Liposomes as contrast agents for ultrasonic imaging

• US 5,456,901 A
• Filed: 02/28/1995
• Issued: 10/10/1995
• Est. Priority Date: 12/22/1989
• Status: Expired due to Term

• Current Assignee: Lantheus Medical Imaging, Inc. (Lantheus Holdings, Inc.)
• Original Assignee: Imarx Pharmaceutical Corp. (Sycamore Entertainment Group, Inc.)
• Inventors: Unger, Evan C.
• Primary Examiner(s): Hollinden, Gary E.
• Assistant Examiner(s): TILL, MARY C
• Application Number:
  US08/395,683
• Time in Patent Office: 224 Days
• Field of Search: 424/450, 424/9, 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 method of providing an image of an internal region of a patient comprising:

(a) administering to the patient 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; and

(b) scanning the patient using ultrasonic imaging to obtain visible images of the region.

2. The method according to claim 1 wherein said liposomes are administered intravascularly, and the vesicles have a mean outer diameter of between about 30 nanometers and about 2 microns.

3. The method according to claim 2;

wherein the patient is scanned in the area of the patient'"'"'s heart.

4. The method according to claim 2 wherein the patient is scanned in the area of the patient'"'"'s arterial system.

5. The method according to claim 2 wherein the patient is scanned in the area of the patient'"'"'s venous system.

6. The method according to claim 2 wherein the patient is scanned in the area of the patient'"'"'s liver, spleen and kidney.

7. The method according to claim 1 wherein the liposomes are administered other than intravascularly and have a mean outer diameter between about 2 microns and about 10 microns.

8. The method of claim 1 wherein the liposomes are comprised of lipids of either natural or synthetic origin selected from the group consisting of fatty acids, lysolipids, dipalmitoylphosphatidylcholine, phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, phosphatidylserine, phosphatidic acid, phosphatidylinositol, sphingomyelin, lysolipids, cholesterol, cholesterol hemisuccinate, glycosphingolipids, glycolipids, glucolipids, sulphatides, and tocopherol hemisuccinate.

10. A method according to claim 1 wherein said contrast enhancing agent is a solid selected from the group consisting of magnetite and solid iodine particles.

13. A method according to claim 1 wherein said contrast enhancing agent is a liquid selected from the group consisting of solubilized iodinated compounds.

9. A method for diagnosing the presence of diseased tissue in a patient comprising:

(a) administering to the patient 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; and

(b) scanning the patient using ultrasonic imaging to obtain visible images of any diseased tissue in the patient.

14. A method according to claim 9 wherein said liposomes are administered intravascularly, and the vesicles have a mean outer diameter of between about 30 nanometers and about 2 microns.

15. A method according to claim 14 wherein the patient is scanned in the area of the patient'"'"'s heart.

16. A method according to claim 14 wherein the patient is scanned in the area of the patient'"'"'s arterial system.

17. A method according to claim 14 wherein the patient is scanned in the area of the patient'"'"'s venous system.

18. A method according to claim 14 wherein the patient is scanned in the area of the patient'"'"'s liver, spleen and kidney.

19. A method according to claim 9 wherein the liposomes are administered other than intravascularly and have a mean outer diameter between about 2 microns and about 10 microns.

20. A method of claim 9 wherein the liposome is comprised of lipid selected from the group consisting of fatty acids, lysolipids, dipalmitoylphosphatidylcholine, phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, phosphatidylserine, phosphatidic acid, phosphatidylinositol, sphingomyelin, lysolipids, cholesterol, cholesterol hemisuccinate, glycosphingolipids, glycolipids, glucolipids, sulphatides, and tocopherol hemisuccinate.

21. A method according to claim 9 wherein said contrast enhancing agent is a solid selected from the group consisting of magnetite and solid iodine particles.

22. A method according to claim 20 wherein said solid iodine particles are selected from the group consisting of iodipamide ethyl ester and metricate.

23. A method according to claim 22 wherein said solid iodine particles are iodipamide ethyl ester.

24. A method according to claim 9 wherein said contrast enhancing agent is a liquid selected from the group consisting of solubilized iodinated compounds.

11. A method according to claim 11 wherein said solid iodine particles are selected from the group consisting of iodipamide ethyl ester and metricate.

12. A method according to claim 11 wherein said solid iodine particles are iodipamide ethyl ester.