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Details for Patent: 6,565,885

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Details for Patent: 6,565,885

Title: Methods of spray drying pharmaceutical compositions
Abstract:Spray drying methods for forming powder compositions for pharmaceutical applications are disclosed. According to one aspect of the invention, the spray drying feed stock comprises a bioactive agent, surfactant, and a blowing agent. Another aspect of the invention is directed to spray drying a feed stock comprising a phospholipid and calcium chloride.
Inventor(s): Tarara; Thomas E. (San Diego, CA), Weers; Jeffry G. (San Diego, CA), Kabalnov; Alexey (Corvallis, OR), Schutt; Ernest G. (San Diego, CA), Dellamary; Luis A. (San Marcos, CA)
Assignee: Inhale Therapeutic Systems, Inc. (San Carlos, CA)
Filing Date:Dec 22, 1998
Application Number:09/219,736
Claims:1. A method for forming a powder comprising perforated microstructures for pharmaceutical applications by spray drying comprising the steps of: providing a feed stock comprising a bioactive agent, surfactant, and a blowing agent wherein said blowing agent is selected from the group consisting of fluorinated compounds, nonfluorinated oils, ammonium salts, alcohols, chloroform, ethyl acetate, acetone, nitrogen, carbon dioxide, camphor, and latex wherein the ratio of blowing agent/surfactant is between 1.0-60 w/w; atomizing said feed stock to produce dispersed droplets; drying said droplets to form perforated microstructures comprising said bioactive agent and surfactant; and collecting said perforated microstructures.

2. The method of claim 1 wherein said blowing agent comprises a nonfluorinated oil.

3. The method of claim 1 wherein said blowing agent comprises a fluorinated compound.

4. The method of claim 3 wherein said fluorinated blowing agent has a boiling point greater than about 60.degree. C.

5. The method of claim 1 wherein said feed stock comprises a colloidal system.

6. The method of claim 5 wherein said colloidal system comprises a fluorocarbon emulsion.

7. The method of claim 6 wherein said fluorocarbon emulsion comprises a fluorocarbon having a boiling point greater than about 60.degree. C.

8. The method of claim 1 wherein said surfactant is selected from the group consisting of phospholipids, nonionic detergents, nonionic block copolymers, ionic surfactants, biocompatible fluorinated surfactants and combinations thereof.

9. The method of claim 1 wherein said surfactant is a phospholipid.

10. The method of claim 9 wherein said phospholipid is selected from the group consisting of dilauroylphosphatidylcholine, dioleylphosphatidylcholine, dipalmitoylphosphatidylcholine, disteroylphosphatidylcholine dibehenoylphosphatidylcholine, diarachidoylphosphatidylcholine and combinations thereof.

11. The method of claim 1 wherein said collected perforated microstructures comprise hollow porous microspheres.

12. The method of claim 1 wherein the aerodynamic diameter of said collected perforated microstructures is between 0.5 .mu.m and 5.0 .mu.m.

13. The method of claim 1 wherein said perforated microstructures have a mean geometric diameter of less than about 5 .mu.m.

14. The method of claim 1 wherein said perforated microstructures have a mean geometric diameter of less than about 3 .mu.m.

15. The method of claim 1 wherein said perforated microstructures comprise greater than about 10% w/w of a surfactant.

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

17. The method of claim 15 wherein said ratio of blowing agent/surfactant is greater than 4.8 w/w.

18. The method of claim 15 wherein said ratio of blowing agent/surfactant is within 10-50 w/w.

19. The method of claim 1 wherein said feed stock comprises an emulsion.

20. A method according to claim 1 wherein the spray dryer inlet temperature is within 60-170.degree. C.

21. The method of claim 20 wherein the spray dryer outlet temperature is within 40-120.degree. C.

22. The method of claim 21 wherein the spray dryer outlet temperature is operated at a temperature at least 20.degree. C. less than the boiling point of the blowing agent.

23. The method of claim 22 wherein the spray dryer outlet temperature is operated at a temperature 50-150.degree. C. less than the boiling point of the blowing agent.

24. The method of claim 12 wherein the perforated microstructures comprise a mean geometric diameter of 1-30 .mu.m.

25. The method of claim 24 wherein the perforated microstructures comprise a mean geometric diameter of less than about 10 .mu.m.

26. The method of claim 25 wherein the perforated microstructures comprise a mean geometric diameter of less than about 5 .mu.m.

27. The method of claim 24 wherein the perforated microstructures comprise a bulk density of less than 0.5 g/cm.sup.3.

28. The method of claim 24 wherein the perforated microstructures comprise a bulk density of less than 0.1 g/cm.sup.3.

29. The method of claim 24 wherein the perforated microstructures comprise a bulk density of less than 0.05 g/cm.sup.3.

30. The method of claim 27 wherein the perforated microstructures are hollow and porous.

31. The method of claim 1 wherein said perforated microstructures comprise greater than about 20% w/w of a surfactant.

32. The method of claim 1 wherein said feed stock comprises calcium chloride.

33. The method of claim 1 wherein the blowing agent is selected from the group consisting of nitrogen and carbon dioxide.

34. The method of claim 1 wherein the blowing agent is selected from the group consisting of ammonium carbonate and camphor.

35. The method of claim 1 wherein the blowing agent comprises a water solubility of less than 10.sup.-6 M.

36. The method of claim 35 wherein the blowing agent comprises a water solubility of less than 10.sup.-3 M.

37. The method of claim 1 wherein the feed stock further comprises a natural or synthetic polymer selected from the group consisting of polylactides, polylactide-glycolides, cyclodextrins, polyacrylates, methylcellulose, carboxymethylcellulose, polyvinyl alcohols, polyanhydrides, polylactams, polyvinyl pyrrolidones, polysaccharides, hyaluronic acid, and proteins.

38. A method for forming a particulate composition for pharmaceutical applications by spray drying comprising: providing a feed stock comprising a phospholipid and calcium chloride; atomizing said feed stock to produce dispersed droplets; drying said droplets in order to form particulates comprising phospholipid and calcium, said particulates comprising a bulk density of less than 0.5 g/cm.sup.3 ; and collecting said particulates.

39. The method of claim 38 wherein the feed stock further comprises a bioactive agent.

40. The method of claim 38 wherein the feed stock comprises a colloidal system selected from the group consisting of emulsions, reverse emulsions, microemulsions, multiple emulsions, particulate dispersions, and slurries.

41. The method of claim 40 wherein said colloidal system comprises an emulsion.

42. The method of claim 40 wherein said colloidal system comprises a particulate dispersion.

43. The method of claim 38 wherein the drying is performed in a spray dryer having an inlet temperature within 60-170.degree. C.

44. The method of claim 43 wherein the spray dryer outlet temperature is within 40-120.degree. C.

45. The method of claim 38 wherein the feed stock comprises 2-50% v/v of a blowing agent selected from the group consisting of fluorinated compounds, non-fluorinated oils, ammonium salts, alcohols, chloroform, ethyl acetate, acetone, nitrogen, carbon dioxide, camphor, and latex.

46. The method of claim 45 wherein the drying is performed in a spray dryer having an outlet temperature operated at a temperature at least 20.degree. C. less than the boiling point of the blowing agent.

47. The method of claim 38 wherein said phospholipid is selected from the group consisting of dilaurylphosphatidylcholine, dioleylphosphatidylcholine, dipalmitoylphosphatidylcholine, disteroylphosphatidylcholine, dibehenoylphosphatidylcholine, diarachidoylphosphatidylcholine and combinations thereof.

48. The method of claim 45 wherein said blowing agent is selected from the group consisting of fluorinated compounds and nonfluorinated oils.

49. The method of claim 45 wherein said blowing agent is selected from the group consisting of nitrogen and carbon dioxide.

50. The method of claim 45 wherein said feed stock comprises a blowing agent to phospholipid ratio of at least 4.8 w/w.

51. The method of claim 50 wherein said blowing agent/phospholipid ratio is within 10-50 w/w.

52. The method of claim 38 wherein the aerodynamic diameter of said collected particulates is between 0.5 .mu.m and 5.0 .mu.m.

53. The method of claim 52 wherein said particulates have a mean geometric diameter between 1-30 .mu.m.

54. The method of claim 52 wherein said particulates have a mean geometric diameter of less than about 10 .mu.m.

55. The method of claim 52 wherein said particulates have a mean geometric diameter of less than about 5 .mu.m.

56. The method of claim 53 wherein the particulates comprise a bulk density of less than 0.1 g/cm.sup.3.

57. The method of claim 53 wherein the particulates comprise a bulk density of less than 0.05 g/cm.sup.3.

58. The method of claim 53 wherein the particulates comprise a tap density of less than 0.1 g/cm.sup.3.

59. The method of claim 56 wherein said collected particulates comprise hollow porous microspheres.

60. The method of claim 38 wherein said particulates comprise greater than about 10% w/w of a phospholipid.

61. The method of claim 38 wherein said particulates comprise greater than about 20% w/w of a phospholipid.

62. The method of claim 38 wherein the feed stock further comprises an amino acid.

63. The method of claim 38 wherein the feed stock further comprises sodium citrate.

64. The method of claim 38 wherein the feed stock further comprises a natural or synthetic polymer selected from the group consisting of polylactides, polylactide-glycolides, cyclodextrins, polyacrylates, methylcellulose, carboxymethylcellulose, polyvinyl alcohols, polyanhydrides, polylactams, polyvinyl pyrrolidones, polysaccharides, hyaluronic acid, and proteins.

65. The method of claim 38 wherein the phospholipid comprises a gel to liquid crystal transition temperature of greater than 40.degree. C.

66. The method of claim 3 wherein the fluorinated compound is selected from the group consisting of perfluorooctyl bromide, perfluorooctyl ethane, and perfluorooctyl iodide.

67. The method of claim 48 wherein the fluorinated compound is selected from the group consisting of perfluorooctyl bromide, perfluorooctyl ethane, and perfluorooctyl iodide.

68. The method of claim 45 wherein the blowing agent is selected from the group consisting of ammonium carbonate, ammonium acetate, ammonium chloride, and camphor.

69. The method of claim 39 wherein the bioactive agent is selected from the group consisting of antiallergics, bronchodilators, pulmonary lung surfactants, analgesics, antibiotics, antiinfectives, leukotriene inhibitors or antagonists, antihistamines, antiinflammatories, antineoplastics, anticholinergics, anesthetics, anti-tuberculars, imaging agents, cardiovascular agents, enzymes, steroids, DNA, viral vectors, antisense agents, proteins, peptides and combinations thereof.

70. The method of claim 69 wherein the bioactive agent is an aminoglycoside antibiotic.

71. The method of claim 69 wherein the bioactive agent is selected from the group consisting of LHRH, goserelin, leuprolide, fentanyl, ergotamine, morphine, lung surfactants, and growth hormone.

72. A method for forming a powder comprising perforated microstructures for pharmaceutical applications by spray drying comprising the steps of: providing a feed stock comprising a bioactive agent, surfactant, and 2-50% v/v of a blowing agent selected from the group consisting of fluorinated compounds, non-fluorinated oils, ammonium salts, alcohols, chloroform, ethyl acetate, acetone, nitrogen, carbon dioxide, camphor, and latex; atomizing said feed stock to produce dispersed droplets; and drying said droplets to form perforated microstructures comprising said bioactive agent and surfactant.

73. A method according to claim 72 further comprising collecting said perforated microstructures.

74. The method of claim 72 wherein said surfactant is a phospholipid is selected from the group consisting of dilaurylphosphatidylcholine, dioleylphosphatidylcholine, dipalmitoylphosphatidylcholine, disteroylphosphatidylcholine, dibehenoylphosphatidylcholine, diarachidoylphosphatidylcholine and combinations thereof.

75. The method of claim 72 wherein said blowing agent is selected from the group consisting of fluorinated compounds and nonfluorinated oils.

76. The method of claim 72 wherein said blowing agent is selected from the group consisting of nitrogen and carbon dioxide.

77. The method of claim 75 wherein said feed stock comprises a blowing agent to surfactant ratio of at least 4.8 w/w.

78. The method of claim 77 wherein said blowing agent/surfactant ratio is within 10-60 w/w.

79. The method of claim 73 wherein the aerodynamic diameter of said collected perforated microstructures is between 0.5 .mu.m and 5.0 .mu.m.

80. The method of claim 79 wherein said perforated microstructures have a mean geometric diameter between 1-30 .mu.m.

81. The method of claim 79 wherein said perforated microstructures have a mean geometric diameter of less than about 10 .mu.m.

82. The method of claim 79 wherein said perforated microstructures have a mean geometric diameter of less than about 5 .mu.m.

83. The method of claim 80 wherein the perforated microstructures comprise a bulk density of less than 0.1 g/cm.sup.3.

84. The method of claim 80 wherein the perforated microstructures comprise a bulk density of less than 0.05 g/cm.sup.3.

85. The method of claim 80 wherein the perforated microstructures comprise a tap density of less than 0.1 g/cm.sup.3.

86. The method of claim 73 wherein said perforated microstructures comprise hollow porous microspheres.

87. The method of claim 72 wherein said perforated microstructures comprise greater than about 20% w/w of a phospholipid.

88. The method of claim 72 wherein the feed stock further comprises an amino acid.

89. The method of claim 72 wherein the feed stock further comprises sodium citrate.

90. The method of claim 72 wherein the feed stock further comprises a natural or synthetic polymer selected from the group consisting of polylactides, polylactide-glycolides, cyclodextrins, polyacrylates, methylcellulose, carboxymethylcellulose, polyvinyl alcohols, polyanhydrides, polylactams, polyvinyl pyrrolidones, polysaccharides, hyaluronic acid, and proteins.

91. The method of claim 74 wherein the phospholipid comprises a gel to liquid crystal transition temperature of great 40.degree. C.

92. The method of claim 75 wherein the blowing agent is a fluorinated compound selected from the group consisting of perfluorooctyl bromide, perfluorooctyl ethane, and perflurooctyl iodide.

93. The method of claim 72 wherein the blowing agent is selected from the group consisting of ammonium carbonate, ammonium acetate, ammonium chloride, and camphor.

94. The method of claim 72 wherein the bioactive agent is selected from the group consisting of antiallergics, bronchodilators, pulmonary lung surfactants, analgesics, antibiotics, antiinfectives, leukotriene inhibitors or antagonists, antihistamines, antiinflanmatories, antineoplastics, anticholinergics, anesthetics, anti-tuberculars, imaging agents, cardiovascular agents, enzymes, steroids, DNA, viral vectors, antisense agents, proteins, peptides and combinations thereof.

95. The method of claim 94 wherein the bioactive agent is an aminoglycoside antibiotic.

96. The method of claim 94 wherein the bioactive agent is selected from the group consisting of LHRH, goserelin, leuprolide, fentanyl, ergotamine, morphine, lung surfactants, and growth hormone.

97. The method of claim 26 wherein the perforated microstructures comprise a bulk density of less than 0.5 g/cm.sup.3.

98. The method of claim 97 wherein the perforated microstructures comprise hollow and porous microspheres.

99. The method of claim 53 wherein the perforated microstructures comprise a bulk density of less than 0.5 g/cm.sup.3.

100. The method of claim 55 wherein the perforated microstructures comprise a bulk density of less than 0.5 g/cm.sup.3.

101. The method of claim 100 wherein the perforated microstructures comprise hollow and porous microspheres.

102. The method of claim 80 wherein the perforated microstructure comprise, a bulk density of less than 0.5 g/cm.sup.3.

103. The method of claim 82 wherein the perforated microstructures comprise a bulk density of less than 0.5 g/cm.sup.3.

104. The method of claim 103 wherein the perforated microstructures comprise hollow and porous microspheres.
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