Patent EP0324938B1 successfully refreshed from Google Patents.
EP0324938B1
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EP
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Concentrated stabilized microbubble-type ultrasonic imaging agent and method of production
Assignee: GE Healthcare AS
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Filing: 1988-12-06
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Granted: 1993-11-18
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Expires: 2008-12-06
Abstract
Abstract A microbubble-type ultrasonic imaging agent is provided comprising a parenterally-administerable aqueous medium containing a dispersion of microspheres predominantly of diameters less than 10 microns, wherein the microspheres consist of gas microbubbles encapsulated with water-insolubilized biocompatible material. The imaging agent is characterized by having a concentration of greater than 100 x 10<6> microspheres per milliliter, and a stability such that this concentration is maintained for over 4 weeks at a temperature of 20 to 25 DEG C. A preferred method of producing the imaging agent is also disclosed.
Inventors
- 👤 Kenneth J. Widder
- 👤 Peter J. Westkaemper
Bibliographic Details
Application Number
—
Jurisdiction
EP
Data Source
google_patents
Last Synchronized
2026-10-23 14:17
CPC Classifications
A; A61; A61B; A61B8/00; A61B8/48; A61B8/481; A61K; A61K49/00; A61K49/22; A61K49/222; A61K49/223
Claims Analysis
Total Claims: 14
Claim 1
Independent Claim
78 words
A concentrated room-temperature stable ultrasonic imaging agent comprising a parenterally administerable aqueous medium containing a dispersion of microspheres at least 80% of which have diameters in the range of 1 to 9 µm, said microspheres consisting of gas microbubbles encapsulated in a water-insolubilized heat-denaturable biocompatible protein, said imaging agent having a homogeneously dispersed concentration of greater than 100 x 10⁶ microspheres per ml and maintaining this concentration for over 4 weeks at a temperature of 20 to 25°C.
Claim 2
Dependent Claim
39 words
The imaging agent of claim 1 which has a homogeneously dispersed concentration of said microspheres greater than 200 x 10⁶ microspheres per ml and which maintains this concentration for over 4 weeks at a temperature of 20 to 25°C.
Claim 3
Dependent Claim
16 words
The imaging agent of claim 1 in which said microbubbles are encapsulated with human serum albumin.
Claim 4
Dependent Claim
26 words
The imaging agent of claim 1 in which said microspheres are suspended in an aqueous solution of the same protein in which the microbubbles are encapsulated.
Claim 5
Dependent Claim
39 words
The imaging agent of claim 4 which has a homogeneously dispersed concentration of from 300 to 600 x 10⁶ microspheres per ml, and which maintains such concentration for at least 8 weeks at a temperature of 20 to 25°C.
Claim 6
Dependent Claim
17 words
The imaging agent of claim 4 or claim 5 in which said protein is human serum albumin.
Claim 7
Dependent Claim
27 words
The imaging agent of claim 4 or claim 5 in which 90% or more of said microspheres have diameters in the range from 2 to 8 µm.
Claim 8
Dependent Claim
88 words
A concentrated room-temperature stable ultrasonic imaging agent for intravenous administration, comprising a sterile aqueous solution of human serum albumin containing a dispersion of microspheres at least 80% of which have diameters in the range of 1 to 9 µm, said microspheres consisting of a bubble of air encapsulated in a water-insolubilized layer of said albumin, said imaging agent having a homogeneously-dispersed concentration of from 300 to 600 x 10⁶ microspheres per ml and maintaining this concentration for at least 8 weeks at a temperature of 20 to 25°C.
Claim 9
Dependent Claim
24 words
The imaging agent of claim 8 in which at least 90% of said microspheres have diameters in the range of 2 to 8 µm.
Claim 10
Independent Claim
131 words
A method of producing a dispersion of microspheres according to any of claims 1 to 9 for use as an ultrasonic imaging agent in which an aqueous solution of a heat-denaturable biocompatible protein is subjected to sonication to form gas microbubbles while heating said solution to insolubilize a portion of the protein, wherein the improvement comprises: during an initial sonication phase directly contacting the tip of the sonicator horn with said solution and carrying out the sonication and heating of said solution without appreciable foaming, then withdrawing the sonicator horn to a position in the ambient atmosphere proximate to the surface of said solution and foaming the solution to increase the population of microbubbles, and encapsulating the microbubbles with denatured protein to obtain a dispersion of stabilized microspheres of increased concentration.
Claim 11
Dependent Claim
13 words
The method of claim 10 in which said protein is human serum albumin.
Claim 12
Dependent Claim
90 words
A method of producing a concentrated dispersion of microspheres for use as an ultrasonic imaging agent in which a solution of human serum albumin is subjected to a sonication process according to claim 10, wherein the improvement comprises holding a body of the thus-obtained microsphere dispersion without agitation for sufficient time to permit the microspheres to rise therein and concentrate in an upper layer above the clarified albumin solution, and separating a portion of the clarified albumin solution from the concentrated layer to obtain a dispersion of greater microsphere concentration.
Claim 13
Dependent Claim
44 words
The method of claim 12 in which said dispersion of greater concentration is fractionated by withdrawing a dispersion containing most of the microspheres while leaving behind a microsphere fraction containing the largest size microspheres which had collected near the upper surface of the dispersion.
Claim 14
Dependent Claim
106 words
The method of claim 12 in which at least 80% of said microspheres have diameters in the range from 1 to 9 µm but include microspheres of larger diameters, which method includes the further steps of holding a body of the microsphere dispersions without agitation for sufficient time to permit at least the microspheres of larger than 10 µm diameter to rise therein and concentrate in an upper layer, and withdrawing a dispersion from beneath said upper layer containing most of the microspheres of less than 10 µm diameter while leaving behind a microsphere fraction containing most of the microspheres of larger than 10 µm diameter.
References Cited (Backward Citations)
No citation records indexed.
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