DK160053B - PROCEDURE FOR MANUFACTURING NON-TOXIC STYRENE, ACRYLIC OR EPOXY RESIN WITH CHOLESTEROL-LOWERING PROPERTIES - Google Patents

Description

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The present invention relates to a process for producing non-toxic styrene, acrylic or epoxy resins with cholesterol lowering properties.

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In particular, ion exchange resins have found utility in the treatment of various pathological conditions, e.g. hyperacidity, prevention of Na + deficiency in the gastrointestinal tract, induction of K + secretion, treatment of 10 nephrotic, pancreatic and cardiac edema, treatment of ulcer, neutralization of gastric acidity, etc.

Of course, every single pathological condition requires a resin with special chemical properties selected from weakly acidic resins, highly acidic resins, weakly basic resins and strong basic resins, provided these resins do not appear toxic to the human organism.

20 The use of ion exchange resins has been especially expanded in recent years in the treatment of hyperlipemia. It is a fact that too high levels of lipids that are essentially cholesterol and triglycerides can cause early arteriosclerosis in the organism with sequences such as heart attack and cerebral thrombosis. Hyperlipemia is therefore a widespread problem for which the final drug has not yet been found.

In order to reduce cholesterol to normal levels, it is necessary both to avoid all the nutrients rich in these or to saturated fats, and at the same time to increase the removal of cholesterol.

It has been found that ionic exchange resins of basic character act in a different way by binding the bile acids in the intestinal tract, thereby interrupting the enterohepatic recirculation with consequent loss of cholesterol.

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In order to carry out this cholesterol-removing method in practice, certain basic anion exchange resins have been prepared containing amino and / or ammonium groups capable of chemically bonding the bile acids.

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The resins so far made and used are essentially Cholestyramine and Cholestypol. The first of these resins is essentially a styrene resin containing quaternary ammonium groups cross-linked with 10 divinylbenzene, while the second is a polymer of N- (2-aminoethyl) -1,2-ethanediamine with chloromethyloxirane. From a theoretical point of view, the chemical action of these resins is apparently clear and can therefore be clearly determined from a quantitative point of view, however, in practice, however, the results obtained have been considerably poorer than one might assume and can be improved. In particular, contrary to the results obtained in in vitro experiments, regardless of their chemical nature, these resins often have too low a capacity to bind cholesterol in vivo, because either the reduction in cholesterol they cause is negligible, or they must be used at very high doses, causing severe gastrointestinal side effects.

25 A very obvious thing would be to produce resins with a higher concentration of functional groups. However, it has been found that by increasing the concentration of the basic functional groups of the resin over a certain limit, whether strong or weak, their activity is reduced rather than increased. However, it has now been found that the activity of the resin depends only to a limited extent on the chemical nature and number of basic functional groups present, while the determining factor is the "availability" of the 35 functional groups for the bile acid molecules, which are known all compounds of steroid build-up and therefore immensely bulky and with low mobility.

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The immediate solution to the problem would therefore appear to be to use linear soluble resins whose functional groups are assumed to have maximum availability.

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However, it has been found that anionic resins of this type are completely unexpectedly in possession of very little activity, because the linear chains which are not bonded together agglomerate in an aqueous environment, in particular due to coordination bonds forming a completely randomized pseudogitter grid in 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.

Similarly, very strongly crosslinked resins have a very low and insufficient activity due to the formation of a too narrow lattice mill that is not available to the bile acid molecules.

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It has now been found that cholesterol-lowering anion exchange resins with very high activity can be obtained by producing resins which have a common degree of crosslinking which are within very well defined critical limits and which are different for each type of resin.

The purpose of the common crosslinking of the process of the invention is to form "masks" in the polymer having an aperture substantially "equal to" the volume of the bile acids, which can thus contact the digestive tract with the highest possible number. active functional groups.

Since functional groups of different chemical species have different volumes and therefore create different degrees of "resistance" and steric hindrance within the "masks", it is clear that the critical effective degree of crosslinking is

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different depending on the chemical nature of the resin. However, it does not in any way depend on whether the resin has a gel-like, microporous or macroporous structure.

For a linear polymer of a predetermined chemical species and with a certain number of basic active groups, i. a polymer having an ion exchange capacity is thereby obtained a predetermined cholesterol lowering effect by producing an accurate degree of uniform crosslinking.

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To achieve this degree of cross-linking and, as a result, the required opening of the meshes formed in the polymer, the cross-linking monomer in the mixture of monomers to be polymerized must be used in a precisely defined percentage.

In order to achieve uniform cross-linking and, as a result, a uniform size of the meshes formed in the polymer, a very low polymerization rate must be used by selecting the catalyst, reaction temperature, monomer concentration in the reaction solution and the catalyst concentration appropriately.

It has been found that the most suitable catalysts for providing the necessary mild polymerization conditions are organic peroxides and especially lauroyl and benzoyl peroxide. It is preferred to use benzoyl peroxide because it has a higher half-life and a better purity and catalyst performance.

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The critical conditions under which the catalysts are to be used to prepare the resins in question are:

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Lauroyl Peroxide - Acrylic: temperature 55-65 ° C; concentration 1-2% - Styrene: temperature 60-70 ° C; concentration 1-3% 5 - Epoxy: temperature 55-65 ° C; concentration 0.5-1.5%

Benzoyl Peroxide - Acrylic: temperature 60-70 ° C; concentration 0.2-1.5% 10 - 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 very easily controllable side reactions at the various stages of the various processes can cause further cross-linking of the polymer network. This can ruin the entire careful construction of the resin if not checked thoroughly enough.

Especially in the case of acrylic resins, this undesirable reaction may occur during the ammonia stage where the polyamines are used.

In the case of styrene resins, the critical step under which chloromethyler is none. In the case of epoxy resins, the difficult step is the amination when using polyamines.

It has been found that these adverse reactions can be avoided in the following way: - Acrylic: at the ammonia step a large excess of polyamines up to 6 to 7 times the stoichiometric amount must be used, 35 - The styrene: at the chloromethylation step a mild catalyst such as .g. ZnC 2 under very weak conditions, i.e. a low temperature diluted system (35-

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6 40 ° C) - Epoxy: at the amination step an excess of polyamine is used at low temperature (35-40 ° C).

As regards the choice of crosslinking agent, theoretically all molecules having two vinyl functions and having a large distance between them can be used as crosslinking agents. In practice, the following are used: divinylbenzene, divinyltoluene, divinylxylene, divinylethylbenzene and the like. Di-vinylbenzene is preferred because of its reactivity and because it is readily available.

It has now unexpectedly been found that the factors that determine the cholesterol-lowering effect of an ion exchange resin and, in particular, the size of the cross-linked "masks" contained therein, are a function of the apparent density in water and the absorbency of the resin for water, for which reason the maximum activity of any resin corresponds to a substantially constant apparent density and a substantially constant water absorption capacity.

The invention thus relates to a process for the production of non-toxic styrene, acrylic or epoxy resins 25 with cholesterol-lowering effect, which is characterized by the characterizing part of the claim.

The special and constant value for apparent density and water absorption ability, for each resin 30, corresponds to predetermined combinations of ion exchange capacity and degree of crosslinking (selected within a critical and accurately defined range) and can therefore be uniquely determined for each resin.

For the present purpose, the apparent density in water has been determined and is defined by the following method:

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7 20 g of dry resin (dried at 40 ° C in a vacuum oven until its weight is constant) is placed in 150-200 ml of water for 24 hours, stirring occasionally. Then the resin is transferred to a glass column which is precisely divided and equipped with a porous base.

Thereafter, the resin bed is expanded countercurrently, with water being supplied in an amount of 10 volumes per unit volume. volume of resin until a layer of 1 to 2 cm above the resin is obtained.

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After standing for 20 minutes, the volume of the resin layer is determined. This measurement is repeated two or three times for each sample so that the error falls within 1%. The density is expressed by the ratio of the dry weight of the resin 15 to its volume in water.

The water absorption capacity of the resin was always determined as follows: 20 g of resin, dried to constant weight at a temperature of 40 ° C under reduced pressure, was placed on a glass plate in an atmosphere saturated with humidity at 25 ° C. until no further weight gain occurs.

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

The cholesterol-lowering effect of the resins was determined in vitro as follows: 30 ml of sodium cholate solution at a concentration of 2 mg / ml in a 0.02 molar solution of phosphate buffer (pH 5) was placed in a conical flask.

35 ml of water and 30 mg of resin are added to the flask.

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After stirring for 5 minutes at 25 ° C, the contents are filtered and the unbound cholic acid is determined by a spectrophotometric method after reaction with sulfuric acid (Kier et al. J. Chim. Invest 40,755, 1952).

5

The activity is expressed by the bound sodium cholate over a certain period of time. Different samples of styrene, acrylic and epoxy resins were prepared with different exchangeability and different degree of crosslinking.

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Using the methods described above, they determined the apparent density, water absorption and activity of each resin. Maximum activity was constantly achieved with resins having an apparent density of 0.18 to 0.20 g dry matter / ml and a water absorbency of 69 to 73 wt%.

This method determined the critical range of ion exchange ability and crosslinking within which it is possible to obtain a very potent cholesterol lowering effect for any type of resin. Using this method, it was found that, in fact, all previously known resins and which have insufficient activity to be considered an effective cholesterol-lowering agent have an apparent density in water that is outside the range of 0.18 to 0.20 g dry matter / ml, and in particular a density and water absorption indicating poor non-uniform cross-linking (the "Cholestyramine" type) or an excessive and non-uniform cross-linking (Lewatit® MP 500 and "Cholestypol" - types of resin).

The strong ion exchange capacity and total ion exchange capacity were also determined for each resin.

The strong ion exchange capacity was determined as follows: 10 g of dry resin was converted to OH by percolating a 5% 35 9

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aqueous NaOH solution until C1 ions were no longer present in the eluate.

The resin was washed thoroughly until the water was neutral.

The 5 OH form was genome-formed to Cl by percolating 400 ml of a 10% aqueous NaCl solution, then washing with 1000 ml of 0 The base found in the eluate was filtered with 0.1 N HCl, with 1 ml of HCl corresponding to 0.01 milliequivalent per ml. g (meq / g).

10

The total interchangeability was determined as follows: 10 g of resin was transferred to the OH form and free amine as described above and treated with 100 ml of 1N HCl, then washed with water until neutral reaction.

15 HCl of the eluate was titrated with 0.1N NaOH, using methyl red as indicator.

The total resilience of the resin is indicated by the 20 milliequivalents of acid not found in the eluate, divided by 10. The critical values determined for the most common types of the anion exchange resins concerned and necessary to obtain good cholesterol. anti-roll effect is as follows: 25

Styrene resins with amino and ammonium groups

Strong interchangeability meq / g 2.8 - 4.0

Total exchangeability meq / g 2.8 - 4.0 Crosslink% 1.5 - 2.5

Acrylic resins with amino and ammonium groups Strong interchangeability meq / g 2.0 - 3.0

Total exchangeability meq / g 5.5 - 8.0

Crosslinking% 10 - 12 35 Epoxy resins with amino and ammonium groups

Strong interchangeability meq / g 2-5

Total exchangeability meq / g 10 - 12.5

Crosslink% 3-4

DK 160053 B

In the case of epoxy resins, the term "crosslinking" refers to the crosslinking only because of the crosslinking agent, ignoring the crosslinking due to the amine.

5

Some practical examples of the subject cholesterol-lowering resins are given below.

EXAMPLE 1 10

Preparation of Microporous Resin (AP2)

A mixture consisting of 33 parts of acrylonitrile, 16 parts of methyl acrylate, 10 parts of technical divinylbenzene (strength 60%), 15 parts of benzoyl peroxide and 40 parts of toluene is suspended in aqueous solution containing 20% by weight of gelatin.

One part of bentonite is added to the suspension.

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

The polymer thus obtained, in the form of opalescent beads, is carefully washed from the rest of the dispersing solution. The porosity is removed by steam distillation and the polymer is dried.

1 part polymer is treated with 5 parts ethylenediamine for 10 hours at 130 ° C. After cooling, the excess 30 amine is removed by repeated washing with water. The product obtained is immersed in 50 parts 1 0 and 50 parts 2 200 ^, cooled to 0 ° C and treated with 400 parts CE 2 Br for 5 hours with stirring.

Then filter, wash with ^ 0, then transfer to the chloride form in a percolation column by slowly percolating 1000 parts of 5% aqueous solution of

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NaCl.

A resin is obtained with the following properties: 5 Crosslink 10%

Strong interchangeability 2.1 meq / g

Total exchange capacity 6.2 meq / g H₂O absorbency 71%

Apparent density 0.186 g / ml Activity 18 τ 0.4 mg bound cholate

Amine Tertiary + Quaternary Type EXAMPLE 2 Preparation of a Standard Acrylic Resin (API)

A mixture consisting of 55 parts of acrylonitrile, 26.5 parts of methyl acrylate, 18.3 parts of technical divinylbenzene (60%) and 0.2 parts of benzoyl peroxide is suspended with stirring in a 20 aqueous solution containing 20% by weight of gelatin. 2 parts of bentonite are added to the suspension. The suspension is heated at 70 ° C for 40 hours.

The polymer obtained is washed, ammoniated, transferred to 25 quaternary form and to the chloride form as described above.

A resin is obtained with the following properties: 30 Crosslink 11%

Strong interchangeability 2.1 meq / g

Total exchange capacity 6.1 meq / g H2O absorbency 70.4%

Apparent density 0.192 g / ml Activity 18 τ 0.4 mg bound cholate

Amine tertiary + neighborhood near type 12

DK 1600S3B

EXAMPLE 3

Preparation of a Standard Styrene Resin (S1) .

To the suspension is added 0.5 parts of bentonite.

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

The prepared polymer is carefully washed from the rest of the dispersing solution and dried.

Then the whole product is chloromethylated with monochloro ether (200 parts) and zinc chloride (65 parts) after it has been expanded in dichloroethane (300 parts), heating the mixture for 7 hours at 35 ° C.

Thereafter, the intermediate obtained is aminated with trimethylamine (180 parts of a 40% aqueous solution) at 45 ° C for 6 hours.

25

The resin obtained had the following properties:

Crosslink 1.5%

Strong exchange rate 3.3 meq / g 30 Total exchange rate 3.3 meq / g H2O absorbency 71.7%

Apparent density 0.180 g / ml

Activity 15 τ 0.4 mg bound cholate

Amine quartersnear type 35

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EXAMPLE 4

Preparation of a standard styrene resin (S 2) A mixture consisting of 95 parts styrene, 3.5 parts technical divinylbenzene (strength 60%) and 0.7 parts benzoyl peroxide is slurried with stirring in an aqueous solution containing 15% wt% gelatin.

To the suspension is added 0.7 parts of bentonite.

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

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

A resin was obtained which had the following properties:

Crosslink 2.1% 20 Strong exchange rate 3.3 meq / g

Total exchange capacity 3.3 meq / g absorbency 71.5%

Apparent density 0.195 g / ml

Activity 15 τ 0.4 mg bound cholate 25 Amine quaternary type Example 5

Preparation of a standard epoxy resin () 30

A mixture of 93.3 parts of epichlorohydrin, 6.5 parts of technical divinylbenzene (strength 60%) and 0.2 parts of benzoyl peroxide is slurried with stirring in an aqueous solution containing 20% by weight of gelatin.

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

35 14

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The prepared polymer is carefully washed from the rest of the dispersing system and dried.

The entire polymer is then treated with 100 parts of ethylene-5 diamine and 40 parts of NaOH flakes at 65 ° C for 10 hours with stirring. The product obtained is washed with water to remove excess amine, then immersed in 50 parts of 50 and 50 parts of Na 2 CO 2 and treated with 500 parts of CH 2 Br for 5 hours at 0 ° C with stirring. Finally, wash, wash with water, then transfer to the chloride form in a percolation column by slowly percolating 1000 parts of a 5% aqueous solution of NaCl.

A resin having the following properties is obtained:

Crosslink 4%

Strong interchangeability 2.1 meq / g

Total exchange capacity 10.5 meq / g H2O absorbency 69.5% 20 Apparent density 0.180 g / ml

Activity 12 τ 0.8 mg of bound cholate

Amine tertiary + quaternary type EXAMPLE 6 25

Preparation of a standard epoxy resin (Eg). <

A mixture of 94.8 parts of epichlorohydrin, 5 parts of technical divinylbenzene (strength 60%) and 0.2 parts of benzoyl peroxide is slurried with stirring in an aqueous solution containing 20% by weight of gelatin.

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

The polymer prepared is washed, aminated and transferred into quaternary form as described in the previous example.

DK 160053B

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A resin having the following properties was obtained:

Crosslink 3%

Strong exchange rate 2.3 meq / g 5 Total exchange rate 10.9 meq / g H 2 O absorbency 70.5%

Apparent density 0.180 g / ml

Activity 12 τ 0.8 mg of bound cholate

Amine tertiary + neighborhood near type 10

In order to explain in more detail the characteristics of the resins in question, these are summarized in the following table, where they are compared with the most well-known commercial resins.

15 20 25 30 35

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The cholesterol-lowering effect of the resins in question was also investigated "in vivo".

To investigate the "in vivo" cholesterol-lowering effect of the various resins, the following experiments were used: 1) Their effect on hypercholesterolemia produced by a diet with increased cholesterol content in rats and rabbits.

2) Their effect on fecal secretion of bile acid in dogs.

1) To induce hypercholesterolemia in rats, animals are maintained on a diet according to what has been described by Nath et al. (J. Nutrit 67, 289, 1959) containing: 20 devitaminized casein 20% dl-methionine 0.4%

Hegsted salt water mixture 4% sucrose 49.1% cholesterol 1% 25 cholic acid 0.5% and vitamins

To induce hypercholesterolemia in rabbits, 1 g / day / animal cholesterol was administered by a gastric probe. Each animal species comprised 84 male animals, namely, the 30 Spraque-Dawley strain rats weighing 200 g on average and New Zealand 3 kg rabbits divided into 12 groups of 7 animals each. All the animals were put into a state of hypercholesterolemia by the feed. One group was not treated while the other 11 groups were treated with 0.5 g / kg one of the resins for 30 days.

The resins were dissolved or suspended in 10% gum arabic adhesive. Only the gum arabic adhesive was administered to the control group.

10 DK 16 Η 3 Β 3 B

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

10 2) To assess the fecal excretion of bile acid, 48 male beagle dogs were used, weighing approx. 8 kg and divided into 12 groups with four animals in each group. All animals were maintained on a standard diet under standard conditions and with the exception of the control group of dogs, 15 all groups in addition to their diet received 2 g / kg / day of one of the resins for 25 days. From the 26th day from the beginning of the experiment, the bile acids were determined in the feces of the dogs, which had fasted for 12 hours in a metabolic box (Grundy et al., J. Lipid Res. 6, 397, 1965; Makita et al., Ann.

Biochem. 5, 523, 1963; Forman et al., Clin.Chem. 14, 348, 1969).

Tables 1 and 2 summarize the results obtained with rats and rabbits brought into hypercholesterolemic state via the diet and treated with various resins.

The cholesterol-lowering effect of the orally administered resins in "in vivo" equilibrium doses was essentially consistent with the results of the "in vitro" experiments.

With regard to this, it was again found that when the resins in question had an apparent density in water of 0.18 to 0.20 g dry matter / ml and a water absorption capacity of 69 to 73% by weight of the polymer weight, they exhibited a cholesterol-lowering effect both in rats and in rabbits which is surprisingly greater than any

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20 has been obtained with other resins. The difference with respect to the prior art resins is all highly significant (P> 0.01).

5 Table 3 shows the bile acid excretion values for dogs treated with 2 g / kg / day with different resins.

It is clear that when the resins in question are administered, there is a significant increase in the fecal bile acid excretion compared to what has been achieved so far with the best resins available at present. Highly significant differences (P> 0.01) are found between the bile acid values excreted with faeces after administration of AP £, AP ^, S ^, S2, E ^ and and values 15 obtained with other resins.

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DK 160053B

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The data shown above clearly indicate that the resins in question, regardless of the chemical nature and physical form of the matrix (microporous, macroporous or gel), are effectively capable of binding bile acids and cause a cholesterol lowering when administered orally. that is greater than what has been achieved so far with known resins.

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Claims (1)

DK Vh'0d3B Patent Claims: Process for the preparation of non-toxic styrene, 5 acrylic or epoxy resins with cholesterol-lowering properties, characterized in that either A) polymerizes styrene slowly with 1.5 - 2.5% divinyl. compound (100%) in the presence of lauroyl peroxide as a catalyst at a concentration of 1-3% at temperatures between 60 and 70 ° C, or in the presence of benzoyl peroxide as a catalyst at a concentration of 0.3 - 1 5% at temperatures of 65 and 75 ° C, whereupon the resulting product is chloromethylated in a diluted system at 35-40 ° C and then aminated, or B) slowly acrylic monomer is polymerized with 10-12% of a divinyl compound (100%). in the presence of lauroyl peroxide as a catalyst at a concentration of 1-2% at a temperature of between 55 and 65 ° C, or in the presence of benzoyl peroxide as a catalyst at a concentration of 0.2 - 1.5% at a temperature of between 60 and 70 ° C, whereupon the product obtained is ammoniated o g is quaternized with up to 2 times the stoichiometric amount of polyamine, or C) epichlorohydrin is slowly polymerized with 3-4% of a divinyl compound (100%) in the presence of lauroyl peroxide as a catalyst at a concentration of 0.5 - 1.5 % at 30 a temperature of between 55 and 65 ° C, or in the presence of benzoyl peroxide as a catalyst at a concentration of 0.2 - 1% at a temperature of between 60 and 70 ° C, at which the product produced is aminated and quaternized. with an excess of polyamine at 35 - 40 ° C to obtain a polymerisate having a definite and evenly distributed degree of cross-linking, which exhibits an apparent density of 0.18 - 0.20 g of dry material in water. / ml, and a water absorbency of 69-73% by weight of the polymeric weight. 5 10 15 20 25 30 35