CA1114997A - Polyvinylbenzenesulfonic acids - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE
Water-soluble polymers having a molecular weight in the range of 100,000 to 2,000,000 including homopolymers and copoly-mers of vinylbenzenesulfonic acids and salts thereof wherein the benzene ring may be substituted by various radicals, composi-tions containing said products and methods useful in the treat-ment 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 unsubsti-tuted vinylbenzenesulfonic acid salts.

Description

p~ f This invention relates to water soluble polymers includ-ing homopolymers and copolymers of vinylbenzenesulfonic acid products, compositions containing said products as the active ingredient and methods of treating peptic ulcers.
Pharmacological studies employing rats, guinea pigs and dogs as the experimental animals indicate that the products of this invention when administered in therapeutic dosages in conventional vehicles are safe and effective in treating peptic ulcers.
The continuing search for an effective antiulcer drug is evidenced by numerous patents and publications which have issued. A number of these publications are directed to sul-fated macroanions and reported in Advances in Drug Research, Vol. 8, Academic Press, pp. 205-334. See also U.S. patent 3,487,150, Dextran Sulphate Treatment of Peptic Ulcers; U. S.
patent 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 3,637,657, Aluminum Complex of Sulfated Polysaccharide and a Process for the Preparation 20 Thereof; and Republic of South Africa patent 683,394, Composi-tions and Methods for Controlling Peptic Ulcers. None, however, disclose compounds wherein the sulfo radical (-SO3~) is on an aromatic ring.

~, 4~ 7 United States 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 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 (1972)). It is known that their formation requires the gastric secretion of acid and pepsin which are normally controlled by neurohormonal interactions.
The present invention provides polymers and copolymers which are effective in treating peptic ulcers.
The polymers, including homopolymers and, alternating, block and random copolymers, of this invention repeating units of a physiologically acceptable salt, ester or amide of the following structural formula:
R

X ~ SO3H

(I) wherein R is hydrogen or methyl and X is hydrogen, alkyl or halogen; and when a copolymer, also having repeating units of the following formula:

CH - C
Rl R2 (II) wherein Rl and R2 are the same or different radicals selected from hydrogen or lower alkyl such as methyl, ethyl, propyl, isopropyl, _-butyl, isobutyl, tert-butyl, pentyl and the like; R3 is selected from acyloxy, for example, ~, alkanoyloxy (Cl-C18) such as acetoxy, propionyloxy, butyryloxy and the like, or aroyloxy such as benzoyloxy and the like, carboxy, carbamoyl, cyano, lower alkoxy, such as methoxy, ethoxy and the like, lower alkoxy carbonyl, such as methoxycarbonyl, ethoxycarbonyl and the like or aryl, for example, mononuclear aryl such as phenyl and the like, the polymer or copolymer having a molecular weight in the range of from 100,000 to about 2,000,000, a molar degree of monosulfonation of at least 50% and containing less than five per-cent of polymers (based on the total weight of sulfonated polymers) having a molecular weight of about 20,000 or less.
A preferred embodiment of this invention is homopolymers or, alternating, block or random copolymers having a molecular weight in the range of from about 300,000 to about 1,000,000 and a molar degree of sul-fonation of at least 50% having repeating units of a physiologically accept-able salt, ester or amide of the following formula:

(Ia) and, when a copolymer, also having repeating units of the formula:

I

(IIa) wherein R2 is hydrogen or lower alkyl and R4 is acetoxy, carboxy, carbamoyl, lower alkoxy, lower alkoxy carbonyl or phenyl and the nontoxic, pharmacologi-cally acceptable salts thereof wherein said polymers have less than 5% of polymers (based on the total weight of sulfonated polymers) having a molec-ular weight of 50,000 or less. The foregoing class of polymers exhibits r~
4~

-particularly good antiulcer activity.
The homopolymers can be isotactic, syndiotactic or atactic.
As used in this specification, the term "molecular weight"
means the viscosity average molecular weight which approximates the weight average molecular weight. For very narrow molecular weight distributions, the weight average and number average molecular weights are quite similar.
The polymer or copolymer can be prepared by a process which comprises:
~ a) sulfonating with a sulfonating agent a polymer of vinyl-benzene or X-substituted vinyl benzene or a copolymer of vinylbenzene or X-substituted vinylbenzene with a monomer selected from alkyl acrylate, alkyl methacrylate, vinyl nitrile, acrylic acid, methacrylic acid, ethylen-ically unsaturated anhydrides, ethylenically unsaturated imides, olefins, vinyl esters and vinyl amides, if necessary removing low molecular weight polymer or copolymer, from the polymerization product so that the product contains less than 5% of polymers or copolymers having a molecular weight of about 20,000 or less and converting the acid to a physiologically accept-able salt, ester or amide; or (b) polymerizing a vinylbenzenesulfonic acid salt, ester or amide or an X-substituted vinylbenzenesulfonic acid salt, ester or amide or copolymerizing a vinylbenzenesulfonic acid salt, ester or amide or an X-sub-stituted vinylbenzenesulfonic acid salt, ester or amide with a monomer select-ed from alkyl acrylate, alkyl methacryla~e, vinyl nitrile, acrylic acid, methacrylic acid, ethylenically unsaturated anhydrides, ethylenically un-saturated imides, olefins, vinyl esters and vinyl amides, if necessary, re-moving lower molecular weight polymer or copolymer from the product so that the product contains less than 5% of polymers or copolymers having a molec-ular weight of about 20,000 or less; and, if required, converting the polymer or copolymer product to a physiologically acceptable salt, ester or amide thereof.

The molecular welght dlstrlbutlon ratlo ls the ratio of the welght average molecular welght (Mw) to the number average molecular wel~ht (~n). For a unlmodal polymer havlng only one molecular welght species the ~w/~n is 1Ø Higher numbers lndlcate broader or multlple dlstrlbutions. The Mw may be determined by llght scattering or ultra centrifugatlon. The Mn can be determined by osmometry or measuring some other colligative property llke boillng polnt. The MW/Mn ls most readily determined by gel permeatlon chromatography, the method used in obtalnlng the values reported ln this in~ention.
; Examples of speclfic monomers whlch can be employed ln the copolymerlzation with elther sulfonated -vinylbenzene or unsulfonated vlnylbenæene lnclude alkyl acrylates and alkyl methacrylates such as methyl acrylate, ethyl acrylate, methyl methacrylate, ethyl methacrylate and the llke, vinyl nitriles, such as acrylo-nitrile and the llke, acrylic acld and methacrylic acid~
ethylenically unsaturated anhydrldes, such as malelc anhydride and the like or ethylenically unsaturated imides such as N-m~thyl maleimide and the like, an ethylenically unsaturated olefin, such as ethylene, propylene, diisobutylene a~d the like, vinyl esters, such as vinyl acetate, vinyl proplonate, vinyl benzoate and the like, vinyl amides, such

2~ as methacrylamide and the llke.

The products Or this lnventlon have shown excellent control and heallng of ulcers employlng typical anlmal models. Essentially complete control of gastric ulcers is obtained on a Shay rat and on a histamine-challenged rat. Excellent control Or duodenal ulcers isobtalned with 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 provides effective and essentially complete protection from ulcer recurrence.
Other utilities of the products include inhibition of the action of pepsln on proteolytic substrates ln protection of proteins from pepsin hydro~ysis; coat~ng - the mucosa to form a protective barrier against acidJ
~ 15 pepsin~ bacteria, fungi and other noxious agents.
The products of this invent~on and in particular poly(sodium vinylbenzenesulfonate) have been discovered to have specific binding affinity to the mucosa of the s~omach and duodenum. The polymer is retained in the stomach five to ten times longer as compared to nonretentive materials. It is believed that the sulfonic polymers of this invention bind or adhere to intact and/or abraded mu~osal tissue to act as a protective coating or barrier to prevent further irritation or erosion and permit heallng.

It ls further believed that the materials of this invention ~nteract with secreted mucous to strengthen the mucous - mechanically and chemlcally to act as a protectlve barrier.

~$1~
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Surprisingly, the p31ymers of this invention also appear to function, at least in part, as antisecretory agents even though they are non-systemic. In histamine challenged guin~a pigs treated with one of the polymers of this invention, a marked decrease in secreted acid is noted accompanied by increased mucous and prevention of duodenal ulcer. By contrast, the histamine challenged control has a high acid output and severe duodenal ulceration.
Pharmacological studies employing rats and dogs as the experimental animals indicate that the instant poly~ers and compositions containing the instant polymsrs are effective in stimulating the formation and secretion of gastric and duodenal mucous to form a protective barrier on the mucosa. Wh~n administered in therapeutic dosages in 1~ conventional vehicles, the instant polymers promote the healing of ulcerations, prevent injury to the mucosal surface and lubricates the intestines.
- lhese polymers can also be employed-in other ulcerative conditions of the gastrointestinal tract such 2~ as reflux esophagitis and the like.

.
. -~ . ' The products, unlike sulfated carbohydrates or sulrated glycoprotelns (for example, heparin) are not anticoagulants either dosed orally or intravenously.
Also, unlike the prior art sulfated and alkyl sulfonated 5-- 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.
The products are completely stable to acid or base hydrolysis and lndeed the sodium salts are thermally stable to 200C.
By contrast, sulfated polysaccharldes are of varlable and broad molecular weight distribution, are hydrolytically unstable both as to backbone and sulfate link and are also thermally unstable.
- 15 The products of this invention are not absorbed systemically into the circulating lymph or blood. Thus, orally administered polymers of this invention are entirely excreted in the feces. There is 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 amylopectln cause ulceration and bleeding ln the caecum of the guinea pig or rabbit when fed at high dosage levels. By contrast the co.npounds of this invention show no caecal ulceration in the normal guinea pig and no gastrointestinal irritation or toxiclty in the rat or dog when fed at doses as high as two grams per kilo for 30 days or more.

_9_ U. S. Pat. No. 3,893,890 dLscloses sulfonated polystyrene polymers and copoly~ers having molecular weights in the range of from 600 to 7,000,000- These polym~rs and copolymers, when fed to guinea pigs or dogs, can cause unpredictable physiological reactions in-cluding extreme irritation and toxicity (see Table II
of this application). W2 have discovered that toxicity and irritation are inversely related to pol~er molecular weight and that either by proper selection of molecular weight and molecular weight distribution, or b~J removal of the low molecular weight material, therapeutic safety is attained. ~his discovery is entirely unexpected since, as noted above, both degraded carrageenan (M. W. about 30,000) an~ sulfated am~lopectin (M. W. about 50 x 10) are reported to be ulceragenic when fed to normal guinea pigs at levels of 1 to 3 g/k t(see, for example, R. Marcus and J. Watt, Gastroenterolo~ o7, 473 (1974) and P. Grasso, et al., Fd. Cosmet ~oxicol llj 555 (1973))o]
Even polymers and copolymars of viscosity average molecular 20 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 broad molecular weight distribution so as to 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 preferred classes of products of this invention. In general, the parameters and preparative techniques are so chosen and defined as to produce antiulcer polymers containing essentially less than five percent of poly~ers of molecular weights of 20,000 or less and prefera'Jly 50,000 or less. This i s .

. ... .

done by preparing polymers having a molecular weight in the range of from about 100,000 to about 2,000,000 having narrow molecular weight distribu-tions ~e.g., Mn/MW = 1.05-1.30) at the lower viscosity average molecular weight or preparing high molecular weight polymers having a wider but speci-fied molecular weight distribution (e.g., MW/Mn = 1.3 to 8) or alternatively by selective removal of low molecular weight fractions by fractional pre-cipation, extraction, ultrafiltration, gel permeation and the like. These methods afford products having not only high antiulcer activity but also a high degree of safety and a high therapeutic index.
The compositions containing the polymers of physiologically acceptable salts, esters or amides of vinylbenzenesulfonic acid ~I, supra) as the active ingredient and also the polymers of physiologically acceptable salts, esters or amides of vinylbenzenesulfonic acid themselves are antiulcer agents which can be administered in a wide v~riety 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 three or four doses per day. Typical formu-lations contain from about 10 to about 20% of the product in a suitably flavored, colored, thickened, preserved, aqueous mixture. 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.

7' .

In addltion, rormulations may contaln combinatlons Or drugs partlcularly sulted to the heallng Or ulcers and rellef Or ulcer pain, for example, antaclds, antl-cholinergics and the like. Other oral drug combinations - 5 are also within the scope of this invention.
The oral daily dosage of the products may be ~ varied over a wide range varying from about 10 mg. to about -; 300 mg./kg./day. The product can be administered in sub-; .~ divided doses in the form of scored tablets or capsules, - 10 however, liquid dosage forms are preferred. These dosage . - . .
- . forms permit the symptomatic adJustment of the dosage to the patient to be treated. An effective amount of the drug is ordinarily supplied at a unit dosage level of from about 10 mg. to about 200 mg./kg. of body weight. Preferably, the range is from about 20 mg. to 150 mg./kg. of body weight/day.
The following examples are lllustrative of how to prepare various composltions containing the active ingredients of this inventlon. However, said examples are merely illustrative and should not be construed as 11m1ting the scope of th1s Inventlon.

_ 12 _ EXAMPLE A - Tablets Containing 500 mg. of Active Ingredient Per Tablet Per Tablet Poly(Sodium Vinylbenzenesulfonate) MW = 400,000; M /Mn ~ 1.1500 mg.
Calcium Phosphate Dibasic73 mg.
Lactose 70 mg.
Corn Starch 50 mg.

Magnesium Stearate 7 mg.
700 mg.
Weigh and pass each ingredient through a No. 40 mesh screen (U.S. Sieve). Blend the ingredients in a twin-shell blender for 10 minutes. Compress tablets to a weight of 700 mg. per tablet on a tablet machine.

EXAMPLE B - Oral Elixir Dosage Form Containing 500 mg. of Active Ingredient Per five ml.

Per 5 ml.
Poly(Sodium Vi_ylbenzenesulfonate) ~ ~
MW = 400,000; M~ Mn = 1.1750 mg.
Sorbitol Solution 70% W/W1000 mg.
Ethyl Alcohol 500 mg.
Propylparaben 5 mg.
FD&C Yellow No. 5 0.2 mg.
Flavoring Agent 0.03 mg.
Purified Water qs Poly(sodium vinylbenzenesulfonate) is dissolved in a portion Gf 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 prop~lparaben is dlssolved in a portion Or ethyl alcohol. -The flavorlng agent ls dissolved in the remaining ethyl alcohol. The two ethanolic solutions are then added to the aqueous solution above. Su~ficient water ls then added . to bring to final volume with continuous agitation.

EXAMPLE C - Oral Solution Dosage Form Containing 500 mg.
of Active Ingredlent per Five ml.
Per 5 ml.
Poly(Sodium. Vinylbenzene sulfonate) MW = 800,000; ~w r "~ 1.1 750 mg.
Propylene Glycol 100 mg.
~ Saccharin Sodium 0.05 mg.
; Propylparaben 5 mg.
Flavorlng Agent 0.03 mg.
.
FD~C Yellow No. 5 0.2 mg.

- Purified Water q9 .~ , .
Poly(sodium vinylbenzenesul~onate) is dissolved in a portion of water by gentle agitation. The saccharin sodium is dissolved ln 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 above 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 so~utions are - 25 then added to the above aqueous solution. Sufficient water is then added to bring to final volume with continuous agitation.

.. . ..

4 ~ ~' EXAI~PL~, D - Dry-filled Capsules,Containing 250 mg. of Active In~r2dient Per C~sule Polytsodiu~ vinJlbenzenesulfonate) Per CaPsule ~W = 220,000; ~w/~n = 1.1 250 mg.
Magnesium Stearate 2.~ m~.
252.5 mg.
Weigh and pass the poly(sodium vinylbenzene-sulfonate) and magnesium stearate tllrough 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 prodlct.
The polymers of this invention may be prepared by either of two routes, either sulfonation of a polyvinyl-benzene or polymerization of a vinylbenzenesulfonic acid salt, ester or amide. The sulfonation procedure comprises treating a polyvinylbsnzene or copoly~er thereof with a sulfonating agent~ for example, sulfur trioxide and the like in the presence of a complexing agent, for example, - an ether such as dichloroethyl ether, dioxane and the like or an amine such as pyridine and the like or an amide such as dimethylformamide and the like or esters such as tri-ethyl phosphate and the like, or sulfuric acid, at a temp-erature in the ran~e of from about -30 to about 305. for a period of time from ab~ut 1/2 to about 12 hours.
A preferred sulfonation procedure comprises treating a solution of linear polystyrene in ethylene di-chloride at a temperature of 0C. or less with a complex formed from sulfur trioxi~e (1 mole) and dichloroethyl ether ~ .

(2 mole). The reaction mixture ls neutrallzed wlth a ba3e such as sodlum hydro~ide, potasslum hydroxlde, sodlum bi-carbonate and the ll~e. A~y excess salt is then re~oved from the aqueous solutlo~ by various procedures such as dialysls and the li;~e to afford a substantially pure aqueous solution of sulfonated polyvinylbenzene which solu-tlon upon removal of the water affords substan~ially pure product.
Alternatively, the sulfonated product may be flltered or centrifuged from the reaction mixture. Any excess sulfonating complex ls removed by washing with a -solvent such as diethyl ether. The product is then dissolved in water and neutralized. The partially or com-pletely neutralized product may also be isolated as a solid by freeæe drying, vacuum drying, spray drying and the like.
When partially neutralized the solid may be formulated with sufficient base to effect complete neutralization upon dis-solution. Convenient bases include the carbonates or bicar-bonates of the alkali metals particularly sodium or potas-sium. The process of filtration prior to nèutralization is a preferred method in that it removes certain low molecula~
weight species The amount of molar sulfonation on the phenyl ring i3 controlled by varying the molar ratio of sulfonabing agent emnloyed. Preferred polJmers are those wherein of the phenyl rin~s present at least 90~ of them are sulfonated.

~ ~4~"~

Percent sul~onatlon is de~lned as the number Or benzene rings in the polymer having at least one ~ulfo radical divided by the number of benzene rin&s in polymer.
A second method for preparing the poly(vlnylben-5~ zenesulfonic acids) comprises the polymerization or copol~J-merization of vinylbenzenesulfonic acid salts by solution polymerization in water or organic solvents such as alcohols, glycols, tertiary amines, amides and mixtures thereo~ employing ~ree radical catalysts including ammonil~n persulfates, peroxides, hydroperoxides and the like. ~edox systems may also be employed as well as ultraviolet radia-tion, The monomer solutions can be in the range of from 10% to 50~ by weight.
Polyvinylbenzenes and copolymers thereo~ suitable ~or sulfonation may be prepared with cationic catalysts such as sulfuric acid or boron tri~luoride complexes, ~ree radi-cal catalysts such as benzoyl peroxide, ammonium persulfate, azobisisobutyronitrile, hydro~en peroYide, tert-butyl hydr~
peroxide or with anionic initiators. The free-radical polymers may be prepared with ~ree-radical catalysts in solution, in disperslon, in emulsion or in bulk by proce-dures well-known to those skilled in the art.
A pre~erred polymerization procedure is anionic polymerization of vinylbenzene or substituted vinylbenzenes.
This procedure affords directly polymers which have a ratio Or weight avera~e rolecular we~ght (~w) to number avera~e molecular weight (Mn) in the range of from about 1 to about 1.3.
Polymer molecular weight is controlled by the amount of monomers and amount of initiator present in the reaction mixture, i.e., grams of monomer Molecular weight = moles cdrib~rt~t~. Initiators which can be employed include lower alkyl lithiums, such as _-butyl lithium and the like, sodium alkyls, sodium aryls such as sodium naphthalene and lithium aryls such as phenyl lithium, aryl ketyls such as sodium benzophenone, finely divided sodium and the l~ke. Solvents in which the reaction can be run include benzene, toluene, aliphatic ethers such as diethyl ether, alicyclic ethers such as dioxane, aliphatic hydrocarbons such as heptane and the like.

A preferred class of polymers are those homopolymers of vinylbenzene polymerized by an anionic initiator to an MW/Mn of less than 1.3 in the molecular weight range of 100,000 to 1,000,000 and postsulfonated with complexed sulfur trioxide to a degree of sulfonation of greater than 90%.
The anionic polymerization is preferably conducted in the absence of reactive chain terminating impurities. This technique generally affords polymers having an MW/Mn of less than 1.3. The reaction is conducted in an inert atmosphere such as dry argon, dry nitrogen and the like. Both the solvent and the monomer to be employed are dried, deoxygenated and titrated with an adduct of the catalyst and monomer to remove impurities. The anionic polymerization is generally conducted at a temperature in the range of from about 0 to .-30C.

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 conver-sion, an MW/Mn approaching 1.5 is 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 11971). The polymer can be isolated by standard methods but is preferably isolated by devolatiliz-ing in a screw extruder to produce essentially monomer-free polymer pellets.
The polyvinylbenzenes useful in this invention may also be prepared by regular solution, bulk or emulsion free radical techniques. In these areas, polymers with wider 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 106, the broad molecular weight distribution of from about 2 to 8 may be used to afford therapeutically safe polyvinylbenzene sulfonates. At an average molecular weight of about 250,000 molecular weight distribution of from about 2.5 to about 3.0 is required to insure that a therapeutically safe polyvinyl-benzene sulfonate is obtained.
Anionic copolymerization essentially affords only "block" copolymers having an MW/Mn of 1.3 or less. Two ; monomers 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 X

1~14~

the dcsired mole~ular weighst. Methyl methacrylate is then added to the poly;neric anions and polymerizes at the en~ 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 fun^tional groups such as carboxy, hydroxy and the like that will dest~oy an anion. Post sulfonation affords a copolymer com~risin~ blocks of polyvinylbenzenesulfonate and poly(methyl mnthacrylate).
j When copolymers are prepared with free radical catalysts, the restriction on what types of comonomers can be employed is less stringent than for anionic polymeriza-tion. Any monomer which can withstand post sulfonation can be employed inclu~ing acrylates, methacrylates, vinyl nitriles, vinyl carboxylic acids, olefins, vinyl esters and other monomers encompassed within Formula II, supra-~ The second method of preparation of the p~oducts (I) of this invention as indicated above involves the polymer-ization or copolymerization of salts, esters or amides of vinylbenzenesulfonic acid and related derivatives thereof.
Specific examples of comonomers that can be employed include - acrylates, methacrylates, vinyl nitriles, Yinyl acids such as methacrylic and acrylic, crotonates, olefins, anhydrides, vinyl esters, vinyl ethers, vinyl imides, vinyl halides, vinyl amides, v-inyl ketones and other typical vinyl and vinylidene monomers. Preferred monomers are methyl methacryl-ate, methacrylic acid acrylic acid, methacrylamide, maleic ; , .

.. . . .
~' , ` ' ' .
~s 1$~4~7 anhydride, acrylonitrile, N-methyl ~aleimide, and styrene In general, the level o~ sul~onic acid monomer ls at least 50~ o~ the copolymer units and pre~erably ~reater than 60~.
Molecular weight is a limiting parameter ln terms Or the viscosity o~ polymer drug solutions and to avoid gelation of the reaction mixture during sulfonation. There-~ore, a practlcal upper limit of molecular weight ~or an unsulfonated polymer or copolymer is 1,000,000.
Included within the scope of this invention are the nontoxic, pharmacologically acceptable salts o~ the instant products It should be understood that mixtures of salts are also included. In general, any base which ~
~orm a salt with the ~oregoing acids and the cation of such base whose pharmacological properties will not cause an adverse physiological effect when ingested by the body sys-tem is considered as being within the scope of this inven-tion; suitable cations thus include, ~or example, the alkali metal and alkaline earth cations, zinc, alu~invm, iron, copper and the li~e, and the cations of ammonia, primary, secondary and tertiary amines, such as mono-lo.~er alkylamines such as t-butyl amine, di-lower al;~ylamines such as diisopropyl amine, tri-lower alkylamines such as triethylamine, nitrogen containing heterocycllc amines, ~or example, piperidine, and thelike, and alkanolami~es su~h as triethanolamine.
Also included within the scope of this invention are the ester and amide derivatives o~ the sul~onic acids g~,7'.
(I) which are prepared by conventlonal methods well-kno~Jn to those skilied in the art and to the extent that sald-derlvatives are both nontoxic and physlologlcally accept-able to the body system and represent a minor amount (less than 50%) of the tbtal product monomer units are considered as being functionally equlvalent to the sul~onic acids and - salts thereof.
The polyvlnylbenzenesulfonlc ac~ds are more susceptible to degradation by actlnic llght or heat than the corresponding salts and should not be heated above 100 C. and should be stored ln llght protected containers or sultably stabilized by chemical methods.
The followlng examples illustrate tne preparation Or the products of thls inve~t~on. Xowever,- the examples ; 15 are merely illustratlve, and it will be apparent to those ~ having ordinary skill in the art that all of the products descrlbed above may also be prepared in an analogous manner - by substituting the appropriate starting materials for those set forth in the examples.

EXAMPLE 1 - Anionic Polymerization of Vinylbenzene Step A - itration of n-Butyl Lithium A solution of n-butyl lithium in hexane (2.4M;
2ml.) is added cautiouily dropwise to a mixture of diethyl ether (5 ml.~ and distilled water (5 ml.) in an Erlenmeyer flask. ~hen the addition is complete, the walls of the rlask are washed with distilled water and a drop of one percent (by weiht) bromophenol blue solution is added.

The solution is titrated with hydrochloric acid (O lOON) until the blue color dissipates. [The total base con~ent of the initiator is determined in the follo-wing manner:
ml. of O.lON 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 2 drop of one percent bromophenol blue.
-10 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 otr.er bases present. Since the "? . 4M" solution gives a total .~p.
base content of 2.63M and a residual base content of 0.15 ir"
the true n-butyl lithium content is 2 48M, i.e., (2.63-0,15).
Step B - Anionic Polymerization of ~inylbenzene .
Benzene (1200 ml.) in a dry two-liter, tnree-necked, round-bottomed flask equipped w1th a three way stopcock, reflux condenser, magnetic stirring bar and therm-meter under argon is brousht to 60 C. Forty milliliters of benzene is transferred to a dry 100 ml. flas~ also under argon and then vinylbenzene (0.4 ml; o.36 g.; 3.5mnoles) and n-butyl lithium in ;exane (0.5 ml. of 2.48 M solution;
1.24 m~oles) is added. This initiator mixture is maintained at room temperature for approx~mately 15 minutes durin~ whi~
time the brilliant orange color of the vinylbenzene n-bu~yl lithium adduct becomes evident. This solution of the ini-' tiator is added to the warm benzene (1160 ml ) until a slight yellow color persists in the warm reaction medium for at least 30 minutes to remove impurities. A 40 ml.
portion of the purlfied benzene is added to a second dry 5~ 100 ml. flas~ under argon and a second initiator solution prepared as above. This afrords a solution of 0.031M in inltiator The benzene tll20 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 30 minutes. The resulting solution is warmed to 30 C and 16 ml. of the 0 031M initiator solution (0.~ 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 sub-sides after one hour. The resulting viscous, orange solu-tion is maintained at 50 C. for 1.5 hours, then cooled to ambient temperature. Approximately one ml. of isopropano is added to quench the reaction. The resultinG colorless solution is transferred to a separatory funnel and added slowly dropwise to three liters of isopropanol while stirri~g vigorously. Good shear1ng action ls necessary here to afford a finely divided sample. The white polyvinylbenzene is collected by filtration. Residual isopropanol is removed under vacuum to af~ord 100 g. of polyvinylbenzene (100~
yield). Analysis by gel permeation chromatograph~r sho~s a n f 1.13 and a molecular weight of 221,000.

- 24 _ .

~4~

By following sl~bstantially the procedure des-cribed in Example 1 above and by employing 100 g. of vinyl-benzenQ and 2.3, 0.28 ~nd 0.13 mmoles of n-butyl lit~ium, there are obtained polyvinylbenzenes having a molecular weight of 49,000; 430,000 and 970,000, respectively, and - an ~w/~n of 1.17, 1.08 and 1.05, respectively.
E.XAMPL~ 2 - Poly(Sodium Vinylbenzenesulfonate) (M~ = 642,000) . One hundred grams of polyvinylbenzene of M. W.
321,0QO and Mw/~n = 3.8 (Aldrich Chemi~ Co.) is sulfonated by following substantially the procedure of Example 3 to afford a polymer having a predicted molecular weignt of aboutr'642,000 and a predicted M~ n = 3.8. Tne polymer was ultrafiltered through a 80,000 cut-off hol~ow fiber unit.
PLE ~ - Sulfonation of P~ in.-~lbenzene Sulfur trioxide (115.3 g.; 1.~4 moles) is added to a cooled (-10C.) solution of ethylene dichloride (3 liter) and dichloroethyl ether (411 grams; 2.88 moles). A
: .20 solution of filtered polyvinylbenzene (100 g.; 0.9 moles) having a viscosity averag~ molecular weight of 200,COO and an ~ /Mn f 1.1 in anhydrous ethylene dic~loride (1000 ml.) is then slowly added keepin~ the additio~ tube above the surface and maintaining the temperature b~tween -lO~C. and -5C. Upon complete addition of the polystyrene-solution, the reaction mixture is permitted to warm up to 15C. and held at that temperature ~or four hours. Delonized water (4000 ml.) ls added and the reaction mixture 3tirred for 15 mlnutes. Aqueous sodium hydroxide (50%) is added to a pH Or 7-10 and stirring continued for 30 minutes. Tne 5~ reaction mixture is allowed to undergo a phase separation for approAYimately 12 hours. The organic layer is removed and the remaining water and poly(~v-inylbenzenesulfo~ate) salt layer is heated at 50 C. under a partial vacuum of about 340 m. Hg to remove any remainin~ organic solvent.
The reaction mixture is then diluted witll an equal volur.e of~resh deionized water (the percent solids at this point is approximately 2.4,J). Sodium sulfate is removed by ultra-filtration with the outlet solution stream recycled to the feed tank. Fresh deionized uater is added to the feed tanlc ; 15 to maintain a constant head. The permeate is collected in a separate receiver and periodically tested for polymer content using a quaternary salt and inor~anic salt level by conductivity. If a precipitate is noted, the dialysis must be stopped and the mer.branes changed. The ultrafiltra~ion is stopped wnen t'ne resistance of the per~eate is rneasured 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 .~f poly(sodium vinylbenzenesulfonate) having a viscosity aver.ce rr.olecular weight of appr~ximatel~J
4' and an l~yrn of less than 1.2.

.
J

- 26_ ' ' `

3~ ~

EXAI~IPI.E 4 - Copolymer of Sodi~n Vinylbenzenes~lronate and Methac~lic Acid (rn~ = 615,000) (2:1) A solution of deionized water (30 ml,) and hydrogen pero~ide (o.66 g,; .0097 mole; 50$) ln a 500 ~.1.
round bottomed three-nec~ed flask equipped with a mechani-cal stirrer, a thermometer, a dropping funnel and a reflux condenser is heated to 60 C. over a 10 minute period. A
~econd solution of sodium vinylbenzenesulfonate (51.8 g;
0,296 mole) and methacrylic acid (12.9 g.; 0.1498 mole) in water (225 ml.) at ~0 C. is added to the reaction flas~
over a 17 minute period. The resulting solution is stirred overni~ht ~20 hours) at ~0 C. ~he solution is ~hen cooled to room temperature, neutralized to pH 7.7 by the addition of a sodium hydro~ride 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 ~. of copolymer as li~ht tan solid (r~ = 615,G00).
Mwr" = 2.5 by gel permeation chromatography.

EX~IPLE 5 - Copolymer of Sodium Vinyl-benzenesulfonate and MethacrJlic A~.~d (r~,l = 850,000) (2.47~
The following solution is prepared in a flas`~ and allowed to stand, under a blan~et of nitrogen, at roo~.
temperature for 13 days:
- Sodium Vin~rlbenzQnesulfonate 2~ ~Du Pont3 91~ ................ 61.~ g. ~0.27l' mole) Methacrylic Acid ................ 12.9 g. (0.15 mole) - Water ........................... 260 ~1.
Ammonium Persulfate .. ,.......... O.5 g. (0.0022 ~ol~) -~ ~14~

The solutlon is neutralized to pH 7.5 by the addltlon o~
~odium hydroxide solution (19,5 g.; .128 mole) and dlal~zed against runnin~ deionized water for 24 hours. The dialyzed solutlon is concentrated and freeze dried to afford 27.8 g.
of the copolymer as a ~Jhite solld, (~ = 850JoO0). M~r" =
2.55 by gel permeation chromatography.

EXAMPLE 6 - Copol~Jmer of Sodium Vinylbenzenesulfonate and MethacrJlic Acid r~J = 628,100 (2.2:1 ) Nitro~en is bubbled through a solut on of sodium vinylbenzenesulfonate (61.8 g,; .274 mole; 91.5~) and methacrylic acid (12.9 g,; .1498 mole) in deionized wa~er (255 ml,) in a 5G0 ml. round bottomJ three nec~ed flask equipped with a mechanical stirrer, a therr.10meter, a reflux condenser and a nitroen ~u~bIer or one hour to deaerate the solution. The solution, under nitrogen, is heated to 50 C. and hydrogen peroxide (1.32 g.; 0.135 molei 35~) is added, This polymerization 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 ~2.2 g,3 .1525 mole). The neutralized solution is dial~Jzed for 48 hours in running deionized water, concentrated to 600 ml.
and lyophilized for 24 hours to afford 62.4 g. of copolymer (M~ = 628,100).
By followin~ substantially the procecure of Example 6, there are obtained copol~;mers having the following ratio and molecular weight:
J a. SVBS~2)/ilAA( 1) ~ = 915,100 b. SVBS (2)/MAA(1) ~ = 686,450; iI" r~ = 2.8.

EXArilPLE 7 - Poly(Ar~onlum Vin~lbenzenesulfonate) A ~olutlon of poly(sodlum vinylbenzene~ul~onate) is put through a column of Amberlite IR-120 in the H+ ~or~
to convert the sodium salt of the polymer to thefree acid.
The solution is titrated to determine the meq. of H~ml.
This solution is then stirred with an equimolar amount of a - 29.8~ a~monium hydroxide solution for one hour. The solu-tion i-s lyophilized to afford poly(ammonlum vinylbenzene-sulfonate).

EXAMPLE 8 - Glvcine S~]t of Polv(Vinyl~enzenesulfonic Aci~,~

A solution of pol~vinylbenzenesulfonic acid)ls stirred with glycine for one hour, concentrated a~d lyo-philized to afford the-glycine salt of ~oly~vinylbenzene-sulfonic acid).

EXA~PLE 9 - Calcium Salt of Poly(Vinyl~enzenesulfonic Acid~
A solution of poly(sodium vinylbenzenesul40nate) in water is passed through a column of Amberli~e IR 120, Ca++ form, to exchange Na+ for Ca++. The effluent from this column is concentrated and freeze dried to afford the cal-cium salt of poly(vinylbenzenesulfonic acid).

; ~ fr~dt ~
.

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EXA~PLEI 0 - Magnesium Salt of Poly(Vinylbenzenesulfonic Acid A dialyzed solution of poly(vinylbenzene-sulfonic acid from E~ample 7 tl30 meq.) is stirred over-night with magnesium carbonate (7.3 g.; 129.2 meq. Mo~+ )-This solution is filtered to remove any insolubles and then dialyzed for 48 hours. The resulting solution is concentrated and freeze dried to afford the magnesium salt of poly(vinylbenzenesulfonic acid~.
EXAMPLE 11 - Copolymer of Sodium Vinylbenzenesulfonate and EJhyl m~thacr~late (2.~
Step A - Copolymer of Vinylbenzene and Eth~l Methacr~Late-A solution of vinylbenzene (78 g.; 0.75 mole), ethyl methacrylate (34.2 g.; 0.30 mole) t benzoyl-peroxide (3.0 g.; 0.011 mole) and toluene (70 ml.) in a one liter round b~ttom flask eaui~ped ~ith ~ mechanical - stirrer, a thermometer, a reflux con~snser ~nd an addition - funnel is heated to reflux (114C.). A second solution containing vinylbsnæene (26 g.; 0.25 mole), ethyl methacrylate (11.4 g.;0.10 mole) and bonzoyl peroxide - (1.0 g.; .004 mole) in toluene (400 ml.) is added from the addition fu~nel over a four hour period. Refluxing i3 continued for an additional two hours. The solution is then evaporated to dr~ness and the glassy residue dissolved in acetone t500 ml.). The polymer is isolated by pouring the acetone solution into methanol t3000 ml.) with stirring. The copoiy~er is collected and dried overnight in a vacuum oven at 40C. to yield 110.0 g.
t73.5% yield) of copoly~er.

3o .
`

~14g~7 Step B - Copoly~er of Sodium VinylbenzenP-sulfon~te L~nd EthY1 MethacrYlat~
_~ To a solution of sulfur trioxid~ (Sulfan B) 1.5 g.; 0.52 mole) in sym-dichloroethyl ether (143.0 g.;
l.0 mole) and ethylene dichioride (700 ml.) at -1~C. in a two liter round-botto~d flask equipped with a thermometer, mechanical stirrer and an addition ~ el is added a solution of a copolymer of vinylbenzene and ethyl methacrylate (53 g.) in ethylene dichlori~e (350 ml.) at -15C. over a 12 minute period. The cooling bath is then removed and the reaction mixture allowed to come to room temperature over a three hour period. A pink solid is removed by fi'~tration and - dissolved in water (600 ml.). Any residual organic solvents are removed and the solution nPutralized to pH 7.8 by the addition o~ a sodium hydroxide solution (50 g.; 0.625 mole; 50~ his neutralized solution is ~ - dialyzed for 48 hours, concentrated and freeze dried to yield 80-5 g. of copolymer~ MW,730,000 ' .

.. -.- . - ....
- . . .
- .
.. . .

- ' -, .

EX~ PI,~ Co})olymer Or Sodium Vin~lbenzen3sulfonato aJ~.1 Metna~ lic A~id (1 0:1.2) A solution of water (50 ml.) and ammonium persulfate (2.0 g.; O.OS7 mole) in a 500 ml. round -bottomed, t~lree necked flask equipped with a mechanic21 stirrer, thermo~leter, dropping funnel and reflux con-denser is heated to 80C. over a thirty minuts period and a solution of sodium vinylbenzensulfonate (20.6 g.;
0.1 mole) and methacrylic acid (8.6 g.; 0.1 mole) in water (100 ~1.) is added over a 17 minute period. The resulting solution is heated at 80-82C. for four hours and allowed to cool overnignt. The cooled solution is neutralized to pH 7.1 b~ the addition qfa sodium hydroxide solution (8.0 g.; 0.1 mole, 50%). The solutlon is dialyzed for 48 hours against running deionized water;
concentrated to about 200-250 ml. and then freeze-dried to afford 22.9 g. (78.6% yield) of the copolymQr as a - white solid. N. 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 of various ratios of sodiu~ vinylbenzenesulfonat* (SVBS) and methacrylic acid (MAA) having the following molecular weights:
- 25 a. SVBS (2.47)/MAA(l) MW=850,ooo ~W/Mn=2.55 b. SVBS (2)/MAA(l) MW-524,ooo ~;~/Mn=2.7 c. SVBS (3)/MAA(l) ~W=282,000 d. SVBS (4)/~A(l) MW-250,000 . .

l~i4 ~,~!~`.

EXA~PL~ Copolymer of Sod1um Vinylbenzenesulfonate and ~Ict~yl ~let'na_ryla'e SteP A'- Copol~.ner of Vin~lbenzene (2.46) and Meth,yl M~thacr~late (i) Vinylbenzene (104 g.; 1.0 mole), metnyl methacrylate (40 g.-; 0.4 mole), benzoyl peroxide (0.5 `~- gO; 0.002 mole) and benzene (50 ml.) is added to a 500 , ml. flask equipped with a stirrer, water condenser and - addition funnel. Benzene (lOO ml.) is placed in an addition fu~el. The system is purged with nitrogen for ten minutes while stirring at room temperature.
The mixture is heated to 80C. 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 ~l.).
The polymer is isolated by adding the benzane solu~ion to vigorously stirred methanol. The solid polymer remo~ed by filtration, washed well with methanol and dried in a i vacuum oven at 60C. to constant weight to afford 120 g.
(85.7~) of product as a white solid.
Step B - Copolymer of Sodium Vinylbenzene- -sulfonate and Methvl Meth~cr,-ilate This sulfonation is conducted substantially as disclosed in Example 12 and by using the following amounts of m~terials: Copolymer of Step A, above, - (35.6 g.; 0.1 mole); sym-2-chloroethyl ether (127 g.;
0.89 mole); Sulfan-B (35.4 g.;O.443 mole); ethylene dichloride (io25 ml.) and sodium hydroxide (50%
solution; 35.0 g.; 1440 ml.). On3 half of the neutralized 3o solution is dialyzed for 48 hour~ and th~n freeze dried to afford 36.2 g. of product as an off-white solid, MW-298,000, ~W/~n=2.1.

~ 33 ~
,, 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 dimethylformamide (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 80C. is added a solution of sodium vinylbenzenesulfonate (41.2 g.; 0.2 mole) methyl methacrylate (5.0 g.; 0.5 mole) in water (250 ml.) and dimethylformamide tDMF) (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 80C.
for an additional 16 hours. This solution is concentrated under reduced pressure to remove the water and dimethylform-amide. The r~sulting glassy polymer is dissolved in water (500 ml.), neutralized to pH 7.5 by the addition of sodiumhydroxide 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.

D 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 80C. with stirring, under nitrogen, and held under these conditions for 20 hours. At the end of this time, the reaction mixture is cooled to 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 - Copolyin~r of So~iu~ Vin~ enzenesulfonate and MethacrYlamide (2 2:1) MW-~26~000 The procedure of E~ample 15 is followed exactly except th~t the amounts are doubled. The neutralized solution is then dialyzed for ~8 hours.
The dialyzed solution is then ultrafiltered (dia--filtered) in two parts using an X~-300 membrane in an *
Amicon TC-l apparatus. ~he ultrafiltration conditions are as follows: Flow rate (over memb ane - 1.0-1.6 liters/
min.; inlet pressure (over m~mbrane) - 30-40 psi;
Filtration rate = varied at 2-30 ml./min., and Air pressure (on pump) = 30-35 psi. ~lring 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 ths ultrafïltration and flush the membran~ with plain ~Iater. Q~ co~pletion 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 meas~^ements indicate a molecular weig'nt of 526~000; monomer distribution -2.2~1 b-r N~R.
~ rr~l4 ~

~ - 3~
. .

L4~'r~
EXAMPLE 17 - Copolymer of Sodium Vinylbenzenesulfonate and Methacr~la~id~ (2.2:1. MW=4!~2.600 The polymerization procedure is substantially the same as in Example 15 using the following amourts of materials: sodiu~ vinylbenzenesulfonat3 t2~7.2 g.;
1.098 mole); water (1080 ml.); methacrylamide (56.7 g~`;
``^ 0.0666 mole); am~onium persulfate (~.5 g.; 0.0065 mole~
and sodium hydroxide (1~95 g.). After the polymerization, - - the solution is nsutralized, diluted to five gallons and dialyzed by pumping this solution through the hollow B fibers of two Dow b/HF~ 1 dialysis beakers, (in series), at the rate of 10 ml./min. while deionized water is pump~d through the beakers (around the hollow fibers) at the rate of 50 ml./min. 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=4~3,oO0.
~ ~de ~ rK

~ , . .

L4C~_ f EXAMPLE 18 - Cop~lym~r of Sodium Vinylbenzenesulro~e and Methac rYl amlde (~.7~:1) M,J=5~ G ~ ~0 A solution of sodium vinylb~nzenesulfonate (302.4 go; 1.3213 mole), methacryla.nide (76.4 g.; o.88 mole) in water (deionized, deaerated, 1,343.4 g. ) in a five liter round bottom four-necked flask equipped ~ith a mechanical stirrer thermometer, reflux condenser, nitrogen inlet tube and a liquid inlet tube is heated under nitrogen with stirring to 75c. To this solution is added ammonium persulfate (3002 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 (deioni~ed,deaerated, 1,286.6 g.) is then p~3mped into the reaction mixture using a variable speed dia-phragm pump at the follo~ing rates: 25 ml. per minute for 15 minutes; 12. 5 ml. per m~nute for 60 min-ltes;
- 6 ml. per minute for 30 minutes and 3 ml. per min-lte for 30 minutes. The reaction mixture is then heated, stirred under nitrogen for an additional two hours and cooled to room temporature. One third of the reaction mixture (1.13 ml.) is placed in the reservoir of the Amicon, TC-l ultrafiltration apparatus to w'nic.h is added sodium chloride (306 g.), dissolv?d in wate-- 25 (3.0 1.) and then additional water added to bring the - total volume to five gallons. ~en gallons of a sodium chloride solution (0.3 N) is placed in the diafiltratio~
medium reservoirs and the pol~neric solution diafiltered using an XM lOO me~brane until all ten g~lons of the sodium chloride solution has passed through the apparatus. The diafiltration is continued using de-ionized water as the diafiltration medium untii a to~al of 33 gallons of filtrate has been collected. Tne retentate (i.e., polym_ric solutio~ which does not pass through the mem~rane) is remov~d from the apparatus, concent.ated and lyoph~li~d to afford 195.8 g. of white solid. Viscosity m~asurements indicate a molecular we-ght of 539,000.
` - EXA.$PLE 1~ - PolY(Sodilm Vin-~lbenzenesul~on~te) Six samples of mono dispersed polyvinyl-benzene (Pres~ure Chemical Company) having molecular weights of 2200; 20,400; 37,000; 110,000; 200,000 and 390,000 all having an ~w/~n of less than 1.10 were sulfonated substantially as described by ths procedure of Example 3 to afford poly(sodium vinylbenzenesulfonates) having molecular weights of 4,400; 40,800; 74,000;
220,000; ~00,000 and 780,0~, respectively, all having a predicted ~ /~ln of less th~n 1.10 and also having a - molar percentage of sulfonation of (~,400 sa~le not - dialyzed) 97~, 82~, 90%, 94%, 95% and 91%, respectively.
~AMPLE 20 - Poly(Sodium Vinvlbenz~nesulfonate) A solution of sodium vinylbenzenesulfonate (144 g.) in water (700 ml_) is treatéd with ammonium persulfate (0.8 g.) and heated for 20 hours at 80C.
T~e standard work up affords poly(sodium vinylbenzene-sulfonate) having a viscosity averags molecular weig~t of 195,000. At 50 mg./kg. orally it gave a 91~ control in a Shay rat. At 100 mg./kg. it gavs 36% control in a histamins guinea pig. At 100 mg./kg. in a steroid rat it gave 41% control. W~.en fed at 1~, 50 and 200 mg./kg.
in sugar water to guinea pigs for 35 days, no significant pathology is noted. In particular, th~re was no irritation 1 30 in the G. I. tract and no moriblmd or d~ad animals.

. .

EX~LE 21 - Choline Pol~stvrenesulfonate Sodium polystyrenesulfonate (20.6 g.) is dissolved in water (15% by weight solution). To this is added 1~.96 g. of anhydrous choline chloride to form the `5 choline polystyrenesulfonate.
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/cnoline polystyrenesulfonate.
10The following data in Table I indicates the antiulcer activity of the instantproducts. Four experimental models were chosen to test.the compounds:
lo Pyloric-Li~ated Rat (1~ Hour Sha~ Rat) Pyloric ligations were formed on anesthetized 15female rats ~200-220 gm.) immediately followed-by ~n 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 curvat~lre and the nonglandular portion of the stomach scored for severity of ulceration by means o~ an arbitrary 0 to scoring system.

_~q 2. Steroid ~reated Rat Female rats (175-190 gms.) were individu~lly housed and given food and water ad libitum. Each animal was then injected subcutaneously, daily for three con-secutive days with 10 mg. ,.c1llisGlonc suspend~d in 0.2ml. of 0.5~ ~thocel solution. Concomit~nt with the P,ed-nisolone injections, each animal received 100 mg. of the test compound in one ml. of water B. I. D. orally. The rats were sacrificed ~n the fourth day, the stomachs removed, opened along the greater curvature and the glandular portion scored for incidence and severity of ulceration.
3. Histamine Induced Ulcer in the Gulnea Pi~
Adult male albino guinea pigs (~00-500 gms.) were given a single intramuscular iniection of hist~mine acid phosphate at lQ mg./kg. suspended in beeswax:
peanut oil (1:9) mixture. The animals were then orally dosed with test compound at 100 mg./G. P.,B. I. D.
(a.m-p.m.) for two consecutive days. The guinea pigs were sacrificed on the morning of the third day. The stomacns with approximatel~ 10 cm. of duoden-l~m attached were re~Qoved. The duodem ~s were then examined f~r perforations and ulcers and sco-ed for incidence and severity of ulceration by means of an arbitrary 0 to scoring system.

4. ~
- Female rats (220-225 gms.) were injected sub-cutaneously with histamine - 2 HCl at 350 mg./rat in a total voll~e of 1.0 ml. Immediately followinO tl~e histamine injection an oral dose of two ml. of a solution containing 50 mg. of the test compound was given to each rat. Twenty ~our hours later, the stomachs with duodenums attached were removed and examined for ulceration.
-4~ --:

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CALCULATION OF % INIIIBI'rIOM
1. Sixteen Hour ShaY Rat Anti-Ulcer Test The stomacils were removed anl then opened along the greater curvature. The stomachs were then scored using the following scheme.
O - Complete absence of hemorrage and ulcers;
1 - one or two small areas of hemorrage and~or ulcers;
2 - approximately 25~ of stomach ulcerated;
3 - 25 to 50% of stomach with ulcers and ~ - perforation and/or extensive ulceration throug'no~lt the mucosa.
2. Histamine Induc~d ~lodenal Ulcer Test in Rats The du~denum 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 ~odenal Ulce~ in the G~linea Pi2 The animals were sacrificed, posted an~ the stomachs with attached duodena (approxim~tely 10 cm.
length) were carefully rem~ved. ~he duodena were then examined for perforations and/or frank ulcers and scored as follows:
O - absence of gross pathology;
1 - l-~ minute duoden~l ulcers;
2 - >~ small areas of ulceration;
3 - severe ulceration and/or colliquative necrotic areas in the duodenum and ~ - perforation.

,.

Ulcer Score - Total n~lmbcr _f ~lo~enal Scored as ~ or 4 Total Nlmber of ~uodena Scored 4. Acute Steroid Ulcer Test Calculations Mean Ulcer Score = Total Number Ulcers + Incidence and Severitr*
Number of ~imals Tested *Severity -0 - no grossly visible ulcer;
1 - 1 to ~ grossly visible ulcers;
- 10 2 - 5 to 9 grossly visible ulcers and - 3 - 10 or more grossly visible ulcers.
m e following criteria have b~en adopted for antiulcer activity as measured in four experimental animal models. Agents which fail to show antiulcer activity in the Shay ~odel and one of the duodenal ulcer models are considered to be in~ctive antiulcer agents:
1. 75-85%-or greater i~ibition o~ gastric - ulcer in the 16-hour shay rat at a single dose of 50 mg./
- 20 rat, P. 0.;
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. 0.;
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, P. 0., B. I. D. for two days; with no toxicity or cecal pathology and 4. 25-40% or greater inhi~ition of gastric ulcer in the three-day St roid ~at model at a dose of 100 ; 30 mg./rat, P. 0., B. I. D~ for three consecutive days with no toxicity or cecal pathology.
% Inhibition = Ulcer Score of Control-Ulcer Sco-e Treated x 103 Ulcer Score Control -~2 -We have found that low molecular weight 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 n3rmal rats).
When fed at one gpk/day to normal guinea pigs, low molecular weight polymers will usually cause bloody caecums o. dsath in seven days. Dogs are also particularly sensitive to the low mole.cular weight polymers at one gpk/day showing GI
bleeding, diarrhea, intestin.~l ulceration and li~er involve-ment. These symptoms often remain even after the test isterminated. High molecular weight polymers can b~ fed to normal guinea pigs and dogs for from 30 to 90 days without any significant pathology. No secondary pathology de~Jelops when the poly~ers of this invention are fed to ulcerated animal models.
~ ne following data in Table II indicates ths toxicity of the low molecular weight compounds. By toxicity is meant that the co~pounds cause caecal bleeding in some o.
the test animals (rabbits or guinea pigs) and genera- G. I.
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Claims (9)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A process for preparing a polymer or copolymer having repeating units of a physiologically acceptable salt, ester or amide of a sulfonic acid of the formula wherein R is hydrogen or methyl and X is hydrogen, alkyl or halogen and, when a copolymer also having repeating units of the formula -CH(R1)C(R2)(R3)-wherein R1 and R2 are the same or different radicals selected from hydrogen or lower alkyl and R is acyloxy, aroyloxy, carboxy, carbamoyl, cyano, lower alkoxy, lower alkoxycarbonyl, or aryl, the polymer or copolymer having a mole-cular weight in the range of from 100,000 to about 2,000,000, a molar degree of monosulfonation of at least 50% and containing less than 5% of polymers or copolymers having a molecular weight of about 20,000 or less, which pro-cess comprises (a) sulfonating with a sulfonating agent a polymer of vinylbenzene or X-substituted vinylbenzene or a copolymer of vinylbenzene or X-substituted vinylbenzene with a monomer selected from alkyl acrylate, alkyl methacrylate, vinyl nitrile, acrylic acid, methacrylic acid, ethylenically unsaturated anhydrides, ethylenically unsaturated imides, olefins, vinyl esters and vinyl amides, if necessary removing low molecular weight polymer or copolymer, from the polymerization product so that the product contains less than 5% of poly-mers or copolymers having a molecular weight of about 20,000 or less and con-verting the acid to a physiologically acceptable salt, ester or amide; or (b) polymerizing a vinylbenzenesulfonic acid salt, ester or amide or an X-substituted vinylbenzenesulfonic acid salt, ester or amide or co-polymerizing a vinylbenzenesulfonic acid salt, ester or amide or an X-substituted vinylbenzenesulfonic acid salt, ester or amide with a monomer selected from alkyl acrylate, alkyl methacrylate, vinyl nitrile, acrylic acid, methacrylic acid, ethylenically unsaturated anhydrides, ethylenically unsaturated imides, olefins, vinyl esters and vinyl amides, if necessary, removing lower molecular weight polymer or copolymer from the product so that the product contains less than 5% of polymers or copolymers having a molecular weight of about 20,000 or less; and, if required, converting the polymer or copolymer product to a physiologically acceptable salt, ester or amide thereof.

2. A process according to claim 1 wherein, if necessary, low molecular weight polymers or copolymers are removed from the product so that the pro-duct contains less than 5% of polymers or copolymers having a molecular weight of about 50,000 or less.

3. A process according to claim 1 wherein a polymer or copolymer of vinylbenzene or X-substituted vinylbenzene is sulfonated by reaction with sulfur trioxide or sulfuric acid.

4. A process according to claim 3 wherein a polymer or copolymer of vinylbenzene or of X-substituted vinylbenzene having a molecular weight in the range of from 100,000 to 1,000,000 and a ratio of weight average molecu-lar weight (Mw) to number average molecular weight (Mn) is less than 1.3.

5. A process according to claim 4 wherein the polymer or copolymer is prepared by anionic polymerization in the presence of an initiator selected from a lower alkyl lithium, sodium alkyl, sodium aryl, lithium aryl, aryl ketyl or finely divided sodium.

6. A process according to claim 3, 4 or 5 wherein the sulfonic acid groups are converted into physiologically acceptable salts by reaction with an amine.

7. A process according to claim 3, 4 or 5 wherein the sulfonic acid groups are converted into physiologically acceptable salts by reaction with an alkanolamine.

8. A process according to claim 3, 4 or 5 wherein the sulfonic acid groups are converted into physiologically acceptable salts by reaction with choline.

9. A polymer or copolymer as defined in claim 1 when prepared by a process according to claim l or an obvious chemical equivalent thereof.