Formulations 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 formulations 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), pharmaceutical packs or kits thereof, and methods of treatment therewith.
1. A formulation comprising (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), water, a surfactant which is vitamin E TPGS, and a polyethylene glycol (PEG) which is PEG 400.
2. The formulation of claim 1 , wherein the concentration of Compound 1 is from about 0.05 to about 3% by weight.
3. The formulation of claim 1 , wherein the concentration of Compound 1 is from about 0.1 to about 2% by weight.
4. The formulation of claim 1 , wherein the concentration of Compound 1 is about 0.12, 0.25, or 0.50% by weight.
5. The formulation of claim 1 , wherein the concentration of polyethylene glycol is from about 40 to about 60% by weight.
6. The formulation of claim 1 , wherein the concentration of polyethylene glycol is from about 45 to about 55% by weight.
7. The formulation of claim 1 , wherein the concentration of polyethylene glycol is about 50% by weight.
8. The formulation of claim 1 , wherein the concentration of Compound 1 is from about 0.05 to about 3% by weight; and the concentration of polyethylene glycol is from about 40 to about 60% by weight.
9. The formulation of claim 1 , wherein the concentration of Compound 1 is from about 0.1 to about 2% by weight; and the concentration of polyethylene glycol is from about 45 to about 55% by weight.
10. The formulation of claim 1 , wherein the concentration of Compound 1 is about 0.12, 0.25, or 0.50% by weight; and the concentration of polyethylene glycol is about 50% by weight.
11. The formulation of claim 1 , wherein the concentration of surfactant is from about 5 to about 15% by weight.
12. The formulation of claim 1 , wherein the concentration of surfactant is from about 10 to about 12% by weight.
13. The formulation of claim 1 , wherein the concentration of surfactant is about 11% by weight.
14. The formulation of claim 1 , wherein the concentration of Compound 1 is from about 0.05 to about 3% by weight, the concentration of polyethylene glycol is from about 40 to about 60% by weight, and the concentration of surfactant is from about 5 to about 15% by weight.
15. The formulation of claim 14 , wherein the concentration of Compound 1 is from about 0.05 to about 3% by weight, the polyethylene glycol is PEG 400 at about 40 to about 60% by weight, and the surfactant is vitamin E TPGS at about 5 to 15% by weight.
16. The formulation of claim 1 , wherein the formulation is about 30 to 50 g.
17. The formulation of claim 1 , wherein the formulation is about 35 to 45 g.
18. The formulation of claim 1 , wherein the formulation is about 40 g.
19. The formulation of claim 1 , wherein the formulation comprises the following:
Amount
Component
(g)
Compound 1
0.05
PEG 400
19.95
Vitamin E TPGS
4.48
Water
15.52.
20. The formulation of claim 1 , wherein the formulation comprises the following:
Amount
Component
(g)
Compound 1
0.10
PEG 400
19.90
Vitamin E TPGS
4.48
Water
15.52.
21. The formulation of claim 1 , wherein the formulation comprises the following:
Amount
Component
(g)
Compound 1
0.20
PEG 400
19.80
Vitamin E TPGS
4.48
Water
15.52.
22. The formulation of claim 1 , wherein the formulation comprises the following:
Amount
Component
(g)
Compound 1
0.30
PEG 400
19.70
Vitamin E TPGS
4.48
Water
15.52.
23. The formulation of claim 1 , wherein the formulation comprises the following:
Amount
Component
(% by weight)
Compound 1
0.10-0.80
PEG 400
48-51
Vitamin E TPGS
10-12
Water
37-40.
24. The formulation of claim 1 , wherein the formulation comprises the following:
Amount
Component
(% by weight)
Compound 1
0.20-0.60
PEG 400
49-50
Vitamin E TPGS
10-12
Water
37-40.
25. The formulation of claim 1 , wherein the formulation comprises the following:
Amount
Component
(% by weight)
Compound 1
0.25
PEG 400
49.75
Vitamin E TPGS
11.20
Water
38.80.
26. The formulation of claim 1 , wherein the formulation comprises the following:
Amount
Component
(% by weight)
Compound 1
0.50
PEG 400
49.50
Vitamin E TPGS
11.20
Water
38.80.
27. The formulation of claim 1 , further comprising a taste masker.
28. The formulation of claim 1 , further comprising an additional therapeutic agent.
29. The formulation of claim 28 , wherein the additional therapeutic agent is selected from a mucolytic agent, bronchodialator, an anti-biotic, an anti-infective agent, an anti-inflammatory agent, a CFTR modulator other than Compound 1, or a nutritional agent.
30. A method of treating a CFTR mediated disease selected from cystic fibrosis, COPD, emphysema, dry-eye disease or osteoporosis in a subject comprising administering to the subject an effective amount of the formulation of claim 1 .
31. The method of claim 30 , wherein the CFTR mediated disease is cystic fibrosis.
32. The method of claim 30 , wherein the method comprises administering an additional therapeutic agent.
33. The method of claim 32 , wherein the additional therapeutic agent is selected from a mucolytic agent, bronchodialator, an anti-biotic, an anti-infective agent, an anti-inflammatory agent, a CFTR modulator other than Compound 1, or a nutritional agent.
34. A pharmaceutical pack or kit comprising the formulation of claim and instructions for use thereof.