Claims for Patent: 6,881,726

Summary for Patent: 6,881,726

Title:	Aqueous compositions containing metronidazole
Abstract:	An aqueous solution of metronidazole in which the concentration of metronidazole is higher than 0.75%. The solution contains a combination of solubility-enhancing agents, one of which is a cyclodextrin such as beta-cyclodextrin and the second is a compound other than a cyclodextrin. Methods of manufacture and therapeutic use of the solution are disclosed.
Inventor(s):	Chang; Yunik (Sonoma, CA), Dow; Gordon J. (Santa Rosa, CA)
Assignee:	Dow Pharmaceutical Sciences (Petaluma, CA)
Application Number:	10/033,835
Patent Litigation and PTAB cases:	See patent lawsuits and PTAB cases for patent 6,881,726
Patent Claims:	1. An aqueous solution that is physically stable for at least one week at 5.degree. C. comprising metronidazole, a first solubility enhancing agent which is betacyclodextrin, and a second solubility enhancing agent which is niacin or niacinamide, wherein in the solution, the concentration of metronidazole is about 1.0% w/w or higher, the concentration of betacyclodextrin is 0.5% w/w or higher, and the concentration of niacinamide or niacin is about 0.5% w/w or higher. 2. The aqueous solution of claim 1 wherein the solubility enhancing agent is niacinamide. 3. The aqueous solution of claim 2 which is a gel. 4. The aqueous solution of claim 1 wherein the solubility enhancing agent is niacin. 5. The aqueous solution of claim 4 which is a gel. 6. The aqueous solution of claim 1 which comprises niacinamide and does not comprise niacin. 7. The aqueous solution of claim 1 wherein the concentration of niacinamide or niacin is about 1.0% w/w or higher. 8. The aqueous solution of claim 7 which comprises niacinamide and does not comprise niacin. 9. The aqueous solution of claim 1 which is a gel. 10. An aqueous solution comprising metronidazole, betacyclodextrin at a concentration of 0.5% w/w or higher, and niacinamide, wherein the solution is free of crystal or precipitate formation when stored for one week at 5.degree. C. 11. The aqueous solution of claim 10 wherein the concentration of betacyclodextrin is about 1% w/w or higher. 12. The aqueous solution of claim 10, which is an aqueous gel solution. 13. A kit for the topical treatment of dermatologic or mucosal disorders comprising a container and an aqueous solution of metronidazole, beta-cyclodextrin, and niacin or niacinamide within said container, wherein the concentration of metronidazole in said solution is higher than 0.75% w/w, the concentration of beta-cyclodextrin is 0.5% w/w or higher, and the concentration of niacin or niacinamide is about 1.0% w/w or higher. 14. The kit of claim 13 wherein the concentration of metronidazole is about 1% w/w or higher. 15. The kit of claim 13 wherein the aqueous solution is a gel. 16. The kit of claim 13 wherein the solution contains niacinamide and is substantially free of niacin. 17. The kit of claim 13 wherein the solution contains niacin and is substantially free of niacinamide. 18. A method for obtaining an aqueous solution containing metronidazole wherein the aqueous solution contains betacyclodextrin at a concentration greater than 0.5% w/w comprising combining in an aqueous fluid metronidazole, betacyclodextrin and niacinamide wherein the amount of the niacinamide combined in the aqueous fluid is sufficient to provide a dissolved concentration of betacyclodextrin greater than 0.5% w/w at a temperature of 5.degree. C. 19. The method of claim 18 wherein the aqueous solution containing betacyclodextrin at a concentration greater than 0.5% w/w and niacinamide is physically stable for one week at 5.degree. C. 20. The method of claim 18 wherein the aqueous solution is an aqueous gel solution. 21. A method for increasing the solubility of metronidazole in aqueous solution comprising combining metronidazole, betacyclodextrin, and niacinamide or niacin in an aqueous fluid, wherein the concentration of betacyclodextrin in the fluid is 0.5% w/w or more and the concentration of niacinamide or niacin in the fluid is about 1.0% or higher. 22. The method of claim 21 wherein the aqueous solution is a gel. 23. The method of claim 21 which comprises combining niacinamide in the fluid. 24. The method of claim 21 which comprises combining niacin in the fluid. 25. The method of claim 21 wherein the solubility of metronidazole is increased to 0.75% w/w or more. 26. The method of claim 25 wherein the solubility of metronidazole is increased to about 1.0% w/w or more. 27. The method of claim 21 wherein the betacyclodextrin and the niacin or niacinamide are dissolved in the aqueous fluid before the metronidazole is combined in the fluid. 28. The method of claim 21 wherein a gelling agent is added to the fluid after the metronidazole, betacyclodextrin, and the niacin or niacinamide are combined in the fluid. 29. A method for increasing the enhancing effect of betacyclodextrin on the solubility of metronidazole in aqueous fluid comprising combining niacin or niacinamide with the betacyclodextrin in the aqueous fluid, wherein the concentration of betacyclodextrin in the fluid is 0.5% or more and the concentration of niacin or niacinamide is about 1.0% w/w or more. 30. The method of claim 29 wherein the niacin or niacinamide is combined in the fluid with the betacyclodextrin and then metronidazole is added to the fluid. 31. The method of claim 29 wherein niacin is combined with the betacyclodextrin in the aqueous fluid. 32. The method of claim 29 wherein niacinamide is combined with the betacyclodextrin in the aqueous fluid. 33. A method for making an aqueous solution of metronidazole greater than 0.75% w/w comprising combining metronidazole, beta-cyclodextrin (BCD), and niacin or niacinamide in an aqueous fluid, wherein the amount of BCD that is combined in the aqueous fluid is sufficient to provide a concentration of BCD in the solution of 0.5% w/w or higher and wherein the aqueous solution is physically stable when stored for one week at 5.degree. C. 34. The method of claim 33 wherein the metronidazole is added to the aqueous fluid after the BCD and the niacin or niacinamide are dissolved in the aqueous fluid. 35. The method of claim 33 which further comprises, after the combination of metronidazole, BCD, and the niacin or niacinamide, adding a gelling agent. 36. An aqueous solution that is made by the method of claim 35. 37. The method of claim 33 wherein niacinamide but not niacin is combined. 38. An aqueous solution that is made by the method of claim 37. 39. The method of claim 33 wherein niacin but not niacinamide is combined. 40. An aqueous solution that is made by the method of claim 39. 41. An aqueous solution that is made by the method of claim 33. 42. The method of claim 33 wherein the betacyclodextrin is crystalline betacyclodextrin. 43. An aqueous solution that is made by the method of claim 42. 44. A method for the treatment of a dermatologic or mucosal disorder comprising topically applying an effective amount of aqueous solution of metronidazole having a concentration higher than 0.75% w/w to the site of the disorder and permitting the metronidazole to treat the disorder, wherein the solution comprises beta-cyclodextrin (BCD) at a concentration of 0.5% w/w or higher and niacin or niacinamide, and wherein the solution is physically stable when stored for one week at 50.degree. C. 45. The method of claim 44, wherein the concentration of metronidazole is about 1% or higher. 46. The method of claim 45 wherein the application is once daily. 47. The method of claim 44 wherein the disorder is rosacea. 48. The method of claim 44 wherein the solution comprises niacin and is substantially free of niacinamide. 49. The method of claim 44 wherein the solution comprises niacinamide and is substantially free of niacin. 50. The method of claim 44 wherein the aqueous solution is a gel.