WO1996016679A1 - Paramagnetic complexes of n-alkyl-n-hydroxylamides of organic acids and emulsions containing same for magnetic resonance imaging (mri) - Google Patents
Paramagnetic complexes of n-alkyl-n-hydroxylamides of organic acids and emulsions containing same for magnetic resonance imaging (mri) Download PDFInfo
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- WO1996016679A1 WO1996016679A1 PCT/US1995/014508 US9514508W WO9616679A1 WO 1996016679 A1 WO1996016679 A1 WO 1996016679A1 US 9514508 W US9514508 W US 9514508W WO 9616679 A1 WO9616679 A1 WO 9616679A1
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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
- A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
- A61K49/18—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes
- A61K49/1806—Suspensions, emulsions, colloids, dispersions
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10S977/00—Nanotechnology
- Y10S977/902—Specified use of nanostructure
- Y10S977/904—Specified use of nanostructure for medical, immunological, body treatment, or diagnosis
- Y10S977/927—Diagnostic contrast agent
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10S977/00—Nanotechnology
- Y10S977/902—Specified use of nanostructure
- Y10S977/904—Specified use of nanostructure for medical, immunological, body treatment, or diagnosis
- Y10S977/927—Diagnostic contrast agent
- Y10S977/928—X-ray agent
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10S977/00—Nanotechnology
- Y10S977/902—Specified use of nanostructure
- Y10S977/904—Specified use of nanostructure for medical, immunological, body treatment, or diagnosis
- Y10S977/927—Diagnostic contrast agent
- Y10S977/929—Ultrasound contrast agent
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10S977/00—Nanotechnology
- Y10S977/902—Specified use of nanostructure
- Y10S977/904—Specified use of nanostructure for medical, immunological, body treatment, or diagnosis
- Y10S977/927—Diagnostic contrast agent
- Y10S977/93—MRI contrast agent
Definitions
- This invention relates to paramagnetic complexes, emulsions containing same, and processes of making and using them. More particularly, this invention relates to novel emulsions that contain water, a dispersed oil phase and a complex of a paramagnetic metal ion and an organic acid chelator, for example DTPA (diethylenetriaminepentaacetic acid), having a C 10 -C 30 saturated aliphatic group and an hydroxyl group bonded to a nitrogen atom.
- DTPA diethylenetriaminepentaacetic acid
- Magnetic resonance imaging has been developed in recent years and, for improved imaging, paramagnetic contrast agents have been given to patients prior to imaging.
- a number of patents disclose paramagnetic MRI contrast agents including, for example, U.S. Patents 4,647,447; 4,859,451; 4,957,939; 4,963,344; 5,021,216; 5,064,636 and 5,120,527; and PCT application WO 92/21017. These patents are considered to be illustrative of prior references in the field and are not intended to be the most pertinent references.
- paramagnetic agents of the type disclosed in the above patents have been administered to the patient in the form of aqueous solutions.
- paramagnetic oil emulsions have been provided for MRI imaging in the gastro-intestinal tract as disclosed in U.S. Patents 5,064,636 and 5,120,527.
- MRI contrast agents that function effectively as organ imaging agents as well as blood pool agents, or for other uses, such as agents for imaging the bone marrow, spleen, liver, or lymph nodes.
- Liposomes have also been studied as MRI contrast agents, and, more recently, as disclosed in PCT application WO 92/2107, lipo soluble contrast agents may be administered in the form of lipid emulsions.
- the contrast agents of the PCT application are useful in the imaging of the liver, blood pool and reticuloendothelial system (RES).
- RES reticuloendothelial system
- MRI contrast agents are needed which function effectively as organ imaging agents as well as blood pool agents, and for general imaging of the reticuloendothelial system. Stable and versatile MRI contrast agents are needed, especially for intravenous use.
- a physiologically acceptable emulsion for enhancement of MRI imaging comprises water, a dispersed oil phase and a complex of a paramagnetic metal ion and an organic chelator having the formula
- the metal ion is a lanthanide element of atomic numbers 58-70 or a transition metal of atomic numbers 21-29, 42 or 44, most preferably selected from a group consisting of Gd(III), Mn(II), iron and dysprosium.
- the organic chelator is preferably an acid selected from the group consisting of ethylenediaminetetraacetic acid and diethylenetriaminepentaacetic acid.
- Mono- or bis(N-alkyl-N-hydroxylamides) having a saturated C 14 -C 22 group are physiologically preferred. It has been established that the unsaturated group may have one, two, or three double bond(s) at a number of different locations in the group, and very fine, stable emulsions are still achieved.
- the MRI emulsions for intravenous administration have an average particle size less than about l micron, preferably on the order of about 0.2 to about 0.4 micron.
- the emulsions comprise water, a dispersed oil phase selected from the group consisting of an oil and a fluorochemical, and mixtures thereof, a surfactant, and a dispersed complex of a paramagnetic metal ion and an organic chelator.
- the emulsified particles of an oil and/or a fluorochemical ("PFC") in water are hereinafter sometimes referred to as the "dispersed oil phase".
- the paramagnetic agent may be effectively suspended or dispersed in the stabilized emulsion for delivery to an animal or human subject.
- the MRI emulsions of this invention are very stable and exhibit excellent storage stability at room temperature or other ambient conditions. Furthermore, the inventive emulsions produce excellent MRI images of organs, blood pool and the RES.
- This invention also includes methods of making emulsions containing paramagnetic agents.
- Other objectives of this invention and advantages will become apparent from the following detailed description.
- the MRI emulsions of this invention comprise an oil and/or a fluorochemical (PFC) emulsified in water and contain a paramagnetic metal chelate complex.
- the chelate complex may act as a surfactant and, thus, additional cosurfactant may not be needed.
- a surfactant is added.
- the oil and/or PFC may be contained in amounts from about 0.5 to 50% by weight. More specifically, for instance, in medical applications for intravenous (IV) MRI contrast agent delivery, the preferred amounts of PFC and/or oil with surfactant are minimum amounts to effectively disperse the agent in a stable emulsion. For oral, rectal, or other delivery, far greater amounts may be desirable.
- w/v% is a practical limit for the oil, or about 55 v/v% for the PFC, because of viscosity limitations for an intravenous product.
- Preferred ranges are about 5 to 20 w/v% for the oil and about 5 to about 50 v/v% for the PFC.
- Emulsions exhibit high viscosity (or a gel-like consistency) at higher oil or PFC levels.
- the surfactant may be contained in amounts from about 0.5 to about 10% by weight, usually about 1-5% by weight of the emulsion.
- the MRI agent may be dispersed in varying amounts up to about 30% by weight, depending upon dose, efficacy and safety requirements.
- an IV emulsion may preferably contain an amount of MRI agent up to about 10% by weight.
- an MRI imaging agent such as a gadolinium salt of a bis(N-alkyl-N-hydroxylamide) of diethylenetriaminepentaacetic acid may be used as high as about 50% or more.
- the emulsions may be diluted with isotonic saline, or other agents, to produce lower concentrations.
- this invention is directed to a physiologically acceptable emulsion for enhancement of MRI imaging comprising water, a dispersed oil phase and a complex of a paramagnetic metal ion and an organic chelator having the formula
- the metal ion is a lanthanide element of atomic numbers 58-70 or a transition metal of atomic numbers 21- 29, 42 or 44, most preferably selected from a group consisting Gd(III), Mn(II), iron and dysprosium.
- the organic chelator is preferably an acid selected from the group consisting of ethylenediaminetetraacetic acid and diethylenetriaminepentaacetic acid.
- Monohydroxylamides or bishydroxylamides of an organic acid selected from a group consisting of diethylenetriaminepentaacetic acid and ethylenediaminetetraacetic acid are used wherein each R 1 is a C 14 -C 22 group selected from the group of stearyl, tetradecyl and hexadecyl.
- chelate complexes include gadolinium diethylenetriaminepentaacetic acid bis(N-stearyl-N-hydroxylamide) , gadolinium diethylenetriaminepentaacetic acid bis(N-tetradecyl-N-hy d r o x y l am i d e ) , a n d g a d o l i n i um diethylenetriaminepentaacetic acid bis(N-hexadecyl-N-hydroxylamide).
- oil is used herein in a general sense to identify a large class of physiologically acceptable substances whether of mineral, vegetable, animal, essential or synthetic origin. Thus, the term “oil” is used herein as applied to a wide range of substances that are quite different in chemical nature.
- mineral oil is derived from petroleum and includes aliphatic or wax-based hydrocarbons, aromatic hydrocarbons or mixed aliphatic and aromatic based hydrocarbons. Also included in the mineral classification are petroleum-derived oils such as refined paraffin oil, and the like.
- oils are chiefly derived from seeds or nuts and include drying oils such as linseed and tung oil; semidrying such as safflower and soy bean oils; nondrying such as castor, cottonseed and coconut oils and edible soap stocks such as palm and coconut oils.
- oils usually occur as fats in tallow, lard and stearic acid sources.
- the liquid animal types include fish oils, oleic acid, sperm oil, etc. and they usually have a high fatty acid content. Included are some vegetable oils, such as olive, cottonseed, corn and peanut, as well as some special fish oils such as cod-liver, haliver, shark liver, and so forth which are used largely as medicines for their high vitamin content.
- a liquid fatty oil such as a mono-, di-, or triglyceride, or a mixture thereof, is the preferred oil.
- Medium chain triglycerides also serve as useful oils according to this invention.
- fluorochemical or "PFC” is used to describe either a highly fluorinated organic compound of perfluorocarbon or fluorinated chemical. Further, these terms are used interchangeably.
- perfluorocarbon includes a "cyclic” or “acyclic” compound of carbon. Substituted derivatives thereof are also included where fluorocarbons have other elements within their structures such as oxygen, hydrogen, nitrogen chlorine and bromine, etc. It should also be noted that the term “perfluorocarbon” is meant to include partially or substantially fluorinated compounds. This is permissible providing that the lack of complete replacement of all hydrogens does not affect the essential non-toxic characteristics of the preferred medical fluorocarbons of this invention.
- perfluorocarbon compounds which may be employed are perfluorotributylamine (FC47), perfluorodecalin (PP5), perfluoromethyldecalin (PP9), perfluorooctylbromide, perfluorotetrahydrofuran (FC80), perfluoroether (PID) [(CF 3 ) 2 CFOCF 2 (CF 2 ) 2 CF 2 OCF(CF 3 ) 2 ] perfluoroether (PUD) [(CF 3 ) 2 CFOCF 2 (CF 2 ) 6 CF 2 OCF(CF 3 ) 2 ], perfluoropolymer (E3) , perfluoropolymer (E4)
- perfluoroetherpolymer (Fomblin Y/01), perfluorododecane, per f luorob i cyc lo [ 4 . 3 . 0 . ] nonane , perfluorotritrimethylblcyclohexane, perfluorotripropylamine, perfluoroisopropyl cyclohexane, perfluoroendotetrahydrodicyclopentadiene, perfluoroadamantane, perfluoroexot e t r a h y d r o d i c y c l o p e n t a d i e n e , p e r f l u o r b i c y c o [ 5 .
- Chlorinated perfluorocarbons such as chloroadamantane and chloromethyladamantane as described in U.S. Patent No. 4,686,024 may be used. Such compounds are described, for example in U.S. Patent Nos. 3,962,439; 3,493,581,
- Surfactants are usually needed to form stable emulsions indicated above where the MRI agent has insufficient surfactant activity. Any suitable surfactant may be employed alone or in combination with other surfactants.
- Any suitable surfactant may be employed alone or in combination with other surfactants.
- egg yolk phospholipids or Pluronics emulsifying agents may be used.
- Pluronics agents are block polymer polyols sold by Wyandotte, e.g., Pluronics F68, having a molecular weight of about 8,000, may be employed. Ethoxylates of cholesterol, diacyl glycerol and dialkyl ether glycerol are useful surfactants.
- block copolymers are made by adding ethylene oxide, propylene oxide and ethylene oxide, in that order, in varying amounts to produce surfactants.
- anionic or cationic surfactants may be used.
- the emulsions of this invention may contain alkylphosphoryl choline or alkylglycerophosphoryl choline surfactants described in Kaufman and Richard, U.S. Ser. No. 791,420, filed November 13, 1991.
- surfactants are 1,2-dioctylglycero-3-phosphoryl choline, 1,2-ditetradecylglycero-3-phosphoryl choline, 1,2-dihexadecylglycero-3-phosphoryl choline, 1,2-dioctadecylglycero-3-phosphoryl choline, 1-hexadecyl-2-tetradecylglycero-3-phosphoryl choline, 1-octadecyl-2-tetradecylglycero-3-phosphoryl choline, 1-tetradecyl-2-octadecylglycero-3-phosphoryl choline, 1-hexadecyl-2- octadecylglycero-3-phosphoryl choline, 1-2-dioctadecylglycero-3-phosphoryl choline, 1-octadecyl-2-hexadecyl-2-he
- 1,3-dialkyl glycerophosphoryl choline surfactants as described in Kaufman and Richard, U.S. Ser. No. 228,224, filed April 15, 1994 may also be used and the disclosure thereof is incorporated herein by references. Mixtures of these novel surfactants with other known surfactants may also be employed.
- Anionic surfactants include alkyl or aryl sulfates, sulfonates, carboxylates or phosphates.
- Cationic surfactants include such as mono-, di-, tri- and tetraalkyl or aryl ammonium salts.
- Non-ionic surfactants include alkyl or aryl compounds, whose hydrophilic part consists of polyoxyethylene chains, sugar molecules, polyalcohol derivatives or other hydrophilic groups.
- Zwitter-ionic surfactants may have a combination of the above anionic or cationic groups, and whose hydrophobic part consists of any other polymer, such as polyisobutylene or polypropylene oxides.
- the emulsions of this invention are made by dispersing the above ingredients in water and homogenizing them.
- the oil and/or PFC are dispersed in the water and enhance the dispersion of the paramagnetic metal chelate complex.
- the surfactant enhances the dispersion by stabilization of the liquid phases. While dispersions may be generally referred to herein as emulsions, it should be understood that they may be considered solutions, micellar solutions, microemulsions, vesicular suspensions, or mixtures of all of these physical states.
- the PFC may be dispersed in the oil and the oil-PFC phase emulsified in the water. However, other possible interfaces and phases are within the scope of the invention.
- emulsion covers all these states and the surfactant is employed to enhance stable mixtures of these physical states of the fluorochemical, oil,paramagnetic metal chelate complex and water phases.
- a fluorochemical and oil may be emulsified in water, as described in the Clark and Shaw European Pat. Appln. 87300454.3 and this application is incorporated herein by reference to describe suitable PFC/oil emulsions as MRI delivery agents.
- the MRI emulsions of this invention are very fine, stable emulsions.
- the criterion for a "fine” emulsion is no visible solid matter microscopically (300-400X) and less than 10 volume % of particles above about 0.8 ⁇ m ("CV").
- the "poor" emulsions of comparative prior art for example, have a large amount of huge (>5 ⁇ m) solids visible under the microscope, as well as greater than 10 volume % of particles above about 0.8 ⁇ m ("CV").
- Figure 1 of the drawings which documents photographically the microscopic appearance of fine and poor emulsions at 300-400 X.
- the fine emulsion contains 2% lecithin, 10% safflower oil and 5% GdDTPA-bis(N-stearyl-N-hydroxylamide) of this invention (Table 9).
- the poor emulsion has the same components except that it contains GdDTPA-bis(stearylamide) of Table 6 for comparison.
- these two complexes make markedly different quality emulsions although the complexes differ only in the hydroxyl group.
- Figure 1 depicts photographs of fine and poor emulsions at 300-400X.
- Figure 2 depicts pre-contrast and post-contrast photographic MRI images of a liver.
- a mechanically stirred mixture of diethylenetriaminepentaacetic (DTPA) dianhydride (1 mole) and anhydrous pyridine (2-24.7 mole; preferably 3.3 mole) in chloroform (0-3 L/mole of DTPA dianhydride; preferably 1 L/mole) was treated dropwise with a solution of the appropriate hydroxylamine (2 mole) in chloroform (0-2.5 L/mole of hydroxylamine; preferably 0.25 L/mole). In some cases, a mild exotherm was apparent. The resulting mixture was then heated at reflux (65oC w/o chloroform solvent) for 17-22 hours.
- the MRI emulsions of this invention that have been made in accordance with the above detailed description were characterized into various categories of emulsions for comparison with other paramagnetic metal ion chelate complexes outside the scope of this invention.
- the paramagnetic metal chelate complexes that make fine emulsions have been categorized as those in accordance with the above general formula where R 1 is a long carbon chain (C 10 -C 30 ) on the nitrogen that is saturated and R 2 is hydroxyl.
- the categories of emulsions and complexes of this invention that make fine emulsions are compared to other emulsions and complexes that make poor emulsions as reported in Table 5.
- a key to the ligands of the complexes of this invention and other complexes is provided in Table 4.
- the emulsions and chelate complexes of category 4 are representative of those HRI chelate complexes that make fine emulsions in accord with this invention. Those emulsions and chelate complexes of categories 1-3 make poor emulsions.
- the tabular summaries for each of the above categories 1-4 are reported in the following Tables 6-8.
- Comparative Category #1 As represented by Table 6, it was found that where R 1 was a single saturated chain and R 2 was hydrogen as represented by GdDTPA-BSA, poor emulsions were made despite a variety of compositions containing a surfactant lecithin, oil and PFDCO. Furthermore, with respect to those emulsions indicated by an asterisk(*), they were too viscous to measure. With reference to Comparative Categories #2 and #3 in Tables 7 and 8, where R 1 and R 2 were two saturated chains or one unsaturated chain and one long chain C)2, the emulsions had huge solids or simply failed to emulsify. In Table 8, the asterisk (*) indicates that the emulsion cracked upon sterilization and the particle sizes were too large to be measured by sub-micron particle sizer.
- the invention is represented by Table 9 where Category No. 4 is shown.
- R 1 was a C 10 -C 30 saturated chain and R 2 was hydroxyl, excellent emulsions were obtained.
- the most preferred paramagnetic metal chelate complex is GdDTPA-BSHA which provides for an excellent emulsion with CVs above 0.8 micron about 1%.
- the MRI utilities of the emulsion have been determined by using an emulsion containing 5% GdDTPA-BSHA to enhance the liver of a rabbit.
- Figure 2 shows that nearly 100% enhancement occurs in the liver after intravenous administration of a 10 ⁇ mole of gadolinium per/kg dose. The enhancement effect on the liver persisted for at least one hour.
- the images were collected with a standard T 1 -weighted spin-echo imaging sequence on a General Electric Signa whole body clinical scanner operating at 1.5 Tesla.
- Examples I and VII were reproduced from U.S. Patent 5,120,527, mentioned in the above background of this invention.
- the emulsions made under this '527 patent according to these procedures do not have visible solids, they have very large particles on the order of 10 to about 30 microns and hence are unacceptable for IV use.
- the composition contained 60mL Geritol®, l50mL melted ice cream, 250mL milk and 100mL corn oil; with other properties including viscosity of 6.05 cp, CM of 8.17 microns and CV of 83.1%.
- the Geritol® emulsion also cracked upon sterilization.
- the GdDTPA emulsion contained 0.5mole (1.0mL) of GdDTPA, 150mL melted ice cream, 250mL milk and 100mL corn oil; with the other properties of the emulsion including a viscosity with 8.18cp, CM of 16.3 microns and CV of 71.8%.
- the emulsions of the '527 patent are unacceptable for IV use and do not have the versatility of the emulsions of this invention. They also lack stability upon sterilization as evidenced by the above experiments.
- other variations or modifications may be made without departing from the spirit and scope of this invention.
Abstract
Description
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Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AU44060/96A AU4406096A (en) | 1994-11-30 | 1995-11-09 | Paramagnetic complexes of N-alkyl-N-hydroxylamides of organicacids and emulsions containing same for magnetic resonance imaging (MRI) |
JP8518809A JPH11500413A (en) | 1994-11-30 | 1995-11-09 | Paramagnetic complexes of N-alkyl-N-hydroxylamides of organic acids and emulsions containing them for magnetic resonance imaging (MRI) |
EP95942846A EP0794801A1 (en) | 1994-11-30 | 1995-11-09 | Paramagnetic complexes of n-alkyl-n-hydroxylamides of organic acids and emulsions containing same for magnetic resonance imaging (mri) |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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US08/346,885 | 1994-11-30 | ||
US08/346,885 US5614170A (en) | 1994-11-30 | 1994-11-30 | Paramagnetic complexes of N-alkyl-N-hydroxylamides of organic acids and emulsions containing same for magnetic resonance imaging (MRI) |
Publications (2)
Publication Number | Publication Date |
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WO1996016679A1 true WO1996016679A1 (en) | 1996-06-06 |
WO1996016679B1 WO1996016679B1 (en) | 1996-08-01 |
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PCT/US1995/014508 WO1996016679A1 (en) | 1994-11-30 | 1995-11-09 | Paramagnetic complexes of n-alkyl-n-hydroxylamides of organic acids and emulsions containing same for magnetic resonance imaging (mri) |
Country Status (6)
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US (1) | US5614170A (en) |
EP (1) | EP0794801A1 (en) |
JP (1) | JPH11500413A (en) |
AU (1) | AU4406096A (en) |
CA (1) | CA2205232A1 (en) |
WO (1) | WO1996016679A1 (en) |
Families Citing this family (7)
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US6028108A (en) * | 1998-10-22 | 2000-02-22 | America Home Products Corporation | Propofol composition comprising pentetate |
BR0307206A (en) | 2002-01-24 | 2004-12-21 | Barnes Jewish Hospital | Integrin-directed Imaging Agents |
US7279150B2 (en) * | 2002-01-24 | 2007-10-09 | Barnes-Jewish Hospital | Chelating agents with lipophilic carriers |
US6869591B2 (en) * | 2002-03-26 | 2005-03-22 | Barnes-Jewish Hospital | Paramagnetic particles that provide improved relaxivity |
AU2005253962A1 (en) | 2004-06-09 | 2005-12-29 | Kereos, Inc. | Lipophilic derivatives of chelate monoamides |
FR2883562B1 (en) | 2005-03-24 | 2009-02-27 | Guerbet Sa | LIPOPHILIC CHELATES AND THEIR USE IN IMAGING |
CN115947672B (en) * | 2023-01-04 | 2024-02-27 | 成都威斯津生物医药科技有限公司 | Compounds, liposomes, and drug carriers for delivery of drugs |
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1994
- 1994-11-30 US US08/346,885 patent/US5614170A/en not_active Expired - Lifetime
-
1995
- 1995-11-09 EP EP95942846A patent/EP0794801A1/en not_active Withdrawn
- 1995-11-09 CA CA002205232A patent/CA2205232A1/en not_active Abandoned
- 1995-11-09 WO PCT/US1995/014508 patent/WO1996016679A1/en not_active Application Discontinuation
- 1995-11-09 JP JP8518809A patent/JPH11500413A/en active Pending
- 1995-11-09 AU AU44060/96A patent/AU4406096A/en not_active Abandoned
Patent Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
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US4957939A (en) * | 1981-07-24 | 1990-09-18 | Schering Aktiengesellschaft | Sterile pharmaceutical compositions of gadolinium chelates useful enhancing NMR imaging |
US4963344A (en) * | 1981-07-24 | 1990-10-16 | Schering Aktiengesellschaft | Method to enhance NMR imaging using chelated paramagnetic ions |
US4963344B1 (en) * | 1981-07-24 | 1992-08-25 | Schering Ag | |
US4826673A (en) * | 1985-01-09 | 1989-05-02 | Mallinckrodt, Inc. | Methods and compositions for enhancing magnetic resonance imaging |
US5120527A (en) * | 1989-10-19 | 1992-06-09 | King Chuen Peter Li | Paramagnetic oil emulsions as mri contrast agents |
WO1992021017A1 (en) * | 1991-05-23 | 1992-11-26 | Unger Evan C | Liposoluble compounds for magnetic resonance imaging |
WO1995033494A1 (en) * | 1994-06-02 | 1995-12-14 | Hemagen/Pfc | Emulsions of paramagnetic contrast agents for magnetic resonance imaging (mri), containing an organic chelator having an unsaturated aliphatic group |
Non-Patent Citations (5)
Also Published As
Publication number | Publication date |
---|---|
JPH11500413A (en) | 1999-01-12 |
AU4406096A (en) | 1996-06-19 |
CA2205232A1 (en) | 1996-06-06 |
EP0794801A1 (en) | 1997-09-17 |
US5614170A (en) | 1997-03-25 |
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