Note: Descriptions are shown in the official language in which they were submitted.
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- 1 - H-~ 6/dlk/jU
NOVEL DRINK MIX FORMULATION
Background of the Invention
Field of the Invention and Prior Art
The present invention relates to a readily-disper-
sible physiologically-effective fiber drink mix com-
prising granules consisting essentially of a blend
of a mineral salt which releases a physiologically-
acceptable gas upon ingestion, a physiologically-
acceptable edible acid, and a gel-forming dietary
fiber, which granules are coated with a gel-forming
dietary fiber, starch, or protein and which may also
advantageously include an orally-ingestible drug or
other pharmaceutically-active compound, such as niacin,
in said granules.
Guar gum (Cyamopsis Tetragonoloba), a galactoman-
nan polysaccharide, and other gel-forming fibers such
as psyllium hydrophilic mucilloid, have been recognized
for some time to have a therapeutic value for lowering
cholesterol and helping to regulate blood sugar. The
cholesterol-lowering properties of guar gum and other
mucilaginous substances were initially recognized by
Fahrenbach et al. (U.S. Patent 3,148,144).
Guar gum is obtained from a luguminous plant which
grows to a height of three to six feet. The Guar plant
bears bean-like pods, each of which contains six to
nine small rounded seeds. The guar seed is typically
composed of 40-46% germ, 38-45% endosperm, and 14-16%
husk. Guar gum is used extensively in the food indus-
try and is recognized as safe by the Food and Drug
Administration as a food additive.
~ti,`Q ?~
- 2 - I~-K 6/dlk/jU
Guar gum is used in the food industry for various
purposes as a food additive. Even at fairly low levels
it presents certain problems, such as difficulty of
dispersing the guar flour in liquids, or the formation
of undissolved lumps or fish eyes of powder, which are
effectively sealed from further hydration by a surface
gel which prevents further solubility or dispersion.
Jenkins et al. (The Lancet, 1975, 1116 and 1977,
779) discovered that a therapeutic dose of guar gum
effective for lowering serum cholesterol or regulating
blood sugar required administration of fairly large
quantities of guar gum per day. In fact, doses of 15
to 20 grams per day were needed to obtain statistically
significant cholesterol reductions.
Stemmle et al. (EPO 0080673) describes many of the
problems associated with the use of guar gum in a
therapeutic dose. Of the various dosage forms, such as
tablets, capsules, and a powder drink mix, problems of
solubility, dispersion, hydration, and gelation are all
described. With respect to a tablet dosage form, it is
widely known that guar gum tablets do not dissolve
properly either in vitro or in vivo. The high pres-
sures needed to manufacture tablets compresses the guar
flour together and, when these tablets are placed in a
gastric simulator or a dissolution apparatus, they do
not dissolve. The guar particles on the surface of the
tablet hydrate to form an impenetrable gel, effectively
sealing off the rest of the tablet, and preventing the
dispersion of the guar. After 24 hours in a dissolu-
tion apparatus, the tablet still remains undissolved,
and sits like a rock at the bottom of the apparatus.
Various additives normally used as disintegrants to
break up tablets, such as crosslinking or wicking
agents or microcrystalline cellulose, do not solve the
problem.
~ 3~
- 3 - H-K 6/dlk/jU
Day and Kuhrts (U.S. Patent 4,824,672) teach the
use of mineral carbonates to enhance dispersion of guar
gum and other gummy fibers.
With respect to powder drink mix dosage forms,
similar problems exist. The guar gum is not only
extremely difficult to mix and dissolve, but what
small amount does hydrate immediately forms a thick
gel, which becomes impossible to drink.
Steinitz (U.S. Patent 2,935,408) describes the use
of a suspension agent with a gum to overcome some of
the problems associated with using gums as stabilizers
in the food industry. In this patent, the gum is
predispersed in a non-aqueous water-free liquid matrix,
thereby to condition it for further dispersal through-
out an aqueous carrier. An example of an ideal suspen-
sion agent was glyceryl monostearate. This results
in a slurry which can be used as a stabilizer to be
added to an aqueous solution such as a gravy, salad
dressing, toppings, jams, etc. This slurry would not
be suitable for a pharmaceuticzl dosage form.
Jordan ~U.S. Patent 3,007,879) teaches the
stabilization of guar gum solutions against viscosity
change, as well as an improved method of mixing such
dispersions, and maintaining a stable high viscosity
over a substantial period of time. Organic acids are
used to stabilize the guar gum solutions, but only
after they have formed a gel.
Jackson, Jr. (U.S. Patent 3,313,800) describes
guar gum coprecipitation with gelatin from hydro-
alcoholic media. The guar gum is dissolved in the
alcohol/water solution and dried. The process is one
of precipitation. This further shows that gelation
of guar gum is a real problem, and many different
solutions to this problem have been attempted.
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Applegren (U.S. Patent 4,754,027) describes coat-
ing fine particles of guar gum with water:solvent and
film-forming fatty acids, film-forming polymers, and
ethyl cellulose. Examples of solvents are ethanol,
lower ketones such as acetone, benzene, xylene, and
toluene. An example is the use of a polymer of di-
methylaminoethyl-methacrylate for the film-forming
agent and acetone:isopropanol (40:60) as solvent. Among
the many drawbacks of his contribution are the use of
lOpollution-causing substances which require special
pollution-control devices and subject the manufacture
to regulatory control; the expense of the film-forming
agents and solvents, making this product very expen-
sive; and failure to provide for a further dispersion
of the fine guar particles within the granules, so
that, after his film dissolves, the guar still has an
impenetrable film of guar gel around the nucleus. In
addition, his particle size and the texture of his
particles create a gritty texture and an objectionable
20mouthfeel to the product and his particles have a
tendency to sink to the bottom when mixed in a liquid,
quite in contrast to the granules of the present
invention, which do not have these shortcomings.
Nittner (U.S. Patent 4,675,312) discloses agglom-
erating a substance such as guar gum with an agglomer-
ating agent such as an animal or vegetable product, so
that the guar is metabolized more slowly in the intes-
tines.
Showa Sangyo (J.P. 59175436) involves inhibiting
30viscosity (gelation) of polysaccharides ~e.g., guar
gum, etc.), by treating them with high pressure or
ultrasonic waves. However, this could destroy the
activity of the guar gum by producing a structural
change.
~ Q ~
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Heath (G.B. Patent 2,030,583) forms a granu-
late of guar gum by agglomeration. This produces
particles which will dissolve in water, producing
drinkable mixtures. Granules of guar are formed by
spraying the powder with atomi~ed water and drying.
Particles of 100 to 1000 microns, with a water content
of 5 to 25% by weight, are created. These granules are
gritty and objectionable to consumers and it has been
found that each granule must be 250 microns at a
maximum or else they do not dissolve, because the outer
layer of the granule gels up and seals off the inner
part of the granule, much like what normally occurs
with the usual guar gum in tablet or capsule form.
Moreover, it is very difficult to control particle
growth when spraying guar with just water. It is
easier to use a carrier such as carboxymethyl cellu-
lose, as taught herein. In addition, much less water
can be used than in the spraying of guar gum particles
with water.
U.S. Patents 4,790,991, 4,747,881, and 4,818,539
describe coating dietary fibers and drugs with a
preswelled hydrocolloid, wherein tbe substrate (drug or
fiber) and the hydrocolloid are not the identical
material, and wherein the substrate contains cholestyr-
amine. The hydrocolloids are selected from the group
consist,ing of natural and modified gums, cellulose,
modified celluloses, pectin, mucillages, modified
starches, etc. Patent 4,747,881 in particular describes
coating locust bean gum with carboxymethylcellulose
(Example 1). There is no mention of the L~se of a
mineral carbonate or bicarbonate or an edible acid or
~s~ nJ
5 _ H-K 6/dlk/ju
of gelatin or a caseinate as coating agents. The
particles created tend to form small spheres which have
a gel coating around their circumference. The hydro-
colloid coating slows down the gelation of the aggre-
gate, but each individual particle does not fully
disperse or hydrate when the hydrocolloid layer dis-
solves and the gastric fluid comes in contact with the
core material (substrate). Furthermore, the hydrocol-
loid is always different than the substrate or core
material.
EPO 0007619 discloses the use of gelatin hydroly-
sates to inhibit the gelation of polysaccharide gums
such as guar or locust bean gums. The gelation of the
gum is inhibited by admixing or blending it with gelatin
and adding an effective quantity of alkalinizer such as
sodium glycinate. The preferred ratio of guar gum to
gelatin, however, is 0.5:1 (Example 1, EPO dO07619),
which means that there is twice as much inhibitor as
guar gum. This severely limits the usefulness of that
invention because guar gum must be taken in large
amounts to be therapeutically effective, and one would
be consuming large amounts of gelatin with it. In a
daily dose of 15 grams of guar gum, one would also be
consuming 30 grams or more of gelatin. This patent
teaches that the inhibition of gelation is believed to
occur when the polysaccharide gum is first hydrated.
"The surface of the polysaccharide gum
particles rapidIy hydrate and associate either by
hydrogen bonding or by electrostatic forces with
the inhibitor, which has dissolved already. The
hydrogen bonding between polysaccharide molecules,
which would otherwise cause gelation, is impeded
by the presence of the inhibitor".
The inhibition is reversed when the mixture is
consumed and reaches the acid environment of the
2 ~
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stomach where there is a pH change. Other protein
hydrolysates and carbohydrate derivatives are also
mentioned as inhibitors, because they are susceptible
to pH change. The formulation also requires an alka-
linizer to adjust the p~ and insure inhibition of
gelation. Nowhere in this patent is mentioned the
coating of guar or other gel-forming fibers with
gelatin or other protein or with any other substance.
GB 2021948 discloses the coating of gums such as
guar gum or locust bean gum with a layer of protein
such as soya flour, gluten, or casein having a greater
tendency to absorb water than the gum. The gum and the
coating substance are mixed in preferably equal amounts
with water to produce a dough which is dried and
crushed. The resulting composition gels slowly when
mixed with water. There is no mention of coating a
mixture or granulate of a gel-forming dietary fiber,
mineral carbonate or bicarbonate, and an edible acid,
with or without a drug, with a protein such as gelatin
or sodium caseinate or the like.
The present invention provides a significant
improvement over all known previous attempts at produc-
ing a gel-forming dietary fiber drink mix by producing
a more readily and completely dispersible and more
completely bioavailable product. The present invention
furthermore provides such a novel delivery system
vehicle for the oral consumption of a drug, such
as niacin, in a powdered drink mix dosage form.
Heretofore, there has not existed a niacin drink
mix which can be consumed in liquid beverage form, and
which virtually eliminates the unpleasant side effects
of niacin such as flushing and itching and having the
skin turn bright red. The following Examples illus-
trate the process and composition of the present
invention and will serve to demonstrate the many
7 HK 6/dlk/ju
benefits of the invention. Insofar as the present
invention provides a more readily dispersible and more
completely dispersible powder drink mix of a gel-
forming dietary fiber, such as guar gum or the like,
and moreover insofar as it provides such a drink
mix which also incorporates an orally-ingestible
biologically-absorbable drug or other active pharma-
ceutical agent, such as niacin, it definitely fulfills
a longstanding need in the art.
OBJECTS OF THE INVENTION
It is an object of the present invention to
provide a readily~dispersible physiologically-effective
drink mix comprising granules consisting essentially
of a blend of a mineral salt which releases a physio-
logically-acceptable gas upon ingestion, a physiologic-
ally-acceptable edible acid, and a gel-forming dietary
fiber, which granules are coated with a gel-forming
dietary fiber, starch, or protein, thereby to provide a
superior dietary fiber drink mix, and a method of
administering gel-forming dietary fiber to a subject
in need thereof by the employment of a such a drink
mix. Another object of the invention is to provide
such a drink mix which includes an orally-ingestible
biologically-absorbable pharmaceutically-active com-
pound, such as a drug or other therapeutic agent, in
said granules and in said drink mix, and a method of
administering such drug or other active pharmaceutical
agent by the employment of such a drink mix. An
additional object of the invention is to provide such a
drink mix which incorporates niacin, thereby providing
a method and means for the convenient administration
of niacin for its antihypercholesterolemic effect and
without unwanted side effects to a subject in need
thereof. Other objects of the invention will become
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apparent hereinafter, and still others will be obvious
to one skilled in the art as the description proceeds.
S~MMARY OF THE INVENTION
The invention, then, comprises the following as-
pects, inter alia, singly or in combination:
A readily-dispersible physiologically-effective
fiber drink mix comprising granules consisting essen-
tially of a blend of a mineral salt which releases a
physiologically-acceptable gas upon ingestion, a
physiologically-acceptable edible acid, and a gel-
forming dietary fiber, said granules being coated with
a gel-forming dietary fiber, starch, or protein
coating, such a
drink mix wherein an orally-ingestible pharmaceu-
tically-active compound is included in said granules,
such a
drink mix wherein said pharmaceutically-active
compound is niacin, such a
drink mix wherein said gel-forming dietary fiber
in said granules is guar gum, such a
drink mix wherein said gel-forming dietary fiber
coating is also guar gum, such a
drink mix wherein said gas released is carbon
dioxide, such a
drink mix wherein said mineral salt is selected
from carbonates and bicarbonates, such a
drink mix wherein the mineral salt is calcium
carbonate, magnesium carbonate, magnesium bicarbonate,
sodium carbonate, sodium bicarbonate, potassium car-
bonate, or potassium bicarbonate, such a
drink mix wherein the acid is a food-grade or-
ganic acid or phosphoric acid, such a
- 9 - H~ 6/bam
drink mix wherein said coating is a guar-gum
coating, such a
drink mix wherein the gel-forming dietary fiber
comprises between about 25~ to about 98~ by weight of
the composition, such a
drink mix wherein the mineral salt comprises
about 1% to about 30% by weight of the composition,
such a
drink mix wherein the physiologically-acceptable
acid comprises about 0.5% to about 10% by weight of the
composition, such a
drink mix wherein the coating on the granules
comprises about 2% to about 25% by weight of the
composition, such a
drink mix wherein the coating on the granules
comprises about 5% to about 10% by weight of the
composition, such a
drink mix wherein an orally-ingestible pharma-
ceutically-active compound is included in said granules
and wherein the amount of the orally-ingestible phar-
maceutically-active compound is about 1% to about 50%
by weight of the composition, such a
drink mix wherein said orally-ingestible pharma-
ceutically-active compound is niacin, such a
drink mix wherein the gel-forming dietary fiber
comprises about 25~ to about 98% by weight of the
composition, the physiologically-acceptable acid
comprises about 0.5% to about 10% by weight of the
composition, the mineral salt comprises about 1% to
about 30% by weight of the composition, and the coating
comprises about 2% to about 25% by weight of the
composition, such a
drink mix wherein the coating comprises about 5%
to about 10~ by weight of the composition, such a
- 10 - HK 6/bam
drink mix wherein the orally-ingestible pharma-
ceutically-active compound is present in granular form,
with a cellulose coating about the granules thereof,
such a
drink mix wherein the niacin is present in granu-
lar form, with a cellulose coating about the granules
thereof, such a
drink mix wherein the coating is a combination of
a carboxymethyl cellulose coating and an ethyl cellu-
10lose coating, such a
drink mix wherein the coating is a combination of
a carboxymethyl cellulose coating and an ethyl cellu-
lose coating, such a
drink mix wherein the acid is citric acid, such a
drink mix wherein the mineral salt is a carbonate
or bicarbonate, such a
drink mix wherein the mineral salt is calcium
carbonate, such a
drink mix wherein the orally-ingestible pharma-
20ceutically-active compound is an analgesic, an anti-
hypercholesterolemic, a vitamin, a stimulant, an
appetite suppressant, or a mineral supplement, such a
drink mix wherein a dispersion of the drink-mix
granules in water or another orally ingestible fluid
provides an effective dosage of the orally-ingestible
pharmaceutically-active compound, and such a
drink mix wherein a dispersion of the drink-mix
granules in water or another orally ingestible fluid
provides an effective dosage of the niacin.
30Moreover, a readily-dispersible fiber drink mix
composition which can be mixed in water or other
liquid and orally ingested, the resulting solution
being effective in reducing serum cholesterol, com-
prising granules consisting essentially of, by weight
of the composition:
~ HK 6/bam
a gel-forming dietary fiber in amount of about 25
to about 98% by weight of the composition,
a mineral salt which releases a physiologically-
acceptable gas upon ingestion, in amount of about
1% to about 30% by weight of the composition,
a pharmacologically-acceptable edible acid in
amount of about 0.5% to about 10% by weight of the
composition,
said granules being coated externally with a
coating selected from the group consisting of a
gel-forming fiber, an animal or vegetable protein,
and a starch, said coating being present in amount
of about 2~ to about 25% by weight of the composition,
such a
composition wherein the external coating is a
gel-forming fiber which is the same as the fiber
present internally of the granules, such a
composition wherein the coating is present in
amount of about 5% to about 10% by weight of the
composition, such a
composition wherein a biologically absorbable
drug or other active therapeutic agent is present in
the granule in amount of about 1% to about 50% by
weight of the composition, and such a
composition wherein the drug or other therapeutic
agent is niacin.
Additionally, a method for effecting the release
of a gel-forming dietary fiber, comprising the step of
preparing the gel-forming dietary fiber in the form of
a readily-dispersible physiologically-effective drink
mix comprising granules consisting essentially of a
blend of the gel-forming dietary fiber, a mineral salt
which releases a physiologically-acceptable gas upon
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ingestion, and a physiologically-acceptable edible
acid, said granules being coated with a gel-forming
dietary fiber, starch, or protein, such a
method wherein an orally-ingestible pharmaceuti-
cally-active compound is included in said granules,
such a
method wherein said pharmaceutically-active com-
pound is niacin, such a
method wherein said gel-forming dietary fiber in
said granules is guar gum, such a
method wherein said gel-forming dietary fiber
coating is also guar gum, such a
method wherein said gas released is carbon dio-
xide, such a
method wherein said mineral salt is selected from
carbonates and bicarbonates, such a
method wherein the mineral salt is calcium car-
bonate, magnesium carbonate, magnesium bicarbonate,
sodium carbonate, sodium bicarbonate, potassium car-
bonate, or potassium bicarbonate, such a
method wherein the acid is a food-grade organic
acid or phosphoric acid, such a
method wherein said coating is a guar-gum coat-
ing, such a
method wherein the gel-forming dietary fiber com-
prises between about 25% to about 98% by weight of the
composition, such a
method wherein the mineral salt comprises about
1% to about 30% by weight of the composition, such a
method wherein the physiologically-acceptable
acid comprises about 0.5% to about 10% by weight of the
composition, such a
- 13 - HK 6/bam
method wherein the coating on the granules com-
prises about 2% to about 25% by weight of the compo-
sition, such a
method wherein the coating on the granules com-
prises about 5% to about 10% by weight of the compo-
sition, such a
method wherein an orally-ingestible pharmaceuti-
cally-active compound is included in said granules and
wherein the amount of the orally-ingestible pharmaceu-
tically-active compound is about 1% to about 50% by
weight of the composition, such a
method wherein said orally-ingestible pharmaceu-
tically-active compound is niacin, such a
method wherein the gel-forming dietary fiber com-
prises about 25% to about 98% by weight of the composi-
tion, the physiologically-acceptable acid comprises
about 0.5% to about 10% by weight of the composition,
the mineral salt comprises about 1% to about 30% by
weight of the composition, and the coating comprises
about 2% to about 25% by weight of the composition,
such a
method wherein the coating comprises about 5% to
about 10% by weight of the composition, such a
method wherein the orally-ingestible pharmaceu-
tically-active compound is present in granular form,
with a cellulose coating about the granules thereof,
such a
method wherein the niacin is present in granular
form, with a cellulose coating about the granules0 thereof, such a
method wherein the coating is a combination of a
carboxymethyl cellulose coating and an ethyl cellulose
coating, such a
- 14 - ~K 6/bam
method wherein the coating is a combination of
a carboxymethyl cellulose coating and an ethyl cellu-
lose coating, such a
method wherein the acid is citric acid, such a
method wherein the mineral salt is a carbonate
or bicarbonate, such a
method wherein the mineral salt is calcium car-
bonate, such a
method wherein the orally-ingestible pharmaceu-
tically-active compound is an analgesic, an antihyper-
cholesterolemic, a vitamin, a stimulant, an appetite
suppressant, or a mineral supplement, such a
method wherein a dispersion of the drink-mix
granules in water or another orally ingestible fluid
provides an effective dosage of the orally-ingestible
pharmaceutically-active compound, and such a
method wherein a dispersion of the drink-mix
granules in water or another orally ingestible fluid
provides an effective dosage of the niacin.
Further, a method for presenting a gel-forming
fiber, comprising the step of preparing the gel-forming
dietary fiber in the form of a fiber drink mix compo-
sition which can be mixed in water or other liquid and
orally ingested, the resulting solution being effective
in reducing serum cholesterol, comprising granules
consisting essentially of, by weight of the composition:
a gel-forming dietary fiber in amount of about 25%
to about 98% by weight of the composition,
a mineral salt which releases a physialogically-
acceptable gas upon ingestion, in amount of about
1% to about 30% by weight of the composition,
- 15 - HK 6/bam
a pharmacologically acceptable edible acid in
amount of about 0.5% to about 10% by weight of the
composition,
said granules being coated externally with a
coating selected from the group consisting of a
gel-forming fiber, an animal or vegetable protein,
and a starch, said coating being present in amount
of about 2% to about 25% by weight of the composition,
such a
method wherein the external coating is a gel-
forming fiber which is the same as the fiber present
internally of the granules, such a
method wherein the coating is present in amount
of about 5% to about 10~ by weight of the composition,
such a
method wherein a biologically absorbable drug or
other active therapeutic agent is present in the
granule in amount of about 1% to about 50% by weight of
the composition, and such a
method wherein the drug or other therapeutic
agent is niacin.
Finally, such a composition wherein the size of
the granules is about 30 to about 110 mesh, preferably
about 50 to about 70 mesh, and such a
method wherein the size of the granules is about
30 to about 110 mesh, preferably about 50 to about 70
mesh.
~ 16 ~ HR 6/dlk/ju
The Dietary Fiber
For purposes of definition in this specification,
the term "dietary fiber~ is defined as "remnants of
plant cells resistant to hydrolysis by the alimentary
enzymes of man, the group of substances that remain in
the ileum but are partly hydrolyzed by bacteria in the
colon", according to JAMA 262, No. 4, 542-546 (July
28, 1989) in the Council Report entitled "Dietary Fiber
and Health", at page 542. This article, moreover,
10gives considerably information as to what constitutes a
"dietary fiber~ and is accordingly incorporated herein
by reference.
Gel-forming dietary fibers include mucillages,
plant gums, pectins or pectic substances, and lignin,
all of which are endogenous compounds of plant mater-
ials which are resistant to digestion by enzymes in the
monogastric stomach or small intestine. Chemically,
nearly all of these plant materials are carbohydrates
composed of repeating monosaccharide (sugar) units.
20Disaccharides have two sugar units, oligosaccharides
three to twelve, and polysaccharides may contain a
million or more. The water-soluble fractions of
these substances form gels in the stomach and intes-
tinal tract and are known to lower serum cholesterol.
Gums and mucillages have no common structure but
are polysaccharides containing several sugars with
alternating monomer structures and may or may not
contain uronic acids. There are many gums found
in plants and cereal grains. Guar and locust bean gums
30are galactomannans, whereas gum arabic is an acidic
polymer of galactose and rhammose. Oat and barley
contain gums, but are not practical for use in the
present application because of the low percentage of
active gum per weight volume. Most of the gums in
- 17 - ~K 6/dlk/ju
the present application are effective at much lower
dosages. Suitable gums include, inter alia, besides
guar gum, the following: locust bean gum, acacia gum,
gum arabic, xanthan gum, carregeenan gum, karaya gum,
tragacanth gum, and ghatti gum.
Pectin substances or pectins are mixtures of
polysaccharides of partially methylated and 1,4-D
galacturonic acid units with side chains containing
arabinose, galactose, xylose, and rhammose. They are
contained in many fruits and vegetables as well as
other plants.
Other suitable gel-forming dietary fibers include
psyllium husks, algal polysaccharides, glucomannan, and
agar, to name a few. Lignin is a non-carbohydrate
polymer of aromatic plant alcohols comprising oxy-
genated phenylpropane units. As a plant matures, more
lignin is produced, which acts as a sort of cement as
it hardens and holds together other plant cell wall
constituents. Lignin passes through the digestive
tract with very little change.
As already mentioned, a recent review of dietary
fiber which mentions these substances is contained in
the following reference: Dietary Fiber and ~ealth,
JAMA 262: No. 4, 542-546 (1989), from the Council on
Scientific Affairs, American Medical Association.
Some gel-forming fibers such as guar gum are used
as binders and disintegrators for compressed tablets,
but at fairly low levels. At higher levels, thes~
gel-forming fibers and gums are known not to dissolve
properly when compressed into tablets.
Various unsuccessful attempts have been made to
solve the problem of improper and incomplete dissolu-
tion of guar gum tablets. EPA 0080673 describes these
problems in detail, and discloses the use of 5 to 30%
of highly-dispersed silica gel in guar tablets.
~ 18 ~ I~K 6/dlk/ju
Normally used tablet disintegrants or additives such as
polyvinylpyrrolidone (crosslinking agent), sodium
carboxymethyl-starch, cornstarch, microcrystalline
cellulose, and so on, do not lead to satisfactory
results. Hard tablets are produced which do not swell
properly, and which form an impenetrable layer of
gel around a powder core which may pass through the
gastrointestinal tract undissolved.
U.S. Patent 4,824,672 describes the use of mineral
carbonates to enhance dispersion of gel-forming dietary
fibers in orally-administrable pharmaceutical composi-
tions for use in reducing serum cholesterol levels.
Such compositions have proved to be very effective in
use for their intended purpose, but do not provide a
satisfactory matrix for providing a prolonged-release
unit dosage formulation of a biologically-absorbable
therapeutic agent or drug, much less an effective
readily-dispersible drink mix.
The foregoing EPO 0080673 mentions the employment
of citric acid with guar gum tablets. The citric acid
and sweeteners were used, according to that disclosure,
to improve the acceptability of the tablets if they
were to be chewed. Accordingly, the citric acid was
there used only to provide flavor and an aromatic
quality to the product. Such formulations did not
contain any mineral carbonate or bicarbonate and,
moreover, when a carboxylic acid such as citric acid
was employed in the compositions of that invention,
"the acid is coated with 1 to 20% of a water-repellent
agent based on the weight of the acid", reportedly to
provide increased storage stability of the product, but
hardly conducive to a readily-dispersible drink mix
formulation of any type.
It is apparent that the prior art has not provided
any suitable readily-dispersible powder drink mix
2 ~ Ll v
~ 19 ~ ~IK 6/dlk/ju
consisting essentially of granules of a gel-forming
dietary fiber such as guar gum or the like, much less
such a readily-dispersible drink mix containing also
an effective dose of a biologically-absorbable thera-
peutic agent or drug.
According to the present invention, however,
excellent readily-dispersible powder drink mix formu-
lations are provided, which consist essentially of
granules of the gel-forming dietary fiber, a physio-
~ogically-acceptable edible acid, preferably a food-
grade organic acid or phosphoric acid, and a mineral
salt which releases a physiologically-acceptable gas
upon ingestion, preferably a mineral carbonate or
bicarbonate which releases carbon dioxide upon inges-
tion, the said granules being coated with a gel-forming
dietary fiber, a protein of vegetable or animal origin,
or a starch. As a further advantageous embodiment of
the present invention, the granules incorporated into
the drink mix of the invention may contain a biologic-
ally-absorbable therapeutic agent or drug, so that an
effective dose of the selected biologically-absorbable
therapeutic agent or drug may be conveniently ingested
in the form of a readily-dispersible and palatable
drink mix upon dispersion of the same in water or
other orally-ingestible fluid, such as a fruit juice or
the like.
The Physiologically-Acceptable Acid
As physiologically-acceptable acid may be employed
any non-toxic and edible acid such as citric, malic,
succinic, ascorbic, fumaric, phosphoric, tartaric,
gluconic, acetic, tannic, lactic, glycollic, or the
like. Food-grade organic acids are preferred and, of
organic food-grade acids, citric, tartaric, and malic
are preferred due to their introduction of a definite
2 ~ $
-20- I~K 6/ju
citrous, grape, and apple flavor into the
composition, respectively.
The Gel-Forming Dietary Fiber
According to the lnvention, any of the foregoing
enumerated gel-forming dietary fibers may be employed,
with gums such as guar gum and the like and psyllium
seed husks in powdered form being preferred, but pectin
or a pectic substance, algal polysaccharides, gluco-
mannan, agar, lignin, or the like, or combinations
thereof, may generally be employed with essentially the
same results.
The Mineral Salt
According to the invention, any mineral salt
which releases a physiologically-acceptable gas upon
ingestion may be employed. Such gas released is
preferably carbon dioxide and the mineral salt is
preferably a mineral carbonate or bicarbonate, with
calcium carbonate, magnesium carbonate, magnesium
bicarbonate, sodium carbonate, and sodium bicarbonate,
as well as the corresponding potassium carbonate and
bicarbonate, being preferred.
The Coating
The gel-forming fiber, protein, or starch coating
agents employed according to the present invention
may be selected from among any of the following
gel-forming dietary fibers previously enumerated,
gelatin, casein, soy, whey, egg, and any of various
starches and modified starches.
- 21 - HK 6/dlk/iu
_ e Particle Size of the Finished Product Granules_ _
The granules of which the readily-dispersible
powder drink mix of the invention consist are advan-
tageously screened to a particle size range of about 30
to about 100 mesh, usually about 40 to 100 mesh,
preferably about 50 to 70 mesh, and are most preferably
sized to pass a 60-mesh screen (U.S. Standard).
Ranges of Ingredients
According to the invention, the range for the
gel-forming dietary fiber in the drink-mix granules
is about 25% to 98% by weight of the composition,
the range of physiologically-acceptable edible acid
is about 0.5% to about 10% by weight of the composi-
tion, the range for the mineral salt is about 1% to
about 30~ by weight of the composition, and the weight
of the gel-forming fiber, animal or vegetable protein,
or starch coating on the particles is about 2% to
about 25% by weight of the composition, preferably
about 5% to 10% by weight of the finished product.
When a drug is present in the granules of the powdered
drink mix, it may conveniently be present in an amount
of about 1% to about 50% by weight of the finished
product. The gel-forming fiber, when employed as
coating, is preferably the same fiber as employed
as an essential part of the matrix of the granules
themselves.
THE INVENTION
It has now been discovered that readily-dispersi-
ble drink mix granules which can be mixed in water or
other liquid and orally ingested and which may option-
ally contain a drug, vitamin, dietary food supplement,
or other active therapeutic agent, and which provide
a unique, readily-dispersible, and advantageous drink-
mix delivery system, can be provided which consist
essentially of a gel-forming fiber, especially guar
- 22 - HK 6/dlk/jU
gum, a physiologically-acceptable edible acid, and
a mineral salt which releases a physiologically-
acceptable gas upon ingestion, the individual particles
being coated with an outer coating consisting essenti-
ally of a gel-forming fiber, an animal or vegetable
protein, or a starch. When mixed in water or other
orally-ingestible liquid, the powdered drink mix is
readily dispersed and, upon ingestion, the outer
coating of the particles is wea~ened or removed by the
action of the acid of the gastrointestinal tract, which
activates the interior of the individual granules,
which dissolves slowly, with the internally-contained
acid and mineral salt cooperating to mechanically
disperse the fiber in a slow and prolonged manner as it
hydrates, the gas released by the mineral salt and
organic or other acid assisting in the slow disintegra-
tion of the granules while the granules are in the
gastrointestinal tract, the gas penetrating and modu-
lating the film of the gel produced from the gel-
forming dietary fiber contained within the individual
granules and thus assisting in the proper disintegra-
tion of the granules and the proper dissolution of all
of the drug or other therapeutic agent when present in
the formulation of the invention. In addition to the
external coating on the individual particles, it is
the combined action of the physiologically-acceptable
edible acid and the mineral salt which releases the
physiologically-acceptable gas upon ingestion which
cooperatively provides the advantageous characteristics
to the formulations of the present invention. The
present invention preferably employs a mineral carbon-
ate or bicarbonate, and a physiologically-acceptable
food-grade organic acid or phosphoric acid which,
as previously set forth, are essential for the proper
~ 23 ~ ~3K 6/dlk/ju
disintegration of the individual particles and disso-
lution of the granules within the intestinal tract.
Drugs or Therapeutic A~ents
Among drugs or therapeutic agents which may be
incorporated according to this invention, but to which
it should not be limited, are:
a. Antipyretics and analgesics such as acetamino-
phen, aspirin and ibuprofen
b. Appetite suppressants such as phenylpropanol-
amine hydrochloride and stimulants such as
caffeine
c. Potassium, KCl, or another mineral supplement
d. Vitamin C
e. Vitamin B-12
f. Antihypercholesterolemics, and especially
Niacin
9. Antitussives, such as dextromethorphan,
dextromethorphan hydrobromide, noscapine,
carbetapentane citrate, and chlophedianol
hydrochloride.
h. Antihistamines, such as chlorpheniramine
maleate, phenindamine tartrate, pyrilamine
maleate, doxylamine succinate, and phenyl-
toloxamine citrate.
i. Decongestants, such as phenylephrine hydro-
chloride, phenylpropanolamine hydrochloride,
pseudoephedrine hydrochloride, and ephedrine.
Preferred particular drugs, minerals, or vitamins
for which the present delivery system is ideally
suited include:
Niacin, Vitamin ~-12, Potassium Chloride, Vitamin
C, Aspirin, Caffeine, Phenylpropanolamine hydrochlor-
ide, Ibuprofen, Pseudoephedrine, Nitroglycerin, and
Gemfibrozil.
~ 24 ~ HK 6/dlk/jU
The active ingredient can be any type of medi-
cation which acts systemically and which can be admini-
stered orally to transmit the active therape~tic agent
into the gastrointestinal tract and into the blood-
stream in therapeutically-effective levels without
early excessive peak concentrations, without being
inactivated by physiological fluids, and without
passing unchanged through the body of the patient or
subject by being excreted unabsorbed.
The Granulation Procedure
The granules employed according to the present
invention are prepared according to standard granula-
tion procedure, as evidenced by the Examples hereof.
When a drug or other active therapeutic agent is to be
included in the composition, and it is desired that it
be released relatively slowly, it is frequently advan-
tageous to pulverize the drug or other therapeutic
agent and to coat the particles thereof prior to
formulation into a granule with the other essential
ingredients of the granules according to the present
invention. Suitable coatings may include, for example,
sodiumcarboxymethylcellulose and, if desired, a second
coating of the drug or other active ingredient par-
ticles may be effected using a further cellulose
derivative such as ethylcellulose, also as evidenced
according to the Examples hereof. When the particles
are formed into granules a~cording to normal granula-
tion procedure, either wet or dry procedure as desired,
taking into consideration the ingredients involved,
they should be screened to provide granules having a
particle size between about 30 and 110 mesh, preferably
50 to 70 mesh, and most preferably about 60 mesh, so
that the coating thereof with the necessary exterior
coating material will provide particles of suitable
- 25 - HX 6/dlk/ju
dimensions for rapid dispersibility in water or other
orally-ingestible liquid. Coating of the granules with
the powdered gel-forming fiber, animal or vegetable
protein, or starch, which is the final step in the
preparation thereof, may be readily effected using a
fluid-bed granulator or other apparatus of the type
which rapidly and conveniently forms a film over the
exterior surfaces of the granules. Of course, such
fluid-bed granulator may also be used in the first
step, that of coating the drug or other active prin-
ciple particles, when such are to be included in the
composition.
DETAILED DESCRIPTION OF PREFERRED EMBOD~MENTS
The following examples are given to illustrate the
present invention, but are not to be construed as
limiting.
Example 1 Niacin-Fiber Drink Mix
A niacin granulate is produced in a fluid-bed
granulator (Glatt Air Techniques, Ramsey, New Jersey).
The niacin is sprayed with Surelease- (Colorcon, West
Point, PA), an ethyl cellulose preparation, to a 10%
level. The resulting granulate is 90% niacin with the
10% Surelease~ coating. The granules are screened to a
60 mesh size, and are blended with the following
ingredients in the same fluid-bed granulator;
Guar gum 74.35%
Calcium Carbonate 10.00%
Citric Acid5.00%
Niacin Granulate
(90%) 6.8 %
Orange Flavor3.00%
Aspartame .50%
Beta Carotene.35%
~ 26 ~ ~K 6/dlk/jU
The foregoing ingredients are blended thoroughly
in the fluid-bed granulator with air, and are spray
dried with a 10~ coating of 225 bloom gelatin dispersed
in water, the final percentage of the gelatin coating
being between about 2% and 25~ by weight, preferably 5%
to 10% by weight, and in this particular case about
7.5~ by weight of the finished granules. ~he resulting
granules are again screened to a 60 mesh size.
These granules can be mixed in water or other
beverage at a dose of 1 teaspoon or 5 grams, to give
an extremely effective antihypercholesterolemic dose
of the niacin, without the guar fiber gelling up
and solidifying. Furthermore, the niacin is not
immediately released in the water so that it does
not go directly into the bloodstream resulting in
the typical niacin side effects of cutaneous flush-
ing, itching, and general irritation. When the
instant drink mix reaches the acid environment of the
stomach or, when left long enough in solution, the
gelatin dissolves, releasing the gel-forming fiber,
calcium carbonate, citric acid and niacin through the
production of carbon dioxide. The release of niacin is
further slowed down by the coating of Surelease~, so
that there is a second-stage gradual release of the
niacin after the fiber has been properly dispersed by
the mineral carbonate and the food-grade acid.
In further embodiments, the same composition is
coated with guar gum, pectin, or with sodium caseinate
(10~) instead of gelatin in the same manner and to the
same extent with similar results.
Clinical Evaluation
A clinical study was conducted with the gelatin-
coated formulation of Example 1 to determine its
effectiveness in cholesterol reduction. Following is a
summary of the results:
2 ~
- 27 - IIK 6/dlk/ju
Twenty-four healthy subjects (10 women, 14
men; ages 33 - 61 years) with moderate to severe
diet-resistant hypercholesterolemia (ranges; total
cholesterol 246-334 mg/dl) were randomly assigned,
either to the formulation of Example 1 (6 grams
t.i.d.) or to a placebo treatment, for a four week
period. All subjects had been following a Step 1
AHA diet. None had endocrine, hepatic, or renal
disorders. Results: (mean+S.D.; N.S.-not signifi-
cant)
NIACIN/FIBER DRINK
0 weeks 4 weeks p
Tot. Chol.298+21 242+29 <0.001
LDL. Chol.216+23 162+26 <0.001
HDL. Chol.52+8 58+13 -0.130
Total/HDL-Chol. 5.8+1.24.3+1.0 <0.001
Total trig.149+62 111+36 -0.103
PLACEBO
0 weeks4 weeks p
291+24289+47 N.S.
214+16 216+46 N.S.
48+7 45+9 N.S.
6.2+1.96.6+1.9 N.S.
133+88137+98 N.S.
There were no significant changes in routine
chemistry tests.
Conclusion: The Guar-Niacin preparation of
Example 1 led to a 25~ reduction in LDL-cholesterol
and a significant reduction in total HDL-cholesterol.
Other fibers, mineral salts, and acids may
obviously replace those employed in the foregoing
Example with or without the added presence of a
pharmaceutically-active compound such as aspirin,
- 28 - HK 6/dlk/ju
Vitamin C, niacin, or the like, to provide an effective
dose of the selected compound for its intended physio-
logical effect.
Example 2 Fiber Drink Mix
Guar Gum (100 mesh) is blended in a fluid-bed
granulator (Glatt Air Techniques, Ramsey, New Jersy)
with calcium carbonate and citric acid. The resulting
blend was composed as follows:
Guar Gum 80%
Calcium Carbonate 15%
Citric Acid powder (60-200 mesh) 5~
The above blend is then spray dried with a coating
of guar gum at a 0.5~ level dissolved in water. The
resulting granules were screened to 60 mesh and, when
stirred in water, dispersed well and did not immedi-
ately gel up. The calcium carbonate and citric acid
helped to disperse the guar gum once the granules began
dissolving, the calcium carbonate by the release of
carbon dioxide in the acid environment of the stomach.
Other fibers, mineral salts, and acids may obviously
replace those employed in the foregoing Example with or
without the added presence of a pharmaceutically-active
compound such as aspirin, Vitamin C, niacin, or the
like, to provide an effective dose of the selected
compound for its intended physiological effect.
Example 3 Nutritional Drink Mix with Fiber
A nutritious drink mix was made according to the
present invention. The following ingredients were
added to a Glatt fluid bed granulator and blended with
air:
Roche Vitamin and Mineral Premix (Roche Vitamins
and Fine Chemicals, Nutley, New Jersey, containing the
- 29 - I~X 6/dlk/ju
USRDA of all vitamins and minerals), guar gum (100
mesh), calcium carbonate, citric acid, L-selenomethio-
nine, beta-carotene, and aspartame. The ingredients
were measured on a weight percentage basis to yield the
following dose:
Each Dose Contains
. Roche Vitamin and Mineral Premix 330 mg
Guar Gum 3 4 g
Calcium Carbonate 200 mg
Citric Acid 150 mg
L-Selenomethionine 200 mcg
Beta Carotene 25,000 I.U.
The foregoing blend is then sprayed with a coating
of sodium caseinate at a 10% level, the weight percent
of the coating being about 10% of the composition,
dried, and blended with orange flavor and aspartame.
The granules have locked-in nutrition which is protec-
ted from oxidation and light by the sodium caseinate
coating. The composition also delivers a dispersed
fiber when it dissolves in the stomach. As in the
previous Examples, the granules can be mixed in water
without immediately dissolving and gelling. When they
reach the acid environment of the stomach, the coating
dissolves and the nutritional components and fiber are
released and dispersed in a gradual manner like food,
by the action of the citric acid in combination with
~he carbon dioxide released by the calcium carbonate.
Other fibers, mineral salts, and acids may
obviously replace those employed in the foregoing
Example with or without the added presence of a
pharmaceutically-active compound such as aspirin,
Vitamin C, niacin, or the like, to pro~ide an effective
dose of the selected compound for its intended physio-
logical effect.
- 30 - iHK 6/dlk':~
-
Additional Examples
Additional Examples too numerous to enumerate may
be substituted for those of the foregoing, involving
only variations in the gel-forming fiber employed, the
pharmacologically-acceptable edible acid, the mineral
salt, and the orally-ingestible biologically-absorbable
drug or other pharmaceutically- or therapeutically-
active compound or principle, when present, employing
any of those mentioned herein in the ranges specified,
as will immediately be apparent to one skilled in the
art.
It is therefore seen that the present invention
provides a readily-dispersible gel-forming dietary
fiber drink mix comprising as essential ingredients a
gel-forming dietary fiber such as guar gum, a pharmaco-
logically-acceptable edible acid, a pharmacologically-
acceptable gas-forming mineral salt, all blended
together into granules and coated with an animal or
vegetable or synthetic protein, starch, or the same or
different gel-forming dietary fiber, which is far
superior to any such delivery system previously avail-
able, and a method of administering a dietary fiber,
with or without contained drug or other pharmaceuti-
cally-active compound, by employment of such an oral
pharmaceutical or dietary composition, all having the
unpredictable and highly advantageous characteristics
and effects as more fully set forth in the foregoing.
It is to be understood that the invention is not
to be limited to the exact details of operation, or to
the exact compositions, methods, procedures, or embodi-
ments shown and described, as obvious modifications and
equivalents will be apparent to one skilled in the art,
and the invention is therefore to be limited only by
the full scope which can be legally accorded to the
appended claims.
