radiopaque, non-biodegradable, water-insoluble iodinated benzyl ethers of poly (vinyl alcohol), prep

专利摘要:
POLY (VINYL ALCOHOL) BENZYLIC ETHERS RADIOPACES, NON-BIODEGRADABLE, INSOLUBLE IN WATER, METHOD OF PREPARATION, INJECTIBLE EMBOLIZING COMPOSITIONS CONTAINING THE SAME AND USE OF THE SAME alcohol, a polyethylene, insoluble in water consisting of a PVA having covalently graft iodinated benzyl groups comprising 1-4 iodine atoms per benzyl group, a process for preparing the same iodine comprising 1-4 iodine atoms per benzyl group in a polar aprotic solvent, presence of a base in anhydrous conditions. Said iodized IPVA benzylether is particularly useful as an embolic agent in an injectable embolic composition. The invention also relates to an embolizing injectable composition comprising said iodinated PVA benzylether and capable of forming a cohesive mass in contact with a body fluid by precipitation of the iodized PVA benzylether. Said injectable embolic composition is particularly useful for the formation in situ of a cohesive mass in a blood vessel or a tumor. The invention also relates to a coating composition containing said iodinated PVA benzyl ether and capable of forming a radiopaque coating on a medical device. The invention also says (...).
公开号:BR112012019754B1
申请号:R112012019754-1
申请日:2011-03-09
公开日:2020-10-20
发明作者:Yves Chevalier；Géraldine Augusti；Coralie Nyffenegger；Eric Doelker；Olivier Jordan；Gert Andersen
申请人:Université Claude Bernard Lyon 1 (Ucbl)；Centre National De La Recherche Scientifique (Cnrs)；Antia Therapeutics S.A；
IPC主号:

专利说明:

Field of invention
[0001] The present invention relates to iodinated, water-insoluble, non-biodegradable, radiopaque polymers and more particularly to iodinated, radiopaque, non-biodegradable, water-insoluble benzyl ethers of water, for use as agents embolizers, for a production process thereof, for injectable embolic compositions containing the same and the uses thereof, for coating compositions containing these, and for micro- and nanoparticles made from these. Fundamentals of the invention
[0002] Blood vessel embolization is important in preventing / controlling bleeding (for example, organ bleeding, gastrointestinal bleeding, vascular bleeding, bleeding associated with an aneurysm) or for the ablation of diseased tissue (for example, tumors, etc.), cutting off your blood supply.
[0003] Endovascular blood vessel embolization is known to be conducted as an alternative to surgical interventions for a variety of purposes, including endovascular treatment of tumors, treatment of injuries such as aneurysms, arteriovenous malformations, arteriovenous fistula, uncontrolled hemorrhage and similar.
[0004] Endovascular embolization of blood vessels is performed through catheterization techniques that allow for selective placement of the catheter in the vascular site to be embolized.
[0005] Recent techniques propose to embolize blood vessels using injectable embolic compositions including polymeric materials such as embolic agents.
[0006] The use of embolic compositions in the treatment of aneurysms or arteriovenous malformations (AVM) is advantageous since polymeric materials fill the interior of the aneurysm or AVM and solidify in the form of the aneurysm or AVM, and thus the aneurysm or AVM will be completely excluded from the bloodstream.
[0007] It is also known that injectable embolic compositions containing polymeric materials as embolic agents can be used for the treatment of tumors by direct puncture. In such a case, the embolizing composition is injected directly into the tumor tissue or into the vascular bed surrounding the tumor using needle technology.
[0008] Known polymeric materials used in embolic compositions include, for example, those in which a preformed polymer in situ precipitates from a carrier solution at the vascular site or within the tumor.
[0009] In embolic compositions, the preformed polymer must be selected to be capable of rapid precipitation to form a well-defined cohesive solid or semi-solid mass, the filling space of the material on contact with blood or any other body in an aqueous environment on a fabric.
[0010] In addition, these compositions must be sterile, stable, biocompatible, and in addition highly radiopaque to allow efficient imaging using current radiology techniques.
[0011] This last property is necessary in order to visualize the embolizing composition during deposition of injection at the vascular site and clinical follow-up.
[0012] A number of documents disclose liquid formulations intended for embolization of blood vessels and containing a pre-formed biocompatible organo-soluble, water-insoluble polymer dissolved in a water-miscible organic solvent, and a water-insoluble solid contrast agent, biocompatible, radiopaque such as tantalum, tantalum oxide, tungsten bismuth trioxide and barium sulfate.
[0013] These known radiopaque embolic compositions, precipitating in contact with blood, are simple physical mixtures of a preformed polymer dissolved in a water-miscible organic solvent and a conventional radiopaque contrast agent.
[0014] US-A-5,580,568 discloses compositions suitable for use in embolic blood vessels comprising a cellulose diacetate polymer, a biocompatible solvent such as DMSO and a water-insoluble contrast agent such as tantalum, oxide of tantalum and barium sulfate.
[0015] US-A-5,851,508 discloses compositions suitable for use in embolizing blood vessels, which comprises a copolymer of ethylene and vinyl alcohol, a biocompatible solvent such as DMSO and a water-insoluble contrast agent, such as tantalum, oxide of tantalum and barium sulfate.
[0016] US-A-5,695,480 discloses compositions for use in embolizing blood vessels that comprise a biocompatible polymer selected from cellulose acetates, cellulose acetate propionates, cellulose acetate butyrates, ethylene copolymers and vinyl alcohol, hydrogels, polyacrylonitrile, polyvinylacetate, nitrocellulose, urethane / carbonate copolymers, styrene / maleic acid copolymers and mixtures thereof, a biocompatible solvent such as DMSO, ethanol and acetone, and a contrast agent, such as tantalum, tantalum oxide , tungsten and barium sulfate.
[0017] However, in these formulations, the radiopaque contrast agent is suspended in the polymer solution, so that these compositions are heterogeneous embolic dispersions.
[0018] Thus, permanent radiopacity cannot be ensured in these compositions, because the chemical incorporation of the contrast agent into the polymer structure is not achieved and the sedimentation of the contrast agent during catheterization or slow release over time in the surrounding areas may occur, which would be a major disadvantage for clinical follow-up and can lead to serious toxic effects.
[0019] A well-known commercially available formulation of this type is ONYX ™, a mixture of ethylene copolymer and vinyl alcohol (EVOH) dissolved in DMSO, with micronized tantalum powder in the liquid polymer / DMSO mixture to provide fluoroscopic visualization.
[0020] ONYX ™ is released through a microcatheter to the target lesion under fluoroscopic control.
[0021] In contact with the body fluid (ie, blood), the solvent (DMSO) quickly diffuses causing the in-situ precipitation of the polymer in the presence of the radiopaque contrast agent, thus forming a radiopaque polymeric implant.
[0022] ONYX ™ is available in a range of liquid viscosities designed to produce release and precipitation characteristics optimized for the type of injury to be treated.
[0023] However, these formulations have the following drawbacks.
[0024] These formulations need careful preparation before use, which is time consuming and can lead to application errors.
[0025] Furthermore, since the radiopaque contrast agent is suspended in the polymer solution, homogeneous radiopacity cannot be ensured in relation to possible sedimentation during embolization. The radiopaque contrast agent also limits the non-invasive follow-up by computed tomography image because of the beam protection artifacts. In addition, entrapment of the metallic radiopaque contrast agent is not ensured so that phase separation can occur.
[0026] As a consequence, the radiopaque contrast agent does not reflect the position of the polymer and the visibility of the implant can be altered during radiological examination accompanied by imaging studies. The release of radiopaque metallic contrast agents is potentially toxic.
[0027] To overcome the disadvantages of formulations containing a radiopaque agent suspended in the polymer solution, some of the present inventors have focused on the need to provide a radiopaque polymer intrinsically for use as an embolizing agent in liquid embolising compositions.
[0028] For this purpose, they have synthesized an iodized poly (vinyl alcohol) (i-PVA) by grafting iodobenzoyl chloride into poly (vinyl alcohol), through ester bonds and tested as a l-PVA polymer.
[0029] The results obtained when such l-PVA is used in liquid embolising compositions have been reported in a number of publications (see O. Jordan et al., 19th European Conference on Biomaterials, 2005. Sorrento, Italia, "Novel organic vehicles for the embolization of vascular malformations and intracranial aneurysms "; O. Jordan et al., Transactions of the 7th World Biomaterials Congress, Sydney, Australia, 706, 2004." Novel Radiopaque Polymer for Interventional Radiology "; O. Jordan et al., American Society of Neuroradiology 42nd annual meeting, Seattle, June 5-11, 2004, "Liquid Embolization of Experimental Wide-Necked Aneurysms with Polyvinyl Alcohol Polymer: A New, Nonadhesive, lodine-Containing Liquid Embolic Agent”; O. Dudeck, O. Jordan et al., Am. J. Neuroradiol., 27: 1900-1906, 2006, "Organic solvents as vehicles for precipitating liquid embolics"; O. Dudeck, O. Jordan et al .; Am. J. Neuroradiol., 27 : 1849-55, October 2006, "Embolization of Experimental Wide-Necke d Aneurysm with lodine- Containing Polyvinyl Alcohol Solubilized in a Low-Angiotoxicity Solvent ”; O. Dudeck, 0. Jordan et al., J. Neurosurg. 104: 290-297, February 2006, "Intrinsically radiopaque iodine- containing polyvinyl alcohol as a liquid embolic agent: evaluation in experimental wide-necked aneurysms") without identification of the l-PVA used.
[0030] However, this l-PVA has no stability with respect to hydrolysis, and when used as an embolizing agent, it undergoes partial degradation leading to potentially toxic degradation products in the body over time.
[0031] Furthermore, since the embolic mass is expected to remain for a long time, sustainable binding of iodinated markers is necessary.
[0032] Therefore, the present inventors have focused their research on the need to provide a new iodized poly (vinyl alcohol), which has improved stability, and surprisingly found a new iodized poly (vinyl alcohol), which has not only improved of stability in relation to hydrolysis, but which is also expected to provide liquid embolizing compositions with a higher concentration of embolizing agent, and therefore a lower volume of an organic solvent, due to its unexpectedly low viscosity in solution, and thus obtained in the present invention. Summary of the invention
[0033] According to a first aspect, the present invention provides a non-biodegradable, radiopaque iodinated poly (vinyl alcohol) benzyl ether, radiopaque (iodinated PVA benzyl ether) consisting of a poly (vinyl alcohol), having groups covalently grafted into it iodinated benzyl comprising 1 to 4 iodine atoms per benzyl group.
[0034] According to a second aspect, the present invention provides a process for the preparation of the iodinated PVA benzylether of the present invention, said process comprising the reaction of a 0 -100% hydrolyzed poly (vinyl alcohol) with a PVA of starting with an iodinated benzyl derivative comprising 1-4 iodine atoms per benzyl group in a polar aprotic solvent, in the presence of a base under anhydrous conditions.
[0035] In accordance with a third aspect, the present invention provides a use of the iodinated PVA benzylether of the present invention as an embolic agent in an injectable embolic composition.
[0036] In accordance with a fourth aspect, the present invention provides an injectable embolic composition comprising the iodized PVA benzyl ether of the present invention and a water miscible biocompatible solvent, which solubilizes the iodinated PVA benzyl ether, where the concentration of the benzyl ether of PVA in the composition is selected in the range of 5 - 65% w / w so that the composition is capable of forming a cohesive mass in contact with a body fluid by precipitation of the iodized PVA benzylether.
[0037] According to a fifth aspect, the present invention provides a use of the injectable embolizing composition of the present invention to form a cohesive mass in a blood vessel in situ such as arteriovenous malformations (AVM) or vascular aneurysms.
[0038] According to a sixth aspect, the present invention provides a use of the injectable embolizing composition of the present invention to form a cohesive mass in situ in a tumor.
[0039] According to a seventh aspect, the present invention provides a use of the injectable embolizing composition of the present invention to form a semi-solid implant in a tumor in situ for the treatment of the tumor by hyperthermia.
[0040] According to an eighth aspect, the present invention provides a use of the injectable embolizing composition of the present invention to form in situ semi-solid implants for the treatment of urinary incontinence.
[0041] According to a ninth aspect, the present invention provides a coating composition to form a coating on a medical device comprising the iodized PVA benzyl ether of the present invention and a solvent solubilizing the iodized PVA benzyl ether, in which the concentration of the benzyl ether of iodinated PVA in the composition is selected in the range of 5 - 65 w / w% so that the composition is able to form a radiopaque coating after application to a medical device and evaporation of the solvent.
[0042] In accordance with a tenth aspect, the present invention provides particles, selected from microparticles and nanoparticles, formed from iodized PVA benzylether of the present invention. Brief description of the figures
[0043] Fig. 1 shows the 1H NMR spectrum of 2,3,5-triiodobenzyl ether of poly (vinyl alcohol) of the present invention prepared according to Example 1.
[0044] Fig. 2 shows the 1H NMR spectrum of 4-iodobenzyl ether of poly (vinyl alcohol) of the present invention prepared according to Example 2.
[0045] Fig. 3a is a photograph showing the precipitation in water of 2,3,5-triiodobenzyl ether of poly (vinyl alcohol) prepared according to Example 1 dissolved at a concentration of 10% w / w in N- methylpyrrolidone (NMP).
[0046] Fig. 3b is a photograph showing the precipitation in water of 2,3,5-triiodobenzyl ether of poly (vinyl alcohol) prepared from PVA 13 kDa according to Example 1, dissolved at a concentration of 33 % w / w in NMP.
[0047] Fig. 4 is a photograph showing the precipitation in water of poly (vinyl alcohol) 4-iodobenzyl ether prepared from PVA 13kDa according to Example 2, dissolved at a concentration of 33% w / w in DMSO.
[0048] Fig. 5 represents a graph showing the change in viscosity [mPa.s] of two solutions containing an iodized benzyl ether PVA of the present invention prepared from PVA 13 kDa in relation to a change in concentration (% w / p) iodized PVA benzyl ether in solution.
[0049] Fig. 6 represents a graph illustrating the radiopacity of two injectable embolic compositions of the present invention, compared to the radiopacity of Onyx ™ 18 and Onyx ™ 34.
[0050] Fig. 7a is a photograph showing the embolization of an aneurysm model with an injectable embolizing composition of the present invention containing 33% w / w ether 2,3,5-triiodobenzyl ether dissolved in NMP .
[0051] Fig. 7b is a photograph showing the embolization of an aneurysm model with an injectable embolic composition of the present invention containing 33% w / w of poly (vinyl alcohol) 4-iodobenzyl ether dissolved in NMP.
[0052] Fig. 7c is a photograph showing the embolization of an aneurysm model with a commercial Onyx ™ 34 embolic composition.
[0053] Fig. 8 shows the 1k NMR spectrum of MTIB-PVA 47kDa of the present invention prepared according to Example 13.
[0054] Figs. 9a and 9b are photographic (Fig. 9a) and fluoroscopic x-ray images (Fig. 9b) of tampons obstructing the hydrogel model obtained from an injectable embolic formulation of the present invention in two concentrations of 30% and 35% w / p in PVA 47kDa 2,3,5-tri-iodobenzyl ether NMP (DS = 58%) as reported in Example 14, with saline flows from right to left.
[0055] Fig. 10 is a photograph showing a buffer obtained in the next injection in the hydrogel model of a mixture of 4-mono-iodobenzyl ether of PVA 61 kDa (DS = 67%) and 2,3,5 - tri ether - PVA 61kDa -iodobenzyl (DS% = 58) at 50: 50% by weight for a total concentration of 33% by weight in NMP as reported in Example 14, where saline flows from right to left.
[0056] Fig. 11a is a photograph showing an injectable viscous embolic formulation of the present invention containing 47kDa PVA 4-monoiodine benz ether (DS = 56%) at a concentration of 33% by weight in NMP loaded with iron nanoparticles superparamagnetic with a concentration of 20% m / V, as reported in Example 16.
[0057] Fig. 11b is a photograph showing a smooth semi-solid hyperthermic implant formed after the injection of the injectable viscous embolic formulation of the present invention shown in fig. 11a in hydrogel model, as reported in Example 16.
[0058] Fig. 12 represents a graph that illustrates the increase in temperature obtained with the hyperthermic implant shown in fig. 11b under exposure to an alternating magnetic field.
[0059] Fig. 13 represents a graph illustrating doxorubicin released from a radiopaque buffer (n = 3, error bars indicate standard error of the mean (SEM)) in saline medium, formed from a formulation injectable embolizer of the present invention as reported in Example 17.
[0060] Fig. 14 represents a catheter coated with a coating composition of the present invention as reported in Example 18.
[0061] Fig. 15 represents a graph illustrating the evolution of the absorbance of nanoparticles degradation products for 47kDa PVA 4-mono-iodobenzyl ether and 47kDa PVA 4-mono-iodobenzoate ether as reported in Example 20.1.
[0062] Fig. 16 represents a graph that illustrates the evolution of the absorbance of nanoparticles degradation products for the 2,3,5-PVA 13kDa ether 2,3,5-triiodiodenazole and PVA 2,3,5-methyl triiododenzoate 13 kDa as reported in Example 20.2. Detailed description of the present invention
[0063] It should be noted that in the present description and claims, the iodinated poly (vinyl alcohol) benzylether of the present invention will be designed as "iodine-benzylether-PVA of the present invention".
[0064] The iodine-benzylether-PVA of the present invention is a radiopaque iodinated poly (vinyl alcohol) benzyl ether, non-biodegradable, insoluble in water, consisting of a poly (vinyl alcohol) with iodinated benzyl groups covalently grafted comprising 1- 4 iodine atoms per benzyl group via ether bonds.
[0065] The Degree of Substitution (DS) of the iodo-benzylether-PVA of the present invention is not particularly limited.
However, in order to provide an appropriate radiopacity for the iodine-benzyl ether-PVA of the present invention, the degree of substitution (DS) is preferably at least 0.2.
[0067] In a preferred embodiment, the degree of substitution is at least 0.4, and more preferably at least 0.5.
[0068] The degree of substitution (DS) is defined as DS = x / (x + y) where x represents the number of repeating units grafted, ex + y represents the total number of repetition units (repeating units grafted and non-grafted repeat units), as calculated from the integration of the iodine-benzyl ether-PVA NMR lines of the present invention.
[0069] To clarify what is meant by grafted and non-grafted repeat units in the iodine-benzyl ether-PVA of the present invention, a grafted repeat unit can be represented by
where n represents the number of iodine atoms in a benzyl group, and an un grafted repeat unit can be represented by

[0070] The iodine content (% I) of the iodine-benzylether-PVA of the present invention is not particularly limited, but should preferably be at least 20% (w / w) to make it sufficiently radiopaque
[0071] In a preferred embodiment of the present invention, the iodine-benzylether -PVA has an iodine content of at least 40% (w / w).
[0072] The iodine-benzyl ether-PVA of the present invention can be either an iodine-benzyl ether-PVA in which all the grafted iodinated benzyl groups are identical, or it can be an iodine-benzyl ether-PVA, in which the grafted iodinated benzyl groups are two or more different iodinated benzyl groups having a different number of iodine atoms.
[0073] When the iodine-benzylether-PVA is grafted with identical iodinated benzyl groups, the iodine content (1%) of the iodine-benzylether-PVA of the present invention can be calculated from the degree of substitution (DS) as follows :
where M (iodine) represents the atomic mass of the iodine atom (ie, ~ 127), n represents the number of iodine atoms per benzyl group (ie, 1 to 4) M (non-grafted) represents the mass molar of a non-grafted repeat unit (ie, - 44) M (grafted) represents the molar mass of a grafted repeat unit (eg ~ 260 when the benzyl group has only one iodine as a substituent, ~ 386 when the benzyl group has only two iodine atoms as substituents, ~ 512, when benzyl group has only three iodine atoms as substituents, and ~ 638 when benzyl group has only four iodine atoms as substituents).
[0074] When the iodine-benzylether-PVA of the present invention is grafted with two or more different iodinated benzyl groups having a different number of iodine atoms, the iodine content (% I) of the iodine-benzylether-PVA of the present invention is the sum of the contributions of each type of graft from iodinated benzyl groups.
[0075] Therefore, the iodine content (% I) of an iodine-benzylether-PVA grafted with two or more different iodinated benzyl groups having a different number of iodine atoms can be calculated by determining the degree of substitution (DS) for each type of iodinated benzyl groups, then by calculating the iodine content (% I) based on said DS using the above formula for each type of iodinated benzyl groups, and finally adding the iodine content (% I) calculated for each type of iodinated benzyl groups.
[0076] For example, for an iodine-benzylether-PVA of the present invention having both mono-iodobenzyl groups and tri-iodobenzyl groups, the iodine content (% I) is the sum of% I for the mono-iodobenzyl groups ( n = 1) plus% I for the triiodiodobenzyl groups.
[0077] The iodine content can also be determined or confirmed by elementary analysis.
[0078] According to the present invention, iodinated benzyl groups grafted onto poly (vinyl alcohol) must comprise 1 - 4 iodine atoms per benzyl group.
[0079] It should be noted that in the present invention, the benzyl group may further comprise other substituents, such as amine, amide, ester and / or carbamyl groups in addition to the iodine atom (s), but in a particularly preferred embodiment of the present invention , the benzyl group comprises only one iodine atom (s) as the substituent (s).
[0080] In a preferred embodiment of the present invention in which all the grafted iodinated benzyl groups are identical, each benzyl group comprises only one iodine atom as the substituent, and more preferably an iodine atom at the C4-position of the benzyl group.
[0081] In another preferred embodiment of the present invention where all the grafted iodinated benzyl groups are identical, each benzyl group comprises only three iodine atoms as substituents, and more preferably three iodine atoms at the C-2, C-3 and C-5 of the benzyl group.
[0082] However, each benzyl group can comprise from 1 to 4 iodine atoms, in any positions on the benzyl group.
[0083] In a preferred embodiment, in which the grafted iodinated benzyl groups are different iodinated benzyl groups having a different number of iodine atoms, the iodine-benzyl ether-PVA of the present invention has grafted both iodinated benzyl groups comprising one atom of iodine at the C4 position and iodinated benzyl groups comprising three iodine atoms at the C-2, C-3 and C-5 positions.
However, the iodine-benzylether-PVA of the present invention may have grafted other types and combinations of iodinated benzyl groups on it, provided that iodinated benzyl groups comprise 1-4 iodine atoms per benzyl group.
[0085] The average molar mass (M) of iodo-benzylether-PVA of the present invention is not particularly limited, and has to be determined, depending on the chosen application.
[0086] The molar mass of the iodine-benzylether-PVA of the present invention can be easily controlled by proper selection of the molar mass (M) of the PVA of the starting polymer to be grafted in the process for the preparation of the iodine-benzylether-PVA of the present invention.
[0087] It should be noted that an iodine-benzylether-PVA with a very high molar mass would not be suitable for use as an embolizing agent in an embolization composition because it would lead to an embolization composition too viscous to be injected through a catheter, and an iodine-benzylether-PVA with a very low molar mass would be unsuitable for use as an embolizing agent in an embolizing liquid composition because iodine-benzylether-PVA does not precipitate as a cohesive mass forming a solid or semi-solid embolic implant.
[0088] In addition, it is notable that an iodine-benzylether-PVA with a high molar mass and therefore providing a high viscosity of the solution is not preferable when used as an embolizing agent in an embolizing composition because the embolizing composition must have a low concentration of embolizing agents in a high volume of solvent, which is not advantageous.
[0089] The average molar mass (M) of the iodine-benzylether-PVA of the present invention depends on the molar mass of the starting polymer PVA used to prepare the iodo-benzylether-PVA of the present invention and the degree of substitution of the iodine-benzylether- PVA of the present invention.
[0090] The iodine-benzylether-PVA of the present invention can be prepared by an etherification reaction of PVA with an iodinated benzyl derivative.
[0091] More particularly, the iodine-benzylether-PVA of the present invention can be prepared by a process comprising reacting a 0 - 100% hydrolyzed poly (vinyl alcohol) (starting PVA) with an iodinated benzyl derivative comprising 1 - 4 atoms of iodine by benzyl group in a polar aprotic solvent, in the presence of a base under anhydrous conditions.
[0092] Poly (vinyl alcohol) (PVA) is a polymeric chain made of carbon atoms with pendant hydroxyl groups, which may also contain some pendant acetyl groups.
[0093] In the process of the present invention, a 0% hydrolyzed poly (vinyl alcohol) means a PVA containing 0% hydroxyl pendant groups and 100% acetyl pendant groups in the polymer chain.
[0094] In the process of the present invention, a 100% hydrolyzed poly (vinyl alcohol) means a PVA containing only hydroxyl pendant groups.
[0095] It should be noted that during the graft reaction, pendant acetyl groups that may be present in the starting PVA are eliminated so that the iodine-benzylether-PVA of the present invention contains only pendent hydroxyl groups and pendant iodinated benzylether groups.
[0096] In a particularly preferred embodiment of the present invention, the process for preparing the iodine-benzylether-PVA of the present invention comprises the reaction of a 75-100% hydrolyzed poly (vinyl alcohol) as the starting PVA with the iodinated benzyl derivative .
[0097] The average molar mass (M) of the starting PVA used in the process of the present invention is not particularly limited, and has to be determined as a function of the average molar mass (M) expected for the end of the iodine-benzylether-PVA, depending on the chosen application.
[0098] However, carrying out the process of the present invention with a PVA with too high a molar mass or too low a molar mass would not lead to an iodine-benzylether-PVA suitable for use as an embolizing agent in an embolizing liquid composition.
[0099] Therefore, the average molar mass (M) of the starting PVA for the preparation of an iodine-benzylether-PVA for use as an embolizing agent in an embolizing liquid composition is preferably not less than 5,000 Daltons and is not greater than than 200,000 Daltons, more preferably in the range of 10,000 to 130,000 Daltons, and even more preferably in the range of 10,000 to 50,000 Daltons.
[00100] For example, commercial PVA that can be used as a starting PVA compound in the process of the present invention can be a pharmaceutical grade PVA obtained from Sigma-Aldrich® Co. with an average weight molar mass (Mw) of 13,000 - 23,000 Daltons and a degree of hydrolysis of 87 - 89%.
[00101] However, any commercial PVA having any degree of hydrolysis can be used to prepare the iodine-benzyl ether-PVA of the present invention according to the process of the present invention.
[00102] In the process of the present invention, the benzyl iodinated derivative is selected as a reagent to be grafted according to the iodine-benzyl ether-PVA to be obtained, and can be for example an iodinated benzyl chloride, an iodized benzyl bromide or an iodized benzyl mesylate.
[00103] In a preferred embodiment, an iodine-benzylether-PVA comprising an iodine atom at the C4 position of all benzyl groups can be prepared using - commercial 4-iodobenzyl bromide (for example obtained from Sigma-Aldrich ® Co.) as a derivative of iodinated benzyl.
[00104] In another preferred embodiment, an iodo-benzyl ether-PVA comprising three iodine atoms in the C-2, C-3 and C-5 positions on all benzyl groups can be prepared using 2,3,5-triiodobenzyl bromide as an iodinated benzyl derivative.
[00105] 2,3,5-triiodobenzyl derivatives can be easily prepared as reported in the experimental part in preparation examples 1-4.
[00106] In another embodiment of the present invention, an iodine-benzylether-PVA comprising both benzyl groups, including an iodine atom at the C4 position and benzyl groups including three iodine atoms at the C-2, C-3 and C- positions 5 can be prepared using a mixture of 4-iodobenzyl bromide and 2,3,5-triiodobenzyl bromide as the iodinated benzyl derivative.
[00107] However, an iodine-benzylether-PVA of the present invention having different benzyl groups grafted onto it can be prepared using any mixture of two or more different iodinated benzyl derivatives comprising 1 to 4 iodine atoms per benzyl group.
The iodinated benzyl derivatives which can be used in the process of the present invention are those commercially available or can be easily prepared by the person skilled in the art, for example from the corresponding iodinated benzoic acid or the corresponding iodinated benzyl alcohol according to conventional methods or according to methods based on those reported in the experimental part in preparation examples 1-4.
[00109] Examples of the polar aprotic solvent for use in the synthesis process of the present invention can include DMSO (dimethylsulfoxide), NMP (N-methylpyrrolidone) and THF (tetrahydrofuran).
[00110] Examples of the base for use in the process of the present invention can include NaOH, KOH and NaH.
[00111] In a preferred embodiment of the process of the present invention, the polar aprotic solvent is NMP and the base is NaOH.
[00112] Kinetic studies have shown that the degree of substitution (DS) is dependent on the time of the graft reaction and normally reaches a maximum value after approximately 1 / 2-15 hours so that the degree of substitution (DS) can be easily fixed by controlling the graft reaction time.
[00113] If necessary, the iodine-benzylether-PVA of the present invention obtained by this process can still be purified by conventional techniques, including but not limited to precipitation / solubilization / precipitation cycles to achieve the required degree of purity.
[00114] The iodine-benzylether-PVA of the present invention is useful as an embolizing agent in an injectable embolic composition.
[00115] The injectable embolizing composition of the present invention comprises the iodine-benzyl ether-PVA of the present invention and a water-miscible, biocompatible, solubilizing solvent of the iodine-benzyl ether-PVA of the present invention.
[00116] For the reason that the viscosity of a polymer solution is known to be very sensitive to the molar mass of the polymer, particularly in high concentration, it is important to properly select the molar mass of the iodine-benzylether-PVA contained in the embolizing composition a so that it is not too high or too low for this application.
[00117] For example, with regard to its molar mass, a preferable iodine-benzylether-PVA for use as an embolic agent in an embolizing composition can be obtained using, as the starting PVA, a PVA with a molar mass of hair less than 5,000 Daltons and not more than 200,000 Daltons, preferably in the range of 10,000 to 130,000 Daltons, and more preferably in the range of 10,000 to 50,000 Daltons.
[00118] The concentration of a polymer in solution also affects not only the viscosity of the polymer solution, but also the precipitation behavior of the polymer.
[00119] The concentration of the iodine-benzylether-PVA of the present invention in the embolizing composition is selected in the range of 5 - 65% w / w, of said selection being dependent on the specific viscosity of the embolizing composition, which in itself depends on the molar mass mean of the iodine-benzylether-PVA of the present invention used in the embolic composition.
[00120] According to the invention, said selection of the concentration of the iodo-benzylether-PVA of the present invention should lead to a composition that is embolizing that is injectable, ie that is not too viscous to be injected, and even more that is capable of forming a cohesive solid or semi-solid mass in contact with an aqueous medium, such as a body fluid by precipitation of the iodo-benzyl ether-PVA.
[00121] Preferably, the concentration of the iodo-benzylether-PVA of the present invention is selected to be as high as possible in order to provide an embolizing composition having a reduced amount of solvent.
[00122] In a particularly preferred embodiment of the present invention, the concentration of the iodo-benzylether-PVA of the present invention in the embolizing composition is selected in the range of 20 - 50% w / w.
[00123] Furthermore, it is preferable that the iodine-benzylether-PVA of the present invention used in the injectable embolizing composition of the present invention has an iodine content (% I) of at least 20% (w / w), and more preferably of at least at least 40% (w / w) in order to provide an improved radiopacity for the embolizing composition and also for the embolic mass formed by precipitation of the iodine-benzylether-PVA with the contact of the embolizing composition with a body fluid.
[00124] The biocompatible, water-miscible solvent used in the injectable embolic composition of the present invention is not particularly limited, as long as it solubilizes the iodine-benzylether-PVA to form a homogeneous solution.
[00125] In a preferred embodiment, the water-miscible, biocompatible solvent is selected from dimethyl sulfoxide, N-methylpyrrolidone, glycofurol, pyrrolidone, ethanol, propylene glycol, polyethylene glycol, solcetal ™, glycerol, tetrahydrofurfuryl alcohol, dimethyl isosorbide , ethyl lactate, hydroxyethylactamide and N, N-dimethylacetamide, and more preferably dimethylsulfoxide (DMSO), N-methylpyrrolidone (NMP) and glycofurol.
[00126] According to an embodiment of the present invention, the injectable embolic composition of the present invention comprises an iodo-benzylether-PVA of the present invention.
[00127] In a preferred embodiment, the iodine-benzylether-PVA of the present invention contained in the injectable embolizing composition of the present invention is an iodo-benzylether-PVA, wherein each benzyl group comprises an iodine atom at the C-4 position (called " 4 monoiodine-benzylether-PVA "or" MIB-PVA "mentioned below).
[00128] In another preferred embodiment, the iodine-benzyl ether-PVA of the present invention contained in the injectable embolizing composition of the present invention is an iodine-benzyl-ether-PVA where each benzyl group comprises 3 iodine atoms in positions C-2, C-3 and C -5 (called "2,3,5-triiodine-benzylether-PVA" or "TIB-PVA" below).
[00129] According to another embodiment of the present invention, the injectable composition of the present invention can comprise two or more different iodo-benzylether-PVA of the present invention having a different number or different position of iodine atoms, provided that the total concentration of the iodo-benzylether-PVA of the present invention contained in the injectable embolic composition is selected in the range of 5 - 65% w / w.
[00130] In a preferred embodiment the injectable embolic composition of the present invention contains 4-monoiodine-benzylether-PVA (MIB-PVA) and 2,3,5-triiodiodo-benzylether-PVA (TIB-PVA) in proportions variables.
[00131] The viscosity and mechanical properties of iodo-benzyl ether-PVA, based on, for example, 4-mono iodo-benzyl ether-PVA (MIB-PVA) or 2,3,5-tri iodo-benzyl ether-PVA (TIB -PVA) are quite different.
[00132] 4-Mono iodo-benzylether-PVA (MIB-PVA) is a softer material than 2,3,5-triiodine-benzylether-PVA (TIB-PVA), it is less fragile and brittle due to its low glass transition temperature (MIB-PVA Tg: 55 ° C, TIB-PVA: 111 ° C).
[00133] Furthermore, solutions of 2,3,5-triiodine-benzylether-PVA (TIB-PVA) in NMP tend to precipitate faster in aqueous environment than 4-mono iodo-benzylether-PVA (MIB-PVA ).
[00134] Thus, mixtures of MIB-PVA and TIB-PVA in varying proportions can be used to adjust the mechanical properties of the final precipitated implant.
[00135] For example, the equal proportions of MIB-PVA and TIB-PVA dissolved in NMP show a formulation viscosity, precipitation time and intermediate mechanical properties between those of MIB-PVA and TIB-PVA.
[00136] MIB-PVA mixtures: TIB-PVA can therefore generate a family of liquid embolising compositions, as illustrated in Example 14.
[00137] The adapted properties of implants can also be obtained using PVA polymers based on two or more types of iodized repeating units.
[00138] For example, as illustrated in Example 13, the PVA polymer grafted with MIB and TIB can be obtained by mixing in vials with equal molar amounts of mono-iodobenzyl derivative and tri-iodobenzyl derivative. The resulting MTIB-PVA copolymer shows a 50: 50 molar ratio of grafted groups 4-monoiodine-benzyl ether and 2,3,5-triiodi-benzylether, corresponding to a mass ratio of 38: 62 MIB: TIB.
[00139] As an MTIB-PVA copolymer has an intermediate glass transition temperature (Tg = 68 ° C) between that of MIB-PVA and TIB-PVA, and Example 15 shows that precipitation also results in intermediate properties between of MIB-PVA and TIB-PVA.
[00140] Likewise, based on copolymers, a whole family of formulations can be obtained, adapting embolic properties of liquids by adapting the molar mass of the copolymer, concentration and MIB / TIB ratio.
[00141] A person skilled in the art will be able to easily determine whether the composition containing the selected concentration of the iodine-benzylether-PVA of the present invention and the selected water-miscible, biocompatible solvent is suitable for use as an embolizing composition by performing a precipitation test of the composition in water.
[00142] The injectable embolizing composition of the present invention is particularly useful when used to form a cohesive solid or semi-solid mass in situ in a blood vessel or tumor for the treatment of humans or other mammalian individuals.
[00143] When the embolizing composition of the present invention is used for embolizing blood vessels, in particular for the treatment of injuries, such as aneurysms, arteriovenous malformations, arteriovenous fistula, and tumors, it is introduced into the blood vessel by means of a catheter. release under fluoroscopy so that after the precipitation of the iodine-benzylether-PVA, the blood vessel is embolized through the embolic mass formed by the precipitated iodine-benzylether-PVA.
[00144] When the embolizing composition of the present invention is used in the treatment of tumors by direct puncture, it is injected directly into the tumor tissue using a needle technology so that after the precipitation of the iodo-benzylether-PVA, the tumor is filled with the embolic mass formed by the precipitated iodo-benzylether-PVA.
[00145] The particular amount of the embolizing composition employed is dictated by the total volume of the vasculature or tissue to be embolized, the concentration of the iodine-benzylether-PVA, the precipitation rate of the iodine-benzylether-PVA, etc .; the determination of such factors lies well within the competence of an expert in the art.
[00146] In an embodiment of the present invention, the injectable embolic composition of the present invention comprises drugs or biopharmaceuticals.
[00147] The injectable embolic composition including drugs or biopharmaceuticals is particularly useful for the formation in situ of a cohesive solid or semi-solid mass loaded with said drugs or biopharmaceuticals and capable of subsequently releasing in-situ through the release of drugs or biopharmaceuticals .
[00148] Example 17 illustrates the release of an anti-cancer agent, doxorubicin hydrochloride, from the precipitated cohesive mass obtained when an injectable embolic composition of the present invention including the anticancer agent is used.
[00149] In another embodiment of the present invention, the injectable embolizing composition comprises superparamagnetic iron oxide nanoparticles (SPIONs).
[00150] The injectable embolizing composition including SPIONs is particularly useful for forming in situ a solid or semi-solid implant loaded with said SPIONs in a tumor for the treatment of the tumor by hyperthermia.
[00151] SPIONs that are used in the injectable embolic composition of the present invention can be suitably coated or encapsulated, or can be immobilized on silica beads.
[00152] SPIONs that can be included in the injectable embolization composition of the present invention can be commercially available SPIONs, for example SPIONs immobilized on silica beads such as MagSilica 50-85 (Evonik, Germany), or they can be for example SPIONS as described in W0-A-2006/125452 or by Matthieu Chastellain et al. "Superparamagnetic Silica-iron Oxide Nanocomposites for Application in Hyperthermia" in Advanced Engineering Materials, 6: 235-241, 2004.
[00153] Example 16 illustrates the in situ formation of a hyperthermic implant using the injectable embolizing composition of the present invention loaded with SPIONs immobilized on silica beads for controlled local hyperthermia.
[00154] Figure 12 represents a graph showing that when the hyperthermic implant obtained in Example 16 is exposed to an alternating magnetic field, the temperature increases, thus demonstrating that the injectable embolic composition of the present invention loaded with SPIONs is applicable for the treatment , for example, of a tumor, due to hyperthermia.
[00155] In another embodiment of the present invention, the injectable embolizing composition of the present invention can be used to form in situ a semi-solid implant for the treatment of urinary incontinence by augmenting local tissue.
[00156] For example, in the context of the treatment of urinary incontinence, a common condition among women, urethral injection is recognized as a standard treatment.
[00157] This consists of injecting, under the bladder mucosa, a biomaterial that creates a bulge in the tissue, thus increasing the closure of the urethra. Collagen is used today, but its effect only lasts a few months.
[00158] Consequently, there is a need for long fasting, non-degradable implants that should offer imaging capability for long-term monitoring.
[00159] Therefore, the injectable embolic composition of the present invention provides an effective alternative.
[00160] The present invention also relates to a coating composition to form a coating on a medical device comprising the iodine-benzyl ether-PVA of the present invention and a solubilizing solvent of iodine-benzyl ether-PVA, wherein the iodine concentration -benzylether-PVA in the composition is selected in the range of 5-65%, so that the composition is able to form a radiopaque coating after application to a medical device and evaporation of the solvent.
[00161] The coating composition of the present invention can be used to deposit a radiopaque coating on medical devices to make them visible on an x-ray image.
[00162] The fabrication of the coating can be achieved by depositing the coating composition of the present invention, followed by drying.
[00163] The thickness of the coating will depend on several factors, including the viscosity of the coating composition.
[00164] In the coating composition of the present invention, solvents that can be used to solubilize iodine-benzyl ether-PVA comprise tetrahydrofuran, dimethylformamide, dichloromethane, N-methylpyrrolidone, dimethylsulfoxide.
[00165] In the case of poorly biocompatible solvent such as dichloromethane, complete removal of the solvent must be obtained before use, which can be obtained by drying by organic solvents that have a low boiling point.
[00166] For example, said coating composition may be useful for coating the tip of a catheter, as reported in Example 17 and illustrated in Figure 14.
[00167] The present invention relates to new particles, such as nanoparticles and microparticles made from the iodine-benzylether-PVA of the present invention.
[00168] Nanoparticles or microparticles can be produced to help or improve the use of x-ray imaging techniques in the medical field.
[00169] For example, the radiopaque particles of the present invention can be used as a contrast agent to mark a specific tissue or follow, after injection, the flow of a physiological fluid.
[00170] In a preferred embodiment, the radiopaque particles of the present invention still contain drugs or pharmaceutical products.
[00171] Radiopaque particles loaded with drugs or biopharmaceuticals can be tracked in the body after its administration, for example, after intratumoral injection.
[00172] Radiopaque particles of the present invention can be produced from the iodine-benzylether-PVA of the present invention using any technique known to those skilled in the art of particle making.
[00173] For example, Example 19 provides means for the manufacture of nanoparticles of different sizes of MIB-PVA 47kDa (DS = 49%) and TIB-PVA 13kDa (DS = 53%) using the nanoprecipitation technique.
[00174] The following examples are intended to illustrate the present invention. However, they cannot be considered, in any case, to limit the scope of the present invention. Examples
[00175] The reactions can be monitored by thin layer chromatography (TLC) on silica with 1/3 mixture of ethyl acetate / hexane as a mobile phase and observation under UV, illumination at a wavelength of 254 nm.
[00176] The 1H and 13C NMR spectra were performed on a 300 MHz Brucker and 400 MHz Brucker spectrophotometer, respectively. Chemical shifts are given in ppm (reference δ = 7.27 (CDCI3), 2.50 (DMSO-d6) for 1H-NMR and δ = 77.1 (CDCb), 39.5 (DMSO-d6) for 13C -RMN).
[00177] The degrees of substitution (DS) were calculated from the integration of the NMR lines of the 1H-NMR spectra of benzyl iodine-ether-PVA.
[00178] Iodine levels were calculated based on the degree of substitution, as explained in the description and confirmed by elementary analysis.
[00179] Iodine-benzylether-PVA radiopacities were evaluated on X-ray visualization of sprayed samples and solutions.
[00180] The IR transmission spectra were recorded on an ESP Nicolet 460 spectrophotometer. The granules were prepared by pressing 1 mg of the compound and 100 mg of pulverized KBr.
[00181] The melting points were determined by differential scanning calorimetry (DSC) on a TA Q200 instrument.
[00182] PVA of 13 kDa is a poly (vinyl alcohol) that has an average molar mass (Mw) of 13000 to 23000 Daltons and a degree of hydrolysis of 87 to 89% and was purchased from Sigma-Aldrich® Co.
[00183] The 47 kDa PVA is Mowiol® 6 to 98, a poly (vinyl alcohol) that has a mean molar mass (Mw) of 47000 Daltons, a degree of hydrolysis from 98.0 to 98.8% and a viscosity 6 mPa.s in 4% water, 20 ° C and was purchased from Sigma-Aldrich® Co.
[00184] The 61 kDa PVA is Mowiol® 10 to 98, a poly (vinyl alcohol) that has an average molar mass (Mw) of 61000 Daltons, a degree of hydrolysis from 98.0 to 98.8% and a viscosity 10 mPa.s in 4% water, 20 ° C and was purchased by Sigma-Aldrich® Co.
[00185] The 125 kDa PVA is Mowiol® 20 to 98, a poly (vinyl alcohol) that has an average molar mass (Mw) of 12500 Daltons, a degree of hydrolysis from 98.0 to 98.8% and a viscosity 20 mPa.s in 4% water, 20 ° C and was purchased by Sigma-Aldrich® Co.
[00186] 2,3,5-triiodobenzoic acid was purchased from Changzhou Dahua Imp. And Exp. Corp. Ltd. (China).
[00187] 4-iodobenzyl bromide was purchased by Sigma-Aldrich® Co ..
[00188] The other reagents were purchased from commercial suppliers and used as received unless otherwise specified.
[00189] THF and CH2CI2 were dried by passing them over a basic activated alumina, AI2O3.
[00190] H2O means deionized water. Preparation of Example 1 - 2,3,5-Triiodobenzyl alcohol synthesis 1

[00191] A solution (1 M) of BHs-tetrahydrofuran (75 mL, 75 mmol) was added dropwise in a solution of 2,3,5-triiodobenzoic acid (5 g, 10 mmol) in dry tetrahydrofuran (10 mL ) maintaining the temperature inside the reactor below 2 ° C under a dry nitrogen gas flow. The reaction mixture was stirred for 1 h15 at 0 ° C, then 1 h at room temperature (18 ° C), and a white precipitate was obtained. Then a cold solution of tetrahydrofuran / H2O 13: 2 (26 mL) was added slowly to the crude mixture (temperature monitored when cooling the reactor) for excess borane hydrolysis and the crude mixture was neutralized by dilution in a chilled solution of NaHCOs ( -100ml). A white precipitate appeared after stirring for 1 h. The solid was recovered by filtration and washed with H2O and cooled absolute ethanol. To remove traces of ethanol after evaporation, the white solid was dissolved in CH2 Cl2 and then evaporated and dried in vacuo. Triiodobenzyl alcohol as a pure white solid was obtained in quantitative yield (4.8 g). PF: 156 to 159 ° C IV: 3186, 2904, 1524, 1400, 1368, 1235, 1144, 1047, 997, 859, 719, 675 CΠT1 1H-NMR (DMSO-d6): 8.16 (d, 1H, J = 2.0 Hz), 7.70 (d, 1H, J = 2.0 Hz), 5.69 (Is, 1H, OH), 4.34 (s, 2H, CH2) 13C-NMR (DMSO -Ó6): 69.83 (CH2), 95.77 (Cq), 109.84 (Cq), 112.99 (Cq), 134.56 (CH), 144.13 (Cq), 149.27 ( CH)
[00192] Preparation of Example 2 - Synthesis of 2,3,5-triiodobenzyl mesylate 2

[00193] Mesyl chloride (0.6 mL, 8 mmol) was added dropwise in a suspension of 2,3,5-triiodobenzyl alcohol 1 (1.94 g, 4 mmol) in dry dichloromethane (30 mL) containing diisopropylethylamine (1.4 mL, 8 mmol) at 0 ° C under a flow of dry nitrogen gas. The reaction mixture was stirred for 1h15 at 0 ° C, then cooled H2O (40 ml) was added. The resulting aqueous phase was extracted with dichloromethane (10 ml). The combined organic extracts were washed with H2O (8 ml) then dried (Na2SO4), filtered and concentrated. The pale yellow solid was also washed with cooled methanol (35 ml). 1.894 g of 2,3,5-triiodobenzyl mesylate as a pure white solid was obtained in 84% yield. PF: 130 - 133 ° C IV: 3026, 1525, 1342, 1330, 1176, 1168, 1008, 975, 862, 836 cm1 1H-NMR (CDCl3): 8.23 (d, 1H, J = 1.5 Hz ), 7.69 (d, 1H, J = 1.5 Hz), 5.23 (s, 2H, CH2), 3.11 (s, 3H, Me) 13C-NMR (CDCl3): 38.29 ( Me), 76.32 (CH2), 94.72 (Cq), 110.8 (Cq), 112.29 (Cq), 136.96 (CH), 140.69 (Cq), 147.48 (CH )
[00194] Preparation of Example 3 - Synthesis of 2,3,5-triiodobenzyl bromide 3

[00195] A solution of phosphorous tribromide (3.8 mL, 40 mmol) was added dropwise in a solution of 2,3,5-triiodobenzyl alcohol 1 (9.72 g, 20 mmol) in dry tetrahydrofuran (50 mL) at 0 ° C under a dry nitrogen gas flow. The reaction mixture was stirred 5 minutes at 0 ° C, then 20 minutes at room temperature (18 ° C), then cooled H2O / DCM (60/60 ml) was added. The resulting aqueous phase was extracted with dichloromethane (2x10 ml). The combined organic extracts were washed with NaHCOsaq (20 ml) and H2O (20 ml) then dried (Na2SO4), filtered and concentrated. The white solid was also washed with cooled methanol (45 ml). 9.35 g of 2,3,5-triiodobenzyl bromide as a pure white solid were obtained in an 85% yield. TF: 120-121 ° C IV_: 710, 866, 980, 1157, 1212, 1398, 1515, 3026 cm -1 NMR (DMSO-d6): 4.81 (s, 2H, CH2), 7.95 (d, 1H, J = 2.1 Hz), 8.18 (d, 1H, J = 2.1 Hz) 13C-NMR (DMSO-d6): 42.33 (CH2), 95.77 (Cq) , 113.95 (Cq), 114.97 (Cq), 137.69 (CH), 144.87 (Cq), 145.92 (CH) Preparation of Example 4 - 2,3,5- Chloride Synthesis triiodobenzyl 4

[00196] Mesyl chloride (4.24 mL, 56 mmol) was added dropwise in a suspension of 2,3,5-triiodobenzyl alcohol 1 (9.72 g, 20 mmol) in dry dichloromethane (140 mL) containing diisopropylethylamine (11 mL, 64 mmol) and lithium chloride (4.24 g, 100 mmol) at 0 ° C under a flow of dry nitrogen gas. The reaction mixture was stirred for 5 h at room temperature, then cooled H2O (100 ml) was added. The resulting aqueous phase was extracted with dichloromethane (2x10 ml). The combined organic extracts were washed with NaHCOsaq (20 ml) and H2O (20 ml) then dried (Na2SO4), filtered and concentrated. The pale yellow solid was also washed with cooled absolute ethanol (25 ml). 9.05 g of 2,3,5-triiodobenzyl chloride as a pure white solid were obtained in a 90% yield. TF: 97 - 98 ° C IV_: 680, 731, 859, 867, 1007, 1133, 1267, 1371, 1439, 1520 cm -1 H-NMR (DMSO-d6): 4.87 (s, 2H, CH2) , 7.92 (d, 1H, J = 1.9 Hz), 8.21 (d, 1H, J = 1.9 Hz) 13C-NMR (DMSO-d6): 53.58 (CH2), 95, 78 (Cq), 113.89 (Cq), 114.65 (Cq), 137.74 (CH), 144.48 (Cq), 146.08 (CH) Preparation of example 5 - Synthesis of 2.3, 5-triiodobenzoate-PVA 13 kDa (TIB / Ester-PVA 13 kDa)

[00197] The graft reaction was adapted from the work reported in "Elaboration of radiopaque iodinated nanoparticles for in situ control of local drug delivery" D. Mawad, H. ouaziz, A. Penciu, H. Mehier, B. Fenet, H. Fessi, Y. Chevalier; Biomaterials 2009, 30, 5667-5674.
[00198] The 13 kDa PVA was dissolved in dry NMP under nitrogen gas flow and a solution of triiodobenzoyl chloride in NMP was added. Then dry pyridine and DMAP were added. After 12 hours, cooled water was added, a slurry material precipitated, filtered and washed with methanol. For the purification step, the raw paste material was dissolved in NMP (concentration: 22% by weight) and cooled ethanol was added. The paste-like material was precipitated, filtered and analyzed by NMR spectrum. The 1H NMR spectrum showed the PVA grafted free of residual reagent, and traces of solvents. In order to eliminate traces of solvents, the grafted PVA was dissolved in THF (concentration: 30% by weight) and chilled water was added. The paste-like material precipitated, was filtered, washed with methanol and dried in vacuo. The grafted PVA was obtained as a brown solid. 1H-NMR ÇDMSO-d6): 1.35 - 1.95 ppm (m, 5.81 au, CH2 PVA chain, 2 (x + y)), 3.81 ppm (s, 2.09 au, CHb chain PVA, y), 4.21 - 4.67 ppm (m, 2.69 au, OH), 5.37 (s, 0.78 au, CHa PVA chain, x), 7.71 ppm (s, 1.0 au, aromatic H, x), 8.34 ppm (s, 1.0 au, aromatic H, x)
[00199] Based on the NMR spectrum, the 13 kDa TIB / Ester-PVA was obtained with a 34% DS. Preparation of Example 6 - Synthesis of 47 kDa 4-mono-iodobenzoate-PVA (47 kDa MIB / ESTER-PVA)

[00200] The reaction conditions were the same as those used for 2,3,5-triiodiodobenzoate-PVA 13 kDa in the Preparation of Example 5. PVA was dissolved in NMP and a solution of 4-mono-iodobenzoyl chloride was added. Then pyridine and DMAP were added. After 6 hours, chilled water was added and a paste material was precipitated, filtered and washed with methanol. For the purification step, the raw paste material was dissolved in NMP (concentration: 14% by weight) (the mixture is yellow, but opaque and all particles are dissolved) and 100 ml of a solution of NaHCCh was added . A solid precipitated, was filtered and washed with methanol. This step was repeated until the monoiodobenzoyl chloride was eliminated. Then the solid was dissolved in NMP (concentration: 19% by weight) and chilled water was added. A solid was precipitated, filtered and washed with methanol. The solid was analyzed by 1H-NMR. 1H NMR (DMSO-d6): 1.05 - 2.4 ppm (m, 5.49 au, PVA CH2 chain, 2 (x + y)), 3.81 ppm (s, 1.28 au, PVA chain CHb, y), 4.21 - 4.67 ppm (m, 0.77 au, OH), 5.37 ppm (s, 1.0 20 au, PVA CHa chain, x), 7.10 - 7, 90 ppm (m, 4.35 au, aromatic H, 4x)
[00201] Based on the NMR spectrum, 47 kDa MIB / Ester-PVA was obtained with a 40% DS.
[00202] Example 1 The 2,3,5-triiodobenzyl bromide graft for PVA to prepare 2,3,4-triiodobenzyl polyvinyl alcohol ether of the present invention (TIB-PVA 13 kDa)

[00203] 294 g of 13 kDa PVA (6 mmol) was dissolved in 20 mL of dry NMP (PVA concentration: 0.3 M) under nitrogen gas flow. The reaction mixture was stirred for 5 minutes at 130 ° C; then the temperature was lowered to 50 ° C. 4.94 g of 2,3,5-triiodobenzylbromide 3 (9 mmol) was added and the reaction mixture was stirred for 10 minutes. Then, 480 mg of dried and crushed NaOH (12 mmol) were added in 10 minutes. After 5 hours, the mixture was cooled to room temperature and 20 ml of cooled water was added with stirring. A solid precipitate appeared and was filtered, washed with methanol and dichloromethane. 3.15 g of crude solid was obtained and analyzed by 1H-NMR to determine that the crude product contained 56% non-grafted triiodobenzylbromide and 30% grafted PVA. To isolate the grafted PVA, the crude solid was dissolved in NMP (concentration: 7% by weight) and the same volume of cooled methanol was added. A paste material precipitated and was filtered, washed with methanol and analyzed by 1 H NMR. The purity of the grafted PVA was 86%. This paste material was dissolved in NMP (concentration: 17% by weight) and the same volume of cooled methanol was added. A paste material precipitated and was filtered, washed with methanol and analyzed by 1 H NMR. The purity of grafted PVA was 97%. To obtain 100% purity, the paste material was dissolved in NMP (concentration: 17% by weight) and the same volume of chilled water was added. The solid precipitate was filtered, washed with methanol to obtain the grafted PVA as a beige solid with 100% purity, as analyzed by NMR in a total yield of 19%.
[00204] To eliminate residual traces of NMP contained in the grafted PVA, the grafted PVA was dissolved in THF (concentration: 13% by weight) and chilled water was added. The grafted PVA (13 kDa TIB-PVA) was precipitated and analyzed by 1H-NMR.
[00205] The 1H-NMR spectrum is represented in Fig. 1 and shows traces of THF in the grafted PVA. 1H-NMR (DMSO-d6): 1.51 - 1.85 (m, 3.8 au, PVA CH2 chain (2 (x + y)), 3.4 -4.05 (m, 1.5 au , PVA CH chain (x + y)), 4.16 - 4.52 (m, 2.4 au, benzyl CH2 and residual OH (2x + y)), 7.60 (s, 1.0 au, H aromatic (x)), 8.04 (s, 1.0 au, aromatic H (x))
[00206] The degree of substitution (DS) was measured from the areas over the peaks of the NMR spectrum calculated from the integration of the NMR lines. The ratio of the area of the aromatic lines to the CH2 area of the PVA chain is x / 2 (x + y) = DS / 2. Consequently, the DS was 0.54 (i.e. DS = 54%).
[00207] The iodine content as calculated from the DS was 69%, and the iodine content as confirmed by the elementary analysis was 64%.
[00208] Example 2 The 4-monoiodobenzyl bromide graft for PVA to prepare 4-monoiodobenzyl poly (vinyl alcohol) ether of the present invention (MIB-PVA 13 kDa)

[00209] 589 mg of PVA of 13 k Da (12 mmol) was dissolved in 40 mL of dry NMP under nitrogen gas flow. The reaction mixture was stirred for 5 minutes at 130 ° C; Then the temperature was lowered to 50 ° C. 5.3 g of 4-iodobenzyl bromide (18 mmol) was added and the reaction mixture was stirred for 10 minutes. After that, 960 mg of dried and crushed NaOH (24 mmol) were added in 10 minutes. After 4 hours, the mixture was cooled to room temperature and 40 ml of cooled water was added with stirring. A paste-like material appeared and was filtered, washed with methanol and dichloromethane. 3.9 g of raw paste material was obtained and analyzed by 1 H NMR to determine that the paste material contained 44% non-grafted 4-iodobenzyl bromide and 56% grafted PVA. To isolate the grafted PVA, the paste material was dissolved in DMF (concentration: 50% by weight) and two volumes of cooled methanol were added. A paste material precipitated and was filtered, washed with methanol and analyzed by 1H-NMR. The purity of the grafted PVA was 80%. This paste material was dissolved in THF (concentration: 50% by weight) and three volumes of cooled methanol were added. A paste material precipitated, was filtered, washed with methanol and analyzed by 1 H NMR. The purity of the grafted PVA was 95%. The paste material was dissolved in THF (concentration: 28% by weight) and two volumes of cooled methanol were added. A paste material appeared, was filtered, and washed with methanol. The purity was 98%. To obtain 100% purity, the grafted PVA was dissolved in THF (concentration: 29% by weight) and three volumes of chilled water were added. A paste material appeared, was filtered, and washed with methanol. After drying, the grafted PVA (13 kDa MIB-PVA) was obtained as an orange solid with a total yield of 24%. The 1 H NMR spectrum of the 13 kDa MIB-PVA is represented in Fig. 2. 1H-NMR (DMSQ-d6): 1.34 - 1.90 (m, 3.8 au, CH2 PVA chain (2 (x + y)), 3.58 - 3.78 (m, 1.5 au , CH PVA chain (x + y)), 4.23 - 4.48 (m, 2.4 au, benzyl CH2 and residual OH (2x + y)), 7.00 (s, 2.0 au, H aromatic (2x)), 7.54 (s, 2.0, aromatic H (2x))
[00210] The degree of substitution (DS) was measured from the areas over the peaks of the NMR spectrum calculated from the integration of the NMR lines. The ratio of the area of the aromatic lines to the area of the CH2 of the PVA chain is 2x / 2 (x + y) = DS. Consequently, the DS was 0.56 (i.e. DS = 56%).
[00211] The expected iodine content as calculated from the DS was 43%, and the iodine content confirmed by the elementary analysis was 43%.
[00212] Example 3 - Precipitation tests
[00213] The 13 kDa TIB-PVA obtained in Example 1 was dissolved in NMP in concentrations of 10% w / w and 33% w / w, and these two compositions were precipitated in water using a syringe with a 0.8 needle mm in diameter. The results obtained are shown in Fig. 3a and Fig. 3b. As shown in Fig. 3a, the injectable composition containing 10% w / w of 13 kDa TIB-PVA dissolved in NMP does not precipitate as a cohesive mass, and therefore is not suitable as an injectable embolic composition of the present invention.
[00214] However, as shown in Fig. 3b, the injectable composition containing 33% of 13 kDa TIB-PVA dissolved in NMP precipitates as a cohesive mass and is therefore suitable as an injectable embolic composition of the present invention.
[00215] Additionally, the 13 kDa MIB-PVA obtained in Example 2 was dissolved in DMSO at a concentration of 33% w / o and this injectable composition was precipitated in water using a 1 ml syringe with a 0.9 mm needle .
[00216] As shown in Fig. 4, the injectable composition containing 33% w / wp / w of MIB-PVA dissolved in DMSO precipitates as a cohesive mass and is therefore suitable as the injectable embolic composition of the present invention.
[00217] Additional experiments show that all compositions containing 13 kDa TIB-PVA dissolved in NMP or 13 kDa MIB-PVA dissolved in DMSO precipitate as a cohesive mass for concentrations above 20% (P / P) -
[00218] Example 4 Embolizing compositions and viscosities
[00219] As viscosity is an important parameter for choosing the concentration of iodine-benzylether-PVA in injectable compositions for embolization, the following experiments were performed.
The 13 kDa MIB-PVA obtained in Example 2 was dissolved in DMSO in concentrations ranging from 20 to 50% w / w, and the viscosities of the solutions were measured.
[00221] The 13 kDa TIB-PVA obtained in Example 1 was dissolved in NMP in concentrations ranging from 20 to 50% w / w, and the viscosities of the solutions were measured.
[00222] Viscosities were measured at a temperature of 25 ° C using a cone-plate rheometer (Bohlin CV0120 from Malvern Instruments).
[00223] Fig. 5 shows the increase in viscosity when the concentration of iodine-benzyl ether-PVA obtained from 13 kDa PVA in the specified solvent increases.
[00224] Therefore, Fig 5 shows that the viscosity of the compositions can be adapted by the concentration of iodo-benzyl ether-PVA, the type of iodo-benzyl ether-PVA, and the nature of the solvent to obtain the high viscosity (ca 500 mPa. s) required for aneurysm embolization as well as lower viscosity (ca 50 mPa.s) suitable for embolization of small capillaries.
[00225] By comparison, the commercial embolising composition Onyx ™ 34 has a viscosity of 55 mPa.s.
[00226] Example 5 Radiopacity of embolic compositions
[00227] The 13 kDa MIB-PVA solutions obtained in Example 2 and 13 kDa TIB-PVA solutions obtained in Example 1 at a 33% w / w concentration in NMP were poured into radiolucent 1 ml Eppendorfs. X-ray absorption was measured on a CT scanner (CT-scan, Skyscan 1076, Skyscan, Belgium) using a 0.5 mm aluminum window, under 50 kV and 200 pA. 180 degrees of tomograms were acquired and reconstructed (Nrecon 1.5.1.4, Skyscan, Belgium), and the pixel gray level was calculated over the entire embolic image (Imaged program, NIH). For calibration in Hounsfied units (HU), water (HU = 0) and air (HU = -1000) were used.
[00228] As shown in Fig. 6, the radiopacity of the composition containing 33% w / w of TIB-PVA 13kDa of Example 1 in NMP is comparable to that of liquid commercial embolic compositions (Onyx ™ 34 and Onyx ™ 18) containing 20% of radiopaque tantalum.
However, the embolizing composition containing 33% w / w MIB-PVA 13kDa from Example 2 in NMP shows lower radiopacity, as expected from its lower iodine content.
[00230] It should be noted that, if left to rest for more than a few minutes, tantalum in Onyx ™ settles, leading to a highly heterogeneous radiopacity.
[00231] From these data, it is expected that a composition containing 55% w / w of 4-monoiodobenzyl ether of poly (vinyl alcohol) in NMP would have a radiopacity comparable to that of ONYX ™ compositions.
[00232] Example 6 Embolization of an aneurysm model
[00233] Two injectable embolic compositions of the present invention and the commercial composition Onyx 34 ™ were tested for their ability to fill an aneurysm model. We used as a model a sphere 10 mm in diameter, placed on a glass tube. The model was washed with saline using a rotary pump at a flow rate of 30 cm / s imitating blood flow. The injectable embolizing composition was injected into the aneurysm model with a 22G needle.
[00234] Fig. 7a shows the embolization of an aneurysm model with an injectable embolizing composition (A) of the present invention containing 33% w / w of TIB-PVA 13kDa obtained in Example 1 in NMP.
[00235] Fig. 7b shows the embolization of an aneurysm model with an injectable embolizing composition (B) of the present invention containing 33% w / w MIB-PVA 13kDa obtained in Example 2 in NMP.
[00236] Fig. 7c shows the embolization of an aneurysm model with a commercial Onyx ™ 34 embolizing composition.
[00237] These Figs. 7a, 7b and 7c clearly illustrate the ability of intrinsically injectable radiopaque injectable compositions (A, B) to completely fill the sphere with a compact mass, in a manner comparable to the commercially available Inyx ™ 34 injectable embolizer composition. (C).
[00238] For all injectable embolic compositions A, B and C, a cohesive mass was formed on the flow within 3 minutes.
[00239] Example 7 Synthesis of 2.3.5-tri-iodobenzylether-PVA from PVA 13kDa (TIB-PVA 13kDa)
[00240] 447mg of PVA 13kPa (9mmol, 1 eq) was dissolved in 30ml of dry NMP (concentration of PVA: 0.3M) under nitrogen gas flow. The reaction mixture was stirred for 5 minutes at 130 ° C, then the temperature was lowered to 50 ° C. 727mg of dry NaOH base (18mmol, 2eq) was added and the mixture was stirred for 10 minutes. Then, 5g of 2,3,5-triiodobenzyl bromide (9mmol, 1 eq) was added. After 30 minutes, the mixture was cooled to room temperature and 30 ml of cold water was added with stirring. A solid precipitate appeared, was filtered and washed with methanol. After the conventional purification steps, 800 mg of TIB-PVA 13kPa including 26% residual NMP was obtained (representing 208 mg of NMP and 592 mg of TIB-PVA 13kPa). 1H-NMR (PMSO-d6): 1.35-1.76 ppm (m, 3.74 water, PVA chain CH2 (2 {x + y)), 1.9 ppm (q, 4.65 water) , CH2) *, 2.1 ppm (t, 3.82 water, CH2) *, 2.6 ppm (s, 5.63 water, CH3) * 3.6-4.0 ppm (m, 1.79 water, CH PVA chain (x + y)), 4.1-4.6 ppm (m, 2.71 water, benzyl CH2 and residual OH (2x + y)), 7.6 ppm (s, 1.04 water , Aromatic H (x)), 8.06 ppm (s, 1.0 water, aromatic H (x))
[00241] Residual NMP The DS calculated from the NMR lines according to the method of Example 1 was 53%.
[00242] Example 8 Synthesis of PVA 47 kDa 2.3.5-tri-iodobenzylether-PVA (TIB-PVA 47kDa)
[00243] The synthesis method identical to that described in Example 7 was used in order to graft 2,3,5 - triiodobenzyl bromide with PVA 47kDa. After the conventional purification steps, TIB-PVA 47kDa including residual NMP was obtained. 1H NMR (DMSO-d6): 1.35-1.76 ppm (m, 3.42 water, PVA chain CH2 (2 (x + y)), 2.1 ppm (t, 3.07 water, CH2) *, 3.6-4.0 ppm (m, 1.81 water, CH of the PVA chain (x + y)), 4.1-4.6 ppm (m, 2.72 water, CH2 of benzyl and residual OH (2x + y)), 7.59 ppm (s, 1.0 water, aromatic H (x)), 8.4 ppm (s, 1.0 water, aromatic H (x))
[00244] Residual NMP The DS calculated from the NMR lines according to the method of Example 1 was 58%.
[00245] Example 9 Synthesis of 2.3.5-tri-iodobenzylether-PVA from PVA 61kDa (TIB-PVA 61 kDa)
[00246] The synthesis method identical to that described in Example 7 was used in order to engraft the 2,3,5 - triiodobenzyl bromide with PVA 61 kDa. After conventional purification steps, TIB-PVA 61 kDa including residual NMP was obtained. 1H NMR (DMSO-c / 6): 1.35-1.76 ppm (m, 4.33 water, PVA chain CH2 (2 (x + y)), 2.1 ppm (t, 6.36 water, CH2) *, 3.6-4.0 ppm (m, 2.23 water, PVA chain CH (x + y)), 4.1-4.6 ppm (m, 2.97 water, Benzyl CH2 and residual OH (2x + y)), 7.59 ppm (s, 1.0 water, aromatic H (x)), 8.5 ppm (s, 1.0 water, aromatic H (x))
[00247] Residual NMP The DS calculated from the NMR lines according to the method of Example 1 was 46%.
[00248] Example 10 Synthesis of 4-mono-iodobenzylether-PVA from PVA 13kDa (MIB-PVA 13kDa)
[00249] 825mg of PVA 13kPa was dissolved in 55ml of dry NMP under a flow of nitrogen at 130 ° C. Then, the temperature was lowered to 50 ° C and 5g of 4-monoiodobenzyl bromide was added. After 10 minutes, 1.35 g of dry sodium hydroxide was added. After 5 hours of reaction time, cold water was added and a paste material appeared. The sticky paste could not be filtered. The water was easily removed, because the material was hit by the walls of the balloon. After the water was poured out, the pasty residue was washed with methanol and dried. After the conventional purification steps, MIB-PVA 13kPa including residual NMP was obtained. 1H-NMR (PMSO-d6): 1.35-1.76 ppm (m, 2.9 water, PVA chain CH2 (2 (x + y)), 1.9 ppm (q, 1.02 water) , CH2) *, 2.1 ppm (t, 1 water, CH2) *, 2.7 ppm (s, 1.5 water, CH3) *, 3.6-3.79 ppm 20 (m, 1.6 water, CH of the PVA chain (x + y)), 4.38-4.48 ppm (m, 2.6 water, benzyl CH2 and residual OH (2x + y)), 7.03 ppm (s, 2.0 water, aromatic H (2x), 7.55 ppm (s, 2.0 water, aromatic H (2x))
[00250] Residual NMP The DS calculated from the NMR lines according to the method of Example 2 was 69%.
[00251] Example 11 Synthesis of 4-mono-iodobenzylether-PVA from PVA 47kDa (MIB-PVA 47kDa)
[00252] The synthesis method identical to that described in Example 10 was used in order to graft 4-monoiodobenzyl bromide with PVA47kDa. After conventional purification steps, 47kDa MIB-PVA including residual NMP was obtained. 1H NMR (DMSO-c / 6): 1.35-1.76 ppm (m, 4.1 water, PVA chain CH2 (2 (x + y)), 1.9 ppm (q, 0.9 water, CH2) *, 2.1 ppm (t, 0.9 water, CH2) *, 2.7 ppm (s, 1.3 water, CH3) *, 3.3 ppm (t, 0.98 water, CH2) *, 3.6-3.79 ppm (m, 1.9 water, CH of the PVA chain (x + y)), 4.38-4.48 ppm (m, 35 2.9 water, CH2 benzyl and residual OH (2x + y)), 7.03 ppm (s, 2.0 water, aromatic H (2x)), 7.55 ppm (s, 2.0 water, aromatic H (2x))
[00253] Residual NMP The DS calculated from the NMR lines according to the method of Example 2 was 49%.
[00254] Example 12 Synthesis of 4-mono-iodobenzylether-PVA from PVA 61 kDa (MIB-PVA 61 kPa)
[00255] The synthesis method identical to that described in Example 10 was used in order to engraft 4 - monoiodobenzyl bromide with PVA 61 kDa. After conventional purification steps, 61 kDa MIB-PVA including residual NMP was obtained. 1H-NMR (DMSO-d6); 1.35-1.76 ppm (m, 3.9 water, PVA chain CH2 (2 (x + y)), 1.9 ppm (q, 2.4 water, CH2) *, 2.1 ppm (t, 2.2 water, CH2) *, 2.7 ppm (s, 3.3 water, CH3) *, 3.6-3.79 ppm (m, 1.4 water, PVA chain CH ( x + y)), 4.38-4.48 ppm (m, 2.7 water, benzyl CH2 and residual OH (2x + y)), 7.00 ppm (s, 1.9 water, aromatic H ( 2x)), 7.54 ppm (s, 2.0 water, aromatic H (2x))
[00256] Residual NMP The DS calculated from the NMR lines according to the method of Example 2 was 51%.
[00257] Example 13 Graft of 4-monoiodobenzyl bromide and 2.3.5-triiodobenzyl bromide of PVA 47kDa to prepare the polymer with grafted mixed units (4-monoiodobenzyl ether) (2.3,5-triiodobenzyl ether) PVA47kDa (MTIB-PVA 47kDa)
[00258] The synthesis was carried out with a 3-burner flask dried under flame and under an atmosphere of N2. Poly (vinyl alcohol) (MW = 47,000, 80 mmol of monomer units, 3.52 g) was placed in the reaction flask which was then purged twice with an N2 vacuum.
[00259] Anhydrous NMP (280 ml_) was transferred from a sealed bottle to the reaction flask, using a cannula. The mixture was stirred for 30 minutes at 130 ° C in order to dissolve the entire polymer. The mixture was subsequently cooled and stirred to 50 ° C. NaOH (2 eq., 160 mmol, 6.4 g), which was ground from sediment into a fine powder, was added in one go. The mixture was stirred at 50 ° C for 30 minutes, resulting in a color change of the solution from yellow to brown. A mixture of 4 - iodobenzyl bromide (0.5 eq, 40 mmol, 11.9 g.) And 2,3,5-triiodobenzyl bromide (0.5 eq, 40 mmol, 22.0 g.), Obtained by mixing the two solids in a beaker with a spatula, where they were added as a powder in one go.
[00260] This resulted in a quick color change from brown to yellow. The mixture was stirred for 1 hour. After cooling to room temperature, the polymer was precipitated by adding the solution dropwise to a volume of well stirred demineralized water (2.8 L), which resulted in the dissolution of solid white flakes. The mixture was then filtered over a P1 glass filter, the white crude material was washed with an additional 500 ml of demineralized water and subsequently twice with 500 ml of acetone. The crude product was dried overnight under vacuum, and redissolved in THF (200 ml). The polymer was then purified by precipitation using toluene as a non-solvent.
[00261] The THF solution was transferred dropwise to a well stirred volume of toluene (2 L) producing a milky white mixture, which was filtered through a P4 glass filter. The white solid material was then washed with 500 ml of acetone and dried overnight under vacuum (~ 10'2 mbar) at 100 ° C, providing 11.5 g of the product as a light brown solid material.
[00262] The DS is calculated from the 1H-NMR spectrum performed on DMSO-d6 containing a small amount of water represented in Figure 8. The following general signs with chemical shifts of the maximum values of the signals are identified: 1. Si δ 8.0 - 8.1 ppm CH (TIB-Phenyl, para position) 2. S2 δ 7.5 - 7.6 ppm CH (TIB-Phenyl, ortho position) 3. S2 δ 7.5 - 7.6 ppm 2 x CH (MIB-Phenyl, meta position) 4 S3 δ 6.9 -7.0 ppm 2 x CH (MIB-Phenyl, ortho position) 5. S4 δ 4.3 - 4.4 ppm CH2 (TIB-Benzyl) 6. S4 δ 4.3 -4.4 ppm CH2 (MIB-Benzyl) 7. S4 δ 4.3 - 4.4 ppm OH (PVA main chain) 8. Sδ δ 3.7 - 3.8 ppm CH (PVA main chain) 9. SΘ δ 3.3 - 3.4 ppm H2O (Water trace) 10. S7 δ 2.4 -2.5 ppm CHD2 (DMSO- d6) 11. If δ 1.4 - 2.6 ppm CH2 (PVA main chain)
[00263] The degrees of substitution (DS) for MIB and TIB separately (DSMIB and DSTIB, respectively) are calculated as: DSMIB = Sa / Sδ DSTIB = 2Si / Sδ
[00264] The general degree of substitution is DS = DSMIB + DSTIB
[00265] The calculated DS of the NMR data are DSMIB = 0.3 (30%) and DSTIB = 0.3 (30%).
[00266]% I is given by
where n1: number of iodine atoms in the aromatic ring of the iodobenzyl unit # 1 n2: number of iodine atoms in the aromatic ring of the iodobenzyl unit # 2 Menxerted-1: molar mass of the iodobenzyl unit # 1 Menxerted-2: mass molar of iodobenzyl unit # 2 p: molar fraction of iodobenzyl unit # 1; p = DSi / (DSi + DS2)
[00267] DS calculated from the MTIB-47kDa PVA NMR lines was 60%.
[00268] The calculated% I of the MTIB-47kDa PVA DS was 62%.
[00269] Example 14 Embolization capacity of various radiopaque polymers or mixture of polymer formulations according to the present invention using a hydro model
[00270] Embolization formulations of the present invention based on the solution of 4-mono-iodobenzyl-PVA (MIB) and 2,3,5-tri-iodobenzyl-PVA (TIB) were synthesized from PVA of various molar masses ( 13,000-23,000, 47,000, 61,000 and 125,000 g / mol abbreviated 13kDa PVA, 47kDa PVA, 61kDa PVA and 125kDa PVA).
[00271] The solutions were prepared by dissolving each of the polymers in NMP at 33% w / w of final concentration (mentioned otherwise).
[00272] In addition, mixtures of MIB-PVA 47kDa and 47kDa TIB-PVA in various ratios (MIB-PVA TIB-PVA 25:75, 40:60, 50:50, 60:40, 75:25 by weight% ) were also assessed.
[00273] Degrees of substitution (DS) of the iodine-benzylether-PVA of the present invention used in this Example were 53% for MIB-PVA 47kDa, 58% for TIB-PVA 47kDa, 67% for 61 kDa MIB-PVA, 58% for TIB-PVA 61 kDa and 61% for 125kDa TIB-PVA.
[00274] Heating to 90 ° C was used to accelerate the dissolution. The liquid embolizing formulations were tested on a hydrogel model made of poly (vinyl alcohol (see Figures 9A and 9B). A 3 mm diameter hole in the hydrogel was fed with the flow of saline solution (10mL / min) using a pump for mimic capillary blood flow. A catheter was inserted and a limited pressure flow deviation formed over the embolization.
[00275] After injecting about 0.1 ml of each embolic, cylindrical polymer plugs can be formed, resulting in capillary obstruction.
[00276] Figures 9a and 9b show the typical buffers obtained with the formulation of the present invention containing TIB-PVA 47kDa, in concentrations of 30% and 35% in NMP.
[00277] The higher polymer concentration showed slightly better embolization capacity in this specific configuration, as well as increased radiopacity.
[00278] In the case of reverse reflux, stopping the injection for 1 to 3 min generally allowed to continue embolization distally.
[00279] The catheters can generally be easily removed, the MIB-PVA and TIB-PVA of the present invention showing little adherence to the catheters.
[00280] TIB-PVA 47kDa, TIB-PVA 61 kDa and TIB-PVA 125kDa could cause embolism of the capillary hydrogel model in a similar way, even with the low molar mass polymer, which demonstrates the lower viscosity of the solution , may be preferred for embolization of small vascular structures, MIB-PVA 47kDa and MIB-PVA 61 kDa can similarly embolize the capillary hydrogel, although presenting a slower precipitation than TIB-PVA.
[00281] Mixtures of MIB-PVA and TIB-PVA in various proportions were also able to completely obstruct the capillary after its precipitation.
[00282] An increasingly faster precipitation was observed with the increase in the amount of TIB-PVA, as well as more difficult, but more fragile than the precipitated mold.
[00283] These results indicate that a whole family of formulations can be obtained using MIB-PVA and TIB-PVA, adapting their properties by adapting the molar mass of the polymer, concentration and proportion MIB-PVA / TIB-PVA.
[00284] Example 15 Embolization capacity of PVA polymers grafted with mono- and tri-iodobenzyl groups
[00285] An MTIB-PVA 47kDa was obtained from Example 13 using equal molar ratio of 4 - monoiodiodenzyme bromide and 2,3,5-triiodobenzyl bromide for synthesis, which corresponds to a MIB: TIB ratio 38:62% by weight. PVA 47kDa of starting material could be replaced for DS = 60%. A liquid embolic formulation was made by dissolving the MTIB-PVA 47kDa in NMP at 33% w / w final concentration. Heating to 90 ° C was used to accelerate the dissolution. The liquid formulations were tested on a hydrogel model made of poly (vinyl alcohol) as shown in Example 14 above. After the injection of about 0.1 mL, the polymer solution in NMP could cause embolism in the lumen of the capillary hydrogel. Polymer plugs can be formed, causing obstruction and flow stop. The catheter can be easily removed. These results highlight that a whole family of formulations can be obtained using MTIB-PVA polymers, adapting their properties by adapting the molar mass of the polymer, the concentration and molar ratio of 4-monoiodobenzyl bromide and 2.3 bromide , 5-triiodobenzyl.
[00286] Example 16 In situ formation of embolizing compositions added with SPIONs containing silica beads for local controlled hyperthermia
[00287] A PVA MIB-47kDa solution having a 56% DS was dissolved in 33% w / w in NMP. Silica beads loaded with superparamagnetic iron oxide nanoparticles (Degussa MagSilica 50-80) were added to this solution at a concentration of 20% w / V. The obtained viscous liquid can be injected through a 21G needle, forming a ball of semi-solid, smooth and brown polymer with 3 min (see Figs. 11a and 11b). The injection in a 3 mm diameter hydrogel model in a direct vessel (similar to Example 14) demonstrated the ability of this formulation to stop the flow of 10 ml / min, imitating the embolization of a natural vessel.
[00288] The paste was precipitated in small cylinders, 6 mm in diameter. This implant was inserted in an adiabatic calorimeter, at room temperature and submitted to an alternating magnetic field, of 9 mT, 141 kHz (Huttinger TIG-2.5 / 300) for five minutes. The temperature recorded by optical probes showed a rapid level increase for a plateau temperature increase of DT = + 16.6 ° C as shown in fig. 12.
[00289] The rapid increase with a slope of 16 ° C / min corresponds to an energy dissipation of 5.1 W / g of iron oxide. This increase in temperature is expected to cause in vivo term ablation of the surrounding tissues.
[00290] Example 17 Loading and release of an anti-cancer agent from a radiopaque precipitated polymer mass
[00291] Doxorubicin hydrochloride was dissolved in N-methyl pyrrolidone (NMP, with 25 mg / ml). 47kDa TIB-PVA having a DS of 58% was added to 33% w / w final concentration. The solution was injected into cylindrical alginate molds to produce 6-mm diameter plugs (about 0.3 g each). The samples loaded with doxorubicin were incubated in 100 ml of saline solution at 37 ° C with shaking. Doxorubicin was quantified by measuring the optical absorption of the supernatant at 479 nm wavelength. Figure 13 shows the gradual release obtained from anti-cancer agents over 3 days.
[00292] Example 18 Coating of medical devices with radiopaque polymer solution
[00293] A radiopaque coating was deposited on a tip of the catheter by immersion and evaporation of the solvent. Briefly, TCE-PVA 47kDa having a DS of 58% was dissolved in NMP at 40 ° C at a final concentration of 33% w / w. The tip of a catheter (Cordis Envoy GC) was immersed for 5 s in the radiopaque polymer solution, removed and dried at room temperature, keeping the catheter under axial rotation to obtain a uniform coating. The tip coated with TIB-PVA 47kDa is illustrated in Figs. 14a and 14b.
[00294] Radiopaque polymers and catheter were joined due to solvent evaporation. Other solvents have been evaluated, such as DMSO, leading to similar radiopaque coatings.
[00295] Example 19 Manufacture of radiopaque benzyl iodine nanoparticles of the present invention by nanoprecipitation
[00296] Radiopaque nanoparticles were prepared by the nanoprecipitation method as follows: 100 mg of MIB-PVA 47kDa having a DS of 49% was dissolved in THF (20 ml) at room temperature to form the diffuse phase. The diffuse phase was then added via syringe to the dispersing phase consisting of a phosphate buffered saline (PBS, 40 ml) containing 0.25% Pluronic ™ F68 surfactant with stirring. The aqueous phase became milky when the organic phase was poured, leading to a homogeneous milky dispersion at the end. THF was evaporated under reduced pressure. The average diameter of the nanoparticles, measured using a Malvern NanoZS instrument, was 170 nm, with a monomodal distribution.
[00297] The same method was used to produce particles with TIB-PVA 13kDa having a DS of 53%.
[00298] The following table, showing the diameter of nanoparticles of TIB-PVA 13 kDa as a function of the concentration of PVA TIB-13kDa in the diffuse phase or the concentration of Pluronic F68 in PBS, further demonstrates that the diameter of nanoparticles could be adapted by varying the concentration of TIB-PVA in the diffuse phase or the concentration of Pluronic F68 in PBS. Smaller particles, in the range of 50-90 nm in diameter, can be obtained using pure water instead of PBS.

[00299] Example 20
[00300] Comparative degradation of radiopaque iodine-benzylether-PVA nanoparticles (ether) versus radiopaque iodobenzoate-PVA (ester)
[00301] 1. Degradation of nanoparticles based on MIB-PVA47kDa
[00302] The degradation of the polymer was monitored through the absorbance of the expected degradation product, 4-monoiodobenzoic acid. Polymer nanoparticles were used for their high specific area. For comparison with ethers, radiopaque polymer esters were prepared in preparations of Examples 5 and 6 (Elaboration of radiopaque iodinated nanoparticles for in situ control of local drug delivery. D. Mawad, H. Mouaziz, A. Penciu, H. Mehier , B. Fenet, H. Fessi, Y. Chevalier; Biomaterials 2009, 30, 5667-5674). The 47kDa MIB-PVA nanoparticles prepared in Example 11 and 13kDa MIB / Ester-PVA prepared in Example 6 Preparation (DS = 49% and 40%, respectively) were then produced by nanosprecipitation in PBS as described in Example 19, both with an average diameter of about 170 nm.
[00303] In order to study the released degradation products, the nanoparticle suspensions were incubated at 37 ° C in phosphate saline buffer (PBS). At the time points data, the nanoparticles were collected by centrifugation and the supernatants from the centrifuged suspensions were analyzed by UV absorbance at 250 nm wavelength - the maximum absorbance of 4-monoiodobenzoic acid.
[00304] Figure 15 shows the time evolution of the absorbance, reflecting the release of degradation products. Considering that the non-measurable release was observed with the ether-based nanoparticles after two months, a clear increase was quickly observed for the ester-based nanoparticles, showing a rapid degradation of the ester-based polymer. These results indicated that ether-based nanoparticles are stable in PBS, even after one month, whereas ester-based nanoparticles are not.
[00305] 2. Degradation of nanoparticles based on TIB-PVA13kDa
[00306] Nanoparticle degradation tests were repeated using the same methods, with TIB-PVA 13kDa obtained in Example 7 and TIB / Ester-13 kDa obtained in the Preparation of Example 5 (DS = 53% and 34%, respectively). Nanoparticles of about 170 nm in diameter were produced in PBS for both polymers.
[00307] The absorbance wavelength was set at 229 nm, corresponding to the expected absorption peak of the expected degradation product, 2,3,5 - triiodobenzoic acid. As described in Figure 16, the absorbance of the ester supernatant slowly increased to 0.16 after one month, corresponding to the release of 8% of the iodized groups. No measurable release was observed with the ether polymer. These results indicate that ether-based nanoparticles are stable in PBS, even after one month, whereas ester-based nanoparticles are not.

权利要求:
Claims (22)
[0001]
1. Poly (vinyl alcohol) iodinated benzyl ether (iodine-benzyl ether-PVA) insoluble in water, non-biodegradable, radiopaque, characterized by the fact that it consists of a poly (vinyl alcohol) that has covalently grafted into the same iodinated benzyl groups comprising 1 to 4 iodine atoms per benzyl group, where the repeating unit grafted into the iodine-benzyl ether-PVA has the following formula:
[0002]
2. Iodine-benzylether-PVA according to claim 1, characterized by the fact that iodine-benzylether-PVA has a degree of substitution (DS) of at least 0.2.
[0003]
3. Iodine-benzylether-PVA, according to claim 1 or 2, characterized by the fact that iodine-benzylether-PVA has an iodine content of at least 40% (P / P) -
[0004]
Iodine-benzylether-PVA according to any one of claims 1 to 3, characterized by the fact that the grafted iodinated benzyl groups are identical iodinated benzyl groups.
[0005]
5. Iodine-benzylether-PVA according to claim 4, characterized by the fact that each benzyl group comprises an iodine atom at the C-4 position.
[0006]
6. Iodine-benzylether-PVA according to claim 4, characterized by the fact that each benzyl group comprises 3 iodine atoms in the C-2, C-3 and C-5 positions.
[0007]
Iodine-benzylether-PVA according to any one of claims 1 to 3, characterized by the fact that the grafted iodinated benzyl groups are two or more different iodinated benzyl groups having a different number of iodine atoms.
[0008]
8. Process for preparing iodine-benzylether-PVA as defined in any one of claims 1 to 7, characterized by the fact that it comprises reacting 75-100% hydrolyzed poly (vinyl alcohol) as a starting PVA with an iodinated benzyl derivative comprising 1 - 4 iodine atoms per benzyl group in a polar aprotic solvent in the presence of a base under anhydrous conditions.
[0009]
9. Process according to claim 8, characterized by the fact that said starting PVA has an average molecular mass (M) ranging from 5000 to 200000 Daltons.
[0010]
10. Process according to claim 8 or 9, characterized by the fact that the iodinated benzyl derivative is a mixture of two or more iodinated benzyl derivatives having different numbers of iodine atoms.
[0011]
Process according to any one of claims 8 to 10, characterized by the fact that the iodinated benzyl derivative is selected from the group consisting of 4-iodobenzylbromide and 2,3,5-triiodobenzylbromide, or a mixture thereof.
[0012]
Process according to any one of claims 8 to 11, characterized by the fact that the polar aprotic solvent is N-methylpyrrolidone (NMP) and the base is sodium hydroxide.
[0013]
13. Use of iodine-benzylether-PVA as defined in any one of claims 1 to 7, characterized by the fact that it is as an embolizing agent in an injectable embolic composition.
[0014]
14. Injectable embolizing composition, characterized by the fact that it comprises iodine-benzylether-PVA as defined in any one of claims 1 to 7 and a water-miscible biocompatible solvent that solubilizes iodine-benzylether-PVA, in which the concentration of iodine-benzylether -PVA in the composition is selected in the range of 5 - 65 w / w% so that the composition is able to form a cohesive mass under contact with a body fluid by the precipitation of the iodine-benzylether-PVA.
[0015]
15. Injectable embolizing composition according to claim 14, characterized by the fact that the concentration of iodine-benzylether-PVA in the composition is selected in the range of 20 - 50 w / w%.
[0016]
16. Injectable embolic composition according to claim 14 or 15, characterized by the fact that the solvent is selected from dimethylsulfoxide (DMSO), N-methylpyrrolidone (NMP) and glycofurol.
[0017]
17. Injectable embolic composition according to any one of claims 14 to 16, characterized in that it comprises two or more different iodo-benzylether-PVA as defined in claims 4 to 6.
[0018]
18. Injectable embolic composition according to any one of claims 14 to 17, characterized by the fact that it also comprises drugs or biopharmaceuticals.
[0019]
19. Injectable embolic composition according to any one of claims 14 to 18, characterized by the fact that it also comprises superparamagnetic iron oxide nanoparticles (SPIONs).
[0020]
20. Coating composition to form a coating on a medical device, characterized in that it comprises iodine-benzylether-PVA as defined in any one of claims 1 to 7 and a solvent that solubilizes iodine-benzylether-PVA, wherein the concentration of iodine-benzylether-PVA in the composition is selected in the range of 5 - 65 w / w% so that the composition is able to form a radiopaque coating after application to a medical device and evaporation of the solvent.
[0021]
21. Radiopaque particles, characterized by the fact that they are selected from nanoparticles and microparticles of iodine-benzylether-PVA as defined in any one of claims 1 to 7.
[0022]
22. Radiopaque particles, according to claim 21, characterized by the fact that it still contains drugs or biopharmaceuticals.

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同族专利:

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公开号 | 公开日

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AU2011226138B2|2015-01-22|

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EP2545085A1|2013-01-16|

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ES2603607T3|2017-02-28|

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KR20130051916A|2013-05-21|

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CA2786398C|2017-06-13|

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PL2545085T3|2017-08-31|

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WO2011110589A1|2011-09-15|

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CN102781974A|2012-11-14|

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US9115230B2|2015-08-25|

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US20130108574A1|2013-05-02|

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US9434800B2|2016-09-06|

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DK2545085T3|2016-12-05|

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JP2013521087A|2013-06-10|

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CA2786398A1|2011-09-15|

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CN102781974B|2014-10-15|

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EP2545085B1|2016-10-19|

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KR101753441B1|2017-07-03|

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EP2365009A1|2011-09-14|

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BR112012019754A2|2016-05-10|

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US20150335779A1|2015-11-26|

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HK1176629A1|2013-08-02|

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AU2011226138A1|2012-07-26|

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JP5696165B2|2015-04-08|

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法律状态:
2018-01-23| B07D| Technical examination (opinion) related to article 229 of industrial property law|

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2018-04-10| B06F| Objections, documents and/or translations needed after an examination request according art. 34 industrial property law|

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2019-05-28| B07E| Notice of approval relating to section 229 industrial property law|Free format text: NOTIFICACAO DE ANUENCIA RELACIONADA COM O ART 229 DA LPI |

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2019-09-17| B06U| Preliminary requirement: requests with searches performed by other patent offices: suspension of the patent application procedure|

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2020-01-14| B06A| Notification to applicant to reply to the report for non-patentability or inadequacy of the application according art. 36 industrial patent law|

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2020-05-26| B09A| Decision: intention to grant|

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2020-10-20| B16A| Patent or certificate of addition of invention granted|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 09/03/2011, OBSERVADAS AS CONDICOES LEGAIS. |

优先权:

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申请号 | 申请日 | 专利标题

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EP10156039A|EP2365009A1|2010-03-10|2010-03-10|Radiopaque, non-biodegradable, water-insoluble iodinated benzyl ethers of poly, preparation method thereof, injectable embolizing compositions containing thereof and use thereof|

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EP10156039.9|2010-03-10|

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PCT/EP2011/053536|WO2011110589A1|2010-03-10|2011-03-09|Radiopaque, non- biodegradable, water - insoluble iodinated benzyl ethers of poly , preparation method thereof, injectable embolizing compositions containing thereof and use thereof|

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