Topical use of Levofloxacin for reducing lung inflammation

• US 8,629,139 B2
• Filed: 10/06/2009
• Issued: 01/14/2014
• Est. Priority Date: 10/07/2008
• Status: Active Grant

• Current Assignee: Horizon Orphan, LLC (Amgen Inc.)
• Original Assignee: Mpex Pharmaceutical, Inc. (Abbvie Incorporated)
• Inventors: Dudley, Michael N., Tsivkovski, Ruslan Y., Griffith, David C., Rodny, Olga
• Primary Examiner(s): OLSON, ERIC
• Application Number:
  US12/574,666
• Publication Number:
  US 20100087386A1
• Time in Patent Office: 1,561 Days
• Field of Search: None
• US Class Current: 514/230.2
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/536 ortho- or peri-condensed with carbocyclic ring systems
• CPC Class Codes: A61K 31/538 ortho- or peri-condensed with carbocyclic ring systems
• CPC Class Codes: A61K 31/5383 ortho- or peri-condensed with heterocyclic ring systems
• CPC Class Codes: A61K 31/7036 having at least one amino group directly attached to the carbocyclic ring, e.g. streptomycin, gentamycin, amikacin, validamycin, fortimicins
• CPC Class Codes: A61K 33/06 Aluminium, calcium or magnesium; Compounds thereof , e.g. clay
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 47/02 Inorganic compounds
• 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 19/04 for non-specific disorders of the connective tissue
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 7/02 Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• CPC Class Codes: C07D 498/14 Ortho-condensed systems
• 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

The present invention relates to methods and compositions for the treatment of pulmonary inflammation. In particular, methods and compositions using aerosol levofloxacin or ofloxacin to reduce pulmonary inflammation are provided.

Claims

1. A method for treating a pulmonary inflammation in the absence of a pulmonary bacterial infection in a subject comprising administering to said subject in need thereof an aerosol of a solution comprising levofloxacin or ofloxacin and a divalent or trivalent cation, wherein the solution comprises a divalent or trivalent cation concentration from about 150 mM to about 250 mM, and a levofloxacin or ofloxacin concentration from about 90 mg/ml to about 125 mg/ml.

2. The method of claim 1, wherein the subject has a disorder selected from the group consisting of asthma, cystic fibrosis (CF), pulmonary fibrosis, chronic bronchitis (CB), bronchiectasis, chronic granulomatous disease, sinusitis, chronic obstructive pulmonary disease (COPD), and pneumonia.

3. The method of claim 1, wherein the solution consists essentially of levofloxacin or ofloxacin and the divalent or trivalent cation.

4. The method of claim 1, wherein the solution comprises chloride.

5. The method of claim 1, wherein the solution comprises no lactose.

6. The method of claim 1, wherein the solution has an osmolality from about 300 mOsmol/kg to about 500 mOsmol/kg, and a pH from about 5 to about 8.

7. The method of claim 1, wherein the solution has an osmolality from about 350 mOsmol/kg to about 425 mOsmol/kg, and a pH from about 5 to about 6.5.

8. The method of claim 1, wherein the solution has a pH from about 5.5 to about 6.5.

9. The method of claim 1, wherein the divalent or trivalent cation is selected from magnesium, calcium, zinc, copper, aluminum, and iron.

10. The method of claim 1, wherein the solution comprises magnesium chloride.

11. The method of claim 1, wherein the solution has a levofloxacin or ofloxacin concentration from about 90 mg/ml to about 110 mg/ml, a magnesium chloride concentration between about 175 mM to about 225 mM, a pH between about 5 to about 7;

an osmolarity of from about 300 mOsmol/kg to about 500 mOsmol/kg, and lacks lactose.

12. 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.

13. 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.

14. 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.

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

16. The method of claim 15, wherein the vibrating mesh nebulizer is a PARI E-FLOW®

nebulizer.

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

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

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

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

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

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

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

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

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

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

27. The method of claim 1, further comprising co-administering an additional active agent selected from the group consisting of anti-inflammatory agent, antibiotic, bronchodilator, anticholinergic, glucocorticoid, eicosanoid inhibitor, and combinations thereof.

28. The method of claim 27, wherein co-administering comprises inhaling the additional active agent.

29. The method of claim 27, wherein the antibiotic is selected from the group consisting of tobramycin, aztreonam, ciprofloxacin, azithromycin, erythromycin tetracycline, quinupristin, linezolid, vancomycin, and chloramphenicol, colisitin and combinations thereof.

30. The method of claim 27, wherein the bronchodilator is selected from the group consisting of salbutamol, levosalbuterol, terbutaline, fenoterol, terbutlaine, pirbuterol, procaterol, bitolterol, rimiterol, carbuterol, tulobuterol, reproterol, salmeterol, formoterol, arformoterol, bambuterol, clenbuterol, indacterol, theophylline, roflumilast, cilomilast, and combinations thereof.

31. The method of claim 27, wherein the anticholinergic is selected from the group consisting of ipratropium, tiotropium, and combinations thereof.

32. The method of claim 27, wherein the glucocorticoid is selected from the group consisting of prednisone, fluticasone, budesonide, mometasone, ciclesonide, beclomethasone, and combinations thereof.

33. The method of claim 27, wherein the eicosanoid inhibitor is selected from the group consisting of montelukast, pranlukast, zafirlukast, zileuton, ramatroban, seratrodast, and combinations thereof.

34. A method for treating a pulmonary inflammation in the absence of a pulmonary bacterial infection in a subject, wherein the pulmonary inflammation is induced by one or more pro-inflammatory cytokines, said method comprising administering to said subject in need thereof an aerosol of a solution comprising levofloxacin or ofloxacin and a divalent or trivalent cation to achieve a reduction in the pulmonary concentration of said cytokine by at least 10%, wherein the solution comprises a divalent or trivalent cation concentration from about 150 mM to about 250 mM, and a levofloxacin or ofloxacin concentration from about 90 mg/ml to about 125 mg/ml.

35. The method of claim 34, wherein the pulmonary concentration of said cytokine is reduced by at least 20%.

36. The method of claim 34, wherein the pulmonary concentration of said cytokine is reduced by at least 40%.

37. The method of claim 34, wherein the pulmonary concentration of said cytokine is reduced by at least 60%.

38. The method of claim 34, wherein the pulmonary concentration of said cytokine is reduced by at least 80%.

39. A method for treating a pulmonary inflammation in the absence of a pulmonary bacterial infection in a subject comprising administering to said subject in need thereof an aerosol of a solution comprising levofloxacin or ofloxacin and a divalent or trivalent cation to achieve a reduction in the pulmonary concentration of one or more pro-inflammatory cytokines selected from IL-1β

, IL-6 and IL-8, whereby the pulmonary inflammation is reduced or suppressed, wherein the solution comprises a divalent or trivalent cation concentration from about 150 mM to about 250 mM, and a levofloxacin or ofloxacin concentration from about 90 mg/ml to about 125 mg/ml.

40. The method of claim 39, wherein the cytokine comprises IL-1β

.

41. The method of claim 39, wherein the cytokine comprises IL-6.

42. The method of claim 39, wherein the cytokine comprises IL-8.

43. A method for treating a pulmonary inflammation in the absence of a pulmonary bacterial infection in a subject, wherein the pulmonary inflammation is induced by one or more mediators selected from TNFα

and LPS, said method comprising administering to said subject in need thereof an aerosol of a solution comprising levofloxacin or ofloxacin and a divalent or trivalent cation, wherein the solution comprises a divalent or trivalent cation concentration from about 150 mM to about 250 mM, and a levofloxacin or ofloxacin concentration from about 90 mg/ml to about 125 mg/ml.

44. A method for reducing the pulmonary concentration of one or more pro-inflammatory cytokine in the absence of a pulmonary bacterial infection in a subject, said method comprising administering to said subject in need thereof an aerosol of a solution comprising levofloxacin or ofloxacin and a divalent or trivalent cation, wherein the solution comprises a divalent or trivalent cation concentration from about 150 mM to about 250 mM, and a levofloxacin or ofloxacin concentration from about 90 mg/ml to about 125 mg/ml.

45. The method of claim 44, wherein the cytokine comprises IL-1β

.

46. The method of claim 44, wherein the cytokine comprises IL-6.

47. The method of claim 44, wherein the cytokine comprises IL-8.