WO2020242935A1 - Méthodes de traitement de la mucoviscidose - Google Patents

Méthodes de traitement de la mucoviscidose Download PDF

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WO2020242935A1
WO2020242935A1 PCT/US2020/034199 US2020034199W WO2020242935A1 WO 2020242935 A1 WO2020242935 A1 WO 2020242935A1 US 2020034199 W US2020034199 W US 2020034199W WO 2020242935 A1 WO2020242935 A1 WO 2020242935A1
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compound
mixture
solid
mmol
cftr
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PCT/US2020/034199
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English (en)
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Weichao George Chen
Sarah Robertson
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Vertex Pharmaceuticals Incorporated
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Publication of WO2020242935A1 publication Critical patent/WO2020242935A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • A61K31/567—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in position 17 alpha, e.g. mestranol, norethandrolone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system

Definitions

  • This disclosure provides methods of treating cystic fibrosis in patients taking oral hormonal therapies, including hormone based oral contraceptives.
  • Cystic fibrosis is a recessive genetic disease that affects
  • the most prevalent disease-causing mutation is a deletion of phenylalanine at position 508 of the CFTR amino acid sequence, and is commonly referred to as the F508del mutation. This mutation occurs in approximately 70% of the cases of cystic fibrosis and is associated with severe disease.
  • CFTR is a cAMP/ ATP -mediated anion channel that is expressed in a variety of cell 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.
  • epithelial 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 which is 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.
  • Chloride transport 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 CT channels, resulting in a vectorial transport. Arrangement of Na + /2C1 /K + co-transporter, Na + -K + -ATPase pump and the basolateral membrane K + channels on the basolateral surface and CFTR on the luminal side coordinate the secretion of chloride via CFTR on the luminal side.
  • Orkambi® (lumacaftor/ivacaftor), which is approved in the United States for the treatment of cystic fibrosis, may substantially decrease hormonal contraceptive exposure, reducing their effectiveness and increasing the incidence of menstruation-associated adverse reactions. Patients taking Orkambi® are not recommended to rely on hormonal therapies as an effective method of contraception (see U.S. Prescribing Information for Orkambi®).
  • Compound I has the following chemical structure:
  • Compound I may also be identified by the chemical name, N-(l,3-dimethylpyrazol-4- yl)sulfonyl-6-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-l-yl]-2-[(4S)-2,2,4- trimethylpyrrolidin-l-yl]pyridine-3-carboxamide.
  • PCT/US2017/065425 discloses Compound I, a method of making Compound I, a method of making Form A of Compound I, as well as deuterated derivatives of Compound I and pharmaceutically acceptable salts thereof.
  • PCT/US2017/065425 also discloses that Compound I is a CFTR modulator with an ECso of 0.07 mM.
  • One aspect of the invention provides methods of treating cystic fibrosis in patients who are simultaneously receiving oral hormonal therapies, including oral hormonal contraceptives. The methods comprise administration of a pharmaceutical composition comprising a compound selected from Compound I, deuterated derivatives of Compound I, and pharmaceutically acceptable salts of Compound I or the deuterated derivatives thereof.
  • the pharmaceutical composition also comprises (i) a compound selected from Compound II, deuterated derivatives of compound II, and pharmaceutically acceptable salts of compound II or the deuterated derivatives thereof, and (ii) a compound selected from Compound III, deuterated derivatives of Compound III, and pharmaceutically acceptable salts of Compound III or the deuterated derivatives thereof.
  • the deuterated derivative of Compound III is Compound Ill-d or a pharmaceutically acceptable salt thereof.
  • Compound I is amorphous.
  • Compound II and Compound III or Compound Ill-d are in amorphous form.
  • Compound I is Form A.
  • crystalline Form A is characterized by an X-ray powder diffractogram having a signal at least one two-theta value chosen from 6.6 ⁇ 0.2, 7.6 ⁇ 0.2, 9.6 ⁇ 0.2, 12.4 ⁇ 0.2, 13.1 ⁇ 0.2, 15.2 ⁇ 0.2, 16.4 ⁇ 0.2, 18.2 ⁇ 0.2, and 18.6 ⁇ 0.2.
  • crystalline Form A is characterized by an X-ray powder diffractogram having a signal at at least one two-theta value chosen from 6.6 ⁇ 0.2, 7.6 ⁇ 0.2, 9.6 ⁇ 0.2, 12.4 ⁇ 0.2, 13.1 ⁇ 0.2, 15.2 ⁇ 0.2, 16.4 ⁇ 0.2, 18.2 ⁇ 0.2, and 18.6 ⁇ 0.2.
  • crystalline Form A is characterized by an X-ray powder diffractogram having a signal at at least three two-theta values chosen from 6.6 ⁇ 0.2, 7.6 ⁇ 0.2, 9.6 ⁇ 0.2, 12.4 ⁇ 0.2,
  • crystalline Form A is characterized by an X-ray powder diffractograph having a signal at at least one two-theta value chosen from 6.6 ⁇ 0.2, 9.6 ⁇ 0.2, 13.1 ⁇ 0.2, 15.2 ⁇ 0.2, and 18.6 ⁇ 0.2.
  • crystalline Form A is characterized by an X-ray powder diffractograph having a signal at at least one two-theta value chosen from 6.6 ⁇ 0.2, 9.6 ⁇ 0.2, 13.1 ⁇ 0.2, 15.2 ⁇ 0.2,
  • crystalline Form A is characterized by an X-ray powder diffractograph having a signal at at least three two-theta values chosen from 6.6 ⁇ 0.2, 9.6 ⁇ 0.2, 13.1 ⁇ 0.2, 15.2 ⁇ 0.2, 18.2 ⁇ 0.2, and 18.6 ⁇ 0.2.
  • crystalline Form A is characterized by an X-ray powder diffractograph having a signal at at least three two-theta values chosen from 6.6 ⁇ 0.2, 9.6 ⁇ 0.2, 13.1 ⁇ 0.2, 15.2 ⁇ 0.2, 18.2 ⁇ 0.2, and 18.6 ⁇ 0.2.
  • crystalline Form A is characterized by an X-ray powder
  • diffractograph having a signal at at least one two-theta value chosen from 6.6 ⁇ 0.2,
  • Crystalline Form A is characterized by an X-ray powder diffractograph having a signal at three two-theta values of 6.6 ⁇ 0.2, 13.1 ⁇ 0.2, 18.2 ⁇ 0.2. In some embodiments, crystalline Form A is characterized by an X- ray powder diffractograph having a signal at six two-theta values of 6.6 ⁇ 0.2, 9.6 ⁇ 0.2, 13.1 ⁇ 0.2, 15.2 ⁇ 0.2, 18.2 ⁇ 0.2, and 18.6 ⁇ 0.2. In some embodiments, Crystalline Form A is characterized by an X-ray powder diffractogram substantially similar to that in FIG. 1. In some embodiments, Crystalline Form A is characterized by an X-ray powder diffractogram substantially similar to that in FIG. 2.
  • Compound II has the following chemical structure:
  • Compound II may also be identified by the chemical name, (R)- 1-(2,2- difluorobenzo[d][l,3]dioxol-5-yl)-/V-(l-(2,3-dihydroxypropyl)-6-fluoro-2-(l-hydroxy-2- methylpropan-2-yl)-lH-indol-5-yl)cyclopropanecarboxamide.
  • Compound III has the following chemical structure:
  • Compound III may also be identified by the chemical name, N-( 5 -hydroxy-2, 4-di -lerl- butyl-phenyl)-4-oxo-lH-quinoline-3-carboxamide.
  • Compound Ill-d has the following chemical structure:
  • Compound Ill-d may also be identified by the chemical name, N-(2-(tert-butyl)-5- hydroxy-4-(2-(methyl-d3)propan-2-yl-l,l,l,3,3,3-d6)phenyl)-4-oxo-l,4- dihydroquinoline-3 -carboxamide.
  • FIG. 1 is an XRPD of Form A of Compound 1.
  • FIG. 2 is an XRPD of a tablet with the composition of Tablet 4.
  • FIG. 3 is a schematic of a Phase 1, open-label, drug-drug interaction study to evaluate the effect of Compound I/tezacaftor/ivacaftor on the pharmacokinetics of oral contraceptives.
  • FIG. 4 is a mean ethinyl estradiol (EE) plasma concentration time profile.
  • FIG. 5 is a mean levonorgestrel (LN) plasma concentration time profile.
  • CFTR cystic fibrosis transmembrane
  • “mutations” can refer to mutations in the CFTR gene or the CFTR protein.
  • A“ CFTR gene mutation” refers to a mutation in the CFTR gene
  • a“CFTR protein mutation” refers to a mutation in the CFTR protein.
  • a genetic defect or mutation, or a change in the nucleotides in a gene in general results in a mutation in the CFTR protein translated from that gene, or a frame shift(s).
  • F508del refers to a mutant CFTR protein which is lacking the amino acid phenylalanine at position 508.
  • a patient who is“heterozygous” for a particular gene mutation has this mutation on one allele, and a different mutation on the other allele.
  • the term“modulator” refers to a compound that increases the activity of a biological compound such as a protein.
  • a CFTR modulator is a compound that increases the activity of CFTR.
  • the increase in activity resulting from a CFTR modulator includes but is not limited to compounds that correct, potentiate, stabilize and/or amplify CFTR.
  • the term“CFTR corrector” refers to a compound that facilitates the processing and trafficking of CFTR to increase the amount of CFTR at the cell surface.
  • Compound I, Compound II, and their pharmaceutically acceptable salts thereof disclosed herein are CFTR correctors.
  • CFTR potentiator refers to a compound that increases the channel activity of CFTR protein located at the cell surface, resulting in enhanced ion transport.
  • Compound Ill-d and Compound III disclosed herein are CFTR potentiators.
  • API active pharmaceutical ingredient
  • the term“pharmaceutically acceptable salt” refers to a salt form of a compound of this disclosure wherein the salt is nontoxic.
  • Pharmaceutically acceptable salts of the compounds of this disclosure include those derived from suitable inorganic and organic acids and bases.
  • Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge, et al. describe pharmaceutically acceptable salts in detail i n ./. Pharmaceutical Sciences , 1977, 66, 1-19.
  • Suitable pharmaceutically acceptable salts are, for example, those disclosed in S. M. Berge, et al. J. Pharmaceutical Sciences, 1977, 66, 1-19.
  • Table 1 of that article provides the following pharmaceutically acceptable salts:
  • Non-limiting examples of pharmaceutically acceptable acid addition salts include: salts formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, or perchloric acid; salts formed with organic acids, such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid; and salts formed by using other methods used in the art, such as ion exchange.
  • Non-limiting examples of pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate,
  • salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N + (CI-4 alkyl)4 salts.
  • alkali and alkaline earth metal salts include sodium, lithium, potassium, calcium, and magnesium.
  • pharmaceutically acceptable salts include ammonium, quaternary ammonium, and amine cations formed using
  • counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and aryl sulfonate.
  • pharmaceutically acceptable salts include besylate and glucosamine salts.
  • XRPD refers to the analytical characterization method of X-ray powder diffraction. XRPD patterns can be recorded at ambient conditions in transmission or reflection geometry using a diffractometer.
  • an X-ray powder diffractogram may include one or more broad signals; and for a crystalline material, an X-ray powder diffractogram may include one or more signals, each identified by its angular value as measured in degrees 2Q (° 2Q), depicted on the abscissa of an X-ray powder diffractogram, which may be expressed as“a signal at ... degrees two-theta,”“a signal at [a] two-theta value(s)of .. and/or“a signal at at least ... two-theta value(s) chosen from
  • A“signal” or“peak” as used herein refers to a point in the XRPD pattern where the intensity as measured in counts is at a local.
  • One of ordinary skill in the art would recognize that one or more signals (or peaks) in an XRPD pattern may overlap and may, for example, not be apparent to the naked eye. Indeed, one of ordinary skill in the art would recognize that some art-recognized methods are capable of and suitable for determining whether a signal exists in a pattern, such as Rietveld refinement.
  • “a signal at ... degrees two-theta,”“a signal at [a] two- theta value[] of .. and/or“a signal at at least ... two-theta value(s) chosen from refer to X-ray reflection positions as measured and observed in X-ray powder diffraction experiments (° 2Q).
  • the repeatability of the angular values is in the range of ⁇ 0.2° 2Q, i.e., the angular value can be at the recited angular value + 0.2 degrees two-theta, the angular value - 0.2 degrees two-theta, or any value between those two end points (angular value +0.2 degrees two-theta and angular value -0.2 degrees two-theta).
  • signal intensities and“peak intensities” interchangeably refer to relative signal intensities within a given X-ray powder diffractogram. Factors that can affect the relative signal or peak intensities include sample thickness and preferred orientation (e.g., the crystalline particles are not distributed randomly).
  • X-ray powder diffractogram having a signal at ... two-theta values refers to an XRPD pattern that contains X-ray reflection positions as measured and observed in X-ray powder diffraction experiments (° 2Q).
  • an X-ray powder diffractogram is“substantially similar to that in [a particular] Figure” when at least 90%, such as at least 95%, at least 98%, or at least 99%, of the signals in the two diffractograms overlap.
  • determining“substantial similarity” one of ordinary skill in the art will understand that there may be variation in the intensities and/or signal positions in XRPD diffractograms even for the same crystalline form.
  • the signal maximum values in XRPD diffractograms in degrees two-theta (°2Q) referred to herein generally mean that value reported ⁇ 0.2 degrees 2Q of the reported value, an art- recognized variance.
  • a crystalline form is “substantially pure” when it accounts for an amount by weight equal to or greater than 90% of the sum of all solid form(s) in a sample as determined by a method in accordance with the art, such as quantitative XRPD.
  • the solid form is “substantially pure” when it accounts for an amount by weight equal to or greater than 95% of the sum of all solid form(s) in a sample.
  • the solid form is “substantially pure” when it accounts for an amount by weight equal to or greater than 99% of the sum of all solid form(s) in a sample.
  • amorphous refers to a solid material having no long range order in the position of its molecules.
  • Amorphous solids are generally supercooled liquids in which the molecules are arranged in a random manner so that there is no well-defined arrangement, e.g., molecular packing, and no long range order.
  • an amorphous material is a solid material having no sharp characteristic crystalline peak(s) in its X-ray power diffraction (XRPD) pattern (i.e., is not crystalline as determined by XRPD). Instead, one or more broad peaks (e.g., halos) appear in its XRPD pattern. Broad peaks are characteristic of an amorphous solid.
  • 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 15% crystallinity (e.g., less than 10% crystallinity or less than 5% crystallinity).
  • crystallinity e.g., less than 10% crystallinity or less than 5% crystallinity.
  • 'substantially amorphous' includes the descriptor, 'amorphous', which refers to materials having no (0%) crystallinity.
  • the term "dispersion” refers to a disperse system in which one substance, the dispersed phase, is distributed, in discrete units, throughout a second substance (the continuous phase or vehicle).
  • the size of the dispersed phase can vary considerably (e.g. colloidal particles of nanometer dimension, to multiple microns in size).
  • the dispersed phases can be solids, liquids, or gases. In the case of a solid dispersion, the dispersed and continuous phases are both solids.
  • a solid dispersion can include a crystalline drug (dispersed phase) in an amorphous polymer (continuous phase); or alternatively, an amorphous drug (dispersed phase) in an amorphous polymer (continuous phase).
  • a solid dispersion includes the polymer constituting the dispersed phase, and the drug constituting the continuous phase. In other embodiments, a solid dispersion includes the drug constituting the dispersed phase, and the polymer constituting the continuous phase.
  • a compound that produces the desired effect for which it is administered e.g., improvement in CF or a symptom of CF, or lessening the severity of CF or a symptom of CF.
  • the exact amount of an effective dose will depend on the purpose of the treatment and will be ascertainable by one skilled in the art using known techniques (see, e.g., Lloyd (1999) The Art, Science and Technology of Pharmaceutical Compounding).
  • treatment generally mean the improvement of CF or its symptoms or lessening the severity of CF or its symptoms in a subject.
  • Treatment includes, but is not limited to, the following: increased growth of the subject, increased weight gain, reduction of mucus in the lungs, improved pancreatic and/or liver function, reduction of chest infections, and/or reductions in coughing or shortness of breath. Improvements in or lessening the severity of any of these symptoms can be readily assessed according to standard methods and techniques known in the art.
  • the term“in combination with,” when referring to two or more compounds, agents, or additional active pharmaceutical ingredients, means the administration of two or more compounds, agents, or active pharmaceutical ingredients to the patient prior to, concurrent with, or subsequent to each other.
  • compositions for used in treating cystic fibrosis in patients who are concurrently receiving oral hormonal therapies, including hormone based oral contraceptives, comprising a first solid dispersion and a second solid dispersion.
  • the pharmaceutical composition for use in the methods of the invention may comprise:
  • the pharmaceutical composition is a single tablet
  • each of Compound II and Compound III or Compound Ill-d is independently substantially amorphous. In some embodiments, each of Compound II and Compound III or Compound Ill-d is independently crystalline. In some embodiments, each of Compound II and Compound III or Compound Ill-d is independently a mixture of forms (crystalline and/or amorphous).
  • the pharmaceutical compositions (e.g., tablets) useful in the methods of the invention comprise a first solid dispersion comprising Compound II and a second solid dispersion comprising Compound III or Compound III- d.
  • each of the first and second solid dispersions independently comprise a plurality of particles having a mean particle diameter of 5 to 100 microns.
  • each of the first and second solid dispersions independently comprise a plurality of particles having a mean particle diameter of 15 to 40 microns.
  • each of the first and second solid dispersions independently comprise a plurality of particles having a mean particle diameter of 15 microns.
  • the first solid dispersions and the first spray dried dispersions of the disclosure independently comprise substantially amorphous
  • the second solid dispersions and the second spray dried dispersions of the disclosure independently comprises substantially amorphous Compound III or Compound Ill-d.
  • dispersions of the disclosure can comprise other excipients, such as polymers and/or surfactants. Any suitable polymers and surfactants known in the art can be used in the disclosure. Certain exemplary polymers and surfactants are as described below.
  • Solid dispersions of any one of Compounds II, III, or Ill-d may be prepared by any suitable method known in the art, e.g., spray drying, lyophilizing, hot melting, or cyrogrounding/cryomilling techniques. For example, see WO2015/160787. Typically such spray drying, lyophilizing, hot melting or cyrogrounding/cryomilling techniques generates an amorphous form of API (e.g., Compounds II, III, or Ill-d).
  • Spray drying is a process that converts a liquid feed to a dried particulate form.
  • a secondary drying process such as fluidized bed drying or vacuum drying may be used to reduce residual solvents to pharmaceutically acceptable levels.
  • spray drying involves contacting a highly dispersed liquid suspension or solution, and a sufficient volume of hot gas to produce evaporation and drying of the liquid droplets.
  • the preparation to be spray dried can be any solution, coarse suspension, slurry, colloidal dispersion, or paste that may be atomized using the selected spray drying apparatus. In one procedure, the preparation is sprayed into a current of warm filtered gas that evaporates the solvent and conveys the dried product to a collector (e.g. a cyclone).
  • the spent gas is then exhausted with the solvent, or alternatively the spent air is sent to a condenser to capture and potentially recycle the solvent.
  • Commercially available types of apparatus may be used to conduct the spray drying.
  • commercial spray dryers are manufactured by Buchi Ltd.
  • Niro e.g., the PSD line of spray driers manufactured by Niro
  • US 2004/0105820; US 2003/0144257 see, US 2004/0105820; US 2003/0144257
  • Removal of the solvent may require a subsequent drying step, such as tray drying, fluid bed drying, vacuum drying, microwave drying, rotary drum drying or biconical vacuum drying.
  • the solid dispersions and the spray dried dispersions of the disclosure are fluid bed dried.
  • the solvent includes a volatile solvent, for example a solvent having a boiling point of less than 100 °C.
  • the solvent includes a mixture of solvents, for example a mixture of volatile solvents or a mixture of volatile and non-volatile solvents.
  • the mixture can include one or more non-volatile solvents, for example, where the non-volatile solvent is present in the mixture at less than 15%, e.g., less than 12%, less than 10%, less than 8%, less than 5%, less than 3%, or less than 2%.
  • solvents are those solvents where the API(s) (e.g., Compound II and/or Compound Ill-d and/or Compound III) has solubilities of at least 10 mg/ml, (e.g., at least 15 mg/ml, 20 mg/ml, 25 mg/ml, 30 mg/ml, 35 mg/ml, 40 mg/ml, 45 mg/ml, 50 mg/ml, or greater).
  • solvents include those solvents where the API(s) (e.g., Compound II and/or Compound Ill-d and/or Compound III) has a solubility of at least 20 mg/ml.
  • Exemplary solvents that could be tested include acetone, cyclohexane, dichloromethane or methylene chloride (DCM), N,N-dimethylacetamide (DMA), N,N- dimethylformamide (DMF), l,3-dimethyl-2-imidazolidinone (DMI), dimethyl sulfoxide (DMSO), dioxane, ethyl acetate, ethyl ether, glacial acetic acid (HAc), methyl ethyl ketone (MEK), N-methyl-2-pyrrolidinone (NMP), methyl tert-butyl ether (MTBE), tetrahydrofuran (THF), pentane, acetonitrile, methanol, ethanol, isopropyl alcohol, isopropyl acetate, and toluene.
  • DCM dimethylacetamide
  • DMF N,N- dimethylformamide
  • DI l,3-d
  • Exemplary co-solvents include DCM/methanol, acetone/DMSO, acetone/DMF, acetone/water, MEK/water, THF/water, dioxane/water.
  • the solvents can be present from 0.1% to 99.9% w/w.
  • water is a co-solvent with acetone where water is present from 0.1% to 15%, for example 9% to 11%, e.g., 10%.
  • water is a co-solvent with MEK where water is present from 0.1% to 15%, for example 9% to 11%, e.g., 10%.
  • the solvent system includes three solvents. Certain exemplary solvents include those described above, for example,
  • MEK MEK, DCM, water, methanol, IPA, and mixtures thereof.
  • the particle size and the temperature drying range may be modified to prepare an optimal solid dispersion. As would be appreciated by skilled practitioners, a small particle size would lead to improved solvent removal. Applicants have found however, that smaller particles may result in low bulk density that, under some circumstances do not provide optimal solid dispersions for downstream processing such as tableting.
  • a solid dispersion e.g., a spray dried dispersion
  • a surfactant or surfactant mixture would generally decrease the interfacial tension between the solid dispersion and an aqueous medium.
  • An appropriate surfactant or surfactant mixture may also enhance aqueous solubility and bioavailability of the API(s) (e.g., Compound II and/or Compound Ill-d and/or Compound III) from a solid dispersion.
  • the surfactants for use in connection with the disclosure include, but are not limited to, sorbitan fatty acid esters (e.g., Spans®), polyoxyethylene sorbitan fatty acid esters (e.g., Tweens®), sodium lauryl sulfate (SLS), sodium dodecylbenzene sulfonate (SDBS) dioctyl sodium sulfosuccinate (Docusate sodium), dioxycholic acid sodium salt (DOSS), Sorbitan Monostearate, Sorbitan Tristearate, hexadecyltrimethyl ammonium bromide (HTAB), Sodium N- lauroylsarcosine, Sodium Oleate, Sodium Myristate, Sodium Stearate, Sodium
  • Palmitate Gelucire 44/14, ethylenediamine tetraacetic acid (EDTA), Vitamin E d-alpha tocopheryl polyethylene glycol 1000 succinate (TPGS), Lecithin, Glutanic acid monosodium monohydrate, Labrasol, PEG 8 caprylic/capric glycerides, Transcutol, di ethylene glycol monoethyl ether, Solutol HS-15, polyethylene glycol/hydroxystearate, Taurocholic Acid, Pluronic F68, Pluronic FI 08, and Pluronic FI 27 (or any other polyoxyethylene-polyoxypropylene co-polymers (Pluronics®) or saturated
  • SLS is used as a surfactant in the solid dispersion of Compound III and/or Ill-d.
  • the amount of the surfactant (e.g., SLS) relative to the total weight of the solid dispersion may be between 0.1 - 15% w/w. For example, it is from 0.5% to 10%, such as from 0.5 to 5%, e.g., 0.5 to 4%, 0.5 to 3%, 0.5 to 2%, 0.5 to 1%, or 0.5%.
  • the amount of the surfactant relative to the total weight of the solid dispersion is at least 0.1% or at least 0.5%.
  • the surfactant would be present in an amount of no more than 15%, or no more than 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2% or 1%.
  • the surfactant is in an amount of 0.5% by weight.
  • Candidate surfactants can be tested for suitability for use in the disclosure in a manner similar to that described for testing polymers.
  • One aspect of the disclosure provides a method of generating a spray dried dispersion comprising (i) providing a mixture of one or more APIs and a solvent; and (ii) forcing the mixture through a nozzle and subjecting the mixture to spray drying conditions to generate the spray dried dispersion.
  • Another aspect of the disclosure provides a method of generating a spray dried dispersion comprising: (i) providing a mixture comprising one or more APIs and a solvent(s); and (ii) forcing the mixture out of a nozzle under spray drying conditions to generate a spray dried dispersion.
  • Another aspect of the disclosure provides a method of generating a spray dried dispersion comprising (i) spraying a mixture through a nozzle, wherein the mixture comprises one or more APIs and a solvent; and (ii) forcing the mixture through a nozzle under spray drying conditions to generate a particle that comprises the APIs.
  • Another aspect of the disclosure provides a spray dried dispersion comprising one or more APIs, wherein the dispersion is substantially free of a polymer, and wherein the spray dried dispersion is generated by (i) providing a mixture that consists essentially of one or more APIs and a solvent; and (ii) forcing the mixture through a nozzle under spray drying conditions to generate the spray dried dispersion.
  • Another aspect of the disclosure provides a spray dried dispersion comprising one or more APIs, wherein the dispersion is generated by (i) providing a mixture that comprising one or more APIs, a polymer(s), and a solvent(s); and (ii) forcing the mixture through a nozzle under spray drying conditions to generate the spray dried dispersion.
  • a spray dried dispersion comprising a particle, wherein the particle comprises one or more APIs and a polymer(s), and wherein the spray dried dispersion is generated by (i) spraying a mixture through a nozzle, wherein the mixture comprises one or more APIs and a solvent; and (ii) forcing the mixture through a nozzle under spray drying conditions to generate the spray dried dispersion.
  • a spray dried dispersion comprising a particle, wherein the particle comprises one or more APIs, and the particle is substantially free of a polymer, and wherein the spray dried dispersion is generated by (i) spraying a mixture through a nozzle, wherein the mixture comprises one or more APIs and a solvent; and (ii) forcing the mixture through a nozzle under spray drying conditions to generate the spray dried dispersion.
  • the one or more APIs are selected from Compound II, Compound Ill-d, and Compound III.
  • Some embodiments further comprise further drying the spray dried dispersion.
  • the spray dried dispersion is dried under reduced pressure.
  • the spray dried dispersion is dried at a temperature of from 50 °C to 100 °C.
  • the solvent comprises a polar organic solvent.
  • polar organic solvents include methylethyl ketone, THF, DCM, methanol, or IP A, or any combination thereof, such as, for example DCM/methanol.
  • the solvent further comprises water.
  • the solvent could be methylethyl ketone/water, THF/water, or methylethyl ketone/water/IPA.
  • the ratio of the polar organic solvent to water is from 70:30 to 95:5 by volume. In other instances, the ratio of the polar organic solvent to water is 90: 10 by volume.
  • Some embodiments further comprise filtering the mixture before it is forced through the nozzle.
  • filtering can be accomplished using any suitable filter media having a suitable pore size.
  • Some embodiments further comprise applying heat to the mixture as it enters the nozzle. This heating can be accomplished using any suitable heating element.
  • the nozzle comprises an inlet and an outlet, and the inlet is heated to a temperature that is less than the boiling point of the solvent.
  • the mixture is forced through the nozzle by a pressurized gas.
  • suitable pressurized gases include those pressurized gas that are inert to the first agent, the second agent, and the solvent.
  • the pressurized gas comprises elemental nitrogen.
  • the pressurized gas has a positive pressure of from 90 psi to 150 psi.
  • a pharmaceutically acceptable composition of the disclosure comprising substantially amorphous API(s) (e.g., Compound II, Compound Ill-d, and Compound III) may be prepared by non-spray drying techniques, such as, for example, cyrogrounding/cryomilling techniques.
  • a composition comprising
  • substantially amorphous API(s) may also be prepared by hot melt extrusion techniques.
  • the solid dispersions (e.g., spray dried dispersions) of the disclosure comprise a polymer(s).
  • Any suitable polymers known in the art can be used in the disclosure.
  • Exemplary suitable polymers include polymers selected from cellulose-based polymers, polyoxyethylene-based polymers, polyethylene-propylene glycol copolymers, vinyl-based polymers, PEO-polyvinyl caprolactam-based polymers, and polymethacrylate-based polymers.
  • the cellulose-based polymers include a methylcellulose, a hydroxypropyl methylcellulose (HPMC) (hypromellose), a hypromellose phthalate (HPMC-P), a hypromellose acetate succinate, and co-polymers thereof.
  • HPMC hydroxypropyl methylcellulose
  • HPMC-P hypromellose phthalate
  • HPMC-P hypromellose acetate succinate
  • the polyoxyethylene-based polymers include a polyethylene-propylene glycol, a polyethylene glycol, a poloxamer, and co-polymers thereof.
  • the vinyl-based polymers include a polyvinylpyrrolidine (PVP), and PVP/VA.
  • the PEO-polyvinyl caprolactam-based polymers include a polyethylene glycol, polyvinyl acetate and polyvinylcaprolactame-based graft copolymer (e.g., Soluplus®).
  • the polymethacrylate-based polymers are synthetic cationic and anionic polymers of dimethylaminoethyl methacrylates, methacrylic acid, and methacrylic acid esters in varying ratios. Several types are commercially available and may be obtained as the dry powder, aqueous dispersion, or organic solution.
  • polymethacrylate-based polymers examples include a poly(methacrylic acid, ethyl acrylate) (1 : 1), a dimethylaminoethyl methacrylate-methylmethacrylate copolymer, and an Eudragit®.
  • the cellulose-based polymer is a hypromellose acetate succinate (also known as hydroxypropyl methylcellulose acetate succinate or HMPCAS) and a hypromellose (also known as hydroxypropyl methylcellulose or HPMC), or a combination of hypromellose acetate succinate and a hypromellose.
  • HMPCAS hydroxypropyl methylcellulose acetate succinate
  • HPMC hydroxypropyl methylcellulose
  • HPMCAS is available in various grades based on the content of acetyl and succinoyl groups (wt%) in the HPMCAS molecule and on particle size.
  • HPMCAS grades L, M, and H are available.
  • HPMCAS-H is a grade that contains about 10-14 wt% of acetyl groups and about 4-8 wt% of succinoyl groups.
  • Each HPMCAS grade is available in two particle sizes, F (fine) and G (granular).
  • HPMC comes in various types (for example, HPMC E, F, J, and K-types).
  • HPMC E type means that there are about 28-30% methoxy groups and about 7-12% hydroxpropoxy groups.
  • HPMC E grades ranging from low to high viscosity.
  • E3 means the viscosity is about 2.4-3.6 millipascal seconds (mPa s) for HPMC measured at 2% in water at 20°C; El 5 means the viscosity is about 12-18 mPa s for the HPMC measured at 2% in water at 20°C; and E50 means the viscosity is about 40-60 mPa s for the HPMC measured at 2% in water at 20°C.
  • the cellulose-based polymer is a hypromellose acetate succinate and a hypromellose, or a combination of hypromellose acetate succinate and a hypromellose.
  • the cellulose-based polymer is hypromellose El 5, hypromellose acetate succinate L or hypromellose acetate succinate H.
  • the polyoxyethylene-based polymer or
  • polyethylene-propylene glycol copolymer is a polyethylene glycol or a pluronic.
  • polyethylene-propylene glycol copolymer is polyethylene glycol 3350 or poloxamer 407.
  • the vinyl-based polymer is a
  • vinylpolyvinylpyrrolidine-based polymer such as polyvinylpyrrolidine K30 or polyvinylpyrrolidine VA 64.
  • the polymethacrylate polymer is Eudragit L100-55 or Eudragit® E PO.
  • the polymer(s) is selected from cellulosic polymers such as HPMC and/or HPMCAS.
  • a polymer is able to dissolve in aqueous media.
  • the solubility of the polymers may be pH independent or pH dependent.
  • the latter include one or more enteric polymers.
  • enteric polymer refers to a polymer that is preferentially soluble in the less acidic environment of the intestine relative to the more acid environment of the stomach, for example, a polymer that is insoluble in acidic aqueous media but soluble when the pH is above 5-6.
  • An appropriate polymer is chemically and biologically inert.
  • the glass transition temperature (Tg) of the polymer is as high as possible.
  • Other polymers have a glass transition temperature that is within 10 to 15 °C of the API.
  • the hygroscopicity of the polymers is as low, e.g., less than 10%.
  • the hygroscopicity of a polymer or composition is characterized at 60% relative humidity.
  • the polymer has less than 10% water absorption, for example less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, or less than 2% water absorption.
  • the hygroscopicity can also affect the physical stability of the solid dispersions. Generally, moisture adsorbed in the polymers can greatly reduce the Tg of the polymers as well as the resulting solid dispersions, which will further reduce the physical stability of the solid dispersions as described above.
  • the polymer is one or more water-soluble polymer(s) or partially water-soluble polymer(s).
  • Water-soluble or partially water-soluble polymers include but are not limited to, cellulose derivatives (e.g.,
  • HPMC hydroxypropylmethylcellulose
  • HPC hydroxypropylcellulose
  • HPC hydroxypropylcellulose
  • HPC hydroxypropylcellulose
  • ethylcellulose ethylcellulose; polyvinylpyrrolidones (PVP); polyethylene glycols (PEG); polyvinyl alcohols (PVA); acrylates, such as polymethacrylate (e.g., Eudragit® E); cyclodextrins (e.g., b-cyclodextin) and copolymers and derivatives thereof, including for example PVP-VA (polyvinylpyrollidone-vinyl acetate).
  • PVP polyvinylpyrrolidones
  • PEG polyethylene glycols
  • PVA polyvinyl alcohols
  • acrylates such as polymethacrylate (e.g., Eudragit® E); cyclodextrins (e.g., b-cyclodextin) and copolymers and derivatives thereof, including for example PVP-VA (polyvinylpyrollidone-vinyl acetate).
  • the polymer is hydroxypropylmethylcellulose (HPMC), such as HPMC E50, HPMC El 5, or HPMC E3.
  • HPMC hydroxypropylmethylcellulose
  • the polymer can be a pH-dependent enteric polymer.
  • pH-dependent enteric polymers include, but are not limited to, cellulose derivatives (e.g., cellulose acetate phthalate (CAP)), hydroxypropyl methyl cellulose phthalates (HPMCP), hydroxypropyl methyl cellulose acetate succinate (HPMCAS), carboxymethylcellulose (CMC) or a salt thereof (e.g., a sodium salt such as (CMC-Na)); cellulose acetate trimellitate (CAT), hydroxypropylcellulose acetate phthalate
  • CAP cellulose derivatives
  • HPMCP hydroxypropyl methyl cellulose phthalates
  • HPMCAS hydroxypropyl methyl cellulose acetate succinate
  • CMC carboxymethylcellulose
  • CAT cellulose acetate trimellitate
  • HPCAP hydroxypropylmethyl-cellulose acetate phthalate
  • MCAP methylcellulose acetate phthalate
  • polymethacrylates e.g., Eudragit® S.
  • the polymer is hydroxypropyl methyl cellulose acetate succinate (HPMCAS). In some embodiments, the polymer is hydroxypropyl methyl cellulose acetate succinate HG grade (HPMCAS-HG).
  • the polymer is a polyvinylpyrrolidone co polymer, for example, avinylpyrrolidone/vinyl acetate co-polymer (PVP/VA)
  • the amount of polymer is typically at least 20%, and preferably at least 30%, for example, at least 35%, at least 40%, at least 45%, or 50% (e.g., 49.5%).
  • the amount is typically 99% or less, and preferably 80% or less, for example 75% or less, 70% or less, 65% or less, 60% or less, or 55% or less.
  • the polymer is in an amount of up to 50% of the total weight of the dispersion (and even more specifically, between 40% and 50%, such as 49%, 49.5%, or 50%).
  • the API e.g., Compound II, Compound Ill-d, or Compound III
  • polymer are present in roughly equal amounts in weight, for example each of the polymer and the drug make up half of the percentage weight of the dispersion.
  • the polymer is present in 49.5 wt % and Compound II, Compound Ill-d, or Compound III is present in 50 wt%.
  • Compound II, Compound Ill-d, or Compound III is present in an amount greater than half of the percentage weight of the dispersions.
  • the polymer is present in 20 wt% and Compound II, Compound Ill-d, or Compound III is present in 80 wt%.
  • the polymer is present in 19.5 wt% and Compound II, Compound Ill-d, or Compound III is present in 80 wt%.
  • the API e.g., Compound II, Compound Ill-d, or Compound III
  • the polymer combined represent 1% to 20% w/w total solid content of the spray drying solution prior to spray drying.
  • Compound II, Compound Ill-d, or Compound III, and the polymer combined represent 5% to 15% w/w total solid content of the spray drying solution prior to spray drying.
  • Compound II, Compound Ill-d, or Compound III and the polymer combined represent 11% w/w total solid content of the spray drying solution prior to spray drying.
  • the dispersion further includes other minor ingredients, such as a surfactant (e.g., SLS).
  • a surfactant e.g., SLS
  • the surfactant is present in less than 10% of the dispersion, for example less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, 1%, or 0.5%.
  • the polymer is present in an amount effective for stabilizing the solid dispersion.
  • Stabilizing includes inhibiting or preventing, the crystallization of an API (e.g., Compound II, Compound Ill-d, or Compound III). Such stabilizing would inhibit the conversion of the API from amorphous to crystalline form.
  • the polymer would prevent at least a portion (e.g., 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, or greater) of the API from converting from an amorphous to a crystalline form.
  • Stabilization can be measured, for example, by measuring the glass transition temperature of the solid dispersion, measuring the amount of crystalline material, measuring the rate of relaxation of the amorphous material, or by measuring the solubility or bioavailability of the API.
  • the polymers for use in the disclosure have a glass transition temperature of no less than 10-15 °C lower than the glass transition temperature of API.
  • the glass transition temperature of the polymer is greater than the glass transition temperature of API, and in general at least 50 °C higher than the desired storage temperature of the drug product. For example, at least 100 °C, at least 105 °C, at least 110 °C, at least 120 °C, at least 130 °C, at least 140 °C, at least 150 °C, at least 160 °C, or greater.
  • the polymers for use in the disclosure have similar or better solubility in solvents suitable for spray drying processes relative to that of an API (e.g., Compound II, Compound Ill-d, or Compound III).
  • an API e.g., Compound II, Compound Ill-d, or Compound III.
  • the polymer will dissolve in one or more of the same solvents or solvent systems as the API.
  • the polymers for use in the disclosure can increase the solubility of an API (e.g., Compound II, Compound Ill-d, or Compound III) in aqueous and physiologically relative media either relative to the solubility of the API in the absence of polymer or relative to the solubility of the API when combined with a reference polymer.
  • the polymers can increase the solubility of Compound II, Compound Ill-d, or Compound III by reducing the amount of amorphous Compound II, Compound Ill-d, or Compound III that converts to a crystalline form(s), either from a solid amorphous dispersion or from a liquid suspension.
  • the polymers for use in the disclosure can decrease the relaxation rate of the amorphous substance.
  • the polymers for use in the disclosure can increase the physical and/or chemical stability of an API (e.g., Compound II, Compound III, or Compound Ill-d).
  • the polymers for use in the disclosure can improve the manufacturability of an API (e.g., Compound II, Compound III, or Compound III- d).
  • an API e.g., Compound II, Compound III, or Compound III- d.
  • the polymers for use in the disclosure can improve one or more of the handling, administration or storage properties of an API (e.g., Compound II, Compound III, or Compound Ill-d).
  • an API e.g., Compound II, Compound III, or Compound Ill-d.
  • the polymers for use in the disclosure have little or no unfavorable interaction with other pharmaceutical components, for example excipients.
  • the suitability of a candidate polymer (or other component) can be tested using the spray drying methods (or other methods) described herein to form an amorphous composition.
  • the candidate composition can be compared in terms of stability, resistance to the formation of crystals, or other properties, and compared to a reference preparation, e.g., a preparation of neat amorphous Compound I, Compound II, Compound III, or Compound Ill-d.
  • a candidate composition could be tested to determine whether it inhibits the time to onset of solvent mediated
  • the first solid dispersion comprises a cellulose polymer.
  • the first solid dispersion comprises hydroxypropyl
  • the first solid dispersion comprises a weight ratio of HPMC to Compound II ranging from 1 : 10 to 1 : 1. In some instances, the weight ratio of HPMC to Compound II is from 1 :3 to 1 :5.
  • the second solid dispersion comprises a cellulose polymer.
  • the second solid dispersion comprises hydroxypropyl methylcellulose acetate succinate (HPMCAS).
  • HPMCAS hydroxypropyl methylcellulose acetate succinate
  • each of the first and second solid dispersions comprises a plurality of particles having a mean particle diameter of 5 to 100 microns.
  • the particles have a mean particle diameter of 5 to 30 microns.
  • the parti cules have a mean particle diameter of 15 microns.
  • the first solid dispersion comprises from 70 wt% to 90 wt% (e.g., from 75 wt% to 85 wt%) of Compound II.
  • the second solid dispersion comprises from 70 wt% to 90 wt% (e.g., from 75 wt% to 85 wt%) of Compound Ill-d or III.
  • each of the first and second solid dispersions is a spray dried dispersion.
  • the pharmaceutical composition disclosed herein further comprise one or more pharmaceutically acceptable excipients, such as pharmaceutically acceptable vehicles, adjuvants, or carriers.
  • the pharmaceutical composition for use in the methods of the disclosure comprises one or more fillers, a disintegrant, and a lubricant.
  • Fillers suitable for the pharmaceutical compositions disclosed herein are compatible with the other ingredients of the pharmaceutical compositions, i.e., they do not substantially reduce the solubility, the hardness, the chemical stability, the physical stability, or the biological activity of the pharmaceutical compositions.
  • 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. com starch, potato starch), sugars (e.g., mannitol, lactose, sucrose, or the like), or any combination thereof.
  • the filler is microcrystalline cellulose.
  • the pharmaceutical compositions comprise one or more fillers in an amount of at least 5 wt% (e.g., at least 20 wt%, at least 30 wt%, or at least 40 wt%) by weight of the pharmaceutical composition.
  • the pharmaceutical compositions comprise from 10 wt% to 60 wt% (e.g., from 20 wt% to 55 wt%, from 25 wt% to 50 wt%, or from 27 wt% to 45 wt%) of filler, by weight of the pharmaceutical composition.
  • the pharmaceutical composition s comprise at least 20 wt% (e.g., at least 30 wt% or at least 40 wt%) of microcrystalline cellulose, for example MCC Avicel PHI 02 or Avicel PH101, by weight of the pharmaceutical composition.
  • the pharmaceutical compositions comprise from 10 wt% to 60 wt% (e.g., from 20 wt% to 55 wt% or from 25 wt% to 45 wt%) of microcellulose, by weight of the pharmaceutical composition.
  • Disintegrants suitable for the pharmaceutical compositions disclosed herein can enhance the dispersal of the pharmaceutical compositions and are compatible with the other ingredients of the pharmaceutical compositions, i.e., they do not substantially reduce the chemical stability, the physical stability, the hardness, or the biological activity of the pharmaceutical compositions.
  • Exemplary disintegrants include croscarmellose sodium, sodium starch glycolate, crospovidone or a combination thereof.
  • the disintegrant is croscarmellose sodium.
  • the pharmaceutical compositions discosed herein comprise disintegrant in an amount of 10 wt% or less (e.g., 7 wt% or less, 6 wt% or less, or 5 wt% or less) by weight of the pharmaceutical composition.
  • the pharmaceutical compositions comprise from 1 wt% to 10 wt% (e.g., from 1.5 wt% to
  • the pharmaceutical compositions comprise 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 pharmaceutical composition.
  • the pharmaceutical compositions comprise from 1 wt% to 10 wt% (e.g., from 1.5 wt% to 7.5 wt% or from
  • the pharmaceutical compositions comprise from 0.1% to 10 wt% (e.g., from 0.5 wt% to 7.5 wt% or from 1.5 wt% to 6 wt%) of disintegrant, by weight of the pharmaceutical composition.
  • the pharmaceutical compositions comprise from 0.1% to 10 wt% (e.g., from 0.5 wt% to 7.5 wt% or from 1.5 wt% to 6 wt%) of disintegrant, by weight of the pharmaceutical composition.
  • compositions comprise from 0.5% to 10 wt% (e.g., from 1.5 wt% to 7.5 wt% or from 2.5 wt% to 6 wt%) of disintegrant, by weight of the pharmaceutical composition.
  • the pharmaceutical compositions disclosed herein comprise a lubricant.
  • a lubricant can prevent adhesion of a mixture compoent to a surface (e.g., a surface of a mixing bowl, a granulation roll, 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 granulator and/or die press.
  • a suitable lubricant for the pharmaceutical compositions disclosed herein is compatible with the other ingredients of the pharmaceutical compositions, i.e., they do not substantially reduce the solubility, the hardness, or the biological activity of the pharmaceutical compositions.
  • Exemplary lubricants include magnesium stearate, sodium stearyl fumarate, calcium stearate, zinc stearate, sodium stearate, stearic acid, aluminum stearate, leucine, glyceryl behenate, hydrogenated vegetable oil or any combination thereof.
  • the lubricant is magnesium stearate.
  • the pharmaceutical compositions comprise 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 pharmaceutical composition.
  • the pharmaceutical compositions comprise from 5 wt% to 0.10 wt% (e.g., from 4.5 wt% to 0.5 wt% or from 3 wt% to 1 wt%) of lubricant, by weight of the pharmaceutical composition.
  • the pharmaceutical compositions comprise 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 pharmaceutical composition.
  • the pharmaceutical compositions comprise from 5 wt% to 0.10 wt% (e.g., from 4.5 wt% to 0.15 wt% or from 3.0 wt% to 0.50 wt%) of magnesium stearate, by weight of the pharmaceutical composition.
  • the pharmaceutical compositions disclosed herein are tablets.
  • Any suitable spray dried dispersions of Compound II, Compound Ill-d, and Compound III can be used for the pharmaceutical compositions disclosed herein.
  • Some examples for Compound II and its pharmaceutically acceptable salts can be found in WO 2011/119984 and WO 2014/014841, all of which are incorporated herein by reference.
  • Some examples for Compound III and its pharmaceutically acceptable salts can be found in WO 2007/134279, WO 2010/019239, WO 2011/019413, WO
  • compositions comprising Compound II and Compound III are disclosed in PCT Publication No. WO 2015/160787, incorporated herein by reference.
  • An exemplary embodiment is shown in the following Table 2:
  • compositions comprising Compound III are disclosed in PCT Publication No. WO 2010/019239, incorporated herein by reference.
  • An exemplary embodiment is shown in the following Table 3:
  • Table 3 Ingredients for Exemplary Tablet of Compound III.
  • compositions comprising Compound III are disclosed in PCT Publication No. WO 2013/130669, incorporated herein by reference.
  • Exemplary mini-tablets ( ⁇ 2 mm diameter, ⁇ 2 mm thickness, each mini-tablet weighing 6.9 mg) was formulated to have 50 mg of Compound III per 26 mini-tablets and 75 mg of Compound III per 39 mini-tablets using the amounts of ingredients recited in Table 4, below.
  • Table 4 Ingredients for mini-tablets for 50 mg and 75 mg potency
  • compositions disclosed herein comprise:
  • compositions disclosed herein comprise:
  • compositions disclosed herein comprise:
  • compositions disclosed herein comprise:
  • the pharmaceutical composition disclosed herein comprise:
  • compositions disclosed herein comprise:
  • compositions disclosed herein comprise:
  • compositions disclosed herein comprise:
  • compositions disclosed herein comprise:
  • compositions disclosed herein comprise:
  • compositions disclosed herein comprise:
  • compositions disclosed herein comprise:
  • compositions disclosed herein comprise:
  • compositions disclosed herein comprise:
  • compositions disclosed herein comprise:
  • the pharmaceutical compositions disclosed herein are tablets.
  • the tablets of the disclosure can be produced by compacting or compressing an admixture or composition, for example, powder or granules, under pressure to form a stable three-dimensional shape (e.g., a tablet).
  • an admixture or composition for example, powder or granules
  • 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.
  • the methods of preparing the tablets disclosed herein comprise (a) mixing Compound I and the first and second solid dispersions to form a first mixture; and (b) compressing a tablet mixture comprising the first mixture into a tablet.
  • the term“mixing” include mixing, blending and combinding.
  • the tablet mixture further comprises one or more pharmaceutically acceptable excipients, and the methods further comprise mixing the first mixture with said one or more excipients to form the tablet mixture. Mixing the first mixture with one or more excipients can be performed in one or more steps.
  • the one or more excipients are mixed to form a second mixture; and the first and second mixtures are mixed together to form the tablet mixture prior to the compression step.
  • the one or more excipients can be mixed with the first mixture in more than one parts, for example, some excipients mixed with the first mixture first and the other excipients followed later.
  • the tablets disclosed herein an intra-granular part and an extra-grandular part as described above, and one or more excipients included in the intra-granular part are mixed to form a second mixture, and one or more excipients included in the extra-granular part are mixed to form a third mixture, and the first mixture are combined with the second mixture, and the combined first and second mixtures are combined with the third mixture to form a tablet mixture.
  • the methods of preparing the tablets disclosed herein comprise:(a) mixing Compound I and the first and second solid dispersions to form a first mixture; (b) mixing the first mixture with one or more of microcrystalline cellulose, croscarmellose sodium and magnesium stearate to form a tablet mixture; and (c) compressing the tablet mixture into a tablet.
  • the methods of preparing the tablets disclosed herein comprise:
  • steps (a), (b), and (c) may occur in any order.
  • the methods disclosed herein further comprise coating the tablet.
  • the methods disclosed herein further comprise granulating the first, second, and/or third mixtures prior to the compression the tablet mixture. Any suitable methods known in the art for granulation and compression of pharmaceutical compositions can be used. It is noted that step (a) can occur prior to step (b) or step (b) can occur prior to step (a).
  • solid forms including powders comprising one or more APIs (e.g., Compound I, Compound II, Compound Ill-d and/or Compound III) and the included pharmaceutically acceptable excipients (e.g. filler, diluent,
  • disintegrant 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 to produce tablets that comply with the demand of mass variation or content uniformity.
  • formulations can be produced using one or more mixing and dry granulations steps. The order and the number of the mixing by granulation. At least one of the excipients and the API(s) can be subject to dry granulation or wet high shear granulation or twin screw wet granulation before compression into tablets. 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. Generally, the mechanical process requires compaction such as the one provided by roller compaction. An example of an alternative method for dry granulation is slugging. In some embodiments, wet granulations instead of the dry granulation can be used.
  • roller compaction is a granulation process comprising mechanical compacting of one or more substances.
  • a pharmaceutical composition comprising an admixture of powders is pressed, that is roller compacted, between two rotating rollers to make a solid sheet that 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.
  • An example of roller compaction equipment is Minipactor® a Gerteis 3W-Polygran from Gerteis
  • tablet compression according to the disclosure 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 tensile strength in the range of from 0.5 MPa to 3.0MPa; such as 1.0 to 2.5MPa, such as in the range of 1.5 to 2.0 MPa.
  • 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 may optionally be sifted to obtain the desired size.
  • the granules can be further blended or lubricated with, for example, magnesium stearate.
  • the granular composition of the disclosure can be compressed on suitable punches into various pharmaceutical formulations in accordance with the disclosure.
  • the tablets can be coated with a film coat.
  • Another aspect of the disclosure provides a method for producing a pharmaceutical composition
  • a method for producing a pharmaceutical composition comprising an admixture of a composition comprising one or more APIs (e.g., Compound I, Compound II, Compound Ill-d and/or Compound III); and one or more excipients selected from: one or more fillers, a diluent, a binder, a glidant, a surfactant, a lubricant, a disintegrant, and compressing the composition into a tablet.
  • APIs e.g., Compound I, Compound II, Compound Ill-d and/or Compound III
  • excipients selected from: one or more fillers, a diluent, a binder, a glidant, a surfactant, a lubricant, a disintegrant, and compressing the composition into a tablet.
  • the tablets disclosed herein can be coated with a film coating and optionally labeled with a logo, other image and/or text using a suitable ink.
  • the tablets disclosed herein can be coated with a film coating, waxed, and optionally labeled with a logo, other image and/or text using a suitable ink.
  • Suitable film coatings and inks are compatible with the other ingredients of the tablets, e.g., they do not substantially reduce the solubility, the chemical stability, the physical stability, the hardness, or the biological activity of the tablets.
  • the suitable colorants and inks can be any color and are water based or solvent based.
  • the tablets disclosed herein are coated with a colorant and then labeled with a logo, other image, and/or text using a suitable ink.
  • the tablets disclosed herein are coated with a film that comprises 2-6 wt% by the weight of the uncoated tablet.
  • the film comprises one or more colorants and/or pigments.
  • the tablets disclosed herein are coated with a film that comprises one or more colorants and/or pigments and wherein the film comprises 2 - 5 wt% by the weight of the uncoated tablet.
  • the tablets disclosed herein are coated with a film that comprises one or more colorants and/or pigments and wherein the film comprises 2 - 4 wt% by the weight of the uncoated tablet.
  • 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.
  • compositions comprising Compound I and/or pharmaceutically acceptable salts thereof are useful in methods of treating cystic fibrosis in patients taking oral hormonal therapies, including oral hormonal
  • the tablets disclosed herein can be administered once a day, twice a day, or three times a day. In some embodiments, one or more of the tablets are administered per dosing. In some embodiments, two tablets per dosing are administered. In some embodiments, two tablets per dosing are administered once a day. In some embodiments,
  • two tablets per dosing are administered twice a day.
  • An effective amount of the APIs e.g., Compound I
  • the tablets disclosed herein are useful for treating cystic fibrosis in patients who are concurrently recieving oral hormonal therapies, including hormone based oral contraceptives.
  • the tablets disclosed herein can be employed in combination therapies. In some embodiments, the tablets disclosed herein can be administered concurrently with, prior to, or subsequent to, at least one active
  • the pharmaceutical compositions are a tablet.
  • the tablets are suitable for oral administration.
  • compositions or medical procedures are useful for treating cystic fibrosis in patients who are concurrently receiving oral hormonal therapies, including hormone based oral contraceptives.
  • Compounds I, II, Ill-d, and III are as depicted above.
  • Compound IV is depicted as having the following structure:
  • a chemical name for Compound IV is 3-(6-(l-(2,2- difluorobenzo[d][l,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2- yl)benzoic acid.
  • a CFTR mutation may affect the CFTR quantity, i.e., the number of CFTR channels at the cell surface, or it may impact CFTR function, i.e., the functional ability of each channel to open and transport ions.
  • Mutations affecting CFTR quantity include mutations that cause defective synthesis (Class I defect), mutations that cause defective processing and trafficking (Class II defect), mutations that cause reduced synthesis of CFTR (Class V defect), and mutations that reduce the surface stability of CFTR (Class VI defect).
  • Mutations that affect CFTR function include mutations that cause defective gating (Class III defect) and mutations that cause defective conductance (Class IV defect).
  • methods of treating, lessening the severity of, or symptomatically treating cystic fibrosis in a patient comprising administering an effective amount of a compound, pharmaceutically acceptable salt thereof, or a deuterated analog of any of the foregoing; or a pharmaceutical composition, of this disclosure to a patient, such as a human, wherein said patient has cystic fibrosis, and wherein said patient is concurrently recieiving an oral hormonal therapy, e.g., an hormone based oral contraceptive.
  • the patient has an F508del/minimal function (MF) genotype, F508del/F508del genotype
  • the patient is heterozygous and has one F508del mutation.
  • minimal function (MF) mutations refer to CFTR gene mutations associated with minimal CFTR function (little-to-no functioning CFTR protein) and include, for example, mutations associated with severe defects in ability of the CFTR channel to open and close, known as defective channel gating or“gating mutations”; mutations associated with severe defects in the cellular processing of CFTR and its delivery to the cell surface; mutations associated with no (or minimal) CFTR synthesis; and mutations associated with severe defects in channel conductance.
  • the patient is heterozygous and has an F508del mutation on one allele and a mutation on the other allele selected from Table 5:
  • API(s) and tablets comprising such API(s) required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the disease, the particular agent, its mode of
  • 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 API(s) and tablets comprising such API(s) of this disclosure 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 API 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, such as a mammal, and even further such as a human.
  • the disclosure also is directed to methods of treatment using isotope-labelled compounds of the afore-mentioned compounds, which have the same structures as disclosed herein except that one or more atoms therein have been replaced by an atom or atoms having an atomic mass or mass number which differs from the atomic mass or mass number of the atom which usually occurs naturally (isotope labelled).
  • isotopes which are commercially available and suitable for the disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, for example 2 H, 3 H, 13 C, 14 C, 15 N, 18 0, 17 0, 31 P, 32 P, 35 S, 18 F and 36 C1, respectively.
  • the isotope-labelled compounds and salts can be used in a number of beneficial ways. They can be suitable for medicaments and/or various types of assays, such as substrate tissue distribution assays.
  • tritium (3 ⁇ 4)- and/or carbon-14 ( 14 C)-labelled compounds are particularly useful for various types of assays, such as substrate tissue distribution assays, due to relatively simple preparation and excellent detectability.
  • deuterium ( 2 H)-labelled ones are therapeutically useful with potential therapeutic advantages over the non- 2 H-labelled compounds.
  • deuterium ( 2 H)-labelled compounds and salts can have higher metabolic stability as compared to those that are not isotope-labelled owing to the kinetic isotope effect described below.
  • the isotope-labelled compounds and salts can usually be prepared by carrying out the procedures disclosed in the synthesis schemes and the related description, in the example part and in the preparation part in the present text, replacing a non-isotope-labelled reactant by a readily available isotope-labelled reactant.
  • the isotope-labelled compounds and salts are deuterium ( 2 H)-labelled ones.
  • the isotope-labelled compounds and salts are deuterium ( 2 H)-labelled, wherein one or more hydrogen atoms therein have been replaced by deuterium.
  • deuterium is represented as“ 2 H” or“D.”
  • deuterium ( 2 H)-labelled compounds and salts can manipulate the oxidative metabolism of the compound by way of the primary kinetic isotope effect.
  • the primary kinetic isotope effect is a change of the rate for a chemical reaction that results from exchange of isotopic nuclei, which in turn is caused by the change in ground state energies necessary for covalent bond formation after this isotopic exchange.
  • Exchange of a heavier isotope usually results in a lowering of the ground state energy for a chemical bond and thus causes a reduction in the rate-limiting bond breakage.
  • the bond breakage occurs in or in the vicinity of a saddle-point region along the coordinate of a multi-product reaction, the product distribution ratios can be altered substantially.
  • the concentration of the isotope(s) (e.g., deuterium) incorporated into the isotope-labelled compounds and salt of the disclosure may be defined by the isotopic enrichment factor.
  • isotopic enrichment factor means the ratio between the isotopic abundance and the natural abundance of a specified isotope.
  • a substituent in a compound of the disclosure is denoted deuterium
  • such compound has an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation).
  • deuteration of one or more metabolically labile positions on a compound or active metabolite may lead to improvement of one or more superior DMPK properties while maintaining biological activity as compared to the corresponding hydrogen analogs.
  • the superior DMPK property or properties may have an impact on the exposure, half-life, clearance, metabolism, and/or even food requirements for optimal absorption of the drug product. Deuteration may also change the metabolism at other non-deuterated positions of the deuterated compound.
  • Compound Ill-d as used herein includes the deuterated compound disclosed in U.S. Patent No. 8,865,902 (which is incorporated herein by reference), and CTP-656.
  • Exemplary embodiments of the disclosure include:
  • a method of treating cystic fibrosis in a patient comprising administering to the patient an effective amount of Compound I or a pharmaceutically acceptable salt thereof, wherein the patient is also taking one or more oral hormonal contraceptive(s). 2. The method of embodiment 1, further comprising administering to the patient one or more additional therapeutic agent(s) prior to, concurrent with, or subsequent to Compound I or a pharmaceutically acceptable salt thereof.
  • a method of treating cystic fibrosis in a patient comprising administering to the patient an effective amount of a pharmaceutical composition comprising Compound I or a pharmaceutically acceptable salt thereof, Compound II or a pharmaceutically acceptable salt thereof, and Compound III, Compound Ill-d, or a pharmaceutically acceptable salt thereof, wherein the patient is also taking one or more oral hormonal contraceptive(s).
  • a pharmaceutical composition comprising Compound I or a pharmaceutically acceptable salt thereof, Compound II or a pharmaceutically acceptable salt thereof, and Compound III, Compound Ill-d, or a pharmaceutically acceptable salt thereof, wherein the patient is also taking one or more oral hormonal contraceptive(s).
  • the pharmaceutical composition has a formulation selected from:
  • spectrometer operating at a 3 ⁇ 4 and 13 C resonant frequency of 400 and 100 MHz respectively, or on a 300 MHz NMR spectrometer.
  • One dimensional proton and carbon spectra were acquired using a broadband observe (BBFO) probe with 20 Hz sample rotation at 0.1834 and 0.9083 Hz/Pt digital resolution respectively. All proton and carbon spectra were acquired with temperature control at 30°C using standard, previously published pulse sequences and routine processing parameters.
  • BBFO broadband observe
  • Optical purity of methyl (2S)-2,4-dimethyl-4-nitro-pentanoate was determined using chiral gas chromatography (GC) analysis on an Agilent 7890A/MSD 5975C instrument, using a Restek Rt-PDEXcst (30m x 0.25mm x 0.25um_df) column, with a 2.0 mL/min flow rate (H2 carrier gas), at an injection temperature of 220°C and an oven temperature of 120°C, 15 minutes.
  • GC chiral gas chromatography
  • the powder x-ray diffraction measurements were performed using PANalyticaFs X-pert Pro diffractometer at room temperature with copper radiation (1.54060 A).
  • the incident beam optic was comprised of a variable divergence slit to ensure a constant illuminated length on the sample and on the diffracted beam side; a fast linear solid state detector was used with an active length of 2.12 degrees 2 theta measured in a scanning mode.
  • the powder sample was packed on the indented area of a zero background silicon holder and spinning was performed to achieve better statistics.
  • a symmetrical scan was measured from 3 - 40 degrees 2 theta with a step size of 0.017 degrees and a scan step time of 15.5s.
  • TPPM15 proton decoupling sequence was used with the field strength of approximately 100 kHz for both 13 C and 19 F acquisitions.
  • Optical purity of methyl (2S)-2,4-dimethyl-4-nitro-pentanoate was determined using chiral gas chromatography (GC) analysis on an Agilent 7890A/MSD 5975C instrument, using a Restek Rt-PDEXcst (30m x 0.25mm x 0.25um_df) column, with a 2.0 mL/min flow rate (H2 carrier gas), at an injection temperature of 220°C and an oven temperature of 120°C, 15 minutes.
  • GC chiral gas chromatography
  • Step 1 methyl-2, 4-dimethyl-4-nitro-pentanoate
  • Tetrahydrofuran THF, 4.5 L was added to a 20 L glass reactor and stirred under N2 at room temperature.
  • 2-Nitropropane 1.5 kg, 16.83 mol
  • DBU 1,8- diazabicyclo[5.4.0]undec-7-ene
  • reaction mixture was concentrated in vacuo then transferred back to the reactor and diluted with methyl /cvV-butyl ether (MTBE) (14 L).
  • 2 M HC1 (7.5 L) was added, and this mixture was stirred for 5 minutes then allowed to settle. Two clear layers were visible - a lower yellow aqueous phase and an upper green organic phase. The aqueous layer was removed, and the organic layer was stirred again with 2 M HC1 (3 L). After separation, the HC1 washes were recombined and stirred with MTBE (3 L) for 5 minutes. The aqueous layer was removed, and all of the organic layers were combined in the reactor and stirred with water (3 L) for 5 minutes.
  • MTBE methyl /cvV-butyl ether
  • a reactor was charged with purified water (2090 L; 10 vol) and then potassium phosphate monobasic (27 kg, 198.4 moles; 13 g/L for water charge). The pH of the reactor contents was adjusted to pH 6.5 ( ⁇ 0.2) with 20% (w/v) potassium carbonate solution. The reactor was charged with racemic methyl-2, 4-dimethyl-4-nitro- pentanoate (209 kg; 1104.6 moles), and Palatase 20000L lipase (13 L, 15.8 kg; 0.06 vol).
  • the reaction mixture was adjusted to 32 ⁇ 2 °C and stirred for 15-21 hours, and pH 6.5 was maintained using a pH stat with the automatic addition of 20% potassium carbonate solution.
  • the reactor was then charged with MTBE (35 L; 5 vol), and the aqueous layer was extracted with MTBE (3 times, 400-1000L).
  • the combined organic extracts were washed with aqueous Na2CCb (4 times, 522 L, 18 % w/w 2.5 vol), water (523 L; 2.5 vol), and 10% aqueous NaCl (314 L, 1.5 vol).
  • the organic layer was concentrated in vacuo to afford methyl (2k)-2,4-di methyl -4-nitro-pentanoate as a mobile yellow oil (>98% ee, 94.4 kg; 45 % yield).
  • a 20 L reactor was purged with N2.
  • the vessel was charged sequentially with DI water-rinsed, damp Raney® Ni (2800 grade, 250 g), methyl (2S)-2,4-dimethyl- 4-nitro-pentanoate (1741g, 9.2 mol), and ethanol (13.9 L, 8 vol).
  • the reaction was stirred at 900 rpm, and the reactor was flushed with H2 and maintained at ⁇ 2.5 bar.
  • the reaction mixture was then warmed to 60 °C for 5 hours.
  • the reaction mixture was cooled and filtered to remove Raney nickel, and the solid cake was rinsed with ethanol (3.5 L, 2 vol).
  • the ethanolic solution of the product was combined with a second equal sized batch and concentrated in vacuo to reduce to a minimum volume of ethanol (-1.5 volumes).
  • Heptane (2.5 L) was added, and the suspension was concentrated again to -1.5 volumes. This was repeated 3 times; the resulting suspension was cooled to 0-5 °C, filtered under suction, and washed with heptane (2.5 L).
  • the product was dried under vacuum for 20 minutes then transferred to drying trays and dried in a vacuum oven at 40 °C overnight to afford (TV)-3, 5, 5-tri methyl pyrrol idin-2-one as a white crystalline solid (2.042 kg, 16.1 mol, 87 %).
  • a glass lined 120 L reactor was charged with lithium aluminum hydride pellets (2.5 kg, 66 mol) and dry THF (60 L) and warmed to 30 °C.
  • the resulting suspension was charged with (3 ⁇ 4 ) -3,5,5-trimethylpyrrolidin-2-one (7.0 kg, 54 mol) in THF (25 L) over 2 hours while maintaining the reaction temperature at 30 to 40 °C. After complete addition, the reaction temperature was increased to 60 - 63 °C and maintained overnight.
  • a 1 L 3 neck round bottom flask was fitted with a mechanical stirrer, a cooling bath, an addition funnel, and a J-Kem temperature probe.
  • the vessel was charged with lithium aluminum hydride (LAH) pellets (6.3 g, 0.1665 mol) under a nitrogen atmosphere.
  • LAH lithium aluminum hydride
  • the vessel was then charged with tetrahydrofuran (200 mL) under a nitrogen atmosphere.
  • the mixture was allowed to stir at room temperature for 0.5 hours to allow the pellets to dissolve.
  • the cooling bath was then charged with crushed ice in water and the reaction temperature was lowered to 0 °C.
  • the addition funnel was charged with a solution of 3,3, 3-trifluoro-2, 2-dimethyl-propanoic acid (20 g, 0.1281 mol) in tetrahydrofuran (60 mL) and the clear pale yellow solution was added drop wise over 1 hour. After the addition was complete the mixture was allowed to slowly warm to room temperature and stirring was continued for 24 hours. The suspension was cooled to 0 °C with a crushed ice-water in the cooling bath and then quenched by the very slow and drop wise addition of water (6.3 ml), followed by sodium hydroxide solution (15 weight %; 6.3 mL) and then finally with water (18.9 mL). The reaction temperature of the resulting white suspension was recorded at 5 °C.
  • the suspension was stirred at ⁇ 5 °C for 30 minutes and then filtered through a 20 mm layer of Celite.
  • the filter cake was washed with tetrahydrofuran (2 x 100 mL).
  • the filtrate was dried over sodium sulfate (150 g) and then filtered.
  • the filtrate was concentrated under reduced pressure to provide a clear colorless oil (15 g) containing a mixture of the product 3,3,3- trifluoro-2,2-dimethyl-propan-l-ol in THF (73 % weight of product ⁇ 10.95g, and 27 wt.% THF as determined by 1H-NMR).
  • a 50L Syrris controlled reactor was started and jacket set to 20 °C, stirring at 150 rpm, reflux condenser (10 °C) and nitrogen purge.
  • MeOH (2.860 L) and methyl (E)-3-methoxyprop-2-enoate (2.643 kg, 22.76 mol) were added and the reactor was capped.
  • the reaction was heated to an internal temperature of 40 °C and the system was set to hold jacket temp at 40 °C. Hydrazine hydrate (1300 g of 55 %w/w, 22.31 mol) was added portion wise via addition funnel over 30 min. The reaction was heated to 60 °C for 1 h.
  • reaction mixture was cooled to 20 °C and triethyamine (2.483 kg, 3.420 L, 24.54 mol) was added portion wise (exothermic), maintaining reaction temp ⁇ 30 °C.
  • the reaction mixture was stirred at 20 °C for 16 h.
  • the reaction solution was partially concentrated to remove MeOH, resulting in a clear light amber oil.
  • the resulting oil was transferred to the 50L reactor, stirred and added water (7.150 L) and heptane (7.150 L).
  • the additions caused a small amount of the product to precipitate.
  • the aqueous layer was drained into a clean container and the interface and heptane layer were filtered to separate the solid (product).
  • the aqueous layer was transferred back to the reactor, and the collected solid was placed back into the reactor and mixed with the aqueous layer.
  • a dropping funnel was added to the reactor and loaded with acetic acid (1.474 kg, 1.396 L, 24.54 mol), then began dropwise addition of acid.
  • the solid was collected by filtration and washed with water (7.150 L), and washed a second time with water (3.575 L) and pulled dry.
  • the crystalline solid was scooped out of the filter into a 20L rotovap bulb and heptane (7.150 L) was added.
  • the mixture was slurried at 45 °C for 30 mins, and then distilled off 1-2 volumes of solvent.
  • the slurry in the rotovap flask was filtered and the solids washed with heptane (3.575 L) and pulled dry.
  • Step A tert- Butyl 3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazole-l-carboxylate
  • Step B 3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)-lH-pyrazole
  • Step C tert- Butyl 2,6-dichloropyridine-3-carboxylate
  • Step D tert- Butyl 2-chloro-6-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-l- yl] pyr idine-3-carboxylate
  • Step F 2-Chloro-/V-(l,3-dimethylpyrazol-4-yl)sulfonyl-6-[3-(3,3,3-trifluoro-2,2- dimethyl-propoxy)pyrazol-l-yl]pyridine-3-carboxamide
  • Step G /V-(l,3-dimethylpyrazol-4-yl)sulfonyl-6-[3-(3,3,3-trifluoro-2,2-dimethyl- propoxy)pyrazol-l-yl]-2-[( V)-2,2,4-trimethylpyrrolidin-l-yl]pyridine-3- carboxamide
  • the reaction mixture was heated at 120 °C for 16 h then cooled to room temperature.
  • the reaction was diluted with DCM (200.0 mL) and HC1 (approximately 172.8 mL of 2 M, 345.5 mmol); aqueous pH ⁇ 1.
  • the phases were separated, and the aqueous phase was extracted with DCM (100.0 mL).
  • the organic phases were combined, washed with water (100.0 mL) (3 x), and dried (Na2S04) to afford an amber solution.
  • the solution was filtered through a DCM-packed silica gel bed (80 g; 4 g/g) and washed with 20% EtOAc/DCM (5 x 200 mL).
  • the combined filtrate/washes were concentrated to afford 22.2 g of an off-white powder.
  • the powder was slurried in MTBE (140 mL) for 30 min.
  • the solid was collected by filtration (paper/sintered-glass) to afford 24 g after air drying.
  • the solid was transferred to a drying dish and vacuum-dried (40 °C/200 torr/N2 bleed) overnight to afford 20.70 g (90%) of a white powder.
  • ESI-MS m/z calc.
  • a reactor was loaded with toluene (300 mL) and 3,3,3-trifluoro-2,2- dimethylpropanoic acid (30 g, 192.2 mmol), capped, purged under nitrogen. The reaction was set to control the internal temperature to 40 °C. A solution of Vitride (65% in toluene approximately 119.6 g of 65 %w/w, 115.4 mL of 65 %w/w, 384.4 mmol) was set up for addition via syringe, and addition was begun at 40 °C, with the target addition temperature between 40 and 50 °C. The reaction was stirred at 40 °C for 90 min.
  • the reaction was cooled to 10 °C then the remaining Vitride was quenched with slow addition of water (6 mL). A solution of 15 % aq NaOH (30 mL) was added in portions, and solids precipitated half way through the base addition. Water (60.00 mL) was added. The mixture was warmed to 30 °C and held for at least 15 mins. The mixture was then cooled to 20 °C. The aqueous layer was removed. The organic layer was washed with water (60 mL x 3), and then washed with brine (60 mL). The washed organic layer was dried under Na2SC>4, followed with MgSCri.
  • Step 2 Preparation of l-(tert-butyl) 4-ethyl 3-(3,3,3-trifluoro-2,2- dimethylpropoxy)- lH-pyrazole- 1 ,4-dicarboxylate
  • a reactor was charged with 3,3,3-trifluoro-2,2-dimethylpropan-l-ol (17.48 g, 123.0 mmol) solution in toluene (250g), l-(tert-butyl) 4-ethyl 3-hydroxy-lH- pyrazole-l,4-dicarboxylate (30.0 g, 117.1 mmol), and PPh3 (35.33 g, 134.7 mmol). The reaction was heated to 40 °C. DIAD (26.09 mL, 134.7 mmol) was weighed and placed into a syringe and added over 10 minutes while maintaining an internal temperature ranging between 40 and 50 °C.
  • DIAD 26.09 mL, 134.7 mmol
  • reaction mixture was then cooled to -2°C to 2 °C over approximately 1 hour and was used without isolation to make ethyl 2-chloro-6-(3- (3,3,3-trifluoro-2,2-dimethylpropoxy)-lH-pyrazol-l-yl)nicotinate.
  • the creamy suspension was allowed to cool to room temperature and was stirred overnight.
  • the solid was collected by filtration (sintered-glass/poly pad).
  • the filter-cake was washed with water (2 x 500- mL).
  • the filter-cake was dried by suction for 1 h but remained wet.
  • the damp solid was transferred to a 10-L Buchi flask for further drying (50 °C/20 torr), but was not effective. Further effort to dry by chasing with i-PrOH was also ineffective.
  • the crystalline Form A of Compound I was also obtained through the following procedure.
  • a suspension of Compound I (150.0 g, 228.1 mmol) in iPrOH (480 mL) and water (120 mL) was heated at 82 °C to obtain a solution.
  • the solution was cooled with a J-Kem controller at a cooling rate of 10 °C/h. Once the temperature reached 74 °C, the solution was seeded with a sample of Compound I in crystalline Form A. Crystallization occurred immediately. The sample was cooled to ⁇ 5 °C, let stir for 1 h, and then the solid was collected by filtration (sintered glass/paper).
  • the filter- cake was washed with i-PrOH (75 mL) (2 x), air-dried with suction, air-dried in a drying dish (120.6 g mostly dried), vacuum-dried (55 °C/300 torr/N2 bleed) for 4 h, and then RT overnight. Overnight drying afforded 118.3 g (87% yield) of a white powder.
  • Example 2 Synthesis of Compound II: (R)-l-(2,2-Difluorobenzo[d][l,3]dioxol-5- yl)-N-(l-(2,3-dihydroxypropyl)-6-fluoro-2-(l-hydroxy-2-methylpropan-2-yl)-lH- indol-5-yl)cyclopropanecarboxamide
  • Step 1 (R)-Benzyl 2-(l-((2,2-dimethyl-l,3-dioxolan-4-yl)methyl)-6-fluoro-5-nitro- lH-indol-2-yl)-2-methylpropanoate and ((S)-2,2-Dimethyl-l,3-dioxolan-4-yl)methyl 2-(l-(((R)-2,2-dimethyl-l,3-dioxolan-4-yl)methyl)-6-fluoro-5-nitro-lH-indol-2-yl)- 2-methylpropanoate
  • Step 2 (R)-2-(l-((2,2-dimethyl-l,3-dioxolan-4-yl)methyl)-6-fluoro-5-nitro-lH- indol-2-yl)-2-methylpropan-l-ol
  • step (A) The crude reaction mixture obtained in step (A) was dissolved in THF (tetrahydrofuran) (42 mL) and cooled in an ice-water bath. LiAlEL (16.8 mL of 1 M solution, 16.8 mmol) was added drop-wise. After the addition was complete, the mixture was stirred for an additional 5 minutes. The reaction was quenched by adding water (1 mL), 15% NaOH solution (1 mL) and then water (3 mL). The mixture was filtered over Celite, and the solids were washed with THF and ethyl acetate.
  • THF tetrahydrofuran
  • Step 3 (R)-2-(5-amino-l-((2,2-dimethyl-l,3-dioxolan-4-yl)methyl)-6-fluoro-lH- indol-2-yl)-2-methylpropan-l-ol
  • Step 4 (R)-l-(2,2-difluorobenzo[d][l,3]dioxol-5-yl)-N-(l-((2,2-dimethyl-l,3- dioxolan-4-yl)methyl)-6-fluoro-2-(l-hydroxy-2-methylpropan-2-yl)-lH-indol-5- yl)cyclopropanecarboxamide
  • Step 5 (R)-l-(2,2-difluorobenzo[d][l,3]dioxol-5-yl)-N-(l-(2,3-dihydroxypropyl)-6- fluoro-2-(l-hydroxy-2-methylpropan-2-yl)-lH-indol-5- yl)cyclopropanecarboxamide
  • Step 1 Carbonic acid 2,4-di-ferf-butyl-phenyl ester methyl ester
  • Step 2 Carbonic acid 2,4-di-fer/-butyl-5-nitro-phenyl ester methyl ester and Carbonic acid 2,4-di-ter/-butyl-6-nitro-phenyl ester methyl ester
  • the ether layer was dried (MgSCri), concentrated and purified by column chromatography (0 - 10% ethyl acetate - hexanes) to yield a mixture of carbonic acid 2,4-di-/er/-butyl-5-nitro-phenyl ester methyl ester and carbonic acid 2,4-di-/er/-butyl-6-nitro-phenyl ester methyl ester as a pale yellow solid (4.28 g), which was used directly in the next step.
  • Table 6.“Tablet 4” Comprising 100 mg Compound I, 50 mg Compound II and 75 mg Compound III.
  • Dissolution testing was performed using USP Apparatus II (paddle), in 0.5% CTAB in 50mM Acetate Buffer pH 4.5 dissolution media, following USP ⁇ 711>. Samples were collected using an autosampler and filtered through 10 pm PVDF filters into HPLC vials for reverse phase HPLC analysis.
  • An optical assay was employed to measure changes in membrane potential to determine the CFTR modulator properties of compounds.
  • the assay utilized fluorescent voltage sensing dyes to measure changes in membrane potential using a fluorescent plate reader (e.g., FLIPR III, Molecular Devices, Inc.) as a readout for increase in functional F508del in NIH 3T3 cells.
  • the driving force for the response was the creation of a chloride ion gradient in conjunction with channel activation and concurrent with compound treatment by a single liquid addition step after the cells had previously been loaded with a voltage sensing dye.
  • NIH3T3 mouse fibroblasts stably expressing F508del were used for optical measurements of membrane potential.
  • the cells were maintained at 37 °C in 5% CO2 and 90 % humidity in Dulbecco’s modified Eagle’s medium supplemented with 2 mM glutamine, 10 % fetal bovine serum, 1 X NEAA, b-ME, 1 X pen/strep, and 25 mM HEPES in 175 cm 2 culture flasks.
  • the cells were seeded at 12,000 cells/well in 384-well matrigel-coated plates.
  • the cells were cultured at 37 °C for 18 - 24 hours and loaded with a voltage sensing dye.
  • the cells were then activated and treated with Compound I. After 18-24 hours, fluorescence from the voltage sensing dye in the cells was measured to assess changes in the membrane potential as a read out for increase in functional F508del CFTR in the NIH3T3 cells.
  • Compound I had an EC50 of less than 3 mM and a % Efficacy of > 100% relative to Compound II.
  • Non-CF and CF airway epithelia were isolated from bronchial tissue, cultured using methods well known in the art, and plated onto Costar® SnapwellTM filters that were precoated with NIH3T3 -conditioned media. After four days the apical media was removed and the cells were grown at an air liquid interface for >14 days prior to use. This resulted in a monolayer of fully differentiated columnar cells that were ciliated, features that are characteristic of airway epithelia.
  • Non-CF human bronchial epithelial (HBE) cells were isolated from non-smokers that did not have any known lung disease.
  • CF-HBE cells were isolated from patients homozygous for F508del (F508del/F508del-HBE) or heterozygous for F508del with a different disease causing mutation on the other allele.
  • the basolateral solution contained (in mM) 145 NaCl, 0.83 K2HPO4, 3.3 KH2PO4, 1.2 MgCk, 1.2 CaCh, 10 Glucose, 10 HEPES (pH adjusted to 7.35 with NaOH) and the apical solution contained (in mM) 145 NaGluconate, 1.2 MgCk, 1.2 CaCk, 10 glucose, 10 HEPES (pH adjusted to 7.35 with NaOH).
  • a basolateral to apical membrane CT concentration gradient was set up as follows. Normal Ringer’s solution 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 CT concentration gradient across the epithelium.
  • Compound I was added either to the basolateral side 18 - 24 hrs prior to assay or to the apical side during the assay.
  • Forskolin (10 mM) was added to the apical side during the assay to stimulate CFTR-mediated CT transport. Chloride current was measured to assess the increase in functional CFTR in the cell membrane.
  • Compound I is a potent, efficacious, and selective next generation CFTR corrector that works by facilitating the processing and trafficking of F508del-CFTR protein to the cell surface, resulting in enhanced chloride transport.
  • Compound 1 was also administered to male Sprague Dawley rats at single nominal oral dose (PO) of 3 mg/kg as a solution in 5% NMP, 30% PEG400, 10% TPGS, 5% PVP-K30 at 5 mL/kg dose volume.
  • PO nominal oral dose
  • Example 9 Coadministration of Compound I/TEZ/IVA with oral hormonal contraceptives
  • PK pharmacokinetics
  • the secondary objectives of this study were to assess the safety of coadministration of Compound ETEZ/IVA in combination with LN/EE in healthy female subjects, and to assess plasma steady state PK of Compound I, TEZ, and IVA during coadministration with LN/EE in healthy female subjects.
  • the study design is shown in FIG. 3.
  • This study enrolled healthy female subjects to evaluate the drug-drug interaction (DDI) between oral contraceptives (OCs) and Compound I/TEZ/IVA.
  • DKI drug-drug interaction
  • OCs oral contraceptives
  • Compound I/TEZ/IVA Compound I/TEZ/IVA
  • Subjects received OC alone during Treatment Period 1, followed by coadministration of OC and Compound I/TEZ/IVA in Treatment Period 2. This is a widely used and accepted design for assessing potential DDIs with OCs.
  • Compound I/TEZ/IVA Dose and Duration
  • the dose regimen for Compound I (200 mg once daily [qd]) was selected on the basis of acceptable tolerability and favorable exposure observed in previous studies.
  • the Compound I dose is the highest dose evaluated in Phase 2.
  • TEZ and IVA are the same as those evaluated in Phase 3 studies of TEZ/IVA (TEZ: 100 mg qd; IVA: 150 mg every 12 hours [ql2h]) and those being evaluated in triple combination with Compound I.
  • Compound ETEZ/IVA parent drugs and relevant metabolites
  • TEZ and its Ml metabolite which have the longest half-lives of all study drugs administered
  • CYP3A4 is the major pathway for the metabolism of Compound I, TEZ, and IVA.
  • EE is characterized as a weak inhibitor of CYP3 A, it is unlikely to have a clinically relevant effect on the PK of Compound I TC. Therefore, the effect of OCs on the PK of Compound I/TEZ/IVA was not assessed.
  • LN and EE are common components of many marketed combined OCs, including extended cycle contraceptives.
  • the 21 -day duration of Treatment Period 1 ensured washout of prior hormonal contraception if the subject switched to study OC and for achievement of steady state for LN and EE.
  • the 10-day coadministration of LN/EE with Compound I/TEZ/IVA in Treatment Period 2 was considered sufficient to evaluate the effect of Compound I/TEZ/IVA on LN and EE PK following multiple dosing, based on the half-lives of approximately 18 hours for EE and 29 hours for LN.
  • LN and EE levels were compared on Day 21 and Day 31. PK samples collected on Days 26, 29, and 30 were used to assess LN/EE levels before intensive PK assessments on Day 31.
  • the duration of uninterrupted LN/EE treatment during the treatment periods is 31 days. This is less than the 84-day uninterrupted treatment period of LN/EE during standard extended-cycle OC use. No placebo pills were administered during Treatment Period 1 and Treatment Period 2.
  • Treatment Period 1 Days 1 through 21
  • subjects took LN 150 pg qd/EE 30 pg qd.
  • Treatment Period 2 Days 22 through 31
  • subjects received Compound I 200 mg qd/TEZ 100 mg qd/IVA 150 mg ql2h in addition to LN 150 pg/EE 30 pg qd.
  • Intensive PK samples were collected on Day 21 after administration of LN/EE alone and on Day 31 after administration of Compound I and LN/EE for 10 days.
  • Table 9 summarizes the PK parameters of LN and EE. Increases in exposure parameters (Cmax and AUCo-24h) of both LN and EE were observed on Day 31 compared to Day 21.
  • AUC0-24h AUC from the time of dosing to 24 hours; AUCO-tlast: AUC from the time of dosing to the last measurable concentration; Cmax: maximum observed concentration; CV%: coefficient of variation; LN/EE: levonorgestrel 150 mg qd/ethinyl estradiol 30 pg qd; N: total sample size (e.g., number of subjects treated); PK: pharmacokinetic; SD: standard deviation; tmax: time of maximum concentration; Compound I TC: Compound 1 200 mg qd/TEZ 100 mg qd/IVA 150 mg ql2h
  • LN AUC0-2411 increased by 23% and EE AUC0-2411 increased by 33% when coadministered with Compound I/TEZ/IVA. Increases in LN and EE exposures of this magnitude are not expected to be clinically relevant.
  • AUC0-241 1 AUC from the time of dosing to 24 hours; AUCo- ti st : AUC from the time of dosing to the last measurable concentration; Cl: confidence interval; C max : maximum observed concentration; GLSM: geometric least squares mean; LN/EE: levonorgestrel 150 pg qd/ethinyl estradiol 30 pg qd; Compound I TC: Compound 1 200 mg qd/TEZ 100 mg qd/IVA 150 mg ql2h
  • PK parameter estimates for Compound I, TEZ, and IVA are presented in Table 11. Table 11. Mean Compound I, TEZ, IVA Exposures after Administration of LN/EE+ Compound I TC
  • AUC area under the concentration versus time curve
  • AUCo- tiast AUC from the time of dosing to the last measurable concentration
  • Cm maximum observed concentration CV%: coefficient of variation
  • IVA ivacaftor
  • LN/EE levonorgestrel 150 mg qd/ethinyl estradiol 30 pg qd
  • N total sample size (e.g., number of subjects treated); SD: standard deviation
  • TEZ tezacaftor
  • t maX time of maximum concentration
  • Compound I TC Compound 1 200 mg qd/TEZ 100 mg qd/IVA 150 mg ql2h
  • Compound I/TEZ/IVA was generally safe and well-tolerated when coadministered with LN/EE for 10 days. All adverse events (AEs) were mild or moderate in severity. There were no clinically relevant findings in laboratory measurements, vital signs, physical examinations, or electrocardiograms. There were no discontinuations due to AEs, significant adverse events, or deaths.
  • Compound I/TEZ/IVA was generally safe and well-tolerated when coadministered with LN/EE for 10 days.

Abstract

La présente invention concerne des procédés de traitement de la mucoviscidose comprenant l'administration du composé I, d'un sel pharmaceutiquement acceptable de celui-ci ou d'une composition pharmaceutique comprenant l'un quelconque des éléments précédents.
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US11253509B2 (en) 2017-06-08 2022-02-22 Vertex Pharmaceuticals Incorporated Methods of treatment for cystic fibrosis
US11426407B2 (en) 2014-10-06 2022-08-30 Vertex Pharmaceuticals Incorporated Modulators of cystic fibrosis transmembrane conductance regulator
US11453655B2 (en) 2016-12-09 2022-09-27 Vertex Pharmaceuticals Incorporated Modulator of the cystic fibrosis transmembrane conductance regulator, pharmaceutical compositions, methods of treatment, and process for making the modulator
US11465985B2 (en) 2017-12-08 2022-10-11 Vertex Pharmaceuticals Incorporated Processes for making modulators of cystic fibrosis transmembrane conductance regulator
US11517564B2 (en) 2017-07-17 2022-12-06 Vertex Pharmaceuticals Incorporated Methods of treatment for cystic fibrosis
CN115536493A (zh) * 2022-10-20 2022-12-30 海门瑞一医药科技有限公司 一种制取3,3,3-三氟甲基-2,2-二甲基丙烷醇的简单方法
US11584761B2 (en) 2019-08-14 2023-02-21 Vertex Pharmaceuticals Incorporated Process of making CFTR modulators
US11591350B2 (en) 2019-08-14 2023-02-28 Vertex Pharmaceuticals Incorporated Modulators of cystic fibrosis transmembrane conductance regulator
US11866450B2 (en) 2018-02-15 2024-01-09 Vertex Pharmaceuticals Incorporated Modulators of Cystic Fibrosis Transmembrane Conductance regulator, pharmaceutical compositions, methods of treatment, and process for making the modulators
US11873300B2 (en) 2019-08-14 2024-01-16 Vertex Pharmaceuticals Incorporated Crystalline forms of CFTR modulators
WO2024031081A1 (fr) * 2022-08-04 2024-02-08 Vertex Pharmaceuticals Incorporated Compositions pour le traitement de maladies médiées par cftr

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* Cited by examiner, † Cited by third party
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US11426407B2 (en) 2014-10-06 2022-08-30 Vertex Pharmaceuticals Incorporated Modulators of cystic fibrosis transmembrane conductance regulator
US11453655B2 (en) 2016-12-09 2022-09-27 Vertex Pharmaceuticals Incorporated Modulator of the cystic fibrosis transmembrane conductance regulator, pharmaceutical compositions, methods of treatment, and process for making the modulator
US11253509B2 (en) 2017-06-08 2022-02-22 Vertex Pharmaceuticals Incorporated Methods of treatment for cystic fibrosis
US11517564B2 (en) 2017-07-17 2022-12-06 Vertex Pharmaceuticals Incorporated Methods of treatment for cystic fibrosis
US11465985B2 (en) 2017-12-08 2022-10-11 Vertex Pharmaceuticals Incorporated Processes for making modulators of cystic fibrosis transmembrane conductance regulator
US11866450B2 (en) 2018-02-15 2024-01-09 Vertex Pharmaceuticals Incorporated Modulators of Cystic Fibrosis Transmembrane Conductance regulator, pharmaceutical compositions, methods of treatment, and process for making the modulators
US11584761B2 (en) 2019-08-14 2023-02-21 Vertex Pharmaceuticals Incorporated Process of making CFTR modulators
US11591350B2 (en) 2019-08-14 2023-02-28 Vertex Pharmaceuticals Incorporated Modulators of cystic fibrosis transmembrane conductance regulator
US11873300B2 (en) 2019-08-14 2024-01-16 Vertex Pharmaceuticals Incorporated Crystalline forms of CFTR modulators
WO2024031081A1 (fr) * 2022-08-04 2024-02-08 Vertex Pharmaceuticals Incorporated Compositions pour le traitement de maladies médiées par cftr
CN115536493A (zh) * 2022-10-20 2022-12-30 海门瑞一医药科技有限公司 一种制取3,3,3-三氟甲基-2,2-二甲基丙烷醇的简单方法

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