Note: Descriptions are shown in the official language in which they were submitted.
114~89Z
VIR.4
Anionic ion exchange resins with cholesterol decreasing properties
This invention relates to anionic ion exchange re6ins for use in
human therapy as cholesterol-decrea6ing sgents.
Ion exchange resins have notably founa use in the treatment of
various pathological states such as hyperacidity, prevention of
Na+ depletion in the gastroenteric tract, induction of K~ depletion,
treatment of nephrotic, pancreatic and cardiac edema, treatment of
ulcer, neutralisation of gastric acidity etc.
Obviously each particular pathological ætate requires a resin of
special chemical characteristics, chosen from the group consisting
of wea~ly acid resins, strongly scid resins, weakly bssic resins,
and strongly bssic res~s, provided that these resins are free
from toxicity towards the human organism.
The use of ion exchange resins has notably been extended in recent
years to the treatment of hyperlipemia6. It is in fact known
that at too high levels of lipids, which are essentially cnolesterol
and triglicerides, early arteriosclerosis can develop in the organism,
with consequences such a6 cardiac infarct and cerebral thrombosis.
Hyperlipemia is therefore a vast problem for which the re~olutive
drug has as yet not been ~ound.
To reduce cholesterol to normal le~els, it iæ necessary to both
e~clude all those foodstuffs which are rich in them or in saturated
fat6, and to increase its elim~ation.
It has been found that ion exchange resins of basic character act
in this second manner by fixing the bile acids at the~intesti~al
.,
~
11~1892
_ 2 -
level, thus interrupting the enterohepatic recycle, with
consequent loss of cholesterol.
In order to carry out this cholesterol-decreasing method on
practical scale, certain basic anionic exchange resin~ have
been produced up to the present time contsining amino and/or
ammonium groups able to chemically fix the bile acids.
~he resins prepared and used up to the present time sre essentially
Cholestyramine and Cholestypol. The first of these resins i8
essentially a styrene resin containing quaternary ammonium groups
cross-linked by divinylbenzene, whereas the second is a polymer
of N_(2_amino ethyl)-1,2-ethanediamine with chloromethyl o~iran.
~lthough from a theoretical aspect the chemical operation¦of these
resins seems clear and therefore clearly determinablejfrom a
qUantitatiYe point of view, in practice the results attsined with
them have been much wor6e than forecs6t, and could be improved.
In particular, often in contrast with the result~ obtained in vitro,
these resin6, whatever their chemical nature, have 8 too low cspacity
for fixing cholate ions in vivo9 becau6e of which either the reduction
in the cholesterol amount which they produce is insignificant, or
they have to be used in very high doses which give rise to serious
side effects at the gastro-intestinal level.
One obvious remedy to all this would seem to be to produce resin~
with a higher concentration of functional groups. ~owever, it
has been found that by increas~ng beyond a certsin limit the
concentration of the basic functional groups of the resin, whether
the~e be strong or weak, their activity reduces rather than increase~.
The present invention is based on the fact that it hss now been
.... , .,, . . _ . . . . . . . . . .
- 1~4189Z
discovered that the activity of the resin depends only to a
limited e~te~t on the chemical nature and number of the basic
functional groups present in it, whereas the determining factor
is the "acce6sibility" of the functional groups to the bile acid
molecules which are notably all compounds of steroid structure
and therefore extremely voluminous and of low mobility.
The immediate answer to the problem as posed would therefore æeem
to be to use linear soluble resins, the functional groups of which
should hsve maximum ~ccessibility.
~owever, it has been found th~t anionic resins of this type completely
unexpectedly po6æess very poor activity in that the linear chains~
which are not bonded together, aggIomerste in an aqueous environment
due mainly to coordination bonds~ to form a completely rsndom pseudo
lattice into which it i6 practically impossible for the large bile
acid molecules to penetrste, and this therefore re ves st of the
sctive group~ from the ion exchange reaction.
In the same manner, highly crosæ_linked resins have a very low and
insufficient activity due to the formation of a too narrow lattice
inaccessible to the bile acid molecules~
According to the pre6ent in~ention~ it has now been found that
chclesterol decreasing anionic eschange resins of very high ~cti~ity
are obtained by producing resins ha~ing a degree of regular cross-
linking which i6 contained within very definite critical l;m~t6
which are different for each type of resin.
The purpo6e of the regular ~ross_linking sccording to the present
invention is to form "meshe~" in the polymer which have an sperture
essentially "corresponding" to the volume of the bile acids, which
can thu6 come into contact in the alimentary canal with the highe~t
, .. . , . . _ . .. . . .
:~141892
_ 4 -
possible number of active functional groups.
~s functional groups of different chemical nature have different
volumes snd therefore create a different degree of attrition and
steric hindrance inside the "meshes", it is apparent that the
critically effective degree of cross-linking will be different
according to the chemical nature of the resinO However, it
in no way depends on whether the re6in has a gel, microporous
or mscroporou6 structureO
In other words, given a linear polymer of a determined chemical
nature and with a certain number of basic active group6, i.e.
a polymer with a certain exchange power, it is provided with ~
determined cholesterol-decreasing àctivity by producing in it a
precise degree of uniform cross-linking.
To obtain this degree of cro6s-linking snd consequently the
required aperture of the meshes formed in the polymer~ the cro6s_
linking monomer in the mixture of monomers to be polymeri6ed
must be used in an exactly defined percentage.
To obtain uniformity of cro6s-linking~ and con~equently 8 uniform
size of meshe6 formed in the polymer, a very low polymerisation
velocity mu6t be used by ~uitably choosing the catalyst~ the
reaction temperature, the monomer concentrstion in the reaction
601vent, and the catalyst concentration.
It has been found that the most suitable catslyst6 for providing
the nece~6arg gentle polymerisation conditions sre organic peroxides
snd in particular lauroyl and benzoyl peroxide. It is preferable
to use benzoyl peroxide because it has a higher hslf life, and a
better purity and initiation effectiveness.
The critical conditions under which the 6aid cataly6t6 must be used
1~41892
-- 5
for producing the resins according to the invention sre:
Lauroyl peroxide
_ Acrylic: temperature 55_65C; concentration 1-2%
_ Styrene: temperature 60-70C; concentration 1-3%
_ Epoxy: temperature 55_65C; concentration 0.5-1.5%
Benzoyl peroxide
_ Acrylic: temperature 60-70C; concentration 0.2-1.5%
_ Styrene: temperature 65_75C; concentration 0.3-1.5%
_ Epoxy: temperature 60-70C; concentration 0.2-1.0%.
It has also been found that certain not easily controllsble
side reactions during the stsges of the variou6 processes can
give rise to further cross-linking of the polymer lattice.
This csn invalidate the whole of the csreful construction of
the resin if it is not suitably checked.
In particular, in acrylic resins this undesirable reaction can
ta~e place during the ammonification 6tage where polyamines sre
used.
In styrene resins the criticsl stage occurs during chloromethylation.
In the case of epoXy resin6, the delicate st~ge is the smination
where poly~mi~e6 sre used~
It has been found that the pars6ite reactions can be prevented ag
fo~low6:
_ Acrylic: in the ammonification stage, a great exces6 of polysmines
must be used, up to 6 to 7 times the stoichiometric
_ Styrene: in the chlore~ethylation stsge a gentle catslyst i~
used such as ZnC12 under ~ery gentle reaction conditions~ i.e.
a dilute system at low temperature (35_40C).
_ Epoxy: in the amination stage an excess of polyamine ~s use~ at
low temperature (35_40OC)
1~4189Z
. ~
With regard to the choice of cross_linking agent, in theory
all molecules hsving two vinyl functions which hsve a large
distsnce between them csn be used as cross-linking sgents.
In reslity the following are used in practice: divinylbe~ene,
divinyltoluene, divinylxylene, divinylethylbenzene snd the like.
Divinylbenzene i~ preferred because of its resctivity and it~
commercisl svsilsbility.
It hs6 now been unexpectedly found thst the fsctors whieh determine
the cholesterol-decreasing ~ctivity of on snion exchsnge resin snd
e6sentially the size of the cross-linkage "meshes" present in it,
are a function of the sppsrent density in water and the sbsorption
cspscity for wster of the resin, becsuse of which the maximum
activity for sny resin corre6ponds to a substantially constant
appsrent density and a substantislly con6tant water absorption
cspscity.
The present invention therefore provides cross-linked snionic
exchange resin~ with cholesterol-decreasing sction,h~ving an
sppsrent den6ity of 0.18 - 0.20 g of dry material~ml, with a
wster absorption capacity of 69-73% by weight~
Thi6 unique and constant vslue corresponds for each resin to
determined combinstions of exchange power and degree of cros~-
linkage (chosen within 8 critical and exsctly defined range),
and which can thus be fixed unambiguously for each resin.
For the purposes of the iresent invention th~e spp~rent density
in water h~s been determined, and i~ to be under6tood hereinsfter
as determined, by the following method:
20 grsms of dry re6in (dried at 40 C in a vacuum oven until tts
weight is constsnt) sre left in 150_200 ml-of water for 24 hours,
1141892
- 7 ~
6tirring occasionally. The resin is then transferred into
a glass column which is exactly graduated and is provided with
a porous baffle.
The resin bed is then expanded in counter-current, and then after
it deposit~ the water is discharged at a rate of 10 volumes per
volume of resin until a head of 1 to 2 cm is left above the
resin~
After standing for 20 minutes, the volume of the resin lsyer is
determined. This measurement is repeated two or three times
on the same sample so that the error becomes contained within
1~. The density is given by the ratio of the dr~ weight of the
resin to its volume in water.
For the purposes of the present invention, the water absorption
capacity of the resin is alw~ys to be understood as determined
by the following method:
3 g of re6in, dried to constant weight at a temperature of 40C
in 8 reduced pressure environment, sre exposed on a glss6 di6c
to sn atmosphere saturated with moisture at 25 C until there i8
no furthe~ weigkt incresse.
The water absorbed is expressed as 8 percentage of the total weight.
The cholesterol-decre~sing ~ctivityof the resin6 was determined ~n
vitro by the following method:
20 ml of 8 sodium cholate solution of 2 mg/mI concentrstion in a
0.02 molar solution of a phosphate buffer (pH 6) sre plsced in 8
conical fla6kO
1 ml of ~2 and 30 mg of re6in sre sdded to the fls6k.
After stirring for five minute6 at 25 C, the contents are filtered~
and the non-fixed cholic scid i8 determined by a spectrophotometric
method after reacting with sulphuric acid (~ier et al. J.Chim.Inve6t
1141892
40, 755, 1952).
The activity is given by the sodium cholate fixed during the
time considered. Some tens of styrene, acrylic snd epoxy resins
were prepsred having different exchsnge powers ~nd different
degree6 of cross-linkage.
~sing the above methods, the apparent density, the water sbsorption
and activity were determined for esch of the re6ins. Maximum
actiYity wPs constantly obtsined with resins hsving sn apparent
density of 0.18 to 0.20 g of dry material/ml snd 3 wster absorption
capacity of 69 to 73% by weight.
By this method, the criticsl range of exchange power and cross-
link~ge were determined between which it is possible to obtsin 8
very high chole6terol-decres6ing activityfor sny type of re~in.
U6ing the same method, it was establi6hed that in reality all
re6ins known up to the present time, and which have an absolutely
insufficient activity to be able to be considered a6 an effectivo
cholesterol_decressing meaDs, have an apparent deDsity in water which
is outside the limits of 0.18 to 0.20 g of dry material~m~, and in
particular a density snd water absorption which indicste poor
non-uniform cross-linkage (Cholestyramine type) or an excessi~e
and non-uniform cross-linkage ~Lewstit ~ ~oa ~nd Cholestypol
types of resin)~
~he stnong exchange power and the total exchange power were also
determined for each resin.
The strong exchange power wss détermi~ed by the following method:
10 g of dry resin are converted to the OH by percolating a 5%
aqueous NaOH solution until Cl ions were no longer found in the
eluate~
.,
` 11418g2
The resin is then abundantly wsshed with wster until neutral.
The OH form is reconverted to Cl by percolsting 400 ml of a
10~ aqueous NaCl solution, then washing with 1000 ml of H20.
The base contained in the eluate is titrated with 0.1 N ~Cl,
1 ml of HCl used corresponding to 0.01 milIiequivalents (meq~
per gram.
The total exchsnge'power was determined by the following method:
IO g of resin, made into th~ OH and free amine form a6 described
in the preceding method~ are treated with 100 ml of lN HCl and
are then washed with water until neutral.
The HCl of the eluate is titrated with O.lN NaOH using methyl red
as indicator.
The total exchange power of the resin is given by the number of
milliequivalent6 of acid not found in the eluate divided by lOo
The critical values which were determined for the most common
types of anion exchange re6ins acc,ording to the invention as
being necessary to give high cholesterol-decreaging power are as
follows:
Styrol resin6 with smino and ammonium groNps
Strong exchange power meq/g 2.8 _ 4.0
Total exchange power-meq/g ~ 2.8 _ 4.0
Cross_linkage % 1.5 - 2.5
Acrylic resins with amino snd smmonium groups
Strong exchange power meq/g 2.0 _ 300
Total exchsnge power,meq/g 5.5 _ 8.o
Cros~_linkage % 10 - 12
Epoxy re6in6 with amino and smmonium group8
Strong exchange power meq/g 2 - 5
Total exchange power meq~g 10 - 12.5
114189Z
-- 10 _
Cross-linkage % 3 - 4
In the case of epoxy resins, the term "cross-link3ge" obviously
indicates only the cross_linkage due to the cro6s-linking agent,
and that due to the amine is ignored.
Some practical examples of cholesterol- decreasing resins according
to the invention are given hereinafter by way of example onlyO
EXAMPI.E 1
Pre~aration of a microporous acrylic resin (AP2)
A mixture consisting of 33 parts of scrylic nitrile, 16 parts of
methyl acrylate, 10 parts of technical divinylbenzene (strength
60%), 1 part of benzoyl peroxide and 40 psrts of toluene is
suspended by agitation in an aqueous 601ution containing 20% of
gelatine by weight.
1 psrt of bentonite i~ added to the suspen6ion.
The su6pension is heated for 40 hours at 65C.
The polymer thus obtained, which is in the form of opaque pearls,
i8 carefully washed from the residues of the dispersing solution.
The pOrosity agent is then removed by steam distillation, and the
polymer is then dried,
1 part of polymer is treated with 5 parts of ethylenediamine for
10 hours at 130C. After cooling, the excess amine is remo~ed by
repeated washing with water. The product obtained is immerse~ in
50 part6 of ~2 and 50 parts of Na2C03~ cooled to O C and treated
with 400 parts of CH2~r for 5 hours under agitation.
It is finally filtered, waæhed with E20 ~nd then put ~nto the
chloride form in a percolation column by slowly percolating 1000
parts of a 5% aqueous solution of NaC10
A resin is obtsined having the following characteristics:
1141892
11
_ Cross_linksge 10%
_ Strong exchange power 2.1 meq/g
- Total exchange power 6.2 me ~ g
- H20 absorption capacity 71%
_ Apparent den~ity 0.186 ~ml
_ Activity 18 + 0.4 m ~cholate fixed
_ Amine tertiary + quaternsry type
' EXAMPL~ 2
Preparation of a standard acrylic resin (APl)
A mixture consisting of 55 parts of acrylic nitr~le, 26.5 parts
of methyl acryIate~ 18.3 p3rts of technical di~inylbenzene (60%)
and 002 parts of benzoyl peroxide i8 suspended by agitatio~ in
an squeous solution containing 20% gelati~e by weight. 2 parts
of bentonite are added to the-6uspension. The suspension ~8
heated for 40 hours st 70C.
The polymer obtained in this msnner is washed~ ammonified~ made
quaternary snd put into the chloride form as in the previous
exsmple.
A re6in is obtained hs~ing the following characteristics:
_ Cross_linkage 11%
_ Strong exchange power 2.1 meq/g
- ~otal exchange power 6~1 me ~ g
- H20 sbsorption capacity 70.4~
_ Apparent density 0.192 g/ml
_ Activity ~ 18 + 0.4 mg~cholste fi~ed
_ Amine tertiary ~ quaternsry type
EXAMP~E 3
Preparation of a standard styrene resin (Sl)
1~4189Z
- ~2 -
A mixture consisting of 96.5 parts of styrene, 2.5 part6 of
technicsl divinylbenzene (60%) snd 1.0 part of benzoyl peroxide
is suspended by sgitstion in an aqueous solution containing 15%
gelatine by weight.
0.7 parts of bentonite sre added to the suspensionO
The suspension is heated for 40 hours at 70Co
The polymer thus obtained i5 carefully washed from the residues
of the dispersing solution and dried.
The entire product is then chloromethylated with monochloroether
(200 parts) and ~inc chloride (65 parts) after expanding it in
dichloroethane (300 parts), heating the mixture for 7 hours at
35C.
~inslly, the intermediate obtained i8 aminated with trimethyl
amine (180 parts of 40~ aqueous solution) at 45 C for 6 hour~. -
A resin is obtained having the following characteristics:
_ Cross_linkage 105%
_ Strong e~change power 3.3 meq/g
_ Total exchange power 3.3 me ~ g
_-H~O absorption capacity 71.7%
_ Apparent density O.loO g/ml
_ Activity 15 t 0.4 mg/cholate fixed
_ Amine quaternar~-type
EXAMPLE 4
PreParation of a standard st~rene resin (S2)
mixture consisting of 9~ psrts of styrene, 305 parts of technic~l
divinylbenzene (strength 60%) snd 007 psrts of benzoyl perox~de ~s
suspended by sgitation in an aqueous solution containing 15~ gelst~ne
~y weight~
? parts of bentonite are added to the suspension.
- 1~4189e
The suspension is heated for 40 hours st 70C.
The polymer obtained is washed, dried, chloromethylated and
aminated as in Example 3.
~ resin i6 obtained having the following characteristics:
_ Cro66_1inksge 2.1~
_ Strong exchange power 3.3 meq/g
_ Total exchange power ~.3-meq/g
~ ~2 absorption capacity 71.5%
_ Apparent density 0.195 g/ml
_ Activity 15 + 0.4 mg/cholate fixed
_ Amine qusternary type
EXA~PLE 5
Pre~aration of a 6tandsrd ePoxy resin (E4?
rhyd rl n
D A mixture consisting of 93.3 psrts of cpiohlorydrinc, 6.5 parts
of technical divinylbenzene (6trength 60O and 0.2 parts of
benzoyl peroxide iB suspended by sgitation in an aqueous solut~on
containing 20~ gelatine by weight.
The suspen~lon is heated at 65C for 40 hours.
The polymer thus obtsined i6 csrefully wsshed from the residues
of the disper6ing 6ystec snd dried.
The whole of the polymer~i6 then treated with 100 part6 of ethylene-
diamine and 40 part6 of NaO~ flakes st 65C for 10 hours under
agitation. ~he product obtained is washèd with water to remove
the exces6 of amine, and i8 then immersed in 50 parts of ~2 snd
50 psrts of Na2C03~ and treated with ~00 parts of C ~r for S hour~
at 0C under agitation. It iB finslIy filtered, washed with water
and i6 then put into the chloride form in 8 percolation colu~n by
1~41892
- 14 _
slowly percolsting 1000 parts of a 5% aqueous solution of NaCl.
A resin is obtained having the following characteristics:
_ Cross-linkage 4%
_ Strong exchange power 2.1 meq/g
_ Totsl exchsnge power 1005 meq/g
~ ~2 sb60rption capscity 69.5%
_ Apparent density 0.180 6/ml
_ Activity 12 + o.8 mg/cholste fixed
_ Amine tertiary + quaternary type ~
EXAMPLE 6
Pre~arstion of a standard ePOx~ resin (E3)
A mixture con6isting of 94D8 psrts of ~ , 5 psrts of
technical divinylbenzene (strength 60~o) and 0.2 psrt6 of benzoyl
peroxide is suspended by agitation in an aqueous solution containing
20~ gelatine by weight.
The 6u6pension is heated at 65 C for 40 hour6.
The polymer thus obtained~ i8 washed, aminated and ~ade quaternsry
as in the previous example.
A resin is obtained having the fo~lowing characteristics:
_ Cross_linkage 3%
_ Strong exchsnge power 2.3 meq/g
_ ~otal exchange power lOo9 meq/g
~ ~2 sb~orption capacity 70.5%
_ Appsrent density 0.180 g/ml
_ Activity 12 ~ 0.~ mg/cholate fi~ed
_ A~ine tertiary + quaternary type
For greater clarity, the characteristic dat~ of the new resins are
summarised in the following tsble, compsred with the ssme dsts for
the most known resins avsilable for some years.
1~4189j~
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7 o 0
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3~ s ~e
114i89Z
- 17
The cholesterol-decressing activity of the new resins according
to the invention was also e~amined 'lin vivo~O
To examine the "in vivo" cholesterol-decreaæing effect of the
various resin6, the following tests were used:
1) Their action on hypercholesterolemia produce~ by a
diet enriched in cholesterol in the rat snd rabbit
23 Their action on the fecal excretion of bile acids in
the dog.
1) To induce hypercholesterolemia in rats, the animals were kept
under a diet in accordance with Nath and colleagues (J. Nutrit
67~; 289~ 1959) containing:
devitaminised cs6ein 20~o
dl-methionine 004%
Hegsted saline mixture 4%
sacchsrose 49.1%
cholesterol 1%
chol~c acid 0.5% and vitamins.
To induce hypercholesterolemia in rabbits, 1 g/day/animal of
cholesterol was administered by means of a gastric probe. Each
snimal species comprised &4 male animals, namely rats of the
Sprague_Dawley stock having an average weight of 200 g snd New
Zesland rabbits of 3 kg, divided into }2 groups of 7 animals each.
All the animals were put into a state of hyperchole~terolemia by
means of a diet. One group underwent no treatment, wheress the
other 11 groups were treated with 0~ ~ kg of one of the resins
for 30 days.
The resins were dissolved or suspended in 10~ gum srabic mucilage~
Only gum arabic mucilage was administered to the control group.
~141892
- 18 _
On the thirtieth d~y of trest~ent all the animal6 were sacrificed
and the total plasmatic cholesterol was measured in the blood
collected from the carotid arteries (Pearson and colleagues
J.ChimOEndocrin.Metabolism 12, 1245, 1952).
2) To evaluate fecal excretion of bile acids, 48 male beagles dogs
weighing about 8 kg were used and were divided into 12 groups of
4 animals each. AlI the animsls were kept under standard diet
snd living, and with the exception of one control group of dogs,
alI groups were given, in addition to their diet~ 2 g/kg¦day of
one of the resins for 25 days. On the 26th day from the beginning
of the experiment, the bile acids were determined in the feces of
the dogs, which were fssted for 12 hours in a metabolic cage
(Grundy and colleagues, J.Lipia Res. 6, 397, 196S;
Ma~ita and colleagues, Ann.Biochem. 5, 523, 1963;
Forman and colleagues, ClinOChem. 14, 348, 1969).
Tsbles 1 and 2 summarise the resu~ts obtained in the rat6 and rabbits
put into a state of hypercholesterolemia by diet, and treated with the
various re6ins exsmined.
The cholesterol_decreasing effect of the resin6 administered orally in
"in vivo" equal-weight doses substantially agreed with the "in vitro"
resultsO
In this respect, it was found that again in this case resins having an
apparent density in water of 0.18 to 0.20 g of dry m3teri~1~ml and a
water sbsorption capacity of 69 to 73% by weight of the weight ~f
polymer have a cholesterol-decreasing effect both in rats snd in rabbits,
which is surprisingly superior to that ever obtained with other resins.
The differences with respect to known resins are all highly significant
(P > 0.013.
- ` 1141892
- 19 _
Tsble 3 shows the bile acid excretion values for dogs treated
with 2 g/kg/day of the various resins.
It csn clearly be seen thst sdmlnistering the resins prepared
sccording to the present invention produces a considerable
incresse in bile acid fecal excretion relative to that obtained
with the best resins commercially available at the present time.
~ighly significant differences (P ~ 0.01) exist between the
b~le acid values e~creted with the feces after administering
AP2, ~Pl, Sl, S2, E4 and E3 and the values obtained with the
other resins.
- 20 - 1~ 4189Z
t~
t~
a~ c~
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~ 9 ' ~ a
.c ~ C~
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1141892
X ~o
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114~89Z
- 23 -
The data heretofore given show clearly that the new resins~
independently of the chemical nature of the matrix and its
physical form (microporous, macroporous or gel) are able to
electively bond the bile acids, and can givé rise to 8 cholesterol-
decressing effect when administered orally~ which is of an extent
superior to that obtained with any resin used up to the present
time.
