Pulmonary delivery of aminoglycosides

• US 20030129140A1
• Filed: 12/19/2002
• Published: 07/10/2003
• Est. Priority Date: 12/19/2001
• Status: Active Grant

• Current Assignee: BGP Products Operations GmbH (Mylan N.V.)
• Original Assignee: Nektar Therapeutics Incorporated
• Inventors: Weers, Jeffry G., Tarara, Thomas E., Venthoye, Geraldine
• Granted Patent: US 7,368,102 B2
• Time in Patent Office: Days
• US Class Current: 424/46
• 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

The present invention is directed to the administration of aminoglycosides. In particular, the present invention is directed to compositions and methods for the pulmonary administration of aminoglycosides. According to a preferred embodiment, compositions and methods are provided for the localized treatment of respiratory infections.

Claims

1. A dispersible dry powder composition for localized delivery to the lung for the treatment of respiratory infections comprising a pharmacologically effective amount of an aminoglycoside, said composition being effective to provide a therapeutically effective therapy via administration of less than 6 unit doses administered by a dry powder inhalation device.

2. A composition according to claim 1 further comprising a pharmaceutically acceptable excipient.

3. A composition according to claim 2 wherein the pharmaceutically acceptable excipient comprises a dispersing agent selected from the group consisting of hydrophobic amino acids and water soluble polypeptides.

4. A composition according to claim 3 wherein the dispersing agent is a hydrophobic amino acid selected from the group consisting of alanine, isoleucine, leucine, methionine, phenylalanine, proline, tryptophan, and valine.

5. A composition according to claim 4 wherein the dispersing agent is leucine.

6. A composition according to claim 1 wherein the aminoglycoside is present in an amount of at least 50% by weight.

7. A composition according to claim 6 wherein the aminoglycoside is present in an amount of at least 60% by weight.

8. A composition according to claim 1 wherein the aminoglycoside is selected from the group consisting of gentamicin, netilmicin, paramecin, tobramycin, amikacin, kanamycin, neomycin, azithromycin, and streptomycin.

9. A composition according to claim 1 having a residual moisture content of less than 15% by weight.

10. A composition according to claim 1 wherein the residual moisture content is less than 8% by weight.

11. A composition according to claim 1 wherein said composition comprises particles having a geometric diameter from 0.5-5 microns.

12. A composition according to claim 1 wherein said composition comprises particles having a mass median aerodynamic diameter less than 5 microns.

13. A composition according to claim 12 wherein said mass median aerodynamic diameter is less than 4.0 microns.

14. A composition according to claim 1 wherein the emitted dose is at least 70%.

15. A composition according to claim 12 comprising at least 75% w/w tobramycin.

16. A composition according to claim 15 comprising at least 85% w/w tobramycin.

17. A composition according to claim 15 further comprising up to 20% w/w of a phospholipid.

18. A composition according to claim 17 comprising a bulk density of greater than 0.10 g/cm³.

19. A composition according to claim 18 comprising a geometric diameter of less than 5 microns.

20. A composition according to claim 19 comprising a hollow and porous morphology.

21. A composition according to claim 15 comprising a tobramycin potency of greater than 60%.

22. A spray dried composition according to any of claims 1-21.

23. A method for administering an aminoglycoside to the lungs of a human patient, said method comprising administering by inhalation the dry powder composition of claim 1 in aerosolized form.

24. A method for administering an aminoglycoside to the lungs of a human patient, said method comprising administering by inhalation the dry powder composition of claim 5 in aerosolized form.

25. The composition of claim 15, wherein said dry powder composition is administered by means of a dry powder inhaler.

26. A method for administering an aminoglycoside comprising:

providing a dry powder composition comprising an aminoglycoside;

dispersing said composition into a gas stream to form a dry powder aerosol; and

delivering said aerosolized powder pulmonarily to a patient at an emitted dose of at least 50%.

27. A method according to claim 26 wherein said composition comprises at least 50% by weight of an aminoglycoside.

28. A method according to claim 26 wherein the aminoglycoside is present in an amount of at least 60 weight %.

29. A method according to claim 26 wherein said dry powder composition is provided in a plurality of unit doses.

30. A method according to claim 29 wherein less than 6 unit doses are provided and are effective to provide a therapeutically effective amount of aminoglycoside throughout a 24 hour period.

31. A method according to claim 30 wherein less than 4 unit doses are provided.

32. A method according to claim 31 wherein the aminoglycoside is selected from the group consisting of gentamicin, netilmicin, paramecin, tobramycin, amikacin, kanamycin, neomycin, azithromycin and streptomycin.

33. A method according to claim 26 wherein the emitted dose is at least 70%.

34. A method for reducing side effects associated with aminoglycoside therapy comprising administering a therapeutically effective amount of an aminoglycoside pulmonarily to achieve localized concentration of aminoglycoside in the lungs.

35. A method according to claim 34 wherein an aminoglycoside and an antibiotic of a different class are administered pulmonarily in rotation.