(19)
(11)EP 2 555 755 B2

(12)NEW EUROPEAN PATENT SPECIFICATION
After opposition procedure

(45)Date of publication and mention of the opposition decision:
10.07.2019 Bulletin 2019/28

(45)Mention of the grant of the patent:
24.08.2016 Bulletin 2016/34

(21)Application number: 11715637.2

(22)Date of filing:  07.04.2011
(51)International Patent Classification (IPC): 
A61K 9/16(2006.01)
A61K 9/28(2006.01)
C07D 405/12(2006.01)
A61K 31/443(2006.01)
C07D 451/02(2006.01)
A61K 9/20(2006.01)
C07D 213/75(2006.01)
C07D 405/14(2006.01)
A61K 31/47(2006.01)
(86)International application number:
PCT/US2011/031519
(87)International publication number:
WO 2011/127241 (13.10.2011 Gazette  2011/41)

(54)

PHARMACEUTICAL COMPOSITIONS OF 3-(6-(1-(2,2-DIFLUOROBENZO[D][1,3]DIOXOL-5-YL) CYCLOPROPANECARBOXAMIDO)-3-METHYLPYRIODIN-2-YL)BENZOIC ACID AND ADMINISTRATION THEREOF

PHARMAZEUTISCHE ZUSAMMENSETZUNGEN VON 3-(6-(1-(2,2-DIFLUORBENZO[D][1,3]DIOXOL-5-YL)-CYCLOPROPANCARBOXAMIDO)-3-METHYLPYRIDIN-2-YL)BENZOESÄURE UND IHRE VERABREICHUNG

COMPOSITIONS PHARMACEUTIQUES DE L'ACIDE 3-(6-(1-(2,2-DIFLUOROBENZO [D] [1,3] DIOXOL-5-YLE) CYCLOPROPANE CARBOXAMIDO)-3-MÉTHYLPYRIDIN-2-YLE) BENZOÏQUE ET LEUR ADMINISTRATION


(84)Designated Contracting States:
AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR
Designated Extension States:
BA ME

(30)Priority: 07.04.2010 US 321729 P
07.04.2010 US 321748 P
22.07.2010 US 366562 P

(43)Date of publication of application:
13.02.2013 Bulletin 2013/07

(60)Divisional application:
16185289.2 / 3150198

(73)Proprietor: Vertex Pharmaceuticals Incorporated
Boston, MA 02210 (US)

(72)Inventors:
  • VERWIJS, Marinus, Jacobus
    Framingham MA 01701 (US)
  • ALARGOVA, Rossitza, Gueorguieva
    Brighton MA 02135 (US)
  • KAUSHIK, Ritu, Rohit
    Watertown MA 02472 (US)
  • KADIYALA, Irina, Nikolaevna
    Newton MA 02457 (US)
  • YOUNG, Christopher, Ryan
    Waltham, MA 02451 (US)

(74)Representative: Oates, Edward Christopher et al
Carpmaels & Ransford LLP One Southampton Row
London WC1B 5HA
London WC1B 5HA (GB)


(56)References cited: : 
WO-A1-2009/073757
WO-A2-2007/134279
WO-A2-2010/037066
WO-A1-2011/133956
WO-A2-2009/076141
  
      


    Description

    TECHNICAL FIELD OF THE INVENTION



    [0001] The invention relates to pharmaceutical compositions comprising 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid (Compound 1), methods for manufacturing such compositions and methods for administering pharmaceutical compositions comprising same.

    BACKGROUND



    [0002] CFTR is a cAMP/ATP-mediated anion channel that is expressed in a variety of cells types, including absorptive and secretory epithelia cells, where it regulates anion flux across the membrane, as well as the activity of other ion channels and proteins. In epithelia cells, normal functioning of CFTR is critical for the maintenance of electrolyte transport throughout the body, including respiratory and digestive tissue. CFTR is composed of approximately 1480 amino acids that encode a protein made up of a tandem repeat of transmembrane domains, each containing six transmembrane helices and a nucleotide binding domain. The two transmembrane domains are linked by a large, polar, regulatory (R)-domain with multiple phosphorylation sites that regulate channel activity and cellular trafficking.

    [0003] The gene encoding CFTR has been identified and sequenced (See Gregory, R. J. et al. (1990) Nature 347:382-386; Rich, D. P. et al. (1990) Nature 347:358-362), (Riordan, J. R. et al. (1989) Science 245:1066-1073). A defect in this gene causes mutations in CFTR resulting in cystic fibrosis ("CF"), the most common fatal genetic disease in humans. Cystic fibrosis affects approximately one in every 2,500 infants in the United States. Within the general United States population, up to 10 million people carry a single copy of the defective gene without apparent ill effects. In contrast, individuals with two copies of the CF associated gene suffer from the debilitating and fatal effects of CF, including chronic lung disease.

    [0004] In patients with cystic fibrosis, mutations in CFTR endogenously expressed in respiratory epithelia lead to reduced apical anion secretion causing an imbalance in ion and fluid transport. The resulting decrease in anion transport contributes to enhance mucus accumulation in the lung and the accompanying microbial infections that ultimately cause death in CF patients. In addition to respiratory disease, CF patients typically suffer from gastrointestinal problems and pancreatic insufficiency that, if left untreated, results in death. In addition, the majority of males with cystic fibrosis are infertile and fertility is decreased among females with cystic fibrosis. In contrast to the severe effects of two copies of the CF associated gene, individuals with a single copy of the CF associated gene exhibit increased resistance to cholera and to dehydration resulting from diarrhea--perhaps explaining the relatively high frequency of the CF gene within the population.

    [0005] Sequence analysis of the CFTR gene of CF chromosomes has revealed a variety of disease-causing mutations (Cutting, G. R. et al. (1990) Nature 346:366-369; Dean, M. et al. (1990) Cell 61:863:870; and Kerem, B-S. et al. (1989) Science 245:1073-1080; Kerem, B-S et al. (1990) Proc. Natl. Acad. Sci. USA 87:8447-8451). To date, greater than 1000 disease-causing mutations in the CF gene have been identified as reported by the scientific and medical literature. The most prevalent mutation is a deletion of phenylalanine at position 508 of the CFTR amino acid sequence, and is commonly referred to as ΔF508-CFTR. This mutation occurs in approximately 70 percent of the cases of cystic fibrosis and is associated with a severe disease. Other mutations include the R117H and G551D.

    [0006] The deletion of residue 508 in ΔF508-CFTR prevents the nascent protein from folding correctly. This results in the inability of the mutant protein to exit the ER, and traffic to the plasma membrane. As a result, the number of channels present in the membrane is far less than observed in cells expressing wild-type CFTR. In addition to impaired trafficking, the mutation results in defective channel gating. Together, the reduced number of channels in the membrane and the defective gating lead to reduced anion transport across epithelia leading to defective ion and fluid transport. (Quinton, P. M. (1990), FASEB J. 4: 2709-2727). Studies have shown, however, that the reduced numbers of ΔF508-CFTR in the membrane are functional, albeit less than wild-type CFTR. (Dalemans et al. (1991), Nature Lond. 354: 526-528; Denning et al., supra; Pasyk and Foskett (1995), J. Cell. Biochem. 270: 12347-50). In addition to ΔF508-CFTR, other disease causing mutations in CFTR that result in defective trafficking, synthesis, and/or channel gating could be up- or downregulated to alter anion secretion and modify disease progression and/or severity.

    [0007] Although CFTR transports a variety of molecules in addition to anions, it is clear that this role (the transport of anions) represents one element in an important mechanism of transporting ions and water across the epithelium. The other elements include the epithelial Na+ channel, ENaC, Na+/2Cl-K+ co-transporter, Na+-K+-ATPase pump and the basolateral membrane K+ channels, that are responsible for the uptake of chloride into the cell.

    [0008] These elements work together to achieve directional transport across the epithelium via their selective expression and localization within the cell. Chloride absorption takes place by the coordinated activity of ENaC and CFTR present on the apical membrane and the Na+-K+-ATPase pump and Cl- channels expressed on the basolateral surface of the cell. Secondary active transport of chloride from the luminal side leads to the accumulation of intracellular chloride, which can then passively leave the cell via Cl- channels, resulting in a vectorial transport. Arrangement of Na+/2Cl-/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. Because water is probably never actively transported itself, its flow across epithelia depends on tiny transepithelial osmotic gradients generated by the bulk flow of sodium and chloride.

    [0009] As discussed above, it is believed that the deletion of residue 508 in ΔF508-CFTR prevents the nascent protein from folding correctly, resulting in the inability of this mutant protein to exit the ER, and traffic to the plasma membrane. As a result, insufficient amounts of the mature protein are present at the plasma membrane and chloride transport within epithelial tissues is significantly reduced. In fact, this cellular phenomenon of defective endoplasmic reticulum (ER) processing of ATP-binding cassette (ABC) transporters by the ER machinery, has been shown to be the underlying basis not only for CF disease, but for a wide range of other isolated and inherited diseases. The two ways that the ER machinery can malfunction is either by loss of coupling to ER export of the proteins leading to degradation, or by the ER accumulation of these defective/misfolded proteins [Aridor M, et al., Nature Med., 5(7), pp 745-751 (1999); Shastry, B.S., et al., Neurochem. International, 43, pp 1-7 (2003); Rutishauser, J., et al., Swiss Med Wkly, 132, pp 211-222 (2002); Morello, JP et al., TIPS, 21, pp. 466- 469 (2000); Bross P., et al., Human Mut., 14, pp. 186-198 (1999)].

    [0010] 3-(6-(1-(2,2-Difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid in salt form is disclosed in International PCT Publication WO 2007056341 as a modulator of CFTR activity and thus as a useful treatment for CFTR-mediated diseases such as cystic fibrosis. Form I of 3-(6-(1-(2,2-Difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid, which is a substantially crystalline and salt-free form known as Compound 1 Form I, is disclosed in United States Patent Application 12/327,902, filed December 4, 2008. Form II and HCl salt Form A of 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin- 2-yl)benzoic acid, Compound 1 Form II and Compound 1 HCl salt Form A, respectively, are disclosed in United States Provisional Patent Application 61/321,729, filed April 7, 2010. All applications are incorporated in their entirety by reference herein. A need remains, however, for pharmaceutical compositions comprising Compound 1 Form I, Form II, or HCl salt Form A that are readily prepared and that are suitable for use as therapeutics.

    SUMMARY



    [0011] The invention relates to pharmaceutical compositions, pharmaceutical preparations, and solid dosage forms comprising 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid (Compound 1) which has the structure below:



    [0012] In one aspect of the invention, defined in claim 1, the invention provides a tablet for oral administration comprising:
    1. a. Compound 1 Form I, Compound 1 Form II, and/or Compound 1 HCl Salt Form A;
    2. b. a filler;
    3. c. a disintegrant;
    4. d. a surfactant;
    5. e. a diluent;
    6. f. a lubricant; and
    7. g. at least one of a glidant and a binder,
    wherein Compound 1 Form I, Compound 1 Form II, and/or Compound 1 HCl Salt Form A wherein Compound 1 Form I, Compound 1 Form II are present in an amount of at least 60 wt% by weight of the composition.

    [0013] In another aspect of the Invention, defined in claim 3, the invention provides a tablet comprising:
    1. a. Compound 1 Form I, Compound 1 Form II, and/or Compound 1 HCl Salt Form A in an amount ranging from about 25 mg to about 250 mg;
    2. b. a filler;
    3. c. a diluent;
    4. d. a disintegrant;
    5. e. a surfactant;
    6. f. a lubricant; and
    7. g. at least one of a binder and a glidant;
      wherein the tablet comprises a binder which is polyvinylpyrrolidone;
      wherein Compound 1 Form I, Compound 1 Form II, and/or Compound 1 HCl Salt Form A is present in an amount of at least 30 wt%.


    [0014] In one embodiment, Compound 1 is in substantially crystalline Form I (Compound 1 Form I). In one embodiment, Compound 1 is in substantially crystalline Form II (Compound 1 Form II). In one embodiment, Compound 1 is in substantially crystalline HCl salt form (Compound 1 HCl Salt Form A). It is understood that the term "Compound 1," as used throughout, includes, amongst other forms, including non-crystalline forms, the following solid state forms: Compound 1 Form I, Compound 1 Form II, and/or Compound 1 HCl Salt Form A.

    [0015] In some embodiments, the pharmaceutical composition comprises 25 mg to 400 mg. In some embodiments, the pharmaceutical composition comprises 25 mg of Compound 1. In some embodiments, the pharmaceutical composition comprises 50 mg of Compound 1. In some embodiments, the pharmaceutical composition comprises 100 mg of Compound 1. In some embodiments, the pharmaceutical composition comprises 125 mg of Compound 1. In some embodiments, the pharmaceutical composition comprises 150 mg of Compound 1. In some embodiments, the pharmaceutical composition comprises 200 mg of Compound 1. In some embodiments, the pharmaceutical composition comprises 250 mg of Compound 1. In some embodiments, the pharmaceutical composition comprises 400 mg of Compound 1.

    [0016] In another aspect, the invention provides a pharmaceutical composition comprising the following components:
    High Shear Granule Blend(%w/w)
    Compound 1 Form I 40-80
    Microcrystalline cellulose 20-40
    Mannitol 10-15
    Croscarmellose Sodium 3
    Polyvinylpyrrolidone 1-10
    Sodium Lauryl Sulfate 1
    Water (removed during drying) 25-40% solids
    Tablet Composition (100 mg dose)(%w/w)
    High shear Granule Blend 95-99
    Croscarmellose Sodium 1-4
    Magnesium Stearate 0.1-1


    [0017] In another embodiment, the invention provides a pharmaceutical composition comprising the following components:
    High Shear Granule Blend(%w/w)
    Compound 1 Form I 50
    Microcrystalline cellulose 30
    Mannitol 13
    Croscarmellose Sodium 2
    Polyvinylpyrrolidone 4
    Sodium Lauryl Sulfate 1
    Water (removed during drying) 25-40% solids
    Tablet Composition (100 mg dose, 205mg image)(%w/w)
    High Shear Granule Blend 97.5
    Croscarmellose Sodium 2.0
    Magnesium Stearate 0.5


    [0018] In another embodiment, the invention provides a pharmaceutical composition comprising the following components:
    High Shear Granule Blend(%w/w)
    Compound 1 Form I 60
    Microcrystalline cellulose 20
    Mannitol 13
    Croscarmellose Sodium 2
    Polyvinylpyrrolidone 4
    Sodium Lauryl Sulfate 1
    Water (removed during drying) 25-40% solids
    Tablet Composition (100 mg dose, 171mg image)(%w/w)
    High Shear Granule Blend 97.5
    Croscarmellose Sodium 2.0
    Magnesium Stearate 0.5


    [0019] In another embodiment, the invention provides a pharmaceutical composition comprising the following components:
    High Shear Granule Blend(%w/w)
    Compound 1 Form I 60
    Microcrystalline cellulose 20
    Mannitol 13
    Croscarmellose Sodium 2
    Polyvinylpyrrolidone 4
    Sodium Lauryl Sulfate 1
    Water (removed during drying) 25-40% solids
    Tablet Composition (200 mg dose, 402mg image)(%w/w)
    High Shear Granule Blend 83
    Microcrystalline cellulose 14
    Croscarmellose Sodium 2
    Magnesium Stearate 1


    [0020] In another embodiment, the invention provides a pharmaceutical composition comprising the following components:
    High Shear Granule Blendmg
    Compound 1 Form I 200
    Microcrystalline cellulose 66
    Mannitol 43
    Croscarmellose Sodium 7
    Polyvinylpyrrolidone 13
    Sodium Lauryl Sulfate 3
    Core Tablet Composition (200 mg dose, 412mg image)mg
    High Shear Granule Blend 332
    Microcrystalline cellulose 56
    Croscarmellose Sodium 8
    Magnesium Stearate 4
    Film Coated Tablet (200 mg dose, 412mg image)mg
    Core Tablet Composition 400
    Film Coat 12
    Wax 0.04


    [0021] In another embodiment, the invention provides a pharmaceutical composition comprising the following components:
    High Shear Granule Blendmg
    Compound 1 Form I 200
    Microcrystalline cellulose 67
    Mannitol 45
    Croscarmellose Sodium 7
    Polyvinylpyrrolidone 10.4
    Sodium Lauryl Sulfate 2.6
    Core Tablet Composition (200 mg dose, 400mg image)mg
    High Shear Granule Blend 332
    Microcrystalline cellulose 56
    Croscarmellose Sodium 8
    Magnesium Stearate 4
    Film Coated Tablet (200 mg dose, 412mg image)mg
    Core Tablet Composition 400
    Film Coat 12
    Wax 0.04


    [0022] In another embodiment, the invention provides a pharmaceutical composition comprising the following components:
    High Shear Granule Blend(%w/w)
    Compound 1 Form I 70
    Microcrystalline cellulose 12
    Mannitol 11
    Croscarmellose Sodium 2
    Polyvinylpyrrolidone 4
    Sodium Lauryl Sulfate 1
    Water (removed during drying) 25-40% solids
    Tablet Composition (100 mg dose, 147 mg image)(%w/w)
    High Shear Granule Blend 97.5
    Croscarmellose Sodium 2.0
    Magnesium Stearate 0.5


    [0023] In another embodiment, the invention provides a pharmaceutical composition comprising the following components:
    High Shear Granule Blend(%w/w)
    Compound 1 Form II 61
    Microcrystalline cellulose 20.3
    Mannitol 13.2
    Croscarmellose Sodium 2
    Polyvinylpyrrolidone 2.7
    Sodium Lauryl Sulfate 0.7
    Tablet Composition (100 mg dose, 197 mg image(%w/w)
    High Shear Granule Blend 83
    Tablet Composition (100 mg dose, 197 mg image)(%w/w)
    Microcrystalline cellulose 14
    Croscarmellose Sodium 2
    Magnesium Stearate 1


    [0024] In another embodiment, the invention provides a pharmaceutical composition comprising the following components:
    High Shear Granule Blendmg
    Compound 1 Form II 100
    Microcrystalline cellulose 33.3
    Mannitol 21.7
    Croscarmellose Sodium 3.3
    Polyvinylpyrrolidone 4.4
    Sodium Lauryl Sulfate 1.1
    Tablet Compositionmg
    High Shear Granule Blend 163.9
    Microcrystalline cellulose 27.6
    Croscarmellose Sodium 3.9
    Magnesium Stearate 2.0


    [0025] In another aspect, the invention provides a pharmaceutical composition in the form of a tablet that comprises Compound 1, and one or more pharmaceutically acceptable excipients, for example, a filler, a disintegrant, a surfactant, a diluent, a binder, a glidant, and a lubricant and any combination thereof, where the tablet has a dissolution of at least about 50% in about 30 minutes. In another embodiment, the dissolution rate is at least about 75% in about 30 minutes. In another embodiment, the dissolution rate is at least about 90% in about 30 minutes.

    [0026] In another aspect, the invention provides a pharmaceutical composition consisting of a tablet that comprises a powder blend or granules comprising Compound 1; and, one or more pharmaceutically acceptable excipients, for example, a filler, a disintegrant, a surfactant, a diluent, a binder, a glidant, and a lubricant, wherein the tablet has a hardness of at least about 5 kP (kP = kilo Ponds; 1 kP = ∼9.8 N). In another embodiment, the tablet has a target friability of less than 1.0% after 400 revolutions. In another aspect, the invention provides a pharmaceutical composition consisting of a tablet that comprises a powder blend or granules comprising Compound 1 Form II, Compound 1; and, one or more pharmaceutically acceptable excipients, for example, a filler, a disintegrant, a surfactant, a diluent, a binder, a glidant, and a lubricant, wherein the tablet has a hardness of at least about 5 kP (kP = kilo Ponds; 1 kP = ∼9.8 N). In another embodiment, the tablet has a target friability of less than 1.0% after 400 revolutions.

    [0027] In another aspect, the invention provides a pharmaceutical composition as described herein further comprising an additional therapeutic agent. In some embodiments, the additional therapeutic agent is N-(5-hydroxy-2,4-ditert-butylphenyl)-4-oxo-1H-quinoline-3-carboxamide.

    [0028] In another aspect, the invention provides a tablet, pharmaceutical composition, or dosage unit form according to any one of claims 1-11 for use in a method of treating cystic fibrosis in a mammal, wherein the method comprises administering to the mammal an effective amount of the tablet, pharmaceutical composition, or dosage unit form. This method may further comprise administering an additional therapeutic agent, wherein in some embodiments, the additional therapeutic agent is N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide.

    [0029] In another aspect of the invention, defined in claim 12, the invention provides a method of producing a pharmaceutical composition comprising the steps of: combining a therapeutically effective amount of Compound 1 Form I, Compound 1 Form II, and/or Compound 1 HCl Salt Form A and at least one granulation excipient selected from the group consisting of: a binder; a glidant; a surfactant; a lubricant; a disintegrant; a filler, a diluent and combinations thereof to form an admixture; mixing and wet granulating the admixture; and compacting the admixture to form the pharmaceutical composition from an admixture of powdered and liquid materials; wherein Compound 1 Form I, Compound 1 Form II, and/or Compound 1 HCl Salt Form A is present in an amount of at least 30 wt% in the pharmaceutical composition.

    BRIEF DESCRIPTION OF DRAWINGS



    [0030] 

    Figure 1 is an X-ray diffraction pattern calculated from a single crystal structure of Compound 1 Form I.

    Figure 2 is an actual X-ray powder diffraction pattern of Compound 1 Form I.

    Figure 3 is an X-ray powder diffraction pattern of Compound 1 Form II.

    Figure 4 provides X-ray diffraction patterns of Compound 1 Form II's selected from:

    1. 1) Compound 1 Form II, Methanol Solvate;
    2. 2) Compound 1 Form II, Ethanol Solvate;
    3. 3) Compound 1 Form II, Acetone Solvate;
    4. 4) Compound 1 Form II, 2-Propanol Solvate;
    5. 5) Compound 1 Form II, Acetonitrile Solvate;
    6. 6) Compound 1 Form II, Tetrahydrofuran Solvate;
    7. 7) Compound 1 Form II, Methyl Acetate Solvate;
    8. 8) Compound 1 Form II, 2-Butanone Solvate;
    9. 9) Compound 1 Form II, Ethyl Formate Solvate; and
    10. 10) Compound 1 Form II, 2-Methyltetrahydrofuran Solvate.

    Figure 5 provides an X-ray diffraction pattern of Compound 1 Form II, Methanol Solvate.

    Figure 6 provides an X-ray diffraction pattern of Compound 1 Form II, Ethanol Solvate.

    Figure 7 provides an X-ray diffraction pattern of Compound 1 Form II, Acetone Solvate.

    Figure 8 provides an X-ray diffraction pattern of Compound 1 Form II, 2-Propanol Solvate.

    Figure 9 provides an X-ray diffraction pattern of Compound 1 Form II, Acetonitrile Solvate.

    Figure 10 provides an X-ray diffraction pattern of Compound 1 Form II, Tetrahydrofuran Solvate.

    Figure 11 provides an X-ray diffraction pattern of Compound 1 Form II, Methyl Acetate Solvate.

    Figure 12 provides an X-ray diffraction pattern of Compound 1 Form II, 2-Butanone Solvate.

    Figure 13 provides an X-ray diffraction pattern of Compound 1 Form II, Ethyl Formate Solvate.

    Figure 14 provides an X-ray diffraction pattern of Compound 1 Form II, 2-Methyltetrahydrofuran Solvate.

    Figure 15 is a differential scanning calorimetry (DSC) trace of Compound 1 Form II, Acetone Solvate.

    Figure 16 is a Thermogravimetric analysis (TGA) plot of Compound 1 Form II, Acetone Solvate.

    Figure 17 is a conformational image of Compound 1 Form II, Acetone Solvate based on single crystal X-ray analysis.

    Figure 18 is a conformational image of the dimer of Compound 1 HCl Salt Form A.

    Figure 19 is an X-ray diffraction pattern of Compound 1 HCl Salt Form A calculated from the crystal structure.

    Figure 20 is an 1HNMR spectrum of Compound 1.

    Figure 21 is an 1HNMR spectrum of Compound 1 HCl salt.

    Figure 22 is a differential scanning calorimetry (DSC) trace of Compound 1 Form I.

    Figure 23 is a conformational picture of Compound 1 Form I based on single crystal X-ray analysis.

    Figure 24 is a conformational image of Compound 1 Form II, Acetone Solvate, based on single crystal X-ray analysis.

    Figure 25 is a solid state 13C NMR spectrum (15.0 kHz spinning) of Compound 1 Form II, Acetone Solvate.

    Figure 26 is a solid state 19F NMR spectrum (12.5 kHz spinning) of Compound 1 Form II, Acetone Solvate.

    Figure 27 is an X-ray diffraction pattern of Compound 1 HCl Salt Form A calculated from the crystal structure.


    DETAILED DESCRIPTION


    DEFINITIONS



    [0031] As used herein, the term "active pharmaceutical ingredient" or "API" refers to a biologically active compound. Exemplary APIs include 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid (Compound 1).

    [0032] The terms "solid form", "solid forms" and related terms, when used herein to refer to 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl) benzoic acid (Compound 1), refer to a solid form e.g. crystals and the like, comprising Compound 1 which is not predominantly in a liquid or a gaseous state.

    [0033] As used herein, the term "substantially amorphous" refers to a solid material having little or no long range order in the position of its molecules. For example, substantially amorphous materials have less than about 15% crystallinity (e.g., less than about 10% crystallinity or less than about 5% crystallinity). It is also noted that the term 'substantially amorphous' includes the descriptor, 'amorphous', which refers to materials having no (0%) crystallinity.

    [0034] As used herein, the term "substantially crystalline" (as in the phrase substantially crystalline Compound 1 Form I, Compound 1 Form II, or Compound 1 HCl Salt Form A) refers to a solid material having predominantly long range order in the position of its molecules. For example, substantially crystalline materials have more than about 85% crystallinity (e.g., more than about 90% crystallinity or more than about 95% crystallinity). It is also noted that the term 'substantially crystalline' includes the descriptor, 'crystalline', which refers to materials having 100% crystallinity.

    [0035] The term "crystalline" and related terms used herein, when used to describe a substance, component, product, or form, means that the substance, component or product is substantially crystalline as determined by X-ray diffraction. (See, e.g., Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott Williams & Wilkins, Baltimore, Md. (2003); The United States Pharmacopeia, 23rd ed., 1843-1844 (1995)).

    [0036] As used herein, the term "composition" generally refers to a composition of two or more components, usually one or more drugs (e.g., one drug (e.g., Compound 1 Form I, Compound 1 Form II, or Compound 1 HCl Salt Form A)) and one or more pharmaceutical excipients.

    [0037] As used herein, the term "solid dosage form" generally refers to a pharmaceutical composition, which when used in an oral mode of administration include capsules, tablets, pills, powders and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier.

    [0038] As used herein, an "excipient" includes functional and non-functional ingredients in a pharmaceutical composition.

    [0039] As used herein, a "disintegrant" is an excipient that hydrates a pharmaceutical composition and aids in tablet dispersion. As used herein, a "diluent" or "filler" is an excipient that adds bulkiness to a pharmaceutical composition.

    [0040] As used herein, a "surfactant" is an excipient that imparts pharmaceutical compositions with enhanced solubility and/or wetability.

    [0041] As used herein, a "binder" is an excipient that imparts a pharmaceutical composition with enhanced cohesion or tensile strength (e.g., hardness).

    [0042] As used herein, a "glidant" is an excipient that imparts a pharmaceutical compositions with enhanced flow properties.

    [0043] As used herein, a "colorant" is an excipient that imparts a pharmaceutical composition with a desired color. Examples of colorants include commercially available pigments such as FD&C Blue # 1 Aluminum Lake, FD&C Blue #2, other FD&C Blue colors, titanium dioxide, iron oxide, and/or combinations thereof. In one embodiment, the pharmaceutical composition provided by the invention is purple.

    [0044] As used herein, a "lubricant" is an excipient that is added to pharmaceutical compositions that are pressed into tablets. The lubricant aids in compaction of granules into tablets and ejection of a tablet of a pharmaceutical composition from a die press.

    [0045] As used herein, "cubic centimeter" and "cc" are used interchangeably to represent a unit of volume. Note that 1 cc = 1 mL.

    [0046] As used herein, "kiloPond" and "kP" are used interchangeably and refer to the measure of force where a kP = approximately 9.8 Newtons.

    [0047] As used herein, "friability" refers to the property of a tablet to remain intact and withhold its form despite an external force of pressure. Friability can be quantified using the mathematical expression presented in equation 1:

    wherein W0 is the original weight of the tablet and Wf is the final weight of the tablet after it is put through the friabilator. Friability is measured using a standard USP testing apparatus that tumbles experimental tablets for 100 or 400 revolutions. Some tablets of the invention have a friability of less than 5.0%. In another embodiment, the friability is less than 2.0%. In another embodiment, the target friability is less than 1.0% after 400 revolutions.

    [0048] As used herein, "mean particle diameter" is the average particle diameter as measured using techniques such as laser light scattering, image analysis, or sieve analysis. In one embodiment, the granules used to prepare the pharmaceutical compositions provided by the invention have a mean particle diameter of less than 1.0 mm.

    [0049] As used herein, "bulk density" is the mass of particles of material divided by the total volume the particles occupy. The total volume includes particle volume, inter-particle void volume and internal pore volume. Bulk density is not an intrinsic property of a material; it can change depending on how the material is processed. In one embodiment, the granules used to prepare the pharmaceutical compositions provided by the invention have a bulk density of about 0.5-0.7 g/cc.

    [0050] An effective amount or "therapeutically effective amount" of a drug compound of the invention may vary according to factors such as the disease state, age, and weight of the subject, and the ability of the compound of the invention to elicit a desired response in the subject. Dosage regimens may be adjusted to provide the optimum therapeutic response. An effective amount is also one in which any toxic or detrimental effects (e.g., side effects) of the compound of the invention are outweighed by the therapeutically beneficial effects.

    [0051] As used herein, and unless otherwise specified, the terms "therapeutically effective amount" and "effective amount" of a compound mean an amount sufficient to provide a therapeutic benefit in the treatment or management of a disease or disorder, or to delay or minimize one or more symptoms associated with the disease or disorder. A "therapeutically effective amount" and "effective amount" of a compound mean an amount of therapeutic agent, alone or in combination with one or more other agent(s), which provides a therapeutic benefit in the treatment or management of the disease or disorder. The terms "therapeutically effective amount" and "effective amount" can encompass an amount that improves overall therapy, reduces or avoids symptoms or causes of disease or disorder, or enhances the therapeutic efficacy of another therapeutic agent.

    [0052] "Substantially pure" as used in the phrase "substantially pure Compound 1 Form I, Compound 1 Form II, or Compound 1 HCl Salt Form A," means greater than about 90% purity. In another embodiment, substantially pure refers to greater than about 95% purity. In another embodiment, substantially pure refers to greater than about 98% purity. In another embodiment, substantially pure refers to greater than about 99% purity.

    [0053] With respect to Compound 1 (e.g., Compound 1 Form I, Compound 1 Form II, Compound 1 HCl Salt Form A), the terms "about" and "approximately", when used in connection with doses, amounts, or weight percent of ingredients of a composition or a dosage form, mean a dose, amount, or weight percent that is recognized by one of ordinary skill in the art to provide a pharmacological effect equivalent to that obtained from the specified dose, amount, or weight percent. Specifically the term "about" or "approximately" means an acceptable error for a particular value as determined by one of ordinary skill in the art, which depends in part on how the value is measured or determined. In certain embodiments, the term "about" or "approximately" means within 1, 2, 3, or 4 standard deviations. In certain embodiments, the term "about" or "approximately" means within 30%, 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, or 0.05% of a given value or range.

    [0054] Unless otherwise specified, the term "Compound 1" includes, but is not limited to, the solid forms of Compound 1 as described herein, e.g. Compound 1 Form I, Compound 1 Form II, or Compound 1 HCl Salt Form A, as well as combinations thereof.

    PHARMACEUTICAL COMPOSITIONS



    [0055] The invention provides pharmaceutical compositions, pharmaceutical formulations and solid dosage forms comprising Compound 1 which may be in substantially crystalline form. In some embodiments, Compound 1 is in crystalline Form I (Compound 1 Form I). In some embodiments, Compound 1 is in crystalline Form II (Compound 1 Form II). In some embodiments, Compound 1 is in crystalline HCl salt form (Compound 1 HCl Salt Form A). In some embodiments of this aspect, the amount of Compound 1 that is present in the pharmaceutical composition is 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 200 mg, 250 mg, or 400 mg. In some embodiments of this aspect, weight/weight relative percent of Compound 1 that is present in the pharmaceutical composition is from 10 to 75 percent. In these and other embodiments, 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid is present as substantially pure Compound 1. "Substantially pure" means greater than ninety percent pure; preferably greater than 95 percent pure; more preferably greater than 99.5 percent pure (i.e., not mixed with other crystalline forms of Compound 1).

    [0056] Thus in one aspect of the invention, defined in claim 1, the invention provides a tablet for oral administration comprising:

    a. Compound 1 Form I, Compound 1 Form II, and/or Compound 1 HCl Salt Form A;

    b. a filler;

    c. a disintegrant;

    d. a surfactant;

    e. a diluent;

    f. a lubricant; and

    g. and at least one of a glidant and a binder

    wherein Compound 1 Form I, Compound 1 Form II, and/or Compound 1 HCl Salt Form A wherein Compound 1 Form I, Compound 1 Form II are present in an amount of at least 60 wt% by weight of the composition.

    [0057] In one embodiment of this aspect, the pharmaceutical composition comprises 25 mg of Compound 1. In another embodiment of this aspect, the pharmaceutical composition comprises 50 mg of Compound 1. In another embodiment of this aspect, the pharmaceutical composition comprises 100 mg of Compound 1. In another embodiment of this aspect, the pharmaceutical composition comprises 125 mg of Compound 1. In another embodiment of this aspect, the pharmaceutical composition comprises 150 mg of Compound 1. In another embodiment of this aspect, the pharmaceutical composition comprises 200 mg of Compound 1. In another embodiment of this aspect, the pharmaceutical composition comprises 250 mg of Compound 1. In another embodiment of this aspect, the pharmaceutical composition comprises 400 mg of Compound 1.

    [0058] In another aspect of the Invention, defined in claim 3, the invention provides a tablet comprising:
    1. a. Compound 1 Form I, Compound 1 Form II, and/or Compound 1 HCl Salt Form A in an amount ranging from about 25 mg to about 250 mg;
    2. b. a filler;
    3. c. a diluent;
    4. d. a disintegrant;
    5. e. a surfactant;
    6. f. a lubricant; and
    7. g. at least one of a binder and a glidant;
      wherein the tablet comprises a binder which is polyvinylpyrrolidone;
      wherein Compound 1 Form I, Compound 1 Form II, and/or Compound 1 HCl Salt Form A is present In an amount of at least 30 wt%. In some embodiments, these tablets comprise Compound 1, wherein Compound 1 is present in an amount of at least 30 wt%, at least 40 wt%, at least 50 wt%, or at least 60 wt% by weight of the tablet.


    [0059] In some embodiments, the pharmaceutical composition comprises Compound 1, a filler, a diluent, a disintegrant, a surfactant, a glidant, and a lubricant. In this embodiment, the composition comprises from about 20 wt% to about 50 wt% (e.g., about 25-35 wt%) of Compound 1 by weight of the composition, and more typically, from 25 wt% to about 45 wt% (e.g., about 28-32 wt%) of Compound 1 by weight of the composition.

    [0060] In some embodiments, the pharmaceutical composition comprises Compound 1, a filler, a diluent, a disintegrant, a surfactant, a binder, and a lubricant. In this embodiment, the composition comprises from about 30 wt% to about 60 wt% (e.g., about 40-55 wt%) of Compound 1 by weight of the composition, and more typically from 35 wt% to about 70 wt% (e.g., about 45-55 wt%) of Compound 1 by weight of the composition.

    [0061] The concentration of Compound 1 in the composition depends on several factors such as the amount of pharmaceutical composition needed to provide a desired amount of Compound 1 and the desired dissolution profile of the pharmaceutical composition.

    [0062] In another embodiment, the pharmaceutical composition comprises Compound 1, in which Compound 1 in its solid form has a mean particle diameter, measured by light scattering (e.g., using a Malvern Mastersizer available from Malvern Instruments in England) of 0.1 microns to 10 microns. In another embodiment, the particle size of Compound 1 is 1 micron to 5 microns. In another embodiment, Compound 1 has a particle size D50 of 2.0 microns.

    [0063] As indicated, in addition to Compound 1, in some embodiments of the invention, the pharmaceutical compositions which are oral formulations also comprise one or more excipients such as fillers, disintegrants, surfactants, diluents, binders, glidants, lubricants, colorants, or fragrances and any combination thereof.

    [0064] Fillers suitable for the invention are compatible with the ingredients of the pharmaceutical composition, i.e., they do not substantially reduce the solubility, the hardness, the chemical stability, the physical stability, or the biological activity of the pharmaceutical composition. Exemplary fillers include: celluloses, modified celluloses, (e.g. sodium carboxymethyl cellulose, ethyl cellulose hydroxymethyl cellulose, hydroxypropylcellulose), cellulose acetate, microcrystalline cellulose, calcium phosphates, dibasic calcium phosphate, starches (e.g. corn starch, potato starch), sugars (e.g., sorbitol) lactose, sucrose, or the like), or any combination thereof.

    [0065] Thus, in one embodiment, the pharmaceutical composition comprises at least one filler in an amount of at least 5 wt% (e.g., at least about 20 wt%, at least about 30 wt%, or at least about 40 wt%) by weight of the composition. For example, the pharmaceutical composition comprises from about 10 wt% to about 60 wt% (e.g., from about 20 wt% to about 55 wt%, from about 25 wt% to about 50 wt%, or from about 27 wt% to about 45 wt%) of filler, by weight of the composition. In another example, the pharmaceutical composition comprises at least about 20 wt% (e.g., at least 30 wt% or at least 40 wt%) of microcrystalline cellulose, for example MCC Avicel PH102, by weight of the composition. In yet another example, the pharmaceutical composition comprises from about 10 wt% to about 60 wt% (e.g., from about 20 wt% to about 55 wt% or from about 25 wt% to about 45 wt%) of microcellulose, by weight of the composition.

    [0066] Disintegrants suitable for the invention enhance the dispersal of the pharmaceutical composition and are compatible with the ingredients of the pharmaceutical composition, i.e., they do not substantially reduce the chemical stability, the physical stability, the hardness, or the biological activity of the pharmaceutical composition. Exemplary disintegrants include croscarmellose sodium, sodium starch glycolate, or a combination thereof.

    [0067] Thus, in one embodiment, the pharmaceutical composition comprises disintegrant in an amount of about 10 wt% or less (e.g., about 7 wt% or less, about 6 wt% or less, or about 5 wt% or less) by weight of the composition. For example, the pharmaceutical composition comprises from about 1 wt% to about 10 wt% (e.g., from about 1.5 wt% to about 7.5 wt% or from about 2.5 wt% to about 6 wt%) of disintegrant, by weight of the composition. In another example, the pharmaceutical composition comprises about 10 wt% or less (e.g., 7 wt% or less, 6 wt% or less, or 5 wt% or less) of croscarmellose sodium, by weight of the composition. In yet another example, the pharmaceutical composition comprises from about 1 wt% to about 10 wt% (e.g., from about 1.5 wt% to about 7.5 wt% or from about 2.5 wt% to about 6 wt%) of croscarmellose sodium, by weight of the composition. In some examples, the pharmaceutical composition comprises from about 0.1% to about 10 wt% (e.g., from about 0.5 wt% to about 7.5 wt% or from about 1.5 wt% to about 6 wt%) of disintegrant, by weight of the composition. In still other examples, the pharmaceutical composition comprises from about 0.5% to about 10 wt% (e.g., from about 1.5 wt% to about 7.5 wt% or from about 2.5 wt% to about 6 wt%) of disintegrant, by weight of the composition.

    [0068] Surfactants suitable for the invention enhance the wettability of the pharmaceutical composition and are compatible with the ingredients of the pharmaceutical composition, i.e., they do not substantially reduce the chemical stability, the physical stability, the hardness, or the biological activity of the pharmaceutical composition. Exemplary surfactants include sodium lauryl sulfate (SLS), sodium stearyl fumarate (SSF), polyoxyethylene 20 sorbitan mono-oleate (e.g., Tween™), any combination thereof, or the like.

    [0069] Thus, in one embodiment, the pharmaceutical composition comprises a surfactant in an amount of about 10 wt% or less (e.g., about 5 wt% or less, about 2 wt% or less, about 1 wt% or less, about 0.8 wt% or less, or about 0.6 wt% or less) by weight of the composition. For example, the pharmaceutical composition includes from about 10 wt% to about 0.1 wt% (e.g., from about 5 wt% to about 0.2 wt% or from about 2 wt% to about 0.3 wt%) of surfactant, by weight of the composition. In another example, the pharmaceutical composition comprises 10 wt% or less (e.g., about 5 wt% or less, about 2 wt% or less, about 1 wt% or less, about 0.8 wt% or less, or about 0.6 wt% or less) of sodium lauryl sulfate, by weight of the composition. In yet another example, the pharmaceutical composition comprises from about 10 wt% to about 0.1 wt% (e.g., from about 5 wt% to about 0.2 wt% or from about 2 wt% to about 0.3 wt%) of sodium lauryl sulfate, by weight of the composition.

    [0070] Binders suitable for the invention enhance the tablet strength of the pharmaceutical composition and are compatible with the ingredients of the pharmaceutical composition, i.e., they do not substantially reduce the chemical stability, the physical stability, or the biological activity of the pharmaceutical composition. Exemplary binders include polyvinylpyrrolidone, dibasic calcium phosphate, sucrose, corn (maize) starch, modified cellulose (e.g., hydroxymethyl cellulose), or any combination thereof.

    [0071] Thus, in one embodiment, the pharmaceutical composition comprises a binder in an amount of at least about 0.1 wt% (e.g., at least about 1 wt%, at least about 3 wt%, at least about 4 wt%, or at least about 5 wt%) by weight of the composition. For example, the pharmaceutical composition comprises from about 0.1 wt% to about 10 wt% (e.g., from about 1 wt% to about 10 wt% or from about 2 wt% to about 7 wt%) of binder, by weight of the composition. In another example, the pharmaceutical composition comprises at least about 0.1 wt% (e.g., at least about 1 wt%, at least about 2 wt%, at least about 3 wt%, or at least about 4 wt%) of polyvinylpyrrolidone, by weight of the composition. In yet another example, the pharmaceutical composition comprises a glidant in an amount ranging from about 0.1 wt% to about 10 wt% (e.g., from about 1 wt% to about 8 wt% or from about 2 wt% to about 5 wt%) of polyvinylpyrrolidone, by weight of the composition.

    [0072] Diluents suitable for the invention may add necessary bulk to a formulation to prepare tablets of the desired size and are generally compatible with the ingredients of the pharmaceutical composition, i.e., they do not substantially reduce the solubility, the hardness, the chemical stability, the physical stability, or the biological activity of the pharmaceutical composition. Exemplary diluents include: sugars, for example, confectioner's sugar, compressible sugar, dextrates, dextrin, dextrose, lactose, mannitol, sorbitol, cellulose, and modified celluloses, for example, powdered cellulose, talc, calcium phosphate, starch, or any combination thereof.

    [0073] Thus, in one embodiment, the pharmaceutical composition comprises a diluent in an amount of 40 wt% or less (e.g., 35 wt% or less, 30 wt% or less, or 25 wt% or less, or 20 wt% or less, or 15 wt% or less, or 10 wt% or less) by weight of the composition. For example, the pharmaceutical composition comprises from about 40 wt% to about 1 wt% (e.g., from about 35 wt% to about 5 wt% or from about 30 wt% to about 7 wt%, from about 25 wt% to about 10 wt%, from about 20 wt% to about 15 wt%) of diluent, by weight of the composition. In another example, the pharmaceutical composition comprises 40 wt% or less (e.g., 35 wt% or less, 25 wt% or less, or 15 wt% or less) of mannitol, by weight of the composition. In yet another example, the pharmaceutical composition comprises from about 35 wt% to about 1 wt% (e.g., from about 30 wt% to about 5 wt% or from about 25 wt% to about 10 wt%) of mannitol, by weight of the composition.

    [0074] Glidants suitable for the invention enhance the flow properties of the pharmaceutical composition and are compatible with the ingredients of the pharmaceutical composition, i.e., they do not substantially reduce the solubility, the hardness, the chemical stability, the physical stability, or the biological activity of the pharmaceutical composition. Exemplary glidants include colloidal silicon dioxide, talc, or a combination thereof.

    [0075] Thus, in one embodiment, the pharmaceutical composition comprises a glidant in an amount of 2 wt% or less (e.g., 1.75 wt%, 1.25 wt% or less, or 1.00 wt% or less) by weight of the composition. For example, the pharmaceutical composition comprises from about 2 wt% to about 0.05 wt% (e.g., from about 1.5 wt% to about 0.07 wt% or from about 1.0 wt% to about 0.09 wt%) of glidant, by weight of the composition. In another example, the pharmaceutical composition comprises 2 wt% or less (e.g., 1.75 wt%, 1.25 wt% or less, or 1.00 wt% or less) of colloidal silicon dioxide, by weight of the composition. In yet another example, the pharmaceutical composition comprises from about 2 wt% to about 0.05 wt% (e.g., from about 1.5 wt% to about 0.07 wt% or from about 1.0 wt% to about 0.09 wt%) of colloidal silicon dioxide, by weight of the composition.

    [0076] In some embodiments, the pharmaceutical composition can include an oral solid pharmaceutical dosage form which can comprise a lubricant that can prevent adhesion of a granulate-bead admixture to a surface (e.g., a surface of a mixing bowl, a compression die and/or punch). A lubricant can also reduce interparticle friction within the granulate and improve the compression and ejection of compressed pharmaceutical compositions from a die press. The lubricant is also compatible with the ingredients of the pharmaceutical composition, i.e., they do not substantially reduce the solubility, the hardness, or the biological activity of the pharmaceutical composition. Exemplary lubricants include magnesium stearate, calcium stearate, zinc stearate, sodium stearate, stearic acid, aluminum stearate, leucine, glyceryl behenate, hydrogenated vegetable oil or any combination thereof. In one embodiment, the pharmaceutical composition comprises a lubricant in an amount of 5 wt% or less (e.g., 4.75 wt%, 4.0 wt% or less, or 3.00 wt% or less, or 2.0 wt% or less) by weight of the composition. For example, the pharmaceutical composition comprises from about 5 wt% to about 0.10 wt% (e.g., from about 4.5 wt% to about 0.5 wt% or from about 3 wt% to about 1 wt%) of lubricant, by weight of the composition. In another example, the pharmaceutical composition comprises 5 wt% or less (e.g., 4.0 wt% or less, 3.0 wt% or less, or 2.0 wt% or less, or 1.0 wt% or less) of magnesium stearate, by weight of the composition. In yet another example, the pharmaceutical composition comprises from about 5 wt% to about 0.10 wt% (e.g., from about 4.5 wt% to about 0.15 wt% or from about 3.0 wt% to about 0.50 wt%) of magnesium stearate, by weight of the composition.

    [0077] Pharmaceutical compositions of the invention can optionally comprise one or more colorants, flavors, and/or fragrances to enhance the visual appeal, taste, and/or scent of the composition. Suitable colorants, flavors, or fragrances are compatible with the ingredients of the pharmaceutical composition, i.e., they do not substantially reduce the solubility, the chemical stability, the physical stability, the hardness, or the biological activity of the pharmaceutical composition. In one embodiment, the pharmaceutical composition comprises a colorant, a flavor, and/or a fragrance. In one embodiment, the pharmaceutical compositions provided by the invention are purple.

    [0078] In some embodiments, the pharmaceutical composition includes or can be made into tablets and the tablets can be coated with a colorant and optionally labeled with a logo, other image and/or text using a suitable ink. In still other embodiments, the pharmaceutical composition includes or can be made into tablets and the tablets can be coated with a colorant, waxed, and optionally labeled with a logo, other image and/or text using a suitable ink. Suitable colorants and inks are compatible with the ingredients of the pharmaceutical composition, i.e., they do not substantially reduce the solubility, the chemical stability, the physical stability, the hardness, or the biological activity of the pharmaceutical composition. The suitable colorants and inks can be any color and are water based or solvent based. In one embodiment, tablets made from the pharmaceutical composition are coated with a colorant and then labeled with a logo, other image, and/or text using a suitable ink. For example, tablets comprising pharmaceutical composition as described herein can be coated with about 3 wt% (e.g., less than about 6 wt% or less than about 4 wt%) of film coating comprising a colorant. The colored tablets can be labeled with a logo and text indicating the strength of the active ingredient in the tablet using a suitable ink. In another example, tablets comprising pharmaceutical composition as described herein can be coated with about 3 wt% (e.g., less than about 6 wt% or less than about 4 wt%) of a film coating comprising a colorant.

    [0079] In another embodiment, tablets made from the pharmaceutical composition are coated with a colorant, waxed, and then labeled with a logo, other image, and/or text using a suitable ink. For example, tablets comprising pharmaceutical composition as described herein can be coated with about 3 wt% (e.g., less than about 6 wt% or less than about 4 wt%) of film coating comprising a colorant. The colored tablets can be waxed with Carnauba wax powder weighed out in the amount of about 0.01% w/w of the starting tablet core weight. The waxed tablets can be labeled with a logo and text indicating the strength of the active ingredient in the tablet using a suitable ink. In another example, tablets comprising pharmaceutical composition as described herein can be coated with about 3 wt% (e.g., less than about 6 wt% or less than about 4 wt%) of a film coating comprising a colorant The colored tablets can be waxed with Carnauba wax powder weighed out in the amount of about 0.01% w/w of the starting tablet core weight. The waxed tablets can be labeled with a logo and text indicating the strength of the active ingredient in the tablet using a pharmaceutical grade ink such as a black ink (e.g., Opacode® S-1-17823, a solvent based ink, commercially available from Colorcon, Inc. of West Point, PA.).

    [0080] One exemplary pharmaceutical composition comprises from about 30 wt% to about 70 wt%, or from about 40 wt% to about 70 wt%, or from about 50 wt% to about 70 wt%) of Compound 1, by weight of the composition. The aforementioned compositions can also include one or more pharmaceutically acceptable excipients, for example, from about 20 wt% to about 50 wt% of a filler; from about 1 wt% to about 5 wt% of a disintegrant; from about 2 wt% to about 0.3 wt% of a surfactant; from about 0.1 wt% to about 5 wt% of a binder; from about 1 wt% to about 30 wt% of a diluent; from about 2 wt% to about 0.05 wt% of a glidant; and from about 5 wt% to about 0.1 wt% of a lubricant. Or, the pharmaceutical composition comprises a composition containing from about 15 wt% to about 70 wt% (e.g., from about 20 wt% to about 40 wt%, from about 25 wt% to about 60 wt%, or from about 30 wt% to about 55 wt%) of Compound 1, by weight of the composition; and one or more excipients, for example, from about 20 wt% to about 50 wt% of a filler; from about 1 wt% to about 5 wt% of a disintegrant; from about 2 wt% to about 0.3 wt% of a surfactant; from about 0.1 wt% to about 5 wt% of a binder; from about 1 wt% to about 30 wt% of a diluent; from about 2 wt% to about 0.05 wt% of a glidant; and from about 5 wt% to about 0.1 wt% of a lubricant. In these exemplary pharmaceutical compositions, Compound 1 is in present as Compound 1 Form I, Compound 1 Form II and/or Compound 1 HCI Salt Form A, and the compositions further comprise a binder which is polyvinylpyrrolidone.

    [0081] Another exemplary pharmaceutical composition comprises about 30 wt% to about 70 wt%, or from about 40 wt% to about 70 wt%, or from about 50 wt% to about 70 wt%) of Compound 1 by weight of the composition, and one or more excipients, for example, from about 20 wt% to about 50 wt% of a filler; from about 1 wt% to about 5 wt% of a disintegrant; from about 2 wt% to about 0.3 wt% of a surfactant; from about 0.1 wt% to about 5 wt% of a binder; from about 1 wt% to about 30 wt% of a diluent; from about 2 wt% to about 0.05 wt% of a glidant; and from about 2 wt% to about 0.1 wt% of a lubricant. In these exemplary pharmaceutical compositions, Compound 1 is in present as Compound 1 Form I, Compound 1 Form II and/or Compound 1 HCl Salt Form A, and the compositions further comprise a binder which is polyvinylpyrrolidone.

    [0082] Another exemplary pharmaceutical composition comprises from about 30 wt% to about 70 wt%, or from about 40 wt% to about 70 wt%, or from about 50 wt% to about 70 wt%) of Compound 1 by weight of the composition, and one or more excipients, for example, from about 20 wt% to about 50 wt% of a filler; from about 1 wt% to about 5 wt% of a disintegrant; from about 2 wt% to about 0.3 wt% of a surfactant; from about 0.1 wt% to about 5 wt% of a binder; from about 1 wt% to about 30 wt% of a diluent; from about 2 wt% to about 0.05 wt% of a glidant; and from about 2 wt% to about 0.1 wt% of a lubricant. In these exemplary pharmaceutical compositions, Compound 1 is in present as Compound 1 Form I, Compound 1 Form II and/or Compound 1 HCl Salt Form A, and the compositions further comprise a binder which is polyvinylpyrrolidone.

    [0083] Another exemplary pharmaceutical composition comprises from about 30 wt% to about 70 wt%, or from about 40 wt% to about 70 wt%, or from about 50 wt% to about 70 wt%) of Compound 1 and one or more excipients, for example, from about 20 wt% to about 50 wt% of a filler; from about 1 wt% to about 5 wt% of a disintegrant; from about 2 wt% to about 0.3 wt% of a surfactant; from about 0.1 wt% to about 5 wt% of a binder; from about 1 wt% to about 30 wt% of a diluent; from about 2 wt% to about 0.05 wt% of a glidant; and from about 2 wt% to about 0.1 wt% of a lubricant. In these exemplary pharmaceutical compositions, Compound 1 is in present as Compound 1 Form I, Compound 1 Form II and/or Compound 1 HCl Salt Form A, and the compositions further comprise a binder which is polyvinylpyrrolidone.

    [0084] Another granular composition formulated into an oral formulation of the invention comprises:
    1. a. about 50 wt% of Compound 1;
    2. b. about 30 wt% of microcrystalline cellulose by weight of the composition;
    3. c. about 13 wt% of mannitol by weight of the composition;
    4. d. about 2 wt% of croscarmellose sodium by weight of the composition;
    5. e. about 4 wt% of polyvinylpyrrolidone by weight of the composition; and
    6. f. about 1 wt% of sodium lauryl sulfate by weight of the composition.


    [0085] Another pharmaceutical oral formulation of the invention comprises:
    1. a. about 50 wt% of a Compound 1 by weight of the composition;
    2. b. about 30 wt% of microcrystalline cellulose by weight of the composition;
    3. c. about 13 wt% of mannitol by weight of the composition;
    4. d. about 4 wt% of croscarmellose sodium by weight of the composition;
    5. e. about 4 wt% of polyvinylpyrrolidone by weight of the composition
    6. f. about 1 wt% of sodium lauryl sulfate by weight of the composition; and
    7. g. about 0.5 wt% of magnesium stearate by weight of the composition.


    [0086] Another pharmaceutical oral formulation of the invention comprises:
    1. a. about 60 wt% of a Compound 1 by weight of the composition;
    2. b. about 20 wt% of microcrystalline cellulose by weight of the composition;
    3. c. about 13 wt% of mannitol by weight of the composition;
    4. d. about 4 wt% of croscarmellose sodium by weight of the composition;
    5. e. about 4 wt% of polyvinylpyrrolidone by weight of the composition
    6. f. about 1 wt% of sodium lauryl sulfate by weight of the composition; and
    7. g. about 0.5 wt% of magnesium stearate by weight of the composition.


    [0087] Another pharmaceutical oral formulation of the invention comprises:
    1. a. about 150 to 250 mg of Compound 1;
    2. b. about 40 to 50 mg of mannitol;
    3. c. about 120 to 130 mg of microcrystalline cellulose;
    4. d. about 10 to 20 mg of croscarmellose sodium;
    5. e. about 10 to 20 mg of polyvinylpyrrolidone;
    6. f. about 1 to 5 mg of sodium lauryl sulfate; and
    7. g. about 1 to 5 mg of magnesium stearate.


    [0088] Another pharmaceutical oral formulation of the invention comprises:
    1. a. about 200 mg of Compound 1;
    2. b. about 43 mg of mannitol;
    3. c. about 123 mg of microcrystalline cellulose;
    4. d. about 15 mg of croscarmellose sodium;
    5. e. about 13 mg of polyvinylpyrrolidone;
    6. f. about 3 mg of sodium lauryl sulfate; and
    7. g. about 4 mg of magnesium stearate.


    [0089] Another pharmaceutical oral formulation of the invention comprises:
    1. a. about 200 mg of Compound 1;
    2. b. about 45 mg of mannitol;
    3. c. about 123 mg of microcrystalline cellulose;
    4. d. about 15 mg of croscarmellose sodium;
    5. e. about 10.4 mg of polyvinylpyrrolidone;
    6. f. about 2.6 mg of sodium lauryl sulfate; and
    7. g. about 4 mg of magnesium stearate.


    [0090] Another pharmaceutical oral formulation of the invention comprises:
    1. a. about 70 wt% of a Compound 1 by weight of the composition;
    2. b. about 12 wt% of microcrystalline cellulose by weight of the composition;
    3. c. about 11 wt% of mannitol by weight of the composition;
    4. d. about 4 wt% of croscarmellose sodium by weight of the composition;
    5. e. about 4 wt% of polyvinylpyrrolidone by weight of the composition
    6. f. about 1 wt% of sodium lauryl sulfate by weight of the composition; and
    7. g. about 0.5 wt% of magnesium stearate by weight of the composition.


    [0091] The pharmaceutical compositions of the invention can be processed into a tablet form, capsule form, pouch form, lozenge form, or other solid form that is suited for oral administration. Thus in some embodiments, the pharmaceutical compositions are in tablet form.

    [0092] In still another pharmaceutical oral formulation of the invention, a shaped pharmaceutical tablet composition having an initial hardness of 5-21 ±kP 6 20 percent comprises: about 49 wt% of a Compound 1; about 29 wt% of microcrystalline cellulose by weight of the composition; about 12.6 wt% of mannitol by weight of the composition; about 4 wt% of croscarmellose sodium by weight of the composition; about 4 wt% of polyvinylpyrrolidone by weight of the composition; about 1 wt% of sodium lauryl sulfate by weight of the composition; and about 0.5 wt% of magnesium stearate by weight of the composition. The amount of Compound 1 in the shaped pharmaceutical tablet ranges from about 25 mg to about 250 mg, for example, 50 mg, or 75 mg, or 100 mg, or 150 mg, 200 mg, or 250 mg Compound 1 per tablet.

    [0093] In certain embodiments, the shaped pharmaceutical tablet contains about 100 mg of Compound 1. In certain embodiments, the shaped pharmaceutical tablet contains about 200 mg of Compound 1.

    [0094] Dissolution can be measured with a standard USP Type II apparatus that employs a dissolution media of 0.1% CTAB dissolved in 900 mL of DI water, buffered at pH 6.8 with 50 mM potassium phosphate monoasic, stirring at about 50-75 rpm at a temperature of about 37 °C. A single experimental tablet is tested in each test vessel of the apparatus. Dissolution can also be measured with a standard USP Type II apparatus that employs a dissolution media of 0.7% sodium lauryl sulfate dissolved in 900 mL of 50 mM sodium phosphate buffer (pH 6.8), stirring at about 65 rpm at a temperature of about 37 °C. A single experimental tablet is tested in each test vessel of the apparatus. Dissolution can also be measured with a standard USP Type II apparatus that employs a dissolution media of 0.5% sodium lauryl sulfate dissolved in 900 mL of 50 mM sodium phosphate buffer (pH 6.8), stirring at about 65 rpm at a temperature of about 37 °C. A single experimental tablet is tested in each test vessel of the apparatus.

    METHODS FOR MAKING COMPOUND 1, COMPOUND 1 FORM I, COMPOUND 1 FORM II, COMPOUND 1 HCl SALT FORM A


    Compound 1



    [0095] Compound 1 is used as the starting point for the other solid state forms and can be prepared by coupling an acid chloride moiety with an amine moiety according to Schemes 1-4.



    [0096] Scheme 1 depicts the preparation of 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarbonyl chloride, which is used in Scheme 3 to make the amide linkage of Compound 1.

    [0097] The starting material, 2,2-difluorobenzo[d][1,3]dioxole-5-carboxylic acid, is commercially available from Saltigo (an affiliate of the Lanxess Corporation). Reduction of the carboxylc acid moiety in 2,2-difluorobenzo[d][1,3]dioxole-5- carboxylic acid to the primary alcohol, followed by conversion to the corresponding chloride using thionyl chloride (SOCl2), provides 5-(chloromethyl)-2,2 difluorobenzo[d][1,3]dioxole, which is subsequently converted to 2-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)acetonitrile using sodium cyanide. Treatment of 2-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)acetonitrile with base and 1-bromo-2-chloroethane provides 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarbonitrile. The nitrile moiety in 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarbonitrile is converted to a carboxylic acid using base to give 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxylic acid, which is converted to the desired acid chloride using thionyl chloride.



    [0098] Scheme 2 depicts an alternative synthesis of the requisite acid chloride. 5-bromomethyl-2,2-difluoro-1,3-benzodioxole is coupled with ethyl cyanoacetate in the presence of a palladium catalyst to form the corresponding alpha cyano ethyl ester. Saponification of the ester moiety to the carboxylic acid gives the cyanoethyl compound. Alkylation of the cyanoethyl compound with 1-bromo-2-chloro ethane in the presence of base gives the cyanocyclopropyl compound. Treatment of the cyanocyclopropyl compound with base gives the carboxylate salt, which is converted to the carboxylic acid by treatment with acid. Conversion of the carboxylic acid to the acid chloride is then accomplished using a chlorinating agent such as thionyl chloride or the like.



    [0099] Scheme 3 depicts the preparation of the requisite tert-butyl 3-(6-amino-3-methylpyridin-2-yl)benzoate, which is coupled with 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarbonyl chloride in Scheme 3 to give Compound 1. Palladium-catalyzed coupling of 2-bromo-3-methylpyridine with 3-(tert-butoxycarbonyl)phenylboronic acid gives tert-butyl 3-(3-methylpyridin-2-yl)benzoate, which is subsequently converted to the desired compound.



    [0100] Scheme 4 depicts the coupling of 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarbonyl chloride with tert-butyl 3-(6-amino-3-methylpyridin-2-yl)benzoate using triethyl amine and 4-dimethylaminopyridine to initially provide the tert-butyl ester of Compound 1.

    Compound 1 Form I



    [0101] Compound 1 Form I is prepared by dispersing or dissolving a salt form, such as the HCl salt, of Compound 1 in an appropriate solvent for an effective amount of time. Treatment of the tert-butyl ester with an acid such as HCl, gives the HCL salt of Compound 1, which is typically a crystalline solid. Compound 1 Form I may also be prepared directly from the t-butyl ester precursor by treatment with an appropriate acid, such as formic acid.

    [0102] The HCl salt of 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid can be used to make Form I by dispersing or dissolving the HCl salt of 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid in an appropriate solvent for an effective amount of time. Other salts of 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid may be used, such as, for example, salts derived from other mineral or organic acids. The other salts result from acid-mediated hydrolysis of the t-butyl ester moiety. Salts derived from other acids may include, for example, nitric, sulfuric, phosphoric, boric, acetic, benzoic and malonic. These salt forms of 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid may or may not be soluble, depending upon the solvent used, but lack of solubility does not hinder formation of Form I. For example, in one embodiment, the appropriate solvent may be water or an alcohol/water mixture such as 50% methanol/water mixture, even though the HCl salt form of 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid is only sparingly soluble in water. In one embodiment, the appropriate solvent is water.

    [0103] The effective amount of time for formation of Form I from the salt of 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid can be any time between 2 to 24 hours or greater. It is recognized that the amount of time needed is inversely proportional to the temperature. That is, the higher the temperature the less time needed to affect dissociation of acid to form Form I. When the solvent is water, stirring the dispersion for approximately 24 hours at room temperature provides Form I in an approximately 98% yield. If a solution of the salt of 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid is desired for process purposes, an elevated temperature may be used. After stirring the solution for an effective amount of time at the elevated temperature, recrystallization upon cooling provides substantially pure Form I. In one embodiment, substantially pure refers to greater than about 90% purity. In another embodiment, substantially pure refers to greater than about 95% purity. In another embodiment, substantially pure refers to greater than about 98% purity. In another embodiment, substantially pure refers to greater than about 99% purity. The temperature selected depends in part on the solvent used and is well within the determination capabilities of one of ordinary skill in the art. In one embodiment, the temperature is between room temperature and about 80 °C. In another embodiment, the temperature is between room temperature and about 40 °C. In another embodiment, the temperature is between about 40 °C and about 60 °C. In another embodiment, the temperature is between about 60 °C and about 80 °C.

    [0104] Compound 1 Form I may also be formed directly from 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)-t-butylbenzoate (cf. Scheme 3), which is a precursor to the salt of Compound 1. Thus, 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)-t-butylbenzoate is allowed to undergo reaction with an appropriate acid, such as, for example, formic acid under appropriate reaction conditions to give Compound 1 Form I.

    [0105] Compound 1 Form I may be further purified by recrystallization from an organic solvent. Examples of organic solvents include, but are not limited to, toluene, cumene, anisol, 1-butanol, isopropyl acetate, butyl acetate, isobutyl acetate, methyl t-butyl ether, methyl isobutyl ketone and 1-propanol-water mixtures. The temperature may be as described above. For example, Form I is dissolved in 1-butanol at 75 °C until it is completely dissolved. Cooling down the solution to 10 °C at a rate of 0.2 °C/min yields crystals of Form I which may be isolated by filtration.

    [0106] In one embodiment, Compound 1 Form I is characterized by one or more peaks at 15.2 to 15.6 degrees, 16.1 to 16.5 degrees, and 14.3 to 14.7 degrees in an X-ray powder diffraction obtained using Cu K alpha radiation. In another embodiment, Compound 1 Form I is characterized by one or more peaks at 15.4, 16.3, and 14.5 degrees. In another embodiment, Compound 1 Form I is further characterized by a peak at 14.6 to 15.0 degrees. In another embodiment, Compound 1 Form I is further characterized by a peak at 14.8 degrees. In another embodiment, Compound 1 Form I is further characterized by a peak at 17.6 to 18.0 degrees. In another embodiment, Compound 1 Form I is further characterized by a peak at 17.8 degrees. In another embodiment, Compound 1 Form I is further characterized by a peak at 16.4 to 16.8 degrees. In another embodiment, Compound 1 Form I is further characterized by a peak at 16.4 to 16.8 degrees. In another embodiment, Compound 1 Form I is further characterized by a peak at 16.6 degrees. In another embodiment, Compound 1 Form I is further characterized by a peak at 7.6 to 8.0 degrees. In another embodiment, Compound 1 Form I is further characterized by a peak at 7.8 degrees. In another embodiment, Compound 1 Form I is further characterized by a peak at 25.8 to 26.2 degrees. In another embodiment, Compound 1 Form I is further characterized by a peak at 26.0 degrees. In another embodiment, Compound 1 Form I is further characterized by a peak at 21.4 to 21.8 degrees. In another embodiment, Compound 1 Form I is further characterized by a peak at 21.6 degrees. In another embodiment, Compound 1 Form I is further characterized by a peak at 23.1 to 23.5 degrees. In another embodiment, Compound 1 Form I is further characterized by a peak at 23.3 degrees. In some embodiments, Compound 1 Form I is characterized by a diffraction pattern substantially similar to that of Figure 1. In some embodiments, Compound 1 Form I is characterized by a diffraction pattern substantially similar to that of Figure 2.

    [0107] In some embodiments, the particle size distribution of D90 is about 82 µm or less for Compound 1 Form I. In some embodiments, the particle size distribution of D50 is about 30 µm or less for Compound 1 Form I.

    Compound 1 Form II



    [0108] Compound 1 Form II is prepared by slurrying Compound 1 Form I in an appropriate solvent at a sufficient concentration for a sufficient time. The slurry is then filtered centrifugally or under vacuum and dried at ambient conditions for sufficient time to yield Compound 1 Form II.

    [0109] In some embodiments, about 20 to 40 mg of Compound 1 Form I is slurried in about 400 to 600 µL of an appropriate solvent. In another embodiment, about 25 to 35 mg of Compound 1 Form I is slurried in about 450 to 550 µL of an appropriate solvent. In another embodiment, about 30 mg of Compound 1 Form I is slurried in about 500 µL of an appropriate solvent.

    [0110] In some embodiments, the time that Compound 1 Form I is allowed to slurry with the solvent is from1 hour to four days. More particularly, the time that Compound 1 Form I is allowed to slurry with the solvent is from1 to 3 days. More particularly, the time is 2 days.

    [0111] In some embodiments, the appropriate solvent is selected from an organic solvent of sufficient size to fit the voids in the crystalline lattice of Compound 1 Form II. In other embodiments, the solvate is of sufficient size to fit in voids measuring about 100 Å3.

    [0112] In other embodiments, the solvent is selected from the group consisting of methanol, ethanol, acetone, 2-propanol, acetonitrile, tetrahydrofuran, methyl acetate, 2-butanone, ethyl formate, and 2-methyl tetrahydrofuran.

    [0113] In other embodiments, a mixture of two or more of these solvents may be used to obtain Compound 1 Form II. Alternatively, Compound 1 Form II may be obtained from a mixture comprising one or more of these solvents and water.

    [0114] In some embodiments, the effective amount of time for drying Compound 1 Form II is 1 to 24 hours. More particularly, the time is 6 to 18 hours. More particularly, the time is about 12 hours.

    [0115] In another embodiment, Compound 1 Form II is prepared by dispersing or dissolving a salt form of Compound 1, such as an HCl salt of Compound 1 in an appropriate solvent for an effective amount of time.

    [0116] Compound 1 Form II as disclosed herein comprises a crystalline lattice of Compound 1 in which voids in the crystalline lattice are empty, or occupied, or partially occupied by one or more molecules of a suitable solvent. Suitable solvents include, but are not limited to, methanol, ethanol, acetone, 2-propanol, acetonitrile, tetrahydrofuran, methyl acetate, 2-butanone, ethyl formate, and 2-methyl tetrahydrofuran. Certain physical characterisics of Compound 1 isostructural solvate forms, such as X-ray powder diffraction, melting point and DSC, are not substantially affected by the particular solvent molecule in question.

    [0117] In one embodiment, Compound 1 Form II is characterized by one or more peaks at 21.50 to 21.90 degrees, 8.80 to 9.20 degrees, and 10.80 to 11.20 degrees in an X-ray powder diffraction obtained using Cu K alpha radiation. In another embodiment, Compound 1 Form II is characterized by one or more peaks at 21.50 to 21.90 degrees, 8.80 to 9.20 degrees, 10.80 to 11.20 degrees, 18.00 to 18.40 degrees, and 22.90 to 23.30 degrees in an X-ray powder diffraction obtained using Cu K alpha radiation. In another embodiment, Compound 1 Form II is characterized by one or more peaks at 21.70, 8.98, and 11.04 degrees. In another embodiment, Compound 1 Form II is characterized by one or more peaks at 21.70, 8.98, 11.04, 18.16, and 23.06 degrees. In another embodiment, Compound 1 Form II is characterized by a peak at 21.50 to 21.90 degrees. In another embodiment, Compound 1 Form II is further characterized by a peak at 21.70 degrees. In another embodiment, Compound 1 Form II is further characterized by a peak at 8.80 to 9.20 degrees. In another embodiment, Compound 1 Form II is further characterized by a peak at 8.98 degrees. In another embodiment, Compound 1 Form II is further characterized by a peak at 10.80 to 11.20 degrees. In another embodiment, Compound 1 Form II is further characterized by a peak at 11.04. In another embodiment, Compound 1 Form II is further characterized by a peak at 18.00 to 18.40 degrees. In another embodiment, Compound 1 Form II is further characterized by a peak at 18.16 degrees. In another embodiment, Compound 1 Form II is further characterized by a peak at 22.90 to 23.30 degrees. In another embodiment, Compound 1 Form II is further characterized by a peak at 23.06 degrees. In another embodiment, Compound 1 Form II is further characterized by a peak at 20.40 to 20.80 degrees. In another embodiment, Compound 1 Form II is further characterized by a peak at 20.63 degrees. In another embodiment, Compound 1 Form II is further characterized by a peak at 22.00 to 22.40 degrees. In another embodiment, Compound 1 Form II is further characterized by a peak at 22.22 degrees. In another embodiment, Compound 1 Form II is further characterized by a peak at 18.40 to 18.80 degrees. In another embodiment, Compound 1 Form II is further characterized by a peak at 18.57 degrees. In another embodiment, Compound 1 Form II is further characterized by a peak at 16.50 to 16.90 degrees. In another embodiment, Compound 1 Form II is further characterized by a peak at 16.66 degrees. In another embodiment, Compound 1 Form II is further characterized by a peak at 19.70 to 20.10 degrees. In another embodiment, Compound 1 Form II is further characterized by a peak at 19.86 degrees.

    [0118] In some embodiments, Compound 1 Form II is characterized by a diffraction pattern substantially similar to that of Figure 3. In some embodiments, Compound 1 Form II is characterized by diffraction patterns substantially similar to those provided in Figure 4.

    [0119] In another embodiment, the solvate that forms Compound 1 Form II is selected from the group consisting of methanol, ethanol, acetone, 2-propanol, acetonitrile, tetrahydrofuran, methyl acetate, 2-butanone, ethyl formate, and 2-methyl tetrahydrofuran. Diffraction patterns are provided for the following Compound 1 Form II: methanol (Figure 5), ethanol (Figure 6), acetone (Figure 7), 2-propanol (Figure 8), acetonitrile (Figure 9), tetrahydrofuran (Figure 10), methyl acetate (Figure 11), 2-butanone (Figure 12), ethyl formate (Figure 13), and 2-methytetrahydrofuran (Figure 14).

    [0120] In another embodiment, the invention provides Compound 1 Form II which exhibits two or more phase transitions as determined by DSC or a similar analytic method known to the skilled artisan. In some embodiments, the DSC of Compound 1 Form II is substantially similar to the DSC trace depicted in Figure 15. In another embodiment of this aspect, the DSC gives two phase transitions. In another embodiment, the DSC gives three phase transitions. In another embodiment, one of the phase transitions occurs between 200 and 207 °C. In another embodiment, one of the phase transitions occurs between 204 and 206 °C. In another embodiment, one of the phase transitions occurs between 183 and 190 °C. In another embodiment, one of the phase transitions occurs between 185 and 187 °C. In another embodiment, the melting point of Compound 1, Solvate Form A is between 183 °C to 190 °C. In another embodiment, the melting point of Compound 1, Solvate Form A is between 185 °C to 187 °C.

    [0121] In another embodiment, Compound 1 Form II comprises 1 to 10 weight percent (wt. %) solvate as determined by TGA. In some embodiments, the TGA of Compound 1 Form II is substantially similar to the TGA trace depicted in Figure 16. In another embodiment, Compound 1 Form II comprises 2 to 5 wt. % solvate as determined by TGA or a similar analytic method known to the skilled artisan.

    [0122] In another embodiment, the conformation of Compound 1 Form II acetone solvate is substantially similar to that depicted in Figure 17, which is based on single X-ray analysis.

    [0123] In another embodiment, Compound 1 Form II acetone solvate has a P21/n space group, and the following unit cell dimensions:






    Compound 1 HCl Salt Form A



    [0124] Compound 1 HCl Salt Form A can be prepared from the HCl salt of Compound 1, by dissolving the HCl salt of Compound 1 in a minimum of solvent and removing the solvent by slow evaporation. In another embodiment, the solvent is an alcohol. In another embodiment, the solvent is ethanol. Slow evaporation is generally carried out by impeding the evaporation of the solvent. For example, in one embodiment, slow evaporation involves dissolving the HCl salt of Compound 1 in a vial and covering the vial with parafilm that contains a hole poked in it.

    [0125] In one embodiment, Compound 1 HCl Salt Form A is characterized by one or more peaks at 8.80 to 9.20 degrees, 17.30 to 17.70 degrees, and 18.20 to 18.60 degrees in an X-ray powder diffraction obtained using Cu K alpha radiation. In another embodiment, Compound 1 HCl Salt Form A is characterized by one or more peaks at 8.80 to 9.20 degrees, 17.30 to 17.70 degrees, 18.20 to 18.60 degrees, 10.10 to 10.50, and 15.80 to 16.20 degrees in an X-ray powder diffraction obtained using Cu K alpha radiation. In another embodiment, Compound 1 HCl Salt Form A is characterized by one or more peaks at 8.96, 17.51, and 18.45 degrees. In another embodiment, Compound 1 HCl Salt Form A is characterized by one or more peaks at 8.96, 17.51, 18.45. 10.33, and 16.01 degrees. In another embodiment, Compound 1 HCl Salt Form A is characterized by a peak at 8.80 to 9.20 degrees. In another embodiment, Compound 1 HCl Salt Form A is characterized by a peak at 8.96 degrees. In another embodiment, Compound 1 HCl Salt Form A is further characterized by a peak at 17.30 to 17.70 degrees. In another embodiment, Compound 1 HCl Salt Form A is characterized by a peak at 17.51 degrees. In another embodiment, Compound 1 HCl Salt Form A is further characterized by a peak at 18.20 to 18.60 degrees. In another embodiment, Compound 1 HCl Salt Form A is further characterized by a peak at 18.45degrees. In another embodiment, Compound 1 HCl Salt Form A is further characterized by a peak at 10.10 to 10.50 degrees. In another embodiment, Compound 1 HCl Salt Form A is further characterized by a peak at 10.33 degrees. In another embodiment, Compound 1 HCl Salt Form A is further characterized by a peak at 15.80 to 16.20 degrees. In another embodiment, Compound 1 HCl Salt Form A is further characterized by a peak at 16.01 degrees. In another embodiment, Compound 1 HCl Salt Form A is further characterized by a peak at 11.70 to 12.10 degrees. In another embodiment, Compound 1 HCl Salt Form A is further characterized by a peak at 11.94 degrees. In another embodiment, Compound 1 HCl Salt Form A is further characterized by a peak at 7.90 to 8.30 degrees. In another embodiment, Compound 1 HCl Salt Form A is further characterized by a peak at 8.14 degrees. In another embodiment, Compound 1 HCl Salt Form A is further characterized by a peak at 9.90 to 10.30 degrees. In another embodiment, Compound 1 HCl Salt Form A is further characterized by a peak at 10.10 degrees. In another embodiment, Compound 1 HCl Salt Form A is further characterized by a peak at 16.40 to 16.80 degrees. In another embodiment, Compound 1 HCl Salt Form A is further characterized by a peak at 16.55 degrees. In another embodiment, Compound 1 HCl Salt Form A is further characterized by a peak at 9.30 to 9.70 degrees. In another embodiment, Compound 1 HCl Salt Form A is further characterized by a peak at 9.54 degrees. In another embodiment, Compound 1 HCl Salt Form A is further characterized by a peak at 16.40 to 16.80 degrees. In another embodiment, Compound 1 HCl Salt Form A is further characterized by a peak at 16.55 degrees. In some embodiments, Compound 1 HCl Salt Form A is characterized as a dimer as depicted in Figure 18.

    [0126] In some embodiments, Compound 1 HCl Salt Form A is characterized by a diffraction pattern substantially similar to that of Figure 19.

    [0127] In another embodiment, the invention features crystalline Compound 1 HCl Salt Form A having a P1 space group, and the following unit cell dimensions:






    METHODS FOR MAKING THE PHARMACEUTICAL COMPOSITIONS



    [0128] The dosage unit forms of the invention can be produced by compacting or compressing an admixture or composition, for example, a powder or granules, under pressure to form a stable three-dimensional shape (e.g., a tablet). As used herein, "tablet" includes compressed pharmaceutical dosage unit forms of all shapes and sizes, whether coated or uncoated.

    [0129] The expression "dosage unit form" as used herein refers to a physically discrete unit of agent appropriate for the patient to be treated. In general, a compacted mixture has a density greater than that of the mixture prior to compaction. A dosage unit form of the invention can have almost any shape including concave and/or convex faces, rounded or angled corners, and a rounded to rectilinear shape. In some embodiments, the compressed dosage forms of the invention comprise a rounded tablet having flat faces. The solid pharmaceutical dosage forms of the invention can be prepared by any compaction and compression method known by persons of ordinary skill in the art of forming compressed solid pharmaceutical dosage forms. In particular embodiments, the formulations provided herein may be prepared using conventional methods known to those skilled in the field of pharmaceutical formulation, as described, e.g., in pertinent textbooks. See, e.g., Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott Williams & Wilkins, Baltimore, Md. (2003); Ansel et al., Pharmaceutical Dosage Forms And Drug Delivery Systems, 7th Edition, Lippincott Williams & Wilkins, (1999); The Handbook of Pharmaceutical Excipients, 4th edition, Rowe et al., Eds., American Pharmaceuticals Association (2003); Gibson, Pharmaceutical Preformulation And Formulation, CRC Press (2001), these references hereby incorporated herein by reference in their entirety.

    Granulation and Compression



    [0130] The invention relates to a method of producing a pharmaceutical composition comprising the steps of: combining a therapeutically effective amount of Compound 1 Form I, Compound 1 Form II, and/or Compound 1 HCl Salt Form A and at least one granulation excipient selected from the group consisting of: a binder; a glidant; a surfactant; a lubricant; a disintegrant; a filler, a diluent and combinations thereof to form an admixture; mixing and wet granulating the admixture; and compacting the admixture to form the pharmaceutical composition from an admixture of powdered and liquid materials; wherein Compound 1 Form I, Compound 1 Form II, and/or Compound 1 HCl Salt Form A is present in an amount of at least 30 wt% in the pharmaceutical composition, as required by claim 12. The invention also relates to a tablet, a pharmaceutical composition, and a dosage unit form as defined in claims 1, 3, 4, 5, and 9. In further aspects disclosed herein, the tablets, pharmaceutical compositions, and dosage unit forms of claims 1-11 can, within the scope of claims 1-11, include powders comprising the active agent Compound 1 and the included pharmaceutically acceptable excipients (e.g. filler, diluent, disintegrant, surfactant, glidant, binder, lubricant, or any combination thereof) which can be subjected to a dry granulation process. The dry granulation process causes the powder to agglomerate into larger particles having a size suitable for further processing. Dry granulation can improve the flowability of a mixture in order to be able to produce tablets that comply with the demand of mass variation or content uniformity.

    [0131] In further aspects disclosed herein, the tablets, pharmaceutical compositions, and dosage unit forms of claims 1-11 can, within the scope of claims 1-11, be produced using one or more mixing and dry granulations steps. The order and the number of the mixing and granulation steps do not seem to be critical. However, at least one of the excipients and Compound 1 can be been subject to dry granulation or wet high shear granulation before compression into tablets. Dry granulation of Compound 1 and the excipients made together prior to tablet compression seem, surprisingly, to be a simple, inexpensive and efficient way of providing close physical contact between the ingredients of the present compositions and formulations and thus results in a tablet formulation with good stability properties. Dry granulation can be carried out by a mechanical process, which transfers energy to the mixture without any use of any liquid substances (neither in the form of aqueous solutions, solutions based on organic solutes, or mixtures thereof) in contrast to wet granulation processes, also contemplated herein. 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.

    [0132] In some aspects disclosed herein, roller compaction is a granulation process comprising highly intensive mechanical compacting of one or more substances. In some aspects disclosed herein, a pharmaceutical composition comprising an admixture of powders is pressed, that is roller compacted, between 2 counter rotating rollers to make a solid sheet which is subsequently crushed in a sieve to form a particulate matter. In this particulate matter, a close mechanical contact between the ingredients can be obtained. An example of roller compaction equipment is Minipactor® a Gerteis 3WPolygran from Gerteis Maschinen+Processengineering AG.

    [0133] In some aspects disclosed herein, tablet compression 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. In a typical aspect disclosed herein the resulting core or tablet has a compressive strength in the range of 1 to 15 kP; such as 1.5 to 12.5 kP, preferably in the range of 2 to 10 kP.

    Brief Manufacturing Procedure



    [0134] In some embodiments, the ingredients are weighed according to the formula set herein. Next, 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. Next, the compacted or slugged blends are milled into granules and sifted to obtain the desired size. Next, the granules can be further lubricated with, for example, magnesium stearate. Next the granular composition of the invention can be compressed on suitable punches into various pharmaceutical formulations in accordance with the invention. Optionally the tablets can be coated with a film, colorant or other coating.

    [0135] Another aspect of the invention provides a method defined in claim 12 for producing a pharmaceutical composition. This method comprises the steps of: combining a therapeutically effective amount of Compound 1 Form I, Compound 1 Form II, and/or Compound 1 HCl Salt Form A and at least one granulation excipient selected from the group consisting of: a binder; a glidant; a surfactant; a lubricant; a disintegrant; a filler, a diluent and combinations thereof to form an admixture; mixing and wet granulating the admixture; and compacting the admixture to form the pharmaceutical composition from an admixture of powdered and liquid materials; wherein Compound 1 Form I, Compound 1 Form II, and/or Compound 1 HCl Salt Form A is present in an amount of at least 30 wt% in the pharmaceutical composition.

    [0136] A wet granulation process is performed to yield the pharmaceutical formulation of the invention from an admixture of powdered and liquid ingredients. For example, a pharmaceutical composition comprising an admixture of a composition comprising Compound 1 and one or more excipients selected from: a filler, a diluent, a binder, a glidant, a surfactant, a lubricant, a disintegrant, are weighed as per the formula set herein. Next, all of the intragranular ingredients are sifted and mixed in a high shear or low shear granulator using water or water with a surfactant or water with a binder or water with a surfactant and a binder to granulate the powder blend. A fluid other than water can also be used with or without surfactant and/or binder to granulate the powder blend. Next, the wet granules can optionally be milled using a suitable mill. Next, water may optionally be removed from the admixture by drying the ingredients in any suitable manner. Next, the dried granules can optionally be milled to the required size. Next, extra granular excipients can be added by blending (for example a filler, a diluent, and a disintegrant). Next, the sized granules can be further lubricated with magnesium stearate and a disintegrant, for example, croscarmellose sodium. Next the granular composition of the invention can be sifted for sufficient time to obtain the correct size and then compressed on suitable punches into various pharmaceutical formulations in accordance with the invention. Optionally, the tablets can be coated with a film, colorant or other coating. The pharmaceutical compositions produced using the method of the invention contain Compound 1 Form I, Compound 1 Form II, and/or Compound 1 HCl Salt Form A in an amount of at least 30 wt%.

    [0137] Each of the ingredients of this exemplary admixture is described above and in the Examples below. Furthermore, the admixture can comprise optional additives, such as, one or more colorants, one or more flavors, and/or one or more fragrances as described above and in the Examples below. In some embodiments, the relative concentrations (e.g., wt%) of each of these ingredients (and any optional additives) in the admixture are also presented above and in the Examples below. The ingredients constituting the admixture can be provided sequentially or in any combination of additions; and, the ingredients or combination of ingredients can be provided in any order. In one embodiment, the lubricant is the last component added to the admixture.

    [0138] In another embodiment, the admixture comprises a composition of Compound 1, and any one or more of the excipients; a binder, a glidant, a surfactant, a diluent, a lubricant, a disintegrant, and a filler, wherein each of these ingredients is provided in a powder form (e.g., provided as particles having a mean or average diameter, measured by light scattering, of 250 µm or less (e.g., 150 µm or less, 100 µm or less, 50 µm or less, 45 µm or less, 40 µm or less, or 35 µm or less)). For instance, the admixture comprises a composition of Compound 1, a diluent, a glidant, a surfactant, a lubricant, a disintegrant, and a filler, wherein each of these ingredients is provided in a powder form (e.g., provided as particles having a mean diameter, measured by light scattering, of 250 µm or less (e.g., 150 µm or less, 100 µm or less, 50 µm or less, 45 µm or less, 40 µm or less, or 35 µm or less)). In another example, the admixture comprises a composition of Compound 1, a diluent, a binder, a surfactant, a lubricant, a disintegrant, and a filler, wherein each of these ingredients is provided in a powder form (e.g., provided as particles having a mean diameter, measured by light scattering, of 250 µm or less (e.g., 150 µm or less, 100 µm or less, 50 µm or less, 45 µm or less, 40 µm or less, or 35 µm or less))

    [0139] In another embodiment, the admixture comprises a composition of Compound 1, and any combination of: a binder, a glidant, a diluent, a surfactant, a lubricant, a disintegrant, and a filler, wherein each of these ingredients is substantially free of water. Each of the ingredients comprises less than 5 wt% (e.g., less than 2 wt%, less than 1 wt%, less than 0.75 wt%, less than 0.5 wt%, or less than 0.25 wt%) of water by weight of the ingredient. For instance, the admixture comprises a composition of Compound 1, a diluent, a glidant, a surfactant, a lubricant, a disintegrant, and a filler, wherein each of these ingredients is substantially free of water. In some embodiments, each of the ingredients comprises less than 5 wt% (e.g.; less than 2 wt%, less than 1 wt%, less than 0.75 wt%, less than 0.5 wt%, or less than 0.25 wt%) of water by weight of the ingredient.

    [0140] In another embodiment, compressing the admixture into a tablet is accomplished by filling a form (e.g., a mold) with the admixture and applying pressure to admixture. This can be accomplished using a die press or other similar apparatus. In some embodiments, the admixture of Compound 1 and excipients can be first processed into granular form. The granules can then be sized and compressed into tablets or formulated for encapsulation according to known methods in the pharmaceutical art. It is also noted that the application of pressure to the admixture in the form can be repeated using the same pressure during each compression or using different pressures during the compressions. In another example, the admixture of powdered ingredients or granules can be compressed using a die press that applies sufficient pressure to form a tablet having a dissolution of about 50% or more at about 30 minutes (e.g., about 55% or more at about 30 minutes or about 60% or more at about 30 minutes). For instance, the admixture is compressed using a die press to produce a tablet hardness of at least about 5 kP (at least about 5.5 kP, at least about 6 kP, at least about 7 kP, at least about 10 kP, or at least 15 kP). In some instances, the admixture is compressed to produce a tablet hardness of between about 5 and 20 kP.

    [0141] In some embodiments, tablets comprising a pharmaceutical composition as described herein can be coated with about 3.0 wt% of a film coating comprising a colorant by weight of the tablet. In certain instances, the colorant suspension or solution used to coat the tablets comprises about 20%w/w of solids by weight of the colorant suspension or solution. In still further instances, the coated tablets can be labeled with a logo, other image or text.

    [0142] In another embodiment, the method for producing a pharmaceutical composition comprises providing an admixture of a solid forms, e.g. an admixture of powdered and/or liquid ingredients, the admixture comprising Compound 1 and one or more excipients selected from: a binder, a glidant, a diluent, a surfactant, a lubricant, a disintegrant, and a filler; mixing the admixture until the admixture is substantially homogenous, and compressing or compacting the admixture into a granular form. Then the granular composition comprising Compound 1 can be compressed into tablets or formulated into capsules as described above or in the Examples below. Alternatively, methods for producing a pharmaceutical composition comprises providing an admixture of Compound 1, and one or more excipients, e.g. a binder, a glidant, a diluent, a surfactant, a lubricant, a disintegrant, and a filler; mixing the admixture until the admixture is substantially homogenous, and compressing/compacting the admixture into a granular form using a roller compactor using a dry granulation composition as set forth in the Examples below or alternatively, compressed/compacted into granules using a high shear wet granule compaction process as set forth in the Examples below. Pharmaceutical formulations, for example a tablet as described herein, can be made using the granules prepared incorporating Compound 1 in addition to the selected excipients described herein.

    [0143] In some embodiments, the admixture is mixed by stirring, blending, shaking, or the like using hand mixing, a mixer, a blender, any combination thereof, or the like. When ingredients or combinations of ingredients are added sequentially, mixing can occur between successive additions, continuously throughout the ingredient addition, after the addition of all of the ingredients or combinations of ingredients, or any combination thereof. The admixture is mixed until it has a substantially homogenous composition.

    [0144] In another embodiment, the present invention comprises jet milling Compound 1, Compound 1 Form I, Compound 1 Form II, Compound 1 HCl Salt Form A in a suitable, conventional milling apparatus using air pressure suitable to produce particles having a significant particle size fraction between 0.1 microns and 50 microns. In another embodiment, the particle size is between 0.1 microns and 20 microns. In another embodiment, the particles size is between 0.1 microns and 10 microns. In another embodiment, the particle size is between 1.0 microns and 5 microns. In still another embodiment, Compound 1, Compound 1 Form I, Compound 1 Form II, Compound 1 HCl Salt Form A has a particle size D50 of 2.0 microns.

    [0145] In various embodiments, a second therapeutic agent can be formulated together with Compound 1 to form a unitary or single dose form, for example, a tablet or capsule.

    [0146] Dosage forms prepared as above can be subjected to in vitro dissolution evaluations according to Test 711 "Dissolution" in United States Pharmacopoeia 29, United States Pharmacopeial Convention, Inc., Rockville, Md., 2005 ("USP"), to determine the rate at which the active substance is released from the dosage forms. The content of active substance and the impurity levels are conveniently measured by techniques such as high performance liquid chromatography (HPLC).

    [0147] In some embodiments, the invention includes use of packaging materials such as containers and closures of high-density polyethylene (HDPE), low-density polyethylene (LDPE) and or polypropylene and/or glass, glassine foil, aluminum pouches, and blisters or strips composed of aluminum or high-density polyvinyl chloride (PVC), optionally including a desiccant, polyethylene (PE), polyvinylidene dichloride (PVDC), PVC/PE/PVDC, and the like. These package materials can be used to store the various pharmaceutical compositions and formulations in a sterile fashion after appropriate sterilization of the package and its contents using chemical or physical sterilization techniques commonly employed in the pharmaceutical arts.

    METHODS FOR ADMINISTERING THE PHARMACEUTICAL COMPOSITIONS



    [0148] In one aspect, the pharmaceutical compositions of the invention can be administered to a patient once daily or about every twenty four hours. Alternatively, the pharmaceutical compositions of the invention can be administered to a patient twice daily or about every twelve hours. These pharmaceutical compositions are administered as oral formulations containing about 25 mg, 50 mg, 100 mg, 125 mg, 150 mg, 200 mg, 250 mg, or 400 mg of Compound 1. In this aspect, in addition to Compound 1, the pharmaceutical compositions comprise a filler; a diluent; a disintegrant; a surfactant; at least one of a binder and a glidant; and a lubricant. For instance, a dose of 400 mg of Compound 1, may comprise two tablets of the invention each containing 200 mg of Compound 1, or four tablets of the invention each containing 100 mg of Compound 1.

    [0149] It will also be appreciated that the compound and pharmaceutically acceptable compositions and formulations of the invention can be employed in combination therapies; that is, Compound 1 and pharmaceutically acceptable compositions thereof can be administered concurrently with, prior to, or subsequent to, one or more other desired therapeutics or medical procedures. The particular combination of therapies (therapeutics or procedures) to employ in a combination regimen will take into account compatibility of the desired therapeutics and/or procedures and the desired therapeutic effect to be achieved. It will also be appreciated that the therapies employed may achieve a desired effect for the same disorder (for example, an inventive compound may be administered concurrently with another agent used to treat the same disorder), or they may achieve different effects (e.g., control of any adverse effects). As used herein, additional therapeutic agents that are normally administered to treat or prevent a particular disease, for example, a CFTR mediated disease, or condition, are known as "appropriate for the disease or condition being treated."

    [0150] In one embodiment, the additional therapeutic agent is selected from a mucolytic agent, bronchodialator, an antibiotic, an anti-infective agent, an anti-inflammatory agent, a CFTR modulator other than Compound 1 of the invention, or a nutritional agent.

    [0151] In one embodiment, the additional agent is (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide. In another embodiment, the additional agent is N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide. In another embodiment, the additional agent is selected from Table 1:
    Table 1.
    1 2 3






    4 5 6






    7 8 9






    10 11 12






    13 14  




     


    [0152] In another embodiment, the additional agent is any combination of the above agents. For example, the composition may comprise Compound 1, (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide, and N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide. In another example, the composition may comprise Compound 1, N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide, and any one of the compounds from Table 1, i.e. compounds 1 through 14 of Table 1, or any combination thereof.

    [0153] In one embodiment, the additional therapeutic agent is an antibiotic. Exemplary antibiotics useful herein include tobramycin, including tobramycin inhaled powder (TIP), azithromycin, aztreonam, including the aerosolized form of aztreonam, amikacin, including liposomal formulations thereof, ciprofloxacin, including formulations thereof suitable for administration by inhalation, levoflaxacin, including aerosolized formulations thereof, and combinations of two antibiotics, e.g., fosfomycin and tobramycin.

    [0154] In another embodiment, the additional agent is a mucolyte. Exemplary mucolytes useful herein includes Pulmozyme ®.

    [0155] In another embodiment, the additional agent is a bronchodialator. Exemplary bronchodialtors include albuterol, metaprotenerol sulfate, pirbuterol acetate, salmeterol, or tetrabuline sulfate.

    [0156] In another embodiment, the additional agent is effective in restoring lung airway surface liquid. Such agents improve the movement of salt in and out of cells, allowing mucus in the lung airway to be more hydrated and, therefore, cleared more easily. Exemplary such agents include hypertonic saline, denufosol tetrasodium ([[(3S,5R)-5-(4-amino-2-oxopyrimidin-1-yl)-3-hydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl] [[[(2R,3S,4R,5R)-5-(2,4-dioxopyrimidin-1-yl)-3,4-dihydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-hydroxyphosphoryl] hydrogen phosphate), or bronchitol (inhaled formulation of mannitol).

    [0157] In another embodiment, the additional agent is an anti-inflammatory agent, i.e., an agent that can reduce the inflammation in the lungs. Exemplary such agents useful herein include ibuprofen, docosahexanoic acid (DHA), sildenafil, inhaled glutathione, pioglitazone, hydroxychloroquine, or simavastatin.

    [0158] In another embodiment, the additional agent is a CFTR modulator other than Compound 1, i.e., an agent that has the effect of modulating CFTR activity. Exemplary such agents include ataluren ("PTC124®"; 3-[5-(2-fluorophenyl)-1,2,4-oxadiazol-3-yl]benzoic acid), sinapultide, lancovutide, depelestat (a human recombinant neutrophil elastase inhibitor), and cobiprostone (7-{(2R, 4aR, 5R, 7aR)-2-[(3S)-1,1-difluoro-3-methylpentyl]-2-hydroxy-6-oxooctahydrocyclopenta[b]pyran-5-yl} heptanoic acid).

    [0159] In another embodiment, the additional agent is a nutritional agent. Exemplary nutritional agents include pancrelipase (pancreating enzyme replacement), including Pancrease®, Pancreacarb®, Ultrase®, or Creon®, Liprotomase® (formerly Trizytek®), Aquadeks®, or glutathione inhalation. In one embodiment, the additional nutritional agent is pancrelipase.

    [0160] In another embodiment, the additional agent is a compound selected from gentamicin, curcumin, cyclophosphamide, 4-phenylbutyrate, miglustat, felodipine, nimodipine, Philoxin B, geniestein, Apigenin, cAMP/cGMP modulators such as rolipram, sildenafil, milrinone, tadalafil, amrinone, isoproterenol, albuterol, and almeterol, deoxyspergualin, HSP 90 inhibitors, HSP 70 inhibitors, proteosome inhibitors such as epoxomicin, lactacystin, etc.

    [0161] In other embodiments, the additional agent is a compound disclosed in WO 2004028480, WO 2004110352, WO 2005094374, WO 2005120497, or WO 2006101740. In another embodiment, the additional agent is a benzo[c]quinolizinium derivative that exhibits CFTR modulation activity or a benzopyran derivative that exhibits CFTR modulation activity. In another embodiment, the additional agent is a compound disclosed in U.S. Pat. No. 7,202,262, U.S. Pat. No. 6,992,096, US20060148864, US20060148863, US20060035943, US20050164973, WO2006110483, WO2006044456, WO2006044682, WO2006044505, WO2006044503, WO2006044502, or WO2004091502. In another embodiment, the additional agent is a compound disclosed in WO2004080972, WO2004111014, WO2005035514, WO2005049018, WO2006099256, WO2006127588, or WO2007044560. In another embodiment, the additional agent is N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide.

    [0162] In one embodiment, 400 mg of Compound 1 may be administered to a subject in need thereof followed by coadministration of 150 mg of N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide (Compound 2). In another embodiment, 400 mg of Compound 1 may be administered to a subject in need thereof followed by co-administration of 250 mg of Compound 2. In these embodiments, the dosage amounts may be achieved by administration of one or more tablets of the invention. For example, administration of 400 mg of Compound 1 may be achieved by administering two tablets each containing 200 mg of Compound 1, or four tablets each containing 100 mg of Compound 1. Compound 2 may be administered as a pharmaceutical composition comprising Compound 2 and a pharmaceutically acceptable carrier. The duration of administration may continue until amelioration of the disease is achieved or until a subject's physician advises, e.g. duration of administration may be less than a week, 1 week, 2 weeks, 3 weeks, or a month or longer. The co-administration period may be preceded by an administration period of just Compound 1 alone. For example, there could be administration of 400 mg of Compound 1 for 2 weeks followed by co-administration of 150 mg or 250 mg of Compound 2 for 1 additional week.

    [0163] In one embodiment, 400 mg of Compound 1 may be administered once a day to a subject in need thereof followed by co-administration of 150 mg of Compound 2 once a day. In another embodiment, 400 mg of Compound 1 may be administered once a day to a subject in need thereof followed by co-administration of 250 mg of Compound 2 once a day. In these embodiments, the dosage amounts may be achieved by administration of one or more tablets of the invention. For example, administration of 400 mg of Compound 1 may be achieved by administering two tablets each containing 200 mg of Compound 1, or four tablets each containing 100 mg of Compound 1. Compound 2 may be administered as a pharmaceutical composition comprising Compound 2 and a pharmaceutically acceptable carrier. The duration of administration may continue until amelioration of the disease is achieved or until a subject's physician advises, e.g. duration of administration may be less than a week, 1 week, 2 weeks, 3 weeks, or a month or longer. The coadministration period may be preceded by an administration period of just Compound 1 alone. For example, there could be administration of 400 mg of Compound 1 for 2 weeks followed by co-administration of 150 mg or 250 mg of Compound 2 for 1 additional week.

    [0164] In one embodiment, 400 mg of Compound 1 may be administered once a day to a subject in need thereof followed by co-administration of 150 mg of Compound 2 every 12 hours. In another embodiment, 400 mg of Compound 1 may be administered once a day to a subject in need thereof followed by co-administration of 250 mg of Compound 2 every 12 hours. In these embodiments, the dosage amounts may be achieved by administration of one or more tablets of the invention. For example, administration of 400 mg of Compound 1 may be achieved by administering two tablets each containing 200 mg of Compound 1, or four tablets each containing 100 mg of Compound 1. Compound 2 may be administered as a pharmaceutical composition comprising Compound 2 and a pharmaceutically acceptable carrier. The duration of administration may continue until amelioration of the disease is achieved or until a subject's physician advises, e.g. duration of administration may be less than a week, 1 week, 2 weeks, 3 weeks, or a month or longer. The coadministration period may be preceded by an administration period of just Compound 1 alone. For example, there could be administration of 400 mg of Compound 1 for 2 weeks followed by co-administration of 150 mg or 250 mg of Compound 2 for 1 additional week.

    [0165] These combinations are useful for treating the diseases described herein including cystic fibrosis. These combinations are also useful in the kits described herein.

    [0166] The amount of additional therapeutic agent present in the compositions of this invention will be no more than the amount that would normally be administered in a composition comprising that therapeutic agent as the only active agent. Preferably the amount of additional therapeutic agent in the presently disclosed compositions will range from about 50% to 100% of the amount normally present in a composition comprising that agent as the only therapeutically active agent.

    THERAPEUTIC USES OF THE COMPOSITION



    [0167] In certain embodiments, the pharmaceutically acceptable compositions comprising Compound 1 and optionally an additional agent are useful for treating or lessening the severity of cystic fibrosis in patients who exhibit residual CFTR activity in the apical membrane of respiratory and non-respiratory epithelia. The presence of residual CFTR activity at the epithelial surface can be readily detected using methods known in the art, e.g., standard electrophysiological, biochemical, or histochemical techniques. Such methods identify CFTR activity using in vivo or ex vivo electrophysiological techniques, measurement of sweat or salivary Cl-concentrations, or ex vivo biochemical or histochemical techniques to monitor cell surface density. Using such methods, residual CFTR activity can be readily detected in patients heterozygous or homozygous for a variety of different mutations, including patients homozygous or heterozygous for the most common mutation, ΔF508, as well as other mutations such as the G551D mutation, or the R117H mutation.

    [0168] In one embodiment, Compound 1, as described herein, or pharmaceutically acceptable compositions thereof, are useful for treating or lessening the severity of cystic fibrosis in patients within certain genotypes exhibiting residual CFTR activity, e.g., class III mutations (impaired regulation or gating), class IV mutations (altered conductance), or class V mutations (reduced synthesis) (Lee R. Choo-Kang, Pamela L., Zeitlin, Type I, II, III, IV, and V cystic fibrosis Tansmembrane Conductance Regulator Defects and Opportunities of Therapy; Current Opinion in Pulmonary Medicine 6:521 - 529, 2000). Other patient genotypes that exhibit residual CFTR activity include patients homozygous for one of these classes or heterozygous with any other class of mutations, including class I mutations, class II mutations, or a mutation that lacks classification.

    [0169] In one embodiment, Compound 1, as described herein, or pharmaceutically acceptable compositions thereof, are useful for treating or lessening the severity of cystic fibrosis in patients within certain clinical phenotypes, e.g., a moderate to mild clinical phenotype that typically correlates with the amount of residual CFTR activity in the apical membrane of epithelia. Such phenotypes include patients exhibiting pancreatic insufficiency or patients diagnosed with idiopathic pancreatitis and congenital bilateral absence of the vas deferens, or mild lung disease.

    [0170] The exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the infection, the particular agent, its mode of administration, and the like. The compounds of the invention are preferably formulated in dosage unit form for ease of administration and uniformity of dosage. The expression "dosage unit form" as used herein refers to a physically discrete unit of agent appropriate for the patient to be treated. It will be understood, however, that the total daily usage of the compounds and compositions of the invention will be decided by the attending physician within the scope of sound medical judgment. The specific effective dose level for any particular patient or organism will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed, and like factors well known in the medical arts. The term "patient", as used herein, means an animal, preferably a mammal, and most preferably a human.

    [0171] Anywhere in the present application where a name of a compound may not correctly describe the structure of the compound, the structure supersedes the name and governs.

    EXAMPLES


    XRPD (X-ray Powder Diffraction)



    [0172] The X-Ray diffraction (XRD) data of Compound 1, Compound 1 Form I, Compound 1 Form II, or Compound 1 HCl Salt Form A were collected on a Bruker D8 DISCOVER powder diffractometer with HI-STAR 2-dimensional detector and a flat graphite monochromator. Cu sealed tube with Kα radiation was used at 40 kV, 35mA. The samples were placed on zero-background silicon wafers at 25°C. For each sample, two data frames were collected at 120 seconds each at 2 different θ2 angles: 8° and 26°. The data were integrated with GADDS software and merged with DIFFRACTplusEVA software. Uncertainties for the reported peak positions are ± 0.2 degrees.

    Jet Milling Description



    [0173] Unmicronized Compound 1, Compound 1 Form I, Compound 1 Form II, or Compound 1 HCl Salt Form A is sieved to de-lump it prior to placing it into the jet mill hopper. All sieves are disposable and received a wipe prior to use. Unmicronized Compound 1, Compound 1 Form I, Compound 1 Form II, or Compound 1 HCl Salt Form A is added to the jet mill hopper at a controlled feeding rate using compressed nitrogen gas. The gas pressure range is 40-45/45-70 (Venturi/Mill) PSI and the feeding rate range is 0.5-1.6 Kg/Hour. The Compound 1, Compound 1 Form I, Compound 1 Form II, or Compound 1 HCl Salt Form A is micronized in the mill through particle-particle and particle-wall collisions and the processed Compound 1, Compound 1 Form I, Compound 1 Form II, or Compound 1 HCl Salt Form A is emptied into the micronized product containers. It is believed that one of ordinary skill in the art may also achieve Compound 1, Compound 1 Form I, Compound 1 Form II, or Compound 1 HCl Salt Form A with a favorable particle size through pin milling based in part on the conditions described above.

    Differential Scanning, Calorimetry (DSC)



    [0174] The Differential scanning calorimetry (DSC) data of Compound 1, Compound 1 Form I, Compound 1 Form II, or Compound 1 HCl Salt Form A were collected using a DSC Q100 V9.6 Build 290 (TA Instruments, New Castle, DE). Temperature was calibrated with indium and heat capacity was calibrated with sapphire. Samples of 3-6 mg were weighed into aluminum pans that were crimped using lids with 1 pin hole. The samples were scanned from 25°C to 350°C at a heating rate of 1.0°C/min and with a nitrogen gas purge of 50 ml/min. Data were collected by Thermal Advantage Q SeriesTM version 2.2.0.248 software and analyzed by Universal Analysis software version 4.1D (TA Instruments, New Castle, DE). The reported numbers represent single analyses.

    Compound 1 Form I, Compound 1 Form II, and Compound 1 HCl Salt Form A Single Crystal Structure Determination



    [0175] Diffraction data were acquired on Bruker Apex II diffractometer equipped with sealed tube Cu K-alpha source and an Apex II CCD detector. The structure was solved and refined using SHELX program (Sheldrick, G.M., Acta Cryst., (2008) A64, 112-122). Based on systematic absences and intensities statistics the structure was solved and refined in P21/n space group.

    [0176] Vitride® (sodium bis(2-methoxyethoxy)aluminum hydride [or NaAlH2(OCH2CH2OCH3)2], 65 wgt% solution in toluene) was purchased from Aldrich Chemicals.

    [0177] 2,2-Difluoro-1,3-benzodioxole-5-carboxylic acid was purchased from Saltigo (an affiliate of the Lanxess Corporation).

    Preparation of (2,2-difluoro-1,3-benzodioxol-5-yl)-methanol.



    [0178] 



    [0179] Commercially available 2,2-difluoro-1,3-benzodioxole-5-carboxylic acid (1.0 eq) was slurried in toluene (10 vol). Vitride® (2 eq) was added via addition funnel at a rate to maintain the temperature at 15-25 °C. At the end of the addition, the temperature was increased to 40 °C for 2 hours (h), then 10% (w/w) aqueous (aq) NaOH (4.0 eq) was carefully added via addition funnel, maintaining the temperature at 40-50 °C. After stirring for an additional 30 minutes (min), the layers were allowed to separate at 40 °C. The organic phase was cooled to 20 °C, then washed with water (2 x 1.5 vol), dried (Na2SO4), filtered, and concentrated to afford crude (2,2-difluoro-1,3-benzodioxol-5-yl)-methanol that was used directly in the next step.

    Preparation of 5-chloromethyl-2,2-difluoro-1,3-benzodioxole.



    [0180] 



    [0181] (2,2-difluoro-1,3-benzodioxol-5-yl)-methanol (1.0 eq) was dissolved in MTBE (5 vol). A catalytic amount of 4-(N,N-dimethyl)aminopyridine (DMAP) (1 mol %) was added and SOCl2 (1.2 eq) was added via addition funnel. The SOCl2 was added at a rate to maintain the temperature in the reactor at 15-25 °C. The temperature was increased to 30 °C for 1 h, and then was cooled to 20 °C. Water (4 vol) was added via addition funnel while maintaining the temperature at less than 30 °C. After stirring for an additional 30 min, the layers were allowed to separate. The organic layer was stirred and 10% (w/v) aq NaOH (4.4 vol) was added. After stirring for 15 to 20 min, the layers were allowed to separate. The organic phase was then dried (Na2SO4) filtered, and concentrated to afford crude 5-chloromethyl-2,2-difluoro-1,3- benzodioxole that was used directly in the next step.

    Preparation of (2,2-difluoro-1,3-benzodioxol-5-yl)-acetonitrile.



    [0182] 



    [0183] A solution of 5-chloromethyl-2,2-difluoro-1,3-benzodioxole (1 eq) in DMSO (1.25 vol) was added to a slurry of NaCN (1.4 eq) in DMSO (3 vol), while maintaining the temperature between 30-40 °C. The mixture was stirred for 1 h, and then water (6 vol) was added, followed by methyl tert-butyl ether (MTBE) (4 vol). After stirring for 30 min, the layers were separated. The aqueous layer was extracted with MTBE (1.8 vol). The combined organic layers were washed with water (1.8 vol), dried (Na2SO4), filtered, and concentrated to afford crude (2,2-difluoro-1,3-benzodioxol-5-yl)-acetonitrile (95%) that was used directly in the next step.

    Synthesis of (2,2-difluoro-1,3-benzodioxol-5-yl)-1-ethylacetate-acetonitrile



    [0184] 



    [0185] A reactor was purged with nitrogen and charged with 900 mL of toluene. The solvent was degassed via nitrogen sparge for no less than 16 h. To the reactor was then charged Na3PO4 (155.7 g, 949.5 mmol), followed by bis(dibenzylideneacetone) palladium (0) (7.28 g, 12.66 mmol). A 10% w/w solution of tert-butylphosphine in hexanes (51.23 g, 25.32 mmol) was charged over 10 min at 23 °C from a nitrogen purged addition funnel. The mixture was allowed to stir for 50 min, at which time 5-bromo-2,2-difluoro-1,3-benzodioxole (75 g, 316.5 mmol) was added over 1 min. After stirring for an additional 50 min, the mixture was charged with ethyl cyanoacetate (71.6 g, 633.0 mmol) over 5 min followed by water (4.5 mL) in one portion. The mixture was heated to 70 °C over 40 min and analyzed by HPLC every 1 - 2 h for the percent conversion of the reactant to the product. After complete conversion was observed (typically 100% conversion after 5 - 8 h), the mixture was cooled to 20 - 25 °C and filtered through a celite pad. The celite pad was rinsed with toluene (2 X 450 mL) and the combined organics were concentrated to 300 mL under vacuum at 60 - 65 °C. The concentrate was charged with 225mL DMSO and concentrated under vacuum at 70 - 80 °C until active distillation of the solvent ceased. The solution was cooled to 20 - 25 °C and diluted to 900 mL with DMSO in preparation for Step 2. 1H NMR (500 MHz, CDCl3) δ 7.16 - 7.10 (m, 2H), 7.03 (d, J = 8.2 Hz, 1H), 4.63 (s, 1H), 4.19 (m, 2H), 1.23 (t, J = 7.1 Hz, 3H).

    Synthesis of (2,2-difluoro-1,3-benzodioxol-5-yl)-acetonitrile.



    [0186] 



    [0187] The DMSO solution of (2,2-difluoro-1,3-benzodioxol-5-yl)-1-ethylacetate-acetonitrite from above was charged with 3 N HCl (617.3 mL, 1.85 mol) over 20 min while maintaining an internal temperature < 40 °C. The mixture was then heated to 75°C over 1 h and analyzed by HPLC every 1 - 2 h for % conversion. When a conversion of > 99% was observed (typically after 5 - 6 h), the reaction was cooled to 20 - 25 °C and extracted with MTBE (2 X 525 mL), with sufficient time to allow for complete phase separation during the extractions. The combined organic extracts were washed with 5% NaCl (2 X 375 mL). The solution was then transferred to equipment appropriate for a 1.5 - 2.5 Torr vacuum distillation that was equipped with a cooled receiver flask. The solution was concentrated under vacuum at < 60°C to remove the solvents. (2,2-Difluoro-1,3-benzodioxol-5-yl)-acetonitrile was then distilled from the resulting oil at 125 - 130 °C (oven temperature) and 1.5 - 2.0 Torr. (2,2-Difluoro-1,3-benzodioxol-5-yl)-acetonitrile was isolated as a clear oil in 66% yield from 5-bromo-2,2-difluoro-1,3-benzodioxole (2 steps) and with an HPLC purity of 91.5% AUC (corresponds to a w/w assay of 95%). 1H NMR (500 MHz, DMSO) δ 7.44 (br s, 1H), 7.43 (d, J = 8.4 Hz, 1H), 7.22 (dd, J = 8.2, 1.8 Hz, 1H), 4.07 (s, 2H).

    Preparation of (2,2-difluoro-1,3-benzodioxol-5-yl)-cyclopropanecarbonitrile.



    [0188] 



    [0189] A mixture of (2,2-difluoro-1,3-benzodioxol-5-yl)-acetonitrile (1.0 eq), 50 wt % aqueous KOH (5.0 eq) 1-bromo-2-chloroethane (1.5 eq), and Oct4NBr (0.02 eq) was heated at 70 °C for 1 h. The reaction mixture was cooled, then worked up with MTBE and water. The organic phase was washed with water and brine. The solvent was removed to afford (2,2-difluoro-1,3-benzodioxol-5-yl)-cyclopropanecarbonitrile.

    Preparation of 1-(2,2-difluoro-1,3-benzodioxol-5-yl)-cyclopropanecarboxylic acid.



    [0190] 



    [0191] (2,2-difluoro-1,3-benzodioxol-5-yl)-cyclopropanecarbonitrile was hydrolyzed using 6 M NaOH (8 equiv) in ethanol (5 vol) at 80 °C overnight. The mixture was cooled to room temperature and the ethanol was evaporated under vacuum. The residue was taken up in water and MTBE, 1 M HCl was added, and the layers were separated. The MTBE layer was then treated with dicyclohexylamine (DCHA) (0.97 equiv). The slurry was cooled to 0 °C, filtered and washed with heptane to give the corresponding DCHA salt. The salt was taken into MTBE and 10% citric acid and stirred until all the solids had dissolved. The layers were separated and the MTBE layer was washed with water and brine. A solvent swap to heptane followed by filtration gave 1-(2,2-difluoro-1,3-benzodioxol-5-yl)-cyclopropanecarboxylic acid after drying in a vacuum oven at 50 °C overnight.

    Preparation of 1-(2,2-difluoro-1,3-benzodioxol-5-yl)-cyclopropanecarbonyl chloride.



    [0192] 



    [0193] 1-(2,2-difluoro-1,3-benzodioxol-5-yl)-cyclopropanecarboxylic acid (1.2 eq) is slurried in toluene (2.5 vol) and the mixture was heated to 60 °C. SOCl2 (1.4 eq) was added via addition funnel. The toluene and SOCl2 were distilled from the reaction mixture after 30 minutes. Additional toluene (2.5 vol) was added and the resulting mixture was distilled again, leaving the product acid chloride as an oil, which was used without further purification.

    Preparation of tert-butyl-3-(3-methylpyridin-2-yl)benzoate.



    [0194] 



    [0195] 2-Bromo-3-methylpyridine (1.0 eq) was dissolved in toluene (12 vol). K2CO3 (4.8 eq) was added, followed by water (3.5 vol). The resulting mixture was heated to 65 °C under a stream of N2 for 1 hour. 3-(t-Butoxycarbonyl)phenylboronic acid (1.05 eq) and Pd(dppf)Cl2·CH2Cl2 (0.015 eq) were then added and the mixture was heated to 80 °C. After 2 hours, the heat was turned off, water was added (3.5 vol), and the layers were allowed to separate. The organic phase was then washed with water (3.5 vol) and extracted with 10% aqueous methanesulfonic acid (2 eq MsOH, 7.7 vol). The aqueous phase was made basic with 50% aqueous NaOH (2 eq) and extracted with EtOAc (8 vol). The organic layer was concentrated to afford crude tert-butyl-3-(3-methylpyridin-2-yl)benzoate (82%) that was used directly in the next step.

    Preparation of 2-(3-(tert-butoxycarbonyl)phenyl)-3-methylpyridine-1-oxide.



    [0196] 



    [0197] tert-Butyl-3-(3-methylpyridin-2-yl)benzoate (1.0 eq) was dissolved in EtOAc (6 vol). Water (0. 3 vol) was added, followed by urea-hydrogen peroxide (3 eq). Phthalic anhydride (3 eq) was then added portionwise to the mixture as a solid at a rate to maintain the temperature in the reactor below 45 °C. After completion of the phthalic anhydride addition, the mixture was heated to 45 °C. After stirring for an additional 4 hours, the heat was turned off. 10% w/w aqueous Na2SO3 (1.5 eq) was added via addition funnel. After completion of Na2SO3 addition, the mixture was stirred for an additional 30 min and the layers separated. The organic layer was stirred and 10% wt/wt aqueous. Na2CO3 (2 eq) was added. After stirring for 30 minutes, the layers were allowed to separate. The organic phase was washed 13% w/v aq NaCl. The organic phase was then filtered and concentrated to afford crude 2-(3-(tert-butoxycarbonyl)phenyl)-3-methylpyridine-1-oxide (95%) that was used directly in the next step.

    Preparation of tert-butyl-3-(6-amino-3-methylpyridin-2-yl)benzoate.



    [0198] 



    [0199] A solution of 2-(3-(tert-butoxycarbonyl)phenyl)-3-methylpyridine-1-oxide (1 eq) and pyridine (4 eq) in acetonitrile (8 vol) was heated to 70 °C. A solution of methanesulfonic anhydride (1.5 eq) in MeCN (2 vol) was added over 50 min via addition funnel while maintaining the temperature at less than 75 °C. The mixture was stirred for an additional 0.5 hours after complete addition. The mixture was then allowed to cool to ambient. Ethanolamine (10 eq) was added via addition funnel. After stirring for 2 hours, water (6 vol) was added and the mixture was cooled to 10 °C. After stirring for 3 hours, the solid was collected by filtration and washed with water (3 vol), 2:1 acetonitrile/water (3 vol), and acetonitrile (2 x 1.5 vol). The solid was dried to constant weight (<1% difference) in a vacuum oven at 50 °C with a slight N2 bleed to afford tert-butyl-3-(6-amino-3-methylpyridin-2-yl)benzoate as a red-yellow solid (53% yield).

    Preparation of 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-cyclopropanecarboxamido)-3-methylpyridin-2-yl)-t-butylbenzoate.



    [0200] 



    [0201] The crude acid chloride described above was dissolved in toluene (2.5 vol based on acid chloride) and added via addition funnel to a mixture of tert-butyl-3-(6-amino-3-methylpyridin-2-yl)benzoate (1 eq), DMAP, (0.02 eq), and triethylamine (3.0 eq) in toluene (4 vol based on tert-butyl-3-(6-amino-3-methylpyridin-2-yl)benzoate). After 2 hours, water (4 vol based on tert-butyl-3-(6-amino-3-methylpyridin-2-yl)benzoate) was added to the reaction mixture. After stirring for 30 minutes, the layers were separated. The organic phase was then filtered and concentrated to afford a thick oil of 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)-t-butylbenzoate (quantitative crude yield). Acetonitrile (3 vol based on crude product) was added and distilled until crystallization occurs. Water (2 vol based on crude product) was added and the mixture stirred for 2 h. The solid was collected by filtration, washed with 1:1 (by volume) acetonitrile/water (2 x 1 volumes based on crude product), and partially dried on the filter under vacuum. The solid was dried to a constant weight (<1% difference) in a vacuum oven at 60 °C with a slight N2 bleed to afford 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)-t-butylbenzoate as a brown solid.

    Preparation of 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid • HCL salt.



    [0202] 



    [0203] To a slurry of 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)-t-butylbenzoate (1.0 eq) in MeCN (3.0 vol) was added water (0.83 vol) followed by concentrated aqueous HCl (0.83 vol). The mixture was heated to 45 ± 5 °C. After stirring for 24 to 48 h, the reaction was complete, and the mixture was allowed to cool to ambient. Water (1.33 vol) was added and the mixture stirred. The solid was collected by filtration, washed with water (2 x 0.3 vol), and partially dried on the filter under vacuum. The solid was dried to a constant weight (<1% difference) in a vacuum oven at 60 °C with a slight N2 bleed to afford 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid • HCl as an off-white solid.

    [0204] An 1HNMR spectrum of Compound 1 is shown in Figure 20 and Figure 21 depicts an 1HNMR spectrum of Compound 1 as an HCl salt.

    [0205] Table 2 below recites the 1HNMR data for Compound I.
    Table 2.
    Compound NoLC/MS M + 1LC/RT minutesNMR
    1 453.3 1.93 1HNMR (400 MHz, DMSO-d6) 9.14 (s, 1H), 7.99-7.93 (m, 3H), 7.80-7.78 (m,1H), 7.74-7.72 (m,1H), 7.60-7.55 (m,2H), 7.41-7.33 (m,2H), 2.24 (s, 3H), 1.53-1.51 (m, 2H), 1.19-1.17 (m, 2H).

    Preparation of Compound 1 Form I, Method A.



    [0206] 



    [0207] A slurry of 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid · HCl (1 eq) in water (10 vol) was stirred at ambient temperature. A sample was taken after stirring for 24 h. The sample was filtered and the solid was washed with water (2 times). The solid sample was submitted for DSC analysis. When DSC analysis indicated complete conversion to Form I, the solid was collected by filtration, washed with water (2 x 1.0 vol), and partially dried on a filter under vacuum. The solid was then dried to a constant weight (<1% difference) in a vacuum oven at 60 °C with a slight N2 bleed to afford Compound 1 Form I as an off-white solid (98% yield). 1H NMR (400 MHz, DMSO-d6) 9.14 (s, 1H), 7.99-7.93 (m, 3H), 7.80-7.78 (m, 1H), 7.74-7.72 (m, 1H), 7.60-7.55 (m, 2H), 7.41-7.33 (m, 2H), 2.24 (s, 3H), 1.53-1.51 (m, 2H), 1.19-1.17 (m, 2H).

    Preparation of Compound 1 Form I, Method B.



    [0208] 



    [0209] A solution of 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)-t-butylbenzoate (1.0 eq) in formic acid (3.0 vol) was heated with stirring to 70 ± 10 °C, for 8 h. The reaction was deemed complete when no more than 1.0% AUC by chromatographic methods of 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)-t-butylbenzoate) remained. The mixture was allowed to cool to ambient. The solution was added to water (6 vol), heated at 50 °C, and the mixture was stirred. The mixture was then heated to 70 ± 10 °C until the level of 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)-t-butylbenzoate was no more than 0.8% (AUC). The solid was collected by filtration, washed with water (2 x 3 vol), and partially dried on the filter under vacuum. The solid was dried to a constant weight (<1% difference) in a vacuum oven at 60 °C with a slight N2 bleed to afford Compound 1 Form I as an off-white solid.

    [0210] The DSC trace of Compound 1 Form I is shown in Figure 22. Melting for Compound 1 Form I occurs at about 204 °C.

    [0211] An X-ray diffraction pattern was calculated from a single crystal structure of Compound 1 Form I and is shown in Figure 1. Table 3 lists the calculated peaks for Figure 1.
    Table 3.
    Peak Rank2θ Angle [degrees]Relative Intensity [%]
    11 14.41 48.2
    8 14.64 58.8
    1 15.23 100.0
    2 16.11 94.7
    3 17.67 81.9
    7 19.32 61.3
    4 21.67 76.5
    5 23.40 68.7
    9 23.99 50.8
    6 26.10 67.4
    10 28.54 50.1


    [0212] An actual X-ray powder diffraction pattern of Compound 1 Form I is shown in Figure 2. Table 4 lists the actual peaks for Figure 2.
    Table 4.
    Peak Rank2θ Angle [degrees]Relative Intensity [%]
    7 7.83 37.7
    3 14.51 74.9
    4 14.78 73.5
    1 15.39 100.0
    2 16.26 75.6
    6 16.62 42.6
    5 17.81 70.9
    9 21.59 36.6
    10 23.32 34.8
    11 24.93 26.4
    8 25.99 36.9


    [0213] Colorless crystals of Compound 1 Form I were obtained by cooling a concentrated 1-butanol solution from 75°C to 10 °C at a rate of 0.2 °C/min. A crystal with dimensions of 0.50 x 0.08 x 0.03 mm was selected, cleaned with mineral oil, mounted on a MicroMount and centered on a Bruker APEX II system. Three batches of 40 frames separated in reciprocal space were obtained to provide an orientation matrix and initial cell parameters. Final cell parameters were obtained and refined based on the full data set.

    [0214] A diffraction data set of reciprocal space was obtained to a resolution of 0.82 Å using 0.5° steps using 30 s exposure for each frame. Data were collected at 100 (2) K. Integration of intensities and refinement of cell parameters were accomplished using APEXII software. Observation of the crystal after data collection showed no signs of decomposition.

    [0215] A conformational picture of Compound 1 Form I based on single crystal X-ray analysis is shown in Figure 23. Compound 1 Form I is monoclinic, P2l/n, with the following unit cell dimensions: a=4.9626(7) Å, b=12.299(2) Å, c=33.075 (4) Å, β=93.938(9)°, V=2014.0 Å3, Z=4. Density of Compound 1 Form I calculated from structural data is 1.492 g/cm3 at 100 K.

    Preparation of Compound 1 Form II from Compound 1 Form I.



    [0216] Compound 1 Form I (approximately 30 mg) was slurried in 500 µL of an appropriate solvent (for example, methanol, ethanol, acetone, 2-propanol, acetonitrile, tetrahydrofuran, methyl acetate, 2-butanone, ethyl formate, and -methyl tetrahydrofuran for two days. The slurry was then filitered centrifugally or under vacuum and was left to dry at ambient temperature overnight to yield Compound 1 Form II.

    [0217] The DSC trace of Compound 1 Form II Acetone Solvate is shown in Figure 15, showing two phase transitions. The melting point for Compound 1 Form II Acetone Solvate occurs at about 188 °C and 205 °C.

    [0218] An actual X-ray powder diffraction pattern of Compound 1 Form II is shown in Figure 3. Table 5 lists the actual peaks for Figure 3 in descending order of relative intensity.
    Table 5.
    2θ Angle [degrees]Relative Intensity [%]
    21.70 100.0
    8.98 65.5
    11.04 57.4
    18.16 55.9
    23.06 55.4
    20.63 53.1
    22.22 50.2
    18.57 49.1
    16.66 47.2
    19.86 35.0


    [0219] Conformational depictions of Compound 1 Form II Acetone Solvate based on single crystal X-ray analysis are shown in Figure 24. The stoichiometry between Compound 1 Form II and acetone is approximately 4.4:1 (4.48:1 calculated from 1H NMR; 4.38:1 from X-ray). The crystal structure reveals a packing of the molecules where there are two voids or pockets per unit cell, or 1 void per host molecule. In the acetone solvate, approximately 92 percent of voids are occupied by acetone molecules. Compound 1 Form II is a monoclinic P21/n space group with the following unit cell dimensions: a = 16.5235(10) Å, b = 12.7425(8) Å, c = 20.5512 (13) Å, α = 90°, β = 103.736(4)°, γ = 90°, V = 4203.3(5) Å3, = 4. The density of Compound 1 in Compound 1 Form II calculated from structural data is 1.430/cm3 at 100 K.

    [0220] A solid state 13C NMR spectrum of Compound 1 Form II Acetone Solvate is shown in Figure 25. Table 6 provides chemical shifts of the relevant peaks.
    Table 6.
     Compound 1 Form II, Acetone Solvate 13C Chem. Shifts.
    Peak #F1 [ppm]Intensity
    1 202.8 6.05
    2 173.3 62.66
    3 171.9 20.53
    4 153.5 28.41
    5 150.9 21.68
    6 150.1 19.49
    7 143.2 45.74
    8 142.3 42.68
    9 140.1 37.16
    10 136.6 26.82
    11 135.9 30.1
    12 134.6 39.39
    13 133.2 23.18
    14 131.0 60.92
    15 128.5 84.58
    16 116.0 34.64
    17 114.2 23.85
    18 112.4 25.3
    19 110.9 24.12
    20 107.8 18.21
    21 32.0 54.41
    22 22.2 20.78
    23 18.8 100


    [0221] A solid state 19F NMR spectrum of Compound 1 Form II Acetone Solvate is shown in Figure 26. Peaks with an asterisk denote spinning side bands. Table 7 provides chemical shifts of the relevant peaks.
    Table 7.
     Compound 1 Form II, Acetone Solvate 19F Chem. Shifts
    PeakF1 [ppm]Intensity
    #  
    1 -41.6 12.5
    2 -46.4 6.77
    3 -51.4 9.05

    Preparation of Compound 1 HCl Salt Form A.



    [0222] Colorless crystals of Compound 1 HCl Salt Form A were obtained by slow evaporation from a concentrated solution of the HCl salt of Compound 1 in ethanol. A crystal with dimensions of 0.30 x 1/5x 0.15 mm was selected, cleaned using mineral oil, mounted on a MicroMount and centered on a Bruker APEXII diffractometer. Three batches of 40 frames separated in reciprocal space were obtained to provide an orientation matrix and initial cell parameters. Final cell parameters were obtained and refined based on the full data set.

    [0223] Figure 18 provides a conformational image of Compound 1 HCl Salt Form A as a dimer, based on single crystal analysis. An X-ray diffraction pattern of Compound 1 HCl Salt Form A calculated from the crystal structure is shown in Figure 27. Table 8 contains the calculated peaks for Figure 27 in descending order of relative intensity.
    Table 8.
    2θ [degrees]Relative Intensity [%]
    8.96 100.00
    17.51 48.20
    18.45 34.60
    10.33 32.10
    16.01 18.90
    11.94 18.40
    8.14 16.20
    10.10 13.90
    16.55 13.30
    9.54 10.10
    16.55 13.30

    Exemplary Oral Pharmaceutical Formulations Comprising Compound 1



    [0224] A tablet was prepared with the components and amounts listed in Table 9 for Exemplary Tablet 1A comprising 100mg of API, i.e. Compound 1 Form I. Exemplary Tablet 1A (formulated to have 100 mg of Compound 1) is prepared using a dry roller compaction device formulation process. In Table 9, grades/brands were microcrystalline cellulose: Avicel PH102; mannitol: Pearlitol SD 100; croscarmellose sodium: Acdisol; and colloidal silica: Cabosil.
    Table 9.
    Roller Compaction Granule Blend(%w/w)
    Compound 1 Form I 30
    Microcrystalline cellulose 42.3
    Mannitol 21.2
    Croscarmellose Sodium 3
    Sodium Lauryl Sulfate 1
    Colloidal Silica 0.5
    Magnesium Stearate 2
    Tablet Composition (100 mg dose, 335 mg image)(%w/w)
    Roller Compaction Granule Blend 99.5
    Magnesium Stearate 0.5


    [0225] A tablet was prepared with the components and amounts listed in Table 10 for Exemplary Tablet 1B comprising 100mg of API, i.e. Compound 1 Form I. Exemplary Tablet 1B (formulated to have 100 mg of Compound 1 Form I) is prepared using a wet high shear granule formulation process. In Table 10, grades/brands were as follows. High Shear Granule Blend - microcrystalline cellulose: Avicel PH101; mannitol: Pearlitol C50; croscarmellose sodium: Acdisol; polyvinylpyrrolidone: Kollidon PVP K30; and in the Tablet Composition - croscarmellose sodium: Acdisol.
    Table 10.
    High Shear Granule Blend(%w/w)
    Compound 1 Form I 50
    Microcrystalline cellulose 30
    Mannitol 13
    Croscarmellose Sodium 2
    Polyvinylpyrrolidone 4
    Sodium Lauryl Sulfate 1
    Water (removed during drying) 25-40% solids
    Tablet Composition (100mg dose, 205 mg image)(%w/w)
    High Shear Granule Blend 97.5
    Croscarmellose Sodium 2.0
    Magnesium Stearate 0.5


    [0226] A tablet was prepared with the components and amounts listed in Table 11 for Exemplary Tablet 1C comprising 100mg of API, i.e. crystalline Compound 1 Form I. Exemplary Tablet 1C (formulated to have 100 mg of crystalline Compound 1 Form I) is prepared using a wet high shear granule formulation process. In Table 11, grades/brands were as follows. High Shear Granule Blend - microcrystalline cellulose: Avicel PH101; mannitol: Pearlitol C50; croscarmellose sodium: Acdisol; polyvinylpyrrolidone: Kollidon PVP K30; and in the Tablet Composition - croscarmellose sodium: Acdisol.
    Table 11.
    High Shear Granule Blend(%w/w)
    Compound 1 Form I 60
    Microcrystalline cellulose 20
    Mannitol 13
    Croscarmellose Sodium 2
    Polyvinylpyrrolidone 4
    Sodium Lauryl Sulfate 1
    Water (removed during drying) 25-40% solids
    Tablet Composition (100mg dose, 171 mg image)(%w/w)
    High Shear Granule Blend 97.5
    Croscarmellose Sodium 2.0
    Magnesium Stearate 0.5


    [0227] A tablet was prepared with the components and amounts listed in Table 12 for Exemplary Tablet 1D comprising 200mg of API, i.e. crystalline Compound 1 Form I. Exemplary Tablet 1D (formulated to have 200 mg of crystalline Compound 1 Form I) is prepared using a wet high shear granule formulation process. In Table 12, grades/brands were as follows. High Shear Granule Blend - microcrystalline cellulose: Avicel PH101; mannitol: Pearlitol C50; croscarmellose sodium: Acdisol; polyvinylpyrrolidone: Kollidon PVP K30; and in the Tablet Composition - microcrystalline cellulose: Avicel PH200; croscarmellose sodium: Acdisol; and magnesium stearate: 5712.
    Table 12.
    High Shear Granule Blend(%w/w)
    Compound 1 Form I 60
    Microcrystalline cellulose 20
    Mannitol 13
    Croscarmellose Sodium 2
    Polyvinylpyrrolidone 4
    Sodium Lauryl Sulfate 1
    Water (removed during drying) 25-40% solids
    Tablet Composition (100 mg dose, 335mg image)(%w/w)
    High Shear Granule Blend 83
    Microcrystalline cellulose 14
    Croscarmellose Sodium 2
    Magnesium Stearate 1.0


    [0228] A tablet was prepared with the components and amounts listed In Table 13 for Exemplary Tablet IE comprising 200 mg of API, i.e. crystalline Compound 1 Form I. Exemplary Tablet 1E (formulated to have 200 mg of crystalline Compound 1 Form I) is prepared using a wet high shear granule formulation process. In Table 13, grades/brands were as follows. High Shear Granule Blend - microcrystalline cellulose: Avicel PH101; mannitol: Pearlitol C50; croscarmellose sodium: Acdisol; polyvinylpyrrolidone: Kollidon PVP K30; and in the Core Tablet Composition - microcrystalline cellulose: Avicel PH200; croscarmellose sodium: Acdisol; and magnesium stearate: 5712; and in the film coat - film coat: Opadry II; wax: Carnauba.
    Table 13.
    High Shear Granule Blendmg
    Compound 1 Form I 200
    Microcrystalline cellulose 66
    Mannitol 43
    Croscarmellose Sodium 7
    Polyvinylpyrrolidone 13
    Sodium Lauryl Sulfate 3
    Core Tablet Composition (200 mg dose, 400 mg image)mg
    High Shear Granule Blend 332
    Microcrystalline cellulose 56
    Croscarmellose Sodium 8
    Magnesium Strearate 4
    Film Tablet Composition (200 mg dose, 412 mg image)mg
    Core Tablet Composition 400
    Film Coat 12
    Wax 0.04


    [0229] A tablet was prepared with the components and amounts listed in Table 14 for Exemplary Tablet 1F comprising 200 mg of API, i.e. crystalline Compound 1 Form I. Exemplary Tablet 1F (formulated to have 200 mg of crystalline Compound 1 Form I) is prepared using a wet high shear granule formulation process. In Table 14, grades/brands were as follows. High Shear Granule Blend - microcrystalline cellulose: Avicel PH101; mannitol: Pearlitol C50; croscarmellose sodium: Acdisol; polyvinylpyrrolidone: Kollidon PVP K30; and in the Core Tablet Composition - microcrystalline cellulose: Avicel PH200; croscarmellose sodium: Acdisol; and magnesium stearate: 5712; and in the film coat - film coat: Opadry II; wax: Carnauba.
    Table 14.
    High Shear Granule Blendmg
    Compound 1 Form I 200
    Microcrystalline cellulose 67
    Mannitol 45
    Croscarmellose Sodium 7
    Polyvinylpyrrolidone 10.4
    Sodium Lauryl Sulfate 2.6
    Core Tablet Composition (200 mg dose, 400 mg Image)mg
    High Shear Granule Blend 332
    Microcrystalline cellulose 56
    Croscarmellose Sodium 8
    Magnesium Strearate 4
    Film Tablet Composition (200 mg dose, 412 mg image)mg
    Core Tablet Composition 400
    Film Coat 12
    Wax 0.04


    [0230] A tablet was prepared with the components and amounts listed in Table 15 for Exemplary Tablet 1G comprising 100 mg of API, i.e. crystalline Compound 1 Form I. Exemplary Tablet 1G (formulated to have 100 mg of crystalline Compound 1 Form I) is prepared using a wet high shear granule formulation process. In Table 15, grades/brands were as follows. High Shear Granule Blend - microcrystalline cellulose: Avicel PH101; mannitol: Pearlitol C50; croscarmellose sodium: Acdisol; polyvinylpyrrolidone: Kollidon PVP K30; and in the Tablet Composition - croscarmellose sodium: Acdisol.
    Table 15.
    High Shear Granule Blend(%w/w)
    Compound 1 Form I 70
    Microcrystalline cellulose 12
    Mannitol 11
    Croscarmellose Sodium 2
    Polyvinylpyrrolidone 4
    Sodium Lauryl Sulfate 1
    Water (removed during drying) 25-40% solids
    Tablet Composition (100 mg dose, 147mg image)(%w/w)
    High Shear Granule Blend 97.5
    Croscarmellose Sodium 2.0
    Magnesium Stearate 0.5


    [0231] A tablet was prepared with the components and amounts listed in Table 16 for Exemplary Tablet 1H comprising 100 mg of API, i.e. crystalline Compound 1 Form I or Form II. Exemplary Tablet 1H (formulated to have 100 mg of crystalline Compound 1 Form I or Form II) is prepared using a wet high shear granule formulation process. In Table 16, grades/brands were as follows. High Shear Granule Blend - microcrystalline cellulose: Avicel PH101; mannitol: Pearlitol C50; croscarmellose sodium: Acdisol; polyvinylpyrrolidone: Kollidon PVP K30; and in the Core Tablet Composition - microcrystalline cellulose: Avicel PH200; croscarmellose sodium: Acdisol; and magnesium stearate: 5712.
    Table 16.
    High Shear Granule Blend(%w/w)
    Compound 1 Form I or Form II 61
    Microcrystalline cellulose 20.3
    Mannitol 13.2
    Croscarmellose Sodium 2
    Polyvinylpyrrolidone 2.7
    Sodium Lauryl Sulfate 0.7
    Tablet Composition (100 mg dose, 197 mg image)(%w/w)
    High Shear Granule Blend 83
    Microcrystalline cellulose 14
    Croscarmellose Sodium 2
    Magnesium Stearate 1


    [0232] A tablet was prepared with the components and amounts listed in Table 17 for Exemplary Tablet 1I comprising 100 mg of API, i.e. crystalline Compound 1 Form I or Form II. Exemplary Tablet 1I (formulated to have 100 mg of crystalline Compound 1 Form I or Form II) is prepared using a wet high shear granule formulation process. In Table 17, grades/brands were as follows. High Shear Granule Blend - microcrystalline cellulose: Avicel PH101; mannitol: Pearlitol C50; croscarmellose sodium: Acdisol; polyvinylpyrrolidone: Kollidon PVP K30; and in the Core Tablet Composition - microcrystalline cellulose: Avicel PH200; croscarmellose sodium: Acdisol; and magnesium stearate: 5712.
    Table 17.
    High Shear Granule Blendmg
    Compound 1 Form I or Form II 100
    Microcrystalline cellulose 33.3
    Mannitol 21.7
    Croscarmellose Sodium 3.3
    Polyvinylpyrrolidone 4.4
    Sodium Lauryl Sulfate 1.1
    Core Tablet Composition (100 mg dose, 197 mg image)mg
    High Shear Granule Blend 163.9
    Microcrystalline cellulose 27.6
    Croscarmellose Sodium 3.9
    Magnesium Stearate 2.0

    Tablet Formation from Roller Compaction Granule Composition


    Equipment/Process


    Equipment



    [0233] Roller Compactors: Alexanderwerk WP 120, Vector TF-Mini, or Vector TF-Labo.

    Screening/Weighing



    [0234] Compound 1 and excipients may be screened prior to or after weigh-out. Appropriate screen sizes are mesh 20, mesh 40, or mesh 60. Compound 1 may be pre-blended with one or more of the excipients to simplify screening.

    Blending



    [0235] Compound 1 and excipients may be added to the blender in different order. The blending may be performed in a Turbula blender or a v-shell blender. The components may be blended for 10 minutes without lubricant followed by additional blending with lubricant for 3 minutes.

    Roller Compaction



    [0236] The blend may be roller compacted in ribbons and milled into granules using an Alexanderwerk WP 120. The rolls used may be the 25 mm rolls using a compaction pressure of 18 to 50 bar, a roller speed of 3 to 12 RPM, and a screw feeder speed of 20 to 80 RPM. The screen sizes of the integrated mill may be 2 mm for the top screen and 0.8 mm for the bottom screen.

    Blending



    [0237] The roller compacted granules may be blended with extra-granular excipients such as fillers and lubricant using a V-shell blender. The blending time may be 5, 3 or 1 minute(s).

    Compression



    [0238] The compression blend has been compressed into tablets using a single station Riva MiniPress with 10 mm tooling. The weight of the tablets for a 100 mg dose may be about 200, 250, or 300 mg.

    Film Coating



    [0239] Tablets may be film coated using a pan coater, such as, for example an O'Hara Labcoat.

    Printing



    [0240] Film coated tablets may be printed with a monogram on one or both tablet faces with, for example, a Hartnett Delta printer.

    Tablet Formation from High Shear Granule Composition


    Equipment/Process


    Equipment



    [0241] Granulator: Procept MiPro with a 250 ml or 1 L granulation bowl.

    Screening/Weighing



    [0242] Compound 1 and excipients may be screened prior to or after weigh-out. Possible screen sizes are mesh 20, mesh 40, or mesh 60. Compound 1 may be pre-blended with one or more of the excipients to simplify screening.

    Granulation Operation



    [0243] Granulation Fluid - SLS and binder are added to purified water and mixed until dissolved. A suitable ratio is 2.5% w/w SLS and 10.0% w/w PVP K30 in water.

    [0244] Granulation - The excipients and compound 1 are added to the granulation bowl. The order of addition may be Compound 1, disintegrant, diluent, and filler. The components may be mixed in the 250 ml bowl for 1 minute at impeller speed 1000 RPM and chopper speed 1000 RPM. Granulation may be performed at an impeller speed of 2000 RPM with a chopper speed of 4000 RPM while adding the granulation fluid with a syringe pump at 1.5 to 4.5 g/min. The fluid addition time may be 4 to 12 minutes. After the required binder fluid is added, the granules may be wet-massed for about 10 seconds to about 1 minute. One notable advantage of the present high shear granulation process is using a granulation fluid that comprises both a surfactant and the binder for better granulation through increased wettability. In one embodiment, the surfactant is SLS.

    Drying



    [0245] The granules may be dried using a vacuum oven, tray dryer, bi-conical dryer, or fluid bed drier. The granules have been dried using a vacuum oven with a nitrogen purge.

    Blending



    [0246] The granules may be blended with extra-granular excipients. The granules have been blended with extragranular disintegrant, diluent, filler, and lubricant. The granules have been blended using the Turbula blender for 3 minutes pre-lubricant and 1 minute with lubricant. A larger scale blender such as a 4-quart V-shell blender may be used.

    Compression



    [0247] The compression blend has been compressed into tablets using a single station Riva MiniPress with 8 mm, or 10 mm tooling. The weight of the tablets for a 100 mg dose may be about 160, 200, or 250 mg.

    Film Coating



    [0248] Tablets may be film coated using a pan coater, such as, for example an O'Hara Labcoat.

    Printing



    [0249] Film coated tablets may be printed with a monogram on one or both tablet faces with, for example, a Hartnett Delta printer.

    Dosing Administration Schedule



    [0250] In another aspect, the invention relates to a tablet, pharmaceutical composition, or dosage unit form according to any one of claims 1-11 for use in a method of treating cystic fibrosis in a subject, wherein the method comprises administering to a subject in need thereof an effective amount of the tablet, pharmaceutical composition, or dosage unit form. In another embodiment, the pharmaceutical composition is administered to the subject once every two weeks. In another embodiment, the pharmaceutical composition is administered to the subject once a week. In another embodiment, the pharmaceutical composition is administered to the subject once every three days. In another embodiment, the pharmaceutical composition is administered to the subject once a day. In one embodiment, when the pharmaceutical composition is a tablet according to Table 9, 10, 11, 12, 13, 14, 15, 16, or 17 dosing is once a day.

    ASSAYS


    Assays for Detecting and Measuring ΔF508-CFTR Correction Properties of Compounds



    [0251] Membrane potential optical methods for assaying ΔF508-CFTR modulation properties of compounds.

    [0252] The optical membrane potential assay utilized voltage-sensitive FRET sensors described by Gonzalez and Tsien (See Gonzalez, J. E. and R. Y. Tsien (1995) "Voltage sensing by fluorescence resonance energy transfer in single cells" Biophys J 69(4): 1272-80, and Gonzalez, J. E. and R. Y. Tsien (1997) "Improved indicators of cell membrane potential that use fluorescence resonance energy transfer" Chem Biol 4(4): 269-77) in combination with instrumentation for measuring fluorescence changes such as the Voltage/Ion Probe Reader (VIPR) See, Gonzalez, J. E., K. Oades, et al. (1999) "Cell-based assays and instrumentation for screening ion-channel targets" Drug Discov Today 4(9): 431-439).

    [0253] These voltage sensitive assays are based on the change in fluorescence resonant energy transfer (FRET) between the membrane-soluble, voltage-sensitive dye, DiSBAC2(3), and a fluorescent phospholipid, CC2-DMPE, which is attached to the outer leaflet of the plasma membrane and acts as a FRET donor. Changes in membrane potential (Vm) cause the negatively charged DiSBAC2(3) to redistribute across the plasma membrane and the amount of energy transfer from CC2-DMPE changes accordingly. The changes in fluorescence emission were monitored using VIPR™ II, which is an integrated liquid handler and fluorescent detector designed to conduct cell-based screens in 96- or 384- well microtiter plates.

    1. Identification of Correction Compounds



    [0254] To identify small molecules that correct the trafficking defect associated with ΔF508-CFTR; a single-addition HTS assay format was developed. The cells were incubated in serum-free medium for 16 hrs at 37 °C in the presence or absence (negative control) of test compound. As a positive control, cells plated in 384-well plates were incubated for 16 hrs at 27 °C to "temperature-correct" ΔF508-CFTR. The cells were subsequently rinsed 3X with Krebs Ringers solution and loaded with the voltage-sensitive dyes. To activate ΔF508-CFTR, 10 µM forskolin and the CFTR potentiator, genistein (20 µM), were added along with Cl--free medium to each well. The addition of Cl--free medium promoted Cl- efflux in response to ΔF508-CFTR activation and the resulting membrane depolarization was optically monitored using the FRET-based voltage-sensor dyes.

    2. Identification of Potentiator Compounds



    [0255] To identify potentiators of ΔF508-CFTR, a double-addition HTS assay format was developed. During the first addition, a Cl--free medium with or without test compound was added to each well. After 22 sec, a second addition of Cl--free medium containing 2 - 10 µM forskolin was added to activate ΔF508-CFTR. The extracellular Cl- concentration following both additions was 28 mM, which promoted Cl- efflux in response to ΔF508-CFTR activation and the resulting membrane depolarization was optically monitored using the FRET-based voltage-sensor dyes.

    3. Solutions



    [0256] Bath Solution #1: (in mM) NaCl 160, KCl 4.5, CaCl2 2, MgCl2 1, HEPES 10, pH 7.4 with NaOH.

    [0257] Chloride-free bath solution: Chloride salts in Bath Solution #1 are substituted with gluconate salts.

    [0258] CC2-DMPE: Prepared as a 10 mM stock solution in DMSO and stored at -20°C. DiSBAC2(3): Prepared as a 10 mM stock in DMSO and stored at -20°C.

    4. Cell Culture



    [0259] NIH3T3 mouse fibroblasts stably expressing ΔF508-CFTR are used for optical measurements of membrane potential. The cells are 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, β-ME, 1 X pen/strep, and 25 mM HEPES in 175 cm2 culture flasks. For all optical assays, the cells were seeded at 30,000/well in 384-well matrigel-coated plates and cultured for 2 hrs at 37 °C before culturing at 27 °C for 24 hrs for the potentiator assay. For the correction assays, the cells are cultured at 27 °C or 37 °C with and without compounds for 16 - 24 hours.

    Electrophysiological Assays for assaying ΔF508-CFTR modulation properties of compounds


    1. Ussing Chamber Assay



    [0260] Using chamber experiments were performed on polarized epithelial cells expressing ΔF508-CFTR to further characterize the ΔF508-CFTR modulators identified in the optical assays. FRTΔF508-CFTR epithelial cells grown on Costar Snapwell cell culture inserts were mounted in an Ussing chamber (Physiologic Instruments, Inc., San Diego, CA), and the monolayers were continuously short-circuited using a Voltage-clamp System (Department of Bioengineering, University of Iowa, IA, and, Physiologic Instruments, Inc., San Diego, CA). Transepithelial resistance was measured by applying a 2-mV pulse. Under these conditions, the FRT epithelia demonstrated resistances of 4 KΩ/cm2 or more. The solutions were maintained at 27 °C and bubbled with air. The electrode offset potential and fluid resistance were corrected using a cell-free insert. Under these conditions, the current reflects the flow of Cl- through ΔF508-CFTR expressed in the apical membrane. The ISC was digitally acquired using an MP100A-CE interface and AcqKnowledge software (v3.2.6; BIOPAC Systems, Santa Barbara, CA).

    2. Identification of Correction Compounds



    [0261] Typical protocol utilized a basolateral to apical membrane Cl- concentration gradient. To set up this gradient, normal ringer was used on the basolateral membrane, whereas apical NaCl was replaced by equimolar sodium gluconate (titrated to pH 7.4 with NaOH) to give a large Cl- concentration gradient across the epithelium. All experiments were performed with intact monolayers. To fully activate ΔF508-CFTR, forskolin (10 µM) and the PDE inhibitor, IBMX (100 µM), were applied followed by the addition of the CFTR potentiator, genistein (50 µM).

    [0262] As observed in other cell types, incubation at low temperatures of FRT cells stably expressing ΔF508-CFTR increases the functional density of CFTR in the plasma membrane. To determine the activity of correction compounds, the cells were incubated with 10 µM of the test compound for 24 hours at 37°C and were subsequently washed 3X prior to recording. The cAMP- and genistein-mediated ISC in compound-treated cells was normalized to the 27°C and 37°C controls and expressed as percentage activity. Preincubation of the cells with the correction compound significantly increased the cAMP- and genistein-mediated ISC compared to the 37°C controls.

    3. Identification of Potentiator Compound



    [0263] Typical protocol utilized a basolateral to apical membrane Cl- concentration gradient. To set up this gradient, normal ringers was used on the basolateral membrane and was permeabilized with nystatin (360 µg/ml), whereas apical NaCl was replaced by equimolar sodium gluconate (titrated to pH 7.4 with NaOH) to give a large Cl- concentration gradient across the epithelium. All experiments were performed 30 min after nystatin permeabilization. Forskolin (10 µM) and all test compounds were added to both sides of the cell culture inserts. The efficacy of the putative ΔF508-CFTR potentiators was compared to that of the known potentiator, genistein.

    4. Solutions



    [0264] Basolateral solution (in mM): NaCl (135), CaCl2 (1.2), MgCl2 (1.2), K2HPO4 (2.4), KHPO4 (0.6), N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid (HEPES) (10), and dextrose (10). The solution was titrated to pH 7.4 with NaOH.

    [0265] Apical solution (in mM): Same as basolateral solution with NaCl replaced with Na Gluconate (135).

    5. Cell Culture



    [0266] Fisher rat epithelial (FRT) cells expressing ΔF508-CFTR (FRTΔF508-CFTR) were used for Ussing chamber experiments for the putative ΔF508-CFTR modulators identified from our optical assays. The cells were cultured on Costar Snapwell cell culture inserts and cultured for five days at 37 °C and 5% CO2 in Coon's modified Ham's F-12 medium supplemented with 5% fetal calf serum, 100 U/ml penicillin, and 100 µg/ml streptomycin. Prior to use for characterizing the potentiator activity of compounds, the cells were incubated at 27 °C for 16 - 48 hrs to correct for the ΔF508-CFTR. To determine the activity of corrections compounds, the cells were incubated at 27 °C or 37 °C with and without the compounds for 24 hours.

    6. Whole-cell recordings



    [0267] The macroscopic ΔF508-CFTR current (IΔF508) in temperature- and test compound-corrected NIH3T3. cells stably expressing ΔF508-CFTR were monitored using the perforated-patch, whole-cell recording. Briefly, voltage-clamp recordings of IΔF508 were performed at room temperature using an Axopatch 200B patch-clamp amplifier (Axon Instruments Inc., Foster City, CA). All recordings were acquired at a sampling frequency of 10 kHz and low-pass filtered at 1 kHz. Pipettes had a resistance of 5 - 6 MΩ when filled with the intracellular solution. Under these recording conditions, the calculated reversal potential for Cl- (ECl) at room temperature was -28 mV. All recordings had a seal resistance > 20 GΩ and a series resistance < 15 MΩ. Pulse generation, data acquisition, and analysis were performed using a PC equipped with a Digidata 1320 A/D interface in conjunction with Clampex 8 (Axon Instruments Inc.). The bath contained < 250 µl of saline and was continuously perifused at a rate of 2 ml/min using a gravity-driven perfusion system.

    7. Identification of Correction Compounds



    [0268] To determine the activity of correction compounds for increasing the density of functional ΔF508-CFTR in the plasma membrane, we used the above-described perforated-patch-recording techniques to measure the current density following 24-hr treatment with the correction compounds. To fully activate ΔF508-CFTR, 10 µM forskolin and 20 µM genistein were added to the cells. Under our recording conditions, the current density following 24-hr incubation at 27°C was higher than that observed following 24-hr incubation at 37 °C. These results are consistent with the known effects of low-temperature incubation on the density of ΔF508-CFTR in the plasma membrane. To determine the effects of correction compounds on CFTR current density, the cells were incubated with 10 µM of the test compound for 24 hours at 37°C and the current density was compared to the 27°C and 37°C controls (% activity). Prior to recording, the cells were washed 3X with extracellular recording medium to remove any remaining test compound. Preincubation with 10 µM of correction compounds significantly increased the cAMP- and genistein-dependent current compared to the 37°C controls.

    8. Identification of Potentiator Compounds



    [0269] The ability of ΔF508-CFTR potentiators to increase the macroscopic ΔF508-CFTR Cl- current (IΔF508) in NIH3T3 cells stably expressing ΔF508-CFTR was also investigated using perforated-patch-recording techniques. The potentiators identified from the optical assays evoked a dose-dependent increase in IΔF508 with similar potency and efficacy observed in the optical assays. In all cells examined, the reversal potential before and during potentiator application was around -30 mV, which is the calculated ECl (-28 mV).

    9. Solutions



    [0270] Intracellular solution (in mM): Cs-aspartate (90), CsCl (50), MgCl2 (1), HEPES (10), and 240 µg/ml amphotericin- B (pH adjusted to 7.35 with CsOH).

    [0271] Extracellular solution (in mM): N-methyl-D-glucamine (NMDG)-Cl (150), MgCl2 (2), CaCl2 (2), HEPES (10) (pH adjusted to 7.35 with HCl).

    10. Cell Culture



    [0272] NIH3T3 mouse fibroblasts stably expressing ΔF508-CFTR are used for whole-cell recordings. The cells are 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, β-ME, 1 X pen/strep, and 25 mM HEPES in 175 cm2 culture flasks. For whole-cell recordings, 2,500 - 5,000 cells were seeded on poly-L-lysine-coated glass coverslips and cultured for 24 - 48 hrs at 27 °C before use to test the activity of potentiators; and incubated with or without the correction compound at 37 °C for measuring the activity of correctors.

    11. Single-channel recordings



    [0273] The single-channel activities of temperature-corrected ΔF508-CFTR stably expressed in NIH3T3 cells and activities of potentiator compounds were observed using excised inside-out membrane patch. Briefly, voltage-clamp recordings of single-channel activity were performed at room temperature with an Axopatch 200B patch-clamp amplifier (Axon Instruments Inc.). All recordings were acquired at a sampling frequency of 10 kHz and low-pass filtered at 400 Hz. Patch pipettes were fabricated from Coming Kovar Sealing #7052 glass (World Precision Instruments, Inc., Sarasota, FL) and had a resistance of 5 - 8 MΩ when filled with the extracellular solution. The ΔF508-CFTR was activated after excision, by adding 1 mM Mg-ATP, and 75 nM of the cAMP-dependent protein kinase, catalytic subunit (PKA; Promega Corp. Madison, WI). After channel activity stabilized, the patch was perifused using a gravity-driven microperfusion system. The inflow was placed adjacent to the patch, resulting in complete solution exchange within 1 - 2 sec. To maintain ΔF508-CFTR activity during the rapid perifusion, the nonspecific phosphatase inhibitor F- (10 mM NaF) was added to the bath solution. Under these recording conditions, channel activity remained constant throughout the duration of the patch recording (up to 60 min). Currents produced by positive charge moving from the intra-to extracellular solutions (anions moving in the opposite direction) are shown as positive currents. The pipette potential (VP) was maintained at 80 mV.

    [0274] Channel activity was analyzed from membrane patches containing ≤ 2 active channels. The maximum number of simultaneous openings determined the number of active channels during the course of an experiment. To determine the single-channel current amplitude, the data recorded from 120 sec of ΔF508-CFTR activity was filtered "off-line" at 100 Hz and then used to construct all-point amplitude histograms that were fitted with multigaussian functions using Bio-Patch Analysis software (Bio-Logic Comp. France). The total microscopic current and open probability (Po) were determined from 120 sec of channel activity. The Po was determined using the Bio-Patch software or from the relationship Po = I/i(N), where I = mean current, i = single-channel current amplitude, and N = number of active channels in patch.

    12. Solutions



    [0275] Extracellular solution (in mM): NMDG (150), aspartic acid (150), CaCl2 (5), MgCl2 (2), and HEPES (10) (pH adjusted to 7.35 with Tris base).

    [0276] Intracellular solution (in mM): NMDG-Cl (150), MgCl2 (2), EGTA (5), TES (10), and Tris base (14) (pH adjusted to 7.35 with HCl).

    13. Cell Culture



    [0277] NIH3T3 mouse fibroblasts stably expressing ΔF508-CFTR are used for excised-membrane patch-clamp recordings. The cells are 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, β-ME, 1 X pen/strep, and 25 mM HEPES in 175 cm2 culture flasks. For single channel recordings, 2,500 - 5,000 cells were seeded on poly-L-lysine-coated glass coverslips and cultured for 24 - 48 hrs at 27 °C before use.

    [0278] Using the procedures described above, the activity, i.e., EC50s, of Compound 1 has been measured and is shown in Table 18.
    Table 18.
    IC50/EC50 Bins: +++ <= 20 <++ <= 50 < +
    PercentActivity Bins: + <= 25.0 < ++ <= 100.0 < +++
    Cmpd. NoBinnedEC50BinnedMaxEfficacy
    1 +++ +++

    1. A tablet for oral administration comprising:
    1. a. 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid (Compound 1) Form I, Compound 1 Form II, and/or Compound 1 HCl Salt Form A wherein Compound 1 Form I, Compound 1 Form II, and/or Compound 1 HCl Salt Form A are present in an amount of at least 60 wt% by weight of the composition;
    2. b. a filler;
    3. c. a diluent;
    4. d. a disintegrant;
    5. e. a surfactant;
    6. f. a lubricant; and
    7. g. at least one of a binder and a glidant.

    2. The tablet of claim 1, wherein Compound 1 Form I, Compound 1 Form II, and/or Compound 1 HCl Salt Form A is present in the tablet in an amount ranging from about 25 mg to about 250 mg.
    3. A tablet comprising:
    1. a. Compound 1 Form I, Compound 1 Form II, and/or Compound 1 HCl Salt Form A in an amount ranging from about 25 mg to about 250 mg;
    2. b. a filler;
    3. c. a diluent;
    4. d. a disintegrant;
    5. e. a surfactant;
    6. f. a lubricant; and
    7. g. at least one of a binder and a glidant;
      wherein the tablet comprises a binder which is polyvinylpyrrolidone;
      wherein Compound 1 Form I, Compound 1 Form II, and/or Compound 1 HCl Salt Form A is present in an amount of at least 30 wt%.

    4. A tablet of one of the following formulations:
    High Shear Granule Blend(%w/w)
    Compound 1 Form I 60
    Microcrystalline cellulose 20
    Mannitol 13
    Croscarmellose Sodium 2
    Polyvinylpyrrolidone 4
    Sodium Lauryl Sulfate 1
    Water (removed during drying) 25-40% solids
    Tablet Composition (100 mg dose, 171 mg image)(%w/w)
    High Shear Granule Blend 97.5
    Croscarmellose Sodium Magnesium 2.0
    Stearate 0.5
    or:
    High Shear Granule Blend(%w/w)
    Compound 1 Form I 60
    Microcrystalline cellulose 20
    Mannitol 13
    Croscarmellose Sodium 2
    Polyvinylpyrrolidone 4
    Sodium Lauryl Sulfate 1
    Water (removed during drying) 25-40% solids
    Tablet Composition (200 mg dose, 402 mg image)(%w/w)
    High Shear Granule Blend 83
    Microcrystalline cellulose 14
    Croscarmellose Sodium 2
    Magnesium Stearate 1.0
    or:
    High Shear Granule Blend(%w/w)
    Compound 1 Form I 70
    Microcrystalline cellulose 12
    Mannitol 11
    Croscarmellose Sodium 2
    Polyvinylpyrrolidone 4
    Sodium Lauryl Sulfate 1
    Water (removed during drying) 25-40% solids
    Tablet Composition (100 mg dose, 147 mg image)(%w/w)
    High Shear Granule Blend 97.5
    Croscarmellose Sodium Magnesium 2.0
    Stearate 0.5
    or:
    High Shear Granule Blend(%w/w)
    Compound 1 Form I or Form II 61
    Microcrystalline cellulose 20.3
    Mannitol 13.2
    Croscarmellose Sodium 2
    Polyvinylpyrrolidone 2.7
    Sodium Lauryl Sulfate 0.7
    Tablet Composition (100 mgdose, 197 mg image)(%w/w)
    High Shear Granule Blend 83
    Microcrystalline cellulose 14
    Croscarmellose Sodium 2
    Magnesium Stearate 1

    5. A pharmaceutical composition comprising a plurality of granules, the composition comprising:
    1. a. Compound 1 Form I, Compound 1 Form II, and/or Compound 1 HCl Salt Form A in an amount of at least 60 wt% by weight of the composition;
    2. b. a filler in an amount ranging from about 20 wt% to about 50 wt% by weight of the composition;
    3. c. a disintegrant in an amount ranging from about 1 wt% to about 5 wt% by weight of the composition;
    4. d. a surfactant in an amount ranging from about 2 wt% to about 0.3 wt% by weight of the composition;
    5. e. a diluent in an amount ranging from about 1 wt% to about 30 wt% by weight of the composition;
    6. f. a lubricant in an amount ranging from about 0.3 wt% to about 5 wt% by weight of the composition; and
    7. g. at least one of a binder in an amount from about 20 wt% to about 45 wt% by weight of the composition or a glidant in an amount ranging from about 0.05 wt% to about 2 wt% by weight of the composition.

    6. The pharmaceutical composition of claim 5, wherein the pharmaceutical composition further comprises at least one additional therapeutic agent.
    7. The pharmaceutical composition of claim 6, wherein the additional therapeutic agent is a CFTR modulator.
    8. The pharmaceutical composition of claim 7, wherein the CFTR modulator is a CFTR potentiator.
    9. A dosage unit form which comprises:
    1. a. at least about 60 wt% of Compound 1, Compound 1 Form I, Compound 1 Form II, and/or Compound 1 HCl Salt Form A;
    2. b. about 20 wt% of microcrystalline cellulose by weight of the composition;
    3. c. about 13 wt% of mannitol by weight of the composition;
    4. d. about 2 wt% of croscarmellose sodium by weight of the composition;
    5. e. about 4 wt% of polyvinylpyrrolidone by weight of the composition;
    6. f. about 1 wt% of sodium lauryl sulfate by weight of the composition; and
    7. g. about 0.5 wt% of magnesium stearate by weight of the composition.
    or
    1. a. at least about 60 wt% of Compound 1, Compound 1 Form I, Compound 1 Form II, and/or Compound 1 HCl Salt Form A;
    2. b. about 34 wt% of microcrystalline cellulose by weight of the composition;
    3. c. about 13 wt% of mannitol by weight of the composition;
    4. d. about 4 wt% of croscarmellose sodium by weight of the composition;
    5. e. about 4 wt% of polyvinylpyrrolidone by weight of the composition;
    6. f. about 1 wt% of sodium lauryl sulfate by weight of the composition; and
    7. g. about 1.5 wt% of magnesium stearate by weight of the composition.
    or
    1. a. about 70 wt% of Compound 1, Compound 1 Form I, Compound 1 Form II, and/or Compound 1 HCl Salt Form A;
    2. b. about 12 wt% of microcrystalline cellulose by weight of the composition;
    3. c. about 11 wt% of mannitol by weight of the composition;
    4. d. about 2 wt% of croscarmellose sodium by weight of the composition;
    5. e. about 4 wt% of polyvinylpyrrolidone by weight of the composition;
    6. f. about 1 wt% of sodium lauryl sulfate by weight of the composition; and
    7. g. about 0.5 wt% of magnesium stearate by weight of the composition.

    10. The tablet, pharmaceutical composition, or dosage unit form of any one of claims 1 to 9, wherein Compound 1 Form I, Compound 1 Form II, and/or Compound 1 HCl Salt Form A has a particle size of 0.1 microns to 50 microns, 0.1 microns to 20 microns, 0.1 microns to 10 microns or 1.0 microns to 5 microns.
    11. The tablet, pharmaceutical composition, or dosage unit form of any one of claims 1 to 10, wherein Compound 1 Form I, Compound 1 Form II, and/or Compound I HCl Salt Form A has a particle size D50 of 2.0 microns.
    12. A method of producing a pharmaceutical composition comprising the steps of: combining a therapeutically effective amount of Compound 1 Form I, Compound 1 Form II, and/or Compound 1 HCl Salt Form A and at least one granulation excipient selected from the group consisting of: a binder; a glidant; a surfactant; a lubricant; a disintegrant; a filler, a diluent and combinations thereof to form an admixture; mixing and wet granulating the admixture; and compacting the admixture to form the pharmaceutical composition from an admixture of powdered and liquid materials;
    wherein Compound 1 Form I, Compound 1 Form II, and/or Compound 1 HCl Salt Form A is present in an amount of at least 30 wt% in the pharmaceutical composition.
    13. The tablet, pharmaceutical composition, or dosage unit form of any one of claims 1 to 11 for use in a method of treating cystic fibrosis
    14. The tablet, pharmaceutical composition, or dosage unit form for use of claim 13, wherein said patient has cystic fibrosis transmembrane receptor (CFTR) with a ΔF508 mutation, a R117H mutation, or a G551D mutation.
    15. The tablet, pharmaceutical composition, or dosage unit form for use of claim 13, wherein the use comprises administering an additional therapeutic agent.
    16. A kit comprising a tablet, pharmaceutical composition, or dosage unit form of any one of claims 1 to 11 and instructions for use thereof.
    17. The kit of claim 16, wherein Compound 1 is Compound 1 Form I and is present in the tablet, pharmaceutical composition, or dosage unit in an amount ranging from 25 mg to about 200 mg.
    18. The pharmaceutical composition of claim 6 or the tablet, pharmaceutical composition, or dosage unit form for use of claim 15, wherein the additional agent is N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide.
    19. The tablet for use of any of claims 13 to 15, or claim 18, wherein the method comprises orally administering to a patient at least once per day or twice per day a tablet comprising:
    1. a. about 25 to 200 mg Compound 1 Form I, Compound 1 Form II, and/or Compound 1 HCl Salt Form A;
    2. b. a filler;
    3. c. a diluent;
    4. d. a disintegrant;
    5. e. a surfactant;
    6. f. at least one of a binder and a glidant; and
    7. g. a lubricant.

    20. The tablet for use of claim 19, wherein the tablet comprises about 25 mg, 75 mg, 100 mg, 150 mg, or 200 mg of Compound 1 Form I, Compound I Form II, and/or Compound 1 HCl Salt Form A.
    21. The tablet for use of claim 20, wherein the method comprises orally administering to a patient once every 12 hours a tablet comprising:
    1. a. about 25 to 200 mg of Compound 1 Form I, Compound 1 Form II, and/or Compound 1 HCl Salt Form A;
    2. b. a filler;
    3. c. a diluent;
    4. d. a disintegrant;
    5. e. a surfactant;
    6. f. at least one of a binder and a glidant; and
    7. g. a lubricant.

    22. The tablet for use of claim 21, wherein the tablet comprises about 25 mg, 75 mg, 100 mg, 150 mg, or 200 mg of Compound 1 Form I, Compound I Form II, and/or Compound 1 HCl Salt Form A.
    24. A tablet of the following formulation:
    High Shear Granule Blend(%w/w)
    Compound 1 Form I 50
    Microcrystalline cellulose 30
    Mannitol 13
    Croscarmellose Sodium 2
    Polyvinylpyrrolidone 4
    Sodium Lauryl Sulfate 1
    Water (removed during drying) 25-40% solids
    Tablet Composition (100 mg dose, 205 mg image)(%w/w)
    High Shear Granule Blend 97.5
    Croscarmellose Sodium 2.0
    Magnesium Stearate 0.5

    25. A tablet of the following formulation:
    High Shear Granule Blend(%w/w)
    Compound 1 Form I 60
    Microcrystalline cellulose 20
    Mannitol 13
    Croscarmellose Sodium 2
    Polyvinylpyrrolidone 4
    Sodium Lauryl Sulfate 1
    Water (removed during drying) 25-40% solids
    Tablet Composition (100 mg dose, 171 mg image)(%w/w)
    High Shear Granule Blend 97.5
    Croscarmellose Sodium 2.0
    Magnesium Stearate 0.5

    26. A tablet of the following formulation:
    High Shear Granule Blend(%w/w)
    Compound 1 Form I 60
    Microcrystalline cellulose 20
    Mannitol 13
    Croscarmellose Sodium 2
    Polyvinylpyrrolidone 4
    Sodium Lauryl Sulfate 1
    Water (removed during drying) 25-40% solids
    Tablet Composition (200 mg dose, 402 mq image)(%w/w)
    High Shear Granule Blend 97.5
    Microcrystalline cellulose 14
    Croscarmellose Sodium 2.0
    Magnesium Stearate 1.0

    27. A tablet of the following formulation:
    High Shear Granule Blendmg
    Compound 1 Form I 200
    Microcrystalline cellulose 66
    Mannitol 43
    Croscarmellose Sodium 7
    Polyvinylpyrrolidone 13
    Sodium Lauryl Sulfate 3
    Core Tablet Composition (200 mg dose, 412mg image)mg
    High Shear Granule Blend 332
    Microcrystalline cellulose 56
    Croscarmellose Sodium 8
    Magnesium Stearate 4
    Film Coated Tablet (200 mg dose, 412 mg image)mg
    Core Tablet Composition 400
    Film Coat 12
    Wax 0.04

    28. A tablet of the following formulation:
    High Shear Granule Blendmg
    Compound 1 Form I 200
    Microcrystalline cellulose 67
    Mannitol 45
    Croscarmellose Sodium 7
    Polyvinylpyrrolidone 10.4
    Sodium Lauryl Sulfate 2.6
    Core Tablet Composition (200 mg dose, 412 mg image)mg
    High Shear Granule Blend 332
    Microcrystalline cellulose 56
    Croscarmellose Sodium 8
    Magnesium Stearate 4
    Film Coated Tablet (200 mg dose, 412 mg image)mg
    Core Tablet Composition 400
    Film Coat 12
    Wax 0.04

    29. A tablet of the following formulation:
    High Shear Granule Blend(%w/w)
    Compound 1 Form I 70
    Microcrystalline cellulose 12
    Mannitol 11
    Croscarmellose Sodium 2
    Polyvinylpyrrolidone 4
    Sodium Lauryl Sulfate 1
    Water (removed during drying) 25-40% solids
    Tablet Composition (100 mg dose, 147 mg image)(%w/w)
    High Shear Granule Blend 97.5
    Croscarmellose Sodium 2.0
    Magnesium Stearate 0.5

    30. A tablet of the following formulation:
    High Shear Granule Blend(%w/w)
    Compound 1 Form I 61
    Microcrystalline cellulose 20.3
    Mannitol 13.2
    Croscarmellose Sodium 2
    Polyvinylpyrrolidone 2.7
    Sodium Lauryl Sulfate 0.7
    Tablet Composition (100 mg dose, 197 mg image)(%w/w)
    High Shear Granule Blend 83
    Microcrystalline cellulose 14
    Croscarmellose Sodium 2
    Magnesium Stearate 1

    31. A tablet of the following formulation:
    High Shear Granule Blendmg
    Compound 1 Form I or Form II 100
    Microcrystalline cellulose 33.3
    Mannitol 21.7
    Croscarmellose Sodium 3.3
    Polyvinylpyrrolidone 4.4
    Sodium Lauryl Sulfate 1.1
    Core Tablet Composition (200 mg dose, 197 mg image)mg
    High Shear Granule Blend 163.9
    Microcrystalline cellulose 27.6
    Croscarmellose Sodium 3.9
    Magnesium Stearate 2.0

    43. A dosage unit form comprising
    1. a. about 60 wt% of Compound 1, Compound 1 Form I, Compound 1 Form II, and/or Compound 1 HCl Salt Form A;
    2. b. about 20 wt% of microcrystalline cellulose by weight of the composition;
    3. c. about 13 wt% of mannitol by weight of the composition;
    4. d. about 2 wt% of sodium croscarmellose sodium by weight of the composition;
    5. e. about 4 wt% of polyvinylpyrrolidone by weight of the composition;
    6. f. about 1 wt% of sodium lauryl sulfate by weight of the composition; and
    7. g. about 0.5 wt% of magnesium stearate by weight of the composition.

    44. A dosage unit form comprising
    1. a. about 60 wt% of Compound 1, Compound 1 Form I, Compound 1 Form II, and/or Compound 1 HCl Salt Form A;
    2. b. about 34 wt% of microcrystalline cellulose by weight of the composition;
    3. c. about 13 wt% of mannitol by weight of the composition;
    4. d. about 4 wt% of sodium croscarmellose sodium by weight of the composition;
    5. e. about 4 wt% of polyvinylpyrrolidone by weight of the composition;
    6. f. about 1 wt% of sodium lauryl sulfate by weight of the composition; and
    7. g. about 1.5 wt% of magnesium stearate by weight of the composition.

    83. A method of treating or lessening the severity of a disease in a subject comprising administering to the subject a tablet, pharmaceutical composition, or dosage unit form of any one of clauses 1 to 44, wherein the disease is cystic fibrosis.
    86. The method of clause 83, wherein said patient has cystic fibrosis transmembrane receptor (CFTR) with a ΔF508 mutation.
    87. The method of clause 83, wherein said patient has cystic fibrosis transmembrane receptor (CFTR) with a R117H mutation.
    88. The method of clause 83, wherein said patient has cystic fibrosis transmembrane receptor (CFTR) with a G551D mutation.
    89. The method of clause 83, wherein the method comprises administering an additional therapeutic agent.


    Claims

    1. A tablet for oral administration comprising:

    a. 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid (Compound 1) Form I, Compound 1 Form II, and/or Compound 1 HCl Salt Form A wherein Compound 1 Form I, Compound 1 Form II, and/or Compound 1 HCl Salt Form A are present in an amount of at least 60 wt% by weight of the composition;

    b. a filler;

    c. a diluent;

    d. a disintegrant;

    e. a surfactant;

    f. a lubricant; and

    g. at least one of a binder and a glidant.


     
    2. The tablet of claim 1, wherein Compound 1 Form I, Compound 1 Form II, and/or Compound 1 HCl Salt Form A is present in the tablet in an amount ranging from about 25 mg to about 250 mg.
     
    3. A tablet comprising:

    a. Compound 1 Form I, Compound 1 Form II, and/or Compound 1 HCl Salt Form A in an amount ranging from about 25 mg to about 250 mg;

    b. a filler;

    c. a diluent;

    d. a disintegrant;

    e. a surfactant;

    f. a lubricant; and

    g. at least one of a binder and a glidant;

    wherein the tablet comprises a binder which is polyvinylpyrrolidone;
    wherein Compound 1 Form I, Compound 1 Form II, and/or Compound 1 HCl Salt Form A is present in an amount of at least 30 wt%.
     
    4. A tablet of one of the following formulations:
    High Shear Granule Blend(%w/w)
    Compound 1 Form I 60
    Microcrystalline cellulose 20
    Mannitol 13
    Croscarmellose Sodium 2
    Polyvinylpyrrolidone 4
    Sodium Lauryl Sulfate 1
    Water (removed during drying) 25-40% solids
    Tablet Composition (100 mg dose, 171 mg image)(%w/w)
    High Shear Granule Blend 97.5
    Croscarmellose Sodium 2.0
    Magnesium Stearate 0.5
    or:
    High Shear Granule Blend(%w/w)
    Compound 1 Form I 60
    Microcrystalline cellulose 20
    Mannitol 13
    Croscarmellose Sodium 2
    Polyvinylpyrrolidone 4
    Sodium Lauryl Sulfate 1
    Water (removed during drying) 25-40% solids
    Tablet Composition (200 mg dose, 402 mg image)(%w/w)
    High Shear Granule Blend 83
    Microcrystalline cellulose 14
    Croscarmellose Sodium 2
    Magnesium Stearate 1.0
    or:
    High Shear Granule Blend(%w/w)
    Compound 1 Form I 70
    Microcrystalline cellulose 12
    Mannitol 11
    Croscarmellose Sodium 2
    Polyvinylpyrrolidone 4
    Sodium Lauryl Sulfate 1
    Water (removed during drying) 25-40% solids
    Tablet Composition (100 mg dose, 147 mg image)(%w/w)
    High Shear Granule Blend 97.5
    Croscarmellose Sodium 2.0
    Magnesium Stearate 0.5
    or:
    High Shear Granule Blend(%w/w)
    Compound 1 Form I or Form II 61
    Microcrystalline cellulose 20.3
    Mannitol 13.2
    Croscarmellose Sodium 2
    Polyvinylpyrrolidone 2.7
    Sodium Lauryl Sulfate 0.7
    Tablet Composition (100 mg dose, 197 mg image)(%w/w)
    High Shear Granule Blend 83
    Microcrystalline cellulose 14
    Croscarmellose Sodium 2
    Magnesium Stearate 1

     
    5. A pharmaceutical composition comprising a plurality of granules, the composition comprising:

    a. Compound 1 Form I, Compound 1 Form II, and/or Compound 1 HCl Salt Form A in an amount of at least 60 wt% by weight of the composition;

    b. a filler in an amount ranging from about 20 wt% to about 50 wt% by weight of the composition;

    c. a disintegrant in an amount ranging from about 1 wt% to about 5 wt% by weight of the composition;

    d. a surfactant in an amount ranging from about 2 wt% to about 0.3 wt% by weight of the composition;

    e. a diluent in an amount ranging from about 1 wt% to about 30 wt% by weight of the composition;

    f. a lubricant in an amount ranging from about 0.3 wt% to about 5 wt% by weight of the composition; and

    g. at least one of a binder in an amount from about 20 wt% to about 45 wt% by weight of the composition or a glidant in an amount ranging from about 0.05 wt% to about 2 wt% by weight of the composition.


     
    6. The pharmaceutical composition of claim 5, wherein the pharmaceutical composition further comprises at least one additional therapeutic agent.
     
    7. The pharmaceutical composition of claim 6, wherein the additional therapeutic agent is a CFTR modulator.
     
    8. The pharmaceutical composition of claim 7, wherein the CFTR modulator is a CFTR potentiator.
     
    9. A dosage unit form which comprises:

    a. at least about 60 wt% of Compound 1, Compound 1 Form I, Compound 1 Form II, and/or Compound 1 HCl Salt Form A;

    b. about 20 wt% of microcrystalline cellulose by weight of the composition;

    c. about 13 wt% of mannitol by weight of the composition;

    d. about 2 wt% of croscarmellose sodium by weight of the composition;

    e. about 4 wt% of polyvinylpyrrolidone by weight of the composition;

    f. about 1 wt% of sodium lauryl sulfate by weight of the composition; and

    g. about 0.5 wt% of magnesium stearate by weight of the composition.

    or

    a. at least about 60 wt% of Compound 1, Compound 1 Form I, Compound 1 Form II, and/or Compound 1 HCl Salt Form A;

    b. about 34 wt% of microcrystalline cellulose by weight of the composition;

    c. about 13 wt% of mannitol by weight of the composition;

    d. about 4 wt% of croscarmellose sodium by weight of the composition;

    e. about 4 wt% of polyvinylpyrrolidone by weight of the composition;

    f. about 1 wt% of sodium lauryl sulfate by weight of the composition; and

    g. about 1.5 wt% of magnesium stearate by weight of the composition.

    or

    a. about 70 wt% of Compound 1, Compound 1 Form I, Compound 1 Form II, and/or Compound 1 HCl. Salt Form A;

    b. about 12 wt% of microcrystalline cellulose by weight of the composition;

    c. about 11 wt% of mannitol by weight of the composition;

    d. about 2 wt% of croscarmellose sodium by weight of the composition;

    e. about 4 wt% of polyvinylpyrrolidone by weight of the composition;

    f. about 1 wt% of sodium lauryl sulfate by weight of the composition; and

    g. about 0.5 wt% of magnesium stearate by weight of the composition.


     
    10. The tablet, pharmaceutical composition, or dosage unit form of any one of claims 1 to 9, wherein Compound 1 Form I, Compound 1 Form II, and/or Compound 1 HCl Salt Form A has a particle size of 0.1 microns to 50 microns, 0.1 microns to 20 microns, 0.1 microns to 10 microns or 1.0 microns to 5 microns.
     
    11. The tablet, pharmaceutical composition, or dosage unit form of any one of claims 1 to 10, wherein Compound 1 Form I, Compound 1 Form II, and/or Compound I HCl Salt Form A has a particle size D50 of 2.0 microns.
     
    12. A method of producing a pharmaceutical composition comprising the steps of:

    combining a therapeutically effective amount of Compound 1 Form I, Compound 1 Form II, and/or Compound 1 HCl Salt Form A and at least one granulation excipient selected from the group consisting of: a binder; a glidant; a surfactant;

    a lubricant; a disintegrant; a filler, a diluent and combinations thereof to form an admixture; mixing and wet granulating the admixture; and compacting the admixture to form the pharmaceutical composition from an admixture of powdered and liquid materials;

    wherein Compound 1 Form I, Compound 1 Form II, and/or Compound 1 HCl Salt Form A is present in an amount of at least 30 wt% in the pharmaceutical composition.


     
    13. The tablet, pharmaceutical composition, or dosage unit form of any one of claims 1 to 11 for use in a method of treating cystic fibrosis
     
    14. The tablet, pharmaceutical composition, or dosage unit form for use of claim 13, wherein said patient has cystic fibrosis transmembrane receptor (CFTR) with a ΔF508 mutation, a R117H mutation, or a G551D mutation.
     
    15. The tablet, pharmaceutical composition, or dosage unit form for use of claim 13, wherein the use comprises administering an additional therapeutic agent.
     
    16. A kit comprising a tablet, pharmaceutical composition, or dosage unit form of any one of claims 1 to 11 and instructions for use thereof.
     
    17. The kit of claim 16, wherein Compound 1 is Compound 1 Form I and is present in the tablet, pharmaceutical composition, or dosage unit in an amount ranging from 25 mg to about 200 mg.
     
    18. The pharmaceutical composition of claim 6 or the tablet, pharmaceutical composition, or dosage unit form for use of claim 15, wherein the additional agent is N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide.
     
    19. The tablet for use of any of claims 13 to 15, or claim 18, wherein the method comprises orally administering to a patient at least once per day or twice per day a tablet comprising:

    a. about 25 to 200 mg Compound 1 Form I, Compound 1 Form II, and/or Compound 1 HCl Salt Form A;

    b. a filler;

    c. a diluent;

    d. a disintegrant;

    e. a surfactant;

    f. at least one of a binder and a glidant; and

    g. a lubricant.


     
    20. The tablet for use of claim 19, wherein the tablet comprises about 25 mg, 75 mg, 100 mg, 150 mg, or 200 mg of Compound 1 Form I, Compound I Form II, and/or Compound 1 HCl Salt Form A.
     
    21. The tablet for use of claim 20, wherein the method comprises orally administering to a patient once every 12 hours a tablet comprising:

    a. about 25 to 200 mg of Compound 1 Form I, Compound 1 Form II, and/or Compound 1 HCl Salt Form A;

    b. a filler;

    c. a diluent;

    d. a disintegrant;

    e. a surfactant;

    f. at least one of a binder and a glidant; and

    g. a lubricant.


     
    22. The tablet for use of claim 21, wherein the tablet comprises about 25 mg, 75 mg, 100 mg, 150 mg, or 200 mg of Compound 1 Form I, Compound I Form II, and/or Compound 1 HCl Salt Form A.
     


    Ansprüche

    1. Tablette zur oralen Verabreichung, umfassend:

    a. 3-(6-(1-(2,2-Difluorbenzo[d][1,3]dioxol-5-yl)cyclopropancarboxamido)-3-methylpyridin-2-yl)benzoesäure (Verbindung 1) Form I, Verbindung 1 Form II und/oder Verbindung 1 HCl-Salz Form A, wobei Verbindung 1 Form I, Verbindung 1 Form II und/oder Verbindung 1 HCl-Salz Form A in einer Menge von mindestens 60 Gew.-% des Gewichts der Zusammensetzung vorliegen,

    b. einen Füllstoff,

    c. ein Verdünnungsmittel,

    d. ein Sprengmittel,

    e. ein Tensid,

    f. ein Schmiermittel und

    g. ein Bindemittel oder/und ein Gleitmittel,


     
    2. Tablette nach Anspruch 1, wobei Verbindung 1 Form I, Verbindung 1 Form II und/oder Verbindung 1 HCl-Salz Form A in der Tablette in einer Menge im Bereich von etwa 25 mg bis etwa 250 mg vorliegt.
     
    3. Tablette, umfassend:

    a. Verbindung 1 Form I, Verbindung I Form II und/oder Verbindung 1 HCl-Salz Form A in einer Menge im Bereich von etwa 25 mg bis etwa 250 mg,

    b. einen Füllstoff,

    c. ein Verdünnungsmittel,

    d. ein Sprengmittel,

    e. ein Tensid,

    f. ein Schmiermittel und

    g. ein Bindemittel oder/und ein Gleitmittel,

    wobei die Tablette ein Bindemittel umfasst, bei dem es sich um Polyvinylpyrrolidon handelt,
    wobei Verbindung 1 Form I, Verbindung 1 Form II und/oder Verbindung 1 HCl-Salz Form A in einer Menge von mindestens 30 Gew.-% vorliegt.
     
    4. Tablette einer der folgenden Formulierungen:
    Unter Anwendung hoher Scherkräfte hergestellte GranulatmischungGew.-%
    Verbindung 1 Form I 60
    Mikrokristalline Cellulose 20
    Mannit 13
    Croscarmellose-Natrium 2
    Polyvinylpyrrolidon 4
    Natriumlaurylsulfat 1
    Wasser (während der Trocknung entfernt) 25-40% Feststoff
    TablettenzusammensetzungGew.-%
    (100 mg Dosis, 171 mg Bild) 
    Unter Anwendung hoher Scherkräfte hergestellte Granulatmischung 97,5
    Croscarmellose-Natrium 2,0
    Magnesiumstearat 0,5
    oder
    Unter Anwendung hoher Scherkräfte hergestellte GranulatmischungGew.-%
    Verbindung 1 Form I 60
    Mikrokristalline Cellulose 20
    Mannit 13
    Croscarmellose-Natrium 2
    Polyvinylpyrrolidon 4
    Natriumlaurylsulfat 1
    Wasser (während der Trocknung entfernt) 25-40% Feststoff
    TablettenzusammensetzungGew.-%
    (200 mg Dosis, 402 mg Bild) 
    Unter Anwendung hoher Scherkräfte hergestellte Granulatmischung 83
    Mikrokristalline Cellulose 14
    Croscarmellose-Natrium 2
    Magnesiumstearat 1,0
    oder
    Unter Anwendung hoher Scherkräfte hergestellte GranulatmischungGew.-%
    Verbindung 1 Form I 70
    Mikrokristalline Cellulose 12
    Mannit 11
    Croscarmellose-Natrium 2
    Polyvinylpyrrolidon 4
    Natriumlaurylsulfat 1
    Wasser (während der Trocknung entfernt) 25-40% Feststoff
    TablettenzusammensetzungGew.-%
    (100 mg Dosis, 147 mg Bild) 
    Unter Anwendung hoher Scherkräfte 97,5
    hergestellte Granulatmischung 2,0
    Croscarmellose-Natrium 0,5
    Magnesiumstearat  
    oder
    Unter Anwendung hoher Scherkräfte hergestellte GranulatmischungGew.-%
    Verbindung 1 Form I oder Form II 61
    Mikrokristalline Cellulose 20,3
    Mannit 13,2
    Croscarmellose-Natrium 2
    Polyvinylpyrrolidon 2,7
    Natriumlaurylsulfat 0,7
    TablettenzusammensetzungGew.-%
    (100 mg Dosis, 197 mg Bild) 
    Unter Anwendung hoher Scherkräfte hergestellte Granulatmischung 83
    Mikrokristalline Cellulose 14
    Croscarmellose-Natrium 2
    Magnesiumstearat 1

     
    5. Pharmazeutische Zusammensetzung, welche eine Mehrzahl von Granulatkörnchen umfasst, wobei die Zusammensetzung Folgendes umfasst:

    a. Verbindung 1 Form I, Verbindung 1 Form II und/oder Verbindung 1 HCl-Salz Form A in einer Menge von mindestens 60 Gew.-% der Zusammensetzung,

    b. einen Füllstoff in einer Menge im Bereich von etwa 20 Gew.-% bis etwa 50 Gew.-% der Zusammensetzung,

    c. ein Sprengmittel in einer Menge im Bereich von etwa 1 Gew.-% bis etwa 5 Gew.-% der Zusammensetzung,

    d. ein Tensid in einer Menge im Bereich von etwa 2 Gew.-% bis etwa 0,3 Gew.-% der Zusammensetzung,

    e. ein Verdünnungsmittel in einer Menge im Bereich von etwa 1 Gew.-% bis etwa 30 Gew.-% der Zusammensetzung,

    f. ein Schmiermittel in einer Menge im Bereich von etwa 0,3 Gew.-% bis etwa 5 Gew.-% der Zusammensetzung und

    g. ein Bindemittel in einer Menge von etwa 20 Gew.-% bis etwa 45 Gew.-% der Zusammensetzung oder/und ein Gleitmittel in einer Menge im Bereich von etwa 0,05 Gew.-% bis etwa 2 Gew.-% der Zusammensetzung.


     
    6. Pharmazeutische Zusammensetzung nach Anspruch 5, wobei die pharmazeutische Zusammensetzung weiterhin mindestens ein zusätzliches Therapeutikum umfasst.
     
    7. Pharmazeutische Zusammensetzung nach Anspruch 6, wobei es sich bei dem zusätzlichen Therapeutikum um einen CFTR-Modulator handelt.
     
    8. Pharmazeutische Zusammensetzung nach Anspruch 7, wobei es sich bei dem CFTR-Modulator um einen CFTR-Potentiator handelt.
     
    9. Einheitsdosisform, welche Folgendes umfasst:

    a. mindestens etwa 60 Gew.-% an Verbindung 1, Verbindung 1 Form I, Verbindung 1 Form II und/oder Verbindung 1 HCl-Salz Form A,

    b. etwa 20 Gew.-% mikrokristalline Cellulose, bezogen auf das Gewicht der Zusammensetzung,

    c. etwa 13 Gew.-% Mannit, bezogen das Gewicht der Zusammensetzung,

    d. etwa 2 Gew.-% Croscarmellose-Natrium, bezogen auf das Gewicht der Zusammensetzung,

    e. etwa 4 Gew.-% Polyvinylpyrrolidon, bezogen auf das Gewicht der Zusammensetzung,

    f. etwa 1 Gew.-% Natriumlaurylsulfat, bezogen auf das Gewicht der Zusammensetzung, und

    g. etwa 0,5 Gew.-% Magnesiumstearat, bezogen auf das Gewicht der Zusammensetzung,

    oder

    a. mindestens etwa 60 Gew.-% an Verbindung 1, Verbindung 1 Form I, Verbindung 1 Form II und/oder Verbindung 1 HCl-Salz Form A,

    b. etwa 34 Gew.-% mikrokristalline Cellulose, bezogen auf das Gewicht der Zusammensetzung,

    c. etwa 13 Gew.-% Mannit, bezogen das Gewicht der Zusammensetzung,

    d. etwa 4 Gew.-% Croscarmellose-Natrium, bezogen auf das Gewicht der Zusammensetzung,

    e. etwa 4 Gew.-% Polyvinylpyrrolidon, bezogen auf das Gewicht der Zusammensetzung,

    f. etwa 1 Gew.-% Natriumlaurylsulfat, bezogen auf das Gewicht der Zusammensetzung, und

    g. etwa 1,5 Gew.-% Magnesiumstearat, bezogen auf das Gewicht der Zusammensetzung,

    oder

    a. etwa 70 Gew.-% an Verbindung 1, Verbindung 1 Form I, Verbindung 1 Form II und/oder Verbindung 1 HCl-Salz Form A,

    b. etwa 12 Gew.-% mikrokristalline Cellulose, bezogen auf das Gewicht der Zusammensetzung,

    c. etwa 11 Gew.-% Mannit, bezogen das Gewicht der Zusammensetzung,

    d. etwa 2 Gew.-% Croscarmellose-Natrium, bezogen auf das Gewicht der Zusammensetzung,

    e. etwa 4 Gew.-% Polyvinylpyrrolidon, bezogen auf das Gewicht der Zusammensetzung,

    f. etwa 1 Gew.-% Natriumlaurylsulfat, bezogen auf das Gewicht der Zusammensetzung, und

    g. etwa 0,5 Gew.-% Magnesiumstearat, bezogen auf das Gewicht der Zusammensetzung.


     
    10. Tablette, pharmazeutische Zusammensetzung oder Einheitsdosisform nach einem der Ansprüche 1 bis 9, wobei Verbindung 1 Form I, Verbindung 1 Form II und/oder Verbindung 1 HCl-Salz Form A eine Teilchengröße von 0,1 Mikron bis 50 Mikron, 0,1 Mikron bis 20 Mikron, 0,1 Mikron bis 10 Mikron oder 1,0 Mikron bis 5 Mikron aufweist.
     
    11. Tablette, pharmazeutische Zusammensetzung oder Einheitsdosisform nach einem der Ansprüche 1 bis 10, wobei Verbindung 1 Form I, Verbindung 1 Form II und/oder Verbindung 1 HCl-Salz Form A eine Partikelgröße D50 von 2,0 Mikron aufweist.
     
    12. Verfahren zur Herstellung einer pharmazeutischen Zusammensetzung, welches die folgenden Schritte umfasst:

    Kombinieren einer therapeutisch wirksamen Menge an Verbindung 1 Form I, Verbindung 1 Form II und/oder Verbindung 1 HCl-Salz Form A und mindestens eines Granulierungsexzipienten ausgewählt aus der Gruppe bestehend aus: einem Bindemittel, einem Gleitmittel, einem Tensid, einem Schmiermittel, einem Sprengmittel, einem Füllstoff, einem Verdünnungsmittel und Kombinationen davon unter Bildung einer Mischung, Mischen und Feuchtgranulieren der Mischung und Verpressen der Mischung unter Bildung der pharmazeutischen Zusammensetzung aus einer Mischung von gepulverten und flüssigen Materialien,

    wobei Verbindung 1 Form I, Verbindung 1 Form II und/oder Verbindung 1 HCl-Salz Form A in der pharmazeutischen Zusammensetzung in einer Menge von mindestens 30 Gew.-% vorliegt.


     
    13. Tablette, pharmazeutische Zusammensetzung oder Einheitsdosisform nach einem der Ansprüche 1 bis 11 zur Verwendung in einem Verfahren zur Behandlung von zystischer Fibrose.
     
    14. Tablette, pharmazeutische Zusammensetzung oder Einheitsdosisform zur Verwendung nach Anspruch 13, wobei der Patient einen Cystic Fibrosis Transmembrane Receptor (CFTR) mit einer ΔF508-Mutation, einer R117H-Mutation oder einer G551D-Mutation aufweist.
     
    15. Tablette, pharmazeutische Zusammensetzung oder Einheitsdosisform zur Verwendung nach Anspruch 13, wobei die Anwendung die Verabreichung eines zusätzlichen therapeutischen Mittels umfasst.
     
    16. Kit, umfassend eine Tablette, eine pharmazeutische Zusammensetzung oder eine Einheitsdosisform nach einem der Ansprüche 1 bis 11 und Anweisungen zu deren Verwendung.
     
    17. Kit nach Anspruch 16, wobei es sich bei Verbindung 1 um Verbindung 1 Form I handelt und diese in der Tablette, der pharmazeutischen Zusammensetzung bzw. der Einheitsdosisform in einer Menge im Bereich von 25 mg bis etwa 200 mg vorliegt.
     
    18. Pharmazeutische Zusammensetzung nach Anspruch 6 oder Tablette, pharmazeutische Zusammensetzung oder Einheitsdosisform zur Verwendung nach Anspruch 15, wobei es sich bei dem zusätzlichen Mittel um N-(5-Hydroxy-2,4-di-tert.-butylphenyl)-4-oxo-1H-chinolin-3-carbonsäureamid handelt.
     
    19. Tablette zur Verwendung nach einem der Ansprüche 13 bis 15, oder Anspruch 18, wobei das Verfahren die mindestens einmal tägliche oder zweimal tägliche orale Verabreichung einer Tablette, umfassend:

    a. etwa 25 bis 200 mg an Verbindung 1 Form I, Verbindung 1 Form II und/oder Verbindung 1 HCl-Salz Form A,

    b. einen Füllstoff,

    c. ein Verdünnungsmittel,

    d. ein Sprengmittel,

    e. ein Tensid,

    f. ein Bindemittel oder/und ein Gleitmittel und

    g. ein Schmiermittel,

    an einen Patienten umfasst.
     
    20. Tablette zur Verwendung nach Anspruch 19, wobei die Tablette etwa 25 mg, 75 mg, 100 mg, 150 mg oder 200 mg an Verbindung 1 Form I, Verbindung 1 Form II und/oder Verbindung 1 HCl-Salz Form A umfasst.
     
    21. Tablette zur Verwendung nach Anspruch 20, wobei das Verfahren die einmal alle 12 Stunden erfolgende orale Verabreichung einer Tablette, umfassend:

    a. etwa 25 bis 200 mg an Verbindung 1 Form I, Verbindung 1 Form II und/oder Verbindung 1 HCl-Salz Form A,

    b. einen Füllstoff,

    c. ein Verdünnungsmittel,

    d. ein Sprengmittel,

    e. ein Tensid,

    f. ein Bindemittel oder/und ein Gleitmittel und

    g. ein Schmiermittel,

    an einen Patienten umfasst.
     
    22. Tablette zur Verwendung nach Anspruch 21, wobei die Tablette etwa 25 mg, 75 mg, 100 mg, 150 mg oder 200 mg an Verbindung 1 Form I, Verbindung 1 Form II und/oder Verbindung 1 HCl-Salz Form A umfasst.
     


    Revendications

    1. Comprimé pour administration orale, comprenant :

    a. de l'acide 3-(6-(1-(2,2-difluorobenzo[d][1,3]-dioxol-5-yl)-cyclopropanecarboxamido)-3-méthyl-pyiridin-2-yl)benzoïque (composé 1) forme I, du composé 1 forme II et/ou du composé 1 sel de HCl forme A, le composé 1 forme I, le composé 1 forme II et/ou le composé 1 sel de HCl forme A étant présent (s) en une quantité d'au moins 60 % en poids par rapport au poids de la composition ;

    b. un excipient de charge ;

    c. un diluant ;

    d. un désintégrant ;

    e. un tensioactif ;

    f. un lubrifiant ; et

    g. au moins un parmi un liant et un régulateur d'écoulement.


     
    2. Comprimé selon la revendication 1, dans lequel le composé 1 forme I, le composé 1 forme II et/ou le composé 1 sel de HCl forme A est/sont présent(s) en une quantité valant d'environ 25 mg à environ 250 mg.
     
    3. Comprimé comprenant :

    a. le composé 1 forme I, le composé 1 forme II et/ou le composé 1 sel de HCl forme A en une quantité valant d'environ 25 mg à environ 250 mg ;

    b. un excipient de charge ;

    c. un diluant ;

    d. un désintégrant ;

    e. un tensioactif ;

    f. un lubrifiant ; et

    g. au moins un parmi un liant et un régulateur d'écoulement ;

    dans lequel le comprimé comprend un liant qui est la polyvinylpyrrolidone ;
    dans lequel le composé 1 forme I, le composé 1 forme II et/ou le composé 1 sel de HCl forme A est/sont présent(s) en une quantité d'au moins 30% en poids.
     
    4. Comprimé de l'une des formulations suivantes :
    Mélange de granules à haut cisaillement(% p/p)
    Composé 1 forme I 60
    Cellulose microcristalline 20
    Mannitol 13
    Croscarmellose sodique 2
    Polyvinylpyrrolidone 4
    Laurylsulfate de sodium 1
    Eau (éliminée au séchage) 25-40 % par rapport aux matières solides
    Composition de comprimé (dose 100 mg, image 171 mg)(% p/p)
    Mélange de granules à haut cisaillement 97,5
    Croscarmellose sodique 2,0
    Stéarate de magnésium 0,5
    ou
    Mélange de granules à haut cisaillement(% p/p)
    Composé 1 forme I 60
    Cellulose microcristalline 20
    Mannitol 13
    Croscarmellose sodique 2
    Polyvinylpyrrolidone 4
    Laurylsulfate de sodium 1
    Eau (éliminée au séchage) 25-40 % par rapport aux matières solides
    Composition de comprimé (dose 200 mg, image 402 mg)(% p/p)
    Mélange de granules à haut cisaillement 83
    Cellulose microcristalline 14
    Croscarmellose sodique 2
    Stéarate de magnésium 1,0
    ou
    Mélange de granules à haut cisaillement(% p/p)
    Composé 1 forme I 70
    Cellulose microcristalline 12
    Mannitol 11
    Croscarmellose sodique 2
    Polyvinylpyrrolidone 4
    Laurylsulfate de sodium 1
    Eau (éliminée au séchage) 25-40 % par rapport aux matières solides
    Composition de comprimé (dose 100 mg, image 147 mg)(% p/p)
    Mélange de granules à haut cisaillement 97,5
    Croscarmellose sodique 2,0
    Stéarate de magnésium 0,5
    ou
    Mélange de granules à haut cisaillement(% p/p)
    Composé 1 forme I ou forme II 61
    Cellulose microcristalline 20,3
    Mannitol 13,2
    Croscarmellose sodique 2
    Polyvinylpyrrolidone 2,7
    Laurylsulfate de sodium 0,7
    Composition de comprimé (dose 100 mg, image 197 mg)(% p/p)
    Mélange de granules à haut cisaillement 83
    Cellulose microcristalline 14
    Croscarmellose sodique 2
    Stéarate de magnésium 1

     
    5. Composition pharmaceutique comprenant une pluralité de granules, la composition comprenant :

    a. le composé 1 forme I, le composé 1 forme II et/ou le composé 1 sel de HCl forme A en une quantité d'au moins 60 % en poids par rapport au poids de la composition ;

    b. un excipient de charge en une quantité valant d'environ 20 % en poids à environ 50 % en poids par rapport au poids de la composition ;

    c. un désintégrant en une quantité valant d'environ 1 % en poids à environ 5 % en poids par rapport au poids de la composition ;

    d. un tensioactif en une quantité valant d'environ 2 % en poids à environ 0,3 % en poids par rapport au poids de la composition ;

    e. un diluant en une quantité valant d'environ 1 % en poids à environ 30 % en poids par rapport au poids de la composition ;

    f. un lubrifiant en une quantité valant d'environ 0,3 % en poids à environ 5 % en poids par rapport au poids de la composition ; et

    g. au moins l'un parmi un liant en une quantité valant d'environ 20 % en poids à environ 45 % en poids de la composition ou un régulateur d'écoulement en une quantité valant d'environ 0,05 % en poids à environ 2 % en poids de la composition.


     
    6. Composition pharmaceutique selon la revendication 5, la composition pharmaceutique comprenant en outre au moins un agent thérapeutique supplémentaire.
     
    7. Composition pharmaceutique selon la revendication 6, dans laquelle l'agent thérapeutique supplémentaire est un modulateur de CFTR.
     
    8. Composition pharmaceutique selon la revendication 7, dans laquelle le modulateur de CFTR est un potentialisateur de CFTR.
     
    9. Forme galénique unitaire qui comprend :

    a. au moins environ 60 % en poids de composé 1, composé 1 forme I, composé 1 forme II et/ou composé 1 sel de HCl forme A ;

    b. environ 20 % en poids de cellulose microcristalline par rapport au poids de la composition ;

    c. environ 13 % en poids de mannitol par rapport au poids de la composition ;

    d. environ 2 % en poids de sodium de croscarmellose par rapport au poids de la composition ;

    e. environ 4 % en poids de polyvinylpyrrolidone par rapport au poids de la composition ;

    f. environ 1 % en poids de laurylsulfate de sodium par rapport au poids de la composition ; et

    g. environ 0,5 % en poids de stéarate de magnésium par rapport au poids de la composition ;

    ou

    a. au moins environ 60 % en poids de composé 1, composé 1 forme I, composé 1 forme II et/ou composé 1 sel de HCl forme A ;

    b. environ 34 % en poids de cellulose microcristalline par rapport au poids de la composition ;

    c. environ 13 % en poids de mannitol par rapport au poids de la composition ;

    d. environ 4 % en poids de sodium de croscarmellose par rapport au poids de la composition ;

    e. environ 4 % en poids de polyvinylpyrrolidone par rapport au poids de la composition ;

    f. environ 1 % en poids de laurylsulfate de sodium par rapport au poids de la composition ; et

    g. environ 1,5 % en poids de stéarate de magnésium par rapport au poids de la composition ;

    ou

    a. environ 70 % en poids de composé 1, composé 1 forme I, composé 1 forme II et/ou composé 1 sel de HCl forme A ;

    b. environ 12 % en poids de cellulose microcristalline par rapport au poids de la composition ;

    c. environ 11 % en poids de mannitol par rapport au poids de la composition ;

    d. environ 2 % en poids de sodium de croscarmellose par rapport au poids de la composition ;

    e. environ 4 % en poids de polyvinylpyrrolidone par rapport au poids de la composition ;

    f. environ 1 % en poids de laurylsulfate de sodium par rapport au poids de la composition ; et

    g. environ 0,5 % en poids de stéarate de magnésium par rapport au poids de la composition.


     
    10. Comprimé, composition pharmaceutique ou forme galénique unitaire de l'une quelconque des revendications 1 à 9, dans lequel/laquelle le composé 1 forme I, le composé 1 forme II et/ou le composé 1 sel de HCl forme A a/ont une taille de particule de 0,1 micromètre à 50 micromètres, 0,1 micromètre à 20 micromètres, 0,1 micromètre à 10 micromètres ou 1,0 micromètre à 5 micromètres.
     
    11. Comprimé, composition pharmaceutique ou forme galénique unitaire de l'une quelconque des revendications 1 à 10, dans lequel/laquelle le composé 1 forme I, le composé 1 forme II et/ou le composé 1 sel de HCl forme A a/ont une taille de particule D50 de 2,0 micromètres.
     
    12. Procédé de production d'une composition pharmaceutique, comprenant les étapes de : réunion d'une quantité thérapeutiquement efficace de composé 1 forme I, composé 1 forme II et/ou composé 1 sel de HCl forme A et d'au moins un excipient de granulation choisi dans le groupe constitué par un liant ; un régulateur d'écoulement ; un tensioactif ; un lubrifiant ; un désintégrant ; un excipient de charge, un diluant et des associations de ceux-ci, pour l'obtention d'un mélange ; le mélange et la granulation par voie humide du mélange ; et le compactage du mélange pour former la composition pharmaceutique à partir d'un mélange de matières en poudre et liquides ; dans lequel le composé 1 forme I, le composé 1 forme II et/ou le composé 1 sel de HCl forme A est/sont présent (s) en une quantité d'au moins 30% en poids de la composition pharmaceutique.
     
    13. Comprimé, composition pharmaceutique ou forme galénique unitaire de l'une quelconque des revendications 1 à 11 pour utilisation dans un procédé de traitement de la fibrose kystique.
     
    14. Comprimé, composition pharmaceutique ou forme galénique unitaire pour utilisation selon la revendication 13, ledit patient ayant un récepteur transmembranaire de fibrose kystique (CFTR) avec une mutation ΔF508, une mutation R117H ou une mutation G551D.
     
    15. Comprimé, composition pharmaceutique ou forme galénique unitaire pour utilisation selon la revendication 13, l'utilisation comprenant l'administration d'un agent thérapeutique supplémentaire.
     
    16. Nécessaire comprenant un comprimé, une composition pharmaceutique ou une forme galénique unitaire de l'une quelconque des revendications 1 à 11 et des directives pour son utilisation.
     
    17. Nécessaire selon la revendication 16, dans lequel le composé 1 est le composé 1 forme I et est présent dans le comprimé, la composition pharmaceutique ou la forme galénique unitaire en une quantité valant de 25 mg à environ 200 mg.
     
    18. Composition pharmaceutique de la revendication 6 ou comprimé, composition pharmaceutique ou forme galénique unitaire pour utilisation selon la revendication 15, où l'agent supplémentaire est le N-(5-hydroxy-2,4-di-tert-butyl-phényl)-4-oxo-1H-quinoléine-3-carboxamide.
     
    19. Comprimé pour utilisation selon l'une quelconque des revendications 13 à 15, ou revendication 18, le procédé comprenant l'administration par voie orale à un patient au moins une fois par jour ou deux fois par jour d'un comprimé comprenant :

    a. environ 25 à 200 mg de composé 1 forme I, composé 1 forme II et/ou composé 1 sel de HCl forme A ;

    b. un excipient de charge ;

    c. un diluant ;

    d. un désintégrant ;

    e. un tensioactif ;

    f. au moins un parmi un liant et un régulateur d'écoulement ; et

    g. un lubrifiant.


     
    20. Comprimé pour utilisation selon la revendication 19, dans lequel le comprimé comprend environ 25 mg, 75 mg, 100 mg, 150 mg ou 200 mg de composé 1 forme I, composé 1 forme II et/ou composé 1 sel de HCl forme A.
     
    21. Comprimé pour utilisation selon la revendication 20, le procédé comprenant l'administration par voie orale à un patient une fois toutes les 12 heures d'un comprimé comprenant :

    a. environ 25 à 200 mg de composé 1 forme I, composé 1 forme II et/ou composé 1 sel de HCl forme A ;

    b. un excipient de charge ;

    c. un diluant ;

    d. un désintégrant ;

    e. un tensioactif ;

    f. au moins un parmi un liant et un régulateur d'écoulement ; et

    g. un lubrifiant.


     
    22. Comprimé pour utilisation selon la revendication 21, dans lequel le comprimé comprend environ 25 mg, 75 mg, 100 mg, 150 mg ou 200 mg de composé 1 forme I, composé 1 forme II et/ou composé 1 sel de HCl forme A.
     




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    Cited references

    REFERENCES CITED IN THE DESCRIPTION



    This list of references cited by the applicant is for the reader's convenience only. It does not form part of the European patent document. Even though great care has been taken in compiling the references, errors or omissions cannot be excluded and the EPO disclaims all liability in this regard.

    Patent documents cited in the description




    Non-patent literature cited in the description