Antibiotic formulations, unit doses, kits, and methods

• US 20070116649A1
• Filed: 09/28/2006
• Published: 05/24/2007
• Est. Priority Date: 09/29/2005
• Status: Abandoned Application

• Current Assignee: Novartis Pharma AG (Novartis Ag)
• Original Assignee: Nektar Therapeutics Incorporated
• Inventors: Dwivedi, Sarvajna, Charan, Chatan
• Application Number:
  US11/529,128
• Publication Number:
  US 20070116649A1
• Time in Patent Office: Days
• US Class Current: 424/45
• CPC Class Codes: A61J 1/065 Rigid ampoules, e.g. glass ampoules
• CPC Class Codes: A61J 1/1412 Containers with closing means, e.g. caps
• CPC Class Codes: A61K 31/573 substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
• CPC Class Codes: A61K 31/7034 attached to a carbocyclic compound, e.g. phloridzin
• 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 9/0019 Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner non-active ingredients are additionally classified in A61K47/00
• 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 9/08 Solutions composition of solutions A61K47/00
• CPC Class Codes: A61K 9/19 lyophilised , i.e. freeze-dried, solutions or dispersions lyophilised products with subsequent particle size reduction A61K9/14; granules or pellets made by lyphilisation A61K9/1682; solid oral dosage forms made by lyophilisation A61K9/2095; lyophilisation additives A61K47/00
• CPC Class Codes: A61M 11/001 Particle size control
• CPC Class Codes: A61M 16/04 Tracheal tubes catheters in general A61M25/00
• CPC Class Codes: A61M 2202/064 Powder
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/08 Bronchodilators
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• 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

Abstract

An aqueous or powder composition includes anti-gram-negative antibiotic or salt thereof being present at an amount ranging from about 100 mg/ml to about 200 mg/ml. Another aqueous or powder composition includes anti-gram-positive antibiotic or salt thereof being present at a concentration ranging from about 0.6 to about 0.9 of the water solubility limit, at 25° C. and 1.0 atmosphere, of the anti-gram-positive antibiotic or salt thereof. Other embodiments include unit doses, kits, and methods.

Claims

1. An aqueous composition for aerosolization comprising:

anti-gram-negative antibiotic or salt thereof being present at an amount from about 100 mg/ml to about 200 mg/ml.

2. The aqueous composition of claim 1, wherein the aqueous composition consists essentially of the anti-gram-negative antibiotic or salt thereof and water.

3. The aqueous composition of claim 1, wherein the amount of the anti-gram-negative antibiotic or salt thereof is from about 110 mg/ml to about 150 mg/ml, or a potency from about 500 μ

g/mg to about 1100 μ

g/mg, or both.

4. The aqueous composition of claim 1, wherein the anti-gram-negative antibiotic or salt thereof comprises aminoglycoside or salt thereof.

5. The aqueous composition of claim 1, wherein the anti-gram-negative antibiotic or salt thereof comprises at least one member selected from gentamicin, amikacin, kanamycin, streptomycin, neomycin, netilmicin, paramecin, tobramycin, and salts thereof.

6. The aqueous composition of claim 1, wherein the anti-gram-negative antibiotic or salt thereof comprises amikacin or salt thereof.

7. The aqueous composition of claim 1, wherein the aqueous composition has a pH from about 4 to about 6.

8. The aqueous composition of claim 1, wherein the aqueous composition has an osmolality ranging from about 90 mOsmol/kg to about 500 mOsmol/kg.

9. The aqueous composition of claim 1, wherein the aqueous composition is preservative-free.

10. The aqueous composition of claim 1, further comprising an additional active agent.

11. The aqueous composition of claim 1, further comprising an additional active agent selected from an anti-inflammatory and a bronchodilator.

12. The aqueous composition of claim 1, further comprising a bronchodilator selected from β

-agonist, anti-muscarinic agent, and steroid.

13. The aqueous composition of claim 1, further comprising albuterol.

14. The aqueous composition of claim 1, further comprising an osmolality adjuster.

15. The aqueous composition of claim 1, wherein no precipitate forms in the aqueous composition when the aqueous composition is stored for 1 year at 25°

C.

16. The aqueous composition of claim 1 and further including an anti-gram positive antibiotic.

17. The aqueous composition of claim 1, wherein the anti-gram-negative antibiotic or salt thereof comprises gentamicin or amikacin or a salt thereof, wherein the aqueous composition consists essentially of the gentamicin or salt thereof and water, wherein the gentamicin or salt thereof is present in an amount from about 80 mg/ml to about 140 mg/ml, wherein the aqueous composition has a pH from about 3 to about 7, and wherein the aqueous composition has an osmolality from about 120 mOsmol/kg to about 300 mOsmol/kg.

18. An aqueous composition, consisting essentially of:

An anti-gram-negative antibiotic or salt thereof;

a bronchodilator; and

water.

19. The aqueous composition of claim 18, wherein the anti-gram-negative antibiotic or salt thereof is present in an amount ranging from about 100 mg/ml to about 200 mg/ml.

20. The aqueous composition of claim 18, wherein the anti-gram-negative antibiotic or salt thereof comprises an aminoglycoside or salt thereof.

21. The aqueous composition of claim 18, wherein the aqueous composition has a pH from about 3 to about 7, and an osmolality from about 90 mOsmol/kg to about 500 mOsmol/kg.

22. The aqueous composition of claim 18, wherein the bronchodilator is present in an amount of at least about 1 mg/ml.

23. The aqueous composition of claim 22, wherein the bronchodilator is selected from β

-agonist, anti-muscarinic agent, and steroid.

24. The aqueous composition of claim 23, wherein the bronchodilator comprises albuterol or salt thereof.

25. An aqueous composition, comprising:

an anti gram-positive antibiotic or salt thereof being present at a concentration from about 0.6 to about 0.9 of the water solubility limit, at 25°

C. and 1.0 atmosphere, of the anti-gram-positive antibiotic or salt thereof.

26. The aqueous composition of claim 25, wherein the anti-gram-positive antibiotic or salt thereof is present in an amount ranging from about 60 mg/ml to about 140 mg/ml, or an osmolality of 90 mOsmol/kg to about 500 mOsmol/kg, or both.

27. The aqueous composition of claim 25, wherein the anti-gram-positive antibiotic or salt thereof comprises macrolide or salt thereof.

28. The aqueous composition of claim 25, wherein the anti-gram-positive antibiotic or salt thereof is selected from vancomycin, erythromycin, clarithromycin, azithromycin, and salts thereof.

29. The aqueous composition of claim 28, wherein the aqueous composition is preservative-free.

30. The aqueous composition of claim 25, further comprising an additional active agent selected from anti-inflammatory, bronchodilator, osmolality adjuster, and combinations thereof.

31. The aqueous composition of claim 30, further comprising bronchodilator selected from β

-agonist, anti-muscarinic agent, and steroid.

32. The aqueous composition of claim 25, further comprising albuterol or salt thereof.

33. The aqueous composition of claim 25, wherein the aqueous composition is made from a powder that has a potency greater than about 900 μ

g/ml after the powder is stored for 1 year at 25°

C.

34. The aqueous composition of claim 25, wherein the anti-gram-positive antibiotic or salt thereof comprises vancomycin or salt thereof, wherein the osmolality adjuster comprises sodium chloride, wherein the aqueous composition consists essentially of the vancomycin or salt thereof, the sodium chloride, and water, wherein the vancomycin or salt thereof is present in an amount ranging from about 60 mg/ml to about 140 mg/ml, wherein the aqueous composition has a pH ranging from about 3 to about 7, wherein the aqueous composition has an osmolality ranging from about 120 mOsmol/kg to about 300 mOsmol/kg.

35. A unit dose, comprising:

a container; and

an aqueous composition, comprising an antibiotic or salt thereof being present at a, and wherein the composition is preservative free.

36. The unit dose of claim 35 wherein, the antibiotic comprises an anti gram-negative, and is present at a concentration from about 90 mg/ml to about 200 mg/ml.

37. The unit dose of claim 36 wherein the antibiotic comprises amikacin.

38. The unit dose of claim 35 wherein, the antibiotic comprises an anti gram-positive, and is present at a concentration from about 550 mg/ml to about 900 mg/ml.

39. The unit dose of claim 38, wherein the anti-gram-positive antibiotic or salt thereof comprises a macrolide or salt thereof.

40. The unit dose of claim 35, wherein the antibiotic comprises amphotericin B.

41. A kit, comprising:

a first container containing a first aqueous solution comprising a first antibiotic or salt thereof; and

a second container containing a second aqueous solution comprising a second antibiotic or salt thereof,

wherein the first and second antibiotics are the same or different, and wherein a concentration, or an amount, or both of the first antibiotic is the same as, or different from an a concentration, or an amount, or both of the second antibiotic.

42. The kit of claim 41, wherein an amount of the first aqueous solution is from about 2 ml to about 5 ml, an amount of the second aqueous solution is from about 5 ml to about 8 ml, a concentration of first antibiotic or salt thereof is from about 100 mg/ml to about 120 mg/ml, and a concentration of second antibiotic or salt thereof is from about 120 mg/ml to about 140 mg/ml.

43. The kit of claim 41, wherein the anti-gram-negative antibiotic or salt thereof comprises aminoglycoside or salt thereof.

44. The kit of claim 43, wherein the anti-gram-negative antibiotic or salt thereof comprises amikacin or a salt thereof.

45. The kit of claim 41, further comprising an aerosol introducer.

46. The kit of claim 41, further comprising a vibrating mesh nebulizer.

47. A kit, comprising:

a first container containing a first aqueous solution comprising anti-gram-negative antibiotic or salt thereof; and

a second container containing a second aqueous solution comprising anti-gram-negative antibiotic or salt thereof,

wherein a concentration, an amount, or both, of the anti-gram-negative antibiotic or salt thereof of the first aqueous solution is different from a concentration, or an amount, or both, of the anti-gram-negative antibiotic or salt thereof of the second aqueous solution.

48. The kit of claim 47, further comprising an aerosol introducer.

49. The kit of claim 48, further comprising a vibrating mesh nebulizer.

50. A unit dose, comprising:

a container; and

a powder comprising anti-gram-positive antibiotic or salt thereof, wherein the powder is present in an amount ranging from about 550 mg to about 900 mg.

51. The unit dose of claim 50, wherein the anti-gram-positive antibiotic or salt thereof comprises a macrolide or salt thereof.

52. The unit dose of claim 50, wherein the anti-gram-positive antibiotic or salt thereof is selected from vancomycin, erythromycin, clarithromycin, azithromycin, and salts thereof.

53. The unit dose of claim 50, wherein the powder has a specific surface area ranging from about 5 m²/g to about 20 m²/g.

54. A kit, comprising:

a first container containing a first composition comprising anti-gram-positive antibiotic or salt thereof; and

a second container containing a second composition comprising water,

wherein the first composition and/or the second composition comprises osmolality adjuster.

55. The kit of claim 54, wherein the first composition comprises powder.

56. The kit of claim 54, wherein the first composition comprises the osmolality adjuster.

57. The kit of claim 54, wherein the second composition comprises the osmolality adjuster.

58. The kit of claim 54, further comprising an aerosol introducer.

59. The kit of claim 58, further comprising a vibrating mesh nebulizer.

60. A kit, comprising:

a first container containing a first antibiotic or salt thereof; and

a second container containing a second antibiotic or salt thereof,

wherein the first and second antibiotics are the same or different, and wherein a concentration, or an amount, or both of the first antibiotic or salt thereof in the first container is different from a concentration, or an amount, or both, of the second antibiotic or salt thereof in the second container.

61. The kit of claim 60 wherein each of the first and second antibiotics comprise a powder.

62. The kit of claim 60 wherein each of the first and second antibiotics comprise a liquid.

63. The kit of claim 60 wherein one of the first or second antibiotics comprises a powder, and the other of the first or second antibiotics comprises a liquid.

64. The kit of claim 60, wherein the solution is preservative-free.

65. The kit of claim 60, further comprising an aerosol introducer.

66. The kit of claim 65, further comprising a vibrating mesh nebulizer.

67. A method of administering an antibiotic formulation to a patient in need thereof, comprising:

aerosolizing an antibiotic formulation to administer the antibiotic formulation to the pulmonary system of the patient,

wherein the antibiotic formulation has a concentration of anti-gram-negative antibiotic or salt thereof ranging from about 100 mg/ml to about 200 mg/ml.

68. The method of claim 67, wherein the antibiotic formulation consists essentially of anti-gram-negative antibiotic or salt thereof and water.

69. The method of claim 67, wherein the aerosolizing comprises forming droplets having a mass median aerodynamic diameter of less than about 10 μ

m.

70. The method of claim 69, wherein the aerosolizing comprises aerosolizing the antibiotic formulation in a vibrating mesh nebulizer.

71. The method of claim 67, wherein the pulmonary administration comprises prophylactic treatment of ventilator associated pneumonia.

72. A method of administering an antibiotic formulation to a patient in need thereof, comprising:

inserting a tube into a trachea of a patient; and

aerosolizing an antibiotic formulation to administer the antibiotic formulation to the lungs of the patient,

wherein the antibiotic formulation consists essentially of anti-gram-negative antibiotic or salt thereof and water.

73. The method of claim 72, wherein the pulmonary administration comprises prophylactic treatment of ventilator associated pneumonia, hospital associated pneumonia, community acquired pneumonia, or combinations thereof.

74. The method of claim 72, wherein the aerosolizing comprises aerosolizing the antibiotic formulation in a vibrating mesh nebulizer.

75. A method of administering an antibiotic formulation to a patient in need thereof, comprising:

dissolving an anti-gram-positive antibiotic or salt thereof in a solvent to form an antibiotic formulation, wherein the anti-gram-positive antibiotic or salt thereof is present at a concentration ranging from about 0.6 to about 0.9 of the water solubility limit, at 25°

C. and 1.0 atmosphere, of the anti-gram-positive antibiotic or salt thereof; and

aerosolizing the antibiotic formulation to administer the antibiotic formulation to the lungs of the patient.

76. A method of administering an antibiotic formulation to a patient in need thereof, comprising:

dissolving an anti-gram-positive antibiotic or salt thereof in a solvent to form an antibiotic formulation; and

aerosolizing the antibiotic formulation to administer the antibiotic formulation to the lungs of the patient, wherein the aerosolizing is conducted within about 16 hours of the dissolving.

77. A method of forming a powder comprising anti-gram-positive antibiotic or salt thereof, the method comprising:

dissolving anti-gram-positive antibiotic or salt thereof in a solvent to form a solution having a concentration ranging from about 60 mg/ml to about 120 mg/ml; and

lyophilizing the solution to form the powder.

78. The method of claim 77, wherein the solvent comprises water.

79. The method of claim 77, wherein the solution is excipient-free.

80. The method of claim 77, wherein the solution is cryoprotectant-free.

81. The method of claim 77, wherein the powder has a water content of less than about 5 wt %.

82. The method of claim 77, wherein the lyophilizing is conducted within about 8 hours of the dissolving.

83. The method of claim 77, wherein the powder is capable of being reconstituted with water at 25°

C. and 1.0 atmosphere and with manual agitation, in less than about 60 seconds.

84. A method of forming a powder comprising anti-gram-positive antibiotic or salt thereof, the method comprising:

dissolving anti-gram-positive antibiotic or salt thereof in a solvent to form a solution having a volume ranging from about 4.5 ml to about 5.5 ml; and

lyophilizing the solution to form the dry powder.

85. The method of claim 84, wherein a concentration of the anti-gram-positive antibiotic or salt thereof in the solution ranges from about 60 mg/ml to about 120 mg/ml.

86. The method of claim 84, wherein the solution is excipient-free.

87. The method of claim 84, wherein the solution is cryoprotectant-free.

88. The method of claim 84, wherein the powder has a water content of less than about 5 wt %.

89. The method of claim 84, wherein the lyophilizing is conducted within about 8 hours of the dissolving.

90. The method of claim 84, wherein the powder is capable of being reconstituted with water at 25°

C. and 1.0 atmosphere and with manual agitation, in less than about 60 seconds.

91. The method of claim 84, wherein the lyophilizing comprises filtering the solution, and freezing the filtered solution to form a frozen solution.