Microbubble precursors and methods for their production and use

• US 4,442,843 A
• Filed: 11/17/1981
• Issued: 04/17/1984
• Est. Priority Date: 11/17/1980
• Status: Expired due to Term

• Current Assignee: Schering Ag (Merck & Co., Inc.)
• Original Assignee: Schering Ag (Merck & Co., Inc.)
• Inventors: Rasor, Julia S., Tickner, Ernest G.
• Primary Examiner(s): HOWELL, KYLE
• Assistant Examiner(s): Yanulis, George
• Application Number:
  US06/322,138
• Time in Patent Office: 882 Days
• Field of Search: 73/600, 73/703, 128/660, 128/662, 128/663
• US Class Current: 424/9.52
• CPC Class Codes: A61B 8/481 involving the use of contrast agent, e.g. microbubbles introduced into the bloodstream analysis of echo signal exploiting properties of a contrast enhancer in devices for short-range imaging with acoustic waves G01S7/52039
• CPC Class Codes: A61K 49/223 Microbubbles, hollow microspheres, free gas bubbles, gas microspheres

Abstract

Microbubbles are formed in a liquid, e.g., blood in order to alter the transmission characteristics thereof to electromagnetic and sonic waves transmitted therethrough, by dissolving therein a solid particulate material, preferably as a suspension in a carrier liquid in which the particulate material is at least temporarily stable, the particles of which are substantially free of microbubbles and have a plurality of gas-filled voids communicating with the surface of the particles and providing nuclei for microbubble formation and the ratio of the mass of the particles to the volume of gas in the voids is sufficient to render the liquid in which the particulate material is dissolved supersaturated with respect to the gas in the voids in the area of the liquid surrounding the microbubbles when they are formed.

Claims

1. In a method for altering the transmission characteristics of a liquid to an electromagnetic or elastic wave transmitted therethrough by dispersing in the liquid an amount of microbubbles effective to substantially alter such transmission characteristics of the liquid in the area thereof containing the microbubbles, the improvement wherein the microbubbles are formed by dissolving in the liquid a solid which is particulate, is substantially free of microbubbles, and consists predominantly of particles which have a plurality of gas-filled voids communicating with the surface of the particles and a plurality of nuclei for microbubble formation and the ratio of the mass of the particles to the volume of gas in the voids is sufficient to render the liquid in which the particulate material is dissolved supersaturated with respect to the gas in the voids in the area of the liquid surrounding the microbubbles.

2. A method according to claim 1, wherein the liquid is aqueous.

3. A method according to claim 2, wherein the liquid is the blood stream of a living being and the particulate solid is non-toxic and physiologically acceptable in the amount dissolved therein.

4. A method according to claim 3, wherein the solid particulate material is glucose, galactose, maltose or sodium chloride.

5. A method according to claim 2, wherein the solid is added as a suspension in a carrier liquid in which the particulate material is at least temporarily stable.

6. A method according to claim 5, wherein the carrier liquid is aqueous and comprises a compound which increases the viscosity thereof.

7. A method according to claim 1, wherein the solid particulate material is predominantly aggregates of at least about 10 microparticles whose average size is from about 1 to 50 micrometers.

8. A method according to claim 7, wherein the liquid is the blood stream of a living being and the particulate solid is non-toxic and physiologically acceptable in the amount dissolved therein and is added thereto as a suspension in carrier liquid in which the particulate material is at least temporarily stable and which is non-toxic and physiologically acceptable in the amount added to the blood stream.

9. A method according to claim 8, wherein the carrier liquid is aqueous and the solid precursor is glucose, galactose, maltose or sodium chloride.

10. A method of enhancing ultrasonic images in the blood of a living test subject, comprising the steps of:

(a) forming a fluid injectable suspension of;

(i) a particulate solid which is non-toxic, physiologically acceptable material, soluble in blood and substantially free of microbubbles, whose particles are aggregates having gas filled voids therebetween of smaller particles having an average size in the range of from 1 to 250 micrometers, with the ratio of the mass of the smaller particles to the volume of gas in the voids therebetween effective to render blood in which the particulate solid is dissolved supersaturated with respect to the gas in the area of the blood surrounding the microbubbles when they form therein;

in

(ii) an amount of a carrier liquid which is non-toxic and physiologically acceptable and in which the particulate material is at least temporarily stable;

(b) injecting a unit dosage amount of the fluid injectable suspension into the venous system of the test subject, thereby forming a cloud of microbubbles in the blood therein; and

(c) obtaining an ultrasonic image of the blood opposite a location containing said microbubbles.

11. A method according to claim 10, wherein the solid particulate material is glucose galactose, maltose or sodium chloride.

12. A method according to claim 10, wherein the carrier liquid is aqueous and has a viscosity substantially greater than water.

13. A method according to claim 12, wherein the particulate solid is glucose, galactose, maltose or sodium chloride.

14. A method according to claim 10, including as an added step determining both the velocity and position of said microbubbles from examination of said ultrasonic image and calculating blood flow rate from said velocity and position measurement.

15. A method according to claim 10, including as an added step calculating blood flow rate from the intensities of two images measured at said location using dye dilution techniques.

16. A method of producing a sterile injectable composition of matter in unit dosage form and adapted for injection into the blood stream of a living being and generating microbubbles therein, comprising a particulate solid which is non-toxic, physiologically acceptable material, soluble in blood and substantially free of microbubbles, whose particles are aggregates having gas filled voids therebetween of smaller particles having an average size in the range of from 1 to 250 micrometers with the ratio of the mass of the smaller particles to the volume of gas in the voids therebetween effective to render blood in which the composition of matter is dissolved supersaturated with respect to the gas in the area of the blood surrounding the microbubbles when they form therein,

comprising forming the solid into aggregates of at least about 10 particles whose average size is from about 1 to 50 micrometers.

17. A method according to claim 16, wherein the solid particulate material is glucose, galactose, maltose or sodium chloride.