Pulmonary delivery of aminoglycosides

• US 7,368,102 B2
• Filed: 12/19/2002
• Issued: 05/06/2008
• Est. Priority Date: 12/19/2001
• Status: Expired due to Term

• Current Assignee: BGP Products Operations GmbH (Mylan N.V.)
• Original Assignee: Nektar Therapeutics
• Inventors: Weers, Jeffry G., Tarara, Thomas E., Venthoye, Geraldine
• Primary Examiner(s): Haghighatian; Mina
• Application Number:
  US10/327,510
• Publication Number:
  US 20030129140A1
• Time in Patent Office: 1,965 Days
• Field of Search: 424/45, 424/46, 424/489, 424/499, 424/450, 514/2, 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

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 composition for delivery of aminoglycoside to the lungs, the composition comprising a volume of particles that forms a respirable unit dose, the particles comprising aminoglycoside, a bulk density of greater than 0.08 g/cm³, a geometric diameter of less than 5 microns, and a mass median aerodynamic diameter of less than 5 microns;

wherein the volume of particles that forms a respirable unit dose is equivalent to, or less than, a capsule volume corresponding to a size #00 capsule, and

wherein administration of less than 6 of the respirable unit doses is effective to provide at least 27.6 mg of aminoglycoside to the lungs.

2. A composition according to claim 1 wherein the particles comprise 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 comprises a hydrophobic amino acid selected from the group consisting of alanine, isoleucine, leucine, methionine, phenylalanine, proline, tryptophan, valine and combinations thereof.

5. A composition according to claim 3 wherein the dispersing agent comprises leucine.

6. A composition according to claim 1 wherein the aminoglycoside comprises a potency of greater than 60%.

7. A composition according to claim 1 wherein the aminoglycoside is selected from the group consisting of gentamicin, netilmicin, paramecin, tobramycin, amikacin, kanamycin, neomycin, streptomycin and their salts and combinations thereof.

8. A composition according to claim 1 having a residual moisture content of below about 15% by weight.

9. A composition according to claim 1 wherein the particles have a geometric diameter from 0.5-5 microns.

10. A composition according to claim 1 wherein the mass median aerodynamic diameter is from 1-4 microns.

11. A composition according to claim 1 wherein the respirable unit dose provides an emitted dose of at least 70%.

12. A composition According to claim 1 wherein the aminoglycoside comprises at least 75% w/w tobramycin or salt thereof.

13. A composition according to claim 1 wherein the aminoglycoside comprises at least 85% w/w tobramycin or salt thereof.

14. A composition according to claim 12 further comprising up to 20% w/w of a phospholipid.

15. A composition according to claim 12 wherein the particles comprise a bulk density of greater than 0.10 g/cm³.

16. A composition according to claim 1 wherein the particles comprise a hollow and porous morphology.

17. A composition according to claim 12 comprising a tobramycin potency of greater than 60%.

18. A spray dried composition according to claim 1 wherein the particles are formed by spray drying.

19. A method for administering aminoglycoside to the lungs, said method comprising administering by inhalation the composition of claim 1 in aerosolized form.

20. A method for administering aminoglycoside to the lungs, said method comprising administering by inhalation the composition of claim 5 in aerosolized form.

21. The composition of claim 19 wherein said composition is administered by an inhaler device.

22. A respirable composition comprising a volume of particles for delivery of aminoglycoside to the lungs of a patient,

the particles comprising (i) aminoglycoside, (ii) phospholipid, (iii) a bulk density of greater than 0.08 g/cm³, (iv) a geometric diameter of 1 to 5 microns, and (v) a mass median aerodynamic diameter of less than 5 microns,

wherein the volume of particles forms a respirable unit dose and the volume of particles is equivalent to, or less than, a capsule volume corresponding to a size #2 capsule, and

wherein administration of less than 6 of the respirable unit doses to the patient is effective to provide at least 27.6 mg of aminoglycoside to the lungs of the patient.

23. A composition according to claim 22 wherein the composition comprises a bulk density of greater than 0.10 g/cm³.

24. A composition according to claim 22 capable of providing at least 27.6 mg of the aminoglycoside to the lungs via 4 respirable unit doses or less.

25. A composition according to claim 22 wherein the aminoglycoside or salt thereof is present in an amount corresponding to 10-60 mg/unit dose.

26. A composition according to claim 22 wherein the aminoglycoside or salt thereof is present in an amount of at least 50% by weight.

27. A composition according to claim 22 wherein the aminoglycoside or salt thereof is present in an amount of at least 80% by weight.

28. A composition according to claim 22 wherein the aminoglycoside is selected from the group consisting of gentamicin, netilmicin, paramecin, tobramycin, amikacin, kanamycin, neomycin, streptomycin and their salts and combinations thereof.

29. A composition according to claim 22 wherein the aminoglycoside comprises at least 75% w/w tobramycin or salt thereof.

30. A composition according to claim 22 wherein the particles comprise 2-25 w/w % of the phospholipid.

31. A composition according to claim 22 wherein the particles comprise a metal ion.

32. A composition according to claim 22 wherein the particles comprise calcium chloride.

33. A composition according to claim 22 wherein the particles comprise spray dried particles having a hollow and porous morphology.

34. A composition according to claim 22 wherein the fill mass of the composition in a unit dose capsule is within 20-100 mg per capsule.

35. A composition according to claim 22 wherein the fill mass of the composition in a unit dose capsule is within 25-60 mg per capsule.

36. A method for administering an aminoglycoside to the lungs, said method comprising administering by inhalation the composition of claim 22 in aerosolized form.

37. A method for administering an aminoglycoside to the lungs to reduce the potential for development of bacteria in the lungs, the method comprising administering by inhalation the composition of claim 22 in aerosolized form, in a course of treatment which is performed over a plurality of days.

38. A composition for delivery of aminoglycoside to the lungs, the composition comprising a volume of particles that forms a respirable unit dose, the particles comprising aminoglycoside, a bulk density of greater than 0.08 g/cm³, a geometric diameter of less than 5 microns and a mass median aerodynamic diameter of from 1-4 microns;

wherein the volume of particles that forms a respirable unit dose is equivalent to, or less than, a capsule volume corresponding to a size #00 capsule, and

wherein administration of less than 6 of the respirable unit doses provides a therapeutically effective dosage of aminoglycoside to the lungs.

39. A composition according to claim 38 wherein the aminoglycoside comprises a potency of greater than 60%.

40. A composition according to claim 38 wherein the aminoglycoside is selected from the group consisting of gentamicin, netilmicin, paramecin, tobramycin, amikacin, kanamycin, neomycin, streptomycin and their salts and combinations thereof.

41. A composition according to claim 38 wherein the particles have a residual moisture content of below about 15% by weight.

42. A composition according to claim 38 wherein the particles have a geometric diameter from 0.5-5 microns.

43. A composition according to claim 38 wherein the aminoglycoside comprises at least 75% w/w tobramycin or salt thereof.

44. A composition according to claim 38 wherein the particles comprise up to 20% w/w of a phospholipid.

45. A composition according to claim 38 wherein the particles comprise a hollow and porous morphology.

46. A composition according to claim 38 wherein the aminoglycoside comprises tobramycin in a potency of greater than 60%.

47. A spray dried composition according to claim 38 wherein the particles are formed by spray dying.

48. A method for administering aminoglycoside to the lungs, the method comprising administering by inhalation the composition of claim 38 in aerosolized form.

49. The method of claim 48 wherein the composition is administered in aerosolized form by an inhaler device.