Bronchodilating beta-agonist compositions and methods

• US 20050009923A1
• Filed: 07/09/2004
• Published: 01/13/2005
• Est. Priority Date: 07/10/2003
• Status: Active Grant

• Current Assignee: Dey Pharma LP (Pfizer Inc.)
• Original Assignee: Dey LP (Pfizer Inc.)
• Inventors: Banerjee, Partha S., Akapo, Samuel O., Chaudry, Imtiaz A.
• Granted Patent: US 7,348,362 B2
• Time in Patent Office: Days
• US Class Current: 514/630
• 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 31/205 Amine addition salts of organic acids; Inner quaternary ammonium salts, e.g. betaine, carnitine
• CPC Class Codes: A61K 31/46 8-Azabicyclo [3.2.1] octane; Derivatives thereof, e.g. atropine, cocaine
• 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 11/06 Antiasthmatics
• CPC Class Codes: A61P 11/08 Bronchodilators

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 pharmaceutical composition, comprising formoterol, or a derivative thereof, in a pharmacologically suitable fluid, wherein the composition is stable during long term storage and the fluid comprises water, and wherein the formoterol free base concentration is about 0.08 μ

g/mL up to about 128 μ

g/mL.

2. The pharmaceutical composition 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 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.

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

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

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

7. The pharmaceutical composition of claim 1, further comprising a tonicity adjusting agent.

8. The pharmaceutical composition of claim 7, 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.

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

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

11. The pharmaceutical composition of claim 10, 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-hydroxypropanesulfonic acid), tris(hydroxyrnethylaminomethane, 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.

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

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

14. The pharmaceutical composition of claim 13, wherein the buffer concentration is from about 0.01 mM to about 150 mM.

15. The pharmaceutical composition of claim 13, wherein the buffer concentration is from about 1 mM to about 50 mM.

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

17. The pharmaceutical composition of claim 13, wherein the buffer concentration is about 20 mM.

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

19. The pharmaceutical composition of claim 8, wherein the ionic strength of the composition is about 0 to about 0.4.

20. The pharmaceutical composition of claim 8, wherein the ionic strength of the composition is about 0.05 to about 0.16.

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

22. The pharmaceutical composition of claim 1, wherein the pH of the composition is about 4.0 to about 6.0.

23. The pharmaceutical composition of claim 1, wherein the pH of the composition is about 4.5 to about 5.5.

24. The pharmaceutical composition of claim 1, wherein the pH of the composition is about 5.0.

25. The pharmaceutical composition of claim 1, wherein the formoterol free base concentration is about 0.08 μ

g/mL to about 86 μ

g/mL.

26. The pharmaceutical composition of claim 1, wherein the formoterol free base concentration is about 0.08 μ

g/mL to about 43 μ

g/mL.

27. The pharmaceutical composition of claim 1, wherein the formoterol free base concentration is about 0.08 μ

g/mL to about 34 μ

g/mL.

28. The pharmaceutical composition of claim 1, wherein the formoterol free base concentration is about 0.08 μ

g/mL to about 26 μ

g/mL.

29. The pharmaceutical composition of claim 1, wherein the formoterol free base concentration is about 0.08 μ

g/mL to about 17 [μ

g/mL.

30. The pharmaceutical composition of claim 1, wherein the formoterol free base concentration is about 34 μ

g/mL.

31. The pharmaceutical composition of claim 1, wherein the formoterol free base concentration is about 30 μ

g/mL.

32. The pharmaceutical composition of claim 1, wherein the formoterol free base concentration is about 25.6 μ

g/mL.

33. The pharmaceutical composition of claim 1, wherein the formoterol free base concentration is about 21.4 μ

g/mL.

34. The pharmaceutical composition of claim 1, wherein the formoterol free base concentration is about 17 μ

g/mL.

35. The pharmaceutical composition of claim 1, wherein the formoterol free base concentration is about 13 μ

g/mL.

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

g/mL.

37. The pharmaceutical composition of claim 1, wherein the formoterol free base concentration is about 9 μ

g/mL.

38. The pharmaceutical composition of claim 1, wherein the formoterol free base concentration is about 7 μ

g/mL.

39. The pharmaceutical composition of claim 1, wherein the formoterol free base concentration is about 4 μ

g/mL.

40. The pharmaceutical composition of claim 1, wherein the formoterol free base concentration is about 2 μ

g/mL.

41. The pharmaceutical composition of claim 1, wherein the formoterol free base concentration is about 0.8 μ

g/mL.

42. The pharmaceutical composition of claim 1, 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.

43. The pharmaceutical composition of claim 1, 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.

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

47. A kit, comprising:

(a) a pharmaceutical composition of claim 1;

and

(b) a nebulizer.

48. The kit of claim 47, wherein the concentration of formoterol free base is about 17 μ

g/mL.

49. The kit of claim 47, wherein the pharmaceutical composition comprises (a) formoterol free base at a concentration of about 17 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.

50. The kit of claim 47, wherein the pharmaceutical composition comprises (a) formoterol free base at a concentration of about 17 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.

51. A combination, comprising:

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

(b) a vial.

52. The combination of claim 51, wherein the pharmaceutical composition comprises (a) formoterol free base at a concentration of about 17 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.

53. The combination of claim 51, wherein the pharmaceutical composition comprises (a) formoterol free base at a concentration of about 17 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.

54. A method for the treatment, prevention, or amelioration of one or more symptoms of bronchoconstrictive disorders, comprising administering an effective amount of the pharmaceutical composition of claim 1 to a subject in need of such treatment.

55. An article of manufacture, comprising packaging material, the composition of claim 1 formulated for single dosage administration, which is useful for treatment, prevention 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, prevention or amelioration of one or more symptoms of diseases or disorders associated with undesired and/or uncontrolled bronchoconstriction.

56. The method of claim 54, further comprising administering 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;

simultaneously with, prior to or subsequent to the formoterol composition.

57. 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.

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

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

60. The pharmaceutical composition of claim 59, wherein the anticholinergic agent is ipratropium bromide, oxitropium bromide, atropine methyl nitrate, tiotropium bromide or glycopyrronium bromide.

61. The pharmaceutical composition of claim 58, wherein the anticholinergic agent is ipratropium bromide.

62. The pharmaceutical composition of claim 59, wherein the ipratropium bromide is present at a concentration of about 100 μ

g/mL to about 500 μ

g/mL.

63. The pharmaceutical composition of claim 59, wherein the ipratropium bromide is present at a concentration of about 150 μ

g/mL to about 350 μ

g/mL.

64. The pharmaceutical composition of claim 59, wherein the ipratropium bromide is present at a concentration of about 200 μ

g/mL to about 300 μ

g/mL.

65. The pharmaceutical composition of claim 59, wherein the ipratropium bromide is present at a concentration of about 250 μ

g/mL.

66. The pharmaceutical composition of claim 60, wherein the anticholinergic agent is tiotropium bromide.

67. The pharmaceutical composition of claim 66, wherein the tiotropium bromide is present at a concentration of about 5 μ

g/mL to about 5 mg/mL.

68. A method for the treatment, prevention, or amelioration of one or more symptoms of bronchoconstrictive disorders, comprising administering an effective amount of the pharmaceutical composition of claim 59 to a subject in need of such treatment.

69. An article of manufacture, comprising packaging material, an aqueous composition comprising the composition of claim 59 formulated for single dosage administration, which is useful for treatment, prevention 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, prevention or amelioration of one or more symptoms of diseases or disorders associated with undesired and/or uncontrolled bronchoconstriction.

82. The method of claim 54, wherein the bronchoconstrictive disorder is chronic obstructive pulmonary disease.

83. The method of claim 54, wherein the bronchoconstrictive disorder is asthma.

84. The method of claim 54, wherein the nebulized formoterol solution has a volume of about 0.1 mL to about 3 mL.

85. The method of claim 54, wherein the nebulized formoterol solution has a volume of about 2 mL.

86. The method of claim 54, wherein the nebulized formoterol solution has a volume of about 1 mL.

87. The method of claim 54, wherein the nebulized formoterol solution has a volume of about 0.5 mL.

88. The pharmaceutical composition of claim 1, wherein the formoterol is formoterol fumarate.

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

90. The pharmaceutical composition of claim 1, wherein the formoterol is (R,R)-formoterol.

91. The pharmaceutical composition of claim 1, wherein the formoterol is (S,S)-formoterol.

92. The combination of claim 51 further comprising a nebulizer.

93. A kit comprising the combination of claim 51, optionally containing instructions for use.

94. The method of claim 56, wherein the bronchoconstrictive disorder is chronic obstructive pulmonary disease.

95. The method of claim 56, wherein the bronchoconstrictive disorder is asthma.

96. The method of claim 56, wherein the nebulized formoterol solution has a volume of about 0.1 mL to about 3 mL.

97. The method of claim 56, wherein the nebulized formoterol solution has a volume of about 2 mL.

98. The method of claim 56, wherein the nebulized formoterol solution has a volume of about 1 mL.

99. The method of claim 56, wherein the nebulized formoterol solution has a volume of about 0.5 mL.

100. The method of claim 68, wherein the bronchoconstrictive disorder is chronic obstructive pulmonary disease.

101. The method of claim 68, wherein the bronchoconstrictive disorder is asthma.

102. The method of claim 68, wherein the nebulized formoterol solution has a volume of about 0.1 mL to about 3 mL.

103. The method of claim 68, wherein the nebulized formoterol solution has a volume of about 2 mL.

104. The method of claim 68, wherein the nebulized formoterol solution has a volume of about 1 mL.

105. The method of claim 68, wherein the nebulized formoterol solution has a volume of about 0.5 mL.

45. A nebulized solution, comprising formoterol fumarate in a pharmacologically suitable fluid, wherein formoterol free base concentration is about 0.08 μ

g/mL to about 128 μ

g/mL.

46. The nebulized solution of claim 45, wherein formoterol free base concentration is about 17 μ

g/mL.

70. A method for the treatment, prevention, or amelioration of one or more symptoms of bronchoconstrictive disorders, comprising administering a pharmaceutical composition comprising formoterol free base via nebulization to a subject in need of such treatment, wherein the formoterol free base amount in a unit dose is about 0.1 μ

g to about 250 μ

g.

71. The method of claim 70, wherein the amount of formoterol free base in a unit dose is about 208 μ

g.

72. The method of claim 70, wherein the amount of formoterol free base in a unit dose is about 140 μ

g.

73. The method of claim 70, wherein the amount of formoterol free base in a unit dose is about 68 μ

g.

74. The method of claim 70, wherein the amount of formoterol free base in a unit dose is about 34 μ

g.

75. The method of claim 70, wherein the amount of formoterol free base in a unit dose is about 26 μ

g.

76. The method of claim 70, wherein the amount of formoterol free base in a unit dose is about 21 μ

g.

77. The method of claim 70, wherein the amount of formoterol free base in a unit dose is about 17 μ

g.

78. The method of claim 70, wherein the amount of formoterol free base in a unit dose is about 14 μ

g.

79. The method of claim 70, wherein the amount of formoterol free base in a unit dose is about 9 μ

g.

80. The method of claim 70, wherein the amount of formoterol free base in a unit dose is about 4 μ

g.

81. The method of claim 70, wherein the amount of formoterol free base in a unit dose is about 1.7 μ

g.

106. The method of claim 70, wherein the bronchoconstrictive disorder is chronic obstructive pulmonary disease.

107. The method of claim 70, wherein the bronchoconstrictive disorder is asthma.

108. The method of claim 70, wherein the nebulized formoterol solution has a volume of about 0.1 mL to about 3 mL.

109. The method of claim 70, wherein the nebulized formoterol solution has a volume of about 2 mL.

110. The method of claim 70, wherein the nebulized formoterol solution has a volume of about 1 mL.

111. The method of claim 70, wherein the nebulized formoterol solution has a volume of about 0.5 mL.