Contrast agents

Abstract

Ultrasonic visualisation of a suject, particularly of perfusion in the myocardium and other tissues, is performed using novel gas-containing contrast agent preparations which promote controllable and temporary growth of the gas phase in vivo following administration and can therefore act as deposited perfusion tracers. The preparations include a coadministerable composition comprising a diffusible component capable of inward diffusion into the dispersed gas phase to promote temporary growth thereof. In cardiac perfusion imaging the preparations may advantageously be coadministered with vasodilator drugs such as adenosine in order to enhance the differences in return signal intensity from normal and hypoperfused myocardial tissue respectively.

1 . A combined preparation for simultaneous, separate or sequential use as a contrast agent in ultrasound imaging, said preparation comprising: 
 i) an injectable aqueous medium having gas dispersed therein; and    ii) a composition comprising a diffusible component capable of diffusion in vivo into said dispersed gas so as at least transiently to increase the size thereof.    
     
     
         2 . A combined preparation as claimed in  claim 1  wherein the dispersed gas comprises air, nitrogen, oxygen, carbon dioxide, hydrogen, an inert gas, a sulphur fluoride, selenium hexafluoride, an optionally halogenated silane, a low molecular weight hydrocarbon, a ketone, an ester, a halogenated low molecular weight hydrocarbon or a mixture of any of the foregoing.  
     
     
         3 . A combined preparation as claimed in  claim 2  wherein the gas comprises a perfluorinated ketone, perfluorinated ether or perfluorocarbon.  
     
     
         4 . A combined preparation as claimed in  claim 3  wherein the perfluorocarbon comprises a perfluoroalkane, perfluoroalkene or perfluorocycloalkane.  
     
     
         5 . A combined preparation as claimed in  claim 2  wherein the gas comprises sulphur hexafluoride or a perfluoropropane, perfluorobutane or perfluoropentane.  
     
     
         6 . A combined preparation as claimed in  claim 1  wherein the dispersed gas is stabilised by a coalescence-resistant surface membrane, a filmogenic protein, a polymer material, a non-polymeric and non-polymerisable wall-forming material or a surfactant.  
     
     
         7 . A combined preparation as claimed in  claim 6  wherein said surfactant comprises at least one phospholipid.  
     
     
         8 . A combined preparation as claimed in  claim 7  wherein at least 75% of the said surfactant material comprises phospholipid molecules individually bearing net overall charge.  
     
     
         9 . A combined preparation as claimed in  claim 8  wherein at least 75% of the film-forming surfactant material comprises one or more phospholipids selected from phosphatidylserines, phosphatidylglycerols, phosphatidylinositols, phosphatidic acids and cardiolipins.  
     
     
         10 . (canceled)  
     
     
         11 . A combined preparation as claimed in  claim 1  wherein the composition comprising the diffusible component is formulated for administration cutaneously, subcutaneously, intramuscularly, intravenously or by inhalation.  
     
     
         12 . A combined preparation as claimed in  claim 1  wherein the composition comprising the diffusible component further comprises a carrier liquid.  
     
     
         13 . A combined preparation as claimed in  claim 12  wherein the diffusible component is dispersed in an aqueous carrier liquid in the form of an oil-in-water emulsion or microemulsion.  
     
     
         14 . A combined preparation as claimed in  claim 13  wherein the diffusible component comprises an aliphatic ether, polycyclic oil, polycyclic alcohol, heterocyclic compound, aliphatic hydrocarbon, cycloaliphatic hydrocarbon or halogenated low molecular weight hydrocarbon.  
     
     
         15 . A combined preparation as claimed in  claim 14  wherein the diffusible component comprises a perfluorocarbon.  
     
     
         16 . A combined preparation as claimed in  claim 15  wherein the perfluorocarbon comprises a perfluoroalkane, perfluoroalkene, perfluorocycloalkane, perfluorocycloalkene or perfluorinated alcohol.  
     
     
         17 . A combined preparation as claimed in  claim 16  wherein the diffusible component comprises perfluoropentane, perfluorohexane or perfluorodimethylcyclobutane.  
     
     
         18 . A combined preparation as claimed in  claim 13  wherein the emulsion is stabilised by a phospholipid surfactant.  
     
     
         19 . A combined preparation as claimed in  claim 18  wherein at least 75% of the said phospholipid surfactant comprises molecules individually bearing net overall charge.  
     
     
         20 . A combined preparation as claimed in  claim 19  wherein at least 75% of the phospholipid surfactant is selected from phosphatidylserines, phosphatidylglycerols, phosphatidylinositols, phosphatidic acids and cardiolipins.  
     
     
         21 . (canceled)  
     
     
         22 . A combined preparation as claimed in  claim 1  which further includes a vasodilator drug.  
     
     
         23 . A combined preparation as claimed in  claim 22  wherein said vasodilator drug is adenosine.  
     
     
         24 . (canceled)  
     
     
         25 . (canceled)  
     
     
         26 . A method of generating enhanced images of a human or non-human animal subject which comprises the steps of: 
 i) injecting a physiologically acceptable aqueous medium having gas dispersed therein into the vascular system of said subject;    ii) before, during or after injection of said aqueous medium administering to said subject a composition comprising a diffusible component capable of diffusion in vivo into said dispersed gas so as at least transiently to increase the size thereof; and    iii) generating an ultrasound image of at least a part of said subject.    
     
     
         27 . (canceled)  
     
     
         28 . A method as claimed in  claim 26  wherein a vasodilator drug is coadministered to the subject.  
     
     
         29 . A method as claimed in  claim 28  wherein said vasodilator drug is adenosine.