US 2011 0052503A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2011/0052503 A1 Almen et al. (43) Pub. Date: Mar. 3, 2011

(54) BIODEGRADABLE CONTRASTAGENTS (30) Foreign Application Priority Data (75) Inventors: Torsten Almen, Lund (SE); Bjarne Dec. 21, 2007 (GB) ...... O725070.7 Brudeli, Lund (SE); Fred Kjelson, Lund (SE); Jo Klaveness, Lund Publication Classification (SE); Jian-Sheng Wang, Lund (SE) (51) Int. Cl. (73) Assignee: OPHARMA TECHNOLOGIES g 19 :08: AB, Lund (SE) (52) U.S. Cl...... 424/9.4; 252/478 (21) Appl. No.: 12/808,318 (57) ABSTRACT (22) PCT Filed: Dec. 22, 2008 The present invention provides a radio-opaque composition (86). PCT No.: PCT/GB2O08/OO.4268 comprising a cleavable, preferably enzymatically-cleavable, derivative of a physiologically tolerable organoiodine com S371 (c)(1), pound and a non-acrylic polymer wherein said derivative is (2), (4) Date: Nov. 8, 2010 incorporated in said non-acrylic polymer.

Patent Application Publication Mar. 3, 2011 Sheet 1 of 5 US 2011/0052503 A1

Degradation of IHA to lohexol

-0-lohexol -u HA

Day2 Day3 Degradation Time --PLLA --PLLA+2%HA aris-PLLA -5%HA -(-PLLA10%IHA-K-PLLA-15%IHA-O-PLLA+20%IHA

Fig. 2 Patent Application Publication Mar. 3, 2011 Sheet 2 of 5 US 2011/0052503 A1

PLLA PLLA2%IHA PLLA+5%IHA PLLAH10%IHA PLLA-15%IHA PLLA20%IHA Sample

ODay 0 Day 10 Day 50 Day 81 Day 10

Fig. 3

Patent Application Publication Mar. 3, 2011 Sheet 3 of 5 US 2011/0052503 A1

Patent Application Publication Mar. 3, 2011 Sheet 4 of 5 US 2011/0052503 A1

Patent Application Publication Mar. 3, 2011 Sheet 5 of 5 US 2011/0052503 A1

US 2011/0052503 A1 Mar. 3, 2011

BODEGRADABLE CONTRASTAGENTS loyloxypropyl-1,2-bis(2,3,5-triiodobenzoate) (see Davy et al. Polymer International 43: 143-154 (1997)), 2,5-diiodo-8- quinolyl methacrylate (see Vazquez et al. Biomaterials 20: 0001. The present invention relates to biodegradable con 2047-2053 (1999)), and 4-iodophenyl methacrylate (see trast media for use in biomaterials, particularly contrast Kruft et al. J. Biomedical Materials Res. 28: 1259-1266 media which are biologically compatible with their surround (1994)) as a monomer in the preparation of the polymer ings, so as to cause no negative influence on blood or other matrix. It is clear however that the resulting polymer will not Surrounding tissues. Additionally, this invention relates to only contain residual unreacted organoiodine monomer, but methods for preparing polymers containing biodegradable that exposure to physiological fluids will result in the release contrast media. Moreover, this invention relates to radio of organoiodine compounds with unclear physiological com opaque objects and methods for rendering objects radio patibility. opaque. 0007. The potential release of contrast agent from the 0002 The ability to render objects radio-opaque is impor polymer matrix is particularly problematic when a biodegrad tant in several fields. For example, in medicine it is important able polymer is used. As the polymer degrades, so the incor for medical devices to be seen in X-ray investigations during porated radio-opaque material is released. Biodegradable medical procedures and post-operative follow-ups. Metallic polymers comprising radio-opaque compounds may be used implants can be monitored easily due to the radio-opacity of in a variety offields, in many of which it is undesirable to have metals. potentially toxic contract agents being released. It would be 0003. In the case of devices which are not radio-opaque, useful for a wide variety of biodegradable polymers to be they can be manufactured to comprise a radio-opaque mate made radio-opaque for use in temporary medical devices. rial, e.g. a compound with the ability to absorb X-rays (often termed an X-ray contrastagent). This allows the placement of 0008 For example biodegradable polymers can be used in the medical device to be monitored, e.g. shortly after an temporary medical devices such as clips, Sutures etc. which operation to insert a prosthesis or over the Subsequent years. are intended to degrade after time, but nonetheless need their In general. Such radio-opaque materials are compounds of positioning monitored for a period after implant. As the bio heavy metals. Where the medical device is manufactured degradable polymer degrades (for example inside the body in from a polymer, the heavy metal compound is incorporated the case of a degradable suture) the contrast agent will be into the polymeras insoluble particles. Barium Sulphate and released and thus insoluble particles or material of unknown Zirconium dioxide are commonly used in this manner. Other physiological compatibility will be released into the sur methods include coating the Surfaces of the object with gold/ rounding tissues. Similar problems are found for non-biode silver ions. Radio-opaque paints and inks with barium Sul gradable polymers as contrast agent compounds will be phate or silver powders physically trapped in the composi released from within the device should it break and from the tions have also been proposed. For non-medical applications, surface of the device due to it being in contact with bodily lead can be used, typically in plated form or compounded into fluids. ceramics. 0009 Current methods therefore have the drawbacks that 0004. There are several disadvantages with the current by their particulate nature and/or the fact that they are not methods of rendering objects radio-opaque. In particular, homogenously distributed within polymers, the contrast medical devices treated with the current methods often have agents reduce the mechanical strength of the polymer matrix. low bio-compatibility because of their radio-opaque fillers. Moreover any release of the radio-opaque material from the Additives in polymeric implants are liable to diffuse into the device distributes highly abrasive particles and/or toxic mate Surroundings and may cause inflammatory responses. This rial. This is particularly problematic in medical applications can in the end cause undesirable responses like necrosis, pain where the mechanical strength of the implant is important and expulsion of the object. and/or it is intended to degrade in the body over time, for 0005 For example most medical stents are constructed example the case of degradable sutures etc. There thus exists from metal, and they are therefore visible via X-ray investi a need for materials which are radio-opaque, mechanically gations. Even though Such metal stents possess certain strong and, if degraded (whether by accidental failure of the favourable characteristics, they also exhibit a number of sig device or intended degradation) release only physiologically nificant disadvantages. The likelihood of restenosis, a bio tolerable substances. logical process where Smooth muscle cells and matrix pro 0010 We have now realized that these problems may be teins further occludes the blood vessels, increases. Other addressed by combining a non-acrylic polymer with a cleav disadvantages with the current methods in the medical and the able, preferably enzymatically-cleavable, derivative of a industrial fields include galvanic corrosion, undesirable physiologically tolerable organoiodine compound. changes in the physical, mechanical and electromagnetic 0011 Viewed from a first aspect, the present invention properties of the devices, high economic cost and cumber provides a radio-opaque composition comprising a cleavable, Some processes for producing the devices. Recently, biocom preferably enzymatically-cleavable, derivative of a physi patible and/or bioresorbable polymer stents made of poly ologically tolerable organoiodine compound and a non mers of glycolic and lactic acid have been proposed for use in acrylic polymer wherein said derivative is incorporated in, medical stent systems. However, these materials suffer from e.g. dissolved in or present as a monomer residue in, said the disadvantage that they are not radio-opaque. non-acrylic polymer. 0006 For devices manufactured from polymers, it has 0012. From a further aspect the invention provides a radio been proposed to utilize a compound comprising an iodophe opaque composition comprising the product of polymerising nyl group linked to an acrylic group via an ester group (e.g. a non-acrylic monomer containing a cleavable, preferably 2-methacryloyloxyethyl (2,3,5-triiodobenzoate), 2-meth enzymatically-cleavable, derivative of a physiologically tol acryloyloxypropyl (2,3,5-triiodobenzoate), and 3-methacry erable organoiodine compound. US 2011/0052503 A1 Mar. 3, 2011

0013 Especially preferably the radio-opaque composi iodpyracet, iodopyrrole, iodoquinol, iofetamine I, iogly tions of the present invention provide an essentially chemi camic acid, iohexyl, iomeglamic acid, iomeprol, iopamidol. cally homogeneous distribution of all components within the iopanoic acid, iopentol, iophendylate, iophenoxic acid, final radio-opaque composition. iopromide, iopronic acid, iopydol, iopydone, iothalamic acid, 0014) Alternatively, the derivative of a physiologically tol iotrolan, ioVersol, ioxiglimic acid, ioxalic acid, ioxilan and erable organoiodine compound can be used to coat the poly ipodate. mer (e.g. polymer beads or articles comprising the polymer) 0020 Examples of derivatives for use in the invention are in order to render the polymer, i.e. articles or compositions those corresponding to existing water soluble non-ionic con comprising it, radio-opaque. This may be achieved, for trast agents (for example those listed above) but with the example, by spraying or dip-coating a polymer-containing water-solubilising hydroxy groups derivatised such that component with an organoiodine compound derivative retention of the organoiodine compound within the polymer according to the invention in liquid form. is facilitated by increasing its solubility in the polymer and 0015. By enzymatically-cleavable derivative of a physi thus the homogeneity of its distribution is also increased and ologically tolerable organoiodine compound is meant any any metabolites produced will correspond to medically derivative which may be cleaved by enzymes particularly approved contrast agents. enzymes endogenous to a human or animal, e.g. mammalian 0021. The use of such derivatives is especially advanta host, to release physiologically tolerable degradation prod geous as any organoiodine compound released from the poly ucts. One example is a physiologically tolerable organoiodine mer, e.g. due to esterase activity of biological fluids, will be in compound attached to a physiologically tolerable polymeriz the form of a physiologically tolerable compound or a com able or polymer-philic group (e.g. an acyl group) via an pound with bio-distribution, bio-elimination and bio-toler enzymatically cleavable bond such as an ester bond. It is a ability closely similar to the known and approved contrast preferred aspect of the invention that the derivative is an ester agents. Before such exposure to esterase activity, derivatisa of an organoiodine compound. Preferred derivatives include tion with lipophilic groups will moreover serve to reduce any iohexylhexa-acetate (IHA), Iopamidol penta-acetate, methyl leaching of the organoiodine compound from the polymer. diatrizoate and dimethyl dipamidate. IHA is especially pre Especially preferred derivatives of physiologically tolerable ferred. organoiodine compounds according to the invention include 10016. The derivatives of organoiodine compounds used in analogues of known non-ionic, monomeric or dimeric orga the invention function as contrast media and are freely soluble noiodine X-ray contrast agents in which solubilising in non-acrylic monomers and/or polymers. The resulting hydroxyl groups are acylated (e.g. acetylated) or formed into composition therefore has a chemically homogenous distri 2,4-dioxacyclopentan-1-yl groups and/or, where the com bution of the organoiodine derivative within the polymer. pound is to be polymerizable, in which a carbonyl- or nitro Such a homogenous composition is advantageous for X-ray gen-attached ring substituent is replaced by a (meth)acryla monitoring as even very small devices will contain sufficient mide group or a (meth) acrylamidoalkylamino carbonyl iodine compound to be detectable. Moreover, homogeneity group), or even more preferably the hydroxyl groups are will also improve the mechanical strength of the composition. derivatized with biodegradable monomers (e.g. esterified 0017. Ideally, the radio-opaque compositions of the inven with glycolic acid, lactic acid or E-hydroxycaproic acid). tion may comprise 0.5 to 80% by weight, preferably 1 to 50% 0022. Examples of conventional non-ionic X-ray contrast by weight, e.g. 2 to 20% by weight, particularly 5 to 15% by agents (i.e. physiologically tolerable organoiodine com weight, i.e. around 10% by weight, cleavable derivative of a physiologically tolerable organoiodine compound. pounds) which may be modified in this way include: iohexyl, 0018. The derivatives can be considered to be prodrugs of iopentol, iodixanol, iobitridol, iomeprol, iopamidol, iopro the corresponding organoiodine compounds in the sense that mide, iotrolan, ioversol and ioxilan. The use of the analogues cleavage (for example by the body's esterases) releases physi of the contrast agents with regulatory approval (e.g. in the US, ologically tolerable organoiodine compounds. Japan, Germany, Britain, France, Sweden or Italy) is pre 0019 Preferably the physiologically tolerable organoiod ferred. The use of the analogues of the monomeric contrast ine compound of the invention is an iodinated contrast agent agents is particularly preferred. Such analogues may be pre with regulatory approval, which includes diatriozinic acid, pared by esterification of the contrast agent (e.g. by acylation iobenguane, iobenzamic acid, iobitriol, iocarmic acid, ioc of hydroxyl groups, e.g. acetylation and/or by preparing alkyl etamic acid, iodamide, iodipamide, iodixanol, iodized oil, esters such as ethyl esters of carboxylic groups). Typical iodoalphionic acid, p-iodianiline, o-iodobenzoic acid, examples of derivatives of physiologically tolerable orga iodochlorohydroxyquin, o-iodohippurate sodium, o-io noiodine compounds according to the invention (non-poly dophenol, p-iodophenol, iodophthalein sodium, iodopsin, merizable biodegradable X-ray prodrugs) are shown below:

I I "> H N." "> H N." O O -o- O O I I I I

O OH O o1 N1)-chi, Diatriozinic acid Diatriozinic butylester prodrug US 2011/0052503 A1 Mar. 3, 2011

-continued

O I rol O I ro. N N irr H ro H Her o-r H 1. OH O OAc O I I I I

H O N OAc H H OH OAc loversol loversol acetate prodrug

O I O O I O horn-r H ^^on AcO N N OAc OH CH, OH I I OAc CH, OAc CH I I O -> O1 CH O 1No1 Iopromide H Iopromide acetate prodrug

OH OAc

OH OAc

HC n H3C N I O NN I O O ~~ O ~~. CH, OH CH3 OAc I I I I O NH O NH

HO OH OAc OAc

Iobitriol Iobitriol acetate prodrug

I t I th HN N^-r" HN N^-r N1 CH O O Hope O O I I I I

O 1No1 CH O 1No1 CH H H Iomeprol Iomeprol ethyl ester prodrug US 2011/0052503 A1 Mar. 3, 2011 4

-continued

CH I O I O

HC3 l OH irH H 1N1 O O Her I I CH3 O N1 O OH H

Ioxiglinic acid

CH3 I O I O

HC3 l OAC r H 1 H 1N1 O O I I CH O N1H O o1 NCH, Ioxiglinic acid prodrug

COOH

I I O I H N H Ho I 1.--> O I I

COOH Iodipamide

O OQ-CH

I I O I

N N H I 1.--> O I I He1 No O Iodipamide ethyl ester prodrug

0023 These non-ionic contrast agents can also be deriva tized to polymerizable monomer derivatives, by Subsequent reaction of an optionally activated alkeneoic acid (e.g. an alkeneoic acid chloride (for example methacrylic acid chlo ride)), or more preferably derivatized with biodegradable/ bioresorbable polymerizable monomers (e.g. esterification with glycolic acid, lactic acid or E-hydroxycaproic acid). US 2011/0052503 A1 Mar. 3, 2011

0024 Examples of polymerizable organoiodine com pounds include:

OH

HO I O

H3C N O N OH O H OH fouls -CH ". I I Hs

O H rol OH Iohexol O OH HO O I O HC N N O H OH O OH I I luoiO O O H r OH Iohexol tri-glycolate OH

HO I O O H3C N N OH N11 oil houl-ch,O O OH I I CH Hs

O N OH H OH Iohexol O OH HO O I O CH3 CH3 HC N N O H OH O OH I I O O

OH O NH ~~

Iohexol tri-lactate US 2011/0052503 A1 Mar. 3, 2011

-continued

OH

HO I O O H3C N N OH H O OH I I

O N OH H OH Iohexol

O OH HO O I O

H3C N N O H OH O OH I I O O

O N O --~" H ~~ OH Iohexol tri-caproate

0025 If desired, some or all of the organoiodine com pounds may take the form of a cross-linking agent carrying at least two and optionally up to 10 or more polymerizable (I) groups (e.g. esters of glycolic acid, lactic acid, e-hydroxyl hexanoic acid and the like). Generally however such cross linking agents will constitute only a minor proportion, e.g. up to 20% (on a molar iodine basis) of the total organoiodine compound used, more preferably up to 10%, especially up to 5%. Such cross-linking agents may conveniently be prepared by reacting conventional X-ray contrast agents of the types mentioned above or their aminobenzene precursors (or partly acylated versions of either thereof) with an optionally acti wherein each R group which may be the same or different, vated alkeneoic acid (e.g. methacrylic acid chloride) or more comprises an acyloxyalkylcarbonylamino, N-(acyloxyalkyl preferably an hydroxyalkane carboxylic acid thereof. carbonyl) acyloxyalkylamino, N-acyloxyalkylcarbonyl-N- alkyl-amino, acyloxyalkylaminocarbonyl, bis(acyloxyalkyl) 0026. Less preferably, the organoiodine compound may aminocarbonyl, N-acyloxyalkyl-N-alkyl-aminocarbonyl, be an iodobenzene free from non-polymerizable lipophilic alkoxyalkylaminocarbonyl, N-alkyl-alkoxyalkylaminocar Substituents (other than iodine of course), e.g. a simple iodo bonyl, bis(alkoxyalkyl)amino-carbonyl, alkoxyalkylcarbo benzene (such as 1,4-diiodobenzene) or a simple iodoami nylamino, N-alkyl-alkoxyalkylcarbonylamino or N-alkoxy nobenzene conjugate with (meth)acrylic acid (e.g. methacry alkylcarbonyl-alkoxyalkylamino group or a triiodophenyl lamido-2,4,6-triiodobenzene) or glycolic acid (e.g. group attached via a 1 to 10 atom bridge (preferably com glycolamido-2,4,6-triiodobenzene). posed of bridging atoms selected from O, N and C) optionally 0027. Alternatively, the derivative of a physiologically tol Substituted by an acyloxyalkyl, acyloxyalkylcarbonyl, acy erable organoiodine compound according to the invention loxyalkylamino, acyloxyalkylcarbonylamino, acyloxyalky may be a compound of formula (I): laminocarbonyl, alkoxyalkyl, alkoxyalkylcarbonyl, alkoxy US 2011/0052503 A1 Mar. 3, 2011

alkylamino, alkoxyalkylcarbonylamino, O 0031. It is especially preferred that the polymer of the alkoxyalkylaminocarbonyl group or by a polymerizable composition is a biodegradable or biocompatible (e.g. physi group, e.g. a hydroxyalkane, (meth)acrylate or (meth)acryla ologically tolerable) polymer. mide group, or one or two R groups is/are a polymerizable 0032. The radio-opaque compositions of the present group, e.g. a hydroxyalkane, (meth)acrylate or (meth)acryla invention may additionally comprise a medical agent, par mide group, optionally attached via a 1 to 10 atom bridge, e.g. ticularly formedical applications. Suchagents are included in an alkylaminocarbonyl or alkylcarbonylamino bridge; or several conventional radio-opaque compositions and may be where one R group is a polymerizable group, one or both of used in similar concentrations in the compositions of the the remaining R groups may be an alkylamino, bisalky invention. lamino, alkylcarbonylamino, N-alkyl-alkylcarbonylamino, 0033. The medical agents may be selected from a wide alkylaminocarbonyl or bis-alkyl-aminocarbonyl group, (e.g. variety of groups, depending on the device for which they are an acetylamino group). In Such compounds, any alkyl or intended and the corresponding organ. Agents (for example alkylene moiety preferably contains 1 to 6 carbon atoms, for use in Stents or stent systems) include anti-proliferative especially 2 to 4 carbon atoms and any bridge optionally agents (paclitaxel and the like), immunosuppressive agents comprises oxygen and/or nitrogen atoms, especially one or (dexamethasone, rapamycin, tacromilus, mycophenolic acid two nitrogen atoms. Moreover, two alkoxy groups in Such and the like), anti-inflammatory agents (aspirin, ibuprofen, compounds, especially groups attached to neighbouring car naproxen and the like) anti-matrix metalloproteinase, lipid bonatoms, may be fused to form a cyclic bis-ether, preferably lowering agents (simvastatin, lovastatin, pravastatin and the containing two ring oxygens and three ring carbons, e.g. as a like), anti-thrombotic agents and antiplatelet agents (e.g. clo 2,4-dioxa-3.3-dimethyl-cyclopentan-1-yl group. In general, pidogrel, ticlodipine, dipyridamole, epoprostenole, ilopros tenole, argatroban and the like). The biocompatible/biore it is preferred that two R groups are carbonyl-attached and Sorbable polymer may comprise antibiotics or antiseptics, that one is nitrogen-attached to the iodobenzene ring. e.g. gentamicin, colistin, erythromycin, clindamicin, penicil 0028. The non-acrylic polymer of the composition of the lins, norfloxacin, chloramphenicol etc. invention will be selected according to the intended use of the 0034. The medical agents are usually added to medical radio-opaque composition and thus will be apparent to the devices by different coating processes (e.g. air knife, immer skilled person. Examples of Suitable polymers are; polysty Sion, curtain coating and the like) or matrix loading. Coating rene, poly(lactic acid) (PLA), poly(e-caprolactone) (PCL), processes are used most frequently, but the agents are only poly(glycolic acid) (PGA), poly(lactide-co-glycolide) deposited onto the device surface and will be released rapidly (PLGA), poly(dioxanone), poly(glycolide-co-trimethylene to the biological Surroundings. Release of a medical agent carbonate), poly(vinyl alcohol) (PVA), poly(vinylpyrroli over a prolonged period can be obtained by matrix loading, a dine), poly(hydroxybutarates), poly(hydroxyvalerate), poly process where the agents are incorporated into the medical (sebaic acid-co-hexadecandioic acid anhydride), poly device. Preferably, in order to maintain the mechanical (orthoester), poly(caprolactams), poly(acrylamides), poly strength of the device (especially when the medical agent (terphthalate), polyether block amides (PEBA), poly contains hydrophilic groups such as alcohols, carboxylic acid (urethane) etc. Polymer blends, alloys, homopolymers, etc.) the medical agents may be in the form of a lipophilic random copolymers, block copolymers and graft copolymers ester, Such as an acyl derivative e.g. an acetyl ester, and/or e.g. are also Suitable. ethyl esters, or any biodegradable prodrug depending on the chemical nature of the agent, whereby to allow its release 0029 Bio-stable/bio-compatible polymers such as polya from the composition over a prolonged period as a result of mides, polyanhydrides, polycarbonates, polyesters, poly esterase activity in the physiological fluids contacting the ethers, poly(hydrocarbons), polyurethanes, polysulfones and composition after implantation. A typical example of Such polysiloxanes, and their copolymers are especially preferred, derivatives are gentamycin poly-acetate, dipyridamol acetate, as are bio-absorbable polymers such as polylactide, polygly epoprostenol ethyl ester and the like. collide, polycaprolactone, poly(dioxanone) tyrosine and their copolymers. Polyhydroxyalkanocarboxylic acids as poly 0035) Some examples of typical prodrugs for use in medi (lactide-co-glycolide) polymers are preferred due to their cal polymers are shown below: biocompatibility and biodegradability properties. 0030 Preferably the polymer comprises polyesters such as poly(L-lactide), poly(D.L-lactide), poly(caprolactone), poly(glycolic acid), poly(lactide-co-glycolide), poly(lactide co-caprolactone), poly(glycolide-co-caprolactone), poly(L- O OH lactide-co-caprolactone-co-glycolide), polytrimethylene car N bonate, poly(3-hydroxybutyrate), poly(3-hydroxyvalerate), Na n OH poly(4-hydroxybutyrate), poly(dioxanone) polyamides Such Hs as poly(caproamide), poly(hexamethylene adipamide), poly HO N (p-phenyleneterephtalamide), polyhydrocarbones such as s 2 poly(ethylene), poly(propylene), poly(1-hexene), poly(1- hexene-co-4-methyl-1,4-hexadiene), poly(tetrafluoroethyl HO ene), poly(vinyl alcohol), polyacetals such as poly(formalde hyde), polyketals, polyglycols, polyurethanes, segmented polyurethanes, polyanhydrides, polyphosphaZenes, polysul O fones, silicones, ABS resins, natural polymers such as col Dipyridamol lagen, fibrin, polysaccharides such as chitosan. US 2011/0052503 A1 Mar. 3, 2011

-continued -continued O

N -- H3C HC O N V CH3 N HC Y ~ S^-> O O N N 2 N O1. CH. > HN O NH), H "> N N, O N CH3 O CH3 O Dipyridamol tetra-acetate O CH

Gentamycin poly-acetate

OH OH Epoprostenol

0.036 Alternatively, such agents may be copolymerized into the polymer by incorporating a polymerizable hydroxy HC3 n1 O alkane and/or ethylenically unsaturated bond coupled via an ester group to the drug moiety, whereby again to release the O medical agent over a prolonged period as a result of esterase O activity. Preferably, the medical agents should be hydrophilic to prevent rapid release and to prevent infection after Surgery. 2 CH3 0037. The present invention further provides a process for producing a radio-opaque composition as herein described wherein said process comprises combining a non-acrylic N-CH 's-CH3 monomer composition with a cleavable, preferably enzymati cally-cleavable, derivative of a physiologically tolerable Epoprostenol di-acetate ethyl ester organoiodine compound and carrying out a polymerization H3C \ CH reaction. The derivative of a physiologically tolerable orga N H noiodine compound may or may not take part in the polymer O ization reaction, i.e. it may be co-polymerizable with the non-acrylic monomer, but is not necessarily so. NH2 O l-H2N 0038. The non-acrylic monomer composition will com prise at least one non-acrylic polymerizable monomer, gen Hs erally a monomer containing a hydroxyalkane group and/or O ethylenically unsaturated bonds, optionally a polymerization initiator, and optionally a cross-linking agent. The polymer ization initiator and cross-linking agent may if desired be added to the monomer mixture during preparation of the \larNHbH radio-opaque composition for use. HC 0039 Most biodegradable polymers are synthesized by Gentamycin condensation polymerization (ring opening polymerization. An example of this is shown below: US 2011/0052503 A1 Mar. 3, 2011

O OH HO O O I O

O catalyst O -- "> ^^ OH catalystheat O OH I I O O O luon O NH ~~ OH Glycolide Iohexol tri-glycolate

O OH I I O O

O OH HO O O O I O CH3 CH3

-- H3C -- "> H Hs O O r^ OH catalystheat O O O OH CH3 I I O O O O OH O NH ~~ O OH CH3 Glycolide Lactide Iohexol tri-lactate US 2011/0052503 A1 Mar. 3, 2011 10

-continued O O CH3 O OH : r O O 4-s-s-s-s-spi n I O O CH3 O CH3 CH3 H3C N r N ^^O s O OH I I O O

OH O N ^^ O OH CH3 O OH les--- O n I O O HC N

O -- rO OH?e--- catalystheat I I O O --~~ OH O ^^o OH

Caprolactone Iohexol tri-caproate O

: O o 2 ~. O OH I O O "> ^^o O H OH ^-n-rol I I O O O N ^^O --~-lii OH

0040. Other biocompatible polymers (polyethylene, e.g. this preferably constitutes up to 5% wt. of the composition, HDPE or polyvinylchloride etc.) are synthesized by addition more preferably, 2% wt., especially 0.1 to 1% wt. of the polymerization, and the non-acrylic organoiodine monomers composition. can also be copolymerized with these polymers to give 0043. The polymerization temperature can vary over a copolymers of biodegradable contrast agents. large range. Preferably the polymerization temperature is in 0041. The polymerization initiator, where present, is pref the range of 50-250° C.; more preferably 100-175° C.; espe erably a physiologically tolerable initiator of polymerization cially preferably 125-175° C. of ethylenically unsaturated monomers, e.g. N,N-dimethyl 0044) The polymerization reaction time can also vary over p-toluidine, N,N-dimethylaminobenzyl alcohol (DMOH) or a large range. Preferably the reaction time is in the range from N,N-dimethylaminobenzyl oleate (DMAO), or, for ring 4 hours to 5 days, more preferably 6 hours to 2 days. opening polymerization typical initiators are tin-2-ethylhex 0045 All these parameters affect the physical and chemi anoate (SnOct), dibutyltin dilaurate, bismuth(III)-n-hex cal properties of the polymer formed i.e. molecular weight, anoate, bismuth Subsalicylate, Stannaous octoate, monomer COIntent etc. hexamethyl-cyclotrisiloxane and the like. The initiator typi 0046. In a preferred process, the cleavable non-polymer cally constitutes 0.01 to 10% wt. of the monomer composi izable derivatives of organoiodine contrast agents are added tion, preferably 0.1 to 5% wt., more preferably 0.5 to 2% wt. (preferably with mixing) to the biodegradable/biocompatible especially 0.1 to 1% wt. polymers (which are, for example, in Solution, bead or pow 0042. If a cross-linking agent (e.g. an organoiodine com der form) and they are typically heated to a melt under stir pound containing two or more polymerizable groups, poly ring. The polymer blend can be extruded and/or moulded ethyleneglycols etc.) is present in the monomer composition, directly, or alternatively cooled to leave the polymer compo US 2011/0052503 A1 Mar. 3, 2011

sition as a solid (e.g. a powder or a film) with the contrast 0055. The present contrast agents are also useful in the agent homogenously distributed therein. production of gastric lap bands for use in the treatment of 0047. The non-acrylic polymer and organoiodine com obesity. The production of radio-opaque lap bands allows for pound may be dissolved in a suitable solvent, e.g. dichlo more effective monitoring of the devices in the human body, romethane, chloroform, dimethylsulfoxide, dimethylforma and more effective treatment of obesity. mide, toluene and the like. The blend can be evaporated under 0056. In addition to intravascular stents and non-cardio reduced pressure to leave the polymer composition as a vascular stents, the present polymers are useful in a number of homogenous Solid. other cardiovascular and vascular devices. For example 0048 More preferably the polymer blend can be spray valves, chordae tendinea replacements, annuloplasty rings, dried to leave polymer beads with organoiodine compounds leaflet repair patches, vascular grafts, vascular tubes, patches homogenously distributed therein. for septal defects, arterial and venous access closure devices 0049. The polymer blend/compositions may be processed (plugs), and the like can be used in replacement repair of heart similar to any engineering thermoplastic in that they can be valves, tubes and the like. melted down and formed into fibres, rods and moulded parts. 0057 More specifically these include medical/surgical Final parts can be extruded, injection moulded, compression tubing e.g. for renal and celial arteriography or for producing moulded, or solvent spun or cast. In some circumstances the mini-balloon catheters, protective sheeting, Surgeons gloves, primary processing may be followed by Subsequent machin intubation sets, heart catheters, stomach tubes, nasal tubes, ing into final parts. thoracic catheters, string, mesh, Suture, braid, Stent, catheter, 0050. The radio-opaque compositions of the present cannula, plug, constrictor, bone anchor, plate, rod, seed, cap invention have a variety of uses. In particular they will be used Sule sheet, tubes, guide wires, shunts, screws, pins, prosthe in the production of radio-opaque articles, for example for ses, films, sponges, balloons, needles, markers, stylets, mem coating articles or moulding articles therefrom. The use of the branes, autotransfusion devices, blood filters, blood gas composition of the invention in the production of radio exchange devices, blood pumps, blood temperature monitors, opaque articles and the articles themselves form a further bone growth stimulators, breathing circuit connectors, bull aspect of the present invention. dog clamps, cannulae, grafts, implantable pumps, impotence 0051. The article may be a medical device. For example and incontinence implants, intra-ocular lenses, leads, lead medical stents, implantable devices for orthopaedics, tissue adapters, lead connectors, nasal buttons, orbital implants, engineering, dental applications, gastric lap bands, drug cardiac insulation pads, cardiac jackets, clips, covers, dila delivery, cancer treatment, other cardiovascular applications, tors, dialysers, disposable temperature probes, domes, drain non-cardiovascular stents such as biliary, oesophagus, vagi age products, drapes, earwicks, electrodes, embolic devices, nal, lung-trachea/bronchus, and the like. In addition, the con oesophageal Stethoscopes, fracture fixation devices, gloves, trast media are Suitable for use in producing implantable, guide wires, hemofiltration devices, hubs, intra-arterial blood radio-opaque discs, plugs, and other devices used to track gas sensors, intracardiac Suction devices, intrauterine pres regions of tissue removal, for example, in the removal of Sure devices, nasal septal splints, nasal tampons, needles, cancerous tissue and organ removal, as well as staples and ophthalmic devices, oxygenators (both sheet and tubular clips Suitable for use in wound closure, attaching tissue to forms of membrane oxygenators), PAP brushes, periodontal bone and/or cartilage, stopping bleeding, tubal ligation, Sur fibre adhesives, pessary, pins, retention cuffs, screws, sheet gical adhesion prevention and the like. ing, sponges, staples, stomach ports, Surgical instruments, 0052 Furthermore, in some preferred embodiments of the transducer protectors, urethral stents, vaginal contraceptives, invention, the present contrast media may be advantageously valves, vessel loops, water and saline bubbles, achtabular used in making various orthopaedic devices including, for cups, annuloplasty ring, aortic/coronary locators, artificial example radio-opaque biodegradable screws, radio-opaque pancreas, balloons, batteries, bone cement, breast implants, biodegradable suture anchors, and the like for use in applica cardiac materials, such as fabrics, felts, films, markers, mesh, tions including the correction, prevention, reconstruction, patches, cement spacers, cochlear implant, defibrillators, and repair of the anterior cruciate ligament (ACL), the rotator generators, orthopaedic implants, pacemakers, patellar but cuff/rotator cup, and other skeletal deformities. tons, penile implant, pledgets, plugs, plates, ports, prosthetic 0053 Other devices, which advantageously can be made heart Valves, sheeting, shunts, stylets, umbilical tape, valved radio-opaque with the present invention includes devices for conduits, Surgical-use cotton and vascular access devices. use in tissue engineering. Examples of Suitable devices 0.058 Preferably the medical device according to the include tissue engineering scaffolds and grafts (such as vas invention is selected from catheters, tubes, strings, meshes, cular grafts, grafts or implants used in nerve regeneration). Sutures, cotton, Stents, cannulae, plugs, plates, rods, guide The present contrast agents may also be added to polymers wires, shunts, screws, pins, prostheses, balloons, needles, used to form a variety of devices effective for use in closing clips, and Staples. internal wounds. For example biodegradable Sutures, clips, 0059) Other preferred devices are scaffolds, drug delivery Staples, barbed of mesh Sutures, implantable organ Supports, systems, endoprostheses of heart Valves, endoprostheses of and the like, for use in various Surgery, cosmetic applications, ligaments, tendons and muscles and dental filling composites. and cardiac wound closures can be formed. 0060. In a further embodiment the present invention pro 0054 Various devices finding use in dental applications vides articles comprising a radio-opaque composition can advantageously be made using radio-opaque composi wherein said radio-opaque composition comprises a cleav tions according to preferred aspects of the present invention. able, preferably enzymatically-cleavable derivative of a For example devices for guided tissue regeneration, alveolar physiologically tolerable organoiodine compound and a ridge replacement for denture wearers, and devices for the polymer, preferably a non-acrylic and/or biodegradable poly Surgeon/dentist can ascertain the placement and continuous mer. The articles according to this embodiment can be any for function of Such implants by simple X-ray imaging. which X-ray monitoring can be envisaged. Preferred articles US 2011/0052503 A1 Mar. 3, 2011

according to this embodiment of the invention include toys or toy components (e.g. building blocks, eyes and buttons for -continued dolls and cuddly animals) and other things which children are likely to ingest. Thus, a further aspect of the invention is a toy comprising a radio-opaque composition wherein said radio OAc opaque composition comprises a polymer and a cleavable, AcO preferably enzymatically-cleavable, derivative of an orga I O noiodine compound. 0061 Moreover, radio-opaque compositions comprising a polymer and the polymer-soluble organoiodine compounds "> N NH ~~. O OAc described herein are also potentially useful in situations when I I the attenuation of X-ray radiation is desired, e.g. in panels in radiography departments or protective shields etc. Radiation protective equipment comprising an organoiodine compound O H roc dissolved in a polymer provides a further aspect of the inven OAC tion. 0062. The invention will now be described further with reference to the following non-limiting Examples. Parts and o = 7, p = 2, q = 1 percentages are by weight unless otherwise indicated. Iohexylhexa-acetate (10 mg) was added to a stirred solution EXAMPLE1 of poly(L-lactide-co-caprolactone-co-glycolide, 70:20:10)(90mg) in CHC1 (2.0 ml) and heated at 40° C. for Stability of Iohexyl Hexa-Acetate in Human Plasma 30 minutes. The mixture was cooled to room temperature, evaporated in vacuo to leave the product as a white crystalline 0063 A stock solution of iohexyl hexa-acetate was pre solid. pared by adding 100 mg. IHA to a 100 ml volumetric flask, followed by 1.0 ml DMSO and deionised water to 100 ml, EXAMPLE 3 giving a final concentration of 1.0 mg/ml. The plasma solu tion was prepared by adding 1.61 ml of the IHA stock solution Preparation of poly(e-caprolactone) with iohexyl to 3.39 ml of citrated bovine plasma, giving a final concen hexa-acetate homogenously distributed therein tration of 300 uM. The citrated human plasma was incubated at 37°C., and 0.25 ml plasma removed at 1, 2, 3, 4, 6, 8, 24, 0066 30 and 48 h. Proteins were discarded from the samples by centrifugal filtration and the resulting filtrates analyzed by HPLC. The concentrations of iohexyl hexa-acetate and iohexyl from 0 to 48 h are plotted in FIG. 1. O

0064. As shown in FIG. 1, the concentration of iohexyl is -- constant the first 8 h, then the concentration increases dra : 4----pi : matically from 8 to 48 h. At the same time the change in iohexyl hexa-acetate concentration follows and opposite trend. The iohexyl hexa-acetate concentration starts to OAc decrease immediately after incubation at 37°C., and after 24 AcO hit is no longer possible to detect any IHA left in the plasma. I O H3C N EXAMPLE 2 r H ro. O OAc Preparation of poly(L-lactide-co-caprolactone-co I I glycolide, 70:20:10) with iohexylhexa-acetate homogenously distributed therein O H rrow 0065 OAC

O O Iohexylhexa-acetate (0.10 g) was added to a stirred solution O O of poly(e-caprolactone) (0.90 g) in CHCl (2.0 ml) and :: o O p qN + pi heated at 40° C. for 30 minutes. The mixture was cooled to CH O room temperature, evaporated in vacuo to leave the productas a white crystalline solid. US 2011/0052503 A1 Mar. 3, 2011 13

EXAMPLE 4 ml). The precipitate was filtered off and dried in vacuo to leave the product as a white crystalline solid. Preparation of poly(lactide-co-glycolide, 50:50) with iohexylhexa-acetate homogenously distributed EXAMPLE 6 therein 0067 Synthesis of Iopamidol Pentaacetate 0069 O

O -- : O pi OAc I CH O OAc

AcO I O

H3C N NH SrirroH O OAc I I OAc OAc O H rrow OAC Acetic anhydride (31.2g, 0.30 mol) was added dropwise to a suspension of iopamidol (20.0g, 25.7 mmol) in pyridine (100 Iohexylhexa-acetate (10 mg) was added to a stirred solution ml) at room temperature. The reaction mixture was stirred for of poly(lactide-co-glycolide, 50:50) (90 mg) in CHCl (2.0 48 h, then poured into water (isotonic, 0.8 L) and the com ml) and heated at 40° C. for 30 minutes. The mixture was pound precipitated out of the solution. The precipitate was cooled to room temperature, evaporated in vacuo to leave the filtered off, and the residue recrystallized to leave the title product as a white crystalline solid. compound as a white crystalline Solid (22.1 g, 86%). 'H-NMR (DMSO-) & 10.13 (s, 1H), 8.92 (t, 1H), 8.81 (d. EXAMPLE 5 1H), 5.26-5.20 (m. 1H), 4.36-4.30 (m, 2H), 4.17-4.12 (m, 8H), 3.31 (s. 2H), 2.10 (d. 2H), 2.03 (brs, 12H), 1.51 (d. 2H). Preparation of Poly(DL-lactide) with iohexylhexa acetate homogenously distributed therein EXAMPLE 7 0068 Synthesis of Methyl Diatrizoate 0070 O CH3

: NullsO pi * | ÖH, O OAc

AcO I O HC N H ro. O OAc I I Methyliodide (1.55g, 10.98 mmol) was added to a mixture of O H roc diatrizoic acid (5.0 g, 8.14 mmol) and CsCO (2.65 g 8.14 OAC mmol) in DMSO (15 ml) and stirred at room temperature for 4 h. Water (70 ml) was added to the reaction mixture and a Iohexylhexa-acetate (0.10 g) was added to a stirred solution white solid precipitated out, filtered off and the residue sepa of poly(DL-lactide) (0.90 g) in CHCl (5.0 ml) and heated at rated with flash chromatography (SiO, CH,Cl) to leave the 40° C. for 30 minutes. The mixture was cooled to room title compound as a white solid (3.25 g 62.5%). "H-NMR temperature and the product precipitated with MeOH (5.0 (DMSO-) 810.04 (s. 2H), 3.31 (s.3H), 2.01 (s, 6H) US 2011/0052503 A1 Mar. 3, 2011 14

EXAMPLE 8 result is outlined in FIG. 3. There was no significant differ ence in bending strength between pure PLLA and PLLA with Synthesis of Dimethyl Iodipamidate added iohexylhexaacetate. 0071 EXAMPLE 12 O O YCH, Dip Coating of PLLA Specimen I I 0075. A pure PLLA specimen was dipped in a saturated O I Solution of iohexylhexaacetate in CH2Cl2. The specimen was H N dried in vacuum at room temperature for 2 h, before the dip N coating process was repeated. The PLLA coated specimen H was dried in vacuum at room temperature overnight. The I O PLLA specimen was visualized by X-ray, seen in FIG. 4. I I EXAMPLE 13 H3C O O Solvent Casting of Polycaprolactone Containing Methyliodide (0.074g. 0.52 mmol) was added to a mixture of Iohexyl Hexaacetate iodipamide (0.20 g, 0.17 mmol) and CsCO, (0.23 g, 0.70 mmol) in DMF (3 ml) and stirred at room temperature for 24 0076 A solution of polycaprolactone (9.0 g) and iohexyl hexaacetate (1.0 g) in CHCl (10 ml) was stirred at 60° C. for h. The reaction mixture was evaporated in vacuo and the 10 minutes, then 0.5, 1.0 and 1.5 ml of the polymer solution residue separated with flash chromatography (SiO2, CH,Cl) was transferred to three vials and dried at 40°C. for 2 h. The to leave the title compound as a white solid (0.15 g 75%). polycaprolactone films containing iohexylhexaacetate were 'H-NMR (CDC1,) 88.49 (s.2H), 3.96 (s, 6H), 1.89 (brs, 4H). visualized with X-ray, seen in FIG. 5a (0.5 ml), 5 b (1.0 ml) 1.40 (brs, 4H) and 5 c (1.5 ml). EXAMPLE 9 Compression Moulding of PLLA (poly-L-lactide) EXAMPLE 1.4 Test Bars Containing Iohexyl Hexaacetate Injection Moulding of Polypropylene Specimens 0072 Iohexylhexaacetate was mixed with PLLA beads to Containing Iohexyl Hexaacetate give powder mixtures with 2, 5, 10, 15 and 20 wt % contrast agent. The mixtures were then compression moulded at 200° 0077 Iohexylhexaacetate (10 g) was mixed with polypro C. for 2 minutes, allowed to cool to room temperature and cut pylene beads (SABICR. RA 12 MN40) (90 g) and the powder into PLLA specimens with dimension 50 mmx5mmx2 mm. mix injection moulded (DEMAG ERGOTech 25-80, screw The specimens were annealed at 70° C. to leave the final temperature 210°C.) to leave polypropylene specimens con specimens. The samples were cut into pieces of 150 mg. taining 10 wt % iohexylhexaacetate. The injection moulded dissolved in CHCl (5.0 ml) and analyzed by HPLC. The polypropylene specimens with 10 wt % iohexylhexaacetate chromatograms showed no degradation of iohexyl hexaac were visualized with by X-ray, seen in FIG. 6. etate. EXAMPLE 1.5 EXAMPLE 10 Injection Moulding of Polyamide Specimens Con Determination of Mass Loss of PLLA Specimens Containing Iohexyl Hexaacetate taining Iohexyl Hexaacetate 0073. The mass loss of PLLA specimens containing 2, 5, 0078 Iohexyl hexaacetate (10 g) was mixed with polya 10, 15 and 20 wt % of iohexylhexaacetate were determined. mide beads (PA6) (90 g) and the powder mix injection moul Three PLLA specimens for each concentration were incu ded (DEMAGERGOTech25-80, screw temperature 240° C.) bated in PBS (phosphate buffered saline) at 37° C., and the to leave polyamide specimens containing 10 wt % iohexyl mass loss was determined by weighing at day 1, 2, 3, 5, 8 and hexaacetate. The injection moulded polyamide specimens 10. The result is outlined in FIG. 2. There was no significant with 10 wt % iohexylhexaacetate were visualized with X-ray, difference in mass loss between pure PLLA and PLLA with seen in FIG. 7. iohexylhexaacetate added. EXAMPLE 16 EXAMPLE 11 Mechanical Testing of PLLA Specimens Containing Injection Moulding of HDPE (High Density Poly Iohexyl Hexaacetate Ethylene) Specimens Containing Iohexyl Hexaac etate (IHA) 0074 The bending strength of PLLA specimens contain ing 2, 5, 10, 15 and 20 wt % of iohexyl hexaacetate were (0079. Iohexylhexaacetate (10 g) was mixed with HDPE determined. Three PLLA specimens for each concentration (HMA016 ExxonMobil) (90 g) and the powder mix injection were incubated in PBS at 37°C., and bending strength at day moulded (DEMAG ERGOTech 25-80, screw temperature 1, 5, 8 and 10 determined by four point bending testing. The 180° C.)) to leave HDPE specimens containing 10 wt % US 2011/0052503 A1 Mar. 3, 2011 iohexyl hexaacetate. The injection moulded HDPE speci acyloxyalkylamino, acyloxyalkylcarbonylamino, acy mens with 10 wt % iohexylhexaacetate were visualized with loxyalkylaminocarbonyl, alkoxyalkyl, alkoxyalkylcar X-ray, seen in FIG.8. bonyl, alkoxyalkylamino, alkoxyalkylcarbonylamino, or alkoxyalkylaminocarbonyl group. EXAMPLE 17 5. The composition as claimed in claim 4 wherein each R Emulsion Polymerization of PS Beads Containing group comprises a triiodophenyl group attached via a 1 to 10 IHA atom bridge composed of bridging atoms selected from O, N and C. 0080. A solution of aqueous 1% PVP K90 (500 ml) in a 6. The composition as claimed in claim 1 wherein said four-necked round-bottom flask is heated to 70° C. with derivative is iohexyl hexaacetate, iopamidol penta-acetate, mechanical stirring. A solution of vinylbenzene (70.0 g, methyl diatrizoate or dimethyl dipamidate. 672.1 mmol), iohexylhexaacetate (30.0g, 27.9 mmol) and 7. The composition as claimed in claim 1 wherein said benzoyl peroxide (3.25 g, 13.4 mmol) is added dropwise and polymer is biodegradable. the emulsion stirred at 70° C. for 24 h, cooled to room tem perature and the PS beads filtered off and the solidlyophilized 8. The composition as claimed in claim 1 wherein said to leave PS beads with iohexylhexaacetate incorporated. polymer is biocompatible. 9. The composition as claimed in claim 1 wherein said 1. A radio-opaque composition comprising a cleavable, polymer comprises polylactic acid, polycaprolactone, polyg preferably enzymatically-cleavable, derivative of a physi lycolic acid, polylactide-co-glycolide. ologically tolerable organoiodine compound and a non 10. The composition as claimed in claim 1 wherein said acrylic polymer wherein said derivative is dissolved in said polymer comprises polyesters such as poly(L-lactide), poly non-acrylic polymer. (D.L-lactide), poly(caprolactone), poly(glycolic acid), poly 2. The composition as claimed in claim 1 wherein said (lactide-co-glycolide), poly(lactide-co-caprolactone), poly derivative is a lipophilic ester of said organoiodine com (glycolide-co-caprolactone), polytrimethylene carbonate, pound. poly(3-hydroxybutyrate), poly(3-hydroxyvalerate), poly(4- 3. The composition as claimed in claim 1 wherein said hydroxybutyrate), poly(dioxanone) polyamides such as poly organoiodine compound is selected from diatrioZinic acid, (caproamide), poly(hexamethylene adipamide), poly(p-phe iobenguane, iobenzamic acid, iobitriol, iocarmic acid, ioc nyleneterephtalamide), polyhydrocarbones Such as poly etamic acid, iodamide, iodipamide, iodixanol, iodized oil, iodoalphionic acid, p-iodianiline, o-iodobenzoic acid, (ethylene), poly(propylene), poly(1-hexene), poly(1-hexene iodochlorhydroxyquin, o-iodohippurate sodium, o-iodophe co-4-methyl-1,4-hexadiene), poly(tetrafluoroethylene), poly nol, p-iodophenol, iodophthalein sodium, iodopsin, (vinyl alcohol), polyacetals such as poly(formaldehyde), iodpyracet, iodopyrrole, iodoquinol, iofetamine 'I, iogly polyketals, polyglycols, polyurethanes, segmented polyure camic acid, iohexyl, iomeglamic acid, iomeprol, iopamidol. thanes, polyanhydrides, polyphosphaZenes, polysulfones, iopanoic acid, iopentol, iophendylate, iophenoxic acid, silicones, ABS resins, natural polymers such as collagen, iopromide, iopronic acid, iopydol, iopydone, iothalamic acid, fibrin, polysaccharides such as chitosan. iotrolan, ioVersol, ioxiglimic acid, ioxalic acid, ioxilan and 11. The composition as claimed in claim 1 wherein said ipodate. polymer is a homopolymer, block copolymer, random 4. The composition as claimed in claim 1 wherein said copolymer, graft copolymer or polymer blend. derivative of a physiologically tolerable organoiodine com 12. The composition as claimed in claim 1 further com pound is a compound of formula (I): prising a medical agent. 13. The composition as claimed in claim 12 wherein said medical agent is selected from anti-proliferative agents (pa (I) clitaxel and the like), immunosuppressive agents (dexam ethasone, rapamycin, tacromilus, mycophenolic acid and the like), anti-inflammatory agents (aspirin, ibuprofen, naproxen and the like) anti-matrix metalloproteinase, lipid lowering agents (simvastatin, lovastatin, pravastatin and the like), anti thrombotic agents, antiplatelet agents (e.g. clopidogrel, ticlo dipine, dipyridamole, epoprostenole, iloprostenole, arga troban and the like), antibiotics and antiseptics, e.g. gentamicin, colistin, erythromycin, clindamicin, penicillins, norfloxacin, chloramphenicol etc. wherein each R group which may be the same or different, comprises an acyloxyalkylcarbonylamino, N-(acyloxy 14. The composition as claimed in claim 12 alkyl carbonyl)acyloxyalkylamino, N-acyloxyalkylcar wherein said medical agent is present in the form of a bonyl-N-alkyl-amino, acyloxyalkylaminocarbonyl, bis lipophilic ester. (acyloxyalkyl)aminocarbonyl, N-acyloxyalkyl-N- 15. A process for producing a radio-opaque composition as alkyl-aminocarbonyl, alkoxyalkylaminocarbonyl, claimed in claim 1 wherein said process comprises adding N-alkyl-alkoxyalkylaminocarbonyl, bis(alkoxyalkyl) said derivative of organoiodine contrast agent to said polymer amino-carbonyl, alkoxyalkylcarbonylamino, N-alkyl and mixing. alkoxyalkylcarbonylamino or N-alkoxyalkylcarbonyl 16. The process as claimed in claim 15 wherein said poly alkoxyalkylamino group or a triiodophenyl group mers are in Solution, bead or powder form. attached via a 1 to 10 atom bridge (preferably composed 17. The process as claimed in claim 15 wherein said deriva of bridging atoms selected from O, N and C) optionally tive of a contrast agent and said polymer are heated to a melt Substituted by an acyloxyalkyl, acyloxyalkylcarbonyl, under stirring. US 2011/0052503 A1 Mar. 3, 2011

18. Use of a radio-opaque composition as claimed in claim shunts, screws, pins, prostheses, balloons, needles, clips, 1 in the manufacture of a radio-opaque article. Staples, scaffolds, drug delivery systems, endoprostheses of 19. A radio-opaque article comprising a radio-opaque heart valves, endoprostheses of ligaments, tendons and composition as claimed in claim 1. muscles and dental filling composites. 23. The article as claimed in claim 19 wherein said article 20. An article coated with a radio-opaque composition as is a toy. claimed in claim 1. 24. The article as claimed in claim 20 wherein said article 21. The article as claimed in claim 19 wherein said article is a medical device. is a medical device. 25. The article as claimed in claim 20 wherein said article 22. The article as claimed in claim 21 wherein said medical is a toy. device is selected from catheters, tubes, strings, meshes, Sutures, stents, cannulae, plugs, plates, rods, guide wires,