Thermal preactivation of gaseous precursor filled compositions

• US 6,548,047 B1
• Filed: 09/15/1997
• Issued: 04/15/2003
• Est. Priority Date: 09/15/1997
• Status: Expired due to Term

• Current Assignee: Lantheus Medical Imaging, Inc. (Lantheus Holdings, Inc.)
• Original Assignee: Bristol-Myers Squibb Company
• Inventors: Unger, Evan C.
• Primary Examiner(s): Dudash, Diana L.
• Assistant Examiner(s): SHARAREH, SHAHNAM J
• Application Number:
  US08/929,847
• Time in Patent Office: 2,038 Days
• Field of Search: 424/9.4, 424/9.5, 424/9.51, 424/9.52, 424/450
• 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 of providing an image of a region of a patient comprising:

heating a composition comprising lipid vesicles encapsulating a gaseous precursor to a temperature at or above the boiling point of the gaseous precursor prior to administering the composition to the patient, wherein the gaseous precursor is a fluorinated compound, and wherein said lipid vesicles comprise at least one phosphatidylcholine, at least one phosphatidylethanolamine, and at least one phosphatidic acid, wherein said phosphatidylcholine is selected from the group consisting of dioleoylphosphatidylcholine, dimyristoylphosphatidylcholine, dipalmitoylphosphatidylcholine, and distearoyl-phosphatidylcholine;

said phosphatidylethanolamine is selected from the group consisting of dipalmitoylphosphatidylethanolamine, dioleoyl-phosphatidylethanolamine, and N-succinyl-dioleoyl-phosphatidylethanolamine; and

said phosphatidic acid is dipalmatoylphosphatidic acid; and

scanning the patient using diagnostic imaging to obtain visible images of the region of the patient.

2. The method of claim 1, comprising heating the composition to a temperature above the boiling point of the gaseous precursor.

3. The method of claim 1, wherein the composition is administered to the patient as an infusion at a rate of less than about 1 cc/second.

4. The method of claim 1, wherein the diagnostic imaging is ultrasound imaging.

5. The method of claim 1, wherein the fluorinated compound is sulfur hexafluoride, a perfluorocarbon or a perfluoroether.

6. The method of claim 5, wherein the fluorinated compound is a perfluorocarbon selected from the group consisting of perfluoromethane, perfluoroethane, perfluoropropane, perfluorocyclopropane, perfluorobutane, perfluorocyclobutane, perfluoropentane, perfluorocyclopentane, perfluorohexane and perfluorocyclohexane.

7. The method of claim 5, wherein the fluorinated compound is a perfluoroether selected from the group consisting of perfluorotetrahydropyran, perfluoromethyltetrahydrofuran, perfluorobutylmethyl ether, perfluoropropylethyl ether, perfluorocyclobutylmethyl ether, perfluorocyclopropylethyl ether, perfluoropropylmethyl ether, perfluorodiethyl ether, perfluorocyclopropylmethyl ether, perfluoromethylethyl ether and perfluorodimethyl ether.

8. The method of claim 5, wherein the fluorinated compound is selected from the group consisting of perfluoropropane, perfluorobutane, perfluoropentane, perfluorohexane and perfluoromethylbutyl ether.

9. The method of claim 1, wherein the composition further comprises a fluorinated liquid.

10. The method of claim 9, wherein the fluorinated liquid is selected from the group consisting of perfluoroheptane, perfluorooctane, perfluorononane, perfluorodecane, perfluorododecane, perfluorodecalin, perfluorododecalin, perfluorooctyliodide, perfluorooctylbromide, perfluorotripropylamine, perfluorotributylamine, perfluorobutylethyl ether, bis(perfluoroisopropyl) ether and bis(perfluoropropyl) ether.

11. The method of claim 1, wherein composition further comprises a targeting ligand.

12. The method of claim 11, wherein the targeting ligand is selected from the group consisting of proteins, peptides and saccharides.

25. The method of claim 1 wherein said phosphatidylcholine comprises dipalmitoylphosphatidylcholine.

26. The method of claim 1 wherein said phosphatidylethanolamine comprises dipalmitoylphosphatidylethanolamine.

29. The method of claim 1 wherein said phosphatidylcholine comprises dipalmitoylphosphatidylcholine and said phosphatidylethanolamine comprises dipalmitoylphosphatidylethanolamine.

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

heating a composition lipid vesicles encapsulating a gaseous precursor to a temperature at or above the boiling point of the gaseous precursor prior to administering the composition to the patient, wherein the gaseous precursor is a fluorinated compound, and wherein said lipid vesicles comprise at least one phosphatidylcholine, at least one phosphatidylethanolamine, and at least one phosphatidic acid, wherein said phosphatidylcholine is selected from the group consisting of dioleoylphosphatidylcholine, dimyristoylphosphatidylcholine, dipalmitoylphosphatidylcholine, and distearoyl-phosphatidylcholine;

said phosphatidylethanolamine is selected from the group consisting of dipalmitoylphosphatidylethanolamine, dioleoyl-phosphatidylethanolamine, and N-succinyl-dioleoyl-phosphatidylethanolamine; and

said phosphatidic acid is dipalmatoylphosphatidic acid; and

scanning the patient using diagnostic imaging to obtain a visible image of any diseased tissue in the patient.

14. The method of claim 13, comprising heating the composition to a temperature above the boiling point of the gaseous precursor.

15. The method of claim 13, wherein the composition is administered to the patient as an infusion at a rate of less than about 1 cc/second.

16. The method of claim 13, wherein the diagnostic imaging is ultrasound imaging.

17. The method of claim 13, wherein the fluorinated compound is sulfur hexafluoride, a perfluorocarbon or a perfluoroether.

18. The method of claim 17, wherein the fluorinated compound is a perfluorocarbon selected from the group consisting of perfluoromethane, perfluoroethane, perfluoropropane, perfluorocyclopropane, perfluorobutane, perfluorocyclobutane, perfluoropentane, perfluorocyclopentane, perfluorohexane and perfluorocyclohexane.

19. The method of claim 17, wherein the fluorinated compound is a perfluoroether selected from the group consisting of perfluorotetrahydropyran, perfluoromethyltetrahydrofuran, perfluorobutylmethyl ether, perfluoropropylethyl ether, perfluorocyclobutylmethyl ether, perfluorocyclopropylethyl ether, perfluoropropylmethyl ether, perfluorodiethyl ether, perfluorocyclopropylmethyl ether, perfluoromethylethyl ether and perfluorodimethyl ether.

20. The method of claim 17, wherein the fluorinated compound is selected from the group consisting of perfluoropropane, perfluorobutane, perfluoropentane, perfluorohexane and perfluoromethylbutyl ether.

21. The method of claim 13, wherein the composition further comprises a fluorinated liquid.

22. The method of claim 21, wherein the fluorinated liquid is selected from the group consisting of perfluoroheptane, perfluorooctane, perfluorononane, perfluorodecane, perfluorododecane, perfluorodecalin, perfluorododecalin, perfluorooctyliodide, perfluorooctylbromide, perfluorotripropylamine, perfluorotributylamine, perfluorobutylethyl ether, bis(perfluoroisopropyl) ether and bis(perfluoropropyl) ether.

23. The method of claim 21, wherein the composition further comprises a targeting ligand.

24. The method of claim 21, wherein the targeting ligand is selected from the group consisting of proteins, peptides and saccharides.

27. The method of claim 13 wherein said phosphatidylcholine comprises dipalmitoylphosphatidylcholine.

28. The method of claim 13 wherein said phosphatidylethanolamine comprises dipalmitoylphosphatidylethanolamine.

30. The method of claim 13 wherein said phosphatidylcholine comprises dipalmitoylphosphatidylcholine and said phosphatidylethanolamine comprises dipalmitoylphosphatidylethanolamine.