Claims for Patent: 8,716,338

Summary for Patent: 8,716,338

Title:	Dosage units of 3-(6-(1-(2,2-difluorobenzo[D] [1,3] dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid
Abstract:	The present invention relates to formulations of 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-- methylpyridin-2-yl)benzoic acid in Form I, pharmaceutical packs or kits thereof, and methods of treatment therewith.
Inventor(s):	Young; Christopher (Waltham, MA)
Assignee:	Vertex Pharmaceuticals Incorporated (Boston, MA)
Application Number:	12/568,717
Patent Claims:	1. A dosage unit comprising 25 to 400 mg of substantially crystalline and salt free 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarbo- xamido)-3-methylpyridin-2-yl)benzoic acid characterized by one or more peaks at 15.2 to 15.6 degrees, 16.1 to 16.5 degrees, and 14.3 to 14.7 degrees in an X-ray powder diffraction obtained using Cu K alpha radiation. 2. The dosage unit of claim 1, wherein the amount of 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-- methylpyridin-2-yl)benzoic acid is 100 to 300 mg. 3. The dosage unit of claim 1, wherein the amount of 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-- methylpyridin-2-yl)benzoic acid is 200 mg. 4. The dosage unit of claim 1, wherein the 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-- methylpyridin-2-yl)benzoic acid is characterized by one or more peaks at about 15.4, 16.3, and 14.5 degrees. 5. The dosage unit of claim 1, wherein the 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-- methylpyridin-2-yl)benzoic acid is further characterized by a peak at 14.6 to 15.0 degrees. 6. The dosage unit of claim 1, wherein the 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-- methylpyridin-2-yl)benzoic acid is further characterized by a peak at 14.8 degrees. 7. The dosage unit of claim 1, wherein the 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-- methylpyridin-2-yl)benzoic acid is further characterized by a peak at 17.6 to 18.0 degrees. 8. The dosage unit of claim 1, wherein the 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-- methylpyridin-2-yl)benzoic acid is further characterized by a peak at 17.8 degrees. 9. The dosage unit of claim 1, wherein the 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-- methylpyridin-2-yl)benzoic acid is further characterized by a peak at 16.4 to 16.8 degrees. 10. The dosage unit of claim 1, wherein the 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-- methylpyridin-2-yl)benzoic acid is further characterized by a peak at 16.6 degrees. 11. The dosage unit of claim 1, wherein the 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-- methylpyridin-2-yl)benzoic acid is further characterized by a peak at 7.6 to 8.0 degrees. 12. The dosage unit of claim 1, wherein the 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-- methylpyridin-2-yl)benzoic acid is further characterized by a peak at 7.8 degrees. 13. The dosage unit of claim 1, wherein the 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-- methylpyridin-2-yl)benzoic acid is further characterized by a peak at 25.8 to 26.2 degrees. 14. The dosage unit of claim 1, wherein the 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-- methylpyridin-2-yl)benzoic acid is further characterized by a peak at 26.0 degrees. 15. The dosage unit of claim 1, wherein the 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-- methylpyridin-2-yl)benzoic acid is further characterized by a peak at 21.4 to 21.8 degrees. 16. The dosage unit of claim 1, wherein the 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-- methylpyridin-2-yl)benzoic acid is further characterized by a peak at 21.6 degrees. 17. The dosage unit of claim 1, wherein the 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-- methylpyridin-2-yl)benzoic acid is further characterized by a peak at 23.1 to 23.5 degrees. 18. The dosage unit of claim 1, wherein the 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-- methylpyridin-2-yl)benzoic acid is further characterized by a peak at 23.3 degrees. 19. The dosage unit of claim 1, wherein the 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-- methylpyridin-2-yl)benzoic acid has a monoclinic crystal system, a P2.sub.1/n space group, and the following unit cell dimensions: a=4.9626 (7) .ANG. .alpha.=90.degree. b=12.2994 (18) .ANG. .beta.=93.938 (9).degree. c=33.075 (4) .ANG. .gamma.=90.degree.. 20. The dosage unit of claim 1, wherein the 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-- methylpyridin-2-yl)benzoic acid is characterized by a diffraction pattern substantially similar to that of FIG. 1. 21. The dosage unit of claim 1, wherein the 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-- methylpyridin-2-yl)benzoic acid is characterized by a diffraction pattern substantially similar to that of FIG. 2. 22. The dosage unit of claim 1, wherein the dosage unit is a solid oral dosage unit. 23. The dosage unit of claim 1, wherein the dosage unit is in the form of a capsule. 24. The dosage unit of claim 1, wherein the dosage unit comprises more than one capsule. 25. The dosage unit of claim 1, wherein the dosage unit comprises 4 capsules of 50 mg of 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-- methylpyridin-2-yl)benzoic acid each. 26. The dosage unit of claim 1, further comprising a filler. 27. The dosage unit of claim 26, wherein the filler is lactose and microcrystalline cellulose. 28. The dosage unit of claim 26, wherein the amount of filler is 40 to 80 percent by weight. 29. The dosage unit of claim 26, wherein the amount of filler is 60 percent by weight. 30. The dosage unit of claim 1, further comprising a disintegrant. 31. The dosage unit of claim 30, wherein the disintegrant is sodium starch glycolate. 32. The dosage unit of claim 30, wherein the amount of disintegrant is 1 to 20 percent by weight. 33. The dosage unit of claim 30, wherein the amount of disintegrant is 10 percent by weight. 34. The dosage unit of claim 1 further comprising a surfactant. 35. The dosage unit of claim 34, wherein the surfactant is an anionic, cationic, or nonionic surfactant. 36. The dosage unit of claim 34, wherein the surfactant is sodium lauryl sulfate. 37. The dosage unit of claim 34, wherein the amount of surfactant is 0.5 to 15 percent by weight. 38. The dosage unit of claim 34, wherein the amount of surfactant is 5 percent by weight. 39. The dosage unit of claim 1, further comprising a glidant or viscosity agent. 40. The dosage unit of claim 39, wherein the glidant is colloidal silicon dioxide. 41. The dosage unit of claim 39, wherein the amount of glidant or viscosity agent is 0.05 to 2 percent by weight. 42. The dosage unit of claim 39, wherein the amount of glidant or viscosity agent is 0.5 percent by weight. 43. The dosage unit of claim 1, further comprising a lubricant. 44. The dosage unit of claim 43, wherein the lubricant is magnesium stearate. 45. The dosage unit of claim 43, wherein the amount of lubricant is 0.05 to 2 percent by weight. 46. The dosage unit of claim 43, wherein the amount of lubricant is 0.5 percent by weight. 47. The dosage unit of claim 1, wherein the dosage unit comprises a capsule comprising 50 mg of 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-- methylpyridin-2-yl)benzoic acid, 40 to 44 percent by weight lactose, 15 to 20 percent by weight microcrystalline cellulose, 10 percent by weight sodium starch glycolate, 5 to 6 percent by weight sodium lauryl sulfate, 0.5 to 0.6 percent by weight colloidal silicon dioxide, and 0.5 percent by weight magnesium stearate. 48. The dosage unit of claim 1, wherein the dosage unit comprises a capsule comprising 25 mg of 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-- methylpyridin-2-yl)benzoic acid. 49. The dosage unit of claim 48, wherein the dosage unit further comprises 40 or 44 percent by weight lactose, 15 to 20 percent by weight microcrystalline cellulose, 10 percent by weight sodium starch glycolate, 5 to 6 percent by weight sodium lauryl sulfate, 0.5 to 0.6 percent by weight colloidal silicon dioxide, and 0.5 percent by weight magnesium stearate. 50. The dosage unit of claim 1, wherein the 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-- methylpyridin-2-yl)benzoic acid has a particle size of 0.1 microns to 50 microns. 51. The dosage unit of claim 1, wherein the 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-- methylpyridin-2-yl)benzoic acid has a particle size of 1.0 microns to 5 microns. 52. The dosage unit of claim 1, wherein the 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-- methylpyridin-2-yl)benzoic acid has a particle size D50 of 2.0 microns. 53. A method of treating cystic fibrosis in a subject comprising administering to a subject in need thereof wherein the subject has a defective gene that causes a deletion of phenylalanine at position 508 of the cystic fibrosis transmembrane conductance regulator amino acid sequence an effective amount of the dosage unit of claim 1. 54. The method of claim 53, wherein the method comprises administering an additional therapeutic agent. 55. The method of claim 54, wherein the additional therapeutic agent is selected from the group consisting of mucolytic agent, bronchodialator, an anti-biotic, an anti-infective agent, an anti-inflammatory agent, a CFTR modulator other than a compound of the present invention, and a nutritional agent. 56. The method of claim 53, wherein the dosage unit is administered to the subject once a week. 57. The method of claim 53, wherein the dosage unit is administered to the subject once a day. 58. A pharmaceutical pack or kit comprising the dosage unit of claim 1 and instructions for use thereof.