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Last Updated: November 26, 2020

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Claims for Patent: 10,081,621

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Summary for Patent: 10,081,621
Title:Solid forms 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)cyclopropanecarboxa- mide
Abstract: The present invention relates to solid forms 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 (Compound 1) in substantially crystalline form (Form A) or amorphous form, pharmaceutical compositions thereof, and methods of treatment therewith.
Inventor(s): Keshavarz-Shokri; Ali (San Diego, CA), Zhang; Beili (San Diego, CA), Alcacio; Tim Edward (San Diego, CA), Lee; Elaine Chungmin (Arlington, MA), Zhang; Yuegang (Wayland, MA), Krawiec; Mariusz (Marlborough, MA)
Assignee: Vertex Pharmaceuticals Incorporated (Boston, MA)
Application Number:14/676,205
Patent Claims: 1. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a solid dispersion comprising substantially amorphous (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 a polymer selected from hydroxypropylmethylcellulose (HPMC) and hydroxypropylmethylcellulose acetate succinate (HPMCAS), wherein the solid substantially amorphous (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 comprises less than about 5% crystalline (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.

2. The pharmaceutical composition of claim 1, wherein the polymer is present in the solid dispersion an amount from 10% by weight to 80% by weight of the solid dispersion.

3. The pharmaceutical composition of claim 1, wherein the substantially amorphous (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydrox- ypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopro- panecarboxamide is present in an amount of about 80% by weight of the solid dispersion.

4. The pharmaceutical composition of claim 1, wherein the polymer is hydroxypropylmethylcellulose (HPMC).

5. The pharmaceutical composition of claim 1, wherein the polymer is hydroxypropylmethylcellulose acetate succinate (HPMCAS).

6. The pharmaceutical composition of claim 1, further comprising an additional therapeutic agent selected from a mucolytic agent, a bronchodilator, an antibiotic, an anti-infective agent, an anti-inflammatory agent, a CFTR potentiator, and a nutritional agent.

7. The pharmaceutical composition of claim 6, wherein the additional agent is the CFTR potentiator N-(5-hydroxy-2,4-di-tert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide.

8. A method of treating cystic fibrosis comprising administering to a patient a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a solid dispersion comprising substantially amorphous (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydrox- ypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopro- panecarboxamide and a polymer selected from hydroxypropylmethylcellulose (HPMC) and hydroxypropylmethylcellulose acetate succinate (HPMCAS), wherein the solid substantially amorphous (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 comprises less than about 5% crystalline (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.

9. The method of claim 8, further comprising administering an additional therapeutic agent selected from a mucolytic agent, a bronchodilator, an antibiotic, an anti-infective agent, an anti-inflammatory agent, a CFTR potentiator, and a nutritional agent.

10. The method of claim 9, wherein the additional therapeutic agent is N-(5-hydroxy-2,4-di-tert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide.

11. The method of claim 8, wherein the patient has CFTR with a mutation selected from .DELTA.F508, R117H, and G551D.

12. The method of claim 11, wherein the patient is heterozygous for the .DELTA.F508 CFTR mutation.

13. The method of claim 11, wherein the patient is homozygous for the .DELTA.F508 CFTR mutation.

14. The method of claim 8, wherein the patient exhibits residual CFTR activity.

15. The method of claim 9, wherein the patient has CFTR with a mutation selected from .DELTA.F508, R117H, and G551D.

16. The method of claim 15, wherein the patient is heterozygous for the .DELTA.F508 CFTR mutation.

17. The method of claim 15, wherein the patient is homozygous for the .DELTA.F508 CFTR mutation.

18. The method of claim 9, wherein the patient exhibits residual CFTR activity.

19. The method of claim 10, wherein the patient has CFTR with a mutation selected from .DELTA.F508, R117H, and G551D.

20. The method of claim 19, wherein the patient is heterozygous for the .DELTA.F508 CFTR mutation.

21. The method of claim 19, wherein the patient is homozygous for the .DELTA.F508 CFTR mutation.

22. The method of claim 10, wherein the patient exhibits residual CFTR activity.

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