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(12) Patent Application Publication (10) Pub. No.: US 2011/0052503 A1 Almen Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2011/0052503 A1 Almen Et Al 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
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