Long-lasting aqueous dispersions or suspensions of pressure-resistant gas-filled microvesicles and methods for the preparation thereof
AssigneeBracco International B.V.
InventorsMichel Schneider, Feng Yan, Jerome Puginier, Marie-Bernadette Barrau, Philippe Bussat, Eva Hybl, Daniel Bichon
Life of this patent
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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.
Claims44
A method of making a contrast agent having resistance against collapse from pressure increases when used in ultrasonic echography, said contrast agent consisting of gas-filled microvesicles suspended in an aqueous liquid carrier phase, the microvesicles being either microbubbles bounded by an evanescent gas/liquid interfacial closed surface, or microballoons bounded by a material envelope filled with a physiologically acceptable gas wherein the gas is bounded by a stabilizing layer of one or more film forming phospholipids in lamellar or laminar form at the gas/liquid interface, said method comprising the step of forming the microvesicles in the presence of a physiologically acceptable gas, or gas mixture comprising a physiologically acceptable gas, or filling preformed microvesicles with said gas, or said gas mixture, said the physiologically acceptable gas being selected from the group consisting of SF6, SeF6, CF4, CBrF3, C4F8, CClF3, CCl2F2, C2F6, C2ClF5, CBrClF2, C2Cl2F4, CBr2F2 and C4F10, said microvesicles having resistance against collapse resulting, at least in part, from pressure increases effective when a suspension of said gas-filled microvesicles is in injected into the bloodstream of a patient.
A method of making a contrast agent having resistance against collapse from pressure increases when used in ultrasonic echography, said contrast agent consisting of gas-filled microvesicles suspended in an aqueous liquid carder carrier phase, the microvesicles being either microbubbles bounded by an evanescent gas/liquid interfacial closed surface, or microballoons bounded by a material envelope filled with a physiologically acceptable gas wherein the gas is bounded by a stabilizing layer of one or more film forming phospholipids in lamellar or laminar form at the gas/liquid interface, said method comprising the steps of:
- preforming the microvesicles or precursors thereof under an atmosphere of a first gas;
- and
- substantially substituting at least a fraction of said first gas with a second gas which is a physiologically acceptable gas, or gas mixture comprising a physiologically acceptable gas, said the physiologically acceptable gas being selected from the group consisting of SF6, SeF6, CF4, CBrF3, C4F8, CClF3, CCl2F2, C2F6, C2ClF5, CBrClF2, C2Cl2F4, CBr2F2 and C4F10, said microvesicles having resistance against collapse resulting, at least in part, from pressure increases effective when a suspension of said gas-filled microvesicles is injected into the bloodstream of a patient.
A method of making a contrast agent for ultrasonic echography which consists of gas-filled microvesicles microbubbles suspended in an aqueous liquid carrier phase, the microvesicles microbubbles having resistance against collapse resulting from pressure increases effective when the said suspensions are injected into the bloodstream of a patient, and the microbubbles being filled with a physiologically acceptable gas wherein the gas is bounded by a stabilizing layer of one or more film forming phospholipids in lamellar or laminar form at the gas/liquid interface, said method comprising the step of forming the microvesicles microbubbles in the presence of a physiologically acceptable gas or gas mixture comprising a physiologically acceptable gas, or filling preformed microvesicles with said gas or said gas mixture, said physiologically acceptable gas being selected from the group consisting of SF6, SeF6, CF4, CBrF3, C4F8, CClF3, CCl2F2, C2F6, C2ClF5, CBrClF2, C2Cl2F4, CBr2F2 and C4F10, said gas or at least a gas in said gas mixture being such that, under standard conditions, the pressure difference ΔP between pressures at which the bubble counts are about 75% and 25% of the original bubble count is at least 25Torr.
A method of making a contrast agent having resistance against collapse from pressure increases when used in ultrasonic echography, said contrast agent consisting of gas-filled microvesicles suspended in an aqueous liquid carrier phase, the microvesicles being microbubbles filled with a gas mixture wherein the gas mixture is bounded by a stabilizing layer of one or more film forming phospholipids in lamellar or laminar form at the gas/liquid interface, said method comprising the step of forming the microvesicles in the presence of the gas mixture comprising a physiologically acceptable gas, selected from the group consisting of SF6, CF4, CBrF3, C4F8, CClF3, C2F6, C2ClF5, CBrClF2, C2Cl2F4 and C4F10, and microvesicles having resistance against collapse resulting, at least in part, from pressure increases effective when a suspension of said gas-filled microvesicles is injected into the bloodstream of a patient.
A method of making a contrast agent having resistance against collapse from pressure increases when used in ultrasonic echography, said contrast agent consisting of gas-filled microvesicles suspended in an aqueous liquid carrier phase, the microvesicles being microballoons consisting of a physiologically acceptable gas bounded by an organic polymer envelope at the gas/liquid interface, said polymer envelope formed from one or more polymers selected from the group consisting of polylactic or polyglycolic acid and their copolymers, denatured albumin, reticulated hemoglobin, and esters of polyglutamic and polyaspartic acids, said method comprising the step of forming the microvesicles in the presence of said physiologically acceptable gas selected from the group consisting of SF6, CF4, CBrF3, C4F8, CClF3, C2F6, C2ClF5, CBrClF2, C2Cl2F4 and C4F10, said microvesicles having resistance against collapse resulting, at least in part, from pressure increases effective when a suspension of said gas-filled microvesicles is injected into the bloodstream of a patient.
A method of making a contrast agent having resistance against collapse from pressure increases when used in ultrasonic echography, said contrast agent consisting of gas-filled microvesicles suspended in an aqueous liquid carrier phase, the microvesicles being microballoons consisting of a gas mixture bounded by an organic polymer envelope at the gas/liquid interface, said polymer envelope formed from one or more polymers selected from the group consisting of polylactic or polyglycolic acid and their copolymers, denatured albumin, reticulated hemoglobin, and esters of polyglutamic and polyaspartic acids, said method comprising the step of forming the microvesicles in the presence of the gas mixture comprising a physiologically acceptable gas, selected from the group consisting of SF6, CF4, CBrF3, C4F8, CClF3, C2F6, C2ClF5, CBrClF2, C2Cl2F4 and C4F10, said microvesicles having resistance against collapse resulting, at least in part, from pressure increases effective when a suspension of said gas-filled microvesicles is injected into the bloodstream of a patient.
A method of making a contrast agent having resistance against collapse from pressure increases when used in ultrasonic echography, said contrast agent consisting of gas-filled microvesicles suspended in an aqueous liquid carrier phase, the microvesicles being microbubbles filled with a gas mixture wherein the gas mixture is bounded by a stabilizing layer of one or more film forming phospholipids in lamellar or laminar form at the gas/liquid interface, said method comprising the steps of:
- preforming the microvesicles or precursors thereof under an atmosphere of a first gas;
- and
- substantially substituting at least a fraction of said first gas with a second gas which is the gas mixture comprising a physiologically acceptable gas selected from the group consisting of SF6, CF4, CBrF3, C4F8, CClF3, C2F6, C2ClF5, CBrClF2, C2Cl2F4 and C4F10, said microvesicles having resistance against collapse resulting, at least in part, from pressure increases effective when a suspension of said gas-filled microvesicles is injected into the bloodstream of a patient.
A method of making a contrast agent having resistance against collapse from pressure increases when used in ultrasonic echography, said contrast agent consisting of gas-filled microvesicles suspended in an aqueous liquid carrier phase, the microvesicles being microballoons consisting of a physiologically acceptable gas bounded by an organic polymer envelope at the gas/liquid interface, said polymer envelope formed from one or more polymers selected from the group consisting of polylactic or polyglycolic acid and their copolymers, denatured albumin, reticulated hemoglobin, and esters of polyglutamic and polyaspartic acids, said method comprising the steps of:
- preforming the microvesicles or precursors thereof under an atmosphere of a first gas;
- and
- substantially substituting at least a fraction of said first gas with a second gas which is the physiologically acceptable gas selected from the group consisting of SF6, CF4, CBrF3, C4F8, CClF3, C2F6, C2ClF5, CBrClF2, C2Cl2F4 and C4F10, said microvesicles having resistance against collapse resulting, at least in part, from pressure increases effective when a suspension of said gas-filled microvesicles is injected into the bloodstream of a patient.
A method of making a contrast agent having resistance against collapse from pressure increases when used in ultrasonic echography, said contrast agent consisting of gas-filled microvesicles suspended in an aqueous liquid carrier phase, the microvesicles being microballoons consisting of a gas mixture bounded by an organic polymer envelope at the gas/liquid interface, said polymer envelope formed from one or more polymers selected from the group consisting of polylactic or polyglycolic acid and their copolymers, denatured albumin, reticulated hemoglobin, and esters of polyglutamic and polyaspartic acids, said method comprising the steps of
- preforming the microvesicles or precursors thereof under an atmosphere of a first gas;
- and
- substantially substituting at least a fraction of said first gas with a second gas which is the gas mixture comprising a physiologically acceptable gas selected from the group consisting of SF6, CF4, CBrF3, C4F8, CClF3, C2F6, C2ClF5, CBrClF2, C2Cl2F4 and C4F10, said microvesicles having resistance against collapse resulting, at least in part, from pressure increases effective when a suspension of said gas-filled microvesicles is injected into the bloodstream of a patient.
A method of making a contrast agent for ultrasonic echography which consists of gas-filled microbubbles suspended in an aqueous liquid carrier phase, the microbubbles having resistance against collapse resulting from pressure increases effective when the said suspension are injected into the bloodstream of a patient and the microbubbles being filled with a gas mixture wherein the gas mixture is bounded by a stabilizing layer of one or more film forming phospholipids in lamellar or laminar form at the gas/liquid interface, said method comprising the step of forming the microbubbles in the presence of the gas mixture comprising a physiologically acceptable gas selected from the group consisting of SF6, CF4, CBrF3, C4F8, CClF3, C2F6, C2ClF5, CBrClF2, C2Cl2F4 and C4F10, said gas or at least a gas in said gas mixture being such that, under standard conditions, the pressure difference ΔP between pressure at which the bubble counts are about 75% and 25% of the original bubbles count is at least 25 Torr.
A method of making a contrast agent for ultrasonic echography which consists of gas-filled microballoons suspended in an aqueous liquid carrier phase, the microballoons having resistance against collapse resulting from pressure increases effective when the said suspensions are injected into the bloodstream of a patient and the microballoons consisting of a physiologically acceptable gas bounded by an organic polymer envelope at the gas/liquid interface, said polymer envelope formed from one or more polymers selected from the group consisting of polylactic or polyglycolic acid and their copolymers, denatured albumin, reticulated hemoglobin, and esters of polyglutamic and polyaspartic acids, said method comprising the step of forming the microballoons in the presence of the physiologically acceptable gas selected from the group consisting of SF6, CF4, CBrF3, C4F8, CClF3, C2F6, C2ClF5, CBrClF2, C2Cl2F4 and C4F10, said gas or at least a gas in said gas mixture being such that, under standard conditions, the pressure difference ΔP between pressures at which the bubble counts are about 75% and 25% of the original bubble count is at least 25 Torr.
A method of making a contrast agent for ultrasonic echography which consists of gas-filled microballoons suspended in an aqueous liquid carrier phase, the microballoons having resistance against collapse resulting from pressure increases effective when the said suspensions are injected into the bloodstream of a patient and the microballoons consisting of a gas mixture bounded by an organic polymer envelope at the gas/liquid interface, said polymer envelope formed from one or more polymers selected from the group consisting of polylactic or polyglycolic acid and their copolymers, denatured albumin, reticulated hemoglobin, and esters of polyglutamic and polyaspartic acids, said method comprising the steps of forming the microballoons in the presence of the gas mixture comprising a physiologically acceptable gas selected from the group consisting of SF6, CF4, CBrF3, C4F8, CClF3, C2F6, C2ClF5, CBrClF2, C2Cl2F4 and C4F10, said gas or at least a gas in said gas mixture being such that, under standard conditions, the pressure difference ΔP between pressures at which the bubble counts are about 75% and 25% of the original bubble count is at least 25 Torr.
Dependencies are inferred from the claim text.