Aerosol fluoroquinolone formulations for improved pharmacokinetics

• US 9,326,936 B2
• Filed: 07/17/2014
• Issued: 05/03/2016
• Est. Priority Date: 10/07/2008
• Status: Active Grant

• Current Assignee: Horizon Orphan, LLC (Amgen Inc.)
• Original Assignee: Raptor Pharmaceuticals Inc. (Amgen Inc.)
• Inventors: Griffith, David C., Dudley, Michael N., Surber, Mark W., Bostian, Keith A., Rodny, Olga
• Primary Examiner(s): RAO, SAVITHA M
• Application Number:
  US14/333,583
• Publication Number:
  US 20140329810A1
• Time in Patent Office: 656 Days
• US Class Current: 1/1
• 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 pharmaceutical composition, comprising an aqueous solution consisting essentially of from about 75 mg/ml to about 150 mg/ml levofloxacin or ofloxacin and from about 160 mM to about 240 mM of a divalent or trivalent 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.

2. The composition of claim 1, wherein the levofloxacin or ofloxacin is present at a concentration from about 80 mg/ml to about 120 mg/ml.

3. The composition of claim 1, wherein the solution consists essentially of from about 90 mg/ml to about 110 mg/ml levofloxacin and from about 180 mM to about 220 mM of a divalent or trivalent cation.

4. The composition of claim 1, 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.

5. The composition of claim 1, wherein the solution consists of 80 mg/ml to 120 mg/ml levofloxacin and from about 160 mM to about 240 mM of a divalent or trivalent cation.

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

7. The composition of claim 1, wherein the divalent or trivalent cation is selected from magnesium chloride, magnesium sulfate, zinc chloride, and copper chloride.

8. The composition of claim 1, wherein the aqueous solution lacks a conventional pharmaceutical carrier or excipient selected from the group consisting of mannitol, lactose, starch, magnesium stearate, sodium saccharine, talcum, cellulose, sodium crosscarmellose, glucose, gelatin, sucrose, and magnesium carbonate.

9. A pharmaceutical composition comprising an aqueous solution consisting essentially of from about 80 mg/ml to about 120 mg/ml levofloxacin or ofloxacin and from about 175 mM to about 225 mM of a divalent or trivalent cation selected from the group consisting of magnesium, calcium, zinc, copper, aluminum, and iron;

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.

10. The pharmaceutical composition of claim 9, wherein the divalent or trivalent cation is magnesium.

11. The composition of claim 9, wherein the aqueous solution consists of the levofloxacin or ofloxacin and the divalent or trivalent cation.

12. The composition of claim 9, 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.

13. The composition of claim 9, wherein the solution consists essentially of from about 80 mg/ml to about 120 mg/ml levofloxacin and from about 175 mM to about 225 mM of a divalent or trivalent cation selected from the group consisting of magnesium, calcium, zinc, copper, aluminum, and iron.

14. A pharmaceutical composition comprising an aqueous solution consisting essentially of from about 90 mg/ml to about 110 mg/ml of levofloxacin and from about 190 mM to about 210 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.

15. The composition of claim 14, wherein the aqueous solution consists essentially of about 100 mg/ml of levofloxacin and about 200 mM magnesium chloride.

16. The composition of claim 14, wherein the aqueous solution has a pH from about 6.0 to about 6.5.

17. The composition of claim 14, wherein the aqueous solution consists of the levofloxacin and the magnesium chloride.