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Details for Patent: 6,139,819

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Details for Patent: 6,139,819

Title: Targeted contrast agents for diagnostic and therapeutic use
Abstract:Novel contrast agents which may be used for diagnostic and therapeutic use. The compositions may comprise a lipid, a protein, polymer and/or surfactant, and a gas, in combination with a targeting ligand. In preferred embodiments, the targeting ligand targets coagula, including emboli and/or thrombi, particularly in patients suffering from an arrhythmic disorder. The contrast media can be used in conjunction with diagnostic imaging, such as ultrasound, as well as therapeutic applications, such as therapeutic ultrasound.
Inventor(s): Unger; Evan C. (Tucson, AZ), Fritz; Thomas A. (Tucson, AZ), Gertz; Edward W. (Paradise Valley, AZ)
Assignee: ImaRx Pharmaceutical Corp. (Tucson, AZ)
Filing Date:Sep 17, 1997
Application Number:08/932,273
Claims:1. A method for providing an image of an internal region of a patient suffering from an arrhythmic disorder, wherein the method comprises (i) administering to the patient a contrast agent which comprises, in an aqueous carrier liposomes encapsulating a fluorinated gas and bearing a targeting ligand, wherein said targeting ligand targets cells or receptors associated with a coagulum and said fluorinated gas is selected from the group consisting of perfluorocarbons and sulfur hexafluoride; and (ii) scanning the patient using ultrasound to obtain a visible image of the region.

2. A method according to claim 1 wherein said liposomes comprise a phospholipid.

3. A method according to claim 2 wherein said phospholipid is selected from the group consisting of phosphatidylcholine, phosphatidylethanolamine and phosphatidic acid.

4. A method according to claim 3 wherein said phosphatidylcholine is selected from the group consisting of dioleoylphosphatidylcholine, dimyristoylphosphatidylcholine, dipalmitoylphosphatidylcholine and distearoylphosphatidylcholine.

5. A method according to claim 4 wherein said phosphatidylcholine is dipalmitoylphosphatidylcholine.

6. A method according to claim 5 wherein said phosphatidylethanolamine is selected from the group consisting of dipalmitoylphosphatidylethanolamine, dioleoylphosphatidylethanolamine, N-succinyldioleoylphosphatidylethanolamine and 1-hexadecyl-2-palmitoylglycerophosphoethanolamine.

7. A method according to claim 6 wherein said phosphatidiylethanolamine is dipalmitoylphosphatidylethanolamine.

8. A method according to claim 3 wherein said phosphatidic acid is dipalmitoylphosphatidic acid.

9. A method according to claim 1 wherein said liposomes further comprise a polymer.

10. A method according to claim 9 wherein said polymer is a hydrophilic polymer.

11. A method according to claim 10 wherein said polymer is polyethylene glycol.

12. A method according to claim 1 wherein said fluorinated gas is a perfluorocarbon.

13. A method according to claim 12 wherein said perfluorocarbon gas is selected from the group consisting of perfluoromethane, perfluoroethane, perfluoropropane, perfluorobutane and perfluorocyclobutane.

14. A method according to claim 1 wherein said gas is derived, at least in part, from a gaseous precursor.

15. A method according to claim 14 wherein said gaseous precursor has a boiling point of greater than about 37.degree. C.

16. A method according to claim 14 wherein said gaseous precursor comprises a fluorinated compound.

17. A method according to claim 16 wherein said fluorinated compound is a perfluorocarbon.

18. A method according to claim 17 wherein said perfluorocarbon is selected from the group consisting of perfluoropentane and perfluorohexane.

19. A method according to claim 1 wherein said targeting ligand is selected from the group consisting of proteins, peptides, saccharides, steroids, steroid analogs, bioactive agents and genetic material.

20. A method according to claim 19 wherein said targeting ligand is selected from the group consisting of proteins, peptides and saccharides.

21. A method according to claim 20 wherein said targeting ligand is selected from the group consisting of proteins and peptides.

22. A method according to claim 1 wherein said liposomes are selected from the group consisting of unilamellar liposomes, oligolamellar liposomes, and multilamellar liposomes.

23. A method according to claim 22, wherein said liposomes comprise unilamellar liposomes.

24. A method according to claim 23, wherein said liposomes comprise one monolayer.

25. A method according to claim 24, wherein said liposomes comprise a phospholipid and said gas is sulfur hexafluoride.

26. A method according to claim 24, wherein said liposomes comprise a phospholipid and said gas is perfluoropropane.

27. A method according to claim 24, wherein said liposomes comprise a phospholipid and said gas is perfluorobutane.

28. A method according to claim 24 wherein said gas is derived, at least in part, from a gaseous precursor.

29. A method according to claim 28, wherein said liposomes comprise a phospholipid and said gas or gaseous precursor is perfluoropentane.

30. A method according to claim 23, wherein said liposomes comprise a bilayer.

31. A method according to claim 30, wherein said liposomes comprise a phospholipid and said gas is sulfur hexafluoride.

32. A method according to claim 30, wherein said liposomes comprise a phospholipid and said gas is perfluoropropane.

33. A method according to claim 30, wherein said liposomes comprise a phospholipid and said gas is perfluorobutane.

34. A method according to claim 30 wherein said gas is derived, at least in part, from a gaseous precursor.

35. A method according to claim 34, wherein said liposomes comprise a phospholipid and said gas or gaseous precursor is perfluoropentane.

36. A method according to claim 22, wherein said liposomes are selected from the group consisting of oligolamellar liposomes and multilamellar liposomes.

37. A method according to claim 36 wherein said liposomes comprise one monolayer.

38. A method according to claim 37, wherein said liposomes comprise a phospholipid and said gas is sulfur hexafluoride.

39. A method according to claim 37, wherein said liposomes comprise a phospholipid and said gas is perfluoropropane.

40. A method according to claim 37, wherein said liposomes comprise a phospholipid and said gas is perfluorobutane.

41. A method according to claim 37 wherein said gas is derived, at least in part, from a gaseous precursor.

42. A method according to claim 41, wherein said liposomes comprise a phospholipid and said gas or gaseous precursor is perfluoropentane.

43. A method according to claim 36, wherein said liposomes comprise a bilayer.

44. A method according to claim 43, wherein said liposomes comprise a phospholipid and said gas is sulfur hexafluoride.

45. A method according to claim 43, wherein said liposomes comprise a phospholipid and said gas is perfluoropropane.

46. A method according to claim 43, wherein said liposomes comprise a phospholipid and said gas is perfluorobutane.

47. A method according to claim 43 wherein said gas is derived, at least in part, from a gaseous precursor.

48. A method according to claim 47, wherein said liposomes comprise a phospholipid and said gas or gaseous precursor is perfluoropentane.

49. A method according to claim 1 wherein said arrhythmic disorder is atrial fibrillation.

50. A method according to claim 1 wherein said coagulum is an embolism or thrombus.

51. A method according to claim 1 wherein said region is the myocardial region.

52. A method according to claim 51 wherein said region is the left atrium.

53. A method according to claim 1 further comprising administering an anticoagulant to the patient.

54. A method according to claim 53 wherein said anticoagulant comprises warfarin.

55. A method according to claim 1 wherein said contrast agent is administered to the patient at a rate which substantially eliminates diagnostic artifacts in the image.

56. A method for diagnosing the presence of a coagulum in a patient suffering from an arrhythmic disorder, wherein the method comprises (i) administering to the patient a contrast agent which comprises, in an aqueous carrier, liposomes having encapsulated therein a fluorinated gas, said liposomes bearing a targeting ligand, wherein said targeting ligand targets cells or receptors associated with a coagulum and said fluorinated gas is selected from the group consisting of perfluorocarbons and sulfur hexafluoride; and (ii) scanning the patient using ultrasound to obtain a visible image of any coagulum in the patient.

57. A method according to claim 56 wherein said liposomes comprise a phospholipid.

58. A method according to claim 57 wherein said phospholipid is selected from the group consisting of phosphatidylcholine, phosphatidylethanolamine and phosphatidic acid.

59. A method according to claim 58 wherein said phosphatidylcholine is selected from the group consisting of dioleoylphosphatidylcholine, dimyristoylphosphatidylcholine, dipalmitoylphosphatidylcholine and distearoylphosphatidylcholine.

60. A method according to claim 59 wherein said phosphatidylcholine is dipalmitoylphosphatidylcholine.

61. A method according to claim 60 wherein said phosphatidylethanolamine is selected from the group consisting of dipalmitoylphosphatidylethanolamine, dioleoylphosphatidylethanolamine, N-succinyldioleoylphosphatidylethanolamine and 1-hexadecyl-2-palmitoylglycerophosphoethanolamine.

62. A method according to claim 61 wherein said phosphatidylethanolamine is dipalmitoylphosphatidylethanolamine.

63. A method according to claim 58 wherein said phosphatidic acid is dipalmitoylphosphatidic acid.

64. A method according to claim 56 wherein said liposomes further comprise a polymer.

65. A method according to claim 64 wherein said polymer is a hydrophilic polymer.

66. A method according to claim 65 wherein said polymer is polyethylene glycol.

67. A method according to claim 56 wherein said fluorinated gas is a perfluorocarbon.

68. A method according to claim 67 wherein said perfluorocarbon gas is selected from the group consisting of perfluoromethane, perfluoroethane, perfluoropropane, perfluorobutane and perfluorocyclobutane.

69. A method according to claim 56 wherein said gas is derived, at least in part, from a gaseous precursor.

70. A method according to claim 69 wherein said gaseous precursor has a boiling point of greater than about 37.degree. C.

71. A method according to claim 70 wherein said gaseous precursor comprises a fluorinated compound.

72. A method according to claim 71 wherein said fluorinated compound is a perfluorocarbon.

73. A method according to claim 72 wherein said perfluorocarbon is selected from the group consisting of perfluoropentane and perfluorohexane.

74. A method according to claim 56 wherein said targeting ligand is selected from the group consisting of proteins, peptides, saccharides, steroids, steroid analogs, bioactive agents and genetic material.

75. A method according to claim 74 wherein said targeting ligand is selected from the group consisting of proteins, peptides and saccharides.

76. A method according to claim 75 wherein said targeting ligand is selected from the group consisting of proteins and peptides.

77. A method according to claim 56 wherein said liposomes are selected from the group consisting of unilamellar liposomes, oligolamellar liposomes, and multilamellar liposomes.

78. A method according to claim 77 wherein said liposomes comprise unilamellar liposomes.

79. A method according to claim 78 wherein said liposomes comprise one monolayer.

80. A method according to claim 79 wherein said liposomes comprise a phospholipid and said gas is sulfur hexafluoride.

81. A method according to claim 79 wherein said liposomes comprise a phospholipid and said gas is perfluoropropane.

82. A method according to claim 79 wherein said liposomes comprise a phospholipid and said gas is perfluorobutane.

83. A method according to claim 79 wherein said gas is derived, at least in part, from a gaseous precursor.

84. A method according to claim 83 wherein said liposomes comprise a phospholipid and said gas or gaseous precursor is perfluoropentane.

85. A method according to claim 78 wherein said liposomes comprise a bilayer.

86. A method according to claim 85 wherein said liposomes comprise a phospholipid and said gas is sulfur hexafluoride.

87. A method according to claim 85 wherein said liposomes comprise a phospholipid and said gas is perfluoropropane.

88. A method according to claim 85 wherein said liposomes comprise a phospholipid and said gas is perfluorobutane.

89. A method according to claim 85 wherein said gas is derived, at least in part, from a gaseous precursor.

90. A method according to claim 89 wherein said liposomes comprise a phospholipid and said gas or gaseous precursor is perfluoropentane.

91. A method according to claim 77 wherein said liposomes are selected from the group consisting of oligolamellar liposomes and multilamellar liposomes.

92. A method according to claim 91 wherein said liposomes comprise one monolayer.

93. A method according to claim 92 wherein said liposomes comprise a phospholipid and said gas is sulfur hexafluoride.

94. A method according to claim 92 wherein said liposomes comprise a phospholipid and said gas is perfluoropropane.

95. A method according to claim 92 wherein said liposomes comprise a phospholipid and said gas is perfluorobutane.

96. A method according to claim 92 wherein said gas is derived, at least in part, from a gaseous precursor.

97. A method according to claim 96 wherein said liposomes comprise a phospholipid and said gas or gaseous precursor is perfluoropentane.

98. A method according to claim 81 wherein said liposomes comprise a bilayer.

99. A method according to claim 98 wherein said liposomes comprise a phospholipid and said gas is sulfur hexafluoride.

100. A method according to claim 98 wherein said liposomes comprise a phospholipid and said gas is perfluoropropane.

101. A method according to claim 98 wherein said liposomes comprise a phospholipid and said gas is perfluorobutane.

102. A method according to claim 98 wherein said gas is derived, at least in part, from a gaseous precursor.

103. A method according to claim 102 wherein said liposomes comprise a phospholipid and said gas or gaseous precursor is perfluoropentane.

104. A method according to claim 56 wherein said arrhythmic disorder is atrial fibrillation.

105. A method according to claim 56 wherein said coagulum is an embolism or thrombus.

106. A method according to claim 56 wherein said coagulum is in a region which is a myocardial region.

107. A method according to claim 106 wherein said region is the left atrium.

108. A method according to claim 56 further comprising administering an anticoagulant to the patient.

109. A method according to claim 108 wherein said anticoagulant comprises warfarin.

110. A method according to claim 56 wherein said contrast agent is administered to the patient at a rate which substantially eliminates diagnostic artifacts in the image.

111. A composition for use in targeting an internal region of a patient suffering from an arrhythmic disorder, wherein the composition comprises liposomes encapsulating a fluorinated gas and bearing a targeting ligand, wherein said targeting ligand targets cells or receptors associated with a coagulum and said fluorinated gas is selected from the group consisting of perfluorocarbons and sulfur hexafluoride.

112. A composition according to claim 111 wherein said liposomes comprise a phospholipid.

113. A composition according to claim 112 wherein said phospholipid is selected from the group consisting of phosphatidylcholine, phosphatidylethanolamine and phosphatidic acid.

114. A composition according to claim 113 wherein said phosphatidylcholine is selected from the group consisting of dioleoylphosphatidylcholine, dimyristoylphosphatidylcholine, dipalmitoylphosphatidylcholine and distearoylphosphatidylcholine.

115. A composition according to claim 114 wherein said phosphatidylcholine is dipalmitoylphosphatidylcholine.

116. A composition according to claim 115 wherein said phosphatidylethanolamine is selected from the group consisting of dipalmitoylphosphatidylethanolamine, dioleoylphosphatidylethanolamine, N-succinyldioleoylphosphatidylethanolamine and 1-hexadecyl-2-palmitoylglycerophosphoethanolamine.

117. A composition according to claim 116 wherein said phosphatidylethanolamine is dipalmitoylphosphatidylethanolamine.

118. A composition according to claim 113 wherein said phosphatidic acid is dipalmitoylphosphatidic acid.

119. A composition according to claim 111 wherein said liposomes further comprise a polymer.

120. A composition according to claim 119 wherein said polymer is a hydrophilic polymer.

121. A composition according to claim 120 wherein said polymer is polyethylene glycol.

122. A composition according to claim 111 wherein said fluorinated gas is a perfluorocarbon.

123. A composition according to claim 122 wherein said perfluorocarbon gas is selected from the group consisting of perfluoromethane, perfluoroethane, perfluoropropane, perfluorobutane and perfluorocyclobutane.

124. A composition according to claim 111 wherein said gas is derived, at least in part, from a gaseous precursor.

125. A composition according to claim 124 wherein said gaseous precursor has a boiling point of greater than about 37.degree. C.

126. A composition according to claim 124 wherein said gaseous precursor is a fluorinated compound.

127. A composition according to claim 126 wherein said fluorinated compound comprises a perfluorocarbon.

128. A composition according to claim 127 wherein said perfluorocarbon is selected from the group consisting of perfluoropentane and perfluorohexane.

129. A composition according to claim 111 wherein said targeting ligand is selected from the group consisting of proteins, peptides, saccharides, steroids, steroid analogs, bioactive agents and genetic material.

130. A composition according to claim 129 wherein said targeting ligand is selected from the group consisting of proteins, peptides and saccharides.

131. A composition according to claim 130 wherein said targeting ligand is selected from the group consisting of proteins and peptides.

132. A composition according to claim 111 wherein said liposomes are selected from the group consisting of unilamellar liposomes, oligolamellar liposomes, and multilamellar liposomes.

133. A composition according to claim 132 wherein said liposomes comprise unilamellar liposomes.

134. A composition according to claim 133 wherein said liposomes comprise one monolayer.

135. A composition according to claim 134 wherein said liposomes comprise a phospholipid and said gas is sulfur hexafluoride.

136. A composition according to claim 134 wherein said liposomes comprise a phospholipid and said gas is perfluoropropane.

137. A composition according to claim 134 wherein said liposomes comprise a phospholipid and said gas is perfluorobutane.

138. A composition according to claim 134 wherein said gas is derived, at least in part, from a gaseous precursor.

139. A composition according to claim 138 wherein said liposomes comprise a phospholipid and said gas or gaseous precursor is perfluoropentane.

140. A composition according to claim 133 wherein said liposomes comprise a bilayer.

141. A composition according to claim 140 wherein said liposomes comprise a phospholipid and said gas is sulfur hexafluoride.

142. A composition according to claim 140 wherein said liposomes comprise a phospholipid and said gas is perfluoropropane.

143. A composition according to claim 140 wherein said liposomes comprise a phospholipid and said gas is perfluorobutane.

144. A composition according to claim 140 wherein said gas is derived, at least in part, from a gaseous precursor.

145. A composition according to claim 144 wherein said liposomes comprise a phospholipid and said gas or gaseous precursor is perfluoropentane.

146. A composition according to claim 132 wherein said liposomes are selected from the group consisting of oligolamellar liposomes and multilamellar liposomes.

147. A composition according to claim 146 wherein said liposomes comprise one monolayer.

148. A composition according to claim 147 wherein said liposomes comprise a phospholipid and said gas is sulfur hexafluoride.

149. A composition according to claim 147 wherein said liposomes comprise a phospholipid and said gas is perfluoropropane.

150. A composition according to claim 147 wherein said liposomes comprise a phospholipid and said gas is perfluorobutane.

151. A composition according to claim 147 wherein said gas is derived, at least in part, from a gaseous precursor.

152. A composition according to claim 151 wherein said liposomes comprise a phospholipid and said gas or gaseous precursor is perfluoropentane.

153. A composition according to claim 146 wherein said liposomes comprise a bilayer.

154. A composition according to claim 153 wherein said liposomes comprise a phospholipid and said gas is sulfur hexafluoride.

155. A composition according to claim 153 wherein said liposomes comprise a phospholipid and said gas is perfluoropropane.

156. A composition according to claim 153 wherein said liposomes comprise a phospholipid and said gas is perfluorobutane.

157. A composition according to claim 153 wherein said gas is derived, at least in part, from a gaseous precursor.

158. A composition according to claim 157 wherein said liposomes comprise a phospholipid and said gas or gaseous precursor is perfluoropentane.

159. A composition according to claim 111 wherein said targeting ligand is associated with said liposome covalently or non-covalently.

160. A composition according to claim 159 wherein said targeting ligand is associated with said liposome covalently.

161. A composition according to claim 160 wherein said covalent association comprises a covalent bond selected from the group consisting of amide, thioamide, ether, ester, thioester, --O--, --S--, --S.sub.n --, where n is greater than 1, carbamate, --NH--, --NR--, where R is alkyl of from 1 to about 4 carbons, urethane, and substituted imidate bonds.

162. A composition according to claim 160 wherein said covalent association further comprises crosslinking.

163. A composition according to claim 160 wherein said targeting ligand is covalently associated with said liposome via a linking group.

164. A composition according to claim 163 wherein said linking group comprises a hydrophilic polymer.

165. A composition according to claim 164 wherein said hydrophilic polymer is selected from the group consisting of polyalkyleneoxides, polyvinyl alcohol, polyvinylpyrrolidones, polyacrylamides, polymethacrylamides, polyphosphazenes, poly(hydroxyalkylcarboxylic acids) and polyoxazolidines.

166. A composition according to claim 165 wherein said hydrophilic polymer comprises a polyalkyleneoxide.

167. A composition according to claim 166 wherein said polyalkyleneoxide is selected from the group consisting of polyethylene glycol and polypropylene glycol.

168. A composition according to claim 167 wherein said polyalkyleneoxide is polyethylene glycol.

169. A composition according to claim 111 wherein said arrhythmic disorder is atrial fibrillation.

170. A composition according to claim 111 wherein said coagulum is an embolism or thrombus.

171. A composition according to claim 111 for use in targeting a coagulum which is in a region which is a myocardial region.

172. A composition according to claim 171 wherein said region is the left atrium.

173. A method according to claim 55 which comprises administering said contrast agent to the patient at a rate of constant infusion.

174. A method according to claim 110 which comprises administering said contrast agent to the patient at a rate of constant infusion.
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