WO2005075531A1 - Copolymeres amphiphiles sequences ou greffes contenant des elements lourds, leur procede de production et leur utilisation en tant qu'agents de contraste pour rayons x - Google Patents

Copolymeres amphiphiles sequences ou greffes contenant des elements lourds, leur procede de production et leur utilisation en tant qu'agents de contraste pour rayons x Download PDF

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WO2005075531A1
WO2005075531A1 PCT/EP2005/000990 EP2005000990W WO2005075531A1 WO 2005075531 A1 WO2005075531 A1 WO 2005075531A1 EP 2005000990 W EP2005000990 W EP 2005000990W WO 2005075531 A1 WO2005075531 A1 WO 2005075531A1
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group
block
amphiphilic block
graft copolymer
carbon atoms
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PCT/EP2005/000990
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German (de)
English (en)
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Andreas Thuenemann
Christoph Kozlowski
Joachim Storsberg
Werner Jaeger
André LASCHEWSKY
Stephan Kubowicz
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Fraunhofer-Gesellschaft Zur Foerderung Der Angewandten Forschung E.V.
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Publication of WO2005075531A1 publication Critical patent/WO2005075531A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/04—X-ray contrast preparations
    • A61K49/0433—X-ray contrast preparations containing an organic halogenated X-ray contrast-enhancing agent
    • A61K49/0447—Physical forms of mixtures of two different X-ray contrast-enhancing agents, containing at least one X-ray contrast-enhancing agent which is a halogenated organic compound
    • A61K49/0461—Dispersions, colloids, emulsions or suspensions
    • A61K49/0466—Liposomes, lipoprotein vesicles, e.g. HDL or LDL lipoproteins, phospholipidic or polymeric micelles
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
    • C08F257/00—Macromolecular compounds obtained by polymerising monomers on to polymers of aromatic monomers as defined in group C08F12/00
    • C08F257/02—Macromolecular compounds obtained by polymerising monomers on to polymers of aromatic monomers as defined in group C08F12/00 on to polymers of styrene or alkyl-substituted styrenes
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
    • C08F265/00—Macromolecular compounds obtained by polymerising monomers on to polymers of unsaturated monocarboxylic acids or derivatives thereof as defined in group C08F20/00
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
    • C08F265/00—Macromolecular compounds obtained by polymerising monomers on to polymers of unsaturated monocarboxylic acids or derivatives thereof as defined in group C08F20/00
    • C08F265/04—Macromolecular compounds obtained by polymerising monomers on to polymers of unsaturated monocarboxylic acids or derivatives thereof as defined in group C08F20/00 on to polymers of esters
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
    • C08F265/00—Macromolecular compounds obtained by polymerising monomers on to polymers of unsaturated monocarboxylic acids or derivatives thereof as defined in group C08F20/00
    • C08F265/10—Macromolecular compounds obtained by polymerising monomers on to polymers of unsaturated monocarboxylic acids or derivatives thereof as defined in group C08F20/00 on to polymers of amides or imides
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
    • C08F291/00—Macromolecular compounds obtained by polymerising monomers on to macromolecular compounds according to more than one of the groups C08F251/00 - C08F289/00
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
    • C08F293/00—Macromolecular compounds obtained by polymerisation on to a macromolecule having groups capable of inducing the formation of new polymer chains bound exclusively at one or both ends of the starting macromolecule
    • C08F293/005—Macromolecular compounds obtained by polymerisation on to a macromolecule having groups capable of inducing the formation of new polymer chains bound exclusively at one or both ends of the starting macromolecule using free radical "living" or "controlled" polymerisation, e.g. using a complexing agent
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
    • C08L51/00—Compositions of graft polymers in which the grafted component is obtained by reactions only involving carbon-to-carbon unsaturated bonds; Compositions of derivatives of such polymers
    • C08L51/003—Compositions of graft polymers in which the grafted component is obtained by reactions only involving carbon-to-carbon unsaturated bonds; Compositions of derivatives of such polymers grafted on to macromolecular compounds obtained by reactions only involving unsaturated carbon-to-carbon bonds
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
    • C08L53/00—Compositions of block copolymers containing at least one sequence of a polymer obtained by reactions only involving carbon-to-carbon unsaturated bonds; Compositions of derivatives of such polymers

Definitions

  • the invention relates to new amphiphilic block copolymers with radiopaque hydrophobic blocks and a high proportion of heavy elements. These polymers can form micelles and can therefore be used as X-ray contrast agents for computed tomography and are the subject of this invention.
  • block and graft copolymers consisting of a hydrophobic and a hydrophilic block form micelles in an aqueous medium. These are often of the core-shell type, the core being formed from the hydrophobic polymer blocks and the shell from the hydrophilic polymer blocks.
  • Computed tomography is an X-ray diagnostic procedure for generating body cross-sectional images that is becoming increasingly important for diagnostics in medicine. Often, intravenous administration of large amounts of contrast medium is necessary, which increases the image quality of the tissue around an organ of interest.
  • Contrast agents for CT are substances that necessarily contain heavy elements, i.e. High atomic number elements, "heavy elements", are included to be radiopaque (x-ray contrast).
  • the radiopaque iodinated contrast agents used today are small water-soluble organic molecules and are based on triiodobenzene derivatives (see W.
  • CT contrast media that have a longer residence time in the vascular space (so-called blood pool agents).
  • macromolecular compounds appeared suitable, as proposed in DE 692 28 999 T2 in the form of iodinated polyamine compounds.
  • these are branched (polyethyleneimines) or dendritic polymers (polyethyleneimine dendrimers) which contain triiodobenzene groups.
  • these contrast agents are difficult to excrete through the kidneys. The reasons for this presumably lie in excessively high molecular weights as well as the strongly positive charge of the polyamine compounds and the associated property of forming strong non-covalent bonds (complex formation of polyethyleneimine) (AF Thünemann, Prag. Polym. Sei. 2002, 27, 1473-1572) ,
  • micelle-forming block copolymers with a hydrophilic and a hydrophobic block.
  • Such copolymers have been extensively investigated, e.g. B. in formulations with drugs against cancer. Above a characteristic critical micellization concentration (cmc), these block copolymers form micelles of the core-shell type.
  • the core of the micelle consists of water-insoluble blocks and drug molecules, the shell of the water-soluble blocks.
  • these drug-laden block copolymer micelles below the cmc disintegrate into the individual molecules. This allows drug release and excretion of the block copolymers, e.g. B. over the kidney.
  • Review articles on this topic can be found e.g. B. at Kataoka et. al., Advanced Drug Delivery Reviews 2001. 47. 113-131.
  • Torchilin suggests using methyl poly (ethylene glycol) block poly ( ⁇ , N- (triiodobenzoyl) -L-lysine as a block copolymer to form the contrast-forming micelles, but block copolymers of this type have significant disadvantages.
  • the first is in that that their synthesis is very complex and comprises a large number of stages first step, a monomethoxy PEG succinate is activated in the presence of dicylohexylcarbodiimide with N-hydroxysuccinimide to monomethoxy PEG succinimidyl succinate. This is followed by implementation with commercially available poly (CBZ) lysine protected in the ⁇ position.
  • the lysine amino groups are then deprotected with hydrogen bromide in acetic acid, and finally the triiodobenzene group is bound to the deblocked amino groups in the form of activated triiodobenzoic acid made from triiodobenzoic acid and N-hydroxysuccinimide.
  • Torchilin and his team received a product in which only 40% of the iodine-containing groups were covalently bound, while 60% were non-covalently attached and only loosely associated with the polymer, as in the purification revealed.
  • the proportion of iodine is 44.7% by weight after synthesis (covalently plus non-covalently bound iodine groups) and 17.7% after purification to remove non-covalently bound triiodobenzoate.
  • This high proportion of non-covalently bound iodine groups (in free triiodobenzoic acid), as mentioned by Torchiline itself, can be potentially toxic to the patient, which in turn severely limits the medical usability.
  • the object of the present invention is to provide an inexpensive to produce, in physiological environment hydrolytically stable contrast agent for X-ray examinations, the heavy element groups are completely covalently integrated into the molecular structure of the agent.
  • the contrast medium should preferably be able to be prepared as a formulation of micelles with low viscosity, the application of which is less painful than the viscous formulations of low molecular weight substances which are customary today. If possible, the aim should be to produce copolymer micelles containing heavy elements that retain their structural integrity even when diluted heavily, i.e. do not disintegrate into their individual components.
  • the object of the invention is achieved by the synthesis of a new type of amphiphilic block and graft copolymers containing heavy elements, in particular iodine.
  • Such polymers can be produced in a cost-effective manner by a simple synthesis sequence. This can advantageously take place in a maximum of three synthesis stages, in which the hydrophilic and hydrophobic blocks are produced step by step and, if necessary, are coupled to one another and, if necessary, are reacted in a final step with a reagent containing heavy elements to form the target compound.
  • the copolymers according to the invention can be converted in an aqueous medium, in particular in a physiological environment, into micelle formulations of the core-shell type which are suitable as X-ray contrast media.
  • the copolymers consist of blocks poly (A) and blocks poly (B) or contain them in large or substantial parts.
  • essential is to be understood as meaning a proportion of at least approximately 70% by weight, preferably at least approximately 80 or 90% by weight.
  • the blocks each contain a repeating unit of two carbon atoms, at least one of which carries a substituent, one of the blocks being a hydrophilic block (Block A) carrying at least one hydrophilic substituent per C 2 carbon unit while the other is a hydrophobic block (block B) whose C 2 carbon unit carries at least one hydrophobic residue.
  • the copolymer according to the invention is thus composed of or using the structural units (A):
  • R 2 is hydrogen, a methyl group or a radical -CH 2 COOR ', -CH 2 C (O) NHR ", -CH 2 C (O) N (R") 2 , -CH 2 OC (0) R ", - Is CH 2 NHR “C (O) R", or -CH 2 C (0) N (R ”) 2 ,
  • R 3 is hydrogen and, moreover, if R 2 is hydrogen, it can be a radical -COOR *, C (O) NHR "or -C (O) N (R") 2 ,
  • R ' is hydrogen, a monovalent metal cation, a corresponding proportion of a polyvalent metal cation, R "or a group (CH 2 CH 2 0) n R 7 , where several radicals R' can have the same or different meaning (s),
  • R " is a straight-chain, branched or cyclic alkyl group with preferably 1 to 8 carbon atoms, a benzyl group, an optionally alkyl-substituted aryl group with preferably 6 to 8 carbon atoms or a group (CH 2 CH 2 0) n R 7 , where several radicals R" can have the same or different meaning (s),
  • R 4 , R 5 and R 6 independently of one another are hydrogen, R ", -OR", -OC (O) R “, -OC (0) OR", -C (O) OR “, -NR 7 C (0) R “, -C (O) NR 7 R", -NHC (O) OR ", -OC (O) NHR", -R 10 -R 10 ', -R 10 ' -R 10 , -R 0 -CH 2 -R 10 ⁇ -R 0 -CH 2 -OR 10 ', -R 10, -CH 2 -R 10 , or -R 10' -CH 2 -OR 10 , with the proviso that at least one of the radicals R 4 , R 5 and R 6 are -R 10 -R 10 ', -R 10 ' -R 10 , -R 10 -CH 2 -R 10 ', -R 10 -CH 2 -OR 10 ', ⁇ R 10 '
  • R 7 is hydrogen, an optionally substituted, straight-chain, branched or cyclic alkyl group with preferably 1 to 12 carbon atoms or an optionally substituted aryl, alkylaryl or arylalkyl group with preferably 6 to 24 carbon atoms,
  • R 8 is an optionally substituted, straight-chain, branched or cyclic alkylene group with preferably 1 to 12 carbon atoms or an arylene, Is alkylarylene or arylalkylene group with preferably 6 to 24 carbon atoms, which may additionally be alkyl-substituted,
  • R 9 is an optionally alkyl-substituted arylene group with preferably 6 to 10 carbon atoms
  • R 10 is an optionally alkyl-substituted aryl or arylene group with preferably 6 to 24 carbon atoms,
  • R 10 ' is an optionally alkyl-substituted arylene or aryl group, preferably having 6 to 24 carbon atoms, which is substituted one or more times with a heavy element, where R 10 and R 10 ' may optionally carry further substituents independently of one another, p and q are each independently an integer from 2 to 1000, and n and r are each an integer from 1 to 1000.
  • “heavy element” is understood to mean a chemical element with an atomic number higher than 31 and lower than 84 with the exception of the elements Kr and Xe, the elements I, Br, Sn, Sb, Te, Bi being preferred and the element l is particularly preferred.
  • R 1 is preferably - (X) -COOR ⁇ , in particular where R 'is equal to the group (CH 2 CH 2 0) n R 7 , the length of the oxoalkylene group from ester group to ester group in the poly A block being able to vary statistically and preferably in the range from 5 to 20.
  • (B) is very particularly preferably a single bond.
  • R 7 is particularly preferably methyl or ethyl.
  • R 2 is preferably hydrogen or methyl, very particularly preferably methyl.
  • R 3 is preferably hydrogen.
  • R 4 is preferably -R 10 -CH 2 -OR 10 ' , where R 10 is very particularly preferably a phenylene group and R 10 ' is particularly preferably a phenyl group which is whole is particularly preferably substituted with iodine or bromine, in particular with up to 3 iodine atoms.
  • (X) is preferably a single bond in a first embodiment, preferably -OC (0) R 8 -, -OC (0) OR 8 - or -C (0) OR 8 - in a second embodiment, preferred in a third embodiment - NR 7 C (O) R 8 -, -C (0) NR 7 R 8 -, -NR 7 C (O) OR 8 -, -N (R 8 -) C (0) OR 7 , -OC (0 ) NHR 8 -, or -N (R 8 -) C (O) R, and in a fourth embodiment preferably -R 9 -.
  • R 5 and R 6 are preferably hydrogen.
  • p is preferably 20 to 500, preferably 50 to 200.
  • q is preferably 10 to 300, more preferably 30 to 80.
  • n and r are preferably 2-100, more preferably 5-50. n is most preferably 6-12.
  • Monomers with which hydrophobic blocks (block B) can be produced by controlled radical or free radical polymerization are e.g. - but not limited to this selection - 4-vinylbenzyl chloride, 3-vinylbenzyl chloride, isomer mixtures of 4- and 3-vinylbenzyl chloride, glycidyl methacrylate, 2-bromoethyl methacrylate, glycidyl acrylate, 2-bromoethyl acrylate. 4-vinylbenzyl chloride is particularly preferred.
  • these blocks can be reacted in a polymer-analogous reaction with a compound containing heavy elements, so that the group containing heavy elements is covalently bound to the polymer.
  • a compound containing heavy elements for example, a poly (4-vinylbenzyl chloride) -containing polymer can be reacted with triiodophenol so that the triiodobenzene group is covalently bound to the polymer backbone to form an ether bond.
  • the heavy element-containing compound can, however, also be used directly as a free-radical (free or controlled) polymerizable monomeric compound for producing a hydrophobic polymer block already containing the heavy element.
  • Monomeric compounds that already contain the heavy element can be - for example - but not limited to this representation or compounds - by reacting e.g. B. 4-vinylbenzyl chloride with e.g. Triiodophenol can be obtained.
  • Monomers with which hydrophilic blocks (Block A) can be produced by controlled radical or free radical polymerization are, for example - but not limited to this selection: Acrylic acid and its monovalent salts, itaconic acid and its monovalent salts,
  • 2-Acrylamidoacetic acid and its monovalent salts N-acryloylsarcosine and its monovalent salts, monovalent salts of 2-acrylamidopropionic acid, monovalent
  • N-acryloyl taurine and its monovalent salts N-acryloyl-N-methyl taurine and its monovalent salts, 2-acrylamido-2-methyl-1-propanesulfonic acid and its salts, all
  • 3-methacrylamidopropionic acid monovalent salts of 4-methacrylamidobutyric acid, monovalent salts of 6-methacrylamidocaproic acid, monovalent salts of
  • Methacrylamidoundecanoic acid monovalent salts of methacrylamidododecanoic acid
  • Particularly preferred monomeric hydrophilic starting compounds are:
  • the radicals R 1 have the meaning - (X) -COOR ', -C (0) NHR ", or - (X) -C (O) NR 2 ⁇ , where R' (CH 2 CH 2 0) n is R 7.
  • R' (CH 2 CH 2 0) n is R 7.
  • R 1 in copolymers according to the invention has the meaning - (X) -COOR ', where (X) is a single bond, where R' in turn is particularly preferably hydrogen or, likewise particularly preferably, (CH 2 CH 2 0) nR 7 .
  • R 7 hydrogen or an alkyl group as defined above is again to be mentioned as preferred for this embodiment.
  • the copolymers according to the invention can be composed mainly or completely of a hydrophilic block poly (A) and a hydrophobic block poly (B). Alternatively, they can consist of three blocks (or contain substantial parts of them), and if the central block is hydrophobic, the two edge blocks are hydrophilic and vice versa. Alternatively, the copolymers according to the invention can be constructed from a block polymer which is grafted with the opposite block in each case.
  • the hydrophilic block (A) itself can be a copolymer of randomly or alternately arranged, hydrophobic and hydrophilic units (A) and (B), provided that the block poly (A) still has such great hydrophilicity that it is water soluble.
  • Suitable hydrophobic monomer units for the construction of such copolymers are, for example, styrene or methyl (meth) acrylate, maleic anhydride, (meth) acrylic acid, styrene sulfonic acid and its salts, vinylbenzoic acid and its salts as hydrophilic monomer units.
  • the block and graft copolymers according to the invention can be produced by radical polymerization. An elegant synthesis consisting of only a few steps follows the following scheme:
  • the invention thus provides copolymers and processes for their preparation
  • an amphiphilic block copolymer by controlled radical polymerization of the hydrophobic, N-oxyl-terminated block (from synthesis step 1) with a suitable hydrophilic monomer (e.g. (meth)) acrylic acid, styrene sulfonic acid, and their salts, maleic anhydride, vinylbenzoic acid and their salts or poly (methoxypolyethylene glycol 350 methacrylate), see Example 1.2),
  • a suitable hydrophilic monomer e.g. (meth) acrylic acid, styrene sulfonic acid, and their salts, maleic anhydride, vinylbenzoic acid and their salts or poly (methoxypolyethylene glycol 350 methacrylate), see Example 1.2
  • a suitable hydrophilic monomer e.g. (meth) acrylic acid, styrene sulfonic acid, and their salts, maleic anhydride, vinylbenzoic acid and their salts or poly (methoxypolyethylene glyco
  • hydrophobic and the hydrophilic block can also be easily interchanged in the synthesis scheme given.
  • heavy-element amphiphilic block or graft copolymers can alternatively also be prepared in only two synthesis steps if, for example, in the scheme described above in step 1 hydrophobic monomers are used which already contain heavy elements.
  • Copolymers in aqueous solvents form micelles and aggregates that have a low viscosity even at high concentrations and a high X-ray
  • Example 1 Polymer synthesis
  • the synthesis was carried out in a thermostattable 100 mL jacketed reactor. 3 mmol of N-fe f / ' aer-butyl-1-diethylphosphono-2,2-dimethylpropylnitroxyl (TBUNO) and 50 g of 4-vinylbenzyl chloride (VBC) were dissolved in toluene. The solution was purged with argon for 1 h and then heated to 75 ° C. 2 mmol of 2,2-azobis (4-methoxy) -2,4-dimethylvaleronitrile (V70, WAKO) were then dissolved in 5 ml of toluene and added to the reaction mixture.
  • TBUNO N-fe f / ' aer-butyl-1-diethylphosphono-2,2-dimethylpropylnitroxyl
  • VBC 4-vinylbenzyl chloride
  • the solution was stirred at 75 ° C for 1 hour to ensure complete disintegration of the V70.
  • the temperature was then raised to 95 ° C. to start the polymerization.
  • the mixture was stopped by allowing the mixture to cool.
  • the polymer solution was poured into 1500 mL methanol and the polymer precipitated.
  • the tube product was dissolved in 100 mL butanone and then precipitated again in 1500 mL methanol, filtered off and dried in vacuo.
  • the yield was 50 g of PVBC.
  • the structural formula of the iodine-containing block copolymer after synthesis step 3 is shown below.
  • the iodine content is 19.08 percent by weight.
  • Example 2 Synthesis of an iodine-containing, micelle-forming diblock copolymer:
  • PVBC Polv (vinylbenzyl chloride)
  • the polymer solution was precipitated in ice-cold diethyl ether and filtered off. That at
  • a quantity of 20 mg of PVBI-b-PMPEG350MA (from example 1, synthesis step 3, compare section 1.3 of example 1) was dissolved in 15 ml of tetrahydrofuran in an ultrasound bath at 50 ° C., mixed dropwise with 20 ml of water at 50 ° C. and with stirring Let stand at constant temperature until the typical smell of tetrahydrofuran had disappeared. The amount of water evaporated was replaced and characterized using dynamic light scattering (A1-SP81 goniometer and ALV-5000 digital correlator from ALV Lasermaschinesgesellschaft, Langen). The hydrodynamic radius of the micelles determined from the light scattering data using the Stokes-Einstein relationship was 62 nm.
  • Viscometric measurements on the micellar solutions were carried out using a solution viscometer with automatic dilution (Viskoboy 2; Lauda) at 30 ° C. in 0.01 N sodium chloride solution.
  • the viscosity of the micelles produced according to Example 2 is low (eg 6 cm 3 g "1 at a concentration of 8 g L " 1 ) and that their intrinsic viscosity also has a low value (approx. 5 cm 3 g "1 ).
  • the viscosity increases linearly with the concentration (gradient approx. 0.16 cm 3 L g " 2 ).
  • the block copolymer micelles thus behave like ideally typical hard spheres with regard to their viscosity. No signs of the formation of higher degrees of association than the desired micelles (e.g. lamellar liquid crystals) were found in the concentration range investigated (2 to 8 g L "1 ).
  • micellar solution of the micelles produced in Example 2 was determined (cf. FIG. 3).
  • the structures were evaluated using the Percus-Yevick model (J. Percus, GH Yevick; Phys, Rev. 110 (1958), 1-13; MS Wertheim, Phys. Rev. Lett. 10 (1963), 321-323; NW Ashcroft et al., Phys. Rev. 145 (1966), 83-90; JA Barker et al., Rev. Mod. Phys.

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Abstract

L'invention concerne des copolymères amphiphiles séquencés ou greffés comportant des blocs hydrophobes radio-opaques et présentant une teneur élevée en métal lourd. Ces copolymères sont constitués ou formés à partir des motifs structuraux (A) = [C(R1R2)-CHR3] et (B) = [C(R4R5)-CHR6], dont la proportion représente au moins 70 % en poids. Les blocs poly(A) et les blocs poly(B) comportent respectivement un motif répétitif constitué de deux atomes de carbone dont au moins un porte un substituant. Le bloc A est un bloc hydrophile qui porte au moins un substituant hydrophile par motif de carbone C2, tandis que le bloc B est un bloc hydrophobe dont le motif carbone C2 porte au moins un groupe hydrophobe. Le bloc B porte en outre une proportion élevée de métal lourd, par liaison covalente. Les copolymères selon l'invention permettent de produire des suspensions micellaires conçues pour être utilisées en tant qu'agents de contraste pour rayons X.
PCT/EP2005/000990 2004-02-03 2005-02-01 Copolymeres amphiphiles sequences ou greffes contenant des elements lourds, leur procede de production et leur utilisation en tant qu'agents de contraste pour rayons x WO2005075531A1 (fr)

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DE200410005304 DE102004005304A1 (de) 2004-02-03 2004-02-03 Schwerelementhaltige amphiphile Block- und Pfropf-Copolymere, Verfahren zu ihrer Herstellung und ihre Verwendung als Röntgenkontrastmittel
DE102004005304.9 2004-02-03

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5567410A (en) * 1994-06-24 1996-10-22 The General Hospital Corporation Composotions and methods for radiographic imaging
US20030162896A1 (en) * 1999-09-01 2003-08-28 Mathias Destarac Gelled aqueous composition comprising a block copolymer containing at least one water-soluble block and one hydrophobic block

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2610935B1 (fr) * 1987-02-13 1989-09-01 Guerbet Sa Polymeres iodes, leurs procedes de preparation et leurs applications comme produits de contraste
EP0436316A1 (fr) * 1989-12-08 1991-07-10 Milos Sovak Agents de contraste pour rayons X pour une opacification prolonguée

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5567410A (en) * 1994-06-24 1996-10-22 The General Hospital Corporation Composotions and methods for radiographic imaging
US20030162896A1 (en) * 1999-09-01 2003-08-28 Mathias Destarac Gelled aqueous composition comprising a block copolymer containing at least one water-soluble block and one hydrophobic block

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