FORMULATIONS OF 3-(6-(1-(2,2-DIFLUOROBENZO[D][1,3]DIOXOL-5-YL) CYCLOPROPANECARBOXAMIDO)-3-METHYLPYRIDIN-2-YL)BENZOIC ACID
A pharmaceutical composition comprising Compound 1, (3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid), and at least one excipient selected from: a filler, a disintegrant, a surfactant, a binder, and a lubricant, the composition being suitable for oral administration to a patient in need thereof to treat a CFTR mediated disease such as Cystic Fibrosis. Processes of preparing pharmaceutical compositions comprising Compound 1 are also disclosed.
1 . A tablet for oral administration comprising:
a. Compound 1, 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 lubricant; and
f. at least one of a binder or a glidant.
2 . The tablet of claim 1 , wherein Compound 1, 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 500 mg.
3 . The tablet of claim 1 , wherein the amount of Compound 1, Compound 1 Form I, Compound 1 Form II, and/or Compound 1 HCl Salt Form A in the tablet ranges from about 15 wt % to about 75 wt % by weight of the tablet.
4 . The tablet of claim 1 , wherein the amount of Compound 1, Compound 1 Form I, Compound 1 Form II, and/or Compound 1 HCl Salt Form A in the tablet ranges from about 40 wt % to about 70 wt % by weight of the tablet.
5 . The tablet of claim 1 having the following formulation:
Roller Compaction Granule Blend
(% w/w)
Compound 1
20-40
Microcrystalline cellulose
30-50
Mannitol
10-30
Croscarmellose Sodium
1-5
Sodium Lauryl Sulfate
0.1-2
Colloidal Silica
0.1-1
Magnesium Stearate
1-3
Tablet Composition
(% w/w)
Roller Compaction Granule Blend
99-99.9
Magnesium Stearate
0.1-1
6 . The tablet of claim 1 having the following formulation:
High Shear Granule Blend
(% w/w)
Compound 1
60-70
Microcrystalline cellulose
5-15
Croscarmellose Sodium
1-5
Sodium Lauryl Sulfate
0.1-2
Polyvinylpyrrolidone
1-5
Tablet Composition
(% w/w)
High Shear Granule Blend
75-89
Microcrystalline cellulose
10-15
Croscarmellose Sodium
1-5
Magnesium Stearate
0.1-5
7 . The tablet of claim 1 having the following formulation:
High Shear Granule Blend
(% w/w)
Compound 1 Form I
60-70
Microcrystalline cellulose
5-15
Croscarmellose Sodium
1-5
Polyvinylpyrrolidone
1-5
Sodium Lauryl Sulfate
0.1-2
Tablet Composition
(% w/w)
High Shear Granule Blend
78-89
Microcrystalline cellulose
10-15
Croscarmellose Sodium
1-5
Magnesium Stearate
0.1-2
Film Coated Tablet
(% w/w)
Core Tablet Composition
95-99
Film Coat
1-5
Wax
Trace
8 . The tablet of claim 1 having the following formulation:
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
(% w/w)
Roller Compaction Granule Blend
99.5
Magnesium Stearate
0.5
9 . The tablet of claim 1 having the following formulation:
High Shear Granule Blend
(% w/w)
Compound 1 Form I
40-80
Microcrystalline cellulose
20-40
Mannitol
10-15
Croscarmellose Sodium
1-5
Polyvinylpyrrolidone
1-10
Sodium Lauryl Sulfate
0.1-2
Tablet Composition
(% w/w)
High Shear Granule Blend
95-99
Croscarmellose Sodium
1-4
Magnesium Stearate
0.1-1
10 . The tablet of claim 1 having 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
Tablet Composition
(% w/w)
High Shear Granule Blend
97.5
Croscarmellose Sodium
2.0
Magnesium Stearate
0.5
11 . The tablet of claim 1 having the following formulation:
High Shear Granule Blend
(% w/w)
Compound 1Form I
60
Microcrystalline cellulose
20
Mannitol
13
Croscarmellose Sodium
2
Polyvinylpyrrolidone
4
Sodium Lauryl Sulfate
1
Tablet Composition
(% w/w)
High Shear Granule Blend
97.5
Croscarmellose Sodium
2.0
Magnesium Stearate
0.5
12 . The tablet of claim 1 having 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
Tablet Composition
(% w/w)
High Shear Granule Blend
83
Microcrystalline cellulose
14
Croscarmellose Sodium
2
Magnesium Stearate
1
13 . The tablet of claim 1 having the following formulation:
Twin Screw Granule Blend
(% w/w)
Compound 1 Form I
60
Microcrystalline cellulose
20
Mannitol
13
Croscarmellose Sodium
2
Polyvinylpyrrolidone
4
Sodium Lauryl Sulfate
1
Tablet Composition
(% w/w)
Twin Screw Granule Blend
83
Microcrystalline cellulose
14
Croscarmellose Sodium
2
Magnesium Stearate
1
14 . The tablet of claim 1 having the following formulation:
Twin Screw Wet Granule Blend
(% w/w)
Compound 1 Form I
80.0
Microcrystalline cellulose
13.6
Croscarmellose Sodium
2.5
Polyvinylpyrrolidone
3.1
Sodium Lauryl Sulfate
0.7
Tablet Composition
(% w/w)
Twin Screw Granule Blend
83
Microcrystalline cellulose
12
Croscarmellose Sodium
4
Magnesium Stearate
1
15 . The tablet of claim 1 having the following formulation:
Twin Screw Granule Blend
(% w/w)
Compound 1 Form I
80.0
Microcrystalline cellulose
13.6
Croscarmellose Sodium
2.5
Polyvinylpyrrolidone
3.1
Sodium Lauryl Sulfate
0.7
Tablet Composition
(% w/w)
Twin Screw Granule Blend
83
Microcrystalline cellulose
12
Croscarmellose Sodium
4
Magnesium Stearate
1
Film Coated Tablet
(% w/w)
Core Tablet Composition
97
Film Coat
3
Wax
Trace
16 . The tablet of claim 1 having the following formulation:
High Shear Granule Blend
mg
Compound 1 Form I
200
Microcrystalline cellulose
66
Mannitol
43
Croscarmellose Sodium
7
Polyvinylpyrrolidone
13
Sodium Lauryl Sulfate
3
Core Tablet Composition
(200 mg dose)
mg
High Shear Granule Blend
332
Microcrystalline cellulose
56
Croscarmellose Sodium
8
Magnesium Stearate
4
Film Coated Tablet
(200 mg dose)
mg
Core Tablet Composition
400
Film Coat
12
Wax
trace
17 . The tablet of claim 1 having the following formulation:
Twin Screw Granule Blend
mg
Compound 1 Form I
200
Microcrystalline cellulose
66
Mannitol
43
Croscarmellose Sodium
7
Polyvinylpyrrolidone
13
Sodium Lauryl Sulfate
3
Core Tablet Composition
(200 mg dose)
mg
Twin Screw Granule Blend
332
Microcrystalline cellulose
56
Croscarmellose Sodium
8
Magnesium Stearate
4
18 . The tablet of claim 1 having the following formulation:
High Shear Granule Blend
mg
Compound 1 Form I
200
Microcrystalline cellulose
67
Mannitol
45
Croscarmellose Sodium
7
Polyvinylpyrrolidone
10.4
Sodium Lauryl Sulfate
2.6
Core Tablet Composition
(200 mg dose)
mg
High Shear Granule Blend
332
Microcrystalline cellulose
56
Croscarmellose Sodium
8
Magnesium Stearate
4
Film Coated Tablet
(200 mg dose)
mg
Core Tablet Composition
400
Film Coat
12
Wax
trace
19 . The tablet of claim 1 having the following formulation:
High Shear Granule Blend
mg
Compound 1 Form I
300
Microcrystalline cellulose
99
Mannitol
64.5
Croscarmellose Sodium
10.5
Polyvinylpyrrolidone
19.5
Sodium Lauryl Sulfate
4.5
Core Tablet Compsoition
(300 mg dose)
mg
High Shear Granule Blend
498
Microcrystalline cellulose
84
Croscarmellose Sodium
12
Magnesium Stearate
6
Film Coated Tablet
(300 mg dose)
mg
Core Tablet Composition
600
Film Coat
18
Wax
trace
20 . The tablet of claim 1 having the following formulation:
High Shear Granule Blend
mg
Compound 1 Form I
300
Microcrystalline cellulose
100.5
Mannitol
67.5
Croscarmellose Sodium
10.5
Polyvinylpyrrolidone
15.6
Sodium Lauryl Sulfate
3.9
Core Tablet Composition
(300 mg dose)
mg
High Shear Granule Blend
498
Microcrystalline cellulose
84
Croscarmellose Sodium
12
Magnesium Stearate
6
Film Coated Tablet
(300 mg dose)
mg
Core Tablet Composition
600
Film Coat
18
Wax
trace
21 . The tablet of claim 1 having 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
Tablet Composition
(% w/w)
High Shear Granule Blend
97.5
Croscarmellose Sodium
2.0
Magnesium Stearate
0.5
22 . The tablet of claim 1 having the following formulation:
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 Compositon
(% w/w)
High Shear Granule Blend
83
Microcrystalline cellulose
14
Croscarmellose Sodium
2
Magnesium Stearate
1
23 . The tablet of claim 1 having the following formulation:
High Shear Granule Blend
mg
Compound 1 Form I or Form II
100
Microcrystalline cellulose
33.3
Mannitol
21.7
Croscarmellose Sodium
3.3
Polyvinylpyrrolidone
4.4
Sodium Lauryl Sulfate
1.1
Core Tablet Composition
(100 mg dose)
mg
High Shear Granule Blend
163.9
Microcrystalline cellulose
27.6
Croscarmellose Sodium
3.9
Magnesium Stearate
2.0
24 . The tablet of claim 1 having the following formulation:
Twin Screw Granule Blend
mg
Compound 1 Form I
200
Microcrystalline cellulose
34.0
Croscarmellose Sodium
6.3
Polyvinylpyrrolidone
7.8
Sodium Lauryl Sulfate
1.8
Core Tablet Composition
(200 mg dose)
mg
Twin Screw Granule Blend
249.9
Microcrystalline cellulose
36.1
Croscarmellose Sodium
12.0
Magnesium Stearate
3.0
25 . The tablet of claim 1 having the following formulation:
Twin Screw Granule Blend
mg
Compound 1 Form I
400
Microcrystalline cellulose
68.0
Croscarmellose Sodium
12.6
Polyvinylpyrrolidone
15.6
Sodium Lauryl Sulfate
3.6
Core Tablet Composition
(400 mg dose)
mg
Twin Screw Granule Blend
499.8
Microcrystalline cellulose
72.2
Croscarmellose Sodium
24.0
Magnesium Stearate
6.0
26 . The tablet of claim 1 having the following formulation:
Twin Screw Granule Blend
mg
Compound 1 Form I
200
Microcrystalline cellulose
34.0
Croscarmellose Sodium
6.3
Polyvinylpyrrolidone
7.8
Sodium Lauryl Sulfate
1.8
Core Tablet Composition
(200 mg dose)
mg
Twin Screw Granule Blend
249.9
Microcrystalline cellulose
36.1
Croscarmellose Sodium
12.0
Magnesium Stearate
3.0
Film Coated Tablet
(200 mg dose, 310 mg total)
mg
Core Tablet Composition
301
Film Coat
9.0
Wax
trace
27 . The tablet of claim 1 having the following formulation:
Twin Screw Granule Blend
mg
Compound 1 Form I
400
Microcrystalline cellulose
68.0
Croscarmellose Sodium
12.6
Polyvinylpyrrolidone
15.6
Sodium Lauryl Sulfate
3.6
Core Tablet Composition
(400 mg dose)
mg
Twin Screw Granule Blend
499.8
Microcrystalline cellulose
72.2
Croscarmellose Sodium
24.0
Magnesium Stearate
6.0
Film Coated Tablet
(400 mg dose, 620 mg total)
mg
Core Tablet Composition
602
Film Coat
18.0
Wax
trace
28 . The tablet of claim 1 , wherein the tablet further comprises at least one additional therapeutic agent.
29 . The tablet of claim 28 , wherein the additional therapeutic agent is a CFTR modulator.
30 . The tablet of claim 29 , wherein the CFTR modulator is a CFTR potentiator.
31 . The tablet of claim 29 , wherein the CFTR modulator is N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide.
32 . The tablet of claim 1 , wherein Compound 1 is in Form I 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.
33 . The tablet of claim 32 , wherein Compound 1 Form I is characterized by one or more peaks at 15.4, 16.3, and 14.5 degrees.
34 . The tablet of claim 1 , wherein Compound 1 is in Form I characterized by a diffraction pattern substantially similar to that of FIG. 1 .
35 . The tablet of claim 1 , wherein Compound 1 is in Form I characterized by a diffraction pattern substantially similar to that of FIG. 2 .
36 . A method of treating or lessening the severity of a disease in a patient comprising administering to the patient the tablet of claim 1 , wherein the disease is selected from cystic fibrosis, asthma, smoke induced COPD, chronic bronchitis, rhinosinusitis, constipation, pancreatitis, pancreatic insufficiency, male infertility, mild pulmonary disease, idiopathic pancreatitis, allergic bronchopulmonary aspergillosis (ABPA), liver disease, hereditary emphysema, hereditary hemochromatosis, coagulation-fibrinolysis deficiencies, protein C deficiency, Type 1 hereditary angioedema, lipid processing deficiencies, familial hypercholesterolemia, Type 1 chylomicronemia, abetalipoproteinemia, lysosomal storage diseases, 1-cell disease/pseudo-Hurler, mucopolysaccharidoses, Sandhof/Tay-Sachs, Crigler-Najjar type II, polyendocrinopathy/hyperinsulemia, Diabetes mellitus, Laron dwarfism, myleoperoxidase deficiency, primary hypoparathyroidism, melanoma, glycanosis CDG type 1, congenital hyperthyroidism, osteogenesis imperfecta, hereditary hypofibrinogenemia, ACT deficiency, Diabetes insipidus (DI), neurophyseal DI, neprogenic DI, Charcot-Marie Tooth syndrome, Perlizaeus-Merzbacher disease, neurodegenerative diseases, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, progressive supranuclear plasy, Pick's disease, several polyglutamine neurological disorders, Huntington's, spinocerebullar ataxia type I, spinal and bulbar muscular atrophy, dentatorubal pallidoluysian, myotonic dystrophy, spongiform encephalopathies, hereditary Creutzfeldt-Jakob disease, Fabry disease, Straussler-Scheinker syndrome, COPD, dry-eye disease, Sjogren's disease, Osteoporosis, Osteopenia, Gorham's Syndrome, chloride channelopathies, myotonia congenita, Bartter's syndrome type III, Dent's disease, hyperekplexia, epilepsy, hyperekplexia, lysosomal storage disease, Angelman syndrome, Primary Ciliary Dyskinesia (PCD), inherited disorders of the structure and/or function of cilia, PCD with situs inversus, PCD without situs inversus, or ciliary aplasia.
37 . The method of claim 36 , wherein the disease is cystic fibrosis, emphysema, COPD, or dry-eye disease.
38 . The method of claim 36 , wherein the disease is cystic fibrosis wherein the patient has a F508del CFTR mutation.
39 . The method of claim 38 , wherein the patient is homozygous for F508del.
40 . The method of claim 38 , wherein the patient is heterozygous for F508del.
41 . The method of claim 36 , wherein the method comprises administering an additional therapeutic agent.
42 . The method of claim 41 , wherein the therapeutic agent is selected from a mucolytic agent, bronchodilator, an anti-biotic, an anti-infective agent, an anti-inflammatory agent, a CFTR potentiator, or a nutritional agent.
43 . The method of claim 41 , wherein the additional therapeutic agent is N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide.
44 . A kit comprising the tablet of claim 1 , and a separate therapeutic agent or pharmaceutical composition thereof.
45 . The kit of claim 44 , wherein the Compound 1 is in Form I.
46 . The kit of claim 44 , wherein the therapeutic agent is a cystic fibrosis corrector other than Compound 1.
47 . The kit of claim 44 , wherein the therapeutic agent is a cystic fibrosis potentiator.
48 . The kit of claim 44 , wherein the therapeutic agent is N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide.
49 . The kit of claim 44 , wherein the tablet of claim 1 and the therapeutic agent are in separate containers.
50 . The kit of claim 49 , wherein the separate containers are bottles.
51 . The kit of claim 49 , wherein the separate containers are vials.
52 . The kit of claim 49 , wherein the separate containers are blister packs.
53 . A continuous process for preparing a tablet comprising Compound 1 comprising the steps of:
a) mixing Compound 1, a filler, and a disintegrant in a blender to form a blend;
b) preparing a granulation solution with water, a binder, and a surfactant;
c) feeding the blend from step a) into a continuous twin screw granulator while adding the granulation solution from step b) to produce granules;
d) drying the granules from step c) and milling them;
e) blending the milled granules from step d) with a filler, disintegrant, and lubricant to form a blend;
f) compressing the blend from step d) into a tablet; and
g) coating the tablet from step e).
54 . The process of claim 53 , wherein Compound 1 is in Form I.