US20170312375A1 - Preparation of a lipid blend and a phospholipid suspension containing the lipid blend - Google Patents

Preparation of a lipid blend and a phospholipid suspension containing the lipid blend Download PDF

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US20170312375A1
US20170312375A1 US15/374,147 US201615374147A US2017312375A1 US 20170312375 A1 US20170312375 A1 US 20170312375A1 US 201615374147 A US201615374147 A US 201615374147A US 2017312375 A1 US2017312375 A1 US 2017312375A1
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lipid
process according
lipid blend
suspension
solution
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US15/374,147
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Poh K. Hui
John E. Bishop
Eleodoro S. Madrigal, Jr.
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Lantheus Medical Imaging Inc
ACP Lantern Acquisition Inc
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Lantheus Medical Imaging Inc
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Publication of US20170312375A1 publication Critical patent/US20170312375A1/en
Assigned to LANTHEUS MEDICAL IMAGING, INC. reassignment LANTHEUS MEDICAL IMAGING, INC. RELEASE BY SECURED PARTY (SEE DOCUMENT FOR DETAILS). Assignors: JPMORGAN CHASE BANK, N.A.
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00Preparations for testing in vivo
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00Preparations for testing in vivo
    • A61K49/22Echographic preparations; Ultrasound imaging preparations ; Optoacoustic imaging preparations
    • A61K49/222Echographic preparations; Ultrasound imaging preparations ; Optoacoustic imaging preparations characterised by a special physical form, e.g. emulsions, liposomes
    • A61K49/226Solutes, emulsions, suspensions, dispersions, semi-solid forms, e.g. hydrogels
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61BDIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B8/00Diagnosis using ultrasonic, sonic or infrasonic waves
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/44Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00Preparations for testing in vivo
    • A61K49/22Echographic preparations; Ultrasound imaging preparations ; Optoacoustic imaging preparations
    • A61K49/222Echographic preparations; Ultrasound imaging preparations ; Optoacoustic imaging preparations characterised by a special physical form, e.g. emulsions, liposomes
    • A61K49/227Liposomes, lipoprotein vesicles, e.g. LDL or HDL lipoproteins, micelles, e.g. phospholipidic or polymeric
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/10Dispersions; Emulsions
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/10Dispersions; Emulsions
    • A61K9/127Liposomes
    • A61K9/1277Processes for preparing; Proliposomes
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/24Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids

Definitions

  • the present invention relates generally to processes for the preparation of a lipid blend and a uniform filterable phospholipid suspension containing the lipid blend, such suspension being useful as an ultrasound contrast agent.
  • Manufacturing of a phospholipid contrast agent can be divided into the following steps: (1) preparation of lipid blend; (2) compounding the bulk solution, which involves the hydration and dispersion of the lipid blend in an essentially aqueous medium to produce a lipid suspension; (3) filtration of the bulk solution through a sterilizing filter(s) to render the suspension free of microbial contaminants; (4) dispensing the sterile suspension into individual vials in a controlled aseptic area; (5) loading the dispensed vials into a lyophilizer chamber to replace the vial headspace gas with perfluoropropane gas (PFP); (6) transferring the sealed vials after gas exchange to an autoclave for terminal sterilization.
  • PFP perfluoropropane gas
  • Phospholipid blends are typically produced by dissolving or suspending the required lipids in an appropriate aqueous or non-aqueous solvent system, and then reducing the volume either by lyophilization or distillation. Ideally, this process produces blended solids with high content uniformity and purity. However, while working well on a small, laboratory scale, this simple approach is frequently problematic upon scale-up to production-size quantities. Difficulties include: (1) maintaining content uniformity during the solvent removal step (due to differential solubilities); (2) maintaining purity (frequently a problem when water is used due to hydrolytic side-reactions); (3) enhancing purity; (4) minimizing solvent volume; and (5) recovery of the final solids (e.g., it is not practical to scrape solids out of a large reactor).
  • lipids are hydrophobic and are not readily soluble in water
  • adding phospholipids or a lipid blend directly into an aqueous solution causes the lipid powder to aggregate forming clumps that are very difficult to disperse.
  • the hydration process cannot be controlled within a reasonable process time.
  • Direct hydration of phospholipids or a lipid blend in an aqueous medium produces a cloudy suspension with particles ranging from 0.6 ⁇ m to to 100 ⁇ m. Due to relatively large particle size distribution, the suspension cannot be filtered at ambient temperature when the suspension solution temperature is below the gel-to-liquid crystal phase transition temperatures of lipids.
  • the lipids would accumulate in the filters causing a restriction in the flow rate, and in most cases, the filters would be completely blocked shortly after. Further reduction in the suspension particle size cannot be achieved through a conventional batching process, even after extended mixing (e.g., 6 hours) at elevated temperatures (e.g., 40° C. to 80° C.) with a commonly used marine propeller.
  • concentrations of the sterile filtrate would have variable lipid content from batch to batch depending on how the lipids are initially hydrated which is in turn determined by the physical characteristics, e.g., morphology, of the starting materials.
  • the presently claimed processes for manufacture of a lipid blend and the subsequent phospholipid suspension are aimed at solving the above issues by providing a practical process that can be easily scaled and adopted to various manufacturing facilities without extensive modification or customization of existing equipment.
  • one object of the present invention is to provide a novel process for preparing a lipid blend.
  • Another object of the present invention is to provide a novel process for preparing a phospholipid suspension from the lipid blend.
  • the present invention provides a novel process for preparing a phospholipid suspension, comprising:
  • step (2) contacting the solution from step (1) with an aqueous solution to form a lipid suspension.
  • the non-aqueous solvent is selected from propylene glycol, ethylene glycol, and polyethylene glycol 300.
  • the non-aqueous solvent is propylene glycol.
  • the lipid blend comprises:
  • the non-aqueous solvent in step (1), is heated to a temperature of about 30 to 70° C. prior to contacting with the lipid blend.
  • the non-aqueous solvent is heated to a temperature of about 50 to 55° C. prior to contacting with the lipid blend.
  • the ratio of lipid blend to non-aqueous solvent is from about 5 mg of lipid blend per mL of non-aqueous solvent to about 15 mg/mL.
  • the ratio of lipid blend to non-aqueous solvent is about 10 mg/mL.
  • the aqueous solution in step (2), is selected from water, saline, a saline/glycerin mixture, and a saline/glycerin/non-aqueous solvent mixture.
  • the aqueous solution is a saline and glycerin mixture.
  • the aqueous solution is a saline, glycerin, and propylene glycol mixture.
  • step (2) the aqueous solution is heated to a temperature of about 45 to 60° C. prior to contacting with the solution from step (1).
  • step (3) the aqueous solution is heated to a temperature of about 50 to 55° C. prior to contacting with the solution from step (1).
  • the process further comprises:
  • step (3) heating the lipid suspension from step (2) to a temperature about equal to or above the highest gel to liquid crystalline phase transition temperature of the lipids present in the suspension.
  • step (3) the lipid suspension is heated to a temperature of at least about 67° C.
  • the process further comprises:
  • step (4) the filtration is performed using two sterilizing filter cartridges.
  • the sterilizing filter cartridges are at a temperature of from about 70 to 80° C.
  • step (4) 0.2 ⁇ m hydrophilic filters are used.
  • the process further comprises:
  • step (4) dispensing the filtered solution from step (4) into a vial.
  • the process further comprises:
  • step (6) exchanging the headspace gas of the vial from step (5) with a perfluorocarbon gas.
  • the perfluorocarbon gas is perfluoropropane.
  • exchange of headspace gas is performed using a lyophilizing chamber.
  • the process further comprises:
  • step (7) the vial is sterilized at about 126-130° C. for 1 to 10 minutes.
  • step (7) the vial is sterilized at about 126-130° C. for 1 to 10 minutes.
  • step (a) the lipids are:
  • the first non-aqueous solvent is a mixture of methanol and toluene.
  • the second non-aqueous solvent is a methyl t-butyl ether.
  • the solution is warmed to a temperature sufficient to complete dissolution of the lipids into the solvent.
  • the solution is warmed to about 25 to 75° C.
  • the solids collected are washed with methyl t-butyl ether and dried in vacuo.
  • the present invention provides a novel phospholipid suspension, comprising:
  • suspension is prepared by the process, comprising:
  • step (2) contacting the solution from step (1) with an aqueous solution to form a lipid suspension
  • step (3) heating the lipid suspension from step (2) to a temperature about equal to or above the highest gel to liquid crystalline phase transition temperature of the lipids present in the suspension;
  • the lipid blend comprises:
  • the non-aqueous solvent is heated to a temperature of about 50 to 55° C. prior to contacting with the lipid blend.
  • the ratio of lipid blend to non-aqueous solvent is about 10 mg/mL.
  • the aqueous solution is a saline, glycerin, and propylene glycol mixture.
  • 0.75 mg/mL of lipid blend are present.
  • the aqueous solution is heated to a temperature of about 50 to 55° C. prior to contacting with the solution from step (1).
  • the lipid suspension is heated to a temperature of at least about 67° C.
  • two 0.2 ⁇ m hydrophilic filters are used.
  • Multigram scale is preferably the scale wherein at least one starting material is present in 10 grams or more, more preferably at least 50 grams or more, even more preferably at least 100 grams or more.
  • Multikilogram scale is intended to mean the scale wherein more than one kilogram of at least one starting material is used.
  • Industrial scale as used herein is intended to mean a scale which is other than a laboratory scale and which is sufficient to supply product sufficient for either clinical tests or distribution to consumers.
  • Lipid blend or phospholipid blend is intended to represent two or more lipids which have been blended.
  • the lipid blend is generally in a powder form.
  • at least one of the lipids is a phospholipid.
  • the lipid blend contains 1,2-dipalmitoyl-sn-glycero-3-phosphatidylcholine (DPPC), 1,2-dipalmitoyl-sn-glycero-3-phosphotidic, mono sodium salt (DPPA), and N-(methoxypolyethylene glycol 5000 carbamoyl)-1,2-dipalmitoyl-sn-glycero-3-phosphatidylethanolamine, monosodium salt (MPEG5000-DPPE).
  • DPPC 1,2-dipalmitoyl-sn-glycero-3-phosphatidylcholine
  • DPPA 1,2-dipalmitoyl-sn-glycero-3-phosphotidic, mono sodium salt
  • MPEG5000-DPPE monosodium salt
  • each lipid present in the blend will depend on the desired end product. Preferred ratios of each lipid are described in the Examples section. A wide variety of other lipids, like those described in Unger et al, U.S. Pat. No. 5,469,854, the contents of which are hereby incorporated by reference, may be used in the present process.
  • Phospholipid as used herein, is a fatty substance containing an oily (hydrophobic) hydrocarbon chain(s) with a polar (hydrophilic) phosphoric head group. Phospholipids are amphiphilic. They spontaneously form boundaries and closed vesicles in aqueous media. Phospholipids constitute about 50% of the mass of animal cell plasma membrane.
  • the lipid blend may be prepared via an aqueous suspension-lyophilization process or an organic solvent dissolution-precipitation process using organic solvents.
  • the desired lipids are suspended in water at an elevated temperature and then concentrated by lyophilization.
  • a dissolution procedure is used.
  • the organic solvent dissolution-precipitation procedure involves contacting the desired lipids (e.g., DPPA, DPPC, and MPEG5000 DPPE) with a first non-aqueous solvent system.
  • This system is typically a combination of solvents, for example CHCl 3 /MeOH, CH 2 Cl 2 /MeOH, and toluene/MeOH.
  • the first non-aqueous solvent is a mixture of toluene and methanol. It may be desirable to warm the lipid solution to a temperature sufficient to achieve complete dissolution. Such a temperature is preferably about 25 to 75° C., more preferably about 35 to 65° C.
  • filtration After dissolution, it may be desired to remove undissolved foreign matter by hot-filtration or cooling to room temperature and then filtering.
  • Known methods of filtration may be used (e.g., gravity filtration, vacuum filtration, or pressure filtration).
  • the solution is then concentrated to a thick gel/semisolid. Concentration is preferably done by vacuum distillation. Other methods of concentrating the solution, such as rotary evaporation, may also be used.
  • the temperature of this step is preferably about 20 to 60° C., more preferably 30 to 50° C.
  • the thick gel/semisolid is then dispersed in a second non-aqueous solvent.
  • the mixture is slurried, preferably near ambient temperature (e.g., 15-30° C.).
  • Useful second non-aqueous solvents are those that cause the lipids to precipitate from the filtered solution.
  • the second non-aqueous solvent is preferably methyl t-butyl ether (MTBE). Other ethers and alcohols may be used.
  • the solids produced upon addition of the second non-aqueous solvent are then collected.
  • the collected solids are washed with another portion of the second non-aqueous solvent (e.g., MTBE).
  • Collection may be performed via vacuum filtration or centrifugation, preferably at ambient temperature. After collection, it is preferred that the solids are dried in vacuo at a temperature of about 20-60° C.
  • the MTBE precipitation also allows for the removal of any MTBE-soluble impurities, which go into the filtrate waste-stream. This potential for impurity removal is not realized when a solution is directly concentrated or lyophilized to a solid.
  • a lipid blend is contacted with a non-aqueous solvent, whereby the lipid blend substantially dissolves in the non-aqueous solvent.
  • the individual lipids may be contacted with the non-aqueous solvent sequentially in the order: DPPC, DPPA, and MPEG5000-DPPE; DPPC, MPEG5000-DPPE, and DPPA; MPEG5000-DPPE, DPPA, and DPPC; or MPEG5000-DPPE, DPPC, and DPPA.
  • the DPPA being the least soluble and least abundant of the lipids is not added first. Adding one of the other lipids prior to or concurrently with adding the DPPA facilitates dissolution of the DPPA.
  • the individual lipids can be combined in their solid forms and the combination of the solids contacted with the non-aqueous solvent.
  • Substantial dissolution is generally indicated when the mixture of lipid blend and non-aqueous solvent becomes clear.
  • phospholipids are generally not water soluble.
  • direct introduction of a blend of phospholipid blend into an aqueous environment causes the lipid blend to aggregate forming clumps that are very difficult to disperse.
  • the present invention overcomes this limitation by dissolving the lipid blend in a non-aqueous solvent prior to introduction of the aqueous solution. This allows one to evenly disperse the lipid blend into a liquid. The liquid dispersion can then be introduced into a desired aqueous environment.
  • Non-aqueous is intended to mean a solvent or mixture of solvents wherein the amount of water present is sufficiently low as to not impede dissolution of the lipid blend.
  • the amount of non-aqueous solvent required will depend on the solubility of the lipid blend and also the final desired concentration of each component. As one of ordinary skill would appreciate, the level of water present in the non-aqueous solvent, which may be tolerated will vary based on the water solubilities of the individual lipids in the lipid blend. The more water soluble the individual phospholipids, the more water which may be present in step (1).
  • propylene glycol is used as the non-aqueous solvent.
  • other members of the polyol family such as ethylene glycol, and polyethylene glycol 300 may be used.
  • the temperature at which step (1) may be performed can range from ambient to the boiling point of the chosen solvent. Preferably the temperature is from about 30 to about 70° C., more preferably about 45 to about 60° C., and even more preferably about 50, 51, 52, 53, 54, or 55° C. When ethylene glycol or polyethylene glycol 300 is used, it is preferred that the temperature be from about 50 to about 60° C. and more preferably about 55° C. Maintaining the solution at an elevated temperature should reduce solution viscosity and ease formulation preparation.
  • a preferred procedure for dissolving the lipid blend is as follows: (a) Add propylene glycol to an appropriate weighing container. (b) Warm the propylene glycol to about 40-80° C. in a heating bath. (c) Weigh the lipid blend into a separate container. (d) When the propylene glycol has reached the desired temperature range, transfer the solution into the container containing the lipid blend. (e) Place the container back into the heating bath until the solution is clear. (f) Mechanically mix the Lipid Blend/Propylene Glycol solution to further assure complete dissolution and uniform dispersion of the lipid blend.
  • the ratio of lipid blend to non-aqueous solvent will, of course, be limited by the solubility of the lipid blend. This ratio will also be influenced by the desired amount of lipid blend in the final formulation. Preferably, the ratio is from about 1 mg of lipid blend per mL of solvent (mg/mL) to about 100 mg/mL. More preferably, the lipid blend is present in about 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 mg/mL. Even more preferably, the lipid blend is present in about 10 mg/mL.
  • the second step involves contacting the solution from step (1) with an aqueous solution to form a lipid suspension.
  • the aqueous solution can be water, saline, a saline/glycerin mixture or a saline/glycerin/non-aqueous solvent mixture.
  • Non-aqueous solvent is as defined previously, preferably propylene glycol.
  • Suspension as used herein, is intended to indicate a dispersion in which insoluble particles are dispersed in a liquid medium.
  • the resulting solution can then be introduced to an aqueous solution.
  • the aqueous solution may contain one or more components selected from sodium chloride, glycerin, and a non-aqueous solvent.
  • the aqueous solution contains glycerin and sodium chloride.
  • a sufficient amount of propylene glycol is present in the aqueous solution, prior to addition of the solution from step 1, in order to achieve the final desired concentration of propylene glycol.
  • the lipid-blend solution is added to water, which may already contain the above-noted additional components. Additional desired components can then be added. It is more preferred that the lipid-blend solution is added a solution of water and sodium chloride (i.e., saline). It is further preferred that the lipid-blend solution is added a solution of water, sodium chloride, and glycerin. It is still further preferred that the lipid-blend solution is added a solution of water, sodium chloride, glycerin, and propylene glycol.
  • sodium chloride i.e., saline
  • the lipid-blend solution is added a solution of water, sodium chloride, and glycerin. It is still further preferred that the lipid-blend solution is added a solution of water, sodium chloride, glycerin, and propylene glycol.
  • 0.1 mg of NaCl are present per mL of formulation.
  • 0.1 mL of Glycerin per mL of formulation is present.
  • a final concentration of 0.1 mL of Propylene Glycol per mL of formulation is preferred.
  • the final pH of the formulation is preferably about 5.5-7.0.
  • the lipid blend is preferably present in an amount of 0.75-1.0 mg/mL of formulation.
  • the temperature of the aqueous solution can range from ambient to 70° C. Preferably, the temperature is about 45 to 60° C., with 50, 51, 52, 53, 54, or 55 being even more preferred.
  • the mixture will need to be agitated, preferably stirred.
  • the pH of the solution may need to be adjusted, depending on the desired final formulation. Either acid (e.g., HCl) or base (e.g., NaOH) can be added to make such an adjustment.
  • the lipid suspension will contain liquid particles of varying sizes.
  • One of the benefits of the present invention is the ability to consistently obtain small particles of a nearly uniform size. Thus, it is preferred that the majority of particles obtained are less than 100 nm in diameter, more preferable less than 50 nm.
  • a preferred procedure for dissolving the lipid blend is as follows: (a) Add Water for Injection (WFI) into a compounding vessel. (b) Start mixing and ensure temperature is from 50-55° C. (c) Add sodium chloride to the compounding vessel. Wait until the solid has completely dissolved before proceeding to the next step. (d) Add glycerin to the compounding vessel. Allow sufficient time for complete mixing. (e) Add the remaining Propylene Glycol that is not in the Lipid Blend/Propylene Glycol solution. Allow time for thorough mixing. (f) Reduce mixing rate to reduce turbulence in the compounding vessel. (g) Add the Lipid Blend/Propylene Glycol solution to the compounding vessel. (h) Readjust mixing to original rate. (i) Add additional WFI if necessary. (j) Continue to mix for approximately 25 minutes and assure complete mixing. (k) Verify and adjust the solution to target pH.
  • WFI Water for Injection
  • Step three involves heating the lipid suspension obtained from step (2) to a temperature about equal to or above the highest gel to liquid crystalline phase transition temperature of the lipids present in the solution.
  • One of the objects of this step is to provide a filterable suspension.
  • a solution/suspension is considered filterable if there is no significant reduction in flow rate within a normal process, and there is no significant increase in the pressure drop in the filtration system.
  • DPPC and DPPA show phase transitions of 41° C. and 67° C. respectively.
  • MPEG5000-DPPE is soluble in water, therefore it does not exhibit a gel-liquid crystal phase transition which is characteristic of most hydrated lipid suspensions.
  • the highest phase transition temperature, 67° C. is preferably used to filter the solution. By maintaining temperature at or beyond 67° C., all the lipids are beyond their respective phase transition, assuring the loose configuration while passing through the filters.
  • Heating may be achieved by jacketing the compounding vessel with a heat exchanging coil.
  • Hot water/steam from a controlled source e.g., a hot water bath, or a water heater, would deliver sufficient heat to maintain the compounding solution at a set temperature.
  • Other heat sources known to those of skill in the art could also be used.
  • Step four is performed by filtering the lipid suspension through a sterilizing filter.
  • the purpose behind this step being to provide a substantially bacteria-free suspension.
  • a filtrate is considered substantially bacteria-free when the probability of the filtrate to contain at least one colony forming microorganism is less than 10 ⁇ 6 .
  • Filtration is preferably done using sterilizing filter cartridges. Also, a means of forcing the solution through the filters may be required (e.g., pumping or pressurizing). Since the solution being filtered needs to be maintained at a temperature at or above the highest gel to liquid crystalline phase transition temperature of the lipids present in the solution, the filtration should be performed at about this same temperature.
  • the filter e.g., sterilizing filter cartridges
  • the filter are preferably enclosed in jacketed filter housings which are continuously heated, e.g., by a hot water stream from a temperature controlled water bath, to ensure that the suspension is above the lipid phase transition temperatures.
  • the temperature of the sterilizing filter is preferably from 50 to 100° C., more preferably from 60 to 90° C., and even more preferably 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, or 80° C.
  • One or more sterilizing filters may be used to filter the suspension.
  • the required number will be based on their effectiveness at removing bacteria. It is preferred that two filters are used.
  • the size of the filter pores will be limited by the need to provide a bacteria-free suspension. Preferably, 0.2 ⁇ m hydrophilic filters are used.
  • a bulk solution of the preferred formulation was continuously filtered through two 0.2 ⁇ m hydrophilic filters for up to 3 hours at a rate of approximately 1 liter per minute (1 L/min.), i.e., passing a total of 180 liters of the suspension solution through the filters.
  • the experimental results shows that there is no apparent blockage of filters. Lipid assays indicates that there is no measurable loss during the filtration process (due to accumulation in the filter medium).
  • a bulk solution of the preferred formulation was compounded at 40° C.-80° C., and the suspension was cooled to ambient temperature prior to sterile filtration. No apparent clogging of the filters were observed indicating the suspension particle size distribution is well below 0.2 ⁇ m of the filter pore size. It is desirable to use heat during filtration in order to ensure maximum recover of the lipid blend in the sterile filtrate (i.e., to minimize potential retention of lipid particles in the filter medium).
  • a preferred procedure for filtering the lipid suspension is as follows: (a) Assure all jacketed filters are at 70° C.-80° C. (b) Assure all valves in the filtration unit are closed. (c) Connect filtration inlet hose to the outlet of the compounding vessel. (d) Open valves to allow solution to pass through the filters. (e) Flush three liters of solution through the filters before collecting filtrate. (f) Continue filtration until complete.
  • Dispensing the filtered solution into a vial completes step five. Preferably, this step is performed in a controlled aseptic area.
  • this step is performed in a controlled aseptic area.
  • the vial selected and amount of suspension delivered to the vial would depend on the end use considered for the lipid suspension.
  • Dispensing can be achieved via a variety of methods, including pipette, hand-held syringe dispenser (e.g., Filamatic® syringe dispensing machine), or industrial auto dispensing machine (e.g., Cozzoli or TL auto filling machine).
  • Step six is performed by exchanging the headspace gas of the vials from step five with a perfluorocarbon gas.
  • a preferred method of exchange is to load the dispensed vials into a lyophilizer chamber and replace the vial headspace gas with a perfluorocarbon gas.
  • a preferred gas is perfluoropropane (PFP).
  • PFP perfluoropropane
  • the vials are sealed at the completion of the vial headspace gas exchange cycle.
  • the lyophilizer chamber pressure is brought back to atmospheric pressure by charging into the chamber with PFP.
  • Vial stoppers are seated to seal the vials.
  • Step seven involves terminally sterilizing a vial after step six.
  • One method of terminal sterilization is through the use of an autoclave.
  • the sealed vials can be terminally sterilized in a steam sterilizer to further enhance the sterility assurance of the product. Care must be taken in the sterilization process as some degradation of lipids may be observed as a result of autoclaving.
  • the vial is sterilized at about 126-130° C. for 1 to 10 minutes.
  • Lipid Blend Target Composition Lipid Name Common Name Wt % Mole % DPPA 1,2-dipalmitoyl-sn- 6.0 10 glycero-3- phosphatidic acid, monosodium salt DPPC 1,2-dipalmitoyl-sn- 53.5 82 glycero-3- phosphatidylcholine MPEG5000 N-(methoxypolyethylene 40.5 8 DPPE glycol 5000 carbamoyl)-1,2- dipalmitoyl-sn-glycero-3- phosphatidylethanola mine, monosodium salt
  • a flask is charged with toluene (3.3 L), methanol (1.2 L), DPPA (59.6 g), DPPC (535 g), and MPEG5000 DPPE (405 g). After rinsing solid contact surfaces with 0.9 L methanol, the slurry is warmed to 45-55° C. until dissolution is complete.
  • the solution is filtered and then concentrated in vacuo at 35-45° C. to a thick gel.
  • Methyl t-butyl ether (MTBE, 5.4 L) is added and the mixture is slurried at 15-30° C.
  • White solids are collected by centrifugation or vacuum filtration, and washed with MTBE (0.9 L). The solids are then placed in a vacuum oven and dried to constant weight at 40-50° C.
  • the dried Lipid Blend is transferred to a bottle and stored at ⁇ 15 to ⁇ 25° C.
  • Phospholipid quantities were adjusted for purity based on a “Use As” value from the certificates of analysis.
  • the batch size (combined phospholipid weight) of this experiment was 2 kg.
  • a rotary evaporation flask is charged sequentially with toluene (3,300 mL), methanol (1,200 mL), DPPA (122.9 g; corrected for “use as” purity of 97.0%), DPPC (1,098.5 g total; 500.8 g from a lot with 98.4% “use as” purity and 597.7 g from a lot with 96.7% “use as” purity), and MPEG5000 DPPE (815.7 g; corrected for “use as” purity of 99.3%).
  • the flask After rinsing residual solids into the flask with methanol (900 mL), the flask is placed on a rotary evaporator (no vacuum) and the slurry is warmed to between 45 and 55° C. (external). After dissolution is complete, the external temperature is reduced to between 35 and 45° C., a vacuum is applied, and the solution is concentrated to a white semi-solid. The flask is removed from the evaporator and solids are broken up with a spatula. The flask is reapplied to the evaporator and concentration is continued.
  • methanol 900 mL
  • MTBE (5,400 mL) is added through the rotary evaporator's addition tube, the vacuum is discontinued, and the mixture is slurried for 15 to 45 min at 15 to 30° C. Solids are isolated by either centrifugal or vacuum filtration, rinsed with MTBE (3,800 mL), and dried to constant weight in a vacuum oven (40 to 50° C.). Prior to transferring to polyethylene bottles with polypropylene caps, solids are delumped through a screen (0.079 inch mesh), affording 1,966.7 g (98%) of lipid blend (SG896) as a white solid.
  • the preferred lipid suspension contains:
  • the finished product fill volume can be from 1.0-2.0 mL/vial.
  • the filtrates have less lipids as compared to the pre-filtration bulk solution.
  • the loss of lipids varies from 12% to 48%.
  • the presently claimed process is useful for preparing ultrasound contrast agents. Such agents should be useful for a variety of imaging applications, including enhancing contrast in echocardiographic and radiologic ultrasound images.

Abstract

The present invention describes processes for the preparation of a lipid blend and a uniform filterable phospholipid suspension containing the lipid blend, such suspension being useful as an ultrasound contrast agent.

Description

    FIELD OF THE INVENTION
  • The present invention relates generally to processes for the preparation of a lipid blend and a uniform filterable phospholipid suspension containing the lipid blend, such suspension being useful as an ultrasound contrast agent.
  • BACKGROUND OF THE INVENTION
  • Manufacturing of a phospholipid contrast agent can be divided into the following steps: (1) preparation of lipid blend; (2) compounding the bulk solution, which involves the hydration and dispersion of the lipid blend in an essentially aqueous medium to produce a lipid suspension; (3) filtration of the bulk solution through a sterilizing filter(s) to render the suspension free of microbial contaminants; (4) dispensing the sterile suspension into individual vials in a controlled aseptic area; (5) loading the dispensed vials into a lyophilizer chamber to replace the vial headspace gas with perfluoropropane gas (PFP); (6) transferring the sealed vials after gas exchange to an autoclave for terminal sterilization. There are three major obstacles in this process: (1) uniformity of the lipid blend; (2) hydration of the lipid blend; (3) uniformity and particle size of the suspension; and, (4) sterile filtration of the suspension through a sterilizing filter(s).
  • Phospholipid blends are typically produced by dissolving or suspending the required lipids in an appropriate aqueous or non-aqueous solvent system, and then reducing the volume either by lyophilization or distillation. Ideally, this process produces blended solids with high content uniformity and purity. However, while working well on a small, laboratory scale, this simple approach is frequently problematic upon scale-up to production-size quantities. Difficulties include: (1) maintaining content uniformity during the solvent removal step (due to differential solubilities); (2) maintaining purity (frequently a problem when water is used due to hydrolytic side-reactions); (3) enhancing purity; (4) minimizing solvent volume; and (5) recovery of the final solids (e.g., it is not practical to scrape solids out of a large reactor).
  • After manufacture of a lipid blend, final compounding typically involves introduction of the blend into an aqueous medium. Since phospholipids are hydrophobic and are not readily soluble in water, adding phospholipids or a lipid blend directly into an aqueous solution causes the lipid powder to aggregate forming clumps that are very difficult to disperse. Thus, the hydration process cannot be controlled within a reasonable process time. Direct hydration of phospholipids or a lipid blend in an aqueous medium produces a cloudy suspension with particles ranging from 0.6 μm to to 100 μm. Due to relatively large particle size distribution, the suspension cannot be filtered at ambient temperature when the suspension solution temperature is below the gel-to-liquid crystal phase transition temperatures of lipids. The lipids would accumulate in the filters causing a restriction in the flow rate, and in most cases, the filters would be completely blocked shortly after. Further reduction in the suspension particle size cannot be achieved through a conventional batching process, even after extended mixing (e.g., 6 hours) at elevated temperatures (e.g., 40° C. to 80° C.) with a commonly used marine propeller.
  • Although filtration at elevated temperatures, i.e., at above the phase transition temperatures of lipids, is possible, a significant amount of larger lipid particles would still be excluded when a normal filtering pressure is used. In turn, concentrations of the sterile filtrate would have variable lipid content from batch to batch depending on how the lipids are initially hydrated which is in turn determined by the physical characteristics, e.g., morphology, of the starting materials.
  • The process of directly hydrating the lipids or lipid blend to produce a uniform suspension and filtration of the suspension through a sterilization filter(s) can be difficult and costly to be scaled-up to any reasonable commercial scale, e.g., >20 L.
  • Thus, the presently claimed processes for manufacture of a lipid blend and the subsequent phospholipid suspension are aimed at solving the above issues by providing a practical process that can be easily scaled and adopted to various manufacturing facilities without extensive modification or customization of existing equipment.
  • SUMMARY OF THE INVENTION
  • Accordingly, one object of the present invention is to provide a novel process for preparing a lipid blend.
  • Another object of the present invention is to provide a novel process for preparing a phospholipid suspension from the lipid blend.
  • These and other objects, which will become apparent during the following detailed description, have been achieved by the inventors' discovery that dissolving a lipid blend in a suitable non-aqueous solvent prior to introduction of an aqueous solution allows for production of a phospholipid suspension.
  • DETAILED DESCRIPTION OF THE INVENTION
  • [1] Thus, in a first embodiment, the present invention provides a novel process for preparing a phospholipid suspension, comprising:
  • (1) contacting a lipid blend with a non-aqueous solvent, whereby the lipid blend substantially dissolves in the non-aqueous solvent; and,
  • (2) contacting the solution from step (1) with an aqueous solution to form a lipid suspension.
  • [2] In a preferred embodiment, the non-aqueous solvent is selected from propylene glycol, ethylene glycol, and polyethylene glycol 300.
    [3] In a more preferred embodiment, the non-aqueous solvent is propylene glycol.
    [4] In another preferred embodiment, the lipid blend, comprises:
  • (a) 1,2-dipalmitoyl-sn-glycero-3-phosphatidylcholine;
  • (b) 1,2-dipalmitoyl-sn-glycero-3-phosphotidic, mono sodium salt; and,
  • (c) N-(methoxypolyethylene glycol 5000 carbamoyl)-1,2-dipalmitoyl-sn-glycero-3-phosphatidylethanolamine, mono sodium salt.
  • [5] In another preferred embodiment, in step (1), the non-aqueous solvent is heated to a temperature of about 30 to 70° C. prior to contacting with the lipid blend.
    [6] In another more preferred embodiment, the non-aqueous solvent is heated to a temperature of about 50 to 55° C. prior to contacting with the lipid blend.
    [7] In another preferred embodiment, the ratio of lipid blend to non-aqueous solvent is from about 5 mg of lipid blend per mL of non-aqueous solvent to about 15 mg/mL.
    [8] In another more preferred embodiment, the ratio of lipid blend to non-aqueous solvent is about 10 mg/mL.
    [9] In another preferred embodiment, in step (2), the aqueous solution is selected from water, saline, a saline/glycerin mixture, and a saline/glycerin/non-aqueous solvent mixture.
    [10] In another more preferred embodiment, the aqueous solution is a saline and glycerin mixture.
    [11] In another more preferred embodiment, the aqueous solution is a saline, glycerin, and propylene glycol mixture.
    [12] In another more preferred embodiment, 6.8 mg/mL of sodium chloride are present, 0.1 mL/mL of glycerin are present, 0.1 mL/mL of propylene glycol are present, and about 0.75 to 1.0 mg/mL of the lipid blend are present.
    [13] In an even more preferred embodiment, 0.75 mg/mL of lipid blend are present.
    [14] In another more preferred embodiment, 1.0 mg/mL of lipid blend are present.
    [15] In another preferred embodiment, in step (2), the aqueous solution is heated to a temperature of about 45 to 60° C. prior to contacting with the solution from step (1).
    [16] In another more preferred embodiment, the aqueous solution is heated to a temperature of about 50 to 55° C. prior to contacting with the solution from step (1).
    [17] In another preferred embodiment, the process further comprises:
  • (3) heating the lipid suspension from step (2) to a temperature about equal to or above the highest gel to liquid crystalline phase transition temperature of the lipids present in the suspension.
  • [18] In another more preferred embodiment, in step (3), the lipid suspension is heated to a temperature of at least about 67° C.
    [19] In another more preferred embodiment, the process further comprises:
  • (4) filtering the lipid suspension through a sterilizing filter.
  • [20] In another even more preferred embodiment, in step (4), the filtration is performed using two sterilizing filter cartridges.
    [21] In a further preferred embodiment, in step (4), the sterilizing filter cartridges are at a temperature of from about 70 to 80° C.
    [22] In another further preferred embodiment, in step (4), 0.2 μm hydrophilic filters are used.
    [23] In another even more preferred embodiment, the process further comprises:
  • (5) dispensing the filtered solution from step (4) into a vial.
  • [24] In another further preferred embodiment, the process further comprises:
  • (6) exchanging the headspace gas of the vial from step (5) with a perfluorocarbon gas.
  • [25] In another even further preferred embodiment, the perfluorocarbon gas is perfluoropropane.
    [26] In another even further preferred embodiment, exchange of headspace gas is performed using a lyophilizing chamber.
    [27] In another even further preferred embodiment, the process further comprises:
  • (7) sterilizing the vial from step (6).
  • [28] In a still further preferred embodiment, in step (7), the vial is sterilized at about 126-130° C. for 1 to 10 minutes.
    [29] In a second embodiment, the present invention provides a novel process for preparing a lipid blend, comprising:
  • (a) contacting at least two lipids with a first non-aqueous solvent;
  • (b) concentrating the solution to a thick gel;
  • (c) contacting the thick gel with a second non-aqueous solvent; and,
  • (d) collecting the resulting solids.
  • [30] In a preferred embodiment, in step (a), the lipids are:
  • (i) 1,2-dipalmitoyl-sn-glycero-3-phosphatidylcholine;
  • (ii) 1,2-dipalmitoyl-sn-glycero-3-phosphotidic, mono sodium salt; and,
  • (iii) N-(methoxypolyethylene glycol 5000 carbamoyl)-1,2-dipalmitoyl-sn-glycero-3-phosphatidylethanolamine, mono sodium salt.
  • [31] In another preferred embodiment, in step (a), the first non-aqueous solvent is a mixture of methanol and toluene.
    [32] In another preferred embodiment, in step (c), the second non-aqueous solvent is a methyl t-butyl ether.
    [33] In another preferred embodiment, in step (a), the solution is warmed to a temperature sufficient to complete dissolution of the lipids into the solvent.
    [34] In another more preferred embodiment, in step (a), the solution is warmed to about 25 to 75° C.
    [35] In another preferred embodiment, in step (d), the solids collected are washed with methyl t-butyl ether and dried in vacuo.
    [36] In a third embodiment, the present invention provides a novel phospholipid suspension, comprising:
  • (a) a lipid blend in an amount of about 0.75-1.0 mg/mL of suspension;
  • (b) sodium chloride in an amount of about 6.8 mg/mL of suspension;
  • (c) glycerin in an amount of about 0.1 mL/mL of suspension;
  • (d) propylene glycol in an amount of about 0.1 mL/mL of suspension; and
  • (e) water;
  • wherein the suspension is prepared by the process, comprising:
  • (1) contacting a lipid blend with a non-aqueous solvent, whereby the lipid blend substantially dissolves in the non-aqueous solvent;
  • (2) contacting the solution from step (1) with an aqueous solution to form a lipid suspension;
  • (3) heating the lipid suspension from step (2) to a temperature about equal to or above the highest gel to liquid crystalline phase transition temperature of the lipids present in the suspension; and,
  • (4) filtering the lipid suspension through a sterilizing filter.
  • [37] In another preferred embodiment, the lipid blend, comprises:
  • (a) 1,2-dipalmitoyl-sn-glycero-3-phosphatidylcholine;
  • (b) 1,2-dipalmitoyl-sn-glycero-3-phosphotidic, mono sodium salt; and,
  • (c) N-(methoxypolyethylene glycol 5000 carbamoyl)-1,2-dipalmitoyl-sn-glycero-3-phosphatidylethanolamine, mono sodium salt.
  • [38] In another more preferred embodiment, the non-aqueous solvent is heated to a temperature of about 50 to 55° C. prior to contacting with the lipid blend.
    [39] In another more preferred embodiment, the ratio of lipid blend to non-aqueous solvent is about 10 mg/mL.
    [40] In another more preferred embodiment, the aqueous solution is a saline, glycerin, and propylene glycol mixture.
    [41] In an ever more preferred embodiment, 0.75 mg/mL of lipid blend are present.
    [42] In another more preferred embodiment, the aqueous solution is heated to a temperature of about 50 to 55° C. prior to contacting with the solution from step (1).
    [43] In another more preferred embodiment, in step (3), the lipid suspension is heated to a temperature of at least about 67° C.
    [44] In another further preferred embodiment, in step (4), two 0.2 μm hydrophilic filters are used.
  • Formulation
  • The present invention is contemplated to be practiced on at least a multigram scale, kilogram scale, multikilogram scale, or industrial scale. Multigram scale, as used herein, is preferably the scale wherein at least one starting material is present in 10 grams or more, more preferably at least 50 grams or more, even more preferably at least 100 grams or more. Multikilogram scale, as used herein, is intended to mean the scale wherein more than one kilogram of at least one starting material is used. Industrial scale as used herein is intended to mean a scale which is other than a laboratory scale and which is sufficient to supply product sufficient for either clinical tests or distribution to consumers.
  • Lipid blend or phospholipid blend, as used herein, is intended to represent two or more lipids which have been blended. The lipid blend is generally in a powder form. Preferably, at least one of the lipids is a phospholipid. Preferably, the lipid blend contains 1,2-dipalmitoyl-sn-glycero-3-phosphatidylcholine (DPPC), 1,2-dipalmitoyl-sn-glycero-3-phosphotidic, mono sodium salt (DPPA), and N-(methoxypolyethylene glycol 5000 carbamoyl)-1,2-dipalmitoyl-sn-glycero-3-phosphatidylethanolamine, monosodium salt (MPEG5000-DPPE). The amount of each lipid present in the blend will depend on the desired end product. Preferred ratios of each lipid are described in the Examples section. A wide variety of other lipids, like those described in Unger et al, U.S. Pat. No. 5,469,854, the contents of which are hereby incorporated by reference, may be used in the present process.
  • Phospholipid, as used herein, is a fatty substance containing an oily (hydrophobic) hydrocarbon chain(s) with a polar (hydrophilic) phosphoric head group. Phospholipids are amphiphilic. They spontaneously form boundaries and closed vesicles in aqueous media. Phospholipids constitute about 50% of the mass of animal cell plasma membrane.
  • Preparation of the Lipid Blend
  • The lipid blend may be prepared via an aqueous suspension-lyophilization process or an organic solvent dissolution-precipitation process using organic solvents. In the aqueous suspension-lyophilization process, the desired lipids are suspended in water at an elevated temperature and then concentrated by lyophilization. Preferably a dissolution procedure is used.
  • Step (a):
  • The organic solvent dissolution-precipitation procedure involves contacting the desired lipids (e.g., DPPA, DPPC, and MPEG5000 DPPE) with a first non-aqueous solvent system. This system is typically a combination of solvents, for example CHCl3/MeOH, CH2Cl2/MeOH, and toluene/MeOH. Preferably, the first non-aqueous solvent is a mixture of toluene and methanol. It may be desirable to warm the lipid solution to a temperature sufficient to achieve complete dissolution. Such a temperature is preferably about 25 to 75° C., more preferably about 35 to 65° C.
  • After dissolution, it may be desired to remove undissolved foreign matter by hot-filtration or cooling to room temperature and then filtering. Known methods of filtration may be used (e.g., gravity filtration, vacuum filtration, or pressure filtration).
  • Step (b):
  • The solution is then concentrated to a thick gel/semisolid. Concentration is preferably done by vacuum distillation. Other methods of concentrating the solution, such as rotary evaporation, may also be used. The temperature of this step is preferably about 20 to 60° C., more preferably 30 to 50° C.
  • Step (c):
  • The thick gel/semisolid is then dispersed in a second non-aqueous solvent. The mixture is slurried, preferably near ambient temperature (e.g., 15-30° C.). Useful second non-aqueous solvents are those that cause the lipids to precipitate from the filtered solution. The second non-aqueous solvent is preferably methyl t-butyl ether (MTBE). Other ethers and alcohols may be used.
  • Step (d):
  • The solids produced upon addition of the second non-aqueous solvent are then collected. Preferably the collected solids are washed with another portion of the second non-aqueous solvent (e.g., MTBE). Collection may be performed via vacuum filtration or centrifugation, preferably at ambient temperature. After collection, it is preferred that the solids are dried in vacuo at a temperature of about 20-60° C.
  • For the following reasons, the organic solvent dissolution-precipitation process is preferred over the aqueous suspension/lyophilization process:
  • (1) Because the lipids are quite soluble in toluene/methanol, solvent volumes are significantly reduced (relative to the aqueous procedure).
  • (2) Because of this increased solubility, the process temperature is also lower relative to the aqueous procedure, thereby avoiding the hydrolytic instability of fatty acid esters.
  • (3) When cooled back to room temperature, the toluene/methanol solution of lipids remains homogeneous, allowing a room temperature filtration to remove solid foreign matter.
  • (4) The MTBE precipitation allows quick and easy isolation of Lipid Blend solids. With the aqueous process, a time-consuming lyophilization process is used to isolate material.
  • (5) The MTBE precipitation also allows for the removal of any MTBE-soluble impurities, which go into the filtrate waste-stream. This potential for impurity removal is not realized when a solution is directly concentrated or lyophilized to a solid.
  • (6) The present process affords uniform solids.
  • Preparation of the Lipid Suspension Step (1):
  • In step one, a lipid blend is contacted with a non-aqueous solvent, whereby the lipid blend substantially dissolves in the non-aqueous solvent. Alternatively, the individual lipids may be contacted with the non-aqueous solvent sequentially in the order: DPPC, DPPA, and MPEG5000-DPPE; DPPC, MPEG5000-DPPE, and DPPA; MPEG5000-DPPE, DPPA, and DPPC; or MPEG5000-DPPE, DPPC, and DPPA. The DPPA, being the least soluble and least abundant of the lipids is not added first. Adding one of the other lipids prior to or concurrently with adding the DPPA facilitates dissolution of the DPPA. In another alternative, the individual lipids can be combined in their solid forms and the combination of the solids contacted with the non-aqueous solvent.
  • Substantial dissolution is generally indicated when the mixture of lipid blend and non-aqueous solvent becomes clear. As noted previously, phospholipids are generally not water soluble. Thus, direct introduction of a blend of phospholipid blend into an aqueous environment causes the lipid blend to aggregate forming clumps that are very difficult to disperse. The present invention overcomes this limitation by dissolving the lipid blend in a non-aqueous solvent prior to introduction of the aqueous solution. This allows one to evenly disperse the lipid blend into a liquid. The liquid dispersion can then be introduced into a desired aqueous environment.
  • Non-aqueous is intended to mean a solvent or mixture of solvents wherein the amount of water present is sufficiently low as to not impede dissolution of the lipid blend. The amount of non-aqueous solvent required will depend on the solubility of the lipid blend and also the final desired concentration of each component. As one of ordinary skill would appreciate, the level of water present in the non-aqueous solvent, which may be tolerated will vary based on the water solubilities of the individual lipids in the lipid blend. The more water soluble the individual phospholipids, the more water which may be present in step (1). Preferably, propylene glycol is used as the non-aqueous solvent. However, other members of the polyol family, such as ethylene glycol, and polyethylene glycol 300 may be used.
  • Mechanically mixing the lipid blend and non-aqueous solvent may be necessary to achieve complete dissolution. One of ordinary skill in the art will recognize that a variety of ways of mixing are available. It is preferred that a high shear homogenizer is used.
  • One of ordinary skill in the art would recognize that raising the temperature of the solvent should aid in dissolution of the lipid blend. The temperature at which step (1) may be performed can range from ambient to the boiling point of the chosen solvent. Preferably the temperature is from about 30 to about 70° C., more preferably about 45 to about 60° C., and even more preferably about 50, 51, 52, 53, 54, or 55° C. When ethylene glycol or polyethylene glycol 300 is used, it is preferred that the temperature be from about 50 to about 60° C. and more preferably about 55° C. Maintaining the solution at an elevated temperature should reduce solution viscosity and ease formulation preparation.
  • A preferred procedure for dissolving the lipid blend is as follows: (a) Add propylene glycol to an appropriate weighing container. (b) Warm the propylene glycol to about 40-80° C. in a heating bath. (c) Weigh the lipid blend into a separate container. (d) When the propylene glycol has reached the desired temperature range, transfer the solution into the container containing the lipid blend. (e) Place the container back into the heating bath until the solution is clear. (f) Mechanically mix the Lipid Blend/Propylene Glycol solution to further assure complete dissolution and uniform dispersion of the lipid blend.
  • The ratio of lipid blend to non-aqueous solvent will, of course, be limited by the solubility of the lipid blend. This ratio will also be influenced by the desired amount of lipid blend in the final formulation. Preferably, the ratio is from about 1 mg of lipid blend per mL of solvent (mg/mL) to about 100 mg/mL. More preferably, the lipid blend is present in about 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 mg/mL. Even more preferably, the lipid blend is present in about 10 mg/mL.
  • Step (2):
  • The second step involves contacting the solution from step (1) with an aqueous solution to form a lipid suspension. The aqueous solution can be water, saline, a saline/glycerin mixture or a saline/glycerin/non-aqueous solvent mixture. Non-aqueous solvent is as defined previously, preferably propylene glycol. Suspension, as used herein, is intended to indicate a dispersion in which insoluble particles are dispersed in a liquid medium.
  • Once complete dissolution of the lipid blend has been achieved (step (1)), the resulting solution can then be introduced to an aqueous solution. The aqueous solution may contain one or more components selected from sodium chloride, glycerin, and a non-aqueous solvent. Preferably the aqueous solution contains glycerin and sodium chloride. Preferably, a sufficient amount of propylene glycol is present in the aqueous solution, prior to addition of the solution from step 1, in order to achieve the final desired concentration of propylene glycol.
  • The order of addition of desired components is not expected to seriously impact the resulting lipid suspension. However, it is preferred that the lipid-blend solution is added to water, which may already contain the above-noted additional components. Additional desired components can then be added. It is more preferred that the lipid-blend solution is added a solution of water and sodium chloride (i.e., saline). It is further preferred that the lipid-blend solution is added a solution of water, sodium chloride, and glycerin. It is still further preferred that the lipid-blend solution is added a solution of water, sodium chloride, glycerin, and propylene glycol.
  • It is preferred that 6.8 mg of NaCl are present per mL of formulation. Preferably, 0.1 mL of Glycerin per mL of formulation is present. A final concentration of 0.1 mL of Propylene Glycol per mL of formulation is preferred. The final pH of the formulation is preferably about 5.5-7.0. The lipid blend is preferably present in an amount of 0.75-1.0 mg/mL of formulation.
  • The temperature of the aqueous solution can range from ambient to 70° C. Preferably, the temperature is about 45 to 60° C., with 50, 51, 52, 53, 54, or 55 being even more preferred. In order to obtain complete dissolution, the mixture will need to be agitated, preferably stirred. Also, the pH of the solution may need to be adjusted, depending on the desired final formulation. Either acid (e.g., HCl) or base (e.g., NaOH) can be added to make such an adjustment.
  • The lipid suspension will contain liquid particles of varying sizes. One of the benefits of the present invention is the ability to consistently obtain small particles of a nearly uniform size. Thus, it is preferred that the majority of particles obtained are less than 100 nm in diameter, more preferable less than 50 nm.
  • A preferred procedure for dissolving the lipid blend is as follows: (a) Add Water for Injection (WFI) into a compounding vessel. (b) Start mixing and ensure temperature is from 50-55° C. (c) Add sodium chloride to the compounding vessel. Wait until the solid has completely dissolved before proceeding to the next step. (d) Add glycerin to the compounding vessel. Allow sufficient time for complete mixing. (e) Add the remaining Propylene Glycol that is not in the Lipid Blend/Propylene Glycol solution. Allow time for thorough mixing. (f) Reduce mixing rate to reduce turbulence in the compounding vessel. (g) Add the Lipid Blend/Propylene Glycol solution to the compounding vessel. (h) Readjust mixing to original rate. (i) Add additional WFI if necessary. (j) Continue to mix for approximately 25 minutes and assure complete mixing. (k) Verify and adjust the solution to target pH.
  • Step (3):
  • Step three involves heating the lipid suspension obtained from step (2) to a temperature about equal to or above the highest gel to liquid crystalline phase transition temperature of the lipids present in the solution.
  • One of the objects of this step is to provide a filterable suspension. A solution/suspension is considered filterable if there is no significant reduction in flow rate within a normal process, and there is no significant increase in the pressure drop in the filtration system.
  • Experimental data indicates that the lipids in the formulation should be beyond their gel to liquid crystalline phase transition in order to simplify sterile filtration. When the lipids are below the phase transition temperature, the suspension particles are rigid. However, when they are above their respective gel-liquid crystal phase transition temperatures, they are in a more loosely organized configuration and thus, more easily filtered.
  • DPPC and DPPA show phase transitions of 41° C. and 67° C. respectively. MPEG5000-DPPE is soluble in water, therefore it does not exhibit a gel-liquid crystal phase transition which is characteristic of most hydrated lipid suspensions. Because the lipids in the preferred formulation all exhibit different gel to liquid phase transitions, the highest phase transition temperature, 67° C., is preferably used to filter the solution. By maintaining temperature at or beyond 67° C., all the lipids are beyond their respective phase transition, assuring the loose configuration while passing through the filters.
  • Heating may be achieved by jacketing the compounding vessel with a heat exchanging coil. Hot water/steam from a controlled source, e.g., a hot water bath, or a water heater, would deliver sufficient heat to maintain the compounding solution at a set temperature. Other heat sources known to those of skill in the art could also be used.
  • Step (4):
  • Step four is performed by filtering the lipid suspension through a sterilizing filter. The purpose behind this step being to provide a substantially bacteria-free suspension. A filtrate is considered substantially bacteria-free when the probability of the filtrate to contain at least one colony forming microorganism is less than 10−6.
  • Filtration is preferably done using sterilizing filter cartridges. Also, a means of forcing the solution through the filters may be required (e.g., pumping or pressurizing). Since the solution being filtered needs to be maintained at a temperature at or above the highest gel to liquid crystalline phase transition temperature of the lipids present in the solution, the filtration should be performed at about this same temperature. In order to accomplish this, the filter (e.g., sterilizing filter cartridges) are preferably enclosed in jacketed filter housings which are continuously heated, e.g., by a hot water stream from a temperature controlled water bath, to ensure that the suspension is above the lipid phase transition temperatures. The temperature of the sterilizing filter is preferably from 50 to 100° C., more preferably from 60 to 90° C., and even more preferably 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, or 80° C.
  • One or more sterilizing filters may be used to filter the suspension. The required number will be based on their effectiveness at removing bacteria. It is preferred that two filters are used. The size of the filter pores will be limited by the need to provide a bacteria-free suspension. Preferably, 0.2 μm hydrophilic filters are used.
  • A bulk solution of the preferred formulation was continuously filtered through two 0.2 μm hydrophilic filters for up to 3 hours at a rate of approximately 1 liter per minute (1 L/min.), i.e., passing a total of 180 liters of the suspension solution through the filters. The experimental results shows that there is no apparent blockage of filters. Lipid assays indicates that there is no measurable loss during the filtration process (due to accumulation in the filter medium).
  • A bulk solution of the preferred formulation was compounded at 40° C.-80° C., and the suspension was cooled to ambient temperature prior to sterile filtration. No apparent clogging of the filters were observed indicating the suspension particle size distribution is well below 0.2 μm of the filter pore size. It is desirable to use heat during filtration in order to ensure maximum recover of the lipid blend in the sterile filtrate (i.e., to minimize potential retention of lipid particles in the filter medium).
  • A preferred procedure for filtering the lipid suspension is as follows: (a) Assure all jacketed filters are at 70° C.-80° C. (b) Assure all valves in the filtration unit are closed. (c) Connect filtration inlet hose to the outlet of the compounding vessel. (d) Open valves to allow solution to pass through the filters. (e) Flush three liters of solution through the filters before collecting filtrate. (f) Continue filtration until complete.
  • Step (5):
  • Dispensing the filtered solution into a vial completes step five. Preferably, this step is performed in a controlled aseptic area. One of ordinary skill in the art would recognize that the vial selected and amount of suspension delivered to the vial would depend on the end use considered for the lipid suspension. Dispensing can be achieved via a variety of methods, including pipette, hand-held syringe dispenser (e.g., Filamatic® syringe dispensing machine), or industrial auto dispensing machine (e.g., Cozzoli or TL auto filling machine).
  • Step (6):
  • Step six is performed by exchanging the headspace gas of the vials from step five with a perfluorocarbon gas. A preferred method of exchange is to load the dispensed vials into a lyophilizer chamber and replace the vial headspace gas with a perfluorocarbon gas. A preferred gas is perfluoropropane (PFP). Other methods of headspace gas exchange known to those of skill in the art may be employed.
  • The vials are sealed at the completion of the vial headspace gas exchange cycle. When the lyophilizer chamber pressure is brought back to atmospheric pressure by charging into the chamber with PFP. Vial stoppers are seated to seal the vials.
  • Step (7):
  • Step seven involves terminally sterilizing a vial after step six. One method of terminal sterilization is through the use of an autoclave. Also, the sealed vials can be terminally sterilized in a steam sterilizer to further enhance the sterility assurance of the product. Care must be taken in the sterilization process as some degradation of lipids may be observed as a result of autoclaving. Preferably, the vial is sterilized at about 126-130° C. for 1 to 10 minutes.
  • Other features of the invention will become apparent in the course of the following descriptions of exemplary embodiments which are given for illustration of the invention and are not intended to be limiting thereof.
  • Examples
  • TABLE 1
    Lipid Blend Target Composition
    Lipid Name Common Name Wt % Mole %
    DPPA 1,2-dipalmitoyl-sn- 6.0 10
    glycero-3-
    phosphatidic acid,
    monosodium salt
    DPPC 1,2-dipalmitoyl-sn- 53.5 82
    glycero-3-
    phosphatidylcholine
    MPEG5000 N-(methoxypolyethylene 40.5 8
    DPPE glycol 5000
    carbamoyl)-1,2-
    dipalmitoyl-sn-glycero-3-
    phosphatidylethanola
    mine, monosodium salt
  • Lipid Blend Manufacturing Procedure
  • Figure US20170312375A1-20171102-C00001
  • A flask is charged with toluene (3.3 L), methanol (1.2 L), DPPA (59.6 g), DPPC (535 g), and MPEG5000 DPPE (405 g). After rinsing solid contact surfaces with 0.9 L methanol, the slurry is warmed to 45-55° C. until dissolution is complete.
  • The solution is filtered and then concentrated in vacuo at 35-45° C. to a thick gel. Methyl t-butyl ether (MTBE, 5.4 L) is added and the mixture is slurried at 15-30° C. White solids are collected by centrifugation or vacuum filtration, and washed with MTBE (0.9 L). The solids are then placed in a vacuum oven and dried to constant weight at 40-50° C. The dried Lipid Blend is transferred to a bottle and stored at −15 to −25° C.
  • In another embodiment of the lipid blend manufacturing procedure of the present invention, the following procedure may also be used.
  • Alternative Lipid Blend Manufacturing Procedure
  • Figure US20170312375A1-20171102-C00002
  • Phospholipid quantities were adjusted for purity based on a “Use As” value from the certificates of analysis. The batch size (combined phospholipid weight) of this experiment was 2 kg.
  • A rotary evaporation flask is charged sequentially with toluene (3,300 mL), methanol (1,200 mL), DPPA (122.9 g; corrected for “use as” purity of 97.0%), DPPC (1,098.5 g total; 500.8 g from a lot with 98.4% “use as” purity and 597.7 g from a lot with 96.7% “use as” purity), and MPEG5000 DPPE (815.7 g; corrected for “use as” purity of 99.3%). After rinsing residual solids into the flask with methanol (900 mL), the flask is placed on a rotary evaporator (no vacuum) and the slurry is warmed to between 45 and 55° C. (external). After dissolution is complete, the external temperature is reduced to between 35 and 45° C., a vacuum is applied, and the solution is concentrated to a white semi-solid. The flask is removed from the evaporator and solids are broken up with a spatula. The flask is reapplied to the evaporator and concentration is continued. After reaching the endpoint (final vacuum pressure2 20 mbar; white, granular, chunky solid), MTBE (5,400 mL) is added through the rotary evaporator's addition tube, the vacuum is discontinued, and the mixture is slurried for 15 to 45 min at 15 to 30° C. Solids are isolated by either centrifugal or vacuum filtration, rinsed with MTBE (3,800 mL), and dried to constant weight in a vacuum oven (40 to 50° C.). Prior to transferring to polyethylene bottles with polypropylene caps, solids are delumped through a screen (0.079 inch mesh), affording 1,966.7 g (98%) of lipid blend (SG896) as a white solid.
  • The preferred lipid suspension contains:
      • 1,2-dipalmitoyl-sn-glycero-3-phosphotidic, mono sodium salt (DPPA);
      • 1,2-dipalmitoyl-sn-glycero-3-phosphatidylcholine (DPPC);
      • N-(methoxypolyethylene glycol 5000 carbamoyl)-1,2-dipalmitoyl-sn-glycero-3-phosphatidylethanolamine, monosodium salt (MPEG5000-DPPE);
      • Propylene Glycol, USP;
      • Glycerin, USP;
      • Sodium Chloride, USP; and,
      • Water for Injection, USP.
  • TABLE 2
    Preferred Contrast Agent Formulations
    Component A* B*
    NaCl, USP 6.8 mg/mL 6.8 mg/mL
    Glycerin, USP 0.1 mL/mL 0.1 mL/mL
    Propylene Glycol, 0.1 mL/mL 0.1 mL/mL
    USP
    Lipid Blend** 1 mg/mL 0.75 mg/mL
    Perfluoropropane >65% >65%
    pH 6.0-7.0 6.0-7.0
    *Formulation A has 1 mg/mL lipid blend. Formulation B has a lipid blend concentration of 0.75 mg/mL.
    **The lipid blend is consist of 53.5 wt. % of DPPC, 6.0 wt. % of DPPA and 40.5 wt. % of MPEG5000-DPPE.
  • TABLE 3
    Preferred Container and Closure
    Component Type
    Vial Wheaton 2802, B33BA,
    2 cc, 13 mm, Type I,
    flint tubing vial
    Stopper West V50 4416/50, 13 mm,
    gray butyl lyo,
    siliconized stoppers
    Seal West 3766, white 13 mm,
    flip-off aluminum seals
  • The finished product fill volume can be from 1.0-2.0 mL/vial.
  • In the preparation of the preferred formulation, when the lipid blend is directly hydrated with the aqueous matrix solution containing water for injection, sodium chloride, glycerin and propylene glycol, the filtrates have less lipids as compared to the pre-filtration bulk solution. The loss of lipids varies from 12% to 48%. These results demonstrate that the sterile filtration process is not effectively controlled, and therefore, the final product lipid content is highly variable.
  • In contrast, using the presently described process, assay results of the lipids in show full recovery of lipids during the filtration process. Variability of assay results around the theoretical targets is within normal assay method variability. Particle size distribution by number, by volume and by reflective intensity of a suspension prepared by first solubilizing lipid blend in propylene glycol indicate that the majority of the particles are less than 50 nm in the pre-filtered bulk solution at 55° C. as well at 70° C. The particle distribution profile does not change after filtration.
  • Utility Section
  • The presently claimed process is useful for preparing ultrasound contrast agents. Such agents should be useful for a variety of imaging applications, including enhancing contrast in echocardiographic and radiologic ultrasound images.
  • Obviously, numerous modifications and variations of the present invention are possible in light of the above teachings. It is therefore to be understood that within the scope of the appended claims, the invention may be practiced otherwise that as specifically described herein.

Claims (21)

1. A process for preparing a phospholipid suspension, comprising:
(1) contacting a lipid blend with a non-aqueous solvent, whereby the lipid blend substantially dissolves in the non-aqueous solvent; and,
(2) contacting the solution from step (1) with an aqueous solution to form a lipid suspension.
2. A process according to claim 1, wherein the non-aqueous solvent is selected from propylene glycol, ethylene glycol, and polyethylene glycol 300.
3. A process according to claim 2, wherein the non-aqueous solvent is propylene glycol.
4. A process according to claim 2, wherein the lipid blend, comprises:
(a) 1,2-dipalmitoyl-sn-glycero-3-phosphatidylcholine;
(b) 1,2-dipalmitoyl-sn-glycero-3-phosphotidic, mono sodium salt; and,
(c) N-(methoxypolyethylene glycol 5000 carbamoyl)-1,2-dipalmitoyl-sn-glycero--3-phosphatidylethanolamine, mono sodium salt.
5. A process according to claim 2, wherein the non-aqueous solvent is heated to a temperature of about 30 to 70° C. prior to contacting with the lipid blend.
6. A process according to claim 5, wherein the non-aqueous solvent is heated to a temperature of about 50 to 55° C. prior to contacting with the lipid blend.
7. A process according to claim 2, wherein the ratio of lipid blend to non-aqueous solvent is from about 5 mg of lipid blend per mL of non-aqueous solvent to about 15 mg/mL.
8. A process according to claim 7, wherein the ratio of lipid blend to non-aqueous solvent is about 10 mg/mL.
9. A process according to claim 2, wherein in step (2), the aqueous solution is selected from water, saline, a saline/glycerin mixture, and a saline/glycerin/non-aqueous solvent mixture.
10. A process according to claim 9, wherein the aqueous solution is a saline and glycerin mixture.
11. A process according to claim 9, wherein the aqueous solution is a saline, glycerin, and propylene glycol mixture.
12. A process according to claim 11, wherein 6.8 mg/mL of sodium chloride are present, 0.1 mL/mL of glycerin are present, 0.1 mL/mL of propylene glycol are present, and about 0.75 to 1.0 mg/mL of the lipid blend are present.
13. A process according to claim 12, wherein 0.75 mg/mL of lipid blend are present.
14. A process according to claim 12, wherein 1.0 mg/mL of lipid blend are present.
15. A process according to claim 2, wherein in step (2), the aqueous solution is heated to a temperature of about 45 to 60° C. prior to contacting with the solution from step (1).
16. A process according to claim 15, wherein the aqueous solution is heated to a temperature of about 50 to 55° C. prior to contacting with the solution from step (1).
17. A process according to claim 1, wherein the process further comprises: (3) heating the lipid suspension from step (2) to a temperature about equal to or above the highest gel to liquid crystalline phase transition temperature of the lipids present in the suspension.
18. A process according to claim 17, wherein in step (3), the lipid suspension is heated to a temperature of at least about 67° C.
19. A process according to claim 17, wherein the process further comprises:
(4) filtering the lipid suspension through a sterilizing filter.
20. A process according to claim 19, wherein in step (4), the filtration is performed using two sterilizing filter cartridges.
21-44. (canceled)
US15/374,147 1998-01-14 2016-12-09 Preparation of a lipid blend and a phospholipid suspension containing the lipid blend Abandoned US20170312375A1 (en)

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US13/195,734 US8658205B2 (en) 1998-01-14 2011-08-01 Preparation of a lipid blend and a phospholipid suspension containing the lipid blend
US13/950,348 US8747892B2 (en) 1998-01-14 2013-07-25 Preparation of a lipid blend and a phospholipid suspension containing the lipid blend
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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10022460B2 (en) 2014-12-31 2018-07-17 Lantheus Medical Imaging, Inc. Lipid-encapsulated gas microsphere compositions and related methods
US10220104B2 (en) 2016-07-06 2019-03-05 Lantheus Medical Imaging, Inc. Methods for making ultrasound contrast agents
US10588988B2 (en) 2016-05-04 2020-03-17 Lantheus Medical Imaging, Inc. Methods and devices for preparation of ultrasound contrast agents

Families Citing this family (26)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20010003580A1 (en) * 1998-01-14 2001-06-14 Poh K. Hui Preparation of a lipid blend and a phospholipid suspension containing the lipid blend
AU2006200015B8 (en) * 1998-01-14 2008-02-21 Dupont Pharmaceuticals Company Preparation of a lipid blend and a phospholipid suspension containing a lipid blend, and contrast agents based on these
US6975924B2 (en) * 1999-12-03 2005-12-13 Baxter International Inc. Method and apparatus for controlling the strategy of compounding pharmaceutical admixtures
CA2443362A1 (en) * 2001-04-03 2002-10-17 Poh K. Hui Stabilization and terminal sterilization of phospholipid formulations
US8541399B2 (en) 2002-02-19 2013-09-24 Resolution Chemicals Limited Solvent-based sterilisation of pharmaceuticals
JP4670083B2 (en) * 2003-02-04 2011-04-13 ブラッコ・シュイス・ソシエテ・アノニム Ultrasonic contrast agent and method for producing the same
ES2531732T3 (en) 2003-12-22 2015-03-18 Bracco Suisse Sa Gas filled microvesicle assembly for contrast imaging
CN1321697C (en) * 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 Ultrasound contrast medium composition with phospholipid as membrane material and its preparation method
US7618651B2 (en) * 2004-06-24 2009-11-17 Idexx Laboratories Pharmaceutical compositions for drug delivery and methods of treating or preventing conditions using same
US7854943B2 (en) 2004-06-24 2010-12-21 Idexx Laboratories Phospholipid gel compositions for drug delivery and methods of treating conditions using same
US7858115B2 (en) * 2004-06-24 2010-12-28 Idexx Laboratories Phospholipid gel compositions for drug delivery and methods of treating conditions using same
AU2005273865B2 (en) 2004-08-18 2011-02-24 Bracco Suisse S.A. Gas-filled microvesicles composition for contrast imaging
US8017159B2 (en) * 2005-11-16 2011-09-13 Idexx Laboratories, Inc. Phospholipid gel compositions for delivery of aptamers and methods of treating conditions using same
WO2010074172A1 (en) * 2008-12-24 2010-07-01 株式会社バイオメッドコア Method for producing liposome and method for dissolving cholesterol
JP5771366B2 (en) * 2009-09-02 2015-08-26 株式会社バイオメッドコア Liposome production apparatus and method
JP2012086166A (en) * 2010-10-20 2012-05-10 Biomedcore Inc Apparatus for producing liposome
JP2016519731A (en) 2013-03-04 2016-07-07 エコージェン パワー システムズ エル.エル.シー.Echogen Power Systems, L.L.C. Heat engine system with high net power supercritical carbon dioxide circuit
TWI552761B (en) * 2013-05-03 2016-10-11 博信生物科技股份有限公司 An lipid-based micro/nano-bubble, and an optimized preparing method and equipment thereof
GB201411423D0 (en) 2014-06-26 2014-08-13 Ge Healthcare As Lipid sterilisation method
EP3212240A4 (en) * 2014-10-30 2018-07-18 Lantheus Medical Imaging, Inc. Lipid encapsulated gas microsphere compositions and related methods
WO2016073252A1 (en) 2014-11-03 2016-05-12 Echogen Power Systems, L.L.C. Active thrust management of a turbopump within a supercritical working fluid circuit in a heat engine system
EP3668488A4 (en) * 2017-08-15 2021-03-24 The Board of Trustees of the Leland Stanford Junior University Polymeric perfluorocarbon nanoemulsions for ultrasonic drug uncaging
US11166846B2 (en) 2019-01-04 2021-11-09 California Institute Of Technology Method for eye lens removal using cavitating microbubbles
RU2745290C2 (en) * 2019-04-12 2021-03-23 Ирина Николаевна Кузнецова Emulsion of perfluorocarbon compounds for biomedical purposes and a method for its production
US11435120B2 (en) 2020-05-05 2022-09-06 Echogen Power Systems (Delaware), Inc. Split expansion heat pump cycle
NL2027237B1 (en) 2020-12-27 2022-07-21 Solstice Pharmaceuticals B V Process for controlled manufacturing of mono-disperse microbubbles

Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5053217A (en) * 1984-03-08 1991-10-01 Phares Pharmaceutical Research Nv Composition and method
US5585112A (en) * 1989-12-22 1996-12-17 Imarx Pharmaceutical Corp. Method of preparing gas and gaseous precursor-filled microspheres
US5738869A (en) * 1993-04-23 1998-04-14 Haxal Ag Transdermal drug preparation
US5776488A (en) * 1994-03-11 1998-07-07 Yoshitomi Pharmaceutical Industries, Ltd. Liposome preparation
US5843473A (en) * 1989-10-20 1998-12-01 Sequus Pharmaceuticals, Inc. Method of treatment of infected tissues
US5853755A (en) * 1993-07-28 1998-12-29 Pharmaderm Laboratories Ltd. Biphasic multilamellar lipid vesicles
US6066331A (en) * 1994-07-08 2000-05-23 Barenholz; Yechezkel Method for preparation of vesicles loaded with biological structures, biopolymers and/or oligomers
US6120794A (en) * 1995-09-26 2000-09-19 University Of Pittsburgh Emulsion and micellar formulations for the delivery of biologically active substances to cells
US6416740B1 (en) * 1997-05-13 2002-07-09 Bristol-Myers Squibb Medical Imaging, Inc. Acoustically active drug delivery systems

Family Cites Families (387)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3015128A (en) 1960-08-18 1962-01-02 Southwest Res Inst Encapsulating apparatus
NL302030A (en) 1962-12-21 1900-01-01
US3291843A (en) 1963-10-08 1966-12-13 Du Pont Fluorinated vinyl ethers and their preparation
BE661981A (en) 1964-04-03
US3594326A (en) 1964-12-03 1971-07-20 Ncr Co Method of making microscopic capsules
US3968203A (en) 1965-10-01 1976-07-06 Jerome G. Spitzer Aerosol astringent composition
US3488714A (en) 1966-09-19 1970-01-06 Dow Chemical Co Formed laminate structure and method of preparation
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
US3532500A (en) 1967-07-25 1970-10-06 Eastman Kodak Co Light sensitive vesicular composition comprising an azido-s-triazine compound
US3557294A (en) 1967-10-12 1971-01-19 Allied Chem Fluorinated ethers as inhalation convulsants
US3479811A (en) 1967-11-29 1969-11-25 Dow Chemical Co Yarn and method of making the same
US3732172A (en) 1968-02-28 1973-05-08 Ncr Co Process for making minute capsules and prefabricated system useful therein
US3650831A (en) 1969-03-10 1972-03-21 Armour Dial Inc Method of cleaning surfaces
US4027007A (en) 1970-12-09 1977-05-31 Colgate-Palmolive Company Antiperspirants formulated with borax
US3873564A (en) 1971-03-03 1975-03-25 Synvar Ass 2-Imidazolinyl-3-oxide-1-oxypropionic acid
US4108806A (en) 1971-12-06 1978-08-22 The Dow Chemical Company Thermoplastic expandable microsphere process and product
US4179546A (en) 1972-08-28 1979-12-18 The Dow Chemical Company Method for expanding microspheres and expandable composition
US3960583A (en) 1974-05-02 1976-06-01 Philadelphia Quartz Company Method of preparing modified hollow, largely spherical particles by spray drying
CH588887A5 (en) 1974-07-19 1977-06-15 Battelle Memorial Institute
US3945956A (en) * 1975-06-23 1976-03-23 The Dow Chemical Company Polymerization of styrene acrylonitrile expandable microspheres
US4138383A (en) 1975-11-24 1979-02-06 California Institute Of Technology Preparation of small bio-compatible microspheres
US4004384A (en) 1976-02-06 1977-01-25 Curoco Stairway unit
GB1523965A (en) 1976-03-19 1978-09-06 Ici Ltd Pharmaceutical compositions containing steroids
US4162282A (en) 1976-04-22 1979-07-24 Coulter Electronics, Inc. Method for producing uniform particles
GB1599881A (en) 1977-02-02 1981-10-07 Millington A R Preparation for diagnostic radiology
CH624011A5 (en) 1977-08-05 1981-07-15 Battelle Memorial Institute
CH621479A5 (en) 1977-08-05 1981-02-13 Battelle Memorial Institute
US4235871A (en) * 1978-02-24 1980-11-25 Papahadjopoulos Demetrios P Method of encapsulating biologically active materials in lipid vesicles
US4192859A (en) 1978-09-29 1980-03-11 E. R. Squibb & Sons, Inc. Contrast media containing liposomes as carriers
US4310506A (en) 1979-02-22 1982-01-12 California Institute Of Technology Means of preparation and applications of liposomes containing high concentrations of entrapped ionic species
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
US4303736A (en) 1979-07-20 1981-12-01 Leonard Torobin Hollow plastic microspheres
US4310505A (en) 1979-11-08 1982-01-12 California Institute Of Technology Lipid vesicles bearing carbohydrate surfaces as lymphatic directed vehicles for therapeutic and diagnostic substances
US4342826A (en) 1980-02-04 1982-08-03 Collaborative Research, Inc. Immunoassay products and methods
US4421562A (en) 1980-04-13 1983-12-20 Pq Corporation Manufacturing process for hollow microspheres
US4344929A (en) 1980-04-25 1982-08-17 Alza Corporation Method of delivering drug with aid of effervescent activity generated in environment of use
US4315514A (en) 1980-05-08 1982-02-16 William Drewes Method and apparatus for selective cell destruction
US4331654A (en) 1980-06-13 1982-05-25 Eli Lilly And Company Magnetically-localizable, biodegradable lipid microspheres
US4442843A (en) 1980-11-17 1984-04-17 Schering, Ag Microbubble precursors and methods for their production and use
DE3173476D1 (en) 1980-11-17 1986-02-20 Schering Ag Composition generating microbubbles
US4681119A (en) 1980-11-17 1987-07-21 Schering Aktiengesellschaft Method of production and use of microbubble precursors
US4657756A (en) 1980-11-17 1987-04-14 Schering Aktiengesellschaft Microbubble precursors and apparatus for their production and use
US4420442A (en) 1981-04-13 1983-12-13 Pq Corporation Manufacturing process for hollow microspheres
US4533254A (en) 1981-04-17 1985-08-06 Biotechnology Development Corporation Apparatus for forming emulsions
EP0068961A3 (en) 1981-06-26 1983-02-02 Thomson-Csf Apparatus for the local heating of biological tissue
US4426330A (en) 1981-07-20 1984-01-17 Lipid Specialties, Inc. Synthetic phospholipid compounds
US4534899A (en) 1981-07-20 1985-08-13 Lipid Specialties, Inc. Synthetic phospholipid compounds
US4569836A (en) 1981-08-27 1986-02-11 Gordon Robert T Cancer treatment by intracellular hyperthermia
IL63734A (en) * 1981-09-04 1985-07-31 Yeda Res & Dev Lipid fraction,its preparation and pharmaceutical compositions containing same
WO1983001068A1 (en) 1981-09-23 1983-03-31 Baker, Alfred, George Hollow, bilayered silicate microspheres
DE3141641A1 (en) 1981-10-16 1983-04-28 Schering Ag, 1000 Berlin Und 4619 Bergkamen ULTRASONIC CONTRAST AGENTS AND THEIR PRODUCTION
BR8107560A (en) 1981-11-19 1983-07-05 Luiz Romariz Duarte ULTRASONIC STIMULATION OF BONE FRACTURE CONSOLIDATION
US4748216A (en) * 1982-01-25 1988-05-31 Hercules Incorporated Purified cycloolefin polymerization composition
US4522803A (en) * 1983-02-04 1985-06-11 The Liposome Company, Inc. Stable plurilamellar vesicles, their preparation and use
US4540629A (en) 1982-04-08 1985-09-10 Pq Corporation Hollow microspheres with organosilicon-silicate walls
JPS58201711A (en) * 1982-05-19 1983-11-24 Eisai Co Ltd Coated liposome containing ubidecarenone
DE3225848A1 (en) 1982-07-07 1984-01-19 Schering AG, 1000 Berlin und 4709 Bergkamen PREPARATION OF CORTICOIDS FOR TOPICAL APPLICATION
FR2534487B1 (en) 1982-10-15 1988-06-10 Dior Christian Parfums METHOD FOR THE HOMOGENEIZATION OF HYDRATED LIPIDAL LAMELLAR PHASE DISPERSIONS, AND SUSPENSIONS OBTAINED THEREBY
EP0111386B1 (en) * 1982-10-26 1987-11-19 University Of Aberdeen Ultrasound hyperthermia unit
US4603044A (en) 1983-01-06 1986-07-29 Technology Unlimited, Inc. Hepatocyte Directed Vesicle delivery system
US4731239A (en) 1983-01-10 1988-03-15 Gordon Robert T Method for enhancing NMR imaging; and diagnostic use
GB8301506D0 (en) 1983-01-20 1983-02-23 Electricity Council Fluorinated ethers
US4718433A (en) 1983-01-27 1988-01-12 Feinstein Steven B Contrast agents for ultrasonic imaging
US4572203A (en) 1983-01-27 1986-02-25 Feinstein Steven B Contact agents for ultrasonic imaging
US4775522A (en) 1983-03-04 1988-10-04 Children's Hospital Research Foundation, A Division Of Children's Hospital Medical Center NMR compositions for indirectly detecting a dissolved gas in an animal
US4981692A (en) 1983-03-24 1991-01-01 The Liposome Company, Inc. Therapeutic treatment by intramammary infusion
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
US4485193A (en) 1983-05-10 1984-11-27 The Dow Chemical Company Expandable synthetic resinous thermoplastic particles, method for the preparation thereof and the application therefor
US4515736A (en) * 1983-05-12 1985-05-07 The Regents Of The University Of California Method for encapsulating materials into liposomes
US4544545A (en) 1983-06-20 1985-10-01 Trustees University Of Massachusetts Liposomes containing modified cholesterol for organ targeting
US4900540A (en) 1983-06-20 1990-02-13 Trustees Of The University Of Massachusetts Lipisomes containing gas for ultrasound detection
JPS607932A (en) * 1983-06-29 1985-01-16 Dai Ichi Seiyaku Co Ltd Preparation of liposome
JPS6019033A (en) 1983-07-12 1985-01-31 Matsumoto Yushi Seiyaku Kk Hollow micro-balloon and preparation thereof
US4519024A (en) 1983-09-02 1985-05-21 At&T Bell Laboratories Two-terminal transistor rectifier circuit arrangement
US4615879A (en) 1983-11-14 1986-10-07 Vanderbilt University Particulate NMR contrast agents for gastrointestinal application
FR2563725B1 (en) 1984-05-03 1988-07-15 Dory Jacques APPARATUS FOR EXAMINING AND LOCATING ULTRASONIC TUMORS WITH A LOCALIZED HYPERTHERMAL TREATMENT DEVICE
SE463651B (en) 1983-12-21 1991-01-07 Nycomed As DIAGNOSTIC AND CONTRACTOR
GB8407557D0 (en) 1984-03-23 1984-05-02 Hayward J A Polymeric lipsomes
CH668554A5 (en) * 1984-04-09 1989-01-13 Sandoz Ag LIPOSOMAS CONTAIN WHICH POLYPEPTIDES WITH INTERLEUKIN-2 ACTIVITY AND METHOD FOR THE PRODUCTION THEREOF.
US4728575A (en) 1984-04-27 1988-03-01 Vestar, Inc. Contrast agents for NMR imaging
US5008109A (en) 1984-05-25 1991-04-16 Vestar, Inc. Vesicle stabilization
US5008050A (en) 1984-06-20 1991-04-16 The Liposome Company, Inc. Extrusion technique for producing unilamellar vesicles
CA1264668C (en) 1984-06-20 1990-01-23 Extrusion techniques for producing liposomes
US4620546A (en) 1984-06-30 1986-11-04 Kabushiki Kaisha Toshiba Ultrasound hyperthermia apparatus
SE8403905D0 (en) 1984-07-30 1984-07-30 Draco Ab LIPOSOMES AND STEROID ESTERS
US4880635B1 (en) 1984-08-08 1996-07-02 Liposome Company Dehydrated liposomes
US4761288A (en) * 1984-09-24 1988-08-02 Mezei Associates Limited Multiphase liposomal drug delivery system
US4767610A (en) 1984-10-19 1988-08-30 The Regents Of The University Of California Method for detecting abnormal cell masses in animals
US4789501A (en) 1984-11-19 1988-12-06 The Curators Of The University Of Missouri Glass microspheres
US4921706A (en) 1984-11-20 1990-05-01 Massachusetts Institute Of Technology Unilamellar lipid vesicles and method for their formation
US4946787A (en) * 1985-01-07 1990-08-07 Syntex (U.S.A.) Inc. N-(ω,(ω-1)-dialkyloxy)- and N-(ω,(ω-1)-dialkenyloxy)-alk-1-yl-N,N,N-tetrasubstituted ammonium lipids and uses therefor
US4753788A (en) * 1985-01-31 1988-06-28 Vestar Research Inc. Method for preparing small vesicles using microemulsification
US4830858A (en) 1985-02-11 1989-05-16 E. R. Squibb & Sons, Inc. Spray-drying method for preparing liposomes and products produced thereby
US4689986A (en) 1985-03-13 1987-09-01 The University Of Michigan Variable frequency gas-bubble-manipulating apparatus and method
US4680171A (en) * 1985-03-15 1987-07-14 William Shell Visualization of a bloodstream circulation with biodegradable microspheres
US5186922A (en) 1985-03-15 1993-02-16 See/Shell Biotechnology, Inc. Use of biodegradable microspheres labeled with imaging energy constrast materials
US4663161A (en) 1985-04-22 1987-05-05 Mannino Raphael J Liposome methods and compositions
WO1986006959A1 (en) 1985-05-22 1986-12-04 Liposome Technology, Inc. Liposome inhalation method and system
US4683092A (en) * 1985-07-03 1987-07-28 Damon Biotech, Inc. Capsule loading technique
DE3677112D1 (en) 1985-08-12 1991-02-28 Battelle Memorial Institute POROESE FILTRATION GLASS BALLS AND METHOD FOR THE PRODUCTION THEREOF.
DE3529195A1 (en) * 1985-08-14 1987-02-26 Max Planck Gesellschaft CONTRAST AGENTS FOR ULTRASONIC EXAMINATIONS AND METHOD FOR THE PRODUCTION THEREOF
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
US4938947A (en) 1985-11-01 1990-07-03 Centre National De La Recherche Scientifique (Cnrs) Aerosol composition for in vivo imaging
US5077036A (en) 1986-01-14 1991-12-31 Alliance Pharmaceutical Corp. Biocompatible stable fluorocarbon emulsions for contrast enhancement and oxygen transport comprising 40-125% wt./volume fluorocarbon combined with a phospholipid
US5080885A (en) 1986-01-14 1992-01-14 Alliance Pharmaceutical Corp. Brominated perfluorocarbon emulsions for internal animal use for contrast enhancement and oxygen transport
US4865836A (en) 1986-01-14 1989-09-12 Fluoromed Pharmaceutical, Inc. Brominated perfluorocarbon emulsions for internal animal use for contrast enhancement and oxygen transport
US4927623A (en) 1986-01-14 1990-05-22 Alliance Pharmaceutical Corp. Dissolution of gas in a fluorocarbon liquid
US4987154A (en) 1986-01-14 1991-01-22 Alliance Pharmaceutical Corp. Biocompatible, stable and concentrated fluorocarbon emulsions for contrast enhancement and oxygen transport in internal animal use
US5514720A (en) 1986-07-09 1996-05-07 Hemagen/Pfc Stable emulsions of highly fluorinated organic compounds
DE3785054T2 (en) 1986-01-24 1993-07-08 Childrens Hosp Medical Center STABLE EMULSIONS OF STRONGLY FLUORED ORGANIC COMPOUNDS.
US5536753A (en) 1986-01-24 1996-07-16 Children's Hospital Research Foundation, A Division Of Children's Hospital Medical Center And Hemagen/Pfc Stable perfluorocarbon and oil emulsions
US5684050A (en) 1986-01-24 1997-11-04 Hemagen/Pfc Stable emulsions of highly fluorinated organic compounds
US4737323A (en) 1986-02-13 1988-04-12 Liposome Technology, Inc. Liposome extrusion method
US4834964A (en) 1986-03-07 1989-05-30 M.R.I., Inc. Use of charged nitroxides as NMR image enhancing agents for CSF
JPH0751496B2 (en) 1986-04-02 1995-06-05 武田薬品工業株式会社 Manufacturing method of liposome
DE3614657A1 (en) 1986-04-30 1987-11-05 Dornier Medizintechnik LIPID VESICLES CONTAINING PHARMAKA, METHOD FOR THE PRODUCTION AND INTRODUCTION THEREOF IN THE BODY OF A LIVING BEING AND RELEASE OF THE PHARMACA CONTAINING IN THE LIPID VESICLES
JPS62286534A (en) 1986-06-04 1987-12-12 Matsumoto Yushi Seiyaku Kk Manufacture of thermal expansion microcapsule
FR2602774B1 (en) 1986-07-29 1990-10-19 Atta NOVEL POLYHYDROXYLATED AND PERFLUOROALKYLATED AMPHIPHILIC MOLECULES HAVING SURFACTANT PROPERTIES
IL79559A0 (en) 1986-07-29 1986-10-31 Univ Ramot Contrast agents for nmr medical imaging
US4728578A (en) 1986-08-13 1988-03-01 The Lubrizol Corporation Compositions containing basic metal salts and/or non-Newtonian colloidal disperse systems and vinyl aromatic containing polymers
US4776991A (en) 1986-08-29 1988-10-11 The United States Of America As Represented By The Secretary Of The Navy Scaled-up production of liposome-encapsulated hemoglobin
US4781871A (en) 1986-09-18 1988-11-01 Liposome Technology, Inc. High-concentration liposome processing method
US4769241A (en) 1986-09-23 1988-09-06 Alpha Therapeutic Corporation Apparatus and process for oxygenation of liquid state dissolved oxygen-carrying formulation
JPS6360943U (en) 1986-10-09 1988-04-22
ZW11287A1 (en) 1986-11-04 1989-01-25 Aeci Ltd Process for the production of an explosive
DE3637926C1 (en) 1986-11-05 1987-11-26 Schering Ag Ultrasonic manometry in a liquid using microbubbles
US5049388A (en) 1986-11-06 1991-09-17 Research Development Foundation Small particle aerosol liposome and liposome-drug combinations for medical use
US4863717A (en) 1986-11-10 1989-09-05 The State Of Oregon Acting By And Through The State Board Of Higher Education On Behalf Of The University Of Oregon Methods for circumventing the problem of free radial reduction associated with the use of stable nitroxide free radicals as contrast agents for magnetic reasonance imaging
US4933121A (en) 1986-12-10 1990-06-12 Ciba Corning Diagnostics Corp. Process for forming liposomes
DK175531B1 (en) 1986-12-15 2004-11-22 Nexstar Pharmaceuticals Inc Delivery vehicle with amphiphil-associated active ingredient
FR2634375B3 (en) * 1988-06-30 1991-07-05 Centre Nat Rech Scient PROCESS FOR THE PREPARATION OF DISPERSIBLE COLLOIDAL LIPID AMPHIPHILIC SYSTEMS IN THE FORM OF SUBMICRON LIPOSOMES
FR2608942B1 (en) 1986-12-31 1991-01-11 Centre Nat Rech Scient PROCESS FOR THE PREPARATION OF COLLOIDAL DISPERSIBLE SYSTEMS OF A SUBSTANCE, IN THE FORM OF NANOCAPSULES
US5174930A (en) * 1986-12-31 1992-12-29 Centre National De La Recherche Scientifique (Cnrs) Process for the preparation of dispersible colloidal systems of amphiphilic lipids in the form of oligolamellar liposomes of submicron dimensions
US5283255A (en) 1987-01-20 1994-02-01 The University Of British Columbia Wavelength-specific cytotoxic agents
US5089181A (en) * 1987-02-24 1992-02-18 Vestar, Inc. Method of dehydrating vesicle preparations for long term storage
CA1321048C (en) 1987-03-05 1993-08-10 Robert W. J. Lencki Microspheres and method of producing same
US5219538A (en) 1987-03-13 1993-06-15 Micro-Pak, Inc. Gas and oxygen carrying lipid vesicles
US5000960A (en) 1987-03-13 1991-03-19 Micro-Pak, Inc. Protein coupling to lipid vesicles
US4722943A (en) * 1987-03-19 1988-02-02 Pierce & Stevens Corporation Composition and process for drying and expanding microspheres
US4895876A (en) 1987-03-20 1990-01-23 Air Products And Chemicals, Inc. Concentrated stable fluorochemical aqueous emulsions containing triglycerides
US4866096A (en) 1987-03-20 1989-09-12 Air Products And Chemicals, Inc. Stable fluorochemical aqueous emulsions
JPS63277618A (en) * 1987-03-31 1988-11-15 Noebia:Kk Production of liposome
CH672733A5 (en) 1987-05-22 1989-12-29 Bracco Ind Chimica Spa
US5053214A (en) * 1987-06-19 1991-10-01 Manville Corporation Process for producing zirconium based granules
ATE111231T1 (en) 1987-06-23 1994-09-15 Nycomed Innovation Ab IMPROVEMENTS IN MAGNETIC RESONANCE IMAGING.
US5354549A (en) 1987-07-24 1994-10-11 Nycomed Imaging As Iodinated esters
US4978483A (en) 1987-09-28 1990-12-18 Redding Bruce K Apparatus and method for making microcapsules
US5178875A (en) * 1991-01-14 1993-01-12 The Board Of Regents, The University Of Texas System Liposomal-polyene preliposomal powder and method for its preparation
US4839702A (en) 1987-11-20 1989-06-13 Bell Communications Research, Inc. Semiconductor device based on charge emission from a quantum well
US4873035A (en) * 1987-11-25 1989-10-10 Abbott Laboratories Preparation of sized populations of liposomes
DE3741201A1 (en) 1987-12-02 1989-06-15 Schering Ag ULTRASONIC PROCESS AND METHOD FOR IMPLEMENTING IT
IE61591B1 (en) 1987-12-29 1994-11-16 Molecular Biosystems Inc Concentrated stabilized microbubble-type ultrasonic imaging agent and method of production
US4844882A (en) 1987-12-29 1989-07-04 Molecular Biosystems, Inc. Concentrated stabilized microbubble-type ultrasonic imaging agent
DE3803972A1 (en) 1988-02-05 1989-08-10 Schering Ag Ultrasound contrast media
US5425366A (en) 1988-02-05 1995-06-20 Schering Aktiengesellschaft Ultrasonic contrast agents for color Doppler imaging
EP0398935B1 (en) 1988-02-05 1994-08-10 Schering Aktiengesellschaft Ultrasonic contrast agents, process for producing them and their use as diagnostic and therapeutic agents
US4898734A (en) 1988-02-29 1990-02-06 Massachusetts Institute Of Technology Polymer composite for controlled release or membrane formation
DE3812816A1 (en) 1988-04-16 1989-11-02 Lawaczeck Ruediger Dipl Phys P METHOD FOR SOLUBILIZING LIPOSOMES AND / OR BIOLOGICAL MEMBRANES AND THE USE THEREOF
US5171755A (en) 1988-04-29 1992-12-15 Hemagen/Pfc Emulsions of highly fluorinated organic compounds
US4893624A (en) 1988-06-21 1990-01-16 Massachusetts Institute Of Technology Diffuse focus ultrasound hyperthermia system
DE3824354A1 (en) 1988-07-19 1990-01-25 Basf Ag METHOD FOR THE PRODUCTION OF CELL-CONTAINING PLASTICS BY THE POLYISOCYANATE-POLYADDITION PROCESS BY MEANS OF STORAGE-STABLE, FUEL-CONTAINING EMULSIONS AND THESE EMULSIONS
US4993415A (en) 1988-08-19 1991-02-19 Alliance Pharmaceutical Corp. Magnetic resonance imaging with perfluorocarbon hydrides
US4996041A (en) 1988-08-19 1991-02-26 Toshiyuki Arai Method for introducing oxygen-17 into tissue for imaging in a magnetic resonance imaging system
DE3828905A1 (en) 1988-08-23 1990-03-15 Schering Ag MEDIALLY COMPOSED OF CAVITATE OR CLATHRATE MAKING HOST / GUEST COMPLEX AS A CONTRAST
US5730954A (en) * 1988-08-23 1998-03-24 Schering Aktiengesellschaft Preparation comprising cavitate- or clathrate-forming host/guest complexes as contrast agent
US5045304A (en) 1988-08-31 1991-09-03 Wayne State University Contras agent having an imaging agent coupled to viable granulocytes for use in magnetic resonance imaging of abscess and a method of preparing and using same
US5410516A (en) 1988-09-01 1995-04-25 Schering Aktiengesellschaft Ultrasonic processes and circuits for performing them
DE3829999A1 (en) 1988-09-01 1990-03-15 Schering Ag ULTRASONIC METHOD AND CIRCUITS THEREOF
US4957656A (en) 1988-09-14 1990-09-18 Molecular Biosystems, Inc. Continuous sonication method for preparing protein encapsulated microbubbles
IL91664A (en) 1988-09-28 1993-05-13 Yissum Res Dev Co Ammonium transmembrane gradient system for efficient loading of liposomes with amphipathic drugs and their controlled release
FR2637182B1 (en) 1988-10-03 1992-11-06 Lvmh Rech COMPOSITIONS BASED ON HYDRATED LIPID LAMID PHASES OR LIPOSOMES CONTAINING AN ECDYSTEROID, PREFERABLY ECDYSTERONE, OR A DERIVATIVE THEREOF; AND COSMETIC, PHARMACEUTICAL, ESPECIALLY DERMATOLOGICAL, SERICULTURE OR PHYTOSANITARY COMPOSITIONS INCORPORATING THE SAME
GB8824593D0 (en) 1988-10-20 1988-11-23 Royal Free Hosp School Med Liposomes
DE68912139T2 (en) 1988-11-09 1994-04-28 Evan C Unger LIPOSOMAL RADIOLOGICAL CONTRAST AGENTS.
US5006343A (en) * 1988-12-29 1991-04-09 Benson Bradley J Pulmonary administration of pharmaceutically active substances
LU87449A1 (en) 1989-02-09 1990-09-19 Oreal PROCESS FOR THE MANUFACTURE OF FOAMS FOR USE IN THE COSMETIC AND PHARMACEUTICAL AREAS AND FOAMS OBTAINED BY THIS PROCESS
FR2645866B1 (en) 1989-04-17 1991-07-05 Centre Nat Rech Scient NEW LIPOPOLYAMINES, THEIR PREPARATION AND THEIR USE
US5114703A (en) 1989-05-30 1992-05-19 Alliance Pharmaceutical Corp. Percutaneous lymphography using particulate fluorocarbon emulsions
ATE92931T1 (en) 1989-06-22 1993-08-15 Atta FLUORINE AND PHOSPHORUS CONTAINING AMPHIPHILIC MOLECULES WITH SURFACE ACTIVE PROPERTIES.
FR2649335B1 (en) 1989-07-05 1991-09-20 Texinfine Sa METHOD AND DEVICE FOR THE DIRECT PRODUCTION OF LIPOSOMES
US5019370A (en) 1989-07-10 1991-05-28 University Of Kentucky Research Foundation Biodegradable, low biological toxicity radiographic contrast medium and method of x-ray imaging
US5194266A (en) 1989-08-08 1993-03-16 Liposome Technology, Inc. Amphotericin B/cholesterol sulfate composition and method
US5100662A (en) * 1989-08-23 1992-03-31 The Liposome Company, Inc. Steroidal liposomes exhibiting enhanced stability
JP2935519B2 (en) 1989-08-28 1999-08-16 シーキンス,ケイ・マイケル Lung cancer hyperthermia treatment via convection with ultrasound and / or perfluorocarbon liquid
US5562608A (en) 1989-08-28 1996-10-08 Biopulmonics, Inc. Apparatus for pulmonary delivery of drugs with simultaneous liquid lavage and ventilation
US5013556A (en) 1989-10-20 1991-05-07 Liposome Technology, Inc. Liposomes with enhanced circulation time
US5620689A (en) 1989-10-20 1997-04-15 Sequus Pharmaceuuticals, Inc. Liposomes for treatment of B-cell and T-cell disorders
US5123414A (en) 1989-12-22 1992-06-23 Unger Evan C Liposomes as contrast agents for ultrasonic imaging and methods for preparing the same
US5305757A (en) 1989-12-22 1994-04-26 Unger Evan C Gas filled liposomes and their use as ultrasonic contrast agents
US5922304A (en) 1989-12-22 1999-07-13 Imarx Pharmaceutical Corp. Gaseous precursor filled microspheres as magnetic resonance imaging contrast agents
US5656211A (en) * 1989-12-22 1997-08-12 Imarx Pharmaceutical Corp. Apparatus and method for making gas-filled vesicles of optimal size
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
US6088613A (en) * 1989-12-22 2000-07-11 Imarx Pharmaceutical Corp. Method of magnetic resonance focused surgical and therapeutic ultrasound
US5733572A (en) * 1989-12-22 1998-03-31 Imarx Pharmaceutical Corp. Gas and gaseous precursor filled microspheres as topical and subcutaneous delivery vehicles
US5705187A (en) * 1989-12-22 1998-01-06 Imarx Pharmaceutical Corp. Compositions of lipids and stabilizing materials
US5149319A (en) 1990-09-11 1992-09-22 Unger Evan C Methods for providing localized therapeutic heat to biological tissues and fluids
US5580575A (en) 1989-12-22 1996-12-03 Imarx Pharmaceutical Corp. Therapeutic drug delivery systems
US5773024A (en) * 1989-12-22 1998-06-30 Imarx Pharmaceutical Corp. Container with multi-phase composition for use in diagnostic and therapeutic applications
US5230882A (en) 1989-12-22 1993-07-27 Unger Evan C Liposomes as contrast agents for ultrasonic imaging and methods for preparing the same
US5352435A (en) 1989-12-22 1994-10-04 Unger Evan C Ionophore containing liposomes for ultrasound imaging
US5542935A (en) * 1989-12-22 1996-08-06 Imarx Pharmaceutical Corp. Therapeutic delivery systems related applications
US6001335A (en) 1989-12-22 1999-12-14 Imarx Pharmaceutical Corp. Contrasting agents for ultrasonic imaging and methods for preparing the same
US5776429A (en) * 1989-12-22 1998-07-07 Imarx Pharmaceutical Corp. Method of preparing gas-filled microspheres using a lyophilized lipids
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
US5469854A (en) 1989-12-22 1995-11-28 Imarx Pharmaceutical Corp. Methods of preparing gas-filled liposomes
US5334381A (en) * 1989-12-22 1994-08-02 Unger Evan C Liposomes as contrast agents for ultrasonic imaging and methods for preparing the same
US5088499A (en) 1989-12-22 1992-02-18 Unger Evan C Liposomes as contrast agents for ultrasonic imaging and methods for preparing the same
US6146657A (en) 1989-12-22 2000-11-14 Imarx Pharmaceutical Corp. Gas-filled lipid spheres for use in diagnostic and therapeutic applications
US5741513A (en) * 1990-02-08 1998-04-21 A. Natterman & Cie. Gmbh Alcoholic aqueous gel-like phospholipid composition, its use and topical preparations containing it
DE4004430A1 (en) 1990-02-09 1991-08-14 Schering Ag CONSTRUCTED POLYALDEHYDE CONSTITUENTS
GB9003821D0 (en) 1990-02-20 1990-04-18 Danbiosyst Uk Diagnostic aid
US5445813A (en) 1992-11-02 1995-08-29 Bracco International B.V. Stable microbubble suspensions as enhancement agents for ultrasound echography
IN172208B (en) 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
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
US5279833A (en) * 1990-04-04 1994-01-18 Yale University Liposomal transfection of nucleic acids into animal cells
US5672585A (en) 1990-04-06 1997-09-30 La Jolla Cancer Research Foundation Method and composition for treating thrombosis
US5368840A (en) 1990-04-10 1994-11-29 Imarx Pharmaceutical Corp. Natural polymers as contrast media for magnetic resonance imaging
US5358702A (en) 1990-04-10 1994-10-25 Unger Evan C Methoxylated gel particle contrast media for improved diagnostic imaging
JPH05506227A (en) 1990-04-10 1993-09-16 イマルクス ファーマシューティカル コーポレーション Polymers as contrast agents for magnetic resonance imaging
US5078994A (en) 1990-04-12 1992-01-07 Eastman Kodak Company Microgel drug delivery system
JPH03297475A (en) 1990-04-16 1991-12-27 Ken Ishihara Controlling method for emission of medicine by means of resonance sound wave
US5264618A (en) 1990-04-19 1993-11-23 Vical, Inc. Cationic lipids for intracellular delivery of biologically active molecules
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
US5091188A (en) * 1990-04-26 1992-02-25 Haynes Duncan H Phospholipid-coated microcrystals: injectable formulations of water-insoluble drugs
US5246707A (en) * 1990-04-26 1993-09-21 Haynes Duncan H Sustained release delivery of water-soluble bio-molecules and drugs using phospholipid-coated microcrystals, microdroplets and high-concentration liposomes
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
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
CA2081560A1 (en) 1990-06-01 1991-12-02 Evan C. Unger Contrast media for ultrasonic imaging
US5196348A (en) 1990-06-11 1993-03-23 Air Products And Chemicals, Inc. Perfluoro-crown ethers in fluorine magnetic resonance spectroscopy of biopsied tissue
US5315997A (en) 1990-06-19 1994-05-31 Molecular Biosystems, Inc. Method of magnetic resonance imaging using diamagnetic contrast
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
FR2665159B1 (en) 1990-07-24 1992-11-13 Rhone Poulenc Sante NEW PYRIDINE AND QUINOLEIN DERIVATIVES, THEIR PREPARATION AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM.
IL95743A (en) 1990-09-19 1993-02-21 Univ Ramot Method of measuring blood flow
US5487390A (en) 1990-10-05 1996-01-30 Massachusetts Institute Of Technology Gas-filled polymeric microbubbles for ultrasound imaging
WO1992005806A1 (en) 1990-10-05 1992-04-16 Sintetica S.A. Method for the preparation of stable suspensions of hollow gas-filled microspheres suitable for ultrasonic echography
IS1685B (en) 1990-12-11 1998-02-24 Bracco International B.V. Method of making liposomes that are endowed with enhanced ability to absorb and contain foreign matter
ATE190354T1 (en) 1990-12-20 2000-03-15 Arch Dev Corp The University O CONTROL OF GENE EXPRESSION BY IONIZING RADIATION
DE4100470A1 (en) 1991-01-09 1992-07-16 Byk Gulden Lomberg Chem Fab Echo contrast agent
US5193237A (en) * 1991-01-28 1993-03-16 Holdredge Terry K Pneumatic wheel chair cushion for reducing ischemic injury
US5107842A (en) 1991-02-22 1992-04-28 Molecular Biosystems, Inc. Method of ultrasound imaging of the gastrointestinal tract
EP0504881B2 (en) 1991-03-22 2000-11-08 Katsuro Tachibana Booster for therapy of diseases with ultrasound and pharmaceutical liquid composition containing the same
GB9106686D0 (en) 1991-03-28 1991-05-15 Hafslund Nycomed As Improvements in or relating to contrast agents
WO1992017436A1 (en) 1991-03-28 1992-10-15 Holmes, Michael, John Cross-linking agent
GB9106673D0 (en) 1991-03-28 1991-05-15 Hafslund Nycomed As Improvements in or relating to contrast agents
US5205290A (en) * 1991-04-05 1993-04-27 Unger Evan C Low density microspheres and their use as contrast agents for computed tomography
US5874062A (en) * 1991-04-05 1999-02-23 Imarx Pharmaceutical Corp. Methods of computed tomography using perfluorocarbon gaseous filled microspheres as contrast agents
US5496535A (en) 1991-04-12 1996-03-05 Alliance Pharmaceutical Corp. Fluorocarbon contrast media for use with MRI and radiographic imaging
US5147631A (en) 1991-04-30 1992-09-15 Du Pont Merck Pharmaceutical Company Porous inorganic ultrasound contrast agents
EP0586524B2 (en) 1991-06-03 2000-11-02 Nycomed Imaging As Improvements in or relating to contrast agents
JP2868335B2 (en) 1991-06-13 1999-03-10 富士通株式会社 Switching system and disconnection notification method in switching system
WO1992022298A1 (en) 1991-06-18 1992-12-23 Unger Evan C Novel liposomal drug delivery systems
CA2112905A1 (en) 1991-07-05 1993-01-21 Michael R. Violante Ultrasmall non-aggregated porous particles entrapping gas-bubbles
CA2112109A1 (en) * 1991-07-05 1993-01-21 Arne Berg Improvements in or relating to contrast agents
GB9116610D0 (en) 1991-08-01 1991-09-18 Danbiosyst Uk Preparation of microparticles
US5283185A (en) * 1991-08-28 1994-02-01 University Of Tennessee Research Corporation Method for delivering nucleic acids into cells
MX9205298A (en) 1991-09-17 1993-05-01 Steven Carl Quay GASEOUS ULTRASOUND CONTRASTING MEDIA AND METHOD FOR SELECTING GASES TO BE USED AS ULTRASOUND CONTRASTING MEDIA
EP0605477B2 (en) 1991-09-17 2007-06-20 GE Healthcare AS Gaseous ultrasound contrast media
US5409688A (en) 1991-09-17 1995-04-25 Sonus Pharmaceuticals, Inc. Gaseous ultrasound contrast media
AU2789192A (en) 1991-10-04 1993-05-03 Mallinckrodt Medical, Inc. Gaseous ultrasound contrast agents
US5362477A (en) 1991-10-25 1994-11-08 Mallinckrodt Medical, Inc. 19F magnetic resonance imaging agents which include a nitroxide moiety
US5264220A (en) 1991-11-12 1993-11-23 Long David M Jr Method of extending the vascular dwell-time of particulate therapeutic and particulate diagnostic agents
US5196183A (en) 1991-12-04 1993-03-23 Sterling Winthrop Inc. Contrast agents for ultrasound imaging
US5403575A (en) 1991-12-12 1995-04-04 Hemagen/Pfc Highly fluorinated, chloro-substituted organic compound-containing emulsions and methods of using them
GB9200387D0 (en) 1992-01-09 1992-02-26 Nycomed As Improvements in or relating to contrast agents
GB9200388D0 (en) 1992-01-09 1992-02-26 Nycomed As Improvements in or relating to contrast agents
GB9200391D0 (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 Long-lasting aqueous suspensions of pressure-resistant gas-filled microvesicles their preparation and contrast agents consisting of them
WO1993015722A1 (en) 1992-02-07 1993-08-19 Syntex (Usa) Inc. Controlled delivery of pharmaceuticals from preformed porous microparticles
JP3325300B2 (en) 1992-02-28 2002-09-17 株式会社東芝 Ultrasound therapy equipment
IL104963A (en) 1992-03-06 1997-09-30 Nycomed Imaging As Contrast agents comprising methylene diester unit- containing biodegradable polymers
US5247935A (en) 1992-03-19 1993-09-28 General Electric Company Magnetic resonance guided focussed ultrasound surgery
WO1993020802A1 (en) 1992-04-09 1993-10-28 Northwestern University Acoustically reflective liposomes and methods to make and use the same
US5858399A (en) 1992-04-09 1999-01-12 Northwestern University Acoustically reflective liposomes and methods to make and use the same
US5339814A (en) 1992-04-14 1994-08-23 Lasker Sigmund E Process for visualizing tissue metabolism using oxygen-17
US5846516A (en) 1992-06-03 1998-12-08 Alliance Pharmaceutial Corp. Perfluoroalkylated amphiphilic phosphorus compounds: preparation and biomedical applications
DE4221256C2 (en) 1992-06-26 1997-07-10 Lancaster Group Ag Galenic composition for topical use
US5334761A (en) * 1992-08-28 1994-08-02 Life Technologies, Inc. Cationic lipids
DE69319438T2 (en) 1992-09-16 1998-12-03 Nycomed Imaging As IMPROVEMENTS TO CONTRAST AGENTS
DE4232755A1 (en) 1992-09-26 1994-03-31 Schering Ag Microparticle preparations made from biodegradable copolymers
US5552155A (en) 1992-12-04 1996-09-03 The Liposome Company, Inc. Fusogenic lipsomes and methods for making and using same
US5326552A (en) * 1992-12-17 1994-07-05 Sterling Winthrop Inc. Formulations for nanoparticulate x-ray blood pool contrast agents using high molecular weight nonionic surfactants
US5558855A (en) 1993-01-25 1996-09-24 Sonus Pharmaceuticals Phase shift colloids as ultrasound contrast agents
SG52198A1 (en) 1993-01-25 1998-09-28 Sonus Pharma Inc Phase shift colloids as ultrasound contrast agents
FR2700952B1 (en) 1993-01-29 1995-03-17 Oreal New cosmetic or dermopharmaceutical compositions in the form of aqueous gels modified by the addition of expanded microspheres.
SE501697C2 (en) * 1993-02-11 1995-04-24 Svenska Mejeriernas Riksforeni Process for the recovery of sphingomyelin
US5362478A (en) 1993-03-26 1994-11-08 Vivorx Pharmaceuticals, Inc. Magnetic resonance imaging with fluorocarbons encapsulated in a cross-linked polymeric shell
ATE264671T1 (en) 1993-02-22 2004-05-15 American Bioscience Inc METHOD FOR THE IN VIVO ADMINISTRATION OF BIOLOGICAL SUBSTANCES AND COMPOSITIONS USABLE THEREFOR
JPH06247842A (en) * 1993-02-23 1994-09-06 Green Cross Corp:The Production of liposome composition
GB9305349D0 (en) 1993-03-16 1993-05-05 Nycomed Imaging As Improvements in or relating to contrast agents
AU6365894A (en) 1993-03-16 1994-10-11 Alliance Pharmaceutical Corporation Fluorocarbon compositions containing a visible or fluorescent label
GB9305351D0 (en) 1993-03-16 1993-05-05 Nycomed Imaging As Improvements in or relating to contrast agents
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
US5567415A (en) 1993-05-12 1996-10-22 The Board Of Regents Of The University Of Nebraska Ultrasound contrast agents and methods for their manufacture and use
US5716597A (en) 1993-06-04 1998-02-10 Molecular Biosystems, Inc. Emulsions as contrast agents and method of 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
CA2166459C (en) 1993-07-02 2000-03-28 Karel J. Lambert Methods for making encapsulated microspheres from heat denatured protein
US5565215A (en) 1993-07-23 1996-10-15 Massachusettes Institute Of Technology Biodegradable injectable particles for imaging
US5798091A (en) * 1993-07-30 1998-08-25 Alliance Pharmaceutical Corp. Stabilized gas emulsion containing phospholipid for ultrasound contrast enhancement
DK0711179T3 (en) 1993-07-30 2005-02-14 Imcor Pharmaceutical Co Stabilized ultrasound microbubble compositions
GB9318288D0 (en) 1993-09-03 1993-10-20 Nycomed Imaging As Improvements in or relating to contrast agents
DK0717617T3 (en) 1993-09-09 2001-02-05 Schering Ag Microparticles containing active ingredients and gas
WO1995012387A1 (en) 1993-11-05 1995-05-11 Amgen Inc. Liposome preparation and material encapsulation method
US5433204A (en) 1993-11-16 1995-07-18 Camilla Olson Method of assessing placentation
US7083572B2 (en) * 1993-11-30 2006-08-01 Bristol-Myers Squibb Medical Imaging, Inc. Therapeutic delivery systems
CZ208995A3 (en) 1993-12-15 1996-01-17 Bracco Research Sa Injectable ultrasound medium, process of its preparation and use
NO940711D0 (en) 1994-03-01 1994-03-01 Nycomed Imaging As Preparation of gas-filled microcapsules and contrast agents for diagnostic imaging
US5667472A (en) 1994-03-18 1997-09-16 Clarus Medical Systems, Inc. Surgical instrument and method for use with a viewing system
ZA952485B (en) 1994-03-28 1995-12-15 Nycomed Imaging As Liposomes
US5545396A (en) 1994-04-08 1996-08-13 The Research Foundation Of State University Of New York Magnetic resonance imaging using hyperpolarized noble gases
CA2189366A1 (en) 1994-05-03 1995-11-09 Kenneth J. Widder Composition for ultrasonically quantitating myocardial perfusion
US5571797A (en) 1994-05-11 1996-11-05 Arch Development Corporation Method of inducing gene expression by ionizing radiation
US5502094A (en) 1994-05-20 1996-03-26 Minnesota Mining And Manufacturing Company Physiologically acceptable emulsions containing perfluorocarbon ether hydrides and methods for use
US5736121A (en) 1994-05-23 1998-04-07 Imarx Pharmaceutical Corp. Stabilized homogenous suspensions as computed tomography contrast agents
US5571498A (en) 1994-06-02 1996-11-05 Hemagen/Pfc Emulsions of paramagnetic contrast agents for magnetic resonance imaging (MRI).
ES2150575T3 (en) 1994-07-07 2000-12-01 Bayer Ag DERIVATIVES OF 3-ARILCICLOPENTAN-1,3-DIONA.
US6159445A (en) 1994-07-20 2000-12-12 Nycomed Imaging As Light imaging 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
US5562893A (en) 1994-08-02 1996-10-08 Molecular Biosystems, Inc. Gas-filled microspheres with fluorine-containing shells
US6113570A (en) * 1994-09-09 2000-09-05 Coraje, Inc. Method of removing thrombosis in fistulae
US5509896A (en) 1994-09-09 1996-04-23 Coraje, Inc. Enhancement of thrombolysis with external ultrasound
JPH08151335A (en) 1994-09-27 1996-06-11 Otsuka Pharmaceut Co Ltd Ultrasonic contrast medium and production thereof
US5540909A (en) 1994-09-28 1996-07-30 Alliance Pharmaceutical Corp. Harmonic ultrasound imaging with microbubbles
US5820873A (en) * 1994-09-30 1998-10-13 The University Of British Columbia Polyethylene glycol modified ceramide lipids and liposome uses thereof
US6027726A (en) * 1994-09-30 2000-02-22 Inex Phamaceuticals Corp. Glycosylated protein-liposome conjugates and methods for their preparation
US5569448A (en) 1995-01-24 1996-10-29 Nano Systems L.L.C. Sulfated nonionic block copolymer surfactants as stabilizer coatings for nanoparticle compositions
EP0727225A3 (en) 1995-02-14 1997-01-15 Sonus Pharma Inc Compositions and methods for directed ultrasound imaging
US5556372A (en) 1995-02-15 1996-09-17 Exogen, Inc. Apparatus for ultrasonic bone treatment
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
WO1996036286A1 (en) 1995-05-15 1996-11-21 Coraje, Inc. Enhancement of ultrasound thrombolysis
US5997898A (en) 1995-06-06 1999-12-07 Imarx Pharmaceutical Corp. Stabilized compositions of fluorinated amphiphiles for methods of therapeutic delivery
US5558092A (en) 1995-06-06 1996-09-24 Imarx Pharmaceutical Corp. Methods and apparatus for performing diagnostic and therapeutic ultrasound simultaneously
US5804162A (en) 1995-06-07 1998-09-08 Alliance Pharmaceutical Corp. Gas emulsions stabilized with fluorinated ethers having low Ostwald coefficients
US6033645A (en) 1996-06-19 2000-03-07 Unger; Evan C. Methods for diagnostic imaging by regulating the administration rate of a contrast agent
US5606973A (en) 1995-06-07 1997-03-04 Molecular Biosystems, Inc. Liquid core microdroplets for ultrasound imaging
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
US6521211B1 (en) 1995-06-07 2003-02-18 Bristol-Myers Squibb Medical Imaging, Inc. Methods of imaging and treatment with targeted compositions
AU709562B2 (en) * 1995-06-07 1999-09-02 Imarx Pharmaceutical Corp. Novel targeted compositions for diagnostic and therapeutic use
US5897851A (en) 1995-06-07 1999-04-27 Sonus Pharmaceuticals, Inc. Nucleation and activation of a liquid-in-liquid emulsion for use in ultrasound imaging
US6139819A (en) 1995-06-07 2000-10-31 Imarx Pharmaceutical Corp. Targeted contrast agents for diagnostic and therapeutic use
US5780010A (en) 1995-06-08 1998-07-14 Barnes-Jewish Hospital Method of MRI using avidin-biotin conjugated emulsions as a site specific binding system
US5958371A (en) 1995-06-08 1999-09-28 Barnes-Jewish Hospital Site specific binding system, nuclear imaging compositions and methods
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
US5840023A (en) 1996-01-31 1998-11-24 Oraevsky; Alexander A. Optoacoustic imaging for medical diagnosis
US6165442A (en) * 1996-02-19 2000-12-26 Nycomed Imaging As Thermally stabilized ultrasound contrast agent
US5879659A (en) * 1996-03-13 1999-03-09 Dupont Pharmaceuticals Company Ternary radiopharmaceutical complexes
US6455277B1 (en) * 1996-04-22 2002-09-24 Amgen Inc. Polynucleotides encoding human glial cell line-derived neurotrophic factor receptor polypeptides
AU736301B2 (en) 1996-05-01 2001-07-26 Imarx Therapeutics, Inc. Methods for delivering compounds into a cell
US5976501A (en) 1996-06-07 1999-11-02 Molecular Biosystems, Inc. Use of pressure resistant protein microspheres encapsulating gases as ultrasonic imaging agents for vascular perfusion
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
US6214375B1 (en) 1996-07-16 2001-04-10 Generex Pharmaceuticals, Inc. Phospholipid formulations
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
CA2263568C (en) * 1996-09-11 2008-12-02 Imarx Pharmaceutical Corp. Methods for diagnostic imaging using a contrast agent and a renal vasodilator
US5846517A (en) 1996-09-11 1998-12-08 Imarx Pharmaceutical Corp. Methods for diagnostic imaging using a renal contrast agent and a vasodilator
DE69738406T2 (en) 1996-10-21 2008-12-04 Ge Healthcare As Improvements in or on contrast agents
WO1998018498A2 (en) 1996-10-28 1998-05-07 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
US6331289B1 (en) 1996-10-28 2001-12-18 Nycomed Imaging As Targeted diagnostic/therapeutic agents having more than one different vectors
EP0973552B1 (en) 1996-10-28 2006-03-01 Amersham Health AS Improvements in or relating to diagnostic/therapeutic agents
EP0991427A2 (en) 1996-10-28 2000-04-12 Marsden, John Christopher Improvements in or relating to diagnostic/therapeutic agents
CA2269985A1 (en) 1996-10-28 1998-05-07 Aslak Godal Improvements in or relating to diagnostic/therapeutic agents
US6210707B1 (en) * 1996-11-12 2001-04-03 The Regents Of The University Of California Methods of forming protein-linked lipidic microparticles, and compositions thereof
US6537246B1 (en) * 1997-06-18 2003-03-25 Imarx Therapeutics, Inc. Oxygen delivery agents 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
US6090800A (en) * 1997-05-06 2000-07-18 Imarx Pharmaceutical Corp. Lipid soluble steroid prodrugs
CA2286052A1 (en) * 1997-04-17 1998-10-29 Lise Sylvest Nielsen A novel bioadhesive drug delivery system based on liquid crystals
WO1998050041A1 (en) 1997-05-06 1998-11-12 Imarx Pharmaceutical Corp. Novel prodrugs comprising fluorinated amphiphiles
US5980936A (en) 1997-08-07 1999-11-09 Alliance Pharmaceutical Corp. Multiple emulsions comprising a hydrophobic continuous phase
GB9717588D0 (en) 1997-08-19 1997-10-22 Nycomed Imaging As Improvements in or relating to contrast agents
US6548047B1 (en) * 1997-09-15 2003-04-15 Bristol-Myers Squibb Medical Imaging, Inc. Thermal preactivation of gaseous precursor filled compositions
US6123923A (en) * 1997-12-18 2000-09-26 Imarx Pharmaceutical Corp. Optoacoustic contrast agents and methods for their use
US20010003580A1 (en) * 1998-01-14 2001-06-14 Poh K. Hui Preparation of a lipid blend and a phospholipid suspension containing the lipid blend
DE69925461T2 (en) 1998-02-09 2006-04-27 Bracco International B.V. TARGETED DISTRIBUTION OF BIOLOGICAL-ACTIVE MEDIA
US6261231B1 (en) * 1998-09-22 2001-07-17 Dupont Pharmaceuticals Company Hands-free ultrasound probe holder
US6398772B1 (en) * 1999-03-26 2002-06-04 Coraje, Inc. Method and apparatus for emergency treatment of patients experiencing a thrombotic vascular occlusion
US6254852B1 (en) * 1999-07-16 2001-07-03 Dupont Pharmaceuticals Company Porous inorganic targeted ultrasound contrast agents
US6572840B1 (en) * 1999-07-28 2003-06-03 Bristol-Myers Squibb Pharma Company Stable microbubbles comprised of a perfluoropropane encapsulated lipid moiety for use as an ultrasound contrast agent
GB9920392D0 (en) 1999-08-27 1999-11-03 Nycomed Imaging As Improvemets in or relating to diagnostic imaging
US6635017B1 (en) * 2000-02-09 2003-10-21 Spentech, Inc. Method and apparatus combining diagnostic ultrasound with therapeutic ultrasound to enhance thrombolysis
US6943692B2 (en) * 2001-02-02 2005-09-13 Bristol-Myers Squibb Pharma Company Apparatus and methods for on-line monitoring of fluorinated material in headspace of vial
CA2474386C (en) * 2002-01-24 2011-07-05 Barnes-Jewish Hospital Integrin targeted imaging agents
US20040062748A1 (en) 2002-09-30 2004-04-01 Mountain View Pharmaceuticals, Inc. Polymer conjugates with decreased antigenicity, methods of preparation and uses thereof
US10279053B2 (en) 2011-07-19 2019-05-07 Nuvox Pharma Llc Microbubble compositions, method of making same, and method using same

Patent Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5053217A (en) * 1984-03-08 1991-10-01 Phares Pharmaceutical Research Nv Composition and method
US5843473A (en) * 1989-10-20 1998-12-01 Sequus Pharmaceuticals, Inc. Method of treatment of infected tissues
US5585112A (en) * 1989-12-22 1996-12-17 Imarx Pharmaceutical Corp. Method of preparing gas and gaseous precursor-filled microspheres
US5738869A (en) * 1993-04-23 1998-04-14 Haxal Ag Transdermal drug preparation
US5853755A (en) * 1993-07-28 1998-12-29 Pharmaderm Laboratories Ltd. Biphasic multilamellar lipid vesicles
US5776488A (en) * 1994-03-11 1998-07-07 Yoshitomi Pharmaceutical Industries, Ltd. Liposome preparation
US6066331A (en) * 1994-07-08 2000-05-23 Barenholz; Yechezkel Method for preparation of vesicles loaded with biological structures, biopolymers and/or oligomers
US6120794A (en) * 1995-09-26 2000-09-19 University Of Pittsburgh Emulsion and micellar formulations for the delivery of biologically active substances to cells
US6416740B1 (en) * 1997-05-13 2002-07-09 Bristol-Myers Squibb Medical Imaging, Inc. Acoustically active drug delivery systems

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10022460B2 (en) 2014-12-31 2018-07-17 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
US11395856B2 (en) 2014-12-31 2022-07-26 Lantheus Medical Imaging, Inc. Lipid-encapsulated gas microsphere compositions and related methods
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
US10583208B2 (en) 2016-07-06 2020-03-10 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
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
US11529431B2 (en) 2016-07-06 2022-12-20 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

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