Patent EA-000900-B1 (EA)
Title: Thermally stabilized contrast agent
Inventor: SWAERD-NORDMO MARIT
IPC: A61K9/127
Filed: 1997-02-19
Abstract: 1. Ultrasound contrast agent, which is freeze-dried and comprises vesicles, containing stabilizer, stabilising a freeze-drying contract agent, in a weight ratio of said stabilizer to the vesicles in said agent of at least 10:1, and which agent is thermally stable at the temperatures less than 65 degree C and has the temperature of vitrification (Tg) exceeding 20 degree C.  2. A contrast agent as claimed in claim 1, wherein said stabilizer is selected from the group consisting of sucrose, maltose H2O, trehalose, raffinose and stachyose, wherein said stabilizer preferably comprises sucrose. 3. A contrast agent as claimed in any one of claims 1 or 2 wherein the weight ratio of said stabilizer to the  vesicles in said agent is at least 20:1. 4. A contrast agent as claimed in any one of claims 1 to 3 wherein the vesicles in said agent contain a halocarbon gas or gas precursor, wherein the above-mentioned halocarbon gas preferably is perfluoroalkane, more preferably the above-mentioned perfluoroalkane is selected from perfluorobutane and perfluoropentane. 5. A contrast agent as claimed in any one of claims 1 to 4 wherein the membrane of the vesicles in said agent comprises a phospholipid. 6. A process for the preparation of a thermally stable ultrasound contrast agent, which comprises freeze-drying an aqueous dispersion comprising a vesicular ultrasound contrast agent and stabilizer or mixture of stabilizers, which stabilise the freeze-dried agent, characterised in that said stabilizer or mixture or stabilizers has a Tg value of at least 20 degree C and a Tg' value (the glass transition temperature of the maximally freeze-concentrated pure aqueous solution of said stabilizer or mixture of stabilizers) of -37 degree C or above, and in that said stabilizer or mixture of stabilizer is present in said dispersion at a weight ratio relative to said vesicular ultrasound contrast agent of at least 10:1. 7. A process as claimed in claim 6, wherein said aqueous dispersion contains from 1 to 50% wt of said stabilizer, said vesicular contrast agent preferably comprisesn a halocarbon gas or gas precursor, more preferably the above-mentioned halocarbon gas is selected from perfluorobutane and perfluoropentane. 8. A process as claimed in claims 6 or 7, wherein said aqueous dispersion comprises a bulking agent, wherein the said bulking agent preferably is a C3 polyol, more preferably - said aqueous dispersion comprises from 3 to 10% wt of said bulking agent. 9. An ultrasound contrast medium comprising an aqueous carrier, stabilizer or mixture of stabilizers, which stabilises the freeze-dried agent and an echogenic vesicular ultrasound contrast agent, characterised in that said stabilizer or mixture of stabilizers has a Tg value of at least 20 degree C and a Tg' value of -37 degree C or above, and in that said stabilizer or mixture of stabilizers is present in said medium at a weight ratio relative to said vesicular ultrasound contrast agent of at least 10:1.  10. A process used in diagnostics of condition of mammal with usage of diagnostic ultrasound imaging, including administering vesicle containing ultrasound contrast medium, which contains said stabilizer or mixture of stabilizers, used while freeze-drying, having a Tg value of at least 20 degree C and Tg' value of -37 degree C or above, at a weight ratio relative to the vesicles of at least 10:1.  11. A process of the storage or transportation of a vesicle containing ultrasound contrast agent, characterised in that as the ultrasound contrast agent the agent as claimed in claim 1 is used and in that storage and transportation takes place at an ambient temperature.  12. A process for the preparation of a vesicle containing ultrasound contrast medium, which comprises dispersing in a physiologically tolerable aqueous dispersion medium freeze-dried contrast agent as claimed in any one of claims 1 to 12.