Bronchodilating compositions and methods

• US 6,814,953 B2
• Filed: 05/03/2002
• Issued: 11/09/2004
• Est. Priority Date: 04/17/2001
• Status: Expired due to Term

• Current Assignee: Dey Pharma LP (Pfizer Inc.)
• Original Assignee: Dey LP (Pfizer Inc.)
• Inventors: Pham, Stephen, Chaudry, Imtiaz A., Banerjee, Partha S., Akapo, Samuel O.
• Primary Examiner(s): Weddington, Kevin E.
• Application Number:
  US10/138,866
• Publication Number:
  US 20020151598A1
• Time in Patent Office: 921 Days
• Field of Search: 514/653, 514/630, 424/45
• US Class Current: 424/45
• CPC Class Codes: A61K 31/165 having aromatic rings, e.g. colchicine, atenolol, progabide
• CPC Class Codes: A61K 31/35 having six-membered rings with one oxygen as the only ring hetero atom
• CPC Class Codes: A61K 31/375 Ascorbic acid, i.e. vitamin C; Salts thereof
• 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: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 11/08 Bronchodilators
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Abstract

Bronchodilating compositions and methods are provided. The compositions are intended for administration as a nebulized aerosol. In certain embodiments, the compositions contain formoterol, or a derivative thereof. Methods for treatment, prevention, or amelioration of one or more symptoms of bronchoconstrictive disorders using the compositions provided herein are also provided.

Claims

1. A kit, comprising:

(a) a pharmaceutical composition, comprising formoterol, or a derivative thereof, in a pharmacologically suitable fluid, wherein the composition is stable during long term storage, the fluid comprises water, and the composition is formulated at a concentration suitable for direct administration to a subject in need thereof; and

(b) a nebulizer.

2. The kit of claim 1, wherein the composition has an estimated shelf-life of greater than 1 month usage time at 25°

C. and greater than or equal to 1 year storage time at 5°

C.

3. The kit of claim 2, wherein greater than about 80% of the initial formoterol is present after 1 month usage time at 25°

C. and 1 year storage time at 5°

C.

4. The kit of claim 1, wherein the composition further comprises a polar solvent.

5. The kit of the claim 4, wherein the polar solvent is a protic solvent.

6. The kit of the claim 5, wherein the composition further comprises a tonicity adjusting agent.

7. The kit of claim 6, wherein the tonicity adjusting agent is ammonium carbonate, ammonium chloride, ammonium lactate, ammonium nitrate, ammonium phosphate, ammonium sulfate, ascorbic acid, bismuth sodium tartrate, boric acid, calcium chloride, calcium disodium edetate, calcium gluconate, calcium lactate, citric acid, dextrose, diethanolamine, dimethylsulfoxide, edetate disodium, edetate trisodium monohydrate, fluorescein sodium, fructose, galactose, glycerin, lactic acid, lactose, magnesium chloride, magnesium sulfate, mannitol, polyethylene glycol, potassium acetate, potassium chlorate, potassium chloride, potassium iodide, potassium nitrate, potassium phosphate, potassium sulfate, propylene glycol, silver nitrate, sodium acetate, sodium bicarbonate, sodium biphosphate, sodium bisulfite, sodium borate, sodium bromide, sodium cacodylate, sodium carbonate, sodium chloride, sodium citrate, sodium iodide, sodium lactate, sodium metabisulfite, sodium nitrate, sodium nitrite, sodium phosphate, sodium propionate, sodium succinate, sodium sulfate, sodium sulfite, sodium tartrate, sodium thiosulfate, sorbitol, sucrose, tartaric acid, triethanolamine, urea, urethan, uridine or zinc sulfate.

8. The kit of claim 7, wherein the tonicity adjusting agent is sodium chloride.

9. The kit of claim 1, wherein the composition further comprises a buffer.

10. The kit of claim 9, wherein the buffer is citric acid/phosphate, acetate, barbital, borate, Britton-Robinson, cacodylate, citrate, collidine, formate, maleate, McIlvaine, phosphate, Prideaux-Ward, succinate, citrate-phosphate-borate (Teorelle-Stanhagen), veronal acetate, MES (2-(N-morpholino)ethanesulfonic acid), BIS-TRIS (bis(2-hydroxyethyl)iminotris(hydroxymethyl)methane), ADA (N-(2-acetamido)-2-iminodiacetic acid), ACES (N-(carbamoylmethyl)-2-aminoethanesulfonic acid), PIPES (piperazine-N,N′

-bis(2-ethanesulfonic acid)), MOPSO (3-(N-morpholino)-2-hydroxypropanesulfonic acid), BIS-TRIS PROPANE (1,3-bis(tris(hydroxymethyl)-methylamino)propane), BES (N,N-bis(2-hydroxyethyl)-2-aminoethanesulfonic acid), MOPS (3-(N-morpholino)propanesulfonic acid), TES (N-tris(hydroxymethyl)methyl-2-aminoethanesulfonic acid), HEPES (N-(2-hydroxyethyl)piperazine-N′

-(2-ethanesulfonic acid), DIPSO (3-(N,N-bis(2-hydroxyethyl)amino)-2-hydroxypropanesulfonic acid), MOBS (4-(N-morpholino)butanesulfonic acid), TAPSO (3-(N-tris(hydroxymethyl)methylamino)-2-hydroxypropanesulfonic acid), tris(hydroxymethylaminomethane, HEPPSO (N-(2-hydroxyethyl)piperazine-N′

-(2-hydroxypropanesulfonic acid), POPSO (piperazine-N,N′

-bis(2-hydroxypropane-sulfonic acid)), TEA (triethanolamine), EPPS (N-(2-hydroxyethyl)piperazine-N′

-(3-propanesulfonic acid), TRICINE (N-tris(hydroxymethyl)methylglycine), GLY-GLY (glycylglycine), BICINE (N,N-bis(2-hydroxyethyl)glycine), HEPBS (N-(2-hydroxyethyl)piperazine-N′

-(4-butanesulfonic acid)), TAPS (N-tris(hydroxy-methyl)methyl-3-aminopropanesulfonic acid), or AMPD (2-amino-2-methyl-1,3-propanediol) buffer.

11. The kit of claim 10, wherein the buffer is citrate buffer.

12. The kit of claim 11, wherein the buffer concentration is from about 0.01 mM to about 150 mM.

13. The kit of claim 12, wherein the buffer concentration is from about 1 mM to about 20 mM.

14. The kit of claim 13, wherein the buffer concentration is about 5 mM.

15. The kit of claim 7, wherein the ionic strength of the composition is about 0 to about 0.4.

16. The kit of claim 15, wherein the ionic strength of the composition is about 0.05 to about 0.16.

17. The kit of claim 1, wherein the pH of the composition is about 2.0 to about 8.0.

18. The kit of claim 17, wherein the pH of the composition is about 4.0 to about 6.0.

19. The kit of claim 18, wherein the pH of the composition is about 4.5 to about 5.5.

20. The kit of claim 19, wherein the pH of the composition is about 5.0.

21. The kit of claim 1, wherein the formoterol free base concentration in the composition is about 5 μ

g/mL to about 2 mg/mL.

22. The kit of claim 21, wherein the formoterol free base concentration in the composition is about 10 μ

g/mL to about 1 mg/mL.

23. The kit of claim 22, wherein the formoterol free base concentration in the composition is about 50 μ

g/mL to about 200 μ

g/mL.

24. The kit of claim 23, wherein the formoterol free base concentration in the composition is about 59 μ

g/mL.

25. The kit of claim 23, wherein the formoterol free base concentration in the composition is about 118 μ

g/mL.

26. The kit of claim 7, wherein the composition further comprises a buffer.

27. The kit of claim 26, wherein the buffer is citric acid/phosphate, acetate, barbital, borate, Britton-Robinson, cacodylate, citrate, collidine, formate, maleate, McIlvaine, phosphate, Prideaux-Ward, succinate, citrate-phosphate-borate (Teorell-Stanhagen), veronal acetate, MES (2-(N-morpholino)ethanesulfonic acid), BIS-TRIS (bis(2-hydroxyethyl)iminotris(hydroxymethyl)methane), ADA (N-(2-acetamido)-2-iminodiacetic acid), ACES (N-(carbamoylmethyl)-2-aminoethanesulfonic acid), PIPES (piperazine-N,N′

-bis(2-ethanesulfonic acid)), MOPSO (3-(N-morpholino)-2-hydroxypropanesulfonic acid), BIS-TRIS PROPANE (1,3-bis(tris(hydroxymethyl)methylamino)propane), BES (N,N-bis(2-hydroxyethyl)-2-aminoethanesulfonic acid), MOPS (3-(N-morpholino)propanesulfonic acid), TES (N-tris(hydroxymethyl)methyl-2-aminoethanesulfonic acid), HEPES (N-(2-hydroxyethyl)piperazine-N′

-(2-ethanesulfonic acid), DIPSO (3-(N,N-bis(2-hydroxyethyl)amino)-2-hydroxypropanesulfonic acid), MOBS ((N-morpholino)-butanesulfonic acid), TAPSO (3-(N-tris(hydroxymethyl)methylamino)-2-hydroxy-propanesulfonic acid), tris(hydroxymethylaminomethane, HEPPSO (N-(2-hydroxyethyl)piperazine-N′

-(2-hydroxypropanesulfonic acid), POPSO (piperazine-N,N′

-bis(2-hydroxypropanesulfonic acid)), TEA (triethanolamine), EPPS (N-(2-hydroxyethyl)piperazine-N′

-(3-propanesulfonic acid), TRICINE (N-tris(hydroxy-methyl)methylglycine), GLY-GLY (glycylglycine), BICINE (N,N-bis(2-hydroxyethyl)glycine), HEPBS (N-(2-hydroxyethyl)piperazine-N′

-(4-butanesulfonic acid)), TAPS (N-tris(hydroxymethyl)methyl-3-aminopropanesulfonic acid), or AMPD (2-amino-2-methyl-1,3-propanediol) buffer.

28. The kit of claim 27, wherein the buffer is citrate buffer.

29. The kit of claim 28, wherein the buffer concentration is from about 0.01 mM to about 150 mM.

30. The kit of claim 29, wherein the buffer concentration is from about 1 mM to about 20 mM.

31. The kit of claim 30, wherein the buffer concentration is about 5 mM.

32. The kit of claim 26, wherein the ionic strength of the composition is about 0 to about 0.4.

33. The kit of claim 32, wherein the ionic strength of the composition is about 0.05 to about 0.16.

34. The kit of claim 26, wherein the pH of the composition is about 2.0 to about 8.0.

35. The kit of claim 34, wherein the pH of the composition is about 4.0 to about 6.0.

36. The kit of claim 35, wherein the pH of the composition is about 4.5 to about 5.5.

37. The kit of claim 36, wherein the pH of the composition is about 5.0.

38. The kit of claim 26, wherein the formoterol free base concentration in the composition is about 5 μ

g/mL to about 2 mg/mL.

39. The kit of claim 28, wherein the formoterol free base concentration in the composition is about 10 μ

g/mL to about 1 mg/mL.

40. The kit of claim 39, wherein the formoterol free base concentration in the composition is about 50 μ

g/mL to about 200 μ

g/mL.

41. The kit of claim 40, wherein the formoterol free base concentration in the composition is about 59 μ

g/mL.

42. The kit of claim 40, wherein the formoterol free base concentration in the composition is about 118 μ

g/mL.

43. The kit of claim 1, wherein the composition comprises (a) formoterol free base at a concentration of about 59 μ

g/mL;

(b) aqueous saline comprising sodium chloride; and

(c) citrate buffer at a concentration of about 5 mM;

wherein the ionic strength of the composition is about 0.05 to about 0.16; and

the pH of the composition is about 5.0.

44. The kit of claim 1, wherein the composition comprises (a) formoterol free base at a concentration of about 118 μ

g/mL;

(b) aqueous saline comprising sodium chloride; and

(c) citrate buffer at a concentration of about 5 mM;

wherein the ionic strength of the composition is about 0.05 to about 0.16; and

the pH of the composition is about 5.0.

45. The kit of claim 1, wherein the composition comprises (a) formoterol free base at a concentration of about 59 μ

g/mL;

(b) aqueous saline comprising sodium chloride; and

(c) citrate buffer at a concentration of about 2 mM;

wherein the ionic strength of the composition is about 0.05 to about 0.16; and

the pH of the composition is about 5.0.

46. The kit of claim 1, wherein the composition comprises (a) formoterol free base at a concentration of about 118 μ

g/mL;

(b) aqueous saline comprising sodium chloride; and

(c) citrate buffer at a concentration of about 2 mM;

wherein the ionic strength of the composition is about 0.05 to about 0.16; and

the pH of the composition is about 5.0.

47. The kit of claim 41, wherein the buffer is citrate buffer.

48. The kit of claim 41, wherein the buffer concentration is about 5 mM.

49. The kit of claim 41, wherein the ionic strength of the composition is about 0.005 to about 0.16.

50. The kit of claim 41, wherein the pH of the composition is about 5.0.

51. The kit of claim 41, wherein the buffer is citrate buffer;

the buffer concentration is about 5 mM;

the ionic strength of the composition is about 0.005 to about 0.16; and

the pH of the composition is about 5.0.

52. The kit of claim 42, wherein the buffer is citrate buffer.

53. The kit of claim 42, wherein the buffer concentration is about 5 mM.

54. The kit of claim 42, wherein the ionic strength of the composition is about 0.05 to about 0.16.

55. The kit of claim 42, wherein the pH of the composition is about 5.0.

56. The kit of claim 42, wherein the buffer is citrate buffer;

the buffer concentration is about 5 mM;

the ionic strength of the composition is about 0.05 to about 0.16; and

the pH of the composition is about 5.0.

57. The kit of claim 1, further comprising one or more of (a) to (j) as follows:

(a) a β

2-adrenoreceptor agonist;

(b) a dopamine (D2) receptor agonist;

(c) an IL-5 inhibitor;

(d) an antisense modulator of IL-5;

(e) a tryptase inhibitor;

(f) a tachykinin receptor antagonist;

(g) milrinone or milrinone lactate;

(h) a leukotriene receptor antagonist;

(i) a 5-lypoxygenase inhibitor;

or (j) an anti-IgE antibody.

58. The kit of claim 10, wherein the buffer comprises citric acid/phosphate buffer, acetate buffer, citrate buffer or phosphate buffer.

59. The kit of claim 26, wherein the buffer comprises citric acid/phosphate buffer, acetate buffer, citrate buffer or phosphate buffer.

60. The kit of claim 12, wherein the buffer concentration is from about 1 mM to about 50 mM.

61. The kit of claim 60, wherein the buffer concentration is about 20 mM.

62. The kit of claim 29, wherein the buffer concentration is from about 1 mM to about 50 mM.

63. The kit of claim 62, wherein the buffer concentration is about 20 mM.

64. The kit of claim 41, wherein the buffer concentration is about 20 mM.

65. The kit of claim 41, wherein the buffer is citrate buffer;

the buffer concentration is about 20 mM;

the ionic strength of the composition is about 0.01 to about 0.16; and

the pH of the composition is about 5.0.

66. The kit of claim 42, wherein the buffer concentration is about 20 mM.

67. The kit of claim 42, wherein the buffer is citrate buffer;

the buffer concentration is about 20 mM;

the ionic strength of the composition is about 0.01 to about 0.16; and

the pH of the composition is about 5.0.

68. The kit of claim 1, further comprising an anticholinergic agent.

69. The kit of claim 68, wherein the anticholinergic agent is ipratropium bromide, oxitropium bromide, atropine methyl nitrate, tiotropium bromide or glycopyrronium bromide.

70. The kit of claim 69, wherein the anticholinergic agent is ipratropium bromide.

71. The kit of claim 70, wherein the ipratropium bromide is present at a concentration of about 5 μ

g/mL to about 5 mg/mL.

72. The kit of claim 69, wherein the anticholinergic agent is tiotropium bromide.

73. The kit of claim 72, wherein the tiotropium bromide is present at a concentration of about 5 μ

g/mL to about 5 mg/mL.

74. A method for the treatment, prevention, or amelioration of one or more symptoms of bronchoconstrictive disorders, comprising administering an effective amount of a pharmaceutical composition to a subject in need of such treatment, wherein the pharmaceutical composition comprises formoterol or a derivative thereof formulated at a concentration suitable for direct administration to a subject in need thereof, in a pharmacologically suitable fluid, wherein the composition is stable during long term storage and the fluid comprises water.

75. The method of claim 74, wherein the composition has an estimated shelf-life of greater than 1 month usage time at 25°

C. and greater than or equal to 1 year storage time at 5°

C.

76. The method of claim 75, wherein greater than about 80% of the initial formoterol is present after 1 month usage time at 25°

C. and 1 year storage time at 5°

C.

77. The method of claim 74, wherein the composition further comprises a polar solvent.

78. The method of claim 77, wherein the polar solvent is a protic solvent.

79. The method of claim 78, wherein the composition further comprises a tonicity adjusting agent.

80. The method of claim 79, wherein the tonicity adjusting agent is ammonium carbonate, ammonium chloride, ammonium lactate, ammonium nitrate, ammonium phosphate, ammonium sulfate, ascorbic acid, bismuth sodium tartrate, boric acid, calcium chloride, calcium disodium edetate, calcium gluconate, calcium lactate, citric acid, dextrose, diethanolamine, dimethylsulfoxide, edetate disodium edetate trisodium monohydrate, fluorescein sodium, fructose, galactose, glycerin lactic acid, lactose, magnesium chloride, magnesium sulfate, mannitol, polyethylene glycol, potassium acetate, potassium chlorate, potassium chloride, potassium iodide, potassium nitrate, potassium phosphate, potassium sulfate, propylene glycol, silver nitrate, sodium acetate, sodium bicarbonate, sodium biphosphate, sodium bisulfite, sodium borate, sodium bromide, sodium cacodylate, sodium carbonate, sodium chloride, sodium citrate, sodium iodide, sodium lactate, sodium metabisulfite, sodium nitrate, sodium nitrite, sodium phosphate, sodium propionate, sodium succinate, sodium sulfate, sodium sulfite, sodium tartrate, sodium thiosulfate, sorbitol, sucrose, tartaric acid, triethanolamine, urea, urethan, uridine or zinc sulfate.

81. The method of claim 80, wherein the tonicity adjusting agent is sodium chloride.

82. The method of claim 74, wherein the composition further comprises a buffer.

83. The method of claim 82, wherein the buffer is citric acid/phosphate, acetate, barbital, borate, Britton-Robinson, cacodylate, citrate, collidine, formate, maleate, McIlvaine, phosphate, Prideaux-Ward, succinate, citrate-phosphate-borate (Teorell-Stanhagen), veronal acetate, MES (2-(N-morpholino)ethanesulfonic acid), BIS-TRIS (bis(2-hydroxyethyl)iminotris(hydroxymethyl)methane), ADA (N-(2-acetamido)-2-iminodiacetic acid), ACES (N-(carbamoylmethyl)-2-aminoethanesulfonic acid), PIPES (piperazine-N,N′

-bis(2-ethanesulfonic acid)), MOPSO (3-(N-morpholino)-2-hydroxypropanesulfonic acid), BIS-TRIS PROPANE (1,3-bis(tris(hydroxymethyl)methylamino)propane), BES (N,N-bis(2-hydroxyethyl)-2-aminoethanesulfonic acid), MOPS (3-(N-morpholino)propanesulfonic acid), TES (N-tris(hydroxymethyl)methyl-2-aminoethanesulfonic acid), HEPES (N-(2-hydroxyethyl)piperazine-N′

-(2-ethanesulfonic acid), DIPSO (3-(N,N-bis(2-hydroxyethyl)amino)-2-hydroxypropanesulfonic acid), MOBS (4-(N-morpholino)-butanesulfonic acid), TAPSO (3-(N-tris(hydroxymethyl)methylamino)-2-hydroxy-propanesulfonic acid), tris(hydroxymethylaminomethane, HEPPSO (N-(2-hydroxyethyl)piperazine-N′

-(2-hydroxypropanesulfonic acid), POPSO (piperazine-N,N′

-bis(2-hydroxypropanesulfonic acid)), TEA (triethanolamine), EPPS (N-(2-hydroxyethyl)piperazine-N′

-(3-propanesulfonic acid), TRICINE (N-tris(hydroxy-methyl)methylglycine), GLY-GLY (glycylglycine), BICINE (N,N-bis(2-hydroxyethyl)glycine), HEPBS (N-(2-hydroxyethyl)piperazine-N′

-(4-butanesulfonic acid)), TAPS (N-tris(hydroxymethyl)methyl-3-aminopropanesulfonic acid), or AMPD (2-amino-2-methyl-1,3-propanediol) buffer.

84. The method of claim 83, wherein the buffer is citrate buffer.

85. The method of claim 84, wherein the buffer concentration is from about 0.01 mM to about 150 mM.

86. The method of claim 85, wherein the buffer concentration is from about 1 mM to about 20 mM.

87. The method of claim 86, wherein the buffer concentration is about 5 mM.

88. The method of claim 87, wherein the ionic strength of the composition is about 0 to about 0.4.

89. The method of claim 88, wherein the ionic strength of the composition is about 0.05 to about 0.16.

90. The method of claim 74, wherein the pH of the composition is about 2.0 to about 8.0.

91. The method of claim 90, wherein the pH of the composition is about 4.0 to about 6.0.

92. The method of claim 91, wherein the pH of the composition is about 4.5 to about 5.5.

93. The method of claim 92, wherein the pH of the composition is about 5.0.

94. The method of claim 74, wherein the formoterol free base concentration in the composition is about 5 μ

g/mL to about 2 mg/mL.

95. The method of claim 94, wherein the formoterol free base concentration in the composition is about 10 μ

g/mL to about 1 mg/mL.

96. The method of claim 95, wherein the formoterol free base concentration in the composition is about 50 μ

g/mL to about 200 μ

g/mL.

97. The method of claim 96, wherein the formoterol free base concentration in the composition is about 59 μ

g/mL.

98. The method of claim 96, wherein the formoterol free base concentration in the composition is about 118 μ

g/mL.

99. The method of claim 80, wherein the composition further comprises a buffer.

100. The method of claim 99, wherein the buffer is citric acid/phosphate, acetate, barbital, borate, Britton-Robinson, cacodylate, citrate, collidine, formate, maleate, McIlvaine, phosphate, Prideaux-Ward, succinate, citrate-phosphate-borate (Teorell-Stanhagen), veronal acetate, MES (2-(N-morpholino)ethanesulfonic acid), BIS-TRIS (bis(2-hydroxyethyl)iminotris(hydroxymethyl)methane), ADA (N-(2-acetamido)-2-iminodiacetic acid), ACES (N-(carbamoylmethyl)-2-aminoethanesulfonic acid), PIPES (piperazine-N,N′

-bis(2-ethanesulfonic acid)), MOPSO (3-(N-morpholino)-2-hydroxypropanesulfonic acid), BIS-TRIS PROPANE (1,3-bis(tris(hydroxymethyl)methylamino)propane), BES (N,N-bis(2-hydroxyethyl)-2-aminoethanesulfonic acid), MOPS (3-(N-morpholino)propanesulfonic acid), TES (N-tris(hydroxymethyl)methyl-2-aminoethanesulfonic acid), HEPES (N-(2-hydroxyethyl)piperazine-N′

-(2-ethanesulfonic acid), DIPSO (3-(N,N-bis(2-hydroxyethyl)amino)-2-hydroxypropanesulfonic acid), MOBS (4-(N-morpholino)-butanesulfonic acid), TAPSO (3-(N-tris(hydroxymethyl)methylamino)-2-hydroxy-propanesulfonic acid), tris(hydroxymethylaminomethane, HEPPSO (N-(2-hydroxyethyl)piperazine-N′

-(2-hydroxypropanesulfonic acid), POPSO (piperazine-N,N′

-bis(2-hydroxypropanesulfonic acid)), TEA (triethanolamine), EPPS (N-(2-hydroxyethyl)piperazine-N′

-(3-propanesulfonic acid), TRICINE (N-tris(hydroxy-methyl)methylglycine), GLY-GLY (glycylglycine), BICINE (N,N-bis(2-hydroxyethyl)glycine), HEPBS (N-(2-hydroxyethyl)piperazine-N′

-(4-butanesulfonic acid)), TAPS (N-tris(hydroxymethyl)methyl-3-aminopropanesulfonic acid), or AMPD (2-amino-2-methyl-1,3-propanediol) buffer.

101. The method of claim 100, wherein the buffer is citrate buffer.

102. The method of claim 101, wherein the buffer concentration is from about 0.01 mM to about 150 mM.

103. The method of claim 102, wherein the buffer concentration is from about 1 mM to about 20 mM.

104. The method of claim 103, wherein the buffer concentration is about 5 mM.

105. The method of claim 99, wherein the ionic strength of the composition is about 0 to about 0.4.

106. The method of claim 105, wherein the ionic strength of the composition is about 0.05 to about 0.16.

107. The method of claim 99, wherein the pH of the composition is about 2.0 to about 8.0.

108. The method of claim 107, wherein the pH of the composition is about 4.0 to about 6.0.

109. The method of claim 108, wherein the pH of the composition is about 4.5 to about 5.5.

110. The method of claim 109, wherein the pH of the composition is about 5.0.

111. The method of claim 99, wherein the formoterol free base concentration in the composition is about 5 μ

g/mL to about 2 mg/mL.

112. The method of claim 111, wherein the formoterol free base concentration in the composition is about 10 μ

g/mL to about 1 mg/mL.

113. The method of claim 112, wherein the formoterol free base concentration in the composition is about 50 μ

g/mL to about 200 μ

g/mL.

114. The method of claim 113, wherein the formoterol free base concentration in the composition is about 59 μ

g/mL.

115. The method of claim 113, wherein the formoterol free base concentration in the composition is about 118 μ

g/mL.

116. The method of claim 74, wherein the composition comprises (a) formoterol free base at a concentration of about 59 μ

g/mL;

(b) aqueous saline comprising sodium chloride; and

(c) citrate buffer at a concentration of about 5 mM;

wherein the ionic strength of the composition is about 0.05 to about 0.16; and

the pH of the composition is about 5.0.

117. The method of claim 74, wherein the composition comprises (a) formoterol free base at a concentration of about 118 μ

g/mL;

(b) aqueous saline comprising sodium chloride; and

(c) citrate buffer at a concentration of about 5 mM;

wherein the ionic strength of the composition is about 0.05 to about 0.16; and

the pH of the composition is about 5.0.

118. The method of claim 74, wherein the composition comprises (a) formoterol free base at a concentration of about 59 μ

g/mL;

(b) aqueous saline comprising sodium chloride; and

(c) citrate buffer at a concentration of about 2 mM;

wherein the ionic strength of the composition is about 0.05 to about 0.16; and

the pH of the composition is about 5.0.

119. The method of claim 74, wherein the composition comprises (a) formoterol free base at a concentration of about 118 μ

g/mL;

(b) aqueous saline comprising sodium chloride; and

(c) citrate buffer at a concentration of about 2 mM;

wherein the ionic strength of the composition is about 0.05 to about 0.16; and

the pH of the composition is about 5.0.

120. The method of claim 113, wherein the buffer is citrate buffer.

121. The method of claim 113, wherein the buffer concentration is about 5 mM.

122. The method of claim 113, wherein the ionic strength of the composition is about 0.05 to about 0.16.

123. The method of claim 113, wherein the pH of the composition is about 5.0.

124. The method of claim 113, wherein the buffer is citrate buffer;

the buffer concentration is about 5 mM;

the ionic strength of the composition is about 0.05 to about 0.16; and

the pH of the composition is about 5.0.

125. The method of claim 114, wherein the buffer is citrate buffer.

126. The method of claim 114, wherein the buffer concentration is about 5 mM.

127. The method of claim 114, wherein the ionic strength of the composition is about 0.05 to about 0.16.

128. The method of claim 114, wherein the pH of the composition is about 5.0.

129. The method of claim 114, wherein the buffer is citrate buffer;

the buffer concentration is about 5 mM;

the ionic strength of the composition is about 0.05 to about 0.16; and

the pH of the composition is about 5.0.

130. The method of claim 74, further comprising administration of one or more of (a) to (j) as follows:

(a) a β

2-adrenoreceptor agonist;

(b) a dopamine receptor agonist;

(c) an IL-5 inhibitor;

(d) an antisense modulator of IL-5;

(e) a tryptase inhibitor;

(f) a tachykinin receptor antagonist;

(g) milrinone or milrinone lactate;

(h) a leukotriene receptor antagonist;

(i) a 5-lypoxygenase inhibitor;

or (j) an anti-IgE antibody.

131. The method of claim 83, wherein the buffer comprises citric acid/phosphate buffer, acetate buffer, citrate buffer or phosphate buffer.

132. The method of claim 99, wherein the buffer comprises citric acid/phosphate buffer, acetate buffer, citrate buffer or phosphate buffer.

133. The method of claim 85, wherein the buffer concentration is from about 1 mM to about 50 mM.

134. The method of claim 133, wherein the buffer concentration is about 20 mM.

135. The method of claim 102, wherein the buffer concentration is from about 1 mM to about 50 mM.

136. The method of claim 135, wherein the buffer concentration is about 20 mM.

137. The method of claim 114, wherein the buffer concentration is about 20 mM.

138. The method of claim 114, wherein the buffer is citrate buffer;

the buffer concentration is about 20 mM;

the ionic strength of the composition is about 0.05 to about 0.16; and

the pH of the composition is about 5.0.

139. The method of claim 115, wherein the buffer concentration is about 20 mM.

140. The method of claim 115, wherein the buffer is citrate buffer;

the buffer concentration is about 20 mM;

the ionic strength of the composition is about 0.05 to about 0.16; and

the pH of the composition is about 5.0.

141. The method of claim 74, further comprising an anticholinergic agent.

142. The method of claim 141, wherein the anticholinergic agent is ipratropium bromide, oxitropium bromide, atropine methyl nitrate, tiotropium bromide or glycopyrronium bromide.

143. The method of claim 142, wherein the anticholinergic agent is ipratropium bromide.

144. The method of claim 143, wherein the ipratropium bromide is present at a concentration of about 5 μ

g/mL to about 5 mg/mL.

145. The method of claim 142, wherein the anticholinergic agent is tiotropium bromide.

146. The method of claim 145, wherein the tiotropium bromide is present at a concentration of about 5 μ

g/mL to about 5 mg/mL.