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WO1993006869A1 - Gaseous ultrasound contrast agents - Google Patents

Gaseous ultrasound contrast agents Download PDF

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Publication number
WO1993006869A1
WO1993006869A1 PCT/US1992/008385 US9208385W WO9306869A1 WO 1993006869 A1 WO1993006869 A1 WO 1993006869A1 US 9208385 W US9208385 W US 9208385W WO 9306869 A1 WO9306869 A1 WO 9306869A1
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WO
WIPO (PCT)
Prior art keywords
gas
ultrasound
mixture
composition
oxygen
Prior art date
Application number
PCT/US1992/008385
Other languages
French (fr)
Inventor
Donald R. Vanderipe
Original Assignee
Mallinckrodt Medical, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Mallinckrodt Medical, Inc. filed Critical Mallinckrodt Medical, Inc.
Publication of WO1993006869A1 publication Critical patent/WO1993006869A1/en

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/22—Echographic preparations; Ultrasound imaging preparations ; Optoacoustic imaging preparations
    • A61K49/222—Echographic preparations; Ultrasound imaging preparations ; Optoacoustic imaging preparations characterised by a special physical form, e.g. emulsions, liposomes
    • A61K49/223—Microbubbles, hollow microspheres, free gas bubbles, gas microspheres

Definitions

  • the present invention relates to composition useful for ultrasound imaging and to the use of such compositions.
  • An object of the present invention is to provide ultrasound agents which would obviate or lessen the problems and disadvantages cited above.
  • This invention relates to ultrasound contrast agents comprising pharmaceutically acceptable gases or gas mixtures capable of forming gas bubbles after administration in the arterial and/or arteriolar circulation and the tissues supplied by said circulation of a warm blooded animal.
  • the gas bubbles are of appropriate size to enhance ultrasound imaging It was quite surprising, and contrary to teachings i physiology and pharmacology, that selected gases o gas mixtures after administration form gas bubble within the arterial circulation under conditions whic provide for diagnostic ultrasound contrast imaging in both 2D echo and Doppler contrast procedures. More importantly, these gases can be transported across the capillary and cell membranes and reform bubbles within the extracellular and intracellular space of the tissue to be imaged.
  • Another feature of this invention is the use of these agents to enhance the contrast of a diagnostic ultrasound procedure on a warm blooded animal. Still another feature is a sterile composition comprising the agent. Another feature is the use of said compositions to enhance the contrast of magnetic resonance imaging.
  • gases and gas mixtures useful in the practice of this invention are best composed of gases which tend to form larger bubbles in the blood and tissues and might be typified by xenon and nitrous oxide and other weakly active general anesthetics such as sulfur hexafluoride.
  • gases which tend to form larger bubbles in the blood and tissues
  • many other types of nontoxic gases, such as other perfluorocarbons would be useful, provided they form bubbles in the blood of the appropriate size.
  • gas mixtures under varying conditions of barometri pressure are useful and advantageous. For example maximum blood/tissue contrast might be expected i cases where the inhaled partial pressure of the ga mixture is retained at a high percentage of th inhaled gases and the barometric pressure of th environment is reduced.
  • the siz of the bubbles should grow and provide enhanced tissu contrast.
  • decreased contrast might b expected with smaller bubbles and, in cases wherei the subject is imaged under hyperbaric conditions, th latter compressing the gas back into solution.
  • composition of such ultrasound contrast gas mixtures may be varied, but in practice should always contain oxygen to insure proper oxygenation if the gas is to be inhaled for a significant period of time.
  • the mixture would be of two or three gases, but might, on occasion, include more complex mixtures.
  • the gas mixtures would be prepared according to th art using those available from the fractionation o air (oxygen, carbon dioxide, nitrogen, xenon, argon, krypton, neon, helium, etc.) and those prepare synthetically, such as the perfluorocarbons, etc.
  • Agents which would not generally be acceptable include the highly potent anesthetic methoxyflurane, and those less potent, but very effective, anesthetics such as chloroform, cyclopropane, halothane, enflurane, diethyl ether, fluoroxene and enflurane.
  • Gases with maximum efficacy would include nitrous oxide, xenon, ethylene, sulfur hexafluoride, argon, and the like.
  • the basis on which the various gases might b optimized would be based on their oil:gas partitio coefficients being reflected in the size of the ga bubbles which they form in the body formed within th body.
  • the potent and clinically use anesthetics listed above form gas bubbles of 4 microns or less, most of which are less than two microns. Ultrasound is poorly reflected by such small bubbles and therefore these agents would be predicted to provide poor contrast especially at safe and/or subanesthetic concentrations.
  • nitrous oxide can form gas bubbles in the body as large as 7-8 microns, a size which provides for excellent ultrasound reflectivity and those gases with similar oil:gas partition coefficients, namely, xenon and ethylene, would be expected to produce similar sized bubbles in the body (Goodman & Gilman above) .
  • gases with very low oil:gas partition coefficients might become less effective by virtue of being too soluble in water.
  • Nitrogen might be such a gas under most physiologic conditions and it has an oil:gas partition coefficient of about 0.1.
  • the gases to provide in vivo ultrasound contrast when inhaled should optimally include those with olive oil:gas partition coefficients between about 10:1 (high) and about 0.01:1 (low), preferably from about 5:1 (high) to 0.1:1 (low).
  • any gas mixture which needs to be inhaled for any significant length of time in order to provide optimal contrast would need to have oxygen as a necessary component gas, usually at about 20% by volume. Examples of effective gas mixtures would include:
  • the agents are used in the usual manner.
  • the gas or gas mixtures may be sterilized prior to administration or administered through a sterile filter.
  • an organ or tissue would be imaged prior to the administration of the gas mixture(s) in order to obtain a control tissue ultrasound signal level.
  • an agent o this invention would be administered by inhalation b the use of equipment well known to the art, eithe from a single gas container with the gases premixed or via the use of gas mixing valves and using two or more gas containers as appropriate.
  • the inhaled gas mixture would then circulate to the tissues via the blood stream and be distributed to each tissue in a manner consistent with the blood supply to the tissue.
  • control (normal) test as described above would be repeated after exercise or following the administration of pharmacologic stress agents to assess blood flow deficits or slower signal build up in low flow areas of the body.
  • Such rest and stress protocols have been used for some time in nuclear medicine as the thallium (Tl-201) stress test.
  • the inhalation of gases to provide the above ultrasound contrast will be for times suitable for ultrasound imaging, usually short periods generally less than about five minutes, but could b prolonged depending on the clinical application, e.g. monitoring of the return of tissue perfusion after period of ischemia.
  • the gas or gas mixtures might be inhaled over broad time frames with the clinical use determining the individual administration protocol.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Acoustics & Sound (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Radiology & Medical Imaging (AREA)
  • Epidemiology (AREA)
  • Physics & Mathematics (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Ultra Sonic Daignosis Equipment (AREA)

Abstract

This invention relates to methods for ultrasound imaging utilizing a gas or mixture of gases capable of forming bubbles after administration.

Description

GASEOUS ULTRASOUND CONTRAST AGENTS
The present invention relates to composition useful for ultrasound imaging and to the use of such compositions.
Since the early days of the use of ultrasound for in vivo diagnostic imaging, there has been an ongoing interest and effort to discover and develop agents suitable for providing contrast to the ultrasound images. Generally, gases have been found to provide the best contrast for intravascular images. The earliest success may have been the work of Gramiak et al., Radiology 92. 939-948 (1969), wherein they demonstrated enhanced echogenicity following the rapid intravascular injection of various solutions in humans. Of those tested, the most echogenic was the dye indocyanine green which was observed to have present in the bottle a minute amount of foam to which the contrast effect was attributed. Since then, many accounts of echogenic contrast have been reported for right heart studies, e.g. shunt detection, after i.v. injection of agitated solutions, including blood, saline. X-ray contrast agent and the like, the agitation forming visible and smaller bubbles within the solutions. However, such agents injected intravenously are restricted to right,heart imaging since the bubbles produced are too large to pass the capillary bed of the lungs where the bubbles ar trapped and easily broken. The use of such bubbles o the left side of the heart has been limited since th requirement of placing an arterial catheter i generally inconsistent with the noninvasive nature o the ultrasound examination. To provide for ga bubbles which can traverse the capillary bed of th lungs and provide for ultrasound echogenicity of th arterial circulation and organs subserved by th arterial circulation, most attempts have feature efforts to entrap or encapsulate gases within smal size-controlled icrospheres or particles composed, for example, of albumin, gelatin, sugars and the like. Such encapsulated gases may then be protected from trapping and breakage during passage through the pulmonary circulation. Although a number of early attempts were made to provide for this performance property, it was not until the mid-1980's that such agents were discovered as described in Feinstein U.S. 4,718,433.
Although these early attempts provide for contrast of the arterial circulation, they have certain disadvantages in their use. Such disadvantages include the need for some agents to be infused continuously or injected frequently in order to provide ongoing contrast because of the lability of these bubbles to the pressures encountered in the arterial circulation. In these cases, relatively hig doses of the encapsulating materials may need to b administered which may affect the safety of th agents. As well, the need to administer these agent by intravenous injections carries all the attendan disadvantages of accessing the vascular space, i.e the needle puncture and risk of bleeding, clotting hematoma, and disease transmission (hepatitis, etc. Finally, none of these agents have a demonstrate ability to cross the capillary endothelium and ente the nonvascular extracellular fluid space or th intracellular space, therein limiting their usefulnes to blood vessel contrast and not permitting tissu perfusion data in a manner similar to the well established nuclear medicine procedure employin thallium-201 for heart imaging studies. Hence, th current agents offer a less than optimal method t provide for arterial ultrasound contrast.
An object of the present invention is to provide ultrasound agents which would obviate or lessen the problems and disadvantages cited above.
This invention relates to ultrasound contrast agents comprising pharmaceutically acceptable gases or gas mixtures capable of forming gas bubbles after administration in the arterial and/or arteriolar circulation and the tissues supplied by said circulation of a warm blooded animal. The gas bubbles are of appropriate size to enhance ultrasound imaging It was quite surprising, and contrary to teachings i physiology and pharmacology, that selected gases o gas mixtures after administration form gas bubble within the arterial circulation under conditions whic provide for diagnostic ultrasound contrast imaging in both 2D echo and Doppler contrast procedures. More importantly, these gases can be transported across the capillary and cell membranes and reform bubbles within the extracellular and intracellular space of the tissue to be imaged.
Another feature of this invention is the use of these agents to enhance the contrast of a diagnostic ultrasound procedure on a warm blooded animal. Still another feature is a sterile composition comprising the agent. Another feature is the use of said compositions to enhance the contrast of magnetic resonance imaging.
The gases and gas mixtures useful in the practice of this invention are best composed of gases which tend to form larger bubbles in the blood and tissues and might be typified by xenon and nitrous oxide and other weakly active general anesthetics such as sulfur hexafluoride. However, many other types of nontoxic gases, such as other perfluorocarbons, would be useful, provided they form bubbles in the blood of the appropriate size. Furthermore, the use of gas mixtures under varying conditions of barometri pressure are useful and advantageous. For example maximum blood/tissue contrast might be expected i cases where the inhaled partial pressure of the ga mixture is retained at a high percentage of th inhaled gases and the barometric pressure of th environment is reduced. In this situation, the siz of the bubbles should grow and provide enhanced tissu contrast. Conversely, decreased contrast might b expected with smaller bubbles and, in cases wherei the subject is imaged under hyperbaric conditions, th latter compressing the gas back into solution. It ma be possible to provide an assessment of relativ differences in tissue perfusion merely through th inhalation of room air and imaging first unde hypobaric conditions to optimize contrast and the reimage as the barometric pressure is increased t monitor the disappearance of contrast. Although such may be possible with room air, any differences should be enhanced by the inhalation of an optimized gas mixture.
The composition of such ultrasound contrast gas mixtures may be varied, but in practice should always contain oxygen to insure proper oxygenation if the gas is to be inhaled for a significant period of time.
Typically, the mixture would be of two or three gases, but might, on occasion, include more complex mixtures. The gas mixtures would be prepared according to th art using those available from the fractionation o air (oxygen, carbon dioxide, nitrogen, xenon, argon, krypton, neon, helium, etc.) and those prepare synthetically, such as the perfluorocarbons, etc.
Normally, 15-25% of oxygen is present.
Although ultrasound contrast may be achievable using room air alone or under hypobaric conditions, optimized formulations and mixtures would be composed of gases which would form bubbles of optimum size in the tissues. Typically, these would be those gases which are poorly soluble in oil and somewhat more soluble in water and which would have a low partition coefficient when exposed to olive oil, i.e., those which would be described as weak or poor anesthetic agents (See Goodman & Gilman, The Pharmacoloqic Basis of Therapeutics, 8th Ed., 282). Such agents for maximum efficacy should have olive oil:gas partition coefficients of less than about 5:1 at 37 degrees centigrade, i.e., body temperature. Agents which would not generally be acceptable include the highly potent anesthetic methoxyflurane, and those less potent, but very effective, anesthetics such as chloroform, cyclopropane, halothane, enflurane, diethyl ether, fluoroxene and enflurane. Gases with maximum efficacy would include nitrous oxide, xenon, ethylene, sulfur hexafluoride, argon, and the like. The basis on which the various gases might b optimized would be based on their oil:gas partitio coefficients being reflected in the size of the ga bubbles which they form in the body formed within th body. Generally, the potent and clinically use anesthetics listed above form gas bubbles of 4 microns or less, most of which are less than two microns. Ultrasound is poorly reflected by such small bubbles and therefore these agents would be predicted to provide poor contrast especially at safe and/or subanesthetic concentrations. However, nitrous oxide can form gas bubbles in the body as large as 7-8 microns, a size which provides for excellent ultrasound reflectivity and those gases with similar oil:gas partition coefficients, namely, xenon and ethylene, would be expected to produce similar sized bubbles in the body (Goodman & Gilman above) . As one progresses toward even lower oil:gas partition coefficients, e.g., sulfur hexafluoride and argon, the size of the bubbles should continue to increase, further enhancing the noted contrast. Although not clearly identified as to point of cut-off, it is probable that gases with very low oil:gas partition coefficients might become less effective by virtue of being too soluble in water. Nitrogen might be such a gas under most physiologic conditions and it has an oil:gas partition coefficient of about 0.1. Therein the gases to provide in vivo ultrasound contrast when inhaled should optimally include those with olive oil:gas partition coefficients between about 10:1 (high) and about 0.01:1 (low), preferably from about 5:1 (high) to 0.1:1 (low). In addition, any gas mixture which needs to be inhaled for any significant length of time in order to provide optimal contrast, would need to have oxygen as a necessary component gas, usually at about 20% by volume. Examples of effective gas mixtures would include:
1) 20% oxygen; 80% sulfur hexafluoride
2) 20% oxygen; 20% nitrogen; 60% nitrous oxide
3) 20% oxygen; 20% nitrogen; 60%xenon
4) 20% oxygen; 20% nitrous oxide; 60% sulfur hexafluoride
5) 20% oxygen; 20% xenon; 60% sulfur hexafluoride
6) 20% oxygen; 20% ethylene; 60% sulfur hexafluoride Clearly, a number of the many synthetic fluorocarbon gases could be substituted for or added to sulfur hexafluoride.
In the practice of this invention, the agents are used in the usual manner. The gas or gas mixtures may be sterilized prior to administration or administered through a sterile filter. For example, an organ or tissue would be imaged prior to the administration of the gas mixture(s) in order to obtain a control tissue ultrasound signal level. This would be accomplished using one of the readily available commerciall marketed ultrasound machines such as Acuson, Toshiba, Hewlett Packard, ATL and the like. Then an agent o this invention would be administered by inhalation b the use of equipment well known to the art, eithe from a single gas container with the gases premixed or via the use of gas mixing valves and using two or more gas containers as appropriate. The inhaled gas mixture would then circulate to the tissues via the blood stream and be distributed to each tissue in a manner consistent with the blood supply to the tissue. By monitoring the ultrasound signal build up, either with 2D echo and/or color Doppler mapping, one could compare the blood flow to various tissues over time. Clearly, such procedures would be readily repeatable following short breathe-out periods and this would allow for both control and stress test studies to be conducted during a short time frame. The control (normal) test as described above would be repeated after exercise or following the administration of pharmacologic stress agents to assess blood flow deficits or slower signal build up in low flow areas of the body. Such rest and stress protocols have been used for some time in nuclear medicine as the thallium (Tl-201) stress test.
Typically, the inhalation of gases to provide the above ultrasound contrast will be for times suitable for ultrasound imaging, usually short periods generally less than about five minutes, but could b prolonged depending on the clinical application, e.g. monitoring of the return of tissue perfusion after period of ischemia. Conversely, one might inhale th gas mixture for a very short period of time in orde to get transient type information such as first pass organ/tissue perfusion, etc. Therein it is envisioned that the gas or gas mixtures might be inhaled over broad time frames with the clinical use determining the individual administration protocol.
It is to be understood that the invention is not to be limited to the exact details of operation or exact compositions or procedures shown or described. Obvious modifications and equivalents will be apparent to one skilled in the art, and the invention is therefore to be limited only by the scope of the appended claims.

Claims

Claims
1. The method of ultrasound imaging of a warm blooded animal comprising administering an ultrasound contrast agent comprising a pharmaceutically acceptable gas or mixture of gases in an ultrasound diagnostic amount for a period suitable to image and thereafter ultrasound imaging said animal, said gas or mixture of gases being capable of forming bubbles after administration of a size appropriate to enhance imaging in the arterial or arteriolar circulation and tissues supplied by said blood circulation.
2. A composition for ultrasound imaging comprising a pharmaceutically acceptable gas or mixture of gases, said gas or mixture of gases being capable after administration of forming bubbles of a size appropriate to enhance imaging in the arterial or arteriolar circulation and tissues supplied by said blood circulation.
3. The composition of claim 2 wherein the ultrasound said gas is xenon.
4. The composition of claim 2 wherein said gas is ethylene.
5. The composition of claim 2 wherein said gas is nitrous oxide.
6. The composition of claim 2 wherein said gas is sulfur hexafluoride.
7. The composition of claim 2 wherein said gas is argon.
8. The composition of claim 2 wherein said gas is selected from the group consisting of a perfluorocarbon gas.
9. The composition of claim 5 wherein the agent additionally contains oxygen.
10. The composition of claim 6 which additionally contains oxygen.
11. The method of claim 1 wherein said gas is xenon or a mixture of xenon and oxygen.
12. The method of claim 1 wherein said gas is ethylene or a mixture of ethylene and oxygen.
13. The method of claim 1 wherein said gas is nitrous oxide or a mixture of nitrous oxide and oxygen.
14. The method of claim 1 wherein said gas is sulfur hexafluoride or a mixture of sulfur hexafluoride or oxygen.
15. The method of claim 1 wherein said gas is argon or a mixture of argon and oxygen.
16. The method of claim 1 wherein said gas is selected from the group consisting of perfluorocarbon gas and mixtures.
17. The method of claim 1 wherein the ultrasound contrast gas procedure is used to image cardiac perfusion at rest and following exercise.
18. The method of claim 1 wherein the ultrasound procedure utilizes the modes of 2D echo, doppler, color doppler or color mapping.
19. The method of claim 1 wherein the ultrasound procedure is used to assess the perfusio of any peripheral noncardiac organ or tissue both a rest and after exercise.
PCT/US1992/008385 1991-10-04 1992-10-02 Gaseous ultrasound contrast agents WO1993006869A1 (en)

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US07/771,300 1991-10-04

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US5348016A (en) * 1989-12-22 1994-09-20 Unger Evan C Apparatus for preparing gas filled liposomes for use as ultrasonic contrast agents
WO1995003835A1 (en) * 1993-07-30 1995-02-09 Alliance Pharmaceutical Corp. Stabilized microbubble compositions for ultrasound
US5393524A (en) * 1991-09-17 1995-02-28 Sonus Pharmaceuticals Inc. Methods for selecting and using gases as ultrasound contrast media
US5406950A (en) * 1993-12-23 1995-04-18 Mallinckrodt Medical, Inc. Inhalable contrast agent
WO1995016467A1 (en) * 1993-12-15 1995-06-22 Bracco Research S.A. Gas mixtures useful as ultrasound contrast media
US5456901A (en) * 1989-12-22 1995-10-10 Unger; Evan C. Liposomes as contrast agents for ultrasonic imaging
US5469854A (en) * 1989-12-22 1995-11-28 Imarx Pharmaceutical Corp. Methods of preparing gas-filled liposomes
WO1996009793A1 (en) * 1994-09-28 1996-04-04 Alliance Pharmaceutical Corp. Harmonic ultrasound imaging with microbubbles
US5542935A (en) * 1989-12-22 1996-08-06 Imarx Pharmaceutical Corp. Therapeutic delivery systems related applications
US5558094A (en) * 1991-09-17 1996-09-24 Sonus Pharmaceuticals, Inc. Methods for using persistent gases as ultrasound contrast media
US5558854A (en) * 1991-09-17 1996-09-24 Sonus Pharmaceuticals Ultrasound contrast media comprising perfluoropentane and perfluorohexane gas
US5558855A (en) * 1993-01-25 1996-09-24 Sonus Pharmaceuticals Phase shift colloids as ultrasound contrast agents
US5558853A (en) * 1993-01-25 1996-09-24 Sonus Pharmaceuticals Phase shift colloids as ultrasound contrast agents
US5580575A (en) * 1989-12-22 1996-12-03 Imarx Pharmaceutical Corp. Therapeutic drug delivery systems
WO1996040288A1 (en) * 1995-06-07 1996-12-19 Mallinckrodt Medical, Inc. Gaseous ultrasound contrast agents and method therefor
WO1998003205A3 (en) * 1996-07-19 1998-03-05 Sonus Pharma Inc Enhanced ultrasound contrast imaging using inhaled gases
US5798091A (en) * 1993-07-30 1998-08-25 Alliance Pharmaceutical Corp. Stabilized gas emulsion containing phospholipid for ultrasound contrast enhancement
US5804162A (en) * 1995-06-07 1998-09-08 Alliance Pharmaceutical Corp. Gas emulsions stabilized with fluorinated ethers having low Ostwald coefficients
US6001332A (en) * 1995-02-16 1999-12-14 The Boc Group Plc Medical gas mixture
US6110443A (en) * 1990-04-02 2000-08-29 Bracco International N.V. Dry stable formation to produce microbubble suspension for ultrasound
WO2002054946A3 (en) * 2001-01-12 2002-10-10 Nycomed Imaging As Ultrasonic imaging of perfusion using gases with different partial pressures
US6569404B1 (en) 1993-01-25 2003-05-27 Amersham Health A/S Phase shift colloids as ultrasound contrast agents
US6613306B1 (en) 1990-04-02 2003-09-02 Bracco International B.V. Ultrasound contrast agents and methods of making and using them
US6881397B2 (en) 1990-04-02 2005-04-19 Bracco International B.V. Long-lasting aqueous dispersions or suspensions of pressure-resistant gas-filled microvesicles and methods for the preparation thereof
US6884407B1 (en) 1996-09-11 2005-04-26 Bristol-Myers Squibb Pharma Company Methods for diagnostic imaging involving the use of a contrast agent and a coronary vasodilator
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US6989141B2 (en) 1990-05-18 2006-01-24 Bracco International B.V. Ultrasound contrast agents and methods of making and using them
US6998107B2 (en) 1991-04-05 2006-02-14 Bristol-Myers Squibb Pharma Comapany Composition comprising low density microspheres
USRE39146E1 (en) 1990-04-02 2006-06-27 Bracco International B.V. Long-lasting aqueous dispersions or suspensions of pressure-resistant gas-filled microvesicles and methods for the preparation thereof
US7078015B2 (en) 1989-12-22 2006-07-18 Imarx Therapeutics, Inc. Ultrasound imaging and treatment
US7083778B2 (en) 1991-05-03 2006-08-01 Bracco International B.V. Ultrasound contrast agents and methods of making and using them
US7083572B2 (en) 1993-11-30 2006-08-01 Bristol-Myers Squibb Medical Imaging, Inc. Therapeutic delivery systems
US7105151B2 (en) 1997-06-18 2006-09-12 Imarx Therapeutics, Inc. Oxygen delivery agents and uses for the same
US7329402B2 (en) 1995-06-07 2008-02-12 Imarx Pharmaceutical Corp. Methods of imaging and treatment
US7405241B2 (en) * 2003-01-15 2008-07-29 Air Liquide Sante (International) Use of N2O in the treatment of post-ischemic brain cell deterioration
US7452551B1 (en) 2000-10-30 2008-11-18 Imarx Therapeutics, Inc. Targeted compositions for diagnostic and therapeutic use
US7612033B2 (en) 1994-11-29 2009-11-03 Imarx Pharmaceutical Corp. Methods for delivering compounds into a cell
WO2011035140A1 (en) 2009-09-18 2011-03-24 Paka Pulmonary Pharmaceuticals, Inc. Methods and compositions for delivery of contrast moieties to the lungs
US9545457B2 (en) 1998-01-14 2017-01-17 Lantheus Medical Imaging, Inc. Preparation of a lipid blend and a phospholipid suspension containing the lipid blend
US9789210B1 (en) 2016-07-06 2017-10-17 Lantheus Medical Imaging, Inc. Methods for making ultrasound contrast agents
US10022460B2 (en) 2014-12-31 2018-07-17 Lantheus Medical Imaging, Inc. Lipid-encapsulated gas microsphere compositions and related methods
US10588988B2 (en) 2016-05-04 2020-03-17 Lantheus Medical Imaging, Inc. Methods and devices for preparation of ultrasound contrast agents

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Cited By (92)

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Publication number Priority date Publication date Assignee Title
US5456901A (en) * 1989-12-22 1995-10-10 Unger; Evan C. Liposomes as contrast agents for ultrasonic imaging
US5580575A (en) * 1989-12-22 1996-12-03 Imarx Pharmaceutical Corp. Therapeutic drug delivery systems
US5542935A (en) * 1989-12-22 1996-08-06 Imarx Pharmaceutical Corp. Therapeutic delivery systems related applications
US5469854A (en) * 1989-12-22 1995-11-28 Imarx Pharmaceutical Corp. Methods of preparing gas-filled liposomes
US5348016A (en) * 1989-12-22 1994-09-20 Unger Evan C Apparatus for preparing gas filled liposomes for use as ultrasonic contrast agents
US7078015B2 (en) 1989-12-22 2006-07-18 Imarx Therapeutics, Inc. Ultrasound imaging and treatment
USRE39146E1 (en) 1990-04-02 2006-06-27 Bracco International B.V. Long-lasting aqueous dispersions or suspensions of pressure-resistant gas-filled microvesicles and methods for the preparation thereof
US6136293A (en) * 1990-04-02 2000-10-24 Bracco International B.V. Stable microbubbles suspensions containing saturated lamellar phospholipids
US6485705B1 (en) 1990-04-02 2002-11-26 Bracco International B.V. Mixable combination for generating a suspension of stable microbubbles for ultrasonic imaging
US6110443A (en) * 1990-04-02 2000-08-29 Bracco International N.V. Dry stable formation to produce microbubble suspension for ultrasound
US6613306B1 (en) 1990-04-02 2003-09-02 Bracco International B.V. Ultrasound contrast agents and methods of making and using them
US6881397B2 (en) 1990-04-02 2005-04-19 Bracco International B.V. Long-lasting aqueous dispersions or suspensions of pressure-resistant gas-filled microvesicles and methods for the preparation thereof
US6896875B2 (en) 1990-04-02 2005-05-24 Bracco International B.V. Mixable combination for generating a suspension of stable microbubbles for ultrasonic imaging
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