Microbubble precursors and apparatus for their production and use

• US 4,657,756 A
• Filed: 09/08/1983
• Issued: 04/14/1987
• 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 L.
• Assistant Examiner(s): Jaworski, Francis J.
• Application Number:
  US06/530,301
• Time in Patent Office: 1,314 Days
• Field of Search: 424/9, 424/180, 128/660-663
• US Class Current: 424/9.52
• CPC Class Codes: A61B 8/06 Measuring blood flow measuring volume flow in general G01F, e.g. G01F1/66, G01F1/72; measuring speed of fluids in general G01P5/00
• 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. A sterile injectable fluid 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 suspension of (a) a particulate solid which is a 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, in (b) an amount of a carrier liquid which is non-toxic and physiologically acceptable and in which the particulate material is at least temporarily stable.

2. A composition of matter according to claim 1 wherein the particulate material is dextrose, galactose, maltose or sodium chloride.

3. A composition of matter according to claim 2 wherein the particulate material is galactose.

4. A composition of matter according to claim 1 wherein the solid particulate material is aggregates of at least about 10 particles whose average size is from about 1 to 50 micrometers.

5. A composition of matter according to claim 1 wherein the carrier liquid is aqueous and has a viscosity substantially greater than water.

6. A composition of matter according to claim 5 wherein the particulate material is glucose, galactose, maltose or sodium chloride.

7. A composition of matter according to claim 6 wherein the particulate material is galactose.

8. A composition according to claim 1 wherein the carrier liquid is an aqueous solution of the particulate solid suspended therein.

9. A composition according to claim 8 wherein the particulate solid is maltose, dextrose, lactose or galactose.

10. A composition according to claim 8 wherein the particulate solid is galactose.

11. A kit for providing a material for forming microbubbles in the bloodstream of a living being comprising (a) a first sealed container comprising means for gaining access to the contents thereof and containing a unit dosage amount of a particulate solid which is a 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, and (b) a second sealed container comprising means for obtaining access to the contents thereof and containing a unit dosage amount of a carrier liquid which is non-toxic and physiologically acceptable and in which the particulate material is at least temporarily stable effective to form a fluid injectable suspension when mixed with the contents of the first container.

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

13. A kit according to claim 12, wherein the solid particulate material is galactose.

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

15. A kit according to claim 12 wherein the solid particulate material is aggregates of at least about 10 particles whose average size is from about 1 to 50 micrometers.

16. A kit according to claim 11 wherein the solid particulate material is maltose, dextrose, lactose, or galactose and the carrier liquid is an aqueous solution thereof having a viscosity substantially greater than water.

17. A kit according to claim 16 wherein the solid particulate material is galactose.