Claims for Patent: 8,252,838

Summary for Patent: 8,252,838

Title:	Diclofenac topical formulation
Abstract:	The present invention provides a gel formulation comprising diclofenac sodium which has superior transdermal flux properties, which may be used for the topical treatment of pain, such as in osteoarthritis.
Inventor(s):	Kisak; Ed (San Diego, CA), Singh; Jagat (Toronto, CA)
Assignee:	Nuvo Research Inc. (Mississauga, CA)
Application Number:	12/134,121
Patent Litigation and PTAB cases:	See patent lawsuits and PTAB cases for patent 8,252,838
Patent Claims:	1. A topical formulation, said topical formulation consisting essentially of: (i) diclofenac sodium present at 1-2% w/w; (ii) DMSO present at 40-50% w/w; (iii) ethanol present at 23-29% w/w; (iv) propylene glycol present at 10-12% w/w; (v) optionally glycerine; (vi) a thickening agent, wherein said thickening agent is hydroxypropyl cellulose, the topical formulation having a viscosity of 500-5000 centipoise; and (vii) water, wherein said topical formulation when applied to the skin has a) a greater drying rate; and b) a transdermal flux of 1.5 times or greater than a comparative liquid formulation as determined by a Franz cell procedure at finite or infinite dosing, wherein the comparative liquid formulation consists of 1.5% diclofenac sodium, 45.5% dimethylsulfoxide, 11.79% ethanol, 11.2% propylene glycol, 11.2% glycerine, and water. 2. The topical formulation of claim 1, wherein the ethanol is present at 26.5%. 3. The topical formulation of claim 1, wherein the ethanol is present at 25%. 4. The topical formulation of claim 1, wherein the ethanol is present at 25.5%. 5. The topical formulation of claim 1, wherein said drying rate results in a residue of at most 50% of a starting amount after 24 hours. 6. The topical formulation of claim 5, wherein said Franz cell procedure is performed at infinite dosing. 7. The topical formulation of claim 1, wherein said diclofenac sodium degrades by less than 0.04% over the course of 6 months. 8. The topical formulation of claim 1, wherein said topical formulation has a pH of 6.0-10.0. 9. The topical formulation of claim 1, wherein said topical formulation when applied topically provides a reduction of pain over 12 weeks. 10. The topical formulation of claim 9, wherein said topical formulation is applied twice daily. 11. The topical formulation of claim 9, wherein said pain is due to osteoarthritis. 12. The formulation of claim 1, having a viscosity of at least 1000 centipoise. 13. The formulation of claim 1, wherein the Franz cell procedure is performed at finite dosing. 14. The formulation of claim 1, wherein the Franz cell procedure is performed at infinite dosing. 15. The formulation of claim 1, wherein transdermal flux is measured at a time of 14 hours, or 18 hours, or 28 hours, or 31 hours or 40 hours or 42 hours after placing the formulations in the Franz cell. 16. The formulation of claim 1, wherein transdermal flux is at least 2.0 times greater than the comparative liquid formulation. 17. The formulation of claim 1, wherein transdermal flux is at least 4.0 times greater than the comparative liquid formulation. 18. The formulation of claim 1, wherein the formulation is dosed at 10 mg per Franz cell and the cell has an area of 0.5 cm.sup.2. 19. The formulation of claim 1, wherein the hydroxypropyl cellulose is present at 2.5% w/w. 20. The formulation of claim 1, wherein the hydroxypropyl cellulose is present at 3.5% w/w. 21. The formulation of claim 1, wherein the concentration of diclofenac sodium is a member selected from group consisting of 1%, 1.5% and 2% w/w, and all fractions in between. 22. The formulation of claim 1, wherein the concentration of DMSO is a member selected from group consisting of 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49% and 50% w/w, and all fractions in between. 23. The formulation of claim 1, wherein the concentration of glycerine is 0-12% w/w. 24. A topical formulation consisting essentially of: (i) 1-2% w/w diclofenac sodium; (ii) 40-50% w/w DMSO; (iii) 10-12% w/w propylene glycol; (iv) 1-30% w/w ethanol; (v) optionally glycerine; (vi) water; and (vii) at least one thickening agent selected from the group consisting of a cellulose polymer, a carbomer polymer, a carbomer derivative, a cellulose derivative, hydroxypropyl cellulose and mixtures thereof, the topical formulation having a viscosity of 500-5000 centipoise, wherein said topical formulation when applied to the skin has a) a greater drying rate; and b) a transdermal flux of 1.5 times or greater as determined by a Franz cell procedure at finite or infinite dosing, than a comparative liquid formulation wherein the comparative liquid formulation consists of 1.5% diclofenac sodium, 45.5% dimethylsulfoxide, 11.79% ethanol, 11.2% propylene glycol, 11.2% glycerine, and water. 25. The topical formulation of claim 24, wherein the at least one thickening agent is selected from the group consisting of a carbomer polymer, a carbomer derivative and mixtures thereof. 26. The topical formulation of claim 25, wherein the at least one thickening agent is selected from the group consisting of carbopol 971, carbopol 981, carbopol 941, carbopol 1342 and ultrez 10. 27. The topical formulation of claim 24, wherein the at least one thickening agent is hydroxypropyl cellulose. 28. The formulation of claim 24, wherein the Franz cell procedure is performed at finite dosing. 29. The formulation of claim 24, wherein the Franz cell procedure is performed at infinite dosing. 30. The formulation of claim 24, wherein transdermal flux is measured at a time of 14 hours, or 18 hours, or 28 hours, or 31 hours or 40 hours or 42 hours after placing the formulations in the Franz cell. 31. The formulation of claim 24, wherein transdermal flux is at least 2.0 times greater than the comparative liquid formulation. 32. The formulation of claim 24, wherein transdermal flux is at least 4.0 times greater than the comparative liquid formulation. 33. The formulation of claim 24, wherein the formulation is dosed at 10 mg per Franz cell and the cell has an area of 0.5 cm.sup.2. 34. The formulation of claim 24, wherein the ethanol is present at 11.2% w/w. 35. The formulation of claim 24, wherein the concentration of diclofenac sodium is a member selected from group consisting of 1%, 1.5% and 2% w/w, and all fractions in between. 36. The formulation of claim 24, wherein the concentration of DMSO is a member selected from group consisting of 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49% and 50% w/w, and all fractions in between. 37. The formulation of claim 24, wherein the formulation has a viscosity of at least 1000 centipoise. 38. The formulation of claim 24, wherein the at least one thickening agent is a cellulose polymer. 39. The formulation of claim 24, wherein the concentration of glycerine is 0-12% w/w. 40. The formulation of claim 24, wherein the formulation has a pH of 6 to 10. 41. The formulation of claim 24, wherein the propylene glycol is present at 11% w/w. 42. The formulation of claim 24, wherein the DMSO is present at 45.5% w/w. 43. The formulation of claim 24, wherein the hydroxypropyl cellulose is present at 2.5% w/w. 44. The formulation of claim 24, wherein the hydroxypropyl cellulose is present at 3.5% w/w. 45. The formulation of claim 24, wherein the hydroxypropyl cellulose is present at 4% w/w. 46. The formulation of claim 24, wherein the ethanol is present at 25% w/w. 47. The formulation of claim 24, wherein the ethanol is present at 25.5% w/w. 48. The formulation of claim 24, wherein the ethanol is present at 26.5% w/w. 49. A topical formulation consisting essentially of: 1-2% w/w diclofenac sodium; 40-50% w/w DMSO; 23-29% w/w ethanol; 10-12% w/w propylene glycol; hydroxypropyl cellulose; and water to make 100% w/w, wherein the topical formulation has a viscosity of 500-5000 centipoise. 50. The formulation of claim 49, wherein the propylene glycol is present at 11% w/w. 51. The formulation of claim 49, wherein the DMSO is present at 45.5% w/w. 52. The formulation of claim 49, wherein the hydroxypropyl cellulose is present at 2.5% w/w. 53. The formulation of claim 49, wherein the hydroxypropyl cellulose is present at 3.5% w/w. 54. The formulation of claim 49, wherein the hydroxypropyl cellulose is present at 4% w/w. 55. The formulation of claim 49, wherein the ethanol is present at 25% w/w. 56. The formulation of claim 49, wherein the ethanol is present at 25.5% w/w. 57. The formulation of claim 49, wherein the ethanol is present at 26.5% w/w. 58. The formulation of claim 49, having a viscosity of at least 1000 centipoise. 59. The formulation of claim 49, wherein the concentration of diclofenac sodium is a member selected from group consisting of 1%, 1.5% and 2% w/w, and all fractions in between. 60. The formulation of claim 49, wherein the concentration of DMSO is a member selected from group consisting of 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49% and 50% w/w, and all fractions in between. 61. The formulation of claim 49, wherein the formulation has a pH of 6 to 10. 62. A method of treating osteoarthritis in a subject suffering from articular pain, said method comprising the topical administration to an afflicted joint area of said subject a therapeutically effective amount of a topical formulation comprising: (i) diclofenac sodium present at 1-2% w/w; (ii) DMSO present at 40-50% w/w; (iii) ethanol present at 1-30% w/w; (iv) propylene glycol present at 10-12% w/w; (v) optionally glycerine; (vi) a thickening agent, wherein said thickening agent is selected from the group consisting of cellulose polymers, carbomer polymers, a carbomer derivative, a cellulose derivative and mixtures thereof, wherein the topical formulation has a viscosity of 500-5000 centipoise; and (vii) water, wherein said topical formulation when applied to the skin has a) a greater drying rate; and b) a transdermal flux of 1.5 times or greater than a comparative liquid formulation as determined by a Franz cell procedure at finite or infinite dosing, wherein the comparative liquid formulation consists of 1.5% diclofenac sodium, 45.5% dimethylsulfoxide, 11.79% ethanol, 11.2% propylene glycol, 11.2% glycerine, and water thereby treating osteoarthritis. 63. The method of claim 62, wherein diclofenac sodium is present at a concentration selected from the group consisting of 1, 1.5, and 2 w/w; DMSO is present at a concentration selected from the group consisting of 42, 43, 44, 45, 45.5, 46, 47, and 48% w/w and fractions in between; ethanol is present at 26.5% w/w; propylene glycol is present at a concentration selected from the group consisting of 10, 11, and 12, % and fractions in between w/w; the thickening agent is hydroxypropylcellulose (HY119), and water is added to make 100% w/w. 64. The method of claim 62, wherein said drying rate results in a residue of at most 50% of a starting amount after 24 hours. 65. The method of claim 64, wherein said Franz cell procedure is performed at infinite dosing. 66. The method of claim 62, wherein said diclofenac sodium degrades by less than 0.04% over the course of 6 months. 67. The method of claim 62, wherein said topical formulation has a pH of 6.0-10.0. 68. The method of claim 62, wherein said topical administration provides a reduction of pain over 12 weeks. 69. The method of claim 68, wherein said topical formulation is applied twice daily.