IE44690B1 - Pharmaceutical compositions containing polyvinylbenzenosulfonic acids - Google Patents

Abstract

Water-soluble polymers having a molecular weight in the range of 100,000 to 2,000,000 including homopolymers and copolymers of vinylbenzenesulfonic acids and salts thereof wherein the benzene ring may be substituted by various radicals, compositions containing said products and methods useful in the treatment of ulcers are disclosed. The products are prepared by polymerization or copolymerization of vinylbenzene or substituted vinylbenzene followed by sulfonation or alternatively by the polymerization or copolymerization of substituted or unsubstituted vinylbenzenesulfonic acid salts.

Description

This invention is concerned with therapeutic compositions, containing water soluble polymers including homopolymers and copolymers of vinylbenzene-sulfonic acid products as the active ingredient, for treating peptic ulcers.

Pharmacological studies employing rats, guinea pigs and dogs as the experimental animals indicate that the compositions of this invention when administered in therapeutic dosages are safe and effective in treating peptic ulcers.

The continuing search for an· effective anti-ulcer drug is evidenced by numerous patents ana publications which have issued. A number of these publications are directed to sulfated macroanions and reported in Advances in Drug Research, Vol. 8, Academic Press, pp. 205-334. See also U.S. Patent No. 3,487,150, DEXTRAN SULPHATE TREATMENT OF PEPTIC ULCERS; U.S. Patent No. 3,518,243, SULFONATED DERIVATIVES OF A GLYCOPEPTIDE EXTRACTED FROM ANIMAL ORGANS USEFUL AS DRUGS AND A PROCESS FOR THE PREPARATION THEREOF; U.S. Patent No. 3,637,657, ALUMINUM COMPLEX OF SULFATED POLYSACCHARIDE AND A PROCESS FOR THE PREPARATION THEREOF; and Republic of South Africa Patent No. 683,394, COMPOSITIONS AND METHODS FOR CONTROLLING PEPTIC ULCERS. None, however, discloses compounds wherein the sulfo radical (-SO^H) is on an aromatic ring.

U.S. Patent No. 3,893,890, PROCESS FOR INHIBITING THE ACTION OF PEPSIN, discloses sulfonated polystyrenes useful for inhibiting pepsin activity. However, the products of that - 3 .Λ invention were tested only in vitro (see column 3, line 43).

The etiology of peptic ulcers is unknown. (For a review, see Rhodes, J., Gastroenterology, 63, 171 (1S72)).

It is known that their formation requires the gascric secretion of acid and pepsin which are normally controlled by neurohormonal interactions.

It has been found that certain compounds containing units of Formula I below are effective in treating peptic ulcers The polymer used in this invention may be homopolymers, 10 by which we mean polymers wherein all of the units are vinylbenzene or alkyl or halo-substituted vinylbenzene units, sulfonated or unsulfonated. They may also be copolymers of such units with other units. All of the polymers, however, have a viscosity average molecular weight from 100,000 to 2,000,000, and at least 50% of the total monomer units therein are vinylbenzenesulfonate units of the following formula: R wherein R is -H or -CH^ and X is -H, alkyl or halo and which polymers contain less than 5 percent by weight of polymer of viscosity average molecular weight of 20,000 or less, preferably 50,000 or less. Also included within the scope of the polymers used in this invention are those of pharmaceutically acceptable salts of the benzene sulfonate units (I) , and the 4 θ 8 © -4-. corresponding amides and esters.

In the case of copolymers, the copolymeric units preferably are units of the formula: R3 ί -CH-C- 2 wherein R and R are the same or different radicals and are each hydrogen or C^ to Cg alkyl such as methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl and tert-butyl, and pentyl; R is acyloxy, for example, alkanoyloxy (C^-C^o) such as acetoxy, propionyloxy or butyryloxy; or aroyloxy such as benzoyloxy, carboxy, carbamoyl, cyano, C^ to Cg alkoxy such as methoxy and ethoxy? c^_g alkoxy carbonyl such as methoxycarbonyl and ethoxycarbonyl or aryl, for example mononuclear aryl such as phenyl.

Preferred are homopolymers or, alternating, block or random copolymers having a molecular weight of from 300,000 to about 1,000,000. Preferred vinylbenzenesulfonate units are units of the formula: -rti _CH- Preferred ''copolymer units are units of the formula: 44630 ? wherein R is hydrogen or to Cg alkyl and R' is acetoxy, carboxy, carbamoyl, lower alkoxy, lower alkoxy carbonyl or phenyl.

The homopolymers can be isotactic, svndiotactic or atactic.

As used in this specification, the term “molecular weight means the viscosity average molecular weight. Tor very narrow molecular weight distributions, weight average and number average molecular weights are quite similar.

Also for the purposes of this specification molecular weight distribution ratio means the ratio of the weight average molecular weight (S ) of a polymer to its number average molecular weight (Rn). For a unimodal polymer having only one molecular weight species the Rw/Nn is 1.0. Higher numbers indicate broader or multiple distributions. The S5 may be determined by light scattering or ultra-centrifugation. The can be determined by osmometry or measuring some other colligative property like boiling point. The M /f? is most readily determined by gel permeation chromatography, the method used in obtaining the values reported in this specification.

Examples of specific monomers which can be employed in the polymerization with either sulfonated vinylbenzene or unsulfonated vinylbenzene include alkyl acrylates and alkyl methacrylates such as methyl acrylate, ethyl acrylate, 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-methyl maleimide, ethylenically unsaturated olefins such as ethylene, propylene and diisobntylene, vinyl esters such as vinyl acetate, vinyl propionate and vinyl benzoate, and vinyl amides such as methacrylamide.

The products used in this invention have shown excellent control and healing of ulcers employing typical animal models. Essentially complete control of gastric ulcers has been obtained in tests on a Shay rat and on a histamine-challenged rat. Excellent control of duodenal ulcers has been obtained v;ith a histamine-challenged guinea pig as well as a steroid-challenged rat. Continued dosage with from one-third to one-quarter of the healing dosage after the ulcer has healed has provided effective and essentially complete protection from ulcer recurrence.

- The polymers used in the invention have also been found to inhibit the action of pepsin on proteolytic substrates, to protect proteins' from pepsin hydrolysis and to coat the mucosa to form a protective barrier against acid, pepsin, bacteria, fungi and other noxious agents.

The said, polymers containing in particular poly (sodium vinylbenzenesulfonate) have been discovered to have specific binding affinity to the mucosa of the stomach and duodenum.

In these cases polymer has been found to be retained in the 44680 stomach five to ten times longer than conventional nonretentive materials. It is believed that the present sulfonic polymers may bind or adhere to intact and/or abraded mucosal tissue to act as a protective coating or barrier to prevent further irritation or erosion and permit healing. It is further believed that active agents used in this invention may interact with secreted mucous to strengthen the mucous mechanically and chemically to act as a protective barrier.

Surprisingly, certain of the present polymers also appear to function, at least in part, as antisecretorv agents even though they are non-systemic. In histamine-challenged guinea pigs treated with one of these polymers a marked decrease in secreted acid has been noted accompanied by increased mucous and prevention of duodenal ulcer. By contrast, the histamine-challenged control had a high acid output and severe duodenal ulceration.

Pharmacological studies employing rats and dogs as the experimental animals indicate that the polymers and compositions containing them may be effective in stimulating the formation and secretion of gastric and duodenal mucous to form a protective barrier on the mucosa. When administered in therapeutic dosages in conventional vehicles the present, polymers have been found to promote the healing of ulcerations, prevent injury to the mucosal surface and lubricate the intestines.

The compositions of the invention can also be employed in other ulcerative conditions of the gastrointestinal tract such as reflux esophagitis.

We have not found the polymers used in the compositions of the invention, as distinct from sulfated carbohydrates or sulfated glycoproteins (for example, heparin) to be anti-coagulants either when dosed orally or intravenously. Also, unlike the prior art sulfated and alkyl sulfonated materials derived from natural products, the aryl sulfonated products can be reproducibly prepared in clearly defined molecular weight ranges and have hydrolytically stable polymeric backbones and stable carbon to sulfur linkages. Products of the invention may be completely stable to acid or base hydrolysis and indeed, when sodium salts, are thermally stable to 200°C. By contrast, sulfated polysaccharides are of variable and broad molecular weight distribution, are hydrolytically unstable both as to backbone and sulfate link and are also thermally unstable.

We have not found the polymers of the compositions of this invention to be absorbed systemically into the circulating lymph or blood. Thus, when orally administered, the said polymers have been found to be entirely excreted in the feces. We have found no absorbed polymer in any of the tissues or organs of treated animals.

It is reported in the literature that materials such as degraded carrageenan and sulfated amylopectin cause ulceration and bleeding in the caecum of the guinea pig or rabbit when fed at high dosage levels. By contrast we have found polymers used in the present invention to show no caecal ulceration in the normal guinea pig and no gastrointestinal irritation or toxicity in the rat or dog when fed at doses as high as two grams per kilo for 30 days or more.

U.S. Patent No. 3,893,890 discloses sulfonated polystyrene polymers and copolymers having molecular weights in the range of from 600 to 7,000,000. These polymers and copolymers, when fed to guinea pigs or dogs, can cause unpredictable physiological reactions including extreme irritation and toxicity (see Table II of this application). We have discovered that toxicity and irritation are inversely related to polymer molecular weight and that by careful selection of molecular weight and molecular weight distribution, for example by removal of the low molecular weight material, therapeutic safety may be attained. This discovery is entirely unexpected since, as noted above, both degraded carrageenan (M.W. about 30,000) and sulfated amylopectin (M.W. about 60 x IO*’) are reported to be ulceragenic when fed to normal guinea pigs at levels of 1 to 3 g/Jc (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 of viscosity average molecular weight of from about 500,000 to about 600,000 or more can show significant degrees of toxicity at dose levels of one gram/kilo/ day when the polymers have such broad molecular weight distribution that they contain undesirable levels of low molecular weight polymers.

This discovery of the toxicity being due to the presence of polymers having molecular weights of up to 50,000 forms a basis for the selection of the preferred class of polymers which are used to make up the compositions of this invention.

As far as molecular weight distribution is concerned it will be apparent that the lower the average molecular weight 4 8 9 θ the lower, the molecular weight distribution should be, otherwise an undesirably high amount of low molecular weight material will be present. As a guide we have found that polymers having an average molecular weight of from 100,000 to 2,000,000 should have narrow molecular weight distributions (i.e., Ma/Bw=1.05 to 1.30) at the lower viscosity average molecular weight but may have a wider molecular weight distribution (i.e. MT/S =1.3 to 8) at the higher w n average molecular weight. A particularly preferred .polymeric mixture has a viscosity average molecular weight of from 400,000 to 500,000 and a molecular weight distribution of 1.05 to 3.

This may be effected by selective removal of low molecular weight fractions, for example by fractional precipitation extraction, ultrafiltration or gel permeation or by the deliberate use cf polymerisation conditions and processes which minimise to the required extent the formation of the low molecular weight material. Such techniques are known in the art and will vary according to the particular polymer to be prepared.

Compositions containing the present polymers as the active ingredient are anti-ulcer agents which can be administered in a wide variety of therapeutic dosages in conventional vehicles.

The products may be administered in a wide variety of pharmaceutically acceptable carriers, for example in a flavored aqueous solution subdivided into a number, usually three or four, of doses per day. Typical formulations contain from about 10 to about 20% of the product in a suitably, flavored, colored, thickened, preserved, aqueous mixture. Subject to the appended claims the liquid dosage form may contain, in addition to water, small amounts of ethanol or other pharmaceutically acceptable solvent or solvents. Other dosage forms include gels prepared with pectin, agar, hydroxyethylcellulose or other approved gelling agents, tablets, capsules, pills, which may be microencapsulated, or enterically coated.

In addition, formulations may contain combinations 5 of drugs particularly suited to the healing of ulcers and relief of ulcer pain, for example antacids, anti-cholinergics and the like. Other drugs may also be used in compositions of this invention.

It is intended that sn adult patient of average body weight (70 kg) should be dosed with 2 to 10 g. of the present polymer per day in acute illness and 0.5 to 2 g. of such polymer per day in chronic illness (or as a preventative dose). Thus, unit dosage forms for adults could contain from 0.1 to 2 g., or even more, of the polymer per unit dosage. In any event the unit dosage forms should be so arranged as to at least cover a dosage range of 10 mg. to about 300 mg./kg. body weight/day, more particularly 10 mg. to about 200 mg./kg. body weight/day, most particularly the range is from about 20 mg. to 150 mg./kg. body weight/day. The product can be administered in subdivided doses in the form of scored tablets or capsules, however, liquid dosage forms are preferred. These dosage forms permit the symptomatic adjustment of the dosage to the patient to be treated.

The following examples illustrate fche preparation of various compositions according to the present invention. 4 6 8® EXAMPLE A - Tablets containing 500 mg. of Active Ingredient per Tablet ?er Tablet Poly(Sodium Vinylbenzenesulfonate) MW = 400,000; S, /S = 1.1 ’ w n 500 tr.g, Calcium Phosphate Dibasic 73 mg, Lactose 70 mg. Corn Starch 50 mg. Magnesium Stearate 7 mg, 700 mg, I Each ingredient is weighed and passed through a Mo. 40 mesh screen (U.S. Sieve). The ingredients arc blended in a twin-shell blender for 10 minutes and compressed to form tablets of a weight of 700 mg. per tablet on a tablet machine. EXAMPLE B - Oral Elixir Dosage Form containing Ingredient per five ml. 500 mg. of .Active Per 5 ml. Poly(Sodium Vinylbenzenesulfonate) MW = 400,000; Μ /TS = 1.1 ’ w n 750 mg. Sorbitol Solution 70% W/W 1C00 rag. Et'nyl Alcohol 500 mg. . Propylparaben 5 mg o FD & C Yellow No. 5 0.2 mg. Flavoring Agent 0.03 mg. Purified Water qs Poly(sodium vinylbenzenesulfonate) is dissolved in a portion of water by gentle agitation. The sorbitol Is added to this solution. The FD & C Yellow No. 5 Is dissolved in a portion of water and added to the above solution. The propyl13 paraben is dissolved ir. a portion of ethyl alcohol. The flavoring agent is dissolved ir. the remaining ethyl alcohol. The two ethanolie solutions are then added to the aqueous solution above. Sufficient water is then added to bring to final volume with continuous agitation.

EXAMPLE C - Oral Solution Dosage Form containing 500 mg. of Active Ingredient per five ml.

Per 5 ml.

Poly(Sodium Vinylbenzene sulfonate) MW = 800,000; R /R < 1.1 750 mg.

Propylene Glycol 100 mg.

Saccharin Sodium 0.05 mg.

Propylparaben 5 mg.

Flavoring Agent 0.03 mg.

FD & C Yellow No. 5 0.2 mg.

Purified Water gs Poly(sodium vinylbenzenesulfonate) is dissolved in a portion of water by gentle agitatiorj. The saccharin sodium 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 propylparaben is dissolved in a small portion of propylene glycol, the flavoring agent is dissolved in the remaining propylene glycol. The two propylene glycol solutions are then added to the above aqueous solution. Sufficient water is then added to bring to final volume with continuous agitation.

EXAMPLE D - Dry-filled Capsules Containing 250 mg. of Active Ingredient per Cansule Pc-r Capsule Poly (Sodium Vinvlbenzencsulfonate) MW = 220,000; = 1.1 250 me.

Magnesium Stearate 2.5 mg. 252.5 mg.

Weigh and pass the poly(sodium vinylbensenesulfonate) and magnesium stearate through a No. 40 mesh screen. Blend the ingredients in a twin-shell blender for ten minutes. Fill each gelatin capsule No. 0 with 252.5 mg. of blended product.

The polymers used in the compositions of this invention may he prepared by either of two· routes, either sulfonation of a polymer containing the vinylbenzene units or polymerization of a vinylbenzenesulfonic acid salt, ester or amide. The sulfonation procedure comprises treating 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 sulfuric acid, at a temperature of -30° to 30°C. for from 1/2 to 12 hours.

A preferred sulfonation procedure comprises treating a solution of linear polystyrene in ethylene dichloride at a temperature of 0°C. or less with a complex formed from sulfur trioxide (1 mole) and dichloroethyl ether (2 mole). The reaction mixture is neutralized with a base such as sodium hydroxide, potassium hydroxide or sodium bicarbonate. Any 44600 excess salt is then removed from the aqueous solution, for example by dialysis to afford a substantially pure aqueous solution of sulfonated polyvinylbenzene which solution upon removal of the water affords substantially pure product.

Alternatively, the sulfonated product may be filtered or centrifuged from the reaction mixture. Any excess sulfonating complex may be removed by washing with a solvent such as diethyl ether. The product is usually then dissolved in water and neutralized. The partially or completely neutralized product may also be isolated as a solid, for example by freeze drying, vacuum drying or spray drying. When partially neutralized the solid may be formulated with sufficient base to effect complete neutralization upon dissolution. Convenient bases include the carbonates or bicarbonates of the alkali metals particularly sodium or potassium. The process of filtration prior to neutralization is a preferred method in that it removes certain low molecular weight species.

The amount of molar sulfonation on the phenyl ring may be controlled by varying the molar ratio of sulfonating agent employed. Preferred polymers are those wherein at least 90% of the aromatic units present are of Formula I above.

A second method for preparing the poly(vinylbenzenesulfonic acids) comprises the polymerization or copolymerization of vinylbenzenesulfonic acid salts by solution polymerization in water or organic solvents such as alcohols, glycols, tertiary amines, amides and mixtures thereof employing free radical catalysts including ammonium persulfates, peroxides and hydroperoxides. Redox systems may also be employed, as may ultra446S0 violet radiation. The monomer solutions can he in the rance of from 10% to 50% by weight.

The vinylbenzene polymers suitable for sulfonation may be prepared with cationic catalysts such as sulfuric acid or boron trifluoride complexes, free radical catalysts such as benzoyl peroxide, ammonium persulfate,.azobisisobutyronitrile, hydrogen peroxide, tert-butyl hydroperoxide or with anionic initiators. The free radical polymers may be prepared with free radical catalysts in solution, in dispersion, in emulsion or in bulk by procedures well-known to those skilled in the art.

- A preferred polymerization procedure is anionic polymerization of the vinylbenzene or substituted vinylbenzene monomer. This procedure may directly yield polymers which have a ratio of weight average molecular weight to number average molecular weight (R^) from 1 to 1.3. Polymer molecular weight is controlled by the amount of monomers and amount of initiator present in the reaction mixture, i.e. Molecular weight is a function of grams of monomer divided by moles of initiator. Initiators which can be employed include lower alkyl lithiums, such as n-butyl lithium, sodium alkyls, sodium aryls such as sodium naphthalene and lithium aryls such as phenyl lithium, aryl ketyls such as sodium benzophenone, and finely divided sodium. Solvents in which the reaction can he run include benzene, toluene, aliphatic ethers such as diethyl ether, alicyclic ethers such as dioxane and aliphatic hydrocarbons such as heptane.

A preferred clans of polymers are homonolymers of vinylbenzene polymerized by an anionic initiator to an /R of 44680 less than 1.3 iri the molecular weight range of 100,000 to 1,000,000 and postsulfonated with coraplexed sulfur trioxide to a degree of sulfonation of the benzene rings greater than 90%.

Anionic polymerization is preferably conducted in the absence of reactive chain terminating impurities. This technique generally affords polymers having an ®w/K of less than 1.3. The reaction may be conducted in an inert atmosphere such as dry argon or dry nitrogen. Both the solvent and the monomer to be employed are usually dried, deoxygenated and titrated with an adduct of the catalyst and monomer to remove impurities. The anionic polymerisation is generally conducted at a temperature in the range of from about 0° to 30°C.

The polyvinylbenzenes can also be prepared by employing standard free radical catalysts, such as those indicated above under conditions such that only partial conversion (30 to 80%) of monomer to polymers occurs. By controlling the ratio of the catalyst to monomer and controlling the amount of conversion, an $w/Rn approaching 1.5 may be obtained. This method is disclosed by J.H. Duerksen and A.E. Hamielec, J. Poly. Sc. Part C, No. 25, 155-166 (1968) and L.H. Peebles, Mol. Wt. Dist. in Polymers, Interscience (1971), The polymer can be isolated by standard methods but is preferably isolated by devolatilizing in a screw extruder to produce essentially monomer-free polymer pellets. 4 6-9 θ The poiyvinylbenzenes useful in this invention may also be prepared by regular solution, bulk or emulsion free radical techniques. In these areas, polymers with· vicier molecular weight distributions are obtained, for example from about 2 to about 8. By selection of a high average molecular weight polyvinylbenzene, for example around 1 x 10^, she broad molecular weight distribution of from about 2 to 8 may be used to afford therapeutically safe polyvinylbenzene sulfonates. An an average molecular weight of about 250,000, molecular weight distribution of from about 2.5 to about 3.0 is required to ensure that a therapeutically safe polyvinylbenzene sulfonate is obtained.

Anionic copolymerization usually can only yield block copolymers when an S3 /fi of 1.3 or less is required. Two monow n mers are copolymerized by an anionic mechanism whereby one monomer reacts with the polymeric anion of the second monomer, for example in the copolymerization of styrene and methyl methacrylate, an initiator . such as n-butyl lithium is employed and the styrene polymerized to the desired molecular weight. Methyl methacrylate is-then added to the polymeric anions and polymerizes at the end of each polystyrene chain to form block copolymers. Monomers suitable for use in anionic copolymerization are those that will polymerize by an anionic mechanism and that do not have functional groups such as carboxy, hydroxy and the like that will destroy an anion. Post sulfonation affords a copolymer comprising blocks of polyvinylbenzenesulfonate and poly(methyl methacrylate). 44890 When copolymers are prepared with free radical catalysts, the restriction on what types of comonomers can be employed is less stringent -char, for anionic polymerization.

Any monomer which can withstand pose sulfonation can be employed including acrylates, methacrylates, vinyl nitriles, vinyl carboxylic acids, olefins, vinyl esters and other monomers encompassed within Formula II above.

The second method of preparation of the polymers (I) useful in this invention as indicated above involves the poly10 merization or copolymerization of salts, esters or amides of vinylbenzenesulfonic acid and related derivatives thereof. Specific examples of comonomers that can ba employed include acrylates, methacrylates, vinyl nitriles, vinyl acids such as methacrylic and acrylic, crotonates, olefins, anhydrides, vinyl esters, vinyl ethers, vinyl imides, vinyl halides, vinyl amides, vinyl ketones and other typical vinyl anti vinylidene monomers. Preferred monomers are methyl methacrylate, methacrylic acid, acrylic acid, methacrylamide, maleic anhydride, acrylonitrile, N-methyl maleimide, and styrene. In general, the level of sulfonic monomer is at least 50% of the copolymer units and preferably greater than 60%.

Molecular weight is a limiting parameter in terms of the viscosity of polymer drug solutions and to avoid gelation of the reaction mixture during sulfonation. Therefore, a practical upper limit of molecular weight for an unsulfonated polymer or copolymer is 1,000,000. included within the scope of this invention are compositions containing the nontoxic, pharmacologically acceptable salts of the polymers. 4 6 80 - 2< In general, any base which will form a salt ivitli the acids, tha cation of which has pharmacological properties which will not cause an adverste physiological effect when ingested hy the body system may be used in the compositions of this invention; suitable cations thus include, for example the alkali metal and alkaline earth cations, zinc, aluminum, iron and copper and the cations of ammonia, primary, secondary and tertiary amines, such as mono-lower alkylamines such as t-butyl amine, di-lower alkylamines such as diisopropyl. amine, tri-lower alkylamines such as triethylamine, nitrogen containing heterocyclic amines, for example piperidine, and alkanolamincs such as triethanolamine.

Also useful in the compositions of this invention are the ester and amide derivatives of the sulfonic acids (I) which are prepared by conventional methods well-known to those skilled in the art and to the extent that said derivatives are both nontoxic and physiologically acceptable to the body system and represent a minor amount (less than 50%) of the total product monomer units they are considered to be functionally equivalent to the sulfonic acids and salts.

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

The following examples illustrate the preparation of some polymers useful in the compositions of this invention. 44600 EXAMPLE 1 _ Poly (vinylbenzene) Step A - Titration of n-Gutyl Lithium A solution of n-butyl lithium in hexane (2,4 M; ml.) is added cautiously dropwise to a mixture of diethyl ether (5 ml.) and distilled water (5 ml.) in an Erlenmeyer flask. When the addition is complete, the walls of the flask are washed with distilled water and a drop of one percent (by weight) bromophenol blue solution is added. The solution is titrated with hydrochloric acid (0.100M) until the blue color dissipates. [The total base content of the initiator is determined in the following manners ml. of 0.10N HCl (normality of HCl) = mmoles of base per 2 ml. n.-butyl lithium^ The bases other than n-butyl lithium present are determined by adding a solution of n-butyl lithium in hexane (2 ml.) to neat, dry allyl bromide under an atmosphere of nitrogen. Distilled water is then added, along with a drop of one percent bromophenol blue. Titration of this mixture with hydrochloric acid affords the concentration of residual base, according to the above equation. This gives the number of millimoles of other bases present. Since the 2.4M'’ solution gives a total base content of 2.63M and a residual base content of 0.15 M the true n-butyl lithium content is 2.4SM, i.e. (2.53-0.15).

Step B - Anionic Polymerization of Vinylbenzene Benzene (1200 ml.) in a dry two-liter, three-necked, round-bottomed flask equipped with a three way stopcock, reflux condenser, magnetic stirring bar and thermometer under argon is brought to 60°C. Forty milliliters of benzene is transferred to a dry 100 ml. flask also under argon and then vinylbenzene (0.4 -22-. 4469θ ml; 0.35 g.; 3.5 mmoles) and n-butyl lithium in hexane (0.5 ml. of 2.48 M solution; 1.24 mmoles).Is added. This initiator mixture Is maintained at room temperature for approximately 15 minutes during which time the brilliant orange color of the vinylbenzene n-butyl lithium adduct becomes evident. This solution of the initiator is added to the warm benzene (1160 ml. until a slight yellow color persists in the warm reacticn medium .for at least 30 minutes to remove impurities. A 40-ol. portion of the purified benzene is added to a second dry .100 ml. flask under argon, and a second initiator solution prepared an above.

This affords a solution of 0.031M in initiator. The benzene (1120 ml.) is. cooled to 10°C. and vinylbenzene.(110 ml.; 100 g.) is added. This solution is titrated with a fresh initiator solution at 10°C. until a slight yellow color Is maintained for minutes. The resulting solution is warmed to 30°C„ and 16 ml. of the 0.031M initiator solution (0.5 mmoles initiator) is added rapidly' in one portion with vigorous stirring. Within 10 minutes, a 30°C. exotherm develops. 'Within 20.minutes, the reaction mixture is very viscous. The exotherm subsides after one hour. The resulting viscous, orange solution is maintained at 50°C..for 1.5 hours, then cooled to ambient temperature. Approximately one ml. of isopropanoi is added to quench the reaction. The resulting colorless solution is transferred to a separatory funnel and added slowly dropwise to three liters of isopropanoi while stirring vigorously. Good shearing action is necessary here to afford a finely divided sample.

The white polyvinylbenzene is collected by filtration. Residual isopropanoi is removed under, vacuum to afford 100 g. of poly23 vinylbenzene (100% yield). Analysis by gel permeation chromatography shows a ^W/Rn of 1.13 and a molecular weight of 221,000.

By following substantially the procedure described 5 in Example 1 above and by employing 100 g. of vinylbenzene and 2.3, 0.28 and 0.13 mmoles of n-butyl lithium, there are obtained polyvinylbenzenes having a molecular weight of 49,000; 430,000 and 970,000, respectively, and an ®wZ^n of 1.17, 1.08 and 1.05, respectively.

EXAMPLE 2 - PolyCSodium Vinylbenzenesulfonate)(MW = 642,000) One hundred grams of polyvinylbenzene of M.W. 321,000 and Rw/Rn = 3*8 (Aldrich Chemical Co.) is sulfonated by following substantially the procedure of Example 3 to afford a polymer having a predicted molecular weight Of about~642,000 and a predicted Rw/Rn = 3.8. The polymer was ultrafiltered through a 80,000 cut-off hollow fiber unit.

EXAMPLE 3 - Po ly (linm Vi ny Iben zen nun 11 on ate) Sulfur trioxide (115.3 g.; 1.44 moles) is added to a cooled (-10°C.) solution of ethylene dichloride (3 liter) and dichloroethyl ether (411 grams; 2.38 moles). A solution of filtered polyvinylbenzene (100 g.· 0.9 moles) having a viscosity average molecular weight of 200,000 and an M /Rn of 1.1 in anhydrous ethylene dichloride (1000 ml.) is then slowly added keeping the addition tube above the surface and maintain25 ing the temperature between -10°C. and -5°C. Upon complete addition of the polystyrene solution, the reaction mixture is permitted to warm up to 15°C. and held at that temperature for g 4 β δ 0 four hours. Deionized water (4000 ml.) Is added and the reaction mixture stirred for 15 minutes. Aqueous sodiumhydroxide (50%) Is added to a pK of 7-10 and stirring continued for 30 minutes. The reaction mixture is allowed to undergo a phase separation for approximately 12 hours. The organic layer is removed ahd the remaining water and poly(vinylbenzenesulfonate) salt layer is heated at 50°C. under a partial vacuum of about 340 m. Hg fo remove any.remaining organicsolvent. - The reaction mixture is then diluted with an equal volume of fresh deionized water (the percent solids at this point is approximately 2.471). Sodium sulfate Is removed by ultra-filtration .with the outlet solution stream recycled to the feed tank. Fresh deionized water Is added to the feed tank to maintain a constant head. The. permeate is collected in a separate receiver and periodically tested for polymer content using a quaternary salt and Inorganic salt'level by conductivity. If a precipitate is. noted, the dialysis must be stopped and the membranes changed.. The ultrafiltration is stopped when the resistance of the permeate is measured with a conductivity bridge at 8-10,000 ohm/cm. After removal of the salt, the remaining solution is concentrated to afford 90-95% yield of poly(sodium vinylbenzenesulfonate) having a viscosity average molecular weight of approximately 400,000 and an ®,/®n of less than 1.2.

EXAMPLE 4 - Copolymer of Sodium Vinylbenzenesulfonate and Methacrylic Acid (MW g 615,000) (2;1) A solution of deionized water (30 ml.) and hydrogen peroxide (0.66 g.; .0097 mole; 50%) in a 500 ml. round bottomed - 25 44690 three-necked flask equipped with a mechanical stirrer, a thermometer, a dropping funnel and a reflux condenser is heated to 60°C. over a 10 minute period. A second solution of sodium vinylbenzenesulfonate (61.8 g; 0.296 mole) and methacrylic acid (12.9 g; 0.1498 mole) in water (225 ml.) at 40°C. is added to the reaction flask over a 17 minute period. The resulting solution is stirred overnight (20 hours) at 60°G. The solution is then cooled to room temperature, neutralized at pH 7.7 by the addition of a sodium hydroxide solution (10.0 g; 0.125 mole; 50%).

The neutralized solution is dialyzed for 48 hours against running deionized water concentrated and freeze dried to afford 60 g. of copolymer as light tan solid (MW = 615,000) Rw/$n = 2.5 by gel permeation chromatography.

EXAMPLE 5 - Cooolymer of Sodium Vinylbensenesulfonate and Methacrylic Acid (MW = 850,000) (2.47:1) .

The following solution is prepared in a flask and allowed to stand, under a blanket of nitrogen, at room temperature for 13 days: Sodium Vinylbenzenesulfonate (duPont) 91%....................61.8 g. (0.274 mole) Methacrylic Acid....................12.9 g. (0.15 mole) Water...............................260 ml.

Ammonium Persulfate.................0.5 g. (0.0022 mole) The solution is neutralized to pH 7.5 by the addition of sodium 25 hydroxide solution (19.5 g.; .128 mole) and dialyzed against running deionized water for 24 hours. The dialyzed solution is concentrated and freeze dried to afford 27.8 g. of the copolymer as a white solid. (MW = 850,000). = 2.55 by gel perm44®®° 2c eation chromatography.

EXAMPLE 6 — Copolymer of Sodium Vinylbenzenesulfonate and Methacrylic Acid MW = 628,100 (2.2:1) Nitrogen is bubbled through a solution of sodium vinyl5 benzenesulfonate (61.8 g.; .274 mole; 91.5%) and methacrylic acid (12.9 g.; .1498 mole) in deionized water (255 ml.) in a 500 ml. round bottom, three necked flask equipped with a mechanical stirrer, a thermometer, a reflux condenser and a nitrogen bubbler for one hour to deaerate the solution. The solution, under nitrogen, is heated to 50°C. and hydrogen peroxide (1.32 g; 0.135 mole; 35%) is added. This polymerisation mixture is stirred at 50°C. under nitrogen for 20 hours, cooled and neutralized to pH 7.5 by the addition of 50% aqueous sodium hydroxide (12.2 g.; .1525 mole). The neutralized solution is dialyzed for 48 hours in running deionized water, concentrated to 600 ml. and lyophilized for 24 hours to afford 62.4 g. of copolymer.

(MW = 628,100).

By following substantially the procedure of Example 6, there are obtained copolymers having the following ratio and ' molecular weight: a. SVBS(2)/MAA(1) MW = 915,100 b. . SVBS(2)/MAA(l) MW = 686,450; Rw/R = 2.8.

EXAMPLE 7 - Poly (Ammonium Vinylbenzenesulfonate) A Solution of poly(sodium vinylbenzenesulfonate) is put through a column of Amberlite IS-120 in the H+ form to convert the sodium salt of the polymer to the free acid (Amberlite is a registered Trade Mark). The solution is titrated to determine the meq. of H /ml. This solution is then stirred with an equimolar amount of a 29.8% ammonium hydroxide solution for one hour. The solution is lyophilised - 27 44690 to afford poly(ammonium vinylbenzenesulfonate).

EXAMPLE 8 - Glycine Salt of Poly(Vlnylbenzenesulfonic Acid) A solution of poly(vlnylbenzenesulfonic acid) is stirred with glycine for one hour, concentrated and lyophilized to afford the glycine salt of poly(vlnylbenzenesulfonic acid). EXAMPLE 9 - Calcium Salt of Poly(Vinvlbenzenesulfonic Acid) A solution of poly(sodium vinylbenzenesulfonate) in water is passed through a column of Amberlite IR 120, Ca++ form, to exchange Na+ for Ca++. The effluent from this column is concentrated and freeze dried to afford the calcium salt of poly(vinylbenzenesulfonic acid).

EXAMPLE 10 - Magnesium Salt of Poly(Vlnylbenzenesulfonic Acid) A dialyzed solution of poly(vinylbenzenesulfonic acid) from Example 7 (130 meq.) is stirred overnight with magnesium carbonate (7.3 g.; 129.2 meq. Mg.++). This solution is filtered to remove any insolubles and then dialyzed for 43 hours. The resulting solution is concentrated and freeze dried to afford the magnesium salt of poly(vlnylbenzenesulfonic acid).

EXAMPLE 11 - Copolymer of Sodium Vinylbenzenesulfonate and Ethyl Methacrylate (2.3:1) Step A - Copolymer of Vinylbenzene and Ethyl Methacrylate A solution of vinylbenzene (73 g.; 0.75 mole), ethyl methacrylate (34.2 g.) 0.30 mole), benzoylperoxide (3.0 g.; 0.011 mole) and toluene (70 ml.) in a one liter round bottom flask equipped with a mechanical stirrer, a thermometer, a reflux condenser and an addition funnel is heated to reflux (114°C.).

A second solution containing vinylbenzene (26 g.· 0.25 mole), ethyl methacrylate (11.4 g.; 0.10 mole) and benzoyl peroxide - 28 (1.0 g.; .004 mole) in toluene (400 ml.) is added from the addition funnel over a four hour period. Refluxing is continued for an additional two hours. The solution is then evaporated to dryness and the glassy residue dissolved in acetone (500 ml.).

The polymer is isolated by pouring the acetono solution into methanol (3000 ml.) with stirring. The copolymer is collected and dried overnight in a vacuum oven at 40°C. to yield 110.0 g. (73.5% yield) of copolymer.

Step B - Copolymer of Sodium Vinylbensenesulfonate and Ethyl Methacrylate To a solution of sulfur trioxide (Sulfan a) (41.5 g.; 0.52 mole) in sym-dichloroethyl ether (143.0 g.; 1.0 mole) and ethylene dichloride (700 ml.) at -14°C. in a two liter roundbottomed flask equipped with a thermometer, mechanical stirrer and an addition funnel is added a solution of a copolymer of vinylbenzene and ethyl methacrylate (53 g.) in ethylene dichloride (350 ml.) at -15°C. over a 12 minute period (Sulfan is a registered Trade Mark). The cooling bath is then removed and the reaction mixture allowed to come to roan temperature over a three hour period. A pink solid is removed by filtration and dissolved in water (C00 ml.). Any residual organic solvents are removed and the solution neutralized to pH 7.8 by the addition of a sodium hydroxide solution (50 g.; 0.625 mole; 50%). This neutralized solution is dialyzed for 48 hours, concentrated and freeze dried to yield 80.5 g. of-copolymer, MW = 730,000.

EXAMPLE 12 - Copolymer of Sodium Vinvlbenzenesulfonate and Methacrylic Acid (1,0:1.2) A.solution of water (50 ml.) and ammonium persulfate (2.0 g.; 0.087 mole) in a 500 ml. round bottomed, three necked - 25 44690 flask equipped with a mechanical stirrer, rhermoroeter, dropping funnel and reflux condenser is heated to 80°C. over a thirty minute period and a solution of sodium vinylbenzenesulfonate (20.6 g.; 0.1 mole) and methacrylic acid (8.6 g.; 0.1 mole) in water (100 ml.) is added over a 17 minute period. The resulting solution is heated at 80°-82°C. for four hours and allowed fo cool overnight. The cooled solution is neutralized to pH 7.1 by the addition of a sodium hydroxide solution (8.0 g.; 0.1 mole, 50%). The solution is dialyzed for 48 hours against running deionised water; concentrated to about 200-250 ml. and then freeze dried to afford 22.9 g. (78.6% yield) of the copolymer as a white solid. Ν. M. R. analysis confirms that this is a 1:1.2 copolymer.

By following substantially the procedure of Example 12, there is obtained other copolymers ol various ration of sodium vinylbenzenesulfonate (SVBS) and methacrylic acid (MAA) having the following molecular weights: a. SVBS (2.47)/MAA (1) MW = 850,000 Mw/i?n = 2.55 b. SVBS (2)/MAA (1) MW = 524,000 R/B =2.7 ’ w n c. SVBS (3)/MAA (1) MW = 282,000 d. SVBS (4)/MAA (1) MW = 250,000 EXAMPLE 13 - Copolymer of Sodium Vinylbenzenesulfonate and Methyl Methacrylate Step A - Copolymer of Vinylbenzene (2.46) and Methyl Methacrylate (1) Vinylbenzene (104 g.; 1.0 mole), methyl methacrylate (40 g.; 0.4 mole), benzoyl peroxide (0.5 g.; 0.002 mole) and benzene (50 ml.) is added to a 500 ml. flask equipped with a stirrer, water condenser and addition funnel. Eenzene (IOC ml.) is placed in an addition funnel. The system is purged with nitrogen for ten minutes while stirring at room temperature.

The mixture is heated to 80°C. under nitrogen for 24 hours with periodic addition of benzene to reduce the viscosity. At the end of the heating period, the reaction mixture is cooled and diluted with benzene (100 ml.). The polymer is isolated by adding the benzene solution to vigorously stirred methanol.

The solid polymer removed by filtration, washed well vd.th methanol and dried in a vacuum oven at 60°C. to constant weight to afford 120 g. (85.7%) of product as a white solid.

Step 8 - Copolymer of Sodium Vinylbenzenesulfonate and Methyl Methacrylate This sulfonation is conducted substantially as disclose: in Example 12 and by using the following amounts of materials: Copolymer of Step A, above, (35.6 q.; 0.1 mole); sym-2-chlor.oet'nyl ether (127 g.; 0.89 mole); Sultan-B (35.4 g.; 0.443 mole); ethylene dichloride (1025.ml.) and sodium hydroxide (50% solution: .0 g.; 1440 ml.). One half of the neutralized solution is dialyzed for 48 hours and then freeze dried to afford 36.2 g. of product as an off-white solid, MW = 298,000, ®W/R, = 2.1.

EXAMPLE 14 - Copolymer of Sodium Vinylbenzenesulfonate. and Methyl Methacrylate (3.8:1) To a solution of ammonium persulfate (4.0 g.; 0.0175 mole), water (150 ml.) and dimethylformamiae (25 ml.) in one liter round bottomed, three necked flask equipped with a mechanical stirrer, a thermometer, an addition funnel and a reflux condenser, at 80°C. is added a solution of sodium vinylbenzenesulfonate - 31 44680 (41.2 g.; 0.2 mole) mcchyl methacrylate (5.0 g.; 0.5 mole) in water (250 ml.) and dimethylformamide (DMi·’) (75 ml.) dropwise over a four hour period. After this addition, a chaser” of ammonium persulfate (0.5 g.) dissolved in water (10 ml.) is added and the solution held at 80°C. for an additional 16 hours.

This solution is concentrated under reduced pressure to remove the water and dimethylformamide. The resulting glassy polymer is dissolved in water (500 ml.), neutralized to pH 7.5 hy the addition of sodium hydroxide solution and dialyzed for 48 hours.

The dialyzed solution is concentrated to 400 ml. and freeze dried to afford 42.5 g. of white solid product, MW = 100,700.

EXAMPLE 15 - Copolymer of Sodium Vinylbenzenesulfonate and Methacrylamide (2.2;1), MW = 350,000 A solution of sodium vinylbenzenesulfonate (82.4 g.; 0.36 mole), methacrylamide (18.9 g.; 0.22 mole), ammonium persulfate (0.5 g.; .002 mole) and water (360 ml.) in a one liter flask is heated to 80°C. with stirring, under nitrogen, and held under these conditions for 20 hours. At the end of this time, the reaction mixture is cooled fo room temperature, neutralized to pH 7.5 by the addition of about 0.5 g. of 25% sodium hydroxide, dialyzed for 48 hours, concentrated to 600 ml. and freeze dried to afford 83 g. of white solid product. MW = 350,000.

EXAMPLE 16 - Copolymer of Sodium Vinylbenzenesulfonate and ' Methacrylamide (2,2;1) MW = 526,000 The procedure of Example 15 is followed exactly except that the amounts are doubled. The neutralized solution is then dialyzed for 48 hours. The dialyzed solution is then ultrafiltered (dia-filtered) in two parts using an XM-300 membrane in — 44690 tl >' an Amicon TC-1 apparatus. (Amicon is a registered Trade Mark). The ultrafiltration conditions are as follo.vs: Flow rate (over membrane)-1. ΟΙ. 6 liters/min.; inlet pressure (over membrane)-30-40 psi.; Filtration rate= varied at 2-30 ml./min., and Air pressure (on pump) = 30-35 psi. During this diafiltration, (deionized water added to retentate as fast as the filtrate is removed in order to keep the volume constant) it is necessary to periodically stop the ultrafiltration and flush the membrane with plain water. On completion of the ultrafiltration, the retentate is concentrated to ca. 600 ml. and freeze dried to afford 92 g. of product as a white solid. Viscosity measurements indicate a molecular weight of 526,000; monomer distribution - 2.2/1 by N. M. It.

EXAMPLE 17 - Copolymer of Sodium Vinylbenzenesulfonate and Methacrylamide (2.2:1 ) MW - 442,600 The polymerization procedure is substantially the same as in Example 15 using the following amounts of materials: sodium vinylbenzenesulfonate (247.2 g.; 1.095 mole); water (1080 ml.); methacrylamide (56.7 g.; 0.0666 mole); ammonium persulfate (1.5 g.; 0.0066 mole) and sodium hydroxide (1.95 g.). After the polymerization, the solution is neutralised, diluted to five gallons and dialyzed by pumping this solution through the hollow fibers of two Dow b/HFD 1 dialysis beakers, (in series), at the rate of 10 ml./min. while deionized water is pumped through the beakers (around the hollow fibers) at the rate of 50 ml./min. (Dow is a registered Trade Mark). The retentate (solution retained by the fibers) is concentrated to ca. 1.5 liters and freeze dried to afford 273 g. white solid product, MW=443,000. 3: EXAMPLE 18 - Copolymer cf Lccium Vinylbenzenesulfonate ano Methacrylamide (3.75:1) ?·.·' = 539,000 A solution of sodium vinylbenzenesulfonate (302.4 g.; 1.3213 mole), methacrylamide (76.4 g.; 0.8S mole) in wafer (deionized, deaerated, 1,343.4 g.) in a five liter round bottom four necked flask equipped with a mechanical stirrer, thermometer, reflux- condenser, nitrogen inlet tube and a liquid inlet tube is heated under nitrogen with stirring to 75°C. To this solution is added ammonium persulfate (3.02 g.; 0.0132 mole) in water (deionized, deaerated, 10.7 g.) and is stirred for 15 minutes. A third solution prepared from sodium vinylbenzenesulfonate (362.9 g.; 1.586 mole) in water (deionized, deaerated, 1,286.6 g.) is then pumped into the reaction mixture using a variable speed diaphragm pump at the following rates: 25 ml. per minute for 15 minutes; 12.5 ml. per minute for 60 minutes; ml. per minute for 30 minutes and 3 ml. per minute for 30 minutes. The reaction mixture is then heated, stirred under nitrogen for an additional two hours and cooled to room temperature. One third of the reaction mixture (1.13 ml.) is placed in the reservoir of the Amicon, TC-1 ultrafiltration apparatus to which is added sodium chloride (306 g.), dissolved in water (3.0 1.) and then additional water added to bring the total volume to five gallons. Ten gallons of a sodium chloride solution (0.3 N) is placed in the diafiltration medium reservoirs and the polymeric solution diafiltered using an XM-100 membrane until all ten gallons of the sodium chloride solution has passed through the apparatus. The diafiltration is continued using deionized water as the diafiltration medium until 44600 3£ a total of 33 gallons of filtrate has been collected. The retentate (i.e. polymeric solution which docs not pass through the membrane) is removed from the apparatus, concentrated and lyophilized to afjford 195.8 g. of white solid. Viscosity measurements indicate a molecular weight of 539,000.

EXAMPLE 19 - Poly(Sodium Vinylbenzenesulfonate) Six samples of mono dispersed polyvinylbensene (Pressure Chemical Company) having molecular weights of 2200; ,400; 37,000; 110,000; 200,000 and 390,000 all having an Π ,/E of less than 1.10 were sulfonated substantial!·/ as w n described by the procedure of Example 3 to afford poly(sodium vinvlbenzenesulfonates) having molecular weights of 4,400; 40,800; 74,000; 220,000; 400,000 and 780,000, respectively, all having a predicted ^w/®n of less than 1.10 and also having a molar percentage of sulfonation of (4,400 sample not dialyzed) 97%, 82%, 90%, 94%, 95% and 91%, respectively.

EXAMPLE 20 - Poly(Sodium Vinylbenzenesulfonate) A solution of sodium vinylbenzenesulfonate (144 g.) in water (700 ml.) is treated with ammonium persulfate (0.8 g.) and heated for 20 hours at 80°C. The standard work up affords poly(sodium vinylbenzenesulfonate) having a viscosity average molecular weight of 195,000. At 50 mg./kg. orally it gave a 91% control in a Shay rat. At 100 mg./kg. it gave 36% control in a histamine guinea pig. . At 100 mg./kg. in a steroid rat it gave 41% control. When fed at 10, 50 and 200 mg./kg. in sugar water to guinea pigs for 35 days, no significant pathology is noted. In particular, there was no irritation in the G. I. tract and no moribund or dead animals. 3'.' 44690 EXAMPLE 21 - Choline Polystvrenesulfonate Sodium polystyrer.esulfor.ate (20.6 g.) is dissolved in water (15% by weight solution). To this is added 13.96 g. of anhydrous choline chloride to form the choline polystyrene5 sulfonate.

By following substantially the procedure described above and by substituting 7.0 g. of choline chloride for the 13.96 g. of choline chloride, there is obtained the sodium/ choline polystyrenesulfonato.

The following data in Table I indicates the antiulcer activity of the instant products. Four experimental models were chosen to test the compounds: 1. Pylorlc-Ligated Rat (16 Hour Shay Rat) Pyloric ligations were formed on anesthetized female rats (200-220 gm.) immediately followed by an oral dose of test compound at 50 mg./rat in a total volume of 2.0 ml. of water. Controls received 2.0 ml. of water. Sixteen hours later the animals were sacrificed. Their stomachs were removed, opened along the greater curvature and the nonglandular portion of the stomach scored for severity of ulceration by means of an arbitrary 0 to 4 scoring system. 2. Steroid Treated Rat Female rats (175-190 gms.) were individually housed and given food and water ad libitum. Each animal was then injected subcutaneously, daily for three consecutive days with mg. Prednisolone suspended in 0.2 ml. of 0.5% Methocel solution (Methocel is a registered Trade Mark).

Concomitant with the Prednisolone injections, each 6S0 _ 3f animal received 100 mg. of the test compound in one ml. of water Β. I. D. orally. The rats were sacrificed or. the fourth day, the stomachs removed, opened along the creater curvature and the glandular portion scored for incidence ana severity of ulceration, 3. Histamine Induced Ulcer in the Guinea Pin Adult male albino guinea pigs (400-500 gms.) were given a single Intramuscular Injection of histamine acid phosphate at 10 mg./leg. suspended in beeswax·peanut oil (1:9) mixture. ! The animals were then orally dosed with text compound at 100 mg./G. Ρ., Β. I. D. (a.m.-p.m.) for two consecutive days, The guinea pigs were sacrificed on the morning of the third day. The stomachs with approximately 10 cm. of duodenum attached were removed. The duodenums were then examined for perforations and ulcers and scored for.incidence and severity of ulceration by means of an arbitrary 0 to 4 scoring system. 4. Histamine Induced Duodenal Ulcer in Kats Female rats (220-225 gms.) were injected subcutaneously with histamine - 2 HCl at 350 mg./rat in a total volume of 1.0 ml. Immediately following the histamine injection an oral dose of two ml. of a solution containing 50 mg. of the test compound was given to each rat. Twentyrour hours later, the stomachs with duodenums attached were removed and examined for ulceration. ... 44680 CALCULATION OF % INHIBITION 1. Sixteen Hour Shay Rat Anti-Ulcer Test The stomachs were removed and then opened along the greater curvature. The stomachs were then scored using the following scheme.

- Complete absence of hemorrage and ulcers; - one or two small areas of hemorrage and/or ulcers; - approximately 25% of stomach ulcerated; - 25 to 50% of stomach with ulcers; and - perforation and/or extensive ulceration throughout the mucosa. 2. Histamine Induced Duodenal Ulcer Test in Rats The duodenum with stomach attached was removed and opened. The duodenum was then inspected for ulceration. The results are reported as the number with duodenal ulcers on an all or none basis. Inhibition was comparison of treated to control with duodenal ulcers. 3. Histamine Induced Duodenal Ulcer in the Guinea Pig The animals were sacrificed, posted and the stomachs with attached duodena (approximately 10 cm. length) were carefully removed. The duodena were then examined for perforations and/or frank ulcers and scored as follows: - absence of gross pathology; - 1_4 minute duodenal ulcers; - > 4 small areas of ulceration; - severe ulceration and/or colliquative necrotic areas in the duodenum; and - perforation. — 3ί 4 0 9 Ό Ulcer Score = Total number of Duodenal Scored ar, 3 or 4 Total Number ot Duodena~Scored 4. Acute Steroid Ulcer Tent Calculations .Mean Ulcer Score = Total Number Ulcers + Incidence and Severity* _ Number of Animals Tested 'Severity 0 - no grossly visible ulcer; - 1 to 4 grossly visible ulcers; - 5 to 9 grossly visible ulcers and. - .10 or more grossly visible ulcers.

Tbs following criteria have been adopted for antiulcer -activity as measured in four experimental animal models. Agents which fail to show anti-ulcer activity in the Shay model and one of the duodenal ulcer models are considered to be inactive anti-ulcer agents: 1. 75-85% or greater inhibition of gastric ulcer in the 16-hour Shay rat at a single dose of 50 mg./rat, P.O.; 2. 25-50% or greater inhibition of duodenal ulcer in the 24-hour histamine rat model at a single dose of 50 mg./ rat, P.O»;; 3.. 25-40% or greater inhibition of duodenal ulcer in the 48-hour histamine guinea pig model at. a daily dose of 100 mg./animal, Ρ.Ο», B.I.D. for two days; with no toxicity or cecal pathology and 4. . 25-40% or.greater inhibition of gastric ulcer in the three-day Steroid rat model at a dose of 100 mg./rat, P.O., B.I.D. for three consecutive days with no toxicity or cecal pathology» % Inhibition = Ulcer Score of-Control-Ulcer Score Treated X 100 Ulcer Score Control 3£ 44690 We have found that low molecular weighs polymers are toxic when dosed to guinea pigs with histamine-induced ulcers and to rats with steroid-induced ulcers. (Low molecular weight polymers show no toxicity in normal rats.) When fed at one gpk/day to normal guinea pigs, low molecular weight polymers will usually cause bloody caecums or death in seven days. Dogs are also particularly sensitive to the low molecular weight polymers at one gpk/day showing GI bleeding, diarrhea, intestinal ulceration and liver involvement. These symptoms often remain even after the test is terminated. High molecular weight polymers can be fed to normal guinea pigs and dogs for from 30 to 90 days without any significant pathology. No secondary pathology develops when the polymers of this invention are fed to ulcerated animal models.

The following data in Table II indicates the toxicity of the low molecular weight compounds. Hy toxicity is meant that the compounds cause caecal bleeding in some of the test animals (rabbits or guinea pigs) and general G.I, ulceration and bleeding in other test animals which may result in death of the animals.

Claims (15)

1. CLAIMS :I. A therapeutic composition for oral administration comprising a polymeric mixture together with a pharmaceutically acceptabl e carrier, at least 50% of the total monomer units of 5 the polymeric mixture being vinylbenzene sulfonate units of the formula: f wherein R is -H or -CH 3 and X is -H, alkyl or halo, or pharmaceutically acceptable nontoxic salts thereof, the polymeric 10 mixture having a viscosity average molecular weight from 100,000 to 2,000,000 and containing less than 5% by weight of polymer of viscosity average molecular weight of 20, 000 or less.

2. A therapeutic composition as claimed in Claim 1 wherein the polymeric mixture also contains units of one or more 15 of the amides and/or of the vinyl benzene sulfonate units and/or units of the formula: -CH(R 1 )C(R 2 )(R 3 )1 2 wherein R and R are the same or different and are each hydrogen or (Cp-Cg)alkyl and R is acyloxy, aroyloxy, carboxy, carbamoyl, 20 cyano, (C^-Cg)alkoxy, (C^-Cg)alkoxy carbonyl or aryl.

3. A therapeutic composition as claimed in Claim 1 or 2 wherein the polymeric mixture has at least 60% of the vinylbenzene sulfonate units. 4. © © ® u

4. A therapeutic composition as claimed in Claim 3 wherein the polymeric mixture, has at least 905 of the vinylbenzene-sulfonate units.

5. A therapeutic composition claimed in any preceding claim wherein polymeric mixture has a viscosity: average molecular 5 weight from 300,000 to 1,000,000. S. A therapeutic composition claimed in any preceding claim wherein the polymeric mixture has a molecular weight distribution from 1.0 5 to 8.

6. 7. A therapeutic composition claimed in any preceding 10 claim wherein R is -Η, X is ~H, and R , if present, is -K.

7. 8. A therapeutic composition claimed in any of Claims 2 - 1 3 to 7 wherein R is -H, and R is acetoxy, carboxy, carbamoyl, (C^-Cg)alkoxy, (C^-Cg)alkoxy carbonyl or phenyl.

8. 9. A therapeutic composition claimed in any preceding 15 claim wherein the polymeric mixture contains less than 55 of polymer of : viscosity average, molecular weight of 50,000 or less.

9. 10. ' A therapeutic composition claimed in any of Claims 2 to 9 wherein the polymeric mixture coritains units of one or more of: vinylbenzene, alkyl acrylate, alkyl methacrylate, vinyl nitrile, 20 acrylic acid, methacrylic acid, ethylenically unsaturated aldehyde ethylenically unsaturated imide, ethylenically unsaturated olefin, vinyl ester, vinyl amide. 45 44690

10. 11. A therapeutic composition as claimed in Claim 10 wherein the polymeric mixture contains units from one or more of: methyl methacrylate, maleic anhydride, methacrylamide, methacrylic acid. 5

11. 12. A therapeutic composition as claimed in Claim 1 wherein the polymeric mixture consists of units of vinylbenzene, over 90% of which are sodium vinylbenzenesulfonate units, the polymeric mixture having a viscosity average molecular weight of from 400,000 to 500,000 and a molecular weight distribution 10 of 1.05 to 3.

12. 13. A therapeutic composition as claimed in any preceding claim in unit dosage form containing from 0.1 to 2 g. of the polymer.

13. 14. A therapeutic composition as claimed in Claim 13 15 in shaped solid pharmaceutical form.

14.

15. A therapeutic composition as claimed in Claim 1 substantially as described in any one of the foregoing Examples A to D.