WO2007129311A2 - Nanoparticules avec agents de contraste pour systeme de delivrance diagnostique pour radiographie et tomodensitometrie - Google Patents

Nanoparticules avec agents de contraste pour systeme de delivrance diagnostique pour radiographie et tomodensitometrie Download PDF

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Publication number
WO2007129311A2
WO2007129311A2 PCT/IL2007/000541 IL2007000541W WO2007129311A2 WO 2007129311 A2 WO2007129311 A2 WO 2007129311A2 IL 2007000541 W IL2007000541 W IL 2007000541W WO 2007129311 A2 WO2007129311 A2 WO 2007129311A2
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Prior art keywords
nano
contrast agent
particle
contrast
particles
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PCT/IL2007/000541
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English (en)
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WO2007129311A3 (fr
Inventor
Leonid Lurya
Andrei Matseav
Israela Becker
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Pan Sci Tech S.A.
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Publication date
Priority claimed from IL175402A external-priority patent/IL175402A0/en
Priority claimed from IL175403A external-priority patent/IL175403A0/en
Application filed by Pan Sci Tech S.A. filed Critical Pan Sci Tech S.A.
Publication of WO2007129311A2 publication Critical patent/WO2007129311A2/fr
Publication of WO2007129311A3 publication Critical patent/WO2007129311A3/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/04—X-ray contrast preparations
    • A61K49/0433—X-ray contrast preparations containing an organic halogenated X-ray contrast-enhancing agent
    • A61K49/0447—Physical forms of mixtures of two different X-ray contrast-enhancing agents, containing at least one X-ray contrast-enhancing agent which is a halogenated organic compound
    • A61K49/0461—Dispersions, colloids, emulsions or suspensions
    • A61K49/0466—Liposomes, lipoprotein vesicles, e.g. HDL or LDL lipoproteins, phospholipidic or polymeric micelles

Definitions

  • the present invention relates to the composition, the preparation method and to the use of nano-p articles, which contain contrast agents, phospholipids and surfactants, as contrast media in radiography.
  • Simple x-ray photography and computer tomography are the nucleus of current medical imaging diagnosis.
  • Hard tissues such as bones and teeth, efficiently absorb x-rays, relative to the surrounding soft tissues, and thereby high contrast x-ray images can be obtained.
  • the difference in x-ray absorption between different soft tissues is relatively small, making it difficult to obtain high contrast images of the internal anatomy of the human body.
  • contrast media are generally used to enhance the contrast of the x-ray images.
  • X-ray imaging is based on differences in electron densities. Therefore, X-ray contrast agents, in current use, contain heavy elements, such as Barium in barium salts, which are used to enhance the visualization of the gastrointestinal system and Iodine in iodinated organic compounds, which are used in the visualization of the cardiovascular system and in parenteral studies.
  • heavy elements such as Barium in barium salts, which are used to enhance the visualization of the gastrointestinal system and Iodine in iodinated organic compounds, which are used in the visualization of the cardiovascular system and in parenteral studies.
  • Iodinated x-ray contrast agents most commonly contain iodinated phenyl groups, typically possessing at least one 2,4,6-triiodophenyl group having at the 3-and/or 5-positions groups such ascarboxyl, carbamoyl, N- alkylcarbamoyl, N-hydroxyalkylcarbamoyl, acylamino, N-alkylacylamino and acylaminomethyl.
  • the need for image enhancement arises from the difficulty of imaging the internal anatomy of the human body. In some procedures large-scale anatomical differences are to be observed, however, it often becomes difficult to distinguish smaller differences or structures.
  • the parameters that control image quality are contrast, blur, and noise.
  • contrast agents allow for anatomical differences to be spread over a wider range of color, allowing more details to be observed.
  • the most applicable method to increase contrast of the human anatomy is through the use of contrast agents.
  • density (structural) differences can be accentuated. Density differences can even be created in places where no real anatomical differences can be distinguished, using an x-ray imaging tool.
  • contrast agents There are different types of contrast agents ranging from gaseous oxygen, carbon dioxide, room air, heavy metals in metallic-insoluble paste, emulsion and colloidal suspension. These substances are synthesized into compounds that can be handled by various organ systems without undesirable effects. These substances absorb x-rays, and are used in a number of methods to increase the contrast of a specific organ or part of the anatomy that needs to be imaged. Common examples of contrast compounds with high atomic weight are barium sulphate and iodine or gadolinium containing substances.
  • contrast media has a particular application e.g., barium sulphate is administered through "barium meals” and enemas to demonstrate the upper and lower digestive tracts and iodinated contrast agents can be injected or orally administrated to allow for greater contrast in images of the blood pool, kidneys and bladder.
  • the contrast agent must be comparably isotonic to the blood osmotic pressure so that the injected solution will be suitable for intravenous administration.
  • the toxicity of the contrast agent is based on the composition of the materials from which it is made.
  • a lethal dose measurement (LD50) has been created for reference and is used when creating and using contrast media.
  • the lethal dose requirements are in the form of grams of iodine/kilogram of body weight. These measurements have been calculated from animal testing results.
  • contrast agents There are two major types of contrast agents: ionic and nonionic.
  • the nonionic agents consist of two types: monomeric and dimeric. The major difference between these two types of contrast agents is the number of iodine atoms per molecule; The dimeric agents hold more iodine atoms per molecule.
  • Non-ionic iodinated x-ray contrast agents are substantially less toxic than the ionic agents by virtue of their lower osmolarity and consequently reduced haemodynamic effects.
  • the main nonionic contrast agents are Iohexol, Iopentol, Iopamidol, Iodixanol, Iopromide, Iotrolan and metrizamide.
  • the Iodixanol and Iotrolan are dimers which, by virtue of their osmolality, may be formulated to be isotonic with blood at concentrations of 300 mg I/ml or above.
  • the molecular size of the molecules of the contrast agent is important when considering where the contrast agent accumulates in order to produce x-ray images: In vascular studies, the contrast agent needs to remain within the bloodstream, in order to demonstrate the arteries, veins and capillaries. As small molecules have been shown to diffuse out of the blood stream at faster rates than large molecules, a contrast agent of large molecules is preferable when it come to vascular studies.
  • hydrophilic contrast agents easily dissolve in water.
  • Hydrophobic contrast agents categorized as lipophilic agents, tend to bind to lipids and other fatty molecules. These properties can be used to specify where within the human body the contrast agent accumulates: Hydrophilic molecules bind to plasma and circulate in the bloodstream throughout the body. Lipophilic substances diffuse into the interstitial fluid volume. In view of their hydrophilic nature, all the heretofore-mentioned x-ray contrast agents have approximately the same extracellular biodistribution and therefore exhibit similar clinical indications and are renally excreted.
  • contrast agents can be oral, intra-venous, or intraarterial.
  • Oral administration of the contrast agent occurs by the intake of a "contrast meal".
  • the contrast agent When swallowed, the contrast agent outlines the esophagus, stomach, and the small intestine. With an enema of the contrast agent, the lower extremities of the digestive tract can be visualized.
  • Intravenous and intra-arterial administration of contrast agent operate in a similar ways. After the injection, the blood rapidly dilutes the contrast agent. The contrast agent starts to diffuse into the capillary bed (both in arterial and venous administration) and into interstitial fluid spaces. As the concentration of contrast media increases within the surrounding tissue, the concentration within the blood starts to increase again (suggesting re- absorption of the contrast medium back into the blood). Due to renal excretion of contrast media out of the blood, the contrast media flux across the capillary walls reaches a momentary equilibrium, after which the renal excretion exceeds the rate of tissue absorption and the contrast medium is excreted from the body in urine.
  • the advantage of x-ray imaging relies heavily upon the fact that accurate images of the internal anatomy can acquired through noninvasive techniques.
  • contrast agents have greatly enhanced the images collected.
  • radiation can be monitored and kept under safe amounts.
  • the amount of radiation absorbed is approximately 20 milliroentgens, which is comparable to the 100 milliroentgens of radiation that one is exposed to (in a year) in natural environment.
  • contrast agent The major side effects of contrast agent are anaphylactoid reactions and contrast-induced nephropathy.
  • Anaphylactoid reactions range from urticaria and itching, to bronchospasm and facial and laryngeal edema.
  • Contrast- induced nephropathy is defined as either a greater than 25% increase of serum creatinine or an absolute increase in serum creatinine of 0.5 mg/dL.
  • the osmolality of the contrast agent is believed to be of great importance in contrast-induced nephropathy.
  • the contrast agent should be isoosmolar to blood. Modern iodinated contrast agents are non-ionic, the older ionic types caused more adverse effects and are not used much anymore.
  • a field in which contrast agent science is rapidly expanding is the long-term blood pool opacification in vascular studies.
  • the vascular capillaries need to be "coated' similarly to the digestive tract to allow for the enhancement of vascular studies.
  • the opsonization process involves the coating of the particles by an antigen protein, opsonin, which is recognizable by macrophages. Then, opsonization is followed, by the phagocytosis and metabolization of the coated (opsonized) particles by the Kupffer cells of the liver and spleen.
  • opsonization involves the coating of the particles by an antigen protein, opsonin, which is recognizable by macrophages. Then, opsonization is followed, by the phagocytosis and metabolization of the coated (opsonized) particles by the Kupffer cells of the liver and spleen.
  • bare particles are suitable for imaging of the liver and the spleen, their half-life in the bloodstream is too short for an efficient blood pool imaging.
  • the objective is to accumulate a sufficient quantity of a contrast agent in the area of interest, namely the blood pool, for a relatively long time while avoiding adverse reactions.
  • This can be achieved by encapsulating the contrast agent.
  • the encapsulation enables the contrast agent to reside in the blood pool for a relatively long time, while shielding the human body from the potential undesired side effects due to the exposure to the contrast agent.
  • Liposomes microscopic artificial phospholipid vesicles
  • micelles amphiphilic compound colloidal particles with lipophilic cores and hydrophilic coronas
  • the sizes, charges, and surface properties of these carriers can be easily changed by adding new ingredients to the lipids or amphiphilic compound mixtures before the liposomes or micelles are prepared, and by varying the preparation methods.
  • the ability of liposomes to entrap different substances into the aqueous phase and the membrane compartment makes them suitable for carrying the diagnostic contrast agents used with different imaging techniques.
  • the varying chemical properties of contrast compounds require specific protocols for loading the liposomes.
  • the imaging techniques differ not only in their sensitivity and resolution, but also in the amounts of diagnostic labels to be delivered into the areas of interest.
  • phospholipid liposomes When phospholipid liposomes are introduced into the circulatory system, they are rapidly sequestered by the cells of the reticuloendothelial system (RES) (half-clearance time ⁇ 30 min). Liver cells are primarily responsible for absorbing the liposomes, and the sequestration is almost independent of the size, charge, and composition of the liposomes. RES uptake can be somewhat decreased by using small liposomes, increasing liposome dose (blocking the RES), pre-saturating the RES with "empty" liposomes or other particles, or modifying the liposome surface with certain "protective" polymers.
  • RES reticuloendothelial system
  • Liposomes with a surface- attached, specific ligand Liposomes with a specific affinity for an affected organ or tissue are believed to increase the efficacy of liposomal pharmaceutical agents, including those used for imaging.
  • Immunoglobulins, primarily of the class G (IgG), are the most promising and widely used targeting species for various drugs and drug carriers, including immunoliposom.es.
  • encapsulated x-ray contrast agents are not widely in use, at present, due to the relatively low loading capacity of the carrying vesicle with contrast agent molecules and low thermodynamic stability. Furthermore, no cost- effective large-scale production of homogeneous preparations of diagnostic encapsulated x-ray contrast media had yet been achieved.
  • the present invention overcomes these difficulties.
  • the invention is a nano-particle, for use as contrast media.
  • the nano-particle of the invention is comprised of one or more types of hydrophilic contrast agents or hydrophobic contrast agents, one or more phospholipids, and one or more surfactants and is characterized in that it consists of at least about 20% (wt/wt) of the contrast agent.
  • the molecular ratio of the phospholipids to the contrast agent can be in the range between 10:1 to 1:10 and is preferably in the range between 2:1 to 1:2.
  • the contrast agent is an iodinated X-ray contrast agent selected from the group which contain iodinated phenyl groups, wherein the iodinated phenyl groups typically possess at least one 2,4,6-triiodophenyl group having, at the 3- and/or 5-positions, groups selected from carboxyl, carbamoyl, N- alkylcarbamoyl, N-hydroxyalkylcarbamoyl, acylamino, N-alkylacylamino and acylaminomethyl, i.e., metrizoic acid, diatriazoic acid, iothalamic acid, ioxaglic acid and salts of these acids.
  • the contrast agent is a non-ionic iodinated X-ray contrast agent selected from the group: iohexol, iopentol, iopamidol, iodixanol, iopromide, iotrolan and metrizamide, including the so-called dimers (i.e., iodixanol and iotrolan).
  • the nano-particle of the invention can be targeted to one or more specific organs or it can be non-targeted.
  • the invention is processes for the preparation of the nano- particle of the first aspect.
  • the process comprises the steps of: a) mixing phospholipids and surfactants until sufficiently dissolved by gentle stirring while heating, preferably to 50-80°C; b) mixing the resulting homogenous oil phase with a preheated water solution of hydrophilic contrast agent while extensively stirring until a homogenous water-in-oil emulsion is obtained; c) cooling the emulsion while stirring; d) mixing the cooled emulsion with a solution comprising surfactants in water that has been preheated, preferably to 50-80°C, until a double water-in-oil-in-water emulsion obtained; e) homogenizing the double water-in-oil-in-water emulsion at high- pressure for two to six subsequent cycles, thereby obtaining particles having a narrow size -range; f) cooling the homogenized emulsion to room temperature; g) separating particles containing contrast agent from unbound fractions; h) collecting the different fractions; i
  • the process comprises the steps of: a) mixing a hydrophobic contrast agent, phospholipids, and surfactants dissolve in organic solvent and co-solvent while stirring, preferably at 35-45°C; b) adding the resulting oil phase homogeneous mixture gradually to the warm water phase buffer solution with extensive stirring until a homogenous oil-in-water emulsion is obtained; c) homogenizing the crude homogenous oil-in-water emulsion at high pressure for 2-6 subsequent cycles; thereby obtaining particles having a narrow size-range; d) cooling the homogenized emulsion to room temperature; e) separating contrast agent-containing particles from unbound fractions; f) collecting the different fractions; g) filter-concentrating the different fractions; and h) storing the different fractions in separate containers.
  • the high-pressure is preferably in the range 500 - 1600 atmospheres; the separation can be done by using a Sephadex G50 column, and the different fractions are stored at temperature between slightly above 0 0 C to 8°C.
  • the organic solvent can be ethyl ethanol and the co-solvent can be propylene glycol.
  • the invention relates to Nano-particles which are produced according to the processes of the second aspect of the invention.
  • the nano-particles of either the first or the third aspects are used as contrast media in radiography.
  • FIG. IA- ID show the elution profiles of the particles obtained at different stages of the process outlined in example 3.
  • Particle based agents for the delivery of therapeutic and diagnostic agents due to their ability to allow long circulation in the bloodstream are well described in the art (see for example, PCT publication No. WO0033890A1).
  • phospholipids based micelles which are capable of carrying a variety of molecules such as radioactive and chemotherapy agents have also been described.
  • radioactive and chemotherapy agents have also been described.
  • thermodynamically stable microemulsions comprised of a continuous mixture of two or more immiscible phases, where one of the phases is homogeneously dispersed and particle size is much smaller than 1 micron.
  • Micro-emulsions are different from well-known sub-micron emulsions.
  • oil droplets are dispersed in a continuous water phase. They are thermodynamically unstable and need high-energy homogenization to obtain necessary particle size that is optimal for their stabilization.
  • Microemulsions contain hydrophobic molecules distributed in surfactant-loaded phase. Microemulsions are thermodynamically stable and may form spontaneously during simple mixing of components.
  • Microemulsions are usually prepared with surfactants, mainly anionic or non- ionic, co-surfactants, and oils.
  • the inventors of the present invention have developed an innovative approach for the preparation of a new kind of colloidal system based on microemulsion technology. This approach provides a rational design of delivery systems with desired properties based on the meticulous selection of appropriate surfactants/co-surfactants composition for the specific X-ray contrast agent of interest.
  • the inventors have found that the use of specific surfactant combination and high pressure homogenization technique allowed them to exploit the carried drug as a building element of nano-p article, stabilized by minimal amount of surfactants rather than well-known entrapment of drug in the inner core of the particle.
  • specific surfactant combinations and a high pressure homogenization technique allowed double-reversed nano-emulsions containing X-ray hydrophilic contrast agent molecules stabilized, in the form of nano- particles, by minimal amounts of biologically compatibles surfactants to be built.
  • contrast agents for medical diagnostics requires safe and efficient delivery systems with particular parameters of distribution in the human body.
  • the system of the invention provides an opportunity for a safe delivery of a variety of contrast agents due to its consolidation into colloidal particles and consequent avoidance of any side effects.
  • the system of the invention significantly encourages efficiency and quality of diagnostic procedures due to the enhancement of contrast effect as a result of the increase of concentration of the contrast agent in the area of interest. This is achieved due to a high loading capacity of the delivery system.
  • An additional advantage of the system of the invention is the possibility of site-specific distribution of the contrast agents in the human body. This may be accomplished by the meticulous design of delivery vesicles with particular properties, such as particle size, surface charge or allocation of specific chemical moieties on the particle surface, that provide certain particle distribution and pharmaco-kinetics behavior, like metabolism and elimination.
  • the present invention is drawn to phospholipid-based particles capable of carrying high loads of contrast agents, which are suitable for x-ray and CT.
  • the present invention relates to radio-opaque agents such as iodine-containing aromatic molecules (e.g., diatrizoate, metrizoate, iothalamate, metrizoate, iodipamide, or triiodobenzoic acid) or bromine- containing molecules (e.g., perfluorooctyl bromide), which together with selected phospholipids and low percentage of surfactants or co-surfactants (0.01-10 % and 0.01-5 % respectively) are capable of forming mixed micelles.
  • radio-opaque agents such as iodine-containing aromatic molecules (e.g., diatrizoate, metrizoate, iothalamate, metrizoate, iodipamide, or triiodobenzoic acid) or bromine- containing molecules (e.
  • the micelles of the present technology are stable particles of 50-600 nm formed by high-pressure homogenization. Such micelle particles exhibit high contrast agent loading capacities with a molecular ratio of the phospholipid to the contrast agent ranging from 10:1 up to 1:10 with optimal values of 2:1 to 1:2. It should be noted, that the micelle particles of the present invention are devoid of an inner lumen as seen in liposomes or polymeric vesicles and are generated without any chemical bond between its components, i.e., the phospholipids, the contrast agents and the surfactants or co-surfactants.
  • Example I Preparation of a diatrizoic acid containing particle
  • Example II Preparation of an Iohexol containing particle
  • a quantity of 3 g of soybean lecithin (S-100, soybean phosphatidyl choline 95% purity), 0.2 g Stearic Acid, Ig SPAN60 (sorbitan monostearate ) and 0.06 g Vitamin E TPGS (D-alpha tocopheryl polyethylene glycol 1000 succinate) were dissolved with 2 g MCT oil (mixture of well defined medium chain triglycerides, Labrafac Lipophile WL1349, Gattefosse) by stirring at 70°C for 1 hour.
  • the homogeneous oil phase was then mixed with 1.5 g 60% solution of Iohexol in water.
  • the resulted primary emulsion was allowed to cool for 2 hours under vigorous stirring and then mixed (600 rpm) with 23.5 g of 0.2% TWEEN 20 solution in water preheated for 70°C.
  • the obtained inversed double emulsion was subjected to high pressure homogenization at 1600 atmospheres for 4 subsequent cycles.
  • Nano-p articles were separated from encapsulated Iohexol with Sephadex G25 column. Particle size distribution was determined by Coulter particle size analyzer. All particles were shown to have a mean diameter around 150 nm.
  • the Iohexol concentration was shown by UV spectrometry at 244 and 260 nm to be 3%.
  • Example III Preparation of an Iohexol containing particle A quantity of 68.4 g of soybean lecithin (S-IOO, soybean phosphatidyl choline 95% purity), 4.56 g Stearic Acid (USP grade), 22.8 g SPAN60 (sorbitan monostearate ) and 1.37 g Vitamin E TPGS (D-alpha tocopheryl polyethylene glycol 1000 succinate) were dissolved with 45.6 g MCT oil (mixture of well defined medium chain triglycerides, Labrafac Lipophile WL1349, Gattefosse) by stirring at 7O 0 C for 1 hour. The homogeneous oil phase was then mixed with 142.7 g 60% solution of Iohexol in water.
  • S-IOO soybean lecithin
  • S-IOO soybean phosphatidyl choline 95% purity
  • S-IOO soybean phosphatidyl choline 95% purity
  • S-IOO soybean phosphatidyl
  • the resulted primary emulsion was allowed to cool for 2 hours while vigorous stirring and then mixed (600 rpm) with 714.5 g 30% Iohexol in 5% Mannitol 1OmM TRIS solution preheated for 70°C. Obtained inversed double emulsion was subjected to high pressure homogenization at 1600 atmospheres for 4 subsequent cycles. Free, unbound to lipid particles molecules of Iohexol were separated from particulate fraction by means of gel filtration using 50 ml Sephadex G50 chromatographic column.
  • the resulted emulsion was subjected for assessment of entrapment efficacy by analytical separation with Sephadex G25 column.
  • Particle size distribution was determined by Coulter particle size analyzer. All particles were shown to have a mean diameter around 150 nm.
  • the Iohexol concentration was shown by UV spectrometry at 260 nm to be 60 mg/ml.
  • Figs. IA- ID show the elution profiles of the particles obtained at different stages of the process outlined in example 3, where: Fig. IA is for the crude non-separated double emulsion; Fig. IB the formulation after separation on Sephadex column and concentration with Pellicon XL device; Fig. 1C the lipid particles (detected at 210 nm); and Fig. ID is for free Iohexol in aqueous solution.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Dispersion Chemistry (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
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Abstract

La présente invention concerne une nanoparticule stable, utilisable en tant que milieu de contraste en radiographie. La nanoparticule de l'invention comprend au moins un agent de contraste, des phospholipides et des tensioactifs et elle est caractérisée par la présence d'au moins environ 20 % (poids/poids) de l'agent de contraste. L'invention concerne également des procédés de préparation des nanoparticules de l'invention.
PCT/IL2007/000541 2006-05-04 2007-05-03 Nanoparticules avec agents de contraste pour systeme de delivrance diagnostique pour radiographie et tomodensitometrie WO2007129311A2 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
IL175403 2006-05-04
IL175402A IL175402A0 (en) 2006-05-04 2006-05-04 Diagnostic delivery system for x-ray contrast agents
IL175402 2006-05-04
IL175403A IL175403A0 (en) 2006-05-04 2006-05-04 Composition and methods of preparation of a diagnostic delivery system containing hydrophilic x-ray contrast agents

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WO2007129311A2 true WO2007129311A2 (fr) 2007-11-15
WO2007129311A3 WO2007129311A3 (fr) 2008-01-31

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012007567A1 (fr) 2010-07-16 2012-01-19 Technical University Of Denmark Radiothérapie guidée par nanoparticules

Citations (9)

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US4192859A (en) * 1978-09-29 1980-03-11 E. R. Squibb & Sons, Inc. Contrast media containing liposomes as carriers
WO1988009165A1 (fr) * 1987-05-22 1988-12-01 Bracco Industria Chimica S.P.A. Composition liposomique opacifiante injectable
WO1989011272A1 (fr) * 1988-05-20 1989-11-30 The Liposome Company, Inc. Complexe agent actif:lipide a rapport eleve
WO1992021384A1 (fr) * 1991-06-03 1992-12-10 Karlshamns Lipidteknik Ab Substance de contraste radiographique
WO1994008626A1 (fr) * 1992-10-16 1994-04-28 Andreas Sachse Procede et dispositif de preparation de systemes disperses liquides
WO1995026205A1 (fr) * 1994-03-28 1995-10-05 Nycomed Imaging A/S Liposomes
EP0759785A1 (fr) * 1995-02-24 1997-03-05 Bracco Research S.A. Suspensions de liposomes utilisees comme produit de contraste de visualisation du pool sanguin intracardiaque
WO1997011683A2 (fr) * 1995-09-27 1997-04-03 Nycomed Imaging A/S Compositions de phospholipides stabilisees
WO2006084382A1 (fr) * 2005-02-11 2006-08-17 University Health Network Compositions et procedes d'imagerie multimodale

Patent Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4192859A (en) * 1978-09-29 1980-03-11 E. R. Squibb & Sons, Inc. Contrast media containing liposomes as carriers
WO1988009165A1 (fr) * 1987-05-22 1988-12-01 Bracco Industria Chimica S.P.A. Composition liposomique opacifiante injectable
WO1989011272A1 (fr) * 1988-05-20 1989-11-30 The Liposome Company, Inc. Complexe agent actif:lipide a rapport eleve
WO1992021384A1 (fr) * 1991-06-03 1992-12-10 Karlshamns Lipidteknik Ab Substance de contraste radiographique
WO1994008626A1 (fr) * 1992-10-16 1994-04-28 Andreas Sachse Procede et dispositif de preparation de systemes disperses liquides
WO1995026205A1 (fr) * 1994-03-28 1995-10-05 Nycomed Imaging A/S Liposomes
EP0759785A1 (fr) * 1995-02-24 1997-03-05 Bracco Research S.A. Suspensions de liposomes utilisees comme produit de contraste de visualisation du pool sanguin intracardiaque
WO1997011683A2 (fr) * 1995-09-27 1997-04-03 Nycomed Imaging A/S Compositions de phospholipides stabilisees
WO2006084382A1 (fr) * 2005-02-11 2006-08-17 University Health Network Compositions et procedes d'imagerie multimodale

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012007567A1 (fr) 2010-07-16 2012-01-19 Technical University Of Denmark Radiothérapie guidée par nanoparticules

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