Pharmaceutical Compositions for the Treatment of CFTR Mediated Diseases

1 . 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.