EP0324938A1
Expired / Lapsed
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: —
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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 10⁶ microspheres per milliliter, and a stability such that this concentration is maintained for over 4 weeks at a temperature of 20 to 25°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 14:55
CPC Classifications
A; A61; A61B; A61B8/00; A61B8/48; A61B8/481; A61K; A61K49/00; A61K49/22; A61K49/222; A61K49/223
Claims Analysis
Total Claims: 20
Claim 1
Independent Claim
69 words
A concentrated room-temperature stable ultrasonic imaging agent comprising a parenterally administerable aqueous medium containing a dispersion of microspheres predominantly of diameters less than 10 microns, which microspheres consist of gas microbubbles encapsulated with water-insolubilized biocompatible material, said imaging agent having a homogeneously dispersed concentration of greater than 100 x 10⁶ microspheres per milliliter and which maintains such concentration for over 4 weeks at a temperature of 20 to 25°C.
Claim 2
Dependent Claim
69 words
A concentrated room-temperature stable ultrasonic imaging agent comprising a parenterally administerable aqueous medium containing a dispersion of microspheres predominantly of diameters less than 10 microns, which microspheres consist of gas microbubbles encapsulated with water-insolubilized biocompatible material, said imaging agent having a homogeneously dispersed concentration of greater than 100 x 10⁶ microspheres per milliliter and which maintains such concentration for over 4 weeks at a temperature of 20 to 25°C.
Claim 3
Dependent Claim
24 words
The imaging agent of claim 1 in which at least 80% of said microspheres have diameters in the range from 1 to 9 microns.
Claim 4
Dependent Claim
42 words
The imaging agent of claim 1 or claim 2 which has a homogeneously dispersed concentration of said microspheres greater than 200 x 10⁶ microspheres per milliliter and which maintains such concentration for over 4 weeks at a temperature of 20 to 25°C.
Claim 5
Dependent Claim
19 words
The imaging agent of claim 1 or claim 2 in which said microbubbles are encapsulated with human serum albumin.
Claim 6
Dependent Claim
84 words
A concentrated room-temperature stable ultrasonic imaging agent comprising a parenterally administrable aqueous soluttion of a heat-denaturable biocompatible protein containing a dispersion of microspheres at least 80% of which have diameters in the range of 1 to 9 microns, said microspheres consisting of an air microbubble encapsulated in a heat-insolubilized layer of said protein, said imaging agent having a homogeneously-dispersed concentrattion greater than 200 x 10⁶ microspheres per milliliter and which maintains such concentration for over 4 weeks at a temperature of 20 to 25°C.
Claim 7
Dependent Claim
84 words
A concentrated room-temperature stable ultrasonic imaging agent comprising a parenterally administrable aqueous soluttion of a heat-denaturable biocompatible protein containing a dispersion of microspheres at least 80% of which have diameters in the range of 1 to 9 microns, said microspheres consisting of an air microbubble encapsulated in a heat-insolubilized layer of said protein, said imaging agent having a homogeneously-dispersed concentrattion greater than 200 x 10⁶ microspheres per milliliter and which maintains such concentration for over 4 weeks at a temperature of 20 to 25°C.
Claim 8
Dependent Claim
39 words
The imaging agent of claim 5 which has a homogeneously dispersed concentration of from 300 to 600 x 10⁶ microspheres per milliliter, and which maintains such concentration for at least 8 weeks at a temperature of 20 to 25°C.
Claim 9
Dependent Claim
17 words
The imaging agent of claim 5 or claim 6 in which said protein is human serum albumin.
Claim 10
Dependent Claim
27 words
The imaging agent of claim 5 or claim 6 in which 90% or more of said microspheres have diameters in the range from 2 to 8 microns.
Claim 11
Dependent Claim
89 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 microns, said microsphere 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 milliliter and which maintains such concentration for at least 8 weeks at a temperature of 20 to 25°C.
Claim 12
Dependent Claim
89 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 microns, said microsphere 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 milliliter and which maintains such concentration for at least 8 weeks at a temperature of 20 to 25°C.
Claim 13
Dependent Claim
24 words
The imaging agent of claim 9 in which at least 90% of said microspheres have diameters in the range from 2 to 8 microns.
Claim 14
Independent Claim
123 words
The method of producing a dispersion of microspheres for use as an ultrasonic imaging agent in which an aqueous solution of a heat-denaturable biocompatible protein is subject 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 15
Independent Claim
123 words
The method of producing a dispersion of microspheres for use as an ultrasonic imaging agent in which an aqueous solution of a heat-denaturable biocompatible protein is subject 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 16
Dependent Claim
13 words
The method of claim 11 in which said protein is human serum albumin.
Claim 17
Independent Claim
122 words
The 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 sonication in contact with the ambient atmosphere to form air microbubbles while heating said solution to insolubilize a portion of the albumin, and encapsulating the microbubbles with denatured albumin to obtain a dispersion of stabilized microspheres of increased concentration, 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 18
Independent Claim
122 words
The 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 sonication in contact with the ambient atmosphere to form air microbubbles while heating said solution to insolubilize a portion of the albumin, and encapsulating the microbubbles with denatured albumin to obtain a dispersion of stabilized microspheres of increased concentration, 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 19
Dependent Claim
45 words
The method of claim 13 in which the 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 20
Dependent Claim
100 words
The method of claim 13 in which said microspheres are predominately of diameters less than 10 microns 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 micron 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 microns diameter while leaving behind a microsphere fraction containing most of the microspheres of larger than 10 micron diameter.
References Cited (Backward Citations)
EP0224934A2
Cited
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