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Claims for Patent: 6,900,184

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Claims for Patent: 6,900,184

Title: Compositions containing pipercillin and tazobactam useful for injection
Abstract:The invention pertains to pharmaceutical compositions of Zosyn.RTM. piperacillin with tazobactam in the presence of a buffer, preferably citrate, a particulate formation inhibitor, preferably EDTA optionally an aminoglycoside which when frozen and thawed or lyophilized and reconstituted reform a solution which has decreased particulate formation.
Inventor(s): Cohen; Jonathan Marc (Monroe, NY), Shah; Syed M. (Hanover, NJ), Ofslager; Christian Luther (Newburgh, NY), Fawzi; Mahdi (Morristown, NJ)
Assignee: Wyeth Holdings Corporation (Madison, NJ)
Application Number:10/413,323
Patent Claims: 1. A pharmaceutical composition comprising effective amounts of (a) piperacillin or a pharmaceutically acceptable salt thereof, (b) tazobactam or a pharmaceutically acceptable salt thereof and, (c) as a particulate formation inhibitor, an aminocarboxylic acid chelating agent or a pharmaceutically acceptable salt thereof.

2. A pharmaceutical composition according to claim 1 further comprising an effective amount of a buffer.

3. A pharmaceutical composition according to claim 1 wherein the piperacillin is piperacillin sodium.

4. A pharmaceutical composition according to claim 1 wherein the tazobactam is tazobactam sodium.

5. A pharmaceutical composition according to claim 1 wherein the particulate formation inhibitor is at least one compound selected from the group ethylenediaminetetraacetic acid (EDTA), diethylenetriaminepentaacetic acid (DTPA), hydroxyethylenediaminetriacetic acid (HEDTA), nitrilotriacetic acid (NTA), and the pharmaceutically acceptable salts thereof.

6. A pharmaceutical composition according to claim 5 wherein the particulate formation inhibitor is EDTA.

7. A pharmaceutical composition according to claim 2 wherein the buffer is citrate.

8. A pharmaceutical composition according to claim 7 wherein the citrate is sodium citrate.

9. A pharmaceutical composition according to claim 1 further comprising an aminoglycoside.

10. A pharmaceutical composition according to claim 9 wherein the aminoglycoside is selected from amikacin and tobramycin.

11. A pharmaceutical composition according to claim 10 wherein the aminoglycoside is amikacin.

12. A pharmaceutical composition according to claim 10 wherein the aminoglycoside is tobramycin.

13. A pharmaceutical composition according to claim 2 further comprising an aminoglycoside.

14. A pharmaceutical composition according to claim 13 wherein the aminoglycoside is selected from amikacin and tobramycin.

15. A pharmaceutical composition according to claim 14 wherein the aminoglycoside is amikacin.

16. A pharmaceutical composition according to claim 15 wherein the aminoglycoside is tobramycin.

17. A pharmaceutical composition according to claim 2 wherein the effective amount of buffer maintains the pH at about 6.0 to about 7.5.

18. A pharmaceutical composition according to claim 17 wherein the pH is about 6.5.

19. A pharmaceutical composition according to claim 1 wherein the composition is a powder.

20. A pharmaceutical composition according to claim 2 wherein the composition is a powder.

21. A pharmaceutical composition of claim 1 wherein the composition is a solution and the piperacillin is present in an amount from about 8 mg/ml to about 500 mg/ml.

22. A pharmaceutical composition of claim 8 wherein the composition is a solution and the sodium citrate buffer is present in an amount from about 0.25 mg/ml to about 25 mg/ml.

23. A pharmaceutical composition according to claim 1 wherein the composition is a solution and the tazobactam is present in an amount from about 0.1 mg/ml to about 125 mg/ml.

24. A pharmaceutical composition according to claim 1 wherein the composition is a solution, said composition further comprising an effective amount of dextrose to render the composition physiologically isosmotic.

25. A pharmaceutical composition according to claim 24 wherein the effective amount of dextrose is from about 5 mg/ml to about 100 mg/ml.

26. A pharmaceutical composition according to claim 15 wherein the composition is a solution and amikacin is present in an amount of about 0.1 mg/ml to about 75 mg/ml.

27. A pharmaceutical composition according to claim 16 wherein the composition is a solution and tobramycin is present in an amount of about 0.1 mg/ml to about 75 mg/ml.

28. A pharmaceutical composition according to claim 11 wherein the composition is a solution and amikacin is present in an amount of about 0.1 mg/ml to about 75 mg/ml.

29. A pharmaceutical composition according to claim 12 wherein the composition is a solution and tobramycin is present in an amount of about 0.1 mg/ml to about 75 mg/ml.

30. A pharmaceutical composition according to claim 6 wherein the composition is a solution and EDTA is present in an amount of about 0.002 mg/ml to about 10 mg/ml.

31. A pharmaceutical composition according to claim 30 wherein the EDTA is present in an amount of about 0.003 mg/ml to about 1 mg/ml.

32. A pharmaceutical composition according to claim 1 wherein said pharmaceutical composition is a dose concentrate in a sealed container wherein said container has a space sufficient for introduction of a volume of aqueous solvent sufficient to form a concentrated solution of said pharmaceutical composition.

33. A pharmaceutical composition according to claim 2 wherein said pharmaceutical composition is a dose concentrate in a sealed container wherein said container has a space sufficient for introduction of a volume of aqueous solvent sufficient to form a concentrated solution of said pharmaceutical composition.

34. A pharmaceutical composition according to claim 1 wherein said pharmaceutical composition is a solution and is a unit dose contained in an IV bag or IV bottle for intravenous administration.

35. A pharmaceutical composition according to claim 2 wherein said pharmaceutical composition is a solution and is a unit dose contained in an IV bag or IV bottle for intravenous administration.

36. A pharmaceutical composition comprising (a) piperacillin or a pharmaceutically acceptable salt thereof in an amount of about 4.0 g calculated as piperacillin free acid, (b) tazobactam or a pharmaceutically acceptable salt thereof in an amount of about 0.5 g calculated as tazobactam free acid, (c) about 1 mg of EDTA or a pharmaceutically acceptable salt of EDTA and (d) water for injection.

37. A pharmaceutical composition according to claim 36 further comprising about 0.2 g of citrate.

38. A pharmaceutical composition according to claim 36 wherein (a) the piperacillin or a pharmaceutically acceptable salt is piperacillin sodium as about 4 g piperacillin free acid, (b) the tazobactam or a pharmaceutically acceptable salt is tazobactam sodium as about 0.5 g of tazobactam free acid, (c) about 1 mg of a sodium salt of EDTA and (d) about 100 ml of water for injection.

39. A pharmaceutical composition according to claim 38 further comprising about 0.2 g of sodium citrate.

40. A pharmaceutical composition according to claim 36, further comprising about 2.0 g of dextrose.

41. A pharmaceutical composition according to claim 36 further comprising an aminoglycoside.

42. A pharmaceutical composition according to claim 41, wherein the aminoglycoside is amikacin and is present in an amount of about 500 mg.

43. A pharmaceutical composition according to claim 41, wherein the aminoglycoside is tobramycin and is present in an amount of about 160 mg.

44. A pharmaceutical composition according to claim 36 wherein the amount of water for injection is 100 ml.

45. A pharmaceutical composition according to claim 36 wherein said composition is frozen and capable of being thawed and, if desired, further diluted with a compatible diluent prior to administration to a mammal.

46. A pharmaceutical composition comprising (a) about 89% piperacillin or a pharmaceutically acceptable salt thereof, (b) about 11% tazobactam or a pharmaceutically acceptable salt thereof and, as a particulate formation inhibitor, about 0.02% of an aminocarboxylic acid chelating agent or a pharmaceutically acceptable salt thereof.

47. A pharmaceutical composition comprising (a) about 85% piperacillin or a pharmaceutically acceptable salt thereof, (b) about 11% tazobactam or a pharmaceutically acceptable salt thereof, (c) about 0.02% of an aminocarboxylic acid chelating agent or a pharmaceutically acceptable salt thereof as a particulate formation inhibitor, and about (d) 4% of a buffer.

48. A pharmaceutical composition according to claim 47 wherein the aminocarboxylic acid chelating agent is EDTA.

49. A pharmaceutical composition according to claim 47 wherein the buffer is citrate.

50. A pharmaceutical composition according to claim 2 wherein the composition is a solution and the piperacillin sodium, tazobactam sodium, citrate as buffer and as particulate formation inhibitor an aminocarboxylic acid chelating agent are present in an amount from about 9 mg/ml to about 125 mg/ml.

51. A pharmaceutical composition according to claim 50 wherein the composition is a solution and the piperacillin sodium, tazobactam sodium, citrate as buffer and as particulate formation inhibitor an aminocarboxylic acid chelating agent are present in an amount from about 14 mg/ml to about 115 mg/ml.

52. A pharmaceutical composition according to claim 51 wherein the composition is a solution and the piperacillin sodium, tazobactam sodium, citrate as buffer and as particulate formation inhibitor an aminocarboxylic acid chelating agent are present in an amount from about 20 mg/ml to about 105 mg/ml.

53. A method for the treatment or control of bacterial infections in a mammal, said infections being caused by piperacillin/tazobactam susceptible bacteria wherein the method comprises administering to said mammal a therapeutically effective amount of the pharmaceutical composition of claim 1.

54. A method for the treatment or control of bacterial infections in a mammal, said infections being caused by piperacillin/tazobactam susceptible bacteria wherein the method comprises administering to said mammal a therapeutically effective amount of the pharmaceutical composition of claim 2.

55. A method for the treatment or control of bacterial infections in a mammal, said infections caused by piperacillin/tazobactam susceptible bacteria wherein the method comprises coadministering a pharmaceutical composition of claim 1 and an aminoglycoside.

56. The method according to claim 55 wherein the aminoglycoside is selected from amikacin and tobramycin.

57. The method according to claim 56 wherein the aminoglycoside is amikacin.

58. The method according to claim 56 wherein the aminoglycoside is tobramycin.

59. A method for the treatment or control of bacterial infections in a mammal, said infections caused by piperacillin/tazobactam susceptible bacteria wherein the method comprises coadministering a pharmaceutical composition of claim 2 and an aminoglycoside.

60. The method according to claim 59 wherein the aminoglycoside is selected from amikacin and tobramycin.

61. The method according to claim 60 wherein the aminoglycoside is amikacin.

62. The method according to claim 60 wherein the aminoglycoside is tobramycin.

63. A process for preparing a lyophilized pharmaceutical composition which comprises the steps of: a) dissolving sodium citrate dihydrate, EDTA, piperacillin, and tazobactam, in an aqueous solvent to form a solution and adjusting the pH of the solution to about 6.5; b) cooling the solution to a temperature below -35.degree. C. in a lyophilizer; c) evacuating the lyophilizer to a pressure of about 300 .mu.M Hg (40 pascals) or less; d) heating the lyophilizer to about +5.degree. C.; e) maintaining the temperature and pressure for a sufficient time to remove water from the aqueous solvent to form a lyophilized solid; f) drying the lyophilized solid at about +45.degree. C. to form a lyophilized composition.

64. The process according to claim 63 further comprising in a step a) dissolving an aminoglycoside with the sodium citrate dihydrate, EDTA, piperacillin and tazobactam.

65. The process according to claim 64 wherein the aminoglycoside is selected from amikacin and tobramycin.

66. The process according to claim 65 wherein the aminoglycoside is amikacin.

67. The process according to claim 65 wherein the aminoglycoside is tobramycin.

68. A process of making a reconstitutable pharmaceutical composition which comprises the steps of: a) dissolving sodium citrate dihydrate, EDTA, piperacillin, and tazobactam, in an aqueous solvent to form a solution and adjusting the pH of the solution to about 6.5; b) cooling the solution to a temperature below -35.degree. C. in a lyophilizer; g) evacuating the lyophilizer to a pressure of about 300 .mu.M Hg (40 pascals) or less; h) heating the lyophilizer to about +5.degree. C.; i) maintaining the temperature and pressure for a sufficient time to remove water from the aqueous solvent to form a lyophilized solid; j) drying the lyophilized solid at about +45.degree. C. to form the reconstitutable pharmaceutical composition.

69. The process according to claim 68 further comprising in step a) dissolving an aminoglycoside with the sodium citrate dihydrate, EDTA, piperacillin and tazobactam wherein the aminoglycoside is amikacin and the amikacin is present in an amount of about 0.1 mg/ml to about 75 mg/ml of the reconstitutable pharmaceutical composition.

70. The process according to claim 68 further comprising in step a) dissolving an aminoglycoside with the sodium citrate dihydrate, EDTA, piperacillin and tazobactam wherein the aminoglycoside is tobramycin and the tobramycin is present in an amount of about 0.1 mg/ml to about 75 mg/ml of the reconstitutable pharmaceutical composition.

71. The process according to claim 68 wherein the EDTA in the composition is present in an amount of about 0.002 mg/ml to about 10 mg/ml.

72. The process according to claim 71 wherein the EDTA is present in an amount of about 0.003 mg/ml to about 1 mg/ml.

73. A process for preparing a pharmaceutical composition which comprises the steps of: a) dissolving an effective amount of sodium citrate dihydrate in an aqueous solvent to form a solution; b) adding effective amounts of piperacillin, and tazobactam; c) adjusting the pH to about 6 5; and d) adding an effective amount of EDTA.

74. The process according to claim 73 further comprising in step b) adding an effective amount of an aminoglycoside with the effective amounts of piperacillin and tazobactam.

75. The process according to claim 74 wherein the aminoglycoside is selected from amikacin and tobramycin.

76. The process according to claim 75 wherein the aminoglycoside is amikacin.

77. The process according to claim 76 wherein the amikacin is present in an amount of about 0.1 mg/ml to about 75 mg/ml.

78. The process according to claim 75 wherein the aminoglycoside is tobramycin.

79. The process according to claim 78 wherein the tobramycin is present in an amount of about 0.1 mg/ml to about 75 mg/ml.

80. The process according to claim 73 wherein the EDTA is present in an amount of about 0.002 mg/ml to about 10 mg/ml.

81. The process according to claim 80 wherein the EDTA is present in an amount of about 0.003 mg/ml to about 1 mg/ml.

82. A process for the manufacture of a reconstitutable pharmaceutical composition in the form of a powder which process comprises the steps of: dissolving effective amounts of (a) piperacillin or a pharmaceutically acceptable salt thereof, tazobactam or a pharmaceutically acceptable salt thereof and, as a particulate formation inhibitor, an aminocarboxylic acid chelating agent or a pharmaceutically acceptable salt thereof in an aqueous solvent to form a solution, (b) adjusting the pH of said solution in the range of about 6.0 to about 7.5 and (c) freeze drying said solution to form a reconstitutable powder.

83. The process according to claim 82 further comprising in step a) dissolving an aminoglycoside with the piperacillin, tazobactam and particulate formation inhibitor.

84. The process according to claim 83 wherein the aminoglycoside is selected from amikacin and tobramycin.

85. The process according to claim 84 wherein the aminoglycoside is amikacin.

86. The process according to claim 84 wherein the aminoglycoside is tobramycin.

87. The process according to claim 82 wherein in step b the pH is adjusted to about 6.5 with an effective amount of a buffer.

88. The process according to claim 87 wherein the buffer is citrate.

89. The process according to claim 88 wherein the citrate is sodium citrate.

90. The process according to claim 73 further comprising step e) freezing or lyophilizing to form the composition.
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