CFTR Mediated Diseases
US15/152,092 Abandoned US20160324846A1 (en) 2012-11-02 2016-05-11 Pharmaceutical Compositions for the Treatment of CFTR Mediated Diseases
US16/722,290 Abandoned US20200338063A1 (en) 2012-11-02 2019-12-20 Pharmaceutical compositions for the treatment of cftr mediated diseases
US18/091,472 Pending US20230364073A1 (en) 2012-11-02 2022-12-30 Pharmaceutical compositions for the treatment of cftr mediated diseases

Family Applications After (3)

Application Number Title Priority Date Filing Date
US15/152,092 Abandoned US20160324846A1 (en) 2012-11-02 2016-05-11 Pharmaceutical Compositions for the Treatment of CFTR Mediated Diseases
US16/722,290 Abandoned US20200338063A1 (en) 2012-11-02 2019-12-20 Pharmaceutical compositions for the treatment of cftr mediated diseases
US18/091,472 Pending US20230364073A1 (en) 2012-11-02 2022-12-30 Pharmaceutical compositions for the treatment of cftr mediated diseases

Country Status (30)

Country Link
US (4) US20140163068A1 (enrdf_load_stackoverflow)
EP (3) EP2914248B2 (enrdf_load_stackoverflow)
JP (4) JP6302923B2 (enrdf_load_stackoverflow)
KR (1) KR102396897B1 (enrdf_load_stackoverflow)
CN (2) CN111671751A (enrdf_load_stackoverflow)
AR (1) AR093340A1 (enrdf_load_stackoverflow)
AU (4) AU2013337730B2 (enrdf_load_stackoverflow)
BR (1) BR112015009913B1 (enrdf_load_stackoverflow)
CA (1) CA2890106C (enrdf_load_stackoverflow)
CL (1) CL2015001148A1 (enrdf_load_stackoverflow)
CY (1) CY1121070T1 (enrdf_load_stackoverflow)
DK (2) DK2914248T4 (enrdf_load_stackoverflow)
ES (2) ES2694290T5 (enrdf_load_stackoverflow)
FI (2) FI3470063T3 (enrdf_load_stackoverflow)
HR (2) HRP20181740T4 (enrdf_load_stackoverflow)
HU (2) HUE039864T2 (enrdf_load_stackoverflow)
IL (2) IL283276B2 (enrdf_load_stackoverflow)
LT (2) LT2914248T (enrdf_load_stackoverflow)
MX (2) MX368353B (enrdf_load_stackoverflow)
NZ (2) NZ708474A (enrdf_load_stackoverflow)
PL (2) PL3470063T3 (enrdf_load_stackoverflow)
PT (2) PT3470063T (enrdf_load_stackoverflow)
RS (2) RS57831B2 (enrdf_load_stackoverflow)
SG (3) SG10201703452PA (enrdf_load_stackoverflow)
SI (2) SI2914248T2 (enrdf_load_stackoverflow)
SM (2) SMT201800590T1 (enrdf_load_stackoverflow)
TR (1) TR201815218T4 (enrdf_load_stackoverflow)
TW (2) TWI736768B (enrdf_load_stackoverflow)
UA (2) UA117464C2 (enrdf_load_stackoverflow)
WO (1) WO2014071122A1 (enrdf_load_stackoverflow)

Cited By (49)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20080306062A1 (en) * 2005-11-08 2008-12-11 Hadida Ruah Sara S Modulators of atp-binding cassette transporters
US20140277687A1 (en) * 2013-03-15 2014-09-18 Monosol Rx, Llc Process for drying a wet film with control of loss on drying
US8962856B2 (en) 2005-08-11 2015-02-24 Vertex Pharmaceuticals Incorporated Modulators of cystic fibrosis transmembrane conductance regulator
US8969386B2 (en) 2007-05-09 2015-03-03 Vertex Pharmaceuticals Incorporated Modulators of CFTR
US9012652B2 (en) 2007-12-07 2015-04-21 Vertex Pharmaceuticals Incorporated Processes for producing cycloalkylcarboxamido-pyridine benzoic acids
US9012473B2 (en) 2007-11-16 2015-04-21 Vertex Pharmaceuticals Incorporated Modulators of ATP-binding cassette transporters
US9079916B2 (en) 2008-02-28 2015-07-14 Vertex Pharmaceuticals Incorporated Heteroaryl derivatives as CFTR modulators
US9102672B2 (en) 2006-11-03 2015-08-11 Vertex Pharmaceuticals Incorporated Azaindole derivatives as CFTR modulators
US9150552B2 (en) 2007-12-07 2015-10-06 Vertex Pharmaceuticals Incorporated Solid forms of 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl) benzoic acid
US9241934B2 (en) 2010-04-07 2016-01-26 Vertex Pharmaceuticals Incorporated Pharmaceutical compositions of 3-(6-(1-(2,2-difluorobenzo[D][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid and administration thereof
US9249131B2 (en) 2003-09-06 2016-02-02 Vertex Pharmaceuticals Incorporated Modulators of ATP-binding cassette transporters
US9254291B2 (en) 2011-11-08 2016-02-09 Vertex Pharmaceuticals Incorporated Modulators of ATP-binding cassette transporters
US9314455B2 (en) 2010-04-07 2016-04-19 Vertex Pharmaceuticals Incorporated Solid forms of 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid
US9321725B2 (en) 2007-12-07 2016-04-26 Vertex Pharmaceuticals Incorporated Processes for producing cycloalkylcarboxamido-pyridine benzoic acids
US9371287B2 (en) 2009-03-20 2016-06-21 Vertex Pharmaceuticals Incorporated Process for making modulators of cystic fibrosis transmembrane conductance regulator
US9399648B2 (en) 2007-08-24 2016-07-26 Vertex Pharmaceuticals Incorporated Isothiazolopyridinones useful for the treatment of (inter alia) cystic fibrosis
US9550761B2 (en) 2004-01-30 2017-01-24 Vertex Pharmaceuticals Incorporated Modulators of ATP-binding cassette transporters
US9701639B2 (en) 2014-10-07 2017-07-11 Vertex Pharmaceuticals Incorporated Co-crystals of modulators of cystic fibrosis transmembrane conductance regulator
WO2017151725A1 (en) * 2016-03-03 2017-09-08 Nivalis Therapeutics, Inc. Formulations of an s-nitrosoglutathione reductase inhibitor
US9758510B2 (en) 2006-04-07 2017-09-12 Vertex Pharmaceuticals Incorporated Modulators of ATP-binding cassette transporters
WO2017187336A1 (en) 2016-04-25 2017-11-02 Druggability Technologies Ip Holdco Limited Complexes of ivacaftor and its salts and derivatives, process for the preparation thereof and pharmaceutical compositions containing them
WO2017187340A1 (en) 2016-04-25 2017-11-02 Druggability Technologies Ip Holdco Limited Pharmaceutical combination composition comprising complex formulations of ivacaftor and lumacaftor and their salts and derivatives, process for their preparation thereof and pharmaceutical compositions containing them
WO2017187338A1 (en) 2016-04-25 2017-11-02 Druggability Technologies Ip Holdco Limited Complexes of lumacaftor and its salts and derivatives, process for the preparation thereof and pharmaceutical compositions containing them
US9931334B2 (en) 2005-12-28 2018-04-03 Vertex Pharmaceuticals Incorporated Solid forms of N[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide
US9974781B2 (en) 2006-04-07 2018-05-22 Vertex Pharmaceuticals Incorporated Modulators of ATP-binding cassette transporters
WO2018093950A1 (en) * 2016-11-16 2018-05-24 Abide Therapeutics, Inc. Pharmaceutical formulations
US10022352B2 (en) 2006-04-07 2018-07-17 Vertex Pharmaceuticals Incorporated Modulators of ATP-binding cassette transporters
US10047053B2 (en) 2011-05-18 2018-08-14 Vertex Pharmaceuticals (Europe) Limited Deuterated CFTR potentiators
US10058546B2 (en) 2012-07-16 2018-08-28 Vertex Pharmaceuticals Incorporated Pharmaceutical compositions of (R)-1-(2,2-difluorobenzo[D][1,3]dioxo1-5-y1)-N-(1-(2,3-dihydroxypropy1)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-y1)-1H-indol-5-y1) cyclopropanecarbox-amide and administration thereof
US10071979B2 (en) 2010-04-22 2018-09-11 Vertex Pharmaceuticals Incorporated Process of producing cycloalkylcarboxamido-indole compounds
US10081621B2 (en) 2010-03-25 2018-09-25 Vertex Pharmaceuticals Incorporated Solid forms of (R)-1(2,2-difluorobenzo[D][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide
US10206877B2 (en) 2014-04-15 2019-02-19 Vertex Pharmaceuticals Incorporated Pharmaceutical compositions for the treatment of cystic fibrosis transmembrane conductance regulator mediated diseases
US10206915B2 (en) 2016-04-25 2019-02-19 Druggability Technologies Ip Holdco Limited Complexes of Ivacaftor and its salts and derivatives, process for the preparation thereof and pharmaceutical compositions containing them
US10231932B2 (en) 2013-11-12 2019-03-19 Vertex Pharmaceuticals Incorporated Process of preparing pharmaceutical compositions for the treatment of CFTR mediated diseases
US10272046B2 (en) 2012-02-27 2019-04-30 Vertex Pharmaceuticals Incorporated Pharmaceutical composition and administrations thereof
US10302602B2 (en) 2014-11-18 2019-05-28 Vertex Pharmaceuticals Incorporated Process of conducting high throughput testing high performance liquid chromatography
US10376501B2 (en) 2016-04-25 2019-08-13 Druggability Technologies Ip Holdco Limited Complexes of lumacaftor and its salts and derivatives, process for the preparation thereof and pharmaceutical compositions containing them
US10383865B2 (en) 2016-04-25 2019-08-20 Druggability Technologies Ip Holdco Limited Pharmaceutical combination composition comprising complex formulations of Ivacaftor and Lumacaftor and their salts and derivatives, process for their preparation thereof and pharmaceutical compositions containing them
US10646481B2 (en) 2008-08-13 2020-05-12 Vertex Pharmaceuticals Incorporated Pharmaceutical composition and administrations thereof
US10662192B2 (en) 2004-06-24 2020-05-26 Vertex Pharmaceuticals Incorporated Modulators of ATP-binding cassette transporters
US10759721B2 (en) 2015-09-25 2020-09-01 Vertex Pharmaceuticals (Europe) Limited Deuterated CFTR potentiators
US11021453B2 (en) 2012-01-06 2021-06-01 Lundbeck La Jolla Research Center, Inc. Carbamate compounds and methods of making and using same
US11034674B2 (en) 2015-05-11 2021-06-15 H. Lundbeck A/S Methods of treating inflammation or neuropathic pain
US11142517B2 (en) 2016-11-16 2021-10-12 H. Lundbeck A/S Crystalline forms of a MAGL inhibitor
US11702393B2 (en) 2020-04-21 2023-07-18 H. Lundbeck A/S Synthesis of a monoacylglycerol lipase inhibitor
US11708331B2 (en) 2017-12-01 2023-07-25 Vertex Pharmaceuticals Incorporated Processes for making modulators of cystic fibrosis transmembrane conductance regulator
US12269831B2 (en) 2020-08-07 2025-04-08 Vertex Pharmaceuticals Incorporated Modulators of cystic fibrosis transmembrane conductance regulator
US12324802B2 (en) 2020-11-18 2025-06-10 Vertex Pharmaceuticals Incorporated Modulators of cystic fibrosis transmembrane conductance regulator
USRE50453E1 (en) 2006-04-07 2025-06-10 Vertex Pharmaceuticals Incorporated Indole derivatives as CFTR modulators

Families Citing this family (44)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
TWI736768B (zh) * 2012-11-02 2021-08-21 美商維泰克斯製藥公司 治療cftr介導疾病之醫藥組合物
US20160074374A1 (en) * 2013-04-26 2016-03-17 Vertex Pharmaceuticals Incorporated Correctors acting through msd1 of cftr protein
SG11201702817SA (en) 2014-10-06 2017-05-30 Vertex Pharma Modulators of cystic fibrosis transmembrane conductance regulator
AU2017240685B2 (en) 2016-03-31 2021-08-12 Vertex Pharmaceuticals Incorporated Modulators of cystic fibrosis transmembrane conductance regulator
CA3037986C (en) 2016-09-30 2024-03-05 Vertex Pharmaceuticals Incorporated Modulator of cystic fibrosis transmembrane conductance regulator, pharmaceutical compositions, methods of treatment, and process for making the modulator
PE20191304A1 (es) 2016-12-09 2019-09-23 Vertex Pharma Modulador del regulador de conductancia de transmembrana de fibrosis quistica, composiciones farmaceuticas, metodos de tratamiento y proceso para producir el modulador
EP3634402A1 (en) 2017-06-08 2020-04-15 Vertex Pharmaceuticals Incorporated Methods of treatment for cystic fibrosis
MA49631A (fr) 2017-07-17 2020-05-27 Vertex Pharma Méthodes de traitement de la fibrose kystique
MX393460B (es) 2017-08-02 2025-03-24 Vertex Pharma Procesos para preparar compuestos de pirrolidina
US10654829B2 (en) 2017-10-19 2020-05-19 Vertex Pharmaceuticals Incorporated Crystalline forms and compositions of CFTR modulators
US11465985B2 (en) 2017-12-08 2022-10-11 Vertex Pharmaceuticals Incorporated Processes for making modulators of cystic fibrosis transmembrane conductance regulator
TWI810243B (zh) 2018-02-05 2023-08-01 美商維泰克斯製藥公司 用於治療囊腫纖化症之醫藥組合物
BR112020015509A2 (pt) 2018-02-15 2021-01-26 Vertex Pharmaceuticals Incorporated macrociclos como moduladores de regulador da condutância transmembrana da fibrose cística, composições farmacêuticas dos mesmos, sua utilização no tratamento da fibrose cística, e processo para sua produção
US20210139514A1 (en) 2018-04-05 2021-05-13 Vertex Pharmaceuticals Incorporated Modulators of cystic fibrosis transmembrane conductance regulator
US11414439B2 (en) 2018-04-13 2022-08-16 Vertex Pharmaceuticals Incorporated Modulators of cystic fibrosis transmembrane conductance regulator, pharmaceutical compositions, methods of treatment, and process for making the modulator
ES2943126T3 (es) 2018-11-14 2023-06-09 Vertex Pharma Métodos para el tratamiento de la fibrosis quística
TWI848092B (zh) 2019-04-03 2024-07-11 美商維泰克斯製藥公司 囊腫纖維化跨膜傳導調節蛋白調節劑
WO2020214921A1 (en) 2019-04-17 2020-10-22 Vertex Pharmaceuticals Incorporated Solid forms of modulators of cftr
US11873300B2 (en) 2019-08-14 2024-01-16 Vertex Pharmaceuticals Incorporated Crystalline forms of CFTR modulators
TWI867024B (zh) 2019-08-14 2024-12-21 美商維泰克斯製藥公司 囊腫纖維化跨膜傳導調節蛋白之調節劑
CA3150738A1 (en) 2019-08-14 2021-02-18 Vertex Pharmaceuticals Incorporated Modulators of cystic fibrosis transmembrane conductance regulator
TW202120517A (zh) 2019-08-14 2021-06-01 美商維泰克斯製藥公司 製備cftr調節劑之方法
US11904006B2 (en) 2019-12-11 2024-02-20 University Of Iowa Research Foundation Poly(diaminosulfide) particle-based vaccine
WO2022194399A1 (en) 2020-07-13 2022-09-22 Idorsia Pharmaceuticals Ltd Macrocycles as cftr modulators
EP4225762A1 (en) 2020-10-07 2023-08-16 Vertex Pharmaceuticals Incorporated Modulators of cystic fibrosis transmembrane conductance regulator
JP2023545080A (ja) 2020-10-07 2023-10-26 バーテックス ファーマシューティカルズ インコーポレイテッド 嚢胞性線維症膜コンダクタンス制御因子モジュレーター
US20230373939A1 (en) 2020-10-07 2023-11-23 Vertex Pharmaceuticals Incorporated Modulators of cystic fibrosis transmembrane conductance regulator
US20240018161A1 (en) 2020-10-07 2024-01-18 Vertex Pharmaceuticals Incorporated Modulators of cystic fibrosis transmembrane conductance regulator
CN116783204A (zh) 2020-10-07 2023-09-19 弗特克斯药品有限公司 囊性纤维化跨膜传导调控因子的调节剂
WO2022076626A1 (en) 2020-10-07 2022-04-14 Vertex Pharmaceuticals Incorporated Modulators of cystic fibrosis transmembrane conductance regulator
US20230382924A1 (en) 2020-10-07 2023-11-30 Vertex Pharmaceuticals Incorporated Modulators of cystic fibrosis transmembrane conductance regulator
WO2022076629A1 (en) 2020-10-07 2022-04-14 Vertex Pharmaceuticals Incorporated Modulators of cystic fibrosis transmembrane conductance regulator
WO2022076620A1 (en) 2020-10-07 2022-04-14 Vertex Pharmaceuticals Incorporated Modulators of cystic fibrosis transmembrane conductance regulator
WO2022076627A1 (en) 2020-10-07 2022-04-14 Vertex Pharmaceuticals Incorporated Modulators of cystic fibrosis transmembrane conductance regulator
KR20230118123A (ko) 2020-12-10 2023-08-10 버텍스 파마슈티칼스 인코포레이티드 낭성 섬유증 치료 방법
WO2022125963A1 (en) * 2020-12-11 2022-06-16 University Of Iowa Research Foundation Compositions comprising molecules for cystic fibrosis treatment
KR20240144973A (ko) 2022-02-03 2024-10-04 버텍스 파마슈티칼스 인코포레이티드 낭성 섬유증 치료 방법
WO2023154291A1 (en) 2022-02-08 2023-08-17 Vertex Pharmaceuticals Incorporated Modulators of cystic fibrosis transmembrane conductance regulator
WO2023196429A1 (en) 2022-04-06 2023-10-12 Vertex Pharmaceuticals Incorporated Modulators of cystic fibrosis transmembrane conductance regulator
WO2023224931A1 (en) 2022-05-16 2023-11-23 Vertex Pharmaceuticals Incorporated Methods of treatment for cystic fibrosis
TW202421102A (zh) 2022-09-15 2024-06-01 瑞士商愛杜西亞製藥有限公司 巨環cftr調節劑與cftr校正子及/或cftr增效劑之組合
EP4587443A1 (en) 2022-09-15 2025-07-23 Idorsia Pharmaceuticals Ltd Macrocyclic cftr modulators
WO2024056779A1 (en) 2022-09-15 2024-03-21 Idorsia Pharmaceuticals Ltd Crystalline form of (3s,7s,10r,13r)-13-benzyl-20-fluoro-7-isobutyl-n-(2-(3-methoxy-1,2,4-oxadiazol-5-yl)ethyl)-6,9-dimethyl-1,5,8,11-tetraoxo-10-(2,2,2-trifluoroethyl)-1,2,3,4,5,6,7,8,9,10,11,12,13,14-tetradecahydro-[1]oxa[4,7,10,14]tetraazacycloheptadecino[16,17-f]quinoline-3-carboxamide
WO2025076235A1 (en) 2023-10-04 2025-04-10 Vertex Pharmaceuticals Incorporated Modulators of cystic fibrosis transmembrane conductance regulator

Family Cites Families (40)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20020017295A1 (en) 2000-07-07 2002-02-14 Weers Jeffry G. Phospholipid-based powders for inhalation
US6777400B2 (en) 2000-08-05 2004-08-17 Smithkline Beecham Corporation Anti-inflammatory androstane derivative compositions
US20100074949A1 (en) 2008-08-13 2010-03-25 William Rowe Pharmaceutical composition and administration thereof
WO2004028480A2 (en) 2002-09-30 2004-04-08 The Regents Of The University Of California Cystic fibrosis transmembrane conductance regulator protein inhibitors and uses thereof
US20050113423A1 (en) 2003-03-12 2005-05-26 Vangoor Frederick F. Modulators of ATP-binding cassette transporters
US6992096B2 (en) 2003-04-11 2006-01-31 Ptc Therapeutics, Inc. 1,2,4-oxadiazole benzoic acid compounds and their use for nonsense suppression and the treatment of disease
WO2004110352A2 (en) 2003-05-16 2004-12-23 The Regents Of The University Of California Compounds having activity in increasing ion transport by mutant-cftr and uses thereof
ATE440825T1 (de) 2003-06-06 2009-09-15 Vertex Pharma Pyrimidin-derivate zur verwendung als modulatoren von atp-bindende kassette transportern
CA2465565A1 (en) * 2003-06-12 2004-12-12 Warner-Lambert Company Llc Pharmaceutical compositions of atorvastatin
US7598412B2 (en) 2003-10-08 2009-10-06 Vertex Pharmaceuticals Incorporated Modulators of ATP-binding cassette transporters
WO2005049018A1 (en) 2003-11-14 2005-06-02 Vertex Pharmaceuticals Incorporated Thiazoles and oxazoles useful as modulators of atp-binding cassette transporters
WO2007056341A1 (en) 2005-11-08 2007-05-18 Vertex Pharmaceuticals Incorporated Heterocyclic modulators of atp-binding cassette transporters
CN1960966A (zh) 2004-03-30 2007-05-09 加利福尼亚大学董事会 含酰肼cftr抑制剂化合物及其用途
EP1765347A4 (en) 2004-06-04 2008-10-01 Univ California COMPOUNDS INVOLVED IN ACCELERATION OF ION TRANSPORT BY MUTANT CFTR AND USES THEREOF
ME02970B (me) 2004-06-24 2018-07-20 Vertex Pharma Modulatori atp-vezujućih kasetnih transportera
US9051342B2 (en) 2004-10-13 2015-06-09 Ptc Therapeutics, Inc. Pyrazole or triazole compounds and their use for the manufacture of a medicament for treating somatic mutation related diseases
EP1865949B1 (en) 2005-03-11 2012-11-14 Vertex Pharmaceuticals Incorporated Modulators of ATP-binding cassette transporters
WO2006101740A2 (en) 2005-03-18 2006-09-28 The Regents Of The University Of California Compounds having activity in correcting mutant-cftr processing and uses thereof
PT2402002T (pt) 2005-04-08 2018-10-08 Ptc Therapeutics Inc Composições de 1,2,4-oxadiazole oralmente activo para terapia de supressão de mutações nonsense
WO2006127588A2 (en) 2005-05-24 2006-11-30 Vertex Pharmaceuticals Incorporated Modulators of atp-binding cassette transporters
RU2008118001A (ru) 2005-10-06 2009-11-20 Вертекс Фармасьютикалз Инкорпорейтед (Us) Модуляторы атф-зависимых транспортеров
EP2332933A1 (en) 2007-05-07 2011-06-15 Novartis AG Epithelial sodium channel (ENaC) inhibitors
RU2010114732A (ru) * 2007-09-14 2011-10-20 Вертекс Фармасьютикалз Инкорпорейтед (Us) Твердые формы n-[2,4-бис(1,1-диметилэтил)-5-гидроксифенил]-1,4-дигидро-4-оксохинолин-3-карбоксамида
UA102534C2 (xx) * 2007-12-07 2013-07-25 Вертекс Фармасьютикалз Инкорпорейтед ТВЕРДА ФОРМА 3-(6-(1-(2,2-ДИФТОРБЕНЗО$d]$1,3]-ДІОКСОЛ-5-ІЛ)-ЦИКЛОПРОПАНКАРБОКСАМІДО)-3-МЕТИЛПІРИДИН-2-ІЛ)БЕНЗОЙНОЇ КИСЛОТИ (ВАРІАНТИ)$ТВЕРДАЯ ФОРМА 3-(6-(1-(2,2-ДИФТОРБЕНЗО$d]$1,3]-ДИОКСОЛ-5-ИЛ)-ЦИКЛОПРОПАНКАРБОКСАМИДО)-3-МЕТИЛПИРИДИН-2-ИЛ)БЕНЗОЙНОЙ КИСЛОТЫ (ВАРИАНТЫ)
MX2010006421A (es) 2007-12-10 2010-06-25 Novartis Ag Compuestos organicos.
CN102112130A (zh) 2008-06-10 2011-06-29 诺瓦提斯公司 作为上皮钠通道阻滞剂的吡嗪衍生物
PT3345625T (pt) * 2008-08-13 2021-02-10 Vertex Pharma Composição farmacêutica e sua administração
BRPI0919550A2 (pt) 2008-09-29 2019-09-10 Vertex Pharma unidades de dosagem de ácido 3-(6-(1-(2,2-difluorobenzo]d][1,3]dioxol-5-il)ciclopropanocarboxamido)-3-metilpiridin-2-il)benzoico
CN102803234A (zh) * 2009-06-02 2012-11-28 霓坎制药有限责任公司 用于治疗疾病的人甲酰基肽受体的拮抗作用
JP2011034380A (ja) * 2009-08-03 2011-02-17 Nitto Denko Corp タッチパネルおよびタッチパネル付表示装置
WO2011028740A1 (en) 2009-09-03 2011-03-10 Glaxo Group Limited ENaC BLOCKERS
WO2011079087A1 (en) 2009-12-23 2011-06-30 Glaxo Group Limited Enac blockers
US8247436B2 (en) 2010-03-19 2012-08-21 Novartis Ag Pyridine and pyrazine derivative for the treatment of CF
US8552034B2 (en) * 2010-04-07 2013-10-08 Vertex Pharmaceuticals Incorporated Pharmaceutical compositions of 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid and administration thereof
CA2796642A1 (en) * 2010-04-22 2011-10-27 Vertex Pharmaceuticals Incorporated Pharmaceutical compositions and administrations thereof
US8372845B2 (en) 2010-09-17 2013-02-12 Novartis Ag Pyrazine derivatives as enac blockers
US10105356B2 (en) * 2011-01-31 2018-10-23 Avalyn Pharma Inc. Aerosol pirfenidone and pyridone analog compounds and uses thereof
US9968607B2 (en) 2011-04-25 2018-05-15 Hetero Research Foundation Pharmaceutical compositions of raltegravir, methods of preparation and methods of use therof
JP2015504920A (ja) * 2012-01-25 2015-02-16 バーテックス ファーマシューティカルズ インコーポレイテッドＶｅｒｔｅｘ Ｐｈａｒｍａｃｅｕｔｉｃａｌｓ Ｉｎｃｏｒｐｏｒａｔｅｄ ３−（６−（１−（２，２−ジフルオロベンゾ［ｄ］［１，３］ジオキソール−５−イル）シクロプロパンカルボキサミド）−３−メチルピリジン−２−イル）安息香酸の製剤
TWI736768B (zh) * 2012-11-02 2021-08-21 美商維泰克斯製藥公司 治療cftr介導疾病之醫藥組合物

Cited By (90)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9249131B2 (en) 2003-09-06 2016-02-02 Vertex Pharmaceuticals Incorporated Modulators of ATP-binding cassette transporters
US9550761B2 (en) 2004-01-30 2017-01-24 Vertex Pharmaceuticals Incorporated Modulators of ATP-binding cassette transporters
US10626111B2 (en) 2004-01-30 2020-04-21 Vertex Pharmaceuticals Incorporated Modulators of ATP-binding cassette transporters
US10662192B2 (en) 2004-06-24 2020-05-26 Vertex Pharmaceuticals Incorporated Modulators of ATP-binding cassette transporters
US8962856B2 (en) 2005-08-11 2015-02-24 Vertex Pharmaceuticals Incorporated Modulators of cystic fibrosis transmembrane conductance regulator
US9856248B2 (en) 2005-08-11 2018-01-02 Vertex Pharmaceuticals Incorporated Modulators of cystic fibrosis transmembrane conductance regulator
US9351962B2 (en) 2005-08-11 2016-05-31 Vertex Pharmaceuticals Incorporated Modulators of cystic fibrosis transmembrane conductance regulator
US11084804B2 (en) 2005-11-08 2021-08-10 Vertex Pharmaceuticals Incorporated Modulators of ATP-binding cassette transporters
US20080306062A1 (en) * 2005-11-08 2008-12-11 Hadida Ruah Sara S Modulators of atp-binding cassette transporters
US9931334B2 (en) 2005-12-28 2018-04-03 Vertex Pharmaceuticals Incorporated Solid forms of N[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide
US10537565B2 (en) 2005-12-28 2020-01-21 Vertex Pharmaceuticals Incorporated Solid forms of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide
US11291662B2 (en) 2005-12-28 2022-04-05 Vertex Pharmaceuticals Incorporated Solid forms of n-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide
US9758510B2 (en) 2006-04-07 2017-09-12 Vertex Pharmaceuticals Incorporated Modulators of ATP-binding cassette transporters
US10987348B2 (en) 2006-04-07 2021-04-27 Vertex Pharmaceuticals Incorporated Modulators of ATP-binding cassette transporters
US10022352B2 (en) 2006-04-07 2018-07-17 Vertex Pharmaceuticals Incorporated Modulators of ATP-binding cassette transporters
US10975061B2 (en) 2006-04-07 2021-04-13 Vertex Pharmaceuticals Incorporated Modulators of ATP-binding cassette transporters
US9974781B2 (en) 2006-04-07 2018-05-22 Vertex Pharmaceuticals Incorporated Modulators of ATP-binding cassette transporters
USRE50453E1 (en) 2006-04-07 2025-06-10 Vertex Pharmaceuticals Incorporated Indole derivatives as CFTR modulators
US10239867B2 (en) 2006-04-07 2019-03-26 Vertex Pharmaceuticals Incorporated Modulators of ATP-binding cassette transporters
US11639347B2 (en) 2006-04-07 2023-05-02 Vertex Pharmaceuticals Incorporated Modulators of ATP-binding cassette transporters
US9102672B2 (en) 2006-11-03 2015-08-11 Vertex Pharmaceuticals Incorporated Azaindole derivatives as CFTR modulators
US9732080B2 (en) 2006-11-03 2017-08-15 Vertex Pharmaceuticals Incorporated Azaindole derivatives as CFTR modulators
US8969386B2 (en) 2007-05-09 2015-03-03 Vertex Pharmaceuticals Incorporated Modulators of CFTR
US9725440B2 (en) 2007-05-09 2017-08-08 Vertex Pharmaceuticals Incorporated Modulators of CFTR
US9399648B2 (en) 2007-08-24 2016-07-26 Vertex Pharmaceuticals Incorporated Isothiazolopyridinones useful for the treatment of (inter alia) cystic fibrosis
US9522145B2 (en) 2007-11-16 2016-12-20 Vertex Pharmaceuticals Incorporated Modulators of ATP-binding cassette transporters
US9012473B2 (en) 2007-11-16 2015-04-21 Vertex Pharmaceuticals Incorporated Modulators of ATP-binding cassette transporters
US9321725B2 (en) 2007-12-07 2016-04-26 Vertex Pharmaceuticals Incorporated Processes for producing cycloalkylcarboxamido-pyridine benzoic acids
US9434717B2 (en) 2007-12-07 2016-09-06 Vertex Pharmaceuticals Incorporated Solid forms of 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl) benzoic acid
US9776968B2 (en) 2007-12-07 2017-10-03 Vertex Pharmaceuticals Incorporated Processes for producing cycloalkylcarboxamido-pyridine benzoic acids
US9150552B2 (en) 2007-12-07 2015-10-06 Vertex Pharmaceuticals Incorporated Solid forms of 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl) benzoic acid
US12065432B2 (en) 2007-12-07 2024-08-20 Vertex Pharmaceuticals Incorporated Solid forms of 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl) benzoic acid
US10597384B2 (en) 2007-12-07 2020-03-24 Vertex Pharmaceuticals Incorporated Solid forms of 3-(6-(1-(2,2-difluorobenzo[D][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl) benzoic acid
US9840499B2 (en) 2007-12-07 2017-12-12 Vertex Pharmaceuticals Incorporated Solid forms of 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl) benzoic acid
US9012652B2 (en) 2007-12-07 2015-04-21 Vertex Pharmaceuticals Incorporated Processes for producing cycloalkylcarboxamido-pyridine benzoic acids
US9751890B2 (en) 2008-02-28 2017-09-05 Vertex Pharmaceuticals Incorporated Heteroaryl derivatives as CFTR modulators
US9504683B2 (en) 2008-02-28 2016-11-29 Vertex Pharmaceuticals Incorporated Heteroaryl derivatives as CFTR modulators
US9079916B2 (en) 2008-02-28 2015-07-14 Vertex Pharmaceuticals Incorporated Heteroaryl derivatives as CFTR modulators
US10646481B2 (en) 2008-08-13 2020-05-12 Vertex Pharmaceuticals Incorporated Pharmaceutical composition and administrations thereof
US11564916B2 (en) 2008-08-13 2023-01-31 Vertex Pharmaceuticals Incorporated Pharmaceutical composition and administrations thereof
US9371287B2 (en) 2009-03-20 2016-06-21 Vertex Pharmaceuticals Incorporated Process for making modulators of cystic fibrosis transmembrane conductance regulator
US9751839B2 (en) 2009-03-20 2017-09-05 Vertex Pharmaceuticals Incorporated Process for making modulators of cystic fibrosis transmembrane conductance regulator
US10906891B2 (en) 2010-03-25 2021-02-02 Vertex Pharmaceuticals Incoporated Solid forms of (R)-1(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide
US10081621B2 (en) 2010-03-25 2018-09-25 Vertex Pharmaceuticals Incorporated Solid forms of (R)-1(2,2-difluorobenzo[D][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide
US11578062B2 (en) 2010-03-25 2023-02-14 Vertex Pharmaceuticals Incorporated Solid forms of (R)-1(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide
US10076513B2 (en) 2010-04-07 2018-09-18 Vertex Pharmaceuticals Incorporated Pharmaceutical compositions of 3-(6-(1-(2,2-difluorobenzo[D][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl) benzoic acid and administration thereof
US9241934B2 (en) 2010-04-07 2016-01-26 Vertex Pharmaceuticals Incorporated Pharmaceutical compositions of 3-(6-(1-(2,2-difluorobenzo[D][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid and administration thereof
US9314455B2 (en) 2010-04-07 2016-04-19 Vertex Pharmaceuticals Incorporated Solid forms of 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid
US11052075B2 (en) 2010-04-07 2021-07-06 Vertex Pharmaceuticals Incorporated Pharmaceutical compositions of 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl) benzoic acid and administration thereof
US10071979B2 (en) 2010-04-22 2018-09-11 Vertex Pharmaceuticals Incorporated Process of producing cycloalkylcarboxamido-indole compounds
US10894773B2 (en) 2011-05-18 2021-01-19 Vertex Pharmaceuticals (Europe) Limited Deuterated CFTR potentiators
US10047053B2 (en) 2011-05-18 2018-08-14 Vertex Pharmaceuticals (Europe) Limited Deuterated CFTR potentiators
US10479766B2 (en) 2011-05-18 2019-11-19 Verex Pharmaceuticals (Europe) Limited Deuterated CFTR potentiators
US9254291B2 (en) 2011-11-08 2016-02-09 Vertex Pharmaceuticals Incorporated Modulators of ATP-binding cassette transporters
US11021453B2 (en) 2012-01-06 2021-06-01 Lundbeck La Jolla Research Center, Inc. Carbamate compounds and methods of making and using same
US12018004B2 (en) 2012-01-06 2024-06-25 H. Lundbeck A/S Carbamate compounds and methods of making and using same
US11530189B2 (en) 2012-01-06 2022-12-20 H. Lundbecka/S Carbamate compounds and methods of making and using same
US12214083B2 (en) 2012-02-27 2025-02-04 Vertex Pharmaceuticals Incorporated Pharmaceutical composition and administrations thereof
US10272046B2 (en) 2012-02-27 2019-04-30 Vertex Pharmaceuticals Incorporated Pharmaceutical composition and administrations thereof
US11752106B2 (en) 2012-02-27 2023-09-12 Vertex Pharmaceuticals Incorporated Pharmaceutical composition and administrations thereof
US11147770B2 (en) 2012-02-27 2021-10-19 Vertex Pharmaceuticals Incorporated Pharmaceutical composition and administrations thereof
US10058546B2 (en) 2012-07-16 2018-08-28 Vertex Pharmaceuticals Incorporated Pharmaceutical compositions of (R)-1-(2,2-difluorobenzo[D][1,3]dioxo1-5-y1)-N-(1-(2,3-dihydroxypropy1)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-y1)-1H-indol-5-y1) cyclopropanecarbox-amide and administration thereof
US20140277687A1 (en) * 2013-03-15 2014-09-18 Monosol Rx, Llc Process for drying a wet film with control of loss on drying
US9303918B2 (en) * 2013-03-15 2016-04-05 Monosol Rx, Llc Process for drying a wet film with control of loss on drying
US10231932B2 (en) 2013-11-12 2019-03-19 Vertex Pharmaceuticals Incorporated Process of preparing pharmaceutical compositions for the treatment of CFTR mediated diseases
US10980746B2 (en) 2014-04-15 2021-04-20 Vertex Pharmaceuticals Incorporated Pharmaceutical compositions for the treatment of cystic fibrosis transmembrane conductance regulator mediated diseases
US11951212B2 (en) 2014-04-15 2024-04-09 Vertex Pharmaceuticals Incorporated Pharmaceutical compositions for the treatment of cystic fibrosis transmembrane conductance regulator mediated diseases
US10206877B2 (en) 2014-04-15 2019-02-19 Vertex Pharmaceuticals Incorporated Pharmaceutical compositions for the treatment of cystic fibrosis transmembrane conductance regulator mediated diseases
US9701639B2 (en) 2014-10-07 2017-07-11 Vertex Pharmaceuticals Incorporated Co-crystals of modulators of cystic fibrosis transmembrane conductance regulator
US10302602B2 (en) 2014-11-18 2019-05-28 Vertex Pharmaceuticals Incorporated Process of conducting high throughput testing high performance liquid chromatography
US11034674B2 (en) 2015-05-11 2021-06-15 H. Lundbeck A/S Methods of treating inflammation or neuropathic pain
US10759721B2 (en) 2015-09-25 2020-09-01 Vertex Pharmaceuticals (Europe) Limited Deuterated CFTR potentiators
WO2017151725A1 (en) * 2016-03-03 2017-09-08 Nivalis Therapeutics, Inc. Formulations of an s-nitrosoglutathione reductase inhibitor
US10376501B2 (en) 2016-04-25 2019-08-13 Druggability Technologies Ip Holdco Limited Complexes of lumacaftor and its salts and derivatives, process for the preparation thereof and pharmaceutical compositions containing them
US10383865B2 (en) 2016-04-25 2019-08-20 Druggability Technologies Ip Holdco Limited Pharmaceutical combination composition comprising complex formulations of Ivacaftor and Lumacaftor and their salts and derivatives, process for their preparation thereof and pharmaceutical compositions containing them
WO2017187336A1 (en) 2016-04-25 2017-11-02 Druggability Technologies Ip Holdco Limited Complexes of ivacaftor and its salts and derivatives, process for the preparation thereof and pharmaceutical compositions containing them
WO2017187340A1 (en) 2016-04-25 2017-11-02 Druggability Technologies Ip Holdco Limited Pharmaceutical combination composition comprising complex formulations of ivacaftor and lumacaftor and their salts and derivatives, process for their preparation thereof and pharmaceutical compositions containing them
US10675277B2 (en) 2016-04-25 2020-06-09 Nangenex Nanotechnology Incorporated Complexes of ivacaftor and its salts and derivatives, process for the preparation thereof and pharmaceutical compositions containing them
US10206915B2 (en) 2016-04-25 2019-02-19 Druggability Technologies Ip Holdco Limited Complexes of Ivacaftor and its salts and derivatives, process for the preparation thereof and pharmaceutical compositions containing them
WO2017187338A1 (en) 2016-04-25 2017-11-02 Druggability Technologies Ip Holdco Limited Complexes of lumacaftor and its salts and derivatives, process for the preparation thereof and pharmaceutical compositions containing them
US11273159B2 (en) 2016-11-16 2022-03-15 H. Lundbeck A/S Pharmaceutical formulations
US11142517B2 (en) 2016-11-16 2021-10-12 H. Lundbeck A/S Crystalline forms of a MAGL inhibitor
AU2017361254B2 (en) * 2016-11-16 2021-09-23 H. Lundbeck A/S. Pharmaceutical formulations
US11993588B2 (en) 2016-11-16 2024-05-28 H. Lundbeck A/S Crystalline forms of a MAGL inhibitor
WO2018093950A1 (en) * 2016-11-16 2018-05-24 Abide Therapeutics, Inc. Pharmaceutical formulations
US12024491B2 (en) 2017-12-01 2024-07-02 Vertex Pharmaceuticals Incorporated Processes for making modulators of cystic fibrosis transmembrane conductance regulator
US11708331B2 (en) 2017-12-01 2023-07-25 Vertex Pharmaceuticals Incorporated Processes for making modulators of cystic fibrosis transmembrane conductance regulator
US11702393B2 (en) 2020-04-21 2023-07-18 H. Lundbeck A/S Synthesis of a monoacylglycerol lipase inhibitor
US12269831B2 (en) 2020-08-07 2025-04-08 Vertex Pharmaceuticals Incorporated Modulators of cystic fibrosis transmembrane conductance regulator
US12324802B2 (en) 2020-11-18 2025-06-10 Vertex Pharmaceuticals Incorporated Modulators of cystic fibrosis transmembrane conductance regulator

Also Published As

Publication number Publication date
UA117464C2 (uk) 2018-08-10
BR112015009913A2 (pt) 2017-07-11
RU2015120798A (ru) 2016-12-27
RS66596B1 (sr) 2025-04-30
HRP20181740T4 (hr) 2024-01-05
HRP20181740T1 (hr) 2018-12-28
TR201815218T4 (tr) 2018-11-21
AR093340A1 (es) 2015-06-03
AU2020204037B2 (en) 2023-10-19
PT3470063T (pt) 2025-03-10
DK2914248T4 (da) 2024-01-02
SI2914248T1 (sl) 2018-12-31
RS57831B2 (sr) 2024-02-29
EP4556008A3 (en) 2025-08-27
PL2914248T3 (pl) 2019-01-31
SMT202500078T1 (it) 2025-03-12
US20200338063A1 (en) 2020-10-29
CY1121070T1 (el) 2020-05-29
ES3009747T3 (en) 2025-03-31
DK2914248T3 (en) 2018-11-26
CN111671751A (zh) 2020-09-18
JP2015535289A (ja) 2015-12-10
EP2914248B1 (en) 2018-09-05
FI2914248T4 (fi) 2023-12-19
HUE070382T2 (hu) 2025-06-28
MX2019011662A (es) 2019-11-18
ES2694290T3 (es) 2018-12-19
PL3470063T3 (pl) 2025-04-14
FI3470063T3 (fi) 2025-03-05
EP2914248A1 (en) 2015-09-09
IL238551A0 (en) 2015-06-30
CL2015001148A1 (es) 2016-02-19
BR112015009913B1 (pt) 2023-04-11
JP2019142956A (ja) 2019-08-29
JP2022034069A (ja) 2022-03-02
AU2018229528A1 (en) 2018-10-11
SI2914248T2 (sl) 2023-12-29
EP3470063A1 (en) 2019-04-17
CA2890106A1 (en) 2014-05-08
SG10201913581UA (en) 2020-02-27
PL2914248T5 (pl) 2024-01-15
SG11201503365YA (en) 2015-06-29
NZ745659A (en) 2020-04-24
NZ708474A (en) 2019-02-22
EP2914248B2 (en) 2023-10-18
HUE039864T2 (hu) 2019-02-28
JP7003085B2 (ja) 2022-02-04
TW201842907A (zh) 2018-12-16
EP4556008A2 (en) 2025-05-21
MX368353B (es) 2019-09-30
RS57831B1 (sr) 2018-12-31
US20160324846A1 (en) 2016-11-10
JP2018090626A (ja) 2018-06-14
AU2020204037A1 (en) 2020-07-09
IL283276B2 (en) 2024-05-01
RU2692676C2 (ru) 2019-06-26
LT3470063T (lt) 2025-02-10
LT2914248T (lt) 2018-11-26
HRP20250100T1 (hr) 2025-03-28
KR20150080609A (ko) 2015-07-09
PT2914248T (pt) 2018-11-29
WO2014071122A1 (en) 2014-05-08
KR102396897B1 (ko) 2022-05-13
TWI736768B (zh) 2021-08-21
JP6302923B2 (ja) 2018-03-28
IL283276B1 (en) 2024-01-01
SMT201800590T1 (it) 2019-01-11
UA123631C2 (uk) 2021-05-05
AU2013337730A1 (en) 2015-06-11
IL238551B (en) 2021-06-30
CA2890106C (en) 2022-08-02
US20230364073A1 (en) 2023-11-16
SG10201703452PA (en) 2017-06-29
DK3470063T3 (da) 2025-01-20
EP3470063B1 (en) 2025-01-01
CN104869982A (zh) 2015-08-26
BR112015009913A8 (pt) 2019-09-17
AU2024200273A1 (en) 2024-02-01
SI3470063T1 (sl) 2025-04-30
RU2019117882A (ru) 2019-10-04
TW201422253A (zh) 2014-06-16
HK1212632A1 (en) 2016-06-17
ES2694290T5 (es) 2024-05-21
AU2013337730B2 (en) 2018-06-14
MX2015005559A (es) 2015-10-29
IL283276A (en) 2021-07-29

Similar Documents

Publication Publication Date Title
US20230364073A1 (en) Pharmaceutical compositions for the treatment of cftr mediated diseases
US20220354797A1 (en) Formulations of 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid
US10231932B2 (en) Process of preparing pharmaceutical compositions for the treatment of CFTR mediated diseases
RU2827711C2 (ru) Фармацевтические композиции для лечения заболеваний, опосредованных трансмембранным регулятором кистозного фиброза cftr
HK40006045A (en) Pharmaceutical compositions for the treatment of cftr mediated diseases
HK40006045B (en) Pharmaceutical compositions for the treatment of cftr mediated diseases
HK1212632B (en) Pharmaceutical compositions for the treatment of cftr mediated diseases
HK1227725A1 (en) Process of preparing pharmaceutical compositions for the treatment of cftr mediated diseases
HK1227725B (en) Process of preparing pharmaceutical compositions for the treatment of cftr mediated diseases

Legal Events

Date Code Title Description
AS Assignment

Owner name: VERTEX PHARMACEUTICALS INCORPORATED, MASSACHUSETTS

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:VERWIJS, MARINUS JACOBUS;KARKARE, RADHIKA;MOORE, MICHAEL DOUGLAS;SIGNING DATES FROM 20131108 TO 20131118;REEL/FRAME:031622/0077

AS Assignment

Owner name: MACQUARIE US TRADING LLC, NEW YORK

Free format text: SECURITY INTEREST;ASSIGNORS:VERTEX PHARMACEUTICALS INCORPORATED;VERTEX PHARMACEUTICALS (SAN DIEGO) LLC;REEL/FRAME:033292/0311

Effective date: 20140709

AS Assignment

Owner name: VERTEX PHARMACEUTICALS INCORPORATED, MASSACHUSETTS

Free format text: ASSIGNEE CHANGE OF ADDRESS;ASSIGNOR:VERTEX PHARMACEUTICALS INCORPORATED;REEL/FRAME:037781/0332

Effective date: 20100126

STCB Information on status: application discontinuation

Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION

AS Assignment

Owner name: VERTEX PHARMACEUTICALS INCORPORATED, MASSACHUSETTS

Free format text: RELEASE BY SECURED PARTY;ASSIGNOR:MACQUARIE US TRADING LLC;REEL/FRAME:040357/0001

Effective date: 20161013

Owner name: VERTEX PHARMACEUTICALS (SAN DIEGO) LLC, CALIFORNIA

Free format text: RELEASE BY SECURED PARTY;ASSIGNOR:MACQUARIE US TRADING LLC;REEL/FRAME:040357/0001

Effective date: 20161013