Details for Patent: 6,309,623

Title:	Stabilized preparations for use in metered dose inhalers
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.
Inventor(s):	Weers; Jeffry G. (San Diego, CA), Schutt; Ernest G. (San Diego, CA), Dellamary; Luis A. (San Marcos, CA), Tarara; Thomas E. (San Diego, CA), Kabalnov; Alexey (Corvallis, OR)
Assignee:	Inhale Therapeutic Systems, Inc. (San Carlos, CA)
Filing Date:	Dec 22, 1998
Application Number:	09/218,212
Claims:	1. A stable respiratory dispersion for the pulmonary delivery of one or more bioactive agents comprising a suspension medium having dispersed therein a plurality of perforated microstructures having a mean aerodynamic diameter of less than 5 .mu.m and comprising at least one bioactive agent wherein said suspension medium comprises at least one propellant and substanially permeates said perforated microstructures wherein more than 30% of the average particle volume of the perforated microstructures is permeated by said suspension medium. 2. The stable 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 stable respiratory dispersion of claim 1 wherein said propellant is a hydrofluoroalkane propellant. 4. The stable respiratory dispersion of claim 3 wherein said hydrofluoroalkane propellant comprises 1,1,1,2-tetrrrluoroethane. 5. The stable respiratory dispersion of claim 3 wherein said hydrofluoroalkane propellant comprises 1,1,1,2,3,3,3-heptafluoro-n-propane. 6. The stable respiratory dispersion of claim 1 wherein said perforated microstructures comprise a surfactant. 7. The stable 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 stable dispersion of claim 6 wherein said perforated microstructures comprise a poloxamer selected from the group consisting of poloxamer 188, poloxamer 407, and poloxamer 338. 9. The stable dispersion of claim 6 wherein said perforated microstructures comprise oleic acid or its alkali salt. 10. The stable respiratory dispersion of claim 6 wherein said surfactant comprises a lipid. 11. The stable respiratory dispersion of claim 10 wherein said lipid has a gel to liquid crystal phase transition greater than about 40.degree. C. 12. The stable respiratory dispersion of claim 10 wherein said lipid is a phospholipid. 13. The stable respiratory dispersion of claim 12 wherein said phospholipid is selected from the group consisting of dilauroylphosphatidylcholine, dioleylphosphatidylcholine, dipalmitoylphosphatidylcholine, disteroylphosphatidyl-choline behenoylphosphatidylcholine, arachidoylphosphatidylcholine and combinations thereof. 14. The stable respiratory dispersion of claim 6 wherein said perforated microstructures comprise greater than about 10% w/w surfactant. 15. The stable respiratory dispersion of claim 14 wherein said surfactant comprises a phospholipid. 16. The stable respiratory dispersion of claim 14 wherein said surfactant comprises oleic acid or its alkali salt. 17. The stable respiratory dispersion of claim 1 wherein said suspension medium and said perforated microstructures have a refractive index differential of less than about 0.4. 18. The stable respiratory dispersion of claim 1 wherein said suspension medium and said perforated microstructures have a refractive index differential of less than about 0.3. 19. The stable respiratory dispersion of claim 1 wherein said perforated microstructures comprise hollow porous microspheres. 20. The stable respiratory dispersion of claim 19 wherein the microspheres comprise a surfactant. 21. The stable respiratory dispersion of claim 1 wherein the mean geometric diameter of the perforated microstructures is between 1 and 5 .mu.m. 22. The stable respiratory dispersion of claim 1 wherein the mean geometric diameter of the perforated microstructures is between 0.5 and 5 .mu.m. 23. The stable respiratory dispersion of claim 1 wherein the mean geometric diameter of the perforated microstructures is between 1 and 3 .mu.m. 24. The stable respiratory dispersion of claim 1 wherein said bioactive agent has a fine particle fraction following aerosolization of greater than 30% . 25. The stable respiratory dispersion of claim 1 wherein said bioactive agent has a fine particle fraction following aerosolization of greater than 50%. 26. The stable respiratory dispersion of claim 1 wherein the density of the perforated microstructures permeated with the suspension medium substantially matches that of the suspension medium. 27. The stable respiratory dispersion of claim 1 wherein said bioactive agent is selected from the group consisting of antiallergics, bronchodilators, pulmonary lung surfactants, analgesics, antibiotics, antiinfectives, leukotriene inhibitors or antagonists, antihistamine, antiinflammatories, antineoplastics, antocholinergics, anesthetics, anti-tuberculars, imaging agents, cardiovascular agents, enzymes, steroids, genetic material, viral vectors, antisense agents, proteins, peptides, and combinations thereof. 28. The stable respiratory dispersion of claim 1 wherein said bioactive agents are selected from the group consisting of steroids, bronchodilators and peptides. 29. The stable respiratory dispersion of claim 1 wherein said bioactive agents are selected from the group consisting of budesonide, fluticasone propionate, salrieterol, formoterol, gentamicin, LHRH, and DNase. 30. A method for forming a stabilized respiratory dispersion comprising the steps of: combining a plurality of perforated microstructures having a mean aerodynamic diameter of less than 5 .mu.m and comprising at least one bioactive agent with a predetermined volume of suspension medium comprising at least one propellant to provide a respiratory blend wherein said suspension medium pernates said microstructures wherein more than 30% of the average particle volume of the perforated microstructures is permeated by said suspension medium; and mixing said respiratory blend to provide a substantidly homogeneous respiratory dispersion. 31. A respiratory dispersion formed according to the method of claim 30. 32. The method of claim 30 further comprising the step of spray drying an oil-in-water emulsion to provide said perforated microstructures wherein the disperse phase of said emulsion comprises a fluorochemical. 33. A respiratory dispersion formed according to the method of claim 32. 34. The method of claim 32 wherein said fluorochemical has a boiling point of greater than 60.degree. C. 35. The method of claim 30, 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. 36. The method of claim wherein said propellant comprises a hydrofluoroalkane propellant. 37. The method of claim 36 wherein said hydrofluoroalkane propellant comprises 1,1,1,2-tetrafluorethane. 38. The method of claim 36 wherein said hydrofluoroalkane propellant comprises 1,1,1,2,3,3,3-heptafluoro-n-propane. 39. The method of claim 30 wherein said perforated microstructures comprise a surfactant. 40. The method of claim 39 wherein said surfactant is selected from the group consisting of phospholipids, nonionic detergents, nonionic block copolymers, ionic surfactants, biocompatible fluorinated surfactants and combinations thereof. 41. The method of claim 39 wherein said surfactant comprises a lipid. 42. The method of claim 41 wherein said lipid has a gel to liquid crystal phase transition greater than 40.degree. C. 43. The method of claim 41 wherein said lipid is a phospholipid. 44. The method of claim 43 wherein said phospholipid is selected from the group consisting of dilauroylphosphatidylcholine, dioleyphosphatidylcholine, dip almitoylphosphatidylcholine, disteroylphosphatidylcholine, behenoylphosphatidylcholine, arachidoylphosphatidylcholine and combinations thereof. 45. The method of claim 39 wherein said perforated microstructures comprise greater than about 10% w/w surfactal. 46. The method of claim 36 wherein said suspension medium and said perforated microstrures have a refractive index differential of less than about 0.4. 47. The method of claim 30 wherein said perforated microstructures comprise hollow microspheres. 48. The method of claim 30 wherein the mean geometric diameter of the perforated microstructures is between 1 and 5 .mu.m. 49. The method of claim 30 wherein the mean aerodynamic diameter of the perforated microstructures is between 0.5 and 5 .mu.m. 50. The method of claim 30 wherein said bioactive agent has a fine particle fraction following aerosolization of greater than 30%. 51. The method of claim 30 wherein the density of the suspended microstructures permeated with the suspension medium substantially matches that of the suspension medium. 52. The method of claim 30 wherein said bioactive agent is selected from the group consisting of antiallergics, bronchodilators, pulmonary lung surfactants, analgesics, antibiotics, leukotriene inhibitors or antagonists, antihistamines, antiinflammatories, antineoplastics, antcholinergics, anesthetics, anti-tuberculars, imaging agents, cardiovascular agents, enzymes, steroids, genetic material, viral vectors, antisense agents, proteins, peptides and combinations thereof. 53. A method for stabilizing a dispersion by reducing attractive van der Waals forces comprising providing a plurality of perforated microstructures having a mean aerodynamic diameter of less than 5 .mu.m and; combining the microstructures with a suspension medium comprising at least one propellant wherein the wherein more than 30% of the average particle volume of the perforated microstrures is permeated by said suspension medium. 54. A dispersion formed according to the method of claim 53. 55. The method of claim 53 wherein said refractive index differential value is less than 0.3. 56. The method of claim 53 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. 57. The method of claim 53 wherein said propellant comprises a hydrofluoroakane propellant. 58. The method of claim 57 wherein said hydrofluoroalkane propellant comprises 1,1,1,2-tetafluoroethane. 59. The method of claim 57 wherein said hydrofluoroalkane propellant comprises 1,1,1,2,3,3,3-heptafluoro-n-propane. 60. The method of claim 53 wherein said perforated microstructures comprise a surfant. 61. The method of claim 60 wherein said surfactant is selected from the group consisting of phospholipids, nonionic detergents, nonionic block copolymers, ionic surfactants, biocompatible fluorinated surfactants and combinations thereof. 62. The method of claim 60 wherein said surfactant comprises a lipid. 63. The method of claim 62 wherein said lipid has a gel to liquid crystal phase transition greater than 40.degree. C. 64. The method of claim 62 wherein said lipid is a phospholipid. 65. The method of claim 64 wherein said phospholipid is selected from the group consisting of dilauroylphosphatidylcholine, dioleylphosphatidylcholine, dipalmitoylphosphatidylcholine, disteroylphosphatidylcholine, behenoylphosphatidylcholine, arachidoylphosphatidylcholine and combinations thereof. 66. The method of claim 53 wherein said perforated microstructures comprise greater than 10% w/w surfactant. 67. The method of claim 53 wherein said perforated microstructures comprise hollow porous microspheres. 68. The method of claim 53 wherein the mean geometric diameter of the perforated microstructures is between 0.5 and 5 .mu.m. 69. The method of claim 53 wherein the mean aerodynamic diameter of the perforated microstructures is between 0.5 and 5 .mu.m. 70. The method of claim 53 the density of the suspended microstructes permeated with the suspension medium substantially matches that of the suspension medium. 71. The method of claim 53 wherein said perforated microstructures comprise a bioactive agent selected from the group consisting of antiallergics, bronchodilators, pulmonary lung surfactants, analgesics, antibiotics, leukotriene inhibitors or antagonists, antihistamines, antiinflammatories, antineoplastics, antcholinergics, anesthetics, anti-tuberculars, imaging agents, cardiovascular agents, enzymes, steroids, genetic material, viral vectors, antisense agents, proteins, peptides and combinations thereof. 72. A respiratory dispersion for the pulmonary delivery of one or more bioactive agents comprising a suspension medium having dispersed therein a plurality of microparticles having a mean aerodynamic diameter of less than 5 .mu.m and comprising greater than about 20% w/w surfactant and at least one bioactive agent wherein said suspension medium comprises at least one propellant. 73. The respiratory dispersion of claim 72 wherein said dispersed microparticles comprise greater than about 30% w/w surfactant. 74. The respiratory dispersion of claim 72 wherein said propellant comprises a compound selected from the group consisting of 1,1,1,2-etrafluoroethane, 1,1,1,2,3,3,3-heptafluoro-n-propane, perfluoroethane, monochlorodifluoromethane, 1,1-difluoroethane and combinations thereof. 75. The respiratory dispersion of claim 72 wherein said propellant is a hydrofluoroalkane propellant. 76. The respiratory dispersion of claim 75 wherein said hydrofluoroalkane propellant comprises 1,1,1,2-tetrafluoroethane. 77. The respiratory dispersion of claim 72 wherein said surfactant is selected from the group consisting of phospholipids, nonionic detergents, nonionic block copolymers, ionic surfactants, biocompatible fluorinated surfactants and combinations thereof. 78. The respiratory dispersion of claim 72 wherein said surfactant comprises a lipid. 79. The respiratory dispersion of claim 78 wherein said lipid has a gel to liquid crystal phase transition greater than about 40.degree. C. 80. The respiratory dispersion of claim 78 wherein said lipid is a phospholipid. 81. The respiratory dispersion of claim 80 wherein said phospholipid is selected from the group consisting of dilauroylphosphatidylcholine, dioleylphosphatidylcholine, dipalmitoylphosphatidylcholine, disteroylphosphatidylcholine, behenoylphosphatidylcholine, arachidoylphosphatidylcholine and combinations thereof. 82. The respiratory dispersion of claim 72 wherein said microparticles comprise perforated microstructures. 83. The respiratory dispersion of claim 82 wherein said perforated microstructures comprise hollow porous microspheres. 84. The respiratory dispersion of claim 83 wherein said hollow porous microspheres have a mean aerodynamic diameter between 0.5 to 5 .mu.m. 85. The respiratory dispersion of claim 72 wherein the mean geometric diameter of the microparticles is between 1 and 5 .mu.m. 86. The respiratory dispersion of claim 72 wherein said bioactive agent is selected from the group consisting of antiallergics, bronchodilators, pulmonary lung surfactants, analgesics, antibiotics, leukotriene inhibitors or antagonists, antihistamines, antiinflammatories, antineoplastics, antcholinergics, anesthetics, anti-tuberculars, imaging agents, cardiovascular agents, enzymes, steroids, genetic material, viral vectors, antisense agents, proteins, peptides and combinations thereof. 87. The stable respiratory dispersion of claim 72 wherein said bioactive agents are selected from the group consisting of budesonide, fluticasone propionate, salmeterol, formoterol and DNase. 88. The stable respiratory dispersion of claim 1 further comprising a creaming or sedimentation time greater than 1 minute. 89. The stable respiratory dispersion of claim 80 wherein the creaming or sedimentation time is greater than 30 minutes. 90. The stable respiratory dispersion of claim 1 wherein the geometric mean diameter of the microstructures is between 1-30 .mu.m. 91. The stable respiratory dispersion of claim 27 wherein the bioactive agent is an antiinfective selected from the group consisting of cephalosporins, macrolides, quinolines, penicillins, streptomycin, sulphonamides, tetracyclines, and pentamidine. 92. The respiratory dispersion of claim 82 wherein said perforated microstructures comprise a poloxamer selected from the group consisting of poloxamer 188, poloxamine 407 and poloxamer 338. 93. The respiratory dispension of claim 82 wherein said perforate microstructures comprise oleic acid or its alkali salt.