Aerosolized fluoroquinolones and uses thereof

• US 8,357,696 B2
• Filed: 01/28/2010
• Issued: 01/22/2013
• Est. Priority Date: 05/18/2005
• Status: Active Grant

• Current Assignee: Horizon Therapeutics US Holding LLC (Amgen Inc.)
• Original Assignee: MPEX Pharmaceuticals Incorporated (Abbvie Incorporated)
• Inventors: Surber, Mark W., Bostian, Keith A., Dudley, Michael N., Rodny, Olga, Griffith, David C.
• Primary Examiner(s): ALSTRUM ACEVEDO, JAMES HENRY
• Application Number:
  US12/695,981
• Publication Number:
  US 20100158957A1
• Time in Patent Office: 1,090 Days
• Field of Search: 514/279, 514/294, 424/405, 424/489, 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 pharmaceutical aerosol for nasal, sinunasal or pulmonary administration comprising a dispersed liquid phase and a continuous gas phase, wherein the dispersed liquid phase:

(a) consists essentially of aqueous droplets comprising an active compound comprising a quinolone antibiotic, and at least one excipient comprising a multivalent metal ion;

(b) has a mass median diameter from about 1 to about 5 μ

m; and

(c) has a droplet size distribution exhibiting a geometrical standard deviation less than or equal to about 3.0 μ

m.

2. The aerosol of claim 1, wherein the dispersed liquid phase has a mass median diameter from 2 to about 5 μ

m.

3. The aerosol of claim 2, wherein the dispersed liquid phase has a droplet size distribution exhibiting a geometrical standard deviation less than or equal to about 2 μ

m.

4. The aerosol of claim 1, wherein the active compound is selected from the group consisting of levofloxacin, gatifloxacin, moxifloxacin, pharmaceutically acceptable salts thereof, isomers thereof, conjugates thereof, prodrugs thereof, and derivatives thereof.

5. The aerosol of claim 1, wherein the active compound is selected from the group consisting of levofloxacin, gatifloxacin, moxifloxacin, and pharmaceutically acceptable salts thereof.

6. The aerosol of claim 1, comprising at least one further active compound optionally selected from non-quinolone antibiotics, antifungals, antivirals, lung surfactant, steroids, mucolytics, heparin, and anti-inflammatory drugs.

7. The aerosol of claim 1, comprising at least one further active compound optionally selected from non-quinolone antibiotics, antifungals, lung surfactant, steroids, mucolytics, and heparin.

8. The aerosol of claim 1, being emitted from an aerosol generator at a rate of at least about 0.1 ml dispersed liquid phase per minute.

9. A liquid pharmaceutical composition for preparing the aerosol of claim 1 having a dynamic viscosity in the range from about 0.8 to about 3 mPa·

s, wherein a volume of not more than about 10 ml of the composition comprises an effective dose of the active compound.

10. The composition of claim 9, wherein the volume is from about 1 to about 5 ml.

11. The composition of claim 9, having a surface tension in the range from about 25 to 80 mN/m.

12. The composition of claim 9, comprising at least one excipient capable of affecting the local bioavailability, the release, and/or the local residence time of the active compound at the site of aerosol deposition.

13. The composition of claim 12, wherein the excipient capable of affecting the local bioavailability, the release, and/or the local residence time of the active compound is selected from the group consisting of complexing agents, polymers, and amphiphilic compounds.

14. The composition of claim 9, comprising at least one excipient capable of enhancing the AUC shape of the active compound.

15. The composition of claim 9, comprising at least one taste-modifying excipient selected from the group consisting of flavors, sweeteners, complexing agents and taste masking agents.

16. The composition of claim 15, wherein the taste masking agent is selected from the group consisting of cyclodextrin, sugar, sugar alcohol, saccharin, aspartame, and arginine.

17. The composition of claim 9, comprising at least one excipient selected from the group of di- or tri-valent metal ions.

34. A method of treating a patient having sinusitis or rhinosinusitis, pneumonia, chronic obstructive pulmonary disease with acute exacerbations, cystic fibrosis with acute exacerbations, wherein the patient is optionally infected with Streptococcus pneumoniae, Haemophilus influenzae or Moraxella catarrhalis;

acute bacterial exacerbations in chronic obstructive pulmonary disease, wherein the patient is optionally infected with Staphylococcus aureus, Streptococcus pneumoniae, Haemophilus influenzae, Haemophilus parainfluenza or Moraxella catarrhalis, the method comprising administering to the patient in need thereof the aerosol of claim 1.

35. The method of claim 34, wherein the patient is in need of treatment of sinusitis, pneumonia, chronic obstructive pulmonary disease with acute exacerbations, or cystic fibrosis with acute exacerbations, wherein the patient is optionally infected with Streptococcus pneumoniae or Haemophilus influenzae.

36. The method of claim 34, wherein the medicament is adapted for twice or once daily administration.

37. The method of claim 34, wherein the administration of a unit dose of the medicament takes not more than about 20 minutes.

38. A method of treating a patient having sinusitis or rhinosinusitis, pneumonia, chronic obstructive pulmonary disease with acute exacerbations, cystic fibrosis with acute exacerbations, wherein the patient is optionally infected with Streptococcus pneumoniae, Haemophilus influenzae or Moraxella catarrhalis;

acute bacterial exacerbations in chronic obstructive pulmonary disease, wherein the patient is optionally infected with Staphylococcus aureus, Streptococcus pneumoniae, Haemophilus influenzae, Haemophilus parainfluenza or Moraxella catarrhalis, the method comprising administering to a patient in need thereof the composition of claim 9.

39. The method of claim 38, wherein the patient is need of treatment of sinusitis, pneumonia, chronic obstructive pulmonary disease with acute exacerbations, or cystic fibrosis with acute exacerbations, wherein the patient is optionally infected with Streptococcus pneumoniae or Haemophilus influenzae.

40. The method of claim 38, wherein the medicament is adapted for twice or once daily administration.

41. The method of claim 38, wherein the administration of a unit dose of the medicament takes not more than about 20 minutes.

18. A pharmaceutical composition for the preparation of an aerosol comprising an active compound comprising a quinolone antibiotic, and an excipient comprising a polymeric compound, wherein the polymeric compound is selected from the group consisting of derivatized cellulose, dextran, polymeric sugar, polyethylene glycols, pectin and cyclodextrins.

19. A kit for the preparation and delivery of a pharmaceutical aerosol for nasal, sinunasal or pulmonary administration comprising a dispersed liquid phase and a continuous gas phase, wherein the dispersed liquid phase:

(a) consists essentially of aqueous droplets comprising an active compound comprising a quinolone antibiotic, and at least one excipient comprising a multivalent metal ion;

(b) has a mass median diameter from about 1 to about 5 μ

m; and

(c) has a droplet size distribution exhibiting a geometrical standard deviation less than or equal to about 3.0 μ

m, wherein the kit comprises a nebulizer and an aqueous liquid composition, said composition comprising an effective dose of the active compound within a volume of not more than about 10 ml.

20. The kit of claim 19, wherein the dispersed liquid phase has a mass median diameter from 2 to about 5 μ

m.

21. The kit of claim 20, wherein the dispersed liquid phase has a droplet size distribution exhibiting a geometrical standard deviation less than or equal to about 2 μ

m.

22. The kit of claim 21, wherein the composition comprises an effective dose of the active compound within a volume from about 1 to about 5 ml.

23. The kit of claim 19, wherein the nebulizer is selected from the group consisting of jet nebulizers, ultrasonic nebulizers, jet collision nebulizers, electrohydrodynamic nebulizers, capillary force nebulizers, perforated membrane nebulizers and perforated vibrating membrane nebulizers.

24. The kit of claim 19, wherein the nebulizer is selected from the group consisting of jet nebulizers, ultrasonic nebulizers, and perforated vibrating membrane nebulizers.

25. The kit of claim 19, wherein the nebulizer is adapted to be capable of aerosolising the liquid composition at a rate of at least about 0.1 ml/min.

26. The kit of claim 19, wherein the nebulizer is adapted to be capable of aerosolizing a volume of the liquid composition comprising an effective dose of the active compound within not more than about 20 minutes.

27. The kit of claim 19, wherein the nebulizer is adapted to be capable of emitting at least about 50 wt.-% of the aqueous liquid composition as aerosol.

28. The kit of claim 19, wherein at least about 40 wt.-% of the loaded dose is comprised of droplets having a diameter of not more than about 5 μ

m.

42. A method of treating a patient having sinusitis or rhinosinusitis, pneumonia, chronic obstructive pulmonary disease with acute exacerbations, cystic fibrosis with acute exacerbations, wherein the patient is optionally infected with Streptococcus pneumoniae, Haemophilus influenzae or Moraxella catarrhalis;

acute bacterial exacerbations in chronic obstructive pulmonary disease, wherein the patient is optionally infected with Staphylococcus aureus, Streptococcus pneumoniae, Haemophilus influenzae, Haemophilus parainfluenza or Moraxella catarrhalis, the method comprising administering a pharmaceutical aerosol with the kit of claim 19 to a patient in need thereof.

43. The method of claim 42, wherein the patient is need of treatment of sinusitis, pneumonia, chronic obstructive pulmonary disease with acute exacerbations, or cystic fibrosis with acute exacerbations, wherein the patient is optionally infected with Streptococcus pneumoniae or Haemophilus influenzae.

29. A method of preparing and delivering an aerosol to a person in need of nasal, sinunasal or pulmonary antibiotic treatment or prophylaxis, said method comprising the steps of:

(a) providing a liquid pharmaceutical composition comprising an effective dose of an active compound comprising a quinolone antibiotic, and at least one excipient comprising a multivalent metal ion in a volume of not more than about 10 ml;

(b) providing a nebulizer capable of aerosolizing said liquid pharmaceutical composition at a total output rate of at least 0.1 ml/min, the nebulizer further being adapted to emit an aerosol comprising a dispersed phase having a mass median diameter from about 1 to about 5 μ

m and a geometrical standard deviation less than or equal to about 3.0 μ

m; and

(c) operating the nebulizer to aerosolize the liquid composition.

30. The method of claim 29, wherein the volume is from about 1 to about 5 ml.

31. The method of claim 30, wherein the dispersed phase has a mass median diameter from 2 to about 5 μ

m.

32. The method of claim 31, wherein the dispersed phase has a distribution exhibiting a geometrical standard deviation less than or equal to about 2.5 μ

m.

33. The method of claim 29, wherein step (c) is conducted to last not more than about 20 minutes and more preferably less than about 5 minutes.