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WO2013121284A1 - Produits iodés destinés à être utilisés pour l'imagerie médicale et leurs procédés de préparation - Google Patents

Produits iodés destinés à être utilisés pour l'imagerie médicale et leurs procédés de préparation Download PDF

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Publication number
WO2013121284A1
WO2013121284A1 PCT/IB2013/000429 IB2013000429W WO2013121284A1 WO 2013121284 A1 WO2013121284 A1 WO 2013121284A1 IB 2013000429 W IB2013000429 W IB 2013000429W WO 2013121284 A1 WO2013121284 A1 WO 2013121284A1
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acid
iodinated
cis
mixture
oil
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PCT/IB2013/000429
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English (en)
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Thierry Vandamme
Xiang Li
Nicolas Anton
Guy Zuber
Minjin ZHAO
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Universite De Strasbourg
Centre National De La Recherche Scientifique
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/58—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4
    • C07D311/70—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4 with two hydrocarbon radicals attached in position 2 and elements other than carbon and hydrogen in position 6
    • C07D311/72—3,4-Dihydro derivatives having in position 2 at least one methyl radical and in position 6 one oxygen atom, e.g. tocopherols
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C403/00—Derivatives of cyclohexane or of a cyclohexene or of cyclohexadiene, having a side-chain containing an acyclic unsaturated part of at least four carbon atoms, this part being directly attached to the cyclohexane or cyclohexene or cyclohexadiene rings, e.g. vitamin A, beta-carotene, beta-ionone
    • C07C403/06—Derivatives of cyclohexane or of a cyclohexene or of cyclohexadiene, having a side-chain containing an acyclic unsaturated part of at least four carbon atoms, this part being directly attached to the cyclohexane or cyclohexene or cyclohexadiene rings, e.g. vitamin A, beta-carotene, beta-ionone having side-chains substituted by singly-bound oxygen atoms
    • C07C403/12—Derivatives of cyclohexane or of a cyclohexene or of cyclohexadiene, having a side-chain containing an acyclic unsaturated part of at least four carbon atoms, this part being directly attached to the cyclohexane or cyclohexene or cyclohexadiene rings, e.g. vitamin A, beta-carotene, beta-ionone having side-chains substituted by singly-bound oxygen atoms by esterified hydroxy groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/62—Halogen-containing esters
    • C07C69/65—Halogen-containing esters of unsaturated acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/76—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/42—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms in positions 2 and 4
    • C07D311/56—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms in positions 2 and 4 without hydrogen atoms in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2603/00—Systems containing at least three condensed rings
    • C07C2603/02—Ortho- or ortho- and peri-condensed systems
    • C07C2603/04—Ortho- or ortho- and peri-condensed systems containing three rings
    • C07C2603/06—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members
    • C07C2603/10—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members containing five-membered rings
    • C07C2603/12—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members containing five-membered rings only one five-membered ring
    • C07C2603/16—Benz[e]indenes; Hydrogenated benz[e]indenes

Definitions

  • the invention refers to the formulation of injectable nano-emulsions containing iodinated agents intended for medical imaging in animals and humans.
  • the nano- emulsions are prepared by a low energy process.
  • the iodinated agents used contain iodine atoms directly fixed on benzenic cycle bound to lipophilic compounds and are prepared using simple chemical processes. These iodinated compounds can be incorporated or can constitute the internal phase of oil-in-water nano-emulsions.
  • Magnetic Resonance Imaging contrast agents like Fe 3 0 4 can also be encapsulated into the lipophilic internal phase of the nano-emulsions.
  • lipophilic fluorescent probes can be incorporated into the lipophilic internal phase of the nano-emulsions.
  • the medical imaging gathers all the means of acquisition and restitution of images starting from various physical phenomena (Magnetic resonance, reflection of waves ultrasounds, radioactivity, absorption of the X-rays,).
  • the use of these imaging images techniques indirectly allows visualizing the physiology or the metabolism of the human body or other animals.
  • the image obtained will make it possible (for example) to show the evolution or the movements of a substance in the living tissue in the course of time, to give a three-dimensional reconstitution of an organ or tissue.
  • the quantitative images also represent the values measured for certain biological parameters in a given volume.
  • the interpretation of medical imaging data makes it possible to obtain information on the anatomy of the organs (size, volume, localization, the form of a possible lesion, etc) or on their operation (physiology, metabolism, etc).
  • the anatomy of the organs size, volume, localization, the form of a possible lesion, etc
  • their operation physiology, metabolism, etc.
  • the tomographic methods are based on the X-rays (conventional radiology, tomodensitometer or CT-scan, angiography,...) maybe on magnetic resonance (MRI), echographic methods (which use the ultrasounds), and finally optical methods (which use the luminous rays).
  • radiopaque contrast agents In order to increase the quality of the image, it is usual to administer some radiopaque contrast agents to the patient, which depends on the technique used and the route of administration. For example, one can note the use of oral barium sulfate suspension (for obtaining images of the digestive tract) ⁇ injectable complex, iron oxide particles, iodinated macromolecule or heavy metals like gadolinium or bismuth. In this last case, it is possible to enhance contrast considerably with these materials, which makes it possible to visualize the whole of arterial-venous network, various tissues or organs.
  • the patent application FR2868320 (Al) described a contrast agent for the MRI characterized in that it comprises a complex including a chelating ligand and a metal ion of transition such as Mn, Co and Fe, the aforementioned ligand carrying a substituent whose electronic elimination or modification by chemical reaction or biochemical with a target substance causes a change of the state of the spin, and in particular of low spin to high spin.
  • the patent application FR2921837 (Al) described a new method of preparation of nanoparticles for the medical imaging including a metal core, an organic stabilizing layer and at least a ligand for the targeting of a pathological tissue.
  • the patent application FR2913886 (Al) refers to the formulation of metal nanoparticles covered with an organic protective coating for the diagnostic by MRI of Alzheimer's disease.
  • EP0616538 (Bl) refers to a new polyamine iodinated macromolecular compound, its preparation method and its use as a contrast agent.
  • the importance of the iodine/macromolecule ratio makes it possible in this case to limit the concentration of contrast agent to be injected.
  • the patent application FR2921660 (Al) refers to hybrid inorganic / organic nanoparticles containing iron carboxylate which are usable as contrast agents and as a reservoir of active ingredients and therefore to allow the targeting of molecules such as pharmaceutically active drugs or markers for diagnosis.
  • Iodinated contrast agents are the most commonly compounds used in X-ray practice. Most iodinated contrast agents contain either the 2,3,5-triiodinated benzene ring or the 2,4,6-triiodinated benzene ring. These tri-iodinated derivatives have been developed for more than 50 years and began with the discovery of X-rays and have been applied as well for the contrast agents with self-assembling properties to limit renal excretion and hence contrast reminiscence in the blood.
  • Torchilin et al. (Torchilin, V. P. ; Frank-Kamenetsky, M. D. ; Wolf, G. L. CT visualization of blood pool in rats by using long-circulating, iodine-containing micelles. Academic Radiology 1999, 6, 61-65) synthesized an iodine-containing amphiphilic block- polymer consisting of iodine-substituted poly-L-lysine (MPEG-iodolysine). The synthesis of the MPEG-PA-poly [£,N-(2,3,5-triiodobenzoyl)]-l-lysine contains 4 principal steps.
  • MPEG-PA NHS ester was firstly synthesized and served the further synthesis of MPEG-PA- P (CBZ) LL diblock-copolymer.
  • succinimidyl 2,3,5-triiodobenzoate was synthesized from N-hydroxysuccinimide (NHS) and 2,3,5-triiodobenzoic acid.
  • MPEG-PA-P (CBZ) LL diblock-copolymer was then reacted to 2,3,5-triiodobenzoic acid NHS ester to form the MPEG-PA-poly [£,N-(2,3,5-triiodobenzoyl)]-l-lysine.
  • This MPEG-iodolysine block- copolymer was then dispersed in an aqueous solution to form micelles with iodine content of 33.8%. After intravenous injection of these micelles, blood opacification in interest regions of aorta, heart, liver and spleen showed no sign of decrease during 3 hours. However, the sufficient X-ray opacities achieved only when the injection volume is close to the critical volume. The synthesis and the purified process of the iodine containing amphiphilic block-polymer are not straightforward.
  • nano-emulsions demonstrated a good in vivo contrast enhancement using micro-CT and a long circulation time over a period of 3 hours after intravenous injection.
  • the synthesis of the iodine containing oil uses the corrosive thionyl chloride.
  • the preparation of iodinated stabilized nano-emulsions is also tedious and relies on the use of chloroform, a solvent classified as a cancerogenic substance, on temperature variation and on high- pressure shear instrument such as an expensive microfluidizer.
  • Aviv et al. (Aviv, H. ; Bartling, S. ; Kieslling, F. ; Margel, S. Radiopaque iodinated copolymeric nanoparticles for X-ray imaging applications. Biomaterials 2009, 30, 5610- 5616) developed iodinated homopolymeric radiopaque nanoparticles using an emulsion polymerization technique based on 2-methacryloyloxyethyl (2,3,5-triiodobenzoate) (MAOTIB).
  • MAOTIB 2-methacryloyloxyethyl (2,3,5-triiodobenzoate
  • the P(MAOETIB-GMA) nanoparticles were prepared by emulsion copolymerization of MAOETIB with a low concentration of glycidyl methacrylate (GMA). These P(MAOETIB-GMA) nanoparticles dispersed in 5% dextrose aqueous solution were well tolerated by the mouse. Good contrast enhancements were visible in the bloodstream and liver after intravenous injection. However, the injected volume is much higher than other nanoparticle based blood pool contrast agent.
  • HEMA 2-hydroxyethyl methacrylate
  • GMA glycidyl methacrylate
  • the blood pool contrast agent FenestraTM Vascular Contrast (Fenestra VC) and the hepatocyte-selective contrast agent FenestraTM Liver Contrast (Fenestra LC) are formulations of polyiodinated triglyceride (ITG), packed into the lipophilic core of synthetic lipid emulsions (LE). These formulations are similar to chylomicron remnants.
  • the ITG is synthesized by coupling 2-monoolein with synthesized 3-amino-2,4, 6- triiodophenyl acids. ITG is then combined with non-iodated triglycerides, phospholipids, cholesterol and a-tocopherol in appropriate ratios.
  • the presence of cholesterol has a strong stabilizing effect on the mean particle diameter and particle size distribution.
  • the lipid mixture is then blended with anhydrous glycerol and water to form a crude oil in water emulsion at a noted temperature under nitrogen, which was prepared further by high-pressure shear processing.
  • Fenestra VC remains over 2 hours in the blood stream after administration.
  • Fenestra LC is generally used to monitor to liver lesion (Martiniova, L. ; Schimel, D. ; Lai, E. W. ; Limpuangthip, A. ; Kvetnansky, R. ; Pacak, K. In vivo micro-CT imaging of liver lesions in small animal models. Methods 2010, 50, 20-25).
  • These iodine-containing emulsions cannot fulfill the properties of blood pool contrast agent and liver specific contrast agent in one single medium.
  • the synthesis of the side of iodinated acid in ITG compound contains several steps and needs corrosive reagents.
  • lipids are needed in the oily phase and the aqueous phase is a mixture of water and glycerol.
  • Osmolality of iodine-containing lipid emulsions is higher than the one of physiology. The process for the preparation of these iodine- containing emulsions is relatively complicated and costly.
  • the inventors have developed an original formulation based on an extremely simple spontaneous emulsification of novel iodinated lipophilic compounds leading to easy industrial scale-ups and commercialization.
  • amphiphilic molecules iodinated directly on the backbone of their lipophilic part.
  • the iodine is fixed on a carbon atom of a molecule comprising one or more double bonds, by a covalent bond without fixing an additional aromatic group like a benzene ring.
  • Said molecules are used as iodinated contrast agents.
  • the present invention refers to the compositions as well as a preparation method of injectable iodinated contrast agents for medical imaging.
  • the iodinated contrast agents described in the present invention are lipophilic molecules iodinated on the benzenic cycle.
  • iodinated on the benzenic cycle we define "iodinated on the benzenic cycle" as being the result of the iodine fixing on a benzene ring.
  • the iodine fixing on a benzene ring was already asserted in various former patents and patent applications (US 4957729, US 6103216, US 7582279, WO 90/07491 and US 2009/311192).
  • the present invention concerns an iodinated lipophilic compound of formula (I) or
  • - X represents a spacer such as a diacid, a diol (like aliphatic diol, polyethylene glycol comprising 1 to 50 ethylene glycol groups) or an amino acid or an oxygen group,
  • R represents a benzene ring with one, two or three iodine atoms, a carboxylic group and/or an alcohol group (or hydroxyl group), said R being bound to AG or X by its carboxylic group or by its hydroxyl group.
  • (Ci-C 5 )alkyl group means a group selected from methyl, ethyl, n-propyl, iso-propyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, sec-pentyl and neopentyl.
  • 2, 3 or 4 R may be found on the AG group.
  • the spacer X is a rest of a diacid, of a diol or of an amino-acid. It may be a -O-CO- bond, formed by the reaction of esterification between a OH group from AG and a carboxylic group of R, or by the reaction of esterification between a OH group from AG and a lactide, or by the reaction of esterification between a carboxylic group from AG and a OH group of R ; it may be a -O- bond formed by reaction to hydroxyl group one from AG and one from ; it may be a - CONH- bond formed between the carboxylic group of AG and the amino group of R.
  • Some examples are the following : O, -O-CO-, -OC(0)CH 2 OC(0)CH 2 OC(0)- -OC(0)CH(CH 3 )OC(0)CH(CH 3 )OC(0)-, -OC(0)-NH, -OC(0)(CH 2 ) 2 OC(0)-NH- , -OC(0)(CH 2 ) 5 NHC(0)-,
  • the unsaturated (C 8 -C 52 ) aliphatic hydrocarbon chains are issued from either fatty acids which may be naturally occurring fatty acids or synthetic fatty acids either natural or synthetic aliphatic hydrocarbon chains ended with an amino group. They are straight or branched carbon chains containing or not double and triple bonds between the carbon atoms.
  • AG is an unsaturated or saturated (C 8 -C 20 ) aliphatic hydrocarbon chain.
  • said AG groups are selected from the group comprising :
  • Alpha-linolenic acid (ALA) 18 3 (n-3) all-cis-9,12,15-octadecatrienoic acid,
  • Eicosatrienoic acid (BE) 20 3 (n-3) all-cis-l l,14,17-eicosatrienoic acid,
  • Docosahexaenoic acid (DHA) 22 6 (n-3) all-cis-4,7,10,13, 16,19-docosahexaenoic acid, Tetracosapentaenoic acid 24: 5 (n-3) AI-cis-9,12,15,18,21-tetracosapentaenoic acid, Tetracosahexaenoic acid (Nisinic acid) 24: 6 (n-3) AI-cis-6,9,12,15, 18,21- tetracosahexaenoic acid,
  • Linoleic acid 18 2 (n-6) all-cis-9,-12-octadecadienoic acid,
  • GLA 18 Gamma-linolenic acid (GLA) 18 : 3 (n-6) all-cis-6,9,12-octadecatrienoic acid,
  • Eicosadienoic acid 20 2 (n-6) all-cis-l l,-14-eicosadienoic acid,
  • DGLA Dihomo-gamma-linolenic acid
  • AA Arachidonic acid
  • Docosadienoic acid 22 2 (n-6) all-cis-13,-16-docosadienoic acid,
  • Adrenic acid 22 4 (n-6) all-cis-7,10, 13,16-docosatetraenoic acid,
  • Docosapentaenoic acid (Osbond acid) 22 5 (n-6) all-cis-4,7, 10,13,16-docosapentaenoic acid,
  • Oleic acid 18 1 (n-9) cis-9-octadecenoic acid,
  • Eicosenoic acid 20 1 (n-9) cis-l l-eicosenoic acid,
  • Mead acid 20 3 (n-9) all-cis-5,8,l l-eicosatrienoic acid,
  • Erucic acid 22 1 (n-9) cis-13-docosenoic acid, and
  • Nervonic acid 24 1 (n-9) cis-15-tetracosenoic acid,
  • glyceryl monocaprylate for example Capmul® MCM C8
  • AG is selected from the group comprising ⁇ -, ⁇ -, ⁇ -tocopherol, tocotrienols, vitamin D, cholesterol, castor oil, vitamin E succinate, vitamin E lactate, glycerol monolinoleate, glycerol monooleate, taurocholic acid, estradiol, warfarin and dolichol.
  • R is selected from 2,3,5- triodiobenzo ' ic acid, 2,4,6-triiodobenzene, 3,5-disubstituted-3,4,6-triiodobenzo ' ic acid,
  • the lipophilic compounds according to the present invention are defined as being compounds which have a chemical structure and groups having a solubility more pronounced in lipophilic organic solvents than in water.
  • the fixing of iodinated benzenic cycle on the spacer or directly on the fatty acid, the sterol or the hydrocarbon chain ended by an amino group is performed using a simple esterification or amidation.
  • the fixing of benzenic cycle comprising one, two or three iodine atoms modifies considerably the physico-chemical properties of the iodinated molecules. This implies an important modification of its physicochemical properties (i.e solubility, impact on the interracial tension, emulsifying properties), and thus of its properties implied in the formulation processes. This is the reason why the formulation of an injectable liquid containing this type of molecule proves to be difficult and why the former patents asserted the presence of iodine atoms on benzene rings fixed at the end of amphiphilic chains.
  • the present invention refers to the use of iodinated lipophilic molecules described above for the manufacture of colloidal systems called nano-emulsions of the type oil in water (still called lipophilic/hydrophilic) prepared by "low energy" techniques.
  • Another object of the invention are colloidal systems containing at least an iodinated compound such as those described above and are formulated with the addition or not of additional iodinated amphiphilic molecules, and can have the following structures:
  • Another object of the invention is a nano-emulsion comprising at least an iodinated compound as defined above.
  • the oil-in-water nano-emulsions according to the invention are characterized by biphasic formulations containing droplets of a non-miscible phase to water dispersed in an aqueous phase, stabilized or not by additional amphiphilic molecules, having droplet diameters lower than 500 nm, advantageously comprised between 20 and 200 nm, more advantageously between 100 and 200 nm.
  • the nano-precipitates systems are colloidal systems which are formed by not- miscible molecules in the aqueous dispersing phase and which, after a controlled precipitation, will form particles having a diameter lower than 500 nm, advantageously comprised between 20 and 200 nm.
  • the auto-assembled systems are colloidal dispersed systems which are formed spontaneously due to thermodynamic phenomena (micelles, microemulsions, ...)
  • a surfactant presenting both hydrophilic part(s) and lipophilic part(s), should be pharmacologically acceptable and should not create any side effects at the administration.
  • a plurality of such surfactants acting as emulsifiers has been known to those skilled in the art for a long time for preparing nano-emulsions aimed to be administered intravenously.
  • the preferable emulsifiers are Cremophor ® ELP, Solutol ® HS 15, Vitamin E-TPGS ® , Poloxamer ® 407, Pluronic ® F68, Soybean lecithin, Tween ® 80, Tween ® 20, Span ® 20, Brij ® 96.
  • preferred emulsifiers are Cremophor ® ELP and Solutol ® HS 15.
  • Cremophor ® ELP is used for the preparation of iodine- containing nano-emulsions.
  • Mean diameter of the particles comprised between 20 and 200 nm, advantageously between 100 and 200 nm.
  • any surfactant known in the art, which is soluble in oil may be used; for example Cremophor® ELP.
  • pH adjuster, osmolarity adjuster and antioxidant agents are also well known from the one skilled in the art.
  • Low-energy processes of formulation are processes for which the stage of emulsification does not imply a consumption of a total energy higher than 50 MegaJ/m 3 . This limit, in term of energy per unit of volume, corresponds to the manufacturing of nano-emulsions by using equipment such as a high pressure homogenizer.
  • the processes of formulation by low-energy used according to the invention are based on the use of the physicochemical properties of the compounds allowing their recovery by a method of spontaneous emulsification or a method of phase inversion by using the temperature. All these techniques are well known from the one skilled in the art.
  • the emulsification step is defined as being the step during which the energy (whatever the form used) is brought to the system with an aim to divide the dispersed phase making it possible to generate the emulsions droplets, i.e. to increase the interfacial surface between the two non miscible phases.
  • the present invention can be executable on a technical point of view only if the iodinated molecule has a lipophilic character and can be dispersed as droplets in an aqueous medium.
  • the process for preparing an oil-in-water nanoemulsion according to the invention comprises the following steps:
  • Wsurfactant and w 0 ii representing respectively the weight of surfactant and the weight of oil
  • step b) adding the mixture obtained in step a) to an aqueous phase in order to have a ratio surfactant/oil/water (SOWR) responding to the following equation :
  • SOWR being comprised between 20 and 80 %, and w su rfacta nt, w water and w oi
  • the present invention provides an easy synthesis process to prepare for example, tocopheryl 2,3,5-triiodobenzoate and a method for the preparation of nano-emulsion as micro-CT contrasting agent using the iodinated oil tocopheryl 2,3,5-triiodobenzoate and a spontaneous emulsified method.
  • Another object of the present invention is a process for the synthesis of tocopheryl 2,3,5-triiodobenzoate of formula (3) by grafting the 2,3,5-triiodobenzoic acid (2) onto the hydroxyl group of tocopherol (1) according to the following scheme :
  • the process comprises:
  • step (b) purifying the synthesized tocopheryl 2,3,5-triiodobenzoate of formula (3) for example by column chromatography on silica gel after step (a) :
  • tocopherol family is made up of four tocopherols (alpha, beta, gamma and delta).
  • Tocopherols of formula (1) consist of a chromanol ring and a saturated side chain of 16 carbon atoms with Ri and R 2 being the same or different from each other and representing H or -CH 3 , and R 3 represent -CH 3 , which defined the different forms of tocopherols.
  • 2,3,5-triiodobenzoic acid to tocopherol will be employed so that the equivalent ratio between them can vary from 1 : 1 to 2 : 1 or, even more preferably, from 1 : 1 to 1.5: 1.
  • tocopheryl 2,3,5-triiodobenzoate can be carried out by using concentrated sulfuric acid or, thionyl chloride or, alternatively, by using the ⁇ , ⁇ '-dicyclohexylcarbodiimide (DCC) and 4-dimethylaminopyridine (DMAP) in organic solvent.
  • DCC ⁇ , ⁇ '-dicyclohexylcarbodiimide
  • DMAP 4-dimethylaminopyridine
  • the method with DCC and DMAP is preferably used.
  • the said product of tocopheryl 2,3,5-triiodobenzoate is desired to be obtained in high yield.
  • the equivalent ratio between DCC and tocopherol preferably vary from 1 : 1 to 1.5 : 1, even more preferably, from 1 : 1 to 1.3 : 1.
  • the DMAP is 10% of the quantity of DCC.
  • AG may be a tocotrienol consisting of a chromanol ring and an unsaturated side chain of 16 carbon atoms with Ri and R 2 being the same or different from each other and representing H or -CH 3 , and R 3 represent - CH 3 .
  • the tocotrienol are illustrated by the following formula :
  • the esterifying process is carried out in dichloromethane.
  • the temperature during the process is kept constant, for instance between 20°C and 30°C by operating according to the conventional methods.
  • lower boiling solvents may lead to partial evaporation, like dichloromethane, small amounts of fresh solvent may be added so as to keep steady solvent volume.
  • the reaction time may range from 20 hours to 30 hours, more preferably from 20 hours to 25 hours.
  • a suitable amount of tocopherol is dissolved in dichloromethane and poured into a flask, and an amount of 2,3,5-triiodobenzoic acid is then added.
  • a suitable amount of DCC is then added slowly into the flask, followed by the addition of DMAP.
  • a suitable amount of fresh dichloromethane is added into the flask so as to compensate the evaporation of solvent.
  • the reaction is carried out at the reaction temperature for a suitable time. At the end of the reaction, the mixture is filtered and extracted, and then purified by column chromatography on silica gel. The tocopheryl 2,3,5-triiodobenzoate is obtained in a pure form.
  • a further object of the present invention is a process for the formulation of a iodine-containing blood pool contrast agent based on nano-emulsions for micro-CT, in which the synthesized iodinated oil of tocopheryl 2,3,5-triiodobenzoate is considered as the oily phase.
  • nano-emulsions according to the present invention containing for example, the iodine-containing lipid of tocopheryl 2,3,5-triiodobenzoate.
  • Another object of the invention is a radiological contrast agent comprising a compound as described above.
  • Another object of the invention is a composition comprising an effective radiological agent comprising a compound according to the invention and oil in water nanoemulsion as carrier for said radiological agent.
  • Still another object of the invention is a contrast agent for X-Ray imaging method comprising a nanoemulsion as disclosed above.
  • Another object of the invention is a X-Ray imaging method comprising the administration to a patient a nanoemulsion as disclosed above.
  • the method of X-Ray imaging comprises the steps of:
  • nano-emulsions emulsions according to the invention can also serve as contrast agent for other medical imaging techniques, such as magnetic resonance imaging (MRI) or fluorescence imaging.
  • medical imaging techniques such as magnetic resonance imaging (MRI) or fluorescence imaging.
  • MRI contrast agents like, for example, iron oxide (Fe 3 0 4 ) superparamagnetic nanoparticle (NPs), can be encapsulated in the lipid core of said nano-emulsions.
  • Fe 3 0 4 NPs are negative MRI contrast agents.
  • the diameter of NPs can vary from a few (1-2 nm) to a few hundred nanometers (300 nm).
  • the nano-emulsions are formulated following the method described above, considering the oil phase as the oil solubilizing the Fe 3 0 4 NPs.
  • the iron oxide nanoparticles or nano-crystals have to be soluble in the lipid medium serving as oily core for the emulsification.
  • This oily phase can be one of the iodinated molecules above presented, or mixed with non-iodinated oil.
  • a lipophilic fluorescent probe can be encapsulated in the iodinated lipid core of nano-emulsions. They will induce fluorescent properties of the nano-emulsions droplets. This signal will depend on the formulation parameters (e.g. fluorescent probe concentration in oil, fluorescent probe concentration in the emulsion).
  • the fluorescent probes can be soluble in the lipid medium serving as oily core for the emulsification . This oily phase can be one of the iodinated molecules above presented, or mixed with non- iodinated oil . Once this solubilization is achieved, the spontaneous emulsification is performed and the resulting nano-emulsions contain the fluorescent agent homogeneously dispersed in the nano-emulsions droplets. Another possibility lies in the covalent g rafting of the fluorescent probe to the lipid molecules serving as oil core of the nano-emulsion .
  • compositions further comprising a contrast agent for Magnetic Resonance Imaging and/or for fluorescence imaging .
  • the contrast agent for Magnetic Resonance Imaging is iron oxide (Fe 3 0 4 ) superparamagnetic nanoparticle (NPs).
  • the iodinated compounds may be used for the manufacture of a composition for use in a X-Ray imaging method .
  • compositions When the composition contains both contrast agents, they may be used for in X- Ray imaging and Magnetic Resonance Imaging or for X-Ray imaging and fluorescence imaging, or for the three together.
  • Another object of the invention is a compound or composition as described above, for its use in a X-Ray imaging method.
  • Still another object of the invention is a composition as described above for its use in X-Ray imaging and Magnetic Resonance Imaging .
  • Still another object of the invention is a composition as described above for its use in in X-Ray imaging and fluorescence imaging .
  • Figure 1 illustrates the contrast enhancement obtained (a) 60 min and (b) 360 min after i.v. injection of iodinated vitamin E as described in the example 1.
  • the arrow emphasizes the contrast in the blood pool .
  • Figure 2 illustrates the contrast enhancement obtained (a) 19 days, (b) 48 days, and (c) 69 days after i .v. injection of iodinated vitamin E as described in the example 1.
  • the arrow emphasizes the contrast in the liver.
  • Figure 3 illustrates the X-ray attenuation in blood over time after vitamin E administration according to example 1.
  • the region of interest (ROI) was placed in the heart.
  • Figure 4 illustrates the X-ray attenuation in the liver over time after vitamin E administration according to example 1.
  • the region of interest (ROI) was placed in the liver.
  • Figure 5 illustrates the viability of cells in function of the iodine concentration in the nano-emulsion suspension for the iodinated product prepared according to example 1.
  • the MTT assays were performed on liver cells, BNL-CL2.
  • Iodine-containing tocopheryl 2,3,5-triiodobenzoate is the oily phase of the nano-emulsions and phosphate buffered saline (PBS) is the aqueous phase of the nano- emulsions for obtaining the physiologic osmolality.
  • PBS phosphate buffered saline
  • Example 1 Synthesis of an iodinated lipophilic compound resulting from Dl-a- tocopherol and 2,3,5-triiodobenzoic acid
  • Dl-a-tocopherol (3.5g, 0.008mol) was added in a round bottom flask containing 200ml dichloromethane stirring at room temperature.
  • the 2,3,5-triiodobenzoic acid (5g, O.Olmol), 4-dimethylaminopyridine (0.18g, 0.0015mol) and ⁇ , ⁇ '- dicyclohexylcarbodiimide (2.3g, O.Ol lmol) were then added respectively and the mixture was stirred for 22h at room temperature.
  • the reaction mixture was then firstly filtered, added water and extracted twice with ethyl acetate.
  • the organic phase was dried over anhydrous Na 2 S0 4 .
  • the solvent was removed in vacuum and the crude iodinated mixture was purified by gradient elution method on silica gel with cyclohexane and ethyl acetate as eluent.
  • the obtained tocopheryl 2,3,5-triiodobenzoate is a yellow viscous oil.
  • reaction product Characterization of the reaction product.
  • the reaction product is characterized by various chemical methods well known in the art:
  • Protocol of emulsification 1 Protocol of emulsification 1 :
  • the mixture A is added to an aqueous phase constituted only of water.
  • the colloidal system obtained in this case is a nano-emulsion which is formed spontaneously, by creating mixed droplets constituted of the compounds XI and X2, dispersed in the aqueous phase.
  • the invention process is illustrated in more detail as follows: Compositions of iodine-containing nano- Quantity
  • PBS Phosphate buffered saline
  • Osmolality 280 mOsm/kg
  • Nano- emulsion Size 76 nm-85 nm lg iodine-containing lipid, tocopheryl 2,3,5-triiodobenzoate is mixed with lg Cremophor ® ELP. 3g phosphate buffered saline is then added into the stirred said mixture. Nano- emulsions formed immediately once these two phases contact under stirring. Nano- emulsions are then sterilized by 0.22 ⁇ membrane before intravenous administration.
  • iodine-containing nano-emulsions prepared in accordance with example 1 were injected in Swiss mouse to investigate the in vivo contrast enhancements on CT scans. Intrapulmonary vessels were immediately contrasted after injecting the iodine-containing nano-emulsions to compare with the baseline image of lOmin before injection. The clear enhancement of the cardiac ventricles and major arterial and venous structures was observed in mouse until 6h and reaching more than 600HU immediately after injection. The contrast enhancement in heart 6h after injection could affirm that the iodine- containing nano-emulsions were still stayed in the bloodstream.
  • liver contrast enhancement continued until 69 days, much longer than other iodinated blood pool contrast agents known in the art and the decreased tendency of liver contrast enhancement was observed from 6 days after one injection without any signs of toxicity.
  • Iodine-containing nano-emulsions according to the invention showed excellent liver contrast enhancement while preserving a prolonged blood circulation, which suggest being as a potential hepatic specific blood pool contrast agent for developing anticancer drugs and evaluating the efficacy of tumor therapeutic in the preclinical setting without re-injection of contrast media during one month in same module. Results are given in figures 1 and 2.
  • colloidal systems formulated from the compound described in example 1 (100 ⁇ containing 8.3 % iodine (w/w)) were injected intravenously in nude mice.
  • the results presented in Figures 1 to 4 show pictures acquired lh, 6h, 19 days, 48 days, 69 days after the nano-emulsion injection, and are focused on heart and liver.
  • a clear vascular contrast is obtained up to 3 days, which allows obtaining clear images of the blood pool. After 3 days, a clear hepatic contrast is obtained at least, up to 69 days.
  • BNL-CL2 cells were seeded in 96-well plates at a concentration of lxlO 4 cells per well in 100 ⁇ _ of medium (Dulbecco's Modified Eagle's Medium, DMEM) containing 10% fetal bovine serum, 1 wt.% glutamine, 1 wt.% of commercial solution of penicillin and streptomycin.
  • the BNL-CL2 cells were then incubated overnight at 37°C under a controlled atmosphere (5% C02 and 95% air).
  • contrast agents of example 1 were incorporated, by substituting the culture medium for a similar one containing variable concentrations of iodinated nano-emulsions.
  • nano-emulsions according to the invention show low toxicity with a LD50 around 80 mg I/mL very higher than the dose used in vivo.
  • Example 2 Synthesis of an iodinated lipophilic compound resulting from ⁇ - tocopherol, ⁇ -tocopherol or ⁇ -tocopherol and 2,3,5-triiodobenzoic acid
  • Iodine-containing oils were synthesized in the same way as in example 1, but with ⁇ - tocopherol, ⁇ -tocopherol or ⁇ -tocopherol. These synthesized iodinated oils respected the d ired properties.
  • ⁇ -tocopherol or ⁇ -tocopherol or ⁇ -tocopherol (0.008mol) was added in a round bottom flask containing 200ml dichloromethane stirring at room temperature.
  • the 2,3,5- triiodobenzoic acid (O.Olmol), 4-dimethylaminopyridine (0.0015mol) and ⁇ , ⁇ '- dicyclohexylcarbodiimide (O.Ol lmol) were then added respectively and the mixture was stirred for 22h at room temperature.
  • a step of mixture of the aforesaid lipophilic iodinated compound containing ⁇ -tocopherol, ⁇ -tocopherol or ⁇ -tocopherol is carried out with the non-iodinated amphiphilic compound (non ionic surfactant like Cremophor ELP).
  • the two compounds are perfectly miscible.
  • This mixture is characterized by a ratio of the weights noted SOR fixed at 50%.
  • This mixture is added to an aqueous phase made up of only water. As for example 1, the proportion of the mixture/aqueous phase is fixed at 40.
  • the obtained colloidal system is a nano-emulsion which is obtained spontaneously, by creating mixed droplets made up by the iodinated and not-iodinated lipophilic and amphiphilic compounds respectively, dispersed in the aqueous phase.
  • Example 3 Synthesis of an iodinated lipophilic compound resulting from the tocotrienols and 2,3,5-triiodobenzoic acid
  • Iodine-containing oils were synthesized in the same way as in example 1, with the four tocotrienols of formula (4) (respectively a-tocotrienol, ⁇ -tocotrienol, ⁇ -tocotrienol and ⁇ - tocotrienol)
  • the difference between tocotrienols and tocopherols is the presence of three double bonds in the side chain of tocotrienols.
  • Ri and R 2 are the same or different from each other and represent H or -CH 3
  • R 3 represent -CH 3 , thus defineing the different forms of tocotrienols.
  • a step of mixture of the aforesaid lipophilic iodinated compound tocotrienols is carried out with the non-iodinated amphiphilic compound (non ionic surfactant like Cremophor ELP).
  • the two compounds are perfectly miscible.
  • This mixture is characterized by a ratio of the weights noted SOR fixed at 50%.
  • This mixture is added to an aqueous phase made up of only water. As for example 1, the proportion of the mixture/aqueous phase is fixed at 40.
  • the obtained colloidal system is a nano-emulsion which is spontaneously obtained, by creating mixed droplets made up by the iodinated and non-iodinated lipophilic and amphiphilic compounds respectively, dispersed in the aqueous phase.
  • Example 4 Synthesis of a lipophilic compound starting from vitamin A and 2,3,5-triiodobenzoic acid.
  • iodine-containing oil was synthesized in the same way as in example 1, with the exception that hydrophobic vitamin A was used instead of vitamin E. This synthesized iodinated oil respected the desired properties.
  • Vitamin A (2.3g, 0.008mol) was added in a round bottom flask containing 200ml dichloromethane stirring at room temperature.
  • the 2,3,5-triiodobenzoic acid (5g, O.Olmol), 4-dimethylaminopyridine (0.18g, 0.0015mol) and ⁇ , ⁇ '- dicyclohexylcarbodiimide (2.3g, 0.01 lmol) were then added respectively and the mixture was stirred for 22h at room temperature.
  • the reaction mixture was then firstly filtered, added water and extracted twice with ethyl acetate.
  • the organic phase was dried over anhydrous Na 2 S0 4 .
  • the solvent was removed in vacuum and the crude iodinated mixture was purified by gradient elution method on silica gel with cyclohexane and ethyl acetate as eluent.
  • the obtained synthesized iodinated oil is yellow viscous oil.
  • a step of mixture of the aforesaid lipophilic iodinated compound containing vitamin A is carried out with the non-iodinated amphiphilic compound (non ionic surfactant like Cremophor ELP).
  • the two compounds are perfectly miscible.
  • This mixture is characterized by a ratio of the weights noted SOR fixed at 50%.
  • the diameter of the droplets obtained is of 112 nm.
  • This mixture is added to an aqueous phase made up of only water. As for example 1, the proportion of the mixture/aqueous phase is fixed at 40.
  • the obtained colloidal system is a nano-emulsion which is obtained spontaneously, by creating mixed droplets made up by the iodinated and not- iodinated lipophilic and amphiphilic compounds respectively, dispersed in the aqueous phase.
  • Example 5 Synthesis of a lipophilic compound from vitamin E, a dilactide and 2,3,5-triiodobenzoic acid.
  • Dl-a-tocopherol (3.5g, 0.008mol) was added in a round bottom flask containing glycolide (1.16g, O.Olmol).
  • glycolide (1.16g, O.Olmol).
  • the 2,3,5-triiodobenzoic acid (5g, O.Olmol), 4-dimethylaminopyridine (0.18g, 0.0015mol) and ⁇ , ⁇ '-dicyclohexylcarbodiimide (2.3g, O.Ol lmol) were then added respectively and the mixture was stirred for 22h at room temperature.
  • the reaction mixture was then firstly filtered, added water and extracted twice with ethyl acetate.
  • the organic phase was dried over anhydrous Na 2 S0 4 .
  • the solvent was removed in vacuum and the crude iodinated mixture was purified by gradient elution method on silica gel with cyclohexane and ethyl acetate as eluent.
  • the obtained tocopheryl 2,3,5- triiodobenzoate is yellow viscous oil.
  • Protocol of emulsification 5.1 A step of mixture of the aforesaid lipophilic iodinated compound is carried out with the non-iodinated amphiphilic compound (non ionic surfactant like Cremophor ELP). The two compounds are perfectly miscible.
  • This mixture is characterized by a ratio of the weights noted SOR fixed at 50%.
  • the diameter of the droplets obtained is of 145 nm.
  • This mixture is added to an aqueous phase made up of only water. As for example 1, the proportion of the mixture/aqueous phase is fixed at 40.
  • the obtained colloidal system is a nano-emulsion which is obtained spontaneously, by creating mixed droplets made up by the iodinated and not- iodinated lipophilic and amphiphilic compounds respectively, dispersed in the aqueous phase.
  • Dl-a-tocopherol (3.5g, 0.008mol) was added in a round bottom flask containing lactide (1.44g, O.Olmol).
  • lactide (1.44g, O.Olmol).
  • the 2,3,5-triiodobenzoic acid (5g, O.Olmol), 4-dimethylaminopyridine (0.18g, 0.0015mol) and ⁇ , ⁇ '-dicyclohexylcarbodiimide (2.3g, O.Ol lmol) were then added respectively and the mixture was stirred for 22h at room temperature.
  • the reaction mixture was then firstly filtered and extracted twice with ethyl acetate.
  • the organic phase was dried over anhydrous Na 2 S0 4 .
  • the solvent was removed in vacuum and the crude iodinated mixture was purified by gradient elution method on silica gel with cyclohexane and ethyl acetate as eluent.
  • the obtained tocopheryl 2,3,5- triiodobenzoate is yellow viscous oil.
  • a step of mixture of the aforesaid lipophilic iodinated compound is carried out with the non-iodinated amphiphilic compound (non ionic surfactant like Cremophor ELP).
  • the two compounds are perfectly miscible.
  • This mixture is characterized by a ratio of the weights noted SOR fixed at 50%.
  • the diameter of the droplets obtained is of 132 nm.
  • This mixture is added to an aqueous phase made up of only water. As for example 1, the proportion of the mixture/aqueous phase is fixed at 40.
  • the obtained colloidal system is a nano-emulsion which is obtained spontaneously, by creating mixed droplets made up by the iodinated and not- iodinated lipophilic and amphiphilic compounds respectively, dispersed in the aqueous phase.
  • iodine-containing oils were synthesized in the same way as in example 1, with the exception that other hydrophobic vitamin as vitamin D2 was used instead of vitamin E. These synthesized iodinated oils respected the desired properties.
  • Vitamin D2 (3.17g, 0.008mol) was added in a round bottom flask containing 200ml dichloromethane stirring at room temperature.
  • the 2,3,5-triiodobenzoic acid (5g, O.Olmol), 4-dimethylaminopyridine (0.18g, 0.0015mol) and ⁇ , ⁇ '- dicyclohexylcarbodiimide (2.3g, 0.01 lmol) were then added respectively and the mixture was stirred for 22h at room temperature.
  • a step of mixture of the aforesaid lipophilic iodinated compound containing vitamin D2 is carried out with the non-iodinated amphiphilic compound (non ionic surfactant like Cremophor® ELP).
  • the two compounds are perfectly miscible.
  • This mixture is characterized by a ratio of the weights noted SOR fixed at 50%.
  • the diameter of the droplets obtained is of 84 nm.
  • This mixture is added to an aqueous phase made up of only water. As for example 1, the proportion of the mixture/aqueous phase is fixed at 40.
  • the obtained colloidal system is a nano-emulsion which is obtained spontaneously, by creating mixed droplets made up by the iodinated and not- iodinated lipophilic and amphiphilic compounds respectively, dispersed in the aqueous phase.
  • Example 7 Synthesis of a lipophilic compound resulting from the cholesterol and 2,3,5-triiodobenzoic acid
  • iodine-containing oils were synthesized in the same way as in example 1, with the exception that cholesterol was used instead of vitamin E. These synthesized iodinated oils respected the desired properties.
  • Cholesterol (3.09g, 0.008mol) was added in a round bottom flask containing 200ml dichloromethane stirring at room temperature.
  • the 2,3,5-triiodobenzoic acid (5g, O.Olmol), 4-dimethylaminopyridinee (0.18g, 0.0015mol) and ⁇ , ⁇ '- dicyclohexylcarbodiimide (2.3g, 0.01 lmol) were then added respectively and the mixture was stirred for 22h at room temperature.
  • the reaction mixture was then firstly filtered, added water and extracted twice with ethyl acetate.
  • the organic phase was dried over anhydrous Na 2 S0 4 .
  • the solvent was removed in vacuum and the crude iodinated mixture was purified by gradient elution method on silica gel with cyclohexane and ethyl acetate as eluent.
  • the obtained synthesized iodinated oil is yellow viscous oil.
  • Protocol of emulsification 7 A step of mixture of the aforesaid lipophilic iodinated compound containing cholesterol is carried out with the non-iodinated amphiphilic compound (non ionic surfactant like Cremophor® ELP). The two compounds are perfectly miscible.
  • This mixture is characterized by a ratio of the weights noted SOR fixed at 50%.
  • the diameter of the droplets obtained is of 95 nm.
  • This mixture is added to an aqueous phase made up of only water. As for example 1, the proportion of the mixture/aqueous phase is fixed at 40.
  • the obtained colloidal system is a nano-emulsion which is obtained spontaneously, by creating mixed droplets made up by the iodinated and not- iodinated lipophilic and amphiphilic compounds respectively, dispersed in the aqueous phase.
  • Example 8 Synthesis of an iodinated lipophilic compound resulting from Castor oil and 2,3,5-triiodobenzoic acid
  • iodine-containing oil was synthesized in the same way as in example 1 with a hydroxyl containing triglyceride of castor oil. The percentage of iodine can be increased in this synthesized oil, because each fatty acid chain in castor oil containing one hydroxyl group. Castor oil (7.5g, 0.008mol) was added in a round bottom flask containing 250ml dichloromethane stirring at room temperature.
  • reaction mixture was firstly filtered, added water and then extracted twice with ethyl acetate. After drying over anhydrous Na 2 S0 4 , the solvent was removed in vacuum and the crude iodinated oil was purified by column chromatography on silica gel.
  • Protocol of emulsification 8 A step of mixture of the aforesaid lipophilic iodinated compound containing castor oil is carried out with the non-iodinated amphiphilic compound (non ionic surfactant like Cremophor ELP). The two compounds are perfectly miscible.
  • This mixture is characterized by a ratio of the weights noted SOR fixed at 75%.
  • the diameter of the droplets obtained is of 150 nm.
  • This mixture is added to an aqueous phase made up of only water. As for example 1, the proportion of the mixture/aqueous phase is fixed at 40.
  • the obtained colloidal system is a nano-emulsion which is obtained spontaneously, by creating mixed droplets made up by the iodinated and not- iodinated lipophilic and amphiphilic compounds respectively, dispersed in the aqueous phase.
  • Example 9 Synthesis of an iodinated lipophilic compound resulting from vitamin E derivatives and 3,5-disubstituted-2,4,6-triodobenzoic acids
  • Iodine-containing oils were synthesized by linking 3,5-disubstituted-2,4,6-triiodobenzoic acids of formula (7) to vitamin E derivatives of formula (8) by esterification or amidation reactions.
  • R and R in the 3,5-disubstituted-2,4,6-triiodobenzoic acids of formula (7) are the same or different from each other and could be varied from OH, O-alkyl, H or alkyl with alkyl representing a (Ci-C 5 )alkyl selected from methyl, ethyl, n-propyl, iso- propyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, sec-pentyl and neopentyl.
  • [, -NH2, -CH3 Functional group X in the vitamin E derivatives of formula (8) is selected from the group comprising OH, R ⁇ OH, -COOH, NH 2 , and CH 3 , with R' 1 , R R 2 and R 3 , which are the same or different from each other represent an alkyl group, alkyl representing a (Ci- C 5 )alkyl selected from methyl, ethyl, n-propyl, iso-propyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, sec-pentyl and neopentyl.
  • a step of mixture of the aforesaid lipophilic iodinated compound containing vitamin E is carried out with the non-iodinated amphiphilic compound (non ionic surfactant like Cremophor® ELP).
  • non ionic surfactant like Cremophor® ELP.
  • This mixture is characterized by a ratio of the weights noted SOR fixed at 50%.
  • This mixture is added to an aqueous phase made up of only water.
  • the proportions of the mixture/aqueous phase are fixed at 40.
  • the obtained colloidal system is a nano-emulsion which is obtained spontaneously, by creating mixed droplets made up by the iodinated and not-iodinated lipophilic and amphiphilic compounds respectively, dispersed in the aqueous phase.
  • Example 10 Synthesis of an iodinated lipophilic compound resulting from vitamin E succinic acid and 2,4,6-triiodophenol
  • an iodine-containing compound was synthesized by esterification.
  • the 2,4,6-triiodophenol was condensed to the carboxyl group of vitamin E succinic acid.
  • Vitamin E succinic acid (4.4g, 0.008mol) was added in a round bottom flask containing 200ml dichloromethane stirring at room temperature.
  • An additional amount of 2,4,6-triiodophenol (4.7g, O.Olmol), 4-dimethylaminopyridine (0.18g, 0.0015mol) and ⁇ , ⁇ '-dicyclohexylcarbodiimide (2.3g, O.Ol lmol) were then added respectively and the mixture was stirred for 24h at the reaction temperature.
  • reaction mixture was firstly filtered, added water and then extracted two times with ethyl acetate. After drying over anhydrous Na 2 S0 4 , the solvent was removed in vacuum and the crude iodinated oil was purified by column chromatography on silica gel.
  • Protocol of emulsification 10 A step of mixture of the aforesaid lipophilic iodinated compound containing vitamin E succinic acid is carried out with the non-iodinated amphiphilic compound (non ionic surfactant like Cremophor® ELP). The two compounds are perfectly miscible.
  • This mixture is characterized by a ratio of the weights noted SOR fixed at 50%.
  • the diameter of the droplets obtained is of 174 nm.
  • This mixture is added to an aqueous phase made up of only water. As for example 1, the proportion of the mixture/aqueous phase is fixed at 40.
  • the obtained colloidal system is a nano-emulsion which is obtained spontaneously, by creating mixed droplets made up by the iodinated and not- iodinated lipophilic and amphiphilic compounds respectively, dispersed in the aqueous phase.
  • Example 11 Synthesis of an iodinated lipophilic compound resulting from fatty acid and 2,4,6-triiodophenol
  • iodine-containing oils were synthesized in the same way as in example 10, with the exception that fatty acids were used instead of vitamin E succinate. These synthesized iodinated oils respected the desired properties.
  • Linoleic acid (2.2g, 0.008mol) was added in a round bottom flask containing 200ml dichloromethane stirring at room temperature. An additional amount of 2,4,6- triiodophenol (4.7g, O.Olmol), 4-dimethylaminopyridine (0.18g, 0.0015mol) and ⁇ , ⁇ '- dicyclohexylcarbodiimide (2.3g, O.Ol lmol) were then added respectively and the mixture was stirred for 24h at the reaction temperature.
  • the reaction mixture was then firstly filtered, added water and extracted twice with ethyl acetate.
  • the organic phase was dried over anhydrous Na 2 S0 4 .
  • the solvent was removed in vacuum and the crude iodinated mixture was purified by gradient elution method on silica gel with cyclohexane and ethyl acetate as eluent.
  • the obtained synthesized iodinated oil is yellow viscous oil.
  • a step of mixture of the aforesaid lipophilic iodinated compound containing fatty acid is carried out with the non-iodinated amphiphilic compound (non ionic surfactant like Cremophor® ELP).
  • non ionic surfactant like Cremophor® ELP.
  • This mixture is characterized by a ratio of the weights noted SOR fixed at 50%.
  • the diameter of the droplets obtained is of 69 nm.
  • This mixture is added to an aqueous phase made up of only water. As for example 1, the proportion of the mixture/aqueous phase is fixed at 40.
  • the obtained colloidal system is a nano-emulsion which is obtained spontaneously, by creating mixed droplets made up by the iodinated and not- iodinated lipophilic and amphiphilic compounds respectively, dispersed in the aqueous phase.
  • Example 12 Synthesis of an iodinated lipophilic compound resulting from Vitamin E succinic acid and 3-amino-2,4 r 6-triiodobenzoic acid Protocol of synthesis 12:
  • iodine-containing oil was synthesized by amidation.
  • 3- amino-2,4,6-triiodobenzoic acid was grafted to the carboxyl group of vitamin E succinic acid .
  • Vitamin E succinic acid (4.4g, 0.008mol) was added in a round bottom flask containing 150 ml dichloromethane stirring at 0°C.
  • Thionyl chloride (1.4g, 0.012mol) was added and the mixture was stirred during 1 hour. The solvent was then evaporated and the mixture was re-dissolved in dichloromethane.
  • the 3-amino-2,4,6-triiodobenzoic acid (5.1g, O.Olmol) was then added in the flask and the mixture was stirred over night at the reaction temperature.
  • reaction mixture was extracted, added water twice with ethyl acetate and the organic phase was dried over anhydrous Na 2 S0 4 .
  • the solvent was removed in vacuum and the crude iodinated oil was purified by column chromatography on silica gel.
  • a step of mixture of the aforesaid lipophilic iodinated compound containing vitamin E succinic acid is carried out with the non-iodinated amphiphilic compound (non ionic surfactant like Cremophor ELP).
  • the two compounds are perfectly miscible.
  • This mixture is characterized by a ratio of the weights noted SOR fixed at 50%.
  • the diameter of the droplets obtained is of 134 nm.
  • This mixture is added to an aqueous phase made up of only water. As for example 1, the proportion of the mixture/aqueous phase is fixed at 40.
  • the obtained colloidal system is a nano-emulsion which is obtained spontaneously, by creating mixed droplets made up by the iodinated and not- iodinated lipophilic and amphiphilic compounds respectively, dispersed in the aqueous phase.
  • Example 13 Synthesis of an iodinated lipophilic compound resulting from Vitamin E lactate and 2,3,5-triiodobenzoic acid
  • iodine-containing oil was synthesized by grafting 2,3,5- triiodobenzoic acid to the hydroxyl group of a vitamin E derivative.
  • the vitamin E derivative was synthesized from vitamin E and t-butyldimethylsilyl ether of lactic acid, prepared with the method mentioned in patent WO9720812A1.
  • Vitamin E (3.5g, 0.008mol) was added in a round bottom flask containing 250ml dichloromethane and the mixture was stirred at room temperature, t-butyldimethylsilyl ether of lactic acid (1.9g, O.Olmol), 4-dimethylaminopyridine (0.18g, 0.0015mol) and ⁇ , ⁇ '- dicyclohexylcarbodiimide (2.3g, O.Ol lmol) were then added respectively and the mixture was stirred overnight at the reaction temperature. After evaporation of the solvent, the reaction mixture was re-dissolved in terahydrofuran containing tetrabutylammonium fluoride.
  • the mixture was stirred at room temperature for thirty minutes and then extracted with water, dried over anhydrous Na 2 S0 4 to obtain the vitamin E derivative.
  • the vitamin E derivative was dissolved in 200ml dichloromethane and an additional amount of 2,3,5-triiodobenzoic acid (5g, O.Olmol), 4- dimethylaminopyridine (0.18g, 0.0015mol) and ⁇ , ⁇ '-dicyclohexylcarbodiimide (2.3g, O.Ol lmol) were then added respectively and the mixture was stirred during 22 hours at the reaction temperature.
  • reaction mixture was firstly filtered, added water and then extracted twice with ethyl acetate. After drying over anhydrous Na 2 S0 4 , the solvent was removed in vacuum and the crude iodinated oil was purified by column chromatography on silica gel.
  • a step of mixture of the aforesaid lipophilic iodinated compound containing vitamin E lactate is carried out with the non-iodinated amphiphilic compound (non ionic surfactant like Cremophor® ELP).
  • the two compounds are perfectly miscible.
  • This mixture is characterized by a ratio of the weights noted SOR fixed at 50%.
  • the diameter of the droplets obtained is of 152 nm.
  • This mixture is added to an aqueous phase made up of only water. As for example 1, the proportion of the mixture/aqueous phase is fixed at 40.
  • the obtained colloidal system is a nano-emulsion which is obtained spontaneously, by creating mixed droplets made up by the iodinated and not- iodinated lipophilic and amphiphilic compounds respectively, dispersed in the aqueous phase.
  • Example 14 Synthesis of an iodinated lipophilic compound resulting from Vitamin E and 2,4,6-triiodobenzene Protocol of synthesis 14:
  • Iodine-containing oils of formula (9) were synthesized by O-alkylation reaction.
  • alkyl represents a (Ci-C 5 )alkyl selected from methyl, ethyl, n-propyl, iso- propyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, sec-pentyl and neopentyl.
  • Protocol of emulsification 14 A step of mixture of the aforesaid lipophilic iodinated compound containing vitamin E is carried out with the non-iodinated amphiphilic compound (non ionic surfactant like Cremophor® ELP). The two compounds are perfectly miscible.
  • This mixture is characterized by a ratio of the weights noted SOR fixed at 50%.
  • This mixture is added to an aqueous phase made up of only water. As for example 1, the proportion of the mixture/aqueous phase is fixed at 40.
  • the obtained colloidal system is a nano-emulsion which is obtained spontaneously, by creating mixed droplets made up by the iodinated and not-iodinated lipophilic and amphiphilic compounds respectively, dispersed in the aqueous phase.
  • Example 15 Synthesis of an iodinated lipophilic compound resulting from tocopherol and 2,4,6-triiodophenol by O-alkylation
  • iodine-containing oil was synthesized by O-alkylation of a- tocopherol.
  • A-tocopherol (3.5g, 0.008mol) was added in a round bottom flask containing 150ml dichloromethane, followed by addition of thionyl chloride (1.4g, 0.012mol) and triethylamine (2.4 g, 0.024mol). The mixture was then stirred for 1 hour at room temperature. The solvent was then evaporated and the mixture purified by extraction with ethyl acetate. The organic phase was then dried over anhydrous Na 2 S0 4 .
  • a step of mixture of the aforesaid lipophilic iodinated compound containing tocopherol acid is carried out with the non-iodinated amphiphilic compound (non ionic surfactant like Cremophor® ELP).
  • non ionic surfactant like Cremophor® ELP.
  • This mixture is characterized by a ratio of the weights noted SOR fixed at 50%.
  • the diameter of the droplets obtained is of 73 nm.
  • This mixture is added to an aqueous phase made up of only water. As for example 1, the proportion of the mixture/aqueous phase is fixed at 40.
  • the obtained colloidal system is a nano-emulsion which is obtained spontaneously, by creating mixed droplets made up by the iodinated and not- iodinated lipophilic and amphiphilic compounds respectively, dispersed in the aqueous phase.
  • Example 16 Synthesis of an iodinated lipophilic compound resulting from ⁇ - tocopherol and potassium iodide
  • Iodine-containing oil was synthesized by direct iodination of the aromatic ring of Vitamin E.
  • ⁇ -tocopherol was iodinated by using potassium iodide and hydrogen peroxide.
  • a 50ml, two necked, round flask was charged with the ⁇ -tocopherol (1.6g, 0.004mol) and potassium iodide (KI) (0.73g, 0.0044mol) in acetic acid (8ml).
  • Aqueous solution (30%) of hydrogen peroxide (H 2 0 2 ) (0.0044mol) was added dropwise to the well-stirred solution, and then the reaction mixture was allowed to stir at room temperature during 16h.
  • reaction mixture was extracted twice with ethyl acetate. After being dried over anhydrous Na 2 S0 4 , the solvent was removed in vacuum and the crude iodinated oil was purified by gradient elution method on silica gel.
  • Protocol of emulsification 16 A step of mixture of the aforesaid lipophilic iodinated compound containing ⁇ -tocopherol is carried out with the non-iodinated amphiphilic compound (non ionic surfactant like Cremophor® ELP). The two compounds are perfectly miscible.
  • This mixture is characterized by a ratio of the weights noted SOR fixed at 50%.
  • the diameter of the droplets obtained is of 109 nm.
  • This mixture is added to an aqueous phase made up of only water. As for example 1, the proportion of the mixture/aqueous phase is fixed at 40.
  • the obtained colloidal system is a nano-emulsion which is obtained spontaneously, by creating mixed droplets made up by the iodinated and not- iodinated lipophilic and amphiphilic compounds respectively, dispersed in the aqueous phase.
  • Example 17 Synthesis of an iodinated lipophilic compound resulting from MaisineTM 35-1 (glycerol monolinoleate) and 2,3,5-triiodobenzoic acid
  • MaisineTM 35-1 (2.84g, 0.008mol) was added in a round bottom flask containing 250ml dichloromethane stirring at room temperature.
  • a step of mixture of the aforesaid lipophilic iodinated (MaisineTM 35-1) compound is carried out with the non-iodinated amphiphilic compound (non ionic surfactant like Cremophor® ELP).
  • the two compounds are perfectly miscible.
  • This mixture is characterized by a ratio of the weights noted SOR fixed at 50%.
  • the diameter of the droplets obtained is of 104 nm.
  • This mixture is added to an aqueous phase made up of only water.
  • the proportion of the mixture/aqueous phase is fixed at 40.
  • the obtained colloidal system is a nano-emulsion which is obtained spontaneously, by creating mixed droplets made up by the iodinated and not- iodinated lipophilic and amphiphilic compounds respectively, dispersed in the aqueous phase.
  • PeceolTM glycerol monooleate
  • PeceolTM (2.85g, 0.008mol) was added in a round bottom flask containing 250ml dichloromethane stirring at room temperature.
  • the 2,3,5-triiodobenzoic acid (lOg, 0.02mol), 4-dimethylaminopyridine (0.36g, 0.003mol) and N,N'-dicyclohexylcarbodiimide (4.6g, 0.022mol) were then added respectively and the mixture was stirred for 22h at room temperature.
  • the reaction mixture was then firstly filtered, added water and extracted twice with ethyl acetate.
  • the organic phase was dried over anhydrous Na 2 S0 4 .
  • the solvent was removed in vacuum and the crude iodinated mixture was purified by gradient elution method on silica gel with cyclohexane and ethyl acetate as eluent.
  • the obtained synthesized iodinated oil is yellow viscous oil.
  • a step of mixture of the aforesaid lipophilic iodinated compound (peceol) is carried out with the non-iodinated amphiphilic compound (non ionic surfactant like Cremophor® ELP).
  • the two compounds are perfectly miscible.
  • This mixture is characterized by a ratio of the weights noted SOR fixed at 50%.
  • the diameter of the droplets obtained is of 94 nm.
  • This mixture is added to an aqueous phase made up of only water. As for example 1, the proportion of the mixture/aqueous phase is fixed at 40.
  • the obtained colloidal system is a nano-emulsion which is obtained spontaneously, by creating mixed droplets made up by the iodinated and not- iodinated lipophilic and amphiphilic compounds respectively, dispersed in the aqueous phase.
  • Example 19 Synthesis of an iodinated lipophilic compound resulting from taurocholic acid and 2,3,5-triiodobenzoic acid
  • Taurocholic acid (4.1g, 0.008mol) was added in a round bottom flask containing 250ml dichloromethane stirring at room temperature.
  • the 2,3,5-triiodobenzoic acid (lOg, 0.02mol), 4-dimethylaminopyridine (0.36g, 0.003mol) and N,N'-dicyclohexylcarbodiimide (4.6g, 0.022mol) were then added respectively and the mixture was stirred for 22h at room temperature.
  • a step of mixture of the aforesaid lipophilic iodinated compound containing taurocholic acid is carried out with the non-iodinated amphiphilic compound (non ionic surfactant like Cremophor® ELP).
  • non ionic surfactant like Cremophor® ELP.
  • This mixture is characterized by a ratio of the weights noted SOR fixed at 50%.
  • the diameter of the droplets obtained is of 165 nm.
  • This mixture is added to an aqueous phase made up of only water. As for example 1, the proportion of the mixture/aqueous phase is fixed at 40.
  • the obtained colloidal system is a nano-emulsion which is obtained spontaneously, by creating mixed droplets made up by the iodinated and not- iodinated lipophilic and amphiphilic compounds respectively, dispersed in the aqueous phase.
  • Example 20 Synthesis of an iodinated lipophilic compound resulting from estradiol and 2,3,5-triidobenzoic acid
  • Estradiol (2.18g, 0.008mol) was added in a round bottom flask containing 250ml dichloromethane stirring at room temperature.
  • the 2,3,5-triiodobenzoic acid (lOg, 0.02mol), 4-dimethylaminopyridine (0.36g, 0.003mol) and N,N'-dicyclohexylcarbodiimide (4.6g, 0.022mol) were then added respectively and the mixture was stirred for 22h at room temperature.
  • the reaction mixture was then firstly filtered, added water and extracted twice with ethyl acetate.
  • the organic phase was dried over anhydrous Na 2 S0 4 .
  • the solvent was removed in vacuum and the crude iodinated mixture was purified by gradient elution method on silica gel with cyclohexane and ethyl acetate as eluent.
  • the obtained synthesized iodinated oil is yellow viscous oil.
  • Protocol of emulsification 20 A step of mixture of the aforesaid lipophilic iodinated compound containing estradiol is carried out with the non-iodinated amphiphilic compound (non ionic surfactant like Cremophor® ELP). The two compounds are perfectly miscible.
  • This mixture is characterized by a ratio of the weights noted SOR fixed at 50%.
  • the diameter of the droplets obtained is of 137 nm.
  • This mixture is added to an aqueous phase made up of only water. As for example 1, the proportion of the mixture/aqueous phase is fixed at 40.
  • the obtained colloidal system is a nano-emulsion which is obtained spontaneously, by creating mixed droplets made up by the iodinated and not- iodinated lipophilic and amphiphilic compounds respectively, dispersed in the aqueous phase.
  • Example 21 Synthesis of an iodinated lipophilic compound resulting from warfarin and 2,3,5-triiobenzoic acid
  • Warfarin (2.47g, 0.008mol) was added in a round bottom flask containing 200ml dichloromethane stirring at room temperature.
  • the 2,3,5-triiodobenzoic acid (5g, O.Olmol), 4-dimethylaminopyridine (0.18g, 0.0015mol) and ⁇ , ⁇ '- dicyclohexylcarbodiimide (2.3g, O.Ol lmol) were then added respectively and the mixture was stirred for 22h at room temperature.
  • a step of mixture of the aforesaid lipophilic iodinated compound containing Warfarin is carried out with the non-iodinated amphiphilic compound (non ionic surfactant like Cremophor® ELP).
  • non ionic surfactant like Cremophor® ELP.
  • This mixture is characterized by a ratio of the weights noted SOR fixed at 50%.
  • the diameter of the droplets obtained is of 102 nm.
  • This mixture is added to an aqueous phase made up of only water. As for example 1, the proportion of the mixture/aqueous phase is fixed at 40.
  • the obtained colloidal system is a nano-emulsion which is obtained spontaneously, by creating mixed droplets made up by the iodinated and not- iodinated lipophilic and amphiphilic compounds respectively, dispersed in the aqueous phase.
  • Example 22 Synthesis of an iodinated lipophilic compound resulting from dolichol and 2,3,5-triiodobenzoic acid
  • Dolichol (11.06g, 0.008mol) was added in a round bottom flask containing 300ml dichloromethane stirring at room temperature.
  • the 2,3,5-triiodobenzoic acid (5g, O.Olmol), 4-dimethylaminopyridine (0.18g, 0.0015mol) and ⁇ , ⁇ '- dicyclohexylcarbodiimide (2.3g, O.Ol lmol) were then added respectively and the mixture was stirred for 22h at room temperature.
  • the reaction mixture was then firstly filtered, added water and extracted twice with ethyl acetate.
  • the organic phase was dried over anhydrous Na 2 S0 4 .
  • the solvent was removed in vacuum and the crude iodinated mixture was purified by gradient elution method on silica gel with cyclohexane and ethyl acetate as eluent.
  • the obtained synthesized iodinated oil is yellow viscous oil.
  • a step of mixture of the aforesaid lipophilic iodinated compound containing dolichol is carried out with the non-iodinated amphiphilic compound (non ionic surfactant like Cremophor ELP).
  • the two compounds are perfectly miscible.
  • This mixture is characterized by a ratio of the weights noted SOR fixed at 50%.
  • the diameter of the droplets obtained is of 78 nm.
  • This mixture is added to an aqueous phase made up of only water. As for example 1, the proportion of the mixture/aqueous phase is fixed at 40.
  • the obtained colloidal system is a nano-emulsion which is obtained spontaneously, by creating mixed droplets made up by the iodinated and not- iodinated lipophilic and amphiphilic compounds respectively, dispersed in the aqueous phase.
  • Example 23 Synthesis of an iodinated lipophilic compound resulting from a- tocopherol, lysine and 2,3,5-triiodobenzoic acid
  • A-tocopherol (3.5g, 0.008mol) was added in a round bottom flask containing 300ml dichloromethane stirring at room temperature.
  • the Bis-Boc lysine (3g,), 4- dimethylaminopyridine (0.18g, 0.0015mol) and ⁇ , ⁇ '-dicyclohexylcarbodiimide (2.3g, 0.01 lmol) were then added respectively and the mixture was stirred for 20h at room temperature.
  • the dichloromethane was removed under reduced pressure. The residue was then dissolved in ethyl acetate.
  • the precipitated dicyclohexylurea was removed by filtration and the organic phase was washed with water, dried over magnesium sulfate and the organic phase was removed by evaporation under reduced pressure.
  • the Boc were then removed by treatment with trifluoracetic acid (20 mL) for 20 min. After evaporation of the excess trifluoroacetic acid, the residue was washed twice with diethylether (10 mL).
  • 2,3,5-triiodobenzoic acid (lOg, 0.02mol), 4-dimethylaminopyridine (0.36g, 0.003mol), N-triethylamine (0.022 mol, 2,2 g) and N,N'-dicyclohexylcarbodiimide (4.6g, 0.022mol) were then added respectively to the amine. The reaction was stirred for 22h at room temperature.
  • a step of mixture of the aforesaid lipophilic iodinated compound is carried out with the non-iodinated amphiphilic compound (non ionic surfactant like Cremophor® ELP).
  • non ionic surfactant like Cremophor® ELP.
  • This mixture is characterized by a ratio of the weights noted SOR fixed at 50%.
  • the diameter of the droplets obtained is of 97 nm.
  • This mixture is added to an aqueous phase made up of only water. As for example 1, the proportion of the mixture/aqueous phase is fixed at 40.
  • the obtained colloidal system is a nano-emulsion which is obtained spontaneously, by creating mixed droplets made up by the iodinated and not- iodinated lipophilic and amphiphilic compounds respectively, dispersed in the aqueous phase.
  • Example 24 Synthesis of an iodinated nanoemulsion containing magnetic resonance imaging agents: formulation of Fe 3 0 4 NPs which present a solubility in self-emulsifying oil.
  • FeCI 2 is reduced by dodecaneamine (DDA) in water with a molar ratio (FeCI2/DDA) of 1 : 7, in a volume of water demineralized of 200 mL at constant temperature of 85°C. After washing with water and acetone, and magnetic separation, the Fe 3 0 4 NPs are dispersed in AGR or AGXR compound as described in the present invention at a concentration of 0.1 M.
  • DDA dodecaneamine
  • FeCI2/DDA molar ratio
  • the nano-emulsions containing Fe 3 0 4 NPs are formed within a few seconds.
  • the concentration of Fe 3 0 4 NPs in oil can vary from 5M to 0.0001 mM SOR can vary from 1% to 99%. SOWR can vary from 1% to 99.9999%.
  • Example 25 Synthesis of an iodinated nanoemulsion containing a fluorescence imaging agent.
  • the lipid fluorescent probes can be boron-dipyrromethene (BODIPY) and analogue structures, Rhodamine and analogue structures, Nitro-benzoxadiazole (NBD) and analogue structures, 2 - -chromen-2-one (Coumarin) and analogue structures, Diphenylhexatriene (l,6-Diphenyl-l,3,5-hexatriene, DPH) and analogue structures, Dansyl amide (5-(dimethylamino)naphthalene-l-sulfonamide) and analogue structures, l,l'-dioctadecyl-3,3,3'3'-tetramethylindocarbocyanine perchlorate (Dil) and analogue structures, Parinairc acid and analogue structures (trans-parinaric acid or c/
  • the fluorescent probe could be grafted onto lipid molecules serving as oil core of the nano-emulsion.
  • Dl-a-tocopherol (3.5g, 0.008mol) was added in a round bottom flask containing 200ml dichloromethane under stirring at room temperature.
  • the fluorescent probe of trans- parinaric acid (2.8g, O.Olmol), 4-dimethylaminopyridine (0.18g, 0.0015mol) and ⁇ , ⁇ '- dicyclohexylcarbodiimide (2.3g, O.Ol lmol) were then added respectively and the mixture was stirred for 22h at room temperature.
  • reaction mixture was then firstly filtered, added water and extracted twice with ethyl acetate.
  • organic phase was dried over anhydrous Na 2 S0 4 .
  • the solvent was removed in vacuum and the crude iodinated mixture was purified by gradient elution method on silica gel with cyclohexane and ethyl acetate as eluent.
  • Fluorescent nano-emulsions are formulated by spontaneous emulsified method mentioned above. Synthesized fluorescent oil of tocopheryl trans- pa rin a roate is used as the oily phase of nano-emulsions. A suitable amount of the tocopheryl frans-parinaroate is firstly mixed with a suitable amount of emulsifier, for example Cremophor® ELP. A suitable amount of the phosphate buffered saline is then added into the stirred said mixture. Nano-emulsions formed immediately once these two phases contact under stirring and sterilized by 0.22 ⁇ membrane before intravenous administration.
  • emulsifier for example Cremophor® ELP

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Abstract

La présente invention concerne un composé lipophile iodé de formule (I) ou (II) : AG-R (I) ou AG-X-R (II), formules dans lesquelles - AG représente une chaîne hydrocarbonée aliphatique (C8-C52), insaturée ou saturée, trouvée dans les acides gras ayant ou non une double liaison, un cycle aromatique insaturé ou saturé ayant une chaîne hydrocarbonée, un stérol, une chaîne hydrocarbonée aliphatique (C8-C52), insaturée ou saturée, terminée par un groupe amino ayant ou non une double liaison, - X représente un espaceur tel qu'un diacide, un diol (comme diol aliphatique, un polyéthylène glycol comprenant 1 à 50 groupes éthylène glycol) ou un acide aminé, - R représente un noyau benzène avec un, deux ou trois atomes d'iode et un groupe carboxylique ou un groupe alcool.
PCT/IB2013/000429 2012-02-14 2013-02-14 Produits iodés destinés à être utilisés pour l'imagerie médicale et leurs procédés de préparation WO2013121284A1 (fr)

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WO2015188040A3 (fr) * 2014-06-05 2016-02-18 The Trustees Of Columbia University In The City Of New York Composition pour une utilisation en imagerie
CN106810526A (zh) * 2015-11-27 2017-06-09 南京理工大学 一种香豆素修饰的维生素d2衍生物及其制备方法和应用
CN107474030A (zh) * 2016-06-08 2017-12-15 首都医科大学 华法林‑阿司匹林缀合物，其合成，抗血栓活性和应用
CN109292784A (zh) * 2018-10-25 2019-02-01 青岛美高集团有限公司 一种硅胶的制备方法以及由此所得的硅胶
CN112125875A (zh) * 2020-08-21 2020-12-25 南京理工大学 维生素E衍生物及其制备方法和在Fe3+特异性检测中的应用

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Publication number Priority date Publication date Assignee Title
WO2015188040A3 (fr) * 2014-06-05 2016-02-18 The Trustees Of Columbia University In The City Of New York Composition pour une utilisation en imagerie
CN106810526A (zh) * 2015-11-27 2017-06-09 南京理工大学 一种香豆素修饰的维生素d2衍生物及其制备方法和应用
CN107474030A (zh) * 2016-06-08 2017-12-15 首都医科大学 华法林‑阿司匹林缀合物，其合成，抗血栓活性和应用
CN109292784A (zh) * 2018-10-25 2019-02-01 青岛美高集团有限公司 一种硅胶的制备方法以及由此所得的硅胶
CN109292784B (zh) * 2018-10-25 2021-10-01 青岛美高集团有限公司 一种硅胶的制备方法以及由此所得的硅胶
CN112125875A (zh) * 2020-08-21 2020-12-25 南京理工大学 维生素E衍生物及其制备方法和在Fe3+特异性检测中的应用
CN112125875B (zh) * 2020-08-21 2022-09-20 南京理工大学 维生素E衍生物及其制备方法和在Fe3+特异性检测中的应用

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