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Last Updated: March 28, 2024

Claims for Patent: 9,012,496


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Summary for Patent: 9,012,496
Title: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)cyclopropanecarbox- amide and administration thereof
Abstract: 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)cyclopropanecarboxa- mide, 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.
Inventor(s): Alargova; Rossitza Gueorguieva (Brighton, MA), Dunbar; Craig Antony (Needham, MA), Kadiyala; Irina Nikolaevna (Newton, MA)
Assignee: Vertex Pharmaceuticals Incorporated (Boston, MA)
Application Number:13/942,617
Patent Claims: 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)cyclopropanecar- boxamide (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: TABLE-US-00043 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;

TABLE-US-00044 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;

TABLE-US-00045 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;

TABLE-US-00046 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

TABLE-US-00047 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.

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