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) about 10 to about 80 micrograms of tiotropium bromide, the tiotropium bromide being the sole active ingredient in the solution;
(ii) water;
(iii) optionally, a tonicity adjusting agent; and
(iv) about 0.01% to about 0.05% by weight of disodium EDTA,
wherein
the inhalation solution is free of preservative and has an osmolality of about 275 to about 325 mOsm/kg,
the inhalation solution contains greater than 90% of the initial amount of tiotropium bromide after being stored for 2 years at 25° C., 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 inhalation solution comprises about 0.01% by weight of disodium EDTA.
6. The inhalation solution according to claim 1 , wherein the inhalation solution comprises about 0.02% by weight of disodium EDTA.
7. The inhalation solution according to claim 1 , wherein the volume of the inhalation solution is between about 0.1 ml to about 5 ml.
8. The inhalation solution according to claim 1 , wherein the volume of the inhalation solution is about 2 ml.
9. The inhalation solution according to claim 1 , wherein the pH of the inhalation solution is about 2.5 to about 3.0.
10. The inhalation solution according to claim 1 , wherein the pH of the inhalation solution is about 3.0.
11. The inhalation solution according to claim 1 , wherein the pH of the inhalation solution is about 2.9.
12. The inhalation solution according to claim 1 , wherein the pH of the inhalation solution is about 2.8.
13. The inhalation solution according to claim 1 , wherein the pH of the inhalation solution is about 2.7.
14. The inhalation solution according to claim 1 , wherein the container is a low density polyethylene container.
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 inhalation solution contains no more than 0.2% of 2-hydroxy-2,2-dithiophen-2-ylacetic acid after 1 month of storage at 40° C. and 75% relative humidity.
18. The inhalation solution according to claim 1 , wherein the inhalation solution contains no more than 0.1% of 2-hydroxy-2,2-dithiophen-2-ylacetic acid after 1 month of storage at 25° C. and 60% relative humidity.
19. 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) about 10 to about 80 micrograms of tiotropium bromide;
(ii) water;
(iii) 0.9% by weight of sodium chloride; and
(iv) about 0.01% to about 0.02% by weight of disodium EDTA,
wherein
the inhalation solution is free of preservative and has an osmolality of about 275 to about 325 mOsm/kg,
the pH of the inhalation solution is between about 2.6 to about 3.0,
the inhalation solution contains greater than 90% of the initial amount of tiotropium bromide after being stored for 2 years at 25° C., and
the inhalation solution is contained in a prefilled container,
the inhalation solution is prepared by (a) adding tiotropium bromide to a solution of sodium chloride and disodium EDTA, where the solution has a pH of 2.6 to 3.0, (b) filtering the solution from step (a), and (c) filling a container with the filtered solution.
20. The inhalation solution according to claim 19 , wherein the tiotropium bromide is anhydrous amorphous tiotropium bromide.
21. 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) about 10 to about 80 micrograms of tiotropium bromide;
(ii) water;
(iii) optionally, a tonicity adjusting agent; and
(iv) optionally a complexing agent, the complexing agent being disodium EDTA,
wherein
the inhalation solution is free of preservative and has an osmolality of about 275 to about 325 mOsm/kg,
the pH of the inhalation solution is between about 2.6 to about 3.0,
the inhalation solution contains greater than 90% of the initial amount of tiotropium bromide after being stored for 2 years at 25° C.,
the inhalation solution contains no more than 1% of 2-hydroxy-2,2-dithiophen-2-ylacetic acid after 1 month of storage at 40° C. and 75% relative humidity; and
the inhalation solution is contained in a prefilled container.
22. The inhalation solution according to claim 21 , wherein the inhalation solution comprises about 0.01% by weight of disodium EDTA.
23. The inhalation solution according to claim 21 , wherein the inhalation solution comprises about 0.02% by weight of disodium EDTA.
24. The inhalation solution according to claim 21 , wherein the volume of the inhalation solution is between about 0.1 ml to about 5 ml.
25. The inhalation solution according to claim 21 , wherein the volume of the inhalation solution is about 2 ml.
26. The inhalation solution according to claim 21 , wherein the pH of the inhalation solution is between about 3.0.
27. The inhalation solution according to claim 21 , wherein the pH of the inhalation solution is between about 2.9.
28. The inhalation solution according to claim 21 , wherein the pH of the inhalation solution is between about 2.8.
29. The inhalation solution according to claim 21 , wherein the pH of the inhalation solution is between about 2.7.
30. The inhalation solution according to claim 21 , wherein the container is a low density polyethylene container.
31. The inhalation solution according to claim 21 , 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 21 , 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 21 , wherein the inhalation solution contains no more than 0.1% of 2-hydroxy-2,2-dithiophen-2-ylacetic acid after 1 month of storage at 25° C. and 60% relative humidity.
34. The inhalation solution according to claim 21 , wherein
the inhalation solution includes a tonicity adjusting agent and a complexing agent,
the inhalation solution is prepared by (a) adding tiotropium bromide to a solution of the tonicity adjusting agent and the complexing agent, where the solution has a pH of 2.6 to 3.0, (b) filtering the solution from step (a), and (c) filling a container with the filtered solution, and
the tiotropium bromide is anhydrous amorphous tiotropium bromide.
35. A stable inhalation solution for the treatment of a respiratory disease, the inhalation solution being suitable for administration with a nebulizer, the inhalation solution consisting of:
(i) about 10 to about 80 micrograms of tiotropium bromide;
(ii) water;
(iii) 0.9% by weight of sodium chloride; and
(iv) about 0.02% by weight of disodium EDTA,
wherein
the inhalation solution is free of preservative and has an osmolality of about 275 to about 325 mOsm/kg,
the inhalation solution contains greater than 95% of the initial amount of tiotropium bromide after being stored for 6 months at 25° C., and
the inhalation solution is contained in a prefilled container.
36. The inhalation solution according to claim 35 , wherein the tiotropium bromide is anhydrous amorphous tiotropium bromide.
37. The inhalation solution according to claim 36 , wherein the inhalation solution is prepared by (a) adding tiotropium bromide to a solution of the sodium hydroxide and the disodium EDTA, where the solution has a pH of 2.6 to 3.0, (b) filtering the solution from step (a), and (c) filling a container with the filtered solution.
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 volume of the inhalation solution is about 2 ml.
40. The inhalation solution according to claim 35 , wherein the pH of the inhalation solution is about 3.0.
41. The inhalation solution according to claim 35 , wherein the pH of the inhalation solution is about 2.9.
42. The inhalation solution according to claim 35 , wherein the pH of the inhalation solution is about 2.8.
43. The inhalation solution according to claim 35 , wherein the pH of the inhalation solution is about 2.7.
44. The inhalation solution according to claim 35 , wherein the inhalation solution contains at least 98% of the initial amount of tiotropium bromide after being stored for 6 months at 25° C.
45. The inhalation solution according to claim 35 , wherein the inhalation solution contains no more than 1% of 2-hydroxy-2,2-dithiophen-2-ylacetic acid after 1 month of storage at 40° C. and 75% relative humidity.
46. The inhalation solution according to claim 35 , wherein the inhalation solution contains no more than 0.2% of 2-hydroxy-2,2-dithiophen-2-ylacetic acid after 1 month of storage at 40° C. and 75% relative humidity.
47. A kit comprising a nebulizer, instructions for using a nebulizer and the inhalation solution according to claim 35 .
48. A method of treating chronic obstructive pulmonary disease in a patient in need thereof, the method comprising administering to the patient the inhalation solution according to claim 35 .
49. 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) about 10 to about 80 micrograms of tiotropium bromide;
(ii) water;
(iii) sodium chloride; and
(iv) about 0.01% to about 0.05% by weight of disodium EDTA,
wherein
the inhalation solution is free of preservative and has an osmolality of about 275 to about 325 mOsm/kg,
the inhalation solution contains greater than 90% of the initial amount of tiotropium bromide after being stored for 2 years at 25° C.,
the inhalation solution is contained in a prefilled container, and
the inhalation solution is prepared by (a) adding tiotropium bromide to a solution of sodium chloride and disodium EDTA, where the solution has a pH of 2.6 to 3.0, (b) filtering the solution from step (a), and (c) filling a container with the filtered solution.
50. 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) about 10 to about 80 micrograms of tiotropium bromide;
(ii) water;
(iii) sodium chloride; and
(iv) disodium EDTA,
wherein
the inhalation solution is free of preservative and has an osmolality of about 275 to about 325 mOsm/kg,
the pH of the inhalation solution is between about 2.6 to about 3.0,
the inhalation solution contains greater than 90% of the initial amount of tiotropium bromide after being stored for 2 years at 25° C.,
the inhalation solution contains no more than 1% of 2-hydroxy-2,2-dithiophen-2-ylacetic acid after 1 month of storage at 40° C. and 75% relative humidity,
the inhalation solution is contained in a prefilled container, and
the inhalation solution is prepared by (a) adding tiotropium bromide to a solution of sodium chloride and disodium EDTA, where the solution has a pH of 2.6 to 3.0, (b) filtering the solution from step (a), and (c) filling a container with the filtered solution.
51. The inhalation solution according to claim 19 , wherein the volume of the inhalation solution is about 2 ml.
52. The inhalation solution according to claim 49 , wherein the volume of the inhalation solution is about 2 ml.
53. The inhalation solution according to claim 50 , wherein the volume of the inhalation solution is about 2 ml.
54. A method of treating chronic obstructive pulmonary disease in a patient in need thereof, the method comprising administering to the patient the inhalation solution according to claim 1 .
55. A method of treating chronic obstructive pulmonary disease in a patient in need thereof, the method comprising administering to the patient the inhalation solution according to claim 19 .
56. A method of treating chronic obstructive pulmonary disease in a patient in need thereof, the method comprising administering to the patient the inhalation solution according to claim 21 .
57. A method of treating chronic obstructive pulmonary disease in a patient in need thereof, the method comprising administering to the patient the inhalation solution according to claim 49 .
58. A method of treating chronic obstructive pulmonary disease in a patient in need thereof, the method comprising administering to the patient the inhalation solution according to claim 50 .