Aerosolized fluoroquinolones and uses thereof

• US 8,546,423 B2
• Filed: 10/22/2009
• Issued: 10/01/2013
• 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:
  US12/604,340
• Publication Number:
  US 20100166673A1
• Time in Patent Office: 1,440 Days
• Field of Search: 514/294, 514/279, 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 lung infection, comprising administering an aerosol of a solution comprising levofloxacin or ofloxacin and a divalent or trivalent cation to a lung.

2. The method of claim 1, wherein the lung infection is caused by one or more of the following bacteria:

Pseudomonas aeruginosa, Pseudomonas fluorescens, Pseudomonas acidovorans, Pseudomonas alcaligenes, Pseudomonas putida, Stenotrophomonas maltophilia, Aeromonas hydrophilia, Escherichia coli, Citrobacter freundii, Salmonella typhimurium, Salmonella typhi, Salmonella paratyphi, Salmonella enteritidis, Shigella dysenteriae, Shigella flexneri, Shigella sonnei, Enterobacter cloacae, Enterobacter aerogenes, Klebsiella pneumoniae, Klebsiella oxytoca, Serratia marcescens, Morganella morganii, Proteus mirabilis, Proteus vulgaris, Providencia alcalifaciens, Providencia rettgeri, Providencia stuartii, Acinetobacter calcoaceticus, Acinetobacter haemolyticus, Yersinia enterocolitica, Yersinia pestis, Yersinia pseudotuberculosis, Yersinia intermedia, Bordetella pertussis, Bordetella parapertussis, Bordetella bronchiseptica, Haemophilus influenzae, Haemophilus parainfluenzae, Haemophilus haemolyticus, Haemophilus parahaemolyticus, Haemophilus ducreyi, Pasteurella multocida, Pasteurella haemolytica, Helicobacter pylori, Campylobacter fetus, Campylobacter jejuni, Campylobacter coli, Borrelia burgdorferi, Vibrio cholera, Vibrio parahaemolyticus, Legionella pneumophila, Listeria monocytogenes, Neisseria gonorrhoeae, Neisseria meningitidis, Burkholderia cepacia, Francisella tularensis, Kingella, and Moraxella.

3. The method of claim 1, wherein the lung infection is caused by one or more of the following bacteria:

Pseudomonas aeruginosa, Stenotrophomonas maltophilia, Haemophilus influenzae, Burkholderia cepacia, and Moraxella.

4. The method of claim 1, wherein the lung infection is caused by a Burkholderia bacteria.

5. The method of claim 1, wherein the lung infection is associated with a bacterial pneumonia.

6. The method of claim 1, wherein the lung infection is caused by a gram-negative anaerobic bacteria.

7. The method of claim 1, wherein the lung infection is caused by one or more of the bacteria selected from the group consisting of Bacteroides fragilis, Bacteroides distasonis, Bacteroides 3452A homology group, Bacteroides vulgatus, Bacteroides ovalus, Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroides eggerthii, and Bacteroides splanchnicus.

8. The method of claim 1, wherein the lung infection is caused by a gram-positive bacteria.

9. The method of claim 1, wherein the lung infection is caused by one or more of the bacteria selected from the group consisting of Corynebacterium diphtherias, Corynebacterium ulcerans, Streptococcus pneumoniae, Streptococcus agalactiae, Streptococcus pyogenes, Streptococcus milleri;

Streptococcus (Group G);

Streptococcus (Group C/F);

Enterococcus faecalis, Enterococcus faecium, Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus saprophyticus, Staphylococcus intermedius, Staphylococcus hyicus subsp. hyicus, Staphylococcus haemolyticus, Staphylococcus hominis, and Staphylococcus saccharolyticus.

10. The method of claim 1, wherein the lung infection is caused by a gram-positive anaerobic bacteria.

11. The method of claim 1, wherein the lung infection is caused by one or more bacteria selected from the group consisting of Clostridium difficile, Clostridium perfringens, Clostridium tetini, and Clostridium botulinum.

12. The method of claim 1, wherein the lung infection is caused by an acid-fast bacteria.

13. The method of claim 1, wherein the lung infection is caused by a Mycobacterium bacteria.

14. The method of claim 13, wherein the lung infection is caused by one or more bacteria selected from the group consisting of Mycobacterium tuberculosis, Mycobacterium avium, Mycobacterium intracellulare, and Mycobacterium leprae.

15. The method of claim 1, wherein the lung infection is caused by an atypical bacteria.

16. The method of claim 1, wherein the lung infection is caused by one or more bacteria selected from the group consisting of Chlamydia pneumoniae and Mycoplasma pneumoniae.

17. 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.

18. The method of claim 1, wherein the aerosol has 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.

19. The method of claim 1, wherein the aerosol has 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.

20. The method of claim 1, wherein the aerosol has 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.

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

22. The method of claim 21, wherein the aerosol has 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.

23. The method of claim 21, wherein the aerosol has 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.

24. The method of claim 21, wherein the aerosol has 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.

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

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

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

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

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

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

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

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

33. The method of claim 1, further comprising the step of alternating the administration of said aerosol with administration of a second inhaled antimicrobial.

34. The method of claim 33, wherein the second inhaled antimicrobial is an aminoglycoside.

35. The method of claim 34, wherein the aminoglycoside is tobramycin.

36. The method of claim 33, wherein the second inhaled antimicrobial is a polymyxin.

37. The method of claim 36, wherein the polymyxin is colistin.

38. The method of claim 33, wherein the second inhaled antimicrobial is a monobactam.

39. The method of claim 38, wherein the monobactam is aztreonam.

40. The method of claim 1, comprising administering the aerosol once daily.

41. The method of claim 1, comprising administering the aerosol twice daily.