Aerosolized fluoroquinolones and uses thereof

• US 8,524,734 B2
• Filed: 10/22/2009
• Issued: 09/03/2013
• Est. Priority Date: 05/18/2005
• Status: Active Grant

• Current Assignee: Horizon Orphan, LLC (Amgen Inc.)
• Original Assignee: Mpex Pharmaceutical, Inc. (Abbvie Incorporated)
• Inventors: Surber, Mark W., Bostian, Keith A., Dudley, Michael N., Lomovskaya, Olga, Griffith, David C.
• Primary Examiner(s): ALSTRUM ACEVEDO, JAMES HENRY
• Application Number:
  US12/604,324
• Publication Number:
  US 20100040560A1
• Time in Patent Office: 1,412 Days
• Field of Search: 514/279, 514/294, 424/405, 424/602, 424/641, 424/646, 424/677, 424/681, 424/682
• US Class Current: 514/294
• CPC Class Codes: A61K 31/5383 ortho- or peri-condensed with heterocyclic ring systems
• CPC Class Codes: A61K 47/02 Inorganic compounds
• CPC Class Codes: A61K 9/0073 Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy; nasal sprays A61K9/0043; inhalation of vapours of volatile or heated drugs, e.g. essential oils or nicotine, A61K9/007; devices A61M
• 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 9/0078 for inhalation via a nebulizer such as a jet nebulizer, ultrasonic nebulizer, e.g. in the form of aqueous drug solutions or dispersions
• CPC Class Codes: A61K 9/5123 Organic compounds, e.g. fats, sugars
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: Y02A 50/30 Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

Disclosed herein are formulations of fluoroquinolones suitable for aerosolization and use of such formulations for aerosol administration of fluoroquinolone antimicrobials for the treatment of pulmonary bacterial infections. In particular, inhaled levofloxacin specifically formulated and delivered for bacterial infections of the lungs is described. Methods include inhalation protocols and manufacturing procedures for production and use of the compositions described.

Claims

1. A method of treating a bacterial infection in a patient having a chronic obstructive pulmonary disease, comprising administering an aerosol of a solution comprising levofloxacin or ofloxacin and a divalent or trivalent cation to a lung of the patient.

2. The method of claim 1, wherein the solution comprises levofloxacin at a concentration from about 100 mM to about 625 mM and magnesium chloride at a concentration from about 125 mM to about 250 mM, has a pH from about 5.5 to about 6.5, and an osmolality from about 350 mOsmol/kg to about 750 mOsmol/kg.

3. The method of claim 1, wherein the aerosol comprises a mass median aerodynamic diameter from about 2 microns to about 5 microns with a geometric standard deviation less than or equal to about 2.5 microns.

4. The method of claim 1, wherein the aerosol comprises a mass median aerodynamic diameter from about 2.5 microns to about 4.5 microns with a geometric standard deviation less than or equal to about 1.8 microns.

5. The method of claim 1, wherein the aerosol comprises a mass median aerodynamic diameter from about 2.8 microns to about 4.3 microns with a geometric standard deviation less than or equal to about 2 microns.

6. The method of claim 1, comprising producing the aerosol with a vibrating mesh nebulizer.

7. The method of claim 6, wherein the aerosol comprises a mass median aerodynamic diameter from about 2 microns to about 5 microns with a geometric standard deviation less than or equal to about 2.5 microns.

8. The method of claim 6, wherein the aerosol comprises a mass median aerodynamic diameter from about 2.8 microns to about 4.3 microns with a geometric standard deviation less than or equal to about 2 microns.

9. The method of claim 6, wherein the aerosol comprises a mass median aerodynamic diameter from about 2.5 microns to about 4.5 microns with a geometric standard deviation less than or equal to about 1.8 microns.

10. The method of claim 1, wherein at least about 20 mg of levofloxacin or ofloxacin is administered to the lung.

11. The method of claim 1, wherein at least about 100 mg of levofloxacin or ofloxacin is administered to the lung.

12. The method of claim 1, wherein at least about 125 mg of levofloxacin or ofloxacin is administered to the lung.

13. The method of claim 1, wherein at least about 150 mg of levofloxacin or ofloxacin is administered to the lung.

14. The method of claim 1, wherein the aerosol is administered to the lung in less than about 10 minutes.

15. The method of claim 1, wherein the aerosol is administered to the lung in less than about 5 minutes.

16. The method of claim 1, wherein the aerosol is administered to the lung in less than about 3 minutes.

17. The method of claim 1, wherein the aerosol is administered to the lung in less than about 2 minutes.

18. A method of treating a bacterial infection in a patient having cystic fibrosis, comprising administering an aerosol of a solution comprising levofloxacin or ofloxacin and a divalent or trivalent cation to a lung of the patient.

19. The method of claim 18, wherein the solution comprises levofloxacin at a concentration from about 100 mM to about 625 mM and magnesium chloride at a concentration from about 125 mM to about 250 mM, has a pH from about 5.5 to about 6.5, and an osmolality from about 350 mOsmol/kg to about 750 mOsmol/kg.

20. The method of claim 18, wherein the aerosol comprises a mass median aerodynamic diameter from about 2 microns to about 5 microns with a geometric standard deviation less than or equal to about 2.5 microns.

21. The method of claim 18, wherein the aerosol comprises a mass median aerodynamic diameter from about 2.5 microns to about 4.5 microns with a geometric standard deviation less than or equal to about 1.8 microns.

22. The method of claim 18, wherein the aerosol comprises a mass median aerodynamic diameter from about 2.8 microns to about 4.3 microns with a geometric standard deviation less than or equal to about 2 microns.

23. The method of claim 18, comprising producing the aerosol with a vibrating mesh nebulizer.

24. The method of claim 23, wherein the aerosol comprises a mass median aerodynamic diameter from about 2 microns to about 5 microns with a geometric standard deviation less than or equal to about 2.5 microns.

25. The method of claim 23, wherein the aerosol comprises a mass median aerodynamic diameter from about 2.8 microns to about 4.3 microns with a geometric standard deviation less than or equal to about 2 microns.

26. The method of claim 23, wherein the aerosol comprises a mass median aerodynamic diameter from about 2.5 microns to about 4.5 microns with a geometric standard deviation less than or equal to about 1.8 microns.

27. The method of claim 18, wherein at least about 20 mg of levofloxacin or ofloxacin is administered to the lung.

28. The method of claim 18, wherein at least about 100 mg of levofloxacin or ofloxacin is administered to the lung.

29. The method of claim 18, wherein at least about 125 mg of levofloxacin or ofloxacin is administered to the lung.

30. The method of claim 18, wherein at least about 150 mg of levofloxacin or ofloxacin is administered to the lung.

31. The method of claim 18, wherein the aerosol is administered to the lung in less than about 10 minutes.

32. The method of claim 18, wherein the aerosol is administered to the lung in less than about 5 minutes.

33. The method of claim 18, wherein the aerosol is administered to the lung in less than about 3 minutes.

34. The method of claim 18, wherein the aerosol is administered to the lung in less than about 2 minutes.

35. A method of treating a bacterial infection in a patient, comprising administering levofloxacin or ofloxacin to the patient to achieve a concentration in a lung of the patient of at least 32 μ

g/ml of levofloxacin or ofloxacin, wherein the levofloxacin or ofloxacin is administered as an aerosol comprising a divalent or trivalent cation.

36. The method of claim 35, wherein the concentration achieved is at least 128 μ

g/ml of levofloxacin or ofloxacin.

37. The method of claim 35, wherein the concentration achieved is at least 512 μ

g/ml of levofloxacin or ofloxacin.

38. The method of claim 35, wherein the concentration achieved is from 800 μ

g/mL to 1600 μ

g/mL of levofloxacin or ofloxacin.

39. The method of claim 35, wherein the aerosol comprises greater than about 50 mg/ml levofloxacin and magnesium chloride, has a pH from about 5.5 to about 6.5, and an osmolality from about 350 mOsmol/kg to about 750 mOsmol/kg.