Ionophore containing liposomes for ultrasound imaging

• US 5,352,435 A
• Filed: 10/27/1992
• Issued: 10/04/1994
• Est. Priority Date: 12/22/1989
• Status: Expired due to Term

• Current Assignee: Lantheus Medical Imaging, Inc. (Lantheus Holdings, Inc.)
• Original Assignee: Evan C. Unger
• Inventors: Unger, Evan C.
• Primary Examiner(s): Hollinden, Gary E.
• Assistant Examiner(s): TILL, MARY C
• Application Number:
  US07/967,974
• Time in Patent Office: 707 Days
• Field of Search: 424/9, 424/450, 128/662.02
• US Class Current: 424/9.51
• CPC Class Codes: A61K 41/0028 Disruption, e.g. by heat or ultrasounds, sonophysical or sonochemical activation, e.g. thermosensitive or heat-sensitive liposomes, disruption of calculi with a medicinal preparation and ultrasounds
• CPC Class Codes: A61K 41/0052 Thermotherapy; Hyperthermia; Magnetic induction; Induction heating therapy
• CPC Class Codes: A61K 47/6911 the form being a liposome
• CPC Class Codes: A61K 47/6941 the form being a granulate or an agglomerate
• CPC Class Codes: A61K 49/1815 compo-inhalant, e.g. breath tests
• CPC Class Codes: A61K 49/223 Microbubbles, hollow microspheres, free gas bubbles, gas microspheres
• CPC Class Codes: A61K 49/227 Liposomes, lipoprotein vesicles, e.g. LDL or HDL lipoproteins, micelles, e.g. phospholipidic or polymeric
• CPC Class Codes: A61K 9/127 Liposomes
• CPC Class Codes: A61K 9/1277 Processes for preparing; Proliposomes
• CPC Class Codes: A61K 9/1278 Post-loading, e.g. by ion or pH gradient

Abstract

Liposomes suitable as ultrasound contrast agents which contain media of various types including gases, gaseous precursors activated by pH, temperature or pressure, as well as other solid or liquid contrast enhancing agents, are described. Methods of using the same as ultrasound contrast agents are also disclosed. The present invention also comprises novel methods for synthesizing liposomes having encapsulated therein gases.

Claims

1. A contrast agent for ultrasonic imaging which comprises an ionophore-containing liposome having encapsulated therein a pH-activated gaseous precursor.

2. A contrast agent according to claim 1 wherein said pH-activated gaseous precursor is selected from the group consisting of metal carbonate and metal bicarbonate salts.

3. A contrast agent according to claim 2 wherein said pH-activated gaseous precursor is sodium bicarbonate.

4. A contrast agent according to claim 1 wherein said ionophore in said ionophore-containing liposome is selected from the group consisting of carbonylcyanide, p-trifluoromethoxyphenylhydrazone, carbonylcyanide M-chlorophenylhydrazone, carbonylcyanide phenylhydrazine, tetrachloro-2-trifluoromethyl benzimidazole, 5,6-dichloro-2-trifluoromethyl benzimidazole, Uncoupler 1799, gramicidin, alamethicin, filipin, etruscomycin, nystatin, pimaricin, amphotericin, valinomycin, enniatin, beauvericin, monomycin, nonactin, monactin, dinactin, trinactin, tetranactin, antamanide, nigericin, monensin, salinomycin, narisin, mutalomycin, carriomycin, dianemycin, septamycin, A-204 A, X-206, X-537 A, A-23187 and dicyclohexyl-18-crown-6.

6. A contrast agent according to claim 1 wherein the liposome is comprised of lipid selected from the group consisting of fatty acids, lysolipids, dipalmitoylphosphatidylcholine, phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, phosphatidylserine, phosphatidylglycerol, phosphatidic acid, phosphatidylinositol, sphingomyelin, lysolipids, cholesterol, cholesterol hemisuccinate, glycosphingolipids, glycolipids, glucolipids, sulphatides, and tocopherol hemisuccinate.

7. A contrast agent according to claim 6 wherein the liposome is comprised of phosphatidylcholine.

8. A contrast agent according to claim 6 wherein the liposome is comprised of cholesterol and phosphatidylchcline.

9. A contrast agent according to claim 1 wherein the liposome has a mean outer diameter of between about 30 nanometers and about 2 microns.

10. A contrast agent according to claim 1 wherein the liposome has a mean outer diameter of between about 2 microns and about 10 microns.

5. A contrast agent for ultrasonic imaging which comprises a liposome having encapsulated therein a solid contrast enhancing agent selected from the group consisting of magnetite and solid iodine particles or a liquid contrast enhancing agent selected from the group consisting of solubilized iodinated compounds.

11. A contrast agent according to claim 5 wherein the liposome is comprised of lipids selected from the group consisting of fatty acids, lysolipids, dipalmitoylphosphatidylcholine, phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, phosphatidylserine, phosphatidylglycerol, phosphatidic acid, phosphatidylinositol, sphingomyelin, lysolipids, cholesterol, cholesterol hemisuccinate, glycosphingolipids, glycolipids, glucolipids, sulphatides, and tocopherol hemisuccinate.

12. A contrast agent according to claim 11 wherein the liposome is comprised of phosphatidylcholine.

13. A contrast agent according to claim 11 wherein the liposome is comprised of cholesterol and phosphatidylchcline.

14. A contrast agent according to claim 5 wherein the liposome has a mean outer diameter of between about 30 nanometers and about two microns.

15. A contrast agent according to claim 5 wherein the liposome has a mean outer diameter of between about 2 microns and about 10 microns.

16. A contrast agent according to claim 5 wherein said contrast enhancing agent is a solid selected from the group consisting of magnetite and solid iodine particles.

17. A contrast agent according to claim 16 wherein said solid iodine particles are iodipamide ethyl ester.

18. A contrast agent according to claim 5 wherein said contrast enhancing agent is a liquid selected from the group consisting of solubilized iodinated compounds.