Aerosol fluoroquinolone formulations for improved pharmacokinetics

• US 9,717,738 B2
• Filed: 04/18/2016
• Issued: 08/01/2017
• Est. Priority Date: 10/07/2008
• Status: Active Grant

• Current Assignee: Horizon Orphan, LLC (Amgen Inc.)
• Original Assignee: Horizon Orphan, LLC (Amgen Inc.)
• Inventors: Surber, Mark W., Bostian, Keith A., Griffith, David C., Dudley, Michael N., Rodny, Olga
• Primary Examiner(s): RAO, SAVITHA M
• Application Number:
  US15/132,122
• Publication Number:
  US 20160287606A1
• Time in Patent Office: 470 Days
• Field of Search: 51421015, 5142302, 424 45
• 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 of treating a chronic pulmonary infection due to Pseudomonas aeruginosa in a subject with cystic fibrosis in need thereof, the method comprising administering to the lungs of the subject with cystic fibrosis an aerosol of a solution comprising about 100 mg/ml of levofloxacin and about 200 mM of magnesium chloride;

wherein the solution has a pH from about 5 to about 7 and an osmolality from about 350 mOsmol/kg to about 400 mOsmol/kg, to treat the chronic pulmonary infection due to Pseudomonas aeruginosa.

2. The method of claim 1, wherein about 240 mg of levofloxacin is administered to the subject.

3. A method of treating a Pseudomonas pulmonary infection in a subject in need thereof, the method comprising administering to the lungs of the subject an aerosol of a solution comprising from about 90 mg/ml to about 110 mg/ml of levofloxacin and from about 190 mM to about 210 mM of a magnesium cation to treat the Pseudomonas pulmonary infection.

4. The method of claim 3, wherein the Pseudomonas is Pseudomonas aeruginosa, Pseudomonas fluorescens, Pseudomonas acidovorans, Pseudomonas alcaligenes, Pseudomonas putida, or a combination of two or more thereof.

5. The method of claim 3, wherein the subject has cystic fibrosis.

6. The method of claim 3, wherein the solution comprises about 100 mg/ml of levofloxacin and about 200 mM of the magnesium cation;

wherein the solution has a pH from about 5 to about 7 and an osmolality from about 300 mOsmol/kg to about 500 mOsmol/kg; and

wherein from about 200 mg to about 280 mg of levofloxacin is administered to the subject.

7. The method of claim 3, wherein from about 230 mg to about 250 mg of levofloxacin is administered to the subject.

8. The method of claim 4, wherein the Pseudomonas is Pseudomonas aeruginosa.

9. The method of claim 6, wherein the solution has a pH from about 6.0 to about 6.5 and an osmolality from about 350 mOsmol/kg to about 400 mOsmol/kg.

10. The method of claim 3, wherein the magnesium cation is in the form of magnesium chloride.

11. A method of treating a Mycobacterium pulmonary infection in a subject in need thereof, the method comprising administering to the lungs of the subject an aerosol of a solution comprising from about 90 mg/ml to about 110 mg/ml of levofloxacin and from about 190 mM to about 210 mM of a magnesium cation to treat the Mycobacterium pulmonary infection.

12. The method of claim 11, wherein the Mycobacterium is Mycobacterium avium, Mycobacterium intracellulare, or a combination thereof.

13. The method of claim 11, wherein the solution comprises about 100 mg/ml of levofloxacin and about 200 mM of the magnesium cation;

wherein the solution has a pH from about 5 to about 7 and an osmolality from about 300 mOsmol/kg to about 500 mOsmol/kg; and

wherein from about 200 mg to about 280 mg of levofloxacin is administered to the subject.

14. The method of claim 13, wherein from about 230 mg to about 250 mg of levofloxacin is administered to the subject.

15. The method of claim 13, wherein about 240 mg of levofloxacin is administered to the subject.

16. The method of claim 13, wherein the solution has a pH from about 6.0 to about 6.5 and an osmolality from about 350 mOsmol/kg to about 400 mOsmol/kg.

17. The method of claim 11, wherein the magnesium cation is in the form of magnesium chloride.

18. A method of treating bronchiectasis in a subject in need thereof, the method comprising administering to the lungs of the subject an aerosol of a solution comprising from about 90 mg/ml to about 110 mg/ml of levofloxacin and from about 190 mM to about 210 mM of a magnesium cation to treat the bronchiectasis.

19. The method of claim 18, wherein the solution comprises about 100 mg/ml of levofloxacin and about 200 mM of the magnesium cation;

wherein the solution has a pH from about 5 to about 7 and an osmolality from about 300 mOsmol/kg to about 500 mOsmol/kg; and

wherein from about 200 mg to about 280 mg of levofloxacin is administered to the subject.

20. The method of claim 19, wherein from about 230 mg to about 250 mg of levofloxacin is administered to the subject.

21. The method of claim 20, wherein from about 230 mg to about 250 mg of levofloxacin is administered to the subject.

22. The method of claim 19, wherein the solution has a pH from about 6.0 to about 6.5 and an osmolality from about 350 mOsmol/kg to about 400 mOsmol/kg.

23. The method of claim 18, wherein the magnesium cation is in the form of magnesium chloride.

24. A method of treating a bacterial pulmonary infection in a subject in need thereof, the method comprising administering to the lungs of the subject an aerosol of a solution comprising from about 90 mg/ml to about 110 mg/ml of levofloxacin and from about 190 mM to about 210 mM of a magnesium cation to treat the bacterial pulmonary infection.

25. The method of claim 24, wherein the solution comprises about 100 mg/ml of levofloxacin and about 200 mM of the magnesium cation;

wherein the solution has a pH from about 5 to about 7 and an osmolality from about 300 mOsmol/kg to about 500 mOsmol/kg; and

wherein from about 200 mg to about 280 mg of levofloxacin is administered to the subject.

26. The method of claim 24, wherein the magnesium cation is in the form of magnesium chloride.

27. The method of claim 25, wherein about 240 mg of levofloxacin is administered to the subject.

28. The method of claim 25, wherein the solution has a pH from about 6.0 to about 6.5 and an osmolality from about 350 mOsmol/kg to about 400 mOsmol/kg.

29. The method of claim 24, wherein the bacterial pulmonary infection is caused by 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, Moraxella, Bacteroides fragilis, Bacteroides distasonis, Bacteroides 3452A homology group, Bacteroides vulgatus, Bacteroides ovalus, Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroides eggerthii, Bacteroides splanchnicus, Corynebacterium diphtheriae, 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, Staphylococcus saccharolyticus, Clostridium difficile, Clostridium perfringens, Clostridium tetini, Clostridium botulinum, Mycobacterium tuberculosis, Mycobacterium avium, Mycobacterium intracellulare, and Mycobacterium leprae, Chlamydia pneumoniae, Mycoplasma pneumoniae, or a combination of two or more thereof.