Thrombolytic agents and methods of treatment for thrombosis

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.

What is claimed is:  
     
         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 microspheres 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 7    wherein said dilution of albumin with dextrose is a 3-fold dilution.  
     
     
         11 . The method of    claim 7    wherein said human serum albumin is a 5% by weight solution.  
     
     
         12 . The method of    claim 7    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 stable microbubbles aproximately 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    wherein said 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 18    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 a thrombus site, said pharmaceutical composition comprising a microbubble ultrasound contrast agent, and thereafter;    applying ultrasound to said site.    
     
     
         25 . A method for lysing a thrombus in an animal comprising: 
 introducing a pharmaceutical composition to said animal by intravenous injection near a thrombus site, said pharmaceutical composition comprising a microbubble ultrasound contrast agent, and thereafter;    applying ultrasound to said site.