GB2050167A - X-ray contrast compositions - Google Patents

Abstract

X-ray contrast compositions having improved cardiac and systemic safety containing approximately 34 to 40% iodine and suitable for use in angiocardiographic procedures comprise an aqueous solution of a mixture of a nonionic X-ray contrast medium and an ionic X-ray contrast medium, the composition having a viscosity of not more than approximately 9-12 centipoises at 37 DEG C, the nonionic X-ray a contrast medium per se in aqueous solution having a viscosity greater than that of the composition at 37 DEG C, and the ionic X-ray contrast medium per se in aqueous solution having a viscosity of less than that of the composition at 37 DEG C. The ionic contrast agents include the pharmaceutically acceptable salts 4 (e.g., sodium, N-methylglucamine etc.) of iothalamic acid (5-acetamido- 2,4,6-triodo-N-methylisophthalamic acid), diatrizoic acid (3,5-diacetamido- 2,4,6-triiodobenzoic acid), ioxaglic acid (2,4,6-triiodo-3-N-hydroxyethylcarbamyl- 5-(2,4, 6-triiodo- 3-N-methylcarbamyl-5-N-methyl-N- acetylaminobenzoyl)glycylaminobenzoic acid, U.S. patent No. 4,065,554), metrizoic acid (3(acetylamino)- 5-(acetylmethylamino)- 2,4,6-triiodobenzoic acid), ioxithalamic acid (5-acetamido-2,4,6-triiodo- N-2-hydroxyethyl isophthalamic acid) and iodamide (3-(acetylamino)- 5-[(acetylamino)methyl]- 2,4,6-triiodobenzoic acid). The non- ionic contrast agents include N,N'- bis-(2,3-dihydroxypropyl)-2,4,6-triiodo- 5-(2-keto-L-gulonamido) isophtalamide, N-(2-hydroxyethyl)- 2,4,6-triiodo-bis-3,5-(2-keto-L-gulonamido) benzamide, L-5- alpha -hydroxypropionylamino- 2,4,6-triiodoisophtalic acid di-(1,3-dihydroxyisopropylamide) and 5-(N-2-hydroxyethylacetamido)- 2,4,6-triiodo-N,N'- bis-2,3-dihydroxypropyl)-isophthalamide, N-(N-methyl-3,5-diacetamido- 2,4,6-triiodobenzoyl)-glucosamine and 3,5-bis-gluconamido-2,4,6- triiodo-N-methylbenzamide.

Description

SPECIFICATION X-ray contrast compositions This invention relates to the field of x-ray contrast media and more particularly to such media having the requisite physical, chemical and safety properties for use in angiocardiographic procedures.

Certain nonionic iodinated x-ray contrast media have demonstrated significantly greater safety or lover toxicity over conventional ionic x-ray contrast media which are administered in the form of salts. Some nonionic x-ray contrast agents are not stable in aqueous solution and need to be lyophilized and reconstituted thereby limiting their convenient usage primarily to low-volume diagnostic procedures such as myelography. Other nonionic x-ray contrast agents exhibit greater water stability with equal or better safety characteristics than the aqueous unstable nonionic agents.Because of their generally superior safety characteristics, nonionic x-ray contrast media have been suggested for use in higher risk angiographic and intravascular radiographic procedures where decreased toxicity would justify the somewhat higher cost of nonionic agents as compared to conventional ionic agents. However, such procedures usually require larger volumes of contrast agent and always require higher (e.g., 37%) iodine concentrations and the viscosity of the contrast agent solution therefore becomes a matter of major importance.

Viscosity is the resistance of a fluid to movement and is characterized by the amount of force required to move a liquid under specified conditions. In angiographic and intravascular procedures, those conditions usually involve an injection syringe (with or without a pressure injector), a catheter, and the vessel(s) to be visualized. Highly viscous solutions are unacceptable in terms of the amount of pressure required for injection or, if a pressure injector is employed, resistance may cause undue catheter pressure. Once in the desired vessel, more viscous contrast media solutions retard the flow of blood by creating a resistance to movement, increase transit and exposure times of the contrast agent solution in that vessel, and thereby increase the probability of that agent to cause untoward effects.While the lowest possible viscosities are desirable for the purpose of angiographic and intravascular procedures, viscosities in the range of 9-12 centipoises at 37"C are presently regarded as maximal.

Unfortunately, most nonionic x-ray contrast media are considerably more viscous than ionic contrast media of equal iodine concentration and have viscosities in excess of 9-12 centipoises at 37"C. For example, the nonionic agent metrizamide (N-(N-methyl-3,5-diacetamido-2,4,6- triiodobenzoyl)-glucosamine, U.S. patent No. 3,701,771) with an iodine concentration of 37% has a viscosity of 16.4-17.0 centipoises at 37"C, whereas the ionic agent sodium iothalamate (the sodium salt of 5-acetamido-2,4,6-triiodo-N-methylisophthalmic acid, U.S. patent No.

3,145,197) of equivalent iodine concentration has a viscosity of 3.6 centipoises at 37"C.

A need exists therefore for rendering nonionic x-ray contrast media of higher viscosity more practically usable in angiographic and intravascular procedures by modification of their physicochemical properties without reduction of iodine content or adverse effect upon the safety properties.

Summary of the Invention Among the several objects of the invention may be noted the provision of x-ray contrast compositions suitable for use in angiocardiographic procedures containing both a nonionic x-ray contrast medium and an ionic x-ray contrast medium and having acceptable viscosity characteristics; the provision of such compositions which afford acceptable iodine content and safety profiles; the provision of compositions of the type described in which the viscosity is lower than that of the nonionic x-ray contrast medium component per se; the provision of such compositions having intravenous toxicities which are generally lower than those of the ionic x-ray contrast medium component per se; and the provision of compositions of the type indicated which are readily prepared. Other objects and features will be in part apparent and in part pointed out hereinafter.

Briefly, the present invention is directed to x-ray contrast compositions comprising an aqueous solution of a mixture of a nonionic x-ray contrast medium and an ionic x-ray contrast medium, the compositions having an iodine concentration of approximately 34 to 40% and a viscosity of not more than approximately 9-12 centipoises at 37"C, the nonionic x-ray contrast medium per se in aqueous solution having a viscosity greater than that of the composition at 37"C, and the ionic x-ray contrast medium per se in aqueous solution having a viscosity of less than that of the composition at 37"C. In a preferred embodiment of the invention, the nonionic x-ray contrast medium component of the compositions is aqueous solution stable.

Description of the Preferred Embodiments In accordance with the present invention, it has now been found that x-ray contrast compositions suitable for use in angiocardiographic procedures may be provided by formulating an aqueous solution of a mixture of a nonionic x-ray contrast medium and an ionic x-ray contrast medium, the compositions having a viscosity of not more than approximately 9-12 centipoises at 37"C. The nonionic x-ray contrast medium component of the compositions per se in aqueous solution has a viscosity greater than that of the compositions at 37"C, while the ionic x-ray contrast medium component per se in aqueous solution has a viscosity of less than that of the compositions at 37"C and generally less than approximately 9-12 centipoises at 37"C. We have thus found that mixtures of more viscous, less toxic nonionic x-ray contrast media and less viscous, more toxic ionic x-ray contrast media may be formulated in optimal ratios to obtain xray contrast media solutions with acceptable viscosity, iodine content and safety profiles and which are useful in angiocardiographic procedures.

While it is not particularly surprising that the viscosity of a solution of a mixture of a nonionic contrast agent and an ionic contrast agent is less than that of a solution of a nonionic contrast agent alone at equal iodine concentrations, we have unexpectedly found that, in certain instances, the safety profile is not only not compromised but is even enhanced over that of either the nonionic contrast agent or the ionic contrast agent alone. Thus, in the case of an aqueous solution of a mixture of metrizamide (31.5% 1) and sodium iothalamate (5.5% I), the safety profile of the mixture exceeded that of either the nonionic or ionic contrast agent alone.

The x-ray contrast compositions of this invention are useful in angiocardiographic procedures (e.g., coronary arteriography, ventriculography and aortography) where higher iodine concentrations are desired and lower viscosities in the range of 9-12 centipoises at 37"C are important from the standpoint of safety and ease of administration. For such procedures, the iodine concentration may range from approximately 34% to 40% and typically is 37%.

There are considerable differences in viscosity between various nonionic x-ray contrast media as iodine concentrations are increased. At higher iodine concentrations, most nonionic x-ray contrast media have viscosities in excess of the 9-1 2 centipoises (at 37"C) range (as determined by the methods set forth in the working examples: and are therefore undesirably viscous for angiocardiographic procedures which involve the use of media with an iodine concentration of 37%. Viscosity could be reduced by a reduction in concentration but this also undesirably decreases diagnostic efficacy.In theory, a reduction in viscosity of nonionic contrast agent/ionic contrast agent mixtures would be predictable because the slope of the viscosity curve for all non ionic contrast agents sharply increases between 30% and 37% iodine concentration and a subsequent reduction in iodine concentration disproportionately reduces viscosity. For example, the viscosity of metrizamide, a non ionic x-ray contrast media solution at an iodine concentration of 37% which is approximately 16.4-17.0 centipoises at 37"C was reduced to approximately 9.2 centipoises at 37"C by iodine replacement with the sodium salt of iothalamic acid in a 85% metrizamide/15% iothalamate iodine contribution ratio.

In general, it has been found that the viscosity of the nonionic x-ray contrast media solution is reduced in a concentration-related manner by the addition of an ionic x-ray contrast agent. As mentioned, most non ionic x-ray contrast agents are more viscous than the conventional ionic xray contrast agents at equal iodine concentrations.An exception to this is the non ionic contrast agent L-5-a-hydroxypropionylamino-2,4, 6-triiodoisophthalic acid di-(1 , 3-dihydroxyisopropylam- ide), U.S. patent No. 4,001,323, known as iopamidol, which has a reported viscosity of between 9.5 and 1 2.3 centipoises at 37"C. The invention, nevertheless, broadly applies to such non ionic contrast agents since it is desirable and advantageous to reduce their viscosity even below that of 9 centipoises at 37"C, since the lower the viscosity the better insofar as the radiologist is concerned.

Further, in accordance with the present invention and as indicated by the test results presented hereinafter, it has been found that the cardiac safety, as determined by coronary perfusion of the isolated rabbit heart, of the mixtures of non ionic and ionic x-ray contrast media is comparable to that of the non ionic contrast media alone or, in the case of certain nonionic contrast media, is better than that of the nonionic media, and that it is always significantly better than that of the ionic contrast media alone. Moreover, as also indicated by the test results presented hereinafter, the systemic safety (as reflected by the intravenous LD50 determinations) of the mixtures of the invention is better than for the ionic contrast agent alone and surprisngly in some instances approximates or exceeds that of the nonionic contrast agent alone.

In general, as the ratio of ionic contrast agent to non ionic contrast agent becomes larger, the greater the reduction in viscosity but also the greater the reduction in the safety profile of the mixture. However, the latter factor does not appear to be as markedly influenced as the former and fairly substantial amounts of the ionic contrast agent can be present before any significant toxicity increase for the mixture can be observed. Accordingly, the optimal formulation for each nonionic contrast agent/ionic contrast agent pair with respect to viscosity and safety profile may be determined on a trial and error basis and each mixture may be unique and display its own particular physicochemical and safety property profile. Those skilled in the art will have no difficulty in determining the optimal ratios of the various possible non ionic contrast agent/ionic contrast agent mixtures or combinations.

The x-ray contrast 50mpositions of the invention are readily prepared either by separately dissolving the nonionic contrast agent end the ionic contrast agent, respectively, in sterile water and then mixing the solutions or by successive dissolution in the same solvent to provide the aqueous solutions of he mixtures of the invention. In the case of the ionic contrast agents, pharmaceutically acceptable salts of the agents, such as the sodium, calcium and/or Nmethylglucamine salts, are employed for dissolution of the anion.The N-methylglucamine (meglumine) salts are less preferable in use because they do not effect as great a reduction in viscosity but, on the Other hand, they are a more effective aid in the dissolution of the ionic contrast agent end can serve to adjust the p to the desired level.

Typically, an x-ray contrast composition of this invention may include, in addition to the nonionic contrast medium and the ionic contrast medium, 150-200 mEq/L or more of sodium (as sodium hydroxide) as a contributor to electrical conductivity, 5-10 mEq/L of calcium (as calcium chloride) as an integral electrolyte to aid in the contractile process of the heart muscle and enough N-methylglucamine to aid in the dissolution of the ionic contrast agent and to adjust the p to the desired range. i.e. 6.8 to 7.8.

While the invention is generally applicable to all mixtures of nonionic contrast agents and ionic contrast agents, a preferred embediment of the invention concerns such mixtures in which the nonionic contrast agent is one which is aqueous solution stable in a manner similar to the ionic contrast agent. The term "aqueous solution stable" as used herein means that en aqueous solution of the agent has an acceptable shelf life, and doesn't require lyophilization or reconstitution prior to usage. Such nonionic contrast agents are particularly useful in the practice of the invention since they are soluble and require no tedious special procedures by the radiologist prior to usage.Among the aqueous solution stable nonionic contrast agents included in this preferred embodiment of the invention may be mentioned N,N'-bis-(2,3-dihydroxypropyl)- 2,4,6-triiodo-5-(2-keto-L-gulonamido) isophthalamide, N-(2-hydroxyethyl)-2,4-6-triiodo-bis-3,5-(2keto-L-gulonamido) benzamide, L-5-α-hydroxypropionylamino-2,4,6-triiodoisophthalic acid di (1,3-dihydroxyisopropylamide) and 5-(N-2-hydroxyethylacetamido)-2,4,6-triido-N,N'-bix-2,3dihydroxypropyl)-isophthalamide. It will be understood that other such non ionic contrast media are also encompassed by the invention.

The nonaqueous solution stable nonionic contrast media within the scope of the invention encompass N-(N-methyl-3,5-diacetamido-2,4,6-triiodobenzoyl)-glucosamine and 3,5-bis-2,3namido-2,4,6-triiodo-N-methylbenzamide.

As far as the ionis contrast agents useful in th5 Practce of me invention are concerned, the' encompass a wide range of agents, including the pharmaceutically acceptable salts (e.g., sodium N-methylglucarmine, etc.) of iothalamic acid (5-acetamido-2,4,6-triiodo-N-methyliso phthalamic acid), diatrieoic acid (3,5-diacetamido-2,4,6-triiodobenzoic acid), io'.'aglic acid (2,4,6- triiodo-3-N-hydroxyethylcarbarnyl-5-(2,4,6-triiodo-3-N-methylcarbamyl-5-N-methyl-N-acetylaminobenzoyl)glycylaminobenzoic acid, U.S. patent No. 4,065, 554), metrizoic acid (3(acetylamino)-5- (acetylmethylamino)-2,4,6-triiodobenzoic acid), ioxithalamic acid (5-acetamido-2,4,6-triiodo-N-2hydroxyethyl isophthalamic acid) and iodarnide (3-(acetylamino)-5-[(acetylamino)methyl]-2,4,6- triiodobenzoic acid). It will be understood that other ionic contrast media are included within the scope of the invention.

In summary we have found in accordance with the present invention that aqueous solutions of mixtures of a non ionic contrast agent and an ionic contrast agent provide x-ray compositions having the physicochemical and safety properties which make them practical for use in angiocardiographic procedures. As the data presented hereinafter show. such compositions not only spay the proper viscosity characteritics but unergiectedly, exhibit either improved safety characteristics or no decrease in this important factor, notwithstanding the fact that a more toxic ionic contrast agent is combined with a less toxic nonionic contrast agent.

The following examples illustrate the practice of the invention.

Example 1 Various aqueous cormbinations of the nonionic x-ray contrast agent, metrizamide (N-(N-methyl3,5-diacetamido-2,4,6-triodobenzoyl)glucosamine, U.S. patent No. 3,701, 771), and the sodium or sodium/N-methylglucamine salts of the ionic x-ray contrast agent. iothalamio acid (5 acetarnido-2,4,6-triiodo-N-methylisophthalamic acid, U.S. patent 3,145,1 97), were prepared at total iodine concentrations of 37% iodine. In all cases, the diluent employed was sterile water for injection and final pH adjustment to 6.9-7.8 was achieved with meglumine. 1 N. NaO or 1 N. HCl as required. The aqueous mixtures of sodium iothalamate or soclium/N-methylglucam- ine iothaiamate and metrizamide were prepared by dissolving each separately and then mixing the solutions. In each case, the total iodine concentration for each formulation was 37% (w/v).

Where feasible, the mixtures contained equal, physiolobic concentrations (150 mEq/L) of sodium.

Measurement of the absolute viscosities (centipoises or cps) of the various contrast media formulations was conducted at 37oe us 25.0 ml samples and the following procedure: A Brookfield Model LVT Synchro-Lectric Viscometer was used with a U.L. Adapter containing a precision cylindrical spindle at RPMs of 12, 30 and 60 for respective cps ranges of 20.1-50.0, 10.1-20.0, and 0-10.0. A 37'C temperature was maintained by complete immersion of the U.L. Adapter tube in a 37"C water bath.

The results of the viscosity determinations for each of the formulations prepared are set forth in Table I.

TABLE I Viscosities of Mixtures of Metrizamide and lothalamic Acid

Contrast Sodium Conc. Viscosity at 37"C Formulation (m Eq / L) (cps) A. Metrizamide 37% 1 O Not determined B. Metrizamide 37% 1 150 18.7 C. Metrizamide 28% 1 1 50 13.0(a' Na/NMG loth. 9% I D. Metrizamide 18.5% i 150 10.0'b' Na/NMG loth. 18.5% E. Metrizamide 9% 1 150 Na/NMG loth. 28% 1 F. Na/NMG loth. 37% 1 150 9.1(as G. Metrizamide 31.5% 1 150 9.2 Na loth. 5.5% i H. Metrizamide 28% B 243 9.2 Na loth. 9% i I. Metrizamide 22% I 400 7.6 Na loth. 1 5% I J. Na loth. 37% 1 970 3.56 'a'Mean of two determinations 'b'Mean of three determinations Determination of Acute Intravenous Toxicity in Mice Groups of 2 or 4 young adult Swiss mice (sexes equally represented with body weights ranging from 1 7.6-24.7 g.) received intravenous injections of the various contrast formulations at doses ranging from 4-14 g I/kg of body weight and an injection rate of 1 ml/minute.

Estimates of the LD50 were made based on cumulative 7-day mortality data and the results are set forth in Table II.

TABLE II Acute Intravenous Toxicity of Mixtures of Metrizamide and lothalamic Acid in the Mouse

Mortalities/Treated as a Function Sodium of Dose (gl/kg) Estimated Contrast Conc. LD50 Formulation (m Eq/L) 4 6 8 10 11.5 12 13 14 (gl/kg) A. Metrizamide 37% 0 0/2 1/4 2/4 13 (No Sodium) B. Metrizamide 37% 150 0/2 3/4 3/4 11 C. Metrizamide 28% 150 1/4 4/4 9 Na/NMG loth 9% D. Metrizamide 18.5% 150 2/4 2/2 7 Na/NMG loth 18.5% 1/2 E. Metrizamide 9% 150 1/1 2/2 2/2 5 Na/NMG loth 28% F. Na/NMG loth. 37% 150 0/2 4/4 2/2 5 G. Metrizamide 31.5% 150 0/2 0/2 3/4 13 Na loth 5.5% H. Metrizamide 28% 243 1/3 2/2 3/4 11 Na loth 9% I. Metrizamide 22% 400 0/2 0/2 1/4 14+ Na loth 15% Isolated Rabbit Heart Experiments Female New Zealand albino rabbits with body weights ranging from 2-4 kg were employed in these experiments.

Coronary perfusion of the isolated rabbit heart was performed with oxygenated Chenoweth's solution (J. Lab. Clin. Med., 31:600-608, 1946) of the following composition: NaCI, 119.8 mM/L; KCI, 5.63 mM/L; Cacti2. 2.16 mM/L; MgCI2, 2.1 mM/L; NaHCO3, 25.0 mM/L, with the aorta of the heat attached to the perfusion nipple of an Anderson-Craver Heart Perfusion Apparatus (J. Pharmacol. Exp. Ther., 93:135-141, 1948). The solution was maintained at a temperature of 37-39"C. Perfusion was maintained under conditions of constant pressure ("'55 cm of.water). Myocardial contractility was measured with a Grass Model FT.03 Force Displacement Transducer connected to a Grass Model 7 Polygraph.Electrocardiogram (ECG) was obtained on a Grass Model 79 Polygraph from right atrial and right ventricular bipolar wick electrodes. Heart rate was determined from the R-R interval of the ECG.

The contrast media formulations were prewarmed to 37"C and given as bolus injections of 4 ml via a side arm of the perfusion apparatus. In experiments with metrizamide alone (no sodium, formulation A), only one injection was made per heart. All other formulations were tested as multiple injections of up to 3 doses/heart provided the heart returned to the control state between injections.

Contrast-induced changes in myocardial contractility and heart rate were expressed as percentage change from control at 15, 30, 60, 120, 1 80 and 240 second intervals after completion of drug administration. Cumulative effects on heart rate and contractility for each formulation were expressed as the relative area under the curve (RAUC) which was the sum of the mean deviation from control (regardless of sign) at each post-injection observation interval.

The electrocardiogram was monitored for arrhythmias. If ventricular fibrillation occurred, contractility and rate data from that injection were not included in grouped data analysis.

The results are set forth in Tables Ill, IV and V.

TABLE III Effects of Mixtures of Metrizamide and lothalamic Acid on Contractility in the Isolated Perfused Rabbit Heart

% Change in Contractility at Various Times (sec) after Contrast Administration (mean # S.E.) Contrasst Formulation Sodium Conc.

(No. of Injections) (mEqL) 0-15s 15-30s 30-60s 120s 180s 240s RAUC* A. Metrizamide 37% 0 51.5#8.2 16.2#19.9 40.5#20.4 13.3#10.9 5.5#5.6 2.2#5.2 129 (N = 9) B. Metrizamide 37% 150 20.5#2.1 -40.2#5.7 85.4#7.9 42.8#4.7 25.7#4.2 12.1#3.7 227 (N = 8) C. Metrizamide 28% 150 -65.0#8.1 61.9#24.5 88.1#14.0 36.6#4.8 26.5#5.5 14.9#3.1 273 Na/NMG loth. 9% (N = 7) D. Metrizamide 18.5% 150 9.5#2.9 -69.9#6.1 97.8#15.4 34.5#10.2 10.9#9.3 1.0#8.6 224 Na/NMG loth. 18.5% (N = 9) E. Metrizamide 9% 150 -70.7#7.8 25.4#20.3 10.1#13.7 4.8#7.1 -1.9#6.2 -3.4#5.6 116 Na/NMG loth. 28% (N = 9) F. Na/NMG loth. 37% 150 -98.0#1.4 -44.0#13.4 -23.8#7.5 -37.3#8.1 -22.8#13.3 -18.9#12.6 246 (N = 5) G. Metrizamide 31.5% 150 18.5#5.0 -25.3#7.2 101.7#2.8 33.2#1.9 20.3#2.8 9.3#2.6 208 Na loth. 5.5% (N = 9) H. Metrizamide 28% 243 -76.6#8.1 58.3#29.7 70.9#8.7 40.3#6.5 27.4#5.9 17.7#5.3 291 Na loth. 9% (N = 6) I. Metrizamide 22% 400 -73.8#10.7 55.2#23.6 51.4#11.4 27.4#10.3 13.0#6.8 5.5#5.2 226 Na loth. 15% (N = 8) *RAUC = Relative Area Under Curve = total deviation (irrespective of sign) from control for 240 sec.

TABLE IV Effects of Mixtures of Metrizamide and lothalamic Acid on Rate of the Isolated Perfused Rabbit Heart

% Change in Contractility at Various Times (sec) after Contrast Administration (mean # S.E.) Contrasst Formulation Sodium Conc.

(No. of Injections) (mEqL) 0-15s 15-30s 120s 30-60s 180s 240s RAUC* A. Metrizamide 37% 0 -6.8#1.6 -7.3#2.3 -4.5#2.4 -6.5#4.0 -2.0#1.1 0.5#1.3 28 (N = 9) B. Metrizamide 37% 150 -7.3#1.7 -6.9#3.6 3.1#5.3 2.7#2.7 0.3#0.5 -1.2#1.1 22 (N = 8) C. Metrizamide 28% 150 -4.8#1.1 -2.1#0.5 0.6#0.8 1.9#1.0 1.6#1.0 1.1#1.1 12 Na/NMG/loth. 9% (N = 7) D. Metrizamide 18.5% 150 -10.8#1.6 -8.2#0.9 7.8#4.5 10.2#4.1 4.3#2.1 3.4#1.3 45 Na/NMG/loth 18.5% (N = 9) E. Metrizamide 9% 150 -7.4#2.8 -5.4#1.7 -2.7#3.9 4.1#1.2 4.0#1.7 1.5#0.6 25 Na/NMG/loth 28% (N = 9) F. Na/NMG loth. 37% 150 -11.1#1.4 -17.2#9.3 2.7#5.2 5.7#5.8 3.6#3.9 2.4#3.1 39 (N = 5) G. Metrizamide 31.5% 150 -10.4#4.8 -7.1#1.6 0.9#1.5 1.7#1.8 1.1#1.5 -0.7#1.1 23 Na loth. 5.5% (N = 9) H. Metriazamide 28% 243 -24.7#5.8 -4.6#1.6 4.5#1.5 7.3#1.0 5.6#1.8 3.5#2.1 36 Na loth. 9% (N = 6) I. Metrizamide 22% 400 -13.6#2.7 -1.1#3.8 -1.1#3.8 7.3#2.6 1.7#1.8 -1.3#1.1 50 Na loth. 15% (N = 8) *RAUC = relative Area Under Curve = total deviation (irrespective of sign) from control for 240 sec.

TABLE V Arrhythmogenic Activity of Mixtures of Metrizamide and lothalamic Acid in the Isolated Rabbit Heart

Incidence of Sodium Ventricular Fibrillation Contrast Conic.

Formulation (mEq/L) #/$ Tested % Other Arrhythmias A. Metrizamide 37% I 0 1/10 10 None B. Metrizamide 37% í 1 50 0 0 None C. Metrizamide 28% 1 150 0 0 None Na/NMG loth. 9% I D. Metrizamide 18.5% 1 150 1/10 10 None Na/NMG loth. 18.5% 1 E. Metrizamide 9% 1 150 1/10 10 None, but bizarre ECG Na/NMG loth. 28% 1 wave conformations F. Na/NMG loth. 37% 1 150 1/7 14 2/7 A-V block(a) G. Metrizamide 31.5% I 150 0/9 0 None Na loth. 5.5% 1 H. Metrizamide 28% I 243 3/9 33 2/9 A-V block(a), Na loth. 9% 1 PVCs(b) Metrizamide 22% 1 400 1/9 11 6/9 A-V block'"' Na loth. 1 5% (a(Atrioventricular Premature ventricular contractions A summary of the physicochemical and toxicological properties of the formulations is presented in Table VI: TABLE VI Summary of Physicochemical and Toxicologinal Properties of Mixtures of Metrizamide and lothalamic Acid Relative Toxicity

Isolated Rabbit Heart Sodium Conc. Visc. Relative Mean Contrast Formulation (mEq/L) (cps) Mouse I.V.b Contr.c Rated Arrhythmiase Toxicity Score A. Metrizamide 37% 0 - 38 44 56 30 42 B. Metrizamide 37% 150 18.7 45 78 44 0 42 C. Metrizamide 28% 150 13.0 56 94 24 0 44 Na/NMG loth. 9% D. Metrizamide 18.5% 150 10.0 71 71 90 30 66 Na/NMG loth. 18.5% E. Metrizamide 9% 150 9.5 100 40 50 30 55 Na/NMG loth. 28% F. Na/NMG loth. 37% 150 9.1 100 84 78 42 76 G. Metrizamide 31.5% 150 9.2 38 71 46 0 39 Na loth. 5.5% H. Metrizamide 28% 243 9.2 45 100 72 100 79 Na loth. 9% I. Metrizamide 22% 400 7.6 34 78 100 33 61 Na loth 15% aThe higher the value the more toxic the formulation.

bEstimated LD50 of most toxic (lowest LD50)/Estimated LD50 for each formulation x 100.

cRAUC for each formulation/highest RAUCX100.

dRAUC for each formulation/highest RAUCX100.

e% (incidence of ventricular fibrillation +A-V block)/(highest % incidence of ventricular fibrillation +A-V block) x 100 An overall mean toxicity score was determined for each x-ray contrast media formulation in the manner indicated in Table VI. The data show that the least toxic formulations were those containing the highest proportions of metrizamide relative to iothalamic acid. Further, the data show that mixtures of metrizamide and iothalamic acid had toxicity profiles which are superior to the ionic agent alone and had much lower viscosities than solutions of the nonionic agent.

Example 2 The following series of x-ray contrast formulations were prepared as described in Example 1.

Series I: Metrizamide/lothalamate Mixtures Formulations: A. Metrizamide 76.76 g (37% 1) Water qs. ad. 100.00 ml B. lothalamic acid 59.70 g (37% 1) NaOH 3.90 g (970 mEq Na+/L) Water qs. ad. 100.00 ml C. Metrizamide 64.90 g (31.3% 1, 85% of total I) lothalamic acid 9.20 g (5.7% 1, 15% of total I) NaOH 0.60 g(150mEqNa+/L) Water qs. ad. 100.00 ml D. Metrizamide 61.00 g (29.4% 1, 80% of total I) lothalamic acid 12.30 g (7.6% 1, 20% of total I) NaOH 0.80 g (200 mEq Na+/L) Water qs. ad. 100.00 ml E. Metrizamide 53.70 g (25.9% 1, 70% of total I) lothalamic acid 17.90 g (11.1%, 30% of total 1) NaOH 0.80 g (200 mEq Na+/L) Meglumine 1.80 g (92 mEq Meg/L) Water qs. ad. 100.00 ml F.Metrizamide 46.10 g (22.2% 1, 60% of total I) lothalamic acid 23.90 g (14.8% 1. 40% of total I) NaOH 0.80 9 (200 mEq Na+/L) Meglumine 3.70 g (190 mEq Meg/L) Water qs. ad. 100.00 ml The pH was adjusted to 7.0-7.8 with a small quantity of NaOH for solutions A-D and with meglumine for solutions E and F.

Series II: Metrizamide/Diatrizoate Mixtures Formulations: A. Metrizamide 76.76 9 (37% 1) Water qs. ad. 100.00 ml B. Diatrizoic acid 59.600 g (37% 1) NaOH 3.890 g (970 mEq Na+/LO CaCl2 (anhydrous) 0.028 g (5 mEq Ca++/L) Water qs. ad. 100.000 ml C. Metrizamide 64.900 g (31.3% 1, 85% of total I) Diatrizoic acid 9.200 g (5.7% I, 15% of total 1) NaOH 0.600 g (150 mEq Na+/L) Water qs. ad. 100.000 ml D. Metrizamide 64.900 g Diatrizoic acid 9.200 g NaOH 0.600 g CaCI2 (anhydrous) 0.028 g (5 mEq Ca++/L) Water qs. ad. 100.000 ml E. Metrizamide 53.100 g (25.6% 1, 70% of total) Diatrizoic acid 18.400 g (11.4% 1, 30% of total I) NaOH 0.800 g (200 mEq Na+/L) Meglumine 1.940 g Water qs. ad. 100.000 ml F.Metrizamide 53.100 g Diatrizoic acid 18.400 g NaOH 0.800 g CaCl2 (anhydrous) 0.028 g (5 mEq Ca+ +/L) Meglumine 1.940 g Water qs. ad. 100.000 ml The pH was adjusted to 7.0-7.8 with a small quantity of NaOH for solutions A-D and with meglumine for solutions E and F.

Series 111: Metrizamide/Metrizoate Mixture Formulations: A. Metrizoic acid 60.8 g (37% 1) As salts of: Na+ 852 mEq/L 4.2 mEq/L Ca++ 46.2 mEq/L Mg++ 34.5 mEq/L Meglumine 756 mg Water qs. ad. 100 ml B. Metrizamide 64.7 g (31.2% 1; 85% of total 1) Metrizoic acid 9.6 g (5.8% 1; 15% of total 1) As salts of: Na+ 134 mEq/L K+ 4.2 mEq/L Ca++ 7.3 mEq/L Mg++ 5.4 mEq/L Meglumine 119 mg Water qs. ad. 100 ml C. Metrizamide 76.76 g (37% 1) Water qs. ad. 100.00 ml The pH of solutions A and B was adjusted to 7.0-7.8 with meglumine and the pH of solution C was adjusted to 7.0-7.8 with NaOH.

Series IV: Metrizamide/loxagla te Mixture Formulations: A. Metrizamide 76.76 9 (37% 1) Water qs. ad. 100.00 ml B. loxaglic acid 61.700 g (37% 1) NaOH 1.940 g (485 mEq Na+/L) CaCl2 (anhydrous) 0.091 9(16.25 mEq Ca++/L) Water qs. ad. 100.000 ml C. Metrizamide 53.100 g (25.6% I, 70% of total I) loxaglic acid 19.000 g (11.4% I, 30% of total I) NaOH 0.600 9(150 mEq Na+/L) CaCI2 (anhydrous) 0.028 g (5 mEq Ca++/L) Water qs. ad. 100.000 ml The pH of solutions A and C was adjusted to 7.0-7.8 with NaOH and the pH of solution B was adjusted to 7.0-7.8 with meglumine.

Series V: N-(2-hydroxethyl)-2,4,6-triiodo-bis-3,5-(2-keto-L-gulonamido)benzamide (MP- 1 0007)/lothalamate Mixtures Formulations: A. MP-10007 89.9 g (37% 1) Water qs. ad. 100.0 ml B. lothalamic acid 59.79 g (37% i) NaOH 3.750 g (937.5 mEq Na+/L) CaCl2 (anhydrous) 0.175 g(31.25 mEq Ca++/L) Water qd. ad. 100.000 ml C. MP-10007 75.577 9 (31.1% I, 85% of total I) lothalamic acid 9.520 9 (5.9% 1, 15% of total I) NaOH 0.600 g(150 mEq Na+/L) CaCl2 (anhydrous) 0.028 g(5 mEq Ca++/L) Waters. ad. 100.000 ml D. MP-10007 89.9 9 (37% 1) Water qs. ad. 100.0 ml E. lothalamic acid 59.70 g (37% 1) NaOH 3.90 g (970 mEq Na+/L) Water qs. ad. 100.00 ml F.MP-10007 79.9 g (32.9% I, 89% of total I) lothalamic acid 6.6 9 (4.1% I, 11% of total I) NaOH 0.44 g (110 mEq Na+/L) Water qs. ad. 100.00 ml G. MP-10007 70.1 9 (28.9% 1, 78% of total I) lothalamic acid 13.2 g (8.1% 1, 22% of total I) NaOH 0.88 9 (220 mEq Na+/L) Water qs. ad. 100.00 ml H. MP-10007 60.2 g (24.8% I, 67% of total I) lothalamic acid 19.8 9 (12.2% 1, 33% of total I) NaOH 1.32 g (330 mEq Na+/L) Water qs. ad. 100.00 ml í. MP-10007 50.2 g (20.7% 1, 56% of total I) lothalamic acid 26.4 9 (16.3% 1, 44% of total I) NaOH 1.76 g (440 mEq Na+/L) Water qs. ad. 100.00 ml J. MP-10007 40.3 g (16.6% 1.45% of total I) lothalamic acid 33.0 9 (20.4% I, 55% of total I) NaOH 2.20 9 (550 mEq Na+/L) Water qs. ad. 100.00 ml The pH of solutions A, B, and C was adjusted to 7.0-7.8 with NaOH; remaining solutions were not pH-adjusted.

Series VI: N, N'-bis-(2, 3-dihydroxypropyl)-2, 4, 6-triiodo-5-(2-keto-L-gulonamido) isophthalamide (MP- 10001 3)/lothalamate Mixtures Formulations: A. MP-10013 85.6 g (37% 1) Water qs. ad. 100.0 ml B. lothalamic acid 59.7 9 (37% 1) NaOH 3.750 9 (937.5 mEq Na'L) CaCl2 (anhydrous) 0.175 g (31.25 mEq Ca++/L) Water qs. ad. 100.000 ml C. MP-10013 71.974 9(31.1% 1, 85% of total I) lothalamic acid 9.520 g (5.9% 1, 15% of total I) NaOH 0.600 9(150 mEq Na+/L) CaCl2 (anhydrous) 0.028 9 (5 mEq Ca+ +/L) Water qs. ad. 100.000 ml D. MP-10013 85.6 9 (37% 1) Water qs. ad. 100.00 ml E. lothalamic acid 59.70 9 (36% I) NaOH 3.90 9 (970 mEq Na+/L) Water qs. ad. 100.00 ml F.MP-10013 75.3 g (32.9% I, 89% of total I) lothalamic acid 6.6 9 (4.1% I, 11% of total I) NaOH 0.44 g (110 mEq Na+/L) Water qs. ad. 100.00 ml G. MP-10013 66.77 g (28.9% 1, 78% of total I) lothalamic acid 13.2 g (8.1% 1, 22% of total I) NaOH 0.88 9 (220 mEq Na+/L) Water qs. ad. 100.00 ml H. MP-10013 56.50 g (24.8% I, 67% of total I) lothalamic acid 19.8 9 (12.2% 1, 33% of total 1) NaOH 1.32 g (330 mEq Na+/L) Water qs. ad. 100.00 ml I. MP-10013 47.94 9 (20.7% 1, 56% of total I) lothalamic acid 26.4 9 (16.3% I, 44% of total I) J.MP-10013 38.52 g (16.6% I, 45% of total I) lothalamic acid 33.0 9 (20.4% 1, 55% of total I) NaOH 2.20 g (550 mEq Na+/L) Water qs. ad. 100.00 ml The pH of solutions A, B, and C was adjusted to 7.0-7.8 with NaOH; remaining solutions were not pH-adjusted.

Series VII: lopamidol/lothalamate Mixture Formulations: A. lothalamic acid 59.700 9 (37% I) NaOH 3.750 9 (935.5 mEq Nat/L)) CaCl2 (anhydrous) 0.175 9(31.3 mEq Ca++/L) Water qs. ad. 100.000 ml B. lopamidol 75.5 9 (37% I) Water qs. ad. 100.00 ml C. lopamidol 63.900 g(31.3% 1, 85% of total I) lothalamic acid 9.200 9 (5.7% I, 15% of total I) NaOH 0.600 9 (150 mEq Na+/L) CaCl2 (anhydrous) 0.028 9 (5 mEq Ca+ +/L) Water qs. ad. 100.00 ml The pH of all the solutions was adjusted to 7.0-7.8 with NaOH.

As to the Series I formulations, viscosity determinations and complete acute intravenous median lethal dose (LD50) determinations in mice were made. As to the Series II, III, IV, V (A, B and C), VI (A, B and C) and VII formulations, viscosity determinations, cardiotoxicity in the isolated rabbit heart preparation (IRHP) and acute intravenous toxicity determinations in mice were made. For Series V and VI formulations D-J, only viscosity determinations were made.

Measurement of the absolute viscosities (centipoises or cps) of the various contrast media formulations was conducted at 37 C using the following procedures: 1. Small Volume Samples (""1.0 ml) A Wells-Brookfield Model LVT Micro-Viscometer was used with water at 37"C (heated by a Haake Model E-12 Heater-Circulator) circulating through the sample cup. A CP-40 stainless steel cone spindle (0.8 angle, 4.8 cm diameter) was employed at RPMs of 6, 12, 30 and 60 for respective cps ranges of 25.8-51.4, 10.3-25.7, 5.2-10.2 and 0-5.1.

2. Large Volume Samples (25.0 ml) A Brookfield Model LVT Synchro-Lectric Viscometer was used with a U.L. Adapter containing a precision cylindrical spindle at RPMs of 12, 30 and 60 for respective cps ranges of 20.1-50.0, 10.1-20.0 and 0-10.0. A 37"C temperature was maintained by complete immersion of the U.L. adapter tube in a 37"C water bath.

The acute intravenous toxicity determinations were made as described in Example 1. In most instances, only range-finding determinations were performed wherein appropriate doses of the contrast media formulations were administered to 1 to 4 mice until sufficient data were obtained to approximate a median lethal dose (LD50). Where complete LD50 determinations were conducted, a minimum of 8 mice per does level were used and calculations were made according to the method of Litchfield and Wilcoxon (J. Pharmacol. Exp. Therap., 96:99, 1949).

The determination of cardiotoxicity in the isolated rabbit heart preparation (IRHP) was carried out as described in Example 1.

The results are summarized in Tables VII-XIII.

TABLE VII SERIES I: Metrizamide/lothalamate Mixtures l.V.

Nonionic/lonic Ionic Viscosity* LD50 (95% Conf. Limit) Formulation Iodine Ratio Salt (cps @ 37"C) (mg l/kg) I-A 100/0 None 17.00 13,000(11,920-14,178) I-B 0/100 Na 3.56 8,600 (7,780-9,506) I-C 85/15 Na 12.08 14,000 (12,442-15,752) I-D 80/20 Na 10.14 14,750 (14,038-15,498) I-E 70/30 Na/NMG 8.01 12,000(10,680-13,483) I-F 60/40 Na/NMG 9.86 9,000(7,697-10,524) *By Brookfield LVT Synchro-Lectric Viscometer These data show that the viscosity of the non-ionic agent (metrizamide) is reduced by substituting iodine content with an ionic agent (iothalamate) without any appreciable reduction in systemic safety until the non-ionic/ionic iodine ratio reaches 60/40. In fact, formulations I-C and l-D appear to be better tolerated.

TABLE VIII SERIES II: Metrizamide/Diatrizoate Mixtures Approx. I.R.H.P. Effects Nonionic/Ionic Ionic Viscosity I.V. LD50 Contract. Force Heart Rate Formulation iodine Ratio Salt (cps @ 37 C) (mg l/kg) (Max %#) (Max %#) Arrhythmias*** 11-A 100/0 - 16.40 13,000 +64 -7 Mild (7% V.F.) 11-B 0/100 Na/Ca 4.44 8,500 -85/ + 41 -22/ + 5 Moderate II-C 85/15 Na 12.10 12,750 -30/ + 76 -13/ + 5 None II-D 85/15 Na/Ca (12.10)** 13,500 - 1/ + 76 -10/ + 3 None II-E 70/30 Na/NMG 9.52 12,500 -62/ + 127 -13/ + 7 None II-F 70/30 Na/Ca/NMG (9.52)** 12,500 -37/ + 102 -12/ + 4 None *By Brookfield LVT Synchro-Lectric Viscometer **Not measured, assumed identical to 11-C and 11-E, respectively, ***V.F. = ventricular fibrillation.

These data show that the ionic agent (diatrizoate) reduces the viscosity of the nonionic agent (metrizamide) without any compromise of systemic safety until the nonionic/ionic iodine ratio reaches 70/30. Cardiotoxic effects in the IRHP test demonstrate that the myocardial depressant effect of the ionic component is attenuated, especially in the formulations containing calcium.

The arrhythmogenic effect of all mixtures was less than that of either nonionic or ionic component alone.

TABLE IX SERIES III: Metrizamide/Metrizoate Mixtures Approx. I.R.H.P. Effects Nonionic/Ionic Ionic Viscosity I.V. LD50 Contract. Force Heart Rate Formulation iodine Ratio Salt (cps @ 37 C) (mg l/kg) (Max %#) (Max %#) Arrhythmias** III-A 0/100 Na/K/CA 3.80 8,000 -97/ + 18 -20/ + 10 Severe Mg/NMG III-B 85/15 Na/K/Ca 10.90 14,500 + 66 -14 + 3 None Mg/NMG III-C 100/0 - 16.40 13,000 + 64 -7 Mild (7% V.F.) *By Brookfield LVT Synchro-Lectric Viscometer **V.F. = ventricular fibrillation.

At the nonionic/ionic ratio employed, viscosity was again decreased without any reduction in systemic safety. The metrizamide/metrizoate mixture was considerably less cardiotoxic than metrizoate alone and even exhibited less of an arrhythmogenic effect than metrizamide alone. TABLE X SERIES IV: Metrizamide/Loxaglate Mixtures Approx. I.R.H.P. Effects Nonionic/Ionic Ionic Viscosity I.V. LD50 Contract. Force Heart Rate Formulation iodine Ratio Salt (cps @ 37 C) (mg l/kg) (Max %#) (Max %#) Arrhythmias** IV-A 100/0 - 16.40 13,000 + 64 -7 Mild (7% V.F.) IV-B 0/100 Na/Ca 12.94 15,000 + 85 -6/ + 6 None IV-C 70/30 Na/Ca 15.68 16,500 + 69 =9? + 3 None *By Brookfield LVT Synchro-Lectric Viscometer **V.F. = ventricular fibrillation.

Because of the already relatively high viscosity of the ionic component (ioxaglate), the viscosity of the mixture was not substantially altered at the ratio tested. Also, unlike other ionic media, ioxaglate alone was less toxic intravenously than metrizamide alone. However, the mixture appeared even less toxic than either individual component.

TABLE XI SERIES V: MP-10007/lothalamate Mixtures Approx. I.R.H.P. Effects Nonionic/Ionic Ionic Viscosity I.V. LD50 Contract. Force Heart Rate Formulation iodine Ratio Salt (cps @ 37 C) (mg l/kg) (Max %#) (Max %#) Arrhythmias** V-A 100/0 - 33.92 18,200 ** ** V.F. (100%) V-B 0/100 Na/Ca 4.92 11,000 -94/ + 44** - 13/ + 4** V.F. (50%) V-C 85/15 Na/Ca 25.31 15,000 -43/ + 93 - 13/ + 16 None These formulations not tested for toxicity V-D 100/0 - 39.78 V-E 0/100 Na 3.90 V-F 89/11 Na 30.27 V-G 78/22 Na 22.00 V-H 67/33 Na 17.09 V-I 56/44 Na 12.44 V-J 45/55 Na 9.82 *By Wells-Brookfield LVT Micro-Viscometer **Cardiodynamic data not included from fibrilating hearts ***V.F. = vantricular fibrillation The above data for formulations V-A, V-B and V-C demonstrate a considerable reduction in the viscosity of the nonionic component.Unlike the results shown in Tables VII-X, systemic safety was slightly reduced although still completely acceptable. In the IRHP, both MP-10007 and Na/Ca iothalamate alone caused ventricular fibrillation. However, the mixture was com pletely devoid of arrhythmogenic activity. Contractile force effects of the mixture were triphasic and moderate while those of Na/Ca iothalamte were initially severe resulting in almost complete cessation of contractions.

TABLE XIII SERIES VI: MP-10013/lothalamate Mixtures Approx. I.R.H.P. Effects Nonionic/Ionic Ionic Viscosity I.V. LD50 Contract. Force Heart Rate Formulation iodine Ratio Salt (cps @ 37 C) (mg l/kg) (Max %#) (Max %#) Arrhythmias*** VI-A 100/0 - 22.92 19,300 ** ** V.F. (100%) VI-B 0/100 Na/Ca 4.92 11,000 -94/ + 44** -13/ + 4** V.F. (50%) VI-C 85/15 Na/Ca 18.63 19,000 -10/ + 161 -13/ + 10 None These formulation not tested for toxicity VI-D 100/0 - 24.93 VI-E 0/100 Na 3.90 VI-F 89/11 Na 19.99 VI-G 78/22 Na 12.82 VI-H 67/33 Na 12.21 VI-I 56/44 Na 10.23 VI-J 45/55 Na 8.24 *By Wells-Brookfield LVT Micor-Viscometer **Cardiodynamic data not included from fibrillating hearts ***V.F. = ventricular fibrillation The results for formulations VI-A, Vl-B and Vl-C again show an appreciable decrease in viscosity without any concomitant reduction in safety exhibited by the mixture. Ventricular fibrillation in the IRHP, induced by both MP-10013 and Na/Ca iothalamate alone, was not produced by the mixture. Contractility was markedly depressed by Na/Ca iothalamte alone but was predominantly increased by the mixture.

TABLE XIII SERIES VII: lopamidol/lothalamate Mixtures Approx. I.R.H.P. Effects Nonionic/Ionic Ionic Viscosity I.V. LD50 Contract. Force Heart Rate Formulation iodine Ratio Salt (cps @ 37 C) (mg l/kg) (Max %#) (Max %#) Arrhythmias*** VII-A 0/100 Na/Ca 4.92 11,000 -94/ + 44** -13/ + 4** V.F. (50%) VII-B 100/0 - 12.32 19,000 ** ** V.F. (100%) VII-C 85/15 Na/Ca 6.41 19,000 -24/ + 83 -13/ + 1 None *By Wells-Brookfield LVT Micro-Viscometer (VII-A) By Brookfield LVT Synchro-Lectric Viscometer (VII-B and C) **Cardiodynamic dta not included for fibrillating hearts ***V.F. = ventricular fibrillation The iopamidol/iothalamate mixture exhibited a markedly reduced viscosity, without any apparent increase in systemic toxicity. The mixture was also considerably less cardiotoxic in terms of ventricular arrhythmias and myocardial depression.

The data of the foregoing experimental work is detailed in Tables XIV-XVIII.

TABLE XIV Viscosities of Nonionic and Ionic Contrast Media Solutions at 37% Iodine Concentrations, Alone and as Mixtures Nonionic Ionic Nonionic/lonic Ionic Salt Viscosity at 37 C Agent Agent Iodine Ratio (Concentration) (cps) Metrizamide 100/0 16.4(a) MP-10007 100/0 36.9(b) MP-10013 100/0 23.9(b) lopamidol 100/0 12.3(C) lothalamate 0/100 Na (970 mEq/L) 3.6(d) - lothalamate 0/100 Na (938 mEq/L) 4,9(c) Ca (31 mEq/L) Diatrizoate 0/100 Na (970 mEq/L) 4.4(d) Ca (5 mEq/L) Metrizoate 0/100 Na (852 mEq/L) 3,8(d) K (4.2 mEq/L) Ca (46 mEq/L) Mg (35 mEq/L) NMG (39 mEq/L) loxaglate 0/100 Na (485 mEq/L) l2.9(d) Ca (16 mEq/L) Metrizamide lothalamate 85/15 Na (150 mEq/L) 12.1(d) Metrizamide lothalamate 80/20 Na (200 mEq/L) 10.1(d) Metrizamide lothalamate 70/30 Na (200 mEq/L) 8.0(d) NMG (92 mEq/L) Metrizamide lothalamate 60/40 Na (200 mEq/L) 9,9(d) NMG (190 mEq/L) Metrizamide Diatrizoate 85/15 Na (150 mEq/L) 12.1(d) Metrizamide Diatrizoate 70/30 Na (200 mEq/L) 9.5(d) NMG (99 mEq/L) Metrizamide Metrizoate 85/15 Na (134 mEq/L) @ 10.9'd' K (4.2 mEq/L) Ca (7.3 mEq/L) Mg (5.4 mEq/L) NMG (6.1 mEq/L) Metrizamide loxaglate 70/30 Na (150 mEq/L) 15,7(d) Ca (5 mEq/L) MP-10007 lothalamate 89/11 Na (110 mEq/L) 30.3(b) MP-10007 lothalamate 85/15 Na (150 mEq/L) 25.3(b) Ca (5 mEq/L) MP-10007 lothalamate 78/22 Na (220 mEq/L) 22.0(b) MP-10007 lothalamate 67/33 Na (330 mEq/L) 17.1(b) MP-10007 lothalamate 56/44 Na (440 mEq/L) 12,4)b) MP-10007 lothalamate 45/55 Na (550 mEq/L) 9.8(b) MP-10013 lothalamate 89/11 Na (110 mEq/L) 20.0 MP-10013 lothalamate 85/15 Na (150 mEq/L) 18.6(C) MP-10013 lothalamate 78/22 Na (220 mEq/L) 12.8(C) MP-10013 lothalamate 67/33 Na (330 mEq/L) 12.2(C) MP-10013 lothalamate 56/44 Na (440 mEq/L) 10.2(C) MP-10013 lothalamate 45/55 Na (550 mEq/L) 8.2(C) lopamidol lothalamate 85/15 Na (150 mEq/L) 6.4(d) Ca (5 mEq/L) (a)Mean of 4 determinations using both Wells-Brookfield Micro-Viscometer and Brookfield Synchro-Lectric Viscometer 'b'Mean of 2 determinations using Wells-Brookfield Micro-Viscometer (c)One determination using Wells-Brookfield Micro-Viscometer (d)One determination using Brookfield Syncrho-Lectric Viscometer TABLE XV Acute Intravenous Toxicities of Nonionic and lonic Contrast Media Solutions at 37% lodine Concentrations, Alone and as Mixtures in Mice Est. Or Actual Nonionic/lonic lonic Dose Levels Deaths/ LD50 (95% C.L.) Contrast Agent(s) lodine Ratio Salt (g l/kg) No.Treated (g l/kg) Metrizamide 100/0 11.0 2/10 13.0 12.5 3/10 (11.9-14.2) 14.0 8/10 NP-10007* 100/0 15.0 1/10 18.2 17.5 2/10 (16.6-20.1) 20.0 7/10 NP-10013* 100/0 17.5 2/10 19.3 18.8 4/10 (18.2-20.5) 20.0 7/10 lopamidol 100/0 19.0 1/2 19.0 20.0 2/2 22.0 2/2 lothalamate 0/100 Na 8.0 2/8 8.6 9.0 5/8 (7.8-9.5) 10.0 8/8 lothalamate 0/100 Na/Ca 7.5 0/1 11.0 10.0 0/1 12.5 1/1 Diatrizoate 0/100 Na/Ca 8.0 1/2 8.5 9.0 2/2 10.0 1/2 12.0 2/2 Metrizoate 0/100 Na/K/Ca 8.0 2/4 8.0 Mg/NMG 10.0 4/4 12.0 2/2 loxaglate 0/100 Na/Ca 15.0 2/4 15.0 16.0 0/2 18.0 2/2 *Tested at a 40% iodine concentration TABLE XV (continued) Acute Intravenous Toxicities of Nonionic and lonic Contrast Media S as Mixtures in Mice Est. Or Actual Nonionic/lonic lonic Dose Levels Deaths/ LD50 (95% C.L.) Contrast Agent(s) lodine Ratio Salt (g l/kg) No.Treated (g l/kg) Metrizamide/lothalamate 85/15 Na 13.0 3/8 14.0 14.0 4/8 (12.4-15.8) 15.0 5/8 80/20 Na 14.0 1/8 14.0 15.0 5/8 (14.0-15.5) 16.0 6/8 70/30 Na/NMG 10.0 0/8 12.0 12.0 4/8 (10.7-13.5) 13.0 5/8 60/40 Na/NMG 8.0 3/8 9.0 9.0 4/8 (7.7-10.5) 10.0 3/8 11.0 6/8 Metrizamide/Diatrizoate 85/15 Na 12.0 0/2 12.8 13.0 3/4 14.0 2/2 85/15 Na/Ca 12.0 1/2 13.5 13.0 2/4 14.0 1/1 70/30 Na/NMG 12.0 1/4 12.5 13.0 2/2 14.0 1/1 70/30 Na/Ca/NMG 11.0 1/2 12.0 12.0 2/4 13.0 2/2 Metrizamide/Metrizoate 85/15 Na/K/Ca 10.0 0/2 14.5 Mg/NMG 13.5 1/4 15.0 3/4 Metrizamide/loxaglate 70/30 Na/Ca 16.0 1/2 16.5 17.5 1/2 19.0 1/1 *Tested at a 40% iodine concentration TABLE XV (continued) Acute Intravenous Toxicities of Nonionic and lonic Contrest media Solutions at 37% lodine Concentrations, Alone and as Mixtures in Mice Est.Or Actual Nonionic/lonic lonic Dose Levels Deaths/ LD50 (95% C.L.) Contrast Agent(s) lodine Ratio Salt (g l/kg) No. Treated (g l/kg) MP-10007/lothalamate 85/15 Na/Ca 10.0 0/1 15.0 15.0 1/1 20.0 1/1 MP-10013/lothalamate 85/15 Na/Ca 10.0 0/1 19.0 15.0 0/1 20.0 1/1 Lopamidol/lothalamate 85/15 Na/Ca 16.0 0/2 19.0 18.0 0/2 20.0 2/2 *Tested at a 40% iodine concentration TABLE XVI Myocardial Contractility Effects of Nonionic and lonic contrast Media Solutions at 37% lodine Concentrations, Alone and as Mixtures in the isolated Rabbit Heart Preparation Contrast Agents(s) Percent Change from Control Contractility at Maximum Mean lonic Salt Times (sec) after Administration (Mean # S.E.) Effect Percent (lodine Ratio) 0-15 15-30 30-60 120 240 (% Change) Change Metrizamide(a) 64.1 29.2 47.9 34.4 1.7 +64 +35 (100/0) #8.9 #15.0 #13.1 #13.1 #3.5 MP-10007(b) Not Determined; 100% Ventricular Fibrillation (100/0) NP-10013(b) Not Determined; 100% Ventricular Fibrillation (100-0) lopamido(b) Not Determined; 100% Ventricular Fibrillation (100-0) lothalamate(c) -94.0 43.5 36.0 -1.0 -39.0 -94 -11 Na/Ca #1.0 #48.5 #16.0 #9.0 #6.0 +44 (0/100) Diatrizoate(b) -84.8 40.8 16.0 0.3 -22.3 -85 -10 Na/Ca #12.6 #10.1 #5.5 #6.8 #11.5 +41 (0/100) Metrizoate(b) -96.8 17.5 16.8 1.3 -3.3 -97 -13 Na/K/Ca/Mg/NMG #3.3 #24.9 #3.2 #2.1 #3.1 +18 (0/100) loxaglate(b) 27.0 9.0 85.0 40. 19.5 +85 +36 Na/Ca #6.7 #5.4 #5.4 #2.3 #1.7 (0/100) Metrizamide/ 20.2 -29.4 76.6 27.6 12.5 -29 +22 Diatrizoate(d) #4.9 #4.5 #9.7 #6.8 #2.8 +77 Na (85/15) Metrizamide/ 53.6 11.8 75.0 30.2 4.6 +75 +35 Diatrizoate(d) #9.4 #8.1 #23.6 #7.8 #2.4 Na/Ca (85/15) (a) N = 14 (b) N = 4 (c) N = 2 (Ventricular fibrillation in 2 others) (d) N = 5 (e) N = 3 TABLE XVI (continued) Myocardial Contractility Effects of Nonionic and lonic contrast Media Solutions at 37% lodine Concentrations, Alone and as Mixtures in the isolated Rabbit Heart Preparation Contrast Agents(s) Percent Change from Control Contractility at Maximum Mean lonic Salt Times (sec) after Administration (Mean # S.E.) Effect Percent (lodine Ratio) 0-15 15-30 30-60 120 240 (% Change) Change Metrizamide/ 20.2 -62.0 126.6 34.8 5.4 -62 +25 Diatrizoate(d) #10.6 #5.1 #44.3 #5.0 #5.3 +127 Na/NMG (70/30) Metrizamide/ 39.4 -35.8 102.0 12.2 -10.6 -36 +21 Diatrizoate(d) #11.0 #11.9 #30.5 #9.1 #13.8 +102 Na/Ca/NMG (70/30) Metrizamide/ 65.8 38.5 56.0 25.0 6.5 +66 +38 Metrizoate(b) #20.3 #16.4 #17.7 #3.7 #3.4 Na/K/Ca/Mg/NMG (85/15) Metrizamide/ 69.5 49.8 66.8 31.8 11.3 +70 +46 loxaglate(b) #15.5 #8.1 #14.0 #2.0 #2.3 Na/Ca(70/30) MP-10007/ 43.0 -43.7 93.0 26.7 -10.0 -44 +22 lothalamate(e) #15.3 #7.7 #25.2 #8.5 #9.3 +93 Na/Ca (85/15) MP-10013/ 95.0 -9.8 160.5 36.3 -6.5 +10 +55 lothalamate(b) #10.8 #15.8 #41.0 #11.0 #11.9 +161 Na/Ca (85/15) lopamidol/ 17.8 -24.3 83.0 33.0 9.0 -24 +24 lothalamate(b) #4.2 #8.9 #12.0 #7.3 #2.7 +83 Na/Ca (85/15) (a) N = 14 (b) N = 4 (c) N = 2 (Ventricular fibrillation in 2 others) (d) N = 5 (e) N = 3 TABLE XVII Heart Rate Effects of Nonionic and lonic Contrast Media Solutions at 37% lodine Concentrations, Alone and as Mixtures in the lsolated Rabbit Heart Preparation Contrast Agents(s) Percent Change from Control Contractility at Maximum Mean lonic Salt Times (sec) after Administration (Mean # S.E.) Effect Percent (lodine Ratio) 0-15 15-30 30-60 120 240 (% Change) Change Metrizamide(a) -7.0 -4.2 -3.5 -3.8 -0.4 -7 -4 (100/0) #1.2 #4.5 #1.8 #3.1 #1.2 MP-10007(b) Not Determined; 100% Ventricular Fibrillation (100/0) MP-10013(b) Not Determined; 100% Ventricular Fibrillation (100/0) lopamido(b) Not Determined; 100% Ventricular Fibrillation (100/0) lothalamate(c) -11.5 -5.5 3.5 -6.5 -12.5 -13 -7 Na/Ca (0/100) #2.5 #4.5 #4.5 #15.5 #10.5 +4 Diatrizoate(b) -21.8 -2.0 4.8 0.5 -13.8 -22 -6 Na/Ca (0/100) #12.5 #3.7 #1.9 #5.6 #11.8 +5 Metrizoate(b) -19.5 -9.3 9.5 8.5 0.5 -20 -2 Na/K/Ca/Mg/NMG #14.8 #5.5 #6.3 #3.7 #2.2 +10 (0/100) loxaglate(b) -5.0 -6.0 4.0 5.8 2.0 -6 0 Na/Ca(0/100) #0.7 #1.0 #1.4 #1.1 #0.9 +6 etrizamide/ -10.4 -13.0 3.8 4.6 -0.6 -13 -3 Diatrizoate(d) #1.6 #2.6 #3.6 #1.6 #1.5 +5 Na (85/15) Metrizamide/ -7.6 -10.4 2.4 0.6 2.8 -10 -2 Diatrizoate(d) #1.6 #2.4 #5.9 #4.4 #1.7 +3 Na/Ca (85/15) Metrizamide/ -9.2 -13.2 6.6 5.4 1.0 -13 -2 Diatrizoate(d) #2.1 #1.9 #3.9 #1.5 #1.0 +7 Na/NMG (70/30) (a) N = 13 (b) N = 4 (c) N = 2 (Ventricular fibrillation in 2 others) (d) N = 5 (e) N = 3 TABLE XVII (continued) Heart Rate Effects of Nonionic and lonic Contrast Media Solutions at 37% lodine Concentrations, Alone and as Mixtures in the lsolated Rabbit Heart Preparation Contrast Agents(s) Percent Change from Control Contractility at Maximum Mean lonic Salt Times (sec) after Administration (Mean # S.E.) Effect Percent (lodine Ratio) 0-15 15-30 30-60 120 240 (% Change) Change Metrizamide/ -9.4 -12.2 2.8 3.6 1.0 -12 -3 Diatrizoate(d) #2.5 #2.6 #5.3 #3.8 #1.5 +4 Na/Ca/NMG (70/30) Metrizamide/ -13.8 -14.0 1.3 3.3 2.8 -14 -4 Metrizoate(b) #1.2 #3.1 #4.3 #1.5 #7.1 +3 Na/K/CA/Mg/NMG (85/15) Metriazmide/ -8.5 -9.0 0.5 2.3 -0.8 -9 -3 loxaglate9b) #0.3 #2.0 #0.3 #0.8 #1.2 +3 Na/Ca (70/30) MP-10007/ -13.7 -18.3 5.3 15.7 2.0 -18 -2 lothalamate(e) #1.2 #2.7 #5.4 #8.4 #6.7 +16 Na/Ca (85/15) MP-10013/ -9.5 -13.0 8.8 9.8 1.8 -13 0 lothalamate(b) #1.6 #3.1 #8.2 #4.2 #1.8 +10 Na/Ca (85/15) lopamidol/ -12.8 -9.3 0.8 0.8 -0.8 -13 -4 lothalamate(b) #1.9 #2.6 #4.7 #4.1 #1.3 +1 Na/Ca (85/15) (a) N = 13 (b) N = 4 (c) N = 2 (Ventricular fibrillation in 2 others) (d) N = 5 (e) N = 3 TABLE XVIII Arrhythmogenic Activity of Nonionic and lonic Contrast Media Solutions at 37% lodine Concentrations. Alone and as Mixtures in the lsolated Rabbit Heart preparation Nonionic Lonic Nonionic/lonic lonic Number of Ventricular Other Arrhythmias Agent Agent lodine Ratio Salt(s) Injections Fibrillation % % Metrizamide 100/0 14 7 0 MP-10007 100/0 4 100 0 MP-10013 100/0 4 100 0 lopamidol 100/0 4 100 0 lothalamate 0/100 Na/Ca 4 50 100(a) Diatrizoate 0/100 Na/Ca 4 0 75(b) Metrizoate 0/100 Na/K/Ca/Mg/NMG 4 0 100(c) loxaglate 0/100 Na/Ca 4 0 0 Metrizamide Diatrizoate 85/15 Na 5 0 0 85/15 Na/Ca 5 0 0 70/30 Na/NMG 5 0 0 70/30 Na/Ca/NMG 5 0 0 Metrizamide Metrizoate 85/15 Na/K/Ca/Mg/NMG 4 0 0 Metrizamide loxaglate 70/30 Na/Ca 4 0 0 MP-10007 lothalamate 85/15 Na/Ca 4 0 0 MP-10013 lothalamate 85/15 Na/Ca 4 0 0 lopamidol lothalamate 85/15 Na/Ca 4 0 0 (a) Ventricular tachycardia, multifocal PVCs, complete A-V dissociation, PACs (b) Ventricular tachycardia, multifocal PVCs (c) Ventricular tachycardia, multifocal PVCs, complete A-V dissociatin, ventricular standstill The relative properties of the nonionic/ionic contrast media mixtures of Examples 1 and 2, including viscosity, are summarized in Table XIX in which all relative values are standardized to a base of 100 (least desirable) to O (most desirable). The results show that, almost exclusively, the respective mixtures are better than either the nonionic or ionic contrast agent alone. TABLE XIX Mean Relative Relative Relative Relative Relative N/1 Relative I.V.Contractility Heart Rate Arrhythmia Overall Formulation 1 Ratio Viscosity Toxicity Effects Effects Effects Properties Metrizamide/lothaimate Metrizamide 100/0 100 38 66 40 5 50 Metrizamide 85/15 74 36 72 40 0 44 Na lothalamate Metrizamdie 75/25 56 45 100 60 37 60 Na lothalamate Metrizamide 75/25 79 56 92 20 0 49 Na/NMG lothalamate Metrizamide 60/40 60 56 81 100 52 70 Na lothalamate Metrizamide 50/50 61 71 81 80 7 60 Na/NMG lothalamate Metrizamide 25/75 58 100 41 40 7 50 Na NMG lothalamate Na/NMG lothalamate 0/100 55 100 83 70 29 67 Na/Ca lothalamate 0/100 30 45 81 80 100 67 Metrizamide/Diatrizoate Metrizamide 100/0 100 65 70 44 9 57 Metrizamide 85/15 74 66 66 67 0 55 Na Diatrizoate Metrizamide 85/15 (74) 63 70 56 0 53 Na/Ca Diatrizoate Metrizamide 70/30 58 68 100 78 0 61 Na/NMG Diatrizoate Metrizamide 70/30 (58) 71 80 67 0 55 Na/Ca/NMG Diatrizoate Na/Ca Diatrizoate 0/100 27 100 66 100 100 77 TABLE XIX (continued) Mean Relative Relative Relative Relative Relative N/1 Relative I.V. Contractility Heart Rate Arrhythmia Overall Formulation 1 Ratio Viscosity Toxicity Effects Effects Effects Properties Metrizamide/Metrizoate Metrizamide 100/0 100 62 92 44 7 61 Mitrizamide 85/15 66 55 100 78 0 60 Na/K/Ca/Mg/NMG Metrizoate Na/K/Ca/Mg/NMG 0/100 23 100 71 100 100 79 Metrizoate Metrizamide/loxaglate Metrizamide 100/0 100 100 76 80 100 91 Metrizamide/ 70/30 96 79 100 80 0 71 Na/Ca loxaglate Na/Ca loxaglate 0/100 78 87 78 100 0 69 MP-10007/lothalamate MP-10007 100/0 100 60 - - 100 87 MP-10007 85/15 69 73 100 100 0 68 Na/Ca lothalamate Na/Ca lothalamate 0/100 13 100 100 73 100 77 MP-10013/lothalamate MP-10013 100/0 100 57 - - 100 86 MP-10013 85/15 78 58 100 100 0 67 Na/Ca lothalamate Na/Ca lothalamate 0/100 21 100 69 89 100 76 lopamido/lothalamate lopamidol 100/0 100 58 - - 100 86 lopamidol 95/15 52 58 77 63 0 50 Na/Ca lothalamate Na/Ca lothalamate 0/100 40 100 100 100 100 88 In view of the above, it will be seen that the several objects of the invention are achieved and other advantageous results attained.

As various changes could be made in the above products and methods without departing from the scope of the invention, it is intended that all matter contained in the above description shall be interpreted as illustrative and not in a limiting sense.

Claims (14)

1. An X-ray contrast composition containing approximately 34 to 40% iodine and suitable for use in angiocardiographic procedures comprising an aqueous solution of a mixture of a nonionic X-ray contrast medium and an ionic X-ray contrast medium, the composition having a viscosity of not more than approximately 9 to 1 2 centipoises at 37"C, the nonionic X-ray contrast medium per se in aqueous solution having a viscosity greater than that of the composition at 37"C and the ionic X-ray contrast medium per se in aqueous solution having a viscosity of less than that of the composition at 37do.

2. A composition as claimed in claim 1 wherein the nonionic X-ray contrast medium per se in aqueous solution has a viscosity of more than approximately 9 to 12 centipoises at 37"C.

3. A composition as claimed in claim 1 or claim 2 wherein the ionic X-ray contrast medium per se in aqueous solution has a viscosity of less than approximately 9 to 1 2 centipoises at 37'C.

4. A composition as claimed in any one of the preceding claims wherein the composition has an acute intravenous toxicity at least as low as that of the ionic X-ray contrast medium per se.

5. A composition as claimed in any one of the preceding claims wherein said composition has an iodine concentration of approximately 37%.

6. A composition as claimed in any one of the preceding claims wherein the nonionic X-ray contrast medium is N-(N-methyl-3, 5-di-acetamido-2,4, 6-triiodobenzoyl)glucosamine.

7. A composition as claimed in any one of claims 1 to 5 wherein the nonionic X-ray contrast medium is 3, 5-bis-gluconamido-2,4, 6-triiodo-N-methylbenzamide.

8. A composition as claimed in any one of claims 1 to 5 wherein the nonionic X-ray contrast medium is N-(2-hydroxyethyl)-2,4, 6-triiodo-bis-3, 5-(2-keto-L-gulonamido)benzamide.

9. A composition as claimed in any one of claims 1 to 5 wherein the nonionic X-ray contrast medium is N, N '-(2, 3-dihydroxypropyl)-2,4,6-triiodo-5-(2-keto-L-gulonamido) isophthalamide.

10. A composition as claimed in any one of claims 1 to 5, wherein the nonionic X-ray contrast medium is L-5-eY-hydroxypropionylamino-2,4,6-triiodoisophthalic acid di( 1 , 3-dihydroxi- sopropylamide).

11. A composition as claimed in any one of claims 1 to 5 wherein the ionic X-ray contrast medium is a pharmaceutically acceptable salt of 5-acetamido-2,4,6-triiodo-N-methylisophthalamic acid.

1 2. A composition as claimed in any one of claims 1 to 5 wherein the X-ray contrast medium is a pharmaceutically acceptable salt of 3, 5-diacetamido-2,4,6-triiodobenzoic acid.

1 3. A composition as claimed in any one of claims 1 to 5 wherein the ionic X-ray contrast medium is a pharmaceutically acceptable salt of 3-(acetylamino)-5-(acetylmethylamino)-2,4,6triiodobenzoic acid.

14. A composition as claimed in any one of claims 1 to 5 wherein the ionic X-ray contrast medium is a pharmaceutically acceptable salt of 2,4,6-triiodo-3-N-hydroxyethylcarbamyl-5 (2,4,6-triiodo-3-N-methylcarbamyl-5-N-glycylamino-benzoic acid.

1 5. A composition as claimed in any one of the preceding claims wherein the nonionic X-ray contrast medium is aqueous solution stabile.

1 6. A composition as claimed in any one of the preceding claims which additionally comprises 1 50 to 200 mEq/L of sodium.

1 7. A composition as claimed in any one of the preceding claims which additionally comprises from 5 to 10 mEq/L of calcium.

1 8. A composition as claimed in any one of the preceding claims which additionally comprises an amount of N-methylglucamine sufficient to bring the pH of the solution within the range of from 6.8 to 7.8.

1 9. A composition as claimed in claim 1 substantially as hereinbefore described with reference to any one of the Examples.