FORMOTEROL/STEROID BRONCHODILATING COMPOSITIONS AND METHODS OF USE THEREOF

• US 20100069342A1
• Filed: 11/24/2009
• Published: 03/18/2010
• Est. Priority Date: 04/17/2001
• Status: Active Grant

• Current Assignee: Mylan Specialty L.P. (Pfizer Inc.)
• Original Assignee: Dey LP (Pfizer Inc.)
• Inventors: Pham, Stephen, Chaudry, Imtiaz A., Banerjee, Partha S.
• Granted Patent: US 8,623,851 B2
• 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 method for the treatment, or amelioration of one or more symptoms of bronchoconstrictive disorders, comprising:

providing a pharmaceutical composition formulated for single dosage administration, wherein;

the composition contains;

(i) formoterol, or a pharmaceutically acceptable salt or 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;

the composition as formulated 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 when stored at 5°

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

the formoterol free base concentration is about 5 μ

g/mL to about 200 μ

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

without dilution, directly administering an effective amount of the composition as provided to a subject in need of such treatment.

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

C. and 1 year storage time at 5°

C.

3. The method of claim 1, wherein the pharmacologically suitable fluid further comprises a polar solvent.

4. The method of claim 3, wherein the polar solvent is a protic solvent.

5. The method of claim 4, wherein the composition further comprises a tonicity adjusting agent.

6. The method of claim 5, 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 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.

7. The method of claim 6, wherein the tonicity adjusting agent is sodium chloride.

8. The method of claim 1, wherein the pharmacologically suitable fluid comprises a buffer.

9. The method of claim 8, 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(hydroxylmethyl)methane), ADA (N-(2-acetamido)-2-iminodiacetic acid), ACES (N-(carbamoylmethyl)-2-aminoethanesulfonaic 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-aminoethanesulfonaic acid), MOPS (3-(N-morpholino)propanesulfonic acid), TES (N-tris(hydroxylmethyl)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(hydroxylmethyl)methylamino)-2-hydroxypropanesulfonic acid), tris(hydroxymethylaminomethane, HEPPSO (N-(2-hydroxyethyl)piperazine-N′

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

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

-(3-propanesulfonic acid), TRICINE (N-tris(hydroxylmethyl)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.

10. The method of claim 9, wherein the buffer is citrate buffer.

11. The method of claim 10, wherein the buffer concentration is from about 0.01 mM to about 150 mM.

12. The method of claim 11, wherein the buffer concentration is from about 1 mM to about 20 mM.

13. The method of claim 12, wherein the buffer concentration is about 5 mM.

14. The method of claim 6, wherein the ionic strength of the composition is about 0 to about 0.4.

15. The method of claim 14, wherein the ionic strength of the composition is about 0.05 to about 0.16.

16. The method of claim 1, wherein the pH of the composition is about 2.0 to about 8.0.

17. The method of claim 16, wherein the pH of the composition is about 4.0 to about 6.0.

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

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

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

g/mL to about 200 μ

g/mL.

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

g/mL to about 200 μ

g/mL.

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

g/mL.

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

g/mL.

24. The method of claim 6, wherein the composition further comprises a buffer.

25. The method of claim 24, 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-(hydroxylmethyl)methane), ADA (N-(2-acetamido)-2-iminodiacetic acid), ACES (N-(carbamoylmethyl)-2-aminoethanesulfonaic 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-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-hydroxypropanesulfonic acid), tris(hydroxymethylaminomethane, HEPPSO(N-(2-hydroxyethyl)piperazine-N′

-(2-hydroxypropanesulfonicacid), POPSO (piperazine-N,N′

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

-(3-propanesulfonic acid), TRICINE (N-tris-(hydroxylmethyl)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.

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

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

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

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

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

31. The method of claim 29, wherein the ionic strength of the composition is about 0.05 to about 0.16.

32. The method of claim 24, wherein the pH of the composition is about 2.0 to about 8.0.

33. The method of claim 32, wherein the pH of the composition is about 4.0 to about 6.0.

34. The method of claim 33, wherein the pH of the composition is about 4.5 to about 5.5.

35. The method of claim 34, wherein the pH of the composition is about 5.0.

36. The method of claim 24, wherein the formoterol free base concentration in the composition is about 10 μ

g/mL to about 200 μ

g/mL.

37. The method of claim 36, wherein the formoterol free base concentration in the composition is about 50 μ

g/mL to about 200 μ

g/mL.

38. The method of claim 37, wherein the formoterol free base concentration in the composition is about 59 μ

g/mL.

39. The method of claim 37, wherein the formoterol free base concentration in the composition is about 118 μ

g/mL.

40. The method of claim 38, wherein the buffer is citrate buffer.

41. The method of claim 38, wherein the buffer concentration is about 5 mM.

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

43. The method of claim 38, wherein the pH of the composition is about 5.0.

44. The method 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.

45. The method of claim 39, wherein the buffer is citrate buffer.

46. The method of claim 39, wherein the buffer concentration is about 5 mM.

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

48. The method of claim 39, wherein the pH of the composition is about 5.0.

49. The method 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.

50. The method of claim 9, wherein the buffer comprises citric acid/phosphate buffer, acetate buffer, citrate buffer or phosphate buffer.

51. The method of claim 24, wherein the buffer comprises citric acid/phosphate buffer, acetate buffer, citrate buffer or phosphate buffer.

52. The method of claim 1, wherein the steroidal anti-inflammatory agent is beclomethasone dipropionate, beclomethasone monopropionate, flunisolide, triamcinolone acetonide, dexamethasone, tipredane, ciclesonid, rofleponide, mometasone, mometasone furoate,

53. The method of claim 52, wherein the steroidal anti-inflammatory agent is budesonide or fluticasone propionate, or a pharmaceutically acceptable salt or hydrate thereof.

54. The method of claim 53, wherein the steroidal anti-inflammatory agent is fluticasone propionate.

55. The method of claim 54, wherein the concentration of fluticasone propionate in the composition is about 5 μ

g/mL to about 2 mg/mL.

56. The method of claim 55, wherein the concentration of fluticasone propionate in the composition is about 75 μ

g/mL to about 1000 μ

g/mL.

57. The method of claim 56, wherein the concentration of fluticasone propionate in the composition is about 125 μ

g/mL or about 250 μ

g/mL.

58. The method of claim 44, wherein the steroidal anti-inflammatory agent is budesonide or fluticasone propionate.

59. The method of claim 49, wherein the steroidal anti-inflammatory agent is budesonide or fluticasone propionate.

60. The method of claim 11, wherein the buffer concentration is from about 1 mM to about 50 mM.

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

62. The method of claim 27, wherein the buffer concentration is from about 1 mM to about 50 mM.

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

64. The method of claim 38, wherein the buffer concentration is about 20 mM.

65. The method 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.

66. The method of claim 39, wherein the buffer concentration is about 20 mM.

67. The method 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.

68. The method of claim 1, wherein the composition further comprises an anticholinergic agent.

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

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

71. The method of claim 70, wherein the ipratropium bromide concentration in the composition is about 5 μ

g/mL to about 5 mg/mL.

76. The method of claim 1, wherein the bronchoconstrictive disorder is asthma, bronchial asthma, allergic asthma, intrinsic asthma, late asthma, airway hyper-responsiveness, chronic obstructive pulmonary diseases (COPDs), COPD associated with cigarette smoking, COPD associated with infections, COPD associated with environmental pollution, COPD associated with occupational dust exposure, chronic bronchitis, emphysema, cor pulmonale associated with pulmonary hypertension, cor pulmonale associated with right ventricular hypertrophy, or cor pulmonale associated with right heart failure.

77. The method of claim 38, wherein the bronchoconstrictive disorder is asthma, bronchial asthma, allergic asthma, intrinsic asthma, late asthma, airway hyper-responsiveness, chronic obstructive pulmonary diseases (COPDs), COPD associated with cigarette smoking, COPD associated with infections, COPD associated with environmental pollution, COPD associated with occupational dust exposure, chronic bronchitis, emphysema, cor pulmonale associated with pulmonary hypertension, cor pulmonale associated with right ventricular hypertrophy, or cor pulmonale associated with right heart failure.

78. The method of claim 39, wherein the bronchoconstrictive disorder is asthma, bronchial asthma, allergic asthma, intrinsic asthma, late asthma, airway hyper-responsiveness, chronic obstructive pulmonary diseases (COPDs), COPD associated with cigarette smoking, COPD associated with infections, COPD associated with environmental pollution, COPD associated with occupational dust exposure, chronic bronchitis, emphysema, cor pulmonale associated with pulmonary hypertension, cor pulmonale associated with right ventricular hypertrophy, or cor pulmonale associated with right heart failure.

80. The method of claim 1, wherein the formoterol is formoterol fumarate dihydrate;

and the steroidal anti-inflammatory agent is fluticasone propionate.

81. The method of claim 80, wherein the concentration of fluticasone propionate in the composition is about 75 μ

g/mL to about 1000 μ

g/mL.

82. The method of claim 81, wherein the concentration of fluticasone propionate in the composition is about 250 μ

g/mL to about 1000 μ

g/mL.

83. The method of claim 81, wherein the concentration of fluticasone propionate in the composition is about 125 μ

g/mL to about 250 μ

g/mL

84. The method of claim 80, wherein the composition further comprises a tonicity adjusting agent, a suspension stabilizer, and the pharmaceutically suitable fluid comprises a buffer.

85. The method of claim 84, 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 method for the treatment or amelioration of one or more symptoms of bronchoconstrictive disorders, comprising:

(i) providing a pharmaceutical composition comprising formoterol, or a pharmaceutically acceptable salt or hydrate thereof in solution, the pharmaceutical composition being in a pharmacologically suitable fluid comprising water that is propellant-free, 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 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, whereby the composition is formulated at a concentration for direct administration to a human in need thereof;

(ii) without dilution, directly administering an effective amount the composition as provided to a human; and

(ii) simultaneously with, prior to, or subsequent to administering the formoterol composition, administering an effective amount of a pharmaceutical composition comprising a steroidal anti-inflammatory agent, or a pharmaceutically acceptable salt or hydrate thereof in suspension, in a pharmacologically acceptable carrier.

73. The method of claim 72, wherein the steroidal anti-inflammatory agent is beclomethasone dipropionate, beclomethasone monopropionate, flunisolide, triamcinolone acetonide, dexamethasone, tipredane, ciclesonid, rofleponide, mometasone, mometasone furoate,

74. The method of claim 73, wherein the steroidal anti-inflammatory agent is fluticasone propionate or budesonide, or a pharmaceutically acceptable salt or hydrate thereof.

75. The method of claim 73, wherein the steroidal anti-inflammatory agent is fluticasone propionate, or a pharmaceutically acceptable salt or hydrate thereof.

79. The method of claim 72, wherein the composition containing formoterol also contains the steroidal anti-inflammatory agent, or a pharmaceutically acceptable salt or hydrate thereof, whereby the formoterol, or a pharmaceutically acceptable salt or hydrate thereof, and the steroidal anti-inflammatory agent, or a pharmaceutically acceptable salt or hydrate thereof, are administered simultaneously.

86. A method for the treatment or amelioration of one or more symptoms of bronchoconstrictive disorders, comprising:

providing a pharmaceutical composition formulated for single dosage administration, wherein;

the composition contains;

(i) formoterol, or a pharmaceutically acceptable salt or 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;

the composition as formulated 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 when stored at 5°

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

the formoterol free base concentration is about 5 μ

g/mL to about 200 μ

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

without dilution, directly administering via nebulization an effective amount of the composition as provided to a subject in need of such treatment.