Methods of spray drying pharmaceutical compositions

• US 6,565,885 B1
• Filed: 12/22/1998
• Issued: 05/20/2003
• Est. Priority Date: 09/29/1997
• Status: Expired due to Term

• Current Assignee: Novartis Pharma AG (Novartis Ag)
• Original Assignee: Inhale Therapeutics Systems Inc (Nektar Therapeutics)
• Inventors: Schutt, Ernest G., Weers, Jeffry G., Dellamary, Luis A., Tarara, Thomas E., Kabalnov, Alexey
• Primary Examiner(s): Dees, Jose′ G.
• Assistant Examiner(s): HAGHIGHATIAN, MINA
• Application Number:
  US09/219,736
• Time in Patent Office: 1,610 Days
• Field of Search: 424/45, 424/46, 424/489, 424/43, 424/9.52, 424/487, 424/450, 514/937, 514/3, 514/4, 530/303, 530/304, 530/305
• US Class Current: 424/489
• 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: Y02A 50/30 Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
• 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

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.

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°

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°

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 μ

m and 5.0 μ

m.

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

m.

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

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°

C.

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

C.

22. The method of claim 21 wherein the spray dryer outlet temperature is operated at a temperature at least 20°

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°

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 μ

m.

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

m.

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

m.

27. The method of claim 24 wherein the perforated microstructures comprise a bulk density of less than 0.5 g/cm³.

28. The method of claim 24 wherein the perforated microstructures comprise a bulk density of less than 0.1 g/cm³.

29. The method of claim 24 wherein the perforated microstructures comprise a bulk density of less than 0.05 g/cm³.

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⁻

6 M.

36. The method of claim 35 wherein the blowing agent comprises a water solubility of less than 10⁻

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.

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

97. The method of claim 26 wherein the perforated microstructures comprise a bulk density of less than 0.5 g/cm³.

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

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/cm³; 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°

C.

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

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°

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 μ

m and 5.0 μ

m.

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

m.

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

m.

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

m.

56. The method of claim 53 wherein the particulates comprise a bulk density of less than 0.1 g/cm³.

57. The method of claim 53 wherein the particulates comprise a bulk density of less than 0.05 g/cm³.

58. The method of claim 53 wherein the particulates comprise a tap density of less than 0.1 g/cm³.

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°

C.

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.

99. The method of claim 53 wherein the perforated microstructures comprise a bulk density of less than 0.5 g/cm³.

100. The method of claim 55 wherein the perforated microstructures comprise a bulk density of less than 0.5 g/cm³.

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

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 μ

m and 5.0 μ

m.

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

m.

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

m.

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

m.

83. The method of claim 80 wherein the perforated microstructures comprise a bulk density of less than 0.1 g/cm³.

84. The method of claim 80 wherein the perforated microstructures comprise a bulk density of less than 0.05 g/cm³.

85. The method of claim 80 wherein the perforated microstructures comprise a tap density of less than 0.1 g/cm³.

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°

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.

102. The method of claim 80 wherein the perforated microstructure comprise, a bulk density of less than 0.5 g/cm³.

103. The method of claim 82 wherein the perforated microstructures comprise a bulk density of less than 0.5 g/cm³.

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