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WO1998003205A2 - Renforcement des contrastes d'echographie par utilisation de gaz inhales - Google Patents

Renforcement des contrastes d'echographie par utilisation de gaz inhales Download PDF

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Publication number
WO1998003205A2
WO1998003205A2 PCT/US1997/012354 US9712354W WO9803205A2 WO 1998003205 A2 WO1998003205 A2 WO 1998003205A2 US 9712354 W US9712354 W US 9712354W WO 9803205 A2 WO9803205 A2 WO 9803205A2
Authority
WO
WIPO (PCT)
Prior art keywords
ultrasound
gas
contrast agent
microbubbles
patient
Prior art date
Application number
PCT/US1997/012354
Other languages
English (en)
Other versions
WO1998003205A3 (fr
Inventor
Steven C. Quay
Original Assignee
Sonus Pharmaceuticals, 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 Sonus Pharmaceuticals, Inc. filed Critical Sonus Pharmaceuticals, Inc.
Priority to AU36652/97A priority Critical patent/AU3665297A/en
Publication of WO1998003205A2 publication Critical patent/WO1998003205A2/fr
Publication of WO1998003205A3 publication Critical patent/WO1998003205A3/fr

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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
    • 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

  • This invention relates generally to enhancement of ultrasound contrast imaging by causing inhalation of gases. More specifically, the invention relates to ultrasound imaging of the left cardiac chambers of the heart or organs of the body receiving blood from the lungs, by intravenous administration of an ultrasound contrast agent in conjunction with inhalation of a gas or gas mixture.
  • Ultrasound imaging is a non-invasive method of imaging the organs and structures of human and animal subjects.
  • the ultrasound image can be enhanced using ultrasound contrast agents.
  • contrast agents for use in diagnostic ultrasound, including echocardiography, have been described.
  • a review of the subject is found in Ophir and Parker, Ultrasound in Med. & Biol. (1 989), 1 5:31 9-333, although research has intensified since the publication of this article.
  • WO 95/33447 teaches the use of fluorocarbon containing emulsions.
  • WO 95/07072 Weitschies et al.
  • WO 95/22994 Heldmann et al.
  • U.S. Pat. No. 5,393,524 teaches a method for selecting and using gases as ultrasound agents whose solubility in air is higher than their solubility in blood.
  • U.S. Pat No. 5,409,688 discloses several such gaseous ultrasound contrast agents.
  • U.S. Pat. No. 5,558,854 specifically describes perfluoropentane and perfluorohexane as effective ultrasound contrast agents.
  • Another approach has been to use compounds that are normally liquids at manufacturing temperatures, but which become gases inside the body. These compounds are then administered in the form of liquid-in-liquid dispersions. For example, U.S. Pat. Nos.
  • 5,858,855 and 5,558,853 teach the use of colloidal dispersions of ultrasonic contrast agents, wherein the dispersed liquid contrast agent has a boiling point at or below the body temperature of the organism to be studied.
  • U.S. Pat. No. 5,595,723 (Quay) teaches methods of preparing such stable colloidal dispersions of ultrasound contrast agents.
  • microbubbles produced using the above approaches permits intravenous administration of ultrasound contrast agents.
  • Injected microbubbles travel through the bloodstream to the right heart, which may then be imaged. After being pumped through the right heart, the microbubbles travel to the lungs and then into the left cardiac chambers of the heart.
  • the lungs are very efficient at outgassing blood.
  • One result of this efficiency is that the size and number of microbubbles reaching the left heart or body is greatly diminished. As a result of this decrease in the number and size of the microbubbles reaching the left chambers of the heart, the intensity of the ultrasound signal is low.
  • the present invention is directed to a method of performing diagnostic imaging wherein the efficacy of contrast agent in imaging the left heart is greatly increased.
  • a subject inhales a selected gas or gas mixture while microbubbles or microbubble precursors of a contrast agent are administered intravascularly.
  • a component of the inhaled gas mixture can be a persistent gas, and can be preferably be the same gas contained in the ultrasound contrast microbubbles being administered into the blood stream.
  • the present invention can also be used to enhance a left heart and body organ ultrasound signal obtained using ultrasound contrast agents other than the gas microbubbles disclosed above.
  • ultrasound contrast agents include gas-containing micro- particles, including microparticles formed from human serum albumin, liposomes, or cross-linked polymers.
  • the agent will include a component which carries microbubbles or forms microbubbles in the blood stream.
  • the invention provides an improvement in ultrasound imaging methods in which microbubbles are peripherally injected into a patient. Many types of such agents have been proposed and the improvement will be valuable with any agent which is subject to significant outgassing as it passes through the lungs. Specifically, the invention is a method of increasing the concentration of a gas in the lungs which will reduce the amount of outgassing by the blood carried agent. To ensure a complete understanding of the invention the following definitions are provided:
  • Surfactants The group of amphiphilic materials which are manufactured by chemical processes or purified from natural sources or processes. These can be anionic, cationic, nonionic, and zwitterionic. Such materials are described in Emulsions: Theory and Practice, Paul Becher, Robert E. Krieger Publishing, Malabar, Florida, 1 965 which is hereby incorporated by reference.
  • Anionic Surfactants A surfactant with a net negative charge.
  • Polvoxypropylene-Polvoxyethylene Glvcol Nonionic Block Copolvmers The surfactants which are available from BASF
  • Performance Chemicals, Parsippan ⁇ , New Jersey under the trade name Pluronic which consists of the group of surfactants designated by the CTFA name of poloxamer 108, 1 88, 21 7, 237, 238, 288, 338, 407, 101 , 105, 122, 123, 124, 1 81 , 182, 183, 1 84, 21 2, 231 , 282, 331 , 401 , 402, 1 85, 21 5, 234, 235, 284, 333, 334, 335, and 403.
  • Pluronic which consists of the group of surfactants designated by the CTFA name of poloxamer 108, 1 88, 21 7, 237, 238, 288, 338, 407, 101 , 105, 122, 123, 124, 1 81 , 182, 183, 1 84, 21 2, 231 , 282, 331 , 401 , 402, 1 85, 21 5, 234, 235, 284, 333, 334, 335, and 403.
  • Fluorine-Containing Surfactant A surfactant containing one or more fluorine atoms.
  • fluorine containing surfactants useful in this invention can be selected from the group consisting of: telomer B containing fluorinated surfactants available from Du Pont, Wilmington, DE under the Trade name of Zonyl (including Zonyl FSA, FSP, FSE, UR, FSJ, FSN, FSO, FSC, FSK, PEG, and TBS).
  • Zonyl including Zonyl FSA, FSP, FSE, UR, FSJ, FSN, FSO, FSC, FSK, PEG, and TBS.
  • the chemical formula of one particularly useful surfactant, PEG Telomer B is given below:
  • fluorine-containing surfactants useful under the present invention include fluorochemical surfactants from 3M Industrial Chemical Products Division, St. Paul, MN under the trade name of Fluorad (including FC-95, FC-98, FC- 99, FC-143, FC-1 70C, FC-171 , FC-430, FC-99, FC-100, FC-120, FC-129, FC-135, FC-431 , FC-740), the perfluoroalkylpoly(oxyethylene) surfactants described by Mathis et al. (J Am Chem Soc 106.
  • Biocompatible Capable of performing functions within or upon a living organism in an acceptable manner, without undue toxicity or physiological or pharmacological effects.
  • High Vapor Pressure Chemical A chemical with a sufficiently high vapor pressure that colloidal dispersions of the chemical as a liquid contain, at the body temperature of an organism undergoing an ultrasound examination, a sufficient quantity of the chemical as a gaseous dispersion to provide a diagnostically useful alteration in the ultrasound data obtained during an examination.
  • biocompatible chemicals that form microbubbles are useful in the invention.
  • Preferred compounds have a boiling point less than 40°C.
  • Most preferred chemicals are fluorine-containing.
  • Chemicals useful as ultrasound contrast agents which are objects of the present invention are disclosed in United States Patents 5,393,524; 5,409,688; 5,558,094 and 5,558,854 which are co- assigned to Sonus Pharmaceuticals Inc., and are hereby incorporated by reference.
  • fluorine containing chemicals useful in the invention include dodecafluoroneopentane, perfluoropropane, perfluorobutane, perfluoropentane, perfluorohexane, perfluorocyclopentane, perfluoroheptane, perfluorooctane, sulfur hexafluoride and mixtures thereof.
  • Fluorine-Containing Compounds A compound containing at least one fluorine atom.
  • Emulsion A colloidal dispersion of one immiscible liquid dispersed in another liquid in the form of droplets, whose diameter, in general, are between 100 and 3000 nm and which is typically optically opaque, unless the dispersed and continuous phases are refractive index matched.
  • Such systems possess a limited stability, generally defined by the application or relevant reference system, which may be enhanced by the addition of amphiphilic materials or viscosity enhancers.
  • Microemulsion A stable liquid monophasic and optically isotropic colloidal dispersion of water and water-immiscible liquids stabilized by amphiphilic materials in which the dispersions have appreciable light scattering properties (meaning they can appear optically clear or milky but are reddish or yellowish if observed by transmitted light) and the diameters of the particles are, in general, between 5 and approximately 140 nm.
  • Aqueous Medium A water-containing liquid which can contain pharmaceutically acceptable additives such as acidifying agents, alkalizing agents, antimicrobial preservatives, antioxidants, buffering agents, chelating agents, complexing agents, solubilizing agents, humectants, solvents, suspending and/or viscosity-increasing agents, tonicity agents, wetting agents or other biocompatible materials.
  • the current invention can be used to improve the efficacy of ultrasound imaging in the body and particularly imaging the left heart.
  • the subject inhales a selected gas or gas mixture while an aqueous medium containing a contrast agent is injected into the bloodstream.
  • the underlying principal of the method of the current invention is that repeated inhalation of the desired gas or gas mixture causes the level of that gas in the lungs to increase substantially. Elevated lung concentrations of the inhaled gas inhibits diffusion of contrast agent from the bloodstream into the lungs. The resulting non- depletion of microbubbles of contrast agent in blood flowing from the lungs enhances the image obtained of anatomical regions receiving this blood.
  • the inhaled gas mixture or any of its components can be persistent (i.e. have low blood solubility), and can be the same gas found in the injected ultrasound contrast microbubbles.
  • C to C 10 fluorocarbon compounds, and sulfur hexafluoride are among the inhaled gases which can work well in the present invention.
  • fluorine containing chemicals useful in the invention include dodecafluoroneopentane, perfluoropropane, perfluorobutane, perfluoropentane, perfluorohexane, perfluorocyclopentane, perfluoroheptane, perfluorooctane, and mixtures thereof
  • the inhalation gas may be administered using known methods.
  • One such method is taught in U.S. Patent No. 5,487,380, which is incorporated herein by reference.
  • This patent discloses an apparatus and method for administration of gaseous anaesthetic by inhalation, where the compound inhaled by the subject is rapidly absorbed into the bloodstream.
  • an aqueous medium is administered intravenously.
  • the injected aqueous medium includes both microbubbles of ultrasound contrast agent and a fluorine-containing surfactant.
  • Emulsions of fluorine-containing surfactants are particularly useful as stabilizers of contrast agents for ultrasonic diagnostics.
  • Fluorosurfactants particularly telomerized fluorosurfactants, stabilize those chemicals capable of forming microbubbles that provide strong ultrasound contrast signals as disclosed in U.S. Patent Nos. 5,558,853 and 5,558,855 (both to Quay, and incorporated herein by reference).
  • fluorine-containing surfactants used are synthetic surfactants.
  • Preferred surfactants are fluorosurfactants, such as the Zonyl and the Fluorad brand series and polyoxypropylene-polyoxyethylene glycol nonionic block copolymers.
  • the nonionic surfactants such as PEG Telomer B, and the anionic surfactants such as Fluorad FC-99.
  • injected fluorine-containing contrast agents used in the agent of the invention those having good biocompatibility and a 5 boiling point less than 40 °C are preferred.
  • perfluorocarbons are most preferred. Examples of these preferred chemicals include dodecafluoroneopentane, perfluoropropane, perfluorobutane, perfluoropentane, perfluorohexane, perfluorocyclopentane, perfluoroheptane,
  • M.W. is molecular weight.
  • B.P. is boiling point.
  • C. Group is chemical group.
  • microbubble precursor is intended to encompass any form of agent which can produce or become a microbubble of the desired gas jn vivo.
  • Example 1 Ultrasound Imaging of Baboon Purpose:
  • Aqueous media containing the various contrast agents shown in Table 1 were prepared. 2. Within 5 minutes prior to injection of the aqueous media, anesthetized baboons began inhaling the corresponding gas mixture shown in Table 1 .
  • the syringe containing the aqueous media was activated as described in WO 96/40282. 4. The activated aqueous media was then intravenously injected via the lateral ear vein.
  • Ultramark 9 ultrasound imaging system equipped with a 7.0 MHz transducer for producing gray scale enhancement of the left heart region.
  • the gain was set to optimize the image between 20 and

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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)
  • Medicinal Preparation (AREA)
  • Ultra Sonic Daignosis Equipment (AREA)

Abstract

La présente invention concerne le renforcement des contrastes d'échographie des cavités cardiaques gauches par inhalation d'un gaz ou d'un mélange gazeux pendant l'injection intraveineuse d'un agent de contraste d'échographie. La concentration accrue du gaz inhalé dans les poumons supprime le dégazage de l'agent de contraste dans les poumons, ce qui maintient des concentrations élevées de l'agent de contraste dans le sang irriguant le coeur gauche et d'autres tissus.
PCT/US1997/012354 1996-07-19 1997-07-16 Renforcement des contrastes d'echographie par utilisation de gaz inhales WO1998003205A2 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU36652/97A AU3665297A (en) 1996-07-19 1997-07-16 Enhanced ultrasound contrast imaging using inhaled gases

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US2252896P 1996-07-19 1996-07-19
US60/022,528 1996-07-19
US89308197A 1997-07-15 1997-07-15
US08/893,081 1997-07-15

Publications (2)

Publication Number Publication Date
WO1998003205A2 true WO1998003205A2 (fr) 1998-01-29
WO1998003205A3 WO1998003205A3 (fr) 1998-03-05

Family

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1997/012354 WO1998003205A2 (fr) 1996-07-19 1997-07-16 Renforcement des contrastes d'echographie par utilisation de gaz inhales

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AU (1) AU3665297A (fr)
WO (1) WO1998003205A2 (fr)

Family Cites Families (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU679428C (en) * 1991-09-17 2006-07-13 Ge Healthcare As Gaseous ultrasound contrast media and method for selecting gases for use as ultrasound contrast media
WO1993006869A1 (fr) * 1991-10-04 1993-04-15 Mallinckrodt Medical, Inc. Agents gazeux de contraste a ultrasons
US5695740A (en) * 1993-05-12 1997-12-09 The Board Of Regents Of The University Of Nebraska Perfluorocarbon ultrasound contrast agent comprising microbubbles containing a filmogenic protein and a saccharide
US5701899A (en) * 1993-05-12 1997-12-30 The Board Of Regents Of The University Of Nebraska Perfluorobutane ultrasound contrast agent and methods for its manufacture and use
NO940711D0 (no) * 1994-03-01 1994-03-01 Nycomed Imaging As Preparation of gas-filled microcapsules and contrasts agents for diagnostic imaging
US5560364A (en) * 1995-05-12 1996-10-01 The Board Of Regents Of The University Of Nebraska Suspended ultra-sound induced microbubble cavitation imaging
JP2001515458A (ja) * 1995-06-07 2001-09-18 マリンクロッド・インコーポレイテッド 気体状超音波造影剤および造影方法

Also Published As

Publication number Publication date
AU3665297A (en) 1998-02-10
WO1998003205A3 (fr) 1998-03-05

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