GB2026501A - Anionic ion exchange resins with cholesterol-decreasing properties - Google Patents

Abstract

Anionic ion exchange resins having cholesterol-reducing properties are characterised by an apparent 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. Non-toxic styrene, acrylic or epichlorohydrin resins are suitable but require different degrees of regular cross-linking within critical limits. They can be produced by polymerization at a low rate using organic peroxides as catalysts and divinyl compounds as cross-linking agents.

Description

SPECIFICATION Anionic ion exchange resins with cholesterol-decreasing properties This invention relates to anionic ion exchange resins for use in human therapy as cholesterol-decreasing agents.

Ion exchange resins have notably found 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 state requires a resin of special chemical characteristics, chosen from the group consisting of weakly acid resins, strongly acid resins, weakly basic resins, and strongly basic resins, 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 hyperlipemias. It is in fact known that at too high levels of lipids, which are essentially cholesterol and triglicerides, early arteriosclerosis can develop in the organism, with consequences such as cardiac infarct and cerebral thrombosis. Hyperlipemia is therefore a vast problem for which the resolutive drug has as yet not been found.

To reduce cholesterol to normal levels, it is necessary to both exclude all those foodstuffs which are rich in them or in saturated fats, and to increase its elimination.

It has been found that ion exchange resins of basic character act in this second manner by fixing the bile acids at the intestinal level, thus interrupting the enterohepatic recycle, with consequent loss of cholesterol.

In order to carry out this chloesterol-decreasing method on a practical scale, certain basic anionic exchange resins have been produced up to the present time containing amino and/or ammonium groups able to chemically fix the bile acids.

The resins prepared and used up to the present time are essentially Cholestyramine and Cholestypol. The first of these resins is essentially a styrene resin containing quaternary ammonium groups cross-linked by divinylbenzene, whereas the second is a polymer of N-(2-amino ethyl)-l, 2-ethanediamine with chloromethyl oxiran. Although from a theoretical aspect the chemical operation of these resins seems clear and therefore clearly determinable from a quantitative point of view, in practice the results attained with them have been much worse than forecast, and could be improved.In particular, often in contrast with the results obtained in vitro, these resins, whatever their chemical nature, have a too low capacity for fixing cholate ions in vivo, because 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 of all this would seem to be to produce resins with a higher concentration of functional groups. However, it has been found that by increasing beyond a certain limit the concentration of the basic functional groups of the resin, whether these be strong or weak, their activity reduces rather than increases. The present invention is based on the fact that it has now been discovered that the activity of the resin depends only to a limited extent on the chemical nature and number of the basic functional groups present in it, whereas the determining factor is the "accessibility" 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 seem to be to use linear soluble resins, the functional groups of which should have maximum accessibility.

However, it has been found that anionic resins of this type completely unexpectedly possess very poor activity in that the linear chains, which are not bonded together, agglomerate in an aqueous environment due mainly to coordination bonds, to form a completely random pseudo lattice into which it is practically impossible for the large bile acid molecules to penetrate, and this therefore removes most of the active groups from the ion exchange reaction.

In the same manner, highly cross-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 present invention, it has now been found that cholesterol-decreasing anionic exchange resins of very high activity are obtained by producing resins having a degree of regular cross-linking which is contained within very definite critical limits, which are different for each type of resin.

The purpose of the regular cross-linking according to the present invention is to form "meshes" in the polymer which have an aperture essentially "corresponding" to the volume of the bile acids, which can thus come into contact in the alimentary canal with the highest possible number of active functional groups.

As functional groups of different chemical nature have different volumes and 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 resin. However, it in no way depends on whether the resin has a gel, microporous or macroporous structure.

In other words, given a linear polymer of a determined chemical nature and with a certain number of basic active groups, i.e. a polymer with a certain exchange power, it is provided with a determined cholesterol-decreasing activity by producting in it a precise degree of uniform cross-linking.

To obtain this degree of cross-linking and consequently the required aperture of the meshes formed in the polymer, the cross-linking monomer in the mixture of monomers to be polymerised must be used in an exactly defined percentage.

To obtain uniformity of cross-linking, and consequently a uniform size of meshes formed in the polymer, a very low polymerisation velocity must be used by suitably choosing the catalyst, the reaction temperature, the monomer concentration in the reaction solvent, and the catalyst concentration.

It has been found that the most suitable catalysts for providing the necessary gentle polymerisation conditions are organic peroxides and in particular lauroyl and benzoyl peroxide. It is preferable to use benzoyl peroxide because it has a higher half life, and a better purity and initiation effectiveness.

The critical conditions under which the said catalysts must be used for producing the resins according to the invention are: Lay royal peroxide - Acrylic: temperature 55-650C; concentration 1-2% - Styrene: temperature 60-70"C; concentration 1-3% - Epoxy: temperature 55-65 C;tconcentration 0.5-1.5% Benzoyl peroxide - Acrylic: temperature 60-70"C; concentration 0.2-1.5% - Styrene: temperature 65-75"C; concentration 0.3-1.5% - Epoxy: temperature 60-70"C; concentration 0.2-1.0%.

It has also been found that certain not easily controllable side reactions during the stages of the various processes can give rise to further cross-linking of the polymer lattice. This can invalidate the whole of the careful construction of the resin if it is not suitably checked.

In particular, in acrylic resins this undesirable reaction can take place during the ammonification stage where polyamines are used.

In styrene resins the critical stage occurs during chloromethylation. In the case of epoxy resins, the delicate stage is the amination where polyamines are used.

It has been found that the parasite reactions can be prevented as follows: - Acrylic: in the ammonification stage, a great excess of poiyamines must be used, up to 6 to 7 times the stoichiometric - Styrene: in the chloromethylation stage a gentle catalyst is used as ZnCI2 under very gentle reaction condtion, i.e. a dilute system at low temperature (35-400C).

- Epoxy; in the amination stage an excess of polyamine is used at low temperature (35-40"C).

With regard to the choice of cross-linking agent, in theory all molecules having two vinyl functions which have a large distance between them can be used as cross-linking agents. in reality the following are used in practice: divinylbenzene, divinyltoluene, divinylxylene, divinylethylbenzene and the like. Divinylbenzene is preferred because of its reactivity and its commercial availability.

It has now been unexpectedly found that the factors which determine the cholesterol-decreasing activity of an anion exchange resin and essentially the size of the cross-linkage "meshes" present in it, are a function of the apparent density in water and the absorption capacity for water of the resin, because of which the maximum activity for any resin corresponds to a substantially constant apparent density and a substantially constant water absorption capacity.

The present invention therefore provides cross-linked anionic exchange resins with cholesteroldecreasing action, having an apparent density of 0.18 - 0.20 g of dry material/ml, with a water absorption capacity of 69-73% by weight.

This unique and constant value cprresponds for each resin to determined combinations of exchange power and degree of cross-linkage (chosen within a critical and exactly defined range), and which can thus be fixed unambiguously for each resin. For the purposes of the present invention the apparent density in water has been determined, and is to be understood hereinafter as determined, by the following method: 20 grams of dry resin (dried at 400C in a vacuum oven until its weight is constant) are left in 150-200 ml of water for 24 hours, stirring 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 deposits 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 layer 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 dry weight of the resin to its volume in water.

For the purposes of the present invention, the water absorption capacity of the resin is always to be understood as determined by the following method: 39 of resin, dried to constant weight at a temperature of 40"C in a reduced pressure environment, are exposed on a glass disc to an atmosphere saturated with moisture at 250C until there is no further weight increase.

The water absorbed is expressed as a percentage of the total weight. The cholesterol-decreasing activity of the resins was determined in vitro by the following method: 20 ml of a sodium cholate solution of 2 mg/ml concentration in a 0.02 molar solution of a phosphate buffer (pH 6) are placed in a conical flask.

1 ml of H2O and 30 mg of resin are added to the flask. After stirring for five minutes at 25 C, the contents are filtered, and the non-fixed cholic acid is determined by a spectrophotometric method after reacting with sulphuric acid (Kier et al. J. Chim. Invest 40,755,1952).

The activity is given by the sodium cholate fixed during the time considered. Some tens of styrene, acrylic and epoxy resins were prepared having different exchange powers and different degrees of cross-linkage.

Using the above methods, the apparent density, the water absorption and activity were determined for each of the resins. Maximum activity was constantly obtained with resins having an apparent density of 0.18 to 0.20 g of dry material/mI and a water absorption capacity of 69 to 73% by weight.

By this method, the critical range of exchange power and cross-linkage were determined between which it is possible to obtain a very high cholesterol-decreasing activity for any type of resin. Using the same method, it was established that in reality all resins known up to the present time, and which have an absolutely insufficient activity to be able to be considered as an effective cholesterol-decreasing means, have an apparent density in water which is outside the limits of 0.18two 0.20 g of dry material/ml, and in particular a density of water absorption which indicate poor nonruniform cross-linkage (Cholestyramine type) or an excessive andnon-uniform cross-linkage (Lewatit MP 500 and Cholestypol types of resin).

The strong exchange power and the total exchange power were also determined for each resin.

The strong exchange power was determined 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 eiuate. The resin is then abundantly washed with water until neutral. The OH- form is reconverted to Cl by percolating 400 ml of a 10% aqueous NaCI solution, then washing with 1000 ml of H2O. The base contained in the eluate is titrated with 0.1 N HCl, 1 ml of HCI used corresponding to 0.01 milliequivalents (meq) per gram.

The total exchange power was determined by the following method: 10 g of resin, made into the OH and free amine form as described in the preceding method, are treated with 100 ml of 1 N HCI and are then washed with water until neutral.

The HCI of the eluate is titrated with 0.1 N NaOH using methyl red as indicator.

The total exchange power of the resin is given by the number of milliequivalents of acid not found in the eluate divided by 10. The critical values which were determined for the most common types of anion exchange resins according to the invention as being necessary to give high cholesterol-decreasing power are as follows:: Styrol resins with amino and ammonium groups 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 and ammonium groups Strong exchange power meq/g 2.0- 3.0 Total exchange power meq/g 5.5- 8.0 Cross-linkage % 10-12 Epoxy resins with amino and ammonium groups Strong exchange power meq/g 2-5 Total exchange power meq/g 10 -12.5 Cross-linkage % In the case of epoxy resins, the term "cross-linkage" obviousiy indicates only the cross-linkage due to the cross-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 only.

EXAMPLE I Preparation of a microporous acrylic resin (AP2) A mixture consisting of 33 parts of acrylic nitrile, 16 parts of methyl acrylate, 10 parts of technical divinylbenzene (strength 60%), 1 part of benzoyl peroxide and 40 parts of toluene is suspended by agitation in an aqueous solution containing 20% of gelatine by weight.

1 part of bentonite is added to the suspension.

The suspension is heated for 40 hours at 65 C.

The polymer thus obtained, which is in the form of opaque pearls, is 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 130"C. After cooling, the excess amine is removed by repeated washing with water. The product obtained is immersed in 50 parts of H20 and 50 parts of Na2C03, cooled to 0 C and treated with 400 parts of CH2Br for 5 hours under agitation.

It is finally filtered, washed with H20 and then put into the chloride form in a percolation column by slowly percolating 1000 parts of a 5% aqueous solution of NaCI.

A resin is obtained having the following characteristics: - Cross-linkage 10% - Strong exchange power 2.1 meq/g -Total exchange power 6.2 meq/g - H20 absorption capacity 71% apparent density 0.186 g/ml - Activity 18 + 0.4 mg/cholate fixed -Amine tertiary + quarternarytype EXAMPLE2 Preparation ofa standard acrylic resin (ASP') A mixture consisting of 55 parts of acrylic nitrile, 26.5 parts of methyl acrylate, 18.3 parts of technical divinylbenzene (60%) and 0.2 parts of benzoyl peroxide is suspended by agitation in an aqueous solution containing 20% gelatine by weight 2 parts of bentonite are added to the suspension. The suspension is heated for 40 hours at 70"C.

The polymer obtained in this manner is washed, ammonified, made quaternary and put into the chloride form as in the previous example.

A resin is obtained having the following characteristics: - Cross-linkage 11% - Strong exchange power 2.1 meq/g -Total exchange power 6.1 meq/g - H20 absorption capacity 70.4% apparent density 0.192 g/ml - Activity 18 t 0.4 mg/cholate fixed - Amine tertiary + quaternary type EXAMPLE 3 Preparation of a standard styrene resin (S7) A mixture consisting of 96.5 parts of styrene, 2.5 parts of technical divinylbenzene (60%) and 1.0 part of benzoyl peroxide is suspended by agitation in an aqueous solution containing 15% gelatine byweight.

0.7 parts of bentonite are added to the suspension. The suspension is heated for 40 hours at 70"C.

The polymer thus obtained is carefully washed from the residues of the dispersing solution and dried.

The entire product is then chloromethylated with monochloroether (200 parts) and zinc chloride (65 parts) after expanding it in dichloroethane (300 parts), heating the mixture for 7 hours at 35"C.

Finally, the intermediate obtained is aminated with trimethyl amine (180 parts of 40% aqueous solution) at 45"C for 6 hours. A resin is obtained having the following characteristics: -Cross-linkage 1.5% - Strong exchange power 3.3 meq/g -Total exchange power 3.3 meq/g - H20 absorption capacity 71.7% - Apparent density 0.180 g/ml - Activity 15 t 0.4 mg/cholate fixed -Amine quaternary type EXAMPLE 4 Preparation ofa standard styrene resin (S2) A mixture consisting of 95 parts of styrene, 3.5 parts of technical divinylbenzene (strength 60%) and 0.7 parts of benzoyl peroxide is suspended by agitation in an aqueous solution containing 15% gelatine by weight.

0.7 parts of bentonite are added to the suspension.

The suspension is heated for 40 hours at 70"C.

The polymer obtained is washed, dried, chloromethylated and aminated as in Example 3.

A resin is obtained having the following characteristics: - Cross-linkage 2.1% - Strong exchange power 3.3 meq/g -Total exchange power 3.3. meq/g - H20 absorption capacity 71.5% apparent density 0.195 g/ml - Activity 15 t 0.4 mg/cholate fixed gamine quaternary type EXAMPLES Preparation ofa standard epoxy resin (E4) A mixture consisting of 93.3 parts of epichlorydrine, 6.5 parts of technical divinylbenzene (strength 60%) and 0.2 parts of benzoyl peroxide is suspended by agitation in an aqueous solution containing 20% gelatine by weight.

The suspension is heated at 65"C for 40 hours.

The polymer thus obtained is carefully washed from the residues of the dispersing system and dried.

The whole of the polymer is then treated with 100 parts of ethylene-diamine and 40 parts of NaOH flakes at 65"C for 10 hours under agitation. The product obtained is washed with water to remove the excess of amine, and is then immersed in 50 parts of H20 and 50 parts of Na2C03, and treated with 500 parts of CH3Br for 5 hours at 0 C under agitation. It is finally filtered, washed with water and is then put into the chloride form in a percolation column by slowly percolating 1000 parts of a 5% aqueous solution of NaCI.A resin is obtained having the following characteristics: - Cross-linkage 4% - Strong exchange power 2;1 ,eq/g -Total exchange power 10.5 meq/g - H2O absorption capacity 69.5% apparent density 0.180 g/ml activity 12 t 0.8 mg/cholatefixed -Amine tertiary + quaternarytype EXAMPLE 6 A mixture consisting of 94.8 parts of epichlorydrine, 5 parts of technical divinylbenzene (strength 60%) and 0.2 parts of benzoyl peroxide is suspended by agitation in an aqueous solution containing 20% gelatine by weight.

The suspension is heated at 650C for 40 hours.

The polymer thus obtained is washed, aminated and made quaternary as in the previous example.

A resin is obtained having the following characteristics: - Cross-linkage 3% - Strong exchange power 2.3 meq/g -Total exchange power 10.9 meq/g - H2O absorption capacity 70.5% - Apparent density 0.180 g/ml - Activity 12 i 0.8 mg/cholate fixed - Amine tertiary + quaternary type For greater clarity, the characteristic data of the new resins are summarised in the following table, compared with the same data for the most known resins available for some years.

Resin name Cholestyramine Lewatit MP500 Lewatit MP62 IRA 458 tert. + Cholestypol sec.+ Resin type quat. styrene quat. styrene tert. styrene quat. acrylic tert. + quat. epoxy Cross-linkage 2 > 5 > 5 > 5 > 5 Strong exchange 2.9 3.6 - 3.6 4.5 power meq/g Total exchange 2.9 3.6 3.6 4.2 4.3 power meq/g H2O absorption > 65 36 28 61 > 65 capacity % Apparent density g/ml 0.047 0.275 0.280 0.34 0.070 Activity mg/cholate fixed 8 # 0.8 6 # 0.8 5 # 0.8 8 # 0.8 6 # 0.8 Resin name AP2 AP1 S1 S2 E4 E3 Resin type tert. + quat tert. + quat quat. quat tert. + quat. tert. + quat.

acrylic acrylic styrene styrene epoxy epoxy Cross-linkage 10 11 1.5 2.1 4 3 Strong exchange 2.1 2.1 3.3 3.2 2.1 2.3 power meq/g Total exchange 6.2 6.1 3.3 3.2 10.5 10.9 power meq/g H2O absorption 71 70.4 71.7 71.5 69.5 70.5 capacity % Apparent density g/ml 0.186 0.192 0.180 0.195 0.180 0.180 Activity mg/cholate fixed 18 # 0.4 18 # 0.4 15 # 0.4 15 # 0.4 12 # 0.8 12 # 0.8 The cholesterol-decreasing activity of the new resins according to the invention was also examined "in vivo".

To examine the "in vivo" cholesterol-decreasing effect of the various resins, the following tests were used: 1) Their action on hypercholesterolemia produced by a diet enriched in cholesterol in the rat and rabbit 2) 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 casein 20% dl-methionine 0.4% Hegsted saiine mixture 4% saccharose 49.1% cholesterol 1% cholic 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 animal species comprised 84 male animals, namely rats of the Sprague-Dawley stock having an average weight of 200 g and New Zealand rabbits of 3 kg, divided into 12 groups of 7 animals each.

All the animals were put into a state of hypercholesterolemia by means of a diet, One group underwent no treatment, whereas the other 11 groups were treated with 0.5 g/kg of one of the resins for 30 days.

The resins were dissolved or suspended in 10% gum arabic mucilage. Only gum arabic mucilage was administered to the control group. On the thirtieth day of treatment all the animals were sacrificed and the total plasmatic cholesterol was measured in the blood collected from the carotid arteries (Pearson and colleagues J. Chim. Endocrin. 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. All the animals were kept under standard diet and living, and with the exception of one control group of dogs, all 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 fasted for 12 hours in a metabolic cage (Grundy and colleagues, J. Lipid Res. 6,397, 1965; Makita and colleagues, Ann. Biochem. 5,523, 1963; Forman and colleagues, Coin, Chem. 14,348, 1969).

Tables 1 and 2 summarise the results obtained in the rats and rabbits put into a state of hypercholesterolemia by diet, and treated with the various resins examined.

The cholesterol-decreasing effect of the resins administered orally in "in vivo" equal-weight doses substantially agreed with the "in vitro" results.

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 material/ml and a water absorption capacity of 69 to 73% by weight of the weight of polymer have a cholesterol-decreasing effect both in rats and 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 > 0.01). Table 3 shows the bile acid excretion values for dogs treated with 2 g/kg/day of the various resins.

It can clearly be seen that administering the resins prepared according to the present invention produces a considerable increase in bile acid fecal excretion relative to that obtained with the best resins commercially available at the present time. Highly significant differences (P > 0.01) exist between the bile acid values excreted with the feces after administering AP2, AP1, Si, S2, E4 and E3 and the values obtained with the other resins.

TABLE 1 Total seric cholesterol values in rats subjected to a Nath diet for 30 days ad treated with various resins Controls Cholestyr- Lewatit Lewatit IRA 458 Cholestypol AP2 AP1 S1 S2 E4 E3 amine MP 500 MP 62 No. rats 7 7 7 7 7 7 7 7 7 7 7 7 mg % 281 120 176 197 131 123 94 91 84 80 112 114 #16.8 #6.2 #12.4 #13.9 #7.3 #5.8 #4.3 #4.3 #3.7 #3.9 #5.1 #5.3 TABLE 2 Total seric cholesterol valuews in rabbits subjected to a cholesterol enriched diet for 30 days and treated with various resins Controls Cholestyr- Lewatit Lewatit IRA 458 Cholestypol AP2 AP1 S1 S2 E4 E3 amine MP 500 MP 62 No.

rabbits 7 7 7 7 7 7 7 7 7 7 7 7 mg % 689 204 488 541 356 210 151 139 128 131 196 198 #21.4 #5.1 #15.6 #17.8 #16.5 #4.2 #3.7 #3.5 #3.6 #4.2 #6.1 #7.2 TABLE 3 Fecal excretion of bile acids in dogs subjected to 25 days treatment with various resins Controls Cholestyr- Lewatit Lewatit IRA 458 Cholestypol AP2 AP1 S1 S2 E4 E3 amine MP 500 MP 62 No. dogs 4 4 4 4 4 4 4 4 4 4 4 4 Mcg/g 678 2310 1210 984 1415 2152 2705 2744 2751 2695 2587 2548 of feces #39 #101 #81 #47 #53 #94 #114 #118 #117 #109 #102 #106 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 give rise to a cholesterol-decreasing effect when administered orally, which is of an extent superior to that obtained with any resin used up to the present time.

Claims (16)

1. Anionic ion exchange resins, 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 a water absorption capacity of 69 to 73% by weight of the polymer weight.

2. Styrene resins as claimed in Claim 1, 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

3. Acrylic resins as claimed in Claim 1, 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

4. Epoxy resins as claimed in Claim 1, with the following characteristics: - cross-linkage 3-4% - strong exchange power 2 -

5 meq/g -total exchange power 10-12.5 meq/g 5.A 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 is polymerised at a low rate so as to give the polymer a critically 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 polymerisation catalyst used is 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.

6. A process as claimed in Claim 5, wherein the organic peroxide is benzoyl peroxide or lauroyl peroxide.

7. A process as claimed in Claim 5, wherein the divinyl compound is divinylbenzene.

8. A process as claimed in Claim 5 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 1 to 3% of lauroyl peroxide as catalyst, at a temperature of 60 to 700C.

9. A process as claimed in Claim 5 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 temperature of 65 to 75"C.

10. A process as claimed in Claim 5 for acrylic resins, 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.

11. A process as claimed in Claim 5 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.

12. A process as claimed in Claim 5 for producing epoxy resins, wherein epichlorydrine 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.

13. A process as claimed in Claim 5 for producing epoxy resins, wherein epichlorydrine 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.

14. Therapeutic compositions with cholesterol-decreasing action, comprising anionic ion exchange resins, in particular non-toxic styrene, acrylic or epoxy resins, having an apparent 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.

15. Anionic ion exchange resins with cholesterol-decreasing properties as herein described.

16. A process for producing anionic ion exchange resins as herein described in any of the Examples