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 0.0005% to about 0.008% by weight of tiotropium or a pharmaceutically acceptable salt thereof;
(ii) water;
(iii) a complexing agent, the complexing agent being disodium EDTA and present at a concentration of about 0.01% to about 0.05% by weight; and
(iv) 0.9% by weight of sodium chloride,
wherein the pH of the composition ranges from 2.5 to 3.0, said composition is free of preservative, and the composition is contained in a prefilled container.
2. A composition according to claim 1 , wherein said composition is administered in nebulized form.
3. A composition according to claim 1 , wherein said composition is a solution.
4. A composition according to claim 1 , wherein tiotropium is present in an amount of about 0.01 mg to about 0.08 mg.
5. A composition according to claim 1 , wherein the volume of the composition in the prefilled container is between about 0.1 ml to about 5 ml.
6. A composition according to claim 1 , wherein the pH of the composition is between about 2.7 to 2.9.
7. A composition according to claim 1 , wherein the pH of the composition is 2.9.
8. A composition according to claim 1 , wherein the osmolality of the composition is between 275 mOsm/kg to 325 mOsm/kg.
9. A pharmaceutical composition consisting essentially of
(i) about 0.0005% to about 0.008% by weight of tiotropium or a pharmaceutically acceptable salt thereof;
(ii) water;
(iii) a complexing agent, the complexing agent being disodium EDTA; and
(iv) 0.9% by weight of sodium chloride,
wherein the pH of the composition ranges from 2.5 to 3.0, said composition is free of preservative, and the concentration of the complexing agent is present at a concentration of about 0.01% to about 0.05% by weight.
10. A composition according to claim 1 , wherein the composition does not require any mixing or dilution prior to administration.
11. A kit comprising a nebulizer, instructions for using the nebulizer and the composition according to claim 1 .
12. The kit according to claim 11 , wherein the nebulizer is selected from a jet nebulizer, ultrasonic nebulizer, vibrating mesh nebulizer and a breath actuated nebulizer.
13. 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 .
14. A process of preparing a pharmaceutical composition comprising about 0.0005% to about 0.008% by weight of tiotropium or a pharmaceutically acceptable salt thereof, water, a complexing agent, and 0.9% by weight of sodium chloride where the composition has a pH ranging from 2.5 to 3.0 and is free of preservative,
wherein the process comprises the steps of:
(a) dissolving sodium chloride in water;
(b) addition of a complexing agent to the solution of step (a);
(c) adjusting the pH of the solution to 2.5 to 3.0;
(d) adding tiotropium or a pharmaceutically acceptable salt thereof;
(e) filtering the solution; and
(f) filling a container with 2 mL of the solution.
15. A composition according to claim 1 , wherein the volume of the composition in the prefilled container is 2 mL.
16. A composition according to claim 1 , wherein the composition comprises about 0.05% by weight of complexing agent.
17. A composition according to claim 1 , wherein the composition comprises about 0.02% by weight of complexing agent.
18. A composition according to claim 1 , wherein the composition comprises about 0.01% by weight of complexing agent.
19. A composition according to claim 1 , wherein the container is a low-density polyethylene container.
20. A composition according to claim 1 , wherein the composition comprises greater than 95% of the initial amount of tiotropium or a pharmaceutically acceptable salt thereof after being stored for 3 months at 25° C. in the container.
21. A composition according to claim 9 , wherein said composition is administered in nebulized form.
22. A composition according to claim 9 , wherein said composition is a solution.
23. A composition according to claim 9 , wherein the tiotropium is present in an amount of about 0.01 mg to about 0.08 mg.
24. A composition according to claim 9 , wherein the volume of the composition is 2 mL.
25. A composition according to claim 9 , wherein the pH of the composition is between about 2.7 to 2.9.
26. A composition according to claim 9 , wherein the pH of the composition is 2.9.
27. A composition according to claim 9 , wherein the osmolality of the composition is between 275 mOsm/kg to 325 mOsm/kg.
28. A composition according to claim 9 , wherein the composition does not require any mixing or dilution prior to administration.
29. A composition according to claim 9 , wherein the composition comprises about 0.05% by weight of complexing agent.
30. A composition according to claim 9 , wherein the composition comprises about 0.02% by weight of complexing agent.
31. A composition according to claim 9 , wherein the composition comprises about 0.01% by weight of complexing agent.
32. A method of relieving bronchospasm associated with chronic obstructive pulmonary disease in a patient by administering to said patient the composition according to claim 9 .
33. A method according to claim 13 , wherein the composition is administered in nebulized form.
34. A method according to claim 32 , wherein the composition is administered in nebulized form.
35. A method according to claim 14 , wherein step (a) comprises dissolving tiotropium bromide in an aqueous solution of sodium chloride and disodium edetate.