DE2704329A1 - THERAPEUTIC AGENT - Google Patents

Description

The invention relates to water-soluble polymers, namely homopolymers and copolymers of vinylbenzenesulfonic acid products, processes for the production of such polymers, preparations, which these products contain as active ingredients and methods of treating gastric ulcers.

Pharmacological studies using rats, guinea pigs and dogs as test animals show that the Products according to the invention when administered in therapeutic Dosages in conventional carriers can be used safely and effectively against gastric ulcers.

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The ongoing research to find effective agents against gastric ulcers is reflected in numerous patents and publications. A large number of these publications relate to sulfated macroanions (cf. Advances in Drug Research, Volume 8, Academic Press, pages 205-334, also US Pat. No. 3,487,150, 3,518,243 and 3,637,657, and SA Pat. No. 683,394. None however, these publications describe compounds in which the sulfor (-SO ₃ H) is attached to an aromatic ring.

U.S. Patent 3,839,890 describes sulfonated polystyrenes which are useful for inhibiting pepsin activity. In the However, the products described in this publication were only tested in vitro (see column 3, line 43).

The etiology of gastric ulcers is unknown (see J. Rhodes "Gastroenterology", 63, 171 (1972)). It is known that their Formation requires gastric secretion of acid and pepsin, which is normally controlled by neurohormonal effects.

It has now been found that certain compounds which contain units of the formula (I) given below, can be used effectively in the treatment of gastric ulcers.

The polymers according to the invention can be "homopolymers ¹¹ , which are to be understood as polymers in which all units consist of vinylbenzene or alkyl or halogen-substituted vinylbenzene units, which may optionally be sulfonated. They can also be copolymers of such units with other units However, all polymers have a viscosity average molecular weight of 100,000 to 2,000,000 with at least 50 percent of the total monomer units being vinylbenzenesulfonate units of the following formula

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(D

SO.H

where R is -H or -CH ₃ and X is -H, alkyl, preferably lower alkyl, where lower alkyl is to be understood as being alkyl groups having 1 to 6 carbon atoms, or halogen, in particular chlorine, bromine or iodine, and where the polymers are less than 5 % By weight of a polymer having a viscosity average molecular weight of 20,000 or less, preferably 50,000 or less. The scope of the invention also includes pharmaceutically acceptable salts of these polymers and the corresponding amides and esters.

In the case of "copolymers", the copolymer units are preferred Units of the formula (II)

-CH

¹ IR ¹

R '

l · R '

(II)

1 2
wherein the substituents R and R can be identical or different and can be hydrogen or a C ₁ - to Cg-alkyl, such as methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl or pentyl, while R is Acyloxy, e.g. alkanoyloxy (C.-Cg) e.g. B. acetoxy, propionyloxy or butyryloxy, or aroyloxy, such as benzoyloxy, carboxy, carbamoyl, cyano, C ₁ -C alkoxy, such as methoxy and ethoxy, lower alkoxycarbonyl, such as methoxycarbonyl and ethoxycarbonyl, or aryl, for example mononuclear aryl such as phenyl, can stand.

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Preference is given to "homopolymers" or, optionally, "block copolymers" or randomly distributed copolymers having a molecular weight of from 300,000 to "about 1,000,000. Preferred vinylbenzenesulfonate units are units of the formula

CH ₂ -CH ₂

Preferred "copolymer units" are units of the formula

, 2 I.

CH,

I c

2 4

where R is hydrogen or Cj-Cg-alkyl and R is acetoxy, Is carboxy, carbamoyl, lower alkoxy, lower alkoxycarbonyl or phenyl.

The "homopolymers" can be isotactic, syndiotactic, or be atactic.

Under the term "molecular weight" this is based on viscosity to understand determined molecular weight. In the case of very of narrow molecular weight distributions, the weight average and number average molecular weights are very similar

Under the term "molecular weight distribution ratio" is the ratio of the weight average molecular weight (M) of a polymer to its number average molecular weight (M) to understand. In the case of a uniform (unimodal) polymer with only one molecular weight species, this is Ratio ML / S 1.0. Higher numbers indicate wider or multiple distributions. The M can be through light scattering or be determined by an ultracentifuge method. The M can be determined by osmometry or by measuring other properties,

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such as the boiling point. The ratio M./M

w η

can be most easily carried out by gel permeation chromatography, the method used to determine the present case specified values is applied.

Examples of specific monomers suitable for polymerization with either sulfonated! Vinylbenzene or non-sulfonated Vinylbenzene which can be used are alkyl acrylates and alkyl methacrylates, such as methyl acrylate, Äthy1acrylat, methyl methacrylate and ethyl methacrylate, vinyl nitriles such as acrylonitrile, acrylic acid and methacrylic acid, ethylenically unsaturated Anhydrides, such as maleic anhydride, ethylenically unsaturated imides, such as N-methylmaleimide, ethylenically unsaturated Olefins such as ethylene, propylene and diisobutylene, vinyl esters such as vinyl acetate, vinyl propionate and vinyl benzoate, and vinyl amides, like methacrylamide.

The products according to the invention can be used in an outstanding manner be used to suppress and heal ulcers, as typical animal models have shown. One essentially Complete suppression of gastric ulcer was found in tests using Shay rats as well as those aroused with histamine Rats noted. In the case of guinea pigs excited with histamine, excellent control of Duodenal ulcers were also found in the steroid-challenged rats. Continuous dosing with 1/3 to 1/4 of the healing dose after the ulcer has healed has effective and essentially complete protection to recurrence of the ulcer.

The products according to the invention are also capable of the effect of To inhibit pepsin on proteolytic substrates, to protect proteins against pepsin hydrolysis and to protect the mucosa forming a protective barrier against acids, pepsin, bacteria, fungi and other harmful agents overlay.

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- 4r -

The products according to the invention, in particular polysodium vinylbenzenesulfonate, show a specific binding affinity to the mucosa of the stomach and duodenum. In these cases that will Polymers retained in the stomach 5 to 10 longer than conventional nonretentive materials. It is believed that the invention Sulphone polymers bond or adhere to intact and / or damaged mucosal tissue capacity and act as a protective coating and barrier to prevent further irritation or erosion and thus a Allow healing. It is further assumed that the materials according to the invention with secreted mucous membrane for mechanical Solidification of the same are able to react and act chemically as a protective barrier.

Certain of the invention appear surprisingly Polymers act, at least in part, as antisecretory agents, even though they are not systemic. In the case of using histamine excited guinea pigs treated with one of the polymers of the present invention showed a noticeable decrease found in secreted acid in a reinforced mucous membrane together with a prevention of duodenal ulcers. In contrast, comparators excited with histamine show one high acidity and severe duodenal ulceration.

Pharmacological studies using rats and dogs as experimental animals show that the polymers as well the preparations in which they are contained effectively promote the formation and secretion of gastric and duodenal mucus able to simulate with the formation of a protective barrier on the mucosa. When administered in therapeutic Dosages in conventional carriers enable the polymers according to the invention to promote the healing of ulcer formations, preventing damage to the mucosal surface will and the bowels will be lubricated.

The polymers of the invention can also be used to heal other ulcer conditions of the gastrointestinal tract as well as both

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For example, reflux oesophagitis can be used.

The products of the invention, unlike sulfated carbohydrates or sulfated glycoproteins (e.g., heparin), have not been found to be anticoagulants when administered either orally or intravenously. In contrast to the known sulfated and alkyl sulfonated materials, which are based on natural products, the aryl sulfonated products can be produced in a reproducible manner in clearly defined molecular weight ranges and have hydrolytically stable polymer backbones and stable carbon-sulfur bonds. Products of the invention may be fully stable to acid or base hydrolysis and, in the case of sodium salt of thermally stable up to 200 ⁰ C By contrast, sulfated polysaccharides an alternating and broad molecular weight distribution, are hydrolytically unstable, both in terms of the basic skeleton and the sulfate linkage and moreover still thermally unstable.

It was not found that the products according to the invention be systemically absorbed into the circulating lymph or blood. Orally administered polymers of the invention become complete excreted with the excrement. No absorbed polymer was found in any of the tissues or organs of treated animals established.

Certain materials such as degraded carrageenan and sulfated amyl pectin are reported in the literature to be a Can cause ulceration and bleeding in the cecum of guinea pigs or rabbits when given at high dosages to be fed. In contrast, it was found that the invention Compounds no cecum ulceration in the case of normal guinea pigs and no gastrointestinal irritation or Causing toxicity in rats or dogs when these animals are used at doses up to 2 g / kg for a period of 30 days or fed over it.

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U.S. Patent 3,893,890 describes sulfonated polystyrene polymers and copolymers with molecular weights between 600 and 7,000,000. Are these polymers and copolymers applied to guinea pigs or dogs fed, then unpredictable physiological reactions can occur, for example extreme irritation and toxicity (See Table II of this US patent). It has been found that the toxicity and irritation are inversely related to the Polymer molecular weight, and that by careful selection of molecular weight and molecular weight distribution, for example, by removing lower molecular weight materials, therapeutic safety is achieved can be. This finding is completely unexpected since, as mentioned above, both carrageenan has been degraded (Molecular weight about 30,000) and sulfated amylopectin (molecular weight about 60 χ 10) is known to have these Materials cause ulcers when fed to normal guinea pigs in amounts of 1 to 3 g / kg (see for example R. Marcus and J. Watt "Gastroenterology", 67, 473 (1974) and P. Grasso et al. "Fd. Cosmet. Toxicol" 11, 555 (1973)). Even polymers and copolymers with viscosity average molecular weights of around 500,000 to about 600,000 or more can cause significant reductions in toxicity at doses of 1 g / kg / day, when these polymers have a broad molecular weight distribution due to the fact that they are undesirable Contains low molecular weight polymers.

This finding that the toxicity is due to the presence of polymers with molecular weights of up to 50,000 forms a basis for the selection of the preferred polymer class, which comprises the products of the invention.

As for the molecular weight distribution, it can be seen that the lower the average molecular weight is, the lower the molecular weight distribution should be, otherwise an undesirably high amount of material with low Molecular weight is present. As a guideline it was found

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that polymers with an average molecular weight of 100,000 to 2,000,000 should have narrow molecular weight distributions (ie M _n / M _w = 1.05-1.30) at a lower average molecular weight determined on the basis of the viscosity, but a broader molecular weight distribution (ie M ^ / M _n = 1.3-8) with a higher average molecular weight. This can be accomplished by selectively removing low molecular weight fractions, for example, by fractional precipitation extraction, ultrafiltration or gel permeation, or by deliberate adherence to polymerization conditions and procedures which minimize the required amount of low molecular weight material formation. Such methods are known and vary depending on the polymer to be produced.

Preparations which contain the polymers according to the invention as active ingredients, as well as the polymers themselves, are suitable agents for combating ulcers and which can be administered in a large number of therapeutic dosages in conventional carriers. The products can be administered in a variety of pharmaceutically acceptable carriers, for example a flavored aqueous solution divided into a number, usually three or four, doses per day. Typical formulations contain about 10 to about 20% of the product in a suitable, flavored and colored, thickened and preserved aqueous mixture. The liquid dosage form can contain, in addition to water, small amounts of ethanol or one or more other pharmaceutically acceptable solvents. Other dosage forms are gels made with pectin, agar, hydroxyethyl cellulose or other recognized gelling agents, tablets, capsules, pills contained in microcapsules or enteric coated.

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In addition, the preparations can contain combinations of active ingredients, which are particularly suitable for healing ulcers and relieving ulcer pain, such as antacids, Anticholinergics or the like. Other active ingredients can also be used in the preparations according to the invention.

An adult patient with an average body weight (70 kg) should 2 to 10 g of the polymer according to the present invention per day in the case of an acute illness and
0.5 to 2 g of the polymer according to the invention per day in the case
a chronic illness (or to prevent it)
to take. Thus, an adult cosmetic dosage form will contain 0.1 to 2 grams or even more of the polymer per unit dosage. In any case, the unit dosage form should be such that at least a dosage range of 10 mg to about 300 mg / kg of body weight / day and in particular of 10 mg to about 200 mg / kg of body weight / day and most preferably of about 20 mg to 150 mg / kg body weight / day is recorded. The product can be administered in divided doses in the form of a variety of tablets or capsules, but liquid dosage forms are preferred. These dosage forms allow the symptomatic adjustment of exposure to the patient to be treated.

The following examples illustrate the preparation of various Preparations which contain the active ingredients according to the invention.

Example A - tablets containing 500 mg of the active ingredient per tablet
contain

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per tablet mg 500 mg 73 mg 70 mg 50 mg 7th

Poly (sodium vinyl benzene sulfonate) molecular weight = 400,000, M / M = 1.1

w η

Calcium phosphate, lactose dibasic

Cornstarch

Magnesium stearate

700 mg

Each ingredient is weighed and passed through a 40 mesh screen (US sieve). The ingredients are in a double bowl mixer mixed for a period of 10 minutes to form tablets weighing 700 mg per tablet compressed in a tableting machine.

Example B - Oral elixir dosage form containing 500 mg of the active ingredient per 5 ml

Poly (sodium vinyl benzene sulfonate) molecular weight = 400,000 M / M = 1.1 Sorbitol solution, 70% (w / w) ethyl alcohol

Propyl paraben

FD&C Yellow No. 5

Flavoring agents

purified water

Poly (sodium vinyl benzene sulfonate) comes in one serving of water dissolved by gentle stirring. The sorbitol is added to the solution. The FD&C Yellow No. 5 comes in one serving of water dissolved and added to the solution described above. The propyl paraben is dissolved in a serving of ethyl alcohol. The flavoring agent is dissolved in the remaining ethyl alcohol. The two ethanol solutions then become the one above added aqueous solution described. Sufficient water is added with continuous stirring to make up

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per 5 ml 750 mg 1000 mg 500 mg 5 mg 0, 2 mg 0, 03 mg qs

to get the final volume.

Example C - Oral solution dosage form containing 500 mg of the active ingredient per 5 ml

per 5 ml mg 750 mg 100 mg mg O, 05 2 mg 5 mg O, 03 O, qs

Poly (sodium vinyl benzene sulfonate) Molecular weight = 800,000, M / M <1.1

Vr Xl

Propylene Glycol Saccharin Sodium PropyIp araben Flavoring agent FD&C Yellow No. 5 purified water

Poly (sodium vinyl benzene sulfonate) comes in one serving of water dissolved by gentle stirring. The sodium saccharin is dissolved in a small portion of water. The FD&C Yellow No. 5 is dissolved in a small portion of water. These two solutions are added to the polymer solution. The propyl paraben is dissolved in a small portion of propylene glycol. The flavoring is in the remaining propylene glycol dissolved. The two propylene glycol solutions are then added to the aqueous solution described above. then add enough water with continuous stirring to achieve the final volume.

Example D - Dry-filled capsules containing 250 mg of the active ingredient per capsule

Poly (sodium vinyl benzene sulfonate) molecular weight = 220,000, M _w / M _n = 1.1 magnesium stearate

Per capsule 250
2 mg
, 5 mg 252 , 5 mg

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The poly (sodium vinyl benzene sulfonate) and the magnesium stearate are weighed and passed through a No. 40 mesh sieve. The ingredients are mixed in a two-bowl mixer during a Mixed for 10 minutes. Then each gelatin capsule No. O containing 252.5 mg of the mixed product filled.

The polymers of the invention can be prepared by one of two methods, either by sulfonating a polymer containing the vinylbenzene units or by polymerizing a vinylbenzenesulfonic acid salt, ester, or amide. The sulfonation method consists in the polymer with a sulfonating agent, for example sulfur trioxide, in the presence of a complexing agent, for example an ether such as dichloroethyl ether or dioxane, or an amine such as pyridine, or an amide such as dimethylformamide, or an ester such as triethyl phosphate, or To treat sulfuric acid at a temperature of -30 to 30 ⁰ C for a period of 1/2 to 12 hours.

A preferred sulfonation method is to treat a solution of a linear polystyrene in ethylene dichloride at a temperature of 0 ⁰ C or below with a complex that has been formed from sulfur trioxide (1 mole) and Dichloräthyläther (2 mol). The reaction mixture is neutralized with a base such as sodium hydroxide, potassium hydroxide or sodium bicarbonate. Any excess salt is then removed from the aqueous solution, for example by dialysis, to obtain a substantially pure aqueous solution of the sulfonated polyvinylbenzene, which solution, after removal of the water, provides a substantially pure product.

The sulfonated product can optionally be filtered off from the reaction mixture or removed therefrom by centrifugation. Any excess sulfonation complex can be removed by washing with a solvent such as diethyl ether. The product is then usually dissolved in water and neutralized. The partially or fully neutralized product can also

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isolated as a solid, for example by freeze-drying, Vacuum drying or spray drying. In the case of a partial neutralization, the solid can with a sufficient Amount of base can be formulated to effect complete neutralization upon dissolution. Conventional bases are the carbonates or bicarbonates of the alkali metals, especially sodium or potassium. The process of filtration before Neutralization is a preferred method because it removes certain low molecular weight species.

The extent of molar sulfonation on the vinyl ring can be determined by varying the molar ratio of the sulfonating agent employed being controlled. Preferred polymers are those in which at least 90% of the aromatic mers present correspond to the formula (I) given above.

A second method for the preparation of the poly (/ iny! Benzenesulfonic acids) consists in vinylbenzenesulfonic acid salts by solution polymerization in water or organic solvents, such as Alcohols, glycols, tertiary amines, amides or mixtures thereof to polymerize or copolymerize, with free Catalysts which produce free radicals are used, for example ammonium persulfates, peroxides and hydroperoxides. Redox systems can also be used, as can UV radiation. The monomer solutions can be between 10 and 50% by weight.

The vinylbenzene polymers that are suitable for sulfonation can be prepared using cationic catalysts, for example using sulfuric acid or boron trifluoride complexes, Furthermore, you can use catalysts that generate free radicals, such as benzoyl peroxide, ammonium persulfate, Azobisisobutyronitrile, hydrogen peroxide or tert-butyl hydroperoxide. Anionic initiators are also suitable. Generated using free radical generating catalysts Polymers can be produced in such a way that the cata-

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lysers used in solution, dispersion, emulsion or in bulk using known methods.

A preferred method of polymerization is anionic polymerization of the vinylbenzene or substituted vinylbenzene monomer. This method can directly provide polymers having a ratio of the weight average molecular weight (M) to the number average molecular weight (M) of 1 to 1.3. The polymer molecular weight is controlled by the amount of monomers as well as the amount of initiator in the reaction mixture, that is, the molecular weight is a function of the number of grams of monomer divided by the number of moles of initiator. Initiators are lower alkyl lithium compounds such as n-butyl lithium _f Natriumalkylverbindungen, Natriumary! Compounds such as sodium naphthalene, and Lithiumarylverbindungen, such as phenyl, Arylketyle as sodium benzophenone, and finely divided sodium. Solvents in which the reaction can be carried out are, for example, benzene, toluene, aliphatic ethers such as diethyl ether, alicyclic ethers such as dioxane, and aliphatic hydrocarbons such as heptane.

A preferred class of polymers are homopolymers of vinylbenzene made with an anionic initiator up to cessation polymerized with an M / M of less than 1.3 in a molecular weight range of 100,000 to 1,000,000 and then with complex-bound sulfur trioxide up to a sulfonation degree of the benzene ring of more than 90% have been sulfonated.

The anionic polymerization is preferably carried out in the absence of reactive impurities that cause chain termination, carried out. This method generally yields polymers with an M / M of less than 1.3. The reaction can be carried out in an inert atmosphere such as dry argon or dry nitrogen. Both the solution

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Both the agent and the monomer to be used are usually dried, deoxygenated and titrated with an adduct of the catalyst and the monomer to remove impurities. The anionic polymerization is generally carried out at a temperature between approximately 0 and 30 ^° C.

The polyvinylbenzenes can also be prepared using conventional standard free radical catalysts, for example the catalysts specified above, conditions being met that only a partial conversion (30 to 80%) of the monomer to the polymers takes place. By controlling the ratio of the catalyst to the monomers and by controlling the degree of conversion, an M / M of approximately 1.5 can be achieved. This method is used by J. H. Duerksen and A. E. Hamielec in "J. Poly. Sc. Part C" No. 25, 155-166 (1968) and by L. H. Peebles "Mol. Wt. Dist. In Polymers ", Interscience (1971). The polymer can be isolated by standard methods, but is preferred by removing the volatile constituents in a screw extruder to obtain essentially monomer-free polymer pellets isolated.

The polyvinylbenzenes suitable according to the invention can also can be prepared in solution, bulk or emulsion by a regular method using free radicals. This gives polymers with a broader molecular weight distribution, for example from approximately 2 to approximately 8 fluctuates. By selecting a polyvinylbenzene having a high average molecular weight, for example about 1x10 one can see the broad molecular weight distribution of about Use 2 to 8 to create therapeutically safe polyvinylbenzene sulfonates. At an average molecular weight of about 250,000, a molecular weight distribution of about 2.5 to about 3.0 is required in order to ensure that a therapeutically safe polyvinylbenzene sulfonate is obtained.

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ί *

An anionic copolymerization can usually be "block copolymers" deliver when a M / M of 1.3 or less is required. Two monomers are copolymerized through an anionic mechanism, one monomer with the polymer anion of the second Monomers reacts, for example in the copolymerization of styrene and methyl methacrylate, with an initiator such as n-butyllithium, is used and the styrene is polymerized to the desired molecular weight. Methyl methacrylate will then added to the polymer anions and polymerizes at the end of each polystyrene chain to form block copolymers. Monomers, which are suitable for use in carrying out anionic copolymerization are those which are based on an anionic mechanism polymerize and have no functional groups, such as carboxy groups, hydroxyl groups or the like. Which a Destroy anion. Post-sulfonation yields a copolymer with blocks of polyvinylbenzenesulfonate and poly (ethyl methacrylate).

Are copolymers using catalysts that generate free radicals produced, then the restriction on the types of comonomers that can be used is less pronounced than in the case an anionic polymerization. Any monomer that can withstand post-sulfonation can be used For example, acrylates, methacrylates, vinyl nitriles, vinyl carboxylic acids, olefins, vinyl esters and other monomers, which do not fall under the formula (II) given above.

The second method for preparing the products (I) according to the present Invention consists in the polymerization or copolymerization of salts, esters or amides of vinylbenzenesulfonic acid or related derivatives thereof. Specific examples of copolymers that can be used are acrylates, Methacrylates, vinyl nitriles, vinyl acids, such as methacrylic acid and acrylic acid, crotonates, olefins, anhydrides, vinyl esters, vinyl ethers, Vinyl imides, vinyl halides, vinyl amides, vinyl ketones, and other typical vinyl and vinylidene monomers. Preferred Monomers are methyl methacrylate, methacrylic acid, acrylic acid,

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270A329

Methacrylamide, maleic anhydride, acrylonitrile, N-methyl maleimide as well as styrene. In general, the content of the sulfonic monomer makes up at least 50% of the copolymer units and preferably more than 60% of these units.

Molecular weight is a limiting parameter regarding the viscosity of polymer drug solutions as well as avoidance gelation of the reaction mixture during sulfonation. Hence there is a practical upper limit on molecular weight in the case of a non-sulfonated polymer or copolymer, 1,000,000.

The scope of the invention also includes non-toxic pharmaceuticals compatible salts of the polymers. In general, any base that forms a salt with the acids falls with the cation has pharmacological properties that do not exert an adverse physiological effect on the body system when ingested, within the scope of the invention. Suitable cations are, for example the alkali and alkaline earth metal cations, zinc, aluminum, iron and copper, also the cations of ammonia, primary, secondary and tertiary amines, such as mono-lower alkylamines, such as tert-butylamine, di-lower alkylamines, such as "! isopropylamine, Tri-lower alkyl amines, such as triethylamine, nitrogen containing heterocyclic amines, such as piperidine, and alkanolamines, such as triethanolamine.

The ester and amide derivatives also fall within the scope of the invention the sulfonic acids (I), which are prepared by conventionally known methods, care being taken that these Derivatives are both non-toxic and physiologically tolerable for the body system and a smaller amount (less than 50%) of the total product monomer units, being functionally equivalent to the sulfonic acids and salts be considered.

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The poly (vinylbenzenesulfonic acid (s)) is or are more susceptible to actinic light or heat than the corresponding salts and should not be ^{heated to more than 100 °} C. and stored in light-protected containers or suitably stabilized by chemical methods.

The following examples illustrate the preparation of some of the present invention Products.

Example 1 - Polyvinyl benzene Stage A - titration of n-butyllithium

A solution of 2 ml (2.4 mol) of η-butyllithium in hexane is used Carefully added dropwise to a mixture of 5 ml of diethyl ether and 5 ml of distilled water in an Erlenmeyer flask. After the addition is complete, the walls of the flask are washed with distilled water, followed by a drop is added to a 1% strength by weight bromophenol blue solution. The solution is titrated with 0.100 η hydrochloric acid until the blue color disappears (the total base content of the initiator is determined in the following way: ml of 0.10 η HCl (normality of HCl) = mmol of base per 2 ml of n-butyllithium). Bases other than n-butyllithium are present in the manner determined that a solution of n-butyllithium in 2 ml of hexane to pure dry allyl bromide under a nitrogen atmosphere is added. Distilled water is then added along with a drop of a 1% bromophenol blue solution. Titration of this mixture with hydrochloric acid gives the concentration of the residual base according to the equation above. This gives the number of millimoles of the other bases present. Since the "2.4m" solution has a total base content of 2.6 3m and gives a residual base content of 0.15m, the true n-butyllithium content is 2.48m; H. (2.63-0.15).

Stage B - Anionic Polymerization of Vinylbenzene

1200 ml of benzene in a dry 2 l three-necked round bottom flask fitted with a three-way stopcock, reflux condenser, magnetic stirrer and

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IS

Thermometer is provided, is brought ^{to 60 0 C under nitrogen.} 40 ml of benzene are then placed in a dry 100 ml flask, also under argon, whereupon 0.4 ml (0.36 g, 3.5 mmol) of vinylbenzene and 0.5 ml of a 2.48 M solution of n-butyllithium in hexane (1 , 24 mmol) can be added. This initiator mixture is held at room temperature for a period of about 15 minutes, during which time the brilliant orange color of the vinylbenzene / n-butyllithium adduct is evident. This initiator solution is added to 1160 ml of the warm benzene until a light yellow color persists in the warm reaction medium for a period of at least 30 minutes to remove impurities. A 40 ml portion of the purified benzene is added to a second dry 100 ml flask under argon and to a second initiator solution prepared in the manner described above. This gives a solution of 0.031m with respect to the initiator. Whereupon 110 ml (100 g) vinyl benzene are added to 1120 ml of benzene are cooled to 10 ⁰ C. This solution is titrated with a fresh initiator solution at 10 ^° C. until a slightly yellow color is maintained for a period of 30 min. The resulting solution is heated to 30 ⁰ C, after which 16 of 0,031m initiator solution (0.5 mmol initiator) ml are added in one portion with vigorous stirring rapidly. An exothermic reaction, which causes a temperature of 30 ^° C., develops within 10 minutes. The reaction mixture is very viscous within 20 minutes. The exothermic reaction stops after one hour. The viscous orange solution obtained is kept at 50 ^° C. for a period of 1.5 hours and then cooled to ambient temperature. About 1 ml of isopropanol is added to stop the reaction. The colorless solution obtained is transferred to a separating funnel and added dropwise to 3 l of isopropanol with vigorous stirring. A good shear effect is required in order to obtain a finely divided sample. The white polyvinylbenzene was collected by filtration. Remaining isopropanol is removed under vacuum. This gives 100 g of polyvinylbenzene (yield 100%).

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Analysis by gel permeation chromatography shows an M / M of 1.13 and a molecular weight of 221,000.

Wf Xl

Essentially in compliance with the procedure described in Example 1 and using 100 g of vinylbenzene and 2.3, 0.28 and 0.13 mmol of n-butyllithium are obtained from polyvinylbenzenes with molecular weights of 49,000, 430,000 and 970,000, respectively, and M / M of 1.17, 1.08 and 1.05, respectively.

Vf Il

Example 2 - Poly (Sodium Vinylbenzenesulfonate) (Molecular Weight = 642,000)

100 grams of polyvinylbenzene having a molecular weight of 321,000 and an M / M of 3.8 (Aldrich Chemical Co.) becomes essentially sulfonated by the method of Example 3 to give a polymer having a predetermined molecular weight of about 642,000 and a predicted M / M of 3.8 is obtained. The poly

w η

mere is filtered through an 80,000 cut-off hollow fiber unit.

Example 3 - Poly (Sodium Vinyl Benzene Sulphonate)

115.3 g (1.44 mol) of sulfur trioxide are added to a solution, cooled to -10 ⁰ C solution of 3 1 ethylene dichloride and 411 g (2.88 mol) Dichloräthyläther. 100 g (0.9 mol) of a solution of a filtered polyvinylbenzene with an average molecular weight determined by viscosity of 200,000 and an M / M of 1.1 in anhydrous ethylene dichloride (1000 ml) is then slowly added with the addition tube above the surface and the temperature is kept between -10 and -5 ⁰ C. When the addition of the polystyrene solution has ended, the reaction mixture is allowed to warm to 15 ° C. and is kept at this temperature for a period of 4 hours. 4000 ml of deionized water are added and the reaction mixture is stirred for a period of 15 minutes. 50% aqueous sodium hydroxide is added to adjust the pH to 7-10 and the stirring is continued for a period of time.

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- «MT -

continued for 30 minutes. The reaction mixture is allowed to phase separate over a period of 12 hours. The organic layer is removed. The remaining water and the polyvinylbenzenesulfonate ^{salt layer are heated to 50 °} C. under a partial vacuum of approximately 340 mm Hg to remove any organic solvent still present. The reaction mixture is then diluted with an equal volume of fresh deionized water (the percentage of solids at this point is approximately 2.4%). Sodium sulfate is removed by ultrafiltration with the outlet solution stream being returned to the feed tank. Fresh deionized water is added to the feed tank to maintain a constant level. The permeate is collected in a separate container and periodically tested for polymer content by conductivity using a quaternary salt and an inorganic salt. If a precipitate is found, dialysis must be stopped and the membranes replaced. The ultrafiltration is stopped when the resistance of the permeate, measured with a conductivity bridge, is 8 to 10,000 ohm / cm. After the salt has been removed, the r ^ p ^ .iche solution is concentrated, poly (sodium vinylbenzenesulfonate) having an average molecular weight as determined by viscosity of about 400,000 and a ^ / M _n of less than 1 in 90 to 95% yield , 2 receives.

Example 4 - Copolymer of Sodium Vinylbenzenesulfonate and

Methacrylic acid (molecular weight = 615,000) (2; 1)

A solution of 30 ml of deionized water and 0.66 g (0.0097 mol, 50%) hydrogen peroxide in a 500 ml round three-neck flask equipped with a mechanical stirrer, thermometer, dropping funnel and reflux at 60 ⁰ C for a period heated by 10 minutes. A second solution of 61.8 g (0.296 moles) of sodium vinylbenzenesulfonate and 12.9 g (0.1498 moles) of methacrylic acid in 225 ml of water

709833/0923

with a temperature of 4 0 ⁰ C is added to the reaction flask over a period of 17 minutes. The received. The solution is stirred ^{at 60 °} C. overnight (20 hours). The solution is then cooled to room temperature and neutralized at pH 7.7 by adding a sodium hydroxide solution (10.0 g, 0.125 mol, 50%). The neutralized solution is dialyzed against running deionized water for 48 hours, concentrated and freeze-dried, 60 g of the copolymer in the form of a light amber solid (molecular weight = 615,000) with an M / M of 2.5, determined by gel permeation chromatography -

w ΙΊ

graphics, receives.

Example 5 - Copolymer of Sodium Vinylbenzenesulfonate and

Methacrylic acid (molecular weight = 850,000) (2.47; 1)

The following solution is made up in a flask and placed under a nitrogen blanket at room temperature leaves for a period of 13 days:

Sodium Vinylbenzenesulfonate (duPont), 91% 61.8 g (0.274 moles)

Methacrylic acid 12.9 g (0.15 mol)

Water 260 ml

Ammonium persulfate 0.5 g (0.0022 mol)

The solution is up to a pH value of 7.5 is neutralized by the addition of 19.5 g (0.128 mol) of a sodium hydroxide solution and dialyzed against running deionized water for a period of 24 hours. The dialyzed solution is concentrated and freeze-dried, 27.8 g of the copolymer being obtained in the form of a white solid (molecular weight = 850,000) M / M = 2.55, determined by gel permeation chromatography.

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Example 6 - Copolymer of Sodium Vinylbenzenesulfonate and

Methacrylic acid (molecular weight = 628100) (2.2: 1)

Nitrogen is passed through a solution of (51.8 g (0.274 mol), 91.5%) sodium vinylbenzenesulfonate and 12.9 g (0.1498 mol) methacrylic acid in 255 ml deionized water in a 500 ml three-necked round bottom flask fitted with a mechanical stirrer , Thermometer, reflux condenser, and nitrogen bubbler, bubbled for 1 hour to deaerate the solution. The solution is ^{heated to 50 °} C. under nitrogen, whereupon 1.32 g (0.135 mol, 35%) hydrogen peroxide are added. The polymerization mixture is ^{stirred at 50 °} C. under nitrogen for a period of 20 hours, and cooled down to a pH value of 7.5 by adding a 50% strength aqueous sodium hydroxide solution in an amount of 12.2 g (0.1525 Mol) neutralized. The neutralized solution is dialyzed in running deionized water over a period of 48 hours, concentrated to 600 ml and freeze dried over a period of 24 hours. This gives 62.4 g of the copolymer (MW = 628100).

Essentially according to the method described in Example 6, copolymers having the following ratios and molecular weights are obtained :

a. SVBS (2) / MAA (D MW = 915100

b. SVBS (2) / MAA (D MW = 686450, M / M = 2.8

Example 7 - Poly (ammonium vinyl benzene sulfonate)

A solution of poly (sodium vinylbenzenesulfonate) is mixed with a column filled with Amberlite IR-120 in the H form to convert the sodium salt of the polymer into the free acid. The solution is titrated to determine the mXq H / ml. This solution is then mixed with an equimolar amount of a 29.8 % ammonium hydroxide solution for a period of 1 hour stirred. The solution is used to obtain polyammonium vinylbenzenesulfonate freeze dried.

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ZO

Example 8 - Glycine Salt of Poly (vinylbenzenesulfonic acid)

A solution of poly (vinylbenzenesulfonic acid) is made with glycine stirred for a period of 1 hour, concentrated and freeze-dried. This gives the glycine salt of Poly (vinylbenzenesulfonic acid).

Example 9 - Calcium Salt of Poly (vinylbenzenesulfonic acid)

A solution of poly (sodium vinyl benzene sulfonate) in water will be used sent through a column filled with Amberlite IR 120 in Ca form in order to exchange Na for Ca. The expiration from this The column is concentrated and freeze-dried to give the calcium salt of polyvinylbenzenesulfonic acid.

Example 10 - Magnesium Salt of Poly (vinylbenzenesulfonic acid)

A dialyzed solution of the poly (vinylbenzenesulfonic acid) from Example 7 (130 meq) is ^{stirred overnight with 7.3 g (129.2 meq Mg ++} ) magnesium carbonate. The solution is filtered to remove any insoluble matter and then dialyzed for a period of 48 hours. The resulting solution is concentrated and freeze-dried to give the magnesium salt of poly (vinylbenzenesulfonic acid).

Example 11 - Copolymer of sodium vinylbenzenesulfonate and ethyl methacrylate ( 2.3: 1)

Stage A - copolymer of vinylbenzene and ethyl methacrylate

A solution of 78 g (0.75 mol) vinylbenzene, 34.2 g (0.30 mol) ethyl methacrylate, 3.0 g (0.011 mol) benzoyl peroxide and 70 ml Toluene in a 1 l round bottom flask equipped with a mechanical stirrer, thermometer, reflux condenser and addition funnel is heated to reflux (114 ° C). A second solution containing 26 g (0.25 mole) vinylbenzene, 11.4 g (0.10 mole) ethyl methacrylate and 1.0 g (0.004 mole) of benzoyl peroxide in 400 ml of toluene is removed from the addition funnel over a period of time

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added for 4 hours. The reflux treatment is continued for an additional 2 hour period. The solution is then evaporated to dryness and the glassy residue is dissolved in 500 ml of acetone. The polymer is isolated by pouring the acetone solution into 3000 ml of methanol with stirring. The copolymer is collected and dried in a vacuum oven at 40 ^{° C. overnight.} This gives 110.0 g (yield 73.5%) of the copolymer.

Stage B - copolymer of sodium vinylbenzenesulfonate and ethyl methacrylate

To a solution of 41.5 g (0.52 mol) of sulfur trioxide (sulfane B) in 143.0 g (1.0 mol) of sym-dichloroethyl ether and 700 ml of ethylene dichloride is added at -14 ° C in a 2 l round bottom flask, the equipped with a thermometer, mechanical stirrer and addition funnel, a solution of 53 g of a copolymer of vinylbenzene and ethyl methacrylate in 350 ml of ethylene dichloride at -15 ° C for a period of 12 minutes. The cooling bath is then removed and the reaction mixture is allowed to come to room temperature over a period of 3 hours. A pink colored solid is removed by filtration * - and dissolved in 600 ml of water. Any remaining organic solvents that are still present are removed, whereupon the solution is neutralized to a pH of 7.8 by adding 50 g (0.625 mol, 50 %) of a sodium hydroxide solution. This neutralized solution is dialyzed, concentrated and freeze-dried over a period of 48 hours to give 80.5 g of a copolymer having a MW of 730,000.

Example 12 - Copolymer of Sodium Vinylbenzenesulfonate and Methacrylic Acid (1.0; 1.2)

A solution of 2.0 g (0.087 mol) of ammonium persulfate in 50 ml water in a 500 ml three-necked round bottom flask equipped with a mechanical stirrer, thermometer, dropping funnel and reflux

709833/0923

is provided cooler, ^{heated to 80 0} C for a period of 30 minutes. A solution of 20.6 g (0.1 mol) of sodium vinylbenzenesulfonate and 8.6 g (0.1 mol) of methacrylic acid in 100 ml of water is added over a period of 17 minutes. The resulting solution is heated to 80-82 ° C. over a period of 4 hours and then allowed to cool overnight. The cooled solution is neutralized to a pH of 7.1 by adding 8.0 g (0.1 mol (50%)) of a sodium hydroxide solution. The solution is dialyzed against running deionized water for 48 hours, concentrated to approximately 200-250 ml and then freeze dried to give 22.9 g (78.6% yield) of the copolymer as a white solid. The NMR analysis confirms that it is a 1: 1, 2 copolymer.

Essentially following the procedure described in Example 12, other copolymers are obtained with different ratios of sodium vinylbenzenesulfonate (SVBS) to methacrylic acid (MAA) and the molecular weights given below: a. SVBS (2.47) / MAA (1) MW = 850,000, \ / \ - 2.55

b. SVBS (2) / MAA (1) MW = 524000 Ά. / Μ ' = 2.7

w η

c. SVBS (3) / MAA (1) MW = 282000

d. SVBS (4) / MAA (1) MW = 250,000

Example 13 - Copolymer of Sodium Vinylbenzenesulfonate and Methyl Methacrylate

Stage A - copolymer of vinylbenzoi (2.46) and methyl methacrylate (1)

104 g (1.0 mol) of vinylbenzoi, 40 g (0.4 mol) of methyl methacrylate, 0.5 g (0.002 mol) of benzoyl peroxide and 50 ml of benzene are placed in a 500 ml flask fitted with a stirrer, water condenser and addition funnel is provided. 100 ml of benzene are poured into an addition funnel. The system runs on nitrogen during a period of 10 minutes with stirring at room temperature

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flushed. The mixture is ^{heated to 80 °} C. under nitrogen for a period of 24 hours, benzene being added periodically to reduce the viscosity. After the heating period has ended, the reaction mixture is cooled and diluted with 100 ml of benzene. The polymer is isolated in such a way that the benzene solution is added to the vigorously stirred methanol. The solid polymer is removed by filtration, washed well with methanol and ^{dried in a vacuum oven at 60 °} C. until a constant weight is established. 120 g (85.7%) of the product are obtained in the form of a white solid.

Stage B - copolymer of sodium vinylbenzenesulfonate and methyl methacrylate '

This sulfonation is carried out essentially in accordance with the procedure described in Example 12, the following amounts of material being used: 35.6 g (0.1 mol) of the copolymer of stage A described above, 127 g (0.89 mol) of sym-2- Ethyl chloride, 35.4 g (0.443 mol) of sulfone B, 1025 ml of ethylene dichloride and 35 g (1440 ml) of a 50% sodium hydroxide solution. One half of the neutralized solution is dialyzed over a period of 48 hours and then freeze-dried to give 36.2 g of the product as a white solid (MW = 298,000, M / O = 2.1).

V * .Ii

Example 14 - Copolymer of sodium vinylbenzenesulfonate and methyl methacrylate (3.8; 1)

To a solution of 4.0 g (0.0175 mole) of ammonium persulfate, 150 ml of water and 25 ml of dimethylformamide in a 1 1 three-necked round bottom flask equipped with a mechanical stirrer, thermometer, addition funnel and reflux condenser, at 80 ⁰ C, a solution of 41.2 g (0.2 mol) of sodium vinylbenzenesulfonate, 5.0 g (0.5 mol) of methyl methacrylate in 250 ml of water and 75 ml of dimethylformamide (DMF) were added dropwise over a period of 4 hours. After this addition, a "chaser" of 0.5g ammonium

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270A329

persulfate, dissolved in 10 ml of water was added, followed by holding the solution at 80 ⁰ C for a further period of 16 hours. This solution is concentrated under reduced pressure to remove the water and dimethylformamide. The glass-like polymer obtained is dissolved in 500 ml of water, neutralized to a pH of 7.5 by adding a sodium hydroxide solution and dialyzed over a period of 48 hours. The dialyzed solution is concentrated to 400 ml and freeze-dried to give 42.5 g of a white solid product (MW = 100,700).

Example 15 - Copolymer of Sodium Vinylbenzenesulfonate and Methacrylamide (2.2; 1) MW = 350,000.

A solution of 82.4 g (0.36 mol) of sodium vinylbenzenesulfonate, 18.9 g (0.22 mol) of methacrylamide, 0.5 g (0.002 mol) of ammonium persulfate and 360 ml of water is brought to 80 ^° C. in a 1 1 flask heated with stirring and under nitrogen and held under these conditions for a period of 20 hours. At the end of this period, the reaction mixture is cooled to room temperature, neutralized to pH 7.5 by the addition of approximately 0.5 g of a 25% sodium hydroxide solution, dialyzed over a period of 48 hours, concentrated to 600 ml and freeze-dried , 83 g of a white solid product (MW = 350,000) being obtained.

Example 16 - Copolymer of Sodium Vinylbenzenesulfonate and Methacrylamide (2.2; 1) MW = 526,000

The procedure described in example 15 is followed exactly, with the exception that the amounts are doubled. The neutralized solution is then used for a period of 4 neutralized for 8 hours. The dialyzed solution is then ultrafiltered (diafiltered) into two parts, whereby one Amicon TC -! - device with an XM-300 membrane

709833/0923

- 99 -

turns. The ultrafiltration conditions are as follows: flow rate (above the membrane) 1.0 to 1.6 l / min; Inlet pressure (across membrane) 2.1 to 2.8 kg / cm *; Filtration rate = variable between 2 and 30 ml / min and air pressure (at the pump) = 2.1 to 2.4 kg / cm ² . During this diafiltration (deionized water is added to the retentate at the rate at which the filtrate is removed in order to keep the volume constant) it is necessary to stop the ultrafiltration periodically and to rinse the membrane with ordinary water. After the ultrafiltration has ended, the retentate is concentrated to approx. 600 ml and freeze-dried, 92 g of the product being obtained in the form of a white solid. Viscosity measurements give a molecular weight of 526,000 and a monomer distribution of 2.2 / 1 as determined by NMR.

Example 17 - Copolymer of Sodium Vinylbenzenesulfonate and Methacrylamide (2.2: 1) MW - 442600

The polymerization method is essentially the same as in Example 15, the following amounts of material being used: 247.2 g (1.098 mol) of sodium vinylbenzenesulfonate, 1080 ml of water, 56.7 g (0.0666 mol) of methacrylamide, 1.5 g (0 0.0066 mol) ammonium persulfate and 1.95 g sodium hydroxide. After the polymerization, the solution is neutralized, diluted to 19 l and dialyzed in such a way that this solution is pumped through the hollow fibers of two Dow b / HFD 1 dialysis beakers (in series) at a rate of 10 ml / min, while ^; ionized water is pumped through the beakers (around the hollow fibers) at a rate of 50 ml / min. The retentate (solution retained by the fibers) is concentrated to 1.5 liters and freeze-dried. This gives 273 g of a white solid product (MW «443000).

709833/0923

Example 18 - Copolymer of Sodium Vinylbenzenesulfonate and Methacrylamide (3.75: 1) MW = 539,000

A solution of 302.4 g (1.3213 mol) of sodium vinyl benzene sulfonate, 76.4 g (0.88 mol) of methacrylamide in 1343.4 g of deionized and deaerated water in a 5 l four-necked round bottom flask, which is supplied with a mechanical stirrer, thermometer, reflux condenser, nitrogen inlet tube and liquid inlet tube is provided heated to 75 ° C. under nitrogen and with stirring. 3.02 g (0.0132 mol) of ammonium persulfate in 10.7 g are added to this solution of deionized and dehydrated water is added, followed by stirring for a period of 15 minutes. A third Solution made from 362.9 g (1.586 moles) of sodium vinylbenzenesulfonate in 1286.6 g of deionized and deaerated water is pumped into the reaction mixture using a variable speed diaphragm pump will. The following speeds are maintained: 25 ml per minute over a period of 15 minutes, 12.5 ml per minute for a period of 60 minutes, 6 ml per minute for a period of 30 minutes and 3 ml per minute for a period of 30 minutes. The reaction mixture is then heated, and so is the nitrogen stirred for a further 2 hours and cooled to room temperature. One third of the reaction mixture (1.13 ml) is in the reservoir of the Amicon TC-1 ultrafiltration device filled, 306 g of sodium chloride, dissolved in 3.0 1 of water, are added, whereupon more water is added to the Set total volume to 19 liters. 38 l of a 0.3 η sodium chloride solution are placed in the diafiltration medium reserve container filled in, whereupon the polymer solution is diafiltered using an XM-100 membrane until all 38 1 of the Sodium chloride solution have run through the apparatus. The diafiltration is so long using deionized Water continued as the diafiltration medium until a total of 125 liters of filtrate had been collected. The retentate (i.e. polymer solution, which does not pass through the membrane) is removed from the device, concentrated and freeze-dried, whereby one

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270A329

195.8 g of a white solid are obtained. Viscosity measurements give a molecular weight of 539,000.

Example 19 - Poly (Sodium Vinylbenzenesulfonate)

Six samples of a monodisperse polyvinylbenzene (Pressure Chemical Company) with molecular weights of 2200, 20400, 37000, 110,000, 200,000 and 390,000 each with M _w / M _n of less than 1.10 are sulfonated essentially as described in Example 3, wherein Polyfcodium vinylbenzenesulfonate) with molecular weights of 4400, 40800, 74000, 220,000, 400,000 and 780000, respectively, each having a predetermined M / M of less than 1.10 and a molar percentage sulfonation of (the 4400 sample is not dialyzed) 97 %, 82%, 90%, 94%, 95% and 91%, respectively.

Example 20 - Poly (Sodium Vinyl Benzene Sulphonate)

A solution of 144 g of sodium vinylbenzenesulfonate in 700 ml of water is treated with 0.8 g of ammonium persulfate and ^{heated to 80 °} C. over a period of 20 hours. The standard work-up gives poly (sodium vinylbenzenesulfonate) with an average molecular weight of 195,000, determined on the basis of the viscosity. When administered orally at 50 mg / kg, this substance enables 91% control in a Shay rat. At 100 mg / kg, 36% control is found in a histamine guinea pig. At 100 mg / kg, 41% control is found in a steroid rat. When feeding guinea pigs in an amount of 10, 50 and 200 mg / kg in sugar water for a period of 35 days, no noticeable pathology is found. In particular, there is no irritation in the gastrointestinal tract, and no dying or dead animals are observed.

Example 21 - Choline Polystyrene Sulphonate

20.6 g of sodium polystyrene sulfonate are dissolved in water (15% strength by weight

709833/0923

3?

Solution) resolved. Then add 13.96 g of an anhydrous choline chloride to form the choline polystyrene sulfonate to.

The sodium / choline polystyrene sulfonate is obtained essentially by the method described above, with 7.0 g of choline chloride being used instead of the 13.96 g of choline chloride.

The following values in Table I show the effectiveness of the products according to the invention against ulcers. To test the Connections are chosen four experimental models.

1. Rats with a closed gastric outlet (16 hour Shay rat)

Anesthetized female rats (200 to 220 g) were the gastric exits sealed, followed by oral route of the test compound at a dose of 50 mg / rat in a total volume of 2.0 ml was administered. Control animals received 2.0 ml of water. The animals were sacrificed 16 hours later. Your stomachs were removed and opened along the greater curvature, indicating the extent of ulceration of the nonglandular portion of the stomach and evaluated using an arbitrary rating system that varies between 0 and 4.

2. Steroid treated rat

Female rats of 175-190 g were housed individually and given food and water ad libitum. In each Animals were then subcutaneously administered 10 mg of prednisolone daily for three consecutive days, suspended in 0.2 ml of a 0.5 % methocel solution, injected. Simultaneously with the prednisolone injections each animal received 100 mg of the test compound in 1 ml of water by the oral route twice a day. The rats were killed on the fourth day, whereupon their stomachs are removed and opened along the greater curvature, and upon the appearance and the Ulcer severity were examined.

709833/0923

3. Histamine-induced ulcers in guinea pigs

Adult male albino guinea pigs (400 to 500 g) were injected intramuscularly once with histamic acid phosphate in an amount of 10 mg / kg suspended in a mixture of beeswax and peanut oil (1: 9). The animals were then orally administered the test compound in an amount of 100 mg / GP twice a day (morning and afternoon) for two consecutive days. The guinea pigs were killed on the morning of the third day. The stomachs with about 10 cm of duodenum attached were removed. The Duodena were then examined for perforations and ulcers, the incidence and severity of ulceration was evaluated by means of a random, fluctuating between 0 and 4 rating system.

4. Histamine-induced duodenal ulcers in rats

Female rats (220 to 225 g) were injected subcutaneously with histamine-2HCl at 350 mg / rat in a total volume of 1.0 ml. Immediately after the histamine injection , an oral dose of 2 ml of a solution containing 50 mg of the test compound was administered to each rat. 24 hours later , the stomachs with the duodena attached were removed and examined for ulceration.

Calculating the percentage of inhibition 1. 16 hour shay rat anti-swelling test

The stomachs were removed and opened along the greater curvature . The stomachs were then rated according to the following scheme:

0 - Complete absence of bleeding from either ulcer.

1 - One or two small areas with a bleeding and / or

Ulcers.

2 - About 25% of the stomach is ulcerated. 3-25 to 50% of the stomach is ulcerated.

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-W-

4 - Perforation and / or severe ulceration all over the mucosa.

2. Ulcer test using rats with a histamine induced duodenal ulcer

The duodenum with the stomach attached was removed and opened. The duodenum was then examined for ulceration. The results are the number of duodenal ulcers on a total or zero basis. The inhibition was determined by comparing the duodenal ulceration in the case of treated and untreated animals.

3. Histamine-induced duodenal ulcers in guinea pigs

The animals were killed, whereupon the stomachs with attached Duodena (approximately 10 cm in length) were carefully removed. The duodena were then perforated and / or open ulcers examined and scored as follows:

0 - lack of pronounced pathology. 1-1 to 4 small duodenal ulcers.

2,> 4 small areas of ulceration.

3 - Severe ulceration and / or tissue disintegration

necrotic sites in the duodenum.

4 - perforation.

Ulcer assessment

Total number of duodena assessed

4. Acute steroid ulcer calculations

Total number of ulcers + occurrence

. ".._, _ ·, ..., __ and severity *

Mean ulcer mark = ^^ _{d &} . _{tested animals}

* Severity

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O - No grossly visible ulcer, 1-1 to 4 grossly visible ulcers, 2-5 to 9 gross ulcers and 3-10 or more gross ulcers.

The antiulcer activity is measured using four experimental Animal models evaluated according to the following criteria.

Means that in the case of the Shay model as well as one of the duodenal ulcer models show no antiulcer activity are considered ineffective antiulcer agents:

1 . 75 to 85% or greater inhibition of gastric ulcer in the case of the 16 hour Shay rat with a single dose of 50 mg / rat, P.O .;

2. 25 to 50% or greater inhibition of duodenal ulcer in the case of the 24 hour histamine rat model in a single dose of 50 mg / rat, P.O .;

3. 25 to 40% or greater inhibition of duodenal ulcer in the case of the 48 hour histamine guinea pig model at a daily dose of 100 mg / animal, P.O., twice daily for a period of 2 days with no toxicity or cecal pathology and

4. 25 to 40% or greater inhibition of gastric ulcer

in the case of the 3 day steroid rat model at a dose of 100 mg / rat P.O., twice for 3 consecutive days without Toxicity or cecal pathology.

ο τ w t. · Ulcer evaluation of treated animals _Ληη % inhibition = ulcer evaluation of comparative animals - * ¹⁰ °

It has been found that low molecular weight polymers are toxic when histamine-induced in guinea pigs Ulcers and administered to rats with steroid-induced ulcers (showing low molecular weight polymers no toxicity in the case of normal rats). When fed at 1 g / kg / day to normal guinea pigs cause low molecular weight polymers to cause blood

709833/0923

like Zo a or death after seven days. Dogs are also particularly sensitive to low molecular weight polymers in the amount of 1 g per kg / day. It will be a Bleeding of the gastrointestinal tract, diarrhea, ulceration in the bowels and impairment of the liver established. These symptoms often linger after the test is finished. High molecular weight polymers can fed to normal guinea pigs and dogs for a period of 30 to 90 days without being fed a significant pathology is detected. No secondary pathology occurs when using the polymers of the invention model animals suffering from ulcers are fed.

The values in Table II below show the toxicity of the low molecular weight compounds. Under toxicity it is to be understood that the compounds cause cecal bleeding in the case of some of the test animals (rabbits or guinea pigs) and generally cause gastrointestinal ulceration and bleeding in other test animals, wherein these phenomena can result in the death of the animals.

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Table I.

rat Rat with steroid (sodium vinylbenzenesulfonate) Guinea pigs with Anti-ulcer activity of the poly 94 buzz Rat with histamine Histamine ulcer Molecular weight shay 82 inactive* duodenal ulcer inactive* 68 21 80 47 4000 84 40 80 50 40000 87 22nd 60 33 74000 89 23 100 - 220000 (Ex. 16) 79 43 48 31 350000 81 32 80 - 400,000 (Ex. 4) 89 41 41 40 526000 78 37 50 32 400,000 (Ex. 5) 87 19th - 19th 615000 (Ex. 21) 82 39 80 21 800000 (Ex. 6) 92 54 - - 850000 (Ex. 6a) 85 47 60 30th 443000 (Ex. 6b) 89 34 - 38 628000 (Ex. 12b) 89 49 - 32 915000 83 23 686450 89 29 25th - 524000 (Ex. 2) 91 23 25th - 298000 23 - 850000 - 642000

* toxic to animals

N) CD

Table II

O
CO
N>

Toxicity comparison: BoIy (sodium vinylbenzenesulfonate, Ηατο- and copolymers with low molecular weight
to such high molecular weight compounds

Length of the sub-molecular weight study of the compound

Dose dose, test animal

bloody Zöka deaths

4 weeks 4 weeks 4 weeks

4 weeks 15 days 15 days 4 weeks

4 weeks 30 days 30 days 7 days

30 days

7 days

26 days

4000

4000

40000

40000

74000

220000

400,000

800000

400,000

615000

850000

(Ex.

850000

628100

628100 steroid rat
Steroid rat
800 mpk normal guinea pig

800 mpk histamine guinea pigs 7/11 800 mpk normal guinea pigs 800 mpk normal guinea pig 800 mpk normal guinea pig

800 mpk normal guinea pig -

Dog no observable

1 g / kg-day for 2 weeks

Customer

1 g / kg-day for 2 weeks. ,. ,

800 mpk normal guinea pig

no observable

5/8 7/8 5/10

3/11 2/6 0/6 0/10

0 / 1C Pathology Patlt) logy 0/10

Change in weight

Loss loss loss

loss

Loss + 70g / animal> 70g / animal

70 g / animal

gAg'day for I weeks

Dog no observable pathology I oche
800 mpk normal guinea pig ·.

800 mpk dog ^: "

XO O CO CO

Claims (1)

Claims 1. Therapeutic agent, characterized by a polymer, in which at least 50% of the total monomer units are comprised of vinylbenzenesulfonate units of the formula consist, wherein R is -H or -CH, and X -H, alkyl, preferably lower alkyl, where lower alkyl groups with 1 to 6 carbon atoms are to be understood, or halogen, in particular chlorine, bromine and iodine, or pharmaceutically acceptable non-toxic salts thereof, where the polymer has a viscosity average molecular weight of 100,000 to 2,000,000 and less than 5% by weight polymer having a viscosity average molecular weight of 20,000 or less. 2 / ^ fProduct according to Claim 1, characterized in that the / J polymer also has units of one or more of the corresponding amides and / or esters and / or units of the formula -CH (R ¹ JC (R ² ) (R ³ ) - 1 2 contains, wherein the substituents R and R, which are the same or different. Can be hydrogen or (C ₁ -Cg) -alkyl and R can be acyloxy, aroyloxy, carboxy, carbamoyl, cyano, (C ₁ -Cg) -AlkOXy, (C ₁ -Cg) alkoxycarbonyl or aryl . 709833/0923 ORIGINAL INSPECTED 3. Product according to claims 1 or 2, characterized in that it contains at least 6P% of the vinylbenzenesulfonate units having. 4. Product according to claim 3, characterized in that it is at least 90% of the vinylbenzenesulfonate units. 5. Product according to one of the preceding claims, characterized characterized in that the polymer has a viscosity average molecular weight of 300,000 to 1,000,000. 6. Product according to one of the preceding claims, characterized characterized in that the polymer has a molecular weight distribution of 1.01 to 8. 7. Product according to one of the preceding claims, characterized in that that R is -H, X is -H and R, if this substituent is present, is -H. 8. Product according to one of claims 2 to 7, characterized in that 1 3 net that R is -H and R is acetoxy, carboxy, carbamoyl, (C ₁ -C ^) - AlkOXy, (C ₁ -C ₄ -) alkoxycarbonyl or phenyl. Io Io 9. Product according to one of the preceding claims, characterized in that that the polymer is less than 5% polymer with an average viscosity determined Contains molecular weight of 50,000 or less. 10. Product according to one of claims 2 to 9, characterized in that that the polymer contains units of one or more of the following components: vinylbenzene, alkyl acrylate, alkyl methacrylate, Vinyl nitrile, acrylic acid, methacrylic acid, ethylenically unsaturated aldehydes, ethylenically unsaturated imides, Ethylenically unsaturated olefins, vinyl esters and vinyl amides. 709833/0923 11. Therapeutic product according to claim 10, characterized in that that the polymer contains units of one or more of the following components: methyl methacrylate, Maleic anhydride, methacrylamide and methacrylic acid. 12. Therapeutic product according to claim 1, characterized in that that it consists of units of vinylbenzene, more than 90% of these units being sodium vinylbenzenesulfonate units and further wherein the polymer has a viscosity average molecular weight from 400,000 to 500,000 and a molecular weight distribution of 3 or less. 13. Product according to one of the preceding claims, characterized characterized in that it is in unit dosage form and contains 0.1 to 2 grams of the polymer. 14. Product according to claim 13, characterized in that it is in the form of a shaped ingestible article. 15. Therapeutic preparation, characterized in that it consists of a therapeutic product according to one of the preceding claims and a pharmaceutically acceptable carrier. In that it is in a unit dosage form, each dosage unit a contains such a quantity of the product according to the claims 1 to 14, that the daily dosage of 10 mg to be treated 16. A therapeutic preparation according to claim 15, characterized in that the polymer / kg body weight of a Person is relieved. 17. Preparation according to claim 16, characterized in that the daily dose is 20 mg / kg to 150 mg / kg. 709833/0923 Process for the preparation of a therapeutic product according to claim 1, characterized in that either (a) a monomer or mixture of monomers containing at least 50% vinylbenzenesulfonate units (or units a pharmaceutically acceptable non-toxic salt thereof) according to claim 1, is polymerized or (b) a polymer is formed which has at least 50% vinylbenzene units of the formula contains, wherein R and X have the meaning given in claim 1, and this polymer is sulfonated in such a way that that the finished polymer has at least 50% vinylbenzenesulfonate units (or units of a pharmaceutically acceptable non-toxic salt thereof), the polymerization is carried out under such conditions that a polymer with an average molecular weight of 100,000 to 2,000,000 determined on the basis of the viscosity, and, moreover, such polymerization conditions are observed that a polymer is produced which is less as 5% by weight of polymer with an average molecular weight of 20,000, determined on the basis of viscosity or less, or thereafter of the polymer product such an amount of a polymer with a base the viscosity average molecular weight of 20,000 or less is separated from that obtained therapeutic polymer product contains less than 5% by weight of such low molecular weight polymer. 19. The method according to claim 18, characterized in that a therapeutic product according to any one of claims 2 to 12 709833/0923 will be produced. 20. A method for producing a therapeutic preparation, characterized in that a therapeutic product according to any one of claims 1 to 12 with a pharmaceutical compatible non-toxic carrier and / or formed into a shaped ingestible unit dosage form will. 21. The method according to claim 18, characterized in that a therapeutic preparation according to claims 15, 16 or 17 is produced. 709633/0923