Gaseous precursor filled microspheres as magnetic resonance imaging contrast agents

• US 5,922,304 A
• Filed: 03/09/1995
• Issued: 07/13/1999
• Est. Priority Date: 12/22/1989
• Status: Expired due to Term

• Current Assignee: Cerevast Medical, Inc.
• Original Assignee: Imarx Pharmaceutical Corp. (Sycamore Entertainment Group, Inc.)
• Inventors: Unger, Evan C.
• Primary Examiner(s): Dees, Jose'G.
• Assistant Examiner(s): Hartley, Michael G.
• Application Number:
  US08/401,974
• Time in Patent Office: 1,587 Days
• Field of Search: 424/9.321, 424/9.32, 424/9.3, 424/9.52, 424/9.51, 424/450, 424/498, 424/9.37, 128/662.02, 128/653.4, 600/458
• US Class Current: 424/9.3
• 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 47/6925 the form being a microcapsule, nanocapsule, microbubble or nanobubble
• CPC Class Codes: A61K 49/1806 Suspensions, emulsions, colloids, dispersions
• CPC Class Codes: A61K 49/1815 compo-inhalant, e.g. breath tests
• CPC Class Codes: A61K 49/1818 particles, e.g. uncoated or non-functionalised microparticles or nanoparticles
• CPC Class Codes: A61K 49/1821 coated or functionalised microparticles or nanoparticles
• CPC Class Codes: A61K 49/22 Echographic preparations; Ultrasound imaging preparations ; Optoacoustic imaging preparations
• 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
• CPC Class Codes: A61K 9/5015 Organic compounds, e.g. fats, sugars
• CPC Class Codes: A61M 5/3145 Filters incorporated in syringes
• CPC Class Codes: G01R 33/5601 involving use of a contrast agent for contrast manipulation, e.g. a paramagnetic, super-paramagnetic, ferromagnetic or hyperpolarised contrast agent

Abstract

Novel gas filled microspheres useful as magnetic resonance imaging (MRI) contrast agents are provided.

Claims

1. A method of providing an image of an internal region of a patient comprising (i) administering to the patient a gaseous precursor filled microsphere, wherein said microsphere contains substantially no sulfide linkages and consists essentially of one or more lipids, one or more lipids bearing polymers, or combinations thereof, (ii) allowing the gaseous precursor to undergo a phase transition from a liquid to a gas in the patient, and (iii) scanning the patient using magnetic resonance imaging to obtain visible images of said region.

3. A method according to claim 1 or 2 wherein the region is the vasculature.

4. A method according to claim 1 or 2 wherein the region is the cardiovascular region.

5. A method according to claim 1 or 2 wherein the region is the gastrointestinal region.

6. A method according to claim 1 or 2 wherein the scanning is of the vasculature of the patient.

7. A method according to claim 1 or 2 wherein the scanning is of the cardiovascular region of the patient.

8. A method according to claim 1 or 2 wherein the scanning is of the gastrointestinal region of the patient.

9. A method according to claim 1 or 2 wherein the scanning is of a region of the patient selected from the following:

intranasal tract;

auditory canal;

intraocular region;

intraperitoneal region;

kidneys;

urethra; and

genitourinary tract.

10. A method of claim 1 wherein said lipid is a phospholipid.

12. A method of claim 1 wherein said microsphere comprises a monolayer.

13. A method of claim 12 wherein said monolayer comprises a phospholipid.

16. A method of claim 1 wherein said gaseous precursor is a perfluorocarbon.

22. A method of claim 1 wherein said microsphere is rehydrated from a lyophilized microsphere.

23. A method of claim 1 wherein said lipid microsphere comprises at least 70 mole percent of at least one lipid.

24. A method of claim 1 wherein said lipid microsphere comprises at least two lipids wherein said first lipid contains substantially no linkages to a polymer and comprises at least 70 mole percent of the total moles of the microsphere, and wherein said second lipid bears a hydrophilic polymer.

25. A method of claim 24 wherein said first lipid comprises:

(i) a neutral lipid, and (ii) a negatively charged lipid, wherein the amount of said negatively charged lipid is greater than 1 mole percent of total lipids present.

26. A method of claim 25 wherein said negatively charged lipid is phosphatidic acid.

27. A method of claim 24 wherein the hydrophilic polymer of said second lipid is selected from the group consisting of polyethyleneglycol, polypropyleneglycol, polyvinylalcohol, and polyvinylpyrrolidone and copolymers thereof.

28. A method of claim 24 wherein the lipids comprise about 77.5 mole percent dipalmitoyl-phosphatidylcholine, about 12.5 mole percent of dipalmitoyl-phosphatidic-acid, and about 10 mole percent of dipalmitoylphosphatidylethanolamine-polyethyleneglycol 5000.

29. A method of claim 24 wherein the lipids comprise about 82 mole percent dipalmitoylphosphatidyl-choline, about 10 mole percent of dipalmitoylphosphatidic acid, and about 8 mole percent of dipalmitoylphosphatidyl-ethanolamine-polyethyleneglycol 5000.

2. A method for diagnosing the presence of a diseased tissue or region in a patient comprising (i) administering to the patient a gaseous precursor filled microsphere, wherein said microsphere contains substantially no sulfide linkages and consists essentially of one or more lipids, one or more lipids bearing polymers, or combinations thereof, (ii) allowing the gaseous precursor to undergo a phase transition from a liquid to a gas in the patient, and (iii) scanning the patient using magnetic resonance imaging to obtain visible images of any diseased tissue or region in the patient.

11. A method of claim 2 wherein said lipid is a phospholipid.

14. A method of claim 2 wherein said microsphere comprises a monolayer.

15. A method of claim 14 wherein said monolayer comprises a phospholipid.

17. A method of claim 11 wherein said gaseous precursor is selected from the group consisting of sulfur hexafluoride, perfluoromethane, perfluoroethane, perfluoropropane, perfluorocyclopropane, perfluorobutane, perfluorocyclobutane, perfluoropentane, perfluorocyclopentane, perfluorohexane, and perfluoroheptane.

18. A method of claim 17 wherein said gaseous precursor is perfluorohexane.

19. A method of claim 17 wherein said gaseous precursor is perfluoropropane.

20. A method of claim 17 wherein said gaseous precursor is selected from the group consisting of perfluoropentane, perfluorocyclopentane, perfluorohexane, and perfluoroheptane.

21. A method of claim 20 wherein said gaseous precursor is perfluoropentane.

30. A method of claim 2 wherein said gaseous precursor is a perfluorocarbon.

31. A method of claim 2 wherein said gaseous precursor is selected from the group consisting of sulfur hexafluoride, perfluoromethane, perfluoroethane, perfluoropropane, perfluorocyclopropane, perfluorobutane, perfluorocyclobutane, perfluoropentane, perfluorocyclopentane, perfluorohexane, and perfluoroheptane.

32. A method of claim 31 wherein said gaseous precursor is perfluorohexane.

33. A method of claim 31 wherein said gaseous precursor is perfluoropropane.

34. A method of claim 31 wherein said gaseous precursor is selected from the group consisting of perfluoropentane, perfluorocyclopentane, perfluorohexane, and perfluoroheptane.

35. A method of claim 31 wherein said gaseous precursor is perfluoropentane.

36. A method of claim 2 wherein said microsphere is rehydrated from a lyophilized microsphere.

37. A method of claim 2 wherein said lipid microsphere comprises at least 70 mole percent of at least one lipid.

38. A method of claim 2 wherein said lipid microsphere comprises at least two lipids wherein said first lipid contains substantially no linkages to a polymer and comprises at least 70 mole percent of the total moles of the microsphere, and wherein said second lipid bears a hydrophilic polymer.

39. A method of claim 38 wherein said first lipid comprises:

(i) a neutral lipid, and (ii) a negatively charged lipid, wherein the amount of said negatively charged lipid is greater than 1 mole percent of total lipids present.

40. A method of claim 39 wherein said negatively charged lipid is phosphatidic acid.

41. A method of claim 38 wherein the hydrophilic polymer of said second lipid is selected from the group consisting of polyethyleneglycol, polypropyleneglycol, polyvinylalcohol, and polyvinylpyrrolidone and copolymers thereof.

42. A method of claim 38 wherein the lipids comprise about 77.5 mole percent dipalmitoyl-phosphatidylcholine, about 12.5 mole percent of dipalmitoyl-phosphatidic acid, and about 10 mole percent of dipalmitoylphosphatidylethanolamine-polyethyleneglycol 5000.

43. A method of claim 38 wherein the lipids comprise about 82 mole percent dipalmitoylphosphatidyl-choline, about 10 mole percent of dipalmitoylphosphatidic acid, and about 8 mole percent of dipalmitoylphosphatidyl-ethanolamine-polyethyleneglycol 5000.