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)cyclopropanecarboxamide
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)cyclopropanecarboxamide (Compound 1) in substantially crystalline form (Form A) or amorphous form, pharmaceutical compositions thereof, and methods of treatment therewith.
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)cyclopropanecarboxamide 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)cyclopropanecarboxamide 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)-cyclopropanecarboxamide.
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-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide 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-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide 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)cyclopropanecarboxamide 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)cyclopropanecarboxamide.
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 ΔF508, R117H, and G551D.
12. The method of claim 11 , wherein the patient is heterozygous for the ΔF508 CFTR mutation.
13. The method of claim 11 , wherein the patient is homozygous for the ΔF508 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 ΔF508, R117H, and G551D.
16. The method of claim 15 , wherein the patient is heterozygous for the ΔF508 CFTR mutation.
17. The method of claim 15 , wherein the patient is homozygous for the ΔF508 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 ΔF508, R117H, and G551D.
20. The method of claim 19 , wherein the patient is heterozygous for the ΔF508 CFTR mutation.
21. The method of claim 19 , wherein the patient is homozygous for the ΔF508 CFTR mutation.
22. The method of claim 10 , wherein the patient exhibits residual CFTR activity.