Abstract: One can impart outstanding resistance against collapse under pressure to gas-filled microvesicle used as contrast agents in ultrasonic echography by using as fillers gases whose solubility in water, expressed in liter of gas by liter of water under standard conditions, divided by the square root of the molecular weight does not exceed 0.003.

Abstract: Novel methods of non-invasive intravascular surgery are disclosed, which include the intravascular administration of a composition comprising gas or gaseous precursor filled vesicles, followed by application of ultrasound in an amount sufficient to induce activation or rupture of the vesicles. The methods optionally also include the step of scanning the patient with diagnostic imaging to determine the presence of the vesicles in the region.

Abstract: Improved therapeutic sclerosing microfoams and methods and devices for making them are provided that have advantage in producing a consistent profile injectable foam with minimal input by the physician yet using high volume percentages of blood dispersible gases, thus avoiding use of potentially hazardous amounts of nitrogen.

Abstract: Novel contrast agents for ultrasound diagnosis and a reproducible process for making the same are described, wherein the contrast agents comprise a microbubble composition comprising a lipid shell, a stabilizer coated on the lipid shell and perfluoropropane gas encapsulated in the lipid shell.

Abstract: Agents for enhancing the contrast in a diagnostic ultrasound procedure comprise colloidal dispersions of the liquid-in-liquid type, i.e., emulsions or microemulsions, in which the dispersed liquid phase is a liquid having a boiling point below the temperature of the animal to be imaged and which therefore undergoes a phase change from a dispersed liquid to a highly echogenic dispersed gaseous foam or kugelschaum following administration to the animal. The liquid state of the dispersed phase allows one to manufacture extremely stable, pharmaceutically acceptable emulsions with particle sizes typically below 1000 nm. The gaseous state at body temperature yields highly echogenic microbubbles, typically below 10,000 nm in diameter, which are effective as ultrasound contrast agents. Intravenous, intraarterial, oral, intraperitoneal, and intrauterine dosage forms, methods of administration, and imaging techniques are described.

Abstract: Microcapsules are prepared by a process comprising the steps of (i) spray-drying a solution or dispersion of a wall-forming material in order to obtain intermediate microcapsules and (ii) reducing the water-solubility of at least the outside of the intermediate microcapsules. Suitable wall-forming materials include proteins such as albumin and gelatin. The microcapsules have walls of 40-500 nm thick and are useful in ultrasonic imaging. The control of median size, size distribution and degree of insolubilization and cross-linking of the wall-forming material allows novel microsphere preparations to be produced.

Abstract: Spray drying methods for forming powder compositions for pharmaceutical applications are disclosed. According to one aspect of the invention, the spray drying feed stock comprises a bioactive agent, surfactant, and a blowing agent. Another aspect of the invention is directed to spray drying a feed stock comprising a phospholipid and calcium chloride.

Abstract: This invention relates to a freeze-dried vesicle containing ultrasound contrast agent containing a freeze-drying stabilizer and thermally stable at temperatures in excess of 20° C.

Abstract: A container comprising an aqueous lipid suspension and a gaseous phase substantially separate from the aqueous stabilizing phase, useful in diagnostic imaging such as ultrasound and magnetic resonance imaging and in therapeutic applications, is disclosed.

Abstract: Novel membrane-forming amphiphilic lipopeptides comprising one or more peptide moieties containing 2-50 aminoacyl residues and one or more hydrocarbon chains containing 5-50 carbon atoms. Such lipopeptides may be used in the formation of stabilized gas microbubble dispersions suitable for use as diagnostic and/or therapeutic agents, for example as ultrasound contrast agents.

Abstract: A method for ligand-based binding of lipid encapsulated particles to molecular epitopes on a surface in vivo or in vitro comprises sequentially administering (a) a site-specific ligand activated with a biotin activating agent; (b) an avidin activating agent; and (c) lipid encapsulated particles activated with a biotin activating agent, whereby the ligand is conjugated to the particles through an avidin-biotin interaction and the resulting conjugate is bound to the molecular epitopes on such surface. The conjugate is effective for imaging by x-ray, ultrasound, magnetic resonance or positron emission tomography. Compositions for use in ultrasonic imaging of natural or synthetic surfaces and for enhancing the acoustic reflectivity thereof are also disclosed.

Abstract: The present invention describes, among other things, the surprising discovery that gaseous precursor filled compositions are profoundly more effective as acoustically active contrast agents when they are thermally preactivated to temperatures at or above the boiling point of the instilled gaseous precursor prior to their in vivo administration to a patient. Further optimization of contrast enhancement is achieved by administering the gaseous precursor filled compositions to a patient as an infusion. Enhanced effectiveness is also achieved for ultrasound mediated targeting and drug delivery.

Abstract: Gas or air filled microbubble suspensions in aqueous phases usable as imaging contrast agents in ultrasonic echography. They contain laminarized surfactants and, optionally, hydrophilic stabilizers. The laminarized surfactants can be in the form of liposomes. The suspensions are obtained by exposing the laminarized surfactants to air or a gas before or after admixing with an aqueous phase. One can impart outstanding resistance against collapse under pressure to these gas-filled microbubbles used as contrast agents in ultrasonic echography by using as fillers gases whose solubility in water, expressed in liter of gas by liter of water under standard conditions, divided by the square root of the molecular weight does not exceed 0.003.

Abstract: This relates to partially acetalized polyvinyl alcohol embolization particles suitable for implanting in the human body, to compositions containing those particles, and to methods of making and using them.

Abstract: Low density microspheres, methods for preparing same, and use of same as contrast agents are described. The microspheres have a void having a volume that comprises at least about 75% of the total volume of the microspheres, and which contains a gas or the vapor of a volatile liquid selected from the group consisting of aliphatic hydrocarbons, chlorofluorocarbons, tetraalkyl silanes and perfluorocarbons.

Abstract: A method for ultrasonic harmonic imaging is disclosed, which uses microbubbles particularly selected for their properties of reradiating ultrasound energy at frequencies other than the exciting frequency.

Abstract: Targeted therapeutic delivery systems comprising gas- or gaseous precursor-filled lipid microspheres comprising a therapeutic are described. Methods for employing such microspheres in therapeutic delivery applications are also provided.

Abstract: Novel ultrasound methods comprising administering to a patient a targeted vesicle composition which comprises vesicles comprising a lipid, protein or polymer, encapsulating a gas, in combination with a targeting ligand, and scanning the patient using ultrasound. The scanning may comprise exposing the patient to a first type of ultrasound energy and then interrogating the patient using a second type of ultrasound energy. The targeting ligand preferably targets tissues, cells or receptors, including myocardial cells, endothelial cells, epithelial cells, tumor cells and the glycoprotein GPIIbIIIa receptor. The methods may be used to detect a thrombus, enhancement of an old or echogenic thrombus, low concentrations of vesicles and vesicles targeted to tissues, cells or receptors.

Abstract: The invention relates to ultrasound contrast agents comprising vesicles comprising a protein capable of formation of gas-containing vesicles, wherein the vesicles contain gas which comprises sulphur hexafluoride or a low molecular weight fluorinated hydrocarbon. These contrast agents exhibit stability in vivo upon administration so as to permit ultrasound visualization while allowing rapid subsequent elimination from the system.

Abstract: A two-phase mixture is provided having a dissolved gas and a suspension of bubbles in a liquid. Methods for making, maintaining, and using the two-phase mixture are also provided. The gas molecules may be introduced into the liquid at a high velocity under elevated pressure to form a supersaturated solution that retains the dissolved gas concentration in solution when the solution is exposed to ambient conditions. The mixture may be used in a number of applications where high concentrations of gas must be retained in solution during prolonged exposure to ambient conditions. An example of use is the treatment of wounds to non-surgically remove dead, devitalized, contaminated and foreign matter from tissue cells. The mixture may be combined with a plastic to encapsulate the suspension of bubbles to minimize liberation of the gas bubbles from the mixture.

Abstract: The invention provides a process for the preparation of a pharmaceutical composition comprising an aqueous dispersion of gas-containing vesicles the membranes whereof comprise an amphiphilic membrane-forming material, said process comprising: (i) generating a liquid dispersion of gas-containing vesicles from a mixture comprising an amphiphilic membrane forming material; (ii) lyophilizing a liquid dispersion of said gas-containing vesicles; (iii) reconstituting the lyophilized product of step (ii) with a sterile aqueous liquid to produce an aqueous dispersion of gas-containing vesicles; and (iv) treating the aqueous dispersion product of step (iii) or the lyophilized product of step (ii) to produce a substantially aggregate-free sterile aqueous dispersion of gas-containing vesicles.

Abstract: Method and apparatus for continuous infusion to a subject of dispersions in which the dispersed phase is susceptible to flotation or sedimentation. The dispersion is controllably delivered from an upper or lower extremity of an essentially vertically positioned. delivery vessel, e.g. syringe 2, and is then admixed with flushing medium, e.g. from infusion minibag 8, prior to administration to the subject. Vertical positioning of the delivery device maximises the distance through which flotation or sedimentation may occur, thereby substantially reducing the effects of separation over a given period of time compared to use of a corresponding horizontal delivery vessel such as a syringe placed in a conventional syringe driver.

Abstract: In accordance with the present invention, there are provided methods for identifying the sentinel lymph node in a drainage field for a tissue or organ in a subject. In select embodiments, the invention allows for the identification of the first or sentinel lymph node that drains the tissue or organ, particularly those tissues associated with neoplastic or infectious diseases and disorders, and within the pertinent lymph drainage basin. Once the drainage basin from the tissue or organ, i.e., the sentinel lymph node, is identified, a preoperative or intraoperative mapping of the affected lymphatic structure can be carried out with a contrast agent. Identification of the first or sentinel lymph node, on the most direct drainage pathway in the drainage field, can be accomplished by a variety of imaging techniques, including ultrasound, MRI, CT, nuclear and others.

Abstract: Gas or air filled microbubble suspensions in aqueous phases usable as imaging contrast agents in ultrasonic echography. They contain laminarized surfactants and, optionally, hydrophilic stabilizers. The laminarized surfactants can be in the form of liposomes. The suspensions are obtained by exposing the laminarized surfactants to air or a gas before or after admixing with an aqueous phase.

Abstract: The present invention provides contrast agents for use in diagnostic ultrasound studies comprising microbubbles of gas or a gas precursor encapsulated by non-proteinaceous crosslinked or polymerised amphiphilic moieties.

Abstract: Methods of and apparatus for preparing temperature activated gaseous precursor-filled liposomes are described. Gaseous precursor-filled liposomes prepared by these methods are particularly useful, for example, in ultrasonic imaging applications and in therapeutic drug delivery systems.

Abstract: The present invention is directed to targeted therapeutic delivery systems comprising a gas or gaseous precursor filled microsphere wherein said gas or gaseous precursor filled microsphere comprises an oil, a surfactant, and a therapeutic compound. Methods of preparing the targeted therapeutic delivery systems are also embodied by the present invention which comprise processing a solution comprising an oil and a surfactant in the presence of a gaseous precursor, at a temperature below the gel to liquid crystalline phase transition temperature of the surfactant to form gas or gaseous precursor filled microsphere, and adding to said microspheres a therapeutic compound resulting in a targeted therapeutic delivery system, wherein said processing is selected from the group consisting of controlled agitation, controlled drying, and a combination thereof.

Abstract: The invention relates to a process for the production of gaseous microparticles for ultrasonic diagnosis, whose wall material is built up from polyesters of &agr;-, &bgr;- or &ggr;- hydroxycarboxylic acids, particles that are produced according to this process, as well as their use in medical diagnosis.

Abstract: Echogenic devices, and methods of making and using such devices, are disclosed. In one aspect, the devices include a porous polymeric material that is preparable by extracting a phase separated composition. In another aspect, the echogenic devices include a polymeric composition having porous particles therein. Preferably the devices are medical devices.

Abstract: One can impart outstanding resistance against collapse under pressure to gas-filled microvesicle used as contrast agents in ultrasonic echography by using as fillers gases whose solubility in water, expressed in liter of gas by liter of water under standard conditions, divided by the square root of the molecular weight does not exceed 0.003.

Abstract: Methods of and apparatus for preparing temperature activated gaseous precursor-filled liposomes are described. Gaseous precursor-filled liposomes prepared by these methods are particularly useful, for example, in ultrasonic imaging applications and in therapeutic drug delivery systems.

Abstract: A novel method for the controlled delivery of therapeutic compounds to a region of a patient, using magnetic resonance focused therapeutic ultrasound, is disclosed.

Abstract: The invention provides a process for the preparation of gas-containing vesicles wherein a mixture of gas, liquid and vesicle membrane forming material is passed through a zone in which it is subject to shear forces exerted by surfaces moving relative to each other at a speed of at least 20 m/s.

Abstract: In accordance with the present invention, there are provided methods for identifying the sentinel lymph node in a drainage field for a tissue or organ in a subject. In select embodiments, the invention allows for the identification of the first or sentinel lymph node that drains the tissue or organ, particularly those tissues associated with neoplastic or infectious diseases and disorders, and within the pertinent lymph drainage basin. Once the drainage basin from the tissue or organ, i.e., the sentinel lymph node, is identified, a pre-operative or intraoperative mapping of the affected lymphatic structure can be carried out with a contrast agent. Identification of the first or sentinel lymph node, on the most direct drainage pathway in the drainage field, can be accomplished by a variety of imaging techniques, including ultrasound, MRI, CT, nuclear and others.

Abstract: A gas emulsion for ultrasound contrast enhancement comprising a plurality of gas bubbles in a liquid medium, the gas bubbles comprising at least one fluoroether selected from the group consisting of CF3OCF2OCF3, CF3(OCF2)2OCF3, CF3(OCF2)3OCF3, and CF3(OCF2)4OCF3.

Abstract: A new and improved method for inducing or pacing atrial and ventricular arrhythmias in animals Embodiments of the invention involve using microbubbles enhanced with an insoluble gas in combination with low frequency ultrasound for its pacing activity. The methods and compositions can be used to pace patients, convert patients out of atrial fibrillation, and as a diagnostic to assess a patient's risk for arrhythmias.

Abstract: Ultrasound contrast agents comprising microbubbles of biocompatible gas, e.g. a sulphur halide or a perfluorocarbon, stabilized by opsonisable amphiphilic material, e.g. a membrane-forming lipid such as a phospholipid, especially a negatively charged phospholipid such as a phosphatidylserine, may exhibit prolonged contrast-generating residence time in the liver following intravenous administration.

Abstract: Targetable diagnostic and/or therapeutically active agents, e.g. ultrasound contrast agents, having reporters comprising gas-filled microbubbles stabilized by monolayers of film-forming surfactants, the reporter being coupled or linked to at least one vector.

Abstract: Targetable diagnostic and/or therapeutically active agents, e.g. ultrasound contrast agents, comprising a suspension in an aqueous carrier liquid of a reporter comprising gas-containing or gas-generating material, said agent being capable of forming at least two types of binding pairs with a target.

Abstract: Methods and devices for enhanced ultrasound detection based upon changing temperature and ultrasound reflectivity of a temperature-dependent contrast agent bound to an ultrasound target are disclosed. The methods and devices can be used for enhanced imaging alone or in conjunction with drug delivery, with therapeutic approaches such as hyperthermia or cryotherapy or with other imaging modalities.

Abstract: A microbubble preparation formed of a plurality of microbubbles comprising a first gas and a second gas surrounded by a membrane such as a surfactant, wherein the first gas and the second gas are present in a molar ratio of from about 1:100 to about 1000:1, and wherein the first gas has a vapor pressure of at least about (760−x) mm Hg at 37 C., where x is the vapor pressure of the second gas at 37 C., and wherein the vapor pressure of each of the first and second gases is greater than about 75 mm Hg at 37 C.

Abstract: Microspheres are prepared by a process comprising (i) spray-drying a solution or dispersion of a wall-forming material in order to obtain intermediate microspheres and (ii) reducing the water-solubility of at least the outside of the intermediate microspheres. Suitable wall-forming materials include proteins such as albumin and gelatin. The microspheres have walls of 40-500 nm thick and are useful in ultrasonic imaging. The control of median size, size distribution and degree of insolubilisation and cross-linking of the wall-forming material allows novel microsphere preparations to be produced. In particular, the microspheres may be 15-20 &mgr;m, targeted to selected areas of the body or of prolonged life in the circulation.

Abstract: The present invention is directed to targeted therapeutic delivery systems comprising a gas or gaseous precursor filled microsphere wherein said gas or gaseous precursor filled microsphere comprises an oil, a surfactant, and a therapeutic compound. Methods of preparing the targeted therapeutic delivery systems are also embodied by the present invention which comprise processing a solution comprising an oil and a surfactant in the presence of a gaseous precursor, at a temperature below the gel to liquid crystalline phase transition temperature of the surfactant to form gas or gaseous precursor filled microsphere, and adding to said microspheres a therapeutic compound resulting in a targeted therapeutic delivery system, wherein said processing is selected from the group consisting of controlled agitation, controlled drying, and a combination thereof.

Abstract: A method and assembly are provided which use cavitation induced by an ultrasound beam for creating a controlled surgical lesion in a selected treatment volume of a patient, such as an internal body cavity or organ. First, a plurality of microbubbles are provided in the treatment volume. Preferably, the threshold for cavitation of microbubbles in the treatment volume is lowered compared with the threshold for cavitation in surrounding tissues. The expected location of the surgical lesion within the treatment volume may be previewed, and then the microbubbles in the treatment volume are cavitated with the ultrasound beam to create the controlled surgical lesion. In addition, substances can be associated with the microbubbles such that cavitation of the microbubbles delivers the substances to the treatment volume. Preferably, the creation of the surgical lesion at the expected lesion location is then verified.

Abstract: A method for removing a gas compound from a site comprising placing cells having gas vesicles under conditions that induce the cells to float to a surface of an aqueous medium, harvesting the cells from the surface of the medium, lysing the cells, separating the gas vesicles from the lysed cells, crosslinking the gas vesicles with a crosslinking agent, loading a gas with a lowered partial pressure for the gas compound to be removed into the gas vesicles, and placing the gas vesicles contacted with a medium such that the gas compound is removed from the site to the medium. Harvesting gas-vesicle-containing cells is achieved by placing the cells under conditions that induce the cells to rise to the surface of an aqueous medium. Then collecting the cells from the surface of the medium. Gas vesicles are isolated by lysing the cells and separating the gas vesicles from the lysate. Once the gas vesicles are isolated, they can be modified, such as by crosslinking with glutaraldehyde.

Abstract: The present invention relates to coated particles comprising a coating and a core particle comprising an active, wherein the coating comprises a gas phase component. The invention also relates to processes for the manufacture of such coated particles comprising (a) providing a coating material comprising a gas phase component and applying the gas containing coating material to a core particle or (b) providing a coating material comprising a gas generating component, applying the coating material to a core particle and treating the coated particles so as to generate a gas from the gas generating component. Furthermore, it also relates to the use of such coated particles in a number of applications.

Abstract: The present invention is directed to charged lipids, compositions comprising charged lipids, and the use of these compositions in drug delivery, targeted drug delivery, therapeutic imaging and diagnostic imaging, as well as their use as contrast agents.

Abstract: The invention relates to microcapsules to a microcapsule with a mean size from a fraction of micrometer to 1000 micrometers having a biodegradable membrane encapsulating a gas core. The membrane comprising one or more biodegradable water insoluble lipids or mixtures thereof and optionally mixtures of the lipids with up to 75% by weight of biodegradable polymers encapsulates the core which is filled with air or a gas. Microcapsules disclosed, may be non-coalescent, dry and instantly dispersible, when in suspension in a physiologically acceptable carrier are useful as delivery vehicles for therapeutically active agents and/or as contrast agents for echographic imaging of organs of human or animal body.

Abstract: In accordance with the present invention, there are provided methods for identifying the sentinel lymph node in a drainage field for a tissue or organ in a subject. In select embodiments, the invention allows for the identification of the first or sentinel lymph node that drains the tissue or organ, particularly those tissues associated with neoplastic or infectious diseases and disorders, and within the pertinent lymph drainage basin. Once the drainage basin from the tissue or organ, i.e., the sentinel lymph node, is identified, a pre-operative or intraoperative mapping of the affected lymphatic structure can be carried out with a contrast agent. Identification of the first or sentinel lymph node, on the most direct drainage pathway in the drainage field, can be accomplished by a variety of imaging techniques, including ultrasound, MRI, CT, nuclear and others.

Abstract: A microbubble preparation formed of a plurality of microbubbles comprising a first gas and a second gas surrounded by a membrane such as a surfactant, wherein the first gas and the second gas are present in a molar ratio of from about 1:100 to about 1000:1, and wherein the first gas has a vapor pressure of at least about (760−x) mm Hg at 37° C., where x is the vapor pressure of the second gas at 37° C., and wherein the vapor pressure of each of the first and second gases is greater than about 75 mm Hg at 37° C.