CH633186A5 - Ion-exchange resins of the anionic type with hypocholesterolaemic properties - Google Patents

Abstract

The new resins are administered by mouth in human treatment as powerful hypocholesterolaemic agents. In particular these are styrene, acrylic and epoxy resins with an apparent density in water of between 0.18 and 0.20 g/dry matter/ml and a water absorption capacity of between 69 and 78 wt-% calculated on the weight of the polymer.

Description

The present invention refers to anionic ion exchange resins to be used in human therapy as cholesterol lowering agents.

It is known that ion exchange resins have found use in the treatment of various pathological states such as: hyperacidity, prevention of depletion of Na + in the gastrointestinal tract, induction of K + depletion, treatment of nephrotic, pancreatic, cardiac edema of the ulcer, neutralization of gastric acidity, etc.

Obviously, each particular pathological state requires a resin with particular chemical characteristics, chosen from the group consisting of: weakly acidic resins, strongly acidic resins, weakly basic resins, strongly basic resins, always starting from the assumption that these are resins without toxicity to the human organism.

It is known that the use of ion exchange resins has been extended in recent years to the treatment of hyper-lipidemias. We know that at too high levels of lipids, essentially cholesterol and triglycerides, early arteriosclerosis can develop in the body, with consequences such as cardiac infarction and cerebral thrombosis. Hyperlipi-demia is therefore a far-reaching problem for which the remedial drug has not been found to date.

It is also known that to reduce cholesterol to normal levels it is necessary to act in part by excluding all those foods that are rich in it or in saturated fats and in part by increasing the elimination of the same.

It has been found that basic ion exchange resins act in this second way by fixing the bile acids in the intestine and therefore interrupting the enterohepatic recycling with consequent loss of cholesterol.

Up to now, some basic exchange-anionic resins have been prepared for the practical realization of this hypocole-sterolemizing principle, containing amine and / or ammonium groups capable of chemically fixing bile acids.

The resins prepared and used to date are essentially Colestyramine and Colestipol. The first of these resins is essentially a styrolic resin containing quaternary ammonium groups, crosslinked by divinylbenzene, while the second is a polymer of N- (2-amino - ethyl) -l, 2-ethan-diamine with chloromethyl-oxirane.

Although from a theoretical point of view the chemical functioning of these resins seems clear and therefore clearly determinable from a quantitative point of view, in practice the results achieved with them have been far lower than expected and are likely to be improved.

In particular, often in contrast with the results obtained in vitro, these resins, whatever their chemical nature, have in vivo an ability to fix the cast ions too low, so either the reduction in the cholesterol rate «} they produce is insignificant o they must be used in very high doses that cause serious gastro-intestinal side effects.

An obvious remedy for all this would seem to be the production of resins with a higher concentration of functional groups. Instead, it has been seen that by increasing the concentration of the basic functional groups of the resin, whether they are strong or weak, beyond a certain limit, the activity instead of increasing decreases.

We have now found, and what we found underlies the present invention, that the resin activity depends only to a limited extent on the chemical nature and on the number of basic functional groups present in it, while the determining factor is constituted by the « accessibility », of functional groups to bile acid molecules, which, as is known, are all compounds with a steroid structure, therefore considerably bulky and with low mobility.

The immediate answer to the problem thus posed would seem to lie in the use of soluble linear resins, whose functional groups should have maximum accessibility.

Conversely, we have found that anionic resins of this type have quite unexpectedly very little activity as the linear chains, not linked together, agglomerate in aqueous environments, thanks above all to coordination bonds, forming a pseudo lattice of the

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633186

completely random, in which it is practically impossible for the large molecules of bile acids to penetrate and which therefore removes most of the active groups from the ion exchange reaction.

In the same way, highly crosslinked resins have very little, insufficient activity, due to the formation of a too narrow lattice, inaccessible to bile acid molecules.

We have now found, and forms the subject of the present invention, that very high activity hypocolymer-kmising anion exchange resins are obtained by producing resins with a degree of regular cross-linking contained within well defined and critical limits, different for each type of resin.

The regular cross-linking according to the present invention has the purpose of forming "links" in the polymer, the opening of which is essentially "corresponding" to the volume of bile acids which thus allow them to come into contact in the digestive tract with as many functional groups as possible active. Since functional groups of a different chemical nature have different volumes, and therefore create a different degree of friction and steric hindrance within the «links», it is obvious that the degree of critically effective cross-linking will differ according to the chemical nature of the resin . However, it is in no way dependent on whether the resin has a gellular, microporous or macroporous structure.

In other words, given a linear polymer of a certain chemical nature and with a certain number of basic active groups, which means a polymer with a certain exchange power, it gives it a certain hypocolest-rolemizing activity giving it a well-defined degree of cross-linking uniform.

To obtain the degree of cross-linking, and therefore the desired opening of the meshes formed in the polymer, the cross-linking monomer must be used in a well-defined percentage in the mixture of monomers to be polymerized.

To obtain instead the crosslinking uniformity, and therefore the uniform size of the meshes formed in the polymer, it is necessary to achieve a very low polymerization rate by choosing appropriately the catalyst, the reaction temperature, the concentration of the monomers in the reaction solvent, the concentration of the catalyst.

We have found that the most suitable catalysts for achieving the necessary mild polymerization conditions are organic peroxides and in particular lauroyl peroxide and benzoyl peroxide. It is preferable to use benzoyl peroxide because it has a longer half-life, a purity and a higher initiation efficiency.

The critical conditions in which the above catalysts must be used for the production of the resins according to the invention are:

Lauroyl peroxide

- Acrylics:

temp.

55-65 ° C;

conc.

1-2%

- Styrolic:

temp.

60-70 ° C;

conc.

1-3%

- Epoxies:

temp.

55-65 ° C;

conc.

0.5-1.5%

Benzoyl peroxide

- Acrylics:

temp.

60-70 ° C;

conc.

0.2-1.5%

- Styrolic:

temp.

65-75 ° C;

conc.

0.3-1.5%

- Epoxies:

temp.

60-70 ° C;

conc.

0.2-1.0%

We have also found that some secondary reactions that are not well controlled in the phases of the various processes can give rise to further crosslinking of the polymeric lattice. This can affect, if not properly checked, all the good construction of the resin.

In particular in acrylic resins this undesired reaction can occur in the ammonization phase, when polyamines are used.

In styrolic resins the critical phase occurs during 5 chloromethylation.

With epoxy resins the delicate phase is ammination, when polyamines are used.

According to our findings, parasitic reactions can be avoided as follows:

io - Acrylics: in the ammonization phase, a large excess of polyamines, up to 6-7 times the stoichiometric, must be used

- Styrolic: in the chloromethylation phase a mild catalyst is used such as ZnCl2 under conditions of

15 very mild reaction, i.e. diluted system and low temperatures (35-40 ° C)

- Epoxy: in the amination phase an excess of polyamine is used at low temperatures (35-40 ° C). As for the choice of crosslinker, in theory

20 all the molecules having two vinyl functions somewhat distant from each other can be used as crosslinking agents. Actually, in practice the following are used: divinylbenzene, divinyltoluene, divinylxylene, divinylethylbenzene and the like. Divinylbenzene is preferred due to its reactivity and commercial availability.

We have also quite unexpectedly found that the factors determining the cholesterol-lowering activity of an anion exchange resin and essentially the size of the crosslinking "meshes" present in it, 30 are a function of the apparent density in water and the absorption capacity of water of the resin, whereby the maximum activity corresponds for any resin to a substantially constant value of apparent density and absorption capacity of H20.

35 The object of the present invention is therefore cross-linked cross-anionic exchange resins with a cholesterol-lowering action having an apparent density of 0.18 0.20 g dry / ml with an H20 absorption capacity of 69-73% by weight.

This unique and constant value will correspond for each resin to determine combinations of exchange power and degree of cross-linking (chosen in a critical and well-defined context) which can thus be set uniquely for each resin.

The apparent density in water, for the purposes of the present finding, has been determined, and must always be understood as determined, by the following method:

20 grams of dry resin (dried at 40 ° C in a vacuum oven until constant weight) are left in 150-200 ml of water for 24 hours, stirring occasionally. The resin is then transferred to a precisely calibrated glass column and provided with a porous septum.

A counter-current expansion of the resin bed is carried out and then, after the deposition, the water is discharged at a rate of 10 volumes per volume of resin until a 1-2 cm head is left on the resin.

After 20 'of rest, the volume of the resin layer is determined. On the same sample, the measurement is repeated 2 or 3 times so that the error is within 1%. The density value is given by the ratio between the dry weight of the resin and its volume in water.

The water absorption capacity of the resin for the purposes of the present invention is always determined on the basis of the following procedure:

65 3 g of resin, brought to constant weight at a temperature of 40 ° C in a reduced pressure environment, are exposed on a glass disk to an atmosphere saturated with humidity at 25 ° C until there is no more weight gain .

633186

4

The absorbed water is expressed as a percentage of the total weight.

The cholesterol lowering activity of the resins was instead determined in vitro with the following method:

20 ml of a sodium solution poured at a concentration of 2 mg / ml into a 0.02 mol solution of phosphate buffer (pH 6) are introduced into an Erlenmeyer flask.

1 ml of H2O and 30 mg of resin are added to the container. After 5 minutes of stirring at 25 ° C, the content is filtered and unsecured cholic acid is determined by spectrophotometric method after reaction with sulfuric acid (Kier et al. J. Chem. Invest. 40, 755, 1952).

The activity is given by the sodium flow fixed over the time considered. Dozens of iron, acrylic, epoxy resins having different exchange power and different degree of crosslinking have been prepared.

For each of these resins, the apparent density, water absorption and activity have been determined with the methods specified above; the maximum activity was constantly obtained with resins having an apparent density of between 0.18 and 0.20 g dry / ml and an absorption capacity of HzO between 69 and 73% by weight.

With this method we have determined the critical range of exchange and crosslinking power within which it is possible to obtain a very high cholesterol-lowering activity with any type of resin.

With the same method we have established that in reality all the resins known to date and which have an absolutely insufficient activity to be considered an effective cholesterol-lowering medium, have an apparent density in water outside the limits of 0.180 - 0.20 g dry / ml, and in particular a density and an absorption H20 which indicate poor non-uniform cross-linking (like Colestyramine) or excessive and non-uniform cross-linking (resins like Lewatit MP 500 and Colestipol).

For each resin we also determined the strong exchange power and the total exchange power.

Strong trading power was determined according to the following method:

10 g of dry resin are converted into OH © form by percolation of an aqueous solution of 5% NaOH until the ion is no longer detectable in the eluate.

The resin is then abundantly washed with water until neutral; the OH © form is converted back to CI © by percolation of 400 ml of an aqueous solution of 10% NaCl and subsequent washing with 1,000 ml of HaO.

The base contained in the eluate is titrated with 0.1 N HCl, 1 ml of HCl used corresponds to 0.01 milliequivalent (meq) per gram.

Total exchange power was determined according to the following method:

10 g of resin, placed in OH form and free amine as described in the previous method are treated with 100 ml of HCl 1 N and then washed with water to neutrality.

The eluate HCl is titrated with 0.1 N NaOH using the methyl-red indicator.

The meq of acid not found in the eluate are, divided by 10, the total exchange power of the resin.

The critical values determined by us for the most common types of anion exchange resins according to the invention to have a high cholesterol lowering power are the following:

Styrol resins with amino groups and ammonium groups

- strong exchange power 2.8-4.0 meq / g

- total exchange power 2,8-4,0 meq / g

- cross-linking 1.5-2.5%

Acrylic resins with seminic groups and ammonium groups

- strong exchange power 2.0-3.0 meq / g

- total exchange power 5.5-8.0 meq / g

- cross-linking 10-12%

Epoxy resins with amino groups and ammonium groups

- strong exchange power 2-5 meq / g

- total exchange power 10-12.5 meq / g

- 3-4% cross-linking

In the case of epoxies, the term cross-linking obviously means only the cross-linking due to the cross-linker and the one due to the amine is neglected.

We will now give here by way of illustration only some examples of practical realization of hypocolymer-lemizing resins according to the invention.

Example 1

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 (60% titer), 1 part of benzoyl peroxide and 40 parts of toluene, is suspended by stirring in an aqueous solution of jelly at 20% by weight.

To the suspension is added 1 part of bentonite. The suspension is heated for 40 hours at 65 ° C. The polymer thus obtained in the form of opaque pearls is carefully washed from the residues of the dispersing solution; the porous material is then removed by steam distillation and dried.

A part of polymer is treated with five parts of ethylene diamine 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 H2O and 50 parts of Na2CO3, cooled to 0 ° C and treated with 400 parts of CH2Br for 5 hours under stirring.

Finally, it is filtered, washed with H2O and then, in a percolation column, chloride is formed by slow percolation of 1000 parts of a 5% aqueous solution of NaCl.

A resin with the following characteristics is obtained:

- cross-linking 10%

- strong exchange power 2,1 meq / g

- total exchange power 6.2 meq / g

- absorption capacity H20 71%

- apparent density 0.186 g / ml

- activity 18 ± 0.4 mg / cast fixed

- tertiary + quaternary amine

Example 2

Preparation of a standard acrylic resin (API)

A mixture consisting of: 55 parts of acrylic nitrile, 26.5 parts of methyl acrylate, 18.3 parts of technical divinylbenzol (60%) and 0.2 parts of benzoyl peroxide, is suspended by stirring in an aqueous solution of jelly at 20% by weight. To the suspensions are added 2 parts of bentonite. The suspension is heated for 40 hours at 70 ° C.

The polymer thus obtained is washed, ammonized, quaternary and put into chloride form as in the previous example.

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633186

A resin with the following characteristics is obtained:

- cross-linking 11%

- strong exchange power 2,1 meq / g

- total exchange power 6.1 meq / g

- absorption capacity H20 70.4%

- apparent density 0.192 g / ml

- activity 18 ± 0.4 mg / cast fixed

- tertiary + quaternary amine

Example 3

Preparation of a standard styrolic resin (St)

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 stirring in an aqueous solution of gelatin at 15% by weight.

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.

Subsequently, all the product is chloromethylated by means of monochloroether (200 parts) and zinc chloride (65 parts) after swelling of the same in dichloroethane (300 parts) by heating the mixture for 7 hours at 35 ° C.

Finally, the intermediate obtained is amine with trimethyl amine (180 parts of 40% aqueous solution) at 45 ° C for 6 hours.

A resin with the following characteristics is obtained:

- cross-linking 1.5%

- strong exchange power 3.3 meq / g

- total exchange power 3,3 meq / g

- absorption capacity H20 71.7%

- apparent density 0.180 g / ml

- activity 15 ± 0.4 mg / cast fixed

- quaternary amine

Example 4

Preparation of a standard styrolic resin (S2)

A mixture consisting of: 95 parts of styrene, 3.5 parts of technical divinylbenzene (60% titer) and 0.7 parts of benzoyl peroxide, is suspended by stirring in an aqueous solution of gelatin at 15% by weight.

0.7 parts of bentonite are added to the suspension. The suspension is heated for 40 hours at 70 ° C. The obtained polymer is washed, dried, chloromethylated and aminated as in example 3.

A resin with the following characteristics is obtained:

- cross-linking 2.1%

- strong exchange power 3.3 meq / g

- total exchange power 3,3 meq / g

- absorption capacity H20 71.5%

- apparent density 0.195 g / ml

- activity 15 ± 0.4 mg / cast fixed

- quaternary amine

Example 5

Preparation of a standard epoxy resin (E4)

A mixture consisting of: 93.3 parts of epichlorohydrin, 6.5 parts of technical divinylbenzol (60% titer) and 0.2 parts of benzoyl peroxide, is suspended by stirring in an aqueous solution of gelatin at 20% by weight. The suspension is heated to 65 ° C for 40 hours. The polymer thus obtained is carefully washed from the residues of the dispersing system and dried.

It is then completely treated with 100 parts of ethylenediamine and 40 parts of NaOH flakes, at 65 ° C for 10 hours, under stirring. The product obtained, washed with H20 from the excess of amine, is immersed in 50 parts of HzO and 50 parts of Na2COa and treated with 500 parts of CH3Br for 5 hours at 0 ° C under stirring. Finally, it is filtered, washed with H2O and then, in a percolation column, chloride is formed by slow percolation of 1000 parts of a 5% aqueous solution of NaCl.

A resin with the following characteristics is obtained:

- crosslinking 4%

- strong exchange power 2,1 meq / g

- total exchange power 10.5 meq / g

- absorption capacity H20 69.5%

- apparent density 0.180 g / ml

- activity 12 ± 0.8 mg / cast fixed

- tertiary + quaternary amine

Example 6

Preparation of a standard epoxy resin (E3)

A mixture consisting of: 94.8 parts of epichlorohydrin, 5 parts of technical divinylbenzene (60% titer) and 0.2 parts of benzoyl peroxide, is suspended by stirring in an aqueous solution of gelatin at 20% by weight.

The suspension is heated to 65 ° C for 40 hours. The polymer thus obtained is washed, aminated and sintered as in the previous example.

A resin with the following characteristics is obtained:

- crosslinking 3%

- strong exchange power 2.3 meq / g

- total exchange power 10.9 meq / g

- absorption capacity H20 70.5%

- apparent density 0.180 g / ml

- activity 12 ± 0.8 mg / cast fixed

- tertiary + quaternary amine

For greater clarity we summarize in the following table the characteristic data relating to the new resins according to the invention in comparison with the same data for the best known resins already on the market for years.

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633186

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The cholesterol lowering activity of the new resins according to the invention has also been highlighted "in vivo".

The following tests were used to highlight the "in vivo" cholesterol-lowering effect of the various resins: 5 1) Action on cholesterol-enriched diet hypercholesterolaemia in rats and rabbits 2) Action on fecal excretion of bile acids in dogs

10 1) To induce hypercholesterolemia in rats, animals were required to eat according to Naht et al. (J. Nutrit. 67,289, 1959) containing:

- devitaminized casein

- dl-methionine saline mixture of Hegsted sucrose cholesterol cholic acid

15

20% 0.4% 4% 49.1% 1% 0.5%

and vitamins.

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To induce hypercholesterolemia in rabbits, 1 g / animal / day of cholesterol was administered by gastric test. Each animal species included 84 male animals in particular Sprague-Dawley strains with an average weight of 200 g, 3 kg New Zealand rabbits divided into 12 groups of 7 animals each.

All the animals were made hypercholesterolemic by diet; one group did not take treatment while the other 11 groups were treated with 0.5 g / kg of one of the resins for 30 days.

The resins were suspended in 10% arabic gum mucilage; only arabic gum mucilage was administered to the control group.

On the 30th day of treatment all animals were sacrificed and total plasma cholesterol was measured on the blood collected from the carotid arteries (Pearson et al. J. Chim. Endocrin. Metabolism 12, 1245, 1952).

2) 48 male beagles weighing about 8 kg were used to evaluate the faecal excretion of bile acids, which were divided into 12 groups of 4 cia-40 animals each. All animals were kept on a standard diet and housing and with the exception of one control dog group, all other groups took 2 g / kg / day of one of the resins for 25 days in addition to the diet.

On the 26th day from the beginning of the experiment on the feces of the 45 dogs fasted for 12 hours in a metabolic cage, the determination of bile acids was carried out (Grundy et al., J. Lipid Res. 6, 397, 1965; Makita et al., Ann. Bio-chem. 5, 523, 1963; Forman et al., Clin. Chem. 14, 348, 1969).

50 Tables 1 and 2 summarize the results obtained in rats and rabbits rendered hypercholesterolemic by diet and treated with the various resins examined.

The cholesterol lowering effect of resins administered orally in equal doses "in vivo" was substantially in agreement with the results obtained "in vitro".

In fact, it has also been found in this case that the resins with apparent density characteristics in water between 0.18 and 0.20 g / dry / ml and with a water absorption capacity between 69 and 73% by weight on the weight of the Polymer 60 have a cholesterol lowering effect both in rats and rabbits surprisingly higher than that ever made with other resins. The differences found with known resins are all highly significant (P> 0.01).

Table 3 shows the values of the excretions of 65 bile acids of dogs treated with 2 g / kg / day of the different resins.

It is clearly observed how the administration of the resins, prepared according to the present invention, produces a

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TABLE 1

Total serum cholesterol values in rats subjected to a Nath diet for 30 days and treated with different resins

Controls

Colestira-mina

Lewatit MP 500

Lewatit MP 62

IRA 458

Colestipol ap2

bees yes s2

E4

es

No. rats mg%

7

281 ± 16.8

7 176 ± 6.2

7 176

± 12.4

7 197 ± 13.9

7 131 ± 7.3

7 123 ± 5.8

7

94

± 4.3

7 91

± 4.3

7 84

± 3.7

7 80

± 3.9

7

112 ± 5.1

7

114 ± 5.3

Total serum cholesterol values in table 2

conìgli subjected to a diet enriched in cholesterol for 30 days and treated with different resins

Controls

Colestira-mina

Lewatit MP 500

Lewatit MP 62

IRA 458

Colestipol ap2

bees yes s2

IS*

E3

No. rabbits mg%

7

689 ± 21.4

7

204 ± 5.1

7

488 ± 15.6

7

541 ± 17.8

7

356 ± 16.5

7

210 ± 4.2

7 151 ± 3.7

7 139 ± 3.5

7 128 ± 3.6

7 131 ± 4.2

7 196 ± 6.1

7 198 ± 7.2

8

The above data clearly demonstrate that the new resins, regardless of the chemical nature of the ma-. trice and physical form (microporous, macroporous or gel-lular) are able to bind in an elective way the bi-5 liary acids and can cause a cholesterol-lowering effect, when administered orally, of a greater amount than that obtained with all resins used to date.

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Claims (10)

633186 1. Anionic type ion exchange resins, made of non-toxic polymers, with strong cholesterol-lowering properties, characterized in that they have an apparent density in water of between 0.18 and 0.20 g / dry / ml with a capacity of water absorption between 69 and 73% by weight on the weight of the polymer. 2. Styrol resins according to claim 1, characterized in that they have: - cross-linking 1.5-2.5% - strong exchange power 2.8-4.0 meq / g - total exchange power 2,8-4,0 meq / g 2 Acrylic resins according to claim 1, characterized in that they have: - cross-linking 10-12% - strong exchange power 2-3.0 meq / g - total exchange power 5.5-8.0 meq / g 4. Epoxy resins according to claim 1, characterized in that they have: - 3-4% cross-linking - strong exchange power 2-5 meq / g - total exchange power 10-12.5 meq / g 5. Process for the production of anionic ion exchange resins, with strong cholesterol-lowering properties, in which a mixture of monomers containing a critical percentage of crosslinking monomer is polymerized at low speed, so as to impart to the polymer a degree of critically predetermined and uniformly distributed cross-linking corresponding to an apparent density in water of between 0.18 and 0.20 g / dry / ml with a water absorption capacity of between 69 and 73% by weight on the weight of the polymer, characterized in that that an organic peroxide in concentrations between 0.2 and 3%, a divinyl compound as a cross-linking agent in a percentage between 1.5 and 12%, at a polymerization temperature between 50 ° and 80 ° C, is used as the polymerization catalyst. 6. Process according to claim 5, characterized in that the organic peroxide is benzoyl peroxide or lauroyl peroxide. 7. Process according to claim 5, characterized in that the divinyl compound is divinylbenzene. 8. Process according to claim 5 for the production of polystyrene resins, characterized in that the styrene is polymerized with 1.5 - 2.5% of divinyl-compound (100%), in the presence of lauroyl peroxide as a catalyst at concentrations by 1 - 3%, at temperatures of 60-70 ° C. 9. Process according to claim 5 for the production of polystyrene resins, characterized in that the styrene is polymerized with 1.5 - 2.5% of divinyl-compound (100%), in the presence of benzoyl peroxide as a concentration catalyst 0.3 - 1.5%, at temperatures of 65-75 ° C. 10. Process according to claim 5 for the production of acrylic resins, characterized in that the acrylic monomers are polymerized with 10 -12% of divinyl compound (100%), in the presence of lauroyl peroxide as a catalyst, at a concentration of 1 - 2%, at temperatures of 55-65 ° C.