Stabilized preparations for use in metered dose inhalers

• US 7,628,978 B2
• Filed: 08/19/2003
• Issued: 12/08/2009
• Est. Priority Date: 09/29/1997
• Status: Expired due to Fees

• Current Assignee: Novartis Pharma AG (Novartis Ag)
• Original Assignee: Novartis Pharma AG (Novartis Ag)
• Inventors: Dellamary, Luis, Schutt, Ernest G., Weers, Jeffry G., Tarara, Thomas E., Kabalnov, Alexey
• Primary Examiner(s): Richter; Johann R
• Assistant Examiner(s): ALSTRUM ACEVEDO, JAMES HENRY
• Application Number:
  US10/644,265
• Publication Number:
  US 20040170568A1
• Time in Patent Office: 2,303 Days
• Field of Search: 424/45, 424/46
• US Class Current: 424/46
• CPC Class Codes: A61K 31/685 one of the hydroxy compounds having nitrogen atoms, e.g. phosphatidylserine, lecithin
• CPC Class Codes: A61K 9/0073 Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy; nasal sprays A61K9/0043; inhalation of vapours of volatile or heated drugs, e.g. essential oils or nicotine, A61K9/007; devices A61M
• CPC Class Codes: A61K 9/0075 for inhalation via a dry powder inhaler [DPI], e.g. comprising micronized drug mixed with lactose carrier particles
• 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: A61K 9/008 comprising drug dissolved or suspended in liquid propellant for inhalation via a pressurized metered dose inhaler [MDI]
• CPC Class Codes: A61K 9/1611 Inorganic compounds
• CPC Class Codes: A61K 9/1617 Organic compounds, e.g. phospholipids, fats
• CPC Class Codes: A61K 9/1635 obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• CPC Class Codes: A61K 9/1641 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
• CPC Class Codes: A61K 9/1652 Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin homeopathic globules A61K9/1623
• CPC Class Codes: A61K 9/1694 resulting in granules or microspheres of the matrix type containing more than 5% of excipient
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 39/00 General protective or antinoxious agents
• CPC Class Codes: Y10S 977/904 for medical, immunological, body treatment, or diagnosis
• CPC Class Codes: Y10S 977/906 Drug delivery
• CPC Class Codes: Y10S 977/926 Topical chemical, e.g. cosmetic or sunscreen

Abstract

Stabilized dispersions are provided for the delivery of a bioactive agent to the respiratory tract of a patient. The dispersions preferably comprise a plurality of perforated microstructures dispersed in a suspension medium that typically comprises a hydrofluoroalkane propellant. As density variations between the suspended particles and suspension medium are minimized and attractive forces between microstructures are attenuated, the disclosed dispersions are particularly resistant to degradation, such as, by settling or flocculation. In particularly preferred embodiments, the stabilized dispersions may be administered to the lung of a patient using a metered dose inhaler.

Claims

1. A respiratory dispersion for the pulmonary delivery of one or more bioactive agents, the dispersion comprising a suspension medium having dispersed therein a plurality of perforated microstructures, the perforated microstructures comprising at least one bioactive agent wherein said suspension medium comprises at least one propellant and permeates said perforated microstructures comprising a mean geometric diameter that is between 0.5 and 5 μ

m.

2. The respiratory dispersion of claim 1, wherein said propellant comprises a compound selected from the group consisting of 1,1,1,2-tetrafluoroethane, 1,1,1,2,3,3,3-heptafluoro-n-propane, perfluoroethane, monochlorodifluoromethane, 1,1-difluoroethane and combinations thereof.

3. The respiratory dispersion of claim 1 wherein said propellant is a hydrofluoroalkane propellant.

4. The respiratory dispersion of claim 3 wherein said hydrofluoroalkane propellant comprises 1,1,1,2-tetrafluoroethane.

5. The respiratory dispersion of claim 3 wherein said hydrofluoroalkane propellant comprises 1,1,1,2,3,3,3-heptafluoro-n-propane.

6. The respiratory dispersion of claim 1 wherein said perforated microstructures comprise a surfactant.

7. The respiratory dispersion of claim 6 wherein said surfactant is selected from the group consisting of phospholipids, nonionic detergents, nonionic block copolymers, ionic surfactants, biocompatible fluorinated surfactants and combinations thereof.

8. The respiratory dispersion of claim 6 wherein said perforated microstructures comprise oleic acid or its alkali salt.

9. The respiratory dispersion of claim 6 wherein said surfactant comprises a lipid.

10. The respiratory dispersion of claim 9 wherein said lipid has a gel to liquid crystal phase transition greater than about 40°

C.

11. The respiratory dispersion of claim 9 wherein said lipid is a phospholipid.

12. The respiratory dispersion of claim 11 wherein said phospholipid is selected from the group consisting of dilauroylphosphatidylcholine, dioleoylphosphatidylcholine, dipalmitoylphosphatidylcholine, distearoylphosphatidylcholine, behenoylphosphatidylcholine, arachidoylphosphatidylcholine and combinations thereof.

13. The respiratory dispersion of claim 6 wherein said perforated microstructures comprise greater than about 10% w/w surfactant.

14. The respiratory dispersion of claim 13 wherein said surfactant comprises a phospholipid.

15. The respiratory dispersion of claim 13 wherein said surfactant comprises oleic acid or its alkali salt.

16. The respiratory dispersion of claim 1 wherein said suspension medium and said perforated microstructures have a refractive index differential of less than about 0.4.

17. The respiratory dispersion of claim 1 wherein said suspension medium and said perforated microstructures have a refractive index differential of less than about 0.3.

18. The respiratory dispersion of claim 1 wherein said perforated microstructures comprise hollow porous microspheres.

19. The respiratory dispersion of claim 18 wherein the perforated microspheres comprise a surfactant.

20. The respiratory dispersion of claim 1 wherein the perforated microstructures comprise a mean geometric diameter that is between 1 and 5 μ

m.

21. The respiratory dispersion of claim 1 wherein the perforated microstructures comprise a mean geometric diameter that is between 0.5 and 5 μ

m.

22. The respiratory dispersion of claim 1 wherein the perforated microstructures comprise a mean geometric diameter that is between 1 and 3 μ

m.

23. The respiratory dispersion of claim 1 wherein said perforated microstructures provide a fine particle fraction following aerosolization of greater than 30%.

24. The respiratory dispersion of claim 1 wherein said perforated microstructures provide a fine particle fraction following aerosolization of greater than 50%.

25. The respiratory dispersion of claim 1 wherein the density differential between the density of the suspended perforated microstructures permeated with the suspension medium and the density of the suspension medium is less than about 0.6 g/cm³.

26. The respiratory dispersion of claim 1 wherein said bioactive agent is selected from the group consisting of antiallergics, bronchodilators, pulmonary lung surfactants, analgesics, antibiotics, leukotriene inhibitors or antagonists, antihistamines, antiinflammatories, antiinfectives, antineoplastics, anticholinergics, anesthetics, anti-tuberculars, imaging agents, cardiovascular agents, enzymes, steroids, genetic material, viral vectors, vaccines antisense agents, proteins, peptides and combinations thereof.

27. The respiratory dispersion of claim 1 wherein said bioactive agent is selected from the group consisting of steroids, bronchodilators and peptides.

28. The respiratory dispersion of claim 1 wherein said bioactive agent is selected from the group consisting of budesonide, fluticasone propionate, salmeterol, formoterol and DNase.

29. A respiratory dispersion for the pulmonary delivery of one or more bioactive agents, the dispersion comprising a suspension medium having dispersed therein a plurality of perforated microstructures, the perforated microstructures comprising greater than about 20% w/w surfactant and at least one bioactive agent wherein said suspension medium comprises at least one propellant and permeates the perforated microstructures comprising a mean geometric diameter that is between 0.5 and 5 μ

m.

30. The respiratory dispersion of claim 29 wherein said dispersed perforated microstructures comprise greater than about 30% w/w surfactant.

31. The respiratory dispersion of claim 29, wherein said propellant comprises a compound selected from the group consisting of 1,1,1,2-tetrafluoroethane 1,1,1,2,3,3,3- heptafluoro-n-propane, perfluoroethane, monochlorodifluoromethane, 1,1-difluoroethane and combinations thereof.

32. The respiratory dispersion of claim 29 wherein said propellant is a hydrofluoroalkane propellant.

33. The respiratory dispersion of claim 32 wherein said hydrofluoroalkane propellant comprises 1,1,1,2-tetrafluoroethane.

34. The respiratory dispersion of claim 29 wherein said surfactant is selected from the group consisting of phospholipids, nonionic detergents, nonionic block copolymers, ionic surfactants, biocompatible fluorinated surfactants and combinations thereof.

35. The respiratory dispersion of claim 29 wherein said perforated microstructures comprise oleic acid or its alkali salt.

36. The respiratory dispersion of claim 29 wherein said surfactant comprises a lipid.

37. The respiratory dispersion of claim 36 wherein said lipid has a gel to liquid crystal phase transition greater than about 40°

C.

38. The respiratory dispersion of claim 36 wherein said lipid is a phospholipid.

39. The respiratory dispersion of claim 38 wherein said phospholipid is selected from the group consisting of dilauroylphosphatidylcholine, dioleoylphosphatidylcholine, dipalmitoylphosphatidylcholine, distearoylphosphatidylcholine, behenoylphosphatidylcholine, arachidoylphosphatidylcholine and combinations thereof.

40. The respiratory dispersion of claim 29 wherein said perforated microstructures comprise hollow porous microspheres.

41. The respiratory dispersion of claim 40 wherein said hollow porous microspheres have a mean aerodynamic diameter between about 0.5 to 5 μ

m.

42. The respiratory dispersion of claim 29 wherein the perforated microstructures comprise a mean geometric diameter that is between 1 and 5 μ

m.

43. The respiratory dispersion of claim 29 wherein said bioactive agent is selected from the group consisting of antiallergics, bronchodilators, pulmonary lung surfactants, analgesics, antibiotics, leukotriene inhibitors or antagonists, antihistamines, antiinfectives, antiinflammatories, antineoplastics, anticholinergics, anesthetics, anti-tuberculars, imaging agents, cardiovascular agents, enzymes, steroids, genetic material, viral vectors, vaccines antisense agents, proteins, peptides and combinations thereof.

44. The respiratory dispersion of claim 29 wherein said bioactive agent is selected from the group consisting of budesonide, fluticasone propionate, salmeterol, formoterol and DNase.

45. A respiratory dispersion for the pulmonary delivery of one or more bioactive agents, the dispersion comprising a suspension medium having dispersed therein a plurality of perforated microstructures, the perforated microstructures comprising a structural matrix of phospholipid and at least one bioactive agent, wherein said suspension medium comprises at least one propellant and permeates said perforated microstructures.

46. The respiratory dispersion of claim 45, wherein said propellant comprises a compound selected from the group consisting of 1,1,1,2-tetrafluoroethane, 1,1,1,2,3,3,3-heptafluoro-n-propane, perfluoroethane, monochlorodifluoromethane, 1,1-difluoroethane and combinations thereof.

47. The respiratory dispersion of claim 45 wherein said propellant is a hydrofluoroalkane propellant.

48. The respiratory dispersion of claim 47 wherein said hydrofluoroalkane propellant comprises 1,1,1,2-tetrafluoroethane.

49. The respiratory dispersion of claim 47 wherein said hydrofluoroalkane propellant comprises 1,1,1,2,3,3,3-heptafluoro-n-propane.

50. The respiratory dispersion of claim 45 wherein said perforated microstructures comprise a surfactant.

51. The respiratory dispersion of claim 50 wherein said surfactant is selected from the group consisting of phospholipids, nonionic detergents, nonionic block copolymers, ionic surfactants, biocompatible fluorinated surfactants and combinations thereof.

52. The respiratory dispersion of claim 50 wherein said perforated microstructures comprise oleic acid or its alkali salt.

53. The respiratory dispersion of claim 50 wherein said surfactant comprises a lipid.

54. The respiratory dispersion of claim 45 wherein said phospholipid has a gel to liquid crystal phase transition greater than about 40°

C.

55. The respiratory dispersion of claim 45 wherein said phospholipid is selected from the group consisting of dilauroylphosphatidylcholine, dioleoylphosphatidylcholine, dipalmitoylphosphatidylcholine, distearoylphosphatidylcholine, behenoylphosphatidylcholine, arachidoylphosphatidylcholine and combinations thereof.

56. The respiratory dispersion of claim 45 wherein said suspension medium and said perforated microstructures have a refractive index differential of less than about 0.4.

57. The respiratory dispersion of claim 45 wherein said suspension medium and said perforated microstructures have a refractive index differential of less than about 0.3.

58. The respiratory dispersion of claim 45 wherein said perforated microstructures comprise hollow porous microspheres.

59. The respiratory dispersion of claim 45 wherein the perforated microspheres comprise calcium.

60. The respiratory dispersion of claim 45 wherein the perforated microstructures comprise a mean geometric diameter that is between 1 and 5 μ

m.

61. The respiratory dispersion of claim 45 wherein the perforated microstructures comprise a mean geometric diameter that is between 0.5 and 5 μ

m.

62. The respiratory dispersion of claim 45 wherein the perforated microstructures comprise a mean geometric diameter that is between 1 and 3 μ

m.

63. The respiratory dispersion of claim 45 wherein said perforated microstructures provide a fine particle fraction following aerosolization of greater than 30%.

64. The respiratory dispersion of claim 45 wherein the density differential between the density of the suspended perforated microstructures permeated with the suspension medium and the density of the suspension medium is less than about 0.6 g/cm³”

.

65. The respiratory dispersion of claim 45 wherein said bioactive agent is selected from the group consisting of antiallergics, bronchodilators, pulmonary lung surfactants, analgesics, antibiotics, leukotriene inhibitors or antagonists, antihistamines, antiinfectives, antiinflammatories, antineoplastics, anticholinergics, anesthetics, anti-tuberculars, imaging agents, cardiovascular agents, enzymes, steroids, genetic material, viral vectors, vaccines antisense agents, proteins, peptides and combinations thereof.

66. The respiratory dispersion of claim 45 wherein said bioactive agent is selected from the group consisting of steroids, bronchodilators and peptides.

67. The respiratory dispersion of claim 45 wherein said bioactive agent is selected from the group consisting of budesonide, fluticasone propionate, salmeterol, formoterol and DNase.

68. A respiratory dispersion for the pulmonary delivery of one or more bioactive agents, the dispersion comprising a suspension medium having dispersed therein a plurality of perforated microstructures, the perforated microstructures comprising a structural matrix of phospholipid, calcium, and at least one bioactive agent, wherein said suspension medium comprises at least one propellant and permeates said perforated microstructures.

69. The respiratory dispersion of claim 68 wherein said propellant comprises a compound selected from the group consisting of 1,1,1,2-tetrafluoroethane, 1,1,1,2,3,3,3-heptafluoro-n-propane, perfluoroethane, monochlorodifluoromethane, 1,1-difluoroethane and combinations thereof.

70. The respiratory dispersion of claim 68 wherein said propellant is a hydrofluoroalkane propellant.

71. The respiratory dispersion of claim 70 wherein said hydrofluoroalkane propellant comprises 1,1,1,2-tetrafluoroethane.

72. The respiratory dispersion of claim 70 wherein said hydrofluoroalkane propellant comprises 1,1,1,2,3,3,3-heptafluoro-n-propane.

73. The respiratory dispersion of claim 68 wherein said perforated microstructures comprise a surfactant.

74. The respiratory dispersion of claim 73 wherein said surfactant is selected from the group consisting of phospholipids, nonionic detergents, nonionic block copolymers, ionic surfactants, biocompatible fluorinated surfactants and combinations thereof.

75. The respiratory dispersion of claim 73 wherein said perforated microstructures comprise oleic acid or its alkali salt.

76. The respiratory dispersion of claim 73 wherein said surfactant comprises a lipid.

77. The respiratory dispersion of claim 68 wherein said phospholipid has a gel to liquid crystal phase transition greater than about 40°

C.

78. The respiratory dispersion of claim 68 wherein said phospholipid is selected from the group consisting of dilauroylphosphatidylcholine, dioleoylphosphatidylcholine, dipalmitoylphosphatidylcholine, distearoylphosphatidylcholine, behenoylphosphatidylcholine, arachidoylphosphatidylcholine and combinations thereof.

79. The respiratory dispersion of claim 68 wherein said suspension medium and said perforated microstructures have a refractive index differential of less than about 0.4.

80. The respiratory dispersion of claim 68 wherein said suspension medium and said perforated microstructures have a refractive index differential of less than about 0.3.

81. The respiratory dispersion of claim 68 wherein said perforated microstructures comprise hollow porous microspheres.

82. The respiratory dispersion of claim 68 wherein the perforated microstructures comprise a mean geometric diameter that is between 1 and 5 μ

m.

83. The respiratory dispersion of claim 68 wherein the perforated microstructures comprise a mean geometric diameter that is between 0.5 and 5 μ

m.

84. The respiratory dispersion of claim 68 wherein the perforated microstructures comprise a mean geometric diameter that is between 1 and 3 μ

m.

85. The respiratory dispersion of claim 68 wherein said bioactive agent has a fine particle fraction following aerosolization of greater than 30%.

86. The respiratory dispersion of claim 68 wherein the density differential between the density of the suspended perforated microstructures permeated with the suspension medium and the density of the suspension medium is less than about 0.6 g/cm³”

.

87. The respiratory dispersion of claim 68 wherein said bioactive agent is selected from the group consisting of antiallergics, bronchodilators, pulmonary lung surfactants, analgesics, antibiotics, leukotriene inhibitors or antagonists, antihistamines, antiinfectives, antiinflammatories, antineoplastics, anticholinergics, anesthetics, anti-tuberculars, imaging agents, cardiovascular agents, enzymes, steroids, genetic material, viral vectors, vaccines antisense agents, proteins, peptides and combinations thereof.

88. The respiratory dispersion of claim 68 wherein said bioactive agent is selected from the group consisting of steroids, bronchodilators and peptides.

89. The respiratory dispersion of claim 68 wherein said bioactive agent is selected from the group consisting of budesonide, fluticasone propionate, salmeterol, formoterol and DNase.

90. A respiratory dispersion for the pulmonary delivery of one or more bioactive agents, the dispersion comprising a suspension medium having dispersed therein a plurality of perforated microstructures, the suspension medium comprising at least one propellant that permeates said perforated microstructures, and the perforated microstructures comprising at least one bioactive agent in a structural matrix comprising at least one phospholipid selected from the group consisting of dilauroylphosphatidylcholine, dioleoylphosphatidylcholine, dipalmitoylphosphatidylcholine, distearoylphosphatidylcholine, behenoylphosphatidylcholine, arachidoylphosphatidylcholine and combinations thereof.

91. The respiratory dispersion of claim 90 wherein the perforated microspheres comprise calcium.

92. The respiratory dispersion of claim 90 wherein the perforated microspheres comprise magnesium.

93. The respiratory dispersion of claim 90 wherein the perforated microstructures comprise a mean geometric diameter that is between 1 and 5 μ

m.

94. The respiratory dispersion of claim 90 wherein the perforated microstructures comprise a mean geometric diameter that is between 0.5 and 5 μ

m.

95. The respiratory dispersion of claim 90 wherein the perforated microstructures comprise a mean geometric diameter that is between 1 and 3 μ

m.

96. A respiratory dispersion for the pulmonary delivery of one or more bioactive agents, the dispersion comprising a suspension medium having dispersed therein a plurality of perforated microstructures, the suspension medium comprising at least one propellant that permeates said perforated microstructures, and the perforated microstructures comprising:

a structural matrix comprising at least one phospholipid selected from the group consisting of dilauroylphosphatidylcholine, dioleoylphosphatidylcholine, dipalmitoylphosphatidylcholine, distearoylphosphatidylcholine, behenoylphosphatidylcholine, arachidoylphosphatidylcholine and combinations thereof; and

at least one bioactive agent selected from the group consisting of antiallergics, bronchodilators, pulmonary lung surfactants, analgesics, antibiotics, leukotriene inhibitors or antagonists, antihistamines, antiinfectives, antiinflammatories, antineoplastics, anticholinergics, anesthetics, anti-tuberculars, imaging agents, cardiovascular agents, enzymes, steroids, genetic material, viral vectors, vaccines antisense agents, proteins, peptides and combinations thereof.

97. The respiratory dispersion of claim 96 wherein the perforated microspheres comprise calcium.

98. The respiratory dispersion of claim 96 wherein the perforated microspheres comprise magnesium.

99. The respiratory dispersion of claim 96 wherein the perforated microstructures comprise a mean geometric diameter that is between 1 and 5 μ

m.

100. The respiratory dispersion of claim 96 wherein the perforated microstructures comprise a mean geometric diameter that is between 0.5 and 5 μ

m.

101. The respiratory dispersion of claim 96 wherein the perforated microstructures comprise a mean geometric diameter that is between 1 and 3 μ

m.