NL8002388A - ROENTGEN CONTRAST. - Google Patents

Description

* * ·· * X-ray contrast media.

Certain non-ionic iodinated X-ray contrast media are safer or less toxic than conventional ionic X-ray contrast media that are administered as a salt.

Some non-ionic X-ray contrast media are unstable as an aqueous solution and must be lyophilized and reconstituted limiting their use primarily to low-volume diagnostic techniques such as myelography. Other non-ionic X-ray contrast media as an aqueous solution are more stable and as safe or safer than the unstable aqueous non-ionic contrast media. Since nonionic contrast agents are generally safer, they are used for higher risk diagnostic techniques such as angiography and intravascular radiography where the lower toxicity outweighs the higher cost of nonionic agents compared to conventional ionic agents. However, these techniques usually require higher volumes of contrast agent and always higher iodine concentrations (e.g. 37%) so that the viscosity of the contrast agent solution weighs heavily. This is especially apparent in angiography and intravascular radiography, where a syringe (with or without a pressure injector) and a catheter are used to introduce the contrast fluid into the vessels. Highly viscous solutions are not suitable for such a system of relatively narrow passages, because the injection pressure becomes too high, or the resistance in the catheter increases when a pressure injector is used. In addition, the blood flow through the viscous contrast fluid in the vessels is slowed, increasing the transit time and exposure time of the contrast agent, which may have undesirable consequences. Therefore, for angiography and intravascular radiography, the viscosity is set at a maximum 800 2 3 88 2 of 9-12 cps at 37 ° C.

Most non-ionic X-ray contrast media, however, are more viscous than the ionic contrast media with the same iodine concentration and have a viscosity greater than 9-12 cps at 37 ° C. The nonionic metrizamide (N- (N-methyl-3,5-diacetamido-2,4,6-triodobenzoyl) -glucosamine, U.S. Patent 3,701,771) with an iodine concentration of 37%, for example, has a viscosity of 16.4-17.0 cps at 37 ° C against 3.6 cps at 37 ° C for the ionic sodium iothalamate (the sodium salt of 5-acetone-10 amido-2,4,6-tri-iodo-N- methyl isophthalminic acid, U.S. Patent 3,145,197) with the same iodine concentration.

According to the invention, an X-ray contrast agent is provided having an iodine concentration required for angiography and intravascular radiography, the viscosity of which is lower than that of the non-ionic contrast agents and the intravenous toxicity is generally lower than that of the ionic contrast agents.

The X-ray contrast medium according to the invention consists of an aqueous solution of a mixture of a non-ionic and an ionic X-ray contrast medium, which solution has an iodine concentration of about 34-40% and a viscosity of no more than about 9-12 cps at 37 ° C. The viscosity of the nonionic contrast agent alone in the aqueous solution is higher than that of the mixture at 37 ° C and the viscosity of the ionic contrast agent alone in the aqueous solution is lower than that of the mixture at 37 ° C Preferably, the non-ionic contrast agent as the aqueous solution is stable.

As far as the safety of the X-ray contrast agent of the invention is concerned, it has surprisingly been found that it is not only acceptable but is greater for certain mixtures than that of the non-ionic contrast agent alone. For example, the safety of an aqueous solution of a mixture of metrizamide (31.5% iodine) and sodium iothalamate (5.5% iodine) is greater than that of metrizamide alone.

The X-ray contrast media of the invention 800 2 3 88 \ 3 I 3 »can be used for angiocardiographic techniques such as coronary artheriography, ventriculography and aortography for which, from the viewpoint of safety and ease of administration, high iodine concentrations and low viscosity of the order of 9 -12 cps at 37 ° C are desired. For such diagnostic techniques, the iodine concentration is generally 34-40%, particularly 37%.

Considerable viscosity differences exist between the various non-ionic X-ray contrast media with increasing iodine concentrations. Most non-ionic contrast agents have a viscosity of greater than 9-12 cps at 37 ° C (determined as indicated in the examples below) at higher iodine concentrations and are therefore less suitable for angiocardiography.

The viscosity could be reduced by reducing the iodine concentration (to less than 37% as usual in angiocar-15 diography), but this makes the diagnosis less clear.

The slope of the viscosity curve for all non-ionic contrast media increases sharply at an iodine concentration between 30 and 37%, so that the viscosity decreases disproportionately by reducing the iodine concentration. For example, the viscosity of metri-20-zamide (a non-ionic X-ray contrast agent solution with an iodine concentration of 37%) is about 16.4-17.0 cps at 37 ° C, when replacing iodine therein with the sodium salt of iothalamic acid in a 85% metrizamide / 15% iothalamate iodine contribution ratio, the viscosity is reduced to 9.2 cps at 37 ° C.

In general, the viscosity of the non-ionic X-ray contrast media solution is reduced in a concentration-related manner by the addition of an ionic X-ray contrast media. As already mentioned, most non-ionic X-ray contrast media are more viscous than the usual ionic X-ray contrast media with the same iodine concentration. An exception to this is the nonionic contrast agent L-5-α-hydroxypropionyl-amino-2,4,6-tri-iodo-isopphthalic acid di (1,3-dihydroxyisopropylamide) known as iopamidol and described in U.S. Patent 4,001. 323, which has a viscosity of 9.5-12.3 cps at 37 ° C.

Mixtures of such non-ionic contrast agents and ionic 800 23 88 4 contrast agents, however, are within the scope of the invention because the lower the viscosity, the better for radiodiagnostic techniques and a viscosity below, for example, 9 cps at 37 ° C is often desired. .

The cardiac safety of the mixtures according to the invention is comparable to that of the non-ionic contrast agent alone and surprisingly sometimes higher, and always higher than that of the ionic contrast agent alone. This is evident from the following test results of coronary perfusion of isolated rabbit heart. Also, the systemic safety of the mixtures is greater than that of the ionic contrast agent alone, and surprisingly sometimes greater than that of the nonionic contrast agent alone, as shown by the test results below from intravenous LD5Q studies.

In general, with an increasing ratio of ionic contrast agent and non-ionic contrast agent, the viscosity of the mixture becomes lower and the safety increases, although this may sometimes only be slightly noticeable in the presence of a considerable amount of ionic contrast agent. The optimum ionic-20 and non-ionic contrast agent ratio in terms of viscosity and safety must therefore be determined on a case-by-case basis.

The X-ray contrast media according to the invention can be prepared simply by dissolving the mixing components separately in sterilized water and mixing the solutions or by dissolving the mixing components one after the other or simultaneously in the same medium. Pharmaceutically acceptable salts such as those of sodium, calcium and / or N-methylglucamine are used to dissolve ionic contrast agents. The salts of N-methylglucamine (meglumine!) Are less preferred because they do not cause a large viscosity decrease. However, until they effectively dissolve the ionic contrast agent, they can serve to adjust the pH.

In addition to the mixing components, the X-ray contrast media of the invention may further contain additives such as sodium (as sodium hydroxide) to increase electrical conductivity (in an amount of 150-200 meq / l), calcium (as 800 2 3 88 i * 5 calcium chloride) as an integral electrolyte to promote cardiac muscle contractions (in an amount of 5-10 meq / l) and enough N-methylglucosamine to dissolve the ionic contrast agent and adjust the pH to 6, for example, 8-7,8, 5 As already mentioned, the non-ionic contrast agent used is an agent which is stable as an aqueous solution, such as the ionic contrast agent. A "stable aqueous solution" is understood to mean an aqueous solution with an acceptable storage or storage time that does not need to be lyophilized or reconstituted before use. Examples of non-ionic contrast agents that form a stable aqueous solution include N, N'-bis (2,3-dihydroxypropyl) -2,4,6-triiodo- 5- (2-keto-L-gulonamido) isophthalamide , N- (2-hydroxyethyl) -2,4,6-tri-iodo-bis-3,5- (2-keto-L-gulonamido) benzamide, L-5-OC-hydroxypropionyla-15 mino-2,4 6-tri-iodo-isophthalic acid di- (1,3-dihydroxyisopropylamide) and 5- {N-2-hydroxyethylacetamido) -2,4,6-tri-iodo-N, N'-bis-2,3-dihydroxypropyl ) isophthalamide. Obviously, this list is not exhaustive.

Examples of non-ionic contrast agents that are unstable as an aqueous solution include N- (N-methyl-3,5-diacetamido-2,4,6-triodobenzoyl) glucosamine and 3,5-bis-gluconamido- 2,4,6-triiodo-N-methylbenzamide.

Examples of ionic contrast agents in the mixtures of the invention include pharmaceutically acceptable salts (eg of sodium and N-methylglucamine) of iothalamic acid (5-acetamido-2,4,6-triodo-N-methylisophthalamic acid), diatrizoic acid ( 3,5-diacetamido-2,4,6-tri-iodobenzoic acid), ioxaglyl acid (2,4,6-tri-iodo-3-N-hydroxyethylcarbamyl-5- (2,4,6-tri-iodo- 3-N-methylcarbarayl-5-N-methyl-N-acetylaminobenzoyl) glycylaminobenzoic acid, U.S. Patent 4,065,554), metrizoic acid (3- (acetyl-amino) -5- (acetylmethylamino) -2,46-tri- iodobenzoic acid), ioxithalamic acid (5-acetamido-2,4,6-tri-iodo-N-2-hydroxyethyl isophthalamic acid) and iodamide (3- (acetylamino) -5- / (acetylamino) methyl __ / - 2,4,6 triiodobenzoic acid). It is clear that this list is not exhaustive either.

800 2 3 88 6

example I

Aqueous mixtures of the nonionic X-ray contrast agent metrizamide (N- (N-methyl-3,5-di-acetamido-2,4,6-triododenzenzl) -glucosamine, U.S. Patent No. 3,701,771) and the sodium salt or sodium / N-methylglucamine

salt of the ionic X-ray contrast medium iothalamic acid (5-acetamido-2,4,6-triodo-N-methylisophthalamic acid, U.S. Patent 3,145,197) with a total iodine concentration of 37%. The water always consisted of sterilized water for injection. The pH of the mixtures was adjusted to 6.9-7.8 with meglumine, IN

NaOH or IN HCl as appropriate. The aqueous mixtures of sodium octalalate or sodium / N-raethylglucamine iothalamate and metrizamide were prepared by dissolving each mixing component separately and mixing the solutions. The total iodine concentration of each aqueous solution of 37% is in parts by weight per parts by volume. Where necessary, the mixtures contain sodium in an equal physiological concentration (150 meq / l).

Absolute viscosity in cps at 37 ° C was determined on 25.0 ml aqueous mixture with a Brookfield Model LVT 20 Synchro-Lectric Viscometer equipped with a U.L. Adapter for the spindles using spindles for a rotation speed of 12, 30 and 60 rpm. for viscosity ranges of 29.1-50.0, 10.1-20.0 and 0-10.0, respectively. The temperature of 37 ° C was maintained by the u.L. Adapter tube to be completely immersed in a water bath at 37 ° C. The viscosity of the mixtures is indicated in table A below.

30 800 23 88 ί * 7

TABLE · A

Viscosity of mixtures of metrizamide and iothalamic acid

Composition Sodium concentration Viscosity at tration meg / liter 37 ° C, cps A. Metrizamide 37% I 0 not determined B. Metrizamide 37% I 150 18.7 C. Metrizamide 28% I 150 13.0 (a)

Na / NMG loth. 9% I

10 D. Metrizamide 18.5% I 150 10.0 (b)

Na / NMG loth. 18.5% I

E. Metrizamide 9% I 150 9.5 (a)

Na / NMG loth. 28% I.

F. Na / NMG loth. 37% I 150 9.1 (a) G. Metrizamide 31.5% I 150 9.2

15 After loth. 5.5% I

H. Metrizamide 28% I 243 9.2

After loth. 9% I

I. Metrizamide 22% 1 400 7.6

After loth. 15% I.

J. Na loth. 37% I 970 3.56 20 ---------—-- (a) average of two determinations, (b) average of three determinations.

Determination of acute intravenous toxicity to mice.

Groups of 2 or 4 adult young Swiss male and female mice weighing 17.6-24.7 g were injected intravenously with the mixtures listed in Table B below at a dose of 4-14 g I / kg body weight and at an injection rate of µl / min. The LD5Q was determined from the cumulative 7-day mortality. The results are summarized in Table B below.

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Tasting asai rabbit heart isolated.

In the following experiments female New Zealand albino rabbits with a body weight of 2-4 kg were used.

Coronary perfusion of isolated rabbit heart was performed with oxygenated Chenoweth's solution (J. Lab. Clin.

Med. 31: 600-608, 1946) having the following composition: NaCl: 119.8 mm / l; KC1: 5.63 mm / 1; CaCl2: 2.16 mm / 1; MgCl2: 2.1 mm / 1; NaHCCy 25.0 mm / 1. The aorta was attached to the perfusion nipple of a Snderson-Craver Heart Perfusion Apparatus (J. Pharmacol. Exp. Ther., 93: 135-141, 1948). The solution was kept at a temperature of 37-39 ° C. The perfusion was performed under constant pressure (about 55 cm water). The myocardial contractility was determined with a Grass Model FT, 03 Force Displacement Transducer connected to a Grass Model 7 Polygraph. The electrocardiogram (ECG) was made on a Grass Model 79 Polygraph with right atrial and right ventricular bipolar wick electrodes. Heart rate was determined from the R-R interval of the electrocardiogram.

The contrast agents were pre-warmed to 37 ° C and administered as 4 ml bolus injections through a side arm of the perfusion device. In the trials with metrizamide only (no sodium, composition A), only a single injection per heart was performed. All other mixtures were administered as multiple injections up to 3 doses per heart as long as the heart returned to the control state between injections.

The changes in myocardial contractility and heart rate induced by the contrast fluids were calculated as the percent change from the control at 15, 30, 60, 120, 180 and 240 sec. after termination of administration, 30 The cumulative influence of each mixture on contractility and heart rate was calculated as the relative area under the curve representing the sum of the mean deviation from control (regardless of sign) at each post-injection observation interval.

The electrocardiogram was examined for the occurrence of arrhythmia. In ventricular vibration, contractility and heart rate were not included in the analysis. The results are summarized in Tables C, D and E below.

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TABLE E

Arrhythmogenic Influence of Mixtures of Metrizamide and Iothalamic Acid on Isolated Rabbit Heart.

g Sodium situation Sodium incidence of Other appearing conc. ventricular parts of (meq / 1) fibrillation arrhythmia

Number of cases per group% A. Metrizamide 37% I 0 1/10 10 None B. Metrizamide 37% I 150 0 0 None c, Metrizamide 28% I 150 0 0 None

Na / NMG loth. 9% I

D, Metrizamide 18.5% I 150 1/10 10 None

Na / NMG loth. 18.5% I

15 E. Metrizamide 9% I 150 1/10 10 None, but un-

Na / NMG loth. 28% I live ECG wave conformations F. Na / NMG loth. 37% I 150 1/7 14 2/7 A-V block (a) G. Metrizamide 31.5% I 150 0/9 0 None

After loth. 5.5% I

20 H. Metrizamide 28% I 243 3/9 33 2/9 A.V block (a),

After loth. 9% I PVCs (b) I. Metrizamide 22% I 400 1/9 11 6/9 A-V block (a)

After loth. 15% I.

25 (a) Atrio-ventricular.

(b) Premature ventricular contractions.

The physico-chemical and toxicological properties of the mixtures used in the tests described above are summarized in Table F below.

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Footnotes Table F: a: the higher the value, the more toxic the mixture.

b: lowest LD5Q / LD50 mixture x 100 c: Rel.opp. for each mixture / highest rel. x 100.

5 d: Rel.opp. for each mixture / highest rel. x 100, e:% (incidence of ventricular fibrillation + A-V block) / (highest% incidence of ventricular fibrillation + A-V block) x 100 The results in Table F show that the mixtures containing the most metrizamide are the least toxic. Furthermore, it appears that the toxicity profile of all the mixtures is better than that of the ionic contrast agent alone, and further that the viscosity is lower than that of solutions of the non-ionic contrast agent alone.

Example II

Proceeding according to example I, the following mixtures were prepared.

Series X: Metrizamlde / lothalamate mixtures.

Composition? A. Metrizamide 76.76 g (37% I)

Water qs, ad, 100.00 ml 20 B. Iothalamic acid 59.70 g (37% 1) +

NaOH 3.90 g (970 meq Na / 1)

Water qs. ad. 100.00 ml C. Metrizamide 64.90 g (31.3% I, 85% of the total% I)

Iothalamic acid 9.20 g (5.7% I, 15% of the total% I)

NaOH 0.60 g (150 meq Na / 1) 25 Water qs. ad. 100.00 ml

D. Metrizamide 61.00 g (29.4% I, 80% of the total% D

Iothalamic acid 12.30 g (7.6%, 20% of the total% I)

NaOH 0.80 g (200 meq Na / 1)

Water qs, ad. 100.00 ml E. Metrizamide 53.70 g (25.9% 1.70% of the total% I) lothalamic acid 17.90 g (11.1% I # 30% of the total% II) 30 NaOH 0, 80 g (200 meq Na / 1)

Meglumine 1.80 g (92 meq Meg / 1)

Water qs, ad, 100.00 ml F. Metrizamide 46.10 g (22.2% I, 60% of the total% I) lothalamic acid 23.90 g (14.8%)> 40% of the total% I )

NaOH 0.80 g (200 meq. Na / 1)

Meglumine 3.70 g (190 meq Meg / 1) 33 Water qs. ad. 100.00 ml 800 2 3 88 18

The pH was adjusted to 7.0-7.8 with a small amount of NaOH for solutions A-D and with meglumine for solutions E and F.

Series II: Metrizamide / disodium triate mixtures 5 Composition: A. Metrizamide 76.76 g (37% I)

Water qs. ad. 100.00 ml B. Diatrizoic acid 59,600 g (37% I) +

NaOH 3,890 g (970 meq Na / 1)

CaCl_ (anhydrous) 0.028 g (5 meq Ca / 1)

Water qs. ad. 100,000 ml

C. Metrizamide 64,900 g (31.3% I, 85% of the total% D

Diatrizoic acid 9,200 g (5.7% 15% of the total% I)

NaOH 0.600 g (150 meq Na + / 1)

Water qs. ad. 100,000 ml D. Metrizamide 64,900 g

Diatrizoic acid 9,200 g 15 NaOH 0,600 g ++

CaCl2 (anhydrous) 0.028 g (5 meq Ca / 1)

Water qs. ad. 100,000 ml E. Metrizamide 53,100 g (25.6% I, 70% of the total% I)

Diatrizoic acid 18,400 g (11.4% I, 30% of the total% I)

NaOH 0.800 (200 meq Na / 1)

Meglumine 1,940 g 20 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 / 1)

Water qs. ad. 100,000 ml

The dH was adjusted to 7.0-7.8 with a small amount of NaOH for solutions A-D and with meglumine for solutions E and F.

Series III: Metrizamide / metrizoate mixtures.

Composition t A. Metrizoic acid as 60.8 g (37% I) salt of Na 852 raeq / 1 K * 4.2 meq / 1

Approx. 46.2 meq / 1

Mg + 34.5 meq / 1

Meglumine 756 mg

Water qs, ad, 100 ml 35 800 2 3 88 19 B, Metrizamide 64.7 g (31.2% I, 85% of total% I)

Metrizoic acid as 9.6 g (5.8% I, 15% of the total% I) salt of: Na * 134 meq / l K * 4.2 meq / l

Ca ** 7.3 meq / l

Mg 5.4 meq / l 5 Meglumine 119 mg

Water qs. ad. 100 ml C. Metrizamide 76.76 g (37% I)

Water qs, ad. 100.00 ml

The pH of solutions A and B was adjusted to 7.0-7.8 with meglumine and that of solution C to 7.0-7.8 with NaOH. 10 Series IV: Metrizamide / ioxa plate mixtures.

Composition: A. Metrizamide 76.76 g (37% I)

Water qs. ad. 100.00 ml B. Ioxaglylic acid 61,700 g (37% I) +

NaOH 1,940 g (485 meq Na / ^ 15 CaCl- (anhydrous) 0.091 g (16.25 meq Ca / 1)

Water qs. ad. 100,000 ml C. Metrizamide 53,100 g (25.6% I, 70% of the total% I)

Ioxaglylic acid 19,000 g (11.4% X, 30% of the total% I)

NaOH 0.600 g (150 meq Na * / 1)

CaCl 2 (anhydrous) 0.028 g (5 meq Ca ++ / 1) 2Q Water qs. ad. 100,000 ml

The pH of solutions A and C was adjusted to 7.0-7.8 with NaOH and that of solution B to 7.0-7.8 with meglumine

Series V: N- (2-hydroxyethyl) -2,4,6-triiodo-bis-3,5- (2-keto-L-qulonamido) benzamide (MP-10007) / iothalamate mixtures.

25 Composition: A, MP-10007 89.9 g (37% X)

Water qs. ad. 100.0 ml B. Iothalamic acid 59.79 g (37% I) +

NaOH 3,750 g (937.5 meq Na ^ l)

CaCl (anhydrous) 0.175 g (31.25 meq Ca / 1)

Water qs. ad. 100,000 ml 30 C. MP-10007 75.577 g (31.1% I, 85% of the total% I)

Iothalamic acid 9.520 g (5.9% I, 15% of the total% I)

NaOH 0.600 g (150 meq Na / 1)

CaCl- (anhydrous) 0.028 (5 meq Ca + A)

Water qs. ad. 100,000 ml D. MP-10007 89.9 g (37% I) 3g Water qs. ad. 100.00 ml 800 2 3 88 20 E. Iothalamic acid 59.70 g (37% I)

NaOH 3.90 g (970 meq Na '/ 1)

Water qs. ad. 100.00 ml P. MP-10007 79.9 g (32.9% I, 89% of the total% I)

Iothalamic acid 6.6 g (4.1% I, H% + of the total% I)

NaOH 0.44 g (110 meq Na / 1)

Water qs. ad. 100.00 ml G. MP-10007 70.1 g (28.9% I, 78% of the total% I)

Iothalamic acid 13.2 g (8.1% I, 22% of the total% I)

NaOH 0.88 g (220 meq Na / 1)

Water qs. ad. 100.00 ml H. MP-10007 60.2 g (24.8% I, 67% of the total% I) 10 Iothalamic acid 19.8 g (12.2% I, 33% of the total% I)

NaOH 1.32 g (330 meq Na + / 1)

Water qs. ad. 100.00 ml I. MP-10007 50.2 g (20.7% I, 56% of the total% I)

Iothalamic acid 26.4 g (16.3% I, 44% of the total% I)

NaOH 1.76 g (440 meq Na + / 1)

Water qs. ad. 100.00 ml 15 J. MP-10007 40.3 g (16.6% I, 45% of the total% I)

Iothalamic acid 33.0 g (20.4% I, 55% of the total% I)

NaOH 2.20 g (550 meq Na + / 1)

Water qs. ad. 100.00 ml

The pH of solutions A, B and C was adjusted to 7.0-7.8 with NaOH; the other solutions kept their original 20 ....

actual pH.

Series VI: N.N, -bis- (2> 3-dihydroxypropyl) -2.4.6-tri-iodo-5- (2-keto-L-gulonamido) isophthalamide (MP-100013) / iothalamate mixtures. Composition: A. MP-10013 85.6 g (37% I) 25 Water qs. ad. 100.0 ml B. Iothalamic acid 59.7 g (37% I)

NaOH 3,750 g (937.5 meq NaVI)

CaCl2 (anhydrous) 0.175 g (31.25 meq Ca / 1)

Water qs. ad. 100,000 ml C. MP-10013 71,974 g (31.1% I, 85% of the total% I)

Iothalamic acid 9.520 g (5.9% I, 15% of the total% I) 30 NaOH 0.600 g (150 meq Na +/- 1)

CaCl2 (anhydrous) 0.028 g (5 meq Ca "" /!)

Water qs. ad. 100,000 ml D. MP-10013 85.6 g (37% I)

Water qs, ad. 100.00 ml 35 800 2 3 88 21 E. Iothalamic acid 59.70 g (36% I)

NaOH 3.90 g (970 meq NaVD

Water qs. ad. 100.00 ml

P. MP-10013 75.3 g (32.9% If 89% of the total% D

Iothalamic acid 6.6 g (4.1% I # 11% of the total% I)

NaOH 0.44 g (110 meq Na / 1) ^ Water qs. ad. 100.00 ml G. MP-10013 66.77 g (28.9% 78% of the total% I)

Iothalamic acid 13.2 g (8.1% If 22J of the total% I) NaOH 0.88 g (220 meq Na / 1)

Water qs. ad. 100.00 ml H. MP-10013 56.50 g (24.8% I, 87% of the total% I) 10 Iothalamic acid 19.8 g (12.2% I »33% of the total% I)

NaOH 1.32 g (330 meq Na / 1)

Water qs. ad. 100.00 ml I. MP-10013 47.94 g (20.7% If 56% of the total% I)

Iothalamic acid 26.4 g (16.3% If 44% of the total% I) J. MP-10013 38.52 g (16.6% If 45% of the total% I)

Iothalamic acid 33.0 g (20.4% I, 55% of the total% I) 1.5 NaOH 2.20 (550 meq Na / 1)

Water qs, ad. 100.00 ml

The pH of solutions A, B and C was adjusted to 7.0-7.8 with NaOH? the other solutions maintained their original pH.

20 Series VII: iopamidol / iothalamate mixtures Composition I A. Iothalamic acid 59,700 g (37% I)

NaOH 3,750 g (935.5 meq Na + / 1)

CaCl_ (anhydrous) 0.175 g (31.3 meq Ca / 1)

Water qs.ad. 100,000 ml 25 B. Iopamidol 75.5 g (37% I)

Water qs. ad. 100.00 ml C. Iopamidol 63,900 g (31.3% I, 85% of the total% I)

Iothalamic acid 9,200 g (5.7% I, 15% of the total% I)

NaOH 0.600 g (150 meq Na / 1)

CaCl_ (anhydrous) 0.028 g (5 meq Ca +/- 1)

Water qs. ad. 100.00 ml. The pH of all solutions was adjusted to 7.0-7.8 with NaOH.

From the Series I mixtures, the viscosity and total acute intravenous median lethal dose (LD ^ Q) were determined in mice. Of the mixtures from series II, m, IV, V (A, B and 33 c), VI (A, B and c) and Vil, the viscosity, cardiotoxicity 800 23 88 22 in isolated rabbit heart preparation (GKHP) and acute intravenous toxicity determined to mice. Only the viscosity of the mixtures of series V and VI D-J was determined.

The absolute viscosity at 37 ° C was determined as follows.

1) small volumes (about 1.0 ml)

For this determination, a Wells-Brookfield Model LVT Micro-Viscometer was used with water circulating through the sample well at 37 ° C. The water was kept at the above temperature 10 with a Haake Model E-12 Heater Circulator. A CP-40 stainless steel tapered spindle (tip angle 0.8 °, diameter 4.8 cm) was used at rotational speeds of 6, 12, 30 and 60 rpm for viscosity ranges of 25.8-51.4, respectively , 10.3-25.7, 5.2-10.2 and 0-5.1 cps.

2) large volumes (25.0 ml).

For this determination, a Brookfield Model LVT Synchro-Lectric viscometer equipped with a L.L.

Adapter for holding precision cylindrical spindles with a rotation speed of 12, 30 and 60 rpm. for viscosity ranges of 20.1-50.0, 10.1-20.0 and 0-10.0 cps, respectively. A temperature of 37 ° C was maintained by fully immersing the U.L. Adapter tube in a 37 ° C water bath.

The acute intravenous toxicity was determined as described in Example 1. In most cases, only global assays were performed in which the contrast agents were administered to 1-4 mice until sufficient data were obtained for an approximate median lethal dose (UD). At least 8 mice per dose were used for 50 complete LD / q assays. The data obtained thereby was processed according to the method of Litchfield and Wilcoxon (J. Pharmacol. Exp. Therap., 96:99, 1949).

Cardiotoxicity in isolated rabbit heart preparation (GKHP) was determined as described in Example 1. The results are summarized in Tables G-M below.

35 800 2 3 88 23

TABLE G

Series I: Metrizamide / iothalamate mixtures

Together- Ratio non-Ionic Viscosi i.v. LD_, mg 1 / - theorem ionic iodine salt at ^ and ionic iodine 37 ° c, ^ 9 (confidence> x_ desired limit 95% IA 100/0 None 17.00 13,000 (11,920-14,178) IB 0/100 Na 3.56 8,600 10 (7,780 - 9,506) IC 85/15 Na 12.08 14,000 (12,442-15,752) tD 80/20 Na 10.14 14,750 (14,038-15,498) IE 70/30 Na / NMG 8.01 12,000 15 (10,680 -13,483) IF 60/40 Na / NMG 9.86 9,000 (7,697 -10,524) χ

Brookfield LVT Synchro-Lectric Viscometer

The results in Table G show that the viscosity of the nonionic contrast agent (metrizamide) is lowered by replacing iodine therein with an ionic contrast agent (iothalamate) without significantly reducing systemic safety to a ratio of non- ionic iodine and ionic iodine of 60:40. Mixtures I-C and I-D appear to be better tolerated.

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The data from the previous tests are detailed in Tables N-R below.

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Footnotes table Rs (a) ventricular tachycardia, multifocal PVCs, total A-v dissociation # PACs.

(b) ventricular tachycardia # multifocal PVCs.

5 (c) ventricular tachycardia, multifocal PVCs # total A-V

dissociation # ventricular arrest.

The properties of the mixtures of Examples I and II including the viscosity were rated with points from 0 (most desired) to 100 (least desired). The point-10 rating is shown in Table S below. It shows that almost all the blends have better properties than the non-ionic and ionic contrast agents separately.

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Claims (37)

1. X-ray contrast agent with an iodine concentration of about 34-40%, particularly suitable for angiocardiography, characterized in that the X-ray contrast agent consists of an aqueous solution of a mixture of a non-ionic X-ray contrast agent and an ionic X-ray contrast medium # which aqueous solution has a viscosity of no more than about 9-12 cps at 37 ° C # where the nonionic contrast agent in aqueous solution only has a higher viscosity at 37 ° C than the aqueous mixture and the ionic contrast agent only in aqueous solution has a lower viscosity at 37 ° C than the aqueous mixture. 2. X-ray contrast agent according to claim 1 #, characterized in that the non-ionic contrast agent only has a viscosity higher than about 9-12 cps at 37 ° C in aqueous solution. X-ray contrast agent according to claim 1 #, characterized in that the ionic contrast agent only has a viscosity lower than about 9-12 cps at 37 ° C in aqueous solution. 20 X-ray contrast agent according to claim 1 #, characterized in that the acute intravenous toxicity is at least as low as that of the ionic contrast agent separately. X-ray contrast agent according to claim 1 #, characterized in that the iodine concentration is about 37%. 25 X-ray contrast agent according to claim 1 #, characterized in that the non-ionic contrast agent is N- (N-methyl-3 # 5-di-acetamido-2,4,6-triodobenzoyl) -glucosamine. X-ray contrast agent according to claim 1 #, characterized in that the non-ionic contrast agent is 3,5-bis-gluconamido-2 # 4,6-triiodo-N-methylbenzamide. X-ray contrast agent according to claim 1 #, characterized in that the non-ionic contrast agent N- (2-hydroxyethyl) -2,4,6-triiodo-bis-3,5- (2-keto-L- gulonamido) benzamide. X-ray contrast agent according to claim 1 # 35, characterized in that the non-ionic contrast agent N, N '- (2,3-di-800 23 88 ν' hydroxypropyl) -2,4,6-tri-iodo-5- (2-keto-L-gulonamido) isof talaunide is> X-ray contrast agent according to claim 1, characterized in that the non-ionic contrast agent is L-5-cX-hydroxy-propionylamino-2,4,6-triiodoisophthalic acid di (1,3-dihydroxyisopropyl amide) . X-ray contrast agent according to claim 1, characterized in that the ionic contrast agent is a pharmaceutically acceptable salt of 5-acetamido-2,4,6-triiodo-N-methylisophthalamic acid. 10 X-ray contrast agent according to claim 1, characterized in that the ionic contrast agent is a pharmaceutically acceptable salt of 3,5-diceetaunido-2,4,6-triiodobenzoic acid. X-ray contrast agent according to claim 1, characterized in that the ionic contrast agent is a pharmaceutically acceptable salt of 3- (acetylamino) -5- (acetylmethylamino) -2,4,6-triodobenzoic acid. X-ray contrast agent according to claim 1, characterized in that the ionic contrast agent is a pharmaceutically acceptable salt of 2,4,6-triiodo-3-N-hydroxyethylcarbamoyl-5-20 (2,4,6-tri-iodo- 3-N-methylcarbamoyl-5-N-glycylaminobenzoic acid X-ray contrast medium according to claim 1, characterized in that the non-ionic contrast medium is stable in aqueous solution. X-ray contrast agent according to claim 15, 25, characterized in that the non-ionic contrast agent in only aqueous solution has a viscosity higher than about 9-12 cps at 37 ° C. 17. X-ray contrast agent according to claim 15, characterized in that the ionic contrast agent only has a viscosity lower in aqueous solution of about 9-12 cps at 37 ° C. The X-ray contrast agent according to claim 15, characterized in that the acute intravenous toxicity is at least as low as that of the ionic contrast agent alone. 35 19. X-ray contrast medium according to claim 15, 800 2 3 88 • k 'mat, characterized in that the iodine concentration is about 37%. 20. X-ray contrast medium according to claim 15, characterized in that the non-ionic contrast medium N- (2-hydroxy-ethyl) -2,4,6-triiodo-bis-3,5- ¢ 2-keto-L- gulonamido) benzamide. 5 X-ray contrast medium according to claim 15, characterized in that the non-ionic contrast medium N, N'-bis (2,3-dihydroxypropyl) -2,4,6-tri-iodo-5- (2-keto-L- gulonamido) isophthalamide. X-ray contrast medium according to claim 15, characterized in that the non-ionic contrast medium L-5-O-hydroxypropionylamino-2,4,6-triodoisophthalic acid di (1,3-dihydroxy | ropyl- amide). X-ray contrast agent according to claim 15, characterized in that the ionic contrast agent is a pharmaceutically acceptable salt of 5-acetamido-2,4,6-triiodo-N-methylisophthalamic acid. X-ray contrast agent according to claim 15, characterized in that the ionic contrast agent is a pharmaceutically acceptable salt of 3,5-diacetamido-2,4,6-triiodobenzoic acid. 20 X-ray contrast agent according to claim 15, characterized in that the ionic contrast agent is a pharmaceutically acceptable salt of 3- (acetylamino) -5- (acetylmethylamino) -2,4,6-triiodobenzoic acid. An X-ray contrast agent according to claim 15, characterized in that the ionic contrast agent is a pharmaceutically acceptable salt of 2,4,6-triiodo-3-N-hydroxyethylcarbamoyl-5- (2,4,6-triiodo- 3-N-methylcarbamovl-5-N-methyl-N-acetylaminobenzoyl) -glycylaminobenzoic acid. 27. A method of operating angiocardiography using an X-ray contrast agent with an iodine concentration of about 34-40%, characterized in that the X-ray contrast agent consists of an aqueous solution of a mixture of a non-ionic contrast agent and an ionic contrast medium, which aqueous solution has a viscosity of not more than about 9-12 cps at 37 ° C, the nonionic 800 2 3 88 contrast agent having only a viscosity at 37 ° C higher than that of the aqueous in aqueous solution mixture and the ionic contrast agent in aqueous solution only has a viscosity at 370 ° C lower than that of the aqueous mixture. The method according to claim 27, characterized in that the non-ionic contrast agent in aqueous solution only has a viscosity greater than about 9-12 cps at 37 ° C. A method according to claim 27, characterized in that the ionic contrast agent has a viscosity of less than about 9-12 cps at 37 ° C only in aqueous solution 10. A method according to claim 27, characterized in that the acute intravenous toxicity of the contrast agent is at least as low as that of the ionic contrast agent separately. A method according to claim 27, characterized in that the iodine concentration of the contrast agent is about 37%. 32. A method according to claim 27, characterized in that the non-ionic contrast agent in aqueous solution 20 is stable. A method according to claim 32, characterized in that the non-ionic contrast agent has a viscosity higher than about 9-12 cps at 37 ° C only in aqueous solution. 34. The method of claim 32, characterized in that the ionic contrast agent in aqueous solution only has a viscosity less than about 9-12 cps at 37 ° C. 35. A method according to claim 32, characterized in that the acute intravenous toxicity of the contrast agent is at least as low as that of the ionic contrast agent separately, A method according to claim 32, characterized in that the iodine concentration of the contrast agent is about 37%. 37. X-ray contrast media and methods of preparation and use thereof as described in the description and examples. 800 23 88