FORMOTEROL/STEROID BRONCHODILATING COMPOSITIONS AND METHODS OF USE THEREOF

• US 20100120734A1
• Filed: 01/22/2010
• Published: 05/13/2010
• Est. Priority Date: 04/17/2001
• Status: Abandoned Application

• Current Assignee: Dey LP (Pfizer Inc.)
• Original Assignee: Dey LP (Pfizer Inc.)
• Inventors: Pham, Stephen, Chaudry, Imtiaz A., Banerjee, Partha S.
• Application Number:
  US12/692,095
• Publication Number:
  US 20100120734A1
• Time in Patent Office: Days
• US Class Current: 514/171
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/167 having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
• CPC Class Codes: A61K 31/191 having two or more hydroxy groups, e.g. gluconic acid
• CPC Class Codes: A61K 31/537 spiro-condensed or forming part of bridged ring systems
• CPC Class Codes: A61K 31/56 Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
• CPC Class Codes: A61K 31/568 substituted in positions 10 and 13 by a chain having at least one carbon atom, e.g. androstanes, e.g. testosterone
• CPC Class Codes: A61K 31/573 substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
• CPC Class Codes: A61K 31/58 containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin digitoxin A61K31/7048
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 47/02 Inorganic compounds
• CPC Class Codes: A61K 47/10 Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
• 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: 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, and a steroidal anti-inflammatory agent. 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 pharmaceutical composition, comprising:

(i) formoterol, or a pharmaceutically acceptable hydrate thereof in solution; and

(ii) a steroidal anti-inflammatory agent, or a pharmaceutically acceptable salt or hydrate thereof in suspension;

in a pharmacologically suitable fluid comprising water that is propellant-free, wherein;

the composition is an aqueous composition formulated so that it is stable during long term storage, whereby 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., whereby greater than 90% of the initial amount of formoterol in the composition remains at such time;

the formoterol free base concentration is about 5 μ

g/mL to about 200 μ

g/mL; and

the composition is formulated at a concentration for direct administration to a human in need thereof.

2. The pharmaceutical composition of claim 1, 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.

3. The pharmaceutical composition of claim 1 that has been nebulized.

4. The pharmaceutical composition of claim 1, wherein the pharmacologically suitable fluid further comprises a polar solvent.

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

6. The pharmaceutical composition of claim 5, further comprising a tonicity adjusting agent.

7. The pharmaceutical composition 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 pharmaceutical composition of claim 7, wherein the tonicity adjusting agent is sodium chloride.

9. The pharmaceutical composition of claim 1, wherein the pharmacologically suitable fluid comprises a buffer.

10. The pharmaceutical composition of claim 9, wherein the buffer is citric acid/phosphate, acetate, barbital, borate, cacodylate, citrate, collidine, formate, maleate, phosphate, 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-amino-ethanesulfonic 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-N¹-(2-hydroxypropanesulfonic acid), POPSO (piperazine-N,N′

-bis(2-hydroxypropane-sulfonic acid)), TEA (triethanolamine), EPPS(N-(2-hydroxyethyl)piperazine-1-N′

-(3-propanesulfonic acid), TRICINE (N-tris(hydroxymethyl)methylglycine)-, GLY-GLY (glycylglycine), WINE (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.

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

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

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

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

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

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

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

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

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

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

21. The pharmaceutical composition of claim 1, wherein the formoterol free base concentration is about 10 μ

g/mL to about 200 μ

g/mL.

22. The pharmaceutical composition of claim 21, wherein the formoterol free base concentration is about 50 g/mL to about 200 μ

g/mL.

23. The pharmaceutical composition of claim 22, wherein the formoterol free base concentration is about 59 μ

g/mL.

24. The pharmaceutical composition of claim 22, wherein the formoterol free base concentration is about 118 μ

g/mL.

25. The pharmaceutical composition of claim 7, further comprising a buffer.

26. The pharmaceutical composition of claim 25, wherein the buffer is citric acid/phosphate, acetate, barbital, borate, cacodylate, citrate, collidine, formate, maleate, phosphate, 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-amino-ethanesulfonic 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-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(hydroxyl-methyl)methyl-3-aminopropanesulfonic acid), or AMPD (2-amino-2-methyl-1,3-propanediol) buffer.

27. The pharmaceutical composition of claim 26, wherein the buffer is citrate buffer.

28. The pharmaceutical composition of claim 27, wherein the buffer concentration is from about 0.01 mM to about 150 mM.

29. The pharmaceutical composition of claim 28, wherein the buffer concentration is from about 1 mM to about 20 mM.

30. The pharmaceutical composition of claim 29, wherein the buffer concentration is about 5 mM.

31. The pharmaceutical composition of claim 25, wherein the ionic strength of the composition is about 0 to about 0.4.

32. The pharmaceutical composition of claim 31, wherein the ionic strength of the composition is about 0.05 to about 0.16.

33. The pharmaceutical composition of claim 25, wherein the pH of the composition is about 2.0 to about 8.0.

34. The pharmaceutical composition of claim 33, wherein the pH of the composition is about 4.0 to about 6.0.

35. The pharmaceutical composition of claim 34, wherein the pH of the composition is about 4.5 to about 5.5.

36. The pharmaceutical composition of claim 35, wherein the pH of the composition is about 5.0.

37. The pharmaceutical composition of claim 25, wherein the formoterol free base concentration is about 10 μ

g/mL to about 200 μ

g/mL.

38. The pharmaceutical composition of claim 37, wherein the formoterol free base concentration is about 50 μ

g/mL to about 200 μ

g/mL.

39. The pharmaceutical composition of claim 38, wherein the formoterol free base concentration is about 59 μ

g/mL.

40. The pharmaceutical composition of claim 38, wherein the formoterol free base concentration is about 118 μ

g/mL.

41. The pharmaceutical composition of claim 23 that has been nebulized.

42. The pharmaceutical composition of claim 24 that has been nebulized.

43. The pharmaceutical composition of claim 39 that has been nebulized.

44. The pharmaceutical composition of claim 40 that has been nebulized.

45. The pharmaceutical composition of claim 25 that has been nebulized.

46. The pharmaceutical composition of claim 39, wherein the buffer is citrate buffer.

47. The pharmaceutical composition of claim 39, wherein the buffer concentration is about 5 mM.

48. The pharmaceutical composition of claim 39, wherein the ionic strength of the composition is about 0.05 to about 0.16.

49. The pharmaceutical composition of claim 39, wherein the pH of the composition is about 5.0.

50. The pharmaceutical composition of claim 39, 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.

51. The pharmaceutical composition of claim 40, wherein the buffer is citrate buffer.

52. The pharmaceutical composition of claim 40, wherein the buffer concentration is about 5 mM.

53. The pharmaceutical composition of claim 40, wherein the ionic strength of the composition is about 0.05 to about 0.16.

54. The pharmaceutical composition of claim 40, wherein the pH of the composition is about 5.0.

55. The pharmaceutical composition of claim 40, 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.

56. The pharmaceutical composition of claim 50 that has been nebulized.

57. The pharmaceutical composition of claim 55 that has been nebulized.

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

59. The pharmaceutical composition of claim 25, wherein the buffer comprises citric acid/phosphate buffer, acetate buffer, citrate buffer or phosphate buffer.

60. The pharmaceutical composition of claim 1, wherein the steroidal anti-inflammatory agent is beclomethasone dipropionate, beclomethasone monopropionate, flunisolide, triamcinolone acetonide, dexamethasone, tipredane, ciclesonid, rofleponide, mometasone, mometasone furoate, RPR 106541 having the formula

61. The pharmaceutical composition of claim 60, wherein the steroidal anti-inflammatory agent is budesonide or fluticasone propionate, or a pharmaceutically acceptable salt or hydrate thereof.

62. The pharmaceutical composition of claim 61, wherein the steroidal anti-inflammatory agent is budesonide, or a derivative thereof.

63. The pharmaceutical composition of claim 62, wherein the budesonide concentration is about 5 μ

g/mL to about 2 mg/mL.

64. The pharmaceutical composition of claim 62, wherein the budesonide concentration is about 75 μ

g/mL to about 500 μ

g/mL.

65. The pharmaceutical composition of claim 62, wherein the budesonide concentration is about 125 μ

g/mL or about 250 μ

g/mL.

66. The pharmaceutical composition of claim 61, wherein the steroidal anti-inflammatory agent is fluticasone propionate.

67. The pharmaceutical composition of claim 66, wherein the concentration of fluticasone propionate is about 5 μ

g/mL to about 2 mg/mL.

68. The pharmaceutical composition of claim 67, wherein the concentration of fluticasone propionate is about 75 μ

g/mL to about 1000 μ

g/mL.

69. The pharmaceutical composition of claim 68, wherein the concentration of fluticasone propionate is about 125 μ

g/mL or about 250 μ

g/mL.

70. The pharmaceutical composition of claim 50, wherein the steroidal anti-inflammatory agent is budesonide or fluticasone propionate.

71. The pharmaceutical composition of claim 55, wherein the steroidal anti-inflammatory agent is budesonide or fluticasone propionate.

75. A combination, comprising:

(a) the pharmaceutical composition of claim 1 formulated for single dosage administration; and

(b) a vial.

76. The combination of claim 75, wherein the aqueous 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.

77. The combination of claim 75, wherein the aqueous 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.

78. An article of manufacture, comprising packaging material, an aqueous composition comprising the composition of claim 1 formulated for single dosage administration, which is useful for treatment or amelioration of one or more symptoms of diseases or disorders associated with undesired and/or uncontrolled bronchoconstriction, and a label that indicates that the composition is used for treatment, amelioration of one or more symptoms of diseases or disorders associated with undesired and/or uncontrolled bronchoconstriction.

79. An article of manufacture, comprising packaging material, the composition of claim 70 formulated for single dosage administration, which is useful for treatment or amelioration of one or more symptoms of diseases or disorders associated with undesired and/or uncontrolled bronchoconstriction, and a label that indicates that the composition is used for treatment or amelioration of one or more symptoms of diseases or disorders associated with undesired and/or uncontrolled bronchoconstriction.

80. An article of manufacture, comprising packaging material, the composition of claim 71 formulated for single dosage administration, which is useful for treatment or amelioration of one or more symptoms of diseases or disorders associated with undesired and/or uncontrolled bronchoconstriction, and a label that indicates that the composition is used for treatment or amelioration of one or more symptoms of diseases or disorders associated with undesired and/or uncontrolled bronchoconstriction.

81. The pharmaceutical composition 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.

82. The pharmaceutical composition of claim 12, wherein the buffer concentration is from about 1 mM to about 50 mM.

83. The pharmaceutical composition of claim 82, wherein the buffer concentration is about 20 mM.

84. The pharmaceutical composition of claim 28, wherein the buffer concentration is from about 1 mM to about 50 mM.

85. The pharmaceutical composition of claim 84, wherein the buffer concentration is about 20 mM.

86. The pharmaceutical composition of claim 39, wherein the buffer concentration is about 20 mM.

87. The pharmaceutical composition of claim 39, 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.

88. The pharmaceutical composition of claim 40, wherein the buffer concentration is about 20 mM.

89. The pharmaceutical composition of claim 40, 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.

90. The pharmaceutical composition of claim 87 that has been nebulized.

91. The pharmaceutical composition of claim 89 that has been nebulized.

94. The combination of claim 75, wherein the aqueous 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 20 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.

95. The combination of claim 75, wherein the aqueous 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 20 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.

96. The pharmaceutical composition of claim 1, further comprising an anticholinergic agent.

97. The pharmaceutical composition of claim 96, wherein the anticholinergic agent is ipratropium bromide, oxitropium bromide, atropine methyl nitrate, tiotropium bromide or glycopyrronium bromide.

98. The pharmaceutical composition of claim 97, wherein the anticholinergic agent is ipratropium bromide.

99. The pharmaceutical composition of claim 98, wherein the ipratropium bromide is present at a concentration of about 5 μ

g/mL to about 5 mg/mL.

103. The pharmaceutical composition of claim 97, wherein the anticholinergic agent is tiotropium bromide.

104. The pharmaceutical composition of claim 98, wherein the tiotropium bromide is present at a concentration of about 5 μ

g/mL to about 5 mg/mL.

106. The pharmaceutical composition of claim 1, wherein the formoterol is formoterol fumarate dihydrate;

and the steroidal anti-inflammatory agent is fluticasone propionate.

107. The pharmaceutical composition of claim 106, wherein the concentration of fluticasone propionate in the composition is about 75 μ

g/mL to about 1000 μ

g/mL.

108. The pharmaceutical composition of claim 107, wherein the concentration of fluticasone propionate in the composition is about 250 μ

g/mL to about 1000 μ

g/mL.

109. The pharmaceutical composition of claim 107, wherein the concentration of fluticasone propionate in the composition is about 125 μ

g/mL to about 250 μ

g/mL

110. The pharmaceutical composition of claim 106, wherein the composition further comprises a tonicity adjusting agent, a suspension stabilizer, and the pharmaceutically suitable fluid comprises a buffer.

111. The pharmaceutical composition of claim 110, wherein the tonicity adjusting agent comprises sodium chloride and sodium edetate, the suspension stabilizer is Polysorbate 80, and the buffer is a sodium citrate buffer.

72. A kit, comprising:

(a) an aqueous composition comprising

(i) formoterol or a pharmaceutically acceptable salt or hydrate thereof in solution, wherein the formoterol is present at a concentration of 5 μ

g/mL to about 200 μ

g/mL; and

(ii) a steroidal anti-inflammatory agent or a pharmaceutically acceptable salt or hydrate thereof in suspension, formulated for single dosage administration, wherein the aqueous composition is propellant-free and 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.; and

(b) a nebulizer.

73. The kit of claim 72, wherein the aqueous 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.

74. The kit of claim 72, wherein the aqueous 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.

92. The kit of claim 72, wherein the aqueous 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 20 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.

93. The kit of claim 72, wherein the aqueous 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 20 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.

100. A combination, comprising:

(a) a composition comprising formoterol, or a pharmaceutically acceptable salt or hydrate thereof in solution, the composition being in a pharmacologically suitable fluid comprising water that is propellant-free, and the composition having an estimated shelf-life of greater than 1 month usage time at 25°

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

C. whereby greater than 90% of the initial amount of formoterol in the compositions remains at such time;

the formoterol free base concentration is about 5 μ

g/mL to about 200 μ

g/mL, and the composition is formulated at a concentration for direct administration to a human in need thereof; and

(b) a composition comprising a bronchodilating steroid, or a pharmaceutically acceptable salt or hydrate thereof in suspension.

101. The combination of claim 100, further comprising a nebulizer.

102. The combination of claim 101 that is packaged as a kit;

optionally comprising instructions for use of the nebulizer; and

optionally comprising instructions for mixing the compositions.

105. A pharmaceutical composition, comprising:

(i) formoterol, or a pharmaceutically acceptable salt or hydrate thereof in solution, at a concentration with reference to the free base of about 5 μ

g/mL to about 200 μ

g/mL; and

(ii) a steroid anti-inflammatory agent, or a pharmaceutically acceptable salt or hydrate thereof in suspension;

in a pharmacologically suitable fluid comprising water, which is propellant-free, wherein;

the composition is an aqueous composition that contains buffer at a concentration of 1-20 mM, has a pH of 4 to 6, an ionic strength of 0.05-0.16, selected so that 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.

112. A sterile unit dose, comprising:

(a) a pharmaceutical composition comprising formoterol or a salt thereof at a concentration of from about 5 μ

g/mL to about 200 μ

g/mL based on formoterol free base, in a pharmacologically suitable solution, wherein the composition further comprises water and a buffer having a concentration of from about 1 mM to about 50 mM, said composition having a pH of about 4.0 to about 6.0, and having an estimated shelf life of greater than 90% after 3 months storage at 25°

C. and after 3 years storage at 5°

C.;

(b) packaged in a pharmaceutical packaging material.

113. The sterile unit dose as in any one of claims 112 wherein said buffer is selected from the group consisting of a citric acid/phosphate buffer, acetate buffer, citrate buffer or phosphate buffer.

114. The sterile unit dose of claim 113 wherein said buffer is present at a concentration of between about 1 mM and about 20 mM.

115. The sterile unit dose as in any one of claims 112 wherein said pharmaceutical packaging material is selected from the group consisting of blister packs, bottles, tubes, inhalers, pumps, bags, vials, containers and syringes.

116. The sterile unit dose of claim 115 wherein said pharmaceutical packaging material is a vial.

117. The sterile unit dose as in any one of claims 112, wherein said buffer has a concentration of from about 1 mM to about 20 mM.

118. The sterile unit dose as in any one of claims 112, wherein said composition has a pH of about 5.

119. The sterile unit dose of claim 117, wherein said buffer has a pH of about 5.

120. The sterile unit dose as in any one of claims 112, wherein said formoterol or a salt thereof is formoterol tartrate.

121. The sterile unit dose of claim 117, wherein said formoterol or a salt thereof is formoterol tartrate.

122. A sterile unit dose, comprising:

(a) a pharmaceutical composition comprising formoterol or a salt thereof at a concentration of from about 5 μ

g/mL to about 200 μ

g/mL based on formoterol free base, in a pharmacologically suitable solution, wherein the composition further comprises water and a buffer selected from the group consisting of citric acid/phosphate buffer, acetate buffer, citrate buffer or phosphate buffer at a concentration of from about 1 mM to about 50 mM, said composition having a pH of about 4.5 to about 5.5;

(b) packaged in a pharmaceutical packaging material.

123. The sterile unit dose of claim 122, wherein said pharmaceutical packaging material is a vial.

124. The sterile unit dose of claim 122, wherein said buffer has a concentration of from about 1 mM to about 20 mM.

125. The sterile unit dose of claim 122, wherein said composition has a pH of about 5.

126. The sterile unit dose of claim 124, wherein said buffer has a pH of about 5.

127. The sterile unit dose of claim 122, wherein said formoterol or a salt thereof is formoterol tartrate.

128. The sterile unit dose of claim 124, wherein said formoterol or a salt thereof is formoterol tartrate.

129. The sterile unit dose of claim 126, wherein said formoterol or a salt thereof is formoterol tartrate.