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
A pharmaceutical composition comprising Compound 1, (R)-1-(2,2-difluorobenzo[d][1,3]dioxo-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.
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, wherein Compound 1 is in a spray dried dispersion; and
b) another 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 one of the following tables:
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;
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;
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;
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; or
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.
11. The method of claim 1 , wherein Compound 1 is administered once a day.
12. The method of claim 1 , wherein 150 mg of Compound 2 is administered.
13. The method of claim 1 , wherein 250 mg of Compound 2 is administered.
14. The method of claim 1 , wherein Compound 1 is administered every 12 hours.
15. The method of claim 1 , wherein Compound 2 is administered every 12 hours.
16. The method of claim 1 , wherein the method comprises administering an additional therapeutic agent.
17. The method of claim 16 , 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.
18. The method of claim 16 , wherein the additional therapeutic agent is a CFTR modulator other than Compound 2.
19. The method of claim 1 , wherein the patient is homozygous for the defective gene.