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(12) Patent Application Publication (10) Pub. No.: US 2013/0323181 A1 Mosher (43) Pub

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(12) Patent Application Publication (10) Pub. No.: US 2013/0323181 A1 Mosher (43) Pub US 2013 0323 181A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2013/0323181 A1 Mosher (43) Pub. Date: Dec. 5, 2013 (54) STABILIZED FORMULATIONS CONTAINING Related U.S. Application Data ODINATED CONTRASTAGENTS AND CYCLODEXTRINS (60) Provisional application No. 61/652,993, filed on May 30, 2012. (71) Applicant: VERROW PHARMACEUTICALS, Publication Classification INC., Lenexa, KS (US) (51) Int. Cl. (72) Inventor: Gerold L. Mosher, Kansas City, MO A614.9/04 (2006.01) (US) (52) U.S. Cl. CPC .................................. A61K 49/0438 (2013.01) (73) Assignee: VERROW PHARMACEUTICALS, USPC ......................................................... 424/9.43 INC., Lenexa, KS (US) (57) ABSTRACT The invention encompasses compositions containing an iodi (21) Appl. No.: 13/787,495 nated contrast agent and a Substituted cyclodextrin wherein the cyclodextrin stabilizes the contrast agent against degra 22) Filed: Mar. 6, 2013 dation byy ultraviolet or visible light exposure.p Patent Application Publication Dec. 5, 2013 Sheet 1 of 2 US 2013/032.3181 A1 FIGURE 1 O.O O.5 1.0 1.5 2.0 2.5 Cyclodextrin:lohexol Mole Ratio FIGURE 2 35 coc 30 O 50 100 150 200 250 TimeAfter First Dose Administration (Seconds) Patent Application Publication Dec. 5, 2013 Sheet 2 of 2 US 2013/032.3181 A1 FIGURE 3 120 - O 50 100 150 200 250 Time After First Dose Administration (Seconds) US 2013/0323 181 A1 Dec. 5, 2013 STABILIZED FORMULATIONS CONTAINING ucts generated by irradiating an iodinated contrast agent with ODINATED CONTRASTAGENTS AND low energy X-rays. Joubert, et al., (Int J Radiation Oncology CYCLODEXTRINS Biol Phys (2005), 62(5): 1486-1496) reported that X-ray irra diation of the iodinated contrast agent iomeprol produced CROSS-REFERENCE TO RELATED iodide and other degradants, and the irradiated contrast agent APPLICATION was toxic to bovine aortic endothelial cells while the non irradiated contrast agent was not toxic. 0001. This application claims the benefit of U.S. Provi 0007 Iodine can also elicitan allergic response. Shionoya, sional Application Ser. No. 61/652,993 filed May 30, 2012, et al., (J Tox Sci (2004), 29(2): 137-145) reported the occur the entire contents of each of which are incorporated herein rence of allergic response in guinea pigs dosed with iodinated by reference. proteins. They also demonstrated the formation of iodine and iodide ions in Solutions containing ionic (iothalamate FIELD OF THE INVENTION Sodium) and non-ionic (iohexyl) contrast media after expo 0002 The invention encompasses liquid formulations sure to ultraviolet light, and that the iodine was then capable comprising an iodinated contrast agent or a salt thereof and a of iodinating proteins. substituted cyclodextrin, wherein the cyclodextrin provides 0008 Degradation of contrast media with resultant forma improved chemical stability of the contrast agent when tion of iodine and iodide species can also result from heat exposed to ultraviolet or visible light irradiation. exposure Such as during heat sterilization, i.e. thermal degra dation, and from exposure to visible and ultraviolet light, i.e. BACKGROUND OF THE INVENTION photodegradation (Eloy, et al., Clin Mater (1991), 7: 89-197). 0003. Iodinated contrast agents are routinely used in diag 0009 Cyclodextrins and their derivatives are widely used nostic and interventional medical procedures to assist in the in liquid formulations to enhance the aqueous solubility of visualization of body organs and the structures around them. hydrophobic compounds by forming inclusion complexes. The chemical structure of these agents includes one or more Their presence informulations can also increase, decrease, or iodine atoms, which imparts the necessary opaqueness have no effect on photodegradation (Glass, et al., Int J Pho towards X-rays. They are most often administered intrave toenergy, (2001), 3: 205-211). nously but can be administered intraarterially, intrathecally, 0010. The inventor has identified improved formulations orally and intraabdominally. They are usually safe and containing iodinated contrast agents and Substituted cyclo adverse effects are generally mild and self-limiting. Nonethe dextrins that demonstrate reduced chemical degradation less, severe or life-threatening reactions and complications when exposed to ultraviolet or visible light. The formulations Cal OCC. are biocompatible and can be rapidly administered into the 0004 Contrast media toxicity and adverse effects can vessels of the heart with little or no alterations of cardiac result from the chemotoxicity of the contrast agent and/or its function. The formulations can also be sterilized by heat degradants, the osmolality of the contrast medium, and the without significant chemical degradation. ionic composition (or lack thereof) of the contrast medium. In coronary angiography, for example, injection of contrast SUMMARY OF THE INVENTION media into the circulatory system has been associated with 0011. The present invention encompasses iodinated con several serious effects on cardiac function. In this procedure trast agent compositions with improved Stabilization against the contrast medium, rather than blood, flows through the chemical degradation caused by exposure of the composi circulatory system for a brief period of time. Due to the tions to visible or ultraviolet light. The invention provides differences in ionic composition between blood and the con aqueous pharmaceutical compositions having a pH of 5 to 8 trast medium, undesirable effects can be observed such as and comprising an iodinated contrast agent or a salt thereof, a arrhythmias, QT-prolongation, reduction in cardiac contrac pharmaceutically acceptable buffering agent, and a Substi tile force, and occurrence of ventricular fibrillation. tuted cyclodextrin present at a contrast agent to Substituted 0005. The occurrence and severity of adverse reactions cyclodextrin mole ratio from 1:0.01 to 1:2. These formula related to high osmolality and ionic content has been reduced tions exhibit less chemical degradation, e.g. less formation of with the discovery and use of nonionic contrast agents. How iodine species, upon exposure to ultraviolet or visible light as ever research into ways to further reduce the potential for compared to a corresponding composition which does not adverse reactions continues. The two main approaches have contain a substituted cyclodextrin. been to form dimeric structures of the contrast agents to 0012. The present invention encompasses ready to use, maintain the iodine content while reducing the osmolality, sterile, injectable, aqueous pharmaceutical compositions and to add Small amounts of physiologic salts to the formu having a pH of 5 to 8 and comprising an iodinated contrast lations. agent and a Substituted cyclodextrin present at a contrast 0006 Another of the potential toxicities of iodinated con agent to substituted cyclodextrin moleratio of 1:0.01 to 1:0.1. trast agents results from the release of iodine following deg These formulations include iodinated contrast agents such as, radation. The released iodine species such as molecular for example, iohexyl, iopamidol, iodixanol, ioVersol, iopro iodine, I, and iodide ion, IT, are thought to be causative mide and ioxaglate. In certain embodiments, the formulation agents intoxicity to the cells of the kidney (Sendeski, M. Clin includes 1 to 4 mg/ml tromethamine (TRIS) buffer, or 0.1 to Exp Pharmacol Physiol (2011) 38: 292-299), a condition 0.6 mg/ml disodium calcium edetate, or both 1 to 4 mg/ml known as contrast induced nephropathy or CIN. Gastaldo et TRIS buffer and 0.1 to 0.6 mg/ml disodium calcium edetate. al., (JSynchrotron Radiat (2011), 18(Pt3): 456-463) reported The substituted cyclodextrin includes sulfoalkyl ether cyclo that iodide causes toxicity in cultured endothelial HMEC dextrins, e.g., a Sulfobutylether beta cyclodextrin, and cells. The toxicity was observed after incubating the cells hydroxyalkyl ether cyclodextrins, e.g., a 2-hydroxypropyl with sodium or potassium iodide, or with the photolysis prod beta cyclodextrin. In certain embodiments, the formulation is US 2013/0323 181 A1 Dec. 5, 2013 packaged in a primary container which does not possess 0022. As used herein, the term “alkalizing agent' is enhanced light shielding properties. In other embodiments, intended to mean a compound used to provide an alkaline the formulation is heat sterilized after it is packaged in the medium. Such compounds include, by way of example and primary container. without limitation, ammonia Solution, ammonium carbonate, diethanolamine, monoethanolamine, potassium hydroxide, BRIEF DESCRIPTION OF THE DRAWINGS Sodium borate, sodium carbonate, Sodium bicarbonate, 0013 FIG. 1 illustrates the binding constant of iohexyl Sodium hydroxide, triethanolamine, diethanolamine, organic with sulfobutylether f3-cyclodextrin at various cyclodextrin: amine base, alkaline amino acids and trolamine and others iohexyl mole ratios. Error is standard error of the mean. known to those of ordinary skill in the art. 0014 FIG. 2 shows the change in cardiac QTc interval in (0023 The terms “alkylene' and “alkyl,” as used herein dogs receiving multiple doses of iohexyl (D) or iohexyl plus (e.g., in the —O—(C-C-alkylene) SO group or in the sulfobutylether beta-cyclodextrin () injected into the left alkylamines), include linear, cyclic, and branched, Saturated coronary artery. Error is standard deviation with n=3. and unsaturated (i.e., containing one double bond) divalent 0015 FIG.3 shows the change in left ventricular
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