WO1991015244A2 - Stable microbubbles suspensions injectable into living organisms - Google Patents

Stable microbubbles suspensions injectable into living organisms Download PDF

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Publication number
WO1991015244A2
WO1991015244A2 PCT/EP1991/000620 EP9100620W WO9115244A2 WO 1991015244 A2 WO1991015244 A2 WO 1991015244A2 EP 9100620 W EP9100620 W EP 9100620W WO 9115244 A2 WO9115244 A2 WO 9115244A2
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WIPO (PCT)
Prior art keywords
air
composition
gas
surfactant
surfactants
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PCT/EP1991/000620
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English (en)
French (fr)
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WO1991015244A3 (en
Inventor
Michel Schneider
Daniel Bichon
Philippe Bussat
Jérôme Puginier
Eva Hybl
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Sintetica S.A.
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Application filed by Sintetica S.A. filed Critical Sintetica S.A.
Priority to EP91907163A priority Critical patent/EP0474833B2/en
Priority to DE69111719T priority patent/DE69111719T3/de
Priority to CA002056371A priority patent/CA2056371C/en
Priority to KR1019910701733A priority patent/KR960002184B1/ko
Publication of WO1991015244A2 publication Critical patent/WO1991015244A2/en
Publication of WO1991015244A3 publication Critical patent/WO1991015244A3/en
Priority to US08/128,540 priority patent/US5380519A/en
Priority to US08/315,347 priority patent/US5531980A/en
Priority to US08/457,581 priority patent/US5567414A/en
Priority to US08/456,385 priority patent/US5658551A/en
Priority to GR950402454T priority patent/GR3017324T3/el
Priority to US08/853,936 priority patent/US6110443A/en
Priority to US08/893,371 priority patent/US7033574B1/en
Priority to US09/115,963 priority patent/USRE39146E1/en
Priority to US09/401,835 priority patent/US20010008626A1/en
Priority to US09/401,838 priority patent/US6613306B1/en
Priority to US09/401,836 priority patent/US20010012507A1/en
Priority to US09/748,120 priority patent/US20010024640A1/en
Priority to US10/061,299 priority patent/US6881397B2/en
Priority to US10/102,684 priority patent/US20030064030A1/en
Priority to US10/120,390 priority patent/US6989141B2/en
Priority to US10/226,244 priority patent/US6896875B2/en
Priority to US10/336,823 priority patent/US20030194376A1/en
Priority to US10/336,760 priority patent/US20030185759A1/en
Priority to US10/809,677 priority patent/US20040208826A1/en
Priority to US10/962,460 priority patent/US20050058605A1/en
Priority to US11/085,169 priority patent/US20050207980A1/en
Priority to US11/231,865 priority patent/US20060034771A1/en
Priority to US11/444,362 priority patent/US20060257321A1/en
Priority to US11/851,769 priority patent/US20080063603A1/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
    • 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
    • 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

Definitions

  • the present invention concerns media adapted for injection into living bodies, e.g. for the purpose of ultrasonic echo ⁇ graphy and, more particularly, injectable liquid compositions comprising microbubbles of air or physiologically acceptable gases as stable dispersions or suspensions in an aqueous liquid carrier.
  • injectable liquid compositions comprising microbubbles of air or physiologically acceptable gases as stable dispersions or suspensions in an aqueous liquid carrier.
  • These compositions are mostly usable as contrast agents in ultrasonic echography to image the inside of blood-stream vessels and other cavities of living beings, e.g. human patients and animals.
  • Other uses however are also contemplated as disclosed hereafter.
  • the invention also comprises dry compositions which, upon admixing with an aqueous carrier liquid, will generate the foregoing sterile suspension of microbubbles thereafter usable as contrast agent for ultrasonic echography and other purposes.
  • microbodies like microspheres or microglobules of air or a gas, e.g. microbubbles or micro- balloons, suspended in a liquid are exceptionally efficient ultrasound reflectors for echography.
  • microbubble specifically designates air or gas glo ⁇ bules in suspension in a liquid which generally results from the introduction therein of air or a gas in divided form, the liquid preferably also containing surfactants or tensides to control the surface properties thereof and the stability of the bubbles.
  • the internal volume of the microbubbles is limited by the gas/liquid interface, or in other words, the microbubbles are only bounded by a rather evanescent envelope involving the molecules of the liquid and surfactant loosely bound at the gas to liquid junction boundary.
  • microcapsule or “microballoon” designates preferably air or gas bodies with a material boundary or envelope formed of molecules other than that of the liquid of suspension, e.g. a polymer membrane wall. Both microbubbles and
  • SUBSTITUTESHEET microballoons- are useful as ultrasonic contrast agents. For instance injecting into the blood-stream of living bodies suspensions of gas microbubbles or microballoons (in the range of 0.5 to 10 ⁇ m ) in a carrier liquid will strongly reinforce ultrasonic echography imaging, thus aiding in the visualization of internal organs. Imaging of vessels and internal organs can strongly help in medical diagnosis, for instance for the detection of cardiovascular and other diseases.
  • EP-A- 123.235 and 122.624 use is made of air trapped in solids.
  • 122.624 claims a liquid carrier contrast composition for ultrasonic echography containing microparticles of a solid surfactant, the latter being optionally combined with micro ⁇ particles of a non-surfactant.
  • the formation of air bubbles in the solution results from the release of the air adsorbed on the surface of the particles, or trapped within the particle lattice, or caught between indivi ⁇ dual particles, this being so when the particles are agitated with the liquid carrier.
  • EP-A- 131.540 also discloses the preparation of microbubbles suspensions in which a stabilized injectable carrier liquid, e.g. a physiological aqueous solution of salt, or a solution of a sugar like maltose, dextrose, lactose or galactose, without viscosity enhancer, is mixed with micro ⁇ particles (in the 0.1 to 1 ⁇ m range) of the same sugars con ⁇ taining entrapped air.
  • a stabilized injectable carrier liquid e.g. a physiological aqueous solution of salt, or a solution of a sugar like maltose, dextrose, lactose or galactose, without viscosity enhancer
  • SUBSTITUTE SHEET injecting (a) into (b) shortly before use together with a physiologically acceptable gas; or adding an acid to (a) and a carbonate to (b), both components being mixed together just before use and the acid reacting with the carbonate to generate C0 2 bubbles; or adding an over-pressurized gas to a mixture of (a) and (b) under storage, said gas being released into microbubbles at the time when the mixture is used for injection.
  • the tensides used in component (a) of US-A- 4,466,442 comprise lecithins; esters and ethers of fatty acids and fatty alcohols with polyoxyethylene and polyoxyethylated polyols like sorbitol, glycols and glycerol, cholesterol; and polyoxy-ethyl- ene-polyoxypropylene polymers.
  • the viscosity raising and stabi ⁇ lizing compounds include for instance mono- and polysaccharides (glucose, lactose, sucrose, dextran, sorbitol); polyols, e.g. glycerol, polyglycols; and polypeptides like proteins, gelatin, oxypolygelatin, plasma protein and the like.
  • equivalent volumes of (a) a 0.5% by weight aqueous solution of Pluronic ⁇ F-68 (a polyoxypropylene-polyoxyethylene polymer) and (b) a 10% lactose solution are vigorously shaken together under sterile conditions (closed vials) to provide a suspension of micro ⁇ bubbles ready for use as an ultrasonic contrast agent and last ⁇ ing for at least 2 minutes. About 50% of the bubbles had a size below 50 ⁇ m.
  • SUBSTITUTESHEET cles or high concentrations of electrolytes and other relatively inert solutes in the carrier liquid may be undesirable physio ⁇ logically in some cases.
  • the suspensions are totally unstable under storage and cannot be marketed as such; hence great skill is required to prepare the microbubbles at the right moment just before use.
  • microcapsules i.e. microballoons with a solid, air-sealed rigid polymeric membrane which perfectly resist for long storage periods in suspension, which have been developed to remedy this shortcoming (see for instance K.J.
  • composition of the present invention as defined in claim l, fully remedies the aforementioned pitfalls.
  • lamellar form defining the condition of at least a portion of the surfactant or surfactants of the present compo ⁇ sition indicates that the surfactants, in strong contrast with the microparticles of the prior art (for instance EP-A- 123.235), are in the form of thin films involving one or more molecular layers (in laminate form). Converting film forming surfactants into lamellar form can easily be done for instance by high pressure homogenization or by sonication under acous ⁇ tical or ultrasonic frequencies. In this connection, it should be pointed out that the existence of Hposomes is a well known and useful illustration of cases in which surfactants, more particularly lipids, are in lamellar form.
  • Llposome solutions are aqueous suspensions of microscopic
  • SUBSTITUTE SHEET vesicles generally spherically shaped, which hold substances encapsulated therein. These vesicles are usually formed of one or more concentrically arranged molecular layers (lamellae) of amphipatic compounds, i.e. compounds having a lipophobic hydro ⁇ philic moiety and a lipophilic hydrophobic moiety. See for instance "Liposome Methodology", Ed. L.D. Leserman et al, Inserm 136, 2-8 May 1982). Many surfactants or tensides, including lipids, particularly phospholipids, can be laminarized to correspond to this kind of structure.
  • the liposomic vesicles are preferably "unloaded", i.e. they do not need to keep encapsulated therein any foreign material other than the liquid of suspension as is normally the object of classic Hposomes.
  • the Hposomes of the present invention will contain an aqueous phase identical or similar to the aqueous phase of the solution itself. Then air or a gas is introduced into the liposome solution so that a
  • SUBSTITUTESHEET suspension of- microbubbles will form, said suspension being stabilized by the presence of the surfactants in lamellar form.
  • the material making the liposome walls can be modified within the scope of the present invention, for instance by covalently grafting thereon foreign molecules designed for specific purposes as will be explained later.
  • a mixture of a lipid and an aqueous liquid carrier is subjected to violent agitation and thereafter sonicated at acoustic or ultrasonic frequencies at room or elevated temperature.
  • a high pressure homogenizer such as the Microfluidizer (R) , which can be purchased from Microfluidics Corp., Newton, MA 02164 USA, can be used advantageously. Large volumes of liposome solutions can be prepared with this apparatus under pressures which can reach 600-1200 bar.
  • microparticles (10 ⁇ m or less) of a hydro- soluble carrier solid (NaCl, sucrose, lactose and other carbo ⁇ hydrates) are coated with an amphipatic agent; the dissolution of the coated carrier in an aqueous phase will yield liposomic vesicles.
  • a hydro- soluble carrier solid NaCl, sucrose, lactose and other carbo ⁇ hydrates
  • insoluble particles e.g. glass or resin microbeads are coated by moistening in a solution of a lipid in an organic solvent followed by removal of the solvent by evaporation.
  • the lipid coated microbeads are thereafter contacted with an aqueous carrier phase, whereby liposomic vesicles will form in that carrier phase.
  • SUBSTITUTE SHEET The introduction of air or gas into a liposome solution in order to form therein a suspension of microbubbles can be ef ⁇ fected by usual means, inter alia by injection, that is, for ⁇ cing said air or gas through tiny orifices into the liposome solution, or simply dissolving the gas in the solution by apply ⁇ ing pressure and thereafter suddenly releasing the pressure. Another way is to agitate or sonicate the liposome solution in the presence of air or an entrappable gas. Also one can generate the formation of a gas within the solution of Hposomes itself, for instance by a gas releasing chemical reaction, e.g. decom ⁇ posing a dissolved carbonate or bicarbonate by acid. The same effect can be obtained by dissolving under pressure a low boil ⁇ ing liquid, for instance butane, in the aqueous phase and thereafter allowing said liquid to boil by suddenly releasing the pressure.
  • a gas releasing chemical reaction e.g. decom ⁇
  • an advantageous method is to contact the dry surfactant in lamellar or thin film form with air or an ad- sorbable or entrappable gas before introducing said surfactant into the liquid carrier phase.
  • the method can be derived from the technique disclosed in GB-A-2,135,647, i.e. solid microparticles or beads are dipped in a solution of a film forming surfactant (or mixture of surfactants) in a volatile solvent, after which the solvent is evaporated and the beads are left in contact with air (or an adsorbable gas) for a time suf ⁇ ficient for that air to become superficially bound to the sur ⁇ factant layer.
  • the beads coated with air filled sur ⁇ factant are put into a carrier liquid, usually water with or without additives, whereby air bubbles will develop within the liquid by gentle mixing, violent agitation being entirely un ⁇ necessary.
  • a carrier liquid usually water with or without additives
  • the solid beads can be separated, for instance by filtration, from the microbubble suspension which is remark ⁇ ably stable with time.
  • insoluble beads or spheres instead of insoluble beads or spheres, one may use as supporting particles water soluble mate ⁇ rials like that disclosed in GB-A- 2,134,869 (carbohydrates or hydrophilic polymers), whereby said supporting particles will eventually dissolve and final separation of a solid becomes un-
  • the material of the parti ⁇ cles can be selected to eventually act as stabilizer or viscosi ⁇ ty enhancer wherever desired.
  • Hposomes i.e. Hposomes which have been prepared normally by means of conventional techniques in the form of aqueous solutions and thereafter dehydrated by usual means, e.g. such as disclosed in US-A- 4,229,360 also incorporated herein as reference.
  • dehydrating Hposomes recom ⁇ mended in this reference is freeze-drying (lyophilization) , i.e. the liposome solution is frozen and dried by evaporation (subli ⁇ mation) under reduced pressure.
  • hydrophilic stabilizer compound Prior to effecting freeze- drying, a hydrophilic stabilizer compound is dissolved in the solution, for instance a carbohydrate like lactose or sucrose or a hydrophilic polymer like dextran, starch, PVP, PVA and the like. This is useful in the present invention since such hydro ⁇ philic compounds also aid in homogenizing the microbubbles size distribution and enhance stability under storage.
  • freeze-drying technique under reduced pressure is very useful because it permits, after drying, to restore the pressure above the dried Hposomes with any entrappable gas, i.e. nitrogen, C0 2 , argon, methane, freon, etc., whereby after dissolution of the Hposomes processed under such conditions suspensions of microbubbles containing the above gases are obtained.
  • any entrappable gas i.e. nitrogen, C0 2 , argon, methane, freon, etc.
  • Microbubbles suspensions formed by applying gas pressure on a dilute solution of laminated lipids in water (0.1 - 10% by weight) and thereafter suddenly releasing the pressure have an even higher bubble concentration, e.g. in the order of 10 10
  • SUBSTITUTESHEET 10 11 bubbles/jnl.
  • the average bubble size is somewhat above 10 ⁇ m, e.g. in the 10 - 50 ⁇ m range.
  • bubble size distribution can be narrowed by centrifugation and layer decantation.
  • the tensides or surfactants which are convenient in this invention can be selected from all amphipatic compounds capable of forming stable films in the presence of water and gases.
  • the preferred surfactants which can be laminarized include the lecithins (phosphatidyl-choline) and other phospholipids, inter alia phosphatidic acid (PA), phosphatidyl-inositol phosphatidyl- ethanolamine (PE) , phosphatidyl-serine (PS), phosphatidyl- glycerol (PG), cardiolipin (CL) , sphingomyelins , the plasmogens, the cerebrosides , etc.
  • PA phosphatidic acid
  • PE phosphatidyl-inositol phosphatidyl- ethanolamine
  • PS phosphatidyl-serine
  • PG phosphatidyl- glycerol
  • CA cardiolipin
  • lipids examples include the phospholipids in general, for example, natural lecithins, such as egg lecithin or soya bean lecithin, or synthetic lecithins such as saturated synthetic lecithins, for example, dimyristoyl phosphatidyl choline, dipalmitoyl phosphatidyl choline or distearoyl phosphatidyl choline or unsaturated synthetic lecithins, such as dioleyl phosphatidyl choline or dilinoleyl phosphatidyl choline, with egg lecithin or soya bean lecithin being preferred.
  • Additives like cholesterol and other substances can be added to one or more of the foregoing lipids in proportions ranging from zero to 50% by weight.
  • Such additives may include other surfactants that can be used in admixture with the film forming surfactants and most of which are recited in the prior art discussed in the introduction of this specification.
  • free fatty acids esters of fatty acids with polyoxyalkylene compounds like polyoxypropylene glycol and polyoxyethylene glycol; ethers of fatty alcohols with polyoxyalkylene glycols; esters of fatty acids with polyoxyalkylated sorbitan; soaps; glycerol-polyal- kylene stearate; glycerol-polyoxyethylene ricinoleate; homo- and copolymers of polyalkylene glycols; polyethoxylated soya-oil and castor oil as well as hydrogenated derivatives; ethers and esters of sucrose or other carbohydrates with fatty acids, fatty alcohols, these being optionally polyoxyakylated; mono-, di- and triglycerides of saturated or unsaturated fatty acids;
  • SUBST1TUTESHEET rides of soya-oil and sucrose.
  • the amount of the non-film form ⁇ ing tensides or surfactants can be up to 50% by weight of the total amount of surfactants in the composition but is preferably between zero and 30%.
  • the total amount of surfactants relative to the aqueous carrier liquid is best in the range of 0.01 to 25% by weight but quantities in the range 0.5 - 5% are advantageous because one always tries to keep the amount of active substances in an in- jectable solution as low as possible, this being to minimize the Introduction of foreign materials into living beings even when they are harmless and physiologically compatible.
  • Further optional additives to the surfactants include: a) substances which are known to provide a negative charge on Hposomes, for example, phosphatldic acid, phosphatidyl- glycerol or dicetyl phosphate; b) substances known to provide a positive charge, for exam ⁇ ple, stearyl amine, or stearyl amlne acetate; c) substances known to affect the physical properties of the lipid films in a more desirable way; for example, capro-lac- tam and/or sterols such as cholesterol, ergosterol, phytosterol, sitosterol, sitosterol pyroglutamate, 7-dehydro-cholesterol or lanosterol, may affect lipid films rigidity; d) substances known to have antioxidant properties to im ⁇ prove the chemical stability of the components in the suspen ⁇ sions, such as tocopherol, propyl gallate, ascorbyl palmitate, or butylated hydroxy toluene.
  • the aqueous carrier in this invention is mostly water with possibly small quantities of physiologically compatible liquids such as isopropanol, glycerol, hexanol and the like (see for instance EP-A- 52.575). In general the amount of the organic hydrosoluble liquids will not exceed 5 - 10% by weight.
  • the present composition may also contain dissolved or suspended therein hydrophilic compounds and polymers defined generally under the name of viscosity enhancers or stabilizers.
  • hydrophilic compounds and polymers defined generally under the name of viscosity enhancers or stabilizers.
  • SUBSTITUTESHEET body to the solutions.
  • the upper concentrations of such additives when totally innocuous can be very high, for instance up to 80 - 90% by weight of solution with Iopamidol and other iodinated X-ray contrast agents.
  • vis ⁇ cosity enhancers like for instance sugars, e.g. lactose, sucrose, maltose, galactose, glucose, etc.
  • hydrophilic poly ⁇ mers like starch, dextran, polyvinyl alcohol, polyvinyl-pyrroli- done, dextrin, xanthan or partly hydrolyzed cellulose oligomers, as well as proteins and polypeptides, the concentrations are best between about 1 and 40% by weight, a range of about 5 - 20% being preferred.
  • the injectable compositions of this invention can also contain physiologically acceptable electro ⁇ lytes; an example is an isotonic solution of salt.
  • the present invention naturally also includes dry storable pulverulent blends which can generate the present microbubble containing dispersions upon simple admixing with water or an aqueous carrier phase.
  • dry blends or formul ⁇ ations will contain all solid ingredients necessary to provide the desired microbubbles suspensions upon the simple addition of water, i.e. principally the surfactants in lamellar form con ⁇ taining trapped or adsorbed therein the air or gas required for microbubble formation, and accessorily the other non-film form ⁇ ing surfactants, the viscosity enhancers and stabilizers and possibly other optional additives.
  • the air or gas entrappment by the laminated surfactants occurs by simply exposing said surfactants to the air (or gas) at room or super- atmospheric pressure for a time sufficient to cause said air or gas to become entrapped within the surfactant.
  • This period of time can be very short, e.g. in the order of a few seconds to a few minutes although over-exposure, i.e. storage under air or under a gaseous atmosphere is in no way harmful.
  • What is impor ⁇ tant is that air can well contact as much as possible of the available surface of the laminated surfactant, i.e. the dry material should preferably be in a "fluffy" light flowing condi ⁇ tion. This is precisely this condition which results from the freeze-drying of an aqueous solution of Hposomes and hydro-
  • the weight ratio of surfactants to hydrophilic viscosity enhancer in the dry formulations will be in the order of 0.1:10 to 10:1, the further optional ingredients, if any, being present in a ratio not exceeding 50% relative to the total of surfactants plus viscosity enhancers.
  • the dry blend formulations of this invention can be prepared by very simple methods. As seen before, one preferred method is to first prepare an aqueous solution in which the film forming lipids are laminarized, for instance by sonication, or using any conventional technique commonly used in the liposome field, this solution also containing the other desired additives, i.e. viscosity enhancers, non-film forming surfact ⁇ ants, electrolyte, etc., and thereafter freeze drying to a free flowable powder which is then stored in the presence of air or an entrappable gas.
  • the other desired additives i.e. viscosity enhancers, non-film forming surfact ⁇ ants, electrolyte, etc.
  • the dry blend can be kept for any period of time in the dry state and sold as such.
  • a known weight of the dry pulverulent formulation in a sterile aqueous phase, e.g. water or a physiologically acceptable medium.
  • the amount of powder will depend on the desired concentration of bubbles in the injectable product, a count of about 10 8 - 10 9 bubbles/ml being generally that from making a 5 - 20% by weight solution of the powder in water. But naturally this figure is only indicative, the amount of bubbles being essentially dependent on the amount of air or gas trapped during manufacture of the dry powder.
  • the manu ⁇ facturing steps being under control, the dissolution of the dry formulations will provide microbubble suspensions with well reproducible counts.
  • microbubble suspensions (bubble in the 0.5 - 10 ⁇ m range) are extraordinarily stable with time, the count originally measured at start staying unchanged or only little changed for weeks and even months; the only observable change is a kind of segregation, the larger bubbles (around 10 ⁇ m) tending to rise faster than the small ones.
  • microbubbles suspensions of this invention can be diluted with very little loss in the number of microbubbles to be expected from dilution, i.e. even in the case of high dilution ratios, e.g. 1/10 2 to 1/10 4 , the microbubble count reduction accurately matches with the dilution ratio.
  • the stability of the bubbles depends on the surfactant in lamellar form rather than on the presence of stabilizers or viscosity enhancers like in the prior art. This property is advantageous in regard to imaging test reproducibillty as the bubbles are not affected by dilution with blood upon injection into a patient.
  • bubbles of this invention versus the microcapsules of the prior art surrounded by a rigid but breakable membrane which may irreversibly fracture under stress is that when the present suspensions are subject to sudden pressure changes, the present bubbles will momentarily contract elastically and then resume their original shape when the pressure is released. This is important in clinical practice when the microbubbles are pumped through the heart and therefore are exposed to alternating pressure pulses.
  • the bubble suspensions of the present invention are also useful in other medical/diagnostic applications where it is desirable to target the stabilized microbubbles to specific sites in the body following their injection, for instance to thrombi present in blood vessels, to atherosclerotic lesions (plaques) in arteries, to tumor cells, as well as for the
  • monoclonal antibodies tailored by genetic engineering, antibody fragments or polypeptides designed to mimic antibodies, bioadhesive polymers, lectins and other site-recognizing mole ⁇ cules to the surfactant layer stabilizing the microbubbles.
  • monoclonal antibodies can be bound to phospholipid bilayers by the method described by L.D. Leserman, P. Machy and J. Barbet ("Liposome Technology vol. Ill" p. 29 ed. by G. Gregoriadis, CRC Press 1984).
  • a palmitoyl antibody is first synthesized and then incorporated in phospholipid bilayers following L. Huang, A. Huang and S.J. Kennel ("Liposome Techno ⁇ logy vol. Ill” p. 51 ed. by G. Gregoriadis, CRC Press 1984).
  • some of the phospholipids used in the present invention can be carefully selected in order to obtain prefer ⁇ ential uptake in organs or tissues or increased half-life in blood.
  • GM1 gangliosides- or phosphatidylinositol-containlng Hposomes preferably in addition to cholesterol, will lead to increased half-lifes in blood after intravenous administration in analogy with A. Gabizon, D. Papahadjopoulos, Proc. Natl Acad. Sci USA 85 (1988) 6949.
  • the gases in the microbubbles of the present invention can include, in addition to current innocuous physiologically acceptable gases like C0 2 , nitrogen, N 2 0, methane, butane, freon and mixtures thereof, radioactive gases such as 133 Xe or 81 Kr are of particular Interest in nuclear medicine for blood circulation measurements, for lung scintigraphy etc.
  • Echogenicity measurements were performed in a pulse - echo system made of a plexiglas specimen holder (diameter 30 mm) and a transducer holder immersed in a constant temperature water bath, a pulser-receiver (Accutron M3010S) with for the receiving part an external pre-amplifier with a fixed gain of 40 dB and an internal amplifier with adjustable gain from -40 to +40 dB.
  • a pulser-receiver Acceler M3010S
  • SUBSTITUTE SHEET 10MHz low-pass, filter was inserted in the receiving part to improve the signal to noise ratio.
  • the A/D board in the IBM PC was a Sonotek STR 832. Measurements were carried out at 2.25, 3.5, 5 and 7.5 MHz.
  • a liposome solution (50 mg lipids per ml) was prepared in distilled water by the REV method (see F. Szoka Jr. and D. Papahadjopoulos, Proc. Natl. Acad. Sci. USA 75 (1978) 4194) using hydrogenated soya lecithin (NC 95 H, Nattermann Chemie, K ⁇ ln, W. Germany) and dicetylphosphate in a molar ratio 9/1.
  • This liposome preparation was extruded at 65°C (to calibrate the vesicle size) through a 1 ⁇ m polycarbonate filter (Nucleopore) .
  • a distilled water solution (100 ml) containing by weight 2% of hydrogenated soya lecithin and dicetylphosphate in a 9/1 molar ratio was sonicated for 15 min at 60-65°C with a Branson probe sonifier (Type 250).
  • the suspension was very stable but after a few days a segregation occurred in the standing phase, the larger bubbles tending to concentrate in the upper layers of the suspension.
  • a hydrogenated soya lecithin/dicetylphosphate suspension in water was laminarized using the REV technique as described in Example 1.
  • Two ml of the liposome preparation were added to 8 ml of 15% maltose solution in distilled water.
  • the resulting solution was frozen at -30°C, then lyophilized under 0.1 Torr. Complete sublimation of the ice was obtained in a few hours. Thereafter, air pressure was restored in the evacuated container so that the lyophilized powder became saturated with air in a few minutes.
  • the dry powder was then dissolved in 10 ml of sterile water under gentle mixing, whereby a microbubble suspension (10 8 -10 9 microbubbles per ml, dynamic viscosity ⁇ 20 mPa.s) was obtained.
  • This suspension containing mostly bubbles in the 1-5 ⁇ m range was stable for a very long period, as numerous bubbles could still be detected after 2 months standing.
  • This microbubble suspension gave a strong response in ultrasonic echography. If in this example the solution is frozen by spraying in air at -30 to -70°C to obtain a frozen snow instead of a monolithic block
  • Example 5A Two ml samples of the liposome solution obtained as described in Example 4 were mixed with 10 ml of an 5% aqueous solution of gelatin (sample 5A), human albumin (sample 5B), dextran (sample 5C) and iopamidol (sample 5D). All samples were lyophilized. After lyophilization and introduction of air, the various samples were gently mixed with 20 ml of sterile water. In all cases, the bubble concentration was above 10 8 bubbles per ml and almost all bubbles were below 10 ⁇ m. The procedure of the foregoing Example was repeated with 9 ml of the liposome pre ⁇ paration (450 mg of lipids) and only one ml of a 5% human albumin solution. After lyophilization, exposure to air and addition of sterile water (20 ml), the resulting solution contained 2 x 10 8 bubbles per ml, most of them below 10 ⁇ m.
  • Lactose 500 mg was finely milled to a particle size of 1-3 ⁇ m, was moistened with a chloroform (5 ml) solution of 100 mg of dimyristoylphosphatidylcholine/cholesterol/dipalmitoylphosphatidic acid (from Fluka) in a molar ratio of 4:1:1 and thereafter evaporated under vacuum in a rotating evaporator.
  • the resulting free flowing white powder was rotated a few minutes under nitrogen at normal pressure and thereafter dissolved in 20 ml of sterile water.
  • a microbubble suspension was obtained with about 10 5 -10 6 microbubbles per ml in the 1-10 ⁇ m size range as ascertained by observation under the microscope.
  • the weight ratio of coated surfactant to water-soluble carrier was 1:5. Excellent results (10 7 -10 8 microbubbles/ml) are also obtained when reducing this ratio to lower values, i.e. down to 1:20, which will actually increase the surfactant efficiency for the intake of air, that is, this will decrease the weight of surfactant necessary for producing the same bubble count.
  • Two-dimensional echocardiography was performed in an expe ⁇ rimental dog following peripheral vein injection of 0.1-2 ml of the preparation obtained in Example 4. Opacification of the left heart with clear outlining of the endocardium was observed, thereby confirming that the microbubbles (or at least a signi ⁇ ficant part of them) were able to cross the pulmonary capillary circulation.
  • a phospholipid/maltose lyophilized powder was prepared as described in Example 4. However, at the end of the lyophi ⁇ lization step, a 133 Xe containing gas mixture was introduced in the evacuated container instead of air. A few minutes later, sterile water was introduced and after gentle mixing a micro ⁇ bubble suspension containing 133 Xe in the gas phase was pro ⁇ quizd. This microbubble suspension was injected into living bodies to undertake investigations requiring use of 133 Xe as tracer. Excellent results were obtained.
  • Hposomes are formed by conventional means but with the addition of a gas or gas precursor in the aqueous composition forming the liposome core (col. 2, lines 15-27).
  • a gas precursor (bicarbonate) is detailed in Examples 1 and 2 of the reference.
  • Using an aqueous carrier with an added gas for encapsulating the gas in the Hposomes will require that the gas be in the form of very small bubbles, i.e. of size similar or smaller than the size of the liposome vesicles.
  • Aqueous media in which air can be entrapped in the form of very small bubbles are disclosed in M.W. Keller et al, J. Ultrasound Med. 5 (1986), 413-498.
  • a quantity of 126 mg of egg lecithin and 27 mg of cholesterol were dissolved in 9 ml of chloroform in a 200 ml round bottom flask.
  • the solution of lipids was evaporated to dryness on a Rotavapor whereby a film of the lipids was formed on the walls of the flask.
  • a 10 ml of a 50% by weight aqueous dextrose solution was sonicated for 5 min according to M.W.
  • the resulting liposome suspen ⁇ sion was subjected to centrlfugation under 5000 g for 15 min to remove from the carrier the air not entrapped in the vesicles. It was also expected that during centrlfugation, the air filled Hposomes would segregate to the surface by buoyancy.
  • An injectable contrast composition was prepared according to Ryan (US-A-4,900,540, col. 3, Example 1). Egg lecithin (126 mg) and cholesterol (27 mg) were dissolved in 9 ml of diethylether. To the solution were added 3 ml of 0.2 molar aqueous bicarbonate and the resulting two phase systems was sonicated until becoming homogeneous. The mixture was evaporated in a Rotavapor apparatus and 3 ml of 0.2 molar aqueous bicarbonate were added.
  • a 1 ml portion of the liposome suspension was injected into the jugular vein of an experimental rabbit, the animal being under condition for heart ultrasonic imaging using an Acuson 128-XP5 ultrasonic imager (7.5 transducer probe for imaging the heart).
  • the probe provided a cross-sectional image of the right and left ventricles (mid-papillary muscle).
  • a light and transient (a few seconds) increase in the outline of the right ventricle was observed.
  • the effect was however much inferior to the effect observed using the preparation of Example 4. No improvement of the imaging of the left ventricle was noted which probably indicates that the C0 2 loaded Hposomes did not pass the pulmonary capillaries barrier.

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EP91907163A EP0474833B2 (en) 1990-04-02 1991-04-02 Stable microbubbles suspensions injectable into living organisms
DE69111719T DE69111719T3 (de) 1990-04-02 1991-04-02 Stabile mikroblasensuspensionen zur injektion in lebewesen.
CA002056371A CA2056371C (en) 1990-04-02 1991-04-02 Stable microbubbles suspensions injectable into living organisms
KR1019910701733A KR960002184B1 (ko) 1990-04-02 1991-04-02 생체에 주사가능한 미소기포현탁액 및 제조방법
US08/128,540 US5380519A (en) 1990-04-02 1993-09-29 Stable microbubbles suspensions injectable into living organisms
US08/315,347 US5531980A (en) 1990-04-02 1994-09-30 Stable microbubbles suspensions injectable into living organisms
US08/456,385 US5658551A (en) 1990-04-02 1995-06-01 Stable microbubbles suspensions injectable into living organisms
US08/457,581 US5567414A (en) 1990-04-02 1995-06-01 Stable microbubbles suspensions injectable into living organisms
GR950402454T GR3017324T3 (en) 1990-04-02 1995-09-06 Stable microbubbles suspensions injectable into living organisms.
US08/853,936 US6110443A (en) 1990-04-02 1997-05-09 Dry stable formation to produce microbubble suspension for ultrasound
US08/893,371 US7033574B1 (en) 1990-04-02 1997-07-15 Stable microbubbles suspensions injectable into living organisms
US09/115,963 USRE39146E1 (en) 1990-04-02 1998-07-15 Long-lasting aqueous dispersions or suspensions of pressure-resistant gas-filled microvesicles and methods for the preparation thereof
US09/401,835 US20010008626A1 (en) 1990-04-02 1999-09-22 Ultrasound contrast agents and methods of making and using them
US09/401,838 US6613306B1 (en) 1990-04-02 1999-09-22 Ultrasound contrast agents and methods of making and using them
US09/401,836 US20010012507A1 (en) 1990-04-02 1999-09-22 Ultrasound contrast agents and methods of making and using them
US09/748,120 US20010024640A1 (en) 1990-04-02 2000-12-27 Ultrasound contrast agents and methods of making and using them
US10/061,299 US6881397B2 (en) 1990-04-02 2002-02-04 Long-lasting aqueous dispersions or suspensions of pressure-resistant gas-filled microvesicles and methods for the preparation thereof
US10/102,684 US20030064030A1 (en) 1990-04-02 2002-03-22 Ultrasound contrast agents and methods of making and using them
US10/120,390 US6989141B2 (en) 1990-05-18 2002-04-12 Ultrasound contrast agents and methods of making and using them
US10/226,244 US6896875B2 (en) 1990-04-02 2002-08-23 Mixable combination for generating a suspension of stable microbubbles for ultrasonic imaging
US10/336,823 US20030194376A1 (en) 1990-05-18 2003-01-06 Ultrasound contrast agents and methods of making and using them
US10/336,760 US20030185759A1 (en) 1990-05-18 2003-01-06 Ultrasound contrast agents and methods of making and using them
US10/809,677 US20040208826A1 (en) 1990-04-02 2004-03-26 Ultrasound contrast agents and methods of making and using them
US10/962,460 US20050058605A1 (en) 1990-04-02 2004-10-13 Long-lasting aqueous dispersions or suspensions of pressure-resistant gas-filled microvesicles and methods for the preparation thereof
US11/085,169 US20050207980A1 (en) 1990-04-02 2005-03-22 Stable microbubbles suspensions injectable into living organisms
US11/231,865 US20060034771A1 (en) 1990-04-02 2005-09-22 Ultrasound contrast agents and methods of making and using them
US11/444,362 US20060257321A1 (en) 1990-04-02 2006-06-01 Ultrasound contrast agents and methods of making and using them
US11/851,769 US20080063603A1 (en) 1990-04-02 2007-09-07 Ultrasound contrast agents and methods of making and using them

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Cited By (92)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0511273A1 (en) * 1989-12-22 1992-11-04 Imarx Pharmaceutical Corp. Liposomes as contrast agents for ultrasonic imaging
EP0554213A1 (en) * 1992-01-24 1993-08-04 BRACCO International B.V. Long-lasting aqueous dispersions or suspensions of pressure-resistant gas-filled microvesicles and methods for the preparation thereof
WO1994009829A1 (en) * 1992-11-02 1994-05-11 Bracco International B.V. Stable microbubble suspensions as enhancement agents for ultrasound echography
WO1994012145A2 (en) * 1992-12-02 1994-06-09 Unilever Plc Cosmetic composition
US5334381A (en) * 1989-12-22 1994-08-02 Unger Evan C Liposomes as contrast agents for ultrasonic imaging and methods for preparing the same
EP0616508A1 (en) * 1991-06-18 1994-09-28 Imarx Pharmaceutical Corp. Gas filled liposomes and their use as ultrasonic contrast agents
US5352435A (en) * 1989-12-22 1994-10-04 Unger Evan C Ionophore containing liposomes for ultrasound imaging
EP0638318A2 (en) 1991-02-15 1995-02-15 BRACCO International B.V. Compositions for increasing the image contrast in diagnostic investigations of the digestive tract
US5393524A (en) * 1991-09-17 1995-02-28 Sonus Pharmaceuticals Inc. Methods for selecting and using gases as ultrasound contrast media
WO1995016467A1 (en) * 1993-12-15 1995-06-22 Bracco Research S.A. Gas mixtures useful as ultrasound contrast media
US5469854A (en) * 1989-12-22 1995-11-28 Imarx Pharmaceutical Corp. Methods of preparing gas-filled liposomes
US5527521A (en) * 1991-04-05 1996-06-18 Imarx Pharmaceutical Corp. Low density microspheres and suspensions and their use as contrast agents for computed tomography and in other applications
US5536489A (en) * 1993-06-04 1996-07-16 Molecular Biosystems, Inc. Emulsions as contrast agents and method of use
US5542935A (en) * 1989-12-22 1996-08-06 Imarx Pharmaceutical Corp. Therapeutic delivery systems related applications
US5558856A (en) * 1992-01-09 1996-09-24 Nycomed Imaging As Microbubble-generating contrast agents for ultrasound and magnetic resonance imaging
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
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
US5578292A (en) * 1991-11-20 1996-11-26 Bracco International B.V. Long-lasting aqueous dispersions or suspensions of pressure-resistant gas-filled microvesicles and methods for the preparation thereof
US5580575A (en) * 1989-12-22 1996-12-03 Imarx Pharmaceutical Corp. Therapeutic drug delivery systems
GB2302650B (en) * 1992-10-10 1997-04-09 Andaris Ltd Targeted diagnostic agents
WO1997029783A1 (en) * 1996-02-19 1997-08-21 Nycomed Imaging A/S Improvements in or relating to contrast agents
WO1998008747A1 (en) 1996-08-27 1998-03-05 Marsden, John Container containing contrast agents
EP0831927A1 (en) * 1995-06-06 1998-04-01 Imarx Pharmaceutical Corp. Stabilized compositions of fluorinated amphiphiles as contrast agents for ultrasound
US5741478A (en) * 1994-11-19 1998-04-21 Andaris Limited Preparation of hollow microcapsules by spray-drying an aqueous solution of a wall-forming material and a water-miscible solvent
WO1998018497A2 (en) * 1996-10-28 1998-05-07 Nycomed Imaging As Contrast agents
WO1998018495A2 (en) * 1996-10-28 1998-05-07 Marsden, John, Christopher Improvements in or relating to diagnostic/therapeutic agents
WO1998018500A2 (en) * 1996-10-28 1998-05-07 Marsden, John, Christopher Improvements in or relating to diagnostic/therapeutic agents
WO1998018501A2 (en) * 1996-10-28 1998-05-07 Marsden, John, Christopher Improvements in or relating to diagnostic/therapeutic agents
WO1998018496A2 (en) * 1996-10-28 1998-05-07 Nycomed Imaging As Contrast agents
US5993805A (en) * 1991-04-10 1999-11-30 Quadrant Healthcare (Uk) Limited Spray-dried microparticles and their use as therapeutic vehicles
US6017310A (en) * 1996-09-07 2000-01-25 Andaris Limited Use of hollow microcapsules
US6022525A (en) * 1991-04-10 2000-02-08 Quadrant Healthcare (Uk) Limited Preparation of diagnostic agents
US6068600A (en) * 1996-12-06 2000-05-30 Quadrant Healthcare (Uk) Limited Use of hollow microcapsules
US6217850B1 (en) 1995-06-07 2001-04-17 Nycomed Imaging As Method of making lyophilized microbubble compositions useful as contrast agents
US6261537B1 (en) 1996-10-28 2001-07-17 Nycomed Imaging As Diagnostic/therapeutic agents having microbubbles coupled to one or more vectors
US6264917B1 (en) 1996-10-28 2001-07-24 Nycomed Imaging As Targeted ultrasound contrast agents
US6322770B1 (en) 1998-03-31 2001-11-27 Dupont Pharmaceuticals Company Indazole vitronectin receptor antagonist pharmaceuticals
US6511649B1 (en) 1998-12-18 2003-01-28 Thomas D. Harris Vitronectin receptor antagonist pharmaceuticals
US6511648B2 (en) 1998-12-18 2003-01-28 Bristol-Myers Squibb Pharma Company Vitronectin receptor antagonist pharmaceuticals
US6524553B2 (en) 1998-03-31 2003-02-25 Bristol-Myers Squibb Pharma Company Quinolone vitronectin receptor antagonist pharmaceuticals
US6537520B1 (en) 1998-03-31 2003-03-25 Bristol-Myers Squibb Pharma Company Pharmaceuticals for the imaging of angiogenic disorders
CN1103605C (zh) * 1997-08-12 2003-03-26 勃勒柯研究有限公司 磁共振成象用可投药组合物及方法
US6548663B1 (en) 1998-03-31 2003-04-15 Bristol-Myers Squibb Pharma Company Benzodiazepine vitronectin receptor antagonist pharmaceuticals
US6558649B1 (en) 1998-12-18 2003-05-06 Bristol-Myers Squibb Pharma Company Vitronectin receptor antagonist pharmaceuticals
US6569404B1 (en) 1993-01-25 2003-05-27 Amersham Health A/S Phase shift colloids as ultrasound contrast agents
US6569402B1 (en) 1998-12-18 2003-05-27 Bristol-Myers Squibb Pharma Company Vitronectin receptor antagonist pharmaceuticals
US6613306B1 (en) 1990-04-02 2003-09-02 Bracco International B.V. Ultrasound contrast agents and methods of making and using them
US6794518B1 (en) 1998-12-18 2004-09-21 Bristol-Myers Squibb Pharma Company Vitronectin receptor antagonist pharmaceuticals
EP1550464A1 (en) * 1993-07-30 2005-07-06 IMCOR Pharmaceutical Co. Stabilized microbubble composition for ultrasound
US6989141B2 (en) 1990-05-18 2006-01-24 Bracco International B.V. Ultrasound contrast agents and methods of making and using them
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
WO2006067201A2 (en) 2004-12-23 2006-06-29 Bracco Research Sa A perfusion assessment method and system based on bolus administration
US7083778B2 (en) 1991-05-03 2006-08-01 Bracco International B.V. Ultrasound contrast agents and methods of making and using them
US7141235B2 (en) 1993-07-30 2006-11-28 Imcor Pharmaceutical Co. Stabilized gas emulsion containing phospholipid for ultrasound contrast enhancement
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WO2007054544A1 (en) 2005-11-10 2007-05-18 Bracco Research Sa Detection of immobilized contrast agent in medical imaging applications based on flow dynamics analysis
WO2008074889A1 (en) 2006-12-21 2008-06-26 Bracco International Bv Detection of the detachment of immobilized contrast agent in medical imaging applications
EP2189112A1 (en) 2008-11-24 2010-05-26 Bracco Research S.A. Real-time perfusion imaging and quantification
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WO2011026866A1 (en) 2009-09-01 2011-03-10 Bracco Suisse Sa Parametric images based on dynamic behavior over time
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WO2011110552A1 (en) 2010-03-09 2011-09-15 Bracco Suisse Sa Initialization of fitting parameters for perfusion assessment based on bolus administration
US8021303B2 (en) 2003-06-12 2011-09-20 Bracco Research Sa System for extracting morphological information through a perfusion assessment process
WO2012020030A1 (en) 2010-08-09 2012-02-16 Bracco Suisse Sa Targeted gas-filled microvesicles
WO2012085072A1 (en) 2010-12-24 2012-06-28 Bracco Suisse Sa Gas-filled microvesicles for use as vaccine
WO2012123229A1 (de) * 2011-03-11 2012-09-20 Innora Gmbh Festes, negatives röntgenkontrastmittel zur darstellung des gastrointestinaltraktes
US8293214B2 (en) 2006-12-19 2012-10-23 Bracco Suisse S.A. Targeting and therapeutic compounds and gas-filled microvesicles comprising said compounds
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EP2599504A2 (en) 2008-02-18 2013-06-05 INSERM (Institut National de la Santé et de la Recherche Médicale) Use of conjugates of fsh receptor ligands and antitumour agents for therapy of cancer
US8491482B2 (en) 2003-06-12 2013-07-23 Bracco Suisse S.A. Blood flow estimates through replenishment curve fitting in ultrasound contrast imaging
WO2015000953A1 (en) 2013-07-03 2015-01-08 Bracco Suisse S.A. Devices and methods for the ultrasound treatment of ischemic stroke
US9072492B2 (en) 2007-12-28 2015-07-07 Bracco Suisse Sa Quantification analysis of immobilized contrast agent in medical imaging applications
WO2015155380A1 (en) * 2014-04-07 2015-10-15 Bracco Suisse Sa Estimation of acoustic level in-situ with non-fundamental analysis
US9248204B2 (en) 2004-08-18 2016-02-02 Bracco Suisse S.A. Gas-filled microvesicles composition for contrast imaging
US9307957B2 (en) 2009-06-08 2016-04-12 Bracco Suisse Sa Auto-scaling of parametric images
US9364569B2 (en) 2003-02-04 2016-06-14 Bracco Suisse S.A. Ultrasound contrast agents and process for the preparation thereof
US9446156B2 (en) 2006-09-05 2016-09-20 Bracco Suisse S.A. Gas-filled microvesicles with polymer-modified lipids
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
US9734584B2 (en) 2012-12-21 2017-08-15 Bracco Suisse Sa Segmentation in diagnostic imaging applications based on statistical analysis over time
US9750821B2 (en) 2003-12-22 2017-09-05 Bracco Suisse S.A. Gas-filled microvesicle assembly for contrast imaging
US9789210B1 (en) 2016-07-06 2017-10-17 Lantheus Medical Imaging, Inc. Methods for making ultrasound contrast agents
EP3150559A4 (en) * 2014-05-28 2018-02-21 Takeda Pharmaceutical Company Limited Antibacterial water
US10022460B2 (en) 2014-12-31 2018-07-17 Lantheus Medical Imaging, Inc. Lipid-encapsulated gas microsphere compositions and related methods
US10130342B2 (en) 2007-12-28 2018-11-20 Bracco Suisse Sa Initialization of fitting parameters for perfusion assessment based on bolus administration
US10258563B2 (en) 2009-04-20 2019-04-16 Drexel University Encapsulation of microbubbles within the aqueous core of microcapsules
US10433817B2 (en) 2015-12-10 2019-10-08 Bracco Suisse S.A. Detection of immobilized contrast agent with dynamic thresholding
US10537622B2 (en) 2014-12-22 2020-01-21 Bracco Suisse S.A. Gas-filled microvesicles for use as vaccine
US10588988B2 (en) 2016-05-04 2020-03-17 Lantheus Medical Imaging, Inc. Methods and devices for preparation of ultrasound contrast agents
US11284910B2 (en) 2015-12-09 2022-03-29 Koninklijke Philips N.V. Interleaved beam pattern for sonothhrombolysis and other vascular acoustic resonator mediated therapies

Families Citing this family (250)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5733572A (en) 1989-12-22 1998-03-31 Imarx Pharmaceutical Corp. Gas and gaseous precursor filled microspheres as topical and subcutaneous delivery vehicles
US6088613A (en) 1989-12-22 2000-07-11 Imarx Pharmaceutical Corp. Method of magnetic resonance focused surgical and therapeutic ultrasound
US6146657A (en) 1989-12-22 2000-11-14 Imarx Pharmaceutical Corp. Gas-filled lipid spheres for use in diagnostic and therapeutic applications
US5776429A (en) 1989-12-22 1998-07-07 Imarx Pharmaceutical Corp. Method of preparing gas-filled microspheres using a lyophilized lipids
US20020150539A1 (en) * 1989-12-22 2002-10-17 Unger Evan C. Ultrasound imaging and treatment
US5656211A (en) * 1989-12-22 1997-08-12 Imarx Pharmaceutical Corp. Apparatus and method for making gas-filled vesicles of optimal size
US6001335A (en) 1989-12-22 1999-12-14 Imarx Pharmaceutical Corp. Contrasting agents for ultrasonic imaging and methods for preparing the same
US5773024A (en) * 1989-12-22 1998-06-30 Imarx Pharmaceutical Corp. Container with multi-phase composition for use in diagnostic and therapeutic applications
US5585112A (en) 1989-12-22 1996-12-17 Imarx Pharmaceutical Corp. Method of preparing gas and gaseous precursor-filled microspheres
US5305757A (en) 1989-12-22 1994-04-26 Unger Evan C Gas filled liposomes and their use as ultrasonic contrast agents
US5705187A (en) * 1989-12-22 1998-01-06 Imarx Pharmaceutical Corp. Compositions of lipids and stabilizing materials
US6551576B1 (en) * 1989-12-22 2003-04-22 Bristol-Myers Squibb Medical Imaging, Inc. Container with multi-phase composition for use in diagnostic and therapeutic applications
US5922304A (en) 1989-12-22 1999-07-13 Imarx Pharmaceutical Corp. Gaseous precursor filled microspheres as magnetic resonance imaging contrast agents
IN172208B (US06818201-20041116-C00086.png) * 1990-04-02 1993-05-01 Sint Sa
US20040208826A1 (en) * 1990-04-02 2004-10-21 Bracco International B.V. Ultrasound contrast agents and methods of making and using them
US5556610A (en) * 1992-01-24 1996-09-17 Bracco Research S.A. Gas mixtures useful as ultrasound contrast media, contrast agents containing the media and method
US20010024638A1 (en) * 1992-11-02 2001-09-27 Michel Schneider Stable microbubble suspensions as enhancement agents for ultrasound echography and dry formulations thereof
AU636481B2 (en) * 1990-05-18 1993-04-29 Bracco International B.V. Polymeric gas or air filled microballoons usable as suspensions in liquid carriers for ultrasonic echography
US20030194376A1 (en) * 1990-05-18 2003-10-16 Bracco International B.V. Ultrasound contrast agents and methods of making and using them
US5562099A (en) * 1990-10-05 1996-10-08 Massachusetts Institute Of Technology Polymeric microparticles containing agents for imaging
GB9106686D0 (en) * 1991-03-28 1991-05-15 Hafslund Nycomed As Improvements in or relating to contrast agents
GB9106673D0 (en) * 1991-03-28 1991-05-15 Hafslund Nycomed As Improvements in or relating to contrast agents
US5874062A (en) 1991-04-05 1999-02-23 Imarx Pharmaceutical Corp. Methods of computed tomography using perfluorocarbon gaseous filled microspheres as contrast agents
US6875420B1 (en) 1991-09-17 2005-04-05 Amersham Health As Method of ultrasound imaging
US6723303B1 (en) 1991-09-17 2004-04-20 Amersham Health, As Ultrasound contrast agents including protein stabilized microspheres of perfluoropropane, perfluorobutane or perfluoropentane
GB9200387D0 (en) * 1992-01-09 1992-02-26 Nycomed As Improvements in or relating to contrast agents
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
US5855865A (en) * 1993-07-02 1999-01-05 Molecular Biosystems, Inc. Method for making encapsulated gas microspheres from heat denatured protein in the absence of oxygen gas
GB9318288D0 (en) * 1993-09-03 1993-10-20 Nycomed Imaging As Improvements in or relating to contrast agents
US7083572B2 (en) * 1993-11-30 2006-08-01 Bristol-Myers Squibb Medical Imaging, Inc. Therapeutic delivery systems
DE4406474A1 (de) 1994-02-23 1995-08-24 Schering Ag Gas enthaltende Mikropartikel, diese enthaltende Mittel, deren Verwendung in der Ultraschalldiagnostik, sowie Verfahren zur Herstellung der Partikel und Mittel
US5736121A (en) * 1994-05-23 1998-04-07 Imarx Pharmaceutical Corp. Stabilized homogenous suspensions as computed tomography contrast agents
US5965109A (en) * 1994-08-02 1999-10-12 Molecular Biosystems, Inc. Process for making insoluble gas-filled microspheres containing a liquid hydrophobic barrier
US5730955A (en) * 1994-08-02 1998-03-24 Molecular Biosystems, Inc. Process for making gas-filled microspheres containing a liquid hydrophobic barrier
WO1998053855A1 (en) * 1997-05-30 1998-12-03 Alliance Pharmaceutical Corp. Methods and apparatus for monitoring and quantifying the movement of fluid
US5540909A (en) * 1994-09-28 1996-07-30 Alliance Pharmaceutical Corp. Harmonic ultrasound imaging with microbubbles
US6743779B1 (en) 1994-11-29 2004-06-01 Imarx Pharmaceutical Corp. Methods for delivering compounds into a cell
IL116328A (en) * 1994-12-16 1999-09-22 Bracco Research Sa Frozen suspension of gas microbubbles in frozen aqueous carrier for use as contrast agent in ultrasonic imaging
TW319763B (US06818201-20041116-C00086.png) 1995-02-01 1997-11-11 Epix Medical Inc
US5830430A (en) 1995-02-21 1998-11-03 Imarx Pharmaceutical Corp. Cationic lipids and the use thereof
US5560364A (en) * 1995-05-12 1996-10-01 The Board Of Regents Of The University Of Nebraska Suspended ultra-sound induced microbubble cavitation imaging
US6521211B1 (en) 1995-06-07 2003-02-18 Bristol-Myers Squibb Medical Imaging, Inc. Methods of imaging and treatment with targeted compositions
US6231834B1 (en) 1995-06-07 2001-05-15 Imarx Pharmaceutical Corp. Methods for ultrasound imaging involving the use of a contrast agent and multiple images and processing of same
US6033645A (en) 1996-06-19 2000-03-07 Unger; Evan C. Methods for diagnostic imaging by regulating the administration rate of a contrast agent
US5804162A (en) * 1995-06-07 1998-09-08 Alliance Pharmaceutical Corp. Gas emulsions stabilized with fluorinated ethers having low Ostwald coefficients
DE69632401T2 (de) * 1995-06-07 2005-05-19 Imarx Pharmaceutical Corp., Tucson Neue zielgerichtete mittel zur diagnostischen und therapeutischen verwendung
US6139819A (en) * 1995-06-07 2000-10-31 Imarx Pharmaceutical Corp. Targeted contrast agents for diagnostic and therapeutic use
US5648098A (en) * 1995-10-17 1997-07-15 The Board Of Regents Of The University Of Nebraska Thrombolytic agents and methods of treatment for thrombosis
EP0877602B1 (de) * 1996-01-24 2002-01-23 Byk Gulden Lomberg Chemische Fabrik GmbH Verfahren zur herstellung von pulverförmigen lungensurfactant-zubereitungen
US6165442A (en) * 1996-02-19 2000-12-26 Nycomed Imaging As Thermally stabilized ultrasound contrast agent
US5611344A (en) * 1996-03-05 1997-03-18 Acusphere, Inc. Microencapsulated fluorinated gases for use as imaging agents
US6245747B1 (en) 1996-03-12 2001-06-12 The Board Of Regents Of The University Of Nebraska Targeted site specific antisense oligodeoxynucleotide delivery method
WO1997040679A1 (en) 1996-05-01 1997-11-06 Imarx Pharmaceutical Corp. Methods for delivering compounds into a cell
US5849727A (en) * 1996-06-28 1998-12-15 Board Of Regents Of The University Of Nebraska Compositions and methods for altering the biodistribution of biological agents
US5837221A (en) * 1996-07-29 1998-11-17 Acusphere, Inc. Polymer-lipid microencapsulated gases for use as imaging agents
US6414139B1 (en) 1996-09-03 2002-07-02 Imarx Therapeutics, Inc. Silicon amphiphilic compounds and the use thereof
US5846517A (en) 1996-09-11 1998-12-08 Imarx Pharmaceutical Corp. Methods for diagnostic imaging using a renal contrast agent and a vasodilator
ES2189974T3 (es) 1996-09-11 2003-07-16 Imarx Pharmaceutical Corp Procedimientos mejorados para la obtencion de imagenes de diagnostico usando un agente de contraste y un vasodilatador.
US20070036722A1 (en) * 1996-10-28 2007-02-15 Pal Rongved Separation processes
US6331289B1 (en) 1996-10-28 2001-12-18 Nycomed Imaging As Targeted diagnostic/therapeutic agents having more than one different vectors
US6090800A (en) 1997-05-06 2000-07-18 Imarx Pharmaceutical Corp. Lipid soluble steroid prodrugs
US6537246B1 (en) * 1997-06-18 2003-03-25 Imarx Therapeutics, Inc. Oxygen delivery agents and uses for the same
US6120751A (en) 1997-03-21 2000-09-19 Imarx Pharmaceutical Corp. Charged lipids and uses for the same
US6143276A (en) 1997-03-21 2000-11-07 Imarx Pharmaceutical Corp. Methods for delivering bioactive agents to regions of elevated temperatures
US20050019266A1 (en) * 1997-05-06 2005-01-27 Unger Evan C. Novel targeted compositions for diagnostic and therapeutic use
US6416740B1 (en) * 1997-05-13 2002-07-09 Bristol-Myers Squibb Medical Imaging, Inc. Acoustically active drug delivery systems
US6245318B1 (en) * 1997-05-27 2001-06-12 Mallinckrodt Inc. Selectively binding ultrasound contrast agents
US6001333A (en) * 1997-09-12 1999-12-14 See; Jackie R. Methods of preparing micro encapsulated agents for use in the detection of tumors by CT imaging
US6548047B1 (en) 1997-09-15 2003-04-15 Bristol-Myers Squibb Medical Imaging, Inc. Thermal preactivation of gaseous precursor filled compositions
US20060165606A1 (en) 1997-09-29 2006-07-27 Nektar Therapeutics Pulmonary delivery particles comprising water insoluble or crystalline active agents
US6565885B1 (en) * 1997-09-29 2003-05-20 Inhale Therapeutic Systems, Inc. Methods of spray drying pharmaceutical compositions
US6309623B1 (en) * 1997-09-29 2001-10-30 Inhale Therapeutic Systems, Inc. Stabilized preparations for use in metered dose inhalers
US6050943A (en) 1997-10-14 2000-04-18 Guided Therapy Systems, Inc. Imaging, therapy, and temperature monitoring ultrasonic system
US6623430B1 (en) 1997-10-14 2003-09-23 Guided Therapy Systems, Inc. Method and apparatus for safety delivering medicants to a region of tissue using imaging, therapy and temperature monitoring ultrasonic system
ZA9811087B (en) * 1997-12-04 1999-06-03 Bracco Research Sa Automatic liquid injection system and method
US6123923A (en) 1997-12-18 2000-09-26 Imarx Pharmaceutical Corp. Optoacoustic contrast agents and methods for their use
US6444192B1 (en) 1999-02-05 2002-09-03 The Regents Of The University Of California Diagnostic imaging of lymph structures
EP1180047B1 (en) * 1999-05-21 2005-09-07 Mallinckrodt Inc. Contrast media resuspension device
AU5457300A (en) * 1999-06-01 2000-12-18 Drexel University Surface stabilized microbubbles for use in ultrasound contrast and drug deliveryagents
US7192698B1 (en) * 1999-08-17 2007-03-20 Purdue Research Foundation EphA2 as a diagnostic target for metastatic cancer
US7220401B2 (en) * 1999-09-24 2007-05-22 Barnes-Jewish Hospital Blood clot-targeted nanoparticles
US20030144570A1 (en) * 1999-11-12 2003-07-31 Angiotech Pharmaceuticals, Inc. Compositions and methods for treating disease utilizing a combination of radioactive therapy and cell-cycle inhibitors
US8404217B2 (en) 2000-05-10 2013-03-26 Novartis Ag Formulation for pulmonary administration of antifungal agents, and associated methods of manufacture and use
US7871598B1 (en) 2000-05-10 2011-01-18 Novartis Ag Stable metal ion-lipid powdered pharmaceutical compositions for drug delivery and methods of use
EP1280520B2 (en) 2000-05-10 2018-03-21 Novartis AG Phospholipid-based powders for drug delivery
EP2286843A3 (en) 2000-06-02 2011-08-03 Bracco Suisse SA Compounds for targeting endothelial cells
AU2001280934A1 (en) * 2000-07-28 2002-02-13 Alliance Pharmaceutical Corp. Methods and compositions to upregulate, redirect or limit immune responses to bioactive compounds
AU2003267309A1 (en) 2000-11-16 2004-04-08 Microspherix Llc Flexible and/or elastic brachytherapy seed or strand
US7914453B2 (en) 2000-12-28 2011-03-29 Ardent Sound, Inc. Visual imaging system for ultrasonic probe
GB0102691D0 (en) 2001-02-02 2001-03-21 Nestle Sa Water soluable powders and tablets
DE10108799A1 (de) * 2001-02-19 2002-09-05 Laser & Med Tech Gmbh Verfahren und Vorrichtung zur Ultraschallimpfung von biologischem Zellmaterial
EP1387637B1 (en) * 2001-04-06 2007-10-31 Bracco Research S.A. Apparatus for measuring local physical parameters in a fluid filled cavity
TWI324518B (en) 2001-12-19 2010-05-11 Nektar Therapeutics Pulmonary delivery of aminoglycosides
EP1587944A4 (en) 2002-03-01 2007-03-21 Dyax Corp KDR AND VEGF / KDR BINDING PEPTIDES AND THEIR USE FOR DIAGNOSTIC AND THERAPEUTIC PURPOSES
US7261876B2 (en) 2002-03-01 2007-08-28 Bracco International Bv Multivalent constructs for therapeutic and diagnostic applications
US8623822B2 (en) 2002-03-01 2014-01-07 Bracco Suisse Sa KDR and VEGF/KDR binding peptides and their use in diagnosis and therapy
ES2506142T3 (es) 2002-03-01 2014-10-13 Dyax Corp. Péptidos de unión a KDR y a VEGF/KDR y su uso en diagnóstico
US7794693B2 (en) 2002-03-01 2010-09-14 Bracco International B.V. Targeting vector-phospholipid conjugates
US7211240B2 (en) 2002-03-01 2007-05-01 Bracco International B.V. Multivalent constructs for therapeutic and diagnostic applications
DE10211886B4 (de) * 2002-03-18 2004-07-15 Dornier Medtech Gmbh Verfahren und Einrichtung zum Erzeugen bipolarer akustischer Impulse
US20040126400A1 (en) * 2002-05-03 2004-07-01 Iversen Patrick L. Delivery of therapeutic compounds via microparticles or microbubbles
DE10223196B4 (de) * 2002-05-24 2004-05-13 Dornier Medtech Systems Gmbh Verfahren und Einrichtung zum Transferieren von Molekülen in Zellen
US20040018237A1 (en) * 2002-05-31 2004-01-29 Perricone Nicholas V. Topical drug delivery using phosphatidylcholine
US6803046B2 (en) 2002-08-16 2004-10-12 Bracco International B.V. Sincalide formulations
CA2499136A1 (en) * 2002-09-16 2004-03-25 Vasogen Ireland Limited Accelerating recovery from trauma
US20070128117A1 (en) * 2003-02-04 2007-06-07 Bracco International B.V. Ultrasound contrast agents and process for the preparation thereof
JP2006517558A (ja) 2003-02-13 2006-07-27 ブラッコ　イメージング　エッセ　ピ　ア コントラスト増強ｘ線位相画像診断
DK2284180T3 (en) 2003-03-03 2015-12-21 Dyax Corp Uses of peptides that specifically bind to the HGF receptor (cMET)
US20040258760A1 (en) * 2003-03-20 2004-12-23 Wheatley Margaret A. Isolated nanocapsule populations and surfactant-stabilized microcapsules and nanocapsules for diagnostic imaging and drug delivery and methods for their production
ITFI20030077A1 (it) * 2003-03-26 2004-09-27 Actis Active Sensors S R L Metodo per l'indagine ecografica tramite mezzi di contrasto
EP1643972A4 (en) * 2003-06-27 2010-01-20 Smithkline Beecham Corp STABILIZED LIPOSOMAL TOPOTECAN COMPOSITION AND METHOD
US7537788B2 (en) * 2003-07-25 2009-05-26 Rubicor Medical, Inc. Post-biopsy cavity treatment implants and methods
US7744852B2 (en) 2003-07-25 2010-06-29 Rubicor Medical, Llc Methods and systems for marking post biopsy cavity sites
US20050020899A1 (en) * 2003-07-25 2005-01-27 Rubicor Medical, Inc. Post-biopsy cavity treatmetn implants and methods
US7358226B2 (en) * 2003-08-27 2008-04-15 The Regents Of The University Of California Ultrasonic concentration of drug delivery capsules
DE10353780A1 (de) * 2003-11-18 2005-06-23 Beiersdorf Ag Partikel aus fester Hülle und potenziell feuchtigkeitsempfindliche oder wasserunlösliche Wirkstoffe enthaltendem flüssigem Kern, Zubereitungen diese enthaltend und Verfahren zu ihrer Herstellung
JP2005154282A (ja) * 2003-11-20 2005-06-16 Mebiopharm Co Ltd ガス封入リポソームの製造法
NO20035401D0 (no) * 2003-12-04 2003-12-04 Amersham Health As Metode
AU2004308757B2 (en) * 2003-12-22 2010-06-17 Bracco Suisse S.A. Assembly of gas-filled microvesicle with active component for contrast imaging
CN1321697C (zh) * 2003-12-23 2007-06-20 中国人民解放军军事医学科学院毒物药物研究所 一种以磷脂类成分为成膜材料的超声造影剂组合物及其制备方法
EP1715897B2 (en) 2004-01-20 2013-10-30 Sunnybrook and Women's College Health Sciences Centre High frequency ultrasound imaging using contrast agents
US7713517B2 (en) * 2004-04-21 2010-05-11 Marval Biosciences, Inc. Compositions and methods for enhancing contrast in imaging
US8357351B2 (en) * 2004-04-21 2013-01-22 Ananth Annapragada Nano-scale contrast agents and methods of use
US8012457B2 (en) 2004-06-04 2011-09-06 Acusphere, Inc. Ultrasound contrast agent dosage formulation
GB2445322B (en) 2004-08-13 2008-08-06 Stichting Tech Wetenschapp Intravasular ultrasound techniques
US7824348B2 (en) 2004-09-16 2010-11-02 Guided Therapy Systems, L.L.C. System and method for variable depth ultrasound treatment
US9011336B2 (en) 2004-09-16 2015-04-21 Guided Therapy Systems, Llc Method and system for combined energy therapy profile
US7393325B2 (en) 2004-09-16 2008-07-01 Guided Therapy Systems, L.L.C. Method and system for ultrasound treatment with a multi-directional transducer
US10864385B2 (en) 2004-09-24 2020-12-15 Guided Therapy Systems, Llc Rejuvenating skin by heating tissue for cosmetic treatment of the face and body
US20120165668A1 (en) 2010-08-02 2012-06-28 Guided Therapy Systems, Llc Systems and methods for treating acute and/or chronic injuries in soft tissue
US8444562B2 (en) 2004-10-06 2013-05-21 Guided Therapy Systems, Llc System and method for treating muscle, tendon, ligament and cartilage tissue
US8535228B2 (en) 2004-10-06 2013-09-17 Guided Therapy Systems, Llc Method and system for noninvasive face lifts and deep tissue tightening
US11235179B2 (en) 2004-10-06 2022-02-01 Guided Therapy Systems, Llc Energy based skin gland treatment
US7758524B2 (en) 2004-10-06 2010-07-20 Guided Therapy Systems, L.L.C. Method and system for ultra-high frequency ultrasound treatment
US8690778B2 (en) 2004-10-06 2014-04-08 Guided Therapy Systems, Llc Energy-based tissue tightening
US20060111744A1 (en) 2004-10-13 2006-05-25 Guided Therapy Systems, L.L.C. Method and system for treatment of sweat glands
JP2008522642A (ja) * 2004-10-06 2008-07-03 ガイデッド セラピー システムズ， エル．エル．シー． 美容強化のための方法およびシステム
US9827449B2 (en) 2004-10-06 2017-11-28 Guided Therapy Systems, L.L.C. Systems for treating skin laxity
PL2409728T3 (pl) 2004-10-06 2018-01-31 Guided Therapy Systems Llc Układ do ultradźwiękowego leczenia tkanki
US8133180B2 (en) 2004-10-06 2012-03-13 Guided Therapy Systems, L.L.C. Method and system for treating cellulite
US9694212B2 (en) 2004-10-06 2017-07-04 Guided Therapy Systems, Llc Method and system for ultrasound treatment of skin
US11883688B2 (en) 2004-10-06 2024-01-30 Guided Therapy Systems, Llc Energy based fat reduction
US11207548B2 (en) 2004-10-07 2021-12-28 Guided Therapy Systems, L.L.C. Ultrasound probe for treating skin laxity
US11724133B2 (en) 2004-10-07 2023-08-15 Guided Therapy Systems, Llc Ultrasound probe for treatment of skin
EP1671627B8 (en) * 2004-12-15 2010-04-07 Dornier MedTech Systems GmbH Improvement of cell therapy and tissue regeneration in patients with cardiovascular and neurological diseases by means of shockwaves
EP1853333A1 (en) * 2004-12-23 2007-11-14 Bracco Research S.A. Liquid transfer device for medical dispensing containers
EP1714642A1 (en) * 2005-04-18 2006-10-25 Bracco Research S.A. Pharmaceutical composition comprising gas-filled microcapsules for ultrasound mediated delivery
US7571336B2 (en) 2005-04-25 2009-08-04 Guided Therapy Systems, L.L.C. Method and system for enhancing safety with medical peripheral device by monitoring if host computer is AC powered
EP1884232A1 (en) * 2005-05-23 2008-02-06 Mebiopharm Co., Ltd. Method of producing liposomes containing gas enclosed therein
CA2826960A1 (en) 2005-12-09 2007-06-14 Bracco Suisse Sa Targeting vector-phospholipid conjugates
EP1797919A1 (en) * 2005-12-16 2007-06-20 Bracco Research S.A. Liquid transfer device for medical dispensing containers
US7967753B2 (en) * 2006-08-01 2011-06-28 Stichting Voor de Technische Wetenschappen of Van Vollenhovenlaan Pulse inversion sequences for nonlinear imaging
US9566454B2 (en) 2006-09-18 2017-02-14 Guided Therapy Systems, Llc Method and sysem for non-ablative acne treatment and prevention
US7976743B2 (en) * 2006-10-16 2011-07-12 Northwestern University Gas-containing liposomes
US20100059390A1 (en) * 2006-11-08 2010-03-11 Yuzhuo Li METHOD AND APARATUS FOR ELECTROCHEMICAL MECHANICAL POLISHING NiP SUBSTRATES
JP2010526589A (ja) 2007-05-07 2010-08-05 ガイデッド セラピー システムズ， エル．エル．シー． 音響エネルギーを使用してメディカントを調節するための方法およびシステム
US20150174388A1 (en) 2007-05-07 2015-06-25 Guided Therapy Systems, Llc Methods and Systems for Ultrasound Assisted Delivery of a Medicant to Tissue
US8052001B2 (en) * 2007-05-10 2011-11-08 Delta Electronics, Inc. Case assembly structure of electronic device
WO2009042621A2 (en) * 2007-09-24 2009-04-02 Mallinckrodt Inc. Injection system having microbubble-enhanced extravasation detection system
CA2708028A1 (en) * 2007-12-05 2009-06-11 Marval Biosciences, Inc. Nano-scale contrast agents and methods of use
US20110105961A1 (en) * 2008-05-23 2011-05-05 Gruber Lewis S Methods, compositions and apparatuses for facilitating regeneration
PT3058875T (pt) 2008-06-06 2022-09-20 Ulthera Inc Sistema para tratamento cosmético e imagiologia
US12102473B2 (en) 2008-06-06 2024-10-01 Ulthera, Inc. Systems for ultrasound treatment
AU2009257279A1 (en) * 2008-06-13 2009-12-17 Marval Biosciences, Inc. Imaging of atherosclerotic plaques using liposomal imaging agents
GB0811856D0 (en) * 2008-06-27 2008-07-30 Ucl Business Plc Magnetic microbubbles, methods of preparing them and their uses
CA2748995C (en) * 2008-10-07 2018-01-16 Bracco Suisse Sa Targeting construct comprising anti-polymer antibody and liposomes or microvesicles binding to the same
US20110045095A1 (en) * 2008-10-08 2011-02-24 The Regents Of The University Of California Polymer-phospholipid shelled microbubbles
EP2376145B1 (en) 2008-12-16 2013-10-16 Bracco Suisse SA Device for bolus administration
CA2748362A1 (en) 2008-12-24 2010-07-01 Michael H. Slayton Methods and systems for fat reduction and/or cellulite treatment
WO2011025893A1 (en) * 2009-08-28 2011-03-03 The Trustees Of Columbia University In The City Of New York Systems, methods, and devices for production of gas-filled microbubbles
EP2477550A4 (en) 2009-09-15 2013-12-04 Univ Columbia SYSTEMS, METHODS AND DEVICES FOR MICROBULLES
US8715186B2 (en) 2009-11-24 2014-05-06 Guided Therapy Systems, Llc Methods and systems for generating thermal bubbles for improved ultrasound imaging and therapy
WO2011084694A1 (en) 2009-12-17 2011-07-14 University Of Pittsburgh-Of The Commonwealth System Of Higher Education Stabilized stat3 decoy oligonucleotides and uses therefor
EP2345732A1 (en) 2010-01-19 2011-07-20 Universite Paris Descartes Methods for intracellular delivery of nucleic acids
WO2011091160A1 (en) * 2010-01-20 2011-07-28 Henry Wu Custom-formulated phospholipid microbubbles and methods and uses thereof
US9504446B2 (en) 2010-08-02 2016-11-29 Guided Therapy Systems, Llc Systems and methods for coupling an ultrasound source to tissue
US9265483B2 (en) 2010-08-06 2016-02-23 The Trustees Of Columbia University In The City Of New York Medical imaging contrast devices, methods, and systems
RU2013105016A (ru) 2010-08-09 2014-09-20 Инсэрм (Институт Насьональ Де Ла Сант Эт Де Ла Решерш Медикаль) Способы и фармацевтические композиции для лечения глазного заболевания у субъекта
ES2725852T3 (es) 2010-09-27 2019-09-27 Siwa Corp Eliminación selectiva de células modificadas por AGE para el tratamiento de la aterosclerosis
US8857438B2 (en) 2010-11-08 2014-10-14 Ulthera, Inc. Devices and methods for acoustic shielding
US8721571B2 (en) 2010-11-22 2014-05-13 Siwa Corporation Selective removal of cells having accumulated agents
EP2474327A1 (en) 2011-01-07 2012-07-11 RWTH Aachen Microdosing of ultrasound contrast agents
JP2014508166A (ja) 2011-03-17 2014-04-03 トランスダーマル バイオテクノロジ インコーポレーテッド 局所的一酸化窒素システム及びその使用方法
WO2012136813A2 (en) 2011-04-07 2012-10-11 Universitetet I Oslo Agents for medical radar diagnosis
WO2013009784A2 (en) 2011-07-10 2013-01-17 Guided Therapy Systems, Llc Systems and method for accelerating healing of implanted material and/or native tissue
KR20190080967A (ko) 2011-07-11 2019-07-08 가이디드 테라피 시스템스, 엘.엘.씨. 조직에 초음파원을 연결하는 시스템 및 방법
US9263663B2 (en) 2012-04-13 2016-02-16 Ardent Sound, Inc. Method of making thick film transducer arrays
US8871255B2 (en) 2012-09-19 2014-10-28 Transdermal Biotechnology, Inc. Treatment of skin and soft tissue infection with nitric oxide
US8871261B2 (en) 2012-09-19 2014-10-28 Transdermal Biotechnology, Inc. Cancer treatments and compositions for use thereof
US8871257B2 (en) 2012-09-19 2014-10-28 Transdermal Biotechnology, Inc. Prevention and treatment of cardiovascular diseases using systems and methods for transdermal nitric oxide delivery
US8871254B2 (en) 2012-09-19 2014-10-28 Transdermal Biotechnology, Inc. Systems and methods for treatment of acne vulgaris and other conditions with a topical nitric oxide delivery system
US8871258B2 (en) 2012-09-19 2014-10-28 Transdermal Biotechnology, Inc. Treatment and prevention of learning and memory disorders
US8871259B2 (en) 2012-09-19 2014-10-28 Transdermal Biotechnology, Inc. Techniques and systems for treatment of neuropathic pain and other indications
US8871260B2 (en) 2012-09-19 2014-10-28 Transdermal Biotechnology, Inc. Methods and compositions for muscular and neuromuscular diseases
US8871262B2 (en) 2012-09-19 2014-10-28 Transdermal Biotechnology, Inc. Compositions and methods for treatment of osteoporosis and other indications
US8871256B2 (en) 2012-09-19 2014-10-28 Transdermal Biotechnology, Inc. Methods and systems for treatment of inflammatory diseases with nitric oxide
US9510802B2 (en) 2012-09-21 2016-12-06 Guided Therapy Systems, Llc Reflective ultrasound technology for dermatological treatments
EP2934740B1 (en) 2012-12-21 2019-12-11 Bracco Suisse SA Gas-filled microvesicles
CN104027893B (zh) 2013-03-08 2021-08-31 奥赛拉公司 用于多焦点超声治疗的装置和方法
US9295647B2 (en) 2013-03-13 2016-03-29 Transdermal Biotechnology, Inc. Systems and methods for delivery of peptides
US9339457B2 (en) 2013-03-13 2016-05-17 Transdermal Biotechnology, Inc. Cardiovascular disease treatment and prevention
US9314417B2 (en) 2013-03-13 2016-04-19 Transdermal Biotechnology, Inc. Treatment of skin, including aging skin, to improve appearance
US9849160B2 (en) 2013-03-13 2017-12-26 Transdermal Biotechnology, Inc. Methods and systems for treating or preventing cancer
US9320758B2 (en) 2013-03-13 2016-04-26 Transdermal Biotechnology, Inc. Brain and neural treatments comprising peptides and other compositions
US9687520B2 (en) 2013-03-13 2017-06-27 Transdermal Biotechnology, Inc. Memory or learning improvement using peptide and other compositions
US9393265B2 (en) 2013-03-13 2016-07-19 Transdermal Biotechnology, Inc. Wound healing using topical systems and methods
US9314422B2 (en) 2013-03-13 2016-04-19 Transdermal Biotechnology, Inc. Peptide systems and methods for metabolic conditions
US20140271731A1 (en) 2013-03-13 2014-09-18 Transdermal Biotechnology, Inc. Cardiovascular disease treatment and prevention
US9750787B2 (en) 2013-03-13 2017-09-05 Transdermal Biotechnology, Inc. Memory or learning improvement using peptide and other compositions
US9295637B2 (en) 2013-03-13 2016-03-29 Transdermal Biotechnology, Inc. Compositions and methods for affecting mood states
US9393264B2 (en) 2013-03-13 2016-07-19 Transdermal Biotechnology, Inc. Immune modulation using peptides and other compositions
US9314423B2 (en) 2013-03-13 2016-04-19 Transdermal Biotechnology, Inc. Hair treatment systems and methods using peptides and other compositions
US20140271938A1 (en) 2013-03-13 2014-09-18 Transdermal Biotechnology, Inc. Systems and methods for delivery of peptides
US9314433B2 (en) 2013-03-13 2016-04-19 Transdermal Biotechnology, Inc. Methods and systems for treating or preventing cancer
US20140271937A1 (en) 2013-03-13 2014-09-18 Transdermal Biotechnology, Inc. Brain and neural treatments comprising peptides and other compositions
US9724419B2 (en) 2013-03-13 2017-08-08 Transdermal Biotechnology, Inc. Peptide systems and methods for metabolic conditions
US9320706B2 (en) 2013-03-13 2016-04-26 Transdermal Biotechnology, Inc. Immune modulation using peptides and other compositions
US9295636B2 (en) 2013-03-13 2016-03-29 Transdermal Biotechnology, Inc. Wound healing using topical systems and methods
US9241899B2 (en) 2013-03-13 2016-01-26 Transdermal Biotechnology, Inc. Topical systems and methods for treating sexual dysfunction
US9387159B2 (en) 2013-03-13 2016-07-12 Transdermal Biotechnology, Inc. Treatment of skin, including aging skin, to improve appearance
US10561862B2 (en) 2013-03-15 2020-02-18 Guided Therapy Systems, Llc Ultrasound treatment device and methods of use
US20160030603A1 (en) 2013-03-15 2016-02-04 Westfaelische Wilhelms-Universitaet Muenster Detection of acute renal allograft rejection
KR101853948B1 (ko) * 2013-07-05 2018-05-02 사회복지법인 삼성생명공익재단 X-선 조영제 및 기포 촉진제를 함유하는 조영 조성물 및 그 제조방법
AU2015247951A1 (en) 2014-04-18 2016-11-17 Ulthera, Inc. Band transducer ultrasound therapy
ES2908203T3 (es) 2014-09-19 2022-04-28 Siwa Corp Anticuerpos anti-age para el tratamiento de inflamación y trastornos autoinmunes
CN104337766A (zh) * 2014-10-09 2015-02-11 唐春林 一种地高辛脂质微泡及其制备方法
US9993535B2 (en) 2014-12-18 2018-06-12 Siwa Corporation Method and composition for treating sarcopenia
SG11201704165VA (en) 2014-12-18 2017-07-28 Bracco Suisse Sa Targeted gas-filled microvesicles formulation
US10358502B2 (en) 2014-12-18 2019-07-23 Siwa Corporation Product and method for treating sarcopenia
KR101853949B1 (ko) 2015-01-02 2018-05-02 사회복지법인 삼성생명공익재단 X-선 조영제 및 기포 촉진제를 함유하는 조영 조성물 및 그 제조방법
DK3405294T3 (da) 2016-01-18 2023-03-13 Ulthera Inc Kompakt ultralydsanordning med ringformet ultralydsmatrice med periferisk elektrisk tilslutning til fleksibel printplade
BR112018015143A2 (pt) 2016-02-09 2018-12-18 Bracco Suisse Sa proteína quimérica recombinante para direcionamento de selectinas
RU2728964C2 (ru) 2016-02-19 2020-08-03 Сива Корпорейшн Способ и композиция для лечения рака, уничтожения метастатических раковых клеток и профилактики метастазов рака, используя антитела к конечным продуктам повышенного гликирования ( AGE)
CN109311975A (zh) 2016-04-15 2019-02-05 Siwa有限公司 用于治疗神经退行性紊乱的抗age抗体
US11213585B2 (en) 2016-06-23 2022-01-04 Siwa Corporation Vaccines for use in treating various diseases and disorders
US10342828B1 (en) * 2016-06-27 2019-07-09 Roderick M. Dayton Fecal oxygenation
KR102593310B1 (ko) 2016-08-16 2023-10-25 얼테라, 인크 이미징 오정렬을 감소시키도록 구성된 초음파 이미징 시스템, 초음파 이미징 모듈 및 이미징 오정렬을 감소시키는 방법
US10925937B1 (en) 2017-01-06 2021-02-23 Siwa Corporation Vaccines for use in treating juvenile disorders associated with inflammation
US10961321B1 (en) 2017-01-06 2021-03-30 Siwa Corporation Methods and compositions for treating pain associated with inflammation
US10858449B1 (en) 2017-01-06 2020-12-08 Siwa Corporation Methods and compositions for treating osteoarthritis
US10995151B1 (en) 2017-01-06 2021-05-04 Siwa Corporation Methods and compositions for treating disease-related cachexia
CA3059803A1 (en) 2017-04-13 2018-10-18 Siwa Corporation Humanized monoclonal advanced glycation end-product antibody
US11110063B2 (en) 2017-08-25 2021-09-07 MAIA Pharmaceuticals, Inc. Storage stable sincalide formulations
US11518801B1 (en) 2017-12-22 2022-12-06 Siwa Corporation Methods and compositions for treating diabetes and diabetic complications
TW202327520A (zh) 2018-01-26 2023-07-16 美商奧賽拉公司 用於多個維度中的同時多聚焦超音治療的系統和方法
US11944849B2 (en) 2018-02-20 2024-04-02 Ulthera, Inc. Systems and methods for combined cosmetic treatment of cellulite with ultrasound
US20200360289A1 (en) * 2019-05-15 2020-11-19 Bracco Suisse Sa Freeze-dried product and gas-filled microvesicles suspension
CN111467266B (zh) * 2020-05-14 2022-10-28 深圳市陆讯纳米科技有限公司 一种臭氧纳米气泡漱口液及制备方法
CN111569683B (zh) * 2020-05-14 2022-04-15 深圳市陆讯纳米科技有限公司 一种高浓度长效臭氧纳米气泡水溶液及制备方法

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4192859A (en) * 1978-09-29 1980-03-11 E. R. Squibb & Sons, Inc. Contrast media containing liposomes as carriers
EP0077752A2 (de) * 1981-10-16 1983-04-27 Schering Aktiengesellschaft Flüssige Mischung zur Aufnahme und Stabilisierung von Gasbläschen zur Verwendung als Kontrastmittel für die Ultraschalldiagnostik und deren Herstellung
EP0123235A2 (de) * 1983-04-15 1984-10-31 Schering Aktiengesellschaft Mikropartikel und Gasblächen enthaltendes Ultraschall-Kontrastmittel
EP0131540A2 (de) * 1983-07-06 1985-01-16 Schering Aktiengesellschaft Ultraschallkontrastmittel sowie dessen Herstellung
WO1988007365A2 (en) * 1987-04-01 1988-10-06 David F Ranney Biodadhesion drug carriers for endothelial and epithelial uptake and lesional localization of therapeutic and diagnostic agents
EP0320433A2 (de) * 1987-12-02 1989-06-14 Schering Aktiengesellschaft Ultraschall- oder Stosswellenarbeitsverfahren und Mittel zu dessen Durchführung
US4900540A (en) * 1983-06-20 1990-02-13 Trustees Of The University Of Massachusetts Lipisomes containing gas for ultrasound detection

Family Cites Families (89)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE77752C (de) * R. A. LISTER, Victoria Iron Works, u. M. PEDERSEN, Dursley, County of Gloucester, Engl Einlafsventil mit Sieb für Milchschleudern
DE52575C (de) * J. E. STROSCHEIN, Apotheker in Berlin S.O., Köpenickerstr. 32 Verfahren zur Erzeugung von Mustern auf Geweben und dergl. mittels Vexirfarbten
DE123235C (US06818201-20041116-C00086.png) *
DE131540C (US06818201-20041116-C00086.png) *
DE320433C (de) * 1915-07-13 1920-09-17 Erich F Huth G M B H Dr Anordnung zum Empfang elektrischer Schwingungen
DE327490C (de) * 1916-05-31 1920-10-13 Heinrich Schemann Kuenstliche Hand
NL302030A (US06818201-20041116-C00086.png) 1962-12-21 1900-01-01
US3968203A (en) 1965-10-01 1976-07-06 Jerome G. Spitzer Aerosol astringent composition
US3615972A (en) 1967-04-28 1971-10-26 Dow Chemical Co Expansible thermoplastic polymer particles containing volatile fluid foaming agent and method of foaming the same
US3650831A (en) 1969-03-10 1972-03-21 Armour Dial Inc Method of cleaning surfaces
US3900420A (en) 1970-05-18 1975-08-19 Felix Sebba Microgas emulsions and method of forming same
US4027007A (en) 1970-12-09 1977-05-31 Colgate-Palmolive Company Antiperspirants formulated with borax
GB1575343A (en) * 1977-05-10 1980-09-17 Ici Ltd Method for preparing liposome compositions containing biologically active compounds
CH621479A5 (US06818201-20041116-C00086.png) * 1977-08-05 1981-02-13 Battelle Memorial Institute
CH624011A5 (US06818201-20041116-C00086.png) * 1977-08-05 1981-07-15 Battelle Memorial Institute
US4235871A (en) 1978-02-24 1980-11-25 Papahadjopoulos Demetrios P Method of encapsulating biologically active materials in lipid vesicles
US4256251A (en) 1978-04-24 1981-03-17 Lawrence M. Smith Surgical staplers and staple
US4276885A (en) * 1979-05-04 1981-07-07 Rasor Associates, Inc Ultrasonic image enhancement
US4265251A (en) * 1979-06-28 1981-05-05 Rasor Associates, Inc. Method of determining pressure within liquid containing vessel
US4316391A (en) 1979-11-13 1982-02-23 Ultra Med, Inc. Flow rate measurement
ATE17311T1 (de) * 1980-11-17 1986-01-15 Schering Ag Praeparat zur erzeugung von mikroblaeschen.
US4681119A (en) 1980-11-17 1987-07-21 Schering Aktiengesellschaft Method of production and use of microbubble precursors
US4442843A (en) * 1980-11-17 1984-04-17 Schering, Ag Microbubble precursors and methods for their production and use
US4657756A (en) 1980-11-17 1987-04-14 Schering Aktiengesellschaft Microbubble precursors and apparatus for their production and use
US4572203A (en) 1983-01-27 1986-02-25 Feinstein Steven B Contact agents for ultrasonic imaging
US4718433A (en) 1983-01-27 1988-01-12 Feinstein Steven B Contrast agents for ultrasonic imaging
GB2134869A (en) * 1983-02-15 1984-08-22 Squibb & Sons Inc Method of preparing liposomes and products produced thereby
GB2135647A (en) * 1983-02-15 1984-09-05 Squibb & Sons Inc Method of preparing liposomes and products produced thereby
US5141738A (en) 1983-04-15 1992-08-25 Schering Aktiengesellschaft Ultrasonic contrast medium comprising gas bubbles and solid lipophilic surfactant-containing microparticles and use thereof
DE3313946A1 (de) 1983-04-15 1984-10-18 Schering AG, 1000 Berlin und 4709 Bergkamen Mikropartikel und gasblaeschen enthaltende ultraschall-kontrastmittel
US4544545A (en) * 1983-06-20 1985-10-01 Trustees University Of Massachusetts Liposomes containing modified cholesterol for organ targeting
US5618514A (en) 1983-12-21 1997-04-08 Nycomed Imaging As Diagnostic and contrast agent
GB8504916D0 (en) * 1985-02-26 1985-03-27 Isc Chemicals Ltd Emulsions of perfluorocarbons in aqueous media
DE3529195A1 (de) † 1985-08-14 1987-02-26 Max Planck Gesellschaft Kontrastmittel fuer ultraschalluntersuchungen und verfahren zu seiner herstellung
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
US4927623A (en) * 1986-01-14 1990-05-22 Alliance Pharmaceutical Corp. Dissolution of gas in a fluorocarbon liquid
EP0245019A3 (en) * 1986-04-30 1989-05-10 Michael A. Davis Low density contrast medium for diagnosis of pathologic conditions
DE3637926C1 (de) 1986-11-05 1987-11-26 Schering Ag Ultraschall-Manometrieverfahren in einer Fluessigkeit mittels Mikroblaeschen
FR2608942B1 (fr) 1986-12-31 1991-01-11 Centre Nat Rech Scient Procede de preparation de systemes colloidaux dispersibles d'une substance, sous forme de nanocapsules
US5283067A (en) * 1987-01-30 1994-02-01 Ciba-Geigy Corporation Parenteral suspensions
US5089181A (en) * 1987-02-24 1992-02-18 Vestar, Inc. Method of dehydrating vesicle preparations for long term storage
CH672733A5 (US06818201-20041116-C00086.png) 1987-05-22 1989-12-29 Bracco Ind Chimica Spa
US4844882A (en) * 1987-12-29 1989-07-04 Molecular Biosystems, Inc. Concentrated stabilized microbubble-type ultrasonic imaging agent
IE61591B1 (en) * 1987-12-29 1994-11-16 Molecular Biosystems Inc Concentrated stabilized microbubble-type ultrasonic imaging agent and method of production
EP0586875A1 (de) 1988-02-05 1994-03-16 Schering Aktiengesellschaft Ultraschallkontrastmittel, Verfahren zu deren Herstellung und deren Verwendung als Diagnostika und Therapeutika
US5425366A (en) * 1988-02-05 1995-06-20 Schering Aktiengesellschaft Ultrasonic contrast agents for color Doppler imaging
US5171755A (en) * 1988-04-29 1992-12-15 Hemagen/Pfc Emulsions of highly fluorinated organic compounds
US5730954A (en) 1988-08-23 1998-03-24 Schering Aktiengesellschaft Preparation comprising cavitate- or clathrate-forming host/guest complexes as contrast agent
DE3828905A1 (de) 1988-08-23 1990-03-15 Schering Ag Mittel bestehend aus cavitate oder clathrate bildenden wirt/gast-komplexen als kontrastmittel
US4957656A (en) 1988-09-14 1990-09-18 Molecular Biosystems, Inc. Continuous sonication method for preparing protein encapsulated microbubbles
DE3934656A1 (de) 1989-10-13 1991-04-18 Schering Ag Verfahren zur herstellung von waessrigen dispersionen
US5776429A (en) 1989-12-22 1998-07-07 Imarx Pharmaceutical Corp. Method of preparing gas-filled microspheres using a lyophilized lipids
US5123414A (en) * 1989-12-22 1992-06-23 Unger Evan C Liposomes as contrast agents for ultrasonic imaging and methods for preparing the same
US5149319A (en) 1990-09-11 1992-09-22 Unger Evan C Methods for providing localized therapeutic heat to biological tissues and fluids
US5228446A (en) * 1989-12-22 1993-07-20 Unger Evan C Gas filled liposomes and their use as ultrasonic contrast agents
US5209720A (en) 1989-12-22 1993-05-11 Unger Evan C Methods for providing localized therapeutic heat to biological tissues and fluids using gas filled liposomes
US5088499A (en) * 1989-12-22 1992-02-18 Unger Evan C Liposomes as contrast agents for ultrasonic imaging and methods for preparing the same
DE4004430A1 (de) 1990-02-09 1991-08-14 Schering Ag Aus polyaldehyden aufgebaute kontrastmittel
GB9003821D0 (en) 1990-02-20 1990-04-18 Danbiosyst Uk Diagnostic aid
IN172208B (US06818201-20041116-C00086.png) * 1990-04-02 1993-05-01 Sint Sa
US5556610A (en) * 1992-01-24 1996-09-17 Bracco Research S.A. Gas mixtures useful as ultrasound contrast media, contrast agents containing the media and method
US5445813A (en) 1992-11-02 1995-08-29 Bracco International B.V. Stable microbubble suspensions as enhancement agents for ultrasound echography
US5137928A (en) 1990-04-26 1992-08-11 Hoechst Aktiengesellschaft Ultrasonic contrast agents, processes for their preparation and the use thereof as diagnostic and therapeutic agents
US5205287A (en) 1990-04-26 1993-04-27 Hoechst Aktiengesellschaft Ultrasonic contrast agents, processes for their preparation and the use thereof as diagnostic and therapeutic agents
US5190982A (en) 1990-04-26 1993-03-02 Hoechst Aktiengesellschaft Ultrasonic contrast agents, processes for their preparation and the use thereof as diagnostic and therapeutic agents
AU636481B2 (en) * 1990-05-18 1993-04-29 Bracco International B.V. Polymeric gas or air filled microballoons usable as suspensions in liquid carriers for ultrasonic echography
US5215680A (en) * 1990-07-10 1993-06-01 Cavitation-Control Technology, Inc. Method for the production of medical-grade lipid-coated microbubbles, paramagnetic labeling of such microbubbles and therapeutic uses of microbubbles
DE4100470A1 (de) 1991-01-09 1992-07-16 Byk Gulden Lomberg Chem Fab Echokontrastmittel
GB9106686D0 (en) * 1991-03-28 1991-05-15 Hafslund Nycomed As Improvements in or relating to contrast agents
GB9106673D0 (en) * 1991-03-28 1991-05-15 Hafslund Nycomed As Improvements in or relating to contrast agents
US5874062A (en) 1991-04-05 1999-02-23 Imarx Pharmaceutical Corp. Methods of computed tomography using perfluorocarbon gaseous filled microspheres as contrast agents
GB9107628D0 (en) 1991-04-10 1991-05-29 Moonbrook Limited Preparation of diagnostic agents
US5147631A (en) 1991-04-30 1992-09-15 Du Pont Merck Pharmaceutical Company Porous inorganic ultrasound contrast agents
US5364612A (en) 1991-05-06 1994-11-15 Immunomedics, Inc. Detection of cardiovascular lesions
DK0586524T3 (US06818201-20041116-C00086.png) * 1991-06-03 1997-05-20 Nycomed Imaging As
DE4127442C2 (de) 1991-08-17 1996-08-22 Udo Dr Gros Wäßrige Dispersion Fluorcarbon enthaltender Phospholipid-Vesikel und ein Verfahren zu ihrer Herstellung
NZ244147A (en) 1991-09-03 1994-09-27 Hoechst Ag Echogenic particles which comprise a gas and at least one shaping substance, and their use as diagnostic agents
US5409688A (en) 1991-09-17 1995-04-25 Sonus Pharmaceuticals, Inc. Gaseous ultrasound contrast media
CZ286149B6 (cs) 1991-09-17 2000-01-12 Sonus Pharmaceuticals, Inc. Plynná prostředí pro zvýšení kontrastnosti obrazu, získaného ultrazvukem a způsob výběru plynů pro toto použití
AU2789192A (en) * 1991-10-04 1993-05-03 Mallinckrodt Medical, Inc. Gaseous ultrasound contrast agents
GB9200388D0 (en) 1992-01-09 1992-02-26 Nycomed As Improvements in or relating to contrast agents
IL104084A (en) 1992-01-24 1996-09-12 Bracco Int Bv Sustainable aqueous suspensions of pressure-resistant and gas-filled blisters, their preparation, and contrast agents containing them
LV10396B (en) * 1992-03-06 1996-02-20 Nycomed Imaging As Novel contrast agents
WO1994009703A1 (en) * 1992-11-02 1994-05-11 Drexel University Surfactant-stabilized microbubble mixtures, process for preparing and methods of using the same
US5716597A (en) * 1993-06-04 1998-02-10 Molecular Biosystems, Inc. Emulsions as contrast agents and method of use
IL110185A (en) 1993-07-02 1999-05-09 Molecular Biosystems Inc Method for making encapsulated gas microspheres from heat denatured protein in the absence of oxygen gas
PT711179E (pt) 1993-07-30 2005-03-31 Imcor Pharmaceutical Company Composicoes de microbolhas estabilizadas para ultra-som
US5601085A (en) 1995-10-02 1997-02-11 Nycomed Imaging As Ultrasound imaging
JP3914757B2 (ja) * 2001-11-30 2007-05-16 デュアキシズ株式会社 ウィルス検査のための装置と方法とシステム

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4192859A (en) * 1978-09-29 1980-03-11 E. R. Squibb & Sons, Inc. Contrast media containing liposomes as carriers
EP0077752A2 (de) * 1981-10-16 1983-04-27 Schering Aktiengesellschaft Flüssige Mischung zur Aufnahme und Stabilisierung von Gasbläschen zur Verwendung als Kontrastmittel für die Ultraschalldiagnostik und deren Herstellung
EP0123235A2 (de) * 1983-04-15 1984-10-31 Schering Aktiengesellschaft Mikropartikel und Gasblächen enthaltendes Ultraschall-Kontrastmittel
US4900540A (en) * 1983-06-20 1990-02-13 Trustees Of The University Of Massachusetts Lipisomes containing gas for ultrasound detection
EP0131540A2 (de) * 1983-07-06 1985-01-16 Schering Aktiengesellschaft Ultraschallkontrastmittel sowie dessen Herstellung
WO1988007365A2 (en) * 1987-04-01 1988-10-06 David F Ranney Biodadhesion drug carriers for endothelial and epithelial uptake and lesional localization of therapeutic and diagnostic agents
EP0320433A2 (de) * 1987-12-02 1989-06-14 Schering Aktiengesellschaft Ultraschall- oder Stosswellenarbeitsverfahren und Mittel zu dessen Durchführung

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of EP0474833A1 *

Cited By (171)

* Cited by examiner, † Cited by third party
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
EP0511273A4 (en) * 1989-12-22 1993-03-31 Evan C Unger Liposomes as contrast agents for ultrasonic imaging
EP0511273A1 (en) * 1989-12-22 1992-11-04 Imarx Pharmaceutical Corp. Liposomes as contrast agents for ultrasonic imaging
US5580575A (en) * 1989-12-22 1996-12-03 Imarx Pharmaceutical Corp. Therapeutic drug delivery systems
US5334381A (en) * 1989-12-22 1994-08-02 Unger Evan C Liposomes as contrast agents for ultrasonic imaging and methods for preparing the same
US5542935A (en) * 1989-12-22 1996-08-06 Imarx Pharmaceutical Corp. Therapeutic delivery systems related applications
US5352435A (en) * 1989-12-22 1994-10-04 Unger Evan C Ionophore containing liposomes for ultrasound imaging
EP0707846A3 (en) * 1989-12-22 1996-07-03 Evan C Unger Method for synthesizing a liposome
US5469854A (en) * 1989-12-22 1995-11-28 Imarx Pharmaceutical Corp. Methods of preparing gas-filled liposomes
US6613306B1 (en) 1990-04-02 2003-09-02 Bracco International B.V. Ultrasound contrast agents and methods of making and using them
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
US6989141B2 (en) 1990-05-18 2006-01-24 Bracco International B.V. Ultrasound contrast agents and methods of making and using them
EP0566601B2 (de) † 1991-01-09 2007-02-21 ALTANA Pharma AG Echokontrastmittel
EP0638318A2 (en) 1991-02-15 1995-02-15 BRACCO International B.V. Compositions for increasing the image contrast in diagnostic investigations of the digestive tract
US5527521A (en) * 1991-04-05 1996-06-18 Imarx Pharmaceutical Corp. Low density microspheres and suspensions and their use as contrast agents for computed tomography and in other applications
US5547656A (en) * 1991-04-05 1996-08-20 Imarx Pharmaceutical Corp. Low density microspheres and their use as contrast agents for computed tomography, and in other applications
US6709650B1 (en) 1991-04-10 2004-03-23 Elam Drug Delivery Limited Spray-dried microparticles and their use as therapeutic vehicles
US6569405B1 (en) 1991-04-10 2003-05-27 Quadrant Healthcare (Uk) Limited Preparation of diagnostic agents
US6022525A (en) * 1991-04-10 2000-02-08 Quadrant Healthcare (Uk) Limited Preparation of diagnostic agents
US5993805A (en) * 1991-04-10 1999-11-30 Quadrant Healthcare (Uk) Limited Spray-dried microparticles and their use as therapeutic vehicles
US7083778B2 (en) 1991-05-03 2006-08-01 Bracco International B.V. Ultrasound contrast agents and methods of making and using them
EP0616508A1 (en) * 1991-06-18 1994-09-28 Imarx Pharmaceutical Corp. Gas filled liposomes and their use as ultrasonic contrast agents
EP0616508A4 (en) * 1991-06-18 1996-06-26 Evan C Unger Gas filled liposomes and their use as ultrasonic contrast agents.
US5558854A (en) * 1991-09-17 1996-09-24 Sonus Pharmaceuticals Ultrasound contrast media comprising perfluoropentane and perfluorohexane gas
US5409688A (en) * 1991-09-17 1995-04-25 Sonus Pharmaceuticals, Inc. Gaseous ultrasound contrast media
US5558094A (en) * 1991-09-17 1996-09-24 Sonus Pharmaceuticals, Inc. Methods for using persistent gases as ultrasound contrast media
US5393524A (en) * 1991-09-17 1995-02-28 Sonus Pharmaceuticals Inc. Methods for selecting and using gases as ultrasound contrast media
US5573751A (en) * 1991-09-17 1996-11-12 Sonus Pharmaceuticals, Inc. Persistent gaseous bubbles as ultrasound contrast media
US5578292A (en) * 1991-11-20 1996-11-26 Bracco International B.V. Long-lasting aqueous dispersions or suspensions of pressure-resistant gas-filled microvesicles and methods for the preparation thereof
US5558856A (en) * 1992-01-09 1996-09-24 Nycomed Imaging As Microbubble-generating contrast agents for ultrasound and magnetic resonance imaging
US5413774A (en) * 1992-01-23 1995-05-09 Bracco International B.V. Long-lasting aqueous dispersions or suspensions of pressure-resistant gas-filled microvesicles and methods for the preparation thereof
EP0554213A1 (en) * 1992-01-24 1993-08-04 BRACCO International B.V. Long-lasting aqueous dispersions or suspensions of pressure-resistant gas-filled microvesicles and methods for the preparation thereof
US6187288B1 (en) 1992-02-11 2001-02-13 Bracco International B.V. Stable microbubble suspensions as enhancement agents for ultrasonic echography
US6939530B2 (en) 1992-10-10 2005-09-06 Quadrant Drug Delivery Limited Preparation of further diagnostic agents
GB2302650B (en) * 1992-10-10 1997-04-09 Andaris Ltd Targeted diagnostic agents
US6344182B1 (en) 1992-10-10 2002-02-05 Quadrant Healthcare (Uk) Limited Preparation of diagnostic agents by spray drying
US6348186B1 (en) 1992-10-10 2002-02-19 Quadrant Healthcare (Uk) Limited Preparation of further diagnostic agents
US6416741B1 (en) 1992-10-10 2002-07-09 Quadrant Healthcare (Uk) Limited Preparation of further diagnostic agents
US6015546A (en) * 1992-10-10 2000-01-18 Quadrant Healthcare (Uk) Limited Preparation of further diagnostic agents
US5957848A (en) * 1992-10-10 1999-09-28 Andaris Limited Preparation of further diagnostic agents
AU666238B2 (en) * 1992-11-02 1996-02-01 Bracco Suisse S.A. Stable microbubble suspensions as enhancement agents for ultrasound echography
US5686060A (en) * 1992-11-02 1997-11-11 Bracco International Bv Stable microbubble suspensions comprising saturated phospholipids for ultrasound echography
US5597549A (en) * 1992-11-02 1997-01-28 Bracco International B.V. Stable microbubble suspensions as enhancement agents for ultrasound echography
US5445813A (en) * 1992-11-02 1995-08-29 Bracco International B.V. Stable microbubble suspensions as enhancement agents for ultrasound echography
US5908610A (en) * 1992-11-02 1999-06-01 Bracco International B.V. Stable microbubble suspensions comprising saturated phospholipios for ultrasonic echography
WO1994009829A1 (en) * 1992-11-02 1994-05-11 Bracco International B.V. Stable microbubble suspensions as enhancement agents for ultrasound echography
WO1994012145A2 (en) * 1992-12-02 1994-06-09 Unilever Plc Cosmetic composition
WO1994012145A3 (en) * 1992-12-02 1994-07-21 Unilever Plc Cosmetic composition
US6183725B1 (en) 1992-12-16 2001-02-06 Bracco Research S.A. Gas mixtures useful as ultrasound contrast media, contrast agents containing the media and method
US5595723A (en) * 1993-01-25 1997-01-21 Sonus Pharmaceuticals Method for preparing storage stable colloids
US5707606A (en) * 1993-01-25 1998-01-13 Sonus Pharmaceuticals, Inc. Phase shift colloids as ultrasound contrast agents
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
US5707607A (en) * 1993-01-25 1998-01-13 Sonus Pharmaceuticals, Inc. Phase shift colloids as ultrasound contrast agents
US6569404B1 (en) 1993-01-25 2003-05-27 Amersham Health A/S Phase shift colloids as ultrasound contrast agents
US5536489A (en) * 1993-06-04 1996-07-16 Molecular Biosystems, Inc. Emulsions as contrast agents and method of use
EP0711127A1 (en) † 1993-06-11 1996-05-15 UNGER, Evan C Methods of preparing gas-filled liposomes
EP0711127B2 (en) † 1993-06-11 2009-01-21 ImaRx Pharmaceutical Corp. Methods of preparing gas-filled liposomes
US7141235B2 (en) 1993-07-30 2006-11-28 Imcor Pharmaceutical Co. Stabilized gas emulsion containing phospholipid for ultrasound contrast enhancement
EP1550464A1 (en) * 1993-07-30 2005-07-06 IMCOR Pharmaceutical Co. Stabilized microbubble composition for ultrasound
WO1995016467A1 (en) * 1993-12-15 1995-06-22 Bracco Research S.A. Gas mixtures useful as ultrasound contrast media
US5741478A (en) * 1994-11-19 1998-04-21 Andaris Limited Preparation of hollow microcapsules by spray-drying an aqueous solution of a wall-forming material and a water-miscible solvent
US6623722B1 (en) 1994-11-19 2003-09-23 Quadrant Healthcare (Uk) Limited Spray-drying microcapsules using an aqueous liquid containing a volatile liquid
EP0831927A1 (en) * 1995-06-06 1998-04-01 Imarx Pharmaceutical Corp. Stabilized compositions of fluorinated amphiphiles as contrast agents for ultrasound
US6217850B1 (en) 1995-06-07 2001-04-17 Nycomed Imaging As Method of making lyophilized microbubble compositions useful as contrast agents
WO2004073750A1 (en) * 1995-06-07 2004-09-02 Harald Dugstad Improvements in or relating to contrast agents
US6221337B1 (en) 1996-02-19 2001-04-24 Nycomed Imaging As Microbubbles surrounded by a monolayer of negatively charged phospholipids as contrast agents
EP1331013A2 (en) * 1996-02-19 2003-07-30 Amersham Health AS Improvements in or relating to contrast agents
EP1331013A3 (en) * 1996-02-19 2004-03-24 Amersham Health AS Improvements in or relating to contrast agents
AP890A (en) * 1996-02-19 2000-11-13 Nycomed Imaging As "Gas-containing contrast agents of use in diagnostic imaging.
WO1997029783A1 (en) * 1996-02-19 1997-08-21 Nycomed Imaging A/S Improvements in or relating to contrast agents
WO1998008747A1 (en) 1996-08-27 1998-03-05 Marsden, John Container containing contrast agents
US6017310A (en) * 1996-09-07 2000-01-25 Andaris Limited Use of hollow microcapsules
US6524552B2 (en) 1996-10-28 2003-02-25 Jo Klaveness Contrast agents
WO1998018500A2 (en) * 1996-10-28 1998-05-07 Marsden, John, Christopher Improvements in or relating to diagnostic/therapeutic agents
WO1998018496A3 (en) * 1996-10-28 1998-07-16 Nycomed Imaging As Contrast agents
WO1998018497A3 (en) * 1996-10-28 1998-07-16 Nycomed Imaging As Contrast agents
WO1998018497A2 (en) * 1996-10-28 1998-05-07 Nycomed Imaging As Contrast agents
US6264914B1 (en) 1996-10-28 2001-07-24 Nycomed Imaging As Contrast agents
WO1998018495A2 (en) * 1996-10-28 1998-05-07 Marsden, John, Christopher Improvements in or relating to diagnostic/therapeutic agents
US6051207A (en) * 1996-10-28 2000-04-18 Nycomed Imaging As Contrast agents
US6264917B1 (en) 1996-10-28 2001-07-24 Nycomed Imaging As Targeted ultrasound contrast agents
WO1998018501A2 (en) * 1996-10-28 1998-05-07 Marsden, John, Christopher Improvements in or relating to diagnostic/therapeutic agents
WO1998018501A3 (en) * 1996-10-28 1998-07-30 Marsden John Christopher Improvements in or relating to diagnostic/therapeutic agents
US6261537B1 (en) 1996-10-28 2001-07-17 Nycomed Imaging As Diagnostic/therapeutic agents having microbubbles coupled to one or more vectors
WO1998018495A3 (en) * 1996-10-28 1998-07-30 Marsden John Christopher Improvements in or relating to diagnostic/therapeutic agents
WO1998018500A3 (en) * 1996-10-28 1998-07-23 Mardsen John Christopher Improvements in or relating to diagnostic/therapeutic agents
WO1998018496A2 (en) * 1996-10-28 1998-05-07 Nycomed Imaging As Contrast agents
US6921525B2 (en) 1996-10-28 2005-07-26 Amersham Health As Contrast agents
US6068600A (en) * 1996-12-06 2000-05-30 Quadrant Healthcare (Uk) Limited Use of hollow microcapsules
CN1103605C (zh) * 1997-08-12 2003-03-26 勃勒柯研究有限公司 磁共振成象用可投药组合物及方法
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
US7052673B2 (en) 1998-03-31 2006-05-30 Bristol-Myers Squibb Pharma Company Pharmaceuticals for the imaging of angiogenic disorders
US6548663B1 (en) 1998-03-31 2003-04-15 Bristol-Myers Squibb Pharma Company Benzodiazepine vitronectin receptor antagonist pharmaceuticals
US6322770B1 (en) 1998-03-31 2001-11-27 Dupont Pharmaceuticals Company Indazole vitronectin receptor antagonist pharmaceuticals
US6524553B2 (en) 1998-03-31 2003-02-25 Bristol-Myers Squibb Pharma Company Quinolone vitronectin receptor antagonist pharmaceuticals
US6537520B1 (en) 1998-03-31 2003-03-25 Bristol-Myers Squibb Pharma Company Pharmaceuticals for the imaging of angiogenic disorders
US6511649B1 (en) 1998-12-18 2003-01-28 Thomas D. Harris Vitronectin receptor antagonist pharmaceuticals
US7090828B2 (en) 1998-12-18 2006-08-15 Bristol-Myers Squibb Pharma Company Vitronectin receptor antagonist pharmaceuticals
US7018611B2 (en) 1998-12-18 2006-03-28 Bristol-Myers Squibb Pharma Company Vitronectin receptor antagonist pharmaceuticals
US7332149B1 (en) 1998-12-18 2008-02-19 Bristol-Myers Squibb Pharma Company Vitronectin receptor antagonist pharmaceuticals
US6558649B1 (en) 1998-12-18 2003-05-06 Bristol-Myers Squibb Pharma Company Vitronectin receptor antagonist pharmaceuticals
US6683163B2 (en) 1998-12-18 2004-01-27 Bristol-Myers Squibb Pharma Company Vitronectin receptor antagonist pharmaceuticals
US6794518B1 (en) 1998-12-18 2004-09-21 Bristol-Myers Squibb Pharma Company Vitronectin receptor antagonist pharmaceuticals
US6818201B2 (en) 1998-12-18 2004-11-16 Bristol-Myers Squibb Pharma Company Vitronectin receptor antagonist pharmaceuticals
US6689337B2 (en) 1998-12-18 2004-02-10 Bristol-Myers Squibb Pharma Company Vitronectin receptor antagonist pharmaceuticals
US6743412B2 (en) 1998-12-18 2004-06-01 Bristol-Myers Squibb Pharma Company Vitronectin receptor antagonist pharmaceuticals
US6569402B1 (en) 1998-12-18 2003-05-27 Bristol-Myers Squibb Pharma Company Vitronectin receptor antagonist pharmaceuticals
US6511648B2 (en) 1998-12-18 2003-01-28 Bristol-Myers Squibb Pharma Company Vitronectin receptor antagonist pharmaceuticals
US7321045B2 (en) 1998-12-18 2008-01-22 Bristol-Myers Squibb Pharma Company Vitronectin receptor antagonist pharmaceuticals
US9364569B2 (en) 2003-02-04 2016-06-14 Bracco Suisse S.A. Ultrasound contrast agents and process for the preparation thereof
EP2335575A3 (en) * 2003-04-15 2011-08-24 Philips Intellectual Property & Standards GmbH Magnetic gas bubble composition and magnetic gas bubble precursor for its manufacture
US8491482B2 (en) 2003-06-12 2013-07-23 Bracco Suisse S.A. Blood flow estimates through replenishment curve fitting in ultrasound contrast imaging
US8021303B2 (en) 2003-06-12 2011-09-20 Bracco Research Sa System for extracting morphological information through a perfusion assessment process
US9750821B2 (en) 2003-12-22 2017-09-05 Bracco Suisse S.A. Gas-filled microvesicle assembly for contrast imaging
US9248204B2 (en) 2004-08-18 2016-02-02 Bracco Suisse S.A. Gas-filled microvesicles composition for contrast imaging
US10076580B2 (en) 2004-08-18 2018-09-18 Bracco Suisse S.A. Gas-filled microvesicles composition for contrast imaging
WO2006067201A2 (en) 2004-12-23 2006-06-29 Bracco Research Sa A perfusion assessment method and system based on bolus administration
US8496591B2 (en) 2004-12-23 2013-07-30 Bracco Suisse S.A. Perfusion assessment method and system based on bolus administration
US7846100B2 (en) 2005-03-03 2010-12-07 Bracco International Bv Medical imaging system based on a targeted contrast agent
WO2007054561A1 (en) 2005-11-10 2007-05-18 Bracco Research Sa Instantaneous visualization of contrast agent concentration in imaging applications
US8634608B2 (en) 2005-11-10 2014-01-21 Bracco Suisse S.A. Instantaneous visualization of contrast agent concentration in imaging applications
WO2007054544A1 (en) 2005-11-10 2007-05-18 Bracco Research Sa Detection of immobilized contrast agent in medical imaging applications based on flow dynamics analysis
US9198639B2 (en) 2005-11-10 2015-12-01 Bracco Suisse S.A. Detection of immobilized contrast agent in medical imaging applications based on flow dynamics analysis
US9446156B2 (en) 2006-09-05 2016-09-20 Bracco Suisse S.A. Gas-filled microvesicles with polymer-modified lipids
US8293214B2 (en) 2006-12-19 2012-10-23 Bracco Suisse S.A. Targeting and therapeutic compounds and gas-filled microvesicles comprising said compounds
WO2008074889A1 (en) 2006-12-21 2008-06-26 Bracco International Bv Detection of the detachment of immobilized contrast agent in medical imaging applications
US8512249B2 (en) 2006-12-21 2013-08-20 Bracco International Bv Detection of the detachment of immobilized contrast agent in medical imaging applications
US9072492B2 (en) 2007-12-28 2015-07-07 Bracco Suisse Sa Quantification analysis of immobilized contrast agent in medical imaging applications
US11607196B2 (en) 2007-12-28 2023-03-21 Bracco Suisse Sa Initialization of fitting parameters for perfusion assessment based on bolus administration
US10130342B2 (en) 2007-12-28 2018-11-20 Bracco Suisse Sa Initialization of fitting parameters for perfusion assessment based on bolus administration
EP2599504A2 (en) 2008-02-18 2013-06-05 INSERM (Institut National de la Santé et de la Recherche Médicale) Use of conjugates of fsh receptor ligands and antitumour agents for therapy of cancer
EP2189112A1 (en) 2008-11-24 2010-05-26 Bracco Research S.A. Real-time perfusion imaging and quantification
US10258563B2 (en) 2009-04-20 2019-04-16 Drexel University Encapsulation of microbubbles within the aqueous core of microcapsules
US11389395B2 (en) 2009-04-20 2022-07-19 Drexel University Encapsulation of microbubbles within the aqueous core of microcapsules
US10688040B2 (en) 2009-04-20 2020-06-23 Drexel University Encapsulation of microbubbles within the aqueous core of microcapsules
US9307957B2 (en) 2009-06-08 2016-04-12 Bracco Suisse Sa Auto-scaling of parametric images
WO2011026866A1 (en) 2009-09-01 2011-03-10 Bracco Suisse Sa Parametric images based on dynamic behavior over time
US8929634B2 (en) 2009-09-01 2015-01-06 Bracco Suisse Sa Parametric images based on dynamic behavior over time
WO2011110552A1 (en) 2010-03-09 2011-09-15 Bracco Suisse Sa Initialization of fitting parameters for perfusion assessment based on bolus administration
US9211348B2 (en) 2010-08-09 2015-12-15 Bracco Suisse S.A. Targeted gas-filled microvesicles
US9333273B2 (en) 2010-08-09 2016-05-10 Bracco Suisse S.A. Targeting constructs
WO2012020030A1 (en) 2010-08-09 2012-02-16 Bracco Suisse Sa Targeted gas-filled microvesicles
WO2012085072A1 (en) 2010-12-24 2012-06-28 Bracco Suisse Sa Gas-filled microvesicles for use as vaccine
US9770411B2 (en) 2010-12-24 2017-09-26 Bracco Suisse S.A. Methods of using gas-filled microvesicles covalently bound to an antigen
WO2012123229A1 (de) * 2011-03-11 2012-09-20 Innora Gmbh Festes, negatives röntgenkontrastmittel zur darstellung des gastrointestinaltraktes
EP2545908A1 (en) * 2011-07-11 2013-01-16 RWTH Aachen Medium for microbubbles or microparticles and preparation thereof
US9734584B2 (en) 2012-12-21 2017-08-15 Bracco Suisse Sa Segmentation in diagnostic imaging applications based on statistical analysis over time
WO2015000953A1 (en) 2013-07-03 2015-01-08 Bracco Suisse S.A. Devices and methods for the ultrasound treatment of ischemic stroke
US10368842B2 (en) 2014-04-07 2019-08-06 Bracco Suisse S.A. Estimation of acoustic level in-situ with non-fundamental analysis
WO2015155380A1 (en) * 2014-04-07 2015-10-15 Bracco Suisse Sa Estimation of acoustic level in-situ with non-fundamental analysis
EP3150559A4 (en) * 2014-05-28 2018-02-21 Takeda Pharmaceutical Company Limited Antibacterial water
US10556256B2 (en) 2014-05-28 2020-02-11 Takeda Pharmaceutical Company Limited Antibacterial water
US10537622B2 (en) 2014-12-22 2020-01-21 Bracco Suisse S.A. Gas-filled microvesicles for use as vaccine
US10022460B2 (en) 2014-12-31 2018-07-17 Lantheus Medical Imaging, Inc. Lipid-encapsulated gas microsphere compositions and related methods
US11395856B2 (en) 2014-12-31 2022-07-26 Lantheus Medical Imaging, Inc. Lipid-encapsulated gas microsphere compositions and related methods
US10583207B2 (en) 2014-12-31 2020-03-10 Lantheus Medical Imaging, Inc. Lipid-encapsulated gas microsphere compositions and related methods
US11284910B2 (en) 2015-12-09 2022-03-29 Koninklijke Philips N.V. Interleaved beam pattern for sonothhrombolysis and other vascular acoustic resonator mediated therapies
US10433817B2 (en) 2015-12-10 2019-10-08 Bracco Suisse S.A. Detection of immobilized contrast agent with dynamic thresholding
US12097270B2 (en) 2016-05-04 2024-09-24 Lantheus Medical Imaging, Inc. Methods and devices for preparation of ultrasound contrast agents
US10588988B2 (en) 2016-05-04 2020-03-17 Lantheus Medical Imaging, Inc. Methods and devices for preparation of ultrasound contrast agents
US10220104B2 (en) 2016-07-06 2019-03-05 Lantheus Medical Imaging, Inc. Methods for making ultrasound contrast agents
US11266749B2 (en) 2016-07-06 2022-03-08 Lantheus Medical Imaging, Inc. Methods for making ultrasound contrast agents
US11344636B2 (en) 2016-07-06 2022-05-31 Lantheus Medical Imaging, Inc. Methods for making ultrasound contrast agents
US11266750B2 (en) 2016-07-06 2022-03-08 Lantheus Medical Imaging, Inc. Methods for making ultrasound contrast agents
US9913919B2 (en) 2016-07-06 2018-03-13 Lantheus Medical Imaging, Inc. Methods for making ultrasound contrast agents
US11529431B2 (en) 2016-07-06 2022-12-20 Lantheus Medical Imaging, Inc. Methods for making ultrasound contrast agents
US9789210B1 (en) 2016-07-06 2017-10-17 Lantheus Medical Imaging, Inc. Methods for making ultrasound contrast agents
US11857646B2 (en) 2016-07-06 2024-01-02 Lantheus Medical Imaging, Inc. Methods for making ultrasound contrast agents
US11925695B2 (en) 2016-07-06 2024-03-12 Lantheus Medical Imaging, Inc. Methods for making ultrasound contrast agents
US10583208B2 (en) 2016-07-06 2020-03-10 Lantheus Medical Imaging, Inc. Methods for making ultrasound contrast agents

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