Non-invasive intravascular thrombolysis using modified ultrasound techniques

• US 20040265393A1
• Filed: 06/10/2004
• Published: 12/30/2004
• Est. Priority Date: 06/13/2003
• Status: Abandoned Application

• Current Assignee: Cerevast Therapeutics, Inc.
• Original Assignee: Cerevast Therapeutics, Inc.
• Inventors: Zutshi, Reena, Unger, Evan C., Matsunaga, Terry O.
• Application Number:
  US10/865,972
• Publication Number:
  US 20040265393A1
• Time in Patent Office: Days
• US Class Current: 424/600
• CPC Class Codes: A61B 17/22004 using mechanical vibrations, e.g. ultrasonic shock waves A61B17/225 takes precedence
• CPC Class Codes: A61B 2017/22001 Angioplasty, e.g. PCTA
• CPC Class Codes: A61B 2017/22008 used or promoted
• CPC Class Codes: A61B 2017/22014 the ultrasound transducer being outside patient's body; with an ultrasound transmission member; with a wave guide; with a vibrated guide wire not applied in A61B17/22012
• CPC Class Codes: A61K 33/00 Medicinal preparations containing inorganic active ingredients
• CPC Class Codes: A61K 33/20 Elemental chlorine; Inorganic compounds releasing chlorine
• 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 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 49/1812 liposomes, polymersomes, e.g. immunoliposomes
• CPC Class Codes: A61P 7/02 Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors

Abstract

A non-invasive method for disrupting a blood clot within the vasculature of a patient using new ultrasound techniques is provided. Lipid vesicles containing a gas or gaseous precursor are administered intravascularly to the patient and ultrasound having a power greater than about 0.5 Watts/cm² to about 20 Watts/cm² for about 10% to about 80% of the duty cycle is applied to the patient for a period of time sufficient to induce rupture of the vesicles adjacent to the site of the blood clot, thereby disrupting the blood clot. Administration of thrombolytic biological agents is not required. Optionally, progress of clot disruption can be monitored using magnetic resonance imaging.

Claims

1. A non-invasive method for disrupting a blood clot within the vasculature of a patient, the method comprising:

(a) administering intravascularly to the patient a vesicle composition comprising, in an aqueous carrier, a lipid and a gas or gaseous precursor; and

(b) applying to the patient ultrasound having a power greater than about 0.5 Watts/cm² to about 20 Watts/cm² for about 10% to about 80% of the duty cycle for a period of time sufficient to induce rupture of the vesicles adjacent to the site of the blood clot, thereby disrupting the blood clot.

2. The method of claim 1, further comprising scanning the patient with diagnostic imaging to monitor disruption of the blood clot.

3. The method of claim 2, wherein the scanning is performed prior to, simultaneously with, or after application of the ultrasound.

4. The method of claim 3, wherein the diagnostic imaging comprises magnetic resonance imaging (MRI).

5. The method of claim 1, wherein the period of time is about 1 minute to about 8 hours.

6. The method of claim 5, wherein the period of time is about 5 minutes to about 2 hours.

7. The method of claim 6, wherein the period of time is for about 1 hour.

8. The method of claim 1, wherein the ultrasound is focused.

9. The method of claim 1, wherein the ultrasound is non-focused.

10. The method of claim 1, wherein mechanical index of the ultrasound is no greater than about 8.0.

11. The method of claim 1, wherein the power is 10 Watts/cm² delivered at 50% of the duty cycle.

12. The method of claim 1, wherein the ultrasound is delivered at from about 0.1% to less than 80% of the duty cycle.

13. The method of claim 1, wherein the blood clot is in the vasculature of the brain.

14. The method of claim 1, wherein the blood clot is associated with rupture of a vulnerable plaque in the vasculature.

15. The method of claim 1, wherein the blood clot is associated with ischemic or hemorrhagic stroke.

16. The method of claim 1, wherein the blood clot is associated with an atherosclerotic plaque.

17. The method of claim 1, wherein the blood clot results from an interventional medical procedure.

18. The method of claim 1, wherein the blood clot results from acute limb ischemia.

19. The method of claim 1, wherein the blood clot is associated with a myocardial infarction.

20. The method of claim 1, wherein the blood clot is associated with a dialysis graft.

21. The method of claim 1, wherein the blood clot is associated with deep vein thrombosis.

22. The method of claim 1, wherein the administration is intravenously.

23. The method of claim 1, wherein the administration is intraarterially.

24. The method of claim 1, wherein the vesicles further comprise a targeting ligand.

25. The method of claim 24, wherein the blood clot is in a vein and the targeting ligand targets fibrin.

26. The method of claim 24, wherein the blood clot is in an artery and the targeting ligand targets platelets.

27. The method of claim 1 wherein the vesicles further comprise a therapeutic agent that is released upon application of the ultrasound.

28. The method of claim 27, wherein the therapeutic agent is a thrombolytic.

29. The method of claim 27, wherein the therapeutic agent is tissue plasminogen activator (tPA).

30. The method of claim 1, wherein the composition further comprises a drug.

31. The method of claim 1, wherein the composition further comprises an anti-coagulant.

32. The method of claim 31, wherein the anti-coagulant is a heparin.

33. The method of claim 1, wherein the method further comprises co-administration of a antihyperlipidemic agent.

34. The method of claim 1 wherein the gas or gaseous precursor are perfluorocarbons containing less than 10 carbon atoms.

35. The method of claim 34, the perfluorocarbons are selected from the group consisting of perfluoropropane, perfluorobutane, perfluorocyclobutane, perfluoromethane, perfluoroethane, perfluorohexane, and perfluoropentane.

36. The method of claim 34, wherein the perfluorocarbon compound is perfluoropropane.

37. The method of claim 34, wherein the perfluorocarbon compound is perfluorobutane.

38. The method of claim 1, wherein the vesicles comprise liposomes.

39. The method of claim 4, wherein the composition further comprises a paramagnetic agent.

40. The method of claim 39, wherein the paramagnetic agent comprises a paramagnetic ion selected from the group consisting of transition, lanthanide and actinide elements.

41. The method of claim 4, wherein the vesicles have an average diameter of about 1 to about 5 microns.

42. The method of claim 41, wherein the vesicles have an average diameter of about 1 to about 3 microns.