NL7905353A - ANION EXCHANGE RESINS WITH CHOLESTEROL-LOWERING ACTIVITIES. - Google Patents

Description

*, <k 70 8016

Texcontor Vaduz establishment

Liechtenstein

Anion exchange resins with cholesterol-lowering activities.

The invention relates to anion exchange resins for use in human therapy as cholesterol-lowering agents. Ion exchange resins have been used in particular to treat a variety of pathological conditions, such as hyperacidity, 4 * 4 * a inhibition of Na deficiency in the gastrointestinal tract, K defense, treatment of renal, pancreatic and cardiac edans, treatment ulcers, neutralization of stomach acid etc.

Obviously, any specific pathological condition 10 requires a resin with special chemical properties, which can be selected from the pocket acid resins, strong acid resins, weak base resins and strong base resins provided that these resins must be free of toxic properties to people.

The use of ion exchange resins has recently expanded to the treatment of hyperlipemia. It is known that excessively high levels of lipids, such as cholesterol and triglycerides, can cause early acteriosclerosis in the organism, resulting in heart attacks and brain oaboses. Hyperlipemia is therefore an important problem, for which an adequate medicine has not yet been found.

In order to lower cholesterol levels to normal, it is necessary to exclude all foods rich in them, especially saturated fats, and to promote their excretion.

It has been found that ion-exchange resins with a basic character account for this second point by binding the bile acids to the intestine, interrupting the intestinal-liver connection resulting in loss of cholesterol. To carry out this cholesterol-lowering method on a practical scale, various basic anion exchange resins are here with amino and / or 790 53 53 2 k ammonium groups that chemically bind the bile acids. Resins so far prepared are mainly cholesteryramine and cholestypol.

The first of these is a substantially styrene, unbuilt resin with quaternary ammonium groups cross-linked by divinyl benzene, while the second is a polymer of N- (2-aminoethyl-1) -1,2-ethanediamine with chloromethyl oxirane. Although from a theoretical point of view the chemical activity of these resins seems clear and easily determinable in terms of the quantitative effect, the practical results have turned out to be much worse than predicted and to. so far hardly improved.

In particular, often unlike. However, the results obtained in vitro were found to have too low a capacity for their chemical nature to bind cholesterol ions in vivo, so that either the reduction in cholesterol levels was insignificant or had to be administered in very high doses, thus obvious side effects in the gastrointestinal tract, occurred.

An obvious remedy seems to be the production of resins with a higher concentration of functional groups. However, it has been found that by increasing above a certain limit the concentration of the basic functional groups of the resin, whether they are weak or strong, their activity decreases rather than diminishes.

The invention is therefore based on the fact that it has now been found that the activity of the resin depends only to a limited extent on the chemical nature and the number of basic functional groups therein, while the determining factor is the accessibility of these functional groups. for bile acid molecules, all bile acids have a steroid structure and are therefore very bulky and have low mobility.

The immediate answer to this problem therefore seems to be the use of linear soluble resins, the functional groups of which have maximum accessibility.

However, it has further been found that anion resins of this type unexpectedly have very poor activity, because the linear chains, which are not bound together, agglomerate mainly in an aqueous medium mainly by coordination bonds and a completely random 790 5 3 53 * 3 pseudo-lattice. forms into which the large bile acid molecules practically cannot penetrate. Thus, most of the active groups disappear as ion exchange sites.

Likewise, strong / cross-linked resins have very low and insufficient activity due to the formation of too narrow a grid inaccessible to bile acid molecules.

According to the invention it has now been found that cholesterol-lowering anion exchange resins with a very high activity are obtained by preparing resins with a regular cross-linking which lies between certain very critical limits, which are different.

are for any type of resin.

The purpose of the regular cross-linking according to the invention is the formation of sieves in the polymer, which have an opening which corresponds substantially to the volume of the bile acids, which can thus be in contact with the largest possible number of active functional groups.

Since functional groups of different chemical nature have different volumes and therefore have different degrees of attraction and steric hindrance within the sieves, it is clear that the critically effective degree of cross-linking will differ depending on the nature of the resin. However, it is independent of whether the resin is a gel, micro-porous or macroporous.

In other words given a linear polymer of a certain chemical nature and at a certain number of basic active groups, ie a polymer with a certain exchange capacity, it obtains a certain cholesterol-lowering activity by giving it an accurate degree of cross-linking.

In order to achieve this degree of cross-linking and thus the desired size of the screenings in the polymer, the cross-linking monomer must be used in the mixture of the polymerized monomers in a precisely defined percentage.

In order to achieve uniformity at crosslinking and thus a uniform size of the screen openings in the polymer, a very low polymerization rate is measured using an appropriately selected 790 5 3 53 i catalyst, an appropriate reaction temperature, an appropriate monomer concentration in the reaction solvent and by the catalyst concentration.

It has been found that the most useful catalysts for the required average polymerization conditions are organic peroxides 2 parts, and in particular lauroyl and benzoyl peroxide. Preferably benzoyl peroxide is used because of its higher half-life, better purity and initiating ability.

The critical conditions under which the catalysts must be used to produce the present resins are: lauroylperoxide acrylic: temperature 55-65 ° C; concentration 1-2 $ - styrene: temperature 60-T0 ° C; concentration 1-3 $ - epoxy: temperature 55-65 ° Ci concentration 0.5-1.5 $ 15 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 DEG-70 DEG C .; concentration 0.2-1.0 $.

It has also been found that certain not easily controllable side reactions can cause further cross-linking of the polymeric lattice during the various process steps. This can damage the entirety of the carefully constructed resin construction if not taken into account. In particular, with acrylic resins during the ammonification using polyamines, these undesired side reactions can occur. With styrene resins, the critical step occurs during the chloromethylation. In the case of epoxy resins, the vulnerable step is amination using polyamines.

It has been found that these parasitic reactions can be counteracted as follows: - acrylic: a large excess of polyamines must be used in the ammonification, 6-7 times the stoichiometric amount; styrene: in the chloromethylation, a mild catalyst such as ZnCl 2 should be used under very mild reaction conditions, i.e.

35 a dilute system at a low temperature of 35 ° -0 ° C.

790 5 3 53 ft 1 5 - epoxy: "In the amination, an excess of polyamine should be used at a low temperature of 35- 0 ° C.

Regarding the choice of cross-linking agent, in theory all molecules with two vinyl functions with a long distance in between can be used as cross-linking agents. In practice, the following are used: divinylbenzene, divinyltoluene, divinylxylene, divinylethylbenzene, and the like. Divinylbenzene is preferred because of its reactivity and the fact that it is commercially available.

It was now unexpectedly found that. the factors determining the cholesterol-lowering activity of an anion exchanger and the size of the cross-linking screen openings contained therein are a function of the apparent density in water and the water's absorption capacity of the resin, thereby maximizing the activity of a given resin corresponds to a substantially constant apparent density and a substantially constant water-absorbing capacity.

The invention therefore relates to cross-linked anion-exchange resins with cholesterol-lowering activity with an apparent density of 0.18-0.20 g dry material / cm 2 and with a water-absorbing capacity of 69-73 wt. %.

This specific and constant value corresponds for each resin to certain combinations of exchange power and degree of cross-linking (selected within a critical and precisely defined range), which can be determined without reservation for each resin. For the purpose of the invention, the apparent density in water has been determined by the following method: 20 g of dry resin (dried at 0 ° C in a vacuum oven until constant

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weight) were stored for 2b hours in 150-200 cm of water with occasional stirring. The resin was then transferred to a glass column, which was accurately calibrated and fitted with a porous throttle plate. The resin bed was then expanded in countercurrent and then after settling, the water was discharged at a rate of 10 volumes per volume of resin until a top layer of 1-2 cm is above the resin, standing for 20 minutes more resin layer determined. This measurement was repeated 2 to 3 times with the same sample until the error is within 15. The density 7905353 * * 6 is determined by the ratio of the dry weight of the resin to its volume in water.

For the purpose of the invention, the. water absorbing capacity of the resin always as determined by the following method: 5 g of resin, dried to constant weight at H0 ° C in a reduced pressure environment, was exposed on an glass disc to an atmosphere which was at 25 ° C with moisture saturated, until the weight did not increase further. The absorbed water is expressed as a percentage of a total weight.

The cholesterol-lowering activity of the resins was determined in vitro, thus: 20 ml of a sodium cholate solution at a concentration of 2 g / l in a 0.02 mole solution of a phosphate buffer at 3 pH. 6 was charged in a conical flask. 1 cm HgO and 30 mg resin were added to this flask. After stirring at 25 ° C for 5 minutes, the contents were filtered and the unbound cholic acid determined by a spectrophotometric method after a reaction with sulfuric acid (Kier, J.

Chim. Invest. j * 0.755 (1952)).

The activity is determined by the sodium cholate bound during this time. A number of styrene, acrylic and epoxy resins were prepared with different exchange power and different sizes of cross-linking.

Using the methods shown above, the apparent density, water absorption and activity for each of these resins were determined. Maximum activity was always achieved with resins with an apparent density of 0.18-0.2 g of dry material / cnr and a water-absorbing capacity of 69-73 wt.

In this way, the critical range of exchange ability and cross-linking between which it is possible to achieve a very high cholesterol-lowering activity for any type of resin was determined.

Using the same method, it was found that in practice all hitherto known resins which are absolutely insufficiently active to be considered effective cholesterol-lowering agents had an apparent density in water which is outside the limits of 0.18-0 , 20 g of dry material per cm 35 and in particular exhibit a density and water absorption which is 3 790 5 3 53 *% τ poor non-uniform cross-linking (cholestyramine type) or excessive and non-uniform cross-linking (Lewatit MP 500 and cholestypol type resins).

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

The strong exchanging power was thus determined: 10 g of dry resin was converted into the OH form by percolating a 5% sodium hydroxide solution until no more Cl ”ions appeared in the eluate.

The resin was then washed abundantly with water until neutral. This OH "form is converted back to the Cl" form by percolating 100 ml of a 10% aqueous NaCl solution, followed by washing with 1000 cm 2 of H 2. The base with the eluate is then titrated d. 3 with 0.1 H HCl, 1 cm HCl corresponding to 0.01 milliequivalent (meq) per gram.

The total exchange capacity was thus determined: 10 g of resin in the ÖH form and the free amine form were treated with 3 100 cm 1 of IT HCl and then washed with water until neutral. The hydrochloric acid of the eluate was then titrated with 0.1 L sodium hydroxide using methyl red as an 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 determined for the most common types of anion exchange resins according to the invention for a high eholesterol mirror-lowering capacity are: as follows: styrene resins with amino and ammonium groups: strong exchange power meq / g 2.8 - U, 0

total exchange power meq / g 2.8 - k, Q

30 cross-linking percentage 1.5 - 2.5

Acrylic resins with amino and ammonium groups: strong exchange capacity meq / g 2.0-3.0 total exchange capacity meq / g 5.5 - 8.0 crosslinking percentage 10 - 12 35 Epoxy resins with amino and ammonium groups: 7905353 7% a highly exchange power meq / g 2-5 total exchange power meq / g 10-12.5 cross-linking percentage age 3 - ^

In the case of epoxy resins, the term "cross-linking" apparently means only the cross-linking caused by the cross-linking agent and the cross-linking caused by the amine is neglected.

The following examples illustrate the. the invention. Example I

Preparation of a microporous acrylic resin (AP2). 10 A mixture of 33 parts of acrylonitrile, dβ parts of methyl acrylate, 10 parts of technical divinylbenzene (60%), 1 part of benzoyl peroxide and 40 parts of toluene was suspended by stirring in an aqueous solution containing 20% by weight. gelatin.

1 part bentonite was added to this suspension. The suspension was kept at 65 ° C for 10 hours. The resulting polymer was in the form of opaque granules and was carefully washed to remove residues of the dispersing solution. The porosity agent was then removed by steam distillation, after which the polymer was dried.

1 part of this polymer was treated with 5 parts of ethylenediamine for 10 hours at 130 ° C. After cooling, the excess amine was removed by repeated washing with water. The product obtained was poured into 50 parts of water and 50 parts of NagCO 2, cooled to 0 ° C and treated with CH 2 Br under 5 hours stirring. Finally, filtration was carried out, washed with water and then brought into the chloride form in a percolation column by slowly passing through 1000 parts of a 5% aqueous solution of NaCl.

Thus, a resin was obtained with the following properties: - cross-linking 10% 30 - strong exchange power 2.1 meq / g - total exchange power 6.2 meq / g - H2O absorption power 11% - apparent density 0.186 g / ml - activity 18 + 0.U mg / cholate bound 35 _ amine tertiary + quaternary type 790 5 3 53 # -j 9

Example II

Preparation of a standard acrylic resin (API)

A mixture 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 5 was suspended in an aqueous solution with 20% by volume of gelatin, while stirring. 2 parts of benzonite were added to this suspension after which the suspension was kept at 0 ° C for 0 hours.

The polymer thus obtained was washed, mononified, quaternized and brought into the chloride form as in the previous example.

Thus, a resin was obtained with the following properties: - cross-linking 11 $ - strong exchange power 2.1 meq / g - total exchange power 6.1 mea / g 15 - HgO absorbing power 70.4 $ - apparent density 0.192 g / ml - activity 18 + 0.4 mg / cholate bound - amine tertiary + quaternary type

Example III

20 Preparation of a standard styrene resin (S ^)

A mixture of 96.5 parts of styrene, 2.5 parts of technical divinylbenzene (60%) and 1.0 part of benzoyl peroxide was slurried in an aqueous solution with 15% gelatin. 0.7 parts of bentonite were added to this suspension and the whole was kept at 100 ° C for 4 hours.

The polymer thus obtained was carefully washed to remove residual dispersion solution and then dried.

This product was then chloromethylated with monochloro ether (200 parts) and 65 parts of zinc chloride and expanded in 300 parts of dichloromethane while the mixture was kept at 35 ° C for 7 hours. Finally, this intermediate was aminated with trimethylamine (180 parts of a 40% aqueous solution) for 6 hours at 45 ° C.

Thus, a resin was obtained with the following properties: 790 53 53 • Γ c 10 - cross-linking 1.5% - strong exchange capacity 3.3 meq / g - total exchange capacity 3.3 meq / g - HgO absorption capacity 71, 7 # 5 - apparent density 0.180 g / ml - activity 15 ± 0.0 mg / cholate bound

amine quaternary type Example IV

Preparation of a standard styrene resin (Sg). A mixture of 95 parts of styrene, 3.5 parts of technical divinyl benzene (60%) and 0.7 parts of benzoyl peroxide was suspended with stirring in an aqueous solution containing 15% by weight of gelatin.

0.7 parts of bentonite were added to this suspension and the whole was kept at 70 ° C for 10 hours.

The resulting polymer was washed, dried, chloromethylated and aminated as described in Example III. Thus, a resin was obtained with the following properties: - cross-linking 2.1% - strong exchange power 3.3 meq / g 20 - total exchange power 3.3 meq / g - HgO absorption power 71.5 # - apparent density 0.195 g / ml - activity 15 + 0.1+ mg / cholate bound - amine quaternary type

Example V

Preparation of a standard epoxy resin (E ^)

A mixture of 93.3 parts of epichlorohydrin, 6.5 parts of technical divinylbenzene (.60%) and 0.2 parts of benzoyl peroxide was suspended with stirring in an aqueous solution containing 20% by weight of gelatin. This suspension was kept at 65 ° C for 1 + 0 hours. The polymer thus obtained was carefully washed to remove residues from the dispersion system and then dried.

This entire polymer was then treated with 100 parts of ethylenediamine and 1 + 0 parts of NaOH flakes for 10 hours at 35 ° C with stirring. The product obtained was washed with water to remove the excess 790 53 53 11 amine and then poured into 50 parts of water and 50 parts of Ha 2 CO 2, after which it was treated for 5 hours with 500 parts CH 2 Br with stirring. ° C Finally, filtration was carried out, washed with water and then chlorinated in a percolation column 5 by passing through 1000 parts of a 5% aqueous HaCl solution, thus obtaining a resin having the following properties : - cross-linking h% - strong exchange power 2.1 meq / g - total exchange power 10.5 meq / g 10 - HgO absorbed power 69.5% - apparent density 0.180 g / ml - activity 12 + 0.8 mg / cholate bound - amine tertiary + quaternary type

Example VI

15 Preparation of a standard encacy resin (E ^)

A mixture of 9-8 parts of epichlorohydrin, 5 parts of technical di-vinylbenzene (60%) and 0.2 parts of benzoyl peroxide was suspended with stirring in an aqueous solution containing 20% by weight of gelatin. This suspension was kept at 65 ° C for 0 hours and the polymer thus obtained was washed, aminated and made quaternary as in the previous example.

Thus, a resin was obtained with the following properties: - cross-linking 3% - strong exchange power 2.3 meq / g 25 - total exchange power 10.9 meq / g - HgO absorption power 10.5% - apparent density 0.180 g / ml - activity 12 + 0.8 mg / cholate bound - amine tertiary + quaternary type 30 For clarity, the characteristic data of the present resins are further summarized in the following table and compared with the same data for the most known resins.

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The cholesterol level lowering activity of the present resins has also been determined in vivo. This in vivo effect of. To determine the resins, the following experiments were performed: 1) Their activity in hypercholesterolaemia caused by a high cholesterol diet in rat and rabbit.

2) Their effect on the faecal excretion of bile acids in the dog.

1) To cause hypercholesterolemia in rats, the animals were kept on a diet according to J. Nutrit 67, 298 {1959) containing: 10 devitaminized casein 20% dl-methionine 0.k%

Hegsted salt mixture 4-% sucrose k9.1% ^ cholesterol 1% 15 cholic acid 0.5% as well as vitamins.

To cause hypercholesterolemia in rats, 1 g / day / animal cholesterol was administered by gavage. Each animal species included 84 males, viz. Sprague-Dawley ratt with an average weight of 200 g and Hieuw Zeeland rabbits of 3 kg, divided into 12 12 groups of 7 animals each. All animals were made hypercholesterolemic through diet. One group received no treatment while the remaining 11 groups were treated with 0.5 g / kg of one of the resins for 30 days.

The resins were dissolved or suspended in a 10% gum arabic solution. The control group received only this gum arabic solution.

On the thirtieth day of treatment, all animals were sacrificed and the total plasma blood cholesterol level collected from the carotid artery was measured (J. Chim. Endocrin. Metabolism 12, 30 1245 (1952)).

2) To measure the faecal excretion of bile acids, 48 male beagle dogs of about 8 kg were used and divided into 12 groups of 4 animals each. All these animals were kept on a standard diet and with the exception of the blank concept, all groups 2 g / kg / day 35 received one of said resins for 25 days. On the 26th day 790 5 3 53 15 after the "start of the experiment, the bile acids" were determined in the faeces of the dogs, which had fasted in a metabolic cage for 12 hours (J. Lipid Hes. 6, 397 (1965)). , Ann. 3ochem. 523 (1963) and Clin. Chem. Ih, 3½ (1969.)) · 5 The following tables show the results in the rats and cine experiments in which the cholesterol-lowering effect of the orally administered resins was similar in vivo. with that in vitro.

It was also found that the resins with an apparent density in water of 0.18 to 0.20 g of dry material / cm and a water absorbing capacity of 69-73 wt.% Of the weight of the polymer in both rats and have a good cholesterol-lowering effect in rabbits, which is superior to that obtained in other resins. The differences compared to the known resins are highly significant (P} 0.01).

15 The last table gives the bile acid excretion values. dogs again, treated with 2 g / kg / day with the various resins.

It also follows from this table that the administration of the resins according to the invention yields a marked increase in bile acid excretion compared to the best known resins. Clearly significant differences (P ^ 0.01) exist between the bile acid values after administration of the present resins A? 2, AP1, S ^, S2, E ^ and compared to the other resins.

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The figures clearly demonstrate that the resins herein, irrespective of the chemical nature of the matrix and the physical form (microporous, macroporous or gel), selectively "bind" the bile acids and, when administered orally, have a cholesterol level lowering effect which is clearly superior to any known resin.

79053 53

Claims (12)

0 V fc 1. ihii non-exchange resins, especially non-toxic styrene, acrylic or epoxy resins with strong cholesterol-lowering activities, which have an apparent density in water of 0.18-0.20 g of dry material per cm and absorbing a water power 5 of 69-73 data # based on the weight of the polymer. Styrene resins according to claim 1 with the following properties: - cross-linking 1.5-2.5% - strong exchange power 2.8 - 0. 0 meq / g 10. total exchange power 2.8-1.0 meq / g Acrylic resins according to claim 1 with the following properties: - cross-linking 10 - 12 # - strong exchange power 2-3.0 meq / g 15. total exchange power 5.5-δ, Ο meq / g h. Epoxy resins according to claim 1 with the following: properties: - cross-linking 3 - 1 # - strong exchange power 2-5 meq / g 20. total exchange power 10-12.5 meq / g. 5. A process for preparing ion-exchange resins with high cholesterol-level lowering properties, characterized in that a mixture of monomers with a critical percentage of cross-linking monomer is slowly polymerized, such that the polymer acquires a critical, predetermined and uniformly distributed degree of cross-linking. corresponding to an apparent density in water of 0.18-0.20 g of drying material / cm and a water-absorbing capacity of 69-73 wt%, wherein the polymerization catalyst is an organic peroxide in a concentration of 0.2 -10 #, and the cross-linking agent used is a divinyl compound in a percentage of 1.5-12 # at a polymerization temperature of 50-80 ° C. 6. Process according to claim 5, characterized in that the 790 53 53 V 'organic peroxide is benzoyl peroxide or laaroyl peroxide. A method according to claim 5, characterized in that the '; divinyl compound is a divinylbenzene. A process according to claim 1 for the preparation of polystyrene-5 resins, wherein the styrene is polymerized with 1.5-2.5 # of vinyl compound (100 #) in the presence of a concentration of 1-3 # of lauroyl peroxide as a catalyst and a temperature of 60-70 ° C. A process according to claim 5 for preparing polystyrene resins, wherein the styrene is polymerized with 1.5-2.5 # di-10 vinyl compound (100) in the presence of 0.3-1.5 # benzoyl peroxide as a catalyst and at a temperature of 65-75 ° C. Process according to claim 5 for preparing acrylic resins, characterized in that the acrylic monomers are polymerized with 10-12 # divinyl compound (100 #) in the presence of 1-2 # lauroyl peroxide as catalyst and at a temperature of 55-65 ° C. A process according to claim 5 for preparing acrylic resins, wherein the acrylic monomer is polymerized with 10-12 # divinyl compound (100 #) in the presence of 0.2-1.5 # benzoyl peroxide as a catalyst and at a temperature of 60-70 ° C. A process according to claim 5 for preparing epoxy resins wherein epichlorohydrin is polymerized with 3-> divinyl compound (100 #) in the presence of 0.5-1.5 # lauroyl peroxide as a catalyst and at a temperature of 55-65 ° C. Process according to claim 5 for preparing epoxy-25 resins, wherein epichlorohydrin with 3-k% divinyl compound (100 #) in the presence of a concentration of 0.2-1.0 # benzoyl peroxide as a catalyst and at a temperature of 60 -70 ° C is polymerized. lU. Pharmaceutical preparations with cholesterol-lowering activity with anion-exchange resins as active substance, in particular without non-toxic styrene, acrylic or epoxy resins with an apparent density in water of 0.18-0.20 g of dry material / cm 5 and a water absorption capacity of 69-73% by weight based on the polymer 79053 53 35