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. 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 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.
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.
[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:
(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:
(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:
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.
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.
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.
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.
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:
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.
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.
This application is a continuation of U.S. patent application Ser. No. 13/195,734, filed Aug. 1, 2011, now pending, which is a divisional of U.S. patent application Ser. No. 10/667,931, filed Sep. 22, 2003, now issued as U.S. Pat. No. 8,084,056, which is a continuation of U.S. patent application Ser. No. 09/229,258, filed Jan. 13, 1999, now abandoned, which claims the benefit under 35 U.S.C. §119(e) of U.S. Provisional Patent Application No. 60/071,332, filed Jan. 14, 1998, the entire contents of each of which are incorporated by reference herein.
Number | Name | Date | Kind |
---|---|---|---|
3015128 | Sommerville et al. | Jan 1962 | A |
3291843 | Fritz et al. | Dec 1966 | A |
3293114 | Kenaga et al. | Dec 1966 | A |
3479811 | Walters | Nov 1969 | A |
3488714 | Walters et al. | Jan 1970 | A |
3532500 | Priest et al. | Oct 1970 | A |
3557294 | Dear et al. | Jan 1971 | A |
3594326 | Himmel et al. | Jul 1971 | A |
3615972 | Morehouse, Jr. et al. | Oct 1971 | A |
3650831 | Jungermann et al. | Mar 1972 | A |
3732172 | Herbig et al. | May 1973 | A |
3873564 | Schneider et al. | Mar 1975 | A |
3945956 | Garner | Mar 1976 | A |
3960583 | Netting et al. | Jun 1976 | A |
3968203 | Spitzer et al. | Jul 1976 | A |
4004384 | Hood | Jan 1977 | A |
4027007 | Messina | May 1977 | A |
4089801 | Schneider | May 1978 | A |
4108806 | Cohrs et al. | Aug 1978 | A |
4138383 | Rembaum et al. | Feb 1979 | A |
4162282 | Fulwyler et al. | Jul 1979 | A |
4179546 | Garner et al. | Dec 1979 | A |
4192859 | Mackaness et al. | Mar 1980 | A |
4224179 | Schneider | Sep 1980 | A |
4229360 | Schneider et al. | Oct 1980 | A |
4235871 | Papahadjopoulos et al. | Nov 1980 | A |
4265251 | Tickner | May 1981 | A |
4276885 | Tickner et al. | Jul 1981 | A |
4303736 | Torobin | Dec 1981 | A |
4310505 | Baldeschwieler et al. | Jan 1982 | A |
4310506 | Baldeschwieler et al. | Jan 1982 | A |
4315514 | Drewes et al. | Feb 1982 | A |
4331654 | Morris | May 1982 | A |
4342826 | Cole | Aug 1982 | A |
4344929 | Bonsen et al. | Aug 1982 | A |
4420442 | Sands | Dec 1983 | A |
4421562 | Sands | Dec 1983 | A |
4426330 | Sears | Jan 1984 | A |
4427649 | Dingle et al. | Jan 1984 | A |
4428924 | Millington | Jan 1984 | A |
4442843 | Rasor et al. | Apr 1984 | A |
4466442 | Hilmann et al. | Aug 1984 | A |
4474773 | Shinitzky et al. | Oct 1984 | A |
4485193 | Rubens et al. | Nov 1984 | A |
4515736 | Deamer | May 1985 | A |
4522803 | Lenk et al. | Jun 1985 | A |
4530360 | Duarte | Jul 1985 | A |
4533254 | Cook et al. | Aug 1985 | A |
4534899 | Sears | Aug 1985 | A |
4540629 | Sands et al. | Sep 1985 | A |
4544545 | Ryan et al. | Oct 1985 | A |
4549892 | Baker et al. | Oct 1985 | A |
4569836 | Gordon | Feb 1986 | A |
4572203 | Feinstein | Feb 1986 | A |
4582756 | Niinuma et al. | Apr 1986 | A |
4586512 | Do-huu et al. | May 1986 | A |
4603044 | Geho et al. | Jul 1986 | A |
4615879 | Runge et al. | Oct 1986 | A |
4620546 | Aida et al. | Nov 1986 | A |
4621023 | Redziniak et al. | Nov 1986 | A |
4636381 | Takada et al. | Jan 1987 | A |
4646756 | Watmough et al. | Mar 1987 | A |
4657756 | Rasor et al. | Apr 1987 | A |
4658828 | Dory | Apr 1987 | A |
4663161 | Mannino et al. | May 1987 | A |
4675310 | Chapman et al. | Jun 1987 | A |
4680171 | Shell | Jul 1987 | A |
4681119 | Rasor et al. | Jul 1987 | A |
4683092 | Tsang | Jul 1987 | A |
4684479 | D'Arrigo | Aug 1987 | A |
4687661 | Kikuchi et al. | Aug 1987 | A |
4689986 | Carson et al. | Sep 1987 | A |
4693999 | Axelsson et al. | Sep 1987 | A |
4718433 | Feinstein | Jan 1988 | A |
4722943 | Melber et al. | Feb 1988 | A |
4728575 | Gamble et al. | Mar 1988 | A |
4728578 | Higgins et al. | Mar 1988 | A |
4731239 | Gordon | Mar 1988 | A |
4737323 | Martin et al. | Apr 1988 | A |
4748216 | Tom | May 1988 | A |
4753788 | Gamble | Jun 1988 | A |
4761288 | Mezei | Aug 1988 | A |
4767610 | Long | Aug 1988 | A |
4774958 | Feinstein | Oct 1988 | A |
4775522 | Clark, Jr. | Oct 1988 | A |
4776991 | Farmer et al. | Oct 1988 | A |
4781871 | West, III et al. | Nov 1988 | A |
4789501 | Day et al. | Dec 1988 | A |
4790891 | Halliday et al. | Dec 1988 | A |
4822534 | Lencki et al. | Apr 1989 | A |
4830858 | Payne et al. | May 1989 | A |
4832941 | Berwing et al. | May 1989 | A |
4834964 | Rosen | May 1989 | A |
4844882 | Widder et al. | Jul 1989 | A |
4863717 | Keana | Sep 1989 | A |
4863740 | Kissel et al. | Sep 1989 | A |
4865836 | Long, Jr. | Sep 1989 | A |
4866096 | Schweighardt | Sep 1989 | A |
4873035 | Wong | Oct 1989 | A |
4877561 | Iga et al. | Oct 1989 | A |
4880635 | Janoff et al. | Nov 1989 | A |
4893624 | Lele | Jan 1990 | A |
4895719 | Radhakrishnan et al. | Jan 1990 | A |
4895876 | Schweighardt et al. | Jan 1990 | A |
4898734 | Mathiowitz et al. | Feb 1990 | A |
4900540 | Ryan et al. | Feb 1990 | A |
4918065 | Stindl et al. | Apr 1990 | A |
4919895 | Heldebrant et al. | Apr 1990 | A |
4921706 | Roberts et al. | May 1990 | A |
4927623 | Long, Jr. | May 1990 | A |
4933121 | Law et al. | Jun 1990 | A |
4938947 | Nicolau et al. | Jul 1990 | A |
4946787 | Eppstein et al. | Aug 1990 | A |
4957656 | Cerny et al. | Sep 1990 | A |
4972002 | Volkert | Nov 1990 | A |
4978483 | Redding, Jr. | Dec 1990 | A |
4981692 | Popescu et al. | Jan 1991 | A |
4984573 | Leunbach | Jan 1991 | A |
4985550 | Charpiot et al. | Jan 1991 | A |
4987154 | Long, Jr. | Jan 1991 | A |
4993415 | Long | Feb 1991 | A |
4996041 | Arai et al. | Feb 1991 | A |
5000960 | Wallach | Mar 1991 | A |
5004611 | Leigh | Apr 1991 | A |
5006343 | Benson et al. | Apr 1991 | A |
5008050 | Cullis et al. | Apr 1991 | A |
5008109 | Tin | Apr 1991 | A |
5013556 | Woodle et al. | May 1991 | A |
5019370 | Jay et al. | May 1991 | A |
5045304 | Schneider et al. | Sep 1991 | A |
5049322 | Devissaguet et al. | Sep 1991 | A |
5049388 | Knight et al. | Sep 1991 | A |
5053214 | Jada | Oct 1991 | A |
5053217 | Lehigh | Oct 1991 | A |
5077036 | Long, Jr. | Dec 1991 | A |
5078994 | Nair et al. | Jan 1992 | A |
5080885 | Long, Jr. | Jan 1992 | A |
5088499 | Unger | Feb 1992 | A |
5089181 | Hauser | Feb 1992 | A |
5091188 | Haynes | Feb 1992 | A |
5100662 | Bolcsak et al. | Mar 1992 | A |
5107842 | Levene et al. | Apr 1992 | A |
5114703 | Wolf et al. | May 1992 | A |
5123414 | Unger | Jun 1992 | A |
5135000 | Akselrod et al. | Aug 1992 | A |
5137928 | Erbel et al. | Aug 1992 | A |
5141738 | Rasor et al. | Aug 1992 | A |
5147631 | Glajch et al. | Sep 1992 | A |
5149319 | Unger | Sep 1992 | A |
5171577 | Griat et al. | Dec 1992 | A |
5171678 | Behr et al. | Dec 1992 | A |
5171755 | Kaufman et al. | Dec 1992 | A |
5174930 | Stainmesse et al. | Dec 1992 | A |
5186922 | Shell et al. | Feb 1993 | A |
5190766 | Ishihara | Mar 1993 | A |
5190982 | Erbel et al. | Mar 1993 | A |
5192549 | Barenolz et al. | Mar 1993 | A |
5194188 | Guitierrez | Mar 1993 | A |
5194266 | Abra et al. | Mar 1993 | A |
5195520 | Schlief et al. | Mar 1993 | A |
5196183 | Yudelson et al. | Mar 1993 | A |
5196348 | Schweighardt et al. | Mar 1993 | A |
5198225 | Meybeck et al. | Mar 1993 | A |
5205287 | Erbel et al. | Apr 1993 | A |
5205290 | Unger | Apr 1993 | A |
5209720 | Unger | May 1993 | A |
5213804 | Martin et al. | May 1993 | A |
5215680 | D'Arrigo | Jun 1993 | A |
5219538 | Henderson et al. | Jun 1993 | A |
5228446 | Unger et al. | Jul 1993 | A |
5230882 | Unger | Jul 1993 | A |
5246707 | Haynes | Sep 1993 | A |
5247935 | Cline et al. | Sep 1993 | A |
5264618 | Felgner et al. | Nov 1993 | A |
5271928 | Schneider et al. | Dec 1993 | A |
5279833 | Rose | Jan 1994 | A |
5281408 | Unger | Jan 1994 | A |
5283185 | Epand et al. | Feb 1994 | A |
5283255 | Levy et al. | Feb 1994 | A |
5305757 | Unger et al. | Apr 1994 | A |
5310540 | Giddey et al. | May 1994 | A |
5315997 | Widder et al. | May 1994 | A |
5315998 | Tachibana et al. | May 1994 | A |
5316771 | Barenholz et al. | May 1994 | A |
5326552 | Na et al. | Jul 1994 | A |
5334381 | Unger | Aug 1994 | A |
5334761 | Gebeyehu et al. | Aug 1994 | A |
5339814 | Lasker | Aug 1994 | A |
5344930 | Riess et al. | Sep 1994 | A |
5348016 | Unger et al. | Sep 1994 | A |
5350571 | Kaufman et al. | Sep 1994 | A |
5352435 | Unger | Oct 1994 | A |
5354549 | Klaveness et al. | Oct 1994 | A |
5358702 | Unger | Oct 1994 | A |
5362477 | Moore et al. | Nov 1994 | A |
5362478 | Desai et al. | Nov 1994 | A |
5368840 | Unger | Nov 1994 | A |
5380411 | Schlief | Jan 1995 | A |
5380519 | Schneider et al. | Jan 1995 | A |
5393513 | Long, Jr. | Feb 1995 | A |
5393524 | Quay | Feb 1995 | A |
5403575 | Kaufman et al. | Apr 1995 | A |
5409688 | Quay | Apr 1995 | A |
5410516 | Uhlendorf et al. | Apr 1995 | A |
5413774 | Schneider et al. | May 1995 | A |
5425366 | Reinhardt et al. | Jun 1995 | A |
5433204 | Olson | Jul 1995 | A |
5445813 | Schneider et al. | Aug 1995 | A |
5456900 | Unger | Oct 1995 | A |
5456901 | Unger | Oct 1995 | A |
5460800 | Walters | Oct 1995 | A |
5469854 | Unger et al. | Nov 1995 | A |
5470582 | Supersaxo et al. | Nov 1995 | A |
5485839 | Aida et al. | Jan 1996 | A |
5487390 | Cohen et al. | Jan 1996 | A |
5496535 | Kirkland | Mar 1996 | A |
5496536 | Wolf | Mar 1996 | A |
5498421 | Grinstaff et al. | Mar 1996 | A |
5501863 | Rossling et al. | Mar 1996 | A |
5502094 | Moore et al. | Mar 1996 | A |
5505932 | Grinstaff et al. | Apr 1996 | A |
5508021 | Grinstaff et al. | Apr 1996 | A |
5512268 | Grinstaff et al. | Apr 1996 | A |
5514720 | Clark, Jr. et al. | May 1996 | A |
5527521 | Unger | Jun 1996 | A |
5529766 | Klaveness et al. | Jun 1996 | A |
5531980 | Schneider et al. | Jul 1996 | A |
5533217 | Holdredge | Jul 1996 | A |
5536489 | Lohrmann et al. | Jul 1996 | A |
5536490 | Klaveness et al. | Jul 1996 | A |
5536753 | Clark, Jr. | Jul 1996 | A |
5539814 | Shoji | Jul 1996 | A |
5540909 | Schutt | Jul 1996 | A |
5542935 | Unger et al. | Aug 1996 | A |
5545396 | Albert et al. | Aug 1996 | A |
5547656 | Unger | Aug 1996 | A |
5552133 | Lambert et al. | Sep 1996 | A |
5552155 | Bailey et al. | Sep 1996 | A |
5556372 | Talish et al. | Sep 1996 | A |
5556610 | Yan et al. | Sep 1996 | A |
5558092 | Unger et al. | Sep 1996 | A |
5558094 | Quay | Sep 1996 | A |
5558853 | Quay | Sep 1996 | A |
5558854 | Quay | Sep 1996 | A |
5558855 | Quay | Sep 1996 | A |
5558856 | Klaveness et al. | Sep 1996 | A |
5560364 | Porter | Oct 1996 | A |
5562608 | Sekins et al. | Oct 1996 | A |
5562893 | Lohrmann | Oct 1996 | A |
5565215 | Gref et al. | Oct 1996 | A |
5567412 | Klaveness et al. | Oct 1996 | A |
5567413 | Klaveness et al. | Oct 1996 | A |
5567414 | Schneider et al. | Oct 1996 | A |
5567415 | Porter | Oct 1996 | A |
5567765 | Moore et al. | Oct 1996 | A |
5569448 | Wong et al. | Oct 1996 | A |
5569449 | Klaveness et al. | Oct 1996 | A |
5571497 | Unger | Nov 1996 | A |
5571498 | Cacheris et al. | Nov 1996 | A |
5571797 | Ohno et al. | Nov 1996 | A |
5573751 | Quay | Nov 1996 | A |
5578292 | Schneider et al. | Nov 1996 | A |
5580575 | Unger et al. | Dec 1996 | A |
5585112 | Unger et al. | Dec 1996 | A |
5593680 | Bara et al. | Jan 1997 | A |
5595723 | Quay | Jan 1997 | A |
5605673 | Schutt et al. | Feb 1997 | A |
5606973 | Lambert et al. | Mar 1997 | A |
5607661 | Berg et al. | Mar 1997 | A |
5612057 | Lanza et al. | Mar 1997 | A |
5612318 | Weichselbaum et al. | Mar 1997 | A |
5614169 | Klaveness et al. | Mar 1997 | A |
5620689 | Allen et al. | Apr 1997 | A |
5626833 | Schutt et al. | May 1997 | A |
5635539 | Clark, Jr. et al. | Jun 1997 | A |
5637289 | Klaveness et al. | Jun 1997 | A |
5639443 | Schutt et al. | Jun 1997 | A |
5639473 | Grinstaff et al. | Jun 1997 | A |
5643553 | Schneider et al. | Jul 1997 | A |
5648095 | Illum et al. | Jul 1997 | A |
5648098 | Porter | Jul 1997 | A |
5656211 | Unger et al. | Aug 1997 | A |
5662931 | Munechika et al. | Sep 1997 | A |
5667472 | Finn et al. | Sep 1997 | A |
5672585 | Pierschbacher et al. | Sep 1997 | A |
5676928 | Klaveness et al. | Oct 1997 | A |
5677472 | Nyberg et al. | Oct 1997 | A |
5679459 | Riess et al. | Oct 1997 | A |
5686060 | Schneider et al. | Nov 1997 | A |
5686102 | Gross et al. | Nov 1997 | A |
5695460 | Siegel et al. | Dec 1997 | A |
5695741 | Schutt et al. | Dec 1997 | A |
5701899 | Porter | Dec 1997 | A |
5705187 | Unger | Jan 1998 | A |
5707352 | Sekins et al. | Jan 1998 | A |
5707606 | Quay | Jan 1998 | A |
5707607 | Quay | Jan 1998 | A |
5711933 | Bichon et al. | Jan 1998 | A |
5715824 | Unger et al. | Feb 1998 | A |
5716597 | Lohrmann et al. | Feb 1998 | A |
5730954 | Albayrak et al. | Mar 1998 | A |
5732707 | Widder et al. | Mar 1998 | A |
5733527 | Schutt | Mar 1998 | A |
5733572 | Unger et al. | Mar 1998 | A |
5736121 | Unger | Apr 1998 | A |
5740807 | Porter | Apr 1998 | A |
5741513 | Ghyczy et al. | Apr 1998 | A |
5769080 | Unger et al. | Jun 1998 | A |
5770222 | Unger et al. | Jun 1998 | A |
5773024 | Unger et al. | Jun 1998 | A |
5776429 | Unger et al. | Jul 1998 | A |
5785950 | Kaufman et al. | Jul 1998 | A |
5798091 | Trevino et al. | Aug 1998 | A |
5804162 | Kabalnov et al. | Sep 1998 | A |
5820873 | Choi et al. | Oct 1998 | A |
5830430 | Unger et al. | Nov 1998 | A |
5840023 | Oraevsky et al. | Nov 1998 | A |
5840661 | Fischer et al. | Nov 1998 | A |
5846517 | Unger | Dec 1998 | A |
5849727 | Porter et al. | Dec 1998 | A |
5853752 | Unger et al. | Dec 1998 | A |
5855865 | Lambert et al. | Jan 1999 | A |
5858399 | Lanza et al. | Jan 1999 | A |
5874062 | Unger | Feb 1999 | A |
5879659 | Edwards et al. | Mar 1999 | A |
5897851 | Quay et al. | Apr 1999 | A |
5922304 | Unger | Jul 1999 | A |
5935553 | Unger et al. | Aug 1999 | A |
5958371 | Lanza et al. | Sep 1999 | A |
5965109 | Lohrmann | Oct 1999 | A |
5965158 | Link et al. | Oct 1999 | A |
5976501 | Jablonski | Nov 1999 | A |
5980936 | Krafft et al. | Nov 1999 | A |
5985246 | Unger | Nov 1999 | A |
5989520 | Lanza et al. | Nov 1999 | A |
5997898 | Unger | Dec 1999 | A |
6001335 | Unger | Dec 1999 | A |
6027726 | Ansell | Feb 2000 | A |
6028066 | Unger | Feb 2000 | A |
6033645 | Unger et al. | Mar 2000 | A |
6033646 | Unger et al. | Mar 2000 | A |
6039557 | Unger et al. | Mar 2000 | A |
6056938 | Unger et al. | May 2000 | A |
6068857 | Weitschies et al. | May 2000 | A |
6071494 | Unger | Jun 2000 | A |
6071495 | Unger et al. | Jun 2000 | A |
6086573 | Siegel et al. | Jul 2000 | A |
6088613 | Unger | Jul 2000 | A |
6090800 | Unger et al. | Jul 2000 | A |
6117414 | Unger | Sep 2000 | A |
6123923 | Unger et al. | Sep 2000 | A |
6139819 | Unger et al. | Oct 2000 | A |
6143276 | Unger | Nov 2000 | A |
6146657 | Unger et al. | Nov 2000 | A |
6150304 | Fischer et al. | Nov 2000 | A |
6159445 | Klaveness et al. | Dec 2000 | A |
6165442 | Swaerd-Nordmo et al. | Dec 2000 | A |
6210707 | Papahadjopoulos et al. | Apr 2001 | B1 |
6231834 | Unger et al. | May 2001 | B1 |
6254852 | Glajch et al. | Jul 2001 | B1 |
6258378 | Schneider et al. | Jul 2001 | B1 |
6261231 | Damphousse et al. | Jul 2001 | B1 |
6261537 | Klaveness et al. | Jul 2001 | B1 |
6315981 | Unger | Nov 2001 | B1 |
6331289 | Klaveness et al. | Dec 2001 | B1 |
6414139 | Unger et al. | Jul 2002 | B1 |
6416740 | Unger | Jul 2002 | B1 |
6443898 | Unger et al. | Sep 2002 | B1 |
6444660 | Unger et al. | Sep 2002 | B1 |
6455277 | Fox et al. | Sep 2002 | B1 |
6461586 | Unger | Oct 2002 | B1 |
6479034 | Unger et al. | Nov 2002 | B1 |
6521211 | Unger et al. | Feb 2003 | B1 |
6528039 | Unger | Mar 2003 | B2 |
6537246 | Unger et al. | Mar 2003 | B1 |
6548047 | Unger | Apr 2003 | B1 |
6551576 | Unger et al. | Apr 2003 | B1 |
6572840 | Toler | Jun 2003 | B1 |
6576220 | Unger | Jun 2003 | B2 |
6635017 | Moehring et al. | Oct 2003 | B1 |
6680047 | Klaveness et al. | Jan 2004 | B2 |
6682502 | Bond et al. | Jan 2004 | B2 |
6716412 | Unger | Apr 2004 | B2 |
6773696 | Unger | Aug 2004 | B2 |
6884407 | Unger | Apr 2005 | B1 |
6943692 | Castner et al. | Sep 2005 | B2 |
6998107 | Unger | Feb 2006 | B2 |
7255875 | Lanza et al. | Aug 2007 | B2 |
7344698 | Lanza et al. | Mar 2008 | B2 |
7344705 | Unger | Mar 2008 | B2 |
20040057991 | Hui et al. | Mar 2004 | A1 |
20050163716 | Unger et al. | Jul 2005 | A1 |
20080118435 | Unger | May 2008 | A1 |
20120027688 | Hui et al. | Feb 2012 | A1 |
20120128595 | Hui et al. | May 2012 | A1 |
20130022550 | Unger et al. | Jan 2013 | A1 |
20130309174 | Hui et al. | Nov 2013 | A1 |
Number | Date | Country |
---|---|---|
B-3035189 | Mar 1993 | AU |
641363 | Sep 1993 | AU |
746067 | Apr 2002 | AU |
25 21 003 | Aug 1976 | DE |
38 03 972 | Aug 1989 | DE |
0 052 575 | May 1982 | EP |
0 077 752 | Apr 1983 | EP |
0 107 559 | May 1984 | EP |
0 216 730 | Apr 1987 | EP |
0 224 934 | Jun 1987 | EP |
0 231 091 | Aug 1987 | EP |
0 243 947 | Nov 1987 | EP |
0 272 091 | Jun 1988 | EP |
0 274 961 | Jul 1988 | EP |
0 314 764 | May 1989 | EP |
0 320 433 | Jun 1989 | EP |
0 324 938 | Jul 1989 | EP |
0 327 490 | Aug 1989 | EP |
0 338 971 | Oct 1989 | EP |
0 349 429 | Jan 1990 | EP |
0 357 164 | Mar 1990 | EP |
0 359 246 | Mar 1990 | EP |
357 163 | Mar 1990 | EP |
0 361 894 | Apr 1990 | EP |
0 382 619 | Aug 1990 | EP |
441 468 | Aug 1991 | EP |
0 458 745 | Nov 1991 | EP |
0 467 031 | Jan 1992 | EP |
0 554 213 | Aug 1993 | EP |
0 561 424 | Sep 1993 | EP |
0 562 641 | Sep 1993 | EP |
0 586 875 | Mar 1994 | EP |
0 614 656 | Sep 1994 | EP |
0 633 030 | Jan 1995 | EP |
0727225 | Aug 1996 | EP |
0 901 793 | Mar 1999 | EP |
0 957 942 | Nov 1999 | EP |
2 700 952 | Aug 1994 | FR |
1044680 | Oct 1966 | GB |
2193095 | Feb 1988 | GB |
62 286534 | Dec 1987 | JP |
SHO 63-60943 | Mar 1988 | JP |
63-277618 | Nov 1988 | JP |
2-149336 | Jun 1990 | JP |
7-505135 | Jun 1995 | JP |
8-151335 | Jun 1996 | JP |
8-511523 | Dec 1996 | JP |
WO-8002365 | Nov 1980 | WO |
WO-8201642 | May 1982 | WO |
WO-8402909 | Aug 1984 | WO |
WO-8501161 | Mar 1985 | WO |
WO-8502772 | Jul 1985 | WO |
WO-8600238 | Jan 1986 | WO |
WO-8601103 | Feb 1986 | WO |
WO-8905040 | Jun 1989 | WO |
WO-8910118 | Nov 1989 | WO |
WO-901952 | Mar 1990 | WO |
WO-9001952 | Mar 1990 | WO |
WO-9004384 | May 1990 | WO |
WO-9004943 | May 1990 | WO |
WO-9014846 | Dec 1990 | WO |
WO-9100086 | Jan 1991 | WO |
WO-9103267 | Mar 1991 | WO |
WO-9109629 | Jul 1991 | WO |
WO-9112823 | Sep 1991 | WO |
WO-9115244 | Oct 1991 | WO |
WO-9115753 | Oct 1991 | WO |
WO-9118612 | Dec 1991 | WO |
WO-9201675 | Feb 1992 | WO |
WO-9205806 | Apr 1992 | WO |
WO-9210166 | Jun 1992 | WO |
WO-9211873 | Jul 1992 | WO |
WO-9215284 | Sep 1992 | WO |
WO-9217212 | Oct 1992 | WO |
WO-9217213 | Oct 1992 | WO |
WO-9217436 | Oct 1992 | WO |
WO-9217514 | Oct 1992 | WO |
WO-9221382 | Dec 1992 | WO |
WO-9222247 | Dec 1992 | WO |
WO-9222249 | Dec 1992 | WO |
WO-9222298 | Dec 1992 | WO |
WO-9300933 | Jan 1993 | WO |
WO-9305819 | Apr 1993 | WO |
WO-9306869 | Apr 1993 | WO |
WO-9309762 | May 1993 | WO |
WO-9313802 | Jul 1993 | WO |
WO-9313809 | Jul 1993 | WO |
WO-9317718 | Sep 1993 | WO |
WO-9320802 | Oct 1993 | WO |
WO-9400110 | Jan 1994 | WO |
WO-9406477 | Mar 1994 | WO |
WO-9407539 | Apr 1994 | WO |
WO-9409829 | May 1994 | WO |
WO-9416739 | Aug 1994 | WO |
WO-9421301 | Sep 1994 | WO |
WO-9421302 | Sep 1994 | WO |
WO-9428780 | Dec 1994 | WO |
WO-9428797 | Dec 1994 | WO |
WO-9428873 | Dec 1994 | WO |
WO-9428874 | Dec 1994 | WO |
WO-9503835 | Feb 1995 | WO |
WO-9506518 | Mar 1995 | WO |
WO-9507072 | Mar 1995 | WO |
WO-9512387 | May 1995 | WO |
WO-9515118 | Jun 1995 | WO |
WO-9516467 | Jun 1995 | WO |
WO-9523615 | Sep 1995 | WO |
WO-9524184 | Sep 1995 | WO |
WO-9526205 | Oct 1995 | WO |
WO-9532005 | Nov 1995 | WO |
WO-9532006 | Nov 1995 | WO |
WO-9604018 | Feb 1996 | WO |
WO-9608234 | Mar 1996 | WO |
WO-9609793 | Apr 1996 | WO |
WO-9628090 | Sep 1996 | WO |
WO-9631196 | Oct 1996 | WO |
WO-9636286 | Nov 1996 | WO |
WO-9640281 | Dec 1996 | WO |
WO-9640285 | Dec 1996 | WO |
WO-9700638 | Jan 1997 | WO |
WO-9740679 | Nov 1997 | WO |
WO-9740858 | Nov 1997 | WO |
WO-9748337 | Dec 1997 | WO |
WO-9800172 | Jan 1998 | WO |
WO-9804292 | Feb 1998 | WO |
WO-9809600 | Mar 1998 | WO |
WO-9810798 | Mar 1998 | WO |
WO-9810799 | Mar 1998 | WO |
WO-9817324 | Apr 1998 | WO |
WO-9818495 | May 1998 | WO |
WO-9818498 | May 1998 | WO |
WO-9818500 | May 1998 | WO |
WO-9818501 | May 1998 | WO |
WO-9842384 | Oct 1998 | WO |
WO-9847487 | Oct 1998 | WO |
WO-9850040 | Nov 1998 | WO |
WO-9850041 | Nov 1998 | WO |
WO-9851284 | Nov 1998 | WO |
WO-9908714 | Feb 1999 | WO |
WO-9913919 | Mar 1999 | WO |
WO-9930620 | Jun 1999 | WO |
WO-9936104 | Jul 1999 | WO |
WO-9939738 | Aug 1999 | WO |
WO-0045856 | Aug 2000 | WO |
WO-0115742 | Mar 2001 | WO |
WO 2004030617 | Apr 2004 | WO |
Entry |
---|
“‘Freon’ Fluorocarbons: Properties and Applications” in DuPont Technical Bulletin G-1 (E.I. DuPont de Nemours and Company, Wilmington, DE), pp. 1-10 (1987). |
“Concise Encylcopedia of Polymer Science and Engineering,” J. Kroschwitz, ed., John Wiley & Sons, New York, pp. 12-13 (1990). |
“Encyclopedia of Polymer Sciences and Engineering,” John Wiley & Sons, New York, 1:164-169 (1985). |
“Properties and Applications of the ‘Freon’ Fluorocarbons” in DuPont Freon Technical Bulletin B-2 (E.I. DuPont de Nemours and Company, Wilmington, DE), pp. 1-11 (1964). |
[No Author Listed] Division of new drug chemistry document relating to Definity. Review date, Feb. 15, 2001. |
[No Author Listed] EMEA Scientific discussion relating to Sonovue. Updated until Oct. 1, 2004. 1 page. |
[No Author Listed] Pages from DuPont website relating to Freon. Last accessed online at http://www.dupont.com/msds/40—37—2011fr.html on Feb. 15, 2002. 5 pages. |
A G. Belykh, Farmakol Toksikol. (MOSC), vol. 44(3), pp. 322-326 (1981) (abstract). |
Acoustic Imaging; AI5200; Convex Curved Linear Array Ultrasound Transducers Operator's Mnaual, Nov. 20, 1989, 4700-0003-1 C, p. 4. |
Anderson et al., “Manganese (III) Complexes in Oxidative Decarboxylation of Acids”, J. Am. Chem. Soc., vol. 92, No. 8, pp. 2450-2460 (1970). |
Arai et al., Transpulmonary passage of Aerosomes®, a pressure stable, lipid based echocardiographic contrast agent: studies in pigs. J Am Coll Cardiol. 1994:23-25A. Abstract only. |
Aronberg, “Techniques”, Computed Body Tomography, Lee, et al., eds., Raven Press, New York, Chapter 2, pp. 9-36 (1988). |
Bangham et al., “Diffusion or Univalent Ions across the Lamellae of Swollen Phospholipids”, J. Mol. Biol., 1965, 13:238-252. |
Barenholz et al., Handbook of Nonmedical Application of Liposomes. CRC Press, 1996. |
Barnhart et al., “Characteristics of ALBUNEX.TM.: Air-Filled Microspheres for Echocardiography Contrast Enhancement,” Investigative Radiology, 25:S162-164 (Sep. 1990). |
Bedu-Addo, F.K., et al., “Effects of polyethyleneglycol chain length and phospholipids acyl chain composition on the interaction of polyethyleneglycol-phospholipid conjugants with phospholipids: implications in liposomal drug delivery,” Pharm. Res., May 1996, 13(5), 710-717. |
Belsito, S., et al., “Sterically stabilized liposomes of DPPC/DPPE-PEG 2000—A spin label ESR & spectrophotometric study,” Biophysical Chem., May 10, 1998, 75(1), 33-43. |
Blomley et al., “Microbubble contrast agents: a new era in ultrasound”; Clinical Review XP008001399, BMJ, vol. 322, pp. 1222-1225 (May 19, 2001). |
Botvinick, Stress imaging: current clinical options for the diagnosis, localization, and evaluation of coronary artery disease. Contemporary Issues Cardiol. Sep. 1995;79(5):1025-57. |
Brochure, Experience, SonicatorTM. Heat Systems-Ultrasonics, Inc. (1987). |
Brown and Langer, Annual Review Medicine, 1988, 39:221 29, Annual Review, Inc., “Transdermal Delivery of Drugs”, pp. 221-229. |
Burn et al., Stress echocardiography. Q J med. 1995;88:755-61. |
Carson et al., “Ultrasound Power and Intensitites Produced by Diagnostic Ultrasound Equipment”, Ultrasound in Med. & Biol., vol. 3, pp. 341-350 (1978). |
Chang, “Semipermeable Aqueous Microcapsules”, Canadian J. Of Phys. And Pharm., 1966, vol. 44, pp. 115-128 (1978). |
Chang, “Semipermeable Microcapsules”, Science, 1964, 146, 524-525. |
Chapman et al., “Biomembrane Phase Transitions”, J. Biol. Chem., vol. 249, pp. 2512-2521 (1974). |
Chapman, “Physiochemical Properties of Phospholipids and Lipid-Water Systems”, Liposome Technology, Gregoriadis, G., ed., Chapter 1, vol. 1, pp. 1-18 (CRC Press, Boca Raton, FL, 1984). |
Cheng et al., “The Production and Evaluation of Contrast-Carrying Liposomes Made with an Automatic High Pressure System”, Investigative Radiology, vol. 22, No. 1, pp. 47-55 (1987). |
Chortkoff et al., “Pharmacokinetics Do Not Explain the Absence of an Anesthetic Effect of Perfluoropropane or Perfluoropentane.” Anesth. Analg., 79, pp. 234-237, 1994. |
Crowe et al., “Preservation of Freeze-Dried Liposomes by Trehalose”, Archives of Biochemistry and Biophysics, vol. 242, pp. 240-247 (1985). |
Crowe et al., “Preservation of Structural and Functional Activity in Lyophilized Sarcoplasmic Reticulum”, Archives of Biochemistry and Biophysics, vol. 220, pp. 477-484 (1983). |
De Jong et al., New ultrasound contrast agents and technological innovations. Ultrasonics. Jun. 1996;34(2-5):587-90. |
Deamer et al., “Permeability of Lipid Bilayers to Water and Ionic Solutes”, Chemistry and Physics of Lipids, vol. 40, pp. 167-188 (1986). |
Deamer, D.W., “Preparation of solvent vaporization liposomes,” Liposome Techn., 1984, vol. 1, Chap. 3, 29-35. |
Deasy, Microencapsulation and Related Drug Processes, vol. 20, Chs. 9 and 10, pp. 195-239 (1983) (Marcel Dekker, Inc., NY). |
deGier et al., “Relations Between Liposomes and Biomembranes”, Annals of New York Academy of Sciences, vol. 308, pp. 85-99 (1978). |
Desir et al., “Assessment of regional myocardial perfusion with myocardial contrast echocardiography in a canine model of varying degrees of coronary stenosis”, American Heart Journal, vol. 127, No. 1, pp. 56-63 (Jan. 1994). |
Ding et al., Chung Kuo Yao Li Hsueh Pao, Sep. 1989; 10(5):473-5 (Abstract only). |
Dittrich, “Cardiac Muscle Ischemia and Infarction”, The Second Annual International Symposium on Contrast Agents in Diagnostic Ultrasound, Atlantic City, NJ (May 7, 1996) (abstract). |
Dorland's Illustrated Medical Dictionary, p. 946, 27th ed. (W.B. Saunders Company, Philadelphia 1988). |
Feigenbaum et al., Circulation, “Identification of Ultrasound Echoes from the Left Ventricle by Use of Intracardiac Injections of Indocyanine Green”, vol. XL1, pp. 615-621 (Apr. 1970). |
Feinstein et al., “Two-Dimensional Contrast Echocardiography. I. In Vitro Development and Quantitative Analysis of Echo Contrast Agents”, JACC, vol. 3, No. 1, pp. 14-20 (1984). |
Feinstein, Steven B., “Myocardial Perfusion Imaging: Contrast Echocardiography Today and Tomorrow,” Journal of the American College of Cardiology, 8(1):251-253 (1986). |
Felgner et al., “Lipofection: A highly efficient, lipid-mediated DNA-transfection procedure”, Proc. Natl. Acad. Sci., vol. 84, pp. 7413-7417 (1987). |
Fitzpatrick, et al., “Metal Ion Catalyzed Decarboxylation: Kinetics and Mechanism of the Oxidative Decarboxylation of Copper (II) Complexes of Aminomalonic Acid in Aqueous Solution”, Inorganic Chemistry, vol. 13, No. 3, pp. 568-574 (1974). |
Frezard, et al., “Fluorinated Phospholipid-Based Vesicles as Potential Drug Carriers: Encapsulation/Sustaining of Drugs and Stability in Human Serum”, Art, Cells, Blood Subs., and Immob. Biotech., 22(4), pp. 1403-1408 (1994). |
Frezard, et al., “Permeability and stability in buffer and in human serum of fluorinated phospholipid-based liposomes”, Biochimica et Biophysica Acta, 1192, pp. 61-70 (1994). |
Fritzsch et al., “Preclinical and Clinical Results with an Ultrasonic Contrast Agent”, Inv. Rad., vol. 23, pp. S302-S305, Sep. 1988. |
Fukuda et al., “Polymer-Encased Vesicles Derived from Dioctadecyldimethylammonium Methacrylate”, J. Am. Chem. Soc., vol. 108, pp. 2321-2327 (1986). |
Gabizon et al., “Liposome formulations with prolonged circulation time in blood and enhanced uptake by tumors”, Proc. Natl. Acad. Sci., vol. 85, pp. 6949-6953 (1988). |
Gaentzler et al., “Perfluoroalkylated Phosphocholines. Improved Synthesis, Surface Activity, Fluorocarbon Emulsifying Capability and Biological Properties”, New Journal of Chemistry 1993, 17(5), 337-344. |
Galjee, Biosis #91:493622, 1991. |
Gardner et al., “A Survey of Intraocular Gas Use in North America”, Arch. Ophthalmol., vol. 106, pp. 1188-1189, Sep. 1988. |
Garelli, et al., “Incorporation of new amphiphilic perfluoroalkylated bipyridine platinum and palladium complexes into liposomes: stability and..” Biochimica et Biophysica Acta, vol. 1127, pp. 41-48 (1992). |
Goldberg, et al., “Ultrasound contrast agents: a review,” Ultrasound in Med. & Biol., 1994, 20(4), 319-333. |
Gramiak et al., “Detection of Intracardiac Blood Flow by Pulsed Echo-Ranging”, Radiology, vol. 100, pp. 415-418 (1971). |
Gregodiadis, G., et al. (Eds.), “Liposome technology: preparation of liposomes,” and Deamer: “Preparation of solvent vaporization liposomes,”CRC Press, Inc., 1984, CRC Press, Inc., XP002101586, vol. 1, 31-35. |
Gregoriadis, G. (Ed.), Liposome technology: preparation of lipsomes, CRC Press, 1994, vol. 1, 7-13. |
Gregoriadis, G., ed., Liposome Technology, vol. I, pp. 29-35, 51-65 and 79-107, CRC Press, Boca Raton, FL 1984. |
Gross, U. et al., “Phosholipid vesiculated fluorocarbons promising trend in blood substitutes” Biomat., Art. Cells & Immob. Biotech., 1992, vol. 20, (2-4) pp. 831-833. |
Gunstone et al., The Lipid Handbook, 2nd Edition. Chapman and Hall Chemical Data Base, 1992. |
Gutknecht et al., “Diffusion of carbon dioxide through lipid bilayer membranes. Effects of carbonic anhydrase, bicarbonate, and unstirred layers”, Chemical Abstracts, vol. 87, 34772q, p. 136 (1977). |
H. Meessen, ed., Microcirculation, Springer-Verlag, Berlin Heidelberg, New York, p. 44 (1997) (German language only). |
Handbook of Pharmaceutical Excipients, American Pharmaceutical Association, Washington, D.C. and The Pharmaceutical Society of Great Britain, London, England, pp. 181-183 (1986). |
Hansrani, et al., “The preparation and properties of sterile intravenous emulsion,” J. Parent. Sci. Tech., 1983, 37(4), 145-150. |
Hautanen, A. et al., “Effects of Modifications of the RGD sequence and its Context on Recognition by the Fibronectin Receptor”, J. Biol. Chem., 1989, 264(3), 1437-1442. |
Hayat et al., Effects of left bundle-branch block on cardiac structure, function, perfusion, and perfusion reserve: implications for myocardial contrast echocardiography versus radionuclide perfusion imaging for the detection of coronary artery disease. Circulation. Apr. 8, 2008;117(14):1832-41. Epub Mar. 31, 2008. |
Hope et al., “Generation of Multilamellar and Unilamellar Phospholipid Vesicles”, Chemistry and Physics of Lipids, vol. 40, pp. 89-107 (1986). |
Hope et al., “Production of large unilamellar vesicles by a rapid extrusion procedure. Characterization of size distribution, trapped volume, and ability to maintain a membrane potential”, Biochimica et Biophysica Acta, vol. 812, pp. 55-65 (1985). |
Hug et al., “Liposomes for the Transformation of Eukaryotic Cells”, Biochimica et Biophysica Acta, 1991, 1097:1-17. |
Hynynen et al., “The Usefulness of a Contrast Agent and Gradient-Recalled Acquisition in a Steady-State Imaging Sequence for Magnetic Resonance Imaging-Guided Noninvasive Ultrasound Surgery,” Investigative Radiology, vol. 29, pp. 897-903 (Oct. 1994). |
Isele, et al., “Large-scale production of liposome containing monomeric zinc phthalocyanine by controlled dilution of organic solvents,” J. Pharm. Sci., 1994, 83(11), 1608-1616. |
J. Vion-Dury et al., J. Pharmacol. Exper. Therm., vol. 250(3), pp. 1113-1118 (1989) (abstract). |
Jackson et al., “Effect of ultrasound therapy on the repair of Achilles tendon injuries in rats.” Medicine and Science in Sports and Exercise, vol. 23, No. 2, pp. 171-176, 1991. |
Jacobs, “Intraocular gas measurement using A-scan ultrasound”, Current Eye Research, vol. 5, No. 8, pp. 575-578 (1986). |
Jain, et al., “Facilitated Transport”, Introduction to Biological Membranes, Ch. 9, pp. 192-231 (J. Wiley and Sons, N.Y. 1980). |
Kaul, Myocardial contrast echocardiography in coronary artery disease: potential applications using venous injections of contrast. Am J Cardiol. Apr. 13, 1995;75(11):61D-68D. |
Kawai et al., “New Procedure for DNA Transfection with Polycation and Dimethyl Sulfoxide”, Molecular and Cellular Biology, vol. 4, No. 6, pp. 1172-1174 (1984). |
Kazuo, M., et al., “Prolonged circulation time in vivo of large unilamellar liposomes composed of distearoyl phosphatidylcholine and cholesterol containing amphipathic poly *ethylene glycol),” Biochimica et Biophysica Acta, 1992, 1128, 44-49. |
Keller et al., “Successful Left Ventricular Opacification Following Peripheral Venous Injection of Sonicated Contrast Agent: An Experimental Evaluation”, LV Contrast Echocardiography, vol. 114, No. 3, pp. 570-575 (1987). |
Keller et al., “The Behavior of Sonicated Albumin Microbubbles Within the Microcirculation: A Basis for Their Use During Myocardial Contrast Echocardiography”, Circulation Res., vol. 65, No. 2, pp. 458-467 (Aug. 1989). |
Kinsler, et al., Fundamentals of Acoustics, third ed., pp. 228-331 (1982). |
Kost et al., Polymers in Medicine II: Biomedical and Pharmaceutical Applications, “Ultrasonic Modulated Drug Delivery Systems”, Chiellini et al., eds., (Plenum Press, New York and London), pp. 387-396 (1985). |
Kuo et al., “Metallocene Antitumor Agents. Solution and Solid-State Molybdenocene Coordination..”, J. Am. Chem. Soc., vol. 113, No. 24, pp. 9027-9045 (1991). |
Lejbkowicz et al., “The response of normal and malignant cells to ultrasound in vitro.” Database BIOSIS, No. 1993:95122245 (abstract only). |
Levene et al., “Characterization of AlbunexTM,” J. Acoust. Soc. Am., 87 (Suppl.1):569-70 (Spring 1990). |
Lincoff et al., “Intravitreal Expansion of Perfluorocarbon Bubbles”, Arch. Ophthalmol., vol. 98, p. 1646, Sep. 1980. |
Lincoff et al., “Intravitreal Longevity of Three Perfluorocarbon Gases”, Arch. Ophthalmol., vol. 98, pp. 1610-1611, Sep. 1980. |
Lincoff et al., “Perfluoro-n-butane: A Gas for Maximum Duration Retinal Tamponade,” Arch Ophthalmology, 101:460-462 (1983). |
Lincoff et al., “The Perfluorocarbon Gases in the Treatment of Retinal Detachment”, Ophthalmology, vol. 90, No. 5, pp. 546-551, May 1983. |
Lindner et al., “Myocardial Perfusion Characteristics and Hemodynamic Profile of MRX-115, a Venous Echocardiographic Contrast Agent, During Acute Myocardial Infarction,” J. Am. Soc. of Echocardiography, vol. 11, No. 1, pp. 36-46 (Jan. 1998). |
Liposome Technology, Gregoriadis, G., ed., vol. I, pp. 1-18, 30-35, 51-65 and 79-107 (CRC Press Inc., Boca Raton, FL, (1984). |
M. Ostro, “Liposomes”, Marcel Dekker, New York, pp. 102-103 (1983). |
M. R. Zalutsky et al., Invest. Radiol., vol. 22(2), pp. 141-147 (1987) (abstract). |
MacDonald, Mammalian Cell Biotechnology: A Practical Approach, M. Butler, ed., (Oxford University Press, New York), Chapter 4, pp. 57-70 (1991). |
MacNaughton et al., “Effects of Gaseous Anaesthetics and Inert Gases on the Phase Transition in Smectic Mesophases of Dipalmitoyl Phosphatidylcholine”, Biochimica et Biophysica Acta, vol. 597, pp. 193-198 (1980). |
Madden et al., “The accumulation of drugs within large unilamellar vesicles exhibiting a proton gradient: a survey”, Chemistry and Physics of Lipids, vol. 53, pp. 37-46 (1990). |
Mann et al., “Formation of Iron Oxides in Unilamellar Vesicles”, Journal of Colloid and Interface Science, vol. 122, No. 2, pp. 326-335 (1988). |
Marsh et al., Handbook of Lipid Bilayers. CRC Press, 1990. |
Marsh, CRC Handbook of Lipid Bilayers (CRC Press, Boca Raton, FL 1990) pp. 139-141. |
Maruyama, K., et al., “Prolonged circulation time in vivo of large unilamellar liposomes composed of distearoyl phosphatidylcholine and cholesterol containing amphipathic ply(ethylene glycol),” Biochimica et Biophysica Acta, 1992, 1128, 44-49. |
Mathews et al., Biochemistry. Benjamin/Cummings Publishing Co., 1990:332-3. |
Mathiowitz et al., “Photochemical Rupture of Microcapsules: A Model System”, Journal of Applied Polymer Science, vol. 26, pp. 809-822 (1981). |
Mathiowitz et al., “Polyanhydride Microspheres as Drug Carriers. II. Microencapsulation by Solvent Removal”, Journal of Applied Polymer Science, vol. 35, pp. 755-774 (1988). |
Mattrey et al., “Perfluorochemicals as US Contrast Agents for Tumor Imaging and Hepatosplenography: Preliminary Clinical Results”, Radiology, vol. 163, No. 2, pp. 339-343 (1987). |
Mattrey et al., “Perfluoroctylbromide: A Liver/Spleen-Specific and Tumor-Imaging Ultrasound Contrast Material”, Radiology, vol. 145, pp. 759-762 (1982). |
Mattrey et al., Gas Emulsions as Ultrasound Contrast Agents; Preliminary Results in Rabbits and Dogs, Investigative Radiology, vol. 29, Jun. Supp. 2, pp. S139-S141, 1994. |
Maxwell, “Therapeutic Ultrasound: Its Effects on the Cellular and Molecular Mechanisms of Inflammation and Repair.” Physiotherapy, vol. 78, No. 6, pp. 421-426, Jun. 1992. |
May et al., “Cationic Liposomes Enable Bovine Herpesvirus Type 2 DNA to Infect Cells”, Acta virol., 1991, 35:107. |
Mayer et al., “Vesicles of Variable Size Produced by a Rapid Extrusion Procedure”, Biochimica et Biophysica Acta, vol. 858, pp. 161-168 (1986). |
Mayhew et al., “Characterization of Liposomes Prepared Using a Microemulsifier”, Biochimica et Biophysica Acta, vol. 775, pp. 169-174 (1984). |
Mayhew et al., “High-Pressure Continuous-Flow System for Drug Entrapment in Liposomes”, Methods in Enzymology, vol. 149, pp. 64-77 (1987). |
McAvoy et al., IEEE Engineering, Ultrasonics Symposium Proceedings, vol. 2, pp. 677-1248 (1989) (abstract). |
Meessen, H. (ed.), Microcirculation, Springer-Verlag, Berlin Heidelberg, New York, 1997, 44. |
Meltzer et al., Transmission of Ultrasonic Contrast Through the Lungs, Ultrasound in Med. & Biol., vol. 7, No. 4, 377-384, 1981. |
Miller et al., “Physiochemical Approaches to the Mode of Action of General Anesthetics,” J. Amer. Soc. Anesthesiologists, 36(4):339-351 (1972). |
Miller, D.L., “Ultrasonic Detection of Resonant Cavitation Bubbles in a Flow Tube by Their Second-Harmonic Emissions”, Ultrasonics, Sep. 1981, 217-224. |
Moseley, et al., Microbubbles: A Novel MR Susceptibility Contrast Agent, abstract, 1991 Napa, California Meeting of the Society for Magnetic Resonance in Medicine. |
Muhlradt et al., “Vitamin B6 Analogs: An Improved Synthesis of 5-Deoxypyridoxal”, New Compounds, vol. 10, pp. 129-130 (1967). |
Nayar et al., “Generation of Large Unilamellar Vesicles From Long-chain Saturated Phosphatidylcholines by Extrusion Techinque”, Biochimica et Biophysica Acta, vol. 986, pp. 200-206 (1989). |
New, R.R.C. (Ed.), “Liposomes a practical approach,” IRL Press, 1990, 62-77. |
Nikolova, A., et al., “Effect of grafted PEG-2000 on the size and permeability of vesicles,” Biochim Biophys Acta, Nov. 22, 1996, 1304(2), 120-128. |
Nomura et al., “US Contrast Enhancement of Hepatic Tumor with Helium Gas Microbubbles: A Preliminary Report”, Jpn. J. Med. Ultrasonics, vol. 18, No. 5 (1991) (Japanese with English language abstract). |
O'Keefe et al., Comparison of stress echocardiography and stress myocardial perfusion scintigraphy for diagnosing coronary artery disease and assessing its severity. Am J Cardiol. Apr. 13, 1995;75(11):25D-34D. |
Ohki, et al., “Short & long range calcium-induced lateral phase separations in ternary mixtures of phosphatidic acid phosphatidylcholine and phosphatidylethanolamine,” Chem. & Physics of Lipids, 1989, 50(2), 109-118. |
Ophir et al., “Contrast Agents in Diagnostic Ultrasound”, Ultrasound in Med. & Biol., vol. 15, No. 4, pp. 319-333 (1989). |
Otis et al., Contrast-enhanced transcranial imaging. Results of an American phase-two study. Stroke. Feb. 1995;26(2):203-9. |
P.N.T. Wells, “Pulse-Echo Methods”, Biomedical Ultrasonics, Academic Press, pp. 209-220 (1977). |
Pantely, “Intravenous Contrast Echocardiography—Tissue Imaging & Quantification of Coronary Blood Flow”, The Second Annual International Symposium on Contrast Agents in Diagnostic Ultrasound, Atlantic City, NJ (May 7, 1996) (abstract). |
Papahadjopoulos et al., Sterically stabilized liposomes:improvements in pharmacokinetics and antitumor therapeutic efficacy. Proc Natl Acad Sci U S A. Dec. 15, 1991;88(24):11460-4. |
Pietersen, “A New Warning System for Fires of Electrical Origin”, CERN European Organization for Nuclear Research, Health and Safety Division, pp. 1-5 (Mar. 1977). |
Porter, et al., “Multifold Sonicated Dilutions of Albumin with Fifty Percent Dextrose Improve Left Ventricular Contrast Videointensity After Intravenous Injection in Human Beings”, Journal of the American Society of Echocardiography, vol. 7, No. 5,pp. 465-471, Sep.-Oct. 1994. |
Porter, et al., “Noninvasive Identification of Acute Myocardial Ischemia and Reperfusion With Contrast Ultrasound Using Intravenous Perfluorpropane-Exposed Sonicated Dextrose Albumin”, Journal of the American College of Cardiology, vol. 26, No. 1, pp. 33-40; 1995. |
Porter, et al., “Thrombolytic enhancement with perfluorocarbon-exposed sonicated dextrose albumin microbubbles”, vol. 132, No. 5, American Heart Journal, pp. 964-968, Nov. 1996. |
Porter, et al., “Visually Discernible Myocardial Echocardiographic Contrast After Intravenous Injection of Sonicated Dextrose Albumin Microbubbles Containing High Molecular Weight, Less Soluble Gases”, Journal of the American College of Cardiology,vol. 25, No. 2, pp. 509-515, Feb. 1995. |
Poznansky et al., “Biological Approaches to the Controlled Delivery of Drugs: A Critical Review”, Pharmacol. Rev., vol. 36, No. 4, pp. 277-336 (1984). |
PR Newswire, Apr. 1, 1986. |
Regen et al., “Polymerized Phosphatidylcholine Vesicles. Synthesis and Characterization,” J. Am. Chem. Soc., vol. 104, No. 3, pp. 191-195 (1982). |
Regen et al., Polymerized phospatidylcholine vesicles. Synthesis and characterization. J Am Chem Soc. 1982;104:791-5. |
Regen, “Polymerized Vesicles”, J. Am. Chem. Soc., vol. 102, pp. 6638-6640 (1980). |
Remington's Pharmaceutical Sciences, John Hoover, managing ed., Mack Publishing Company, Easton, PA, pp. 295-298; 736; 1242-1244 (1975). |
Riess, J.G., “Fluorine in our arteries,” New J.Chem., XP-000990897, 1995, 19, 891-909 (English abstract). |
Riess, J.G., “Introducing a new element-fluorine-into the liposomal membrane”, Liposome Res., 1995, XP-000525914, 5(3), 413-430. |
Ring et al., Clinical Weekly, 52, pp. 595-598 (1974) (English abstract). |
Robinson, et al., F.J. Fry, ed., Ultrasound: Its Applications in Medicine and Biology, Elsevier Scientific Publishing Company, vol. 3, Chap. XI, pp. 593-596 (1978). |
Rose, A. and Rose, E., “The Condensed Chemical Dictionary”, Reinhold Publishing, New York, pp. 728 and 743 (1966). |
Sankaram et al., “Cholesterol-Induced Fluid-Phase Immiscibility in Membranes”, Proc. Natl. Acad. Sci., vol. 88, pp. 8686-8690 (1991). |
Santaella, C. et al., “Emulsification of Fluorocarbons Using Perfluoroalkylated Glycerophosphocholines as Surfactants or Co-Surfactants”, New J. Chem., 1992, 16(3), 399-404. |
Santaella, et al., “Extended in Vivo Blood Circulation Time of Fluorinated Liposomes”, FEBS 13463, vol. 336, No. 3, pp. 481-484 (1993). |
Sato et al., “Recent Aspects in the Use of Liposomes in Biotechnology and Medicine”, Prog. Lipid Res., vol. 31, No. 4, pp. 345-372 (1992). |
Scarpa et al., “Cation Permeability of Liposomes as a Function of the Chemical Composition of the Lipid Bilayers”, Biochimica et Biophysica Acta, vol. 241, pp. 789-797 (1971). |
Schutt et al., “Osmotically Stabilized Microbubble Sonographic Contrast Agents”, Acad. Radiol., vol. 3, Suppl. 2, pp. S188-S190 (Aug. 1996). |
Scientific Apparatus Catalog 92/93 (VWR Scientific, 1991), “Syringes”, pp. 1511-1513; “Filtration, Syringe Filters”, pp. 766-768; “Filtration, Membranes”, pp. 750-753; “Filtration, Filter Holders”, p. 744. |
Seibyl, Biois #94:339104, 1994. |
Sekins et al., “Lung Cancer Hyperthermia via Ultrasound and PFC Liquids”, Published in Proceedings of 5th International Symposium on Hyperthermic Oncology, Kyoto, Japan, (3 pages) (Aug. 29-Sep. 3, 1998). |
Senior et al., “Influence of surface hydrophilicity of liposomes on their interaction with plasma protein and clearance from the circulation: studies with poly(ethylene glycol)-coated vesicles.” Biochimica et Biophysica Acta. 1991. 1062. pp. 77-82. |
Senior et al., RAMP-1 and RAMP-2 Investigators. Detection of coronary artery disease with perfusion stress echocardiography using a novel ultrasound imaging agent: two Phase 3 international trials in comparison with radionuclide perfusion imaging. Eur J Echocardiogr. Jan. 2009;10(1):26-35. |
Senior, Imagify (perflubutane polymer microspheres) injectable suspension for the assessment of coronary artery disease. Expert Rev Cardiovasc Ther. May 2007;5(3):413-21. |
Sharma et al., “Emulsification Methods for Perfluorochemicals.” Drug Development and Industrial Pharmacy, 14 (15-17), pp. 2371-2376 (1988). |
Shiina et al., “Hyperthermia by Low-frequency Synthesized Ultrasound”, IEEE Engineering, pp. 879-880, vol. 2 (1988) (abstract). |
Shinoda, K. et al., “Colloidal Surfactants; Some Physiochemical Properties”, Chapter 1, pp. 1-96, Academic Press, New York, 1963. |
Sibernagl, D., Pocket Atlas of Physiology ,Georg Thieme Verlag, Stuttgart New York, 1983, 156-157 (German language only). Kinsler, et al., Fundamentals of Acoustics, third ed., pp. 228-331 (1982). |
Sigel, H., ed., Metal Ions in Biological Systems: Antibiotics and Their Complexes, vol. 19 (Marcel Dekker, N.Y. 1985). |
Simons et al., “Antisense c-myb oligonucleotides inhibit intimal arterial smooth muscle cell accumulation in vivo”, Nature, vol. 359, pp. 67-70 (1992). |
Sinkula et al., “Rationale for Design of Biologically Reversible Drug Derivatives: Prodrugs”, J. Pharm. Sci. 1975, 64:181-210. |
Sole-Violan, L., “Partition Coefficients of Mixed Fluorocarbon-Hydrocarbon Compounds Between Fluorocarbons and Hexadecane. Relevance of Fluorocarbon Emulsion Stabilization”, New J. Chem., 1993, 17(8,9), 581-583. |
Sonne et al., Left ventricular opacification after intravenous injection of Albunex. The effect of different administration procedures. Int J Card Imaging. Mar. 1995;11(1):47-53. |
Srinivasan, et al., “Characterization of Binding Sites, Extent of Binding, and Drug Interactions of Oligonucleotides with albumin”, Antisense Research and Development, vol. 5, pp. 131-139, 1995. |
Stelmashok et al., Koordinatsinonnaya Khimiya, vol. 3, No. 4, pp. 524-557 (1977) (Russian and English and language versions). |
Sutherland et al., “Color Doppler Myocardial Imaging: A New Technique for the Assessment of Myocardial Function”, J. Am. Soc. Of Echocardiogr, 1994, 7(5), 441-458. |
Swanson et al., “Enhancement Agents for Ultrasound: Fundamentals”, Pharmaceuticals in Medical Imaging, Chapter 22, pp. 682-687 (1990). |
Szoka et al., Procedure for preparation of liposomes with large internal aqueous space and high capture by reverse-phase evaporation. Proc. Natl. Acad. Sci., vol. 75, No. 9, pp. 4194-4198 (1978). |
Szoka, et al., “Comparative properties and methods of preparation of liqid vesicles (Liposomes),” Ann. Rev. Biophys. Bioeng., 1980,9, 467-508. |
Takeuchi et al., “Enhanced Visualization of Intravascular Thrombus with the Use of a Thrombus Targeting Ultrasound Contrast Agent (MRX408): Evidence From in Vivo Experimental Echocardiographic Studies”, The Journal of the American College of Cardiology, vol. 31, No. 2, Suppl. A, p. 57A, Abstract XP-000952675, Feb. 1998 and 47th Annual Scientific Session of American College of Cardiology, Atlanta, GA, Mar. 29, 1998-Apr. 1, 1998. |
Talsma, et al., “Liposomes as drug delivery systems, part I, Preparation,” Pharmaceutical Technology, Oct. 1992, 96-106. |
Ten Cate et al., “Two-Dimensional Contract Echocardiography. II: Transpulmonary Studies”, JACC, vol. 3, No. 1, pp. 21-27 (1984). |
Ter-Pogossian, Physical principles and instrumentation. Computed Body Tomography. Lee et al., eds., Raven Press, New York. Chapter 1. pp. 1-7 (1988). |
Thanassi, “Aminomalonic Acid. Spontaneous Decarboxylation and Reaction with 5-Deoxypyridoxal”, Biochemistry 1970, 9(3), 525-532. |
Thompson, Larry, “At Age 2, Gene Therapy Enters a Growth Phase”, Science 1992, 258:744-746. |
Tilcock et al., “99mTc-labeling of Lipid Vesicles Containing the Lipophilic Chelator PE-DTTA: Effect of Tin-to-chelate Ratio, Chelate Content and Surface Polymer on Labeling Efficiency and Biodistribution Behavior.” 2211b Nuclear Medicine and Biology, 21, No. 1, pp. 89-96, 1994. |
Tilcock et al., “Liposomal Gd-DTPA: Preparation and Characterization of Relaxivity”, Radiology, vol. 171, No. 1, pp. 77-80 (1989). |
Tilcock et al., “PEG-coated Lipid Vesicles with Encapsulated Technetium-99m as Blood Pool Agents for Nuclear Medicine”, 2211b Nuclear Medicine and Biology, 1994, 21(2), 165-170. |
Trevino, L, et al., “Incorporation of a perfluoroalkylalkane (rfrh) into the phospholipid bilayer of dmpc liposomes results in greater encapsulation stability”, Journal of Liposome Research, 1994, vol. 4 (2) pp. 1017-1028. |
Trubetskoy et al., “Cationic liposomes enhance targeted delivery and expression of exogenous DNA . . . ”, Biochimica et Biophysica Acta, vol. 1131, pp. 311-313 (1992). |
Tsutsui et al., Comparison of low-mechanical index pulse sequence schemes for detecting myocardial perfusion abnormalities during vasodilator stress echocardiography. AmJ Cardiol. Mar. 1, 2005;95(5):565-70. |
Tuncay et al., “Expression of Genes Associated with Tissue Remodeling Upon Ultrasound Perturbation in the Gingival Fibroblast.” Journal of Dental Research, vol. 75, p. 143, 1996 (abstract only). |
Uemura, Biosis #80: 105491, 1979. |
Uemura, Embase, #79180131, 1979. |
Ulendorf, “Physics of Ultrasound Contrast Imaging: Scattering in the Linear Range”, IEEE Transactions on Ultrasonics, Ferrolectrics, and Frequency Control, 1994, 41(1), 70-79. |
Umemura et al., “Studies on Sonodynamic Cancer Therapy”, IEEE, O-7803-0785, pp. 354-355 (1992). |
Unger et al., “Hepatic Metastases: Liposomal Gd-DTPA-enhanced MR Imaging”, Radiology, vol. 171, No. 1, pp. 81-85 (1989). |
Unger et al., “Liposomal MR Contrast Agents”, J. Liposome Research, 4(2), pp. 811-834 (1994). |
Unger, et al., “Gas filled lipid bilayers as imaging contrast agents,” J. Liposome Res., 1994, 4(2), 861-874. |
Unger, et al., “Gas-filled lipid bilayers as ultrasound contrast agent,” Invest. Radiol., 1994, 29S2, S134-S136. |
Unger, et al., “In Vitro Studies of a New Thrombus-Specific Ultrasound Contrast Agent”, American Journal of Cardiology, vol. 81, No. 12, Suppl. A, pp. 58G-61G, XP-002087505, Jun. 12, 1998 and Symposium: Ninth International Congress on Echocardiography: Clinical Cardiology, 1997. |
Villanueva et al., “Characterization of Spatial Patterns of Flow Within the Reperfused Myocardium by Myocardial Contrast Echocardiography”, Circulation, vol. 88, No. 6, pp. 2596-2606 (Dec. 1993). |
Violante et al., “Particulate Suspensions as Ultrasonic Contrast Agents for Liver and Spleen”, Inv. Rad., vol. 23, pp. S294-S297, Sep. 1988. |
Wade et al., Handbook of Pharmaceutical Excipients, 2nd Ed. American Pharmaceutical Association, Washington. 1994. |
Wang, et al., “Low Intensity Ultrasound Treatment Increases Strength in a Rat Femoral Fracture Model”, Journal of Orthopaedic Research, 1994, 12(1), 40-47. |
Wei et al., “Quantification of Myocardial Blood Flow With Ultrasound-Induced Destruction of Microbubbles Administered as a Constant Venous Infusion,” Circulation, vol. 97, pp. 473-483 (1998). |
Wheatley et al., “Contrast Agents for Diagnostic Ultrasound: Development and Evaluation of Polymer-Coated Microbubbles,” Biomaterials, 11:713-717 (1990). |
Williams, “Human Gene Therapy: Searching for Better Vectors”, ASM News [American Society for Microbiology] vol. 58, pp. 67-69 (1992). |
Wolf, A., et al., “The effect of lysophosphatidylcholine on coronary and renal circulation in the rabbit,” Lipids, 1991, 26(3), 223-226 (Abstract, 1 page). |
Woodle et al., “Versatility in lipid compositions showing prolonged circulation . . . ”, Biochimica et Biophysica Acta 1992, 1105:193-200. |
Wu, Y., et al., “Binding and lysing of blood clots using MRX-408,” Investigate Radiology, 1998, 33(12), 880-885. |
Xie, et al., “Acute Myocardial Ischemia and Reperfusion can be Visually Identified Non-invasively with Intravenous Perfluoropropane-Enhanced Sonicated Dextrose Albumin Ultrasound Contrast”, Circulation, vol. 90, No. 4, Part 2, Abstract 2989, Oct. 1994. |
Yang et al., “Exposure to Low-Intensity Ultrasound Increases Aggrecan Gene Expression in a Rat Femur Fracture Model.” Journal of Orthopaedic Research, vol. 14, No. 5, pp. 802-809, 1996. |
Yuda et al., Prolongation of liposome circulation time by various derivatives of polyethyleneglycols. Biol Pharm Bull. Oct. 1996;19(10):1347-51. |
Yeung et al., “Preparation of Microencapsulated Liposomes”, J. Microencapsulation, 1988, vol. 5, 331-337. |
Young et al., “Effect of therapeutic ultrasound on the healing of full-thickness excised skin lesions.” Ultrasonics, vol. 28, No. 3, pp. 175-180, 1990. |
Young et al., “The Effect of Therapeutic Ultrasound on Angiogenesis.” Ultrasound in Medicine and Biology, vol. 16, No. 3, pp. 261-269, 1990. |
Yu et al., Incremental value of parametric quantitative assessment of myocardial perfusion by triggered Low-Power myocardial contrast echocardiography. J Am Coll Cardiol. May 19, 2004;43(10):1807-13. |
Yu, S.-H., et al., “Effect of pulmonary surfactant protein B (SP-B) and calcium on phospholipids adsorption and squeeze-out of phosphatidylglycerol frombinary phospholipids monolayers containing dipalmitoylphosphatidylcholine,” Biochimica et Biophysica Acta, 1992, 1126, 26-34. |
Zarif et al., “Synergistic Stabilization of Perfluorocarbon-Pluronic F-68 Emulsion by Perfluoroalkylated Polylhydroxylated Surfactants.” JAOCS, vol. 66, No. 10, pp. 1515-1523, 1989. |
Zarif, L. et al., “Biodistribution and excretion of a mixed luorocarbon-hydrocarbon “dowel” emulsion as determined by 19-F NMR”, Artificial Cells, Blood Substitutes, and Immobilization Biotechnology, 1994, vol. 22,(4) pp. 1193-1198. |
Zhou et al., “Targeted delivery of DNA by liposomes and polymers”, J. of Controlled Release, vol. 19, pp. 269-274 (1992). |
Dams et al., Accelerated blood clearance and altered biodistribution of repeated injections of sterically stabilized liposomes. J Pharmacol Exp Ther. Mar. 2000;292(3):1071-9. |
Ishida et al., Accelerated clearance of PEGylated liposomes in rats after repeated injections. J Control Release. Feb. 14, 2003;88(1):35-42. |
Millennium Research Group, US contrast agent and radiopharmaceutical market saw a 15 percent decline between 2010 and 2012. Business Wire. Dec. 20, 2012; 3 pages. http://www.businesswire.com/news/home/20121220005837/en/Contrast-Agent-Radiopharmaceutical-Market-15-Percent-Decline [last accessed Aug. 19, 2013]. |
Frielinghaus et al., End effects in poly(styrene)/poly(ethylene oxide) copolymers. Macromolecules. 2001;34(4):1096-104. |
Medved et al., Study of phase equilibriums of aqueous mixtures of polyethylene oxides with terminal groups of different hydrophilicity. Zhumal Prikladnoi Khimii. 1980;53(7)1 669-71. CAPLUS Abstract Accession No. 1980:551033. |
Richter et al., Antibodies against polyethylene glycol produced in animals by immunization with monomethoxy polyethylene glycol modified proteins. Int Arch Allergy Appl Immunol. 1983;70(2):124-31. |
Richter et al., Polyethylene glycol reactive antibodies in man: titer distribution in allergic patients treated with monomethoxy polyethylene glycol modified allergens or placebo, and in healthy blood donors. Int Arch Allergy Appl Immunol. 1984;74(1):36-9. Abstract Only. |
Sherman et al., Role of the methoxy group in immune responses to mPEG-protein conjugates. Bioconjug Chem. Mar. 21, 2012;23(3):485-99. doi: 10.1021/bc200551b. Epub Mar. 7, 2012. |
Unsworth et al., Protein-resistant poly(ethylene oxide)-grafted surfaces: chain density-dependent multiple mechanisms of action. Langmuir. Mar. 4, 2008;24(5):1924-9. doi: 10.1021/la702310t. Epub Jan. 25, 2008. |
Kitzman et al., Efficacy and safety of the novel ultrasound contrast agent perflutren (DEFINITY) in patients with suboptimal baseline left ventricular echocardiographic images. Am J Cardiol. Sep. 15, 2000;86(6):669-74. |
Kurt et al., Impact of contrast echocardiography on evaluation of ventricular function and clinical management in a large prospective cohort. J Am Coll Cardiol. Mar. 3, 2009;53(9):802-10. |
Wang et al., Anti-PEG IgM elicited by injection of liposomes is involved in the enhanced blood clearance of a subsequent dose of PEGylated liposomes. J Control Release. Jun. 4, 2007;119(2):236-44. Epub Feb. 24, 2007. |
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