X-RAY CONTRAST AGENT

10Z8788 The present invention relates to X-ray contrast agents consisting of or comprising a polymer in which polymer iodine substituted aromatic groups are bound by bonds of covalent character.

Water-soluble polymers of the above mentioned types are disclosed e.g. in Swedish Patent Specifications Nos. 348,110 and 348,111. Due to their solubility in water they affect the body to be examined inter alia by exerting an osmotic pressure.

This pressure is, however, lower than that exerted by earlier known low molecular weight water-soluble contrast agents.

Accordingly, when suitable, X-ray contrast agents with very slight solubility in water are used, preferably in the form of suspensions. The most well-known examples of this are the use of suspensions of barium sulfate for the visualization of the gastro-intestinal tract and of sparingly soluble organic iodine compounds for bronchoçraphy. Disadvantages of such i agents, however, are well known, for instance, suspensions of these sharp-cornered hard particles are completely non-physiological. :

Even if their solubility is very poor they are not completely insoluble and their particle size tends to increase in course of time when they are in the form of suspensions. Suspensions of e.g. barium sulfate can affect the rate of passage in the gastro- :.

intestinal canal and may cause constipation. The sedimention rate may be too high due to a high specific weight. Thus, it can be seen that there is a demand for an improved X-ray contrast agent.

According to the present invention there is provided an x-ray contrast polymer which is insoluble in water and other solvents but upon contact with water attains the consistency of a soft gel which influences its environment to a very small extent.

i . ... . !. . "..

i0 îOZ8788 For use as an X-ray contrast agent for e.g. the gastro-intestinal canal, it can be given the consistency of a soft foodstuff, e.g.

the consistency of a soft porridge or gruel, whereby it is more physiological than the media used hitherto, e.g. suspensions of barium sulfate. The polymer according to the invention may be given such structure that it cannot be degraded into water-soluble fragments under the conditions existing in the body cavity into which it is introduced. According to another embodiment the contrast agent acoeording to the invention may be given such a structure that it is degraded to water-soluble products in a controllable way under the conditions existing in the body cavity into which it is introduced.

The present invention provides an X-ray contrast polymer which contains iodine-substituted aromatic groups which have X-ray contrast properties and which are bound in or to the polymer by bonds of covalent character, and which polymer also contains hydrophilic groups, the polymer being in the form of a threedimensional network held together bybonds of covalent character and being insoluble in water but swellable in water to give a gel containing from 10 to 99% by weight of water.

Stable iodine substituted aromatic groups are preferably chosen, i.e. such groups in which the iodine atoms cannot leave the aromatic group either under the physiological conditions of use of the contrast agent or under normal storage conditions.

Accordingly, such groups are chosen in which the iodine atoms are directly bound to aromatic rings. A great number of such iodinesubstituted aromatic groups are known e.g. from other X-ray contrast agents. The iodine-substituted aromatic groups are bound by bonds of covalent character in an insoluble polymer which oeonsists of i0 8788 a practically endless three-dimensional network which is held together by bonds of covalent character so that the choice of such groups is often not as critical as in the case of other more or less water-soluble contrast agents because the contrast agent of the present invention is insoluble in water.

Because of the three-dimensional network held together by bonds of covalent character and the hydrophilic groups the contrast substances of the invention are swellable in water but insoluble in water at different temperatures, e.g. within the range of from 0°C to100°C. They are thus insoluble at normal storage temperatures (e.g. 5°C to 25°C) as well as at body temperature (37 °C). They may be dried at e.g.50°C or60°C and aqueous suspensions thereof o may be heat-sterilized at even higher temperatures, e.g. II0 C, without being brought into solution provided that linkages are chosen which can withstand higher temperatures.

Each iodine-substituted aromatic group is bound in the three-dimensional network by at least one bond of covalent character. As iodine-substituted aromatic groups it is most easy to choose iodo benzene derivative groups such as tri-iodobenzene derivative groups.

Examples of these are 2,4,6-triiodobenzoic acid-3-and/or 5-derivative groups. Thus, the polymeric product may, for instance, contain iodine-substituted aromatic groups of the formula Z1 • I I , z2 30H or physiologically acceptable salts thereof, wherein Z1 and Z2 each represents one of the following groups v H o R " N ° , .

R1 N ° , R3 R3 R2 . N . CH2 , . N . CH2 . , R4 .

R5 R5 N . CO . or N . CO . , i0 wherein R, R2, R4 , and R5 each represents a hydrogen atom, a lower alkyl group having at most 5 carbon atoms, preferably a methyl or ethyl group, or a lower hydroxy alkyl group having at most 5 carbon atoms, preferably a 2-hydroxyethyl, 2-hydroxypropyl or 2,3-di-hydroxypropyl group and R1 and R3 each represents a hydrogen atom or a lower alkanoyl group having at most 5 carbon atoms, preferably an acetyl or propionyl group, a lower alkyl group having at most 5 carbon atoms, preferably a methyl or ethyl group or a lower hydroxyalkyl group having at most 5 carbon atoms, preferably a 2-hydroxyethyl, 2-hydroxypropyl or 2,3-dihydroxypropyl group, at most one of the groups Z1 and Z2 being a hydrogen atom and at least one of the groups Z1 and Z2 having a remaining free bond, said remaining free bond or bonds (indicated above by means of a long stroke) bonding the iodine-substituted aromatic group in the three-dimensional network.

An iodine-substituted aromatic group may, for instance, be I N " . N I • I ...... .i and salts thereof wherein R1 has the above given significance eogo an acetyl group; or l R o N o I • • îl o I and salts thereof, wherein R has the significance given above e.g. a methyl or ethyl group or a hyerogen atom and R1 has the significance given above eog. an acetyl group; or I o co + o o I . o I COOH N or salts thereof, wherein R1 has the significance given above e.g. an aCetyl group, and R5 has the significance given above, i0 eog. a methyl group or I I o o o I COOH or salts thereof, wherein R1 has the significance given above, eogo an acetyl group» and R4 and R5 each have the above given significance, eog° a methyl group or • •/ •• + +i 2' • + H I 8788 I ° îl o I COOH or salts thereof wherein R1 has the significance given above eog° an acetyl group; or COOH COOH o R or salts thereof wherein RI and R3 has the significance given above eogo an acetyl group and R2 has the significance given above e°go a methyl group or a hydrogen atom. Other examples of Iodine-substituted aromatic groups are I o o 0 o I and I o o I One or more different types of iodine-substituted aromatic groups e°g. of the above given kind may simultaneously be an integral part of the polymer according to the invention° . • H.. .... .

• • i • • " • • • i0 10Z8788 The polymeric compound contains hydrophilic groups, for instance carboxy and/or hydroxyl and/or amino groups° The carboxyl groups may, for instance, be bound directly to the iodine-substituted aromatic groups and the hydroxyl groups and/or the amino groups be positioned in those parts of the three-dimensional network which bind together the iodine-substituted aromatic groups° The polymeric product may be in the form of physiologically tolerable salts, eogo when it contains carboxyl groups and/or amino groups° Examples of such salts are sodium sal monoethanolamine salts and methylglucamine salts (e.go when carboxyl groups are present) and hydrochlorides (e.go when amino groups are present).

The iodine -substituted aromatic groups may either be embodied directly as links in the fundamental skeleton or may project from the fundamental skeleton in the three-dimensional network° The iodine-substituted aromatic groups may, for instance, be connected to each other by straight or branched chain aliphatic bridges so that the product contains a three-dimensional network. These aliphatic bridges may advantageously contain hydrophilic groups cog.

hydroxyl groups and/or amino groups which may also be substituted. • For ìnstance, the polymeric product may contain straight or branched . ... .....

chain aliphatic saturated hydrocarbon chains, which preferably comprise from 3 to 30 carbon atoms, eog. from 3 to 20 carbon atoms» and which may optionally be substituted by hydroxyl groups or by other hydrophilic groups and which may optionally be interrupted by one or more oxygen atoms and/or amino groups» the iodinesubstituted aromatic groups being connected to each other by such chains to give a three-dimensional polymeric product which is insoluble but swellable in water.

According to one embodiment of the invention, the lO IOZ8788 three-dimensional network is not degradable in the body cavity where the polymeric contrast agent is to be used« According to another embodiment of the invention the three-dimensional network is degradable, eogo enzymatically degradable in the body cavity where the polymeric contrast agent is to be used° In the latter case linkages which are breakable in the body cavity in question are present in the meshes of the network° In such a case the network may, for instance, be breakable by hydrolases dehydrogenases or oxidases. Examples of such linkages are amide linkages which are breakable by amidases, ester linkages which are breakable by esterases, and glucoside linkages which are breakable by glu cos idases o The invention also provides a method for the preparation of a polymer of the invention, wherein one or more at least monofunctional iodine-substituted aromatic compounds and one or more at least bifunctional cross-linking agents are brought to react with each other in one or more steps, possibly in the presence of other functional substances, at least one of the reacting substances containing at least one hydrophilic group or giving rise to such a group in the reaction product, to form the desired polymer which contains hydrophilic groups and which consists of a three-dimensional network held together by bonds of covalent character and which polymer is insoluble but swellable in water to give a gel which contains from i0 to 99% by weight of water« An X-ray contrast polymer according to the invention may, for instance, be prepared by reacting a sufficient amount of one at least bifunctional cross-linking agent with eogo a water-soluble straight or branched chain polymer containing iodine-substituted aromatic groups which polymer also contains functional groups which • ii"¸ •• i ¸ ': ,i i,!,..': i ..• H.

are able to react with the at least bifunctional cross-linking agent° Examples of such functional groups in the polymer are -OH I and -NH groups° Water soluble polymers to be used as such starting materials and containing iodine-substituted aromatic groups as well as functional groups, eog. -OH groups, are described, for instance» in Swedish Patent Specifications Nos° 348,110 och 348,111o Examples of at least bifunctional cross-linking agents are compounds of the type Y o o o i0 X ° AI Z (I) and X A2 Z (II) wherein X, Y and Z each represents a halogen atom, preferably a chlorine or bromine atom, and A1 and A2 each represents a straight or branched chain monoor polyhydroxyl substituted aliphatic saturated hydrocarbon chain which preferably comprises from 3 to carbon atoms, eog. from 3 to 20 carbon atoms, and which may be interrupted by one or more oxygen atoms» or the corresponding epoxy compounds obtainable from the compound (I) or (II) by splitting off a hydrogen halide. As examples of bifunctional compounds of the formula X " Å1 " Z and corresponding epoxy compounds obtainable from X ° AI Z by splitting off hydrogen halide the following compounds may be mentioned:

C x0/-CHCH2 o 0 o (CH2 )nI o 0 . CH2 o CH%%DESCRIPTION%% - wherein nI is an integer from 2 to 4, c - cs° c ° Oo c ° c o o° c , c o°c °cs-c , 0 c -7,, o « o O o o "20 "2o°" "2 o ",-7 o o '"=çT" • .o.

and -9 l0 10Z8788 cHa CHa o O o c.a cH(o.)o O o o c\ 0 0 or the corresponding halogen hydrins and bifunctional glycerol derivatives of the formula Xo C o CH(OH) o C o Z» eogo dichlorohydrin and dibromohydrin or the corresponding epoxy compounds of the formula C ÕwCH o C o Z obtainable by splitting off hydrogen halide e°g° epichlorohydrin and epibromohyùrino Another example of such a bifunctional compound is 1,2-3,4-diepoxybutane of the formula C - CH ° CHk-/CH2 0 An example of trifunctional cross-linking agents which comprise epoxy compounds corresponding to compounds of the formula Y o x. Ae . z is CH2,õ CH o C oOoC o HoC oO.C o C õCI o Examples of other cross-linking agents are diisocyanates and dicarboxylic acid dihalogenides, for example, dicarboxylic acid dichlorides which may be reacted with hydroxyl groups and amino groups to obtain the desired three-dimensional network.

The water-soluble polymer is reacted with a sufficient amount of at least bifunctional agent to a gel which is insoluble in water, ioeo to form a practically endless three-dimensional network. Thus, e0 g0 , the water-soluble polymers described in the above mentioned Swedish Patent Specifications Nos« 348,110 and 348,111 may be reacted in alkaline aqueous solution with some of the above mentioned diepoxides or halogen hydrins (cross-linking agents) in such an amount that a gel insoluble but swellable in water is formed by cross-linking of the polymeric chains° (Diepoxides and corresponding halogen hydrins are reacting» for instance, with hydroxyl groups to form ether linkages°) These cross-linking agents also - I0 - 10Z8788 have the advantage that hydroxyl groups are introduced into the bridges and thus additional hydrophilic groups are introduced into the three-dimensional network° Another possible process for preparing a polymer according to the invention is to bind iodine-substituted aromatic groups with bonds of covalent character to a three-dimensional network which is pre-prepared and insoluble in water and which contains hydrophilic groups and functional groups (but which does not contain any iodine-containing groups)° In this case the pre-prepared, waterinsoluble network may be non-degradable or degradable, eogo by enzymes as a result of the presence of breakable linkages eogo of the above mentioned kind° An example of such a network is starch which has been comparatively occasionally cross-linked by means of epichlorohydrin or 1,4-butaneùioldiglycide ether to give an insoluble swellable gelo The hydroxyl groups in this network may be made use of for the binding of iodine-substituted aromatic groups» eogo via ester linkages. Such a hydroxyl group-containing network may thus be reacted with eog. tetraiodophthalic acid anhydride one of the carboxylic groups thereof becoming bound to the network via an ester linkage« The most simple way of preparing the polymer according to the invention is, however, to carry out polymerization as well as cross-linking in one and the same operation. In this case there may» for instance, be used at least one iodine-substitnted aromatic substance which is at least bifunctional» i.e. contains at least two reactive groups which are able to react with eogo some of the above mentioned cross-linking agents. For instance, the aromatic substance or substances may contain two reactive hydrogen atoms.

At the polymerisation with the above mentioned diepoxides or hydrogen - Il - 10Z8788 halides hydroxyl groups are obtained in the bridges between the two iodine-substituted groups, which hydroxyl groups then react with a sufficient amount of additional diepoxide or hydrogen halide SO that a cross-linked water-insoluble, swellable network is ohrained. Examples of such bifunctional iodine-substituted aromatic substances are . co co o I I \ I-' H-N. -/ , N-H H-N . Ç "ì " CO o N-H I . . I and I , . I COOH COOH and N,N'- bis-(2,4,6-triiodo-3-carboxyphenyl)-adipic amide and bis-[(2»4,6-triiodo-3-carboxylphenyl)-carbamolymethyl]-ether, lO wherein the hydrogen atoms at the nitrogen atoms may react with the above mentioned cross-linking agents. In these compounds the hydrogen atoms at the nitrogen atoms may, for instance, first be exchanged against other groups which contain functional groups such as -OH and -Nil groups. For instance, by reaction with - CH . CH2 0H or C \ / el . CH2 . CH(OH) . CH2 0H the group -CH2 . CH(OH) . CH2 0H may be introduced. It may also be possible to introduce at the nitrogen atoms side chains containing enzymatically breakable linkages, for example amide linkages and such functional groups which are able to react with the cross-linking agent at the functional groups and the iodine-substituted aromatic rings may be situated on either side of aid enzymatically breakable linkages. (Other examples of iodine-substituted aromatic substances containing hydroxy groups which are able to react with crosslinking agents are, for instance, described in Swedish Patent Specification No. 344,166.) It is also possible to use aniodine-substituted aromatic substance which is non-functional, i.e. which only contains one reactive group which can react with the above mentioned crosslinking agents. Examples of such substances are co co H. . N-H CH3 • • . N-H I . • I and I . . I COOH i wherein the hydrogen atom at the nitrogen atom is able to react with the cross-linking agent« On reaction with, for instance, the above mentioned cross-linking diepoxide a bridge between two iodine-substituted aromatic groups may first be formed° Owing to the fact that the bridges contain hydroxyl groups» polymerisation and cross-linking may take place with a sufficient amount of crosslinking agent to give an insoluble gelo In order to facilitate polymerisation and cross-linking it is also possible to add polyfunctional substances eogo containing amino groups and/or hydroxyl groups which can react with the cross-linking agent° Examples of such substances are ammonia» monoethanolamine» diethanolamine» l»2-diaminoethane or triethanolamine. In this way it is also possible to introduce amino groups in the network» so that swelling of the gel eogo in acid gastric juice may be increased° The i0dine-substituted aromatic groups may thus for instance be connected to each other by means of straight or branched chain aliphatic bridges which contain hyŒErophilic groups such as hydroxyl groups so that the polymeric product contains a three-dimensional network° The polymeric product may, Z 10Z 788 for instance, contain straight or branched chain hydrophilically substituted, saturated hydrocarbon chains which preferably con in from 3 to 30 carbon atoms, eog. from 3 to 20 carbon atoms and which may be interrupted by one or more oxygen atoms and/or amíno groups, the iodine-substituted aromatic groups being connected to each other by such chains so that the polymeric product contains a three-dimensional network and is insoluble but swellable in wate r.

According to the invention the three-dimensional network of the polymeric product may be prepared in such a way that it is not degradable under the conditions existing in the body cavity where the polymeric contrast product is used° To this effect, for instance, saturated aliphatic hydrocarbon chains are chosen which are substituted with hydroxyl groups and which may be interrupted by one or more oxygen atoms, said chains connecting the iodine-substituted aromatic groups in the three-dimensional network via linkages which are not broken enzymatically or in any other way under the conditions in question° A network non-degradable in the body cavity is chosen, for instance, when it is desired that the contrast agent should pass through the gastrointestinal tract in unaltered condition and not set free any water-soluble fragments° According to the invention the three-dimensional network of the polymeric product may also be prepared in such a way that it is degradable under the conditions existing in the body cavity where the polymeric contrast product is used so that the waterinsoluble polymeric product is degraded to water-soluble fragments in the body cavity. To this effect the three-dimensional network may, for instance, be enzymatically degradable by containing k ï lO 8788 linkages which are breakable by hydrolaseso Examples of linkages of this kind are amide linkages which are breakable by amidases.

In this connectbn, for instance, chains of the before-mentioned kind is chosen in the three-dimensional network which chains in addition contain breakable linkages, preferably enzymatically breakable linkages. The breakable linkage, eogo an amide linkage, may, for instance, be present even in the chain of the at least bifunctional cross-linking agent° It may also be present in the iodine-substituted aromatic compound« The breakable linkage may, for instance, also be obtained by incorporating into the meshes of the three-dimensional network during the polymerisation process a bifunctional amide the amide linkage of which is breakable by amidases and the functional groups of which, situated on each side of the amide linkage, are able to react with the cross-linking agent« Breakable linkages in the network so that the waterinsoluble polymeric product can be degraded to water-soluble fragments in the body cavity are chosen, for instance, for certain body cavities lacking outward escape ducts, eogo the spinal marrow canal» lymphatic vessels and blood vessels° Even in some other cases such as bronchography networks with breakable linkages are suitably used° In doing this the contrast agent may be given such properties so as to gradually also disappear from such body cavities° The iodine content of the polymeric products may» of course» be varied within very wide limits« The iodine content is chosen in such a way that a sufficient contrast effect of the polymer is obtained for the intended use° The iodine content of the dry polymer may be more than 2 (percent by weight) for example, more than 5 preferably more than 10 for instance, i0 8788 more than 20 o For instance, the iodine content of the dry polymers may be less than 70 for example, less than 60 for instance, less than 50 e.go less than 40 o The degree of swelling in water of the polymeric contrast product may be varied by varying the size of the meshes in the three-dimensional network and by varying the number of hydrophilic groups such as carboxylic groups and/or hydroxyl groups and/or amino groups° The size of the meshes in the three-dimensional network may be varied by variation of the length and number of cross-linking bridges° As mentioned above a degree of swelling is chosen such that the aqueous gel resulting after swelling of the polymer in water contains more than i0 by weight of water and less than 99 byweight of water° The gels may thus contain more than and less than 98 of water» eogo more than 20 and less than 97 of water° For instance» the gel may contain more than 25, 30, 0, 50» 60» 70 or 80 by weight of water° It may» for instance» contain less than 95, 90» 80» 70» 60, 50 or 0 by weight of water° When the degree of swelling is to be measured more water than required for the swelling is suitably poured on the dry polymeric product» whereafter when the swelling is completed the water which is not an integral part of the gel is removes and the content of water in the gel is determined° In doing this» for instance, a known amount of dry polymer is allowed to swell in water and then the swollen gel is weighed or a calculation of the dry weight may be performed on a known amount of water-swollen gelo The degree of swelling may suitably be determined at 25°Co For practical use when the polymer is present in the form of fine particles it is suitable to determine the volume occupied by the particle mass after swelling in 10í 8788 water (or possibly in other aqueous liquids) in which case the liquid between the particles is also included° To this effect x gram of the dry polymeric product in the form of fine particles is poured into a graduated vessel whereafter excess water is poured into the vessel. The volume y in ml occupied by the waterswollen parti°le mass is read off° 1 gram of the dry particles corresponds in this case to a water-swollen particle suspension of Y ml o x For instance, 1 g of dry particles may give a water-swollen particle mass the total volume of which is more than 1o5 ml and less than i00 ml» such as more than io7 ml and less than 80 mlo e.go more than 2 ml and less than 40 ml, for instance, this volume may be at least 3 ml or at least 4 mlo For instance» this volume may be at most 20 ml or at most 15 ml o Preferably the polymeric contrast agent is used in the form of parti°les. These may be spherical or possess irregular shape. In general» it is used in the form of very small particleso Suitably the parti°le size (in water-swollen condition) lies substantially within the range of from O,Olg to lO00g, preferably within the range of from 0,1g to 500g, e.go within the range of from ig to 00g» such as within the range of from Sg to lOOgo As an example there may be mentioned an average particle size lying within the range of from 0.1g to 200g, eog° within the range of from ig-to lO0g» such as within the range of 10g to 50go Very small particles are chosen eogo when a low sedimentation rate is desired for a suspension e°g. for gastro-intestinal investigations or when the agent should be used for e.go angiographies, lymphographies, bronchographies and myelographieso A suspension., • i of extremely small particles has the advantage that it can be l0 8788 handled and used as a liquid without any contrast agent being present therein in dissolved form with the effects brought about thereby. Accordingly, such a suspension has some of the advantages of a solution but lacks some of the disadvantages thereof, Cog. a high osmotic pressure.

The polymeric product may be obtained in the form of particles either by preparing the polymerisates in the form of greater pieces (bulk polymerization) which are then disintegrated» e.g. by grinding, or by preparing the product directly in the form of round particles by bead polymerization (dispersion polymerization)° In the latter case the reaction mixture is dispersed into droplets in an inert liquid immiscible therewith whereupon the gel particles formed at the reaction in the droplets are recovered.

The contrast agents according to the invention may be used for the visualìzation by means of X-rays of body cavities to which wa sr-insoluble contrast agents may be applied, e.g. in the form of a suspension. The contrast-giving polymers may be used without any admixture of other substances but in general they are used in admixture e.g. with physiologically tolerable carriers, Cog. water or aqueous liquids, e.g. containing physiologically acceptable salts or other substances such as glucose. They may also be mixed with other water-soluble or water-insoluble contrast agents, e.g. in order to increase the contrast effect. By using mixtures of e.g.

traditional water-soluble contrast agents and the contrast agents according to the invention a lower osmotic effect and fewer toxicological effects are achieved than ån case when a solution of the same iodine content of only common soluble contrast agents is used. The contrast polymers of the invention are especially valuable, for instance, for the X-ray investigation of the gastrol0 10í 8788 intestinal tract. For such an investigation a contrast polymer of the invention is administered orally or rectally° Suitably the contrast polymer is supplied in the form of small particles, very small particles being chosen when a slow sedimentation of the particles is desired in suspension preparations of the contrast polymers and for Cog. the gastro-intestinal canal, or when the dimensions of the body cavities, eogo the blood vessels, are such as to require very small particles° The most simple way of administering a contrast polymer is in particle form in the form of a suspension in an aqueous physiologically acceptable liquid, such as in water, a syrup, milk or in a dilute physiologically acceptable aqueous solution of a salt, eogo in 0oi percent or 0°9 percent aqueous solution of NaC1 or in a salt solution of a composition similar to the one of the fluids in the body cavity to be examined° Such suspensions may easily be prepared locally for the X-ray investigation by stìrring up the contrast polymer in particle form in a suitable liquid« The suspensions may also be prepared on a factory scale in which case the suspensions suitably are poured into glass bottles or into bottles or bags of plastics materials, which then are sealed and may be heat sterilized in an autoclave« To the suspensions there may also be added other physiologically acceptable substances such as substances which increase their stability, for instance tetracemin disodium, and/or antibacterial substances and/or flavouring agents and/or substances which have influence upon e.go the gastro-intestinal function° A suspension may be administered eogo orally with simplicity and without any discoeforto In the form of an enema it may easily be given rectally° Suspensions of very small particles may be injected by means of a hypodermic syringeor may be introduced by means of a catheter, ./i 3..

l0 e.g. in the spinal marrow canal or in blood vessels.

The dosage of the contrast polymers of the invention is chosen in accordance with the particular case, a sufficient amount being given in order to obtain a sufficient contrast effect at Xray investigation. In this way, for instance, the gastrointestinal tract can be visualized in a favourable way° When the contrast polymers of the invention, e.g. in the form of suspensions, are given orally the passage rate of the contrast polymer in different parts of the gastro-intestinal tract may be determined by taking X-ray pictures at different times after the administration of the contrast polymer, the contrast-giving, small» water-swollen gel particles affecting the function of the gastro-intestinal tract to a very slight extent or not at all.

As the contrast polymers according to the invention are insoluble in water and the contrast-giving iodine-containing groups are bound by covalent bonds to the three-dimensional network which is held together by covalent bonds no substances are released which can affect the body cavity to be examined or which can be resorbed and affect other parts of the body if a nondegradable network is chosen. When a degradable network is chosen, e.g. one that is enzymatically degradable, the rate of degradation may be made so low that the release of the fragments takes place so slowly that the body cavity and other parts of the body are not affected appreciably. As the contrast polymers of the invention are swellable in water and, when swollen, have the consistency of a soft gel they are extremely well physiologically acceptable e.g.

in the gastro-intestinal canal. Because of their favourable properties they may also be used in fields where the present insoluble contrast agents are avoided. On swelling the specific t ' t l0 $028788 weight of the contrast polymers decreases so that the sedimentation rate of small particles of the contrast polymers is low in comparison with particles of the same size of other agents with a higher specific weight° By varying the structure of the network and by introducing different substituents the specific weight may also be varied« In comparison with insoluble or slightly soluble contrasts agents hitherto used, eogo barium sulphate and certain sparingly soluble organic iodine compounds, the disadvantages of which are well known, the contrast polymers according to the present invention have considerable ad antageso Example 1 302 grams of 5-acetylamino-2,4,6-triiodo-N-methyl-isophthalic acid monoamide are dissolved in 250 ml of 5 molar aqueous solution of sodium hydroxide at 20°Co 240 ml of 1,4-butanedioldiglycide ether are added dropwise at 20°C while stirring for minutes. The temperature As then increased to 40"C and stirring is continued at this temperature for 90 mino Then the reaction mixture is allowed to stand for 2 days at 20°C without stirring, a continuous gel lump being formed from the contents of the reaction vessel° The gel is cut into smaller pieces and washed well with water until the washing water is neutral° Then water is poured over the pieces of gel and a 1 molar aqueous solution of HC1 is added to gave a pH of about 2° After 24 hours the pieces of gel are washed with water whereafter water is poured over the pieces of gel and a I molar aqueous solution of NaOH added to give a pH about 9° The pieces of gel are then washed with water until the washings become neutral° Such a water-swollen piece of gel contains about 5? percent by weight of water. The pieces of gel swollen in water are then ground in a mill to a small particle size. (To l0 an average particle size in water-swollen condition of about 50g or about 5go) The water-swollen particles are washed well with water and then with mixtures of water and ethanol of increasing ethanol content and finally with ethanol and then with acetone whereafter they are dried in vacuo at 50°Co About 460 g of substance in particle form are obtained. The particles are insoluble in water, ethanol and acetone but swell in water° 1 gram of the dry powder swells to about 4°5 ml of particle suspension in water. 1 gram of the dry powder swells to about 5 ml of particle suspension in 0oi normal HCIo 1 gram of the dry powder swells to about 4 ml of particle suspension in a 0oi percent solution of NaCI in water. The iodine content of the substance is about 32.5 percent by weight° A suspension of the particles in a 0oi percent aqueous solution of NaCI is prepared, the amount of particles being 16 g per i00 ml suspension. To the suspension there are also added i0 mg of tetracemin disodium per I00 ml of suspension° While being stirred the suspension is poured into bottles which are then sealed and sterilized by autoclaving at II0°c for minutes.

The suspension is given orally or rectally after shaking, the gastro-intestinal tract being visualized by X-ray photographing in a favourable way. When the suspension is given orally it is possible to determine the rate of passage in the gastrointestinal tract by taking X-ray pictures at different times after the administraion of the contrast agent, the contrastgiving small swollen inert gel grains affecting the function of the gastro-intestinal tract to a very small extent or even not at all. For instance, dogs having a body weight of about 15 kg 10Z8788 may be given eogo 30 to 120 ml of the suspension in such investigations.

368 g of 5-acetylamino-2,4»6-triiodo-N-methyl-isophthalic acid-monoamide are suspended into a mixture of 45 ml of water and 165 ml of 5 molar aqueous solution of sodium hydroxide at 20°Co While stirring Z6,8 ml of glycidol are added dropwise at 40ec slowly for 120 minutes, whereafter stirring is continued at this temperature for additional 90 minutes. The reaction mixture is then allowed to stand at 20 for about 18 hours° Then 15 ml of a molar aqueous solution of sodium hydroxide are added° While stirring 114 ml of 1,4-butanedioldiglycide ether are then added dropwise slowly at 40ec over a period of 120 minutes whereafter stirring is continued at this temperature for additional 90 minutes. The reaction mixture is then allowed to stand at 20ec about 20 hours° Then 75 ml of water are added and the mixture is stirred at 40°C0 while continuing stirring 37,5 ml of glycidol are added dropwise slowly at 40°C over a period of 120 minutes.

The reaction mixture is then allowed to stand at 20°C for about hours, whereafter the reaction mixture is diluted with water to 750 ml« while stirring 240 ml of l»4-butanedioldiglycide ether are added dropwise at 20eC over a period of 30 minutes, whereafter the reaction mixture is stirred at 40ec for 120 minutes° The reaction mixture is then allowed to stand at 20°C for 4 days° The contents of the reaction vessel are thereby transformed into a continuous lump of gelo The gel is cut into smaller pieces and washed well with water° An aqueous solution of ÆI is added to give a pH of about 2o After 24 hours the pieces of gel are washed with water and a 1 molar aqueous solution of NaOH is added 10Z8788 to give a pH of about 90 After 24 hours the pieces of gel are then washed with water until the washing water is neutral« Such a water swollen piece of gel contains about 53 percent by weight of water° Then the pieces of gel swollen in water are ground in a mill to a small particle size° (To an average particle size in water-swollen condition of less than about 50 or about 5 o) The water-swollen particles are washed and dried as in Example io About 710 g of substance in particle form are obtained. The iodine content of the substance is about 25 percent by weight.

The particles are insoluble in water and other solvents but swell in water° 1 gram of the dry powder swells to about 4 ml of particle suspension in water, to about 3 ml of particle suspension in a 0.i normal aqueous solution of HCI, to about 3°5 ml of particle suspension in a 0ol percent solution of NaCI in wa r and to about 3°5 ml in a 0.2 M sodium phosphate buffer in water of pli 7.3.

A suspension of the particles in a 0oi percent aqueous solution of NaCI is prepared, the amount of particles being 19 g per i00 ml suspension° To the suspension there am also added i0 mg of tetracemin disodium per i00 ml suspension° The pH-value of the suspension is adjusted by means of NaOH and HCl to 7°3° While stirring the suspension it is poured into bottles which then are sealed and sterilized by autoclaving at 110°C for 45 mino The suspension is given orally or rectally after shaking up» a dosage being chosen which in the particular case is sufficient to obtain the desired contrast effect at X-ray investigation. The gastro-intestinal tract may in this case be visualized and the passage of the contrast agent may be followed° l0 Example 302 g of 5-acetylamino-2,4,6-triiodo-N-methyl-isophthalic acid monoamide are dissolved in 250 ml of a 5 molar aqueous solution of sodium hydroxide at 20°Co While stirring 30 ml of 1,4-butanedioldiglycide ether are added dropwise at 20° over a period of 30 minutes° Then 250 ml of 1,4-butanedioldiglycide ether and 50 ml of an aqueous solution of NH4CI which contains 10o7 g of NH4CI are added simultaneously from two different vessels over a period of 60 minutes at 20"C while stirring° Then the mixture is stirred at 0°C for 2 hours, whereafter the reaction mixture is allowed to stand at 20" without stirring for days, a continuous lump of gel being formed from the contents of the reaction vessel. The gel is cut into smaller pieces which are washed and treated with HCI and NaOH solutions as described in Example l o The water-swollen pieces of gel contain about 85 percent by weight of water° Then the water-swollen pieces of gel are ground in a mill to a small particle size° (To an average particle size in water-swollen condition of about 50 - 100B or about 5B).

The water-swollen particles are washed well with water and dried as in Example io About 455 g of substance in particle form are obtained° The particles are insoluble in water, ethanol and acetone, but swell in water° 1 gram of the dry powder swells to about 13 ml of particle suspension in water, to about ml of particle suspension in 0ol normal HCl, to about 12 ml of particle suspension in a 0ol percent solution of NaCl in water and to about 7 ml in a 0°2 M sodium phosphate buffer in water of pli 7o3 The iodine content of the dry substance is about 29°8 percent by weight.

If the gel particles suspended in e.go water or in a 10Z8788 0oi percent aqueous solution of NaCI are given orally to dogs the gastro-intestinal tract can be visualized by X-ray photographing in a favourable way, and the passage rate of the Xray contrast giving particle suspension may be determined in different parts of the gastro-intestinal tract° Thus, for instance» dogs having a body weight of about 15 kg may be given e«go i00 ml of a suspension containing 5 or 6 g of particles per i00 ml.

Example 4 In this experiment a water-soluble iodine containing polymer is first prepared and isolated, which polymer then is reacted with a bifunctional cross-linking agent to form a water-insoluble but water-swellable three-dimensional network° a) Preparation of a water-soluble iodine-containing polluter 245°6 g of 5-acetylamino-2,4,6-triiodo-N-methyl-isophtalic acid monoamide are dissolved in a mixture of 30 ml of water and ii0 ml of 5 molar aqueous solution of sodium hydroxide° 51o2 ml of glycidol are slowly added dropwise while stirring at 30°C over a period of 2 hours° The reaction mixture is then allowed to stand at 20"C until next day. Then i0 ml of a 5 molar aqueous solution of NaOH are added. 78 ml of 1,4-butanedioldiglycide ether are slowly added dropwise while stirring at 30"C over a period of 4 hours° The reaction mixture is then allowed to stand at 20°C until next day. Then I00 ml of water are added while stirring° While continuing the stirring 20 ml of glycidol are slowly added dropwise at 30°C over a period of 4 hours. The reaction mixture is then allowed to and at 20°C until next day° The reaction mixture is neutralized by means of a 6 molar aqueous solution of HClo 2o7 litres of acetone are added, whereupon the i l0 10Z8788 polymeric substance precipitates. The precipitate is separated and dissolved by the addition of water (about 120 ml)o The polymer is re-precipitated by the addition of 1.2 litres of acetone. The polymer is dissolved in water and re-precipitated with acetone for additional three times in a similar way. The polymeric substance is dried in vacuo at 50°C. About 350 g are obtained.

The ìodine content of the polymeric substance is about 35 percent by weight. The weight average molecular weight ( ) is about 6000° b) Preparation of a water-insoluble but water-swellable cross-linked iodine-containing polyandrie product 120 g of the water-soluble polymer are dissolved in 2 molar aqueous solution of NaOH to a volume of the solution of 200 ml. 60 ml of 1,4-butanedioldiglycide ether are added dropwise at 25*C while stirring over a period of 2 hours. While continuing the stirring the temperature is then held at 40*C for one hour. Then the reaction mixture is allowed to stand at 20*Cfor 4 days without stirring, a continuous gel being formed in the reaction vessel. The gel is then cut into smaller pieces which are treated as in Example l. (A water-swollen washed piece of gel contains about 86 percent by weight of water). The pieces of gel swollen in water are ground in a mill to a small particle size (about 50 or about 5 ). The water-swollen particles are washed well with water and then with a 0.I percent aqueous solution of NaC1. The particles are suspended in a 0oi percent aqeuous solution of NaCl to a total volume of the suspension of 1200 mlo (A small sample of the particles is washed with wa r and dried in vacuo at 50°C, The iodine content of the substance is about 24.5 percent by weight. The particles are insoluble in water and other solvents but swell in water° 1 gram of the dry powder swells to l0 $0Z8788 about 19 ml of particle suspension in water and to about the half thereof in 0oi normal hydrochloric acid.) The above mentioned suspension in a 0oi percent sodium chloride solution is given orally to dogs in a dosage sufficient for the visualization of the gastro-intestinal tract on X-ray examination° Example 307 g of 3-acetylamino-5-acetylamino-2,4,6-triiodobenzoic acid are dissolved in 250 ml of a 5 molar aqueous solution of NaOHo At 20"C 20 ml triethanolamine and 260 ml of 1,4-butanedioldiglycide ether are added dropwise from two different funnels over a period of 1 hour while stirring° The temperature is then held at 40°C for 2.5 hours under continued stirring° Then the reaction mixture is allowed to stand at 20°C for 4 days without stirring, a continuous gel being formed in the reaction vessel° The gel is then cut into smaller pieces which are washed well with water until the washing water is neutral. Such a water-swollen piece of gel contains about 81 percent by weight of water. Then the pieces of gel swollen in water are ground in a mill to a small particle size less than 50 o The water-swollen particles are washed and dried as in Example l. About 450 g of substance in particle form are obtained. The iodine content of the dry substance is about 28 percent by weight. The particles are insoluble in water and other solvents such as ethanol and acetone but swell in water. 1 gram of the dry powder swells to about l0 ml of particle suspension in water, to about 4,5 ml of particle suspension in a 0ol normal aqueous solution of HC1, to about 9 ml of particle suspension in a 0ol percent solution of NaC1 in water and to about 6,5 ml of particle suspension in 0.2 M sodium phosphate buffer in water of v l0 pli 7.3.

In a similar way as in the examples above suspensions in aqueous liquids are prepared which suspensions are well suited as contrast agents for the X-ray examination of eogo the gastrointestinal tract.

Example 6 314 g of 3-acetylamino-5-acetyl-methylamino-2 6-triiodobenzoic aciù are dissolved in 250 ml of a 5 molar aqueous solution of NaOHo 320 ml of l -butanedioldigluciùe ether are added dropwise over one hour while stirring at 20°Co While continuing stirring the temperature is then held at 0°C for hours.

Then the reaction mixture is allowed to stand at 20°C for days without stirring, a continuous gel being formed. The gel is cut into smaller pieces which are washed well with water, an aqueous solution of HC1 is added to bring the pH to about 2o After 24 hours the pieces of gel are washed with water whereafter an aqueous solution of NaOH is added to bring the pH to about 9o After 1 day the pieces of gel are washed well with water until the washing water is neutral. Such a water-swollen piece of gel contains about 49 percent by weight of water° Then the pieces of gel swollen in water are ground in a mill to a small particle size° (To an average partìcle size in water-swollen condition of about 50 - lO0 or about 5 ) The water-swollen particles are washed well and dried as in Example l. About 550 g of substance in particle form are obtained° The iodine content of the substance is about 25°4 per cent by weight° The particles are insoluble in water and other solvents such as ethanol and acetone but swell in water° 1 gram of the dry powder swells to about 3°5 ml of particle suspension in water, to about 2°5 ml of particle suspension in a 0ol l0 10í 8788 normal aqueous solution of HCl, to about 3 ml of particle suspension in a 0ol percent solution of NaCl in water and to about 3 ml in 0°2 M sodium phosphate buffer in water of pH 7°3. Suspensions of the particles in water, syrup or milk are prepared by stirring, for instance 15 g or 20 g of particles per i00 ml of suspension being used° Such suspensions may easily be prepared before an Xray investigation and are then administered orally. The dosage is chosen in accordance with the case in question, an amount being given which is sufficient to obtain the desired contrast effect in e.go the gastro-intestinal tract on irradiation with X-rays and photography and the rate of passage of the contrast agent through the gastro-intestinal tract can be demonstrated Cog. in dogs° Example 7 31 g of 3-acetylamino-5-acetyl-methylamino-2,4,6-triiodobenzoic acid are dissolved in 250 ml of a 5 molar aqueous solution of NaOHo 50 ml of triethanolamine and 3 0 ml of lo - butanedioldiglycide ether are simultaneously added dropwise at 20"C over a period of 1 hour from two different funnels while stirring« The temperature is then held at 0°C for hours while continuing stirring« Then the reaction mixture is allowed to stand at 20*C for days without stirring, a continuous gel being formed° The gel is then cut into smaller pieces which are washed well with water. Then HC1 is added to bring the pH to about 2. After 2 hours the pieces of gel are washed with water» whereafter NaOH is added to bring the pH to about 9o After I day the pieces of gel are washed well with water until the washing water is neutral.

Such a water-swollen piece of gel contains about 71 percent by weight of water° Then the pieces of gel swollen in water are ground in a mill to a small particle size° (To an average particle ,11 l0 8788 size in water-swollen condition of about 50 or about 5 ) The water-swollen particles are washed and dried as in Example I.

About 470 g of substance in particle form are obtained. The iodine content of the substance is about 20.6 percent by weight. The particles are insoluble in water and other solvents such as ethanol and acetone but swell in water. 1 gram of the dry powder swells to a good 6 ml of particle suspension in water, to about 7 ml of particle suspension in a 0.I normal aqueous solution of HCI, to about 6 ml of particle suspension in a 0.i percent solution of NaC1 in water and to about 6 ml in 0.2 M sodium phosphate buffer in water of pH 7.3° Due to the fact that the three-dimensional network of the gel contains carboxyl groups as well as amine groups only a moderate difference is present in the degree of swelling in 0.I normal HC1 (acid gastric juice) and in aqueous solutions of salts of pH within the range of 6 - 8 (intestine juice).

In a similar way as in the examples above suspensions are prepared in aqueous liquids, which suspensions are well suited as contrast medium for X-ray investigation of e.g. the gastrointestinal tract.

Example 8 278 g of 3-acetylamino-2,4,6-triiodobenzoic acid are suspended while stirring in 200 ml of a 5 molar aqueous solution of NaOho Thereafter 25 ml of triethanolamine are added° 280 ml 1,4-butanedioldiglycide ether are added dropwise over 1 hour at 20°C while stirring. The temperature is then held at 40°C for hours while continuing stirring. Then the reaction mixture is allowed to stand at 20°C for 6 days without stirring, a continuous gel being formed in the reaction vessel. The gel is then cut into smaller pieces, which are washed well with water until the washing ï i0 $0 $788 water is neutral° Then water is poured over the pieces of gel and a i molar aqueous solution of HC1 is added to bring the pH to about 2. 24 hours thereafter the pieces of gel are washed with water whereafter water is poured over the pieces of gel and a 1 molar aqueous solution of NaOH added to bring the pH to about 9o After i day the pieces of gel are washed well with water until the washing water is neutral. Such a water-swollen gel piece contains about 64 percent by weight of water° Then the pieces of gel swollen in water are ground in a mill to a small particle size.

(To a particle size in the order of about 50 or about 5 o) The water-swollen particles are washed well with wa r and dried as in Example i. About 450 g of substance in particle form are obtained. The iodine content of the dry substance is about 27 percent by weight. The particles are insoluble in water and other solvents such as ethanol and acetone but swell in water° i gram of the dry powder swells to a little less than 5 ml of particle suspension in water, to a good 3 ml of particle suspension in a 0.I normal aqueous solution of HCI and to about 4°5 ml of particle suspension in a 0.1 percent solution of NaCI in water° In a similar way as in the examples above suspensions of the particles are prepared. These suspensions are good contrast agents for the X-ray examination of eogo the gastro-intestinal tract.

Example 9 120.8 g Of 5-acetylamino-2 » 4,6-triodo-N-methyl-isophthalic acid monoamide are dissolved at 25°C in 80 ml of a 5 molar aqueous solution of sodium hydroxide added with 5 ml of water° 133 ml of l» -butanedÆoldiglycide ether are added dropwise at 0°C over a period of 45 minutes while stirring° Then the mixture is stirred ' -[ .»ìat 40°C for 1.5 hours, thereafter the reaction mixture is allowed romand at 20°C for 2 days without stirring» a continuous lump of gel being formed from the contents of the reaction vessel° The gel is cut into smaller pieces and washed well with water until the washing water is neutral° Then water is poured over the pieces of gel and a 1 molar aqueous solution of HCI is added to bring the pH to about 2o After 24 hours the pieces of gel are washed with water, whereafter water is poured over the pieces of gel and a 1 molar aqueous solution of NaOH added to bring the pH to about 9.

i0 The pieces of gel are then washed with water until the washing water is neutral° Such a water-swollen piece of gel which is practically as clear as water and transparent contains about percent by weight of water. Then the pieces of gel swollen with water are ground in a mill to a small particle size (average particle size in water-swollen condition about 50B)o The waterswollen particles are washed well with water on a filter and dried as in Example i. About 240 grams of substance in particle form are obtained° The particles are insoluble in water, ethanol and acetone but swell in water. 1 gram of the dry powder swells to about 4.5 ml of particle suspension in water. The iodine content of the dry substance is about 27 percent by weight° The particles are ground further in water-swollen condition, particle fractions of an average particle size of the orders of 0.2B and lB and 5B and 20B being recovered° Suspensions are prepared from the particles in a similar way as in the examples above. The suspensions may also be mixed with conventional contrast agents for the visualization of body cavities (e.g. the gastro-intestinal tract), a sufficient amount being given to a sufficient contrast effect on X-ray investigation° In a similar way as in the examples above iodinecontaining contrast gels are prepared by using other at least bifunctional bridge forming agents e0 g0 1,2-ethanedioldiglycide ether, 1,3-butanedioldiglycide ether, 1,3-glyceroldiglycide ether, diglycide ether and 1,2-3,4-diepoxybutaneo Similarly the iodine substituted aromatic substances may be varied° These contrast agents, preferably in the form of suspensions of small particles, are well suited for the visualization of eogo the gastro-intestinal tract° Examples of preparations which also contain an addition of wa insoluble contrast substances are suspensions in water of very small particles of the insoluble but water-swellable contrast substances according to the present invention, in the water of which suspensions have been dissolved e.go the methylglucamine salt or the sodium salt of 3-acetylamino-5-acetyl-methylamino-2,4, 6-triiodobenzoic acid or of 3-acetylamino-5-acetylamino-2,4,6triiodobenzoic acid or of 5-acetylamino-2,4,6-triioùo-N-methylisophthalic acid monoamide or one or more of the contrast substances according to Swedish Patents No° 344,166, 348,110 and 348,111 and the pH of which suspensions, when necessary, have been adjusted to physiologically acceptable values, the total iodine content of the preparations being, for instance, 50, 60, 150» 200, 250, 300 and 350 mg of iodine per 1 ml of suspension° For instance, 95 to 5 (such as 90 to I0 ) of the iodine content of the preparations may in these cases originate from the waterinsoluble particles and the remainder from the water-soluble contrast substances° L • • 10; 5788 E THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

i. A method for the preparation of an X-ray contrast polymer which contains iodine-substituted aromatic groups which have X-ray contrast properties and which are bound in or to the polymer by bonds of covalent character, and which polymer also contains hydrophilic groups, the polymer being in the form of a threedimensional network held together by bonds of covalent character and being insoluble in water but swellable in water to give a gel containing from l0 to by weight of water, which comprises reacting cneor more at least monofunctional iodine-substituted aromatic compounds having X-ray contrast properties and one or more at least bifunctional cross-linking agents with each other in one or more steps, at least one of the reacting substances containing at least one hydrophilic group or giving rise to such a group in the reaction product to form the desired polymer.

2. Method as claimed in claim i, wherein one at least bifunctional cross-linking agent is reacted with a water-soluble straight or branched polymer containing iodine-substituted aromatic groups and functional groups which are able to react with the at least bifunctional cross-linking agent.

3. Method as claimed in claim l, wherein the iodine-substituted aromatic groups are bound fo a preformed water-insoluble three-dimensional network containing hydrophilic groups and functional groups by bonds of covalent character, by means of reactions know per se.

o Method as claimed in claim l, wherein the aromatic compound or compounds is or are at least bifunctional.

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