Tiotropium inhalation solution for nebulization
The present invention relates to a sterile pharmaceutical composition comprising tiotropium or a pharmaceutically acceptable salt thereof, for inhalation via nebulization to a subject (e.g. a human). The invention also relates to a process for preparing the pharmaceutical composition and its use in the treatment of respiratory diseases such as chronic obstructive pulmonary disease (COPD) in a subject.
1. A stable inhalation solution for the treatment of a respiratory disease, the inhalation solution being suitable for administration with a nebulizer, the inhalation solution comprising:
(i) tiotropium bromide;
(ii) citric acid;
(iii) sodium citrate;
(iv) sodium chloride; and
(ii) water,
wherein
the inhalation solution is substantially free of preservative and complexing agent and has an osmolality of about 200 to about 500 mOsm/kg, and
the inhalation solution is contained in a prefilled container.
2. The inhalation solution according to claim 1 , wherein the tiotropium bromide is anhydrous tiotropium bromide.
3. The inhalation solution according to claim 1 , wherein the tiotropium bromide is anhydrous amorphous tiotropium bromide.
4. The inhalation solution according to claim 1 , wherein the tiotropium bromide is tiotropium bromide monohydrate.
5. The inhalation solution according to claim 1 , wherein the solution comprises about 10 to about 80 micrograms of tiotropium bromide.
6. The inhalation solution according to claim 1 , wherein the volume of the inhalation solution is between about 0.1 ml to about 5 ml.
7. The inhalation solution according to claim 1 , wherein the volume of the inhalation solution is about 2 ml, and the solution comprises about 10 to about 80 micrograms of tiotropium bromide.
8. The inhalation solution according to claim 1 , wherein the pH of the inhalation solution is about 2.5 to about 3.0.
9. The inhalation solution according to claim 1 , wherein the pH of the inhalation solution is about 3.0.
10. The inhalation solution according to claim 1 , wherein the pH of the inhalation solution is about 2.9.
11. The inhalation solution according to claim 1 , wherein the pH of the inhalation solution is about 2.8.
12. The inhalation solution according to claim 1 , wherein the pH of the inhalation solution is about 2.7.
13. The inhalation solution according to claim 1 , wherein the container is a low density polyethylene container.
14. The inhalation solution according to claim 1 , wherein the inhalation solution contains greater than 90% of the initial amount of tiotropium bromide after being stored for 2 years at 25° C.
15. The inhalation solution according to claim 1 , wherein the inhalation solution contains greater than 95% of the initial amount of tiotropium bromide after being stored for 2 years at 25° C.
16. The inhalation solution according to claim 1 , wherein the inhalation solution contains greater than 98% of the initial amount of tiotropium bromide after being stored for 2 years at 25° C.
17. The inhalation solution according to claim 1 , wherein the solution comprises 0.9% by weight of sodium chloride.
18. A stable inhalation solution for the treatment of a respiratory disease, the inhalation solution being suitable for administration with a nebulizer, the inhalation solution comprising:
(i) tiotropium bromide;
(ii) a buffer;
(iii) water; and
(iv) a complexing agent in an amount of less than 0.1% by weight,
wherein the inhalation solution is substantially free of preservative.
19. The inhalation solution according to claim 18 , wherein the tiotropium bromide is anhydrous tiotropium bromide.
20. The inhalation solution according to claim 18 , wherein the tiotropium bromide is anhydrous amorphous tiotropium bromide.
21. The inhalation solution according to claim 18 , wherein the tiotropium bromide is tiotropium bromide monohydrate.
22. The inhalation solution according to claim 18 , wherein the solution comprises about 10 to about 80 micrograms of tiotropium bromide.
23. The inhalation solution according to claim 18 , wherein the volume of the inhalation solution is between about 0.1 ml to about 5 ml.
24. The inhalation solution according to claim 18 , wherein the volume of the inhalation solution is about 2 ml, and the solution comprises about 10 to about 80 micrograms of tiotropium bromide.
25. The inhalation solution according to claim 18 , wherein the pH of the inhalation solution is about 2.5 to about 3.0.
26. The inhalation solution according to claim 18 , wherein the pH of the inhalation solution is about 3.0.
27. The inhalation solution according to claim 18 , wherein the pH of the inhalation solution is about 2.9.
28. The inhalation solution according to claim 18 , wherein the pH of the inhalation solution is about 2.8.
29. The inhalation solution according to claim 18 , wherein the pH of the inhalation solution is about 2.7.
30. The inhalation solution according to claim 18 , wherein the inhalation solution contains greater than 90% of the initial amount of tiotropium bromide after being stored for 2 years at 25° C.
31. The inhalation solution according to claim 18 , wherein the inhalation solution contains greater than 95% of the initial amount of tiotropium bromide after being stored for 2 years at 25° C.
32. The inhalation solution according to claim 18 , wherein the inhalation solution contains greater than 98% of the initial amount of tiotropium bromide after being stored for 2 years at 25° C.
33. The inhalation solution according to claim 18 , wherein the solution further comprises 0.9% by weight of sodium chloride.
34. The inhalation solution according to claim 18 , wherein the inhalation solution has an osmolality of about 275 to about 325 mOsm/kg.
35. A stable inhalation solution for administration with a nebulizer, the inhalation solution comprising:
(i) tiotropium bromide;
(ii) a buffer; and
(iii) water,
wherein the inhalation solution is substantially free of preservative and complexing agent.
36. The inhalation solution according to claim 35 , wherein the tiotropium bromide is anhydrous tiotropium bromide.
37. The inhalation solution according to claim 35 , wherein the tiotropium bromide is anhydrous amorphous tiotropium bromide.
38. The inhalation solution according to claim 35 , wherein the tiotropium bromide is tiotropium bromide monohydrate.
39. The inhalation solution according to claim 35 , wherein the solution comprises about 10 to about 80 micrograms of tiotropium bromide.
40. The inhalation solution according to claim 35 , wherein the volume of the inhalation solution is between about 0.1 ml to about 5 ml.
41. The inhalation solution according to claim 35 , wherein the volume of the inhalation solution is about 2 ml, and the solution comprises about 10 to about 80 micrograms of tiotropium bromide.
42. The inhalation solution according to claim 35 , wherein the pH of the inhalation solution is about 2.5 to about 3.0.
43. The inhalation solution according to claim 35 , wherein the pH of the inhalation solution is about 3.0.
44. The inhalation solution according to claim 35 , wherein the pH of the inhalation solution is about 2.9.
45. The inhalation solution according to claim 35 , wherein the pH of the inhalation solution is about 2.8.
46. The inhalation solution according to claim 35 , wherein the pH of the inhalation solution is about 2.7.
47. The inhalation solution according to claim 35 , wherein the inhalation solution contains greater than 90% of the initial amount of tiotropium bromide after being stored for 2 years at 25° C.
48. The inhalation solution according to claim 35 , wherein the inhalation solution contains greater than 95% of the initial amount of tiotropium bromide after being stored for 2 years at 25° C.
49. The inhalation solution according to claim 35 , wherein the inhalation solution contains greater than 98% of the initial amount of tiotropium bromide after being stored for 2 years at 25° C.
50. The inhalation solution according to claim 35 , wherein the solution further comprises 0.9% by weight of sodium chloride.
51. The inhalation solution according to claim 35 , wherein the inhalation solution has an osmolality of about 275 to about 325 mOsm/kg.
52. A stable inhalation solution for the treatment of a respiratory disease, the inhalation solution being suitable for administration with a nebulizer, the inhalation solution comprising:
(i) tiotropium bromide;
(ii) a buffer;
(iii) sodium chloride; and
(iv) water,
wherein the inhalation solution is substantially free of preservative and complexing agent and has an osmolality of about 200 to about 500 mOsm/kg, and the inhalation solution is contained in a prefilled container.
53. The inhalation solution according to claim 52 , wherein the tiotropium bromide is anhydrous tiotropium bromide.
54. The inhalation solution according to claim 52 , wherein the tiotropium bromide is anhydrous amorphous tiotropium bromide.
55. The inhalation solution according to claim 52 , wherein the tiotropium bromide is tiotropium bromide monohydrate.
56. The inhalation solution according to claim 52 , wherein the solution comprises about 10 to about 80 micrograms of tiotropium bromide.
57. The inhalation solution according to claim 52 , wherein the volume of the inhalation solution is between about 0.1 ml to about 5 ml.
58. The inhalation solution according to claim 52 , wherein the volume of the inhalation solution is about 2 ml, and the solution comprises about 10 to about 80 micrograms of tiotropium bromide.
59. The inhalation solution according to claim 52 , wherein the pH of the inhalation solution is about 2.5 to about 3.0.
60. The inhalation solution according to claim 52 , wherein the pH of the inhalation solution is about 3.0.
61. The inhalation solution according to claim 52 , wherein the pH of the inhalation solution is about 2.9.
62. The inhalation solution according to claim 52 , wherein the pH of the inhalation solution is about 2.8.
63. The inhalation solution according to claim 52 , wherein the pH of the inhalation solution is about 2.7.
64. The inhalation solution according to claim 52 , wherein the inhalation solution contains greater than 90% of the initial amount of tiotropium bromide after being stored for 2 years at 25° C.
65. The inhalation solution according to claim 52 , wherein the inhalation solution contains greater than 95% of the initial amount of tiotropium bromide after being stored for 2 years at 25° C.
66. The inhalation solution according to claim 52 , wherein the inhalation solution contains greater than 98% of the initial amount of tiotropium bromide after being stored for 2 years at 25° C.
67. The inhalation solution according to claim 52 , wherein the solution comprises 0.9% by weight of sodium chloride.
68. The inhalation solution according to claim 1 , wherein the osmolality of about 275 to about 325 mOsm/kg.
69. The inhalation solution according to claim 18 , wherein the inhalation solution has an osmolality of about 200 to about 500 mOsm/kg.
70. The inhalation solution according to claim 35 , wherein the inhalation solution has an osmolality of about 200 to about 500 mOsm/kg.
71. The inhalation solution according to claim 52 , wherein the osmolality of about 275 to about 325 mOsm/kg.