Systems and methods for the delivery of corticosteroids

• US 20070249572A1
• Filed: 12/20/2006
• Published: 10/25/2007
• Est. Priority Date: 12/20/2005
• Status: Abandoned Application

• Current Assignee: Tika Lakemedel AB (Astrazeneca PLC)
• Original Assignee: Verus Pharmaceuticals, Inc. (Astrazeneca PLC)
• Inventors: Hill, Malcolm
• Application Number:
  US11/643,757
• Publication Number:
  US 20070249572A1
• Time in Patent Office: Days
• US Class Current: 514/178
• 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 31/56 Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
• CPC Class Codes: A61K 31/58 containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin digitoxin A61K31/7048
• CPC Class Codes: A61K 47/40 Cyclodextrins; Derivatives thereof
• CPC Class Codes: A61K 9/0078 for inhalation via a nebulizer such as a jet nebulizer, ultrasonic nebulizer, e.g. in the form of aqueous drug solutions or dispersions
• CPC Class Codes: A61M 11/00 Sprayers or atomisers specially adapted for therapeutic purposes in general B05B; aerosol containers B65D83/14
• CPC Class Codes: A61P 11/08 Bronchodilators

Abstract

The present invention relates to methods and systems for the delivery of a corticosteroid comprising (1) an inhalable aqueous mixture comprising a corticosteroid and a solubility enhancer and (2) an inhalable nebulizer, wherein the delivery of the aqueous mixture comprising the corticosteroid by the nebulizer results in an enhanced pharmacokinetic profile of the corticosteroid as compared to conventional inhalable therapies and/or increase lung deposition.

Claims

1. An inhalable composition comprising about 250 μ

g or less of a single corticosteroid, a solvent and a solubility enhancer, wherein upon administration of the composition to a subject through a device, the composition achieves a rate of increasing concentration of the corticosteroid inside the device of about 5 μ

g/ml per minute or less over administration of the corticosteroid through the device, and wherein the composition is substantially free of active pharmaceutical agents other than the corticosteroid.

2. The composition of claim 1, wherein the composition achieves a rate of increasing concentration of the corticosteroid inside the device of about 5 μ

g/ml per minute or less over the first three minutes of administration.

3. The composition of claim 1, wherein the composition achieves a rate of increasing concentration of the single corticosteroid inside the device of about 3.5 μ

g/ml per minute or less over the first 3 minutes of administration.

4. The composition of claim 1, wherein the composition achieves a rate of increase in concentration of the single corticosteroid inside the device of about 5% per minute or less over the first 3 minutes of administration.

5. The composition of claim 1, wherein the solvent comprises water.

6. The composition of claim 1, wherein the solubility enhancer is selected from the group consisting of propylene glycol, non-ionic surfactants, tyloxapol, polysorbate 80, vitamin E-TPGS, macrogol-15-hydroxystearate, phospholipids, lecithin, purified and/or enriched lecithin, phosphatidylcholine fractions extracted from lecithin, dimyristoyl phosphatidylcholine (DMPC), dipalmitoyl phosphatidylcholine (DPPC), distearoyl phosphatidylcholine (DSPC), cyclodextrins and derivatives thereof, SAE-CD derivatives, SBE-α

-CD, SBE-β

-CD, SBE1-β

-CD, SBE4-β

-CD, SBE7-β

-CD, SBE-γ

-CD, dimethyl β

-CD, hydroxypropyl-β

-cyclodextrin, 2-HP-β

-CD, hydroxyethyl-β

-cyclodextrin, hydroxypropyl-γ

-cyclodextrin, hydroxyethyl-γ

-cyclodextrin, dihydroxypropyl-β

-cyclodextrin, glucosyl-α

-cyclodextrin, glucosyl-β

-cyclodextrin, diglucosyl-β

-cyclodextrin, maltosyl-α

-cyclodextrin, maltosyl-β

-cyclodextrin, maltosyl-γ

-cyclodextrin, maltotriosyl-β

-cyclodextrin, maltotriosyl-γ

-cyclodextrin, dimaltosyl-β

-cyclodextrin, methyl-β

-cyclodextrin, carboxyalkyl thioether derivatives, ORG 26054, ORG 25969, hydroxypropyl methylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, copolymers of vinyl acetate, vinyl pyrrolidone, sodium lauryl sulfate, dioctyl sodium sulfosuccinate, and combinations thereof.

7. The composition of claim 1, wherein the solubility enhancer comprises SBE7-β

-CD.

8. The composition of claim 1, wherein the device is a nebulizer.

9. The composition of claim 1, wherein the device is a Pari eFlow nebulizer.

10. The composition of claim 1, wherein the composition comprises the single corticosteroid in a nominal dosage of about 60 μ

g.

11. The composition of claim 1, wherein the composition comprises the single corticosteroid in a nominal dosage of about 120 μ

g.

12. An inhalable composition comprising an effective amount of a single corticosteroid, a solvent and a solubility enhancer, wherein upon administration of the composition to a subject through a device, the composition achieves a rate of increasing concentration of the corticosteroid inside the device of 60% or less of a rate of increasing concentration of the corticosteroid inside the device achieved by an inhalable suspension comprising the corticosteroid without a solubility enhancer administered under the same conditions, and wherein the composition is substantially free of active pharmaceutical agents other than the corticosteroid.

13. The composition of claim 12, wherein the rate of increasing concentration of the single corticosteroid inside the device is achieved over the first 3 minutes, during the second and third minutes or during the third minute of administration.

14. The composition of claim 12, wherein administration of the composition through the device is achieved over five minutes or less, and administration of the inhalable suspension is achieved over five minutes or less.

15. The composition of claim 14, wherein the time of administration of the composition through the device and the time of administration of the inhalable suspension are the same.

16. The composition of claim 14, wherein the time of administration of the composition through the device and the time of administration of the inhalable suspension are different.

17. The composition of claim 12, wherein the composition comprises about 40, about 60, about 120, about 125, about 240, about 250, about 500, about 1000, about 1500, or about 2000 μ

g of the corticosteroid.

18. The composition of claim 12, wherein the solvent comprises water.

19. The composition of claim 12, wherein the solubility enhancer is selected from the group consisting of propylene glycol, non-ionic surfactants, tyloxapol, polysorbate 80, vitamin E-TPGS, macrogol-15-hydroxystearate, phospholipids, lecithin, purified and/or enriched lecithin, phosphatidylcholine fractions extracted from lecithin, dimyristoyl phosphatidylcholine (DMPC), dipalmitoyl phosphatidylcholine (DPPC), distearoyl phosphatidylcholine (DSPC), cyclodextrins and derivatives thereof, SAE-CD derivatives, SBE-α

-CD, SBE-β

-CD, SBE1-β

-CD, SBE4-β

-CD, SBE7-β

-CD, SBE-γ

-CD, dimethyl β

-CD, hydroxypropyl-β

-cyclodextrin, 2-HP-β

-CD, hydroxyethyl-β

-cyclodextrin, hydroxypropyl-γ

-cyclodextrin, hydroxyethyl-γ

-cyclodextrin, dihydroxypropyl-β

-cyclodextrin, glucosyl-α

-cyclodextrin, glucosyl-β

-cyclodextrin, diglucosyl-β

-cyclodextrin, maltosyl-α

-cyclodextrin, maltosyl-β

-cyclodextrin, maltosyl-γ

-cyclodextrin, maltotriosyl-β

-cyclodextrin, maltotriosyl-γ

-cyclodextrin, dimaltosyl-β

-cyclodextrin, methyl-β

-cyclodextrin, carboxyalkyl thioether derivatives, ORG 26054, ORG 25969, hydroxypropyl methylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, copolymers of vinyl acetate, vinyl pyrrolidone, sodium lauryl sulfate, dioctyl sodium sulfosuccinate, and combinations thereof.

20. The composition of claim 12, wherein the solubility enhancer comprises SBE7-β

-CD.

21. The composition of claim 12, wherein the device is selected from jet nebulizers, ultrasonic nebulizers, pulsating membrane nebulizers, nebulizers with a vibrating mesh or plate with multiple apertures, and nebulizers comprising a vibration generator and an aqueous chamber.

22. A method of generating fine particles from an inhalable composition comprising:

forming the composition by adding a solvent and a solubility enhancer to an effective amount of a single corticosteroid, wherein the composition is substantially free of active pharmaceutical agents other than the corticosteroid; and

operating a nebulizer to produce fine particles of the composition,

wherein upon administration of the composition to a subject through the nebulizer, the composition achieves a rate of increasing concentration of the corticosteroid inside the nebulizer of 60% or less of a rate of increasing concentration of the corticosteroid inside the nebulizer achieved by an inhalable suspension comprising the corticosteroid without a solubility enhancer administered under the same conditions.

23. The method of claim 22, wherein the rate of increasing concentration of the single corticosteroid inside the device is achieved over the first 3 minutes, during the second and third minutes or during the third minute of administration.

24. The method of claim 22, wherein administration of the composition through the nebulizer is achieved over five minutes or less, and administration of the inhalable suspension is achieved over five minutes or less.

25. The method of claim 24, wherein the time of administration of the composition through the nebulizer and the time of administration of the inhalable suspension are the same.

26. The method of claim 24, wherein the time of administration of the composition through nebulizer and the time of administration of the inhalable suspension are different.

27. The method of claim 22, wherein the composition comprises about 40, about 60, about 120, about 125, about 240, about 250, about 500, about 1000, about 1500, or about 2000 μ

g of the single corticosteroid.

28. The method of claim 22, wherein the solvent comprises water.

29. The method of claim 22, wherein the solubility enhancer is selected from the group consisting of propylene glycol, non-ionic surfactants, tyloxapol, polysorbate 80, vitamin E-TPGS, macrogol-15-hydroxystearate, phospholipids, lecithin, purified and/or enriched lecithin, phosphatidylcholine fractions extracted from lecithin, dimyristoyl phosphatidylcholine (DMPC), dipalmitoyl phosphatidylcholine (DPPC), distearoyl phosphatidylcholine (DSPC), cyclodextrins and derivatives thereof, SAE-CD derivatives, SBE-α

-CD, SBE-β

-CD, SBE1-β

-CD, SBE4-β

-CD, SBE7-β

-CD, SBE-γ

-CD, dimethyl β

-CD, hydroxypropyl-β

-cyclodextrin, 2-HP-β

-CD, hydroxyethyl-β

-cyclodextrin, hydroxypropyl-γ

-cyclodextrin, hydroxyethyl-γ

-cyclodextrin, dihydroxypropyl-β

-cyclodextrin, glucosyl-α

-cyclodextrin, glucosyl-β

-cyclodextrin, diglucosyl-β

-cyclodextrin, maltosyl-α

-cyclodextrin, maltosyl-β

-cyclodextrin, maltosyl-γ

-cyclodextrin, maltotriosyl-β

-cyclodextrin, maltotriosyl-γ

-cyclodextrin, dimaltosyl-β

-cyclodextrin, methyl-β

-cyclodextrin, carboxyalkyl thioether derivatives, ORG 26054, ORG 25969, hydroxypropyl methylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, copolymers of vinyl acetate, vinyl pyrrolidone, sodium lauryl sulfate, dioctyl sodium sulfosuccinate, and combinations thereof.

30. The method of claim 29, wherein the solubility enhancer comprises SBE7-β

-CD.

31. The method of claim 22, wherein the device is selected from jet nebulizers, ultrasonic nebulizers, pulsating membrane nebulizers, nebulizers with a vibrating mesh or plate with multiple apertures, and nebulizers comprising a vibration generator and an aqueous chamber.

32. An inhalation system for delivering a therapeutically effective dose of a single corticosteroid to a patient comprising:

(a) an aqueous inhalation mixture comprising the corticosteroid, a solvent and a solubility enhancer, wherein the composition is substantially free of active pharmaceutical agents other than the corticosteroid and

(b) a nebulizer

wherein upon administration of the mixture to a subject through the nebulizer, the mixture achieves a rate of increasing concentration of the corticosteroid inside the nebulizer of 60% or less of a rate of increasing concentration of the corticosteroid inside the nebulizer achieved by an inhalable suspension comprising the corticosteroid without a solubility enhancer administered under the same conditions.

33. The system of claim 32, wherein the rate of increasing concentration of the single corticosteroid inside the device is achieved over the first 3 minutes, during the second and third minutes or during the third minute of administration.

34. The system of claim 32, wherein administration of the composition through the nebulizer is achieved over five minutes or less, and administration of the inhalable suspension is achieved over five minutes or less.

35. The system of claim 34, wherein the time of administration of the composition through the nebulizer and the time of administration of the inhalable suspension are the same.

36. The system of claim 34, wherein the time of administration of the composition through the nebulizer and the time of administration of the inhalable suspension are different.

37. The system of claim 32, wherein the mixture comprises about 40, about 60, about 120, about 125, about 240, about 250, about 500, about 1000, about 1500, or about 2000 μ

g of the single corticosteroid.

38. The system of claim 32, wherein the solvent comprises water.

39. The system of claim 32, wherein the solubility enhancer is selected from the group consisting of propylene glycol, non-ionic surfactants, tyloxapol, polysorbate 80, vitamin E-TPGS, macrogol-15-hydroxystearate, phospholipids, lecithin, purified and/or enriched lecithin, phosphatidylcholine fractions extracted from lecithin, dimyristoyl phosphatidylcholine (DMPC), dipalmitoyl phosphatidylcholine (DPPC), distearoyl phosphatidylcholine (DSPC), cyclodextrins and derivatives thereof, SAE-CD derivatives, SBE-α

-CD, SBE-β

-CD, SBE1-β

-CD, SBE4-β

-CD, SBE7-β

-CD, SBE-γ

-CD, dimethyl β

-CD, hydroxypropyl-β

-cyclodextrin, 2-HP-β

-CD, hydroxyethyl-β

-cyclodextrin, hydroxypropyl-γ

-cyclodextrin, hydroxyethyl-γ

-cyclodextrin, dihydroxypropyl-β

-cyclodextrin, glucosyl-α

-cyclodextrin, glucosyl-β

-cyclodextrin, diglucosyl-β

-cyclodextrin, maltosyl-α

-cyclodextrin, maltosyl-β

-cyclodextrin, maltosyl-γ

-cyclodextrin, maltotriosyl-β

-cyclodextrin, maltotriosyl-γ

-cyclodextrin, dimaltosyl-β

-cyclodextrin, methyl-β

-cyclodextrin, carboxyalkyl thioether derivatives, ORG 26054, ORG 25969, hydroxypropyl methylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, copolymers of vinyl acetate, vinyl pyrrolidone, sodium lauryl sulfate, dioctyl sodium sulfosuccinate, and combinations thereof.

40. The system of claim 39, wherein the solubility enhancer comprises SBE7-β

-CD.

41. The system of claim 32, wherein the nebulizer is selected from jet nebulizers, ultrasonic nebulizers, pulsating membrane nebulizers, nebulizers with a vibrating mesh or plate with multiple apertures, and nebulizers comprising a vibration generator and an aqueous chamber.

42. A method for the treatment of a bronchoconstrictive disorder in a patient in need of treatment thereof, comprising:

forming a composition by adding a solvent and a solubility enhancer to an amount of a single corticosteroid, wherein the composition is substantially free of active pharmaceutical agents other than the corticosteroid; and

operating a nebulizer,

wherein upon administration of the composition to a subject through the nebulizer, the composition achieves a rate of increasing concentration of the corticosteroid inside the nebulizer of 60% or less of a rate of increasing concentration of the corticosteroid inside the nebulizer achieved by an inhalable suspension comprising the corticosteroid without a solubility enhancer administered under the same conditions.

43. The method of claim 42, wherein the rate of increasing concentration of the single corticosteroid inside the device is achieved over the first 3 minutes, during the second and third minutes or during the third minute of administration.

44. The method of claim 42, wherein administration of the composition through the nebulizer is achieved over five minutes or less, and administration of the inhalable suspension is achieved over five minutes or less.

45. The method of claim 44, wherein the time of administration of the composition through the nebulizer and the time of administration of the inhalable suspension are the same.

46. The method of claim 44, wherein the time of administration of the composition through the nebulizer and the time of administration of the inhalable suspension are different.

47. The method of claim 42, wherein the composition comprises about 40, about 60, about 120, about 125, about 240, about 250, about 500, about 1000, about 1500, or about 2000 μ

g of the single corticosteroid.

48. The method of claim 42, wherein the solvent comprises water.

49. The method of claim 42, wherein the solubility enhancer is selected from the group consisting of propylene glycol, non-ionic surfactants, tyloxapol, polysorbate 80, vitamin E-TPGS, macrogol-15-hydroxystearate, phospholipids, lecithin, purified and/or enriched lecithin, phosphatidylcholine fractions extracted from lecithin, dimyristoyl phosphatidylcholine (DMPC), dipalmitoyl phosphatidylcholine (DPPC), distearoyl phosphatidylcholine (DSPC), cyclodextrins and derivatives thereof, SAE-CD derivatives, SBE-α

-CD, SBE-β

-CD, SBE1-α

-CD, SBE4-β

-CD, SBE7-β

-CD, SBE-γ

-CD, dimethyl β

-CD, hydroxypropyl-β

-cyclodextrin, 2-HP-β

-CD, hydroxyethyl-β

-cyclodextrin, hydroxypropyl-γ

-cyclodextrin, hydroxyethyl-γ

-cyclodextrin, dihydroxypropyl-β

-cyclodextrin, glucosyl-α

-cyclodextrin, glucosyl-β

-cyclodextrin, diglucosyl-β

-cyclodextrin, maltosyl-α

-cyclodextrin, maltosyl-β

-cyclodextrin, maltosyl-γ

-cyclodextrin, maltotriosyl-β

-cyclodextrin, maltotriosyl-γ

-cyclodextrin, dimaltosyl-β

-cyclodextrin, methyl-β

-cyclodextrin, carboxyalkyl thioether derivatives, ORG 26054, ORG 25969, hydroxypropyl methylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, copolymers of vinyl acetate, vinyl pyrrolidone, sodium lauryl sulfate, dioctyl sodium sulfosuccinate, and combinations thereof.

50. The method of claim 49, wherein the solubility enhancer comprises SBE7-β

-CD.

51. The method of claim 42, wherein the device is selected from jet nebulizers, ultrasonic nebulizers, pulsating membrane nebulizers, nebulizers with a vibrating mesh or plate with multiple apertures, and nebulizers comprising a vibration generator and an aqueous chamber.

52. The method of claim 42, wherein the bronchoconstrictive disorder is selected from the group consisting of asthma, pediatric asthma, bronchial asthma, allergic asthma, intrinsic asthma, chronic obstructive pulmonary disease (COPD), chronic bronchitis, and emphysema.

53. An inhalable composition comprising about 250 μ

g or less of budesonide, a solvent and a solubility enhancer, wherein upon administration of the composition to a subject through a device, the composition achieves a rate of increasing concentration of budesonide inside the device of about 5 μ

g/ml per minute or less over administration of the budesonide through the device, and wherein the composition is substantially free of active pharmaceutical agents other than the corticosteroid.

54. The composition of claim 53, wherein the composition achieves a rate of increasing concentration of the budesonide inside the device of about 5 μ

g/ml per minute or less over the first three minutes of administration.

55. The composition of claim 54, wherein the composition achieves a rate of increasing concentration of budesonide inside the device of about 3.5 μ

g/ml per minute or less over the first 3 minutes of administration.

56. The composition of claim 53, wherein the composition achieves a rate of increase in concentration of budesonide inside the device of about 5% per minute or less over the first 3 minutes of administration.

57. The composition of claim 53, wherein the solvent comprises water.

58. The composition of claim 53, wherein the solubility enhancer is selected from the group consisting of propylene glycol, non-ionic surfactants, tyloxapol, polysorbate 80, vitamin E-TPGS, macrogol-15-hydroxystearate, phospholipids, lecithin, purified and/or enriched lecithin, phosphatidylcholine fractions extracted from lecithin, dimyristoyl phosphatidylcholine (DMPC), dipalmitoyl phosphatidylcholine (DPPC), distearoyl phosphatidylcholine (DSPC), cyclodextrins and derivatives thereof, SAE-CD derivatives, SBE-α

-CD, SBE-β

-CD, SBE1-β

-CD, SBE4-β

-CD, SBE7-β

-CD, SBE-γ

-CD, dimethyl β

-CD, hydroxypropyl-β

-cyclodextrin, 2-HP-β

-CD, hydroxyethyl-β

-cyclodextrin, hydroxypropyl-γ

-cyclodextrin, hydroxyethyl-γ

-cyclodextrin, dihydroxypropyl-β

-cyclodextrin, glucosyl-α

-cyclodextrin, glucosyl-β

-cyclodextrin, diglucosyl-β

-cyclodextrin, maltosyl-α

-cyclodextrin, maltosyl-β

-cyclodextrin, maltosyl-γ

-cyclodextrin, maltotriosyl-β

-cyclodextrin, maltotriosyl-γ

-cyclodextrin, dimaltosyl-β

-cyclodextrin, methyl-β

-cyclodextrin, carboxyalkyl thioether derivatives, ORG 26054, ORG 25969, hydroxypropyl methylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, copolymers of vinyl acetate, vinyl pyrrolidone, sodium lauryl sulfate, dioctyl sodium sulfosuccinate, and combinations thereof.

59. The composition of claim 58, wherein the solubility enhancer comprises SBE7-β

-CD.

60. The composition of claim 53, wherein the device is a nebulizer.

61. The composition of claim 60, wherein the device is a Pari eFlow nebulizer.

62. The composition of claim 53, wherein the composition comprises budesonide in a nominal dosage of about 60 μ

g.

63. The composition of claim 53, wherein the composition comprises budesonide in a nominal dosage of about 120 μ

g.

64. An inhalable composition comprising an effective amount of budesonide, a solvent and a solubility enhancer, wherein upon administration of the composition to a subject through a device, the composition achieves a rate of increasing concentration of budesonide inside the device of 60% or less of a rate of increasing concentration of budesonide inside the device achieved by an inhalable suspension comprising budesonide without a solubility enhancer administered under the same conditions, and wherein the composition is substantially free of active pharmaceutical agents other than the corticosteroid.

65. The composition of claim 64, wherein the rate of increasing concentration of budesonide inside the device is achieved over the first 3 minutes, during the second and third minutes or during the third minute of administration.

66. The composition of claim 64, wherein administration of the composition through the device is achieved over five minutes or less, and administration of the inhalable suspension is achieved over five minutes or less.

67. The composition of claim 66, wherein the time of administration of the composition through the device and the time of administration of the inhalable suspension are the same.

68. The composition of claim 66, wherein the time of administration of the composition through the device and the time of administration of the inhalable suspension are different.

69. The composition of claim 64, wherein the composition comprises about 40, about 60, about 120, about 125, about 240, about 250, about 500, about 1000, about 1500, or about 2000 μ

g of budesonide.

70. The composition of claim 64, wherein the solvent comprises water.

71. The composition of claim 64, wherein the solubility enhancer is selected from the group consisting of propylene glycol, non-ionic surfactants, tyloxapol, polysorbate 80, vitamin E-TPGS, macrogol-15-hydroxystearate, phospholipids, lecithin, purified and/or enriched lecithin, phosphatidylcholine fractions extracted from lecithin, dimyristoyl phosphatidylcholine (DMPC), dipalmitoyl phosphatidylcholine (DPPC), distearoyl phosphatidylcholine (DSPC), cyclodextrins and derivatives thereof, SAE-CD derivatives, SBE-α

-CD, SBE-β

-CD, SBE1-β

-CD, SBE4-β

-CD, SBE7-β

-CD, SBE-γ

-CD, dimethyl β

-CD, hydroxypropyl-β

-cyclodextrin, 2-HP-β

-CD, hydroxyethyl-β

-cyclodextrin, hydroxypropyl-γ

-cyclodextrin, hydroxyethyl-γ

-cyclodextrin, dihydroxypropyl-β

-cyclodextrin, glucosyl-α

-cyclodextrin, glucosyl-β

-cyclodextrin, diglucosyl-β

-cyclodextrin, maltosyl-α

-cyclodextrin, maltosyl-β

-cyclodextrin, maltosyl-γ

-cyclodextrin, maltotriosyl-β

-cyclodextrin, maltotriosyl-γ

-cyclodextrin, dimaltosyl-β

-cyclodextrin, methyl-β

-cyclodextrin, carboxyalkyl thioether derivatives, ORG 26054, ORG 25969, hydroxypropyl methylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, copolymers of vinyl acetate, vinyl pyrrolidone, sodium lauryl sulfate, dioctyl sodium sulfosuccinate, and combinations thereof.

72. The composition of claim 71, wherein the solubility enhancer comprises SBE7-β

-CD.

73. The composition of claim 64, wherein the device is selected from jet nebulizers, ultrasonic nebulizers, pulsating membrane nebulizers, nebulizers with a vibrating mesh or plate with multiple apertures, and nebulizers comprising a vibration generator and an aqueous chamber

74. A method of generating fine particles from an inhalable composition comprising:

forming the composition by adding a solubility enhancer to an effective amount of budesonide, wherein the composition is substantially free of active pharmaceutical agents other than the budesonide; and

operating a nebulizer to produce fine particles of the composition,

wherein upon administration of the composition to a subject through the nebulizer, the composition achieves a rate of increasing concentration of budesonide inside the nebulizer of 60% or less of a rate of increasing concentration of budesonide inside the nebulizer achieved by an inhalable suspension comprising budesonide without a solubility enhancer administered under the same conditions.

75. The method of claim 74, wherein the rate of increasing concentration of budesonide inside the device is achieved over the first 3 minutes, during the second and third minutes or during the third minute of administration.

76. The method of claim 74, wherein administration of the composition through the nebulizer is achieved over five minutes or less, and administration of the inhalable suspension is achieved over five minutes or less.

77. The method of claim 76, wherein the time of administration of the composition through the nebulizer and the time of administration of the inhalable suspension are the same.

78. The method of claim 76, wherein the time of administration of the composition through nebulizer and the time of administration of the inhalable suspension are different.

79. The method of claim 74, wherein the composition comprises about 40, about 60, about 120, about 125, about 240, about 250, about 500, about 1000, about 1500, or about 2000 μ

g of budesonide.

80. The method of claim 74, wherein the solvent comprises water.

81. The method of claim 74, wherein the solubility enhancer is selected from the group consisting of propylene glycol, non-ionic surfactants, tyloxapol, polysorbate 80, vitamin E-TPGS, macrogol-15-hydroxystearate, phospholipids, lecithin, purified and/or enriched lecithin, phosphatidylcholine fractions extracted from lecithin, dimyristoyl phosphatidylcholine (DMPC), dipalmitoyl phosphatidylcholine (DPPC), distearoyl phosphatidylcholine (DSPC), cyclodextrins and derivatives thereof, SAE-CD derivatives, SBE-α

-CD, SBE-β

-CD, SBE1-β

-CD, SBE4-β

-CD, SBE7-β

-CD, SBE-γ

-CD, dimethyl β

-CD, hydroxypropyl-β

-cyclodextrin, 2-HP-β

-CD, hydroxyethyl-β

-cyclodextrin, hydroxypropyl-γ

-cyclodextrin, hydroxyethyl-γ

-cyclodextrin, dihydroxypropyl-β

-cyclodextrin, glucosyl-α

-cyclodextrin, glucosyl-β

-cyclodextrin, diglucosyl-β

-cyclodextrin, maltosyl-α

-cyclodextrin, maltosyl-β

-cyclodextrin, maltosyl-γ

-cyclodextrin, maltotriosyl-β

-cyclodextrin, maltotriosyl-γ

-cyclodextrin, dimaltosyl-β

-cyclodextrin, methyl-β

-cyclodextrin, carboxyalkyl thioether derivatives, ORG 26054, ORG 25969, hydroxypropyl methylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, copolymers of vinyl acetate, vinyl pyrrolidone, sodium lauryl sulfate, dioctyl sodium sulfosuccinate, and combinations thereof.

82. The method of claim 81, wherein the solubility enhancer comprises SBE7-β

-CD.

83. The method of claim 74, wherein the device is selected from jet nebulizers, ultrasonic nebulizers, pulsating membrane nebulizers, nebulizers with a vibrating mesh or plate with multiple apertures, and nebulizers comprising a vibration generator and an aqueous chamber.

84. An inhalation system for delivering a therapeutically effective dose of budesonide to a patient comprising:

(a) an aqueous inhalation mixture comprising budesonide and a solubility enhancer, wherein the composition is substantially free of active pharmaceutical agents other than the corticosteroid; and

(b) a nebulizer

wherein upon administration of the mixture to a subject through the nebulizer, the mixture achieves a rate of increasing concentration of budesonide inside the nebulizer of 60% or less of a rate of increasing concentration of budesonide inside the nebulizer achieved by an inhalable suspension comprising budesonide without a solubility enhancer administered under the same conditions.

85. The system of claim 84, wherein the rate of increasing concentration of budesonide inside the device is achieved over the first 3 minutes, during the second and third minutes or during the third minute of administration.

86. The system of claim 84, wherein administration of the composition through the nebulizer is achieved over five minutes or less, and administration of the inhalable suspension is achieved over five minutes or less.

87. The system of claim 86, wherein the time of administration of the composition through the nebulizer and the time of administration of the inhalable suspension are the same.

88. The system of claim 86, wherein the time of administration of the composition through the nebulizer and the time of administration of the inhalable suspension are different.

89. The system of claim 84, wherein the mixture comprises about 40, about 60, about 120, about 125, about 240, about 250, about 500, about 1000, about 1500, or about 2000 μ

g of budesonide.

90. The system of claim 84, wherein the solvent comprises water.

91. The system of claim 84, wherein the solubility enhancer is selected from the group consisting of propylene glycol, non-ionic surfactants, tyloxapol, polysorbate 80, vitamin E-TPGS, macrogol-15-hydroxystearate, phospholipids, lecithin, purified and/or enriched lecithin, phosphatidylcholine fractions extracted from lecithin, dimyristoyl phosphatidylcholine (DMPC), dipalmitoyl phosphatidylcholine (DPPC), distearoyl phosphatidylcholine (DSPC), cyclodextrins and derivatives thereof, SAE-CD derivatives, SBE-α

-CD, SBE-β

-CD, SBE1-β

-CD, SBE4-β

-CD, SBE7-β

-CD, SBE-γ

-CD, dimethyl β

-CD, hydroxypropyl-β

-cyclodextrin, 2-HP-β

-CD, hydroxyethyl-β

-cyclodextrin, hydroxypropyl-α

-cyclodextrin, hydroxyethyl-γ

-cyclodextrin, dihydroxypropyl-β

-cyclodextrin, glucosyl-α

-cyclodextrin, glucosyl-β

-cyclodextrin, diglucosyl-β

-cyclodextrin, maltosyl-α

-cyclodextrin, maltosyl-β

-cyclodextrin, maltosyl-γ

-cyclodextrin, maltotriosyl-β

-cyclodextrin, maltotriosyl-γ

-cyclodextrin, dimaltosyl-β

-cyclodextrin, methyl-β

-cyclodextrin, carboxyalkyl thioether derivatives, ORG 26054, ORG 25969, hydroxypropyl methylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, copolymers of vinyl acetate, vinyl pyrrolidone, sodium lauryl sulfate, dioctyl sodium sulfosuccinate, and combinations thereof.

92. The system of claim 91, wherein the solubility enhancer comprises SBE7-β

-CD.

93. The system of claim 84, wherein the device is selected from jet nebulizers, ultrasonic nebulizers, pulsating membrane nebulizers, nebulizers with a vibrating mesh or plate with multiple apertures, and nebulizers comprising a vibration generator and an aqueous chamber.

94. A method for the treatment of a bronchoconstrictive disorder in a patient in need of treatment thereof, comprising:

forming a composition by adding a solubility enhancer to an amount of budesonide, wherein the composition is substantially free of active pharmaceutical agents other than the budesonide; and

operating a nebulizer,

wherein upon administration of the composition to a subject through the nebulizer, the composition achieves a rate of increasing concentration of budesonide inside the nebulizer of 60% or less of a rate of increasing concentration of budesonide inside the nebulizer achieved by an inhalable suspension comprising budesonide without a solubility enhancer administered under the same conditions.

95. The method of claim 94, wherein the rate of increasing concentration of budesonide inside the device is achieved over the first 3 minutes, during the second and third minutes or during the third minute of administration.

96. The method of claim 94, wherein administration of the composition through the nebulizer is achieved over five minutes or less, and administration of the inhalable suspension is achieved over five minutes or less.

97. The method of claim 96, wherein the time of administration of the composition through the nebulizer and the time of administration of the inhalable suspension are the same.

98. The method of claim 96, wherein the time of administration of the composition through the nebulizer and the time of administration of the inhalable suspension are different.

99. The method of claim 94, wherein the composition comprises about 40, about 60, about 120, about 125, about 240, about 250, about 500, about 1000, about 1500, or about 2000 μ

g of budesonide.

100. The method of claim 94, wherein the solvent comprises water.

101. The method of claim 94, wherein the solubility enhancer is selected from the group consisting of propylene glycol, non-ionic surfactants, tyloxapol, polysorbate 80, vitamin E-TPGS, macrogol-15-hydroxystearate, phospholipids, lecithin, purified and/or enriched lecithin, phosphatidylcholine fractions extracted from lecithin, dimyristoyl phosphatidylcholine (DMPC), dipalmitoyl phosphatidylcholine (DPPC), distearoyl phosphatidylcholine (DSPC), cyclodextrins and derivatives thereof, SAE-CD derivatives, SBE-α

-CD, SBE-β

-CD, SBE1-β

-CD, SBE4-β

-CD, SBE7-β

-CD, SBE-γ

-CD, dimethyl β

-CD, hydroxypropyl-β

-cyclodextrin, 2-HP-β

-CD, hydroxyethyl-β

-cyclodextrin, hydroxypropyl-γ

-cyclodextrin, hydroxyethyl-γ

-cyclodextrin, dihydroxypropyl-β

-cyclodextrin, glucosyl-α

-cyclodextrin, glucosyl-β

-cyclodextrin, diglucosyl-β

-cyclodextrin, maltosyl-α

-cyclodextrin, maltosyl-β

-cyclodextrin, maltosyl-γ

-cyclodextrin, maltotriosyl-β

-cyclodextrin, maltotriosyl-γ

-cyclodextrin, dimaltosyl-β

-cyclodextrin, methyl-β

-cyclodextrin, carboxyalkyl thioether derivatives, ORG 26054, ORG 25969, hydroxypropyl methylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, copolymers of vinyl acetate, vinyl pyrrolidone, sodium lauryl sulfate, dioctyl sodium sulfosuccinate, and combinations thereof.

102. The method of claim 101, wherein the solubility enhancer comprises SBE7-β

-CD.

103. The method of claim 94, wherein the device is selected from jet nebulizers, ultrasonic nebulizers, pulsating membrane nebulizers, nebulizers with a vibrating mesh or plate with multiple apertures, and nebulizers comprising a vibration generator and an aqueous chamber.

104. The method of claim 94, wherein the bronchoconstrictive disorder is selected from the group consisting of asthma, pediatric asthma, bronchial asthma, allergic asthma, intrinsic asthma, chronic obstructive pulmonary disease (COPD), chronic bronchitis, and emphysema.