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 pharmaceutical composition comprising
(i) about 0.0001% to about 0.03% by weight of anhydrous tiotropium bromide;
(ii) water;
(iii) a complexing agent, the complexing agent being disodium EDTA and present at a concentration of less than 0.1% by weight,
wherein the composition is free of preservative.
2. A composition according to claim 1 , wherein the composition is in a solution form for nebulization.
3. A composition according to claim 1 , wherein tiotropium is present in an amount of about 0.001 mg to about 0.3 mg.
4. A composition according to claim 1 , wherein tiotropium is present in an amount of about 0.005 mg to about 0.2 mg.
5. A composition according to claim 1 , wherein the complexing agent is present in an amount of about 0.05% by weight.
6. A composition according to claim 1 , wherein the complexing agent is present in an amount of about 0.02% by weight.
7. A composition according to claim 1 , wherein the complexing agent is present in an amount of about 0.01% by weight.
8. A composition according to claim 1 , wherein the composition further comprises sodium chloride.
9. A composition according to claim 8 , wherein the sodium chloride is present in an amount up to about 0.9% by weight.
10. A composition according to claim 1 , wherein the composition is contained in a prefilled container.
11. A composition according to claim 1 , wherein the volume of the composition is between about 0.1 ml to about 5 ml.
12. A composition of claim 1 , wherein the volume of the composition is about 2 ml.
13. A composition according to claim 1 , wherein the pH of the composition is between about 2.5 to about 3.5.
14. A composition according to claim 13 , wherein the pH of the composition is about 3.0.
15. A composition according to claim 13 , wherein the pH of the composition is about 2.9.
16. A composition according to claim 13 , wherein the pH of the composition is about 2.8.
17. A composition according to claim 13 , wherein the pH of the composition is about 2.7.
18. A composition according to claim 1 , wherein the osmolality of the composition is between 275 mOsm/kg to 325 mOsm/kg.
19. A kit comprising a nebulizer, instructions for using a nebulizer and the composition according to claim 1 .
20. A method of relieving bronchospasm associated with chronic obstructive pulmonary disease in a patient by administering to said patient the composition according to claim 1 .
21. A process of preparing a pharmaceutical composition comprising about 0.0001% to about 0.03% by weight of tiotropium or a pharmaceutically acceptable salt thereof, water, about 0.01% to about 0.1% by weight of a complexing agent, and about 0.9% by weight of sodium chloride, wherein the composition has a pH ranging from about 2.5 to about 3.5 and is free of preservative, the process comprising the steps of:
(a) dissolving sodium chloride in water to form a solution;
(b) adding a complexing agent to the solution of step (a);
(c) adjusting the pH of the solution of step (b) to about 2.5 to about 3.5;
(d) adding tiotropium or a pharmaceutically acceptable salt thereof;
(e) filtering the solution of step (d); and
(f) filling a container with the solution of step (e).
22. A prefilled container containing about 2 mL of an aqueous pharmaceutical composition comprising
(i) from about 10 to about 80 μg of tiotropium bromide;
(ii) sodium chloride; and
(iii) about 0.01% by weight of disodium EDTA,
wherein the composition is free of preservative, and the composition has a pH of from about 2.5 to about 3.5.
23. A prefilled container containing about 2 mL of an aqueous pharmaceutical composition comprising
(i) from about 10 to about 80 μg of tiotropium bromide;
(ii) sodium chloride; and
(iii) about 0.02% by weight of disodium EDTA,
wherein the composition is free of preservative, and the composition has a pH of from about 2.5 to about 3.5.
24. A prefilled container containing about 2 mL of an aqueous pharmaceutical composition comprising
(i) from about 10 to about 80 μg of tiotropium bromide;
(ii) sodium chloride; and
(iii) about 0.05% by weight of disodium EDTA,
wherein the composition is free of preservative, and the composition has a pH of from about 2.5 to about 3.5.
25. The prefilled container of claim 22 , wherein the sodium chloride is present at about 0.9% by weight.
26. The prefilled container of claim 25 , wherein the pH of the pharmaceutical composition is about 2.7.
27. The prefilled container of claim 25 , wherein the pH of the pharmaceutical composition is about 2.8.
28. The prefilled container of claim 25 , wherein the pH of the pharmaceutical composition is about 2.9.
29. The prefilled container of claim 25 , wherein the pH of the pharmaceutical composition is about 3.0.
30. The prefilled container of claim 22 , wherein the tiotropium bromide is anhydrous tiotropium bromide.
31. The prefilled container of claim 22 , wherein the tiotropium bromide is anhydrous amorphous tiotropium bromide.
32. The prefilled container of claim 22 , wherein the prefilled container consists essentially of about 2 mL of an aqueous pharmaceutical composition for nebulization consisting essentially of
(i) from about 10 to about 80 μg of anhydrous tiotropium bromide;
(ii) about 0.9% by weight of sodium chloride; and
(iii) about 0.01% by weight of disodium EDTA,
wherein
(a) the composition is free of preservative,
(b) the composition has a pH of from about 2.7 to about 3.0,
(c) the container is composed of low density polyethylene, and
(d) the composition contains greater than about 98% of the initial amount of tiotropium bromide after being stored for 3 months at 25° C.
33. The prefilled container of claim 32 , wherein the pH of the composition is about 3.0.
34. The prefilled container of claim 32 , wherein the pH of the composition is about 2.9.
35. The prefilled container of claim 32 , wherein the pH of the composition is about 2.8.
36. A composition according to claim 13 , wherein the pH of the composition is about 2.7.
37. The prefilled container of claim 32 , wherein the composition, after 1 month of storage at 40° C. at 75% relative humidity, is substantially free of 2-hydroxy-2,2-dithiophen-2ylacetic acid.
38. The prefilled container of claim 22 , wherein the osmolality of the composition is between 275 mOsm/kg to 325 mOsm/kg.
39. The prefilled container of claim 23 , wherein composition comprises 0.9% by weight of sodium chloride.