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Details for Patent: 6,551,576

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Details for Patent: 6,551,576

Title: Container with multi-phase composition for use in diagnostic and therapeutic applications
Abstract:A container comprising an aqueous lipid suspension and a gaseous phase substantially separate from the aqueous stabilizing phase, useful in diagnostic imaging such as ultrasound and magnetic resonance imaging and in therapeutic applications, is disclosed.
Inventor(s): Unger; Evan C. (Tucson, AZ), Matsunaga; Terry (Tucson, AZ), Yellowhair; David (Tucson, AZ)
Assignee: Bristol-Myers Squibb Medical Imaging, Inc. (Princeton, NJ)
Filing Date:Mar 31, 1998
Application Number:09/052,075
Claims:1. A container comprising an aqueous lipid suspension phase and a gaseous phase, wherein said gaseous phase is substantially separate from said aqueous lipid suspension phase and consists essentially of a single perfluorocarbon gas, and said aqueous lipid suspension phase comprises at least one phosphatidylcholine, at least one phosphatidylethanolamine, and at least one phosphatidic acid, wherein said phosphatidylcholine is selected from the group consisting of dioleoylphosphatidylcholine, dimyristoylphosphatidylcholine, dipalmitoylphosphatidylcholine, and distearoyl-phosphatidylcholine; said phosphatidylethanolamine is selected from the group consisting of dipalmitoylphosphatidylethanolamine, dioleoyl-phosphatidylethanolamine, and N-succinyl-dioleoyl-phosphatidylethanolamine; and said phosphatidic acid is dipalmatoylphosphatidic acid.

2. A container of claim 1 wherein said perfluorocarbon gas is selected from the group consisting of perfluoromethane, perfluoroethane, perfluoropropane, perfluorobutane, perfluorocyclobutane, perfluoropentane, and perfluorohexane.

3. A container of claim 2 wherein said perfluorocarbon gas is perfluoropropane.

4. A container of claim 2 wherein said perfluorocarbon gas is perfluoropentane.

5. A container of claim 2 wherein said perfluorocarbon gas is perfluorohexane.

6. A container of claim 1 wherein said aqueous lipid suspension phase further comprises a targeting ligand.

7. A container of claim 6 wherein said targeting ligand is polyethyleneglycol or polyvinylpyrrolidone.

8. A container of claim 1 wherein said phosphatidylethanolamine is present in an amount of from about 2.5 mole percent to about 8.0 mole percent based on total moles of said lipids in said aqueous lipid suspension phase.

9. A container of claim 1 wherein said phosphatidylcholine, said phosphatidylethanolamine, and said phosphatidic acid are in a mole percent ratio of about 82%:8%:10%.

10. A container of claim 1 wherein said phosphatidylcholine is dipalmitoylphosphatidylcholine, said phosphatidylethanolamine is dipalmitoylphosphatidylethanolamine, and said phosphatidic acid is dipalmitoylphosophatidic acid.

11. A container of claim 10 wherein said phosphatidylethanolamine is dipalmitoylphosphatidylethanolamine-PEG5000.

12. A container of claim 11 wherein said dipalmitoylphosphatidylethanolamine-PEG5000 is present in an amount from about 2.5 mole percent to about 8 mole percent based on total moles of said lipids in said aqueous lipid suspension phase.

13. A container of claim 12 wherein said dipalmitoylphosphatidylcholine, said dipalmitoylphosphatidylethanolamine-PEG5000, and said dipalmitoylphosophatidic acid are in a mole percent ratio of about 82%:8%:10%.

14. A container of claim 1 wherein at least a portion of said lipids are in a lipid monolayer in said aqueous lipid suspension phase.

15. A container of claim 14 wherein said aqueous lipid suspension phase further comprises polyethyleneglycol.

16. A container of claim 14 wherein said perfluorocarbon gas is perfluoropropane.

17. A container of claim 14 wherein said perfluorocarbon gas is perfluoropentane.

18. A container of claim 14 wherein said perfluorocarbon gas is perfluorohexane.

19. A container of claim 1 wherein at least a portion of said lipids are in a lipid bilayer in said aqueous lipid suspension phase.

20. A container of claim 19 wherein said aqueous lipid suspension phase further comprises polyethyleneglycol.

21. A container of claim 19 wherein sad perfluorocarbon gas is perfluoropropane.

22. A container of claim 19 wherein said perfluorocarbon gas is perfluoropentane.

23. A container of claim 19 wherein said perfluorocarbon gas is perfluorohexane.

24. A container of claim 1 wherein at least a portion of said lipids are in a lipid multilayer in said aqueous lipid suspension phase.

25. A container of claim 24 wherein said aqueous lipid suspension phase further comprises polyethyleneglycol.

26. A container of claim 24 wherein said perfluorocarbon gas is perfluoropropane.

27. A container of claim 24 wherein said perfluorocarbon gas is perfluoropentane.

28. A container of claim 24 wherein said perfluorocarbon gas is perfluorohexane.

29. A container of claim 1 wherein said aqueous lipid suspension phase has been rehydrated from a lyophilized composition.

30. A container of claim 1 wherein said aqueous lipid suspension phase further comprises a therapeutic or diagnostic agent.

31. A container of claim 30 wherein said diagnostic agent is an MRI contrast enhancing agent.

32. A container of claim 31 wherein said MRI contrast enhancing agent is a paramagnetic ion.

33. A container of claim 1 wherein said aqueous lipid suspension phase further comprises a suspending agent.

34. A container of claim 1 wherein said aqueous lipid suspension phase further comprises a viscosity modifying agent.

35. A container of claim 1 wherein said container is sterilized.

36. A container which contains a composition for use in diagnostic imaging, wherein the composition comprises an aqueous lipid suspension phase and a gaseous phase, wherein said gaseous phase is substantially separate from said aqueous lipid suspension phase and consists essentially of a single perfluorocarbon gas, and said aqueous lipid suspension phase comprises at least one phosphatidylcholine, at least one phosphatidylethanolamine, and at least one phosphatidic acid, wherein said phosphatidylcholine is selected from the group consisting of dioleoylphosphatidylcholine, dimyristoylphosphatidylcholine, dipalmitoylphosphatidylcholine, and distearoyl-phosphatidylcholine; said phosphatidylethanolamine is selected from the group consisting of dipalmitoylphosphatidylethanolamine, dioleoyl-phosphatidylethanolamine, and N-succinyl-dioleoyl-phosphatidylethanolamine; and said phosphatidic acid is dipalmatoylphosphatidic acid.

37. A container of claim 36 wherein said diagnostic imaging is ultrasound imaging or magnetic resonance imaging.

38. A container comprising an aqueous lipid suspension phase and a gaseous phase, wherein said gaseous phase comprises a fluorinated gas and is substantially separate from said aqueous lipid suspension phase, and said aqueous lipid suspension phase comprises at least one phosphatidylcholine, at least one phosphatidylethanolamine, and at least one phosphatidic acid, wherein said phosphatidylcholine is selected from the group consisting of dioleoylphosphatidylcholine, dimyristoylphosphatidylcholine, dipalmitoylphosphatidylcholine, and distearoyl-phosphatidylcholine; said phosphatidylethanolamine is selected from the group consisting of dipalmitoylphosphatidylethanolamine, dioleoyl-phosphatidylethanolamine, and N-succinyl-dioleoyl-phosphatidylethanolamine; and said phosphatidic acid is dipalmatoylphosphatidic acid.

39. A container of claim 38 wherein said fluorinated gas is sulfur hexafluoride or a perfluorocarbon.

40. A container of claim 39 wherein said fluorinated gas is sulfur hexafluoride.

41. A container of claim 39 wherein said fluorinated gas is a perfluorocarbon.

42. A container of claim 31 wherein said perfluorocarbon is selected from the group consisting of perfluoromethane, perfluoroethane, perfluoropropane, perfluorobutane, perfluorocyclobutane, perfluoropentane, and perfluorohexane.

43. A container of claim 42 wherein said perfluorocarbon is perfluoropropane.

44. A container of claim 43 wherein said gaseous phase further comprises nitrogen.

45. A container of claim 42 wherein said perfluorocarbon is perfluoropentane.

46. A container of claim 45 wherein said gaseous phase further comprises nitrogen.

47. A container of claim 42 wherein said perfluorocarbon is perfluorohexane.

48. A container of claim 47 wherein said gaseous phase further comprises nitrogen.

49. A container of claim 38 wherein said gaseous phase further comprises air, oxygen, nitrogen, carbon dioxide, or combinations thereof.

50. A container of claim 38 wherein said gaseous phase further comprises a paramagnetic gas.

51. A container of claim 50 wherein said paramagnetic gas is selected from the group consisting of oxygen, oxygen.sup.17 (.sup.17 O.sub.2), neon, Xenon, and rubidium enriched hyperpolarized xenon.

52. A container of claim 38 wherein said gaseous phase comprises said fluorinated gas selected from the group consisting of perfluoropropane, perfluorobutane, perfluorocyclobutane, perfluoromethane, perfluoroethane, perfluoropentane, perfluorohexane, sulfur hexafluoride, and a second gas selected from the group consisting of air, nitrogen, oxygen, carbon dioxide, neon, helium, krypton, xenon, rubidium enriched hyperpolarized xenon, and oxygen.sup.17 (.sup.17 O.sub.2).

53. A container of claim 38 wherein said aqueous lipid suspension phase further comprises a targeting ligand.

54. A container of claim 53 wherein said targeting ligand is polyethyleneglycol or polyvinylpyrrolidone.

55. A container of claim 38 wherein said phosphatidylethanolamine is present in an amount of from about 2.5 mole percent to about 8.0 mole percent based on total moles of said lipids in said aqueous lipid suspension phase.

56. A container of claim 38 wherein said phosphatidylcholine, said phosphatidylethanolamine, and said phosphatidic acid are in a mole percent ratio of about 82%:8%:10%.

57. A container of claim 38 wherein said phosphatidylcholine is dipalmitoylphosphatidylcholine, said phosphatidylethanolamine is dipalmitoylphosphatidylethanolamine, and said phosphatidic acid is dipalmitoylphosophatidic acid.

58. A container of claim 57 wherein said phosphatidylethanolamine is dipalmitoylphosphatidylethanolamine-PEG5000.

59. A container of claim 58 wherein said dipalmitoylphosphatidylethanolamine-PEG5000 is present in an amount from about 2.5 mole percent to about 8 mole percent based on total moles of said lipids in said aqueous lipid suspension phase.

60. A container of claim 59 wherein said dipalmitoylphosphatidylcholine, said dipalmitoylphosphatidylethanolamine-PEG5000, and said dipalmitoylphosophatidic acid are in a mole percent ratio of about 82%:8%:10%.

61. A container of claim 38 wherein at least a portion of said lipids are in a lipid monolayer in said aqueous lipid suspension phase.

62. A container of claim 61 wherein said aqueous lipid suspension phase further comprises polyethyleneglycol.

63. A container of claim 61 wherein said fluorinated gas is sulfur hexafluoride.

64. A container of claim 61 wherein said fluorinated gas is perfluoropropane.

65. A container of claim 64 wherein said gaseous phase further comprises nitrogen.

66. A container of claim 61 wherein said fluorinated gas is perfluoropentane.

67. A container of claim 66 wherein said gaseous phase further comprises nitrogen.

68. A container of claim 61 wherein said fluorinated gas is perfluorohexane.

69. A container of claim 68 wherein said gaseous phase further comprises nitrogen.

70. A container of claim 38 wherein at least a portion of said lipids are in a lipid bilayer in said aqueous lipid suspension phase.

71. A container of claim 70 wherein said aqueous lipid suspension phase further comprises polyethyleneglycol.

72. A container of claim 70 wherein said fluorinated gas is sulfur hexafluoride.

73. A container of claim 70 wherein said fluorinated gas is perfluoropropane.

74. A container of claim 73 wherein said gaseous phase further comprises nitrogen.

75. A container of claim 70 wherein said fluorinated gas is perfluoropentane.

76. A container of claim 75 wherein said gaseous phase further comprises nitrogen.

77. A container of claim 70 wherein said fluorinated gas is perfluorohexane.

78. A container of claim 77 wherein said gaseous phase further comprises nitrogen.

79. A container of claim 38 wherein at least a portion of said lipids are in a lipid multilayer in said aqueous lipid suspension phase.

80. A container of claim 79 wherein said aqueous lipid suspension phase further comprises polyethyleneglycol.

81. A container of claim 79 wherein said fluorinated gas is sulfur hexafluoride.

82. A container of claim 79 wherein said fluorinated gas is perfluoropropane.

83. A container of claim 82 wherein said gaseous phase further comprises nitrogen.

84. A container of claim 79 wherein said fluorinated gas is perfluoropentane.

85. A container of claim 84 wherein said gaseous phase further comprises nitrogen.

86. A container of claim 79 wherein said fluorinated gas is perfluorohexane.

87. A container of claim 86 wherein said gaseous phase further comprises nitrogen.

88. A container of claim 38 wherein said aqueous lipid suspension phase has been rehydrated from a lyophilized composition.

89. A container of claim 38 wherein said aqueous lipid suspension phase further comprises a therapeutic or diagnostic agent.

90. A container of claim 89 wherein said diagnostic agent is an MRI contrast enhancing agent.

91. A container of claim 90 wherein said MRI contrast enhancing agent is a paramagnetic ion.

92. A container of claim 38 wherein said aqueous lipid suspension phase further comprises a suspending agent.

93. A container of claim 38 wherein said aqueous lipid suspension phase further comprises a viscosity modifying agent.

94. A container of claim 38 wherein said container is sterilized.

95. A container which contains a composition for use in diagnostic imaging, wherein the composition comprises an aqueous lipid suspension phase and a gaseous phase, wherein said gaseous phase comprises a fluorinated gas and is substantially separate from said aqueous lipid suspension phase, and said aqueous lipid suspension phase comprises at least one phosphatidylcholine, at least one phosphatidylethanolamine, and at least one phosphatidic acid, wherein said phosphatidylcholine is selected from the group consisting of dioleoylphosphatidylcholine, dimyristoylphosphatidylcholine, dipalmitoylphosphatidylcholine, and distearoyl-phosphatidylcholine; said phosphatidylethanolamine is selected from the group consisting of dipalmitoylphosphatidylethanolamine, dioleoyl-phosphatidylethanolamine, and N-succinyl-dioleoyl-phosphatidylethanolamine; and said phosphatidic acid is dipalmatoylphosphatidic acid.

96. A container of claim 95 wherein said diagnostic imaging is ultrasound imaging or magnetic resonance imaging.

97. A container comprising an aqueous lipid suspension phase and a gaseous phase, wherein said gaseous phase is substantially separate from said aqueous lipid suspension phase and comprises a substantially insoluble gas in combination with a soluble gas, and said aqueous lipid suspension phase comprises lipids, wherein said lipids comprise at least one phosphatidylcholine, at least one phosphatidylethanolamine, and at least one phosphatidic acid wherein said phosphatidylcholine is selected from the group consisting of dioleoylphosphatidylcholine, dimyristoylphosphatidylcholine, dipalmitoylphosphatidylcholine, and distearoyl-phosphatidylcholine; said phosphatidylethanolamine is selected from the group consisting of dipalmitoylphosphatidylethanolamine, dioleoyl-phosphatidylethanolamine, and N-succinyl-dioleoyl-phosphatidylethanolamine; and said phosphatidic acid is dipalmatoylphosphatidic acid.

98. A container of claim 97 wherein said substantially insoluble gas is sulfur hexafluoride or a perfluorocarbon.

99. A container of claim 98 wherein said substantially insoluble gas is sulfur hexafluoride.

100. A container of claim 98 wherein said substantially insoluble gas is a perfluorocarbon.

101. A container of claim 100 wherein said perfluorocarbon is selected from the group consisting of perfluoromethane, perfluoroethane, perfluoropropane, perfluorobutane, perfluorocyclobutane, perfluoropentane, and perfluorohexane.

102. A container of claim 101 wherein said perfluorocarbon is perfluoropropane.

103. A container of claim 102 wherein said soluble gas is nitrogen.

104. A container of claim 101 wherein said perfluorocarbon is perfluoropentane.

105. A container of claim 104 wherein said soluble gas is nitrogen.

106. A container of claim 101 wherein said perfluorocarbon is perfluorohexane.

107. A container of claim 106 wherein said soluble gas is nitrogen.

108. A container of claim 97 wherein said soluble gas is air, oxygen, nitrogen, carbon dioxide, or combinations thereof.

109. A container of claim 97 wherein said substantially insoluble gas or soluble gas comprises a paramagnetic gas.

110. A container of claim 109 wherein said paramagnetic gas is selected from the group consisting of oxygen, oxygen.sup.17 (.sup.17 O.sub.2), neon, xenon, and rubidium enriched hyperpolarized xenon.

111. A container of claim 97 wherein said substantially insoluble gas is selected from the group consisting of perfluoropropane, perfluorobutane, perfluorocyclobutane, perfluoromethane, perfluoroethane, perfluoropentane, perfluorohexane, and sulfur hexafluoride, and said soluble gas is selected from the group consisting of air, nitrogen, oxygen, and carbon dioxide.

112. A container of claim 97 wherein said aqueous lipid suspension phase further comprises a targeting ligand.

113. A container of claim 112 wherein said targeting ligand is polyethyleneglycol or polyvinylpyrrolidone.

114. A container of claim 97 wherein said phosphatidylethanolamine is present in an amount of from about 2.5 mole percent to about 8.0 mole percent based on total moles of said lipids in said aqueous lipid suspension phase.

115. A container of claim 97 wherein said phosphatidylcholine, said phosphatidylethanolamine, and said phosphatidic acid are in a mole percent ratio of about 82%:8%:10%.

116. A container of claim 97 wherein said phosphatidylcholine is dipalmitoylphosphatidylcholine, said phosphatidylethanolamine is dipalmitoylphosphatidylethanolamine, and said phosphatidic acid is dipalmitoylphosophatidic acid.

117. A container of claim 116 wherein said phosphatidylethanolamine is dipalmitoylphosphatidylethanolamine-PEG5000.

118. A container of claim 117 wherein said dipalmitoylphosphatidylethanolamine-PEG5000 is present in an amount from about 2.5 mole percent to about 8 mole percent based on total moles of said lipids in said aqueous lipid suspension phase.

119. A container of claim 118 wherein said dipalmitoylphosphatidylcholine, said dipalmitoylphosphatidylethanolamine-PEG5000, and said dipalmitoylphosophatidic acid are in a mole percent ratio of about 82%:8%:10%.

120. A container of claim 97 wherein at least a portion of said lipids are in a lipid monolayer in said aqueous lipid suspension phase.

121. A container of claim 120 wherein said aqueous lipid suspension phase further comprises polyethyleneglycol.

122. A container of claim 120 wherein said substantially insoluble gas is sulfur hexafluoride.

123. A container of claim 120 wherein said substantially insoluble gas is perfluoropropane.

124. A container of claim 123 wherein said soluble gas nitrogen.

125. A container of claim 120 wherein said substantially insoluble gas is perfluoropentane.

126. A container of claim 125 wherein said soluble gas is nitrogen.

127. A container of claim 120 wherein said substantially insoluble gas is perfluorohexane.

128. A container of claim 127 wherein said soluble gas is nitrogen.

129. A container of claim 97 wherein at least a portion of said lipids are in a lipid bilayer in said aqueous lipid suspension phase.

130. A container of claim 129 wherein said aqueous lipid suspension phase further comprises polyethyleneglycol.

131. A container of claim 129 wherein said substantially insoluble gas is sulfur hexafluoride.

132. A container of claim 129 wherein said substantially insoluble gas is perfluoropropane.

133. A container of claim 132 wherein said soluble gas is nitrogen.

134. A container of claim 129 wherein said substantially insoluble gas is perfluoropentane.

135. A container of claim 134 wherein said soluble gas is nitrogen.

136. A container of claim 129 wherein said fluorinated gas is perfluorohexane.

137. A container of claim 136 wherein said soluble gas is nitrogen.

138. A container of claim 97 wherein at least a portion of said lipids are in a lipid multilayer in said aqueous lipid suspension phase.

139. A container of claim 138 wherein said aqueous lipid suspension phase further comprises polyethyleneglycol.

140. A container of claim 138 wherein said substantially insoluble gas is sulfur hexafluoride.

141. A container of claim 138 wherein said substantially insoluble gas is perfluoropropane.

142. A container of claim 141 wherein said soluble gas is nitrogen.

143. A container of claim 138 wherein said substantially insoluble gas is perfluoropentane.

144. A container of claim 143 wherein said soluble gas is nitrogen.

145. A container of claim 138 wherein said substantially insoluble gas is perfluorohexane.

146. A container of claim 145 wherein said soluble gas is nitrogen.

147. A container of claim 97 wherein said aqueous lipid suspension phase has been rehydrated from a lyophilized composition.

148. A container of claim 97 wherein said aqueous lipid suspension phase further comprises a therapeutic or diagnostic agent.

149. A container of claim 148 wherein said diagnostic agent is an MRI contrast enhancing agent.

150. A container of claim 149 wherein said MRI contrast enhancing agent is a paramagnetic ion.

151. A container of claim 97 wherein said aqueous lipid suspension phase further comprises a suspending agent.

152. A container of claim 97 wherein said aqueous lipid suspension phase further comprises a viscosity modifying agent.

153. A container of claim 97 wherein said container is sterilized.

154. A container which contains a composition for use in diagnostic imaging, wherein the composition comprises an aqueous lipid suspension phase and a gaseous phase, wherein said gaseous phase is substantially separate from said aqueous lipid suspension phase and comprises a substantially insoluble gas in combination with a soluble gas, and said aqueous lipid suspension phase comprises at least one phosphatidylcholine, at least one phosphatidylethanolamine, and at least one phosphatidic acid, wherein said phosphatidylcholine is selected from the group consisting of dioleoylphosphatidylcholine, dimyristoylphosphatidylcholine, dipalmitoylphosphatidylcholine, and distearoyl-phosphatidylcholine; said phosphatidylethanolamine is selected from the group consisting of dipalmitoylphosphatidylethanolamine, dioleoyl-phosphatidylethanolamine, and N-succinyl-dioleoyl-phosphatidylethanolamine; and said phosphatidic acid is dipalmatoylphosphatidic acid.

155. A container of claim 154 wherein said diagnostic imaging is ultrasound imaging or magnetic resonance imaging.
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