Aerosol fluoroquinolone formulations for improved pharmacokinetics

• US 8,815,838 B2
• Filed: 10/06/2009
• Issued: 08/26/2014
• Est. Priority Date: 10/07/2008
• Status: Active Grant

• Current Assignee: Horizon Therapeutics US Holding LLC (Amgen Inc.)
• Original Assignee: MPEX Pharmaceuticals Incorporated (Abbvie Incorporated)
• Inventors: Griffith, David C., Dudley, Michael N., Surber, Mark W., Bostian, Keith A., Rodny, Olga
• Primary Examiner(s): RAO, SAVITHA M
• Application Number:
  US12/574,680
• Publication Number:
  US 20100087416A1
• Time in Patent Office: 1,785 Days
• Field of Search: 514/210.15, 514/230.2, 424/45
• US Class Current: 514/210.15
• CPC Class Codes: A61K 31/4375 the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
• CPC Class Codes: A61K 31/47 Quinolines; Isoquinolines
• 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 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 9/0078 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: 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 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• 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 the field of antimicrobial agents. In particular, the present invention relates to the use of aerosolized fluoroquinolones formulated with divalent or trivalent cations and having improved pulmonary availability for the treatment and management of bacterial infections of the lung and upper respiratory tract.

Claims

1. A method for treating a pulmonary infection, comprising administering to a human having said pulmonary infection an aerosol of a solution comprising levofloxacin or ofloxacin and a divalent or trivalent cation to achieve a maximum lung sputum concentration (C_max) of at least 1200 mg/L and a lung sputum area under the curve (AUC) of at least 1500 h·

mg/L, wherein the solution comprises a divalent or trivalent cation concentration from about 50 mM to about 400 mM, and a levofloxacin or ofloxacin concentration from between about 50 mg/ml to about 200 mg/ml.

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

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

4. The method of claim 1, comprising achieving a maximum lung sputum concentration (C_max) of at least 1700 mg/L.

5. The method of claim 1, comprising achieving a maximum lung sputum concentration (C_max) of at least 2000 mg/L.

6. The method of claim 1, comprising achieving a maximum lung sputum concentration (C_max) of at least 3000 mg/L.

7. The method of claim 1, comprising achieving a maximum lung sputum concentration (C_max) of at least 4000 mg/L.

8. The method of claim 1, comprising achieving a lung sputum area under the curve (AUC) of at least 1700 h·

mg/L.

9. The method of claim 1, comprising achieving a lung sputum area under the curve (AUC) of at least 2000 h·

mg/L.

10. The method of claim 1, comprising achieving a lung sputum area under the curve (AUC) of at least 3000 h·

mg/L.

11. The method of claim 1, comprising achieving a lung sputum area under the curve (AUC) of at least 4000 h·

mg/L.

12. The method of claim 1, wherein the solution comprises a divalent or trivalent cation concentration from about 100 mM to about 300 mM, and a levofloxacin or ofloxacin concentration from about 75 mg/ml to about 150 mg/ml.

13. The method of claim 1, 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.

14. The method of claim 1, wherein the solution comprises an osmolality from about 300 mOsmol/kg to about 600 mOsmol/kg, and a pH from about 5 to about 8.

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

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

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

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

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

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

20. The method of claim 1, wherein the human has a pulmonary disorder selected from the group consisting of cystic fibrosis, chronic obstructive pulmonary disease, chronic bronchitis, bronchiectasis, and asthma.

21. The method of claim 1, wherein the pulmonary infection comprises one or more bacteria selected from the group consisting of 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.

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

23. The method of claim 1, wherein the pulmonary 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.

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

25. The method of claim 1, wherein the pulmonary 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.

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

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

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

29. The method of claim 1, wherein the pulmonary infection is caused by one or more bacteria selected from the group consisting of Mycobacterium tuberculosis, Mycobacterium avium, Mycobacterium intracellulare, and Mycobacterium leprae.

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

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

32. 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.

33. 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.

34. 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.

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

36. The method of claim 35, wherein the vibrating mesh nebulizer is a PARI E-FLOW®

nebulizer.

37. The method of claim 1, wherein a respirable drug dose (RDD) of at least about 20 mg of levofloxacin or ofloxacin is administered to the lung.

38. The method of claim 1, wherein a respirable drug dose (RDD) of at least about 100 mg of levofloxacin or ofloxacin is administered to the lung.

39. The method of claim 1, wherein a respirable drug dose (RDD) of at least about 125 mg of levofloxacin or ofloxacin is administered to the lung.

40. The method of claim 1, wherein a respirable drug dose (RDD) of at least about 150 mg of levofloxacin or ofloxacin is administered to the lung.

41. The method of claim 1, wherein a loaded dose of at least about 100 mg is aerosolized.

42. The method of claim 1, wherein a loaded dose of at least about 200 mg is aerosolized.

43. The method of claim 1, wherein a loaded dose of at least about 300 mg is aerosolized.

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

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

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

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

48. The method of claim 1, further comprising co-administering an additional active agent selected from the group consisting of antibiotics, bronchodilators, anticholinergics, glucocorticoids, eicosanoid inhibitors, CFTR modulators, agents to restore airway surface liquid, anti-inflammatory agents, and combinations thereof.

49. The method of claim 48, wherein co-administering comprises inhaling the additional active agent.

50. The method of claim 48, wherein the antibiotic is selected from the group consisting of tobramycin, aztreonam, ciprofloxacin, azithromycin, tetracycline, quinupristin, linezolid, vancomycin, and chloramphenicol, colisitin and combinations thereof.

51. The method of claim 48, 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.

52. The method of claim 48, wherein the anticholinergic is selected from the group consisting of ipratropium, tiotropium, and combinations thereof.

53. The method of claim 48, wherein the glucocorticoid is selected from the group consisting of prednisone, fluticasone, budesonide, mometasone, ciclesonide, beclomethasone, and combinations thereof.

54. The method of claim 48, wherein the CFTR modulator is selected from the group consisting of VX-770, atluren, VX-809, and combinations thereof.

55. The method of claim 48, wherein the agents to restore airway surface liquid is selected from the group consisting of denufosol, mannitol, GS-9411, SPI-8811, and combinations thereof.

56. The method of claim 48, wherein the anti-inflammatory agent is selected from the group consisting of ibuprofen, sildenafil, simavastatin, and combinations thereof.

57. The method of claim 48, wherein the eicosanoid inhibitor is selected from the group consisting of montelukast, pranlukast, zafirlukast, zileuton, ramatroban, seratrodast, and combinations thereof.

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

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

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

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

60. A method of treating a chronic lung infection, comprising administering to a subject having a chronic lung infection an aerosol of a solution comprising levofloxacin or ofloxacin and a divalent or trivalent cation to achieve a maximum lung sputum concentration (C_max) of at least 1200 mg/L and a lung sputum area under the curve (AUC) of at least 1500 h·

mg/L, wherein the solution comprises a divalent or trivalent cation concentration from about 50 mM to about 400 mM, and a levofloxacin or ofloxacin concentration from between about 50 mg/ml to about 200 mg/ml.

61. The method of claim 60, wherein the solution consists essentially of levofloxacin or ofloxacin and the divalent or trivalent cation.

62. The method of claim 60, wherein the solution comprises no lactose.

63. The method of claim 60, wherein the human has a pulmonary disorder selected from the group consisting of cystic fibrosis, chronic obstructive pulmonary disease, chronic bronchitis, bronchiectasis, pneumonia, and asthma.

64. The method of claim 60, wherein the solution comprises a divalent or trivalent cation concentration from about 100 mM to about 300 mM, and a levofloxacin or ofloxacin concentration from about 75 mg/ml to about 150 mg/ml.

65. The method of claim 60, 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.

66. The method of claim 60, wherein the solution comprises an osmolality from about 300 mOsmol/kg to about 600 mOsmol/kg, and a pH from about 5 to about 8.

67. The method of claim 60, wherein the solution comprises an osmolality from about 350 mOsmol/kg to about 425 mOsmol/kg, and a pH from about 5 to about 6.5.

68. The method of claim 60, wherein the solution comprises a pH from about 5.5 to about 6.5.

69. The method of claim 60, wherein the divalent or trivalent cation is selected from magnesium, calcium, zinc, copper, aluminum, and iron.

70. The method of claim 60, wherein the solution comprises magnesium chloride.

71. The method of claim 60, further comprising co-administering an additional active agent selected from the group consisting of antibiotics, bronchodilators, anticholinergics, glucocorticoids, eicosanoid inhibitors, and combinations thereof.

72. The method of claim 71, wherein co-administering comprises inhaling the additional active agent.

73. The method of claim 71, wherein the antibiotic is selected from the group consisting of tobramycin, aztreonam, ciprofloxacin, azithromycin, tetracycline, quinupristin, linezolid, vancomycin, and chloramphenicol, colisitin and combinations thereof.

74. The method of claim 71, 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.

75. The method of claim 71, wherein the anticholinergic is selected from the group consisting of ipratropium, tiotropium, and combinations thereof.

76. The method of claim 71, wherein the glucocorticoid is selected from the group consisting of prednisone, fluticasone, budesonide, mometasone, ciclesonide, beclomethasone, and combinations thereof.

77. The method of claim 71, wherein the eicosanoid inhibitor is selected from the group consisting of montelukast, pranlukast, zafirlukast, zileuton, ramatroban, seratrodast, and combinations thereof.

78. The method of claim 60, comprising administering the aerosol once daily.

79. The method of claim 60, comprising administering the aerosol twice daily.