Compositions for sustained action product delivery and methods of use thereof

• US 20030166509A1
• Filed: 11/20/2002
• Published: 09/04/2003
• Est. Priority Date: 11/20/2001
• Status: Abandoned Application

• Current Assignee: Civitas Therapeutics, Inc. (Acorda Therapeutics Incorporated), President and Fellows of Harvard College (Harvard Corporation)
• Original Assignee: Advanced Inhalation Research, Inc. (Alkermes Incorporated)
• Inventors: Tsapis, Nicolas, Edwards, David A., Weitz, David A., Hrkach, Jeffrey S., Batycky, Richard P., Schmitke, Jennifer L.
• Application Number:
  US10/300,070
• Publication Number:
  US 20030166509A1
• Time in Patent Office: Days
• US Class Current: 514/3
• 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 9/1617 Organic compounds, e.g. phospholipids, fats
• CPC Class Codes: A61K 9/1623 Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
• CPC Class Codes: A61K 9/1652 Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin homeopathic globules A61K9/1623
• CPC Class Codes: A61K 9/1664 Compounds of unknown constitution, e.g. material from plants or animals oils, fats, waxes, shellac A61K9/1617
• CPC Class Codes: A61K 9/1688 resulting in pure drug agglomerate optionally containing up to 5% of excipient
• CPC Class Codes: A61K 9/1694 resulting in granules or microspheres of the matrix type containing more than 5% of excipient
• CPC Class Codes: A61K 9/5161 Polysaccharides, e.g. alginate, chitosan, cellulose derivatives; Cyclodextrin

Abstract

The present invention features pharmaceutical compositions comprising nanoparticles containing a sustained release bioactive agent, method of making such compositions, and method of therapy using such compositions.

Claims

1. A pharmaceutical composition comprising spray dried particles, said particles comprising sustained action nanoparticles, said nanoparticles comprising a bioactive agent and having a geometric diameter of about 1 micron or less.

2. The pharmaceutical composition of claim 1, wherein said nanoparticles have a geometric diameter of between about 25 nanometers and about 1 micron or less.

3. The pharmaceutical composition of claim 1, wherein said nanoparticles have a geometric diameter of between about 25 nanometers and less than 1 micron.

4. The pharmaceutical composition of claim 1, wherein said spray dried particles have an aerodynamic diameter between about 1 μ

m and about 6 μ

m.

5. The pharmaceutical composition of claim 1, wherein said spray dried particles comprises 100% by weight nanoparticles.

6. The pharmaceutical composition of claim 1, wherein said spray dried particles comprises at least 75% by weight nanoparticles.

7. The pharmaceutical composition of claim 1, wherein said spray dried particles comprises at least 50% by weight nanoparticles.

8. The pharmaceutical composition of claim 1, wherein said spray dried particles comprises at least 25% by weight nanoparticles.

9. The pharmaceutical composition of claim 1, wherein said spray dried particles comprises at least 5% by weight nanoparticles.

10. The pharmaceutical composition of claim 1, further comprising an additive.

11. The pharmaceutical composition of claim 10, wherein said additive is an excipient.

12. The pharmaceutical composition of claim 11, wherein said excipient is selected from the group consisting of phospholipids, polypeptides, polysaccharides, polyanhydrides, amino acids, polymers, proteins, surfactants, cholesterol, fatty acids, fatty acid esters, sugars and combinations thereof.

13. The pharmaceutical composition of claim 12, wherein said phospholipid is selected from the group consisting of phosphatidylcholines, phosphatidylethanolamines, phosphatidylglycerols, phosphatidylserines, phosphatidylinositols and combinations thereof.

14. The pharmaceutical composition of claim 10, wherein said additive is a bioactive agent.

15. The pharmaceutical composition of claim 14, wherein said bioactive agent is selected from the group consisting of a therapeutic agent, a diagnostic agent, and a prophylactic agent.

16. The pharmaceutical composition of claim 15, wherein said therapeutic agent is selected from the group consisting of insulin, estradiol, rifampin, ethambutol, pyrazinamide and albuterol.

17. The pharmaceutical composition of claim 10, wherein said additive is a second bioactive agent, and wherein the release of said second bioactive agent from said particles is faster than the release of said bioactive agent contained in said nanoparticle.

18. The pharmaceutical composition of claim 17, wherein said second bioactive agent and said bioactive agent comprising said nanoparticle are the same.

19. The pharmaceutical composition of claim 17, wherein said second bioactive agent and said bioactive agent comprising said nanoparticle are different.

20. The pharmaceutical composition of claim 17, wherein said additive is a second bioactive agent, and wherein the release of said second bioactive agent from said particles is a sustained release.

21. The pharmaceutical composition of claim 17, wherein said second bioactive agent is selected from the group consisting of a therapeutic agent, a diagnostic agent, and a prophylactic agent.

22. The pharmaceutical composition of claim 21, wherein said second bioactive agent is selected from the group consisting of insulin, estradiol, rifampin ethambutol and pyrazinamide.

23. The pharmaceutical composition of claim 1, wherein said nanoparticle is biodegradable.

24. The pharmaceutical composition of claim 23, wherein said nanoparticle is polymeric.

25. The pharmaceutical composition of claim 23, wherein said nanoparticle is nonpolymeric.

26. The pharmaceutical composition of claim 1, wherein said nanoparticle is non-biodegradable.

27. The pharmaceutical composition of claim 26, wherein said nanoparticle is polymeric.

28. The pharmaceutical composition of claim 27, wherein said nanoparticle comprises polystyrene.

29. The pharmaceutical composition of claim 28, further comprising lactose or hydroxypropylcellulose.

30. The pharmaceutical composition of claim 1, wherein said nanoparticle is a bead.

31. The pharmaceutical composition of claim 30, wherein said bead is a polystyrene bead.

32. The pharmaceutical composition of claim 30, wherein said bead is a polystyrene latex bead.

33. The pharmaceutical composition of claim 30, wherein said bioactive agent is incorporated into said bead.

34. The pharmaceutical composition of claim 1, wherein said composition is respirable.

35. The pharmaceutical composition of claim 1, wherein said particles are formulated to dissolve into said nanoparticles.

36. A pharmaceutical composition comprising phospholipid-containing biodegradable particles, said particles having a geometric diameter of between about 4 microns and about 8 microns and an aerodynamic diameter of between about 1 micron and about 3 microns, said particles comprising between about 5% and about 80% by weight nanoparticles, said nanoparticles having a geometric diameter of between about 25 nanometers and about 1 micron, and wherein said nanoparticles are carboxylate modified polystyrene beads.

37. A pharmaceutical composition comprising phospholipid-containing biodegradable particles, said particles having a geometric diameter of between about 5 microns and about 8 microns and an aerodynamic diameter of between about 2.5 and about 3.5, said particles comprising between about 5% and about 70% by weight nanoparticles, said nanoparticles having a geometric diameter of between about 25 nanometers and about 1 micron, and wherein said nanoparticles are carboxylate modified polystyrene beads.

38. A pharmaceutical composition comprising phospholipid-containing biodegradable particles, said particles having a geometric diameter of between about 8 microns and about 12.5 microns and an aerodynamic diameter of between about 2 microns and about 3 microns, said particles comprising between about 5 and about 85% by weight nanoparticles, said nanoparticles having a geometric diameter of between about 25 nanometers and about 1 micron, and wherein said nanoparticles are carboxylate modified polystyrene beads.

39. A pharmaceutical composition comprising phospholipid-containing biodegradable particles, said particles having a geometric diameter of between about 7.5 microns and about 15 microns and an aerodynamic diameter of between about 4.5 and about 7.5, said particles comprising between 5 and 90% by weight nanoparticles, said nanoparticles having a geometric diameter of between about 25 nanometers and about 1 micron, and wherein said nanoparticles are colloidal silica.

40. A pharmaceutical composition comprising phospholipid-containing biodegradable particles and nanoparticles, wherein said nanoparticles comprise Rifampicin and one or more phospholipids.

41. A method of treating a condition in a patient, comprising the step of administering to said patient a pharmaceutical composition comprising spray dried particles, said particles comprising sustained action nanoparticles, said nanoparticles comprising a bioactive agent and having a geometric diameter of about 1 micron or less.

42. The method of claim 41, wherein said nanoparticles have a geometric diameter of between about 25 nanometers and less than 1 micron.

43. The method of claim 41, wherein said spray dried particles have an aerodynamic diameter between about 1 micron and about 10 microns.

44. The method of claim 41, wherein said spray dried particles comprise 100% by weight nanoparticles.

45. The method of claim 41, wherein said spray dried particles comprise at least 75% by weight nanoparticles.

46. The method of claim 41, wherein said spray dried particles comprise at least 50% by weight nanoparticles.

47. The method of claim 41, wherein said spray dried particles comprise at least 25% by weight nanoparticles.

48. The method of claim 41, wherein said spray dried particles comprise at least 5% by weight nanoparticles.

49. The method of claim 41, wherein said pharmaceutical composition further comprises an additive.

50. The method of claim 49, wherein said additive is an excipient.

51. The method of claim 50, wherein said excipient is selected from the group consisting of phospholipids, polypeptides, polysaccharides, polyanhydrides, amino acids, polymers, proteins, surfactants, cholesterol, fatty acids, fatty acid esters, sugars and combinations thereof.

52. The method of claim 51, wherein said phospholipid is selected from the group consisting of phosphatidylcholines, phosphatidylethanolamines, phosphatidylglycerols, phosphatidylserines, phosphatidylinositols and combinations thereof.

53. The method of claim 49, wherein said additive is a bioactive agent.

54. The method of claim 53, wherein said bioactive agent is selected from the group consisting of a therapeutic agent, a diagnostic agent, and a prophylactic agent.

55. The method of claim 54, wherein said therapeutic agent is selected from the group consisting of insulin, estradiol, rifampin, ethambutol, pyrazinamide and albuterol.

56. The method of claim 49, wherein said additive is a second bioactive agent, and wherein the release of said second bioactive agent from said particles is faster than the release of said bioactive agent contained in said nanoparticle.

57. The method of claim 56, wherein said second bioactive agent and said bioactive agent comprising said nanoparticle are the same.

58. The method of claim 56, wherein said second bioactive agent and said bioactive agent comprising said nanoparticle are different.

59. The method of claim 56, wherein said additive is a second bioactive agent, and wherein the release of said second bioactive agent from said particles is a sustained release.

60. The method of claim 56, wherein said second bioactive agent is selected from the group consisting of a therapeutic agent, a diagnostic agent, and a prophylactic agent.

61. The method of claim 60, wherein said second bioactive agent is selected from the group consisting of insulin, estradiol, rifampin, ethambutol and pyrazinamide.

62. The method of claim 41, wherein said nanoparticle is biodegradable.

63. The method of claim 62, wherein said nanoparticle is polymeric.

64. The method of claim 62, wherein said nanoparticle is nonpolymeric.

65. The method of claim 41, wherein said nanoparticle is non-biodegradable.

66. The method of claim 65, wherein said nanoparticle is polymeric.

67. The method of claim 66, wherein said nanoparticle comprises polystyrene.

68. The method of claim 65, wherein said nanoparticle is nonpolymeric.

69. The method of claim 41, wherein said nanoparticle is a bead.

70. The method of claim 69, wherein said bead is a polystyrene bead.

71. The method of claim 69, wherein said bead is a polystyrene latex bead.

72. The method of claim 69, wherein said bioactive agent is incorporated into said bead.

73. The method of claim 41, wherein said pharmaceutical composition is respirable.

74. The method of claim 73, wherein said administering is done by inhalation.

75. The method of claim 74, wherein said inhalation comprises delivery primarily to the deep lung.

76. The method of claim 74, wherein said inhalation comprises delivery primarily to the central airways.

77. The method of claim 74, wherein said inhalation comprises delivery primarily to the upper airways.

78. The method of claim 41, wherein said particles are formulated to release said nanoparticles.

113. The method of claim 41, wherein said nanoparticles have a geometric diameter of between about 25 nanometers and about 1 micron or less.

79. A method of making spray dried particles comprising sustained action nanoparticles, said nanoparticles comprising a bioactive agent and having a geometric diameter of about 1 micron or less, said method comprising the steps of spray drying a solution comprising said nanoparticles or reagents capable of forming nanoparticles under conditions that form spray dried particles.

80. The method of claim 79, wherein said nanoparticles have a geometric diameter of between about 25 nanometers and less than 1 micron.

81. The method of claim 79, wherein said spray dried particles have an aerodynamic diameter between about 1 micron and about 13 microns.

82. The method of claim 79, wherein said spray dried particles comprises at least 100% by weight nanoparticles.

83. The method of claim 79, wherein said spray dried particles comprises at least 75% by weight nanoparticles.

84. The method of claim 79, wherein said spray dried particles comprises at least 50% by weight nanoparticles.

85. The method of claim 79, wherein said spray dried particles comprises at least 25% by weight nanoparticles.

86. The method of claim 79, wherein said spray dried particles comprises at least 5% by weight nanoparticles.

87. The method of claim 79, wherein said spray dried particles further comprises an additive.

88. The method of claim 87, wherein said additive is an excipient.

89. The method of claim 88, wherein said excipient is selected from the group consisting of phospholipids, polypeptides, polysaccharides, polyanhydrides, amino acids, polymers, proteins, surfactants, cholesterol, fatty acids, fatty acid esters, sugars and combinations thereof.

90. The method of claim 89, wherein said phospholipid is selected from the group consisting of phosphatidylcholines, phosphatidylethanolamines, phosphatidylglycerols, phosphatidylserines, phosphatidylinositols and combinations thereof.

91. The method of claim 87, wherein said additive is a bioactive agent.

92. The method of claim 91, wherein said bioactive agent is selected from the group consisting of a therapeutic agent, a diagnostic agent, and a prophylactic agent.

93. The method of claim 92, wherein said therapeutic agent is selected from the group consisting of insulin, estradiol, rifampin, ethambutol, pyrazinamide and albuterol.

94. The method of claim 87, wherein said additive is a second bioactive agent, and wherein the release of said second bioactive agent from said particles is faster than the release of said bioactive agent contained in said nanoparticle.

95. The method of claim 94, wherein said second bioactive agent and said bioactive agent comprising said nanoparticle are the same.

96. The method of claim 94, wherein said second bioactive agent and said bioactive agent comprising said nanoparticle are different.

97. The method of claim 94, wherein said additive is a second bioactive agent, and wherein the release of said second bioactive agent from said particles is a sustained release.

98. The method of claim 94, wherein said second bioactive agent is selected from the group consisting of a therapeutic agent, a diagnostic agent, and a prophylactic agent.

99. The method of claim 98, wherein said second bioactive agent is selected from the group consisting of insulin, estradiol, rifampin, ethambutol and pyrazinamide.

100. The method of claim 79, wherein said nanoparticle is biodegradable.

101. The method of claim 100, wherein said nanoparticle is polymeric.

102. The method of claim 100, wherein said nanoparticle is nonpolymeric.

103. The method of claim 79, wherein said nanoparticle is non-biodegradable.

104. The method of claim 103, wherein said nanoparticle is polymeric.

105. The method of claim 104, wherein said nanoparticle comprises polystyrene.

106. The method of claim 103, wherein said nanoparticle is nonpolymeric.

107. The method of claim 79, wherein said nanoparticle is a bead.

108. The method of claim 107, wherein said bead is a polystyrene bead.

109. The method of claim 107, wherein said bead is a polystyrene latex bead.

110. The method of claim 107, wherein said bioactive agent is incorporated into said bead.

111. The method of claim 79, wherein said pharmaceutical composition is respirable.

112. The method of claim 79, wherein said particles are formulated to dissolve into said nanoparticles.

114. The method of claim 79, wherein said nanoparticles have a geometric diameter of between about 25 nanometers and about 1 micron or less.

115. A composition comprising spray dried particles, said particles comprising sustained action nanoparticles, said nanoparticles comprising a nutraceutical agent and having a geometric diameter of about 1 micron or less.

116. The composition of claim 115, wherein said nanoparticles have a geometric diameter of between about 25 nanometers and about 1 micron or less.

117. The composition of claim 115, wherein said nanoparticles have a geometric diameter of between about 25 nanometers and less than 1 micron.

118. The composition of claim 115, wherein said spray dried particles have an aerodynamic diameter between about 1 μ

m and about 6 μ

m.

119. The composition of claim 115, wherein said spray dried particles comprises 100% by weight nanoparticles.

120. The composition of claim 115, wherein said spray dried particles comprises at least 75% by weight nanoparticles.

121. The composition of claim 115, wherein said spray dried particles comprises at least 50% by weight nanoparticles.

122. The composition of claim 115, wherein said spray dried particles comprises at least 25% by weight nanoparticles.

123. The composition of claim 115, wherein said spray dried particles comprises at least 5% by weight nanoparticles.

124. A method of treating a nutritional deficiency in a patient comprising the step of administering to said patient a composition comprising spray dried particles, said particles comprising sustained action nanoparticles, said nanoparticles comprising a nutraceutical agent and having a geometric diameter of about 1 micron or less.

125. The method of claim 124, wherein the nutraceutical agent is selected from the group consisting of a vitamin, a mineral and a nutritional supplement.