EP0689462A1 - Improvements in or relating to contrast agents - Google Patents

Improvements in or relating to contrast agents

Info

Publication number
EP0689462A1
EP0689462A1 EP94909227A EP94909227A EP0689462A1 EP 0689462 A1 EP0689462 A1 EP 0689462A1 EP 94909227 A EP94909227 A EP 94909227A EP 94909227 A EP94909227 A EP 94909227A EP 0689462 A1 EP0689462 A1 EP 0689462A1
Authority
EP
European Patent Office
Prior art keywords
contrast agent
gas
administration
generating
substance
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP94909227A
Other languages
German (de)
English (en)
French (fr)
Inventor
Arne Aabye
Arne Berg
Harald Dugstad
Kari Dyvik
Per Antonius Foss
Jo Klaveness
Jonny Ostensen
P L Rongved
Per Strande
Helge Tolleshaug
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
GE Healthcare AS
Original Assignee
Nycomed Imaging AS
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 Nycomed Imaging AS filed Critical Nycomed Imaging AS
Publication of EP0689462A1 publication Critical patent/EP0689462A1/en
Withdrawn legal-status Critical Current

Links

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
    • 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
    • A61K49/227—Liposomes, lipoprotein vesicles, e.g. LDL or HDL lipoproteins, micelles, e.g. phospholipidic or polymeric
    • 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 to novel contrast agents, more particularly to new microparticulate contrast agents of use in diagnostic imaging.
  • Ultrasound imaging is based on penetration of ultrasound waves, e.g. in the frequency range 1-10 MHz, into a human or animal subject via a transducer, the ultrasound waves interacting with interfaces of body tissues and fluids. Contrast in an ultrasound image derives from differential reflection/absorption of the sound waves at such interfaces; results may be enhanced by the use of Doppler techniques, including the use of colour Doppler to evaluate blood flow.
  • contrast agents it may be advantageous to increase the difference in acoustic properties of different tissues/fluids using contrast agents, and since the use of indocyanine green in 1968 as the first ultrasound contrast agent many other potential agents have been examined. These include emulsions, solid particles, water-soluble compounds, free gas bubbles and various types of encapsulated gas- containing systems. It is generally accepted that low density contrast agents which are easily compressible are particularly efficient in terms of the acoustic backscatter they generate; gas-containing and gas- generating systems thus tend to exhibit markedly greater efficacy than other types of contrast agent.
  • Echovist* based on gas-containing galactose microcrystals
  • Levovist* comprising gas-containing galactose microcrystals coated with fatty acid
  • Albunex* which comprises gas bubbles encapsulated by partially denatured human serum albumin.
  • Gas-containing contrast media are also known to be effective in magnetic resonance (MR) imaging, e.g. as susceptibility contrast agents which will act to reduce MR signal intensity.
  • Oxygen-containing contrast media also represent potentially useful paramagnetic MR contrast agents.
  • gases such as carbon dioxide may be used as negative oral contrast agents.
  • a general disadvantage of most existing gas- containing and gas-generating contrast agents is their relative lack of stability in vivo. This is a particular problem in areas such as echocardiography, where there is a need for improved contrast agents capable of generating microbubbles sufficiently small to pass through the pulmonary capillary bed (i.e. typically having a size of less than about 10 ⁇ m, preferably less than about 7 ⁇ m) and so permit visualisation of the left side of the heart, and which are preferably sufficiently stable to survive several passages of circulation.
  • contrast agents should exhibit good storage stability over substantial periods of time, e.g. up to more than one year, preferably 2 to 3 years or more.
  • the present invention is based on our finding that microparticulate materials which are capable of chemical generation of gas after formulation with an appropriate carrier liquid, e.g. water for injection, and/or after administration to a subject, e.g. as a result of exposure to blood or another body fluid, may be useful as contrast agents in diagnostic imaging.
  • Such agents may be distinguished from existing microparticulate contrast agents such as the above- mentioned Echovist ® and Levovist ® , where microbubble generation is essentially only a physical process involving gas entrained on or in the microparticles, e.g. as inclusions in the voids of their crystal structures and/or adhered to their surfaces. It will be appreciated that use of the contrast agents of the invention may lead to generation of microbubbles from such physically adsorbed gas as well as from chemically generated gas, and that this may enhance the overall intensity of the contrast effect.
  • Contrast agents containing chemically gas- generating substances encapsulated in liposomes have previously been described in, for example, O-A-9109629. Since stable liposomes of necessity require a hydrophilic core, the encapsulated substances will typically be present as a solution in water or another relatively hydrophilic solvent; such contrast agents will be limited in their contrast effect by the maximum loading of gas-generating substance which may be introduced into solution in the liposome cores. Furthermore, such liposome products will tend to exhibit lower long term storage stability than dry microparticulate materials according to the present invention, as a result of factors such as vesicle fusion and leakage.
  • a contrast agent comprising a microparticulate substance capable of chemically generating gas upon formulation of the contrast agent in a carrier liquid and/or upon administration of the formulated contrast agent to a human or animal subject.
  • contrast agents may be used in a variety of diagnostic imaging techniques, including ultrasound, MR and X-ray imaging, their uses in diagnostic ultrasonic imaging and MR imaging, e.g. as susceptibility contrast agents, constituting preferred features of the invention.
  • the gas-generating substance may, for example, be a single compound which reacts chemically (which term is used herein to include enzy atically) to produce gas following administration to a subject, e.g. as a result of decomposition induced thermally or by pH change or as a result of enzymatic degradation.
  • non-toxic inorganic and organic carbonates e.g. alkali metal and alkaline earth carbonates and bicarbonates, arginine carbonate and compounds of formula RO.CO.OM where R is an organic group and M represents a physiologically acceptable cation, will generate carbon dioxide in the conditions of pH prevailing in the blood stream, as will compounds such as aminomalonates.
  • Carboxylic acids such as malonic acid, ct-cyano acids, ⁇ -nitro acids, ⁇ -aryl acids, ⁇ -keto acids, ⁇ , ⁇ , ⁇ - trihalo acids, 0-keto acids and ;0, 7 -unsaturated acids decarboxylate relatively easily and may do so spontaneously in vivo, with generation of carbon dioxide.
  • Methylene diesters e.g. prepared using techniques such as are described in O-A-9317 18 and O-A-9318070, the contents of which are incorporated herein by reference
  • Such double ester derivatives e.g. of compounds such as dextrans, may therefore provide useful contrast agents in accordance with the invention.
  • Hydrogen peroxide which may be present as an anti- oxidant-stabilised solid formulation or particle matrix, as a polyvinylpyrrolidone-hydrogen peroxide complex (see e.g. O-A-9107184) or in precursor form, e.g. as sodium perborate tetrahydrate (see e.g. EP-A-0253772) or urea peroxide (see e.g. O-A-9011248) , is enzymatically degraded with evolution of oxygen.
  • contrast agents according to the invention remain stable after formulation, e.g. as solutions in injectable media such as water for injection, gas generation not commencing until actual administration.
  • injectable media such as water for injection
  • gas-generating substance comprises compounds which react with water to generate gas; contrast agents using such compounds will begin to produce microbubbles immediately upon formulation into e.g. water for injection.
  • Representative compounds of this type include hydrides such as sodium borohydride or calcium hydride; acetylenides such as sodium acetylenide; carbides such as calcium carbide; N-carboxy anhydrides (see e.g. J. Am. Chem. Soc. 112 (1990) , pp. 7414-7416) , which react to yield carbon dioxide and an amino acid; and polycarbonates (see e.g. Pope et al. in Org. Synth. Coll. Vol. VI (1988), p. 418), e.g. compounds of formula
  • n is at least 2, which react with water to generate carbon dioxide.
  • the gas-generating substance may comprise a plurality of compounds, which may be stored separately or in combination, and which interact when, for example, they are formulated into water for injection.
  • examples include traditional effervescent systems, typically containing a carbonate or bicarbonate (e.g. with a non-toxic alkali or alkaline earth metal) and an organic acid such as tartaric, succinic or citric acid.
  • Other representative combined formulations include calcium percarbonate/sodium bicarbonate/citric acid, 5-nitrofuryl acrylate/ethylenediaminetetraacetic acid/ascorbic acid/tartaric acid/sodium metabisulphite/ sodium bicarbonate, and long-chain polyphosphates/ sodium bicarbonate.
  • the microparticulate material may if desired be stabilised, e.g. by being coated with or encapsulated in an appropriate biocompatible material, which may for example be chosen to be dissolvable and/or biodegradable.
  • suitable biocompatible material which may for example be chosen to be dissolvable and/or biodegradable.
  • Representative materials thus include polyethylene glycols, pluronics, albumin, gelatin, starch, collagen, dextrans, polylactide/polyglycolide, block copolymers and biodegradable polymers such as are described in O-A-9204392, WO-A-9317718 and WO-A- 9318070.
  • the coating/encapsulation may incorporate ionophores such as nigericin to facilitate proton transfer therethrough in cases where the gas-generating substance is activated by pH change.
  • microparticulate material may advantageously be stabilised in proliposome form, e.g. as described by Payne et al. in J. Pharm. Sci. 75 (1986), pp. 325-329, Katare et al. in J. Microencapsulation 1_ (1990) , pp. 455-462 and Ibid. 8 . (1991), pp. 1-7, the contents of which are incorporated herein by reference.
  • Essentially such products comprise microparticulate material coated with liposome generating material (e.g. a phospholipid such as phosphatidylcholine, hydrogenated phosphatidylcholine or hydrogenated phosphatidylserine) in dry form.
  • liposome generating material e.g. a phospholipid such as phosphatidylcholine, hydrogenated phosphatidylcholine or hydrogenated phosphatidylserine
  • Products of this type typically comprise dry, free-flowing powders and exhibit particularly good long term storage stability. Liposome formation will normally accompany gas generation when the product is formulated in an aqueous carrier liquid such as water for injection.
  • the coating material may be such that it is substantially impermeable or otherwise inert to the carrier liquid but is modified or activated on or immediately prior to administration, e.g. to exhibit enhanced permeability, for example as a result of pH change or enzyme activity, so leading to liposome formation and gas generation in vivo following administration.
  • Aqueous suspensions and dispersions of this latter class of proliposomes may thus exhibit good storage stability and constitute a further feature of the invention.
  • aqueous formulations may if desired be enhanced by appropriate selection of conditions such as pH, for example by buffering the formulation to slight alkalinity, to ensure that substantially no gas generation occurs prior to their administration.
  • conditions such as pH, for example by buffering the formulation to slight alkalinity, to ensure that substantially no gas generation occurs prior to their administration.
  • the liposomes generated by contrast agents in proliposome form may assist in stabilising the microbubbles which are generated by virtue of their long residence times in e.g. the vascular system.
  • microparticulate material in contrast agents according to the invention may incorporate a solute serving to generate an osmotic gradient to enhance diffusion of fluid through any coating into the material.
  • microbubbles may in general be enhanced by the microparticles of the gas-generating substance themselves acting as condensation nuclei.
  • the microparticles may also have porous or spongy structures, e.g. containing the gas-generating material in pores or networks of the structure or having gas pockets or cavities formed on the surface of the particles; the flexibility of such structures will enhance their echogenicity relative to more rigid gas- containing systems.
  • the contrast agents of the invention may be prepared by any convenient method, e.g. by micronising the gas-generating substance. Any desired coating or encapsulating material may be applied before or after such micronisation.
  • a preferably hydrophilic micronised gas-generating substance may be dispersed in a volatile lipophilic solvent in which the desired coating material is dissolved before, during or after the dispersion step, the solvent thereafter being removed, e.g. under reduced pressure, to yield a coated microparticulate product according to the invention.
  • Coating/encapsulation may likewise be effected using conventional methods, e.g. fluidised bed, spray, moulding, dipping, coacervation-phase separation. multiorifice centrifugal and solvent evaporation techniques, to give coatings having appropriate composition, thickness and permeability, in one or more layers.
  • the contrast agents of the invention may, for example, be administered enterally or parenterally, although there may be advantages in particular applications in administration directly into body cavities such as the Fallopian tubes. In general, however, intravascular administration, most commonly by intravenous injection, is most likely to be employed, in order to enhance vascular imaging, including cardiac and extracardiac perfusion.
  • contrast agents for intravenous administration should generate microbubbles small enough to pass through the capillary bed of the pulmonary system.
  • the agents should therefore preferably be such as to generate microbubbles having diameters of less than 10 ⁇ m, preferably in the range 0.2-8 ⁇ m, e.g. 0.3-7 ⁇ m; the microparticles may, for example, conveniently have an average size of 1-7 ⁇ m, e.g. 1-4 ⁇ m.
  • Substantially larger microparticle and microbubble sizes e.g. up to 500 ⁇ , may be useful in applications such as gastrointestinal imaging.
  • the following non-limitative examples serve to illustrate the invention.
  • Phosphatidylcholine (2.5g) was added to a suspension of anhydrous sodium bicarbonate (log) in chloroform (30 ml) and allowed to dissolve. The solvent was then removed under reduced pressure at 40°C to yield a solid product.
  • the acoustic effect of the formulated products from Examples 1-3 was determined by further diluting them ten-fold with Isoton II (Coulter Electronics Limited, Luton, England) , placing the diluted samples in cells in a water bath maintained at 37°C and measuring the acoustic backscatter using a 3.5 MHz single element transducer in a pulse-reflection technique. In all cases a strong acoustic backscatter from the interior of the cell was observed, whereas a reference measurement on a cell containing only Isoton II showed no acoustic backscatter.
  • Isoton II Coulter Electronics Limited, Luton, England
  • Aerosol OT (1.75g)
  • Tween 60 (l.Og) dissolved in water (50 ml) was added and the resulting mixture was emulsified using an Ystral homogeniser, yielding a fine emulsion.

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  • Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Acoustics & Sound (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Radiology & Medical Imaging (AREA)
  • Physics & Mathematics (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Medicinal Preparation (AREA)
  • Ultra Sonic Daignosis Equipment (AREA)
EP94909227A 1993-03-16 1994-03-16 Improvements in or relating to contrast agents Withdrawn EP0689462A1 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
GB939305351A GB9305351D0 (en) 1993-03-16 1993-03-16 Improvements in or relating to contrast agents
GB9305351 1993-03-16
PCT/GB1994/000522 WO1994021302A1 (en) 1993-03-16 1994-03-16 Improvements in or relating to contrast agents

Publications (1)

Publication Number Publication Date
EP0689462A1 true EP0689462A1 (en) 1996-01-03

Family

ID=10732118

Family Applications (1)

Application Number Title Priority Date Filing Date
EP94909227A Withdrawn EP0689462A1 (en) 1993-03-16 1994-03-16 Improvements in or relating to contrast agents

Country Status (15)

Country Link
EP (1) EP0689462A1 (ja)
JP (1) JPH08507781A (ja)
KR (1) KR960700760A (ja)
CN (1) CN1121314A (ja)
AU (1) AU695529B2 (ja)
BR (1) BR9406199A (ja)
CA (1) CA2158359A1 (ja)
CZ (1) CZ237195A3 (ja)
FI (1) FI954326A (ja)
GB (1) GB9305351D0 (ja)
HU (1) HUT72984A (ja)
NO (1) NO953638L (ja)
PL (1) PL310657A1 (ja)
SK (1) SK113795A3 (ja)
WO (1) WO1994021302A1 (ja)

Families Citing this family (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB9106673D0 (en) * 1991-03-28 1991-05-15 Hafslund Nycomed As Improvements in or relating to contrast agents
US5409688A (en) * 1991-09-17 1995-04-25 Sonus Pharmaceuticals, Inc. Gaseous ultrasound contrast media
US5333613A (en) * 1993-03-23 1994-08-02 Delineate Microparticles as ultrasonic contrast media
US5897851A (en) * 1995-06-07 1999-04-27 Sonus Pharmaceuticals, Inc. Nucleation and activation of a liquid-in-liquid emulsion for use in ultrasound imaging
GB9511488D0 (en) * 1995-06-07 1995-08-02 Nycomed Imaging As Improvements in or relating to contrast agents
GB9622711D0 (en) 1996-10-31 1997-01-08 British Tech Group Instrument having enhanced ultrasound visibility
US6278893B1 (en) * 1998-01-05 2001-08-21 Nycomed Imaging As Method of magnetic resonance imaging of a sample with ex vivo polarization of an MR imaging agent
US20010003580A1 (en) 1998-01-14 2001-06-14 Poh K. Hui Preparation of a lipid blend and a phospholipid suspension containing the lipid blend
US20070110674A1 (en) * 2005-07-29 2007-05-17 Yuhong Xu Sono-active liposomes and lipid particles and use thereof as contrast agents and active-agent delivery systems
NZ733010A (en) 2014-12-31 2023-01-27 Lantheus Medical Imaging Inc Lipid-encapsulated gas microsphere compositions and related methods
IL262647B2 (en) 2016-05-04 2023-03-01 Lantheus Medical Imaging Inc Methods and devices for preparing sharpness factors for ultrasound
US9789210B1 (en) 2016-07-06 2017-10-17 Lantheus Medical Imaging, Inc. Methods for making ultrasound contrast agents
GB201821049D0 (en) * 2018-12-21 2019-02-06 Ge Healthcare As Ultrasound contrast agent and methods for use therof

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4900540A (en) * 1983-06-20 1990-02-13 Trustees Of The University Of Massachusetts Lipisomes containing gas for ultrasound detection
US4684479A (en) * 1985-08-14 1987-08-04 Arrigo Joseph S D Surfactant mixtures, stable gas-in-liquid emulsions, and methods for the production of such emulsions from said mixtures
JPH0678247B2 (ja) * 1988-10-04 1994-10-05 大塚製薬株式会社 Ｎｍｒ造影用鉄含有製剤
US5147631A (en) * 1991-04-30 1992-09-15 Du Pont Merck Pharmaceutical Company Porous inorganic ultrasound contrast agents
EP0627942B1 (en) * 1992-03-06 1999-09-15 Nycomed Imaging As Improvements in or relating to contrast agents

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9421302A1 *

Also Published As

Publication number Publication date
BR9406199A (pt) 1995-12-12
HU9502693D0 (en) 1995-11-28
KR960700760A (ko) 1996-02-24
GB9305351D0 (en) 1993-05-05
HUT72984A (en) 1996-06-28
NO953638D0 (no) 1995-09-15
JPH08507781A (ja) 1996-08-20
AU6215394A (en) 1994-10-11
PL310657A1 (en) 1995-12-27
SK113795A3 (en) 1997-02-05
CN1121314A (zh) 1996-04-24
WO1994021302A1 (en) 1994-09-29
FI954326A (fi) 1995-10-11
NO953638L (no) 1995-09-15
CZ237195A3 (en) 1996-05-15
AU695529B2 (en) 1998-08-13
FI954326A0 (fi) 1995-09-14
CA2158359A1 (en) 1994-09-29

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