US2014163068A1PendingUtilityA1
Pharmaceutical Compositions for the Treatment of CFTR Mediated Diseases
Est. expiryNov 2, 2032(~6.3 yrs left)· nominal 20-yr term from priority
A61P 43/00A61P 3/12A61P 1/16A61P 1/00A61P 11/00A61P 1/18A61K 31/443A61K 9/20A61K 9/2027A61K 31/47A61K 9/14A61K 9/2013A61K 9/2095A61K 9/2054A61K 9/2077A61K 9/0053A61K 9/10A61K 45/06A61K 9/1605A61K 9/2004
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Claims
Abstract
Pharmaceutical compositions comprising 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid (Compound 1) in Form I and a solid dispersion comprising substantially amorphous N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide (Compound 2), methods of treating, lessening the severity of, or symptomatically treating CFTR mediated diseases, such as cystic fibrosis, methods of manufacturing, methods of administering, and kits thereof are disclosed.
Claims
exact text as granted — not AI-modified1 . A pharmaceutical composition comprising a fixed dosage amount of 3-(6-(1-(2,2-difluorobenzo[d][1,3] dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid (Compound 1) Form I and a solid dispersion comprising substantially amorphous N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide (Compound 2).
2 . The pharmaceutical composition of claim 1 further comprising:
a. a filler;
b. a disintegrant;
c. a surfactant; and
d. a binder;
referred to as PC-I.
3 . The pharmaceutical composition of claim 1 , comprising 30 to 55 percent by weight Compound 1 Form I, and 10 to 45 percent by weight solid dispersion comprising substantially amorphous Compound 2.
4 . The pharmaceutical composition of claim 2 having the following formulation:
% by wgt.
Compound 1 Form I
35-50
Solid dispersion comprising
25-40
substantially amorphous
Compound 2
Microcrystalline cellulose
10-20
Croscarmellose sodium
1-3
Sodium lauryl sulfate
0.5-2
Polyvinylpyrrolidone
0-5
referred to as PC-II.
5 . A pharmaceutical composition comprising:
a. Compound 1 Form I; b. a solid dispersion comprising substantially amorphous Compound 2; c. a filler; d. a disintegrant; e. a surfactant; f. a binder; and g. a lubricant;
referred to as PC-III.
6 . The pharmaceutical composition of claim 5 , comprising about 100 to 250 mg of Compound 1 Form I, and about 80 to 150 mg of substantially amorphous Compound 2.
7 . The pharmaceutical composition of claim 5 , comprising about 200 mg of Compound 1 Form I, and about 125 mg of substantially amorphous Compound 2.
8 . The pharmaceutical composition of claim 5 , comprising about 200 mg of Compound 1 Form I, and about 83 mg of substantially amorphous Compound 2.
9 . The pharmaceutical composition of claim 5 , comprising about 150 mg of Compound 1 Form I, and about 125 mg of substantially amorphous Compound 2.
10 . The pharmaceutical composition of claim 5 , comprising 25 to 50 percent by weight Compound 1 Form I, and 15 to 35 percent by weight a solid dispersion comprising substantially amorphous Compound 2.
11 . The pharmaceutical composition of claim 5 having the following formulation:
% by wgt.
Compound 1 Form I
25-50
A solid dispersion comprising
15-35
substantially amorphous
Compound 2
Microcrystalline cellulose
20-30
Croscarmellose sodium
3-10
Sodium lauryl sulfate
0.5-2
Polyvinylpyrrolidone
0-5
Magnesium stearate
0.5-2
referred to as PC-IV.
12 . The pharmaceutical composition of claim 5 , further comprising a colorant and a wax.
13 . The pharmaceutical composition of claim 2 , wherein the pharmaceutical composition is a solid oral pharmaceutical composition.
14 . The pharmaceutical composition claim 13 , wherein the solid oral pharmaceutical composition is a granule.
15 . The granule of claim 14 having the following formulation:
% by wgt.
Compound 1 Form I
43
Solid dispersion comprising
34
substantially amorphous
Compound 2
Microcrystalline cellulose
17
Croscarmellose sodium
2
Sodium lauryl sulfate
1
Polyvinylpyrrolidone
3
referred to as PC-V.
16 . The granule of claim 14 having the following formulation:
% by wgt.
Compound 1 Form I
38
Solid dispersion comprising
40
substantially amorphous
Compound 2
Microcrystalline cellulose
16
Croscarmellose sodium
2
Sodium lauryl sulfate
1
Polyvinylpyrrolidone
3
referred to as PC-VI.
17 . The granule of claim 14 having the following formulation:
% by wgt.
Compound 1 Form I
51
Solid dispersion comprising
27
substantially amorphous
Compound 2
Microcrystalline cellulose
16
Croscarmellose sodium
2
Sodium lauryl sulfate
1
Polyvinylpyrrolidone
3
referred to as PC-VII.
18 . The pharmaceutical composition of claim 5 , wherein the pharmaceutical composition is a solid oral pharmaceutical composition.
19 . The pharmaceutical composition claim 18 , wherein the solid oral pharmaceutical composition is a tablet.
20 . The tablet claim 19 having the following formulation:
% by wgt.
Compound 1 Form I
35
Solid dispersion comprising
28
substantially amorphous
Compound 2
Microcrystalline cellulose
26
Croscarmellose sodium
6
Sodium lauryl sulfate
1
Polyvinylpyrrolidone
3
Magnesium stearate
1
referred to as PC-VIII.
21 . The tablet of claim 19 having the following formulation:
% by wgt.
Compound 1 Form I
31
Solid dispersion comprising
32
substantially amorphous
Compound 2
Microcrystalline cellulose
26
Croscarmellose sodium
6
Sodium lauryl sulfate
1
Polyvinylpyrrolidone
3
Magnesium stearate
1
referred to as PC-IX.
22 . The tablet of claim 19 having the following formulation:
% by wgt.
Compound 1 Form I
41
Solid dispersion comprising
22
substantially amorphous
Compound 2
Microcrystalline cellulose
26
Croscarmellose sodium
6
Sodium lauryl sulfate
1
Polyvinylpyrrolidone
3
Magnesium stearate
1
referred to as PC-X.
23 . The tablet of claim 19 having the following formulation:
mg
Compound 1 Form I
200
Solid dispersion comprising
156
substantially amorphous
Compound 2
Microcrystalline cellulose
150
Croscarmellose sodium
34
Sodium lauryl sulfate
4
Polyvinylpyrrolidone
15
Magnesium stearate
6
referred to as PC-XI.
24 . The tablet of claim 19 having the following formulation:
mg
Compound 1 Form I
150
Solid dispersion comprising
156
substantially amorphous
Compound 2
Microcrystalline cellulose
129
Croscarmellose sodium
30
Sodium lauryl sulfate
4
Polyvinylpyrrolidone
13
Magnesium stearate
5
referred to as PC-XII.
25 . The tablet of claim 19 having the following formulation:
mg
Compound 1 Form I
200
Solid dispersion comprising
104
substantially amorphous
Compound 2
Microcrystalline cellulose
128
Croscarmellose sodium
29
Sodium lauryl sulfate
4
Polyvinylpyrrolidone
13
Magnesium stearate
5
referred to as PC-XIII.
26 . The tablet of claim 19 having the following formulation:
% by wgt.
Compound 1 Form I
34
Solid dispersion comprising
27
substantially amorphous
Compound 2
Microcrystalline cellulose
25
Croscarmellose sodium
6
Sodium lauryl sulfate
1
Polyvinylpyrrolidone
3
Magnesium stearate
1
Colorant
3
referred to as PC-XIV.
27 . The tablet of claim 19 having the following formulation:
% by wgt.
Compound 1 Form I
30
Solid dispersion comprising
31
substantially amorphous
Compound 2
Microcrystalline cellulose
25
Croscarmellose sodium
6
Sodium lauryl sulfate
1
Polyvinylpyrrolidone
3
Magnesium stearate
1
Colorant
3
referred to as PC-XV.
28 . The tablet of claim 19 having the following formulation:
% by wgt.
Compound 1 Form I
40
Solid dispersion comprising
21
substantially amorphous
Compound 2
Microcrystalline cellulose
25
Croscarmellose sodium
6
Sodium lauryl sulfate
1
Polyvinylpyrrolidone
3
Magnesium stearate
1
Colorant
3
referred to as PC-XVI.
29 . The tablet claim 19 having the following formulation:
mg
Compound 1 Form I
200
Solid dispersion comprising
156
substantially amorphous
Compound 2
Micro crystalline cellulose
150
Croscarmellose sodium
34
Sodium lauryl sulfate
4
Polyvinylpyrrolidone
15
Magnesium stearate
6
Colorant
17
referred to as PC-XVII.
30 . The tablet of claim 19 having the following formulation:
mg
Compound 1 Form I
200
Substantially amorphous
125
Compound 2
Microcrystalline cellulose
150
Croscarmellose sodium
34
Sodium lauryl sulfate
4
Polyvinylpyrrolidone
15
Magnesium stearate
6
Colorant
17
referred to as PC-XVIII.
31 . The tablet of claim 19 having the following formulation:
mg
Compound 1 Form I
150
Solid dispersion comprising
156
substantially amorphous
Compound 2
Microcrystalline cellulose
129
Croscarmellose sodium
29
Sodium lauryl sulfate
4
Polyvinylpyrrolidone
13
Magnesium stearate
5
Colorant
15
referred to as PC-XIX.
32 . The tablet of claim 19 having the following formulation:
mg
Compound 1 Form I
200
Solid dispersion comprising
104
substantially amorphous
Compound 2
Microcrystalline cellulose
128
Croscarmellose sodium
29
Sodium lauryl sulfate
4
Polyvinylpyrrolidone
13
Magnesium stearate
5
Colorant
14
referred to as PC-XX.
33 . The tablet of claim 19 having the following formulation:
mg
Compound 1 Form I
200
Solid dispersion comprising
83
substantially amorphous
Compound 2
Microcrystalline cellulose
128
Croscarmellose sodium
29
Sodium lauryl sulfate
4
Polyvinylpyrrolidone
13
Magnesium stearate
5
Colorant
14
referred to as PC-XXI.
34 . The tablet of claim 19 having the following formulation:
Component
% by wgt.
Compound 1 Form I
20-40
Solid dispersion comprising
30-40
substantially amorphous
Compound 2
Microcrystalline cellulose
20-30
Croscarmellose sodium
1-10
Polyvinylpyrrolidone
1-5
Sodium lauryl sulfate
0.1-1
Magnesium stearate
0.5-1.5
referred to as PC-XXII.
35 . The tablet of claim 19 having the following formulation:
Component
mg/Tablet
Compound 1 Form I
100
Solid dispersion comprising
156
substantially amorphous
Compound 2
Microcrystalline cellulose
55
Croscarmellose sodium
7
Polyvinylpyrrolidone
11
Sodium lauryl sulfate
3
Total Granules
332
Croscarmellose sodium
18
Microcrystalline cellulose
53
Magnesium stearate
4
Total Tablet
407
referred to as PC-XXIII.
36 . The tablet of claim 19 having the following formulation:
Component
mg/Tablet
Compound 1 Form I
150
Solid dispersion comprising
156
substantially amorphous
Compound 2
Microcrystalline cellulose
65
Croscarmellose sodium
8
Polyvinylpyrrolidone
13
Sodium lauryl sulfate
4
Total Granules
396
Croscarmellose sodium
22
Microcrystalline cellulose
64
Magnesium stearate
5
Total Tablet
487
referred to as PC-XXIV.
37 . The tablet of claim 19 having the following formulation:
Component
mg/Tablet
Compound 1 Form I
75
Solid dispersion
156
comprising
substantially
amorphous
Compound 2
Microcrystalline
49
cellulose
Croscarmellose
6
sodium
Polyvinylpyrrolidone
10
Sodium lauryl sulfate
3
Total Granules
299
Croscarmellose
17
sodium
Microcrystalline
48
cellulose
Magnesium stearate
4
Core Tablet
368
Pink Opadry
11
Total Tablet
379
referred to as PC-XXV.
38 . A method of treating, lessening the severity of, or symptomatically treating cystic fibrosis in a patient comprising administering to the patient an effective amount of the pharmaceutical composition of claim 1 .
39 . The method of claim 38 , wherein the pharmaceutical composition has the formulation of any one of PC-I to PC-XXV.
40 . The method of claim 38 , wherein the patient has a ΔF508 CFTR mutation.
41 . The method of claim 40 , wherein the patient is homozygous in ΔF508.
42 . The method of claim 40 , wherein the patient is heterozygous in ΔF508.
43 . A method of preparing a granule comprising wet granulating the following components:
a. Compound 1 Form I; b. a solid dispersion comprising substantially amorphous Compound 2; c. a filler; d. a disintegrant; e. a surfactant; and f. a binder.
44 . A method of preparing a tablet comprising compressing:
i) a plurality of granular pharmaceutical compositions comprising the following components:
a. Compound 1 Form I;
b. a solid dispersion comprising substantially amorphous Compound 2;
c. a filler;
d. a disintegrant;
e. a surfactant; and
f. a binder;
ii) a disintegrant; iii) a filler; and iv) a lubricant.
45 . A continuous process for preparing a tablet comprising Compound 1 Form I and a solid dispersion comprising substantially amorphous Compound 2 comprising the steps of:
a) mixing Compound 1 Form I, a solid dispersion comprising substantially amorphous Compound 2, 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; and f) compressing the blend from step e) into a tablet.
46 . A kit comprising the pharmaceutical composition of claim 1 and a separate therapeutic agent.
47 . The kit of claim 46 , wherein the pharmaceutical composition and the therapeutic agent are in separate containers.
48 . The kit of claim 47 , wherein the containers are bottles, vials, or blister packs, or combination thereof.Join the waitlist — get patent alerts
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