NO123472B - - Google Patents

Description

X-ray contrast agent.

The invention relates to an X-ray contrast agent calculated

for making body cavities visible during X-ray examinations.

The X-ray contrast agent according to the invention is charac-

characterized in that it contains a water-soluble, linear or branched polymer with an average molecular weight of at least 5000, which polymer is made up of alternating 2,4,6-triiodobenzoic acid derivative groups and intermediate equal or branched aliphatic hydroxyl group-containing bridges, containing 3~30 carbon atoms, preferably 3-10 carbon atoms, and may possibly be interrupted by one or more oxygen bridges.

According to the invention, the 2,4,6-triiodobenzoic acid derivative groups can be 3,5-diamino-2,4,6-triiodobenzoic acid derivative groups such as 3,5-diacylamino-2,4,6-triiodobenzoic acid derivative groups, where the acyl group is one with a maximum of 5 carbon atoms, preferably an acetyl or propionyl group, as particularly good X-ray contrast is achieved. The triiodobenzoic acid derivative groups can also be 3-amino-5-aminomethyl-2,4,6-triiodobenzoic acid derivative groups or 5-amino-2,4,6-triiodo-isophthalic acid monoamide derivative groups.

According to the invention, the polymer can advantageously be made up of alternating groups with the formulas

. where R is an acyl group with a maximum of 5 carbon atoms or a hydrogen atom, or physiologically tolerable salts thereof, and bridges with the formula - A -, where A is an alkylene group substituted with one or more hydroxyl groups with 3-30 carbon atoms, preferably 3-10 carbon atoms , and possibly interrupted by one or more oxygen bridges, as a preparation is obtained with a good contrast effect and which is easily collected in body cavities. The bridging group A can thus be one with the formulas -CH2.CH(OH)-CH2.O.CH2.CH(OH).CH2- or -CH2.CH(OH).CH2.O.C<H>2.CH2. O.CH2.CH(OH).CH2- or -CH2.CH(OH) .CH2-0. (CH^.O.CHg.ClKOH) .CH2- or -CH2.CH(0H).CH2.0.CH2.CH(0H).CH2.O.CH2.CH(OH).CH2- or

-CH2.CH(OH).CH2-.

Other examples of the iodinated benzoic acid derivative group in the polymer are

or physiologically tolerable salts thereof.

A preparation according to the invention consists of a mixture, e.g. an aqueous solution or a mixture with a physiologically tolerable solid carrier, the preparation preferably having the form of a

tablet or other appropriate dosage unit, and so that the mixture contains one or more of the above-mentioned polymers as active contrast material.

The upper limit for the average molecular weight is chosen depending on the hollowness in the body, which is to be made visible with the help of the X-ray contrast agent. If the preparation e.g. is to be used for the gastrointestinal tract, very high values can be allowed, up to several million, and as an example the numbers 1 million or 500,000 can be mentioned as numbers for the average molecular weight. Should the preparation be used for e.g. blood vessel or urinary tract, a value for the average molecular weight that does not exceed approx. 200,000. As an example, a product with an average molecular weight (Mw) of approx. 100,000. If the preparation is to be used for such examinations where it is desired that the X-ray contrast agent used for visualization is to be excreted through the kidneys, the molecular weight is chosen lower than the renal threshold, e.g. below 50,000, appropriate at approx. 20,000.

The polymer is usually used in the form of a physiologically tolerable salt, e.g. sodium salt, tris-hydroxymethylaminomethane or methylglucamine salt.

The hydroxy group content of the polymer can vary. However, a hydroxyl group content that is on average approx. two hydroxyl groups per bridge. To achieve

a better solubility in water than otherwise, if this is desirable with regard to the product's intended use, you can choose a bridge with an average of approx. four or even more hydroxyl groups. If the number of hydroxyl groups in the bridge is insufficient, the

it is possible to introduce several such, e.g. by introducing glycerol ether groups.

The relative iodine content in the polymer can be varied within wide limits, depending on the intended application. An iodine content that exceeds approx. 15%. As a rule, even values that significantly exceed approx. 20$, e.g. within the range of 25-55$. The relative iodine content can be influenced by the length of the bridging group, by the number of hydroxyl groups and oxygen bridges therein, by the length of any acyl groups R (stated above) and by the type of cations, when the polymer is in the form of a salt.

Compared to X-ray photography in use

of currently common X-ray contrast agents, the agent according to the invention offers new possibilities within diagnostics, which is based on the fact that the contrast agents included in this agent have different resorption and excretion properties than conventional X-ray contrast agents. As they contain hydroxyl groups, they have good solubility properties and are well tolerated physiologically. The high molecular weight also results in a lower osmotic pressure than that resulting from the use of conventional agents.

As an example of the body cavities that can be made visible

with the X-ray contrast agent according to the invention, the gastrointestinal tract can be mentioned. For use in this, the high-molecular-weight contrast agent in solid or dissolved form is administered orally, whereby it passes through the gastrointestinal tract without being resorbed, and thus affects the body to a very small extent.

The intestine can also be visualized by administering the high-molecular-weight X-ray contrast agent in question rectally in the form of an enema. Other examples are the visualization of blood vessels and the heart,

and thereby it is achieved that the contrast agent, when injected in the form of a solution, disappears more slowly from the blood than normal contrast agents due to its larger molecular size. If the molecular size is chosen below the renal threshold, excretion in the urine can also be achieved and thereby valuable information about the urinary tract.

Further examples of the use of the iodinated polymer contrast agent are hysterosalpingography, cholangiography, lymphography, urethrography and sialography.

The use of the X-ray contrast agent according to the invention otherwise takes place in the usual way, namely that the body to which it is taken is illuminated with X-rays, and photography or direct observation on a fluorescent screen or other usual X-ray methodology is carried out in the usual way. The dosage of the contrast agent according to the invention is chosen according to the nature of the case, so that sufficient contrast density is achieved.

As a carrier for the polymer, common additives such as water in the case of injection solutions and solid diluents in the case of tablets can be used.

The hitherto unknown polymer, which is included in the X-ray contrast agent according to the invention, can be produced by copolymerization of substances containing the iodine-containing benoic acid derivative groups as well as other functional groups and a bifunctional substance containing an aliphatic bridge with 3-30 carbon atoms and hydroxyl groups or groups such as e.g. epoxide groups, which can form hydroxyl groups during polymerization.

An advantageous way of preparing suitable compounds consists in reacting a bifunctional triiodobenzoic acid derivative, e.g. 3>5-diacylamino-2,4,6-triiodobenzoic acid, with a diepoxide such as bis-/~2,3-epoxypropyl7-ether or 1,2-ethanediol diglycid ethers or 1,4-butanediol diglycid ethers or glycerin diglycid ethers or corresponding halohydrins, preferably chloro- or bromohydrins, or with epichlorohydrin or epibromohydrin, appropriately in an alkaline environment. Another example is to polymerize 3-amino-5-amino-methyl-2,4,6-triiodobenzoic acid or derivatives thereof in a similar way, e.g. acyl derivatives such as the acetyl derivative.

The bridges formed from the diepoxide will thereby contain hydroxyl groups. If epichlorohydrin is used, a hydroxyl group is obtained in the bridge. If the diepoxides are used, at least two hydroxyl groups are obtained in the bridge.

During polymerisation, other multi-functional substances can also be added, e.g. NH^ or amines such as diamines, or polyhydroxyl compounds such as pentaerythritol to facilitate a polymerization to higher molecular weight values.

If you want to further increase the hydroxyl group content

and thus the solubility, e.g. for oral preparations, the formed high-molecular hydroxyl group-containing polymers can be reacted with glycidol in an alkaline environment, whereby glycerol ethers are formed.

An excess of diepoxide can also be used during polymerization, which results in a higher content of hydroxyl groups in the polymer. Like other polymers, the products can be fractionated by fractional precipitation or gel filtration.

In examples 1-4 below, a copolymer of 3,4-diacetylamino-2,4,6-triiodobenzoic acid with 1,2-ethanediol diglycid ether is used, which was prepared by reacting the starting materials in a solution of sodium hydroxide during approx. 24 hours, after which the solution was neutralized with hydrochloric acid and the desired fraction extracted by fractional precipitation with acetone.

If the preparation according to the invention is in the form of an aqueous solution, it may be appropriate that the polymers are included herein in a concentration of at least approx. 10-20$ depending on the area of application. Values of over $30, yes over $40 or even over $50 can also be considered.

The X-ray contrast agent according to the invention will be explained in more detail with the help of some examples.

Example 1.

An enema is prepared from 40 g of polymer as discussed in

the preceding with an average molecular weight of 120,000 and 0.5 g of NaCl when dissolving the substances in water to a solution volume of 100 ml,

PH<=>7.

When the enema is administered rectally to rabbits, the gastrointestinal tract can be visualized by X-rays and photography. Example 2.

A solution of 40 g of polymer as mentioned above with an average molecular weight of 170,000 and 0.2 g of NaCl is prepared by dissolving the substances in water to a solution volume of 100 ml.

The pH value is regulated to 7-

When the solution is administered orally to rabbits, the gastrointestinal tract can be visualized using X-rays and photography.

Example 3-

A solution of 40 g of polymer as mentioned above with an average molecular weight of 80,000 and 0.8 g of NaCl is prepared by dissolving the substances in water to a solution volume of 100 ml. The pH value is adjusted to 7.3 - 7.4 with hydrochloric acid and NaOH. The solution is filtered and filled into bottles which are closed and sterilized by autoclaving.

By injecting the solution into blood vessels of rabbits

these and the cavities of the heart can be visualized using X-rays and photography.

Example 4.

A solution of 30 g of polymer is prepared which

mentioned above with an average molecular weight of 20,000 and 0.8 g of NaCl by dissolving the substances in water to a solution volume of 100 ml. The pH value is adjusted to 7.3-7»4 with HC1 and NaOH. The solution is filtered and filled into bottles which are closed and sterilized by autoclaving.

By intravenous injection of the solution into rabbits

and subsequent x-ray examination of the kidney area and photography, contrast filling of the renal pelvis, urinary tract and bladder is revealed.

In a similar way as in the above-mentioned examples, X-ray images can be obtained by using as X-ray contrast medium polymers with different average molecular weights produced by polymerization of 3,5-diacetylamino-2,4,6-triiodbenzoic acid with 1,4-butanediol diglycides or 3-amino-5 -aminomethyl-2,4,6-triiodobenzoic acid or derivatives thereof with diepoxides such as 1,4-butanediol diglycidethers or 1,2-ethanediol diglycidethers.

Example 5.

61.4 g of 3-acetylamino-5-acetylamino-2,4,6-triiodobenzoic acid were dissolved in 60 ml of 4-n aqueous solution of sodium hydroxide. Over the course of 6 hours, 24 ml of 1,4-butanediol diglycides were added slowly with stirring at 20°C. The reaction mixture stood at 20°C for 24 hours and was then neutralized to pH 7 with acetic acid. The solution was then dialyzed for several days against water, after which it was evaporated to dryness in vacuum at 50°C. The average molecular weight of the produced product was approx. 33,000.

25 g of the polymer (in the form of the sodium salt thereof)

was dissolved in water so that the solution volume was 50 ml. The solution's pH value is adjusted to 7>3 with NaOH and HC1. The solution was filtered and filled into bottles which were closed and sterilized by autoclaving at 110°C.

The solution was injected into the veins of rabbits, whereby the veins could be visualized by X-ray photography.

The solution was also injected into the arteries of rabbits, whereby not only these arteries but also the diverting veins could be visualized by X-ray photography. When injecting a corresponding dose of conventional monomeric contrast media into the same arteries, the abducting veins could not be visualized in the same advantageous way. The contrast agent in question thus offers particular diagnostic possibilities.

Example 6.

61.4 g of 5-acetylamino-2,4,6-triiodo-N-methylisophthalic acid monoamide was dissolved in 60 ml of 4-n aqueous solution of sodium hydroxide. 20 ml of 1,4-butanediol diglycides are slowly added dropwise while stirring at 20°C. The reaction mixture was left at 20°C for 2 days. The product formed was precipitated with 3_n hydrochloric acid. The polyacid was dissolved again by adding water and 4-n aqueous sodium hydroxide solution until the polyacid had dissolved

as sodium salt. The product was then precipitated again in acid form by the addition of 3-n hydrochloric acid. The product was washed with water and dried in vacuum at 50°C. The product is soluble as sodium salt. Aqueous

solutions of the sodium salt can be fractionated with acetone. The average molecular weight was approx. 7•000. 25 g of the polymer in acid form was dissolved in water by adding methylglucamine to pH 7.3, the amount of water being chosen so that the volume of the solution was 50 ml. The solution was filtered and filled into bottles which were closed and sterilized by autoclaving at 110°C.

The solution was injected into the veins of rabbits, as the veins could be visualized by X-ray photography. X-rays of the kidney area and photography show after some time contrast filling of the renal pelvis, urinary tract and bladder.

The solution was also injected into the arteries of rabbits, as not only these arteries but also the leading veins were visualized by X-ray photography. By injecting a corresponding dose of ordinary monomeric contrast agent into the same arteries, the abducting veins could not be visualized in the same advantageous way. The contrast agent according to the invention thus provides new diagnostic possibilities.

Example 7.

61.4 g of 3-acetylamino-5-acetylamino-2,4,6-triiodobenzoic acid were dissolved in 60 ml of 4-n aqueous solution of sodium hydroxide. Over the course of 5 hours, 20 ml of 1,4-butanediol diglycides were added slowly with stirring at 20°C. The reaction mixture was left at 20°C for 2 days, after which it was neutralized with hydrochloric acid to pH 7. The polymeric product formed was precipitated with acetone. It was redissolved in water and precipitated by the addition of 3-n HCl. The formed polyacid was again dissolved by adding water and a 4-n aqueous solution of sodium hydroxide until the polyacid had dissolved as the sodium salt. The product was then again precipitated in acid form by the addition of 3-n hydrochloric acid. The product was washed with water and dried in vacuum at 50°C. The product is soluble as sodium salt. Aqueous solutions of the sodium salt can be fractionated with acetone. The average molecular weight was approx. 10,000. 25 g of polymer in acid form was dissolved in water by adding methylglucamine to pH 7.3, the amount of water being chosen so that the volume of the solution was 50 ml. The solution was filtered and filled into bottles which were closed and sterilized by autoclaving at 110°C.

The solution was injected into the veins of rabbits, whereby the veins could be visualized by X-ray photography. X-ray examination of the kidney area and photography show, after a period of time, contrast filling of the renal pelvis, urinary tract and bladder.

The solution was also injected into arteries of rabbits, since not only these arteries, but also abducting veins could be visualized by X-ray photography. By injecting a corresponding dose of ordinary monomeric contrast agents into the same arteries, the abducting veins could not be visualized in the same advantageous way, so that the contrast agent in question offers particular diagnostic possibilities.

Example 8.

61.4 g of 3-acetylamino-5-acetylamino-2,4,6-triiodbenzoic acid was dissolved in 70 ml of 4-n aqueous solution of sodium hydroxide. 12.8 ml of glycidol was slowly added dropwise while stirring at 20°C. The reaction mixture was allowed to stand at 20°C for 2 days. (During the reaction, the hydrogen atoms on the nitrogen atoms are replaced by the substituent -CH2-CH(OH)-CH2OH). Then, 24 ml of 1,4-butanediol diglycidether was slowly added dropwise while stirring at 20°C. The reaction mixture was allowed to stand at 20°C for 24 hours. (The diepoxide thereby polymerises the iodine-containing monomer units by reacting with the hydroxyl groups in the above-mentioned glycerol derivative). The reaction mixture was neutralized with 6-n hydrochloric acid to pH 7, after which the sodium salt of the polymer was precipitated with acetone. The product was dissolved in some water, after which it was again precipitated with acetone and vacuum dried at 50°C. The average molecular weight was approx. 15,000.

This polymeric product is distinguished by particularly good solubility in water thanks to the selected bridge between the iodine-containing monomer units, which is provided with several hydroxyl groups. The product also has good solubility in acidic gastric juice and is therefore well suited for oral use to visualize the gastrointestinal tract. This is demonstrated by orally giving neutral solutions of this product to rats and rabbits, whereby it can be used e.g. 40 or 50 g of fabric per 100 ml solution. In this way, the gastrointestinal tract could be made visible in an advantageous way without toxic effects on the animals.

Example 9»

Completely analogous to example 8, instead 61.4 g of 5_acetylamino-2,4,6-triiodo-N-methylisophthalic acid monoamide was polymerized in the same way, and an analogous polymer product emerged. This product is also distinguished by very good solubility in water and, moreover, good solubility in acidic gastric juice and is therefore particularly suitable for oral use to visualize the gastrointestinal tract. Neutral solutions were prepared containing 40 and 50 g of substance per 100 ml solution. Rats and rabbits received such solutions orally, as the gastrointestinal tract could be made visible in an advantageous manner.

Example 10.

, 245.6 g of 5-acetylamino-2,4,6-triiodo-N-methylisophthalic acid monoamide was suspended in 140 ml of 4-N aqueous NaOH. At 30°C, 51.2 ml of glycidol was slowly added dropwise over 5 hours with constant stirring. The reaction mixture was left for one hour at 30°C and then 16 hours at approx. 20°C, after which 10 ml of 5-n aqueous NaOH was added. Then 72 ml of 1,4-butanediol diglycides were added dropwise with stirring during 5 hours at 30°C. The reaction mixture was left for a further 1 hour at 30°C and then 18 hours at approx. 20°C. Then 100 ml of water was added and the mixture was stirred for 2 hours at 30°C. Then 20 ml of glycidol was added dropwise with constant stirring over the course of 2 hours, at 30°C. The reaction mixture was left for 2 hours at 30°C and then 23 hours at approx. 20°C. With stirring, 6-n aqueous HCl was added dropwise to adjust the pH to 1.6. The solution was kept at this pH for 2 hours. No precipitate was formed. The solution was neutralized with 4-n aqueous NaOH to pH 7.0. 400 ml of water was added followed by 2500 ml of acetone to precipitate the polymer. After one day, the supernatant was separated from the syrupy lower phase containing the sodium salt of the polymeric polyacid formed during the reaction. 200 ml of water He added to the lower phase and then 1000 ml of acetone. After one day, the supernatant was separated from the lower phase, after which 3 further reprecipitations with acetone were carried out in the same way. The precipitate was dried at 50°C in vacuum. The substance formed was used for animal experiments. The yield was

292 g. The product contained 0.8% NaCl. The iodine content of the sodium salt of the polymeric contrast agent obtained was 36%. The average molecular weight determined by light scattering was 6500.

For animal experiments, an aqueous solution of the sodium salt of the polymeric contrast agent containing 50 g of substance per 100 ml solution.

The animal experiments showed that this polymeric contrast agent was non-toxic after oral and intraperitoneal administration and that it was an excellent contrast agent for visualization of the gastrointestinal tract. No precipitation was obtained in the acidic gastric juice.

Claims (2)

1, X-ray contrast agent, characterized in that it contains a water-soluble, linear or branched polymer with an average molecular weight of at least 5000, which polymer is made up of alternating 2,4,6-triiodobenzoic acid derivative groups and intervening linear or branched aliphatic hydroxyl group-containing bridges containing 3-30 carbon atoms , preferably 3-10 carbon atoms, and may optionally be interrupted by one or more oxygen bridges. 2. X-ray contrast agent according to claim 1, characterized in that the 2,4,6-triiodobenzoic acid derivative groups are 3j5 -diamino-2,4,6-triiodobenzoic acid derivative groups such as 3,5-diacylamino-2,4,6-triiodobenzoic acid derivative groups where the acyl group is one with a maximum of 5 carbon atoms, preferably an acetyl or propionyl group. 3- X-ray contrast agent according to any one of the preceding claims, characterized in that the polymer is made up of alternating groups with the formula where R is an acyl group with a maximum of 5 carbon atoms, or et hydrogen atom, or physiologically tolerable salts thereof, and bridges with the formula -A-, where A is an alkylene group substituted by one or more hydroxyl groups with 3-30 carbon atoms, preferably 3-10 carbon atoms, and optionally interrupted by one or more oxygen bridges.