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 contrac alkylene groups and monovalent alkyl groups, respectively. tility, LV dP/dT, in dogs receiving multiple doses of The term "alkanol in this text likewise includes linear, cyclic iohexyl (D) or iohexyl plus sulfobutylether beta-cyclodextrin and branched, Saturated and unsaturated alkyl components of () injected into the left coronary artery. Error is standard the alkanol groups, in which the hydroxyl groups may be deviation with n=3. situated at any position on the alkyl moiety. The term “cycloalkanol includes unsubstituted or substituted (e.g., by DETAILED DESCRIPTION OF THE INVENTION methyl or ethyl)cyclic alcohols. 0024. As used herein, the term “antioxidant’ is intended to 0016. Unless otherwise specified, all percentages and mean an agent that inhibits oxidation and thus is used to amounts expressed herein and elsewhere in the specification prevent the deterioration of preparations by the oxidative should be understood to refer to percent by weight. The con process. Such compounds include, by way of example and centration is denoted in mg/mL. Also, the term “about, when without limitation, acetone, potassium metabisulfite, potas used in reference to a range of values, should be understood to sium Sulfite, ascorbic acid, ascorbyl palmitate, citric acid, refer to either value in the range, or to both values in the range. butylated hydroxyanisole, butylated hydroxytoluene, hypo 0017. As used throughout, ranges are used as shorthand phosphorous acid, monothioglycerol, propyl gallate, Sodium for describing each and every value that is within the range. ascorbate, sodium citrate, Sodium sulfide, Sodium sulfite, Any value within the range can be selected as the terminus of sodium bisulfite, sodium formaldehyde sulfoxylate, thiogly the range. colic acid and sodium metabisulfite and others knownto those 0018 All documents, for example, scientific publications, of ordinary skill in the art. patents, patent applications and patent publications, recited (0025. As used herein, the term “biocompatible” refers to herein are hereby incorporated by reference in their entirety to formulations that do not produce a toxic, injurious, or immu the same extent as if each individual document was specifi nological response to living tissue or to compounds that pro cally and individually indicated to be incorporated by refer duce only an insubstantial toxic, injurious, or immunological ence in its entirety. In the event of a conflict in a definition in response. The heart and coronary arteries are particularly the present disclosure and that of a cited reference, the present Susceptible to injury from injection of large amounts of solu disclosure controls. tions that have ionic compositions different than the blood they are displacing. Several iodinated contrast agent formu DEFINITIONS lations have been made more biocompatible through the addi 0019. The indefinite articles “a” and “an as used herein in tion of Small amounts of sodium and/or calcium ions. the specification and in the claims, unless clearly indicated to 0026. As used herein, the term “buffering agent' is the contrary, should be understood to mean “at least one.” intended to mean a compound used to resist change in pH 0020. As used herein, “or” is understood to mean inclu upon storage, dilution or addition of acid or alkali. Such sively or, i.e., the inclusion of at least one, but including more compounds include, by way of example and without limita than one, of a number or list of elements. Only terms clearly tion, acetic acid, Sodium acetate, adipic acid, benzoic acid, indicated to the contrary, such as “exclusively' or “exactly Sodium benzoate, citric acid, maleic acid, monobasic sodium one of will refer to the inclusion of exactly one element of a phosphate, dibasic sodium phosphate, lactic acid, tartaric number or list of elements. acid, tromethamine and its salts, meglumine, glycine, potas 0021. As used herein, the term “acidifying agent' is sium metaphosphate, potassium phosphate, sodium bicar intended to mean a compound used to provide an acidic bonate, sodium tartrate and Sodium citrate anhydrous and medium. Such compounds include, by way of example and dihydrate and others known to those of ordinary skill in the without limitation, acetic acid, acidic amino acids, citric acid, art. fumaric acid and other alpha hydroxy acids, hydrochloric 0027. As used herein the term “chelating agent” refers to acid, ascorbic acid, phosphoric acid, Sulfuric acid, tartaric organic compounds which complex or sequester metal ions acid and nitric acid and others known to those of ordinary skill and reduce their potential to interact in drug degradation in the art. pathways Such as those involving free radicals or oxidation US 2013/0323 181 A1 Dec. 5, 2013 reduction. Such compounds include, by way of example and although, for the sake of brevity, generally "comprising is without limitation, ethylenediaminetetraacetic acid (EDTA, utilized in the compositions described herein. edetate), citric acid, fumaric acid, malic acid, pentetic acid, 0031. As used herein the term “cyclodextrin” or “CD” and/or salts thereof, maltol, and others known to those of refers to compounds encompassed by the formula 1: ordinary skill in the art. Preferred chelating agents include citric acid and/or salts thereof, and the disodium, trisodium, tetrasodium, and disodium calcium salts of EDTA. Formula 1

0028 By "complexed' is meant “being part of a clathrate or inclusion complex with', i.e., a complexed contrast agent is part of a clathrate or inclusion complex with a Substituted cyclodextrin. Cyclodextrins are cone-shaped cyclic carbohy drates containing 6, 7, or 8 glucopyranose units. The interior cavity of the cyclodextrin structure is hydrophobic and pro vides a haven for hydrophobic compounds, which can fit part or all of their structure into these cavities, forming inclusion complexes. This inclusion complexation only occurs if there is sufficient enthalpic or entropic energetics to drive the inclu sion (Brewster, ME and Loftsson T. Cyclodextrins as phar maceutical solubilizers, Advanced Drug Delivery Reviews, 0032 wherein n is 4, 5 or 6 and R is at each occurrence 59 (2007) 645-666). In addition, the geometry must allow for —OH. The terms alpha-cyclodextrin, beta-cyclodextrin and at least partial insertion of the compound into the cyclodextrin gamma-cyclodextrin refer to cyclodextrins wherein n is 4, 5 cavity. Agents soluble in water, such as iodinated contrast and 6 respectively. The term “substituted cyclodextrin” or agents, will typically interact poorly or not at all with the “SCD” refers to a cyclodextrin of the formula 1 wherein R is hydrophobic cavities of cyclodextrins, and form no inclusion selected at each occurrence from —OH or a different chemi complexes. cal substituent and at least one R is the different chemical Substituent. The substituted cyclodextrin can contain a single 0029. The actual percent of a compound that is complexed type of chemical substituent or more than one type within the will vary according to the complexation equilibrium constant same cyclodextrin molecule. For example, a cyclodextrin can characterizing the complexation of a specific Substituted have one —OH group substituted with a sulfoalkyl ether cyclodextrinto a specific compound and to the concentrations substituent and another —OH group substituted with a of the substituted cyclodextrin and compound available for hydroxyalkyl ether substituent. Substituted cyclodextrin complexation. The complexation constant between a cyclo compounds include, by way of example and without limita dextrin and an insoluble agent can be determined experimen tion, sulfoalkyl ether cyclodextrins, hydroxyalkyl ether tally by conducting phase solubility studies (Higuchi, T. and cyclodextrins, sulfoalkyl ether-hydroxyalkyl ether cyclodex trins, sulfoalkylether-alkyl ether cyclodextrins, alkylether Connors, K. A. in Advances in Analytical Chemistry and cyclodextrins, hydroxybutenyl ether derivatives, hydroxy Instrumentation Vol. 4 Reilly, Charles N. Ed., John Wiley & butenyl sulfonate or sulfinate derivatives and mixtures Sons., 1965, pp. 117-212) where the solubility of a drug is thereof, carboxyalkyl thio derivatives, and others known to determined in the presence of increasing amounts of a cyclo those of ordinary skill in the art. dextrin or substituted cyclodextrin. When the agent is water 0033. The number of hydroxyl groups in a cyclodextrin soluble, as is the case with the iodinated contrast agents, an that have been replaced by a different chemical substituent is alternate approach must be used such as the membrane per represented by a number referred to as the degree of substi meation method described by Ono, et al. (Eur. J. Pharm. Sci., tution (DS). It should be noted that preparation of substituted 8 (1999) 133-139) or variations thereof. cyclodextrins occurs in a controlled, although not exact man ner. For this reason, the degree of Substitution is actually a 0030. As used herein, the transitional phrases “compris number representing the average number of Substituent ing', 'consisting essentially of and "consisting of define groups per cyclodextrin. For example, SBE7-3-CD, has an the scope of the appended claims with respect to what un average of about 7 sulfobutylether substitutions per beta (B) recited additional components, if any, are excluded from the cyclodextrin and HP4-B-CD has an average of about 4 scope of the claim. The term “comprising is intended to be hydroxypropyl Substitutions. In addition, the regiochemistry inclusive or open-ended and does not exclude additional, of substitution of the hydroxyl groups of the cyclodextrin is un-recited elements or method steps. The phrase “consisting variable with regard to the substitution of specific hydroxyl groups of each hexose ring. For this reason, Substitution of of excludes any element, step, or ingredient not specified in different hydroxyl groups is likely to occur during manufac the claim. The phrase “consisting essentially of limits the ture of the substituted cyclodextrin, and a particular substi Scope of a claim to the specified materials or steps and those tuted cyclodextrin will possess a preferential, although not that do not materially affect the basic and novel characteristic exclusive or specific, Substitution pattern. (s) of the claimed invention. All compositions or formulations 0034. As used herein the term "sulfoalkyl ether cyclodex identified hereincan, in alternate embodiments, be more spe trin” or “SAE-CD refers to compounds encompassed by the cifically defined by any of the transitional phrases "compris formula 1 wherein: n is 4, 5 or 6: R is independently selected ing”, “consisting essentially of and "consisting of at each occurrence from —OH or a —O(C-C alkylene) US 2013/0323 181 A1 Dec. 5, 2013

SOY group; and at least one R is independently a ther substituted with at least one —OH; at least one R is —O(C-C alkylene)SOTY' group, preferably a —O(CH) independently —O(C-C alkylene)SOTY" wherein Y is a SOY group, wherein m is 2 to 6, preferably 2 to 4. (e.g. pharmaceutically acceptable cation; and at least one R is –OCHCHCHSOY" or OCHCHCHCHSO.Y.) independently a —O(C-C alkylene) group further substi and Y is independently selected at each occurrence from the tuted with at least one —OH. In certain illustrative embodi group consisting of pharmaceutically acceptable cations. In ments, n is 5; R is at each occurrence —OH, -O((CH)) certain illustrative embodiments, n is 5; R is at each occur SONa", or - OCHCH(OH)CH; at least one R is rence —OH or —O((CH))SONa"; and at least one R is independently —O((CH))SONa"; and at least one R is independently —O((CH))SONa". In certain embodi independently —OCHCH(OH)CH. In certain embodi ments, the SAE-CD is represented by formula 2: ments, the SAE-HAE-CD is represented by formula 2 wherein R=(OH), or (OCHCHCHCHSOONa), or (OCH2CH(OH)CH) and where n=2 to 6 and p=1 to 6, more Formula 2 preferably where n=3 or 4 and p3 or 4. R 0038. As used herein the term "sulfoalkyl ether-alkyl ether cyclodextrin' or “SAE-AE-CD refers to compounds encom O passed by the formula 1, wherein: n is 4, 5 or 6: R is inde R pendently selected at each occurrence from —OH, -O(C- O O R ... O C alkylene)SOTY wherein Y is a pharmaceutically R R O acceptable cation, or a —O(C-C alkylene) group; at least R one R is independently —O(C-C alkylene)SOY R wherein Y" is a pharmaceutically acceptable cation; and at least one R is independently a —O(C-C alkylene) group. R O O In certain illustrative embodiments, n is 5; R is at each R occurrence —OH, - O((CH))SO-Na', or —OCH2CH: R at least one R is independently —O((CH))SONa"; and at O R R least one R is independently —OCHCH. In certain embodiments, the SAE-AE-CD is represented by formula 2 O R wherein R=(OH), or (OCHCHCHCHSOONa), or R O (OCHCH,), and where n=4 or 6 and p-4 or 6. In certain O R illustrative embodiments, the SAE-AE-CD is sulfobutylether R R 3.5-ethylether 3.5-beta-cyclodextrin (SBE3.5-EE3.5-B-CD). '-o In certain other illustrative embodiments, the SAE-AE-CD is O sulfobutylether 4-ethylether 4-beta-cyclodextrin (SBE4 O R EE4-f3-CD). Sulfoalkyl ether-alkyl ether cyclodextrins are R disclosed in U.S. Pat. No. 7,625,878 0039. As used herein the term “alkyl ether cyclodextrin' or “AE-CD refers to compounds encompassed by the for 0035 wherein R=(OH), O mula 1 wherein: n is 4, 5 or 6: R is independently selected at (OCHCHCHCHSOONa), and where n=6 to 7. In certain each occurrence from —OHora—O(C-C alkylene) group; illustrative embodiments, the sulfoalkyl ether cyclodextrin and wherein at least one R is independently a —O(C-C, (SAE-CD) is sulfobutyl ether 7-beta-cyclodextrin (SBE7-B- alkylene) group. In certain illustrative embodiments, R is at CD). each occurrence —OH or —OCH; at least one R is inde 0036. As used herein the term “hydroxyalkyl ether cyclo pendently —OCH; and at least one R is independently dextrin' or “HAE-CD refers to compounds encompassed by —OH. These alkyl ether cyclodextrins are referred to as “par the formula 1 wherein: n is 4, 5 or 6: R is independently tially methylated cyclodextrins. In certain illustrative selected at each occurrence from —OHora —O(C-C alky embodiments, n is 5; R is at each occurrence —OH or lene) group further substituted with at least one —OH; and —OCH; and at least one R is independently —OCH. In wherein at least one R is independently a —O(C-C alky certain embodiments, the AE-CD is represented by formula 2 lene) group further substituted with at least one —OH. In wherein R—(OH), or (OCH), and where n=4. In certain certain illustrative embodiments, n is 5; R is at each occur illustrative embodiments, the AE-CD is methyl 4-beta-cyclo rence —OH or —OCH-CH(OH)CH; and at least one R is dextrin (Mea-B-CD). independently —OCHCH(OH)CH. In certain embodi 0040. As used herein the term “hydroxybutenyl ether ments, the HAE-CD is represented by formula 2 wherein cyclodextrin' or “HBen-CD” refers to compounds encom R=(OH), or (OCHCHOHCH), and where n=4 to 6. In passed by the formula 1 wherein: n is 4, 5 or 6: R is inde certain illustrative embodiments, the HAE-CD is 2-hydrox pendently selected at each occurrence from —OH, ypropyl-4-beta-cyclodextrin. In certain other illustrative OCHCH(OX)CHCH OCH(CHCH)CHOX, embodiments, the HAE-CD is 2-hydroxypropyl-6-beta-cy OCHCH(OX)CHCHSOM, OCHCH(OX)CH clodextrin. (SOM)CHSOM, OCH(CHOX)CHCHSOM, or 0037. As used herein the term "sulfoalkyl ether-hydroxy –OCH(CHOX)CH(SOM)CHSOM where X is H or alkyl ether cyclodextrin” or “SAE-HAE-CD refers to com another hydroxybutenyl group and M is a pharmaceutically pounds encompassed by the formula 1, wherein: n is 4, 5 or 6: acceptable cation; and wherein at least one R is indepen R is independently selected at each occurrence from —OH, dently OCHCH(OX)CHCH, OCH(CHCH)CHOX, —O(C-C alkylene)SOY" wherein Y" is a pharmaceuti OCHCH(OX)CHCHSOM, OCHCH(OX)CH cally acceptable cation, or a —O(C-C alkylene) group fur (SOM)CHSOM, OCH(CHOX)CHCHSOM, or US 2013/0323 181 A1 Dec. 5, 2013

–OCH(CHOX)CH(SOM)CHSOM where X is H or gasses include, by way of example and without limitation, another hydroxybutenyl group and M is a pharmaceutically argon, nitrogen, helium, carbon dioxide and others known to acceptable cation. Hydroxybutenyl ether cyclodextrins are those of ordinary skill in the art. disclosed in U.S. Pat. No. 6,479,467 and U.S. Pat. No. 6,610, 0045. As used herein the term "iodinated contrast agent' 671. refers to iodine containing organic compounds used to assist 0041 As used herein the term “carboxyalkylthio cyclo in the visualization of body organs and the structures around dextrin' or "CAT-CD refers to compounds encompassed by them in diagnostic and interventional medical procedures the formula 1 wherein: n is 4, 5 or 6: R is independently using X-rays. The iodine present in the compounds blocks selected at each occurrence from —OH or a S(CH) part of the X-rays and thus provides a contrasting visualiza COM group where Z is 1-4, and M is a pharmaceutically tion to the Surroundings not containing the contrast. The acceptable cation; and wherein at least one R is indepen chemical structure of iodinated contrast agents contains a dently a S(CH2)COM group where Z is 1-4 and M is a benzene ring substituted with 1, 2, or 3 iodine atoms. Various pharmaceutically acceptable cation. In certain embodiments additional chemical groups are Substituted onto the benzene n is 6 and eight of the R1 groups are - SCH-CHCOM, ring to impart desired properties such as increased water where M is sodium. In certain embodiments, the CAT-CD is solubility. These groups can be ionic or neutral in charge and SugammadexTM (trade name Bridion). Carboxyalkyl thio two of the iodinated benzene rings can be attached together cyclodextrins are disclosed in U.S. Pat. No. 6,949,527. with various chemical linking groups to form dimeric com 0042. The liquid formulation of the invention will com pounds. Dimeric iodinated contrast agents can be advanta prise an effective amount of an iodinated contrast agent or a geous since solutions containing them can contain the same salt thereof. An effective amount of an iodinated contrast amount of iodine as a corresponding monomeric Solution but agent, or salt thereof, is an amount or quantity of the iodinated have a lower osmolality. contrast agent, or salt thereof, that will block X-rays and 0046. The iodinated contrast agents can be divided into provide a visual contrast between the agent and Surrounding four groups; ionic monomers, ionic dimers, nonionic mono tissue when administered to a Subject undergoing an X-ray mers, and nonionic dimers. Examples of ionic monomers procedure. include but are not limited to, acetrizoic acid, diatrizoic acid, 0043. As used herein the term “heat sterilization” refers to iodamic acid, ioglicic acid, iopanoic acid, iopronic acid, iota the process of exposing materials to elevated temperatures for lamic acid, ioxitalamic acid, ipodic acid, metrizoic acid, and/ Sufficient time and temperature to kill or inactivate any micro or salts thereof. Examples of ionic dimers include but are not organisms present to a level acceptable for the intended use of limited to, iocarmic acid, iodipamide, iodoxamic acid, ioxa the materials. For pharmaceutically acceptable solutions glic acid, and/or salts thereof. Examples of nonionic mono intended for parenteral administration, the generally accept mers include but are not limited to, iobitridol, iohexyl, iome able level is a 10 microbial survivor probability, meaning prol, iopamidol, iopentol, iopromide, iosimide, ioVersol, there is less than one chance in 1 million that viable micro ioXilan, and metrizamide. Examples of nonionic dimers organisms are present. The heat sterilization can be con include but are not limited to, iodixanol, ioforminol, and ducted with dry heat in a chamber expressly designed for that iotrolan. purpose, or by Steam sterilization in a chamber called an 0047. In one embodiment of any of the compositions autoclave. Steam sterilization is typically conducted at a tem described herein, the iodinated contrastagent is selected from perature of about 121-123°C. for periods of 15 to 30 minutes, the group consisting of the ionic agents iocarmic acid, iodi though other temperatures and durations may be used, for pamide, iodoxamic acid, ioxaglic acid, acetrizoic acid, dia example 115-116°C. for at least 30 minutes, 126-129° C. for trizoic acid, iodamic acid, ioglicic acid, iopanoic acid, at least 10 minutes or 134-138°C. for at least 3 minutes. Dry iopronic acid, iothalamic acid, ioxitalamic acid, ipodic acid, heat Sterilization typically requires higher temperatures and metrizoic acid, and their pharmaceutically acceptable salts, exposure times than steam heat sterilization, for example and the nonionic agents iodixanol, ioforminol, iotrolan, 160° C. for at least 180 minutes, 170° C. for at least 60 iobitridol, iohexyl, iomeprol, iopamidol, iopentol, iopro minutes or 180°C. for at least 30 minutes. Other temperatures and times can be used for both steamsterilization and dry heat mide, iosimide, ioVersol, ioxilan, and metrizamide. sterilization as known by those skilled in the art. Materials 0048. The iodinated contrast agentiopamidol is sold under which have undergone the process of heat sterilization are the names Iopamiro(a), IsoVue(R), IopamironTM and Nio said to be “heat sterilized”. In general, compositions of the pamTM. Iodixanol is sold under the name Visipaque?R). Iover invention are heat sterilized after packaging into a primary sol is sold under the name OptirayTM.Iopromide is sold under container. Requirements for sterilization of Solutions and the name Ultravist(R). Ioxaglate is sold under the name methods for evaluating sterility can be found in various phar Hexabrix R (which contains ioxaglate meglumine and ioxag macopeial compendia of standards such as the United States late sodium). Iohexyl is sold under the name Omnipaque R. Pharmacopeia, the Japanese Pharmacopoeia, the European 0049. As used herein the term "iodine content” refers to Pharmacopoeia, the International Pharmacopeia, the British the amount of organically bound iodine contained in the Pharmacopoeia, the Indian Pharmacopoeia, the Pharmaco chemical structure of an iodinated contrast agent or in a poeia of the People's Republic of China, and others. formulation of an iodinated contrast agent. It is commonly 0044 As used herein the term “inert gas” refers to a gas reported as the percentage by weight of the contrast agent, or normally used to provide an inert atmosphere in containers the weight per Volume concentration in a solution comprising containing pharmaceutical compositions. The gas is added to the contrast agent. For example, iohexyl has a molecular the containers to displace oxygen that is present and prevent weight of 821.14 g/mole and contains 3 iodine atoms of the oxygen from facilitating degradation of the composition. molecular weight 126.9 g/mole in each molecule. Its iodine When the composition is a liquid, the gas is also sometimes content is 46.36%. An iohexyl solution formulation compris passed through the liquid to displace dissolved oxygen. Inert ing 755 mg/mL iohexyl contains 350 mg iodine per milliliter US 2013/0323 181 A1 Dec. 5, 2013

or 350 mg/mL. The iodine content of contrast agent formu amine and (C-C)-cycloalkanolamine, and other cations lations commonly used in X-ray procedures ranges from 140 known to be pharmaceutically acceptable to those skilled in to 400 mgl/mL. the art. 0050. As used herein, the term "iodine species' refers to 0054 As used herein, the term “pharmaceutically accept those forms of iodine that are formed by degradation of an able container” is intended to mean a container closure sys iodinated contrast agent by photolysis (e.g. after irradiation tem that: protects the drug product, for example, from factors by ultraviolet or visible light) or by exposure to thermal stress that can cause degradation of the dosage form over its shelf Such as by autoclaving. These iodine species are no longer life; is compatible with the drug product, for example, the organically bound to the contrast agent's chemical structure. packaging components will not interact Sufficiently to cause Exemplary iodine species include iodide (F), triiodide (I), unacceptable changes in the quality of either the drug or the iodate (IO), and elemental iodine (I2). The iodine species packaging component. Such as absorption or adsorption of the are in equilibrium with each other and can interconvert drug Substance, degradation of the drug Substance that is depending on the pH of the medium. Analysis of each of the induced by extractables/leachables from the container, pre individual species is possible, but the easiest analysis is to cipitation, and changes in pH; and is safe, for example, a convert all the species to F through the addition of an excess container that does not leach harmful or undesirable amounts of sodium thiosulfate. The F can then be measured by chro of substances to which a patient will be exposed when being matographic separation with ultraviolet detection at 230 nm. treated with the product, or in the case of injectable formula tions, the container will protect the formulation from the 0051. As used herein the term “pH adjusting agent' is an introduction of microbes and not contain pyrogens. Contain agent to increase or decrease the desired pH of the formula ers useful for injectable formulations are often sterilized prior tion when admixed into the formulation. The pH of the liquid to and/or after being filled with the formulation. Pharmaceu formulation will generally range from about pH 5.5 to about tically acceptable containers include, but are not limited to, pH 8.0; however, liquid formulations having higher or lower polymer or glass bottles, vials, Syringes or cartridges for pH values can also be prepared. It is contemplated that the autoinjectors. Containers for autoinjectors are described for iodinated contrast agent chemical stability can be increased example in U.S. Pat. Nos. 5,383,858, 5,997,502, 6,322,535, by optimizing the pH as well as the mole ratio of substituted and 6,402.718. Suitable pharmaceutically acceptable con cyclodextrin to contrast agent. The pH of the composition tainers include an evacuated container, a Syringe, bag, pouch, may be adjusted using an appropriate pH adjusting agent, ampoule, Vial, bottle, or any pharmaceutically acceptable Such as a Suitable acid, base, amine, or any combination device known to those skilled in the art for the delivery of thereof. Preferably, a pH adjusting agent used in the formu liquid formulations. To shield the compositions from light, lation include hydrochloric acid, Sodium hydroxide, amines, amber colored vials or syringes can be used, and/or the pack ammonium hydroxide, nitric acid, phosphoric acid, Sulfuric aging can further include a light barrier, Such as an aluminum acid, citric acid, organic acids, and/or salts thereof, and any overpouch. Containers with light-shielding properties by combination thereof. nature have poor light permeability. In these containers, dur 0052. As used herein, the phrase “pharmaceutically ing production steps or during storage-related quality tests, acceptable' is employed herein to refer to those compounds, visual or mechanical inspection for any insoluble foreign materials, compositions, and/or dosage forms which are, matter is difficult to perform. By the combined use of these within the scope of Sound medical judgment, Suitable for use light-shielding materials, their light-shielding properties can in contact with the tissues of human beings and animals be further enhanced. Containers that do not possess enhanced without excessive toxicity, irritation, allergic response, or light shielding properties, i.e., are transparent, are those con other problem or complication, commensurate with a reason tainers which do not shield light from entering the container. able benefit/risk ratio. As used herein, a “pharmaceutically In the field of quality control or quality tests, use of transpar acceptable liquid carrier' is any aqueous medium used in the ent vials is desirable. pharmaceutical sciences for dilution or dissolution of 0055 As used herein, the term “primary container' is parenteral formulations. In a specific embodiment, the term intended to mean a pharmaceutically acceptable container “pharmaceutically acceptable” means generally accepted by that has direct physical contact with the drug product or or approved by a regulatory agency of the Federal or a state formulation. This include, for example, an evacuated con government or listed in the U.S. Pharmacopeia or other gen tainer, a Syringe, a bag, pouch, ampoule, Vial, bottle, or any erally recognized pharmacopeia for use in animals, and more pharmaceutically acceptable device known to those skilled in particularly in humans. The term “carrier” refers to a diluent, the art for the delivery of liquid formulations. adjuvant, excipient, or vehicle with which a formulation of 0056. As used herein, the term “photolysis” is intended to the invention is administered. Such pharmaceutical carriers mean chemical degradation that occurs when a compound is can be liquids, such as water, saline, aqueous Solutions and irradiated with ultraviolet or visible light. The degradants the like. When administered to a patient, the formulations of formed by photolysis of iodinated contrastagents include, but the invention and pharmaceutically acceptable vehicles are are not limited to, iodine species. preferably sterile. Water is a preferred vehicle when the com 0057 Ready to use, injectable formulations described pound of the invention is administered intravenously or herein are stable, allow medical personal to use prepared intraarterially. containers containing an injectable formulation off the shelf 0053 As used herein, the term “pharmaceutically accept without additional preparation, avoid potential contamina able cation' is intended to mean a cation selected from the tion problems, and eliminate dosage errors. Additional ben group comprising H', alkali metals (e.g., Li, Na', K"), alka efits of premixed, ready to use, injectable pharmaceutical line earth metals (e.g., Ca", Mg"), ammonium ions and compositions include convenience and ease of use, improved amine cations such as the cations of (C-C)-alkylamines, safety for patients (due to elimination of dosage errors and piperidine, pyrazine, (C-C)-alkanolamine, ethylenedi Solution contamination), reduction of medical waste, and US 2013/0323 181 A1 Dec. 5, 2013

ease of administration in emergency situations. Such phar 0064. In one embodiment, the iodinated contrast agent is maceutical compositions described herein require no dilution selected from the group consisting of iopamidol, iodixanol, prior to administration. iopromide and ioxaglate. In another embodiment, the iodi nated contrast agent is selected from the groups consisting of Compositions of the Invention iohexyl, ioversol, diatrizoate meglumine and ioxaglate and 0058. The invention encompasses compositions indicated the Substituted cyclodextrin is selected from the groups con for intravascular administration in Subjects requiring radio sisting of Sulfoalkylether cyclodextrins, partially methylated graphic visualization. Intravascular injection of these agents cyclodextrins, sulfoalkylether alkylether cyclodextrins and opacifies those vessels in the path of flow of the contrast sulfoalkyl ether hydroxyalkyl ether cyclodextrins. agent, permitting radiographic visualization of the internal 0065. In one embodiment, the substituted cyclodextrin is structures until significant dilution and elimination occurs. any one of the cyclodextrins described herein. In another 0059. The invention is based on the finding that certain embodiment, the substituted cyclodextrin is selected from the compositions containing iodinated contrast agents and a Sub groups consisting of Sulfoalkylether cyclodextrins, 2-hydrox stituted cyclodextrin show reduced degradation when ypropyl cyclodextrins, partially methylated cyclodextrins exposed to ultraviolet or visible light. and sulfoalkylether alkylether cyclodextrins. In a further 0060. The compositions of the invention encompasses liq embodiment, the substituted cyclodextrin is selected from a uid formulations including an iodinated contrast agent or a group consisting of a Sulfobutyl ether beta-cyclodextrin, a salt thereof that can be administered parenterally, for sulfobutyl ether gamma-cyclodextrin, a sulfobutyl ether example, intravenously or intraarterially, to a Subject in need alpha-cyclodextrin, a Sulfopropyl ether beta-cyclodextrin, a thereof. sulfobutylether ethylether beta-cyclodextrin, a 2-hydrox 0061. In one embodiment, the invention provides an aque ypropyl beta cyclodextrin, and a partially methylated beta ous pharmaceutical composition having a pH of 5 to 8 and cyclodextrin. In one embodiment, the substituted cyclodex comprising an iodinated contrast agent; a pharmaceutically trin is a sulfobutyl ether beta cyclodextrin with an average acceptable buffering agent; and a Substituted cyclodextrin degree of substitution of 7, i.e. SBE-7-BCD. In another present at a contrast agent to Substituted cyclodextrin mole embodiment, the substituted cyclodextrin is a 2-hydroxypro ratio from 1:0.01 to 1:2. In an embodiment, the composition pyl beta cyclodextrin with an average degree of Substitution will exhibit a reduction in formation of iodine species when of 6.3 or 4.3, e.g., HP-6.3-BCD or HP-4.3-3CD. exposed to ultraviolet (UV) light as compared to a corre 0066. In one embodiment, the UV light exposure is 119 sponding composition, without a substituted cyclodextrin, watt hours per square meter. In another embodiment, the UV exposed to the same ultraviolet light. In certain embodiments, light exposure is 159 watt hours per square meter. In one the composition exhibits at least a 3% reduction to at least a embodiment, the visible light exposure is 0.65 million lux 60% reduction of iodine species. In certain embodiments, the hours. In another embodiment, the visible light exposure if composition exhibits at least a 3% at least a 5%, at least a 0.52 million lux hours. 10%, at least a 20%, at least a 30%, at least a 40%, at least a 0067. In certain embodiments, the composition is heat 50%, or at least a 60%, reduction in formation of iodine sterilized prior to exposure to the UV or visible light. In one species as compared to the corresponding composition. embodiment, the heat sterilization comprises steam steriliza 0062. In another embodiment, the invention provides an tion. In another embodiment, the steam sterilization occurs at aqueous pharmaceutical composition having a pH of 5 to 8 115-116°C. for at least 30 minutes, 121-123°C. for at least 15 and comprising an iodinated contrast agent selected from the minutes, 126-129° C. for at least 10 minutes, or 134-138°C. group consisting of iohexyl, iopromide, ioVersol, ioxaglate, for at least 3 minutes. In other embodiments, the composition and iodixanol; a pharmaceutically acceptable buffering is dry heat sterilized prior to exposure to the UV or visible agent; and a substituted cyclodextrin present at a contrast light. In one embodiment, the dry heat sterilization occurs at agent to substituted cyclodextrin mole ratio from 1:0.01 to 160° C. for at least 180 minutes, 170° C. for at least 60 1:2. In an embodiment, the composition will exhibit a reduc minutes or 180°C. for at least 30 minutes. In another embodi tion in formation of iodine species when exposed to visible ment, the heat sterilization is conducted at a sufficient tem light as compared to a corresponding composition, without a perature and for a sufficient time to assure at least a 10 substituted cyclodextrin, exposed to the same visible light. In microbial survivor probability. certain embodiments, the composition exhibits at least a 3% 0068. In one embodiment, the pharmaceutically accept reduction to at least a 60% reduction of iodine species. In able buffering agent is any of the buffering agents described certain embodiments, the composition exhibits at least a 3% herein. In another embodiment the pharmaceutically accept at least a 5%, at least a 10%, at least a 20%, at least a 30%, at able buffering agent is selected from the group consisting of least a 40%, at least a 50%, or at least a 60%, reduction in tromethamine (TRIS), phosphate, and meglumine, and their formation of iodine species as compared to the corresponding pharmaceutically acceptable salts. In one embodiment, the composition. composition has a pH of 6.5 to 7.7. In another embodiment, 0063. In one embodiment, the iodinated contrast agent is the composition has a pH of 7.4. In another embodiment, the any one of the iodinated contrast agents described herein, composition further comprises one or more components including but not limited to the ionic agents iocarmic acid, selected from the group consisting of pH adjusting agents, iodipamide, iodoxamic acid, ioxaglic acid, acetrizoic acid, antioxidants, chelating agents, and inert gasses. Examples of diatrizoic acid, iodamic acid, ioglicic acid, iopanoic acid, Such components are described elsewhere herein. iopronic acid, iothalamic acid, ioxitalamic acid, ipodic acid, 0069. In one embodiment, the composition has an iodine metrizoic acid, and their pharmaceutically acceptable salts, content of about 19 mg/mL to about 400 mg/mL. In another and the nonionic agents iodixanol, ioforminol, iotrolan, embodiment, the iodine content is 111 mg/mL to about 400 iobitridol, iohexyl, iomeprol, iopamidol, iopentol, iopro mg/mL. In another embodiment, the iodine contentis greater mide, iosimide, ioVersol, ioXilan, and metrizamide. than 150 mg/mL and less than or equal to 400 mg/mL. US 2013/0323 181 A1 Dec. 5, 2013

0070. In one embodiment, the contrast agent to substituted 0076. In one embodiment, the iodinated contrast agent is cyclodextrin mole ratio is from about 1:0.01 to about 1:2. In iopamidol, the substituted cyclodextrin is a sulfobutylether another embodiment, the contrast agent to Substituted cyclo beta cyclodextrin or a 2-hydroxypropyl beta cyclodextrin, dextrin mole ratio is from about 1:0.02 to about 1:2. In and the composition has an iodine content greater than 150 another embodiment, the contrast agent to Substituted cyclo mg/mL and less than or equal to 400 mg/ml. In a further dextrin moleratio is from greater than about 1:0.025 to 1:2. In embodiment, the substituted cyclodextrin is a sulfobutylether one embodiment, the contrast agent to Substituted cyclodex beta cyclodextrin with an average degree of substitution of 7. trin mole ratio is from about 1:0.01 to about 1:0.1. In another i.e. SBE-7-3CD. In another embodiment, the substituted embodiment, the contrast agent to Substituted cyclodextrin cyclodextrin is a 2-hydroxypropyl beta cyclodextrin with an mole ratio is from about 1:0.02 to about 1:0.1. In another average degree of substitution of 4.3 or 6.3, e.g., HP-4.3-f30D embodiment, the contrast agent to Substituted cyclodextrin or HP-6.3-BCD. In one embodiment, the composition has a mole ratio is from greater than about 1:0.025 to 1:0.1. pH of 6.5 to 7.5. In another embodiment, the pH of the 0071. In one embodiment, the invention provides a ready composition is 7.4. In another embodiment, the composition to use, sterile, injectable aqueous pharmaceutical composi comprises 1.0 mg/ml tromethamine and 0.26 to 0.48 mg/ml tion have a pH of 5 to 8 and comprising an iodinated contrast disodium calcium edetate. In one embodiment, the iopamidol selected from the group consisting of iohexyl, iopamidol. to substituted cyclodextrin is 1:0.02 to 1:0. 1 or greater than iodixanol, ioVersol, and iopromide; 1 to 4 mg/ml 1:0.025 to 1:0.1. In another embodiment, the iodine content tromethamine (TRIS) buffer, 0.1 to 0.6 mg/mL disodium of the composition is 200 mg/ml. calcium edetate; and a substituted cyclodextrin selected from 0077. In one embodiment, the iodinated contrast agent is the group consisting of sulfobutylether beta cyclodextrins and iopromide, the substituted cyclodextrin is a sulfobutylether 2 hydroxypropyl beta cyclodextrins, wherein the substituted beta cyclodextrin or a 2-hydroxypropyl beta cyclodextrin, cyclodextrin is presentata contrastagent to Substituted cyclo and the composition has an iodine content greater than 150 dextrin moleratio from about 1:0.01 to 1:0.1. In one embodi mg/mL and less than or equal to 400 mg/ml. In a further ment, the composition is packaged in a primary container that embodiment, the substituted cyclodextrin is a sulfobutylether does not possess enhanced light shielding properties. beta cyclodextrin with an average degree of substitution of 7. 0072. In one embodiment, the composition is heat steril i.e. SBE-7-3CD. In another embodiment, the substituted ized after it is packaged in the primary container. In another cyclodextrin is a 2-hydroxypropyl beta cyclodextrin with an embodiment, the heat sterilization comprises steam steriliza average degree of substitution of 4.3 or 6.3, e.g., HP-4.3-f30D tion or dry heat sterilization. In one embodiment, the steam or HP-6.3-BCD. In one embodiment, the composition has a sterilization occurs at 115-116° C. for at least 30 minutes, pH of 6.5 to 8.0. In another embodiment, the pH of the 121-123°C. for at least 15 minutes, 126-129°C. for at least 10 composition is 7.4. In another embodiment, the composition minutes, or 134-138° C. for at least 3 minutes. In another comprises 2.42 mg/ml tromethamine and 0.1 mg/ml diso embodiment, the dry heat sterilization occurs at 160° C. for at dium calcium edetate. In one embodiment, the iopromide to least 180 minutes, 170° C. for at least 60 minutes or 180° C. substituted cyclodextrin is 1:0.02 to 1:0.1 or greater than for at least 30 minutes. 1:0.025 to 1:0.1. In another embodiment, the iodine content 0073. In one embodiment, the composition has an iodine of the composition is 340, 300 or 370 mg/ml. content greater than 150 mg/mL and less than or equal to 400 0078. In one embodiment, the iodinated contrast agent is mg/mL. In one embodiment, the pH of the composition is 6.5 iodixanol, the substituted cyclodextrin is a sulfobutylether to 7.7. beta cyclodextrin or a 2-hydroxypropyl beta cyclodextrin, 0074. In one embodiment, the iodinated contrast agent is and the composition has an iodine content greater than 150 iohexyl, iopamidol, ioversol or iopromide and the iodinated mg/mL and less than or equal to 400 mg/ml. In a further contrast agent is present at a molar concentration greater than embodiment, the substituted cyclodextrin is a sulfobutylether 394.1 mM and less than or equal to 1051 mM. In another beta cyclodextrin with an average degree of substitution of 7. embodiment, the iodinated contrast agent is iodixanol, and i.e. SBE-7-3CD. In another embodiment, the substituted the iodixanol is present at a molar concentration greater than cyclodextrin is a 2-hydroxypropyl beta cyclodextrin with an 197.1 mM and less than or equal to 525.4 mM. average degree of substitution of 4.3 or 6.3, e.g., HP-4.3-f30D 0075. In one embodiment, the iodinated contrast agent is or HP-6.3-BCD. In one embodiment, the composition has a iohexyl, the substituted cyclodextrin is a sulfobutylether beta pH of 6.8 to 7.7. In another embodiment, the pH of the cyclodextrin or a 2-hydroxypropyl beta cyclodextrin, and the composition is 7.4. In another embodiment, the composition composition has an iodine content greater than 150 mg/mL comprises 1.21 mg/ml tromethamine and 0.1 mg/ml diso and less than or equal to 400 mg/ml. In a further embodi dium calcium edetate. In another embodiment, the composi ment, the substituted cyclodextrin is a sulfobutylether beta tion further comprises 1.11 mg/ml to 1.87 mg/ml of sodium cyclodextrin with an average degree of Substitution of 7, i.e. chloride and 0.044 mg/ml to 0.074 mg/ml of calcium chloride SBE-7-3CD. In another embodiment, the substituted cyclo dihydrate. In one embodiment, the iodixanol to substituted dextrin is a 2-hydroxypropyl beta cyclodextrin with an aver cyclodextrin is 1:0.02 to 1:0.1 or greater than 1:0.025 to 1:0.1. age degree of substitution of 4.3 or 6.3, e.g., HP-4.3-3CD or In another embodiment, the iodine content of the composition HP-6.3-80D. In one embodiment, the composition has a pH is 270 or 320 mg/ml. of 6.8 to 7.7. In another embodiment, the pH of the compo 0079. In one embodiment, the iodinated contrast agent is sition is 7.4. In another embodiment, the composition com ioversol, the substituted cyclodextrin is a sulfobutylether beta prises 1.21 mg/ml tromethamine and 0.1 mg/ml disodium cyclodextrin or a 2-hydroxypropyl beta cyclodextrin, and the calcium edetate. In one embodiment, the iohexyl to substi composition has an iodine content greater than 150 mg/mL tuted cyclodextrin is 1:0.02 to 1:0.1 or greater than 1:0.025 to and less than or equal to 400 mg/ml. In a further embodi 1:0.1. In another embodiment, the iodine content of the com ment, the substituted cyclodextrin is a sulfobutylether beta position is 155, 180, 240, 300, 350 or 400 mg/ml. cyclodextrin with an average degree of Substitution of 7, i.e. US 2013/0323 181 A1 Dec. 5, 2013

SBE-7-3CD. In another embodiment, the substituted cyclo I0086. An antioxidant may be but need not be added to the dextrin is a 2-hydroxypropyl beta cyclodextrin with an aver formulation of the invention. Preferred antioxidants include age degree of substitution of 4.3 or 6.3, e.g., HP-4.3-3CD or EDTA and salts thereof, sodium metabisulfite and pentetate, HP-6.3-80D. In one embodiment, the composition has a pH for example. of 6.0 to 7.4. In another embodiment, the pH of the compo I0087. A chelating agent may be but need not be added to sition is 7.1. In another embodiment, the composition com the formulation of the invention. Preferred chelating agents prises 3.6 mg/ml tromethamine and 0.2 mg/ml disodium cal include EDTA and salts thereof, and citric acid and salts cium edetate. In one embodiment, the ioversol to substituted thereof. cyclodextrin is 1:0.02 to 1:0.1 or greater than 1:0.025 to 1:0.1. I0088. The chemical stability of the liquid formulations of In another embodiment, the iodine content of the composition the invention can be enhanced by: adding an antioxidant, is 160,240, 300,320 or 350 mg/ml. adding a chelating agent, adjusting the pH of the liquid car 0080. In another embodiment, the invention provides a rier, and/or eliminating or minimizing the presence of oxygen ready to use, Sterile, injectable aqueous pharmaceutical com in the formulation. position have a pH of 5 to 8 and comprising ioxaglate, I0089. In view of the above description and the examples wherein the ioxaglate comprises ioxaglate meglumine and below, one of ordinary skill in the art will be able to practice ioxaglate Sodium: 0.1 to 0.6 mg/mL disodium calcium ede the invention as claimed without undue experimentation. The tate; and a Substituted cyclodextrin selected from the group foregoing will be better understood with reference to the consisting of sulfobutylether beta cyclodextrins and 2 following examples that detail certain compositions accord hydroxypropyl beta cyclodextrins, wherein the substituted ing to the present invention. All references made to these cyclodextrin is presentata contrastagent to Substituted cyclo examples are for the purposes of illustration and not limita dextrin mole ratio from about 1:0.01 to 1:0.1. tion. The following examples should not be considered 0081. In one embodiment, the composition is packaged in exhaustive or exclusive, but merely illustrative of only a few a primary container that does not possess enhanced light of the many embodiments contemplated by the invention, as shielding properties. combinations of the foregoing embodiments are contem plated. 0082 In one embodiment, the composition is heat steril ized after it is packaged in the primary container. In another EXAMPLES embodiment, the heat sterilization comprises steam steriliza tion or dry heat sterilization. In one embodiment, the steam Example 1 sterilization occurs at 115-116° C. for at least 30 minutes, 121-123°C. for at least 15 minutes, 126-129°C. for at least 10 Complexation of Sulfobutylether Beta-Cyclodextrin minutes, or 134-138° C. for at least 3 minutes. In another with Iohexyl embodiment, the dry heat sterilization occurs at 160° C. for at least 180 minutes, 170° C. for at least 60 minutes or 180° C. 0090 The membrane permeation method for determining for at least 30 minutes. complexation is founded on the concept that uncomplexed 0083. In one embodiment, the substituted cyclodextrin is a agents will pass through a semi-permeable membrane sulfobutylether beta cyclodextrin or a 2-hydroxypropyl beta whereas a cyclodextrin or an agent complexed with a cyclo cyclodextrin. In a further embodiment, the substituted cyclo dextrin will not pass, if the membrane pore size is selected dextrin is a sulfobutylether beta cyclodextrin with an average carefully. The permeation rate of the agentis dependent on the degree of substitution of 7, i.e. SBE-7-BCD. In another amounts of uncomplexed agent on either side of the mem embodiment, the substituted cyclodextrin is a 2-hydroxypro brane as a function of time. One can place cyclodextrin and pyl beta cyclodextrin with an average degree of Substitution agent on one side of a membrane (donor side) and measure the of 4.3 or 6.3, e.g., HP-4.3-BCD or HP-6.3-3CD. In one amount of agent crossing over time into the receptor side, and embodiment, the composition has a pH of 6.0 to 7.6. In by using appropriate equations calculate the fraction of another embodiment, the pH of the composition is 7.0. In one uncomplexed agent present in the donor side solution. One embodiment, the composition comprises 393 mg of ioxaglate can then calculate the effective binding constant between the meglumine and 196 mg of ioxaglate Sodium. In another cyclodextrin and the agent. embodiment, the composition comprises 0.1 mg/ml disodium 0091. Ono, et al. described the equations and experimental calcium edetate. In one embodiment, the ioxaglate to Substi setup for the model where the permeation is allowed to con tuted cyclodextrin is 1:0.02 to 1:0.1 or greater than 1:0.025 to tinue for extended time. When the time course is limited such 1:0.1. In another embodiment, the iodine content of the com that the concentration of agent on the donor side does not vary position is 320 mg/ml. significantly and that appearing on the receptor side is very 0084. In any of the ready to use, sterile, injectable aqueous Small relative to the donor side, the equations collapse to a pharmaceutical compositions described herein, the composi simple direct dependency (X) of permeation rate (J) on the tion may further comprise one or more components selected free and uncomplexed concentration of agent on the donor from the group consisting of pH adjusting agents, antioxi side (C) as in Equation 1. dants, chelating agents, and inert gasses. J-X(Cron.) Equation 1 0085. The formulations of the inventions described herein 0092. One can measure the permeation rate of an agent also include water. Specific embodiments of the invention across a semi-permeable membrane in the absence or pres include pyrogen-free, sterile water as liquid carrier. The water ence of a cyclodextrin, and by dividing the rate in the presence can comprise other components described herein. Water Suit of the cyclodextrin by the rate in its absence one can deter able for injection is suitable for use in the liquid formulation mine the fraction of agent uncomplexed in the presence of of the invention. that concentration of cyclodextrin. The experiment is US 2013/0323 181 A1 Dec. 5, 2013

repeated with other concentrations of cyclodextrin to obtain cmx1 cm (3 mL) quartz cuvettes having 2 clear sides and 2 the fraction of uncomplexed agent at each cyclodextrin con sides etched. Lids were placed on the cuvettes and sealed with centration. a wrap of ParafilmR) around the joint. The cuvettes were 0093. The complexation or binding constant, K, for a 1:1 placed in a photolysis chamber, upright on a flat Surface cyclodextrin:agent interaction is defined as: beneath and centered between two horizontal 24 inch fluo rescent lamps, (GE, black light F20T12, 20 watt for ultravio ACD Equation 2 let, or Philips F20T12/CW, 20 watt for visible) placed 6 cm T (A0)(CDo)) apart. The cuvettes were positioned such that their two clear where Ao and CDo are the uncomplexed concentrations of sides were facing the two lamps. Cuvettes were spaced ~2 cm agent and cyclodextrin respectively, and ACD is the concen from each other, and no closer than 15 cm from the ends of the tration of the complex. The corresponding mass balance lamps. This positioning allowed reproducible light exposure equations are: to all cuvettes. 0098. The lamps were switched on and the solutions irra CD, CDoF-FACDI Equation 3 diated for 18 to 24 hours for the ultraviolet (UV) lamps or 72 to 90 hours for the visible (VIS) light lamps. At the end of the At Alo-FACD Equation 4 selected irradiation time, the cuvettes were removed from the where CD and Aare the total amounts of cyclodextrin photolysis chamber and mixed by inversion 2-times. The caps and agent respectively. Equations 2, 3, and 4 can be combined were then removed and 40 microliter aliquots taken and and rearranged to give an equation for CDo: diluted with 1 mL of an aqueous solution containing -0.9 mg/mL Sodium thiosulfate. The thiosulfate solution con KICDol’-(KICDrf-KIA al+1)(CDof-fA tell-O Equation 5 Verted any I, IO, and IT present in the solution to I Such that total iodine species could be determined in one assay. This equation can be solved in an iterative fashion using 0099. The diluted solutions were assayed by high pressure Newton’s approximation or other methods to generate values liquid chromatography (HPLC) using a 4.6x250 mm, C-18, 5 for free cyclodextrin at fixed values for K.A. and CD. micron particle size, reversed phase column with detection at The corresponding values for free agent are then calculated 280 nm for the contrast agent and 230 nm for the thiosulfate from equations 2 and 3. and the iodide ion (I). A mobile phase of 30.70 methanol: 0094 Values of A, and CD, used on the donor side aqueous buffer (50 mM. KHPO+7 mL/L 40% tetrabutyl in permeation experiments are entered into Equation 5 and ammonium hydroxide) at 0.75 mL/min was used for elution. then various values of Kinput until the calculated value of Injection volume was 20 microliters. External standards were free agent on the donor side matches the value obtained in prepared containing each contrast agent, potassium iodide, each experiment. and sodium thiosulfate solution and analyzed along with the 0095. This procedure was used in an experiment evaluat irradiated samples. The results were reported as weight per ing the complexation of sulfobutylether beta-cyclodextrin centage iodide formed (mg iodide/mg contrast agent times with the iodinated contrast agent, iohexyl. Aqueous solutions 100). containing iohexylicyclodextrin moles ratios of 1:0, 1:0.25, 1:0.5, 1:1, and 1:1.5 were placed on the donor side of semi Example 3 permeable cellulose ester ultrafiltration membranes (Molecu lar/Por(R), Spectrum laboratories, molecular weight cutoff of Determination of UV and VIS Light Exposure in 1000 daltons) mounted in side-by side diffusion chambers. Photolysis Experiments Aqueous solutions of the cyclodextrin, adjusted to provide 0100 A 2% solution of quinine hydrochloride dihydrate equal osmotic strength to the donor side, were placed on the was prepared in distilled water. The solution was filled into receptor side. The permeation rates for the appearance of quartz cuvettes, caps were placed on the cuvettes and sealed iohexyl into the solution on the receptor side of the membrane with Parafilm. One cuvette was wrapped with aluminum foil were measured by assaying the receptor Solutions periodi to serve as a control and one was left unwrapped. The cuvettes cally over time using high pressure liquid chromatography. were placed under the fluorescent lamps as in Example 2 and 0096. Results of the study are depicted in FIG. 1. The exposed to UV light for 39 hours. Over the course of irradia complexation constant is shown to be very low, averaging tion, the cuvettes were periodically removed from the pho about 9.5 M' indicating very low complexation. Complex tolysis chamber and the UV absorbance of the solutions mea ation constants are typically between 50-2000M (Loftsson, sured at 400 nM using a UV spectrophotometer. The et al. Cyclodextrins in Drug Delivery, Expert Opin Drug absorbance reading of the control Solution was subtracted from the reading of the irradiated Solution to give an absor Deliv, (2005) 2(2):335-351) and values lower than about bance due to the light exposure. The control cuvette was 50M indicate little to no interaction between the cyclodex re-wrapped with foil and the cuvettes returned to the photoly trin and agent. sis chamber. The time during which the cuvettes were not in the light chamber was not included in the measured exposure Example 2 time. The process was repeated with fresh quinine Solution and VIS light exposure for 144 hours. Irradiation of Aqueous Solutions Containing 0101 The absorbance readings at 400 nm due to light Iodinated Contrast Agents exposure were plotted against time of exposure and the result 0097 Aqueous solutions comprising iodinated contrast ing correlation used to determine the UV and VIS light expo agents were prepared and evaluated in a photolysis chamber Sure. A change in absorbance reading of 0.45 was assumed as described in the ICH guidance document, Q1B Photosta equivalent to 200 watt hours/square meter for the UV light bility Testing of New Drug Substances and Products, avail and a change of 0.51 was assumed equivalent to 1.2 million able from the US Food and Drug Administration, incorpo lux hours for the VIS light. The UV lamps provided 6.62 rated herein by reference. The solutions were placed in 1 watts/square meter and the VIS lamps provided 7180 lux. US 2013/0323 181 A1 Dec. 5, 2013

Example 4 -continued Effect of Contrast Agent:SCD Mole Ratio on Calcium Calcium Disodium Chloride Sodium Photostability of Contrast Agents Towards UV Light Contrast Contrast TRIS Edetate Dihydrate Chloride Irradiation Agent Agent (M) (mg/mL) (mg/mL) (mg/mL) (mg/mL)

0102 Aqueous solutions were prepared containing 50 Iowersol O.OS 3.6 O.O11 O O mM contrast agent by diluting commercially available solu Iopromide O.OS 2.42 O.OOS2 O O tions with water. Tromethamine HCl buffer (TRIS), was Ioxaglate O.OS O O.O12 O O added to solutions as necessary to increase the TRIS content Iohexol O.OS 1.21 OOOO64 O O to that of the commercial product before dilution. Composi tion of the solutions in the absence of SCD is shown in the following table. (0103 SCD was added to the solutions at various mole ratios and the pH of the solutions adjusted to 7.4 with 0.1N hydrochloric acid or 0.1N sodium hydroxide. The solutions Calcium Calcium were irradiated with UV light for 18 hours (119 watt hours/ Disodium Chloride Sodium m) then processed, analyzed and reported as in Example 2. Contrast Contrast TRIS Edetate Dihydrate Chloride The SCDs evaluated were sulfobutyl ether beta-cyclodextrin Agent Agent (M) (mg/mL) (mg/mL) (mg/mL) (mg/mL) with an average degree of substitution of 7 (SBE-7-3CD), and Iopamidol O.OS 1.O O.O2S O O two 2-hydroxypropyl beta-cyclodextrin derivatives having Iodixanol O.OS 1.2 O.OOS2 O.OOS2 O.1320 6.3 (HP-6.3-3CD) and 4.3 (HP-4.3-3CD) average degrees of substitution. TABLE 1. Iodide degradants formed (wt %) in the absence and presence of varying amounts and type of SCD at pH 7.4. The percent change in iodide degradants formed as compared to control is also listed in parentheticals. Contrast:SCD Mole Ratio

SCD 1:O 1:O.O1 1:O.O2 1:O.O2S 1:O.OS 1:0.1 1:O.S 1:1 1:2 Iopamidol

SBE-7-BCD 0.553 O.S32 ind n n O.476 O.393 nic O.342 (control) (-3.8%) (-13.9%) (-28.9%) (-38.2%) HP-6.3-BCD 0.553 O.S47 ind n n n n nic O394 (control) (-1.1%) (-28.7%) HP-4-3-3CD 0.553 O.541 ind n n n n nic O439 (control) (-2.2%) (-20.6%) Iodixanol

SBE-7-BCD O-269 O.254 O.231 n n n n O.193 O.18O (control) (-5.6%) (-14.1%) (-28.3%) (-33.1%) HP-6.3-BCD O-269 nic ind n n n n nic O.244 (control) (-9.3%) Iowersol

SBE-7-BCD 1.2O O.995 O.859 n n n n O498 O.387 (control) (-17.1%) (-28.4%) (-58.5%) (-67.8%) HP-6.3-BCD 1.2O nic ind n n n n nic O.783 (control) (-34.8%) Iopromide

SBE-7-BCD O.672 O.483 O.407 n n n n O311 O.272 (control) (-28.1%) (-39.4%) (-53.9%) (-59.5%) HP-6.3-BCD O.672 nic ind n n n n nic O424 (control) (-36.9%) Ioxaglate

SBE-7-BCD O.282 O.242 O.228 n n n n O.190 O.171 (control) (-14.2%) (-19.1%) (-32.6%) (-39.4%) HP-6.34-3CD O.282 nic ind n n n n nic O.213 (control) (-24.5%) Iohexol

SBE-7-BCD 0.773 670 ind n 0.655 0.585 O460 nic O.343 (control) (-13.3%) (-15.3%) (-24.3%) (-40.5%) (-55.6%) HP-6.3-BCD 0.773 nic ind O.670 O.6SO nic ind nic ind (control) (-13.3%) (-15.9%) HP-4-3-3CD 0.773 nic ind O.689 O.659 nic ind nic ind (control) (-10.9%) (-14.7%)

ind = not determined US 2013/0323 181 A1 Dec. 5, 2013

0104. The SCDs stabilized the contrast agents against 8% less and up to 64% less iodide degradants after exposure photolysis by UV irradiation at all mole ratios tested. to UV light as compared to those composition which con tained no SCD. Example 5 Example 6 Effect of pH and SCD on the Stability of Contrast Agents Following UV Light Irradiation Effect of TRIS Buffer Content and SCD on the 0105 Aqueous solutions were prepared containing 50 Stability of Iopamidol Following UV Light mM contrast agent by diluting commercially available solu Irradiation tions with distilled water. Tromethamine HCl buffer (TRIS), was added to some solutions to increase the buffer content. 0.108 Solutions were prepared containing 100 mMiopa Composition of the solutions in the absence of SCD is shown midol, 0.05 mg/mL calcium disodium edetate, varying in the following table. amounts of tromethamine buffer, and 0 or 5 mMSBE-7-f30D (iopamidol:SCD mole ratio of 1:0.05) in distilled water. The pH of the solutions was adjusted to 7.4 with 0.1N hydrochlo Calcium Calcium ric acid. The solutions were irradiated with UV light for 18 Disodium Chloride Sodium hours (119 watt hours/m) then processed, analyzed and Contrast Contrast TRIS Edetate Dihydrate Chloride reported as in Example 2. Results of the study are presented in Agent Agent (M) (mg/mL) (mg/mL) (mg/mL) (mg/mL) the table below. Iopamidol O.OS 2.42 O.O2S O O Iodixanol O.OS 1.2 O.OOS2 O.OOS2 O.1320 Iowersol O.OS 3.6 O.O11 O O TABLE 3 Iopromide O.OS 2.42 O.OOS2 O O Ioxaglate O.OS O O.O12 O O Iodide degradants formed (wt %) in the absence and presence of Iohexol O.OS 2.42 O.OOO64 O O SCD and various amounts of TRIS buffer.

01.06 The solutions were divided and SBE-7-BCD added Iopamidol:SCD to one aliquot at a contrast agent:SCD mole ratio of 1:1. The Starting TRIS buffer Mole Ratio % Change in iodide pH of the solutions was adjusted to 5, 6, 7, 7.4 or 8 with 0.1N hydrochloric acid or sodium hydroxide. The solutions were pH content (mM) 1:O 1:O.OS degradants irradiated with UV light for 18 hours (119 watt hours/m) 7.4 5 0.875 0.746 -14.7% then processed, analyzed and reported as in Example 2. The 7.4 7.5 O.951 O.871 -8.4% results are presented in the table below. 7.4 10 1.07 O.978 -8.6% 7.4 15 1.07 1.00 -6.5% TABLE 2 7.4 2O 1.13 1.09 -3.5% Iodide degradants formed (wt %) in the absence and presence of SCD at various starting pH values. The percent change in iodide degradants formed in the presence of the SCD is also listed. 0109. The presence of the SCD stabilized the iopamidol Contrast Agent:SCD pH solution against photolysis at TRIS buffer concentrations of 5 to 20 mM and an iopamidol:SCD mole ratio of 1:0.05. Agent mole ratio 5 6 7 7.4 8 opamidol O O.366 0.373 O.626 O.670 0.829 : O.265 0.282 0.373 O434 0.761 Example 7 % Change -27.6% -24.4% -40.4% -35.1% -8.2% odixanol O 0.154 ind ind O-269 O.342 : O.139 nic ind O.193 0.313 Effect of Buffer Type and SCD on the Stability of % Change -9.7% nic ind -28.3% -8.5% Iohexyl Following UV Light Irradiation oversol O 0.408 ind ind 1.2O 1.46 : O.230 nic ind O.498 0.774 % Change -43.6% nic ind -58.5% -47% 0110 Aqueous solutions were prepared containing 473 opromide O 0.284 ind ind O.672 0.979 mMiohexyl and 10 mMtromethamine HCl (TRIS) or sodium : O.195 nic ind O.311 O.470 phosphate buffer along with the presence or absence of sul % Change -31.3% nic ind -53.9% -52% oxaglate O 0.216 ind ind O.282 0.341 fobutyl ether B-cyclodextrin (SBE7-B-CD) and disodium cal : O.16S nic ind O.190 O.272 cium edetate. The pH of the solutions was adjusted to 8.0 with % Change -23.6% nic ind -32.6% -20.2% ohexol O O.S33 O.S83 O.886 140 2.44 0.1N hydrochloric acid or 0.1N sodium hydroxide. Aliquots : O.285 0.32O O.391 OSO2 1.29 of the solutions were irradiated with ultraviolet (UV) light for % Change -46.5% -45.1% -55.9% -64.1% -47.1% 24 hours (159 watt hours/m), then processed, analyzed and reported as in Example 2, with the exception that the iohexyl 0107 The presence of the SCD stabilized the contrast peak was measured at 300 nm for both samples and standards. agents against photolysis at all pH values tested. As shown in Results of the study are presented in the table below along Table 2, all compositions containing SCD produced at least with the Solution compositions. US 2013/0323 181 A1 Dec. 5, 2013 13

TABLE 4 light for 18 hours (119 watt hours/m) and other aliquots irradiated with visible (VIS) light for 90 hours (0.65 million Iodide degradants formed (wt %) in the absence and presence of lux hours). The Solutions were then processed, analyzed and SCD and various amounts of TRIS and sodium phosphate buffers. reported as in Example 2, with the exception that the iohexyl Calcium peak was measured at 300 nm for both samples and standards. Sodium Disodium I- % Change Iohexol:SBE7-B-CD TRIS Phosphate Edetate formed in iodide Results of the study are presented in the table below along Mole Ratio (mM) (mM) (mg/mL) (wt %) degradants with the SCD used. The SCDs included derivatives prepared 1:O 10 O.196 from alpha, beta, and gamma CD to evaluate the effect of CD 1:O.OS 10 O.128 -34.7% cavity size. Various Substituents, including one derivative 1:0.1 10 O. 120 -38.8% containing more than one type of Substituent, and degrees of substitution (DS) were also evaluated. TABLE 5 % Change CD Average Iohexol:SCD I formed (wt %) in iodide SCD Ring Substituent DS Mole Ratio UV VIS degradants None (Control) O.107 O.O617 – Crsymeb beta Methyl 4 1:O.OS 0.0969 0.0601 -9.4% (UV) -2.6% (Vis) 4 1:0.1 0.0936 0.0577 -12.5% (UV) –6.5% (Vis) SBEYCD gamma Sulfobutyl 2.0 1:O.OS O.101 0.0611 -5.6% (UV) -1% (Vis) SBECCD alpha Sulfobutyl 3.9 1:O.OS 0.0753 0.0545 -29.6% (UV) -11.7% (Vis) SPEBCD beta Sulfopropyl 4.0 1:O.OS 0.0867 0.0574 – 19% (UV) –7% (Vis) SBE-EE-BCD beta Sulfobutyl 3.5 1:O.OS 0.0825 0.0584 -22.9% (UV) Ethyl 3.5 –5.3% (Vis) SBE4.6YCD Control – O.141 O.OS75 SBEYCD gamma Sulfobutyl 4.6 1:O.OS O.115 0.0469 -18.4% (UV) -18.4% (Vis)

TABLE 4-continued 0113. Each of the SCDs stabilized iohexyl against pho tolysis by both UV and visible light. Iodide degradants formed (wt %) in the absence and presence of SCD and various amounts of TRIS and sodium phosphate buffers. Example 9 Calcium Sodium Disodium I % Change Iohexol:SBE7-B-CD TRIS Phosphate Edetate formed in iodide Effect of SCDs on the Stability of Contrast Agents Mole Ratio (mM) (mM) (mg/mL) (wt %) degradants Subjected to Thermal and/or Photolytic Stress 1:O 10 O.1 O.219 1:O.OS 10 O.1 O.171 -21.9% 0114 Aqueous Solutions were prepared containing 50 1:O 10 O.S39 1:O.OS 10 O.SO4 -6.5% mM iodinated contrast agent, 10 mM tromethamine HCl 1:0.1 10 O469 -1.3% buffer (TRIS), with and without sulfobutylether beta-cyclo 1:O 10 O.1 O.S2O dextrin with an average degree of substitution ~7 (SBE7-B- 1:O.OS 10 O.1 0.477 -8.3% CD), or 2-hydroxypropyl beta-cyclodextrin with an average 0111. The SCD stabilized iohexyl against photolysis by degree of substitution of -6.3 (HP6.3-8-CD) or -4.3 (HP4.3- UV light in the presence of either tromethamine or sodium B-CD). The iohexyl solution was prepared by dissolving solid phosphate buffer at pH 8. The SCD also stabilized formula iohexyl powder while the other solutions were prepared by tions containing the metal chelator disodium calcium edetate. diluting commercial formulated products and adding suffi cient TRIS buffer to reach 10 mM. The pH of the solutions Example 8 was adjusted to 7.4 with 0.1N hydrochloric acid. Effect of CD Ring Size and Substituents on the 0115 Aliquots of the solutions were irradiated with vis Stability of Iohexyl Following UV and VIS Light ible light for 72 hours (0.52 million lux hours). Other aliquots Irradiation were autoclaved for 20 minutes at 121° C., cooled to room temperature and then irradiated with ultraviolet light for 18 0112 Aqueous solutions were prepared containing 473 hours (119 watt hours/m). The solutions were then pro mMiohexyl (180 mg I/mL), 10 mMtromethamine HCl buffer cessed, analyzed and reported as in Example 2, except that the (TRIS), with and without various SCDs. The pH of the solu chromatographic peaks of the contrast agents were evaluated tions was adjusted to 7.4 with 0.1N hydrochloric acid. Ali at 300 nm for both samples and standards. Results of the study quots of the solutions were irradiated with ultraviolet (UV) are presented in the tables below. US 2013/0323 181 A1 Dec. 5, 2013 14

TABLE 6 Iodide formed (wt %) after irradiation with visible light. The percent change in iodide degradants formed in the presence of the SCD is also listed. Contrast Agent:SCD Mole Ratio

Agent Prepared from SCD 1:O 1:O.O1 1:O.O2S 1:O.OS 1:0.1 1:O.S 1:2 Iohexol powder SBE7-B-CD 0.355 0.337 nic O.316 O.313 O.274 O.183 (-5.1%) (-11%) (-11.8%) (-22.8%) (-48.5%) HP6.3-B-CD 0.355 n/d O.346 (0.341 ind nic ind (-2.5%) (-3.9%) HP4.3-B-CD 0.355 n/d O.331 O.324 ind nic ind (-6.8%) (-8.7%) Iopamidol Isovue (R-M200 SBE7-B-CD 0.356 n/d nic ind 0.355 nic ind (-0.3%) Iodixanol Visipaque (R) 320 SBE7-B-CD 0.153 ind nic ind O.142 nic ind (-7.2%) Iowersol Optiray TM 350 SBE7-B-CD 0.304 n/d nic ind O.301 nic ind (-1%) Iopromide Ultravist (R) 370 SBE7-B-CD 0.311 ind nic ind O-269 nic ind (-13.8%) Ioxaglate Hexabrix (R) SBE7-B-CD 0.231 ind nic ind O.211 nic ind (-8.6%)

TABLE 7 Iodide formed (wt % x 10') after autoclaving. The percent change in iodide degradants formed in the presence of the SCD is also listed. Contrast Agent:SCD Mole Ratio Agent Prepared from SCD 1:O.O1 1:O.O2S 1:O.OS 1:0.1 1:O.S 1:2 Iohexol powder SBE7-B-CD 3.35 3.24 ind 2.77 4.98 4.07 248 (-3.3%) (-17.3%) (-26%) HP6.3-B-CD 3.35 ind 1.96 3.46 ind nic nic (-41.5%) HP4.3-3-CD 3.35 ind 3.00 1.43 ind nic nic (-10.4%) (-57.3%) Iopamidol ISOvue (R)-M2OO SBE7-B-CD 3.55 ind ind nic 1.99 nic nic (-43.9%) Iodixanol Visipaque (R) 320 SBE7-B-CD S.49 ind ind nic 3.26 nic nic (-40.6%) Iowersol Optiray TM 350 SBE7-B-CD 4.52 ind ind nic 3.80 nic nic (-30.8%) Iopromide Ultravist (R) 370 SBE7-B-CD 2.96 ind ind nic 2.48 nic nic (-16.2%) Ioxaglate Hexabrix (R) 1.39 ind ind nic 1.43 nic nic (+2.8%)

TABLE 8 Iodide formed (wt %) after autoclaving then irradiation with ultraviolet light. The percent change in iodide degradants formed in the presence of the SCD is also listed. Contrast Agent:SCD Mole Ratio Agent Prepared from SCD 1:O.O1 1:O.O2S 1:O.OS 1:0.1 1:O.S 1:2 Iohexol powder SBE7-B-CD O.730 O.693 ind O.S74 O.S26 O384 O.282 (-5.1%) (-21.4%) (-27.9%) (-47.4%) (-61.4%) HP6.3-B-CD O.730 ind O.656 O.603 ind nic nic (-10.1%) (-17.4%) HP4.3-3-CD O.730 ind O.637 O.616 ind nic nic (-12.7%) (-15.6%) Iopamidol ISOvue (R)-M2OO SBE7-B-CD ind ind nic O.470 nic nic (-13%) Iodixanol Visipaque (R) 320 SBE7-B-CD O.292 ind ind nic O.220 nic nic (-24.7%) Iowersol Optiray TM 350 ind ind nic O.S45 nic nic (-18%) US 2013/0323 181 A1 Dec. 5, 2013 15

TABLE 8-continued Iodide formed (wt %) after autoclaving then irradiation with ultraviolet light. The percent change in iodide degradants formed in the presence of the SCD is also listed. Contrast Agent:SCD Mole Ratio Agent Prepared from SCD 1:O 1:O.O1 1:O.O2S 1:O.OS 1:0.1 1:O.S 1:2 Iopromide Ultravist (R) 370 SBE7-B-CD 0.487 n/d ind nic O.330 nic nic (-32.3%) Ioxaglate Hexabrix (R) SBE7-B-CD 0.392 n/d ind nic O.332 nic nic (-15.3%)

TABLE 9 Iodide formed (wt %) after autoclaving then irradiation with visible light. The percent change in iodide degradants formed in the presence of the SCD is also listed. Contrast Agent:SCD Mole Ratio Agent Prepared from SCD 1:O 1:O.O1 1:O.O2S 1:O.OS 1:0.1 1:O.S 1:2 Iohexol powder SBE7-B-CD 0.392 0.392 ind O.334 0.327 O.262 O.163 (-0%) (-14.8%) (-16.6%) (-33.4%) (-58.4%) HP6.3-3-CD 0.392 n/d O.32O O.313 ind nic nic (-18.4%) (-20.2%) HP4.3-3-CD 0.392 n/d O.317 O.30S ind nic nic (-19.1%) (-22.2%) Iopamidol Isovue (R-M200 SBE7-B-CD 0.348 n/d ind nic O.344 nic nic (-1.1%)

0116. The SCDs provided stabilization towards degrada TABLE 10 tion by visible light at all mole ratios evaluated. Samples that were autoclaved and then irradiated by ultraviolet light irra Effect of buffer content on the pH and amount of iodide formed (wt %) diation were also stabilized by SCDs at all mole ratios. The after autoclaving or autoclaving plus irradiation with UV or visible light. contrast agents that were autoclaved and then irradiated with The percent change in iodide degradants formed in the presence of the visible light were stabilized by the SCDs only at agenticyclo SCD is also listed. dextrin mole ratios greater than 1:0.01. SBE7- Iodide Formed (wt %)

Example 10 TRIS B-CD pH pH post Post VIS UV mM mM initial autoclave Autoclave Irradiation Irradiation

Effect- 0 of Buffer Content and SCD on pH and O O 7.4 6.4 O.O151 O.465 0.444 Stability after Autoclaving and Irradiation with UV 2.5 O 7.4 7.3 O.OO296 O.606 O.470 or Visible Light 5 O 7.4 7.2 O.OO283 O.672 O.S10 7.5 O 7.4 7.2 O.OO181 O.656 0.571 (0117 Aqueous solutions were prepared containing 50 10 O 7.4 7.3 O.OOO86 O.662 O646 mM iohexyl, 0, 2.5, 5, 7.5, or 10 mM tromethamine HC1 O 2.5 7.4 6.6 O.OO933 O.472 0.373 (TRIS) buffer, with and without 2.5 mM sulfobutylether beta- (-16.0%) cyclodextrin with an average degree of substitution -7 2.5 2.5 7.4 7.5 O.OO183 O.464 O.368 (SBE7-3-CD). The pH of the solutions was adjusted to 7.4 (-23.4%) (-21.7%) with 0.1N hydrochloric acid and the solutions were trans- 5 2.5 7.4 7.5 O.OO174 O.640 O421 ferred to glass vials. The vials were stoppered, crimp-capped (-4.8%) (-17.4%) and autoclaved for 20 minutes at 121° C. The pH of the 7.5 2.5 7.4 7.4 O.OO170 O. 613 O465 autoclaved solutions was measured after the solutions were at (-6.6%) (-18.6%) room temperature. 10 2.5 7.4 7.4 OOO214 0.612 O.514 0118 Aliquots of the autoclaved solutions were irradiated (-7.6%) (-20.4%) with visible light for 72 hours (0.52 million lux hours) and other aliquots irradiated with ultraviolet light for 18 hours (119 watt hours/m). The solutions were then processed, ana- 0119. In the absence of a buffer agent, the pH of the lyzed and reported as in Example 2, except that the chromato iohexyl solution dropped after autoclaving by a full pH unit in graphic peak of the iohexyl was evaluated at 300 nm for both the absence of the SCD and by 0.8 units in its presence. Less samples and standards. Results of the study are presented in of the iodide degradant was observed in the presence of the the table below. SCD after UV irradiation regardless of the amount of buffer US 2013/0323 181 A1 Dec. 5, 2013 16 present. When a buffer was present, the SCD also stabilized formulations were placed in glass vials, sealed with rubber the solutions against photolysis by visible light irradiation. stoppers and aluminum crimps, and autoclaved at 121°C. for 20 minutes. Aliquots of the autoclaved solutions were Example 11 exposed to UV light for 24 hours (159 watt hours/m) or VIS light for 72 hours (0.52 million lux hours) as in Example 2. Effect of SCD on Stability of Concentrated Contrast The Solutions were then processed, analyzed and reported as Agent Solutions After Autoclaving and Irradiation in Example 2, with the following two exceptions: 1) the with UV or Visible Light chromatographic peaks of the contrast agents were evaluated 0120 Aqueous formulations were prepared containing at 300 nm for both samples and standards, and 2) only 20 iodinated contrast agents at concentrations used commer microliter sample aliquots were taken and diluted for HPLC cially in medical procedures. Sulfobutylether f3-cyclodex analysis due to the higher concentrations used in this study. trin, Sodium salt, average degree of Substitution ~7 Results of the study are presented in the table below along (SBE7CD) was added at varying agent:CD mole ratios. The with the Solution compositions. TABLE 11 Iodide formed (wt %) after autoclaving or autoclaving plus irradiation with UV or visible light. The percent change in iodide degradants formed in the presence of the SCD is also listed. Contrast CaNa2 Agent Agent:SBE7CD TRIS Edetate CaCl2.H2O NaCl Iodide Formed (wt % (mg I/mL) Mole ratio (mg/mL) (mg/mL) (mg/mL) (mg/mL) Autoclaved UV VIS Iohexol, pH 7.4

400 O .2 O. O O O.OOO69 O. 142 O.O3OO 400 :O.O2 .2 O. O O 0.00075 O. 106 O.O215 (-25.4%) (-28.3%) 400 O.OS .2 O. O O O.OO109 O.O958 O.O164 (-32.5%) (-45.3%) 400 :O.10 .2 O O O O.OOO26 O.OS42 O.OO6S (-61.8%) (-78.3%) 350 O .2 O O O O.00244 O.O96S O.O391 350 O.OS .2 O O O OOOO24 O.OS64 O.O26S (-41.6%) (-32.2%) 3OO O .2 O O O O.OO293 O.100 O.O417 3OO O.OS .2 O O O OOOO40 0.0717 O.O385 (-28.3%) (-76.7%) 240 O .2 O O O O.OO391 O.118 O.OS36 240 O.OS .2 O O O O.OO117 O.O928 O.0491 (-21.3%) (-8.4%) 18O O .2 O O O O.O097 O.156 O.OSO3 18O O.OS .2 O O O O.O1 OS O.127 O.O476 (-18.6%) (-5.4%) 155 O .2 O O O O.OOO21 O.153 O.0488 155 :O.O2 .2 O O O O.OOO19 O.121 O.0432 (-20.9%) (-11.5%) 155 O.OS .2 O O O OOOO16 O. 111 O.O417 (-27.4%) (-14.5%) 155 :O.10 .2 O O O OOOO16 O.O979 O.O362 (-36.0%) (-25.8%) 140 O .2 O O O O.00474 O.191 O.O967 140 O.OS .2 O O O O.OO287 O.151 O.O893 (-20.9%) (-7.6%) Iopamidol, pH 7

2OO O O O.26 O O O.OO347 O.1SO 0.0570 2OO O.OS O O.26 O O O.OO338 O.145 O.OS74 (-3.3%) Iopromide, pH 7.4

370 O 2.42 O.1 O O O.00111 O.O989 O.O392 370 O.OS 2.42 O.1 O O O.OOO720 O.O780 O.O3S1 (-21.1%) (-10.4%) 3OO O 2.42 O.1 O O O.OO145 O. 110 O.0493 3OO O.OS 2.42 O.1 O O O.00118 O. 102 O.O426 (-7.3%) (-13.6%) 240 O 2.42 O.1 O O O.00204 O.129 O.OSO4 240 O.OS 2.42 O.1 O O O.OO217 O. 113 O.O413 (-12.4%) (-18.0%) 150 O 2.42 O.1 O O O.OO383 O.148 0.0735 150 O.OS 2.42 O.1 O O O.OO289 O. 110 OO671 (-25.7%) (-8.7%) US 2013/0323 181 A1 Dec. 5, 2013 17

TABLE 1 1-continued Iodide formed (wt %) after autoclaving or autoclaving plus irradiation with UV or Visible light. The percent change in iodide degradants formed in the presence of the SCD is also listed. Contrast CaNa2 Agent Agent:SBE7CD TRIS Edetate CaCl2.H.O. NaCl Iodide Formed (wt % (mg I/mL) Mole ratio (mg/mL) (mg/mL) (mg/mL) (mg/mL) Autoclaved UV VIS Ioversol, pH 7.1

3SO 1:0 3.6 O.2 O O O.O124 O.118 O.O283 3SO 1:O.OS 3.6 O.2 O O O.O120 O.O864 O.O2SO (-26.8%) (-11.7%) 32O 1:0 3.6 O.2 O O O.O130 O.123 O.O323 32O 1:O.OS 3.6 O.2 O O O.O127 0.0778 0.0277 (-36.7%) (-14.2%) 3OO 1:0 3.6 O.2 O O O.O13S O.134 O.O.361 3OO 1:O.OS 3.6 O.2 O O O.O129 O-111 O.O298 (-17.2%) (-17.4%) 24O 1:0 3.6 O.2 O O O.O160 O.156 O.O454 240 1:O.OS 3.6 O.2 O O O.O162 O.126 O.O4(OO (-19.2%) (-11.9%) 16O 1:0 3.6 O.2 O O O.O244 O.225 0.0717 16O 1:O.OS 3.6 O.2 O O O.O241 O.171 O.O646 (-24.0%) (-9.9%) Ioxaglate, pH 7.0

**320 1:0 O O O O O.OO457 O.114 O.O197 **320 1:0.05 O O O O O.OO329 O.O845 O.O175 (-25.9%) (-11.2%) Iodixanol, pH 7.4

32O 1:0 1.2 O.1 O.044 1.11 O.O132 0.0751 O.O26S 32O 1:O.OS 1.2 O.1 O.044 1.11 O.O13S O.O743 O.O2S1 (-1.1%) (-5.3%) 27O 1:0 1.2 O.1 O.074 1.87 O.O167 O.O845 O.O325 27O 1:O.OS 1.2 O.1 O.074 1.87 O.O161 O.O791 O.O288 (-6.4%) (-11.4%) **contained 393 mg of ioxaglate meglumine and 196 mg of ioxaglate sodium, together providing 320 mg Iml, The meglumine salt serves as a buffering agent,

0121 The presence of the SCD stabilized the solutions 1:0.025. The addition of the SCD added 154 mM Sodium to against degradation by autoclaving in most, but not all, for the Solution as its counterion. The formulations also con mulations. The SCD stabilized all formulations against deg tained 0.1 mg/mL edetate calcium disodium hydrate, and 1.2 radation from autoclaving+ultraviolet light irradiation. The mg/mL tromethamine buffer, with the pH of each solution SCD stabilized all formulations except iopamidol against adjusted to 7.4 with 1N HC1. The solutions were sterilized by degradation from autoclaving+visible light irradiation. filtration through a 0.22 micron filter. Example 12 0.124. Each formulation was rapidly injected into the left main coronary artery of an instrumented anesthetized 6-10 Effect of SCDs on the Cardiovascular month old Beagle dog as 5 doses of 4 mL each, administered Electrophysiology and Hemodynamics of Iohexyl at ~1 mL/sec with 10 seconds between doses. Thirty minutes Following Intra-Arterial Administration after the last dose, the procedure was repeated with the second 0122) The ionic content of contrastagent formulations can formulation. The overall process was repeated in two addi have injurious effects on the heart when the blood in the heart tional animals. is displaced briefly by the contrast agent. Baath, et al. (Acta 0.125. The instrumentation provided measurement of right Radiologica 31 (1990) Fasc.1 pp. 99-104) demonstrated in heart pressure, left ventricular pressure, aortic pressure, car isolated perfused rabbit hearts that a small amount of sodium diac output and electrocardiography (ECG). The specific (19-38 mM) added to a contrast formulation was beneficial in parameters measured were: systolic artery pressure (SAP), minimizing decreases in contractile force while 154 mM mean aortic pressure (MAP), diastolic aortic pressure (DAP), Sodium caused a large decrease in contractile force. The SAE left ventricular systolic pressure (LVSP), left ventricular end CDs, SAE-HAE-CDs, and the SAE-AE-CDs all have ionic diastolic pressure (LVEDP), left ventricle dp/dt (an indi Substituents requiring counterions. The effects of the sodium rect measure of contractile force), left ventricle dP/dt, salt of an SAE-CD were evaluated in an instrumented dog cardiac output (CO), systemic vascular resistance (SVR), model. pulmonary vascular resistance (PVR), pulmonary artery pres 0123 Aqueous formulations were prepared containing Sure (PAP), monophasic action potential duration 755 mg/mL iohexyl without (formulation 1) or with (formu (MAPDsoo, sooooo...), heart rate (HR), and from the ECG, PR lation 2) Sulfobutylether B-cyclodextrin, Sodium salt (average interval, QRS duration, QT/QTc interval, JT/JTc interval (as degree of substitution ~7) at an iohexyl:SCD mole ratio of needed) and arrhythmogenesis. US 2013/0323 181 A1 Dec. 5, 2013

0.126 Results: 10. The composition of claim 1, wherein the substituted 0127. There were no notable effects of intracoronary cyclodextrin is selected from the group consisting of Sul iohexyl administration (formulation 1) on most measured foalkylether cyclodextrins, 2-hydroxypropyl cyclodextrins, cardiovascular parameters. Variables including LV contrac partially methylated cyclodextrins and sulfoalkylether alky tility and QTc interval were notably, yet transiently, altered lether cyclodextrins. following the iohexyl regimen. Results for QTc interval and 11. The composition of claim 1, wherein the iodinated contractility are shown in FIGS. 2 and 3 respectively. contrast agent is selected from the group consisting of 0128. In addition to these transient quantitative changes, iohexyl, ioVersol, diatrizoate meglumine and ioxaglate, and qualitative alterations in electrocardiographic morphology the Substituted cyclodextrin is selected from the group con were observed. These were generally concomitant with sisting of Sulfoalkylether cyclodextrins, partially methylated physical injection of the iohexyl Solution into the coronary cyclodextrins, sulfoalkylether alkylether cyclodextrins and artery, and likely associated with brief myocardial ischemia sulfoalkyl ether hydroxyalkyl ether cyclodextrins. from interruption of arterial flow. The changes consisted of 12. The composition of claim 1, wherein the iodinated QRS complex widening along with ST segment depression. contrast agent is selected from the group consisting of iopa Scattered premature Ventricular contractions were also noted. midol, iodixanol, and iopromide. ECG morphology returned to normal within five minutes 13. The composition of claim 1, wherein the composition after the last iohexyl injection. has an iodine content greater than 150 mgl/mL and less than 0129. Administration of formulation 2 containing the or equal to 400 mgl/mL. SCD gave similar quantitative and qualitative changes as 14. The composition of claim 10, where the substituted formulation 1 demonstrating that the additional Sodium con cyclodextrin is selected from the group consisting of sulfobu tent provided by the SCD surprisingly had no detrimental tyl ether beta-cyclodextrin, Sulfobutyl ether gamma-cyclo effect on cardiac function. dextrin, sulfobutyl ether alpha-cyclodextrin, sulfopropyl 0130. The above is a detailed description of particular ether beta-cyclodextrin, sulfobutylether ethylether beta-cy embodiments of the invention. It will be appreciated that, clodextrin, 2-hydroxypropyl beta cyclodextrin, and partially although specific embodiments of the invention have been methylated beta cyclodextrin. described herein for purposes of illustration, various modifi 15. The composition of claim 14, wherein the substituted cations may be made without departing from the spirit and cyclodextrin is a sulfobutyl ether beta-cyclodextrin with an Scope of the invention. Accordingly, the invention is not lim average degree of Substitution of 7. ited except by the appended claims. All of the embodiments 16. The composition of claim 14, wherein the substituted disclosed and claimed herein can be made and executed with cyclodextrin is a 2-hydroxypropyl beta cyclodextrin with an out undue experimentation in light of the present disclosure. average degree of substitution of 6.3 or 4.3. 1. An aqueous pharmaceutical composition comprising: 17. The composition of claim 1, wherein the ultraviolet an iodinated contrast agent; light exposure is 119 watt hours per square meter. a pharmaceutically acceptable buffering agent; and 18. The composition of claim 1, wherein the ultraviolet a Substituted cyclodextrin present at a contrast agent: Sub light exposure is 159 watt hours per square meter. stituted cyclodextrin mole ratio from 1:0.01 to 1:2: 19. The composition of claim 1, wherein the composition wherein the composition has a pH of 5 to 8 and wherein the exhibits at least a 5% reduction information of iodine species composition exhibits at least a 3% reduction in formation of when exposed to ultraviolet light as compared to the corre iodine species when exposed to ultraviolet light as compared sponding composition. to a corresponding composition, without a Substituted cyclo 20. The composition of claim 1, wherein the composition dextrin, exposed to the same UV light. exhibits at least a 10% reduction in formation of iodine spe 2. The composition of claim 1, wherein the composition is cies when exposed to ultraviolet light as compared to the heat sterilized prior to exposure to the UV light. corresponding composition. 3. The composition of claim 2, wherein the heat steriliza 21. The composition of claim 1, wherein the composition tion comprises steam sterilization. exhibits at least a 20% reduction in formation of iodine spe 4. The composition of claim3, wherein the steamsteriliza cies when exposed to ultraviolet light as compared to the tion occurs at 115-116°C. for at least 30 minutes, 121-123°C. corresponding composition. for at least 15 minutes, 126-129°C. for at least 10 minutes, or 22. The composition of claim 1, wherein the composition 134-138°C. for at least 3 minutes. exhibits at least a 30% reduction in formation of iodine spe 5. The composition of claim 1, wherein the pharmaceuti cies when exposed to ultraviolet light as compared to the cally acceptable buffering agent is selected from the group corresponding composition. consisting of tromethamine, phosphate, and meglumine, and 23. The composition of claim 1, wherein the composition their pharmaceutically acceptable salts. exhibits at least a 40% reduction in formation of iodine spe 6. The composition of claim 1, wherein the pH of the cies when exposed to ultraviolet light as compared to the composition is 6.5 to 7.7. corresponding composition. 7. The composition of claim 1, wherein the pH of the 24. The composition of claim 1, wherein the composition composition is 7.4. exhibits at least a 50% reduction in formation of iodine spe 8. The composition of claim 1, wherein the contrast agent: cies when exposed to ultraviolet light as compared to the substituted cyclodextrin mole ratio is from 1:0.02 to 1:2. corresponding composition. 9. The composition of claim 1, further comprising one or 25. The composition of claim 1, wherein the composition more components selected from the group consisting of pH exhibits at least a 60% reduction in formation of iodine spe adjusting agents, antioxidants, chelating agents and inert gas cies when exposed to ultraviolet light as compared to the SCS. corresponding composition. US 2013/0323 181 A1 Dec. 5, 2013 19

26. An aqueous pharmaceutical composition comprising: 40. The composition of claim 35, wherein the pH of the an iodinated contrast agent selected from the group con composition is 6.5 to 7.7. sisting of iohexyl, iopromide, ioVersol, ioxaglate and 41. The composition of claim 34 or 35, wherein the iodi iodixanol: nated contrast agent is iohexyl, the Substituted cyclodextrin is a pharmaceutically acceptable buffering agent; and a sulfobutylether beta-cyclodextrin, and the composition has a Substituted cyclodextrin present at a contrast agent: Sub an iodine content greater than 150 mgl/ml and less than or stituted cyclodextrin mole ratio from 1:0.01 to 1:2. equal to 400 mgl/ml. wherein the composition has a pH of 5 to 8 and wherein the 42. The composition of claim 41, wherein the sulfobu composition exhibits at least a 3% reduction in formation of tylether beta-cyclodextrin has an average degree of Substitu iodine species when exposed to visible light as compared to a tion of 7. corresponding composition, without a Substituted cyclodex 43. The composition of claim 41, wherein the pH of the trin, exposed to the same visible light. composition is 6.8 to 7.7. 27. The composition of claim 26, wherein the composition 44. The composition of claim 41, comprising 1.21 mg/ml is heat sterilized prior to exposure to the visible light. tromethamine and 0.1 mg/ml disodium calcium edetate. 28. The composition of claim 27, wherein the heat steril 45. The composition of claim 41, wherein the iohexyl: ization comprises steam sterilization. sulfobutylether beta-cyclodextrin moleratio is from 1:0.02 to 29. The composition of claim 28, wherein the steam ster 1:0.1 ilization occurs at 115-116° C. for at least 30 minutes, 121 46. The composition of claim 41, wherein the composition 123° C. for at least 15 minutes, 126-129° C. for at least 10 has an iodine content of 155, 180, 240, 300, 350 or 400 minutes, or 134-138°C. for at least 3 minutes. mgl/mL. 30. The composition of claim 26 or 27, wherein the sub 47. The composition of claim 34 or 35, wherein the iodi stituted cyclodextrin is presentata contrast agent:Substituted nated contrast agent is iopamidol, the Substituted cyclodex cyclodextrin mole ratio from 1:0.02 to 1:2. trin is a sulfobutylether beta-cyclodextrin, and the composi 31. The composition of claim 30, wherein the substituted tion has an iodine content greater than 150 mgl/ml and less cyclodextrin is present at a contrast agent.Substituted cyclo than or equal to 400 mgl/ml. dextrin mole ratio from greater than 1:0.025 and less than or 48. The composition of claim 47, wherein the sulfobu equal to 1:2. tylether beta-cyclodextrin has an average degree of Substitu 32. The composition of claim 26, wherein the visible light tion of 7. exposure is 0.65 million lux hours. 33. The composition of claim 26, wherein the visible light 49. The composition of claim 47, wherein the pH of the exposure is 0.52 million lux hours. composition is 6.5 to 7.5. 34. A ready to use, sterile, injectable aqueous pharmaceu 50. The composition of claim 47, comprising 1.0 mg/ml tical composition comprising: tromethamine and 0.26 to 0.48 mg/ml disodium calcium ede an iodinated contrast agent selected from the group con tate. sisting of iohexyl, iopamidol, iodixanol, ioVersol, and 51. The composition of claim 47, wherein the iopamidol: iopromide; sulfobutylether beta-cyclodextrin moleratio is from 1:0.02 to 1 to 4 mg/mL tromethamine (TRIS) buffer; 1:0.1 0.1 to 0.6 mg/mL disodium calcium edetate; and 52. The composition of claim 47, wherein the composition a Substituted cyclodextrin selected from the group consist has an iodine content of 200 mgl/mL. ing of sulfobutylether beta-cyclodextrin, and 2-hydrox 53. The composition of claim 34 or 35, wherein the iodi ypropyl beta-cyclodextrin, wherein the substituted nated contrast agent is iopromide, the Substituted cyclodex cyclodextrin is present at a contrast agent:Substituted trin is a sulfobutylether beta-cyclodextrin, and the composi cyclodextrin mole ratio from 1:0.01 to 1:0.1: tion has an iodine content greater than 150 mgl/ml and less wherein the composition has a pH of 5 to 8 and wherein the than or equal to 400 mgl/ml. composition is packaged in a primary container that does not 54. The composition of claim 53, wherein the sulfobu possess enhanced light shielding properties. tylether beta-cyclodextrin has an average degree of Substitu 35. The composition of claim 34, wherein the composition tion of 7. has been heat sterilized. 55. The composition of claim 53, wherein the pH of the 36. The composition of claim 35, wherein the composition composition is 6.5 to 8.0. has an iodine content greater than 150 mg/mL and less than 56. The composition of claim 53, comprising 2.42 mg/ml or equal to 400 mg/mL. tromethamine and 0.1 mg/ml disodium calcium edetate. 37. The composition of claim 35, wherein the iodinated 57. The composition of claim 53, wherein the iopromide: contrast agent is iohexyl, iopamidol, ioVersol or iopromide, sulfobutylether beta-cyclodextrin mole ratio is 1:0.02 to 1:0. and the iodinated contrast agent is present at a molar concen 1. tration greater than 394.1 mM and less than or equal to 1051 58. The composition of claim 53, wherein the composition mM. has an iodine content of 240, 300 or 370 mgl/mL. 38. The composition of claim 35, wherein the iodinated 59. The composition of claim 34 or 35, wherein the iodi contrast agent is iodixanol, and the iodixanol is present at a nated contrast agent is iodixanol, the Substituted cyclodextrin molar concentration greater than 197.1 mM and less than or is a sulfobutylether beta-cyclodextrin, and the composition equal to 525.4 mM. has an iodine content greater than 150 mgl/ml and less than or 39. The composition of claim35, further comprising one or equal to 400 mgl/ml. more components selected from the group consisting of pH 60. The composition of claim 59, wherein the sulfobu adjusting agents, antioxidants, chelating agents, and inert tylether beta-cyclodextrin has an average degree of Substitu gasses. tion of 7. US 2013/0323 181 A1 Dec. 5, 2013 20

61. The composition of claim 59, wherein the pH of the ioxaglate, wherein the ioxaglate comprises ioxaglate composition is 6.8 to 7.7. meglumine and ioxaglate Sodium; 62. The composition of claim 59, comprising 1.21 mg/ml 0.1 to 0.6 mg/mL disodium calcium edetate; and tromethamine and 0.1 mg/ml disodium calcium edetate. a Substituted cyclodextrin selected from the group consist 63. The composition of claim 62, further comprising 1.11 ing of sulfobutylether beta-cyclodextrin, and 2-hydrox mg/ml to 1.87 mg/ml of sodium chloride and 0.044 mg/ml to ypropyl beta-cyclodextrin, wherein the substituted 0.074 mg/ml of calcium chloride dihydrate. cyclodextrin is present at a contrast agent:Substituted 64. The composition of claim 59, wherein the iodixanol: cyclodextrin mole ratio from 1:0.01 to 1:0.1: sulfobutylether beta-cyclodextrin mole ratio is from 1:0.02 to wherein the composition has a pH of 5 to 8 and wherein the 1:0.1 composition is packaged in a primary container that does not 65. The composition of claim 59, wherein the composition possess enhanced light shielding properties. has an iodine content of 270 or 320 mgl/mL. 73. The composition of claim 72, wherein the composition 66. The composition of claim 34 or 35, wherein the iodi has been heat sterilized. nated contrast agentis ioVersol, the Substituted cyclodextrin is 74. The composition of claim 72 or 73, wherein the sub a sulfobutylether beta-cyclodextrin, and the composition has stituted cyclodextrin is a sulfobutylether beta-cyclodextrin, an iodine content greater than 150 mgl/ml and less than or and the composition has an iodine content greater than 150 equal to 400 mgl/ml. mgl/ml and less than or equal to 400 mgl/ml. 67. The composition of claim 66, wherein the sulfobu 75. The composition of claim 72 or 73, wherein the sul tylether beta-cyclodextrin has an average degree of Substitu fobutylether beta-cyclodextrin has an average degree of Sub tion of 7. stitution of 7. 68. The composition of claim 66, wherein the pH of the 76. The composition of claim 72 or 73, wherein the pH of composition is 6.0 to 7.4. the composition is 6.0 to 7.6 69. The composition of claim 66, comprising 3.6 mg/ml 77. The composition of claim 72 or 73, comprising 393 mg tromethamine and 0.2 mg/ml disodium calcium edetate. of ioxaglate meglumine and 196 mg of ioxaglate Sodium. 70. The composition of claim 66, wherein the ioversol: sulfobutylether beta-cyclodextrin mole ratio is from 1:0.02 to 78. The composition of claim 72 or 73, wherein the ioxag 1:0.1 late:sulfobutylether beta-cyclodextrin mole ratio is from 1:0. 71. The composition of claim 66, wherein the composition O2 to 1:0.1 has an iodine content of 160,240, 300, 320 or 350 mgl/mL. 79. The composition of claim 72 or 73, wherein the com 72. A ready to use, sterile, injectable aqueous pharmaceu position has an iodine content of 320 mgl/mL. tical composition comprising: k k k k k