CA2205232A1 - 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)Info
- Publication number
- CA2205232A1 CA2205232A1 CA002205232A CA2205232A CA2205232A1 CA 2205232 A1 CA2205232 A1 CA 2205232A1 CA 002205232 A CA002205232 A CA 002205232A CA 2205232 A CA2205232 A CA 2205232A CA 2205232 A1 CA2205232 A1 CA 2205232A1
- Authority
- CA
- Canada
- Prior art keywords
- emulsion
- group
- physiologically acceptable
- complex
- subject
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
Classifications
-
- 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
-
- 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
-
- 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
Abstract
Emulsions of paramagnetic contrast agents, and processes of making and using them are disclosed. The emulsions 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 C10-C30 saturated aliphatic group and a hydroxyl group bonded to the nitrogen atom. The emulsions are very stable and therapeutically acceptable for intravenous administration to enhance MRI imaging.
Description
s CA 0220~232 l997-05-l3 W O 96/16679 PCTnUS95tl4508 PARAMAGNETIC COMPLEXES OF N-~T~Y~-N-~Yn~nrYLANIDE8 OF
OPG~NTC ACIDR AND EMUL8ION8 CON~T~TNG 8ANE FOR M~N~TIC
RE80NANCE IMAGING (NRI) CAL FIE~D OF T~E lNV~ ~lON
This invention relates to paramagnetic complexes, emulsions cont~ining 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 ClO-C30 saturated aliphatic group and an hydroxyl group bonded to a nitrogen atom. The emulsions are very stable and are therapeutically acceptable for intravenous administration to ~nh~c~ MRI imaging.
BACRGROUND OF TEE l~.V~ lON
Magnetic resonance imaging (MRI) has been developed in recent years and, for im~ved 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 -CA 0220~232 1997-0~-13 92/21017. These patents are considered to be illustrative .
of prior re~erences in the field ~n~ n~t int~nd~d to bc thc moEt p~rtincnt rcfcr~ncq~
Paramagnetic agents of the type disclosed in the above patents have been ~minictered to the patient-in the form of aqueous solutions. In addition, 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. There has been a cont;nlling effort to develop complexes of paramagnetic metal ions as 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 W0 92/2107, lipo soluble contrast agents may be ~;n;~tered 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).
Notwithst~n~;ng the prior efforts in the field, there is a continuing need for improved MRI contrast agents. In particular, 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~IENDED SHE~ET
IPEA/EP
S~JMMARY OF THE lNv~ihlloN
This invention is directed to paramagnetic complexes for MRI and emulsions cont~; n; ng same. 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 M-OC-CH2 CE~-C0-M
N-CH2-CH2-(N-CH2cH2)~-N \
wherein from 2 to 5 M groups are hydroxyl, n=0 to 2, and ~ (~5~ ov.~, any remaining M group is NRI~, each Rl is a C10-C30 saturated aliphatic group and ~ is hydroxyl. It has been discovered that ~ery fine and stable emulsions may be made using such chelate complexes. These emulsions remain stable after heat stabilization. Moreover, these emulsions may be used intravenously and provide excellent MRI images.
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. Mon~- ~r ~s!N-alkyl-N-hydroxylamides) having a saturated C~4-C~ group are AMENGED SHEET
IPEA/EP
CA 0220S232 1997-0~-13 W O96/16679 PCTrUS95/14508 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 1 micron, preferably on the order of about 0.2 to about 0.4 micron. In other embodiments, 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.
In ~ollL~ast to prior MRI agents and compositions, the MRI emulsions of this invention are very stable and exhibit ~yr~llent 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.
CA 0220~232 1997-0~-13 Dl ~T~ n DESCRIPTION OF ~ lNVI~ . lON
The MRI emulsions of this invention comprise an oil and/or a fluorochemical (PFC) emulsified in water and contain a paramagnetic metal chelate complex. In certain cases, the chelate complex may act as a surfactant and, thus, additional cosurfactant may not be needed. In most cases, a surfactant is ~ . In general, 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. For IV
use, about 25 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. Generally, the MRI agent may be dispersed in varying amounts up to about 30% by weight, depending upon dose, efficacy and safety requirements. Thus, an IV
emulsion may preferably contain an amount of MRI agent up to about 10% by weight. For instance, in oral or rectal ~m;~;stration, an MRI imaging agent such as a gadolinium CA 0220~232 1997-0~-13 WO96tl6679 PCT~S95114508 salt of a bis(N-alkyl-N-hydroxylamide) of diethylenetriaminepentaacetic acid may be used as high as about 50% or more. If desired, the emulsions may be diluted with isotonic saline, or other agents, to produce lower concentrations. These components are identified with greater particularity as follows.
A. ParamaqnetiG Metal Chelate Complex In a broad form, 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 N--CH2--CH2--(N--cH2cH2) n~N \
M--OC--CH2 Cl 2 CH2--CO--M
CO-M
20 wherein from 2 to 5 M groups are hydroxyl, n=O to 2, and any remaining M group is NR1R2, each R1 is a C10-C30 saturated aliphatic group and R2 is hydroxyl. It has been discovered that very fine and stable emulsions may be made using such chelate complexes. Moreover, these emulsions may be used intravenously and provide excellent MRI
images.
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 d~Losium. The organic chelator is preferably an acid selected from the CA 0220~232 1997-0~-13 group consisting of ethylPne~; Ar inetetraacetic acid and diethylenetriamin~pentaacetic acid. Monohydroxylamides or bishydroxylamides of an organic acid selected from a group consisting of diethylenetriaminepentaacetic acid and ethylenediaminetetraacetic acid are used wherein each R~
is a C~4-Cn group selected from the group of stearyl, tetradecyl and h~Y~ecyl.
Specific examples of chelate complexes include gadolinium diethylenetriaminepentaacetic acid bis(N-s t e a r y 1 - N - h y d r o x y 1 a m i d e) , g a d o 1 i n i u m diethylenetriaminepentaacetic acid bis(N-tetradecyl-N-h y d r o x y 1 a m i d e ) , a n d g a d o 1 i n i u m diethylenetriaminepentaacetic acid bis(N-hexadecyl-N-hydroxylamide).
B. Oil The term "oil" is used herein in a general sense to identify a large class of physiologically acceptable substAncP~ whether of mineral, vegetable, animal, essential or synthetic origin. Thus, the term "oil" is used herein as applied to a wide range of subst~n~ec that are quite different in chemical nature. In the classification of oils by type or function, for example 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.
In the vegetable classification, oils are chiefly derived CA 0220~232 1997-0~-13 WO 96/16679 PCI/US9~/14508 from seeds or nuts and include drying oils such as l;nc~e~
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.
In the animal classification, 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.
C. Fluorochemical In this description, "fluorochemical" or "PFC"
is used to describe either a highly fluorinated organic compound of perfluorocarbon or fluorinated chemical.
Further, these terms are used interchangeably. The term "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 CA 0220~232 1997-0~-13 permissible providing that the lack of complete replacement of all hydrogens does not affect the essential non-toxic characteristics of the pref erred medical f luorocarbons of this invention . Among the perf luorocarbon compounds which may be employed are perfluorotributylamine (FC47), perfluorodecalin (PP5), perf luoromethyldecalin (PP9 ), perf luorooctylbromide , perf luorotetrahydrof uran ( FC8 0 ), perf luoroether ( PID ) [ (CF3) 2CFOCF2 (CF2) 2CF20CF (CF3) 2] perfluoroether (PIID) t (CF3) 2CFOCF2 (CF2) 6CF20CF (CF3) 2] ~
perfluoropolymer (E3) [CF3CHF(OCF2CF)20CF2CF2CF3~, perf luoropolymer ( E4 ) t CF3CHF ( OCF2CF ) 3OCF2CF2CF3 ]
perfluoroetherpolymer (Fomblin Y/Ol), perfluorododecane, p e r f l u o r o b i c y c l o t 4 . 3 . 0 . ] n o n a n e, perf luorotritrimethylblcyclohexane, perfluorotripropylamine, perfluoroisopropyl cyclohP~Ane, perf luoroendotetrahydrodicyclopentadiene, perf luoroadamantane, perf luoroexo-t 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 l o t 5 . 3 . 0 . ~ d e c a n e, perfluorotetramethylcycloheYA~, perfluoro-l-methyl-4--isopropylcyclohexane, perf luoro-n-butylcyclohexane, perf luorodimethylbicyclo t 3 . 3 . l . ] nnn;~n~, perf luoro-l-methyl adamantane, perf luoro-l-methyl-4-t butylcyclohexane, p e r f l u o r o d e c a h y d r o a c e n a p t h a n e, , CA 0220~232 1997-0~-13 perf luorotrimethylbicyclo [3.3.1. ] nonane, perf luoro-l-methyl adamantane, perf luoro-l-methyl-4-t butylcyclohexane, perf luorodecahydroacenaphthene, perf luorotrimethylbicyclo [3.3.1. ] r~on~nP ~ perf luoro-n-S lln~c~ne, perfluorotetr~lec~hydrorhe~nthrene, perfluoro-1, 3, 5, 7 - t e t r a m e t h y 1 a d a m a n t a n e, perf luorododecahydrof luorene, perf luoro-1-3 -dimethyladamantane, perf luoro-n-octylcyclohexane, perf luoro-7-methyl bicyclo t 4.3Ø ] nonane, perf luoro-p-10 d i i s o p r o p y 1 c y c 1 o h e x a n e, p e r f 1 u o r o - m -diisopropylcyclohexane, perf luoro-4-methyloctahydroquinolidiz ine, perf luoro-N-methyl-decahydroquinoline, F-methyl-l-oxadecalin, perf luorooctahydroquinolidizine, perf luoro 5,6-dihydro-5-15 decene, perf luoro-4, 5-dihydro-4-octene, perf luorodichlorooctane and perf luorobischlorobutyl ether .
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 20 example in U.S. Patent Nos. 3,962,439; 3,493,581, 4,110,474, 4,186,253; 4,187,252; 4,252,824; 4,423,077;
4,443,480; 4,534,978 and 4,542,147, European Patent Application Nos. 80710 and 158,996, British Patent specification 1,549,018 and German Offen. 2,650,586. Of 25 course, it should be understood that mixtures of any of these highly f luorinated organic compounds may also be used in the emulsions and processes of this invention.
CA 0220~232 1997-0~-13 WO96/16679 PCT~S95/14~08 D. 8urfactant 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. For example, 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 mol~c~ r weight of about 8,000, may be employed. Ethoxylates of cholesterol, diacyl glycerol and dialkyl ether glycerol are useful surfactants. Also, using backbones of cholesterol, diacyl glycerol or dialkyl ether glycerol, block copolymers are made by A~; ng ethylene oxide, propylene oxide and ethylene oxide, in that order, in varying amounts to produce surfactants. In some applications for nonintravenous use, 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. Specific examples of these surfactants are 1,2-dioctylglycero-3-phosphoryl choline, l,2-ditetradecylglycero-3-phosphoryl choline, 1,2-dihexadecylglycero-3-phosphoryl choline, 1,2-di-octadecylglycero-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-hexadecylglycero-3-phosphoryl choline, 1-tetradecyl-2-hPY~Pcylglycero-3-phosphoryl choline, 2,2-ditetradecyl-1-phosphoryl choline ethane and l-hexadecyl-tetradecylglycero-3-phosphoryl choline. The 1,3-dialkyl glycerophosphoryl choline surfactants as described in K~llf~ and Richard, U.S. Ser. ~o. 228,224, filed April 15, 1994 may also be used and tho dicclosurc thcrc~of i3 ;~c~ tD~ in ky rafor~n~c. 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 lS 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.
E. Emul~ion Characteristics The emulsions of this invention are made by dispersing the above ingredients in water and homogenizing them. The oil and/or ~FC are dispersed in the water and ~ nce the dispersion of the paramagnetic metal chelate complex. The surfactant enhances the dispersion by A~END D SHEET
IPEAIEP
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. Accordingly, the term "emulsion" as used herein covers all these states and the surfactant is employed to P~h~nrP stable mixtures of these physical states of the fluorochPmi~
oil,paramagnetic metal chelate complex and water ph~C~.
For example, a fluorochemical and oil may be emulsified in water,as described in the Clar~ and Shaw European Pat.
~ ~ic~ p~o~ d~-' ~ c~L5cri~hD~ o Appln. 87300454.3 ~ ~ t";~ aE~plication i~ lnGOrpOr t~?~
hc~cin by rcfcrcnc~ t~ Aoec~;~ suitable PFC/oil emulsions as MRI delivery agents.
The MRI emulsions of this invention are very fine, stable emulsions. The criterion for a "~ine"
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 ~omr~rative 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").
Reference is made to Figure 1 of the drawinas which documents photographically the microscopic appearance of fine and poor emulsions at 300-400 X. In Figure 1, the AMEN~ED SHEET
IPE~EP
CA 0220~232 lgg7-o~-l3 WO96/16679 PCT~S95/14508 fine emulsion contains 2~ lecithin, 10% safflower oil and 5% &dDTPA-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. Thus, these two complexes make markedly different quality emulsions although the complexes differ only in the hydroxyl group.
= ~ . . =_ CA 0220~232 1997-0~-13 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.
The following non-limiting examples illustrate the various emhoA;ments of this invention.
General Procedure for DTPA Bis~N-al~yl-N-hYdroxyl mide~) Under a static nitrogen atmosphere or a CaS04 drying tube, a me~h~;cally 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 a~L~iate 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 (65 C w/o chloroform solvent) for 17-22 hours.
Wor~up Procedure A: After cooling to ambient temperature, the resulting reaction mixture was diluted with acetone (4-5 L/L of CHC13) and cooled to 0 C. The resulting solid was filtered and washed with acetone. In some cases, the resulting solid was purified further by recrystallization from appropriate solvent to give the corresponding DTPA Bis(N-alkyl-N-hydroxylamide) (SeeTable 1 for more details). These compounds were characterized by elemental analyses (see Table 2), infrared CA 0220~232 1997-0~-13 WO 96116679 PCT/US9S/14~08 spectroscopy, proton and carbon nuclear magnetic resonance spectroscopy. High performance liquid chromatography was also used to assess purity on some derivatives.
Workup Procedure B: If no precipitate was obt~ine~ with acetone dilution on a small aliquot, the resulting reaction mixture was washed with 5% HCl to remove the pyridine and then with saturated brine solution. After drying over MgS04, conc~ntration in vacuo yielded the crude DTPA Bis(N-alkyl-N-hydroxylamide) as a beige, glassy material (See Table 1 for more details). In some cases, column chromatography on silica gel with chloroform and methanol mixtures was used to remove trace impurities.
These compounds were characterized further by elemental analyses (see Table 3), infrared spectroscopy, proton and carbon nuclear magnetic reson~nc~ spectroscopy. High performance liquid chromatography was also used to assess purity.
The above procedures were used to make various DTPA Bis(N-alkyl-N-hydroxylamide) ligands. The following Table 1 provides a variety of N Rl R2 groups under the above general formula in accordance with Workup A or B.
E c ~5 ~,, 5 ~ 5 X E~
~ U~ . ~
s ,Y~ Y o o o -5 ~t r~ _ X -- ~~ ~
CA 0220~232 1997-0~-13 wos6ll667s PCT~S9S114508 General Procedure for Gadolinium Complexes with DTPA
Bis(N-alkYl-N-hydroxylamide) ~icands A stoichiometric equivalent of gadolinium oxide and the corresponding DTPA Bis(N-alkyl-N-hydroxylamide) in 75:22:3 (V/V/V) CHCl3:CH3OH:H2O (~O.1 mole of complex/L of solvent) was heated at reflux with stirring for 18-25 hrs.
After cooling to ambient temperature, the solution was filtered through Celite to remove trace Gd2O3. The filtrate was co~c~ntrated in vacuo to yield an off-white solid or glass. The resulting solid was recrystallized from appropriate solvent or slurried in hot acetone as shown in Table 2 unless noted otherwise. In some cases, the resulting solid was dried in a vacuum oven at 50-65 C
and 29" Hg vacuum overnight. Successful complexation was evident by the dissolution of Gd2O3 into the organic solvent mix, thin layer chromatography (TLC) relative to the free ligand and infrared spectroscopy. Alternatively, GdCl3-6H2O could be used to form the complex. Completion of the reaction could be monitored by TLC. Upon completion of the reaction, aq. NaOH was used to neutralize the reaction mixture and precipitated NaCl was removed by filtration through Celite. In general, high performance liquid chromatography (HPLC) of the isolated products were greater than 90~ one component. In the case of the unsymmetrically N,N-disubstituted DTPA hydroxylamides, four major peaks were evident by TLC and HPLC analyses suggesting isomers due to the two achiral nitrogen atoms in the complexed ligand and restricted rotation around CA 0220~232 lgg7-o~-l3 WO96/16679 PCT~S95/14508 amide bonds. Elemental analyses of these complexes were also performed and reported in Table 3.
PCI~/US95/14508 o g ~,~
C X V~ V~
E ~' ~ ~
E ~ E
;X~
S ~ = ==
Z ~ ~ ' V C~ ~
--~ î~
_ 3 o~ ~oD
.
~t _ _ _ X _ V ~ o ~
C,~ _ _ _ o , Z --E ~
s 3 ô ~ o~
E S ~'~~'-S ~ 9 7 ~
~ -- X
Y ~ ~ ~r Z ~ ~
~~~ 5 Z Z ~
U
O O O
C ~E~
E
CA 0220~232 lgg7-o~-l3 WO96/16679 PCT~S95/14508 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 cQmrArison with other paramagnetic metal ion chelate complexes outside the scope of this invention.
According to this invention, the paramagnetic metal chelate complexes that make fine emulsions have been categorized as those in accordance with the above general formula where Rl is a long carbon chain (ClO-C30) on the nitrogen that is saturated and ~ 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.
S~r:
3 C~ ~ ~ m~
mmmmmmm . .- ..
~3~ ~
~ 0~
~ , a ~ ~ ~
~ E~Zz E~ m m ~ ~ ~ m ~3 m m WO 96/16679 PCT/US9!i/14508 Table 5. C~t~ories of ~ ;ons and CoInp'~YPs Rl R2 Category #¦
Poor (comparative) C,l0 - Saturated H
s C,l0 - Saturated C,~ - Saturated 2 C,lo - Unsa:lul~ted C)2 Sat./Unsat. 3 F~ne (invention) C,lo ~ Saturated OH 4 CA 0220~232 l997-0~-l3 WO96/16679 PCT~S95/14508 As may be determined from the above Table 5, the emulsions and chelate complexes of category 4 are representative of those MRI chelate complexes that make fine emulsions in accord with this invention. Those emulsions and chelate complexes of categories 1-3 make poor emulsions. The t~h~ r summaries for each of the above categories 1-4 are reported in the following Tables 6-8.
WO 96/16679 PCT/~JS95114508 ~ Y X ~ ~ X X ~ ~
v ~ ~ ~ x 8 ~ o t' X X ~ ~ ~
U ~o X ._ ,_ I_ ~ ~ ~ ~ ~o ~ _ ~ ~ x ~ o ~ ~
~_~___~___ ~o C ~ o * * o~ ~ ~ _ ~ _ ~ ~ X
D O
~ 00 3 ~ ~ .--~ ~ v OD -- -- -- -- -- -- -- _ _ _ ~
OPG~NTC ACIDR AND EMUL8ION8 CON~T~TNG 8ANE FOR M~N~TIC
RE80NANCE IMAGING (NRI) CAL FIE~D OF T~E lNV~ ~lON
This invention relates to paramagnetic complexes, emulsions cont~ining 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 ClO-C30 saturated aliphatic group and an hydroxyl group bonded to a nitrogen atom. The emulsions are very stable and are therapeutically acceptable for intravenous administration to ~nh~c~ MRI imaging.
BACRGROUND OF TEE l~.V~ lON
Magnetic resonance imaging (MRI) has been developed in recent years and, for im~ved 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 -CA 0220~232 1997-0~-13 92/21017. These patents are considered to be illustrative .
of prior re~erences in the field ~n~ n~t int~nd~d to bc thc moEt p~rtincnt rcfcr~ncq~
Paramagnetic agents of the type disclosed in the above patents have been ~minictered to the patient-in the form of aqueous solutions. In addition, 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. There has been a cont;nlling effort to develop complexes of paramagnetic metal ions as 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 W0 92/2107, lipo soluble contrast agents may be ~;n;~tered 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).
Notwithst~n~;ng the prior efforts in the field, there is a continuing need for improved MRI contrast agents. In particular, 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~IENDED SHE~ET
IPEA/EP
S~JMMARY OF THE lNv~ihlloN
This invention is directed to paramagnetic complexes for MRI and emulsions cont~; n; ng same. 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 M-OC-CH2 CE~-C0-M
N-CH2-CH2-(N-CH2cH2)~-N \
wherein from 2 to 5 M groups are hydroxyl, n=0 to 2, and ~ (~5~ ov.~, any remaining M group is NRI~, each Rl is a C10-C30 saturated aliphatic group and ~ is hydroxyl. It has been discovered that ~ery fine and stable emulsions may be made using such chelate complexes. These emulsions remain stable after heat stabilization. Moreover, these emulsions may be used intravenously and provide excellent MRI images.
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. Mon~- ~r ~s!N-alkyl-N-hydroxylamides) having a saturated C~4-C~ group are AMENGED SHEET
IPEA/EP
CA 0220S232 1997-0~-13 W O96/16679 PCTrUS95/14508 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 1 micron, preferably on the order of about 0.2 to about 0.4 micron. In other embodiments, 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.
In ~ollL~ast to prior MRI agents and compositions, the MRI emulsions of this invention are very stable and exhibit ~yr~llent 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.
CA 0220~232 1997-0~-13 Dl ~T~ n DESCRIPTION OF ~ lNVI~ . lON
The MRI emulsions of this invention comprise an oil and/or a fluorochemical (PFC) emulsified in water and contain a paramagnetic metal chelate complex. In certain cases, the chelate complex may act as a surfactant and, thus, additional cosurfactant may not be needed. In most cases, a surfactant is ~ . In general, 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. For IV
use, about 25 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. Generally, the MRI agent may be dispersed in varying amounts up to about 30% by weight, depending upon dose, efficacy and safety requirements. Thus, an IV
emulsion may preferably contain an amount of MRI agent up to about 10% by weight. For instance, in oral or rectal ~m;~;stration, an MRI imaging agent such as a gadolinium CA 0220~232 1997-0~-13 WO96tl6679 PCT~S95114508 salt of a bis(N-alkyl-N-hydroxylamide) of diethylenetriaminepentaacetic acid may be used as high as about 50% or more. If desired, the emulsions may be diluted with isotonic saline, or other agents, to produce lower concentrations. These components are identified with greater particularity as follows.
A. ParamaqnetiG Metal Chelate Complex In a broad form, 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 N--CH2--CH2--(N--cH2cH2) n~N \
M--OC--CH2 Cl 2 CH2--CO--M
CO-M
20 wherein from 2 to 5 M groups are hydroxyl, n=O to 2, and any remaining M group is NR1R2, each R1 is a C10-C30 saturated aliphatic group and R2 is hydroxyl. It has been discovered that very fine and stable emulsions may be made using such chelate complexes. Moreover, these emulsions may be used intravenously and provide excellent MRI
images.
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 d~Losium. The organic chelator is preferably an acid selected from the CA 0220~232 1997-0~-13 group consisting of ethylPne~; Ar inetetraacetic acid and diethylenetriamin~pentaacetic acid. Monohydroxylamides or bishydroxylamides of an organic acid selected from a group consisting of diethylenetriaminepentaacetic acid and ethylenediaminetetraacetic acid are used wherein each R~
is a C~4-Cn group selected from the group of stearyl, tetradecyl and h~Y~ecyl.
Specific examples of chelate complexes include gadolinium diethylenetriaminepentaacetic acid bis(N-s t e a r y 1 - N - h y d r o x y 1 a m i d e) , g a d o 1 i n i u m diethylenetriaminepentaacetic acid bis(N-tetradecyl-N-h y d r o x y 1 a m i d e ) , a n d g a d o 1 i n i u m diethylenetriaminepentaacetic acid bis(N-hexadecyl-N-hydroxylamide).
B. Oil The term "oil" is used herein in a general sense to identify a large class of physiologically acceptable substAncP~ whether of mineral, vegetable, animal, essential or synthetic origin. Thus, the term "oil" is used herein as applied to a wide range of subst~n~ec that are quite different in chemical nature. In the classification of oils by type or function, for example 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.
In the vegetable classification, oils are chiefly derived CA 0220~232 1997-0~-13 WO 96/16679 PCI/US9~/14508 from seeds or nuts and include drying oils such as l;nc~e~
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.
In the animal classification, 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.
C. Fluorochemical In this description, "fluorochemical" or "PFC"
is used to describe either a highly fluorinated organic compound of perfluorocarbon or fluorinated chemical.
Further, these terms are used interchangeably. The term "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 CA 0220~232 1997-0~-13 permissible providing that the lack of complete replacement of all hydrogens does not affect the essential non-toxic characteristics of the pref erred medical f luorocarbons of this invention . Among the perf luorocarbon compounds which may be employed are perfluorotributylamine (FC47), perfluorodecalin (PP5), perf luoromethyldecalin (PP9 ), perf luorooctylbromide , perf luorotetrahydrof uran ( FC8 0 ), perf luoroether ( PID ) [ (CF3) 2CFOCF2 (CF2) 2CF20CF (CF3) 2] perfluoroether (PIID) t (CF3) 2CFOCF2 (CF2) 6CF20CF (CF3) 2] ~
perfluoropolymer (E3) [CF3CHF(OCF2CF)20CF2CF2CF3~, perf luoropolymer ( E4 ) t CF3CHF ( OCF2CF ) 3OCF2CF2CF3 ]
perfluoroetherpolymer (Fomblin Y/Ol), perfluorododecane, p e r f l u o r o b i c y c l o t 4 . 3 . 0 . ] n o n a n e, perf luorotritrimethylblcyclohexane, perfluorotripropylamine, perfluoroisopropyl cyclohP~Ane, perf luoroendotetrahydrodicyclopentadiene, perf luoroadamantane, perf luoroexo-t 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 l o t 5 . 3 . 0 . ~ d e c a n e, perfluorotetramethylcycloheYA~, perfluoro-l-methyl-4--isopropylcyclohexane, perf luoro-n-butylcyclohexane, perf luorodimethylbicyclo t 3 . 3 . l . ] nnn;~n~, perf luoro-l-methyl adamantane, perf luoro-l-methyl-4-t butylcyclohexane, p e r f l u o r o d e c a h y d r o a c e n a p t h a n e, , CA 0220~232 1997-0~-13 perf luorotrimethylbicyclo [3.3.1. ] nonane, perf luoro-l-methyl adamantane, perf luoro-l-methyl-4-t butylcyclohexane, perf luorodecahydroacenaphthene, perf luorotrimethylbicyclo [3.3.1. ] r~on~nP ~ perf luoro-n-S lln~c~ne, perfluorotetr~lec~hydrorhe~nthrene, perfluoro-1, 3, 5, 7 - t e t r a m e t h y 1 a d a m a n t a n e, perf luorododecahydrof luorene, perf luoro-1-3 -dimethyladamantane, perf luoro-n-octylcyclohexane, perf luoro-7-methyl bicyclo t 4.3Ø ] nonane, perf luoro-p-10 d i i s o p r o p y 1 c y c 1 o h e x a n e, p e r f 1 u o r o - m -diisopropylcyclohexane, perf luoro-4-methyloctahydroquinolidiz ine, perf luoro-N-methyl-decahydroquinoline, F-methyl-l-oxadecalin, perf luorooctahydroquinolidizine, perf luoro 5,6-dihydro-5-15 decene, perf luoro-4, 5-dihydro-4-octene, perf luorodichlorooctane and perf luorobischlorobutyl ether .
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 20 example in U.S. Patent Nos. 3,962,439; 3,493,581, 4,110,474, 4,186,253; 4,187,252; 4,252,824; 4,423,077;
4,443,480; 4,534,978 and 4,542,147, European Patent Application Nos. 80710 and 158,996, British Patent specification 1,549,018 and German Offen. 2,650,586. Of 25 course, it should be understood that mixtures of any of these highly f luorinated organic compounds may also be used in the emulsions and processes of this invention.
CA 0220~232 1997-0~-13 WO96/16679 PCT~S95/14~08 D. 8urfactant 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. For example, 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 mol~c~ r weight of about 8,000, may be employed. Ethoxylates of cholesterol, diacyl glycerol and dialkyl ether glycerol are useful surfactants. Also, using backbones of cholesterol, diacyl glycerol or dialkyl ether glycerol, block copolymers are made by A~; ng ethylene oxide, propylene oxide and ethylene oxide, in that order, in varying amounts to produce surfactants. In some applications for nonintravenous use, 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. Specific examples of these surfactants are 1,2-dioctylglycero-3-phosphoryl choline, l,2-ditetradecylglycero-3-phosphoryl choline, 1,2-dihexadecylglycero-3-phosphoryl choline, 1,2-di-octadecylglycero-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-hexadecylglycero-3-phosphoryl choline, 1-tetradecyl-2-hPY~Pcylglycero-3-phosphoryl choline, 2,2-ditetradecyl-1-phosphoryl choline ethane and l-hexadecyl-tetradecylglycero-3-phosphoryl choline. The 1,3-dialkyl glycerophosphoryl choline surfactants as described in K~llf~ and Richard, U.S. Ser. ~o. 228,224, filed April 15, 1994 may also be used and tho dicclosurc thcrc~of i3 ;~c~ tD~ in ky rafor~n~c. 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 lS 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.
E. Emul~ion Characteristics The emulsions of this invention are made by dispersing the above ingredients in water and homogenizing them. The oil and/or ~FC are dispersed in the water and ~ nce the dispersion of the paramagnetic metal chelate complex. The surfactant enhances the dispersion by A~END D SHEET
IPEAIEP
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. Accordingly, the term "emulsion" as used herein covers all these states and the surfactant is employed to P~h~nrP stable mixtures of these physical states of the fluorochPmi~
oil,paramagnetic metal chelate complex and water ph~C~.
For example, a fluorochemical and oil may be emulsified in water,as described in the Clar~ and Shaw European Pat.
~ ~ic~ p~o~ d~-' ~ c~L5cri~hD~ o Appln. 87300454.3 ~ ~ t";~ aE~plication i~ lnGOrpOr t~?~
hc~cin by rcfcrcnc~ t~ Aoec~;~ suitable PFC/oil emulsions as MRI delivery agents.
The MRI emulsions of this invention are very fine, stable emulsions. The criterion for a "~ine"
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 ~omr~rative 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").
Reference is made to Figure 1 of the drawinas which documents photographically the microscopic appearance of fine and poor emulsions at 300-400 X. In Figure 1, the AMEN~ED SHEET
IPE~EP
CA 0220~232 lgg7-o~-l3 WO96/16679 PCT~S95/14508 fine emulsion contains 2~ lecithin, 10% safflower oil and 5% &dDTPA-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. Thus, these two complexes make markedly different quality emulsions although the complexes differ only in the hydroxyl group.
= ~ . . =_ CA 0220~232 1997-0~-13 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.
The following non-limiting examples illustrate the various emhoA;ments of this invention.
General Procedure for DTPA Bis~N-al~yl-N-hYdroxyl mide~) Under a static nitrogen atmosphere or a CaS04 drying tube, a me~h~;cally 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 a~L~iate 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 (65 C w/o chloroform solvent) for 17-22 hours.
Wor~up Procedure A: After cooling to ambient temperature, the resulting reaction mixture was diluted with acetone (4-5 L/L of CHC13) and cooled to 0 C. The resulting solid was filtered and washed with acetone. In some cases, the resulting solid was purified further by recrystallization from appropriate solvent to give the corresponding DTPA Bis(N-alkyl-N-hydroxylamide) (SeeTable 1 for more details). These compounds were characterized by elemental analyses (see Table 2), infrared CA 0220~232 1997-0~-13 WO 96116679 PCT/US9S/14~08 spectroscopy, proton and carbon nuclear magnetic resonance spectroscopy. High performance liquid chromatography was also used to assess purity on some derivatives.
Workup Procedure B: If no precipitate was obt~ine~ with acetone dilution on a small aliquot, the resulting reaction mixture was washed with 5% HCl to remove the pyridine and then with saturated brine solution. After drying over MgS04, conc~ntration in vacuo yielded the crude DTPA Bis(N-alkyl-N-hydroxylamide) as a beige, glassy material (See Table 1 for more details). In some cases, column chromatography on silica gel with chloroform and methanol mixtures was used to remove trace impurities.
These compounds were characterized further by elemental analyses (see Table 3), infrared spectroscopy, proton and carbon nuclear magnetic reson~nc~ spectroscopy. High performance liquid chromatography was also used to assess purity.
The above procedures were used to make various DTPA Bis(N-alkyl-N-hydroxylamide) ligands. The following Table 1 provides a variety of N Rl R2 groups under the above general formula in accordance with Workup A or B.
E c ~5 ~,, 5 ~ 5 X E~
~ U~ . ~
s ,Y~ Y o o o -5 ~t r~ _ X -- ~~ ~
CA 0220~232 1997-0~-13 wos6ll667s PCT~S9S114508 General Procedure for Gadolinium Complexes with DTPA
Bis(N-alkYl-N-hydroxylamide) ~icands A stoichiometric equivalent of gadolinium oxide and the corresponding DTPA Bis(N-alkyl-N-hydroxylamide) in 75:22:3 (V/V/V) CHCl3:CH3OH:H2O (~O.1 mole of complex/L of solvent) was heated at reflux with stirring for 18-25 hrs.
After cooling to ambient temperature, the solution was filtered through Celite to remove trace Gd2O3. The filtrate was co~c~ntrated in vacuo to yield an off-white solid or glass. The resulting solid was recrystallized from appropriate solvent or slurried in hot acetone as shown in Table 2 unless noted otherwise. In some cases, the resulting solid was dried in a vacuum oven at 50-65 C
and 29" Hg vacuum overnight. Successful complexation was evident by the dissolution of Gd2O3 into the organic solvent mix, thin layer chromatography (TLC) relative to the free ligand and infrared spectroscopy. Alternatively, GdCl3-6H2O could be used to form the complex. Completion of the reaction could be monitored by TLC. Upon completion of the reaction, aq. NaOH was used to neutralize the reaction mixture and precipitated NaCl was removed by filtration through Celite. In general, high performance liquid chromatography (HPLC) of the isolated products were greater than 90~ one component. In the case of the unsymmetrically N,N-disubstituted DTPA hydroxylamides, four major peaks were evident by TLC and HPLC analyses suggesting isomers due to the two achiral nitrogen atoms in the complexed ligand and restricted rotation around CA 0220~232 lgg7-o~-l3 WO96/16679 PCT~S95/14508 amide bonds. Elemental analyses of these complexes were also performed and reported in Table 3.
PCI~/US95/14508 o g ~,~
C X V~ V~
E ~' ~ ~
E ~ E
;X~
S ~ = ==
Z ~ ~ ' V C~ ~
--~ î~
_ 3 o~ ~oD
.
~t _ _ _ X _ V ~ o ~
C,~ _ _ _ o , Z --E ~
s 3 ô ~ o~
E S ~'~~'-S ~ 9 7 ~
~ -- X
Y ~ ~ ~r Z ~ ~
~~~ 5 Z Z ~
U
O O O
C ~E~
E
CA 0220~232 lgg7-o~-l3 WO96/16679 PCT~S95/14508 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 cQmrArison with other paramagnetic metal ion chelate complexes outside the scope of this invention.
According to this invention, the paramagnetic metal chelate complexes that make fine emulsions have been categorized as those in accordance with the above general formula where Rl is a long carbon chain (ClO-C30) on the nitrogen that is saturated and ~ 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.
S~r:
3 C~ ~ ~ m~
mmmmmmm . .- ..
~3~ ~
~ 0~
~ , a ~ ~ ~
~ E~Zz E~ m m ~ ~ ~ m ~3 m m WO 96/16679 PCT/US9!i/14508 Table 5. C~t~ories of ~ ;ons and CoInp'~YPs Rl R2 Category #¦
Poor (comparative) C,l0 - Saturated H
s C,l0 - Saturated C,~ - Saturated 2 C,lo - Unsa:lul~ted C)2 Sat./Unsat. 3 F~ne (invention) C,lo ~ Saturated OH 4 CA 0220~232 l997-0~-l3 WO96/16679 PCT~S95/14508 As may be determined from the above Table 5, the emulsions and chelate complexes of category 4 are representative of those MRI chelate complexes that make fine emulsions in accord with this invention. Those emulsions and chelate complexes of categories 1-3 make poor emulsions. The t~h~ r summaries for each of the above categories 1-4 are reported in the following Tables 6-8.
WO 96/16679 PCT/~JS95114508 ~ Y X ~ ~ X X ~ ~
v ~ ~ ~ x 8 ~ o t' X X ~ ~ ~
U ~o X ._ ,_ I_ ~ ~ ~ ~ ~o ~ _ ~ ~ x ~ o ~ ~
~_~___~___ ~o C ~ o * * o~ ~ ~ _ ~ _ ~ ~ X
D O
~ 00 3 ~ ~ .--~ ~ v OD -- -- -- -- -- -- -- _ _ _ ~
~D O
c~ ~ o ~o ~~ ~ ~ ~ ~"8 " ~~
._ ~s c.~
6 ~ ~ ~
6 ~ 6 6 ~ 6 ~ 9 ~ 9 ~ ~2 .c c, u~ u u~ u~ u u~ ~ ~ 3 ~~
-O c mc mmmmmmmm ~.
6 6 ~ ~ 6 ~ o ~Q ~ ~ Q ~ ~ ~ Q ~ ~ Z l~
o ~
~r .~ O --~ I
a ~_ ~ ~
O ,~
Cl~ _ ~ C ~ ~o 00 00 X
~a ~ a S LLv~ ~ ~
U o U O
V " O O O V " O O O O O
_ _ _ _ _ _ _ _ _ ._ ~ e ~ ~ O E ~
-~ _ _ o V ~
S ~,, ~ X l_ ~
O O O
O
~ _ oo ~o ~ C ~ C
~ o~ X ~ X
O ~
~ ~ 000 e c ~ @~
C 8. ~
o~~~ ~
aR
CA 0220~232 1997-0~-13 WO 96/16679 PCTIUS95/14!;08 With respect to Comparative Category #l as represented by Table 6, it was found that where Rl was a single saturated chain and R2 was hydrogen as represented by GdDTPA-BSA, poor emulsions were made despite a variety of compositions cont~;n;~g a surfactant lecithin, oil and PFDC0. 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 Rl and R2 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.
In contrast, the invention is represented by Table 9 where Category No. 4 is shown. In other words, where Rl was a C~0-C30 saturated chain and R2 was hydroxyl, excellent emulsions were obtained.
Furthermore, at the present time, 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 a~;n;~tration of a 10 ~mole of gadolinium CA 0220~232 1997-0~-13 W096/16679 PCT~S95/14508 per/kg dose. The enhancement effect on the liver persisted for at least one hour. The images were collected with a st~n~rd T~-weighted spin-echo imaging sequence on a General Electric Signa whole body clinical scanner operating at 1.5 Tesla.
For comparison with the emulsions of this invention, Examples I and VII were reproduced from U.S.
Patent 5,120,527, mentioned in the above background of this invention. Although 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. With respect to the emulsion cont~in;ng Geritol~, the composition contained 60mL Geritol~, 150mL
melted ice cream, 250mL milk and lOOmL 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 (l.OmL) of GdDTPA, 150mL melted ice cream, 250mL
milk and lOOmL 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%. In summary, 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.
WO96/16679 PCT~S95/14508 In view of the above detailed description, other variations or modifications may be made without departing from the spirit and scope of this invention.
What is claimed is:
c~ ~ o ~o ~~ ~ ~ ~ ~"8 " ~~
._ ~s c.~
6 ~ ~ ~
6 ~ 6 6 ~ 6 ~ 9 ~ 9 ~ ~2 .c c, u~ u u~ u~ u u~ ~ ~ 3 ~~
-O c mc mmmmmmmm ~.
6 6 ~ ~ 6 ~ o ~Q ~ ~ Q ~ ~ ~ Q ~ ~ Z l~
o ~
~r .~ O --~ I
a ~_ ~ ~
O ,~
Cl~ _ ~ C ~ ~o 00 00 X
~a ~ a S LLv~ ~ ~
U o U O
V " O O O V " O O O O O
_ _ _ _ _ _ _ _ _ ._ ~ e ~ ~ O E ~
-~ _ _ o V ~
S ~,, ~ X l_ ~
O O O
O
~ _ oo ~o ~ C ~ C
~ o~ X ~ X
O ~
~ ~ 000 e c ~ @~
C 8. ~
o~~~ ~
aR
CA 0220~232 1997-0~-13 WO 96/16679 PCTIUS95/14!;08 With respect to Comparative Category #l as represented by Table 6, it was found that where Rl was a single saturated chain and R2 was hydrogen as represented by GdDTPA-BSA, poor emulsions were made despite a variety of compositions cont~;n;~g a surfactant lecithin, oil and PFDC0. 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 Rl and R2 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.
In contrast, the invention is represented by Table 9 where Category No. 4 is shown. In other words, where Rl was a C~0-C30 saturated chain and R2 was hydroxyl, excellent emulsions were obtained.
Furthermore, at the present time, 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 a~;n;~tration of a 10 ~mole of gadolinium CA 0220~232 1997-0~-13 W096/16679 PCT~S95/14508 per/kg dose. The enhancement effect on the liver persisted for at least one hour. The images were collected with a st~n~rd T~-weighted spin-echo imaging sequence on a General Electric Signa whole body clinical scanner operating at 1.5 Tesla.
For comparison with the emulsions of this invention, Examples I and VII were reproduced from U.S.
Patent 5,120,527, mentioned in the above background of this invention. Although 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. With respect to the emulsion cont~in;ng Geritol~, the composition contained 60mL Geritol~, 150mL
melted ice cream, 250mL milk and lOOmL 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 (l.OmL) of GdDTPA, 150mL melted ice cream, 250mL
milk and lOOmL 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%. In summary, 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.
WO96/16679 PCT~S95/14508 In view of the above detailed description, other variations or modifications may be made without departing from the spirit and scope of this invention.
What is claimed is:
Claims (40)
1. A complex of a paramagnetic metal ion and an organic chelator having the formula wherein from 2 to 5 M groups are hydroxyl, n=0 to 2, and at least one M group is NR1R2, each R1 is a C10-C30 saturated aliphatic group and R2 is hydroxyl.
2. The complex of claim 1 wherein said metal ion is a lanthanide element of atomic numbers 58-70 or a transition metal of atomic numbers 21-29, 42 or 44.
3. The complex of claim 1 wherein said metal ion is selected from a group consisting Gd(III), Mn(II), iron and dysprosium.
4. The complex of claim 1 wherein said organic chelator is an acid selected from the group consisting of ethylenediaminetetraacetic acid and diethylenetriaminepentaacetic acid.
5. The complex of claim 1 wherein each R1 is C14-C22.
6. The complex of claim 1 wherein the organic chelator is a mono or bis(N-alkyl-N-hydroxylamide) where R1 is selected from the group consisting of stearyl, tetradecyl and hexadecyl.
7. The complex of claim 1 wherein said complex is selected from the group of gadolinium diethylenetriaminepentaacetic acid bis(N-stearyl-N-hydroxylamide), gadolinium diethylenetriaminepentaacetic acid bis(N-tetradecyl-N-hydroxylamide), or gadolinium diethylenetriaminepentaacetic acid bis(N-hexadecyl-N-hydroxylamide).
8. 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 wherein from 2 to 5 M groups are hydroxyl, n=0 to 2, and any remaining M group is NR1R2, each R1 is a C10-C30 saturated aliphatic group and R2 is hydroxyl.
9. The physiologically acceptable emulsion of claim 8 wherein said metal ion is a lanthanide element of atomic numbers 58-70 or a transition metal of atomic numbers 21-29, 42 or 44.
10. The physiologically acceptable emulsion of claim 8 wherein said metal ion is selected from a group consisting Gd(III), Mn(II), iron and dysprosium.
11. The physiologically acceptable emulsion of claim 8 wherein said organic chelator is an acid selected from the group consisting of ethylenediaminetetraacetic acid and diethylenetriaminepentaacetic acid.
12. The physiologically acceptable emulsion of claim 8 wherein each R1 is C14-C22.
8. 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 wherein from 2 to 5 M groups are hydroxyl, n=0 to 2, and any remaining M group is NR1R2, each R1 is a C10-C30 saturated aliphatic group and R2 is hydroxyl.
9. The physiologically acceptable emulsion of claim 8 wherein said metal ion is a lanthanide element of atomic numbers 58-70 or a transition metal of atomic numbers 21-29, 42 or 44.
10. The physiologically acceptable emulsion of claim 8 wherein said metal ion is selected from a group consisting Gd(III), Mn(II), iron and dysprosium.
11. The physiologically acceptable emulsion of claim 8 wherein said organic chelator is an acid selected from the group consisting of ethylenediaminetetraacetic acid and diethylenetriaminepentaacetic acid.
12. The physiologically acceptable emulsion of claim 8 wherein each R1 is C14-C22.
8. 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 wherein from 2 to 5 M groups are hydroxyl, n=0 to 2, and at least one M group is NR1R2, each R1 is a C10-C30 saturated aliphatic group and R2 is hydroxyl.
9. The physiologically acceptable emulsion of claim 8 wherein said metal ion is a lanthanide element of atomic numbers 58-70 or a transition metal of atomic numbers 21-29, 42 or 44.
10. The physiologically acceptable emulsion of claim 8 wherein said metal ion is selected from a group consisting Gd(III), Mn(II), iron and dysprosium.
11. The physiologically acceptable emulsion of claim 8 wherein said organic chelator is an acid selected from the group consisting of ethylenediaminetetraacetic acid and diethylenetriaminepentaacetic acid.
12. The physiologically acceptable emulsion of claim 8 wherein each R1 is C14-C22.
13. The physiologically acceptable emulsion of claim 8 wherein the organic chelator is a mono or bis(N-alkyl-N-hydroxylamide) where R1 is selected from the group consisting of stearyl, tetradecyl and hexadecyl.
14. The physiologically acceptable emulsion of claim 8 wherein said complex is gadolinium diethylenetriaminepentaacetic acid bis(N-stearyl-N-hydLoxylamide), gadolinium diethylenetriaminepentaacetic acid bis(N-tetradecyl-N-hydroxylamide), or gadolinium diethylenetriaminepentaacetic acid bis(N-hexadecyl-N
hydroxylamide).
hydroxylamide).
15. The physiologically acceptable emulsion of claim 8 having an average particle size less than about 1 micron.
16. The emulsion of claim 8 that is stable after heat stabilization with less than 10 volume % of particles above about 0.8 micron.
17. The emulsion of claim 8 wherein the oil phase contains about 5 to about 25% w/v oil or about 5 to about 55% v/v fluorochemical.
18. The emulsion of claim 8 wherein the oil is selected from the group consisting of mono-, di- and triglycerides, and mixtures thereof.
19. The emulsion of claim 17 wherein a surfactant is present in an amount of about 0.5 to about 10% by weight of the emulsion.
20. A physiologically acceptable emulsion for enhancement of MRI imaging comprising water, a dispersed oil phase selected from the group consisting of an oil and fluorochemical, and mixtures thereof, a surfactant, and a complex of a paramagnetic metal ion and an organic chelator having the formula wherein from 2 to 5 M groups are hydroxyl, n=0 to 2 and any remaining M group is NR,R2, each R1 is a C10-C30 saturated aliphatic group and R2 is hydroxyl.
20. A physiologically acceptable emulsion for enhancement of MRI imaging comprising water, a dispersed oil phase selected from the group consisting of an oil and fluorochemical, and mixtures thereof, a surfactant, and a complex of a paramagnetic metal ion and an organic chelator having the formula wherein from 2 to 5 M groups are hydroxyl, n=0 to 2 and any remaining M group is NR,R2, each R1 is a C10-C30 saturated aliphatic group and R2 is hydroxyl.
20. A physiologically acceptable emulsion for enhancement of MRI imaging comprising water, a dispersed oil phase selected from the group consisting of an oil and fluorochemical, and mixtures thereof, a surfactant, and a complex of a paramagnetic metal ion and an organic chelator having the formula wherein from 2 to 5 M groups are hydroxyl, n=0 to 2 and at least one M group is NR1R2, each Rl is a C10-C30 saturated aliphatic group and R2 is hydroxyl.
21. The physiologically acceptable emulsion of claim 20 wherein said metal ion is a lanthanide element of atomic numbers 58-70 or a transition metal of atomic numbers 21-29, 42 or 44.
22. The physiologically acceptable emulsion of claim 20 wherein said metal ion is selected from a group consisting Gd(III), Mn(II), iron and dysprosium.
23. The physiologically acceptable emulsion of claim 20 wherein said organic chelator is an acid selected from the group consisting of ethylenediaminetetraacetic acid and diethylenetriaminepentaacetic acid.
24. The physiologically acceptable emulsion of claim 20 wherein each R1 is C14-C22.
25. The physiologically acceptable emulsion of claim wherein said complex is gadolinium diethylenetriaminepentaacetic acid bis(N-stearyl-N-hydroxylamide), gadolinium diethylenetriaminepentaacetic acid bis(N-tetradecyl-N-hydroxylamide), or gadolinium diethylenetriaminepentaacetic acid bis(N-hexadecyl-N-hydroxylamide).
26. The emulsion of claim 20 wherein the fluorochemical is selected from the group consisting of perfluorodecalin, perfluoromethyldecalin, perfluorodimethyladamantane, perfluorooctylbromide, perfluoro-4-methyloctahydroquinolidizine, perfluoro-N-methyl-decahydroquinoline, F-methyl-1-oxadecalin, p e r f l u o r o b i c y c l o ( 5 . 3 . 0 . ) d e c a n e , perfluorooctahydroquinolidizine, perfluoro 5,6-dihydro-5-decene, perfluoro-4,5-dihydro-4-octene, perfluorodichlorooctane, perfluorobischlorobutyl ether, and chlorinated perfluorocarbons, and mixtures thereof.
27. The emulsion of claim 20 that is stable after heat sterilization with less than 10 volume % of particles above about 0.8 micron.
28. The emulsion of claim 20 wherein the oil phase contains about 5 to about 25% w/v oil or about 5 to about 55% v/v fluorochemical.
29. The emulsion of claim 20 wherein the oil is selected from the group consisting of mono-, di- and triglycerides, and mixtures thereof.
30. The emulsion of claim 20 having an average particle size less than about 1 micron.
31. The emulsion of claim 30 having an average particle size of about 0.2 to about 0.4 micron.
32. The emulsion of claim 28 wherein the surfactant is present in an amount from about 0.5 to about 10% by weight of the emulsion.
33. The method for MRI imaging of a subject comprising administering to such subject an image-modifying effective amount of the complex of claim 1.
34. The method for MRI imaging of a subject comprising administering to such subject an image-modifying effective amount of the complex of claim 3.
35. The method for MRI imaging of a subject comprising administering to such subject an image-modifying effective amount of the emulsion of claim 8.
36. The method for MRI imaging of a subject comprising intravenously administering to such subject an image-modifying effective amount of the emulsion of claim 20.
37. The method for MRI imaging of a subject comprising administering to such subject an image-modifying effective amount of the emulsion of claim 22.
38. The method for MRI imaging of a subject comprising administering to such subject an image-modifying effective amount of the emulsion of claim 24.
39. The method for MRI imaging of a subject comprising administering to such subject an image-modifying effective amount of the emulsion of claim 27.
40. The method for MRI imaging of a subject comprising intravenously administering to such subject an image-modifying effective amount of the emulsion of claim 28.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US346,885 | 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 (1)
| Publication Number | Publication Date |
|---|---|
| CA2205232A1 true CA2205232A1 (en) | 1996-06-06 |
Family
ID=23361430
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002205232A Abandoned CA2205232A1 (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)
| Country | Link |
|---|---|
| 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)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6028108A (en) * | 1998-10-22 | 2000-02-22 | America Home Products Corporation | Propofol composition comprising pentetate |
| US7279150B2 (en) * | 2002-01-24 | 2007-10-09 | Barnes-Jewish Hospital | Chelating agents with lipophilic carriers |
| CA2474386C (en) | 2002-01-24 | 2011-07-05 | Barnes-Jewish Hospital | Integrin targeted imaging agents |
| US6869591B2 (en) * | 2002-03-26 | 2005-03-22 | Barnes-Jewish Hospital | Paramagnetic particles that provide improved relaxivity |
| WO2005122891A1 (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 |
Family Cites Families (25)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5331209B2 (en) * | 1973-10-05 | 1978-09-01 | ||
| US3993581A (en) * | 1973-10-05 | 1976-11-23 | The Green Cross Corporation | Process for preparing stable oxygen transferable emulsion |
| US4110474A (en) * | 1977-08-26 | 1978-08-29 | Suntech, Inc. | Tetramethylpentane blood substitutes |
| US4187252A (en) * | 1977-08-26 | 1980-02-05 | Suntech, Inc. | Tetramethylpentane blood substitutes |
| US4186253A (en) * | 1978-10-10 | 1980-01-29 | The Green Cross Corporation | Perfusate for preserving organ to be transplanted and preserving method |
| US4252827A (en) * | 1979-05-23 | 1981-02-24 | The Green Cross Corporation | Oxygen-transferable fluorocarbon emulsion |
| US4957939A (en) * | 1981-07-24 | 1990-09-18 | Schering Aktiengesellschaft | Sterile pharmaceutical compositions of gadolinium chelates useful enhancing NMR imaging |
| US4647447A (en) * | 1981-07-24 | 1987-03-03 | Schering Aktiengesellschaft | Diagnostic media |
| CA1187882A (en) * | 1981-11-27 | 1985-05-28 | Kazumasa Yokoyama | Perfluoro compound and emulsion thereof |
| US4443480A (en) * | 1982-04-12 | 1984-04-17 | Children's Hospital Medical Center | Artificial blood and other gas transport agents |
| US4423077A (en) * | 1982-07-27 | 1983-12-27 | The University Of Pennsylvania | Perfluorochemical emulsion artificial blood |
| EP0103358B1 (en) * | 1982-08-07 | 1986-10-08 | Green Cross Corporation | Perfluoro-1-azatricyclic amine compound |
| US4534978A (en) * | 1982-12-28 | 1985-08-13 | The Green Cross Corporation | Perfluorocycloamines |
| DE3324235A1 (en) * | 1983-07-01 | 1985-01-10 | Schering AG, 1000 Berlin und 4709 Bergkamen | NEW COMPLEX ILLUMINATORS, COMPLEX AND COMPLEX SALTS |
| CA1257828A (en) * | 1984-04-16 | 1989-07-25 | William Mccormick | Perfluoro compound dispersions containing reduced amounts of surfactant and process of preparation |
| US4859451A (en) * | 1984-10-04 | 1989-08-22 | Salutar, Inc. | Paramagnetic contrast agents for MR imaging |
| US4826673A (en) * | 1985-01-09 | 1989-05-02 | Mallinckrodt, Inc. | Methods and compositions for enhancing magnetic resonance imaging |
| US4686024A (en) * | 1985-02-01 | 1987-08-11 | The Green Cross Corporation | Novel perfluoro chemicals and polyfluorinated compounds and process for production of the same |
| US5399340A (en) * | 1987-09-24 | 1995-03-21 | Schering Aktiengesellschaft | Use of amide complex compounds |
| US5064636A (en) * | 1989-10-19 | 1991-11-12 | Li King C P | Paramagnetic oil emulsions as enteric MRI contrast agents |
| US5120527A (en) * | 1989-10-19 | 1992-06-09 | King Chuen Peter Li | Paramagnetic oil emulsions as mri contrast agents |
| US5154914A (en) * | 1990-03-12 | 1992-10-13 | Research Corporation Technologies, Inc. | Methods of diagnostic image analysis using lipophilic contrast agents |
| US5217706A (en) * | 1990-11-21 | 1993-06-08 | Mallinckrodt Medical, Inc. | Complexes and compositions for magnetic resonance imaging |
| AU660033B2 (en) * | 1991-05-23 | 1995-06-08 | Imarx Pharmaceutical Corp. | Liposoluble compounds for magnetic resonance imaging |
| US5571498A (en) * | 1994-06-02 | 1996-11-05 | Hemagen/Pfc | Emulsions of paramagnetic contrast agents for magnetic resonance imaging (MRI). |
-
1994
- 1994-11-30 US US08/346,885 patent/US5614170A/en not_active Expired - Lifetime
-
1995
- 1995-11-09 AU AU44060/96A patent/AU4406096A/en not_active Abandoned
- 1995-11-09 WO PCT/US1995/014508 patent/WO1996016679A1/en not_active Application Discontinuation
- 1995-11-09 CA CA002205232A patent/CA2205232A1/en not_active Abandoned
- 1995-11-09 JP JP8518809A patent/JPH11500413A/en active Pending
- 1995-11-09 EP EP95942846A patent/EP0794801A1/en not_active Withdrawn
Also Published As
| Publication number | Publication date |
|---|---|
| AU4406096A (en) | 1996-06-19 |
| EP0794801A1 (en) | 1997-09-17 |
| JPH11500413A (en) | 1999-01-12 |
| WO1996016679A1 (en) | 1996-06-06 |
| US5614170A (en) | 1997-03-25 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US5571498A (en) | Emulsions of paramagnetic contrast agents for magnetic resonance imaging (MRI). | |
| US5980936A (en) | Multiple emulsions comprising a hydrophobic continuous phase | |
| US5439669A (en) | Biological imaging emulsions containing alkyl- or alkylglycerophosphoryl choline surfactants and methods of use | |
| US5833948A (en) | Blood-pool imaging composition comprising micelles containing a lipophilic chelating agent and a non-ionic surfactant | |
| Krafft et al. | Emulsions and microemulsions with a fluorocarbon phase | |
| DE69934827T2 (en) | AMPHIPATIC POLYCARBOXYLCHELATE AND COMPLEX WITH PARAMAGNETIC METAL AS AN MRI CONTRAST | |
| US5985941A (en) | Method of making hepatocyte-selective oil-in-water emulsion | |
| US9700866B2 (en) | Surfactant systems for delivery of organic compounds | |
| JPH06507904A (en) | Oil-soluble compounds for magnetic resonance imaging | |
| WO1998005301A1 (en) | Multiple emulsions comprising a hydrophobic continuous phase | |
| US5635539A (en) | Stable emulsions of highly fluorinated organic compounds | |
| CA2205232A1 (en) | Paramagnetic complexes of n-alkyl-n-hydroxylamides of organic acids and emulsions containing same for magnetic resonance imaging (mri) | |
| CA2591554A1 (en) | (polyalkoxy)sulfonate surface modifiers | |
| US20040258744A1 (en) | Blood-pool carrier for lipophilic imaging agents | |
| US5582813A (en) | Iodine-containing fluorocarbon contrast agents | |
| EP0841896B1 (en) | Reverse gels comprising a continuous fluorinated phase | |
| JP2002363278A (en) | Polyalkylene oxide-modified phospholipid and method for producing the same | |
| JP2583066B2 (en) | Novel medical preparation of Ara-C derivative | |
| WO2007129311A2 (en) | Nano-particles with contrast agents for diagnostic delivery system for x-ray and ct | |
| JPH04356417A (en) | Fat emulsion for intravenous injection | |
| JP2001302507A (en) | Perfluorocarbon emulsion |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request | ||
| FZDE | Discontinued |