Claims for Patent: 5,529,766

Summary for Patent: 5,529,766

Title:	Contrast agents
Abstract:	The invention relates to ultrasound contrast agents comprising vesicles comprising a protein capable of formation of gas-containing vesicles, wherein the vesicles contain gas which comprises sulphur hexafluoride or a low molecular weight fluorinated hydrocarbon. These contrast agents exhibit stability in vivo upon administration so as to permit ultrasound visualization while allowing rapid subsequent elimination from the system.
Inventor(s):	Klaveness; Jo (Oslo, NO), Rongved; Pal (Nesoddtaugen, NO), Strande; Per (Oslo, NO)
Assignee:	Nycomed Imaging AS (Oslo, NO)
Application Number:	08/119,218
Patent Claims:	1. Microbubbles comprising a protein capable of formation of gas-containing microbubbles, said microbubbles containing gas comprising sulphur hexafluoride or a low molecular weight fluorinated hydrocarbon. 2. Microbubbles as claimed in claim 1 wherein said hydrocarbon is perfluorinated. 3. Microbubbles as claimed in claim 1 wherein said protein is albumin, gelatin or y-globulin. 4. Microbubbles as claimed in claim 3 wherein said protein is human serum albumin. 5. An aqueous dispersion comprising microbubbles as claimed in claim 1. 6. An aqueous dispersion comprising microbubbles as claimed in claim 2. 7. An aqueous dispersion comprising microbubbles as claimed in claim 3. 8. An aqueous dispersion comprising microbubbles as claimed in claim 4. 9. Microbubbles as claimed in claim 1 wherein said protein is crosslinked with crosslinking groups containing biodegradable linkages. 10. Microbubbles as claimed in claim 9 wherein the crosslinking groupings contain biodegradable linkages selected from the group consisting of amide, imide, imine, ester, anhydride, acetal, carbamate, carbonate, carbonate ester and disulphide groups. 11. Microbubbles as claimed in claim 10 wherein the crosslinking groups contain biodegradable linkages of formula where Y and Z, which may be the same or different, are --O--, --S-- or --NR.sup.3 ; R.sup.1 and R.sup.2, which may be the same or different, are hydrogen atoms or carbon-attached monovalent organic groups or together represent a carbon-attached divalent organic group; R.sup.3 is a hydrogen atom or an organic group; and the symbols n, which may be the same or different, are zero or 1. 12. Microbubbles as claimed in claim 1 having an average size of 0.1-10 .mu.m. 13. Microbubbles as claimed in claim 12 having an average size of 1-7 .mu.m. 14. Microbubbles as claimed in claim 9 having an average size of 0.1-10 .mu.m. 15. Microbubbles as claimed in claim 14 having an average size of 1-7 .mu.m. 16. An aqueous dispersion comprising microbubbles as claimed in claim 9. 17. A diagnostic ultrasound contrast agent comprising microbubbles as claimed in claim 9. 18. A contrast agent as claimed in claim 17 having a half-life in vivo of not more than 48 hours. 19. A contrast agent as claimed in claim 17 wherein said microbubbles are dispersed in an aqueous carrier. 20. A process for the preparation of a contrast agent which comprises generating microbubbles comprising a protein capable of formation of gas-containing microbubbles, said microbubbles containing gas comprising sulphur hexafluoride or a low molecular weight fluorinated hydrocarbon. 21. A process as claimed in claim 20 which comprises shaking or sonicating a protein-containing mixture in the presence of sulphur hexafluoride or a low molecular weight fluorinated hydrocarbon to generate a fluid dispersion of said microbubbles. 22. A process as claimed in claim 21 wherein said protein-containing mixture comprises protein in an aqueous medium. 23. A process as claimed in claim 21 wherein said hydrocarbon is perfluorinated. 24. A process for the preparation of a contrast agent which comprises crosslinking, microbubbles comprising a protein capable of formation of gas-containing microbubbles, said microbubbles containing gas comprising sulphur hexafluoride or a low molecular weight fluorinated hydrocarbon, and said crosslinking introducing crosslinking groups which contain biodegradable linkages. 25. A process as claimed in claim 24 wherein crosslinking is effected using a crosslinking agent of formula (I) where X is a linking group containing one or more biodegradable linkages selected from the group consisting of amide, imide, imine, ester, anhydride, acetal, carbamate, carbonate, carbonate ester and disulphide groups; and A.sup.1 and A.sup.2, which may be the same or different, are functional groups reactive with proteins. 26. A process as claimed in claim 24 wherein crosslinking is effected using a crosslinking agent of formula (I) where X is a linking group containing one or more biodegradable linkages of formula where Y and Z, which may be the same or different, are --O--, --S-- or --NR.sup.3 ; R.sup.1 and R.sup.2, which may be the same or different, are hydrogen atoms or carbon-attached monovalent organic groups or together represent a carbon-attached divalent organic group; R.sup.3 is a hydrogen atom or an organic group; and the symbols n, which may be the same or different, are zero or 1; and A.sup.1 and A.sup.2, which may be the same or different, are functional groups reactive with proteins. 27. A process as claimed in claim 25 in which A.sup.1 and A.sup.2 are both aldehyde groups. 28. A process as claimed in claim 26 in which A.sup.1 and A.sup.2 are both aldehyde groups. 29. A process as claimed in claim 24 wherein said hydrocarbon is perfluorinated. 30. A method of enhancing ultrasound images of a vascular system comprising administering to said system a diagnostic ultrasound contrast agent according to claim 17.