Thrombolytic agents and methods of treatment for thrombosis

• US 5,980,950 A
• Filed: 04/03/1997
• Issued: 11/09/1999
• 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:
  US08/832,532
• Time in Patent Office: 950 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 solution consisting essentially of a mixture of dextrose and albumin wherein said destrose comprises from about 3.75% to about 40% by weight of said solution to said animal by intravenous injection near a thrombus site and thereafter applying ultrasound to said site, said dextrose and albumin mixture comprising a plurality of microbubbles with a diameter of from about 0.1 to 10 microns,

said microbubbles having a protein coated shell and an internal atmosphere comprising a gas which is insoluble in blood.

2. The method of claim 1 wherein said protein coated shell is an albumin coated shell.

3. The method of claim 1 wherein said insoluble gas is selected from the group consisting of perfluoromethane, perfluoroethane, perfluoropropane, perfluorobutane and perfluoropentane.

4. The method of claim 3 wherein said prefluorocarbon gas is perfluorobutane.

5. The method of claim 3 wherein said perfluorocarbon gas is perfluoropropane.

6. The method of claim 1 wherein said pharmaceutical compositions are created by 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% 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.

7. The method of claim 6 wherein said dilution of albumin with dextrose is a 3-fold dilution.

8. The method of claim 6 wherein said human serum albumin is a 5% by weight solution.

9. A method for treating thrombosis in animals comprising:

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

(i) an aqueous albumin-dextrose solution containing between about a two fold and about an eight fold dilution of about a 5% by weight solution of dextrose and between about 2% to about 10% by weight human serum albumin; and

(ii) microbubbles, having a protein coated shell and a gaseous content of which contain an amount of perfluorocarbon gas effective for achieving a stable concentration of about 5×

10⁸ microspheres per ml;

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

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

10. The method of claim 9 wherein said step of introducing said composition to said thrombus is by intravenous injection.

11. The method of claim 9 wherein said protein coated shell is an albumin coated shell.

12. The method of claim 9 wherein said perfluorocarbon gas is selected from the group consisting of perfluoromethane, perfluoroethane, perfluoropropane, perfluorobutane and perfluoropentane.

13. The method of claim 12 wherein said perfluorocarbon gas is perfluorobutane.

14. The method of claim 12 wherein said perfluorocarbon gas is perfluoropropane.

15. The method of claim 9 wherein said pharmaceutical composition is created by 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 a 5% by weight dextrose solution; 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.

16. The method of claim 15 wherein said dilution of albumin with dextrose is a 3-fold dilution.

17. The method of claim 13 wherein said human serum albumin is a 5% by weight solution.