Note: Descriptions are shown in the official language in which they were submitted.
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
--FH-CH2--
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:
CH2- CH2
S03H
(Ia)
and, when a copolymer, also having repeating units of the formula:
R2
I
- CH2 -
(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.
-5-
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~
.
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
.
- 10 -
. ... .
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.
-11-
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
- 13 -
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.
- 16
~ ~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.
- 18 -
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
-- 19 --
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
- 21 -
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.
- 22 -
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-
'
- 23 -
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.
- 28-
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 ~
.
.. , .... . ~
~$~
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
32
. .
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.
- 34 -
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
- 20
~ , . .
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
- 37-
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.
38
. .
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~ -
-:
~ ~ ~"4 -j .-; ~!
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.
ulceration and bleeding in other test animals which may re-
sult in death of the animals.
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