Use of aerosolized levofloxacin for treating cystic fibrosis

• US 9,700,564 B2
• Filed: 03/05/2012
• Issued: 07/11/2017
• Est. Priority Date: 09/04/2009
• Status: Active Grant

• Current Assignee: Horizon Orphan, LLC (Amgen Inc.)
• Original Assignee: Horizon Orphan, LLC (Amgen Inc.)
• Inventors: Morgan, Elizabeth E., Dudley, Michael N., Griffith, David C., Loutit, Jeffery S., Lomovskaya, Olga
• Primary Examiner(s): Stevens, Mark V
• Application Number:
  US13/412,423
• Publication Number:
  US 20120276153A1
• Time in Patent Office: 1,954 Days
• 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 31/5383 ortho- or peri-condensed with heterocyclic ring systems
• CPC Class Codes: A61K 33/06 Aluminium, calcium or magnesium; Compounds thereof , e.g. clay
• CPC Class Codes: A61K 33/14 Alkali metal chlorides; Alkaline earth metal chlorides
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• 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 9/08 Solutions composition of solutions A61K47/00
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/08 Bronchodilators
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• 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

Methods for treating cystic fibrosis. The method includes administering to a human in need thereof an aerosol solution comprising levofloxacin or ofloxacin and a divalent or trivalent cation. More particularly, the method includes administering the aerosol solution to a human having a pulmonary infection comprising P. aeruginosa.

Claims

1. A method for treating a pulmonary infection in a human having cystic fibrosis, wherein the pulmonary infection comprises Pseudomonas aeruginosa, the method comprising:

administering via inhalation 240 mg of levofloxacin twice daily for 28 days to the human having cystic fibrosis to treat the Pseudomonas aeruginosa pulmonary infection;

wherein the levofloxacin is in an aerosol of a solution comprising levofloxacin at a concentration from about 90 mg/ml to about 110 mg/ml, a magnesium cation at a concentration from about 175 mM to about 225 mM, 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.

2. The method of claim 1, wherein the magnesium cation is in the form of magnesium chloride.

3. The method of claim 2, wherein the solution comprises a levofloxacin concentration of about 100 mg/ml, a magnesium chloride concentration of about 200 mM, a pH between about 6.0 to about 6.5, and an osmolality of between about 300 mOsmol/kg to about 500 mOsmol/kg, and lacks lactose.

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

5. The method of claim 1, wherein the aerosol is produced by a vibrating mesh nebulizer.

6. The method of claim 1, further comprising administering an antibiotic, a bronchodilator, an anticholinergic agent, a glucocorticoid, an eicosanoid inhibitor, or a combination of two or more thereof.

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

8. The method of claim 1, further comprising administering by inhalation dornase alpha, azithromycin, salbutamol, pancrelipase, sodium chloride, seretide, vitamin A, vitamin D, vitamin E, vitamin K, or a combination of two or more thereof.

9. The method of claim 1, wherein the method achieves an increase in the CFQ-R respiratory domain greater than 3.

10. The method of claim 9, wherein the method achieves an increase in the CFQ-R respiratory domain greater than 5.

11. The method of claim 9, wherein the CFQ-R respiratory domain includes respiratory, body image, digestion, eating, emotion, health perception, physical, role/school, social, treatment burden, vitality, and weight.

12. A method for treating a pulmonary Pseudomonas aeruginosa infection in a human in need thereof, wherein the human has cystic fibrosis;

the method comprising;

administering via inhalation 240 mg of levofloxacin twice daily for 28 days to the human having cystic fibrosis to treat the Pseudomonas aeruginosa pulmonary infection;

wherein the levofloxacin is present in an aerosol of a solution comprising about 100 mg/ml of levofloxacin and about 200 mM of magnesium chloride, and 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.

13. The method of claim 12, wherein the method provides one or more of the following:

an increase in a CFQ-R respiratory domain greater than 1;

(ii) a reduction in the density of Pseudomonas aeruginosa by at least 40%;

(iii) an increase in FEV₁ of at least 2%;

(iv) in increase in FEF 25-75 of at least 5%;

(iv) a hazard ratio less than 1.0;

(v) a dose-normalized serum C_max of levofloxacin greater than 2 μ

g/L/mg;

or

(vi) a dose-normalized serum AUC of levofloxacin of at least 20 (ng·

h/L) mg.

14. The method of claim 12, wherein the method does not result in a greater than 16-fold increase in minimum inhibitory concentration of the Pseudomonas aeruginosa strain in the human having the highest minimum inhibitory concentration relative to other Pseudomonas aeruginosa strains.

15. The method of claim 12, wherein the human is a pediatric patient.

16. The method of claim 12, wherein the aerosol of the solution has a mass median aerodynamic diameter from about 2 microns to about 5 microns with a geometric standard deviation less than or equal to 2.5 microns.

17. The method of claim 12, wherein the solution has a pH from about 6.0 to about 6.5, and an osmolality from about 300 mOsmol/kg to about 500 mOsmol/kg.

18. The method of claim 17, wherein the solution has a pH of about 6.2 and an osmolality of about 383 mOsmol/kg.

19. The method of claim 17, further comprising administering an antibiotic, a bronchodilator, an anticholinergic agent, a glucocorticoid, an eicosanoid inhibitor, or a combination of two or more thereof.

20. A method for treating a pulmonary Pseudomonas aeruginosa infection in a human in need thereof, wherein the human has cystic fibrosis;

the method comprising;

administering via inhalation 240 mg of levofloxacin twice daily for 28 days, and thereafter discontinuing administration of the levofloxacin for 28 days, to treat the Pseudomonas aeruginosa pulmonary infection in the human having cystic fibrosis;

wherein the levofloxacin is present in an aerosol of a solution comprising about 90 mg/ml to about 110 mg/ml of levofloxacin and about 175 mM to about 225 mM of magnesium chloride, and 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.

21. The method of claim 20, wherein the solution comprises about 100 mg/ml of levofloxacin and about 200 mM of magnesium chloride, and wherein the solution has a pH from about 6.0 to about 6.5, and an osmolality from about 300 mOsmol/kg to about 500 mOsmol/kg.

22. The method of claim 20, wherein the human is a pediatric patient.

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

24. The method of claim 20, further comprising administering an antibiotic, a bronchodilator, an anticholinergic agent, a glucocorticoid, an eicosanoid inhibitor, or a combination of two or more thereof.