CA1141892A - Anionic ion exchange resins with cholesterol decreasing properties - Google Patents

Abstract

ABSTRACT

These resins are in particular non toxic styrene, acrylic or epoxy resins, with strong cholesterol-decreasing properties which have an apparent density in water of 0.18 to 0.20 g of dry material/ml and water absorption capacity of 69 to 73% by weight of the po lymer weight.
The process for producing anionic ion exchange resins with strong cholesterol-decreasing properties in which a mixture of monomers containing a critical percentage of cross-linking monomer, consists of polymerising at a low rate so as to give the polymer a criti-cally predetermined and uniformly distributed degree of cross-linkage, corresponding to an apparent density in water of 0.18 to 0.20 of dry material/ml with water absorption capacity of 69 to 73% by weight of the polymer weight, wherein the polymerisat-ion catalyst used in an organic peroxide in a concentration of 0.2 to 3%, and the cross-linking agent used is a divinyl compound in a percentage of 1.5 to 12%, at a polymerisation temperature of 50° to 80°C.

Description

114~89Z
VIR.4 Anionic ion exchange resins with cholesterol decreasing properties This invention relates to anionic ion exchange re6ins for use in human therapy as cholesterol-decrea6ing sgents.
Ion exchange resins have notably founa use in the treatment of various pathological states such as hyperacidity, prevention of Na+ depletion in the gastroenteric tract, induction of K~ depletion, treatment of nephrotic, pancreatic and cardiac edema, treatment of ulcer, neutralisation of gastric acidity etc.
Obviously each particular pathological ætate requires a resin of special chemical characteristics, chosen from the group consisting of wea~ly acid resins, strongly scid resins, weakly bssic resins, and strongly bssic res~s, provided that these resins are free from toxicity towards the human organism.
The use of ion exchange resins has notably been extended in recent years to the treatment of hyperlipemia6. It is in fact known that at too high levels of lipids, which are essentially cnolesterol and triglicerides, early arteriosclerosis can develop in the organism, with consequences such a6 cardiac infarct and cerebral thrombosis.
Hyperlipemia is therefore a vast problem for which the re~olutive drug has as yet not been ~ound.
To reduce cholesterol to normal le~els, it iæ necessary to both e~clude all those foodstuffs which are rich in them or in saturated fat6, and to increase its elim~ation.
It has been found that ion exchange resins of basic character act in this second manner by fixing the bile acids at the~intesti~al ., ~

11~1892 _ 2 -level, thus interrupting the enterohepatic recycle, with consequent loss of cholesterol.
In order to carry out this cholesterol-decreasing method on practical scale, certain basic anionic exchange resin~ have been produced up to the present time contsining amino and/or ammonium groups able to chemically fix the bile acids.
~he resins prepared and used up to the present time sre essentially Cholestyramine and Cholestypol. The first of these resins i8 essentially a styrene resin containing quaternary ammonium groups cross-linked by divinylbenzene, whereas the second is a polymer of N_(2_amino ethyl)-1,2-ethanediamine with chloromethyl o~iran.
~lthough from a theoretical aspect the chemical operation¦of these resins seems clear and therefore clearly determinablejfrom a qUantitatiYe point of view, in practice the results attsined with them have been much wor6e than forecs6t, and could be improved.
In particular, often in contrast with the result~ obtained in vitro, these resin6, whatever their chemical nature, have 8 too low cspacity for fixing cholate ions in vivo9 becau6e of which either the reduction in the cholesterol amount which they produce is insignificant, or they have to be used in very high doses which give rise to serious side effects at the gastro-intestinal level.
One obvious remedy to all this would seem to be to produce resin~
with a higher concentration of functional groups. ~owever, it has been found that by increas~ng beyond a certsin limit the concentration of the basic functional groups of the resin, whether the~e be strong or weak, their activity reduces rather than increase~.
The present invention is based on the fact that it hss now been .... , .,, . . _ . . . . . . . . . .

- 1~4189Z

discovered that the activity of the resin depends only to a limited e~te~t on the chemical nature and number of the basic functional groups present in it, whereas the determining factor is the "acce6sibility" of the functional groups to the bile acid molecules which are notably all compounds of steroid structure and therefore extremely voluminous and of low mobility.
The immediate answer to the problem as posed would therefore æeem to be to use linear soluble resins, the functional groups of which should hsve maximum ~ccessibility.
~owever, it has been found th~t anionic resins of this type completely unexpectedly po6æess very poor activity in that the linear chains~
which are not bonded together, aggIomerste in an aqueous environment due mainly to coordination bonds~ to form a completely rsndom pseudo lattice into which it i6 practically impossible for the large bile acid molecules to penetrste, and this therefore re ves st of the sctive group~ from the ion exchange reaction.
In the same manner, highly crosæ_linked resins have a very low and insufficient activity due to the formation of a too narrow lattice inaccessible to the bile acid molecules~
According to the pre6ent in~ention~ it has now been found that chclesterol decreasing anionic eschange resins of very high ~cti~ity are obtained by producing resins ha~ing a degree of regular cross-linking which i6 contained within very definite critical l;m~t6 which are different for each type of resin.
The purpo6e of the regular ~ross_linking sccording to the present invention is to form "meshe~" in the polymer which have an sperture essentially "corresponding" to the volume of the bile acids, which can thu6 come into contact in the alimentary canal with the highe~t , .. . , . . _ . .. . . .

:~141892 _ 4 -possible number of active functional groups.
~s functional groups of different chemical nature have different volumes snd therefore create a different degree of attrition and steric hindrance inside the "meshes", it is apparent that the critically effective degree of cross-linking will be different according to the chemical nature of the resinO However, it in no way depends on whether the re6in has a gel, microporous or mscroporou6 structureO
In other words, given a linear polymer of a determined chemical nature and with a certain number of basic active group6, i.e.
a polymer with a certain exchange power, it is provided with ~
determined cholesterol-decreasing àctivity by producing in it a precise degree of uniform cross-linking.
To obtain this degree of cro6s-linking snd consequently the required aperture of the meshes formed in the polymer~ the cro6s_ linking monomer in the mixture of monomers to be polymeri6ed must be used in an exactly defined percentage.
To obtain uniformity of cro6s-linking~ and con~equently 8 uniform size of meshe6 formed in the polymer, a very low polymerisation velocity mu6t be used by ~uitably choosing the catalyst~ the reaction temperature, the monomer concentrstion in the reaction 601vent, and the catalyst concentration.
It has been found that the most suitable catslyst6 for providing the nece~6arg gentle polymerisation conditions sre organic peroxides snd in particular lauroyl and benzoyl peroxide. It is preferable to use benzoyl peroxide because it has a higher hslf life, and a better purity and initiation effectiveness.
The critical conditions under which the 6aid cataly6t6 must be used 1~41892 for producing the resins according to the invention sre:
Lauroyl peroxide _ Acrylic: temperature 55_65C; concentration 1-2%
_ Styrene: temperature 60-70C; concentration 1-3%
_ Epoxy: temperature 55_65C; concentration 0.5-1.5%
Benzoyl peroxide _ Acrylic: temperature 60-70C; concentration 0.2-1.5%
_ Styrene: temperature 65_75C; concentration 0.3-1.5%
_ Epoxy: temperature 60-70C; concentration 0.2-1.0%.
It has also been found that certain not easily controllsble side reactions during the stsges of the variou6 processes can give rise to further cross-linking of the polymer lattice.
This csn invalidate the whole of the csreful construction of the resin if it is not suitably checked.
In particular, in acrylic resins this undesirable reaction can ta~e place during the ammonification 6tage where polyamines sre used.
In styrene resins the criticsl stage occurs during chloromethylation.
In the case of epoXy resin6, the delicate st~ge is the smination where poly~mi~e6 sre used~
It has been found that the pars6ite reactions can be prevented ag fo~low6:
_ Acrylic: in the ammonification stage, a great exces6 of polysmines must be used, up to 6 to 7 times the stoichiometric _ Styrene: in the chlore~ethylation stsge a gentle catslyst i~
used such as ZnC12 under ~ery gentle reaction conditions~ i.e.
a dilute system at low temperature (35_40C).
_ Epoxy: in the amination stage an excess of polyamine ~s use~ at low temperature (35_40OC) 1~4189Z
. ~

With regard to the choice of cross_linking agent, in theory all molecules hsving two vinyl functions which hsve a large distsnce between them csn be used as cross-linking sgents.
In reslity the following are used in practice: divinylbe~ene, divinyltoluene, divinylxylene, divinylethylbenzene snd the like.
Divinylbenzene i~ preferred because of its resctivity and it~
commercisl svsilsbility.
It hs6 now been unexpectedly found thst the fsctors whieh determine the cholesterol-decreasing ~ctivity of on snion exchsnge resin snd e6sentially the size of the cross-linkage "meshes" present in it, are a function of the sppsrent density in water and the sbsorption cspscity for wster of the resin, becsuse of which the maximum activity for sny resin corre6ponds to a substantially constant appsrent density and a substantislly con6tant water absorption cspscity.
The present invention therefore provides cross-linked snionic exchange resin~ with cholesterol-decreasing sction,h~ving an sppsrent den6ity of 0.18 - 0.20 g of dry material~ml, with a wster absorption capacity of 69-73% by weight~
Thi6 unique and constant vslue corresponds for each resin to determined combinstions of exchange power and degree of cros~-linkage (chosen within 8 critical and exsctly defined range), and which can thus be fixed unambiguously for each resin.
For the purposes of the iresent invention th~e spp~rent density in water h~s been determined, and i~ to be under6tood hereinsfter as determined, by the following method:
20 grsms of dry re6in (dried at 40 C in a vacuum oven until tts weight is constsnt) sre left in 150_200 ml-of water for 24 hours, - 7 ~

6tirring occasionally. The resin is then transferred into a glass column which is exactly graduated and is provided with a porous baffle.
The resin bed is then expanded in counter-current, and then after it deposit~ the water is discharged at a rate of 10 volumes per volume of resin until a head of 1 to 2 cm is left above the resin~
After standing for 20 minutes, the volume of the resin lsyer is determined. This measurement is repeated two or three times on the same sample so that the error becomes contained within 1~. The density is given by the ratio of the dr~ weight of the resin to its volume in water.
For the purposes of the present invention, the water absorption capacity of the resin is alw~ys to be understood as determined by the following method:
3 g of re6in, dried to constant weight at a temperature of 40C
in 8 reduced pressure environment, sre exposed on a glss6 di6c to sn atmosphere saturated with moisture at 25 C until there i8 no furthe~ weigkt incresse.
The water absorbed is expressed as 8 percentage of the total weight.
The cholesterol-decre~sing ~ctivityof the resin6 was determined ~n vitro by the following method:
20 ml of 8 sodium cholate solution of 2 mg/mI concentrstion in a 0.02 molar solution of a phosphate buffer (pH 6) sre plsced in 8 conical fla6kO
1 ml of ~2 and 30 mg of re6in sre sdded to the fls6k.
After stirring for five minute6 at 25 C, the contents are filtered~

and the non-fixed cholic scid i8 determined by a spectrophotometric method after reacting with sulphuric acid (~ier et al. J.Chim.Inve6t 40, 755, 1952).
The activity is given by the sodium cholate fixed during the time considered. Some tens of styrene, acrylic snd epoxy resins were prepsred having different exchsnge powers ~nd different degree6 of cross-linkage.
~sing the above methods, the apparent density, the water sbsorption and activity were determined for esch of the re6ins. Maximum actiYity wPs constantly obtsined with resins hsving sn apparent density of 0.18 to 0.20 g of dry material/ml snd 3 wster absorption capacity of 69 to 73% by weight.
By this method, the criticsl range of exchange power and cross-link~ge were determined between which it is possible to obtsin 8 very high chole6terol-decres6ing activityfor sny type of re~in.
U6ing the same method, it was establi6hed that in reality all re6ins known up to the present time, and which have an absolutely insufficient activity to be able to be considered a6 an effectivo cholesterol_decressing meaDs, have an apparent deDsity in water which is outside the limits of 0.18 to 0.20 g of dry material~m~, and in particular a density snd water absorption which indicste poor non-uniform cross-linkage (Cholestyramine type) or an excessi~e and non-uniform cross-linkage ~Lewstit ~ ~oa ~nd Cholestypol types of resin)~
~he stnong exchange power and the total exchange power were also determined for each resin.
The strong exchange power wss détermi~ed by the following method:
10 g of dry resin are converted to the OH by percolating a 5%
aqueous NaOH solution until Cl ions were no longer found in the eluate~
., ` 11418g2 The resin is then abundantly wsshed with wster until neutral.
The OH form is reconverted to Cl by percolsting 400 ml of a 10~ aqueous NaCl solution, then washing with 1000 ml of H20.
The base contained in the eluate is titrated with 0.1 N ~Cl, 1 ml of HCl used corresponding to 0.01 milIiequivalents (meq~
per gram.
The total exchsnge'power was determined by the following method:
IO g of resin, made into th~ OH and free amine form a6 described in the preceding method~ are treated with 100 ml of lN HCl and are then washed with water until neutral.
The HCl of the eluate is titrated with O.lN NaOH using methyl red as indicator.
The total exchange power of the resin is given by the number of milliequivalent6 of acid not found in the eluate divided by lOo The critical values which were determined for the most common types of anion exchange re6ins acc,ording to the invention as being necessary to give high cholesterol-decreaging power are as follows:
Styrol resin6 with smino and ammonium groNps Strong exchange power meq/g 2.8 _ 4.0 Total exchange power-meq/g ~ 2.8 _ 4.0 Cross_linkage % 1.5 - 2.5 Acrylic resins with amino snd smmonium groups Strong exchange power meq/g 2.0 _ 300 Total exchsnge power,meq/g 5.5 _ 8.o Cros~_linkage % 10 - 12 Epoxy re6in6 with amino and smmonium group8 Strong exchange power meq/g 2 - 5 Total exchange power meq~g 10 - 12.5 -- 10 _ Cross-linkage % 3 - 4 In the case of epoxy resins, the term "cross-link3ge" obviously indicates only the cross_linkage due to the cro6s-linking agent, and that due to the amine is ignored.
Some practical examples of cholesterol- decreasing resins according to the invention are given hereinafter by way of example onlyO
EXAMPI.E 1 Pre~aration of a microporous acrylic resin (AP2) A mixture consisting of 33 parts of scrylic nitrile, 16 parts of methyl acrylate, 10 parts of technical divinylbenzene (strength 60%), 1 part of benzoyl peroxide and 40 psrts of toluene is suspended by agitation in an aqueous 601ution containing 20% of gelatine by weight.
1 psrt of bentonite i~ added to the suspen6ion.
The su6pension is heated for 40 hours at 65C.
The polymer thus obtained, which is in the form of opaque pearls, i8 carefully washed from the residues of the dispersing solution.
The pOrosity agent is then removed by steam distillation, and the polymer is then dried, 1 part of polymer is treated with 5 parts of ethylenediamine for 10 hours at 130C. After cooling, the excess amine is remo~ed by repeated washing with water. The product obtained is immerse~ in 50 part6 of ~2 and 50 parts of Na2C03~ cooled to O C and treated with 400 parts of CH2~r for 5 hours under agitation.
It is finally filtered, waæhed with E20 ~nd then put ~nto the chloride form in a percolation column by slowly percolating 1000 parts of a 5% aqueous solution of NaC10 A resin is obtsined having the following characteristics:

_ Cross_linksge 10%
_ Strong exchange power 2.1 meq/g - Total exchange power 6.2 me ~ g - H20 absorption capacity 71%
_ Apparent den~ity 0.186 ~ml _ Activity 18 + 0.4 m ~cholate fixed _ Amine tertiary + quaternsry type ' EXAMPL~ 2 Preparation of a standard acrylic resin (APl) A mixture consisting of 55 parts of acrylic nitr~le, 26.5 parts of methyl acryIate~ 18.3 p3rts of technical di~inylbenzene (60%) and 002 parts of benzoyl peroxide i8 suspended by agitatio~ in an squeous solution containing 20% gelati~e by weight. 2 parts of bentonite are added to the-6uspension. The suspension ~8 heated for 40 hours st 70C.
The polymer obtained in this msnner is washed~ ammonified~ made quaternary snd put into the chloride form as in the previous exsmple.
A re6in is obtained hs~ing the following characteristics:
_ Cross_linkage 11%
_ Strong exchange power 2.1 meq/g - ~otal exchange power 6~1 me ~ g - H20 sbsorption capacity 70.4~
_ Apparent density 0.192 g/ml _ Activity ~ 18 + 0.4 mg~cholste fi~ed _ Amine tertiary ~ quaternsry type EXAMP~E 3 Preparation of a standard styrene resin (Sl) 1~4189Z

- ~2 -A mixture consisting of 96.5 parts of styrene, 2.5 part6 of technicsl divinylbenzene (60%) snd 1.0 part of benzoyl peroxide is suspended by sgitstion in an aqueous solution containing 15%
gelatine by weight.
0.7 parts of bentonite sre added to the suspensionO
The suspension is heated for 40 hours at 70Co The polymer thus obtained i5 carefully washed from the residues of the dispersing solution and dried.
The entire product is then chloromethylated with monochloroether (200 parts) and ~inc chloride (65 parts) after expanding it in dichloroethane (300 parts), heating the mixture for 7 hours at 35C.
~inslly, the intermediate obtained i8 aminated with trimethyl amine (180 parts of 40~ aqueous solution) at 45 C for 6 hour~. -A resin is obtained having the following characteristics:
_ Cross_linkage 105%
_ Strong e~change power 3.3 meq/g _ Total exchange power 3.3 me ~ g _-H~O absorption capacity 71.7%
_ Apparent density O.loO g/ml _ Activity 15 t 0.4 mg/cholate fixed _ Amine quaternar~-type PreParation of a standard st~rene resin (S2) mixture consisting of 9~ psrts of styrene, 305 parts of technic~l divinylbenzene (strength 60%) snd 007 psrts of benzoyl perox~de ~s suspended by sgitation in an aqueous solution containing 15~ gelst~ne ~y weight~
? parts of bentonite are added to the suspension.

- 1~4189e The suspension is heated for 40 hours st 70C.
The polymer obtained is washed, dried, chloromethylated and aminated as in Example 3.
~ resin i6 obtained having the following characteristics:
_ Cro66_1inksge 2.1~
_ Strong exchange power 3.3 meq/g _ Total exchange power ~.3-meq/g ~ ~2 absorption capacity 71.5%
_ Apparent density 0.195 g/ml _ Activity 15 + 0.4 mg/cholate fixed _ Amine qusternary type EXA~PLE 5 Pre~aration of a 6tandsrd ePoxy resin (E4?
rhyd rl n D A mixture consisting of 93.3 psrts of cpiohlorydrinc, 6.5 parts of technical divinylbenzene (6trength 60O and 0.2 parts of benzoyl peroxide iB suspended by sgitation in an aqueous solut~on containing 20~ gelatine by weight.
The suspen~lon is heated at 65C for 40 hours.
The polymer thus obtsined i6 csrefully wsshed from the residues of the disper6ing 6ystec snd dried.
The whole of the polymer~i6 then treated with 100 part6 of ethylene-diamine and 40 part6 of NaO~ flakes st 65C for 10 hours under agitation. ~he product obtained is washèd with water to remove the exces6 of amine, and i8 then immersed in 50 parts of ~2 snd 50 psrts of Na2C03~ and treated with ~00 parts of C ~r for S hour~
at 0C under agitation. It iB finslIy filtered, washed with water and i6 then put into the chloride form in 8 percolation colu~n by 1~41892 - 14 _ slowly percolsting 1000 parts of a 5% aqueous solution of NaCl.
A resin is obtained having the following characteristics:
_ Cross-linkage 4%
_ Strong exchange power 2.1 meq/g _ Totsl exchsnge power 1005 meq/g ~ ~2 sb60rption capscity 69.5%
_ Apparent density 0.180 6/ml _ Activity 12 + o.8 mg/cholste fixed _ Amine tertiary + quaternary type ~

Pre~arstion of a standard ePOx~ resin (E3) A mixture con6isting of 94D8 psrts of ~ , 5 psrts of technical divinylbenzene (strength 60~o) and 0.2 psrt6 of benzoyl peroxide is suspended by agitation in an aqueous solution containing 20~ gelatine by weight.
The 6u6pension is heated at 65 C for 40 hour6.
The polymer thus obtained~ i8 washed, aminated and ~ade quaternsry as in the previous example.
A resin is obtained having the fo~lowing characteristics:
_ Cross_linkage 3%
_ Strong exchsnge power 2.3 meq/g _ ~otal exchange power lOo9 meq/g ~ ~2 sb~orption capacity 70.5%
_ Appsrent density 0.180 g/ml _ Activity 12 ~ 0.~ mg/cholate fi~ed _ A~ine tertiary + quaternary type For greater clarity, the characteristic dat~ of the new resins are summarised in the following tsble, compsred with the ssme dsts for the most known resins avsilable for some years.

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The cholesterol-decressing activity of the new resins according to the invention was also e~amined 'lin vivo~O
To examine the "in vivo" cholesterol-decreaæing effect of the various resin6, the following tests were used:
1) Their action on hypercholesterolemia produce~ by a diet enriched in cholesterol in the rat snd rabbit 23 Their action on the fecal excretion of bile acids in the dog.
1) To induce hypercholesterolemia in rats, the animals were kept under a diet in accordance with Nath and colleagues (J. Nutrit 67~; 289~ 1959) containing:
devitaminised cs6ein 20~o dl-methionine 004%
Hegsted saline mixture 4%
sacchsrose 49.1%
cholesterol 1%
chol~c acid 0.5% and vitamins.
To induce hypercholesterolemia in rabbits, 1 g/day/animal of cholesterol was administered by means of a gastric probe. Each snimal species comprised &4 male animals, namely rats of the Sprague_Dawley stock having an average weight of 200 g snd New Zesland rabbits of 3 kg, divided into }2 groups of 7 animals each.
All the animals were put into a state of hyperchole~terolemia by means of a diet. One group underwent no treatment, wheress the other 11 groups were treated with 0~ ~ kg of one of the resins for 30 days.

The resins were dissolved or suspended in 10~ gum srabic mucilage~
Only gum arabic mucilage was administered to the control group.

~141892 - 18 _ On the thirtieth d~y of trest~ent all the animal6 were sacrificed and the total plasmatic cholesterol was measured in the blood collected from the carotid arteries (Pearson and colleagues J.ChimOEndocrin.Metabolism 12, 1245, 1952).

2) To evaluate fecal excretion of bile acids, 48 male beagles dogs weighing about 8 kg were used and were divided into 12 groups of 4 animals each. AlI the animsls were kept under standard diet snd living, and with the exception of one control group of dogs, alI groups were given, in addition to their diet~ 2 g/kg¦day of one of the resins for 25 days. On the 26th day from the beginning of the experiment, the bile acids were determined in the feces of the dogs, which were fssted for 12 hours in a metabolic cage (Grundy and colleagues, J.Lipia Res. 6, 397, 196S;
Ma~ita and colleagues, Ann.Biochem. 5, 523, 1963;
Forman and colleagues, ClinOChem. 14, 348, 1969).
Tsbles 1 and 2 summarise the resu~ts obtained in the rat6 and rabbits put into a state of hypercholesterolemia by diet, and treated with the various re6ins exsmined.
The cholesterol_decreasing effect of the resin6 administered orally in "in vivo" equal-weight doses substantially agreed with the "in vitro"

resultsO
In this respect, it was found that again in this case resins having an apparent density in water of 0.18 to 0.20 g of dry m3teri~1~ml and a water sbsorption capacity of 69 to 73% by weight of the weight ~f polymer have a cholesterol-decreasing effect both in rats snd in rabbits, which is surprisingly superior to that ever obtained with other resins.
The differences with respect to known resins are all highly significant (P > 0.013.

- ` 1141892 - 19 _ Tsble 3 shows the bile acid excretion values for dogs treated with 2 g/kg/day of the various resins.
It csn clearly be seen thst sdmlnistering the resins prepared sccording to the present invention produces a considerable incresse in bile acid fecal excretion relative to that obtained with the best resins commercially available at the present time.
~ighly significant differences (P ~ 0.01) exist between the b~le acid values e~creted with the feces after administering AP2, ~Pl, Sl, S2, E4 and E3 and the values obtained with the other resins.

- 20 - 1~ 4189Z
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114~89Z

The data heretofore given show clearly that the new resins~
independently of the chemical nature of the matrix and its physical form (microporous, macroporous or gel) are able to electively bond the bile acids, and can givé rise to 8 cholesterol-decressing effect when administered orally~ which is of an extent superior to that obtained with any resin used up to the present time.

Claims (9)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A process for producing anionic ion exchange resins, in particular non toxic styrene acrylic or epoxy resins, with strong cholesterol-decreasing properties, which have an ap-parent density in water of 0.18 to 0.20 g of dry material/
ml and a water absorption capacity of 69 to 73% by weight of the polymer weight, in which a mixture of monomers con-taining a critical percentage of cross-linking monomer is polymerised at a low rate so as to give the polymer a crit-ically predetermined and uniformly distributed degree of cross-linkage, corresponding to an apparent density in water of 0.18 to 0.20 of dry material/ml with a water absorption capacity of 69 to 73% by weight of the polymer weight, wherein the polmerisation catalyst used is an organic perox-ide in a concentration of 0.2 to 3% and the cross-linking agent used is a divinyl compound in a percentage of 1.5 to 12% at a polymerization temperature of 50% to 80%C.

2. A process as claimed in claim 1 wherein the organic per-oxide is benzoyl peroxide or lauryl peroxide.

3. A process as claimed in claim 1, wherein the divinyl compound is divinylbenzene.

4. A process as claimed in claim 1 for producing polystyrene resins with the following characteristics:

- cross-linkage 1.5-2.5%
- strong exchange power 2.8-4.0 meq/g - total exchange power 2.8-4.0 meq/g wherein the styrene is polymerised with 1.5 to 2.5% of divinyl compound (100%) in the presence of a concentration of 1 to 3%
of lauroxyl peroxide as catalyst, at a temperature of 60 to 70°C.

5. A process as claimed in claim 1 for producing polystyrene resins, wherein the styrene is polymerised with 1.5 to 2.5%
of divinyl compound (100%) in the presence of a concentration of 0.3 to 1.5% of benzoyl peroxide as catalyst, at a tempera-ture of 65 to 75°C.

6. A process as claimed in claim 1 for producing acrylic resins with the following characteristics:

- cross-linkage 10-12%
- strong exchange power 2-3.0 meq/g - total exchange power 5.5-8.0 meq/g wherein the acrylic monomers are polymerised with 10 to 12% of divinyl compound (100%) in the presence of a concentration of 1 to 2% of lauroyl peroxide as catalyst at a temperature of 55 to 65 C.

7. A process as claimed in claim 1 for producing acrylic resins, wherein the acrylic monomers are polymerised with 10 to 12% of divinyl compound (100%) in the presence of a concentration of 0.2 to 1.5% of benzoyl peroxide as catalyst at a temperature of 60 to 70°C.

8. A process as claimed in claim 1 for producing epoxy resins with the following characteristics:

- cross-linkage 3-4%
- strong exchange power 2-5 meq/g - total exchange power 10-12.5 meq/g wherein epichlorhydrin is polymerised with 3 to 4% of divinyl compound (100%) in the presence of a concentration of 0.5 to 1.5% of lauroyl peroxide as catalyst, at a temperature of 55 to 65°C.

9. A process as claimed in claim 1 for producing epoxy resins, wherein epichlorhydrin is polymerised with 3 to 4% of divinyl compound (100%) in the presence of a concentration of 0.2 to 1.0% of benzoyl peroxide as catalyst, at a temperature of 60 to 70°C.