IP Library › Patent Application 14656043
Patent Application
App. No. 14/656,043

Pharmaceutical Compositions of (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 Administration Thereof

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Quick Facts
Patent No.
US None
App. No.
14/656,043
Abstract

A pharmaceutical composition comprising 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 at least one excipient selected from: a filler, a disintegrant, a surfactant, a glidant 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. Methods for treating a patient in need thereof include administering the pharmaceutical composition of Compound 1 are also disclosed.

Claims (316)

1 . A method for treating cystic fibrosis in a patient, comprising coadministering:

a) a pharmaceutical composition comprising 5 to 250 mg of (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 (Compound 1) and a pharmaceutically acceptable carrier; and

b) a pharmaceutical composition comprising 100 to 300 mg N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide (Compound 2) and a pharmaceutically acceptable carrier;

wherein the patient has a defective gene that causes a deletion of phenylalanine at position 508 of the cystic fibrosis transmembrane conductance regulator amino acid sequence.

2 . The method of claim 1 , wherein the pharmaceutically acceptable carrier in part a) comprises:

a. a filler;

b. a disintegrant;

c. a lubricant; and

d. a glidant.

3 . The method of claim 1 , wherein the 5 to 250 mg of Compound 1 is administered prior to the 100 to 300 mg of Compound 2.

4 . The method of claim 1 , wherein the 5 to 250 mg of Compound 1 is administered concurrently with the 100 to 300 mg of Compound 2.

5 . The method of claim 1 , wherein the 5 to 250 mg of Compound 1 is administered subsequent to the 100 to 300 mg of Compound 2.

6 . The method of claim 1 , wherein Compound 1 is in the form of Compound 1 Amorphous Form.

7 . The method of claim 1 , wherein Compound 1 or Compound 1 Amorphous Form is present in the tablet in an amount of about 10 mg.

8 . The method of claim 1 , wherein Compound 1 or Compound 1 Amorphous Form is present in the tablet in an amount of about 30 mg.

9 . The method of claim 1 , wherein Compound 1 or Compound 1 Amorphous Form is present in the tablet in an amount of about 100 mg.

10 . The method of claim 1 , wherein the tablet has the formulation set forth in the following table:

Final Blend

Composition

Component

Function

% w/w

Tablet (mg/tablet)

50% Compound 1/

Active as a

50.00

10.0 SDD

49.5% HPMCAS-

spray dried

(5.00 Compound 1)

HG/0.5% sodium

dispersion

lauryl sulfate

(SSD)

Microcrystalline

Filler

22.62

4.52

cellulose

Lactose

Filler

22.63

4.53

Monohydrate

Crosscarmelose

Disintegrant

3.00

0.60

Sodium

Magnesium Stearate

Lubricant

0.25

0.05

Colloidal Silica

Glidant

1.00

0.20

Dioxide

Intragranular

99.5

content

Extragranular Blend

Colloidal Silica

Glidant

0.25

0.05

Dioxide

Magnesium Stearate

Lubricant

0.25

0.05

Extragranular

0.5

content

Total

100.00

20.0

11 . The method of claim 1 , wherein the tablet has the formulation set forth in the following table:

Final Blend

Composition

Component

Function

% w/w

Tablet (mg/tablet)

50% Compound 1/

Active as a

9.53

20.00 SDD

49.5% HPMCAS-

spray dried

(10.00 Compound 1)

HG/0.5% sodium

dispersion

lauryl sulfate

(SSD)

Microcrystalline

Filler

43.24

90.80

cellulose

Lactose

Filler

43.24

90.80

Monohydrate

Crosscarmelose

Disintegrant

3.00

6.30

Sodium

Magnesium Stearate

Lubricant

0.50

1.05

Colloidal Silica

Glidant

0.50

1.05

Dioxide

Total

100.00

210.0

12 . The method of claim 1 , wherein the tablet has the formulation set forth in the following table:

Final Blend

Composition

Component

Function

% w/w

Tablet (mg/tablet)

50% Compound 1/

Active as a

50.00

100.0 SDD

49.5% HPMCAS-

spray dried

(50.00

HG/0.5% sodium

dispersion

Compound 1)

lauryl sulfate

(SSD)

Microcrystalline

Filler

22.62

45.20

cellulose

Lactose Monohydrate

Filler

22.63

45.30

Crosscarmelose

Disintegrant

3.00

6.0

Sodium

Magnesium Stearate

Lubricant

0.25

0.5

Colloidal Silica

Glidant

1.00

2.0

Dioxide

Intragranular

99.5

content

Extragranular Blend

Colloidal Silica

Glidant

0.25

0.5

Dioxide

Magnesium Stearate

Lubricant

0.25

0.5

Extragranular

0.5

content

Total

100.00

200.0

13 . The method of claim 1 , wherein the tablet has the formulation set forth in the following table:

Final Blend

Composition

Component

Function

% w/w

Tablet (mg/tablet)

50% Compound 1/

Active as a

50.00

200.0 SDD

49.5% HPMCAS-

spray dried

(100.00

HG/0.5% SLS

dispersion

Compound 1)

(SSD)

Microcrystalline

Filler

22.63

90.5

cellulose (Avicel

PH101)

Lactose Monohydrate

Filler

22.63

90.5

(Foremost 310)

Crosscarmelose

Disintegrant

3.00

12.0

Sodium (AcDiSol)

Magnesium Stearate

Lubricant

0.25

1.0

Colloidal Silica

Glidant

1.00

4.0

Dioxide (Cabot M5P)

Intragranular

99.5

content

Extragranular Blend

Colloidal Silica

Glidant

0.25

1.0

Dioxide (Cabot M5P)

Magnesium Stearate

Lubricant

0.25

1.0

Extragranular

0.5

content

Total

100.00

400.0

14 . The method of claim 1 , wherein the tablet has the formulation set forth in the following table:

Final Blend

Composition

Component

Function

% w/w

Tablet (mg/tablet)

50% Compound 1/

Active as a

50.00

500.0 SDD

49.5% HPMCAS-

spray dried

(250.00

HG/0.5% SLS

dispersion

Compound 1)

(SSD)

Microcrystalline

Filler

22.63

226.3

cellulose (Avicel

PH101)

Lactose Monohydrate

Filler

22.63

226.3

(Foremost 310)

Crosscarmelose

Disintegrant

3.00

30.0

Sodium (AcDiSol)

Magnesium Stearate

Lubricant

0.25

2.5

Colloidal Silica

Glidant

1.00

10.0

Dioxide (Cabot M5P)

Intragranular

99.5

content

Extragranular Blend

Colloidal Silica

Glidant

0.25

2.5

Dioxide (Cabot M5P)

Magnesium Stearate

Lubricant

0.25

2.5

Extragranular

0.5

content

Total

100.00

1000.0

15 . The method of claim 1 , wherein Compound 1 is administered once a day.

16 . The method of claim 1 , wherein 150 mg of Compound 2 is administered.

17 . The method of claim 1 , wherein 250 mg of Compound 2 is administered.

18 . The method of claim 1 , wherein Compound 1 is administered every 12 hours.

19 . The method of claim 1 , wherein Compound 2 is administered every 12 hours.

20 . The method of claim 1 , wherein the method comprises administering an additional therapeutic agent.

21 . The method of claim 20 , wherein the additional therapeutic agent is a mucolytic agent, bronchodialator, an antibiotic, an anti-infective agent, an anti-inflammatory agent, a CFTR modulator other than Compound 2, or a nutritional agent.

22 . The method of claim 20 , wherein the additional therapeutic agent is a CFTR modulator other than Compound 2.

23 . The method of claim 1 , wherein the patient is homozygous for the defective gene.

Assignments (1)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Sep 14, 2015
From: ALARGOVA, ROSSITZA GUEORGUIEVA; DUNBAR, CRAIG ANTONY; NIKOLAEVNA, KADIYALA IRINA
To: VERTEX PHARMACEUTICALS INCORPORATED
Reel/Frame 036552/0782 →