Novel methods of ultrasound treatment using gas or gaseous precursor-filled compositions

• US 20010031243A1
• Filed: 03/21/2001
• Published: 10/18/2001
• Est. Priority Date: 09/15/1997
• Status: Active Grant

• Current Assignee: Cerevast Medical, Inc.
• Original Assignee: Imarx Pharmaceutical Corp. (Sycamore Entertainment Group, Inc.)
• Inventors: Unger, Evan C.
• Granted Patent: US 6,716,412 B2
• Time in Patent Office: Days
• 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 49/227 Liposomes, lipoprotein vesicles, e.g. LDL or HDL lipoproteins, micelles, e.g. phospholipidic or polymeric

Abstract

The present invention describes, among other things, the surprising discovery that gaseous precursor filled compositions are profoundly more effective as acoustically active contrast agents when they are thermally preactivated to temperatures at or above the boiling point of the instilled gaseous precursor prior to their in vivo administration to a patient. Further optimization of contrast enhancement is achieved by administering the gaseous precursor filled compositions to a patient as an infusion. Enhanced effectiveness is also achieved for ultrasound mediated targeting and drug delivery.

Claims

1. A method for lysing an intravascular blood clot in the brain of a patient, said method comprising:

(i) administering a vesicle composition comprising, in an aqueous carrier, gas or gaseous precursor-filled vesicles comprising lipids, proteins or polymers to the patient, and (ii) applying ultrasonic energy to the brain of the patient in an amount sufficient to cavitate or rupture at least a portion of said vesicles.

2. A method according to

claim 1

, wherein said vesicle composition is administered as an intravascular infusion.

3. A method according to

claim 2

, wherein said vesicle composition is administered as an intra-arterial infusion.

4. A method according to

claim 1

, wherein said gas or gaseous precursor comprises a perfluorocarbon.

5. A method according to

claim 4

, wherein said perfluorocarbon is selected from the group consisting of perfluoromethane, perfluoroethane, perfluoropropane, perfluorocyclopropane, perfluorobutane, perfluorocyclobutane, perfluoropentane, perfluorocyclopentane, perfluorohexane and perfluorocyclohexane.

6. A method according to

claim 5

flurther comprising heating said composition to a temperature above the boiling point of said perfluorocarbon.

7. A method according to

claim 5

, wherein said perfluorocarbon is selected from the group consisting of perfluoropropane, perfluorocyclopropane, perfluorobutane, and perfluorocyclobutane.

8. A method according to

claim 1

, wherein said vesicles comprise liposomes.

9. A method according to

claim 1

, wherein said vesicles comprise a phospholipid.

10. A method according to

claim 9

, wherein said phospholipid is selected from the group consisting of phosphatidylcholine, phosphatidylethanolamine and phosphatidic acid.

11. A method according to

claim 10

wherein said phosphatidylcholine is selected from the group consisting of dioleoylphosphatidylcholine, dimyristoylphosphatidylcholine, dipalmitoylphosphatidylcholine and distearoylphosphatidylcholine.

12. A method according to

claim 11

wherein said phosphatidylcholine comprises dipalmitoylphosphatidylcholine.

13. A method according to

claim 10

wherein said phosphatidylethanolamine is selected from the group consisting of dipalmitoylphosphatidylethanolamine, dioleoylphosphatidylethanolamine, N-succinyldioleoylphosphatidylethanolamine and 1-hexadecyl-2-pahmitoylglycerophosphoethanolamine.

14. A method according to

claim 13

wherein said phosphatidylethanolamine comprises dipalmitoylphosphatidylethanolamine.

15. A method according to

claim 10

wherein said phosphatidic acid comprises dipalmitoylphosphatidic acid.

16. A method according to

claim 1

further comprising a hydrophilic polymer.

17. A method according to

claim 16

, wherein said hydrophilic polymer comprises polyethylene glycol.

18. A method according to

claim 1

, wherein said vesicles fuirther comprise a targeting ligand.

19. A method according to

claim 18

, wherein said targeting ligand is covalently bound to said vesicles via a hydrophilic polymer linking group.

20. A method according to

claim 18

, wherein said targeting ligand targets cells or receptors selected from the group consisting of endothelial cells and the glycoprotein GPIIbIIIa receptor.

21. A method according to

claim 20

, wherein said targeting ligand is selected from the group consisting of proteins, peptides, saccharides, steroids, steroid analogs, bioactive agents and genetic material.

22. A method according to

claim 21

, wherein said targeting ligand is selected from the group consisting of proteins, peptides and saccharides.

23. A method according to

claim 22

, wherein said targeting ligand is selected from the group consisting of proteins and peptides.

24. A method according to

claim 23

, wherein said targeting ligand comprises a peptide.

25. A method according to

claim 24

, wherein said peptide comprises a sequence selected from the group consisting of Arg-Gly-Asp and Lys-Gln-Ala-Gly-Asp-Val.

26. A method according to

claim 1

, wherein said u ltr asound is applied through an acoustic window.

27. A method according to

claim 26

, wherein said acoustic window comprises a surgically created window in the skull.

28. A method according to

claim 1

, wherein said ultrasound is applied in a pulsed and focused mode.

29. A method according to

claim 1

, wherein said vesicles further comprise a bioactive agent.

30. A method according to

claim 28

, wherein said bioactive agent is selected from the group consisting of anti-coagulation agents, circulatory agents, anti-inflammatories, corticosteroids, tissue plasminogen activator, streptokinase, and urokinase.

31. A method according to

claim 1

further comprising scanning the patient with diagnostic imaging to identify the location of said blood clot in the brain.

32. A method according to

claim 31

, wherein said scanning is performed after initiating administration of said vesicle composition.

33. A method according to

claim 31

, wherein said diagnostic imaging comprises nuclear medicine imaging.

34. A method according to

claim 31

, wherein said diagnostic imaging comprises ultrasound imaging.