US20130186801A1 - Formulations of 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid - Google Patents

Formulations of 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid Download PDF

Info

Publication number
US20130186801A1
US20130186801A1 US13/750,069 US201313750069A US2013186801A1 US 20130186801 A1 US20130186801 A1 US 20130186801A1 US 201313750069 A US201313750069 A US 201313750069A US 2013186801 A1 US2013186801 A1 US 2013186801A1
Authority
US
United States
Prior art keywords
compound
tablet
microcrystalline cellulose
croscarmellose sodium
granule blend
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
US13/750,069
Other languages
English (en)
Inventor
Marinus Jacoubus Verwijs
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
Application filed by Vertex Pharmaceuticals Inc filed Critical Vertex Pharmaceuticals Inc
Priority to US13/750,069 priority Critical patent/US20130186801A1/en
Assigned to VERTEX PHARMACEUTICALS INCORPORATED reassignment VERTEX PHARMACEUTICALS INCORPORATED ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: VERWIJS, MARINUS JACOBUS
Publication of US20130186801A1 publication Critical patent/US20130186801A1/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 US15/093,582 priority patent/US20160324788A1/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 US15/655,354 priority patent/US20180008546A1/en
Priority to US16/523,493 priority patent/US20200085750A1/en
Priority to US17/174,764 priority patent/US20220354797A1/en
Abandoned legal-status Critical Current

Links

Images

Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/28Dragees; Coated pills or tablets, e.g. with film or compression coating
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61JCONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
    • A61J3/00Devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms
    • A61J3/10Devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms into the form of compressed tablets
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435Heterocyclic 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
    • A61K31/44Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/443Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with oxygen as a ring hetero atom
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435Heterocyclic 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
    • A61K31/47Quinolines; Isoquinolines
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435Heterocyclic 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
    • A61K31/47Quinolines; Isoquinolines
    • A61K31/4709Non-condensed quinolines and containing further heterocyclic rings
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12Carboxylic acids; Salts or anhydrides thereof
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38Cellulose; Derivatives thereof
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/0012Galenical forms characterised by the site of application
    • A61K9/0053Mouth and digestive tract, i.e. intraoral and peroral administration
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/14Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/14Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605Excipients; Inactive ingredients
    • A61K9/1617Organic compounds, e.g. phospholipids, fats
    • A61K9/1623Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/14Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605Excipients; Inactive ingredients
    • A61K9/1629Organic macromolecular compounds
    • A61K9/1652Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/2004Excipients; Inactive ingredients
    • A61K9/2013Organic compounds, e.g. phospholipids, fats
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/2004Excipients; Inactive ingredients
    • A61K9/2022Organic macromolecular compounds
    • A61K9/2027Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/2004Excipients; Inactive ingredients
    • A61K9/2022Organic macromolecular compounds
    • A61K9/205Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/2072Pills, 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
    • A61K9/2077Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/2095Tabletting 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
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/28Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806Coating materials
    • A61K9/2833Organic macromolecular compounds
    • A61K9/286Polysaccharides, e.g. gums; Cyclodextrin
    • A61K9/2866Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/10Laxatives
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/18Drugs for disorders of the alimentary tract or the digestive system for pancreatic disorders, e.g. pancreatic enzymes
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00Drugs for disorders of the respiratory system
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00Drugs for disorders of the respiratory system
    • A61P11/02Nasal agents, e.g. decongestants
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00Drugs for disorders of the respiratory system
    • A61P11/06Antiasthmatics
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00Drugs for genital or sexual disorders; Contraceptives
    • A61P15/10Drugs for genital or sexual disorders; Contraceptives for impotence
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00Drugs for skeletal disorders
    • A61P19/08Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00Drugs for skeletal disorders
    • A61P19/08Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00Drugs for disorders of the muscular or neuromuscular system
    • A61P21/02Muscle relaxants, e.g. for tetanus or cramps
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00Drugs for disorders of the muscular or neuromuscular system
    • A61P21/04Drugs for disorders of the muscular or neuromuscular system for myasthenia gravis
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • A61P25/08Antiepileptics; Anticonvulsants
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • A61P25/14Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • A61P25/14Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16Anti-Parkinson drugs
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • A61P25/28Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00Drugs for disorders of the senses
    • A61P27/02Ophthalmic agents
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00Drugs for disorders of the metabolism
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00Drugs for disorders of the metabolism
    • A61P3/06Antihyperlipidemics
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00Drugs for disorders of the metabolism
    • A61P3/08Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00Antineoplastic agents
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00Drugs for disorders of the endocrine system
    • A61P5/14Drugs for disorders of the endocrine system of the thyroid hormones, e.g. T3, T4
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00Drugs for disorders of the endocrine system
    • A61P5/18Drugs for disorders of the endocrine system of the parathyroid hormones
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00Drugs for disorders of the blood or the extracellular fluid
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00Drugs for disorders of the blood or the extracellular fluid
    • A61P7/10Antioedematous agents; Diuretics
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00Drugs for disorders of the cardiovascular system
    • A61P9/04Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2121/00Preparations for use in therapy

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), methods for manufacturing such compositions and methods for administering pharmaceutical compositions comprising same.
  • CFTR is a cAMP/ATP-mediated anion channel that is expressed in a variety of cells types, including absorptive and secretory epithelia cells, where it regulates anion flux across the membrane, as well as the activity of other ion channels and proteins. In epithelia cells, normal functioning of CFTR is critical for the maintenance of electrolyte transport throughout the body, including respiratory and digestive tissue.
  • CFTR is composed of approximately 1480 amino acids that encode a protein made up of a tandem repeat of transmembrane domains, each containing six transmembrane helices and a nucleotide binding domain. The two transmembrane domains are linked by a large, polar, regulatory (R)-domain with multiple phosphorylation sites that regulate channel activity and cellular trafficking.
  • CFTR cystic fibrosis
  • a defect in this gene causes mutations in CFTR resulting in cystic fibrosis (“CF”), the most common fatal genetic disease in humans. Cystic fibrosis affects approximately one in every 2,500 infants in the United States. Within the general United States population, up to 10 million people carry a single copy of the defective gene without apparent ill effects. In contrast, individuals with two copies of the CF associated gene suffer from the debilitating and fatal effects of CF, including chronic lung disease.
  • CF cystic fibrosis
  • the most prevalent mutation is a deletion of phenylalanine at position 508 of the CFTR amino acid sequence, and is commonly referred to as F508del-CFTR. This mutation occurs in approximately 70 percent of the cases of cystic fibrosis and is associated with a severe disease. Other mutations include the R117H and G551D.
  • F508del-CFTR in the membrane are functional, albeit less than wild-type CFTR.
  • F508del-CFTR other disease causing mutations in CFTR that result in defective trafficking, synthesis, and/or channel gating could be up- or down-regulated to alter anion secretion and modify disease progression and/or severity.
  • CFTR transports a variety of molecules in addition to anions
  • this role represents one element in an important mechanism of transporting ions and water across the epithelium.
  • the other elements include the epithelial Na + channel, ENaC, Na + /2Cl ⁇ /K + co-transporter, Na + -K + -ATPase pump and the basolateral membrane K + channels, that are responsible for the uptake of chloride into the cell.
  • Chloride absorption takes place by the coordinated activity of ENaC and CFTR present on the apical membrane and the Na + -K + -ATPase pump and Cl— channels expressed on the basolateral surface of the cell.
  • Secondary active transport of chloride from the luminal side leads to the accumulation of intracellular chloride, which can then passively leave the cell via Cl ⁇ channels, resulting in a vectorial transport.
  • Compound 1 in salt form is disclosed in International PCT Publication WO 2007056341 as a modulator of CFTR activity and thus as a useful treatment for CFTR-mediated diseases such as cystic fibrosis.
  • Compound 1 Form I which is substantially crystalline and salt-free, is disclosed in United States Published Patent Application US20090170905, filed Dec. 4, 2008.
  • Compound 1 Form II and Compound 1 HCl salt Form A are disclosed in United States Published Patent Application US20110263654, filed Apr. 7, 2011. All applications are incorporated in their entirety by reference herein.
  • Compound 1 as part of a combination with ivacaftor (N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide), 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 ivacaftor).
  • FDA Food and Drug Administration
  • This demonstrates a significant unmet need for the effective treatment of the cause of cystic fibrosis over symptomatic treatments.
  • 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 formulations and processes for preparing them in a continuous and controlled manner.
  • the invention relates to pharmaceutical compositions, pharmaceutical preparations, and solid dosage forms comprising 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid (Compound 1) which has the structure below:
  • the invention provides a pharmaceutical composition comprising:
  • a glidant or a binder f. a glidant or a binder.
  • Compound 1 is in substantially one of its crystalline solid forms. In one embodiment, Compound 1 is in substantially crystalline Form I (Compound 1 Form I). In one embodiment, Compound 1 is in substantially crystalline Form II (Compound 1 Form II). In one embodiment, Compound 1 is in substantially crystalline HCl salt form (Compound 1 HCl Salt Form A). It is understood that the term “Compound 1,” as used throughout, includes, amongst other forms, including non-crystalline forms, the following solid state forms: Compound 1 Form I, Compound 1 Form II, and/or Compound 1 HCl Salt Form A.
  • the pharmaceutical composition comprises 25 mg to 400 mg. In some embodiments, the pharmaceutical composition comprises 25 mg of Compound 1. In some embodiments, the pharmaceutical composition comprises 50 mg of Compound 1. In some embodiments, the pharmaceutical composition comprises 100 mg of Compound 1. In some embodiments, the pharmaceutical composition comprises 125 mg of Compound 1. In some embodiments, the pharmaceutical composition comprises 150 mg of Compound 1. In some embodiments, the pharmaceutical composition comprises 200 mg of Compound 1. In some embodiments, the pharmaceutical composition comprises 250 mg of Compound 1. In some embodiments, the pharmaceutical composition comprises 300 mg of Compound 1. In some embodiments, the pharmaceutical composition comprises 400 mg of Compound 1.
  • the invention provides a pharmaceutical composition comprising the following components:
  • roller Compact Granule Blend Compound 1 20-40 Microcrystalline cellulose 30-50 Mannitol 10-30 Croscarmellose Sodium 1-5 Sodium Lauryl Sulfate 0.1-2 Colloidal Silica 0.1-1 Magnesium Stearate 1-3 Tablet Composition Roller Compaction Granule Blend 99-99.9 Magnesium Stearate 0.1-1
  • the invention provides a pharmaceutical composition comprising the following components:
  • the invention provides a pharmaceutical composition comprising the following components:
  • the invention provides a pharmaceutical composition comprising the following components:
  • roller Compaction Granule Blend Compound 1 Form I 30 Microcrystalline cellulose 42.3 Mannitol 21.2 Croscarmellose Sodium 3 Sodium Lauryl Sulfate 1 Colloidal Silica 0.5 Magnesium Stearate 2 Table Composition Roller Compaction Granule Blend 99.5 Magnesium Stearate 0.5
  • the invention provides a pharmaceutical composition comprising the following components:
  • the invention provides a pharmaceutical composition comprising the following components:
  • the invention provides a pharmaceutical composition comprising the following components:
  • the invention provides a pharmaceutical composition comprising the following components:
  • High Shear Granule Blend (% w/w) Compound 1 Form I 60 Microcrystalline cellulose 20 Mannitol 13 Croscarmellose Sodium 2 Polyvinylpyrrolidone 4 Sodium Lauryl Sulfate 1 Tablet Composition (% w/w) High Shear Granule Blend 83 Microcrystalline cellulose 14 Croscarmellose Sodium 2 Magnesium Stearate 1
  • the invention provides a pharmaceutical composition comprising the following components:
  • Twin Screw Granule Blend (% w/w) Compound 1 Form I 60 Microcrystalline cellulose 20 Mannitol 13 Croscarmellose Sodium 2 Polyvinylpyrrolidone 4 Sodium Lauryl Sulfate 1 Tablet Composition (% w/w) Twin Screw Granule Blend 83 Microcrystalline cellulose 14 Croscarmellose Sodium 2 Magnesium Stearate 1
  • the invention provides a pharmaceutical composition comprising the following components:
  • Twin Screw Granule Blend (% w/w) Compound 1 Form I 80.0 Microcrystalline cellulose 13.6 Croscarmellose Sodium 2.5 Polyvinylpyrrolidone 3.1 Sodium Lauryl Sulfate 0.7 Tablet Composition (% w/w) Twin Screw Granule Blend 83 Microcrystalline cellulose 12 Croscarmellose Sodium 4 Magnesium Stearate 1
  • the invention provides a pharmaceutical composition comprising the following components:
  • Twin Screw Granule Blend (% w/w) Compound 1 Form I 80.0 Microcrystalline cellulose 13.6 Croscarmellose Sodium 2.5 Polyvinylpyrrolidone 3.1 Sodium Lauryl Sulfate 0.7 Tablet Composition (% w/w) Twin Screw Granule Blend 83 Microcrystalline cellulose 12 Croscarmellose Sodium 4 Magnesium Stearate 1 Film Coated Tablet (% w/w) Core Tablet Compostion 97 Film Coat 3 Wax Trace
  • the invention provides a pharmaceutical composition comprising the following components:
  • High Shear Granule Blend (% w/w) Compound 1 Form I 200 Microcrystalline cellulose 66 Mannitol 43 Croscarmellose Sodium 7 Polyvinylpyrrolidone 13 Sodium Lauryl Sulfate 03 Core Tablet Composition mg (200 mg dose) High Shear Granule Blend 332 Microcrystalline cellulose 56 Croscarmellose Sodium 8 Magnesium Stearate 4 Film Coated Tablet mg (200 mg dose) Core Tablet Compostion 400 Film Coat 12 Wax trace
  • the invention provides a pharmaceutical composition comprising the following components:
  • Twin Screw Granule Blend mg Compound 1 Form I 200 Microcrystalline cellulose 66 Mannitol 43 Croscarmellose Sodium 7 Polyvinylpyrrolidone 13 Sodium Lauryl Sulfate 3 Core Tablet Composition mg (200 mg dose) Twin Screw Granule Blend 332 Microcrystalline cellulose 56 Croscarmellose Sodium 8 Magnesium Stearate 4
  • the invention provides a pharmaceutical composition comprising the following components:
  • High Shear Granule Blend mg Compound 1 Form I 200 Microcrystalline cellulose 67 Mannitol 45 Croscarmellose Sodium 7 Polyvinylpyrrolidone 10.4 Sodium Lauryl Sulfate 2.6 Core Tablet Composition mg (200 mg dose) High Shear Granule Blend 332 Microcrystalline cellulose 56 Croscarmellose Sodium 8 Magnesium Stearate 4 Film Coated Tablet mg (200 mg dose) Core Tablet Composition 400 Film Coat 12 Wax trace
  • the invention provides a pharmaceutical composition comprising the following components:
  • High Shear Granule Blend mg Compound 1 Form I 300 Microcrystalline cellulose 99 Mannitol 64.5 Croscarmellose Sodium 10.5 Polyvinylpyrrolidone 19.5 Sodium Lauryl Sulfate 4.5 Core Tablet Composition mg (300 mg dose) High Shear Granule Blend 498 Microcrystalline cellulose 84 Croscarmellose Sodium 12 Magnesium Stearate 6 Film Coated Tablet mg (300 mg dose) Core Tablet Composition 600 Film Coat 18 Wax trace
  • the invention provides a pharmaceutical composition comprising the following components:
  • High Shear Granule Blend mg Compound 1 Form I 300 Microcrystalline cellulose 100.5 Mannitol 67.5 Croscarmellose Sodium 10.5 Polyvinylpyrrolidone 15.6 Sodium Lauryl Sulfate 3.9 Core Tablet Composition mg (300 mg dose) High Shear Granule Blend 498 Microcrystalline cellulose 84 Croscarmellose Sodium 12 Magnesium Stearate 6 Film Coated Tablet mg (300 mg dose) Core Tablet Composition 600 Film Coat 18 Wax trace
  • the invention provides a pharmaceutical composition comprising the following components:
  • High Shear Granule Blend (% w/w) Compound 1 Form I 70 Microcrystalline cellulose 12 Mannitol 11 Croscarmellose Sodium 2 Polyvinylpyrrolidone 4 Sodium Lauryl Sulfate 1 Tablet Composition (% w/w) High Shear Granule Blend 97.5 Croscarmellose Sodium 2.0 Magnesium Stearate 0.5
  • the invention provides a pharmaceutical composition comprising the following components:
  • High Shear Granule Blend (% w/w) Compound 1 Form I or Form II 61 Microcrystalline cellulose 20.3 Mannitol 13.2 Croscarmellose Sodium 2 Polyvinylpyrrolidone 2.7 Sodium Lauryl Sulfate 0.7 Tablet Composition (% w/w) High Shear Granule Blend 83 Microcryslalline cellulose 14 Croscarmellose Sodium 2 Magnesium Stearate 1
  • the invention provides a pharmaceutical composition comprising the following components:
  • High Shear Granule Blend mg Compound 1 Form I or Form II 100 Microcrystalline cellulose 33.3 Mannitol 21.7 Croscarmellose Sodium 3.3 Polyvinylpyrrolidone 4.4 Sodium Lauryl Sulfate 1.1 Core Tablet Composition mg (100 mg dose) High Shear Granule Blend 163.9 Microcrystalline cellulose 27.6 Croscarmellose Sodium 3.9 Magnesium Stearate 2.0
  • the invention provides a pharmaceutical composition comprising the following components:
  • Twin Screw Granule Blend mg Compound 1 Form I 200 Microcrystalline cellulose 34.0 Croscarmellose Sodium 6.3 Polyvinylpyrrolidone 7.8 Sodium Lauryl Sulfate 1.8 Core Tablet Composition mg (200 mg dose) Twin Screw Granule Blend 249.9 Microcrystalline cellulose 36.1 Croscarmellose Sodium 12.0 Magnesium Stearate 3.0
  • the invention provides a pharmaceutical composition comprising the following components:
  • Twin Screw Granule Blend mg Compound 1 Form I 400 Microcrystalline cellulose 68.0 Croscarmellose Sodium 12.6 Polyvinylpyrrolidone 15.6 Sodium Lauryl Sulfate 3.6 Core Tablet Composition mg (400 mg dose) Twin Screw Granule Blend 499.8 Microcrystalline cellulose 72.2 Croscarmellose Sodium 24.0 Magnesium Stearate 6.0
  • the invention provides a pharmaceutical composition comprising the following components:
  • Twin Screw Granule Blend mg Compound 1 Form I 200 Microcryslalline cellulose 34.0 Croscarmellose Sodium 6.3 Polyvinylpyrrolidone 7.8 Sodium Lauryl Sulfate 1.8 Core Tablet Composition mg (200 mg dose) Twin Screw Granule Blend 249.9 Microcrystalline cellulose 36.1 Croscarmellose Sodium 12.0 Magnesium Stearate 3.0 Film Coated Tablet mg (200 mg dose, 310 mg total) Core Tablet Composition 301 Film Coat 9.0 Wax trace
  • the invention provides a pharmaceutical composition comprising the following components:
  • Twin Screw Granule Blend mg Compound 1 Form I 400 Microcrystalline cellulose 68.0 Croscarmellose Sodium 12.6 Polyvinylpyrrolidone 15.6 Sodium Lauryl Sulfate 3.6 Core Tablet Composition (400 mg dose) mg Twin Screw Granule Blend 499.8 Microcrystalline cellulose 72.2 Croscarmellose Sodium 24.0 Magnesium Stearate 6.0 Film Coated Tablet (400 mg dose, 620 mg total) mg Core Tablet Composition 602 Film Coat 18.0 Wax trace
  • the invention provides a pharmaceutical composition in the form of a tablet that comprises Compound 1, and one or more pharmaceutically acceptable excipients, for example, a filler, a disintegrant, a surfactant, a diluent, a binder, a glidant, and a lubricant and any combination thereof, where the tablet has a dissolution of at least about 50% in about 30 minutes.
  • the dissolution rate is at least about 75% in about 30 minutes.
  • the dissolution rate is at least about 90% in about 30 minutes.
  • the tablet has a target friability of less than 1.0% after 400 revolutions.
  • the invention provides a pharmaceutical composition as described herein further comprising an additional therapeutic agent.
  • the additional therapeutic agent is N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide.
  • the invention provides a method of treating a CFTR mediated disease in a mammal comprising administering to the mammal an effective amount of a pharmaceutical composition as described herein.
  • the CFTR mediated disease is cystic fibrosis, emphysema, COPD, or osteoporosis.
  • the CFTR mediated disease is cystic fibrosis.
  • This method may further comprise administering an additional therapeutic agent, wherein in some embodiments, the additional therapeutic agent is selected from a mucolytic agent, bronchodilator, an anti-biotic, an anti-infective agent, an anti-inflammatory agent, a CFTR potentiator, or a nutritional agent.
  • the additional therapeutic agent is N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide.
  • the patient has a F508del-CFTR mutation.
  • the patient is homozygous for F508del.
  • the patient is heterozygous for F508del.
  • the invention features a kit comprising a tablet of the present invention, and a separate therapeutic agent or pharmaceutical composition thereof.
  • the Compound 1 in the tablet is in Form I.
  • the therapeutic agent is a cystic fibrosis corrector other than Compound 1.
  • the therapeutic agent is a cystic fibrosis potentiator.
  • the therapeutic agent is N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide.
  • the tablet and the therapeutic agent are in separate containers.
  • the separate containers are bottles.
  • the separate containers are vials.
  • the separate containers are blister packs.
  • the invention provides a process for making the pharmaceutical compositions described herein by a roller compaction process comprising the steps of screening and weighing Compound 1 and excipients; blending Compound 1 and excipients for a suitable amount of time; roller compacting the blend into ribbons and milling the ribbons into 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.
  • the invention provides a process for making the pharmaceutical compositions described herein by a high shear granulation process comprising the steps of screening and weighing Compound 1 and excipients; mixing Compound 1 and excipients while adding a granulation fluid comprising surfactant and a binder at a suitable mixing speed 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.
  • 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 and excipients; mixing Compound 1 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 and excipients; mixing Compound 1 and excipients in a blender and feeding the blend into a continuous granulator while adding a granulation fluid comprising surfactant and a binder at
  • 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. 3 is an X-ray powder diffraction pattern of Compound 1 Form II.
  • FIG. 4 provides X-ray diffraction patterns of Compound 1 Form II's selected from:
  • FIG. 5 provides an X-ray diffraction pattern of Compound 1 Form II, Methanol Solvate.
  • FIG. 6 provides an X-ray diffraction pattern of Compound 1 Form II, Ethanol Solvate.
  • FIG. 7 provides an X-ray diffraction pattern of Compound 1 Form II, Acetone Solvate.
  • FIG. 8 provides an X-ray diffraction pattern of Compound 1 Form II, 2-Propanol Solvate.
  • FIG. 9 provides an X-ray diffraction pattern of Compound 1 Form II, Acetonitrile Solvate.
  • FIG. 10 provides an X-ray diffraction pattern of Compound 1 Form II, Tetrahydrofuran Solvate.
  • FIG. 11 provides an X-ray diffraction pattern of Compound 1 Form II, Methyl Acetate Solvate.
  • FIG. 12 provides an X-ray diffraction pattern of Compound 1 Form II, 2-Butanone Solvate.
  • FIG. 13 provides an X-ray diffraction pattern of Compound 1 Form II, Ethyl Formate Solvate.
  • FIG. 14 provides an X-ray diffraction pattern of Compound 1 Form II, 2-Methyltetrahydrofuran Solvate.
  • FIG. 15 is a differential scanning calorimetry (DSC) trace of Compound 1 Form II, Acetone Solvate.
  • FIG. 16 is a Thermogravimetric analysis (TGA) plot of Compound 1 Form II, Acetone Solvate.
  • FIG. 17 is a conformational image of Compound 1 Form II, Acetone Solvate based on single crystal X-ray analysis.
  • FIG. 18 is a conformational image of the dimer of Compound 1 HCl Salt Form A.
  • FIG. 19 is an X-ray diffraction pattern of Compound 1 HCl Salt Form A calculated from the crystal structure.
  • FIG. 20 is an 1 HNMR spectrum of Compound 1.
  • FIG. 21 is an 1 HNMR spectrum of Compound 1 HCl salt.
  • FIG. 22 is a differential scanning calorimetry (DSC) trace of Compound 1 Form I.
  • FIG. 23 is a conformational picture of Compound 1 Form I based on single crystal X-ray analysis.
  • FIG. 24 is a conformational image of Compound 1 Form II, Acetone Solvate, based on single crystal X-ray analysis.
  • FIG. 25 is a solid state 13 C NMR spectrum (15.0 kHz spinning) of Compound 1 Form II, Acetone Solvate.
  • FIG. 26 is a solid state 19 F NMR spectrum (12.5 kHz spinning) of Compound 1 Form II, Acetone Solvate.
  • FIG. 27 is an X-ray diffraction pattern of Compound 1 HCl Salt Form A calculated from the crystal structure.
  • FIG. 28 is a graph depicting Compound 1 pH gradient dissolution profiles for a tablet made by a high shear granulation (HSG) process and a twin screw wet granulation (TSWG) process (LOD stands for loss on drying, a measure to define the amount of water in a powder/granule).
  • HSG high shear granulation
  • TSWG twin screw wet granulation
  • CTR cystic fibrosis transmembrane conductance regulator
  • a “ ⁇ F508” or “F508del” 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 particular phenylalanine.
  • a patient who is “homozygous” for a particular mutation e.g. F508del, has the same mutation on both alleles.
  • a patient who is “heterozygous” for a particular mutation e.g. F508del, has this mutation on one allele, and a different mutation on the other allele.
  • CFTR corrector refers to a compound that augments or induces the amount of functional CFTR protein to the cell surface, resulting in increased functional activity.
  • CFTR potentiator refers to a compound that augments or induces the channel activity of CFTR protein located at the cell surface, resulting in increased functional activity.
  • API active pharmaceutical ingredient
  • exemplary APIs include 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid (Compound 1).
  • solid form when used herein to refer to 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid (Compound 1), refer to a solid form e.g. crystals and the like, comprising Compound 1 which is not predominantly in a liquid or a gaseous state.
  • 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)).
  • composition generally refers to a composition of two or more components, usually one or more drugs (e.g., one drug (e.g., Compound 1 Form I, Compound 1 Form II, or Compound 1 HCl Salt Form A)) and one or more pharmaceutical excipients.
  • drugs e.g., one drug (e.g., Compound 1 Form I, Compound 1 Form II, or Compound 1 HCl Salt Form A)
  • pharmaceutical excipients e.g., one drug (e.g., Compound 1 Form I, Compound 1 Form II, or Compound 1 HCl Salt Form A)
  • solid dosage form generally refers to a pharmaceutical composition, which when used in an oral mode of administration include capsules, tablets, pills, powders and granules.
  • the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier.
  • an “excipient” includes functional and non-functional ingredients in a pharmaceutical composition.
  • a “disintegrant” is an excipient that hydrates a pharmaceutical composition and aids in tablet dispersion.
  • a “diluent” or “filler” is an excipient that adds bulkiness to a pharmaceutical composition.
  • a “surfactant” is an excipient that imparts pharmaceutical compositions with enhanced solubility and/or wettability.
  • 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 with a desired color.
  • examples of 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 pharmaceutical composition provided by the invention is purple.
  • 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 withhold 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 drug 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, Compound 1 Form II, or Compound 1 HCl Salt Form A,” 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. In certain embodiments, 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.
  • Compound 1 includes, but is not limited to, the solid forms of Compound 1 as described herein, e.g. Compound 1 Form I, Compound 1 Form II, or Compound 1 HCl Salt Form A, as well as combinations thereof.
  • the invention provides pharmaceutical compositions, pharmaceutical formulations and solid dosage forms comprising Compound 1 which may be in substantially crystalline form.
  • Compound 1 is in crystalline Form I (Compound 1 Form I).
  • Compound 1 is in crystalline Form II (Compound 1 Form II).
  • Compound 1 is in crystalline HCl salt form (Compound 1 HCl Salt Form A).
  • the amount of Compound 1 that is present in the pharmaceutical composition is 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 200 mg, 250 mg, or 400 mg.
  • weight/weight relative percent of Compound 1 that is present in the pharmaceutical composition is from 10 to 75 percent.
  • 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid is present as substantially pure Compound 1.
  • “Substantially pure” means greater than ninety percent pure; preferably greater than 95 percent pure; more preferably greater than 99.5 percent pure (i.e., not mixed with other crystalline forms of Compound 1).
  • the invention provides a pharmaceutical composition comprising:
  • a glidant or a binder g. a glidant or a binder.
  • the pharmaceutical composition comprises 25 mg of Compound 1. In another embodiment of this aspect, the pharmaceutical composition comprises 50 mg of Compound 1. In another embodiment of this aspect, the pharmaceutical composition comprises 100 mg of Compound 1. In another embodiment of this aspect, the pharmaceutical composition comprises 125 mg of Compound 1. In another embodiment of this aspect, the pharmaceutical composition comprises 150 mg of Compound 1. In another embodiment of this aspect, the pharmaceutical composition comprises 200 mg of Compound 1. In another embodiment of this aspect, the pharmaceutical composition comprises 250 mg of Compound 1. In another embodiment of this aspect, the pharmaceutical composition comprises 300 mg of Compound 1. In another embodiment of this aspect, the pharmaceutical composition comprises 400 mg of Compound 1.
  • the pharmaceutical compositions comprises Compound 1, wherein Compound 1 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 %, at least 60 wt %, or at least 70 wt %) by weight of the composition.
  • Compound 1 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 %, at least 60 wt %, or at least 70 wt %) by weight of the composition.
  • the pharmaceutical composition comprises Compound 1, a filler, a diluent, a disintegrant, a surfactant, a glidant, and a lubricant.
  • the composition comprises from about 20 wt % to about 50 wt % (e.g., about 25-35 wt %) of Compound 1 by weight of the composition, and more typically, from 25 wt % to about 45 wt % (e.g., about 28-32 wt %) of Compound 1 by weight of the composition.
  • the pharmaceutical composition comprises Compound 1, a filler, a diluent, a disintegrant, a surfactant, a binder, and a lubricant.
  • the composition comprises from about 30 wt % to about 60 wt % (e.g., about 40-55 wt %) of Compound 1 by weight of the composition, and more typically from 35 wt % to about 70 wt % (e.g., about 45-55 wt %) of Compound 1 by weight of the composition.
  • the concentration of Compound 1 in the composition depends on several factors such as the amount of pharmaceutical composition needed to provide a desired amount of Compound 1 and the desired dissolution profile of the pharmaceutical composition.
  • the pharmaceutical composition comprises Compound 1, in which Compound 1 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 is 1 micron to 5 microns.
  • Compound 1 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.
  • 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 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, 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; from about 0.1 wt % to about 5 wt % of a binder; from about 1 wt % to about 30 wt % of a diluent; from about 2 wt % to about 0.05 wt % of a glidant; and from about 5 wt % to about 0.1 wt % of a lubricant.
  • 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
  • the pharmaceutical composition comprises a composition containing from about 15 wt % to about 70 wt % (e.g., from about 20 wt % to about 40 wt %, from about 25 wt % to about 60 wt %, or from about 30 wt % to about 55 wt %) of Compound 1, by weight of the composition; and one or more 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; from about 0.1 wt % to about 5 wt % of a binder; from about 1 wt % to about 30 wt % of a diluent; from about 2 wt % to about 0.05 wt % of a glidant; and from about 5 wt
  • 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 by weight of the composition, and one or more 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; from about 0.1 wt % to about 5
  • 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 by weight of the composition, and one or more 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; from about 0.1 wt % to about 5
  • 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 and one or more 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; from about 0.1 wt % to about 5 wt % of
  • the invention is a granular pharmaceutical composition comprising:
  • Another granular composition formulated into an oral formulation of the invention comprises:
  • a pharmaceutical oral formulation of the invention comprises:
  • Another pharmaceutical oral formulation of the invention comprises:
  • Another pharmaceutical oral formulation of the invention comprises:
  • Another pharmaceutical oral formulation of the invention comprises:
  • magnesium stearate g. about 1 to 5 mg of magnesium stearate.
  • Another pharmaceutical oral formulation of the invention comprises:
  • magnesium stearate g. about 4 mg of magnesium stearate.
  • Another pharmaceutical oral formulation of the invention comprises:
  • magnesium stearate g. about 4 mg of magnesium stearate.
  • Another pharmaceutical oral formulation 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.
  • a shaped pharmaceutical tablet composition having an initial hardness of 5-21 kP ⁇ 20 percent comprises: about 30 wt % of Compound 1; about 42 wt % of microcrystalline cellulose by weight of the composition; about 21 wt % of mannitol by weight of the composition; about 3 wt % of sodium croscarmellose sodium by weight of the composition; about 1 wt % of sodium lauryl sulfate by weight of the composition; about 2.5 wt % of magnesium stearate by weight of the composition; and about 0.5 wt % of colloidal silica by weight of the composition.
  • the amount of Compound 1 in the shaped pharmaceutical tablet ranges from about 25 mg to about 250 mg, for example, 50 mg, or 75 mg, or 100 mg, or 150 mg, 200 mg, or 250 mg Compound 1 per tablet.
  • a shaped pharmaceutical tablet composition having an initial hardness of 5-21 kP ⁇ 20 percent comprises: about 49 wt % of a Compound 1; about 29 wt % of microcrystalline cellulose by weight of the composition; about 12.6 wt % of mannitol by weight of the composition; about 4 wt % of sodium croscarmellose sodium by weight of the composition; about 4 wt % of polyvinylpyrrolidone by weight of the composition; about 1 wt % of sodium lauryl sulfate by weight of the composition; and about 0.5 wt % of magnesium stearate by weight of the composition.
  • the amount of Compound 1 in the shaped pharmaceutical tablet ranges from about 25 mg to about 250 mg, for example, 50 mg, or 75 mg, or 100 mg, or 150 mg, 200 mg, or 250 mg Compound 1 per tablet.
  • the shaped pharmaceutical tablet contains about 100 mg of Compound 1. In certain embodiments, the shaped pharmaceutical tablet contains about 200 mg of Compound 1.
  • Another aspect of the invention provides a pharmaceutical formulation consisting of a tablet or capsule that includes a Compound 1 and other excipients (e.g., a filler, a disintegrant, a surfactant, a binder, a glidant, 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.
  • a Compound 1 e.g., a filler, a disintegrant, a surfactant, a binder, a glidant, a colorant, a lubricant, or any combination thereof
  • the pharmaceutical composition consists of a tablet that includes Compound 1 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, or 250 mg and one or more excipients (e.g., a filler, a disintegrant, a surfactant, a binder, a glidant, 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, a glidant, a colorant, a lubricant, or any combination thereof
  • the pharmaceutical composition consists of a tablet that comprises a composition comprising Compound 1; and one or more excipients from: a filler, a diluent, a disintegrant, a surfactant, a binder, a glidant, and a lubricant, 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.
  • a dissolution e.g., at least about 60%, at least about 70%, at least about 80%, at least about 90%, or at least about 99%
  • the tablet comprises a composition comprising at least about 25 mg (e.g., at least about 30 mg, at least about 40 mg, or at least about 50 mg) of Compound 1; and one or more excipients from: a filler, a diluent, a disintegrant, a surfactant, a binder, a glidant, and a lubricant.
  • a filler e.g., at least about 30 mg, at least about 40 mg, or at least about 50 mg
  • excipients from: a filler, a diluent, a disintegrant, a surfactant, a binder, a glidant, and a lubricant.
  • the tablet comprises a composition comprising at least about 25 mg (e.g., at least about 30 mg, at least about 40 mg, at least about 50 mg, at least about 100 mg, or at least 150 mg) of Compound 1 and one or more excipients from: a filler, a diluent, a disintegrant, a surfactant, a binder, a glidant, and a lubricant.
  • 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 the other solid state forms 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 carboxylic 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.
  • Scheme 4 depicts the coupling of 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarbonyl chloride with tert-butyl 3-(6-amino-3-methylpyridin-2-yl)benzoate using triethyl amine and 4-dimethylaminopyridine to initially provide the tert-butyl ester of Compound 1.
  • 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 appropriate solvent may be water or an alcohol/water mixture such as 50% methanol/water mixture, even though the HCl salt form of 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid is only sparingly soluble in water.
  • the appropriate solvent is water.
  • the effective amount of time for formation of 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 I. When the solvent is water, stirring the dispersion for approximately 24 hours at room temperature provides 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.
  • the temperature selected depends in part on the solvent used and is well within the determination capabilities of one of ordinary skill in the art. In one embodiment, the temperature is between room temperature and about 80° C. In another embodiment, the temperature is between room temperature and about 40° C. In another embodiment, the temperature is between about 40° C. and about 60° C. In another embodiment, the temperature is between about 60° C. and about 80° C.
  • Compound 1 Form I may also be formed directly from 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)-t-butylbenzoate (cf. Scheme 3), which is a precursor to the salt of Compound 1.
  • 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.
  • 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 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.
  • Compound 1 Form I is further characterized by a peak at 21.6 degrees. In another embodiment, Compound 1 Form I is further characterized by a peak at 23.1 to 23.5 degrees. In another embodiment, Compound 1 Form I is further characterized by a peak at 23.3 degrees. In some embodiments, Compound 1 Form I is characterized by a diffraction pattern substantially similar to that of FIG. 1 . In some embodiments, Compound 1 Form I is characterized by a diffraction pattern substantially similar to that of FIG. 2 .
  • 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 1 Form II is prepared by slurrying Compound 1 Form I in an appropriate solvent at a sufficient concentration for a sufficient time. The slurry is then filtered centrifugally or under vacuum and dried at ambient conditions for sufficient time to yield Compound 1 Form II.
  • about 20 to 40 mg of Compound 1 Form I is slurried in about 400 to 600 ⁇ L of an appropriate solvent. In another embodiment, about 25 to 35 mg of Compound 1 Form I is slurried in about 450 to 550 ⁇ L of an appropriate solvent. In another embodiment, about 30 mg of Compound 1 Form I is slurried in about 500 ⁇ L of an appropriate solvent.
  • the time that Compound 1 Form I is allowed to slurry with the solvent is from 1 hour to four days. More particularly, the time that Compound 1 Form I is allowed to slurry with the solvent is from 1 to 3 days. More particularly, the time is 2 days.
  • the appropriate solvent is selected from an organic solvent of sufficient size to fit the voids in the crystalline lattice of Compound 1 Form II. In other embodiments, the solvate is of sufficient size to fit in voids measuring about 100 ⁇ 3 .
  • the solvent is selected from the group consisting of methanol, ethanol, acetone, 2-propanol, acetonitrile, tetrahydrofuran, methyl acetate, 2-butanone, ethyl formate, and 2-methyl tetrahydrofuran.
  • Compound 1 Form II may be obtained from a mixture comprising one or more of these solvents and water.
  • the effective amount of time for drying Compound 1 Form II is 1 to 24 hours. More particularly, the time is 6 to 18 hours. More particularly, the time is about 12 hours.
  • Compound 1 Form II is prepared by dispersing or dissolving a salt form of Compound 1, such as an HCl salt of Compound 1 in an appropriate solvent for an effective amount of time.
  • Compound 1 Form II as disclosed herein comprises a crystalline lattice of Compound 1 in which voids in the crystalline lattice are empty, or occupied, or partially occupied by one or more molecules of a suitable solvent.
  • suitable solvents include, but are not limited to, methanol, ethanol, acetone, 2-propanol, acetonitrile, tetrahydrofuran, methyl acetate, 2-butanone, ethyl formate, and 2-methyl tetrahydrofuran.
  • Certain physical characteristics of Compound 1 isostructural solvate forms, such as X-ray powder diffraction, melting point and DSC, are not substantially affected by the particular solvent molecule in question.
  • Compound 1 Form II is characterized by one or more peaks at 21.50 to 21.90 degrees, 8.80 to 9.20 degrees, and 10.80 to 11.20 degrees in an X-ray powder diffraction obtained using Cu K alpha radiation.
  • Compound 1 Form II is characterized by one or more peaks at 21.50 to 21.90 degrees, 8.80 to 9.20 degrees, 10.80 to 11.20 degrees, 18.00 to 18.40 degrees, and 22.90 to 23.30 degrees in an X-ray powder diffraction obtained using Cu K alpha radiation.
  • Compound 1 Form II is characterized by one or more peaks at 21.70, 8.98, and 11.04 degrees.
  • Compound 1 Form II is characterized by one or more peaks at 21.70, 8.98, 11.04, 18.16, and 23.06 degrees. In another embodiment, Compound 1 Form II is characterized by a peak at 21.50 to 21.90 degrees. In another embodiment, Compound 1 Form II is further characterized by a peak at 21.70 degrees. In another embodiment, Compound 1 Form II is further characterized by a peak at 8.80 to 9.20 degrees. In another embodiment, Compound 1 Form II is further characterized by a peak at 8.98 degrees. In another embodiment, Compound 1 Form II is further characterized by a peak at 10.80 to 11.20 degrees. In another embodiment, Compound 1 Form II is further characterized by a peak at 11.04.
  • Compound 1 Form II is further characterized by a peak at 18.00 to 18.40 degrees. In another embodiment, Compound 1 Form II is further characterized by a peak at 18.16 degrees. In another embodiment, Compound 1 Form II is further characterized by a peak at 22.90 to 23.30 degrees. In another embodiment, Compound 1 Form II is further characterized by a peak at 23.06 degrees. In another embodiment, Compound 1 Form II is further characterized by a peak at 20.40 to 20.80 degrees. In another embodiment, Compound 1 Form II is further characterized by a peak at 20.63 degrees. In another embodiment, Compound 1 Form II is further characterized by a peak at 22.00 to 22.40 degrees.
  • Compound 1 Form II is further characterized by a peak at 22.22 degrees. In another embodiment, Compound 1 Form II is further characterized by a peak at 18.40 to 18.80 degrees. In another embodiment, Compound 1 Form II is further characterized by a peak at 18.57 degrees. In another embodiment, Compound 1 Form II is further characterized by a peak at 16.50 to 16.90 degrees. In another embodiment, Compound 1 Form II is further characterized by a peak at 16.66 degrees. In another embodiment, Compound 1 Form II is further characterized by a peak at 19.70 to 20.10 degrees. In another embodiment, Compound 1 Form II is further characterized by a peak at 19.86 degrees.
  • Compound 1 Form II is characterized by a diffraction pattern substantially similar to that of FIG. 3 . In some embodiments, Compound 1 Form II is characterized by diffraction patterns substantially similar to those provided in FIG. 4 .
  • the solvate that forms Compound 1 Form II is selected from the group consisting of methanol, ethanol, acetone, 2-propanol, acetonitrile, tetrahydrofuran, methyl acetate, 2-butanone, ethyl formate, and 2-methyl tetrahydrofuran. Diffraction patterns are provided for the following Compound 1 Form II: methanol ( FIG. 5 ), ethanol ( FIG. 6 ), acetone ( FIG. 7 ), 2-propanol ( FIG. 8 ), acetonitrile ( FIG. 9 ), tetrahydrofuran ( FIG. 10 ), methyl acetate ( FIG. 11 ), 2-butanone ( FIG. 12 ), ethyl formate ( FIG. 13 ), and 2-methyltetrahydrofuran ( FIG. 14 ).
  • the invention provides Compound 1 Form II which exhibits two or more phase transitions as determined by DSC or a similar analytic method known to the skilled artisan.
  • the DSC of Compound 1 Form II is substantially similar to the DSC trace depicted in FIG. 15 .
  • the DSC gives two phase transitions.
  • the DSC gives three phase transitions.
  • one of the phase transitions occurs between 200 and 207° C.
  • one of the phase transitions occurs between 204 and 206° C.
  • one of the phase transitions occurs between 183 and 190° C.
  • one of the phase transitions occurs between 185 and 187° C.
  • the melting point of Compound 1, Solvate Form A is between 183° C. to 190° C.
  • the melting point of Compound 1, Solvate Form A is between 185° C. to 187° C.
  • Compound 1 Form II comprises 1 to 10 weight percent (wt. %) solvate as determined by TGA. In some embodiments, the TGA of Compound 1 Form II is substantially similar to the TGA trace depicted in FIG. 16 . In another embodiment, Compound 1 Form II comprises 2 to 5 wt. % solvate as determined by TGA or a similar analytic method known to the skilled artisan.
  • the conformation of Compound 1 Form II acetone solvate is substantially similar to that depicted in FIG. 17 , which is based on single X-ray analysis.
  • Compound 1 Form II acetone solvate has a P2 1 /n space group, and the following unit cell dimensions:
  • Compound 1 HCl Salt Form A can be prepared from the HCl salt of Compound 1, by dissolving the HCl salt of Compound 1 in a minimum of solvent and removing the solvent by slow evaporation.
  • the solvent is an alcohol.
  • the solvent is ethanol.
  • Slow evaporation is generally carried out by impeding the evaporation of the solvent.
  • slow evaporation involves dissolving the HCl salt of Compound 1 in a vial and covering the vial with parafilm that contains a hole poked in it.
  • Compound 1 HCl Salt Form A is characterized by one or more peaks at 8.80 to 9.20 degrees, 17.30 to 17.70 degrees, and 18.20 to 18.60 degrees in an X-ray powder diffraction obtained using Cu K alpha radiation.
  • Compound 1 HCl Salt Form A is characterized by one or more peaks at 8.80 to 9.20 degrees, 17.30 to 17.70 degrees, 18.20 to 18.60 degrees, 10.10 to 10.50, and 15.80 to 16.20 degrees in an X-ray powder diffraction obtained using Cu K alpha radiation.
  • Compound 1 HCl Salt Form A is characterized by one or more peaks at 8.96, 17.51, and 18.45 degrees.
  • Compound 1 HCl Salt Form A is characterized by one or more peaks at 8.96, 17.51, 18.45. 10.33, and 16.01 degrees. In another embodiment, Compound 1 HCl Salt Form A is characterized by a peak at 8.80 to 9.20 degrees. In another embodiment, Compound 1 HCl Salt Form A is characterized by a peak at 8.96 degrees. In another embodiment, Compound 1 HCl Salt Form A is further characterized by a peak at 17.30 to 17.70 degrees. In another embodiment, Compound 1 HCl Salt Form A is characterized by a peak at 17.51 degrees. In another embodiment, Compound 1 HCl Salt Form A is further characterized by a peak at 18.20 to 18.60 degrees.
  • Compound 1 HCl Salt Form A is further characterized by a peak at 18.45 degrees. In another embodiment, Compound 1 HCl Salt Form A is further characterized by a peak at 10.10 to 10.50 degrees. In another embodiment, Compound 1 HCl Salt Form A is further characterized by a peak at 10.33 degrees. In another embodiment, Compound 1 HCl Salt Form A is further characterized by a peak at 15.80 to 16.20 degrees. In another embodiment, Compound 1 HCl Salt Form A is further characterized by a peak at 16.01 degrees. In another embodiment, Compound 1 HCl Salt Form A is further characterized by a peak at 11.70 to 12.10 degrees. In another embodiment, Compound 1 HCl Salt Form A is further characterized by a peak at 11.94 degrees.
  • Compound 1 HCl Salt Form A is further characterized by a peak at 7.90 to 8.30 degrees. In another embodiment, Compound 1 HCl Salt Form A is further characterized by a peak at 8.14 degrees. In another embodiment, Compound 1 HCl Salt Form A is further characterized by a peak at 9.90 to 10.30 degrees. In another embodiment, Compound 1 HCl Salt Form A is further characterized by a peak at 10.10 degrees. In another embodiment, Compound 1 HCl Salt Form A is further characterized by a peak at 16.40 to 16.80 degrees. In another embodiment, Compound 1 HCl Salt Form A is further characterized by a peak at 16.55 degrees.
  • Compound 1 HCl Salt Form A is further characterized by a peak at 9.30 to 9.70 degrees. In another embodiment, Compound 1 HCl Salt Form A is further characterized by a peak at 9.54 degrees. In another embodiment, Compound 1 HCl Salt Form A is further characterized by a peak at 16.40 to 16.80 degrees. In another embodiment, Compound 1 HCl Salt Form A is further characterized by a peak at 16.55 degrees. In some embodiments, Compound 1 HCl Salt Form A is characterized as a dimer as depicted in FIG. 18 .
  • Compound 1 HCl Salt Form A is characterized by a diffraction pattern substantially similar to that of FIG. 19 .
  • the invention features crystalline Compound 1 HCl Salt Form A having a P ⁇ 1 space group, and the following unit cell dimensions:
  • the dosage unit forms of the invention can be produced by 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.
  • dosage unit form 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 unit form 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 dosage forms of the invention comprise a rounded tablet having flat faces.
  • the solid pharmaceutical dosage forms 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. See, e.g., Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott Williams & Wilkins, Baltimore, Md. (2003); Ansel et al., Pharmaceutical Dosage Forms And Drug Delivery Systems, 7th Edition, Lippincott Williams & Wilkins, (1999); The Handbook of Pharmaceutical Excipients, 4 th edition, Rowe et al., Eds., American Pharmaceuticals Association (2003); Gibson, Pharmaceutical Preformulation And Formulation, CRC Press (2001), these references hereby incorporated herein by reference in their entirety.
  • solid forms including powders comprising the active agent Compound 1 and the included pharmaceutically acceptable excipients (e.g. filler, diluent, disintegrant, surfactant, glidant, binder, lubricant, or any combination thereof) can be subjected to a dry granulation process.
  • the dry granulation process causes the powder to agglomerate into larger particles having a size suitable for further processing. Dry granulation can improve the flowability of a mixture in order to be able to produce tablets that comply with the demand of mass variation or content uniformity.
  • Formulations as described herein may be produced using one or more mixing and dry granulations steps.
  • the order and the number of the mixing and granulation steps do not seem to be critical.
  • at least one of the excipients and Compound 1 can be been subject to dry granulation or wet high shear granulation before compression into tablets. Dry granulation of Compound 1 and the excipients made together prior to tablet compression seem, surprisingly, to be a simple, inexpensive and efficient way of providing close physical contact between the ingredients of the present compositions and formulations and thus results in a tablet formulation with good stability properties.
  • Dry granulation can be carried out by a mechanical process, which transfers energy to the mixture without any use of any liquid substances (neither in the form of aqueous solutions, solutions based on organic solutes, or mixtures thereof) in contrast to wet granulation processes, also contemplated herein.
  • the mechanical process requires compaction such as the one provided by roller compaction.
  • An example of an alternative method for dry granulation is slugging.
  • roller compaction is a granulation process comprising highly intensive mechanical compacting of one or more substances.
  • a pharmaceutical composition comprising an admixture of powders is pressed, that is roller compacted, between 2 counter rotating rollers to make a solid sheet which is subsequently crushed in a sieve to form a particulate matter. In this particulate matter, a close mechanical contact between the ingredients can be obtained.
  • roller compaction equipment is Minipactor® a Gerteis 3W-Polygran from Gerteis Maschinen+Processengineering AG.
  • tablet compression according to the invention can occur without any use of any liquid substances (neither in the form of aqueous solutions, solutions based on organic solutes, or mixtures thereof), i.e. a dry granulation process.
  • the resulting core or tablet has a compressive strength in the range of 1 to 15 kP; such as 1.5 to 12.5 kP, preferably in the range of 2 to 10 kP.
  • 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 and one or more excipients selected from: a filler, a diluent, a binder, a glidant, 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 and one or more excipients selected from: a filler, a diluent, a binder, a glidant, a surfactant, a lubricant, 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 or a twin screw 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 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.
  • 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 tetrachlorosilicate
  • FIG. 28 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 and Compound 1 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 may be prepared continuously according to the below flow chart.
  • 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, and any one or more of the excipients; a binder, a glidant, 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 ⁇ m or less)).
  • the admixture comprises a composition of Compound 1, a diluent, a glidant, a surfactant, 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 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 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)).
  • the admixture comprises a composition of Compound 1, a diluent, a binder, a surfactant, 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 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 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)
  • the admixture comprises a composition of Compound 1, and any combination of: a binder, a glidant, a diluent, a surfactant, a lubricant, a disintegrant, and a filler, wherein each of these ingredients is substantially free of water.
  • Each of the ingredients comprises less than 5 wt % (e.g., less than 2 wt %, less than 1 wt %, less than 0.75 wt %, less than 0.5 wt %, or less than 0.25 wt %) of water by weight of the ingredient.
  • the admixture comprises a composition of Compound 1, a diluent, a glidant, a surfactant, a lubricant, a disintegrant, and a filler, wherein each of these ingredients is substantially free of water.
  • each of the ingredients comprises less than 5 wt % (e.g., less than 2 wt %, less than 1 wt %, less than 0.75 wt %, less than 0.5 wt %, or less than 0.25 wt %) of water by weight of the ingredient.
  • 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 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 and one or more excipients selected from: a binder, a glidant, 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. Then the granular composition comprising Compound 1 can be compressed into tablets or formulated into capsules as described above or in the Examples below.
  • a solid forms e.g. an admixture of powdered and/or liquid ingredients
  • the admixture comprising Compound 1 and one or more excipients selected from: a binder, a glidant, a diluent, a surfactant, a lub
  • methods for producing a pharmaceutical composition comprises providing an admixture of Compound 1, and one or more excipients, e.g. a binder, a glidant, 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 roller compactor using a dry granulation composition as set forth in the Examples below or alternatively, compressed/compacted into granules 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 in addition to the selected excipients described herein.
  • the admixture is mixed by stirring, blending, shaking, or the like using hand mixing, a mixer, a blender, any combination thereof, or the like.
  • mixing can occur between successive additions, continuously throughout the ingredient addition, after the addition of all of the ingredients or combinations of ingredients, or any combination thereof.
  • the admixture is mixed until it has a substantially homogenous composition.
  • the present invention comprises jet milling Compound 1, Compound 1 Form I, Compound 1 Form II, Compound 1 HCl Salt Form A 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.
  • Compound 1, Compound 1 Form I, Compound 1 Form II, Compound 1 HCl Salt Form A has a particle size D50 of 2.0 microns.
  • a second therapeutic agent can be formulated together with Compound 1 to form a unitary or single dose form, for example, a tablet or capsule.
  • 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 or 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, or 400 mg of Compound 1.
  • the pharmaceutical compositions comprise a filler; a diluent; a disintegrant; a surfactant; at least one of a binder and a glidant; and a lubricant.
  • a dose of 400 mg of Compound 1 may comprise two tablets of the invention each containing 200 mg of Compound 1, or four tablets of the invention each containing 100 mg of Compound 1.
  • the compound and pharmaceutically acceptable compositions and formulations of the invention can be employed in combination therapies; that is, Compound 1 and pharmaceutically acceptable compositions thereof can be administered concurrently with, prior to, or subsequent to, one or more other desired therapeutics or medical procedures.
  • the particular combination of therapies (therapeutics or procedures) to employ in a combination regimen will take into account compatibility of the desired therapeutics and/or procedures and the desired therapeutic effect to be achieved.
  • the therapies employed may achieve a desired effect for the same disorder (for example, an inventive compound may be administered concurrently with another agent used to treat the same disorder), or they may achieve different effects (e.g., control of any adverse effects).
  • additional therapeutic agents that are normally administered to treat or prevent a particular disease for example, a CFTR mediated disease, or condition, are known as “appropriate for the disease or condition being treated.”
  • the additional therapeutic agent is selected from a mucolytic agent, bronchodialator, an antibiotic, an anti-infective agent, an anti-inflammatory agent, a CFTR modulator other than Compound 1 of the invention, 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 N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide.
  • the additional agent is selected from Table 1:
  • the additional agent is any combination of the above agents.
  • the composition may comprise Compound 1, (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, and N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide.
  • the composition may comprise Compound 1, N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide, and any one of the compounds from Table 1, i.e. compounds 1 through 14 of Table 1, or any combination thereof.
  • the additional therapeutic agent is an antibiotic.
  • antibiotics useful herein include tobramycin, including tobramycin inhaled powder (TIP), azithromycin, 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 CFTR modulator other than Compound 1, i.e., an agent that has the effect of modulating CFTR activity.
  • CFTR modulator other than Compound 1, i.e., an agent that has the effect of modulating CFTR activity.
  • 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).
  • 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 modulators 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.
  • 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 is trimethylangelicin. In another embodiment, the additional agent is a compound disclosed in WO 2012171954, incorporated herein in its entirety by reference.
  • the additional agent is a compound disclosed in WO 2004028480, WO 2004110352, WO 2005094374, WO 2005120497, or WO 2006101740.
  • the additional agent is a benzo[c]quinolizinium derivative that exhibits CFTR modulation activity or a benzopyran derivative that exhibits CFTR modulation 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.
  • the additional agent is N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide.
  • 600 mg of Compound 1 may be administered to a subject in need thereof followed by co-administration of 250 mg of N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide (Compound 2).
  • the dosage amounts may be achieved by administration of one or more tablets of the invention.
  • administration of 600 mg of Compound 1 may be achieved by administering three tablets each containing 200 mg of Compound 1, four tablets each containing 150 mg of Compound 1, or one table of 400 mg Compound 1 and one tablet of 200 mg Compound 1.
  • Compound 2 may be administered as a pharmaceutical composition comprising Compound 2 and a pharmaceutically acceptable carrier.
  • 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, or a month or longer.
  • the co-administration period may be preceded by an administration period of just Compound 1 alone. For example, there could be administration of 600 mg of Compound 1 for 2 weeks followed by co-administration of 250 mg of Compound 2 for 1 additional week. In another embodiment, 600 mg of Compound 1 may be administered bid (twice daily) for 28 days followed by 250 mg of Compound 2 administered bid (twice daily) for 28 days.
  • 600 mg of Compound 1 may be administered qd (once a day) for 28 days followed by 250 mg of Compound 2 administered qd (once a day) for 28 days.
  • 600 mg of Compound 1 may be administered qd (once a day) for 28 days followed by co-administration of 600 mg of Compound 1 qd (once a day) and 250 mg of Compound 2 q12 h (once every 12 hours) for 28 days.
  • 600 mg of Compound 1 may be administered qd (once a day) and 250 mg of Compound 2 administered qd (once a day).
  • 600 mg of Compound 1 may be administered to a subject in need thereof followed by co-administration of 450 mg of N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide (Compound 2).
  • the dosage amounts may be achieved by administration of one or more tablets of the invention.
  • administration of 600 mg of Compound 1 may be achieved by administering three tablets each containing 200 mg of Compound 1, or four tablets each containing 150 mg of Compound 1.
  • Compound 2 may be administered as a pharmaceutical composition comprising Compound 2 and a pharmaceutically acceptable carrier. 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, or a month or longer.
  • the co-administration period may be preceded by an administration period of just Compound 1 alone.
  • 600 mg of Compound 1 may be administered bid (twice daily) for 28 days followed by 450 mg of Compound 2 administered bid (twice daily) for 28 days.
  • 400 mg of Compound 1 may be administered to a subject in need thereof followed by co-administration of 350 mg of N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide (Compound 2).
  • the dosage amounts may be achieved by administration of one or more tablets of the invention.
  • administration of 400 mg of Compound 1 may be achieved by administering two tablets each containing 200 mg of Compound 1, or four tablets each containing 100 mg of Compound 1.
  • Compound 2 may be administered as a pharmaceutical composition comprising Compound 2 and a pharmaceutically acceptable carrier. 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, or a month or longer.
  • the co-administration period may be preceded by an administration period of just Compound 1 alone.
  • 400 mg of Compound 1 may be administered q8 h (every 8 hours) for 28 days followed by 350 mg of Compound 2 administered q8 h (every 8 hours) for 28 days.
  • 400 mg of Compound 1 may be administered to a subject in need thereof followed by co-administration of 250 mg of N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide (Compound 2).
  • the dosage amounts may be achieved by administration of one or more tablets of the invention.
  • administration of 400 mg of Compound 1 may be achieved by administering two tablets each containing 200 mg of Compound 1, or four tablets each containing 100 mg of Compound 1.
  • Compound 2 may be administered as a pharmaceutical composition comprising Compound 2 and a pharmaceutically acceptable carrier. 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, or a month or longer.
  • the co-administration period may be preceded by an administration period of just Compound 1 alone.
  • 400 mg of Compound 1 may be administered bid (twice daily) for 28 days followed by 250 mg of Compound 2 administered bid (twice daily) for 28 days.
  • 400 mg of Compound 1 may be administered bid (twice daily) for 28 days followed by 250 mg of Compound 2 administered qd (once daily) for 28 days.
  • 400 mg of Compound 1 may be administered qd (once a day) for 28 days followed by co-administration of 400 mg of Compound 1 qd (once a day) and 250 mg of Compound 2 q12 h (once every 12 hours) for 28 days.
  • 400 mg of Compound 1 may be administered bid (twice daily) and 250 mg of Compound 2 administered qd (once daily).
  • 400 mg of Compound 1 may be administered once a day to a subject in need thereof followed by co-administration of 150 mg of Compound 2 once a day.
  • the dosage amounts may be achieved by administration of one or more tablets of the invention.
  • administration of 400 mg of Compound 1 may be achieved by administering two tablets each containing 200 mg of Compound 1, or four tablets each containing 100 mg of Compound 1.
  • Compound 2 may be administered as a pharmaceutical composition comprising Compound 2 and a pharmaceutically acceptable carrier.
  • 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, or a month or longer.
  • the co-administration period may be preceded by an administration period of just Compound 1 alone. For example, there could be administration of 400 mg of Compound 1 for 2 weeks followed by co-administration of 150 mg or 250 mg of Compound 2 for 1 additional week.
  • 400 mg of Compound 1 may be administered once a day to a subject in need thereof followed by co-administration of 150 mg of Compound 2 every 12 hours. In another embodiment, 400 mg of Compound 1 may be administered once a day to a subject in need thereof followed by co-administration of 250 mg of Compound 2 every 12 hours. In these embodiments, the dosage amounts may be achieved by administration of one or more tablets of the invention. For example, administration of 400 mg of Compound 1 may be achieved by administering two tablets each containing 200 mg of Compound 1, or four tablets each containing 100 mg of Compound 1.
  • Compound 2 may be administered as a pharmaceutical composition comprising Compound 2 and a pharmaceutically acceptable carrier.
  • 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, or a month or longer.
  • the co-administration period may be preceded by an administration period of just Compound 1 alone. For example, there could be administration of 400 mg of Compound 1 for 2 weeks followed by co-administration of 150 mg or 250 mg of Compound 2 for 1 additional week.
  • 200 mg of Compound 1 may be administered qd (once a day) for 28 days followed by co-administration of 200 mg of Compound 1 qd (once a day) and 250 mg of Compound 2 q12 h (once every 12 hours) for 28 days.
  • the 100 mg, 200 mg, and 300 mg of Compound 1 tablets may be combined to form a number of different dosage amounts.
  • dosage amounts of 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1000 mg, 1100 mg, or 1200 mg of Compound 1 may be administered by using the 100 mg, 200 mg, and 300 mg tablet formulations and multiples thereof.
  • a dosage amount of 900 mg of Compound 1 may be administered using 3 300 mg tablets of Compound 1.
  • a dosage amount of 600 mg of Compound 1 may be administered using 3 200 mg tablets of Compound 1 or 2 300 mg tablets of Compound 1. Any of the preceding dosage amounts of this paragraph my be administered with the amounts of Compound 2 and/or dosage schedules of the preceding 3 paragraphs.
  • 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 features a kit comprising a tablet of the present invention, and a separate therapeutic agent or pharmaceutical composition thereof.
  • the Compound 1 in the tablet is in Form I.
  • the therapeutic agent is a cystic fibrosis corrector other than Compound 1.
  • the therapeutic agent is a cystic fibrosis potentiator.
  • the therapeutic agent is N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide.
  • the tablet and the therapeutic agent are in separate containers.
  • the separate containers are bottles.
  • the separate containers are vials.
  • the separate containers are blister packs.
  • 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 of the invention to the patient, 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, abetalipoproteinemia,
  • Compound 1 as part of a combination with ivacaftor (N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide), 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 ivacaftor).
  • FDA Food and Drug Administration
  • This demonstrates a significant unmet need for the effective treatment of the cause of cystic fibrosis over symptomatic treatments.
  • 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 formulations and processes for preparing them in a continuous and controlled manner.
  • 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 of the invention to the patient, 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, malignant hyperthermia, and catechol
  • 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 of the invention to the patient, 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 of the invention to the patient, wherein the patient possesses the CFTR genetic mutation G551D.
  • the patient is homozygous for G551D.
  • the patient is heterozygous for G551D wherein the other CFTR genetic mutation is any one of F508del, G542X, N1303K, W1282X, R117H, R553X, 1717-1G->A, 621+1G->T, 2789+5G->A, 3849+10kbC->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 F508del, G542X, N1303K, W1282X, R117H, R553X, 1717-1G->A, 621+1G->T, 2789+5G->A, 3849+10kbC->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 of the invention to the patient, wherein the patient possesses the CFTR genetic mutation F508del.
  • the patient is homozygous for F508del.
  • the patient is heterozygous for F508del wherein the other CFTR genetic mutation is any one of G551D, G542X, N 1303 K, W1282X, R117H, R553X, 1717-1G->A, 621+1G->T, 2789+5G->A, 3849+10kbC->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, N 1303 K, W1282X, R117H, R553X, 1717-1G->A, 621+1G->T, 2789+5G->A, 3849+10kbC->T, R1162X, G85E, 3120+1G->A, ⁇ I507, 1898
  • the pharmaceutically acceptable compositions of the present invention comprising Compound 1 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 pharmaceutical compositions comprising Compound 1 are useful for treating, lessening the severity of, or symptomatically treating cystic fibrosis in patients who exhibit little to no residual CFTR activity.
  • the pharmaceutical compositions comprising Compound 1 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.
  • a residual CFTR inducer or augmenter can be done 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 of the present invention comprising Compound 1, 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).
  • Class I mutations not synthesized
  • class II mutation misfolding
  • class III mutations impaired regulation or gating
  • class IV mutations altered conductance
  • class V mutations reduced synthesis
  • compositions of the present invention comprising Compound 1, 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 of the present invention comprising Compound 1, 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 of the present invention comprising Compound 1, 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
  • Sjögren's Syndrome a chronic obstructive pulmonary disease
  • COPD chronic obstructive pulmonary disease
  • CFTR dry eye disease
  • Sjögren'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 Sjögrens'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.
  • Sjögrens'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 a pharmaceutical composition of the present invention.
  • the anion channel is a chloride channel or a bicarbonate channel.
  • 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.
  • XRD X-Ray diffraction
  • Unmicronized Compound 1, Compound 1 Form I, Compound 1 Form II, or Compound 1 HCl Salt Form A is sieved to de-lump it prior to placing it into the jet mill hopper. All sieves are disposable and received a wipe prior to use. Unmicronized Compound 1, Compound 1 Form I, Compound 1 Form II, or Compound 1 HCl Salt Form A is added to the jet mill hopper at a controlled feeding rate using compressed nitrogen gas.
  • the gas pressure range is 40-45/45-70 (Venturi/Mill) PSI and the feeding rate range is 0.5-1.6 Kg/Hour.
  • the Compound 1, Compound 1 Form I, Compound 1 Form II, or Compound 1 HCl Salt Form A is micronized in the mill through particle-particle and particle-wall collisions and the processed Compound 1, Compound 1 Form I, Compound 1 Form II, or Compound 1 HCl Salt Form A is emptied into the micronized product containers. It is believed that one of ordinary skill in the art may also achieve Compound 1, Compound 1 Form I, Compound 1 Form II, or Compound 1 HCl Salt Form A with a favorable particle size through pin milling based in part on the conditions described above.
  • 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.
  • tert-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. 20 An 1 HNMR spectrum of Compound 1 is shown in FIG. 20 and FIG. 21 depicts an 1 HNMR spectrum of Compound 1 as an HCl salt.
  • the DSC trace of Compound 1 Form I is shown in FIG. 22 . 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. 23 A conformational picture of Compound 1 Form I based on single crystal X-ray analysis is shown in FIG. 23 .
  • Density of Compound 1 Form I calculated from structural data is 1.492 g/cm 3 at 100 K.
  • Compound 1 Form I (approximately 30 mg) was slurried in 500 ⁇ L of an appropriate solvent (for example, methanol, ethanol, acetone, 2-propanol, acetonitrile, tetrahydrofuran, methyl acetate, 2-butanone, ethyl formate, and -methyl tetrahydrofuran for two days. The slurry was then filtered centrifugally or under vacuum and was left to dry at ambient temperature overnight to yield Compound 1 Form II.
  • an appropriate solvent for example, methanol, ethanol, acetone, 2-propanol, acetonitrile, tetrahydrofuran, methyl acetate, 2-butanone, ethyl formate, and -methyl tetrahydrofuran
  • the DSC trace of Compound 1 Form II Acetone Solvate is shown in FIG. 15 , showing two phase transitions.
  • the melting point for Compound 1 Form II Acetone Solvate occurs at about 188° C. and 205° C.
  • FIG. 3 An actual X-ray powder diffraction pattern of Compound 1 Form II is shown in FIG. 3 .
  • Table 5 lists the actual peaks for FIG. 3 in descending order of relative intensity.
  • FIG. 24 Conformational depictions of Compound 1 Form II Acetone Solvate based on single crystal X-ray analysis are shown in FIG. 24 .
  • the stoichiometry between Compound 1 Form II and acetone is approximately 4.4:1 (4.48:1 calculated from 1 H NMR; 4.38:1 from X-ray).
  • the crystal structure reveals a packing of the molecules where there are two voids or pockets per unit cell, or 1 void per host molecule.
  • approximately 92 percent of voids are occupied by acetone molecules.
  • the density of Compound 1 in Compound 1 Form II calculated from structural data is 1.430/cm 3 at 100 K.
  • FIG. 26 A solid state 19 F NMR spectrum of Compound 1 Form II Acetone Solvate is shown in FIG. 26 . Peaks with an asterisk denote spinning side bands. Table 7 provides chemical shifts of the relevant peaks.
  • Colorless crystals of Compound 1 HCl Salt Form A were obtained by slow evaporation from a concentrated solution of the HCl salt of Compound 1 in ethanol.
  • a crystal with dimensions of 0.30 ⁇ 1 ⁇ 5 ⁇ 0.15 mm was selected, cleaned using mineral oil, mounted on a MicroMount and centered on a Bruker APEXII diffractometer.
  • 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.
  • FIG. 18 provides a conformational image of Compound 1 HCl Salt Form A as a dimer, based on single crystal analysis.
  • An X-ray diffraction pattern of Compound 1 HCl Salt Form A calculated from the crystal structure is shown in FIG. 27 .
  • Table 8 contains the calculated peaks for FIG. 27 in descending order of relative intensity.
  • a tablet was prepared with the components and amounts listed in Table 9 for Exemplary Tablet 1A comprising 100 mg of API, i.e. Compound 1 Form I.
  • Exemplary Tablet 1A (formulated to have 100 mg of Compound 1) is prepared using a dry roller compaction device formulation process.
  • grades/brands were microcrystalline cellulose: Avicel PH102; mannitol: Pearlitol SD 100; croscarmellose sodium: Acdisol; and colloidal silica: Cabosil.
  • roller Compaction Granule Blend (% w/w) Compound 1 Form I 30 Microcrystalline cellulose 42.3 Mannitol 21.2 Croscarmellose Sodium 3 Sodium Lauryl Sulfate 1 Colloidal Silica 0.5 Magnesium Stearate 2 Tablet Composition (100 mg dose, 335 mg image) (% w/w) Roller Compaction Granule Blend 99.5 Magnesium Stearate 0.5
  • a tablet was prepared with the components and amounts listed in Table 10 for Exemplary Tablet 1B comprising 100 mg of API, i.e. Compound 1 Form I.
  • Exemplary Tablet 1B (formulated to have 100 mg of Compound 1 Form I) is prepared using a wet high shear granule formulation process.
  • grades/brands were as follows. High Shear Granule Blend—microcrystalline cellulose: Avicel PH101; mannitol: Pearlitol C50; croscarmellose sodium: Acdisol; polyvinylpyrrolidone: Kollidon PVP K30; and in the Tablet Composition—croscarmellose sodium: Acdisol.
  • a tablet was prepared with the components and amounts listed in Table 11 for Exemplary Tablet 1C comprising 100 mg of API, i.e. crystalline Compound 1 Form I.
  • Exemplary Tablet 1C (formulated to have 100 mg of crystalline Compound 1 Form I) is prepared using a wet high shear granule formulation process.
  • grades/brands were as follows. High Shear Granule Blend—microcrystalline cellulose: Avicel PH101; mannitol: Pearlitol C50; croscarmellose sodium: Acdisol; polyvinylpyrrolidone: Kollidon PVP K30; and in the Tablet Composition—croscarmellose sodium: Acdisol.
  • a tablet was prepared with the components and amounts listed in Table 12 for Exemplary Tablet 1D comprising 200 mg of API, i.e. crystalline Compound 1 Form I.
  • Exemplary Tablet 1D (formulated to have 200 mg of crystalline Compound 1 Form I) is prepared using a wet high shear granule formulation process.
  • grades/brands were as follows.
  • High Shear Granule Blend microcrystalline cellulose: Avicel PH101; mannitol: Pearlitol C50; croscarmellose sodium: Acdisol; polyvinylpyrrolidone: Kollidon PVP K30; and in the Tablet Composition—microcrystalline cellulose: Avicel PH200; croscarmellose sodium: Acdisol; and magnesium stearate: 5712.
  • a tablet was prepared with the components and amounts listed in Table 13 for Exemplary Tablet 1E comprising 200 mg of API, i.e. crystalline Compound 1 Form I.
  • Exemplary Tablet 1E (formulated to have 200 mg of crystalline Compound 1 Form I) is prepared using a wet high shear granule formulation process.
  • grades/brands were as follows.
  • High Shear Granule Blend microcrystalline cellulose: Avicel PH101; mannitol: Pearlitol C50; croscarmellose sodium: Acdisol; polyvinylpyrrolidone: Kollidon PVP K30; and in the Core Tablet Composition—microcrystalline cellulose: Avicel PH200; croscarmellose sodium: Acdisol; and magnesium stearate: 5712; and in the film coat—film coat: Opadry II; wax: Carnauba.
  • a tablet was prepared with the components and amounts listed in Table 14 for Exemplary Tablet 1F comprising 200 mg of API, i.e. crystalline Compound 1 Form I.
  • Exemplary Tablet 1F (formulated to have 200 mg of crystalline Compound 1 Form I) is prepared using a wet high shear granule formulation process.
  • grades/brands were as follows.
  • High Shear Granule Blend microcrystalline cellulose: Avicel PH101; mannitol: Pearlitol C50; croscarmellose sodium: Acdisol; polyvinylpyrrolidone: Kollidon PVP K30; and in the Core Tablet Composition—microcrystalline cellulose: Avicel PH200; croscarmellose sodium: Acdisol; and magnesium stearate: 5712; and in the film coat—film coat: Opadry II; wax: Carnauba.
  • a tablet was prepared with the components and amounts listed in Table 15 for Exemplary Tablet 1G comprising 100 mg of API, i.e. crystalline Compound 1 Form I.
  • Exemplary Tablet 1G (formulated to have 100 mg of crystalline Compound 1 Form I) is prepared using a wet high shear granule formulation process.
  • grades/brands were as follows. High Shear Granule Blend—microcrystalline cellulose: Avicel PH101; mannitol: Pearlitol C50; croscarmellose sodium: Acdisol; polyvinylpyrrolidone: Kollidon PVP K30; and in the Tablet Composition—croscarmellose sodium: Acdisol.
  • a tablet was prepared with the components and amounts listed in Table 16 for Exemplary Tablet 1H comprising 100 mg of API, i.e. crystalline Compound 1 Form I or Form II.
  • Exemplary Tablet 1H (formulated to have 100 mg of crystalline Compound 1 Form I or Form II) is prepared using a wet high shear granule formulation process.
  • grades/brands were as follows.
  • High Shear Granule Blend microcrystalline cellulose: Avicel PH101; mannitol: Pearlitol C50; croscarmellose sodium: Acdisol; polyvinylpyrrolidone: Kollidon PVP K30; and in the Core Tablet Composition—microcrystalline cellulose: Avicel PH200; croscarmellose sodium: Acdisol; and magnesium stearate: 5712.
  • a tablet was prepared with the components and amounts listed in Table 17 for Exemplary Tablet II comprising 100 mg of API, i.e. crystalline Compound 1 Form I or Form II.
  • Exemplary Tablet II (formulated to have 100 mg of crystalline Compound 1 Form I or Form II) is prepared using a wet high shear granule formulation process.
  • grades/brands were as follows.
  • High Shear Granule Blend microcrystalline cellulose: Avicel PH101; mannitol: Pearlitol C50; croscarmellose sodium: Acdisol; polyvinylpyrrolidone: Kollidon PVP K30; and in the Core Tablet Composition—microcrystalline cellulose: Avicel PH200; croscarmellose sodium: Acdisol; and magnesium stearate: 5712.
  • a tablet was prepared with the components and amounts listed in Table 18 for Exemplary Tablet 1J comprising 300 mg of API, i.e. crystalline Compound 1 Form I.
  • Exemplary Tablet 1J (formulated to have 300 mg of crystalline Compound 1 Form I) is prepared using a wet high shear granule formulation process.
  • grades/brands were as follows.
  • High Shear Granule Blend microcrystalline cellulose: Avicel PH101; mannitol: Pearlitol C50; croscarmellose sodium: Acdisol; polyvinylpyrrolidone: Kollidon PVP K30; and in the Core Tablet Composition—microcrystalline cellulose: Avicel PH200; croscarmellose sodium: Acdisol; and magnesium stearate: 5712; and in the film coat—film coat: Opadry II; wax: Carnauba.
  • a tablet was prepared with the components and amounts listed in Table 19 for Exemplary Tablet 1K comprising 300 mg of API, i.e. crystalline Compound 1 Form I.
  • Exemplary Tablet 1K (formulated to have 300 mg of crystalline Compound 1 Form I) is prepared using a wet high shear granule formulation process.
  • grades/brands were as follows.
  • High Shear Granule Blend microcrystalline cellulose: Avicel PH101; mannitol: Pearlitol C50; croscarmellose sodium: Acdisol; polyvinylpyrrolidone: Kollidon PVP K30; and in the Core Tablet Composition—microcrystalline cellulose: Avicel PH200; croscarmellose sodium: Acdisol; and magnesium stearate: 5712; and in the film coat—film coat: Opadry II; wax: Carnauba.
  • a tablet was prepared with the components and amounts listed in Table 20 for Exemplary Tablet 1L comprising 200 mg of API, i.e. crystalline Compound 1 Form I.
  • Exemplary Tablet 1L (formulated to have 200 mg of crystalline Compound 1 Form I) is prepared using a twin screw wet granulation formulation process.
  • grades/brands were as follows.
  • Twin Screw Granule Blend microcrystalline cellulose: Avicel PH101; croscarmellose sodium: Acdisol; polyvinylpyrrolidone: Kollidon PVP K30; and in the Core Tablet Composition—microcrystalline cellulose: Avicel PH200; croscarmellose sodium: Acdisol; and magnesium stearate: 5712; and in the film coat—film coat: Opadry II; wax: Carnauba.
  • a tablet was prepared with the components and amounts listed in Table 21 for Exemplary Tablet 1M comprising 400 mg of API, i.e. crystalline Compound 1 Form I.
  • Exemplary Tablet 1M (formulated to have 400 mg of crystalline Compound 1 Form I) is prepared using a twin screw wet granule formulation process.
  • grades/brands were as follows.
  • Twin Screw Granule Blend microcrystalline cellulose: Avicel PH101; croscarmellose sodium: Acdisol; polyvinylpyrrolidone: Kollidon PVP K30; and in the Core Tablet Composition—microcrystalline cellulose: Avicel PH200; croscarmellose sodium: Acdisol; and magnesium stearate: 5712; and in the film coat—film coat: Opadry II; wax: Carnauba.
  • Roller Compactors Alexanderwerk WP 120, Vector TF-Mini, or Vector TF-Labo.
  • Compound 1 and excipients may be screened prior to or after weigh-out. Appropriate 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 or a v-shell blender.
  • the components may be blended for 10 minutes without lubricant followed by additional blending with lubricant for 3 minutes.
  • the blend may be roller compacted in ribbons and milled into granules using an Alexanderwerk WP 120.
  • the rolls used may be the 25 mm rolls using a compaction pressure of 18 to 50 bar, a roller speed of 3 to 12 RPM, and a screw feeder speed of 20 to 80 RPM.
  • the screen sizes of the integrated mill may be 2 mm for the top screen and 0.8 mm for the bottom screen.
  • the roller compacted granules may be blended with extra-granular excipients such as fillers and lubricant using a V-shell blender.
  • the blending time may be 5, 3 or 1 minute(s).
  • the compression blend has been compressed into tablets using a single station Riva MiniPress with 10 mm tooling.
  • the weight of the tablets for a 100 mg dose may be about 200, 250, or 300 mg.
  • 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.
  • Granulator Procept MiPro with a 250 ml or 1 L granulation bowl.
  • 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.
  • 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.
  • Granulation The excipients and compound 1 are added to the granulation bowl.
  • the order of addition may be Compound 1, disintegrant, diluent, and filler.
  • the components may be mixed in the 250 ml bowl for 1 minute at impeller speed 1000 RPM and chopper speed 1000 RPM.
  • Granulation may be performed at an impeller speed of 2000 RPM with a chopper speed of 4000 RPM while adding the granulation fluid with a syringe pump at 1.5 to 4.5 g/min.
  • the fluid addition time may be 4 to 12 minutes.
  • the granules may be wet-massed for about 10 seconds to about 1 minute.
  • One notable advantage of the present high shear 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.
  • the granules may be reduced in size using a screen mill or a cone mill.
  • the granules may be dried using a vacuum oven, tray dryer, bi-conical dryer, or fluid bed drier.
  • the granules have been dried using a vacuum oven with a nitrogen purge.
  • the granules may be blended with extra-granular excipients.
  • the granules have been blended with extra-granular disintegrant, diluent, filler, and lubricant.
  • the granules have been blended using the Turbula blender for 3 minutes pre-lubricant and 1 minute with lubricant.
  • a larger scale blender such as a 4-quart V-shell blender may be used.
  • the compression blend has been compressed into tablets using a single station Riva MiniPress with 8 mm, or 10 mm tooling.
  • the weight of the tablets for a 100 mg dose may be about 160, 200, or 250 mg.
  • 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.
  • 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 reduced in size using a screen mill or a cone mill
  • 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 invention relates to a method of treating a CFTR mediated disease in a subject comprising administering to a subject in need thereof an effective amount of the pharmaceutical composition provided by the invention.
  • the pharmaceutical composition is administered to the subject once every two weeks.
  • the pharmaceutical composition is administered to the subject once a week.
  • the pharmaceutical composition is administered to the subject once every three days.
  • the pharmaceutical composition is administered to the subject once a day.
  • 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.
  • a double-addition HTS assay format was developed. During the first addition, a CY-free medium with or without test compound was added to each well. After 22 sec, a second addition of CY-free medium containing 2-10 ⁇ M forskolin was added to activate F508del-CFTR. The extracellular CY concentration following both additions was 28 mM, which promoted CY efflux in response to F508del-CFTR activation and the resulting membrane depolarization was optically monitored using the FRET-based voltage-sensor dyes.
  • 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 are substituted with gluconate salts.
  • CC2-DMPE Prepared as a 10 mM stock solution in DMSO and stored at ⁇ 20° C.
  • DiSBAC 2 (3) Prepared as a 10 mM stock in DMSO and stored at ⁇ 20° C.
  • NIH3T3 mouse fibroblasts stably expressing F508del-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, 13-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.
  • 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. Under these conditions, the current reflects the flow of Cl ⁇ through F508del-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 F508del-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 F508del-CFTR potentiators was compared to that of the known potentiator, genistein.
  • Basolateral solution in mM: NaCl (135), CaCl 2 (1.2), MgCl 2 (1.2), K 2 HPO 4 (2.4), KHPO 4 (0.6), N-2-hydroxyethylpiperazine-N′-2-ethanesulfonic acid (HEPES) (10), and dextrose (10).
  • the solution was titrated to pH 7.4 with NaOH.
  • FRT Fisher rat epithelial cells expressing F508del-CFTR
  • FRT ⁇ F508-CFTR Fisher rat epithelial cells expressing F508del-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 F508del-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 F508del-CFTR current (I ⁇ F508 ) in temperature- and test compound-corrected NIH3T3 cells stably expressing F508del-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.
  • F508del-CFTR potentiators to increase the macroscopic F508del-CFTR Cl ⁇ current (I ⁇ F508 ) in NIH3T3 cells stably expressing F508del-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).
  • Intracellular solution in mM: Cs-aspartate (90), CsCl (50), MgCl 2 (1), HEPES (10), and 240 ⁇ g/ml amphotericin-B (pH adjusted to 7.35 with CsOH).
  • Extracellular solution (in mM): N-methyl- D -glucamine (NMDG)-Cl (150), MgCl 2 (2), CaCl 2 (2), HEPES (10) (pH adjusted to 7.35 with HCl).
  • NIH3T3 mouse fibroblasts stably expressing F508del-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 F508del-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 F508del-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 F508del-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 F508del-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).
  • Extracellular solution (in mM): NMDG (150), aspartic acid (150), CaCl 2 (5), MgCl 2 (2), and HEPES (10) (pH adjusted to 7.35 with Tris base).
  • Intracellular solution in mM: NMDG-Cl (150), MgCl 2 (2), EGTA (5), TES (10), and Tris base (14) (pH adjusted to 7.35 with HCl).
  • NIH3T3 mouse fibroblasts stably expressing F508del-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, 13-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.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Diabetes (AREA)
  • Neurology (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Biomedical Technology (AREA)
  • Neurosurgery (AREA)
  • Hematology (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Pulmonology (AREA)
  • Endocrinology (AREA)
  • Molecular Biology (AREA)
  • Biophysics (AREA)
  • Rheumatology (AREA)
  • Obesity (AREA)
  • Cardiology (AREA)
  • Pain & Pain Management (AREA)
  • Psychology (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Inorganic Chemistry (AREA)
  • Hospice & Palliative Care (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Otolaryngology (AREA)
  • Psychiatry (AREA)
  • Gynecology & Obstetrics (AREA)
  • Reproductive Health (AREA)
US13/750,069 2012-01-25 2013-01-25 Formulations of 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid Abandoned US20130186801A1 (en)

Priority Applications (5)

Application Number Priority Date Filing Date Title
US13/750,069 US20130186801A1 (en) 2012-01-25 2013-01-25 Formulations of 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid
US15/093,582 US20160324788A1 (en) 2012-01-25 2016-04-07 Formulations of 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid
US15/655,354 US20180008546A1 (en) 2012-01-25 2017-07-20 Formulations of 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid
US16/523,493 US20200085750A1 (en) 2012-01-25 2019-07-26 Formulations of 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid
US17/174,764 US20220354797A1 (en) 2012-01-25 2021-02-12 Formulations of 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
US201261590479P 2012-01-25 2012-01-25
US201261651218P 2012-05-24 2012-05-24
US201261691898P 2012-08-22 2012-08-22
US201261708691P 2012-10-02 2012-10-02
US13/750,069 US20130186801A1 (en) 2012-01-25 2013-01-25 Formulations of 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US15/093,582 Continuation US20160324788A1 (en) 2012-01-25 2016-04-07 Formulations of 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid

Publications (1)

Publication Number Publication Date
US20130186801A1 true US20130186801A1 (en) 2013-07-25

Family

ID=47679064

Family Applications (5)

Application Number Title Priority Date Filing Date
US13/750,069 Abandoned US20130186801A1 (en) 2012-01-25 2013-01-25 Formulations of 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid
US15/093,582 Abandoned US20160324788A1 (en) 2012-01-25 2016-04-07 Formulations of 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid
US15/655,354 Abandoned US20180008546A1 (en) 2012-01-25 2017-07-20 Formulations of 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid
US16/523,493 Abandoned US20200085750A1 (en) 2012-01-25 2019-07-26 Formulations of 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid
US17/174,764 Pending US20220354797A1 (en) 2012-01-25 2021-02-12 Formulations of 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid

Family Applications After (4)

Application Number Title Priority Date Filing Date
US15/093,582 Abandoned US20160324788A1 (en) 2012-01-25 2016-04-07 Formulations of 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid
US15/655,354 Abandoned US20180008546A1 (en) 2012-01-25 2017-07-20 Formulations of 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid
US16/523,493 Abandoned US20200085750A1 (en) 2012-01-25 2019-07-26 Formulations of 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid
US17/174,764 Pending US20220354797A1 (en) 2012-01-25 2021-02-12 Formulations of 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid

Country Status (29)

Country Link
US (5) US20130186801A1 (zh)
EP (1) EP2806859B1 (zh)
JP (1) JP2015504920A (zh)
KR (1) KR20140117612A (zh)
CN (2) CN104168890A (zh)
AU (1) AU2013212003C1 (zh)
BR (1) BR112014018378B1 (zh)
CA (2) CA3128556A1 (zh)
CL (1) CL2014001979A1 (zh)
CY (1) CY1122197T1 (zh)
DK (1) DK2806859T3 (zh)
ES (1) ES2742277T3 (zh)
HK (2) HK1199205A1 (zh)
HR (1) HRP20191439T1 (zh)
HU (1) HUE044676T2 (zh)
IL (1) IL233830B (zh)
LT (1) LT2806859T (zh)
ME (1) ME03464B (zh)
MX (1) MX355183B (zh)
NZ (1) NZ727015A (zh)
PL (1) PL2806859T3 (zh)
PT (1) PT2806859T (zh)
RS (1) RS59262B1 (zh)
RU (1) RU2644723C2 (zh)
SG (2) SG11201404404QA (zh)
SI (1) SI2806859T1 (zh)
UA (1) UA114619C2 (zh)
WO (1) WO2013112804A1 (zh)
ZA (1) ZA201405590B (zh)

Cited By (36)

* 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
US8716338B2 (en) 2008-09-29 2014-05-06 Vertex Pharmaceuticals Incorporated Dosage units of 3-(6-(1-(2,2-difluorobenzo[D] [1,3] dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid
US8742122B2 (en) 2010-04-07 2014-06-03 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
US8802868B2 (en) 2010-03-25 2014-08-12 Vertex Pharmaceuticals Incorporated Solid forms of (R)-1(2,2-difluorobenzo[D][1,3]dioxo1-5-yl)-N-(1-(2,3-dihydroxypropyl-6-fluoro-2-(1-hydroxy-2-methylpropan2-yl)-1H-Indol-5-yl)-Cyclopropanecarboxamide
US8816093B2 (en) 2007-12-07 2014-08-26 Vertex Pharmaceuticals Incorporated Processes for producing cycloalkylcarboxamido-pyridine benzoic acids
US8846753B2 (en) 2005-12-28 2014-09-30 Vertex Pharamaceuticals Incorporated Modulators of ATP-binding cassette transporters
US8853415B2 (en) 2003-09-06 2014-10-07 Vertex Pharmaceuticals Incorporated Modulators of ATP-binding cassette transporters
US8889875B2 (en) 2008-03-31 2014-11-18 Vertex Pharmaceuticals Incorporated Pyridyl derivatives as CFTR modulators
US8912199B2 (en) 2006-04-07 2014-12-16 Vertex Pharmaceuticals Incorporated Modulators of ATP-binding cassette transporters
US8952050B2 (en) 2006-04-07 2015-02-10 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
US8969386B2 (en) 2007-05-09 2015-03-03 Vertex Pharmaceuticals Incorporated Modulators of CFTR
US9012473B2 (en) 2007-11-16 2015-04-21 Vertex Pharmaceuticals Incorporated Modulators of ATP-binding cassette transporters
WO2015073231A1 (en) * 2013-11-12 2015-05-21 Vertex Pharmaceuticals Incorporated Process of preparing pharmaceutical compositions for the treatment of cftr mediated diseases
US20150182480A1 (en) * 2012-08-13 2015-07-02 Inserm (Institut National De La Sante Et De La Recherche Medicale) Methods and Pharmaceutical Compositions for Treatment of Cystic Fibrosis
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
US9254291B2 (en) 2011-11-08 2016-02-09 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
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
US9670163B2 (en) 2005-12-28 2017-06-06 Vertex Pharmaceuticals Incorporated Solid forms of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide
US9701639B2 (en) 2014-10-07 2017-07-11 Vertex Pharmaceuticals Incorporated Co-crystals of modulators of cystic fibrosis transmembrane conductance regulator
CN107033120A (zh) * 2016-02-03 2017-08-11 苏州旺山旺水生物医药有限公司 1-(2,2-二氟苯并[d][1,3]二氧杂环戊烯-5-基)-环丙烷甲酸的制备方法及其中间体
US10022352B2 (en) 2006-04-07 2018-07-17 Vertex Pharmaceuticals Incorporated Modulators of ATP-binding cassette transporters
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
EP3339306A4 (en) * 2015-08-11 2019-01-02 Crystal Pharmatech Co., Ltd. Novel crystal form of 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxole-5-yl)cyclopropane formamido)-3-methylpyridine-2-yl)benzoic acid and preparation method thereof
US10206877B2 (en) 2014-04-15 2019-02-19 Vertex Pharmaceuticals Incorporated Pharmaceutical compositions for the treatment of cystic fibrosis transmembrane conductance regulator 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
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

Families Citing this family (29)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
LT2914248T (lt) * 2012-11-02 2018-11-26 Vertex Pharmaceuticals Incorporated Farmacinės kompozicijos, skirtos cftr medijuotų ligų gydymui
US20160074374A1 (en) * 2013-04-26 2016-03-17 Vertex Pharmaceuticals Incorporated Correctors acting through msd1 of cftr protein
WO2016057572A1 (en) 2014-10-06 2016-04-14 Mark Thomas Miller Modulators of cystic fibrosis transmembrane conductance regulator
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
HUP1600269A2 (hu) 2016-04-25 2017-10-30 Druggability Tech Ip Holdco Ltd Lumacaftornak, sóinak és származékainak komplexei, eljárás azok elõállítására és azok gyógyászati készítményei
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
HUP1600271A2 (hu) 2016-04-25 2017-10-30 Druggability Tech Ip Holdco Ltd Ivacaftor és Lumacaftor sóinak és származékainak komplexei, eljárás azok elõállítására és azok gyógyszerészetileg elfogadható készítményei
GEP20217329B (en) 2016-09-30 2021-12-10 Vertex Pharma Modulator of cystic fibrosis transmembrane conductance regulator, pharmaceutical compositions, methods of treatment, and process for making the modulator
EA202192783A1 (ru) 2016-12-09 2022-02-24 Вертекс Фармасьютикалз Инкорпорейтед Модулятор регулятора трансмембранной проводимости при муковисцидозе, фармацевтические композиции, способы лечения и способ получения указанного модулятора
AU2018279646B2 (en) 2017-06-08 2023-04-06 Vertex Pharmaceuticals Incorporated Methods of treatment for cystic fibrosis
CA3069226A1 (en) 2017-07-17 2019-01-24 Vertex Pharmaceuticals Incorporated Methods of treatment for cystic fibrosis
MX2020001302A (es) 2017-08-02 2020-03-20 Vertex Pharma Procesos para preparar compuestos de pirrolidina.
TWI719349B (zh) 2017-10-19 2021-02-21 美商維泰克斯製藥公司 Cftr調節劑之結晶形式及組合物
CA3085006A1 (en) 2017-12-08 2019-06-13 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
SI3752510T1 (sl) 2018-02-15 2023-03-31 Vertex Pharmaceuticals Incorporated Makrocikli kot modulatorji regulatorja transmembranske prevodnosti pri cistični fibrozi, farmacevtski sestavki iz le-teh, njihova uporaba pri zdravljenju cistične fibroze in postopek za njihovo proizvodnjo
US20210139514A1 (en) 2018-04-05 2021-05-13 Vertex Pharmaceuticals Incorporated Modulators of cystic fibrosis transmembrane conductance regulator
EP3774825A1 (en) 2018-04-13 2021-02-17 Vertex Pharmaceuticals Incorporated Modulators of cystic fibrosis transmembrane conductance regulator, pharmaceutical compositions, methods of treatment, and process for making the modulator
CN112262143A (zh) 2018-05-21 2021-01-22 星座制药公司 甲基修饰酶的调节剂、其组合物和用途
UY38630A (es) 2019-04-03 2020-10-30 Vertex Pharma Agentes moduladores del regulador de la conductancia transmembrana de la fibrosis quística
BR112022001161A2 (pt) * 2019-07-24 2022-06-07 Constellation Pharmaceuticals Inc Formas cristalinas de 7-cloro-2-(4-(3-metoxiazetidin-1-il)ciclo-hexil)-2,4-dimetil-n-((6-metil-4-(metiltio)-2-óxo-1,2-di-hidropiridin-3-il)metil)benzo[d][1,3]dioxol-5-carboxamida
CN114599657A (zh) 2019-08-14 2022-06-07 弗特克斯药品有限公司 Cftr调节剂的结晶形式
TW202115092A (zh) 2019-08-14 2021-04-16 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
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
WO2022194399A1 (en) 2020-07-13 2022-09-22 Idorsia Pharmaceuticals Ltd Macrocycles as cftr modulators
WO2024056798A1 (en) 2022-09-15 2024-03-21 Idorsia Pharmaceuticals Ltd Macrocyclic cftr modulators
WO2024056791A1 (en) 2022-09-15 2024-03-21 Idorsia Pharmaceuticals Ltd Combination of macrocyclic cftr modulators with cftr correctors and / or cftr potentiators
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

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20090170905A1 (en) * 2007-12-07 2009-07-02 Ali Keshavarz-Shokri Solid forms of 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid

Family Cites Families (28)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
NZ538809A (en) 2002-09-30 2008-06-30 Univ California Thiazolidinone 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
PL3345895T3 (pl) 2003-04-11 2020-05-18 Ptc Therapeutics, Inc. Związek kwasu 1,2,4-oksadiazolobenzoesowego i jego zastosowanie do supresji mutacji nonsensownych i leczenia choroby
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
DE602004022819D1 (de) 2003-06-06 2009-10-08 Vertex Pharma Von atp-bindende kassette transportern
EP1680411A2 (en) 2003-10-08 2006-07-19 Vertex Pharmaceuticals Incorporated Modulators of atp-binding cassette transporters containing cycloalkyl or pyranyl groups
CN101675928A (zh) 2003-11-14 2010-03-24 沃泰克斯药物股份有限公司 可用作atp-结合弹夹转运蛋白调控剂的噻唑和噁唑
EA011074B1 (ru) 2004-03-30 2008-12-30 Дзе Риджентс Оф Дзе Юниверсити Оф Калифорния Гидразидсодержащие соединения - ингибиторы cftr и их применение
WO2005120497A2 (en) 2004-06-04 2005-12-22 The Regents Of The University Of California Compounds having activity in increasing ion transport by mutant-cftr and uses thereof
EP1781253A1 (en) * 2004-07-01 2007-05-09 Warner-Lambert Company LLC Preparation of pharmaceutical compositions containing nanoparticles
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
WO2006048699A1 (en) * 2004-11-04 2006-05-11 Wockhardt Limited Pharmaceutical compositions of antihistamine and decongestant
EP1865949B1 (en) 2005-03-11 2012-11-14 Vertex Pharmaceuticals Incorporated Modulators of ATP-binding cassette transporters
EP1863522A4 (en) 2005-03-18 2010-11-10 Univ California CORRECTIVE TO THE PROCESSING OF MUTANT CFTR IMPACT COMPOUNDS AND ITS APPLICATIONS
PL2402002T3 (pl) 2005-04-08 2018-11-30 Ptc Therapeutics, Inc. Kompozycje zawierające kwas 1,2,4-oksadiazolobenzoesowy i ich zastosowania do leczenia chorób związanych z przedwczesnym kodonem stop
ATE533749T1 (de) 2005-05-24 2011-12-15 Vertex Pharma Modulatoren von atp-bindenden kassettentransportern
RU2008118001A (ru) 2005-10-06 2009-11-20 Вертекс Фармасьютикалз Инкорпорейтед (Us) Модуляторы атф-зависимых транспортеров
PT1945632E (pt) 2005-11-08 2013-12-24 Vertex Pharma Moduladores heterocíclicos de transportadores de cassete de ligação a atp
AU2008335439A1 (en) * 2007-12-07 2009-06-18 Vertex Pharmaceuticals Incorporated Formulations of 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid
JP5242704B2 (ja) * 2008-02-01 2013-07-24 グラクソスミスクライン・リミテッド・ライアビリティ・カンパニー 粒状材料の性質を予測する方法および装置ならびにそれから調製される剤形
GB0813709D0 (en) * 2008-07-26 2008-09-03 Univ Dundee Method and product
AR073709A1 (es) * 2008-09-29 2010-11-24 Vertex Pharma Unidades de dosis de acido 3-(6-(1-(2,2-difluorobenzeno (d) (1,3) dioxol-5-il) ciclopropancarboxamido)-3-metilpiridin-2-il) benzoico
JP2012525895A (ja) * 2009-05-07 2012-10-25 ジーイーエイ・ファーマ・システムズ・リミテッド 錠剤の製造モジュール及び錠剤の連続製造方法
US8247436B2 (en) 2010-03-19 2012-08-21 Novartis Ag Pyridine and pyrazine derivative for the treatment of CF
RS54783B1 (sr) * 2010-04-07 2016-10-31 Vertex Pharma Čvrste forme 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioksol-5-il)ciklopropankarboksiamido)-3-metilpiridin-2-il)benzoeve kiseline
DK3150198T3 (da) * 2010-04-07 2021-11-01 Vertex Pharma Farmaceutiske sammensætninger af 3-(6-(1-(2,2-difluorbenzo[d][1,3]dioxol-5-yl)-cyclopropancarboxamido)-3-methylpyriodin-2-yl)benzoesyre og indgivelse deraf
ITMI20111068A1 (it) 2011-06-14 2012-12-15 Azienda Ospedaliera Universitaria I Ntegrata Di Ve Trimetilangelicina come correttore di cftr in cellule dell'epitelio bronchiale
HUE054389T2 (hu) * 2013-11-12 2021-09-28 Vertex Pharma Eljárás CFTR-mediálta betegségek kezelésére szolgáló gyógyászati kompozíciók elõállítására

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20090170905A1 (en) * 2007-12-07 2009-07-02 Ali Keshavarz-Shokri Solid forms of 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
ALLEGRA(TM) Prescribing Information (from the FDA website issued May 12, 2003). *

Cited By (83)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8853415B2 (en) 2003-09-06 2014-10-07 Vertex Pharmaceuticals Incorporated Modulators of ATP-binding cassette transporters
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
US9856248B2 (en) 2005-08-11 2018-01-02 Vertex Pharmaceuticals Incorporated Modulators of cystic fibrosis transmembrane conductance regulator
US8962856B2 (en) 2005-08-11 2015-02-24 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
US9216969B2 (en) 2005-11-08 2015-12-22 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
US11084804B2 (en) 2005-11-08 2021-08-10 Vertex Pharmaceuticals Incorporated Modulators of ATP-binding cassette transporters
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
US8846753B2 (en) 2005-12-28 2014-09-30 Vertex Pharamaceuticals Incorporated 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
US9670163B2 (en) 2005-12-28 2017-06-06 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
US8952050B2 (en) 2006-04-07 2015-02-10 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
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
US11639347B2 (en) 2006-04-07 2023-05-02 Vertex Pharmaceuticals Incorporated Modulators of ATP-binding cassette transporters
US8912199B2 (en) 2006-04-07 2014-12-16 Vertex Pharmaceuticals Incorporated Modulators of ATP-binding cassette transporters
US10239867B2 (en) 2006-04-07 2019-03-26 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
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
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
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
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
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
US9776968B2 (en) 2007-12-07 2017-10-03 Vertex Pharmaceuticals Incorporated Processes for producing cycloalkylcarboxamido-pyridine benzoic acids
US9012652B2 (en) 2007-12-07 2015-04-21 Vertex Pharmaceuticals Incorporated Processes for producing cycloalkylcarboxamido-pyridine benzoic acids
US8816093B2 (en) 2007-12-07 2014-08-26 Vertex Pharmaceuticals Incorporated Processes for producing cycloalkylcarboxamido-pyridine benzoic acids
US9321725B2 (en) 2007-12-07 2016-04-26 Vertex Pharmaceuticals Incorporated Processes for producing cycloalkylcarboxamido-pyridine benzoic acids
US9079916B2 (en) 2008-02-28 2015-07-14 Vertex Pharmaceuticals Incorporated Heteroaryl derivatives as CFTR modulators
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
US8889875B2 (en) 2008-03-31 2014-11-18 Vertex Pharmaceuticals Incorporated Pyridyl 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
US9192606B2 (en) 2008-09-29 2015-11-24 Vertex Pharmaceuticals Incorporated Dosage units of 3-(6-(1-(2,2-difluorobenzo[d] [1,3] dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid
US8716338B2 (en) 2008-09-29 2014-05-06 Vertex Pharmaceuticals Incorporated Dosage units of 3-(6-(1-(2,2-difluorobenzo[D] [1,3] dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid
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
US8802868B2 (en) 2010-03-25 2014-08-12 Vertex Pharmaceuticals Incorporated Solid forms of (R)-1(2,2-difluorobenzo[D][1,3]dioxo1-5-yl)-N-(1-(2,3-dihydroxypropyl-6-fluoro-2-(1-hydroxy-2-methylpropan2-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
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
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
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
US8742122B2 (en) 2010-04-07 2014-06-03 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
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
US9254291B2 (en) 2011-11-08 2016-02-09 Vertex Pharmaceuticals Incorporated Modulators of ATP-binding cassette transporters
US11147770B2 (en) 2012-02-27 2021-10-19 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
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
US9402821B2 (en) * 2012-08-13 2016-08-02 Inserm (Institut National De La Sante Et De La Recherche Medicale) Methods and pharmaceutical compositions for treatment of cystic fibrosis
US20150182480A1 (en) * 2012-08-13 2015-07-02 Inserm (Institut National De La Sante Et De La Recherche Medicale) Methods and Pharmaceutical Compositions for Treatment of Cystic Fibrosis
KR102280372B1 (ko) 2013-11-12 2021-07-22 버텍스 파마슈티칼스 인코포레이티드 Cftr 매개된 질환 치료용 약제학적 조성물의 제조 방법
WO2015073231A1 (en) * 2013-11-12 2015-05-21 Vertex Pharmaceuticals Incorporated Process of preparing pharmaceutical compositions for the treatment of cftr mediated diseases
KR20160086885A (ko) * 2013-11-12 2016-07-20 버텍스 파마슈티칼스 인코포레이티드 Cftr 매개된 질환 치료용 약제학적 조성물의 제조 방법
AU2014349010B2 (en) * 2013-11-12 2020-01-30 Vertex Pharmaceuticals Incorporated Process of preparing pharmaceutical compositions for the treatment of CFTR mediated diseases
AU2014349010C1 (en) * 2013-11-12 2020-08-06 Vertex Pharmaceuticals Incorporated Process of preparing pharmaceutical compositions for the treatment of CFTR mediated diseases
EP3068392A4 (en) * 2013-11-12 2017-05-31 Vertex Pharmaceuticals Inc. Process of preparing pharmaceutical compositions for the treatment of cftr mediated diseases
US10231932B2 (en) 2013-11-12 2019-03-19 Vertex Pharmaceuticals Incorporated Process of preparing pharmaceutical compositions for the treatment of CFTR mediated diseases
CN105848657A (zh) * 2013-11-12 2016-08-10 沃泰克斯药物股份有限公司 制备用于治疗cftr介导的疾病的药物组合物的方法
US10980746B2 (en) 2014-04-15 2021-04-20 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
US11951212B2 (en) 2014-04-15 2024-04-09 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
EP3339306A4 (en) * 2015-08-11 2019-01-02 Crystal Pharmatech Co., Ltd. Novel crystal form of 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxole-5-yl)cyclopropane formamido)-3-methylpyridine-2-yl)benzoic acid and preparation method thereof
US10308641B2 (en) * 2015-08-11 2019-06-04 Crystal Pharmatech Co., Ltd. Crystal form of 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxole-5-yl)cyclopropane formamido)-3-methylpyridine-2-yl)benzoic acid and preparation method thereof
CN107033120A (zh) * 2016-02-03 2017-08-11 苏州旺山旺水生物医药有限公司 1-(2,2-二氟苯并[d][1,3]二氧杂环戊烯-5-基)-环丙烷甲酸的制备方法及其中间体

Also Published As

Publication number Publication date
CA3128556A1 (en) 2013-08-01
HK1199205A1 (zh) 2015-06-26
US20220354797A1 (en) 2022-11-10
SG11201404404QA (en) 2014-10-30
AU2013212003C1 (en) 2018-02-08
AU2013212003A1 (en) 2014-08-21
IL233830B (en) 2019-03-31
ES2742277T3 (es) 2020-02-13
SG10201606135TA (en) 2016-09-29
JP2015504920A (ja) 2015-02-16
RU2644723C2 (ru) 2018-02-13
AU2013212003B2 (en) 2017-05-25
HUE044676T2 (hu) 2019-11-28
CN108066306B (zh) 2021-09-07
RU2014134456A (ru) 2016-03-20
PL2806859T3 (pl) 2019-11-29
CY1122197T1 (el) 2020-11-25
ZA201405590B (en) 2016-08-31
EP2806859A1 (en) 2014-12-03
US20200085750A1 (en) 2020-03-19
CN108066306A (zh) 2018-05-25
BR112014018378A2 (pt) 2021-06-08
DK2806859T3 (da) 2019-08-05
US20180008546A1 (en) 2018-01-11
CL2014001979A1 (es) 2015-04-10
IL233830A0 (en) 2014-09-30
BR112014018378A8 (pt) 2017-07-11
KR20140117612A (ko) 2014-10-07
BR112014018378B1 (pt) 2022-05-31
CN104168890A (zh) 2014-11-26
PT2806859T (pt) 2019-09-04
MX2014009117A (es) 2015-02-04
EP2806859B1 (en) 2019-05-15
CA2862859A1 (en) 2013-08-01
ME03464B (me) 2020-01-20
LT2806859T (lt) 2019-10-25
NZ727015A (en) 2017-12-22
SI2806859T1 (sl) 2019-11-29
HK1255336A1 (zh) 2019-08-16
US20160324788A1 (en) 2016-11-10
MX355183B (es) 2018-04-09
HRP20191439T1 (hr) 2019-11-15
UA114619C2 (uk) 2017-07-10
WO2013112804A1 (en) 2013-08-01
CA2862859C (en) 2022-08-02
RS59262B1 (sr) 2019-10-31

Similar Documents

Publication Publication Date Title
US20220354797A1 (en) Formulations of 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid
US11052075B2 (en) 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
US20230364073A1 (en) Pharmaceutical compositions for the treatment of cftr mediated diseases
US10231932B2 (en) Process of preparing pharmaceutical compositions for the treatment of CFTR mediated diseases
AU2016213697B2 (en) 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
AU2015205839B2 (en) 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

Legal Events

Date Code Title Description
AS Assignment

Owner name: VERTEX PHARMACEUTICALS INCORPORATED, MASSACHUSETTS

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:VERWIJS, MARINUS JACOBUS;REEL/FRAME:030411/0191

Effective date: 20130312

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 (SAN DIEGO) LLC, CALIFORNIA

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

Effective date: 20161013

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