Inhalable powder containing tiotropium

• US 7,070,800 B2
• Filed: 10/11/2001
• Issued: 07/04/2006
• Est. Priority Date: 10/12/2000
• Status: Expired due to Term

• Current Assignee: Boehringer Ingelheim Pharma GmbH & Company Kg (C.H. Boehringer Sohn AG & Co. KG)
• Original Assignee: Boehringer Ingelheim Pharmaceuticals Incorporated (C.H. Boehringer Sohn AG & Co. KG)
• Inventors: Walz, Michael, Boeck, Georg, Bechtold-Peters, Karoline, Doerr, Rolf
• Primary Examiner(s): Azpuru, Carlos A.
• Application Number:
  US09/975,418
• Publication Number:
  US 20020110529A1
• Time in Patent Office: 1,727 Days
• Field of Search: 424/489, 424/493, 424/46, 424/434, 424/435, 424/451, 424/456
• US Class Current: 424/434
• CPC Class Codes: A61K 31/439 the ring forming part of a bridged ring system, e.g. quinuclidine 8-azabicyclo [3.2.1] octanes A61K31/46
• CPC Class Codes: A61K 9/0075 for inhalation via a dry powder inhaler [DPI], e.g. comprising micronized drug mixed with lactose carrier particles
• CPC Class Codes: A61K 9/14 Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles microspheres A61K9/16; microcapsules A61K9/50; nanocapsules, nanoparticles of the matrix type A61K9/51
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 11/08 Bronchodilators
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Abstract

The invention relates to powdered preparations containing tiotropium for inhalation, processes for preparing them as well as their use in preparing a pharmaceutical composition for the treatment of respiratory complaints, particularly for the treatment of COPD (chronic obstructive pulmonary disease) and asthma.

Claims

1. An inhalable powder comprising 0.04 to 0.8% of tiotropium in admixture with a physiologically acceptable excipient, wherein the excipient consists of a mixture of coarser excipient with an average particle size of 15 to 80 μ

m and finer excipient with an average particle size of 1 to 9 μ

m, the proportion of the finer excipient constituting 1 to 20% of the total amount of excipient, wherein the inhalable proportion of active substance is released reproducibly in low variability amounts when administered to a patent.

2. An inhalable powder according to claim 1, wherein the tiotropium is present in the form of the chloride, bromide, iodide, methanesulphonate, para-toluenesulphonate or methyl sulphate thereof.

5. An inhalable powder according to one of claims 1, 2, 3 or 4, wherein the excipient consists of a mixture of coarser excipient with an average particle size of 17 to 50 μ

m and finer excipient with an average particle size of 2 to 8 μ

m.

6. An inhalable powder according to one of claims 1, 2, 3 or 4, wherein the proportion of finer excipient in the total amount of excipient is 3 to 15%.

7. An inhalable powder according to one of claims 1, 2, 3 or 4, wherein the tiotropium used has an average particle size of 0.5 to 10 μ

m.

8. An inhalable powder according to one of claims 1, 2, 3 or 4, wherein one or more monosaccharides, disaccharides, oligo- or polysaccharides, polyalcohols, salts thereof, or mixtures thereof are used as the excipients.

9. An inhalable powder according to claim 8, wherein glucose, arabinose, lactose, saccharose, maltose, dextrane, sorbitol, mannitol, xylitol, sodium chloride, calcium carbonate or mixtures thereof are used as the excipients.

10. An inhalable powder according to claim 9, wherein glucose or lactose or mixtures thereof are used as the excipients.

11. A process for preparing an inhalable powder according to one of claims 1 to 4, comprising:

(a) mixing coarser excipient fractions with finer excipient fractions to obtain an excipient mixture, and (b) mixing the excipient mixture thus obtained with the tiotropium.

12. A method of treating a disease that is responsive to the administration of tiotropium, comprising administering to a host in need thereof an inhalable powder according to one of claims 1 to 4 or 12.

13. A method according to claim 12, wherein the disease is asthma or COPD.

16. An inhalable powder according to one of claim 1, 2, 3 or 4, wherein the excipient consists of a mixture of coarser excipient with an average particle size of 20 to 30 μ

m and finer excipient with an average particle size of 3 to 7 μ

m.

17. An inhalable powder according to one of claim 1, 2, 3 or 4, wherein the proportion of finer excipient in the total amount of excipient is 5 to 10%.

18. An inhalable powder according to one of claim 1, 2, 3 or 4, wherein the tiotropium used has an average particle size of 1 to 6 μ

m.

19. An inhalable powder according to one of claim 1, 2, 3 or 4, wherein the tiotropium used has an average particle size of 2 to 5 μ

m.

20. An inhalable powder according to claim 10, wherein lactose monohydrate is used as the excipient.

3. An inhalable powder comprising between 0.048 and 0.96% of tiotropium bromide in admixture with a physiologically acceptable excipient, wherein the excipient consists of a mixture of coarser excipient with an average particle size of 15 to 80 μ

m and finer excipient with an average particle size of 1 to 9 μ

m, the proportion of the finer excipient constituting 1 to 20% of the total amount of excipient, wherein the inhalable proportion of active substance is released reproducibly in low variability amounts when administered to a patent.

4. An inhalable powder comprising between 0.05 and 1% of tiotropium bromide monohydrate in admixture with a physiologically acceptable excipient, wherein the excipient consists of a mixture of coarser excipient with an average particle size of 15 to 80 μ

m and finer excipient with an average particle size of 1 to 9 μ

m, the proportion of the finer excipient constituting 1 to 20% of the total amount of excipient, wherein the inhalable proportion of active substance is released reproducibly in low variability amounts when administered to a patent.

14. An inhalable powder according to claim 4 comprising 0.1 to 0.8% of tiotropium bromide monohydrate.

15. An inhalable powder according to claim 4 comprising 0.2 to 0.5% of tiotropium bromide monohydrate.

21. An inhalable powder comprising between 0.2 and 0.5% of tiotropium bromide monohydrate in admixture with lactose monohydrate as the physiologically acceptable excipient, wherein the excipient consists of a mixture of coarser excipient with an average particle size of 20 to 30 μ

m and finer excipient with an average particle size of 3 to 7 μ

m, the proportion of the finer excipient constituting 5 to 10% of the total amount of excipient, wherein the inhalable proportion of active substance is released reproducibly in low variability amounts when administered to a patent.

22. An inhalable powder comprising 0.04 to 0.8% of tiotropium in admixture with a physiologically acceptable excipient, said inhalable powder prepared by a process comprising:

(a) mixing coarser excipient having an average particle size of 15 to 80 μ

m and finer excipient having an avenge particle size of 1 to 9 μ

m, wherein the proportion of the finer excipient constitutes 1 to 20% of the total amount of excipient, to obtain an excipient mixture, and (b) mixing the excipient mixture thus obtained with the tiotropium, wherein the inhalable proportion of active substance is released reproducibly in low variability amounts when administered to a patent.

23. An inhalable powder according to claim 22, wherein the tiotropium is present in the form of the chloride, bromide, iodide, methanesulphonate, para-toluenesulphonate or methyl sulphate thereof.

28. An inhalable powder according to one of claim 22, 23, 24 or 25, wherein the coarser excipient has an average particle size of 17 to 50 μ

m and the finer excipient has an average particle size of 2 to 8 μ

m.

29. An inhalable powder according to one of claim 22, 23, 24 or 25, wherein the coarser excipient has an average particle size of 20 to 30 μ

m and the finer excipient has an average particle size of 3 to 7 μ

m.

30. An inhalable powder according to one of claim 22, 23, 24 or 25, wherein the proportion of finer excipient in the total amount of excipient is 3 to 15%.

31. An inhalable powder according to one of claim 22, 23, 24 or 25, wherein the proportion of finer excipient in the total amount of excipient is 5 to 10%.

32. An inhalable powder according to one of claim 22, 23, 24 or 25, wherein the tiotropium used has an average particle size of 0.5 to 10 μ

m.

33. An inhalable powder according to one of claim 22, 23, 24 or 25, wherein the tiotropium used has an average particle size of 1 to 6 μ

m.

34. An inhalable powder according to one of claim 22, 23, 24 or 25, wherein the tiotropium used has an average particle size of 2 to 5 μ

m.

35. An inhalable powder according to one of claim 22, 23, 24 or 25, wherein one or more monosaccharides, disaccharides, oligo- or polysaccharides, polyalcohols, salts thereof, or mixtures thereof are used as the excipients.

36. An inhalable powder according to claim 35, wherein glucose, arabinose, lactose, saccharose, maltose, dextrane, sorbitol, mannitol, xylitol, sodium chloride, calcium carbonate or mixtures thereof are used as the excipients.

37. An inhalable powder according to claim 36, wherein glucose or lactose or mixtures thereof are used as the excipients.

38. An inhalable powder according to claim 37, wherein lactose monohydrate is used as the excipient.

40. A method of treating a disease that is responsive to the administration of tiotropium, comprising administering to a host in need thereof an inhalable powder according to one of claim 22, 23, 24 or 25 or 39.

41. A method according to claim 40, wherein the disease is asthma or COPD.

24. An inhalable powder comprising between 0.048 and 0.96% of tiotropium bromide in admixture with a physiologically acceptable excipient, said inhalable powder prepared by a process comprising:

(a) mixing coarser excipient having an average particle size of 15 to 80 μ

m and finer excipient having an average particle size of 1 to 9 μ

m, wherein the proportion of the finer excipient constitutes 1 to 20% of the total amount of excipient, to obtain an excipient mixture, and (b) mixing the excipient mixture thus obtained with the tiotropium bromide, wherein the inhalable proportion of active substance is released reproducibly in low variability amounts when administered to a patent.

25. An inhalable powder comprising between 0.05 and 1% of tiotropium bromide monohydrate in admixture with a physiologically acceptable excipient, said inhalable powder prepared by a process comprising:

(a) mixing coarser excipient having an average particle size of 15 to 80 μ

m and finer excipient having an average particle size of 1 to 9 μ

m, wherein the proportion of the finer excipient constitutes 1 to 20% of the total amount of excipient, to obtain an excipient mixture, and (b) mixing the excipient mixture thus obtained with the tiotropium bromide monohydrate, wherein the inhalable proportion of active substance is released reproducibly in low variability amounts when administered to a patent.

26. An inhalable powder according to claim 25 comprising 0.1 to 0.8% of tiotropium bromide monohydrate.

27. An inhalable powder according to claim 25 comprising 0.2 to 0.5% of tiotropium bromide monohydrate.

39. An inhalable powder comprising between 0.2 and 0.5% of tiotropium bromide monohydrate in admixture with lactose monohydrate as a physiologically acceptable excipient, said inhalable powder prepared by a process comprising:

(a) mixing coarser lactose monohydrate excipient having an average particle size of 20 to 30 μ

m and finer lactose monohydrate excipient having an average particle size of 3 to 7 μ

m, wherein the proportion of the finer lactose monohydrate excipient constitutes 5 to 10% of the total amount of excipient, to obtain an excipient mixture, and (b) mixing the excipient mixture thus obtained with the tiotropium bromide monohydrate, wherein the inhalable proportion of active substance is released reproducibly in low variability amounts when administered to a patent.