Pulmonary delivery of aminoglycoside

• US 8,715,623 B2
• Filed: 10/31/2007
• Issued: 05/06/2014
• Est. Priority Date: 12/19/2001
• Status: Active Grant

• Current Assignee: BGP Products Operations GmbH (Mylan N.V.)
• Original Assignee: Novartis Ag
• Inventors: Tarara, Thomas E., Weers, Jeffry G., Venthoye, Geraldine
• Primary Examiner(s): Haghighatian, Mina
• Application Number:
  US11/981,986
• Publication Number:
  US 20080063606A1
• Time in Patent Office: 2,379 Days
• Field of Search: 424/45, 424/46, 424/489, 514/34, 514/37, 514/39, 514/41
• US Class Current: 424/45
• CPC Class Codes: A61K 31/7036 having at least one amino group directly attached to the carbocyclic ring, e.g. streptomycin, gentamycin, amikacin, validamycin, fortimicins
• 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 9/1617 Organic compounds, e.g. phospholipids, fats
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/08 Bronchodilators
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics

Abstract

A dispersible powder composition comprises aminoglycoside for delivery to the lungs. The composition is effective to provide a therapeutically effective therapy via administration of less than 6 respirable unit doses by inhalation, wherein each unit dose comprises a volume of 0.30 to 0.95 mL.

Claims

1. A dispersible powder composition comprising particles comprising an aminoglycoside and a phospholipid for delivery to the lungs by inhalation, wherein the particles have a geometric diameter of less than 5 microns, the composition being effective to provide a therapeutically effective therapy via administration of less than 6 respirable unit doses, and wherein each respirable unit dose comprises a volume of 0.30 to 0.95 ml.

2. A composition according to claim 1 wherein the composition comprises from about 50% to about 99% by weight aminoglycoside.

3. A composition according to claim 2 wherein the particles further comprise calcium chloride.

4. A composition according to claim 1 wherein the respirable unit dose is provided in a capsule, the capsule comprising hydroxypropylmethylcellulose.

5. A composition according to claim 1 wherein the particles have a bulk density of between 0.08 and 0.20 g/cm³.

6. A composition according to claim 1 wherein each respirable unit dose comprises a fill mass of between 25 and 50 mg, and said fill mass comprises between about 14-35 mg of aminoglycoside or salt thereof.

7. A composition according to claim 1 wherein the particles have a mass median aerodynamic diameter less than 5 microns.

8. A composition according to claim 1 having a pH of between 7 and 10.

9. A composition according to claim 1 wherein each respirable unit dose comprises a volume equivalent to a size #00 capsule or smaller capsule size.

10. A composition according to claim 1 wherein each respirable unit dose comprises a volume equivalent to a size #2 capsule or smaller capsule size.

11. A composition according to claim 1 wherein the aminoglycoside comprises tobramycin or salt thereof.

12. A composition according to claim 1 comprising calcium.

13. A composition according to claim 1 wherein the particles are spray dried particles.

14. A composition according to claim 1 wherein each respirable unit dose comprises 10-60 mg of aminoglycoside or salt thereof.

15. A composition according to claim 1 wherein the aminoglycoside comprises one or more of gentamicin, netilmicin, paramecin, tobramycin, amikacin, kanamycin, neomycin, and streptomycin.

16. A composition according to claim 1 wherein the particles have a moisture content of less than 15% by weight.

17. A composition according to claim 1 wherein the composition provides therapeutically effective therapy via administration of less than 5 respirable unit doses comprising the composition.

18. A method for administering a composition, the method comprising administering by inhalation less than 6 respirable unit doses of the composition according to claim 1 to provide at least 27.6 mg of aminoglycoside to the lungs.

19. A method for treating cystic fibrosis, the method comprising administering a pharmacologically effective amount of aminoglycoside comprising tobramycin to the lungs from a respirable unit dose according to claim 1.

20. A method for administering aminoglycoside to reduce the potential for development of bacteria in the lungs, the method comprising administering a pharmacologically effective amount of aminoglycoside to the lungs from a respirable unit dose according to claim 1.

25. A composition according to claim 1 wherein the particles are hollow and porous.

26. A composition according to claim 1 wherein each respirable unit dose comprises an emitted dose greater than 70%.

27. A composition according to claim 1 wherein the particles have a bulk density of less than 0.20 g/cm³.

21. A capsule comprising a composition for delivery of aminoglycoside to the lungs by inhalation, the composition including particles comprising phospholipid and aminoglycoside, the aminoglycoside comprising tobramycin, a geometric diameter less than 5 microns, a mass median aerodynamic diameter less than 5 microns, and a bulk density of greater than 0.08 g/cm³, wherein the capsule comprises a volume that is equivalent to, or less than, a capsule volume corresponding to a size #2 capsule, and wherein the capsule contains aminoglycoside or salt thereof, in an amount of 10-60 mg, whereby an effective dose of the aminoglycoside can be administered to the lungs using less than 6 capsules.

22. A pulmonary delivery method comprising administering a pharmacologically effective amount of tobramycin to the lungs by providing a composition comprising particles dispersed from less than 6 capsules by an inhalation device, the particles comprising a matrix of phospholipid and;

tobramycin or a salt thereof, a bulk density of greater than 0.08 g/cm³, and having a pH of 7 or higher, wherein an effective amount of the tobramycin can be administered to the lungs in less than 6 respirable unit doses.

28. A method according to claim 22 wherein the particles comprise tobramycin or salt thereof in a potency of greater than 60%.

29. A method according to claim 22 wherein at least 27.6 mg of the tobramycin or salt thereof can be administered to the lungs in less than 6 respirable doses.

23. A dispersible powder composition comprising particles comprising phospholipid and tobramycin or salt thereof, the particles characterized by a geometric diameter of less than 5 microns, a mass median aerodynamic diameter of less than 5 microns, and a bulk density of between 0.08 g/cm³ and 0.20 g/cm³, wherein the amount of tobramycin or salt thereof in the particles is from about 50% to about 99%, wherein the composition is in the form of a unit dose containing the tobramycin or salt thereof in an amount of 10-60 mg, wherein a therapeutic dose of the tobramycin or salt thereof can be administered to the lungs in less than 6 respirable unit doses, each unit dose comprising a volume of 0.30 mL to 0.95 mL.

24. A respirable unit dose according to claim 23 comprising a volume equivalent to a size #0 capsule or less.

30. A composition according to claim 23 wherein the unit dose comprises a volume of less than 0.68 mL.

31. A composition according to claim 23 wherein the unit dose is contained in a size 2 capsule.

32. A composition according to claim 23 wherein the particles further comprise calcium chloride.

33. A composition according to claim 23 wherein the particles are hollow and porous.