Aqueous compositions containing metronidazole
View Patent ↗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 niacin or niacinamide. Methods of manufacture and therapeutic use of the solution are disclosed.
1. A method for making an aqueous composition containing a dissolved concentration of metronidazole greater than 0.75% w/w comprising combining metronidazole, beta-cyclodextrin (BCD), and niacin or niacinamide in an aqueous fluid, wherein the BCD and the niacin or niacinamide are combined in the aqueous fluid in amounts that provide a synergistic effect on the solubility of metronidazole.
2. The method of claim 1 wherein the aqueous composition is physically stable when stored for one week at 5° C.
3. The method of claim 1 wherein the metronidazole is added to the aqueous fluid after the BCD and the niacin or niacinamide are dissolved in the aqueous fluid.
4. The method of claim 1 which further comprises, after the combination of metronidazole, BCD, and the niacin or niacinamide, adding a gelling agent.
5. The method of claim 1 wherein niacinamide but not niacin is combined.
6. The method of claim 1 wherein niacin but not niacinamide is combined.
7. An aqueous composition that is made by the method of claim 1 .
8. An aqueous composition that is made by the method of claim 4 .
9. An aqueous composition that is made by the method of claim 5 .
10. An aqueous composition that is made by the method of claim 6 .
11. A method for the treatment of a dermatologic or mucosal disorder comprising topically applying an effective amount of an aqueous composition 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 composition comprises beta-cyclodextrin (BCD) and niacin or niacinamide in amounts that provide a synergistic effect on the solubility of metronidazole, and wherein the composition is physically stable when stored for one week at 5° C.
12. The method of claim 11 wherein the concentration of metronidazole is 1% or higher.
13. The method of claim 12 wherein the application is once daily.
14. The method of claim 11 wherein the disorder is rosacea.
15. The method of claim 11 wherein the composition comprises niacin and is substantially free of niacinamide.
16. The method of claim 11 wherein the composition comprises niacinamide and is substantially free of niacin.
17. The method of claim 11 wherein the aqueous composition is a gel.
18. A kit for the topical treatment of dermatologic or mucosal disorders comprising a container and an aqueous composition of metronidazole, beta-cyclodextrin, and niacin or niacinamide within said container, wherein the concentration of metronidazole in said composition is higher than 0.75% w/w, wherein the amounts of betacyclodextrin and niacin or niacinamide are sufficient to provide a synergistic effect on the solubility of metronidazole, and wherein the aqueous composition is physically stable when stored for one week at 5° C.
19. The kit of claim 18 wherein the concentration of niacin or niacinamide is 1.0% w/w or higher.
20. The kit of claim 19 wherein the concentration of beta-cyclodextrin is 0.5% w/w or higher.
21. The kit of claim 18 wherein the concentration of metronidazole is 1% w/w or higher.
22. The kit of claim 18 wherein the aqueous composition is a gel.
23. The kit of claim 18 wherein the composition contains niacinamide and is substantially free of niacin.
24. The kit of claim 18 wherein the composition contains niacin and is substantially free of niacinamide.
25. An aqueous solution that is physically stable for at least one week at 5° 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 0.75% w/w or higher and the first and second solubility enhancing agents are present in amounts that provide a synergistic effect on the solubility of metronidazole.
26. The aqueous solution of claim 25 wherein the concentration of betacyclodextrin is 0.5% w/w or higher.
27. The aqueous solution of claim 25 wherein the concentration of niacinamide or niacin is 0.5% w/w or higher.
28. The aqueous solution of claim 25 wherein the solubility enhancing agent is niacinamide.
29. The aqueous solution of claim 25 wherein the solubility enhancing agent is niacin.
30. The aqueous solution of claim 25 which comprises niacinamide and does not comprise niacin.
31. The aqueous solution of claim 25 wherein the concentration of niacinamide or niacin is 1.0% w/w or higher.
32. The aqueous solution of claim 31 which comprises niacinamide and does not comprise niacin.
33. The aqueous solution of claim 25 which is a gel.
34. The solution of claim 25 wherein the concentration of metronidazole is 1.0% w/w or higher.
35. A method for increasing the solubility of metronidazole in aqueous fluid to a concentration of 0.75% w/w or higher comprising combining metronidazole, betacyclodextrin, and niacinamide or niacin in an aqueous fluid, wherein the betacyclodextrin and the niacinamide or niacin are present in amounts that provide a synergistic effect on the solubility of metronidazole.
36. The method of claim 35 wherein the concentration of betacyclodextrin in the fluid is 0.5% w/w or more.
37. The method of claim 35 wherein the concentration of niacinamide or niacin in the fluid is 1.0% or higher.
38. The method of claim 35 wherein the aqueous fluid is a gel.
39. The method of claim 35 which comprises combining niacinamide in the fluid.
40. The method of claim 35 which comprises combining niacin in the fluid.
41. The method of claim 35 wherein the solubility of metronidazole is increased to 1.0% w/w or more.
42. The method of claim 35 wherein the betacyclodextrin and the niacin or niacinamide are dissolved in the aqueous fluid before the metronidazole is combined in the fluid.
43. The method of claim 35 wherein a gelling agent is added to the fluid after the metronidazole, betacyclodextrin, and the niacin or niacinamide are combined in the fluid.
44. A method for increasing the enhancing effect of betacyclodextrin on the solubility of metronidazole at a concentration of 0.75% w/w or higher in aqueous fluid comprising combining niacin or niacinamide with the betacyclodextrin in the aqueous fluid in amounts that provide a synergistic effect on the solubility of metronidazole.
45. The method of claim 44 wherein the concentration of betacyclodextrin in the fluid is 0.5% or more.
46. The method of claim 44 wherein the concentration of niacin or niacinamide is 1.0% w/w or more.
47. The method of claim 44 wherein the niacin or niacinamide is combined in the fluid with the betacyclodextrin and then metronidazole is added to the fluid.
48. The method of claim 44 wherein niacin is combined with the betacyclodextrin in the aqueous fluid.
49. The method of claim 44 wherein niacinamide is combined with the betacyclodextrin in the aqueous fluid.
50. An aqueous solution comprising metronidazole at a concentration of 0.75% w/w or higher, betacyclodextrin, and niacinamide or niacin, wherein the solution contains betacyclodextrin and niacinamide or niacin in amounts that provide a synergistic effect on the solubility of metronidazole and wherein the solution is free of crystal or precipitate formation when stored for one week at 5° C.
51. The aqueous solution of claim 50 wherein the concentration of metronidazole is 1% w/w or higher.
52. The aqueous solution of claim 50 which is an aqueous gel solution.