Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
-- 1 --
4-16372/16373;-/CGC 1267/1268
CA
Hypocholesterolaemic gel formulation containing a pharmaceutically
acceptable non-di~estible anion exchange resin
Background of the invention
Pharmaceutically acceptable particulate sparingly crosslinked non-
digestible quaternary ammonium substituted polystyrene anicn exchange
resins, such as cholestyramine resin powdert are known hypo-
cholesterolaemic agents.
Such resins are administered oral:Ly, generally in the form of a powder
which is admixed with a beverage, such as water, milk, fruit juice or
other non-carbonated beverage, or with highly fluid soups or pulpy fruits
with a high moisture content such as applesauce or crushed pineapple. In
the intestinal tract the indigestible resin adsorbs and combines with
bile acids to form an insoluble complex which is excreted. The increased
loss of bile acids due to resin administration leads to an increased
oxidation of cholesterol to bile acids, a decrease in beta lipoprotein or
low density lipoprotein plasma levels and a decrease in serum
cholesterol levels. Although the oral administration of such resins
results in an increase in hepatic synthesis of cholesterol, plasma
cholesterol levels fall.
Accordingly, such resins are useful in the reduction of elevated serum
cholesterol levels in patients with hypercholesterolemia and in the
relief of pruritis.
~' .
:l 3~36~
Unfortunately such resins in particulate form characteristically
exhibit a chalky, gritty texture or taste in the mouth Gf the
patient, even when combined with a beverage, soup or pulpy frult. In
some patients, this undesirable characteristic of the resin may
elicit a gagging reflex. As a result, patient compllance to the oral
self administration of the reæin may be reduced.
It ls thsrefore an ob~ect of the present invention to provide a
pharmaceutically acceptable semisolid composition containing an
effective hypocholesterolaemic amount of a p~rticulate sparingly
crosslinked non-digestible quaternary ammonium substituted poly-
styrene anion exchange resin which possesses a high degree of
palatability.
It i8 a further ob~ect of the present invention to provide a method
for treating by oral administration an effective hypocholesterolaemic
amount of such semisolid composition.
These and other ob~ects of the invention are apparent from the
following specification disclosure:
Detailed description of the invention
One embodiment of the present invention i~ a semisolid palatable
hypocholesterolaemic formulation for oral admlnistration to a
patient comprising an effective hypocholesterolaemic amount of a
uniform gelled dispersion of
(a) between about 8 and about 20 percent by weight of a particulate
sparingly crosslinked non-digestible quaternary ammonium substituted
polystyrene anion exchange re~in having an average particle size
below about 100 microns;
(b) between about l.5 and about 16 percent by weight of a
pharmaceutically acceptable gelling agent;
~3~ 57
(c) between about 0.015 and about 10 percent by weight of a natural
or synthetic phsrmaceutically acceptable sweetenQr;
(d) be-tween about 0.05 and about 2 percent by weight of a
pharmaceutically acceptable organic acidulent;
(e) between about 0.05 and about 5 percent by weight of one or more
pharmaceutically acceptabl~ flavouring or coloring agent~ ~r
mixtures thereof; and
(f) the remainder water.
The particulate resin component (a) belongs to the class of pharma-
ceutically acceptable particulate anion exchangs resin useful in the
reduction of chole~terol and triglycerid~ levels and the relief of
pruritis in patients suffering from bile stasls. Such resins po~sess
quaternary ammonium groups attached to a polystyrene containing
backbone. Preferably such quaternary groups are tri-lower alkyl
ammonium groups wherein the nitrogen thereof i8 attached to the
phenyl moiety of the styryl group. The most preferred lower alkyl
group i9 methyl. Further the resin is sparingly crosslinked, e.g.
with a conventlonal divlnyl cros31inking agent, especially divinyl
benzene. The aMount of crosslinker present in the final resin is
generally below about 5 %, preferably between about 1 and about 4 %,
most preferably about 2 %, by weight of dry re6in. The resin can be
prepared, for example, as described in U.S. Patent No. 2,591,573.
The quaternary ammonium resin is in the form o~ a pharmaceutically
acceptable ~alt thereof, such as the chloride, acetate, sulfate or
the like. Generally, useful resins are those having a water content
greater than about 65 % by weight after equilibration with air at
100 % relative humidity at about 20C. Mo~t preferably, the resin
employed is chole~tyramlne resin U.S.P.. The resin should be milled
such that the average particle slze i8 less than about 100 microns.
Preferably, at least about 80 percent of the resin particles have a
particle size betweeen about 20 and about 100 microns, with less
~3~
than about 0.5 % of the particles having a particle size greater
than about 200 microns. Preferably, the amount of resin in the
cnmposition is between about 12 and about 18 percent by weight.
Component (b) consists nf a pharmaceutically acceptable gelling
agent, such as gelatin USP, which is soluble in hot water, e.g.
above about 35C, and, in the preferred amount of 4 to 16 % by
weight employed, forms a stable elastic shape retaining colloidal
solution within which the resin component i.8 substantially uniformly
dispersed upon cooling to room temperature, e.g. about 20C. The
most preferred amount of gelatin employed i8 between about 5 to
about 10 percent by welght of the formulation. The preferred gelatin
is gelatin USP, type A. The gelatin component in the amount~
specified also assists in masking the chalky taste characteristics
of the resin.
The gelling agent present in component (b) also consist3 of a
pharmaceutically acceptable water compatable gum, to provide smooth
spresdability and ma3king of the resln by coating and au~pending the
same, preferably acacia, carrageenan, xanthan or tragacanth gums or
mixtures thereof. Most preferred is tragacanth gum. Preferably, the
gum is present in the composition in an amount between about 2 and
about 3 percent by weight, in order to assi~t in ma~l~ing the chalky
taste characteristic~ of the resin and to provide spraadability.
The pharmaceutlcally acceptable organic acidulent (d) is present in
combination with the sweetener and the gelling agent for the purpo~e
of further ma~king the unpleasant mouth feel of the active agent
re~in, and include, for example adipic acid, ascorbic acid, citric
acid, malic acid and tartaric acid or mixtures thereoE. Again the
optimum amount will, in part, depend upon the particular acidulent
chosen. Preferably, the amount of acidulent is between about 0.1 and
about 0.5 percent by weight. The mnst preferred acidulent i3 adipic
acid.
~3~365~7
The pha~maceutlcally accep~able flavourlng and coloring agents (e)
may be selected from any of a wide variety of known agents and
include ph~rma~eutically acceptable colors as well as artificial and
natural flavors, including lime, cherry, orange, banana, ~pearmint,
lemon, raspberry, blueberry, vanilla, strawberry, cinnamon, pepper-
mint and the like, a6 well as mixtures thereof.
Also, if desired, minor amounts, preferably between aoout 0.01 to
about 1.0 percent of pharmaceutically acceptable preservatives,
stabillzers or anti-binding agents and the like may be present in
the composition. Suitable preservatives include potassium sorbate
and sodium propionate. As an anti-binding agent, to reduce the
potential of constipation in some patients, methyl cellulose is
preferred.
The present invention also relates to a process for the preparatlon
of the above-mentioned pharmaceutical compositions which comprises
micronizing the anion exchange resin (a) to an average particle size
below about 10 microDs 9 preparing an aqueous solution of the
pharmaceutically acceptable gelling agent (b) at temperatures above
35C and adding components ~c~, (d) and (e) at lower or elevated
temperatures to the suspension and allowing ths su~penslon to cool
to temperature~ below 35C.
~hen gelatin is used, prior to cooling and consequent gelatini~a-
tion, the disper~ed liquid, containing uniformly suspended resin can
be poured into indivldual containers or molds of desired shape and
size where the liquid sol hardeD~ to the desired elastic shaye
retaining colloidal solution contalning the uniformly di~persed
particulate resin. A~ an alternate embodlment, the gelatiniza~ion
can be performed in trays, or the like, and un-lt do~e form~ can be
obtained by, for example, cutting portlons therefrom.
~3~ 57
When gum is used, the spreadable composition can then be placed into an
ointment or toothpaste type tube or the like, for multiple dosing, or in
unit dose containers. The active agent containing spreadable composition
may be orally administered as is or may be spread on a cereal wafer,
biscuit, or bread or the like.
The unit dose may vary widely, depending on the condition treated, but is
preferably between about 2 and 16 grams of active agent resin, most
preferably about 4 grams of active agent resin.
The following examples are for illustrative purposes only and are not
intended to limit the scope of the invention. All parts are by weight.
Example 1: 2.0 parts by weight gelatin USP, type A is dissolved in
24.0 parts by weight water at 60C with stirring. After stirring the
solution for 3 minutes, 4.0 parts by weight of dry cholestyramine,
Dowex~ lx2 made by Dow Chemical Co., Midland, Mich. and containing about
2 % of divinyl benzene crosslinking agent, which has been milled and
screened to obtain an average particle size less than about 100 microns,
with about 80 percent having a particle size between about 20 to
about 100 microns, and 0.07 parts by weight aspartame are added to the
solution with stirring at 60C. After stirring for an additional
3 minutes, there is then added to the liquid mixture maintained at 60C,
0.10 parts by weight adipic acid and 0.10 parts by weight of a mixture of
artificial strawberry flavor and FD&C Red dissolved in ethanol. After
stirring the mixture for an additional 5 minutes, the uniformly di-
stributed suspension of resin in the resulting solution is placed in
rectangular molds where, upon allowing the mixture to cool to room
temperature for a period oE two hours, the stable elastic shape retaining
colloidal solution, or gel, containing the resin uniformly dispersed
therein, is obtained.
'``;~ `
:1~3~8~
Example 2: 4.0 parts by weight of dry cholestyramine~ "DOWEX lx2"
made by Dow Chemical Co., Midland, Mich. and containing about 2 % of
divinyl benzene cros~linkin~ agent, is milled and screened to obtain
an average particle size less than about 100 microns, with about 80
percent having a particle size between about 20 to about 100
microns, and dry blended with 0.07 parts by weight tragacanth gum
and 0.07 parts by weight aspartame. The resulting bl~nd is then
added with mixing to 24.0 parts by weight water and mixed thoroughly
for 5 minutes at 40C. To this mixture there is then added
0.10 parts by weight adipic acid, and 0.1 parts artificial banana
flavor admixed with FD~C Yellow dissolved in ethanol. The resultant
composition is then thoroughly mixed for another 5 minutes until a
smooth, palatable, easily spreadable blend is obtained.
Example 3: A composition identical in composition components to
those of Example~ 1 and 2 prepared, except that 0.2 parts of methyl
cellulose is added to the solution with aspartame and resin. Due to
the additlonal presence of methyl cellulose, the incidence o~
possible constipation ls minimized.
,
