Thrombolytic agents and methods of treatment for thrombosis

• US 6,197,345 B1
• Filed: 11/08/1999
• Issued: 03/06/2001
• Est. Priority Date: 10/17/1995
• Status: Expired due to Term

• Current Assignee: Board of Regents of the University of Nebraska
• Original Assignee: Board of Regents of the University of Nebraska
• Inventors: Porter, Thomas R.
• Primary Examiner(s): Harrison, Robert H.
• Application Number:
  US09/435,050
• Time in Patent Office: 484 Days
• Field of Search: 424/490, 424/491, 424/493, 424/9.52, 128/660.01
• US Class Current: 424/490
• CPC Class Codes: A61K 31/02 Halogenated hydrocarbons
• 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 9/5052 Proteins, e.g. albumin

Abstract

The foregoing invention relates to a new microbubble preparation and thrombolytic therapy which relies on microbubbles and ultrasound for its lytic activity. The pharmaceutical composition of the invention comprises a liquid solution of microbubbles with an internal atmosphere enhanced with the perfluorocarbon gas which cavitate in the presence of an ultrasound field following intravenous injection or infusion of said composition into said host. For thrombolysis the area of a thrombus is exposed to an ultrasound field in the presence of the microbubbles and significant lysis is experienced. The method and pharmaceutical composition of the invention exhibit thrombolytic properties similar to those of other thrombolytic agents such as urokinase and are less toxic and are clot specific in that they do not introduce a systemic lytic state to a said animal.

Claims

1. A method of treating thrombosis in animals comprising the steps of:

introducing a pharmaceutical composition to a thrombus site by intravenous injection, said pharmaceutical composition comprising a plurality of gas filled microbubbles with a diameter of from about 0.1 to 10 microns and a pharmaceutically acceptable carrier, and thereafter;

applying ultrasound to said site.

2. The method of claim 1 wherein said gas is an insoluble gas.

3. The method of claim 1 wherein said microbubbles are protein coated.

4. The method of claim 1 wherein said carrier is a 5% solution of dextrose.

5. The method of claim 3 wherein said protein coated microbubbles are albumin coated microspheres.

6. The method of claim 2 wherein said insoluble gas is selected from the group consisting of perfluoromethane, perfluoroethane, perfluoropropane, perfluorobutane and perfluoropentane.

7. The method of claim 6 wherein said perfluorocarbon gas is perfluorobutane.

8. The method of claim 6 wherein said perfluorocarbon gas is perfluoropropane.

9. The method of claim 1 further comprising the following steps:

mixing an aqueous solution comprising 2% to about 10% by weight of human serum albumin diluted about two fold to about eight fold with 5% to 50% by weight dextrose; and

exposing said solution to a sonication horn to generate stable microbubbles from about 0.1 to 10 microns in diameter, to create said pharmaceutical composition.

10. The method of claim 9 wherein said dilution of albumin with dextrose is a 3-fold dilution.

11. The method of claim 9 wherein said human serum albumin is a 5% by weight solution.

12. The method of claim 9 wherein said dextrose is a 5% by weight solution.

13. A method for treating thrombosis in animals comprising:

(a) obtaining a pharmaceutical composition which consists essentially of;

a solution of microbubbles approximately 0.1 to 10 microns in diameter, and a pharmaceutically acceptable carrier;

(b) introducing said pharmaceutical composition to said thrombus; and

(c) exposing said pharmaceutical composition and said thrombus to an ultrasound field for a time sufficient to lyse said thrombus.

14. The method of claim 13 wherein said step of introducing said agent to said thrombus is by intravenous injection.

15. The method of claim 13 wherein said dextrose is a 5% solution.

16. The method of claim 13 wherein said protein coated microbubbles are albumin coated microspheres.

17. The method of claim 13 wherein said perfluorocarbon gas is selected from the group consisting of perfluoromethane, perfluoroethane, perfluoropropane, perfluorobutane and perfluoropentane.

18. The method of claim 17 wherein said perfluorocarbon gas is perfluorobutane.

19. The method of claim 17 wherein said perfluorocarbon gas is perfluoropropane.

20. The method of claim 13 further comprising the following steps:

mixing an aqueous solution comprising 2% to about 10% by weight of human serum albumin diluted about two fold to about eight fold with 5% to 50% by weight dextrose; and

exposing said solution to a sonication horn to create cavitation at particulate sites in said solution generating stable microspheres from about 0.1 to 10 microns in diameter, to form said pharmaceutical composition.

21. The method of claim 20 wherein said dilution of albumin with dextrose is a 3-fold dilution.

22. The method of claim 20 wherein said human serum albumin is a 5% by weight solution.

23. The method of claim 20 wherein said dextrose is a 5% by weight solution.

24. A method for lysing a thrombus in an animal comprising:

introducing a pharmaceutical composition to said animal by intravenous injection near the site of the thrombus, said pharmaceutical composition comprising a microbubble ultrasound contrast agent, and thereafter;

applying ultrasound to said site.