Formoterol/steroid bronchodilating compositions and methods of use thereof

• US 8,716,348 B2
• Filed: 03/21/2011
• Issued: 05/06/2014
• Est. Priority Date: 04/17/2001
• Status: Expired due to Fees

• Current Assignee: Mylan Specialty L.P. (Pfizer Inc.)
• Original Assignee: Dey Pharma LP (Pfizer Inc.)
• Inventors: Banerjee, Partha S., Chaudry, Imtiaz A., Pham, Stephen
• Primary Examiner(s): Padmanabhan, Sreeni
• Assistant Examiner(s): Kantamneni, Shobha
• Application Number:
  US13/052,792
• Publication Number:
  US 20110166202A1
• Time in Patent Office: 1,142 Days
• Field of Search: 514/727, 514/730, 514/734, 514/189, 514/170, 514/177, 514/178, 514/182, 514/653, 514/630, 514/169, 424/45, 424/400
• US Class Current: 514/653
• 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 packaged 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 80% 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 118 μ

g/mL; and

the composition is formulated at a concentration for direct administration without dilution to a human in need thereof.

2. The pharmaceutical composition of claim 1, wherein greater than about 90% 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, proplyene glycol, silver nitrate, sodium acetate, sodium bicarbonate, sodium biphosphate, sodium bisulfite, 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, 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, cacodylate, citrate, collidine, formate, maleate, phosphate, succinate, veronal acetate, MES (2-(N-morpholino)ethanesulfonic acid), ADA (N-(2-acetamido)-2-iminodiacetic acid), ACES (N-(carbamoylmethyl)-2-amino-ethanesulfonaic acid), PIPES (piperazine-N,Nt-bis(2-ethanesulfonic acid)), MOPSO (3-(N-morpholino)-2-hydroxypropanesulfonic acid), BES (N,N-bis(2-hydroxyethyl)-2-aminoethanesulfonaic 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), HEPPSO(N-(2-hydroxyethyl)piperazine-N′

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

-bis(2-hydroxypropane-sulfonic acid)), 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 pharmaceutical composition of claim 10, wherein the buffer is citrate buffer.

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

13. The pharmaceutical composition of claim 12, wherein the buffer concentration is 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 4.0 to about 6.0.

18. The pharmaceutical composition of claim 17, wherein the pH of the composition is about 4.5 to about 5.5.

19. The pharmaceutical composition of claim 18, wherein the pH of the composition is about 5.0.

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

g/mL to about 118 μ

g/mL.

21. The pharmaceutical composition of claim 20, wherein the formoterol free base concentration is about 50 μ

g/mL to about 118 μ

g/mL.

22. The pharmaceutical composition of claim 21, wherein the formoterol free base concentration is about 59 μ

g/mL.

23. The pharmaceutical composition of claim 21, wherein the formoterol free base concentration is about 118 μ

g/mL.

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

25. The pharmaceutical composition of claim 24, wherein the buffer is citric acid/phosphate, acetate, barbital, cacodylate, citrate, collidine, formate, maleate, phosphate, succinate, veronal acetate, MES (2-(N-morpholino)ethanesulfonic acid), ADA (N-(2-acetamido)-2-iminodiacetic acid), ACES (N-(carbamoylmethyl)-2-amino-ethanesulfonaic acid), PIPES (piperazine-N,N-bis(2-ethanesulfonic acid)), MOPSO (3-(N-morpholino)-2-hydroxypropanesulfonic acid), BES (N,N-bis(2-hydroxyethyl)-2-aminoethanesulfonaic 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), HEPPSO(N-(2-hydroxyethyl)piperazine-N′

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

-bis(2-hydroxypropane-sulfonic acid)), 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.

26. The pharmaceutical composition of claim 25, wherein the buffer is citrate buffer.

27. The pharmaceutical composition of claim 26, wherein the buffer concentration is about 0.01 mM to about 150 mM.

28. The pharmaceutical composition of claim 27, wherein the buffer concentration is about 1 mM to about 20 mM.

29. The pharmaceutical composition of claim 28, wherein the buffer concentration is about 5 mM.

30. The pharmaceutical composition of claim 24, wherein the ionic strength of the composition is about 0 to about 0.4.

31. The pharmaceutical composition of claim 30, wherein the ionic strength of the composition is about 0.05 to about 0.16.

32. The pharmaceutical composition of claim 24, wherein the pH of the composition is about 4.0 to about 6.0.

33. The pharmaceutical composition of claim 32, wherein the pH of the composition is about 4.5 to about 5.5.

34. The pharmaceutical composition of claim 33, wherein the pH of the composition is about 5.0.

35. The pharmaceutical composition of claim 24, wherein the formoterol free base concentration is about 10 μ

g/mL to about 118 μ

g/mL.

36. The pharmaceutical composition of claim 35, wherein the formoterol free base concentration is about 50 μ

g/mL to about 118 μ

g/mL.

37. The pharmaceutical composition of claim 36, wherein the formoterol free base concentration is about 59 μ

g/mL.

38. The pharmaceutical composition of claim 36, wherein the formoterol free base concentration is about 118 μ

g/mL.

39. The pharmaceutical composition of claim 22 that has been nebulized.

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

41. The pharmaceutical composition of claim 37 that has been nebulized.

42. The pharmaceutical composition of claim 38 that has been nebulized.

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

44. The pharmaceutical composition of claim 37, wherein the buffer is citrate buffer.

45. The pharmaceutical composition of claim 37, wherein the buffer concentration is about 5 mM.

46. The pharmaceutical composition of claim 37, wherein the ionic strength of the composition is about 0.05 to about 0.16.

47. The pharmaceutical composition of claim 37, wherein the pH of the composition is about 5.0.

48. The pharmaceutical composition of claim 37, 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.

49. The pharmaceutical composition of claim 38, wherein the buffer is citrate buffer.

50. The pharmaceutical composition of claim 38, wherein the buffer concentration is about 5 mM.

51. The pharmaceutical composition of claim 38, wherein the ionic strength of the composition is about 0.05 to about 0.16.

52. The pharmaceutical composition of claim 38, wherein the pH of the composition is about 5.0.

53. The pharmaceutical composition of claim 38, 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.

54. The pharmaceutical composition of claim 48 that has been nebulized.

55. The pharmaceutical composition of claim 53 that has been nebulized.

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

57. The pharmaceutical composition of claim 24, wherein the buffer comprises citric acid/phosphate buffer, acetate buffer, citrate buffer or phosphate buffer.

58. 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

59. The pharmaceutical composition of claim 58, wherein the steroidal anti-inflammatory agent is budesonide or fluticasone propionate, or a pharmaceutically acceptable salt or hydrate thereof.

60. The pharmaceutical composition of claim 59, wherein the steroidal anti-inflammatory agent is fluticasone propionate.

61. The pharmaceutical composition of claim 60, wherein the concentration of fluticasone propionate is about 5 μ

g/mL to about 2 mg/mL.

62. The pharmaceutical composition of claim 61, wherein the concentration of fluticasone propionate is about 75 μ

g/mL to about 1000 μ

g/mL.

63. The pharmaceutical composition of claim 62, wherein the concentration of fluticasone propionate is about 125 μ

g/mL or about 250 μ

g/mL.

64. The pharmaceutical composition of claim 48, wherein the steroidal anti-inflammatory agent is budesonide or fluticasone propionate.

65. The pharmaceutical composition of claim 53, wherein the steroidal anti-inflammatory agent is budesonide or fluticasone propionate.

69. A combination, comprising:

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

(b) a vial.

70. The combination of claim 69, 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.

71. The combination of claim 69, 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.

72. 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.

73. An article of manufacture, comprising packaging material, the composition of claim 64 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.

74. An article of manufacture, comprising packaging material, the composition of claim 65 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.

75. 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.

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

77. The pharmaceutical composition of claim 76, wherein the buffer concentration is about 20 mM.

78. The pharmaceutical composition of claim 27, wherein the buffer concentration is from about 1 mM to about 50 mM.

79. The pharmaceutical composition of claim 78, wherein the buffer concentration is about 20 mM.

80. The pharmaceutical composition of claim 37, wherein the buffer concentration is about 20 mM.

81. The pharmaceutical composition of claim 37, 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.

82. The pharmaceutical composition of claim 38, wherein the buffer concentration is about 20 mM.

83. The pharmaceutical composition of claim 38, 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.

84. The pharmaceutical composition of claim 81 that has been nebulized.

85. The pharmaceutical composition of claim 83 that has been nebulized.

88. The combination of claim 69, 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.

89. The combination of claim 69, 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.

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

91. The pharmaceutical composition of claim 90, wherein the anticholinergic agent is ipratropium bromide, oxitropium bromide, atropine methyl nitrate, tiotropium bromide or glycopyrronium bromide.

92. The pharmaceutical composition of claim 91, wherein the anticholinergic agent is ipratropium bromide.

93. The pharmaceutical composition of claim 92, wherein the ipratropium bromide is present at a concentration of about 5 μ

g/mL to about 5 mg/mL.

97. The pharmaceutical composition of claim 91, wherein the anticholinergic agent is tiotropium bromide.

98. The pharmaceutical composition of claim 92, wherein the tiotropium bromide is present at a concentration of about 5 μ

g/mL to about 5 mg/mL.

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

and the steroidal anti-inflammatory agent is fluticasone propionate.

101. The pharmaceutical composition of claim 100, wherein the concentration of fluticasone propionate in the composition is about 75 μ

g/mL to about 1000 μ

g/mL.

102. The pharmaceutical composition of claim 101, wherein the concentration of fluticasone propionate in the composition is about 250 μ

g/mL to about 1000 μ

g/mL.

103. The pharmaceutical composition of claim 101, wherein the concentration of fluticasone propionate in the composition is about 125 μ

g/mL to about 250 μ

g/mL.

104. The pharmaceutical composition of claim 100, wherein the composition further comprises a tonicity adjusting agent and a suspension stabilizer, and wherein the pharmaceutically suitable fluid comprises a buffer.

105. The pharmaceutical composition of claim 104, 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.

66. 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 118 μ

g/mL; and

(ii) a steroidal anti-inflammatory agent or a pharmaceutically acceptable salt or hydrate thereof in suspension, wherein the composition is formulated for single dosage direct administration without dilution, 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.

67. The kit of claim 66, 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.

68. The kit of claim 66, 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.

86. The kit of claim 66, 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.

87. The kit of claim 66, 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.

94. A combination, comprising:

(a) a packaged composition comprising formoterol, or a pharmaceutically acceptable salt or hydrate thereof in solution, wherein the solution is 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 118 μ

g/mL, and the composition is formulated at a concentration for direct administration without dilution to a human in need thereof; and

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

95. The combination of claim 94, further comprising a nebulizer.

96. The combination of claim 95 that is packaged as a kit;

optionally comprising instructions for use of the nebulizer; and

optionally comprising instructions for mixing the compositions.

99. A packaged 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 118 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.; and

wherein the composition is formulated for direct administration to a patient without dilution.