WO1999053965A1 - Ameliorations relatives a des agents de contraste - Google Patents

Ameliorations relatives a des agents de contraste Download PDF

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Publication number
WO1999053965A1
WO1999053965A1 PCT/GB1999/001234 GB9901234W WO9953965A1 WO 1999053965 A1 WO1999053965 A1 WO 1999053965A1 GB 9901234 W GB9901234 W GB 9901234W WO 9953965 A1 WO9953965 A1 WO 9953965A1
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WIPO (PCT)
Prior art keywords
contrast agent
gas
oil phase
ultrasound
drug
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Application number
PCT/GB1999/001234
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English (en)
Inventor
Balin Balinov
Roald Skurtveit
Unni Nordby Wiggen
Jonny ØSTENSEN
Original Assignee
Marsden, John, Christopher
Nycomed Imaging As
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Application filed by Marsden, John, Christopher, Nycomed Imaging As filed Critical Marsden, John, Christopher
Priority to JP2000544368A priority Critical patent/JP2002512208A/ja
Priority to EP99918143A priority patent/EP1073474A1/fr
Priority to AU36177/99A priority patent/AU3617799A/en
Publication of WO1999053965A1 publication Critical patent/WO1999053965A1/fr

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    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
    • A61K41/0028—Disruption, e.g. by heat or ultrasounds, sonophysical or sonochemical activation, e.g. thermosensitive or heat-sensitive liposomes, disruption of calculi with a medicinal preparation and ultrasounds

Definitions

  • This invention relates to ultrasound imaging, more particularly to novel contrast agent preparations and their use in ultrasound imaging, for example in visualising tissue perfusion.
  • contrast agents comprising dispersions of microbubbles of gases are particularly efficient backscatterers of ultrasound by virtue of the low density and ease of compressibility of the microbubbles.
  • Such microbubble dispersions if appropriately stabilised, may permit highly effective ultrasound visualisation of, for example, the vascular system and tissue microvasculature, often at advantageously low doses.
  • ultrasonography to assess blood perfusion (i.e. blood flow per unit of tissue mass) is of potential value in, for example, tumour detection, tumour tissue typically having different vascularity from healthy tissue, and studies of the myocardium, e.g. to detect myocardial infarctions.
  • a problem with the application of existing ultrasound contrast agents to cardiac perfusion studies is that the information content of images obtained is degraded by attenuation caused by contrast agent present in the ventricles of the heart .
  • ultrasonic visualisation of a subject in particular of perfusion in the myocardium and other tissues, may be achieved and/or enhanced by means of gas-containing contrast agent preparations which promote controllable and temporary growth of the gas phase in vivo following administration.
  • gas-containing contrast agent preparations may be - 2 - used to promote controllable and temporary retention of the gas phase, for example in the form of microbubbles, in tissue microvasculature, thereby enhancing the concentration of gas in such tissue and accordingly enhancing its echogenicity, e.g. relative to the blood pool .
  • gas as a deposited perfusion tracer differs markedly from existing proposals regarding intravenously administrable microbubble ultrasound contrast agents. Thus it is generally thought necessary to avoid microbubble growth since, if uncontrolled, this may lead to potentially hazardous tissue embolisation. Accordingly it may be necessary to limit the dose administered and/or to use gas mixtures with compositions selected so as to minimise bubble growth in vivo by inhibiting inward diffusion of blood gases into the microbubbles (see e.g. O-A-9503835 and O-A-9516467) .
  • a composition comprising a dispersed gas phase is coadministered with a composition comprising at least one substance which has or is capable of generating a gas or vapour pressure in vivo sufficient to promote controllable growth of the said dispersed gas phase through inward diffusion thereto of molecules of gas or vapour derived from said substance, which for brevity is hereinafter referred to as a "diffusible component", although it will be appreciated that transport mechanisms other than diffusion may additionally or alternatively be involved in operation of the invention, as discussed in greater detail hereinafter.
  • contrast agent preparations of O-A-9817324 permit control of factors such as the probability and/or rate of growth of the dispersed gas by selection of appropriate constituents of the coadministered compositions, whereas administration of the aforementioned phase shift colloids alone may lead to generation of microbubbles which grow uncontrollably and unevenly, possibly to the extent where at least a proportion of the microbubbles may cause potentially dangerous embolisation of, for example, the myocardial vasculature and brain (see e.g. Schwarz , Advances in Echo- Contras t [1994 (3 ) ] , pp. 48-49) .
  • O-A-9640282 An activation technique for such colloidal dispersions, involving application of hypobaric forces thereto, is described in O-A-9640282 ; typically this involves partially filling a syringe with the emulsion and subsequently forcibly withdrawing and then releasing the plunger of the syringe to generate a transient pressure change which causes formation of gas microbubbles within the emulsion. This is an inherently somewhat cumbersome technique which may fail to give consistent levels of activation.
  • O-A-9725097 discloses the administration of aqueous dispersions of superheated droplets of water- immiscible liquids which may be vaporised in vivo under the influence of radiation or ultrasound, which are said to induce homogeneous nucleation of the droplets.
  • the dispersions may be used, inter alia , to form diagnostic contrast agents or selectively to deliver drugs to a localised body region.
  • the present invention is based on the finding that volatile emulsions of the phase shift colloid type in which gas-containing heterogeneous nucleation sites are associated with the emulsion droplets possess a number of valuable advantages.
  • they permit perfusion imaging to be carried out in similar manner to that described in O-A- 9817324 , but without the need to administer two separate compositions, thereby facilitating handling of the products.
  • factors such as the ultimate size of the gas microbubbles generated by the volatile dispersed phase may be controlled through parameters such as the droplet size of the emulsion and the nature and location of the nucleation sites which may readily be set during manufacture of the contrast agent .
  • the high yield of liquid-to-gas phase transition resulting from the presence of nucleation sites make it possible accurately to forecast the size of the formed microbubbles, so permitting controlled retention with a high safety profile .
  • an ultrasound contrast agent comprising an injectable oil-in-water emulsion wherein there are gas-containing nucleation sites associated with droplets of the dispersed oil phase.
  • the invention further provides a method of generating enhanced images of a human or non-human animal subject which comprises the steps of injecting a contrast agent as defined above into the vascular system of said subject and generating an ultrasound image of at least a part of said subject.
  • the dispersed oil phase may comprise one or more appropriately volatile components where at least one component is at least partially insoluble in and immiscible with water.
  • This component or mixture of components is advantageously a liquid at processing and storage temperature, which may for example be as low as -10°C if the aqueous phase contains appropriate antifreeze material, while being a gas or exhibiting sufficient vapour pressure, e.g. at least 50 mm Hg, preferably at least 100 mm Hg, at body temperature.
  • emulsifiable oil phase components include aliphatic ethers such as diethyl ether; polycyclic oils or alcohols such as menthol, camphor or eucalyptol ; heterocyclic compounds such as furan or dioxane; aliphatic hydrocarbons, which may be saturated or unsaturated and straight chained or branched, e.g.
  • n-butane n-pentane, 2- methylpropane, 2-methylbutane, 2 , 2-dimethylpropane, 2,2- dimethylbutane, 2 , 3-dimethylbutane, 1-butene, 2-butene, 2-methylpropene, 1, 2-butadiene, 1 , 3 -butadiene, 2-methyl- - 6 -
  • Representative halogenated hydrocarbons include dichloromethane, methyl bromide, 1, 2-dichloroethylene, 1, 1-dichloroethane, 1-bromoethylene, 1-chloroethylene, ethyl bromide, ethyl chloride, 1-chloropropene, 3- chloropropene, 1-chloropropane, 2-chloropropane and t- butyl chloride.
  • halogen atoms are fluorine atoms, for example as in dichlorofluoromethane, trichlorofluoromethane, 1,2- dichloro-1, 2-difluoroethane, 1, 2-dichloro-l, 1, 2 , 2- tetrafluoroethane, 1,1, 2-trichloro-l, 2,2- trifluoroethane, 2-bromo-2-chloro-l , 1, 1-trifluoroethane, 2-chloro-l, 1, 2-trifluoroethyl difluoromethyl ether, 1- chloro-2, 2, 2-trifluoroethyl difluoromethyl ether, partially fluorinated alkanes (e.g.
  • pentafluoropropanes such as 1H, 1H, 3H-pentafluoropropane , hexafluorobutanes, nonafluorobutanes such as 2H-nonafluoro- t-butane, and decafluoropentanes such as 2H, 3H-decafluoropentane)
  • partially fluorinated alkenes e.g. heptafluoropentenes such as 1H, 1H, 2H-heptafluoropent-1-ene, and nonafluorohexenes such as 1H, 1H, 2H-nonafluorohex-1-ene
  • fluorinated ethers e.g.
  • perfluorocarbons examples include perfluoroalkanes such as perfluorobutanes, perfluoropentanes, perfluorohexanes (e.g.
  • perfluoro-2- methylpentane perfluoroheptanes, perfluorooctanes , perfluorononanes and perfluorodecanes
  • perfluorocycloalkanes such as perfluorocyclobutane, perfluorodimethyl-cyclobutanes, perfluorocyclopentane and perfluoromethylcyclopentane
  • perfluoroalkenes such as perfluorobutenes (e.g. perfluorobut-2-ene or perfluorobuta-1, 3-diene) , perfluoropentenes (e.g. perfluoropent-1-ene) and perfluorohexenes (e.g.
  • perfluoro-2-methylpent-2-ene or perfluoro-4-methylpent- 2-ene) perfluorocycloalkenes such as perfluorocyclopentene or perfluorocyclopentadiene
  • perfluorinated alcohols such as perfluoro- -butanol .
  • Such at least partially water- insoluble/immiscible volatile substances may contain dissolved materials which significantly increase the vapour pressure of the mixture.
  • Such ' solute materials include gases such as air; nitrogen; oxygen; carbon dioxide; hydrogen; inert gases such as helium, argon, xenon or krypton; sulphur fluorides such as sulphur hexafluoride, disulphur decafluoride or trifluoromethylsulphur pentafluoride; selenium hexafluoride; optionally halogenated silanes such as methylsilane or dimethylsilane; low molecular weight hydrocarbons (e.g.
  • alkanes such as methane, ethane, a propane, a butane or a pentane, cycloalkanes such as cyclopropane, cyclobutane or cyclopentane, alkenes such as ethylene, propene, propadiene or a butene, or alkynes such as acetylene or propyne; ethers such as dimethyl ether; ketones; esters; halogenated low molecular weight hydrocarbons (e.g. containing up to 7 carbon atoms); or mixtures of any of the foregoing.
  • Gases such as air, oxygen and carbon dioxide, which have substantial solubility in fluorocarbon liquids, are preferred.
  • the emulsion will typically be stabilized by one or more surfactants or other encapsulating material. It will be appreciated that the nature of such material may significantly affect factors such as the rate of growth of volatilised gas.
  • surfactants include - 8 - fatty acids (e.g. straight chain saturated or unsaturated fatty acids, for example containing 10-20 carbon atoms) and carbohydrate and triglyceride esters thereof, phospholipids (e.g. a lecithin or a fluorine- containing phospholipid) , proteins (e.g.
  • albumins such as human serum albumin
  • block copolymer surfactants e.g. polyoxyethylene-polyoxypropylene block copolymers such as Pluronics, or extended polymers such as acyloxyacyl polyethylene glycols, for example polyethyleneglycol methyl ether 16-hexadecanoyloxy- hexadecanoate, e.g. wherein the polyethylene glycol moiety has a molecular weight of 2300, 5000 or 10000
  • fluorine-containing surfactants e.g.
  • emulsion droplets may also be stabilised by wall-forming encapsulating material, so that the dispersed phase is in the form of microcapsules containing the volatile liquid, or by incorporation into porous structures such as latex particles.
  • Representative wall-forming materials include polymers such as polylactic acid, polycaprolactone, polycyanoacrylate and polyesters (e.g. as described in O-A-9317718) .
  • Nucleation sites may be present within the dispersed oil phase droplets or within surfactant or other encapsulating or stabilizing membranes surrounding the droplets; such membranes may themselves act as nucleation sites per se. Alternatively appropriate nucleation sites may be present in contact with the outside of such membranes.
  • nucleation sites may, for example, take the form of - 9 - dispersed gas microbubbles, e.g. in the form of free microbubbles, surfactant- or lipid-stabilised microbubbles, polymer- or protein-encapsulated microbubbles, gas-containing porous solid microparticles such as aerogels or zeolites, gas entrapped in holes crevices or other irregularities of rough-surfaced solid microparticles, gas-containing polymeric microparticles or gas-containing entities such as fullerenes, clathrates or nanotubes .
  • Such contrast agents may readily be prepared by dispersing the nucleation site- containing material in the oil phase and then generating an oil-in-water emulsion in per se known manner, using one or more appropriate dispersing agents.
  • the interfacial properties of nucleation sites may, for example, be varied by selection of a dispersing agent for the nucleation sites, or by chemical modification of the nucleation site surface, e.g. by silanisation or plasma modification.
  • a dispersing agent for the nucleation sites or by chemical modification of the nucleation site surface, e.g. by silanisation or plasma modification.
  • the presence of surface irregularities, cavities, edges, crevices or other structural defects which assist a gas phase in spreading on the interface may also be advantageous.
  • the nucleation sites may be selected to have interfacial properties which allow them to be located at the water-volatile oil interface. This may, for example, be achieved by choosing a dispersing agent for the nucleation sites which allows the surface of a nucleation site to be partly wetted by both the volatile oil and the aqueous phase. If necessary the surface of the nucleation site may be adjusted by chemical modification (e.g. plasma modification), rinsing etc.
  • chemical modification e.g. plasma modification
  • the boiling point of the dispersed oil phase of the emulsion should not exceed 42°C, i.e that the sum of partial pressures from the volatile component (s) of the oil phase should - 10 - exceed one atmosphere at 42°C.
  • microbubbles may be generated either in vivo or immediately prior to injection by appropriate temperature and/or pressure modifications or application of external activating influences such as sound, ultrasound or radiation.
  • external activating influences such as sound, ultrasound or radiation.
  • Microbubbles generated from contrast agents according to the present invention are characterised by a readily controllable rate of growth and final size; they may, for example be designed to grow to a size of e.g. 10-20 ⁇ m in order to exhibit controlled retention in tissue microvasculature, e.g. in the myocardium, or may be designed to grow to a size of e.g. 1-7 ⁇ m so that they behave as free-flowing contrast agents.
  • liquid-to-gas phase shift in emulsion droplets in the presence of nucleation sites ensures a highly efficient and rapid transformation of the liquid, hence limiting diffusion of volatile substance between separated particles and thus limiting uncontrolled bubble growth.
  • the material inside one emulsion droplet may be transformed to one bubble.
  • n is number of moles of substance to make one bubble and is related to the radius of the emulsion droplet, r e , by Equation (2) - 11 -
  • Equation (2) Equation (2)
  • d is 1.66 g/ml
  • M w 288 g/mol
  • T 298 K
  • p 1 atm
  • the emulsion droplet should therefore have a size slightly below 2 ⁇ m in order to give a microbubble of size 10 ⁇ m which is therefore capable of temporary retention.
  • nucleation site For the nucleation site to occupy 50% of such an emulsion droplet, its size should be below 1.6 ⁇ m. More preferably the nucleation site should occupy less than 20% of the emulsion droplet, so that its size should be below 1.2 ⁇ m; even more preferably, the nucleation site should occupy less than 10% of the liquid volume and so should have a size below 1 ⁇ m. In order to ensure boiling of a sufficiently high number of emulsion droplets, a sufficiently high number of nucleation sites should be added. The nucleation sites will be distributed on the liquid carrier particles by simple Boltzmann distribution, and calculations may be made to estimate the amount of nucleation sites to be added for a given fraction of the liquid carrier particles to contain at least one nucleation site. - 12 -
  • Activation of the phase transition from liquid to gas may be obtained by simply heating to temperatures above the boiling point of the volatile liquid.
  • a volatile oil with boiling point below body temperature should be used.
  • bubble nucleation rate may be low also at elevated temperatures, the volatile liquid may have a boiling point well below body temperature.
  • presence of nucleation sites may lower the barrier for phase shift so that nucleation can be induced by means of an external influence.
  • Products in which gas formation is activated by ultrasonication or like treatment may be particularly advantageous in that they may be highly storage-stable prior to activation and use.
  • contrast agents according to the invention will tend to be temporarily retained in tissue in concentrations proportional to the regional rate of tissue perfusion. Accordingly, when using ultrasound imaging modalities such as conventional or harmonic B- mode imaging where the display is derived directly from return signal intensities, images of such tissue may be interpreted as perfusion maps in which the displayed signal intensity is a function of local perfusion. This is in contrast to images obtained using free-flowing contrast agents, where the regional concentration of contrast agent and corresponding return signal intensity depend on the actual blood content rather than the rate of perfusion of local tissue.
  • a vasodilating drug for example selected from adenosine, dipyridamole, nitroglycerine, isosorbide mononitrate, prazosin, doxazosin, dihydralazine, hydralazine, sodium nitroprusside, pentoxyphylline, amelodipine, felodipine, isradipine, nifedipine, nimodipine, verapamil, diltiazem and nitrous oxide.
  • a vasodilating drug for example selected from adenosine, dipyridamole, nitroglycerine, isosorbide mononitrate, prazosin, doxazosin, dihydralazine, hydralazine, sodium nitroprusside, pentoxyphylline, amelodipine, felodipine, isradipine, nifedipine, nimodipine, verapamil, d
  • the contrast agents of the invention do not suffer such diffusion or transport limitations, and since their retention in myocardial tissue may also rapidly be terminated by the methods described above, the period of vasodilatation needed to achieve cardiac perfusion imaging in accordance with this embodiment of the invention may be very short, for example less than one minute. This will reduce the duration of any possible discomfort caused to patients by administration of vasodilator drugs.
  • adenosine is a particularly useful vasodilating drug, being both an endogenous substance and having a very short-lasting action as evidenced by a blood pool half-life of only a few seconds.
  • Vasodilatation will accordingly be most intense in the heart, since the drug will tend to reach more distal tissues in less than pharmacologically active concentrations.
  • adenosine may be necessary during cardiac imaging in accordance with this embodiment of the invention; by way of example, an initial administration of 150 ⁇ g/kg of adenosine may be made substantially simultaneously with administration of the contrast agent composition, followed 10 seconds later by slow injection of a further 150 ⁇ g/kg of adenosine, e.g. over a period of 20 seconds.
  • contrast agents of the invention may usefully be employed in therapeutic applications such as drug delivery agents.
  • hydrophobic drugs may be dissolved in the volatile oil phase to achieve an advantageously high drug load.
  • Therapeutics may also be incorporated into any encapsulating membrane or may be dissolved in the aqueous carrier phase.
  • Therapeutics - 15 - may also be present as nano- or micro-sized particles which may function as additional nucleation sites.
  • the induced liquid-to-gas transition may be utilised in applications such as ultrasound therapy.
  • the liquid-to-gas phase transition may provide microbubbles with a size sufficient to embolize capillaries, and hence may block blood flow to a site of interest, for instance a tumour, following appropriate application of localised ultrasound.
  • the microbubbles may also absorb ultrasound energy and hence may provide heating of a site of interest which may be utilised in hyperthermia treatment. Furthermore, the liquid to gas transition may be very rapid, providing shear forces or microstreaming with a damaging effect on surrounding cells; this may be useful in cell killing, for example in treatment of cancer.
  • a spatula edge of micronised kaolin is added to 2 ml perfluoropentane (b.p. 28°C) containing 0.2 ml FluoradTM FC-171 surfactant.
  • a milky white dispersion is obtained after gently shaking by hand.
  • 0.1 ml of the above dispersion is mixed with 1 ml water by shaking on an Espe Capmix ® for 30 seconds, yielding an emulsion with droplet size slightly above 1 ⁇ m.
  • a droplet of the emulsion is placed on a cooling/heating stage, and heated to 37°C while following the process in a microscope. Several 10 ⁇ m droplets appear, demonstrating a rapid liquid-to-gas phase shift in the emulsion droplets.
  • a tube containing the emulsion is dipped in a water bath maintained at 37°C so that only one part of the emulsion is heated.
  • the turbidity immediately increases significantly in that part of the emulsion which is heated relatively to the non-heated emulsion, demonstrating the formation of small gas bubbles after heating.
  • a spatula edge of micronised zeolite is added to 2 ml perfluoropentane (b.p. 28°C) containing 0.2 mg perfluorooctanoic acid.
  • the sample is sonicated using a Branson W385 sonicator horn at 50% output power for two minutes while keeping the sample in an ice bath.
  • 0.1 ml of the above dispersion is mixed with 1 ml water by shaking on an Espe Capmix ® for 45 seconds, yielding an emulsion.
  • a sample of the emulsion (1 ⁇ l) is suspended in Isoton II (55 ml) at room temperature, and acoustic attenuation - 17 - is measured as a function of time using two broadband transducers with centre frequencies of 3.5 MHz and 5.0 MHz respectively, in a pulse-echo technique.
  • the acoustic attenuation is weak.
  • the sample is then heated step-wise and acoustic attenuation is measured for each temperature. When the sample temperature is around 30°C, a substantial increase in acoustic attenuation can be observed.
  • This experiment demonstrates how a nucleation site-containing emulsion of a volatile substance can transform to a microbubble dispersion around its boiling point. It also demonstrates the change in acoustic properties and the product's usefulness as an ultrasound contrast agent.
  • Example 2 is repeated without adding micronised zeolite to the perfluoropentane phase.
  • heating to temperatures well above 40°C leads only to a slight increase in acoustic attenuation. This demonstrates the requirement for nucleation sites to be associated with the dispersed phase.
  • the mixture is mixed hot with an Ultra Turax T25 mixer at 20,000 rpm for 1 minute.
  • the emulsion is homogenised at 60°C using an Emulsiflex C5 high-pressure homogeniser, operating at a peak pressure of 200,000 kPa and allowing five passes of the sample.
  • the median size of the obtained emulsion is around 300 nm.
  • the emulsion is then frozen on a dry ice/methanol bath and - 18 - lyophilised for 48 hours, giving a white powder. Electron microscopy indicates the formation of gas- filled nanocapsules .
  • the polymer particles are dispersed in water and excess human serum albumin is removed by dialysis. The remaining polymer nanocapsules are dried under reduced pressure.
  • This experiment demonstrates how a nucleation site-containing emulsion of a volatile substance can transform to a microbubble dispersion well below its boiling point when the emulsion is exposed to external ultrasound. It also demonstrates the change in acoustic properties and the product ' s usefulness as an ultrasound contrast agent .
  • a dog is anaesthetised, a mid-line sternotomy is performed, and the anterior pericardium is removed.
  • Mid-line short-axis B-mode imaging of the heart is performed through a low-attenuating 30 mm silicone rubber spacer, using an ATL HDI-3000 scanner equipped with a P3-2 transducer.
  • the framerate is 40 Hz and the mechanical index is 1.1.
  • Example 5 is repeated except that a perfluorodimethylcyclobutane emulsion phase is used without added polymeric nanocapsules. Tn vivo ultrasound imaging - 20 - indicates limited acoustic efficacy of the emulsion. This comparative experiment shows the necessity for gas- filled nucleation site associated with the emulsion droplets .

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Abstract

L'invention concerne des agents de contraste pour imagerie par ultrasons du type colloïde de déphasage. Ces agents de contraste contiennent des émulsions d'huiles volatiles dans de l'eau et comportent des sites de nucléation contenant du gaz associés avec des gouttelettes de la phase huileuse dispersée (par exemple, contenus dans celle-ci), de façon à améliorer l'efficacité et la régulation de la transition de phase liquide à phase gazeuse.
PCT/GB1999/001234 1998-04-22 1999-04-22 Ameliorations relatives a des agents de contraste WO1999053965A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
JP2000544368A JP2002512208A (ja) 1998-04-22 1999-04-22 造影剤における改良または造影剤に関する改良
EP99918143A EP1073474A1 (fr) 1998-04-22 1999-04-22 Ameliorations relatives a des agents de contraste
AU36177/99A AU3617799A (en) 1998-04-22 1999-04-22 Improvements in or relating to contrast agents

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
GB9808581.4 1998-04-22
GBGB9808581.4A GB9808581D0 (en) 1998-04-22 1998-04-22 Improvements in or relating to contrast agents
US8488298P 1998-05-08 1998-05-08

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US09673160 A-371-Of-International 2000-12-11
US10/719,697 Continuation US20040131547A1 (en) 1998-04-22 2003-11-21 Contrast agents

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Cited By (4)

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WO2004045586A1 (fr) * 2002-11-15 2004-06-03 Bioserentach Co., Ltd. Preparation solidifiee visant a favoriser l'absorption medicamenteuse
EP2459182A1 (fr) * 2009-07-30 2012-06-06 University of Zürich Formulation injectable de traitement et de protection de patients souffrant de réaction inflammatoire ou d un événement d'ischémie-reperfusion
WO2015047103A1 (fr) * 2013-09-27 2015-04-02 Phoenix Solutions As Administration de médicaments médiée par ultrasons
US11406722B2 (en) 2017-03-16 2022-08-09 The Board Of Regents Of The University Of Texas System Nanodroplets with improved properties

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JP4822702B2 (ja) * 2004-12-24 2011-11-24 独立行政法人科学技術振興機構 造影剤

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WO1994021301A1 (fr) * 1993-03-16 1994-09-29 Holmes, Michael, John Perfectionnements apportes aux agents de contraste
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WO2004045586A1 (fr) * 2002-11-15 2004-06-03 Bioserentach Co., Ltd. Preparation solidifiee visant a favoriser l'absorption medicamenteuse
EP2459182A1 (fr) * 2009-07-30 2012-06-06 University of Zürich Formulation injectable de traitement et de protection de patients souffrant de réaction inflammatoire ou d un événement d'ischémie-reperfusion
US9296678B2 (en) 2009-07-30 2016-03-29 University Of Zurich Injectable formulation for treatment and protection of patients having an Inflammatory Reaction or an Ischemia-reperfusion event
EP2459182B1 (fr) * 2009-07-30 2017-09-06 University of Zürich Formulation injectable pour le traitement et la protection de patients souffrant de réaction inflammatoire ou d'un événement d'ischémie-reperfusion
WO2015047103A1 (fr) * 2013-09-27 2015-04-02 Phoenix Solutions As Administration de médicaments médiée par ultrasons
US11406722B2 (en) 2017-03-16 2022-08-09 The Board Of Regents Of The University Of Texas System Nanodroplets with improved properties

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GB9808581D0 (en) 1998-06-24

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