Stable microbubble suspensions as enhancement agents for ultrasound echography and dry formulations thereof
First Claim
1. An ultrasound contrast agent comprising an aqueous suspension of gas filled microbubbles comprising a saturated phospholipid, a fatty acid, a hydrophilic stabilizer, and SF6, wherein the amount of the saturated phospholipid in the suspension is less than about 0.01% by weight.
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Abstract
Disclosed are injectable suspensions of gas filled microbubbles in an aqueous carrier liquid usable as contrast agents in ultrasonic echography. The suspensions comprise amphipathic compounds of which at least one may be a laminarized phospholipid as a stabiliser of the microbubbles against collapse with time and pressure. The concentration of phospholipids in the carrier liquid is below 0.01% wt but is at least equal to or above that at which phospholipid molecules are present solely at the gas microbubble-liquid interface. Also disclosed are methods of preparation of the stable suspensions of gas filled microbubbles, as well as dry formulations which, upon reconstitution in an aqueous carrier liquid, will form the injectable suspensions of gas filled microbubbles of the invention and methods of making and using the same The preferred dry formulations are stable when stored over time and at temperatures above ambient temperature and further comprise a lipid acid preserving agent additive.
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Citations
60 Claims
- 1. An ultrasound contrast agent comprising an aqueous suspension of gas filled microbubbles comprising a saturated phospholipid, a fatty acid, a hydrophilic stabilizer, and SF6, wherein the amount of the saturated phospholipid in the suspension is less than about 0.01% by weight.
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11. A method of imaging a region of a body comprising:
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(a) administering to the body an aqueous suspension of gas filled microbubbles comprising a saturated phospholipid, a fatty acid, a hydrophilic stabilizer, and SF6, wherein the amount of the saturated phospholipid in the suspension is less than 0.01% by weight; and
(b) imaging the body. - View Dependent Claims (12, 13, 14, 15, 16, 17, 18, 19, 20, 21)
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- 22. A dry formulation of an ultrasound contrast agent comprising a saturated phospholipid, a fatty acid, and a hydrophilic stabilizer, wherein upon dissolution in an aqueous carrier liquid, the dry formulation will form a suspension of microbubbles comprising SF6 in which the amount of saturated phospholipid in the suspension is less than about 0.01% by weight.
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35. A method of preparing a contrast agent comprising an aqueous suspension of gas filled microbubbles comprising SF6 and saturated phospholipid, wherein the amount of saturated phospholipid in the suspension is less than about 0.01% by weight, the method comprising:
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(a) dissolving at least one saturated phospholipid, a fatty acid, and a hydrophilic stabilizer in an organic solvent to form a solution;
(b) freeze drying or spray drying the solution to form a dried powder;
(c) contacting the dried powder with SF6; and
(d) mixing the freeze dried or spray dried powder with an aqueous carrier phase.
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36. A method of preparing a dry formulation of an ultrasound contrast agent, wherein upon dissolution in an aqueous carrier liquid, the dry formulation will form a suspension of microbubbles comprising SF6 and saturated phospholipid, wherein the amount of the saturated phospholipid in the suspension is less than about 0.01% by weight, the method comprising:
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(a) dissolving at least one saturated phospholipid, a fatty acid, and a hydrophilic stabilizer in an organic solvent to form a solution;
(b) freeze drying or spray drying the solution to form a dried powder; and
(c) contacting the dried powder with SF6.
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37. A method of preparing a dry formulation of an ultrasound contrast agent, wherein upon dissolution in an aqueous carrier liquid, the dry formulation will form a suspension of microbubbles comprising SF6 and saturated phospholipid, wherein the amount of the saturated phospholipid in the suspension is less than about 0.01% by weight, the method comprising:
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(a) dissolving at least one saturated phospholipid and a hydrophilic stabilizer in an organic solvent to form a solution;
(b) freeze drying or spray drying the solution to form a dried powder;
(c) mixing the dried powder with a fatty acid to form a mixture; and
(d) contacting the mixture with SF6.
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- 38. An ultrasound contrast agent comprising an aqueous suspension of gas filled microbubbles comprising a saturated phospholipid, a preserving agent, SF6, and a hydrophilic stabilizer, wherein the amount of saturated phospholipid in the suspension is less than about 0.01% by weight, and the preserving agent comprises a fatty acid.
- 48. A dry formulation of an ultrasound contrast agent comprising a saturated phospholipid, a preserving agent, and a hydrophilic stabilizer, wherein the preserving agent comprises a fatty acid, and upon dissolution in an aqueous carrier liquid, the dry formulation will form a suspension of microbubbles comprising SF6 in which the amount of saturated phospholipid in the suspension is less than about 0.01% by weight.
Specification