Note: Descriptions are shown in the official language in which they were submitted.
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PALATABLE HYDROXYPROPYL METHYLCELLULOSE F?THER POWDER WITH SPECIFIED PARTICLE
SIZE
Background of the Invention
This invention relates to dry powder and dry mix formulations of
water-soluble, high-viscosity grade hydroxypropyl methylcellulose compositions
for
non-systemic use in effecting reduction in serum lipid levels, particularly
total serum
cholesterol, and LDL cholesterol levels.
The use of cellulose ethers in edible compositions and, in particular,
Ip pharmaceutical products, is well known. A common function of the cellulose
ether in
such uses is to serve as a controlled release agent. Typically, however, only
minimal
quantities of the cellulose ether, representing only a small percentage of a
total
formulation, are required in such uses.
A variety of compounds are currently known to be useful in reducing
~ 5 serum cholesterol levels in humans. However, many of these compounds,
including
both systemic and non-systemic compounds, have undesirable side effects or
have
certain characteristics that lead to difficulties in patient compliance with
their use. For
example, characteristics such as the sandiness) grittiness, throat irritation,
difficulty in
dispersion and phase separation of known non-systemic compounds lead to very
poor
patient compliance. Accordingly) the search for new non-systemic compounds
useful
in reducing serum cholesterol levels in humans continues to be an important
field of
research.
Cholestyramine is an important) non-systemic compound known to be
effective in treating high blood cholesterol Levels (also known as
25 hYPercholesterolemia), which are believed to be responsible in many cases
for
arteriosclerosis in humans. Cholestyramine, which is typically orally consumed
in order
to effect its cholesterol lowering or controlling properties, is astringent
and
unpleasant to swallow. The cholestyramine also has the side effect of inducing
constipation. Processes and compositions including cholestyramine are known,
such as
30 those described in US-A-3,308,020) US-A-3,3133,281, US-A-3,499,960 and
US-A-3,947,272.
It is known that substantially water soluble vegetable fibers such as
psyllium, guar, and (3-glucans may exert cholesterol lowering effects, but
these soluble
fibers are not very efficacious on a per gram basis. Also, because these
soluble
35 vegetable fibers are easily metabolized by colonic bacteria (causing
extensive
anaerobic production of methane, carbon dioxide, and hydrogen), these
vegetable
fibers are known to cause gross flatulence) bloating and grave abdominal
discomfort
when administered to humans in therapeutically effective doses. Furthermore,
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psyllium seed husk is typically contaminated with fragments of proteinaceous
hull,
which carries the allergens known to be associated with psyllium.
Ground psyllium seed is recognized far its ability to lower serum
cholesterol levels in human patients. EP-A-0 362 926 describes the use of
products
containing psyllium seed husk known to be effective in reducing human serum
cholesterol levels. EP-A-0 309 029 describes cookies containing psyllium and
polyol
polyesters which are useful in reducing blood cholesterol levels.
EP-A-0 323 666 describes the use of products containing cholestyramine in
combination with psyllium or with polyol polyesters as orally administered
yp cholesterol-lowering compositions.
Recently, various forms and formulations of hydroxypropyl
methylcellulose (HPMC) have been discussed as cholesterol lowering agents
(e.g., WO-
A-US92/01515, and WO-A-US92/01511). US-A-5,281,584 discusses a baked
formulation
for similar use. Although these references use an HPMC of high number average
15 molecular weight, the formulations are not those of the present invention.
Previously, cellulose ethers, such as carboxymethylcellulose and
methylcellulose, have been administered as bulk laxatives in the form of
tablets,
powders (e.g., EP-B1-0 119479), and suspensions in highly concentrated sugar
solutions. These cellulose ethers differ significantly (e.g., chemical
structure, molecular
2p weight, and viscosity) from the HPMC of the present invention and have a
different
intended use.
In order to administer non-systemic compounds, such as those discussed
above, a suitable formulation is required. For various reasons, such
formulations are
not easily prepared for cellulose ethers.
25 Tableted cellulose ethers, for example, do not readily disperse and
dissolve in the digestive tract. The outer portion of the tablet quickly forms
a gel-like
hydrated coating of the partially hydrated cellulose ether which inhibits
break-up of
the tablet and greatly retards hydration of the interior portions of the
tablet.
Accordingly, the tablet is often excreted as an intact gel-coated mass. Thus,
when
3o employed in tablet form, cellulose ethers have greatly reduced efficacy.
British Patent 1,280,150 teaches that blending of a cellulose ether with
from 1 to 20 percent of a water-soluble food, such as sucrose, will aid
dissolution of the
cellulose ether in cold water, without formation of lumps. This was an attempt
to
improve upon earlier known formulations for cellulose ethers which had
covalently
35 bonded glyoxal. Glyoxal is not desired, as it is toxic when ingested.
A bulk laxative composition is described in EP-B-0 119 479 which teaches
that 2 grams of finely powdered 100,000 cP viscosity grade hydroxypropyl
methylcellulose dispersed in about 25 grams of Tang'" brand orange flavored
instant
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drink mix (distributed by General Foods Corporation, White Plains) NY, USA),
provides
a formulated product for delivering a therapeutic dose of the cellulose ether
to treat
constipation.
Various cellulose ethers have been used as bulk laxatives wherein a
concentrated sugar solution is first prepared iin water and the cellulose
ether is then
dispersed therein. This method was used to nninimize full hydration and
dissolution of
the cellulose ether, and to minimize viscosity buildup. (For example, see US-A-
2,701,782.) However, such suspensions are vE~ry thick and semi-gelatinous,
have a slimy
mouth feel, are extremely sweet, and are thus not appealing to the patient.
Depak Phadke et at., US-A-5,266,334, discloses water-dispersible, sugar-
free powder mixtures of maltodextrin with rnethylceliulose or HPMC in
formulations
for use as bulk laxatives. The cellulose ether ins taught as being present as
a fine
powder in admixture, not as an encrusted material. The HPMC particle size is
taught
to be less than 40 mesh (400 Nm), preferably less than 60 mesh (250 Nm).
~ 5 Dhirin Shah et al., US-A-4,732,917, teaches the preparation of sucrose
coated low molecular weight methylcellulose where the ratio of methylcellulose
to
sucrose is about 2:1, and the dry powder has the consistency of fine flour.
This dry
powder, prepared by the method described in the patent, cannot be dispersed
directly
into water without gelling and requires a "carrier" formulation.
ZO Evidence of the unpalatability of non-systemic compositions currently
being marketed to treat hypercholesterolemia is the well known low rate of
compliance by human patients in adhering to diets requiring daily consumption
of
these compositions. This low compliance inclicates a definite need for
hypocholesteremia-controlling compositions which are more palatable and more
25 effective than known compositions.
The present invention addresses the noncompliance problem by using a
composition in a method for reducing serum cholesterol levels in human
patients by
providing a suitable formulation to aid in the efficacy of the HPMC and
promote
compliance by the patient.
30 Summary of the Invention
The present invention concerns cool-water dispersible, dry powder
compositions for non-systemic use of high molecular weight (HMW) HPMC which
has
been milled to a specified particle size distrilpution, with or without
encrustation or
other surface treatment, for dispersion into consumable liquids or for
consumption in
35 reconstituted dry mixes, sauces, instant-set puddings and baked goods. The
compositions are used for reduction of serum cholesterol levels in mammals,
especially
humans. Processes for preparing the formulations and their modes of
administration
are also provided.
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A coo!-water dispersible, dry mix powder hydroxypropyl methylcellulose
composition of the present invention comprises an hydroxypropyl
methylcellulose
which has
(a) a particle size distribution having an upper limit of less than or equal
to
five percent of the particles of hydroxypropyl methyicellufose larger than
about 600 Nm and having a lower limit of less than or equal to fifty
percent of the particles of hydroxypropyl methylcellulose smaller than
about 180 Nm; and
(b) a viscosity, in a 2 weight percent aqueous solution at 20°C, from
greater than about 10,000 cP to 2,000,000 cP.
A preferred embodiment of the present invention comprises encrusting
the above hydroxypropyl methylcellulose with an encrusting agent such as
sucrose,
maltodextrin or other suitable encrusting agent.
The present compositions of the present invention can be used for
reducing serum cholesterol in a non-ruminant mammal, especially humans, in
need of
such treatment which comprises administering to the mammal from about 1 to
about
8 g per dose of the above hydroxypropyl methylcellulose composition) with or
without
encrustation.
A process for preparing an aqueous dispersion of a water soluble high
molecular weight hydroxypropyl methylcellulose requires only mild agitation in
cool
water which comprises:
a) grinding, milling or screening a high molecular weight hydroxypropyl
methylcellulose to obtain a particle size distribution with less than 50% of
the particles smaller than about 180 Nm and less than S% of the particles
larger than about 600 Nm; and
b) optionally encrusting the high molecular weight hydroxypropyl
methylcellulose with an encrusting agent of a natural sugar or
maltodextrin at a ratio of the encrusting agent relative to the
hydroxypropyl methylcellulose from about 0.5:1 to about 2:1 w/w, and
then milling or screening the encrusted hydroxypropyl methylcellulose
through a 16 mesh screen; and
c) optionally adding a flavoring agent; and
d) optionally adding one or more additive materials selected from the
group consisting of preservatives, buffers, colorants, anti-caking agents,
antioxidants, opacifiers, vitamins) minerals, and setting agents.
Detailed Description of the Invention
The formulations of the present invention provide high molecular weight
(HMW) HPMC in a highly-hydrated, predispersed form without resorting to hot-
water
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dispersion (i.e., above the thermal gelation temperature of the HPMC). In the
compositions of the present invention, the HPMC is present in a daily
consumption
amount by humans of from about 2 grams to about 30 grams.
For the purposes of this invention several of the terms used herein are
defined as follows.
"HPMC" means hydroxypropyl methylcelluiose having a number average
molecular weight greater than about 80,000 daltons (10,000 cP viscosity
grade).
"High molecular weight" for the HPMC ethers of this invention refers to
those HPMC ethers having a number-average molecular weight greater than about
80,000 daltons. HPMC ethers having a number average molecular weight greater
than
150,000 daltons are designated as having ultra-high molecular weight (UHMW).
HPMC for use in this invention has a number average molecular weight
preferably
greater than about 100,000 daltons, more preferably greater than about
140,000 daltons, and most preferably greater than about 150,000 daltons. The
HPMC
15 ethers have an upper limit for number average molecular weight of less than
or equal
to 400,000 daltons. HPMC of the type used in this invention has a methoxy
substitution of from about 19 percent to about 24 percent and a hydroxypropoxy
substitution of from about 4 percent to about 12 percent.
In order to correlate the number average molecular weig ht to viscosity
20 grade, the following table is provided.
CORRELATION TABLE
Number Average Viscosity Grade
Molecular Weight cP
M~ ( daltons
~ 5 80,000 10,000
100,000 25,000
140,000 50,000
150,000 100,000
220,000 400,000
30 260,000 500,000
400,000 2,000,000
35 The HPMCs of this invention are those which are of a high-viscosity grade
or are of high viscosity. By "high-viscosity grade" or "high viscosity" is
meant those
cellulose ethers which, when in a 2 weight percent aqueous solution, exhibit a
viscosity
at 20°C of greater than about 10,000 centipoise (cP) (10,000 mPa~s) and
may have a
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viscosity as high as 2,000,000 cP (2,000,000 mPa~s). Such viscosities may
generally be
measured by conventional methods, for example, by measuring the viscosity of
an
aqueous solution of the polymers at the desired concentration in Ubbelohde
capillary
viscometer tubes at the specified temperature. The cellulose ethers of this
invention,
when in a 2 weight percent aqueous solution at 20°C, exhibit a
viscosity ranging from
about 10,000 cP (10,000 mPa~s), preferably from about 25,000 cP (25,000
mPa~s), to
about 2,000,000 cP (2,000,000 mPa.s). More preferably, the cellulose ethers of
this
invention, when in a 2 weight percent aqueous solution at 20°C, exhibit
a viscosity
ranging from about 50,000 cP to about 800,000 cP, most preferably from about
100,000 cP (100,000 mPa~s) to about 500,000 cP (500,000 mPa~s). Conversely, by
"low-viscosity grade" is meant those cellulose ethers which, when in a 2
weight
percent aqueous solution, exhibit a viscosity at 20°C below about
10,000 cP
(10,000 mPa~s).
For the purposes of this invention, milling and screening of the HPMC
compositions can be carried out on any equipment which is capable of achieving
the
specified particle size distribution without subjecting the composition to
heating
above 50°C. For the preparation of HPMC fluff, an Alpine brand fan
beater mill fit
with a screen having 0.4 mm diameter holes gave satisfactory results. A
variety of
other mild intensity mechanical impact mills are capable of giving similar
results,
20 including wing beater, pin, hammer and knife mills. For preparation of the
granulated
derivatives, grinding the dried encrusted HPMC through a Fitz brand mill with
the
appropriate screen size provides the desired particle size distribution.
When the HPMC of this invention is milled andlor screened until it has the
desired particle size distribution, the HPMC thus formed is termed the
z5 pharmaceutically active ingredient. This pharmaceutically active ingredient
is a white
fluffy solid of a particular particle size distribution, and is referred to
herein as "fluff"
or the "pharmaceutically active ingredient". When the fluff is modified with
an
encrusting agent so that the composition of the HPMC has an encrusting
component)
and a particular particle size distribution is achieved by milling and/or
sieving, it is
30 referred to as a "granulated derivative". When either the fluff or the
granulated
derivative is blended with other ingredients to obtain the final dosage form,
it is
referred to herein as a "formulated product". When all or any of the forms
(i.e., fluff,
granulated derivative and formulated product) are intended, they are referred
to
herein as "compositions".
35 For the compositions to exhibit palatability in the formulated product
(especially in drinkable formulated products), the particle size distribution
of the
HPMC fluff is important. The upper limit on the desired fluff particle size
distribution
is that it have less than or equal to five percent ( <_ 5%) of the HPMC
particles larger
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than about 600 Nm (0.6 mm, 30 mesh screen), and preferably less than about 2%.
Larger particles cause grittiness in the liquid form of the formulated
product. The
lower limit on the fluff particle size distribution is that it have less than
or equal to fifty
percent ( <_ 50%) of the HPMC particles smaller than about 180 Nm (0.18 mm, 80
mesh
screen), preferably less than about forty percent (40%), and more preferably
less than
about thirty percent (30%). Small particles cause the formation of froth, air
pockets,
stubs, and rapid viscosity buildup when the formulated product is dispersed
into water
or other liquid for consumption. The above mesh sizes are US sieve series
sizes, ASTM
E-11-61.
When UHMW HPMC is ground to a conventional fine powder (100,000 cP
viscosity grade, 80% through 80 mesh screen) is incorporated into a baked
product
(e.g., a 25-30 g cookie containing 5 g HPMC), the cookie literally turns into
chewing
gum when chewed. This result is unacceptable in a formulated product for the
purposes of the present invention. However, vvhen this same HPMC is milled
through
a 0.4 mm screen on an Alpine mill, fluff is obtained. This fluff has a much
lower surface
area than the conventional powder. When this fluff is incorporated into a
cookie (e.g.,
a 25-30 g cookie containing 5 g of HPMC fluff), the cookie can be chewed and
swallowed with essentially no gumminess. Thus palatability is greatly
enhanced.
When UHMW HPMC is ground to .a conventional fine powder (100,000 cP
viscosity grade; 80% through 80 mesh screen; 2.5 to 5 g) is dry dispersed in
28 g of a
powdered orange flavored drink mix, the resulting formulation when mixed into
250
mL of cool water (0-20°C), barely disperses at the 2.5 g level and
clumps severely at the
5 g level. In contrast, when HPMC fluff of the same viscosity grade (2.5 to S
g) is dry
dispersed in 28 g of a powdered orange flavored drink mix, the formulated
product
disperses readily at both concentrations when mixed into 250 mL of cool water.
The compositions of the present invention provide HPMC in a form that is
readily dispersible in cool water (0-20°C) and suitable for preparation
of palatable oral
dosages containing from about 1 to about 8 g, preferably from about 2 to 5 g
of
HPMC, per dose for oral administration in the treatment of elevated serum
cholesterol
levels. The large quantity of HPMC that may be dispersed in water is very
surprising
and is far in excess of what was previously believed possible while still
maintaining a
palatable formulation.
The fluff form of HPMC has the advantage of being able to deliver the
HPMC in a highly hydrated and predispersed form into the stomach, without
resorting
to either comestible dosage forms or to hot uv~ater/hot liquid dispersion of
the HPMC.
In this context, "comestible" implies incorporation of the HPMC into a baked
cookie or
biscuit form, normally comprising about 5 g of the HPMC in a baked good of
about 25
to 35 g total weight. The comestible is to be chewed and accompanied by
ingestion of
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about 8 ounces (225 g) of water or other liquid. In this same context, "hot
water" or
"hot liquid" dispersion is taken to be dispersion into water or other liquid
(for
example, lemonade, cocoa, and hot chocolate) at a temperature of about
85°C or
higher. This temperature is well above the known (50-70°C) thermal
gelation
temperature range of the present HPMC.
The fluff form of HPMC permits administering HPMC in doses from about
1 g per dose, especially from greater than 3 g per dose, and more especially
for doses
equal to or greater than 5 g per dose, in a palatable manner. These doses of
HPMC
were previously very difficult to attain while retaining sufficient
palatability to
encourage patient compliance. It was very unexpected that although HPMC fluff
has a
large particle size, it is not gritty when dispersed in aqueous fluids.
The fact that the fluff form permits HPMC to be prehydrated for oral
administration, while the formulation containing the dry fluff can be both fat
and
cholesterol free, is a very important consideration in any non-systemic
cholesterol
~ 5 treatment formulation. Thus the present compositions and formulated
products have
significant advantages over those previously known.
Optionally, the HPMC fluff can be coated with an encrusting component
to make a granulated derivative. The encrusting agent can be a natural sugar,
such as
sucrose, glucose, fructose, corn syrup solids, and the like, where sucrose is
preferred.
20 The amount of encrusting component, when a natural sugar, relative to the
HPMC is
from about 0.25:1 to about 4:1 (w/w), preferably from about 0.5:1 to about 3:1
(w/w),
more preferably from about 0.75:1 to about 2:1 (w/w), most preferably about
1:1
(w/w).
The encrusting agent can also be selected from low molecular weight
25 sugar polymers and sugar derivatives and their mixtures, such as
maltodextrins,
sorbitol and the like. The preferred ratio of HPMC fluff to encrusting
component
remains about 1:1 (w/w). Surprisingly, the resulting granulate can be milled
to a large
particle size distribution and retain excellent properties. Handling the dry
powder is
very easy and little unencrusted HPMC is found after the milling. When a
granulated
30 derivative (1:1 w/w) UHMW HPMC:sucrose was made, and ground through a 16
mesh
screen so that more than 40% of the particles fell between 18 mesh and 2.5
mesh,
another 30% between 25 and 40 mesh and only about 10% below 60 mesh, the
granulated derivative displayed remarkable properties. This granulated
derivative
(e.g., 5 to 10 g) can be dispersed directly into 6-8 oz of cool fruit juices
or water,
35 without resorting to any further formulation aids, to provide smooth, grit-
free
dispersions with very slow viscosity build.
The granulated derivative HPMC can be readily admixed with other dry
mix powders to create a formulated product. For example, usually a flavoring
agent is
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present in the formulated product. Examples of added flavorings are powdered
fruit
drinks, powdered hot drink mixes such as cocoa mix, powdered lemonade mix and
the
like. Such dry mix powders are well known to persons skilled in this art and
have been
discussed as well in the various references given hereinabove.
In addition to the foregoing, one or more other additive materials such as
preservatives, buffers, colorants, anti-caking agents, antioxidants,
opacifiers, vitamins
and minerals, and setting agents, which are commonly employed in food,
beverage or
drug substances may be employed in a conventional manner.
The high-viscosity grade, water-soluble cellulose ethers of the present
invention are inert, non-ionic cellulose ethers which are known to be edible.
The
high-viscosity grade cellulose ethers used in a~n edible composition are
characterized in
that the high-viscosity grade cellulose ethers meet the specifications of the
United
States Pharmacopeia (USP) and: (1) are resistant to bacterial fermentation in
the large
bowel of the non-ruminant mammals and, therefore, do not cause gas production
~ 5 resulting from such fermentation, (2) are sub<.;tantialfy inert to attack
by enzymes
found in the digestive tract, (3) do not produce the allergic responses
characteristic of
certain vegetable fibers, and (4) interfere minimally with micronutrient
absorption.
The present UHMW HPMC thus differs from the cellulose ethers
mentioned in the above references, such as the bulk laxative composition
described in
EP-B-0 119 479, because of the quantity of the HPMC per dose, the high
molecular
weight and viscosity of the particular HPMC of the present invention, and the
particle
size distribution of the HPMC employed.
The cellulose ethers used in the present invention may be prepared by any
of a number of known processes. Illustrative processes are set forth in US-A-
3,342,805;
US-A-3,388,082; US-A-3,709,876; US-A-4,477,657; US-A-4,410,693; and US-A-
4,820,813, the disclosures of which are hereby incorporated by reference.
Generally, a
specific cellulose ether is prepared by the formation of an alkali cell uiose
by the
addition of sodium hydroxide to cellulose. The alkali cellulose is then
reacted with an
appropriate alkylating agent or agents. Thereafter, the cellulose ether
product is
Purified, dried, and ground. US-A-4,820,813 teaches the preparation of a high
molecular weight cellulose ether which is ground under conditions of mild
mechanical
impact such as those encountered in a high speed, air swept impact milt (e.g.,
an
Alpine mill). This mild impact process is a cutting or dicing process for
particle size
reduction, which preserves molecular weight: and, therefore, viscosity. The
method of
measuring viscosity affects the resulting value obtained since solutions of
high
molecular weight cellulose ethers are shear thinning. Thus viscosity values
are method
dependent. For example, when the viscosity of a solution of one HPMC was
measured
using a rotational viscometer at very slow speed, the viscosity reading was
106,000 cP
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CA 02275902 1999-06-22
WO 98127989 PCT/US96/20663
(0.5 rpm, 1 sec'' shear); but when the viscosity was determined according to
the USP
method in which the viscosity of a 1 % solution is measured using a Ubbelohde
capillary viscometer and extrapolated to a concentration of 2%, the viscosity
value was
420,000 cP.
From other experiments, it is known that HPMC ground in an Alpine mill
using a 2.0 mm bore screen provides aqueous dispersions that exhibit a taste
and/or
feel of being gritty. Thus an inappropriate particle size makes such
incorrectly ground
HPMCs unsuitable for the present invention.
Generally, 2.0 mm bore screen Alpine milled HPMC does not produce a
suitable pharmaceutically active ingredient or fluff. The reason is that the
particle size
distribution of this product contains numerous fluff particles ( > 5%) larger
in size than
600 Nm (30 mesh), and these fluff particles impart grittiness to liquid
suspensions made
from a formulated product containing this fluff. Thus the product has poor
palatability. The fluff particles are also too large to permit an homogeneous
character
to the formulated product dry powder mix, because the fluff particles tend to
segregate out of the dry powder mix.
Similarly, an HPMC (? 10,000 cP viscosity grade) milled to a fine powder as
generally known in the art is unsatisfactory as a pharmaceutically active
ingredient for
the purposes of this invention. Such conventionally ball milled HPMC particles
have an
2p average particle size of less than 180 Nm (80 mesh). Such powders carry
adhering air
into the liquid suspensions prepared from them, which causes frothing and
foaming.
The HPMC powder particles tend to reaggregate and form dry-centered lumps due
to
their poor wet-out properties (anthropomorphic), while causing rapid viscosity
buildup from the few particles which do hydrate in suspension, due to their
very high
25 surface area and rapid dissolution. This rapid (<3 min) viscosity buildup
quickly
renders the suspension gelatinous and unfit or unpalatable for consumption.
The cellulose ethers employed in the present invention must be readily
water-soluble. As used herein, the term "readily water-soluble" means that two
grams of a powdered or ground cellulose ether of the present invention can be
30 dispersed by stirring into 100 grams of water at a temperature between
about 0°C and
100°C to provide) upon complete hydration, a substantially clear
solution or dispersion
(gel) when the dispersion is brought to a temperature of 20°C.
A unique characteristic of the formulated products of the present
invention is that they can all be dispersed directly into cool liquids, at
temperatures
35 below the thermal gelation range of HPMC (50-70°C). Another unique
attribute of the
formulated products of this invention is that they can be directly dispersed
into cool
water or other aqueous based systems to obtain palatable products for human
consumption, using only simple spoon stirring. With the particle size
distribution of
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the fluff and/or granulated derivative as specified herein, it is not
necessary to resort
to either the use of hot liquids or high shear stirring devices to obtain
palatable, non-
gooey, non-gelatinous dispersions of the HPA~IC pharmaceutically active
ingredient.
For comparison, one attempted rnethod of administering 2-3 g of UHMW
HPMC to human subjects was to admix HPMC fluff with about 15 g of sugar-free
hot
chocolate drink mix, then stir this formulated product into 250 mL of hot
(80°C) water
to form a hot beverage. In practice, the beverage preparation proceeds
smoothly. The
water temperature is well above the 50-70°C thermal gelation
temperature of the
HPMC) so the HPMC simply disperses in the hot liquid without appreciably
hydrating or
dissolving. However, as the beverage cools, hydration and dissolution of the
HPMC
begins. By the time the beverage has cooled to the upper limit of human
thermal
endurance (i.e., about 50°C), the HPMC has gelatinized in the beverage
to a single,
slithery mucousal mass which is absolutely nauseating.
Formulated products containing the HPMCs of this invention can be
~ 5 Prepared by mild agitation of mixtures of the fluff or granulated
derivative with the
other dry powder formulating agents, using any suitable dry powder blending
equipment (e.g., ribbon, double cone, Lodige or the like) or by stirring or
shaking
using the usual appliances in a kitchen, or by manual means.
No fats or oils are added to (unless desired for a flavoring or such purpose)
z0 or are required in the present formulated products.
By using the coarser HPMC fluff) such as is obtained by milling through a
0.4 mm screen in an Alpine mill, a slower dissolution rate of the HPMC is
achieved than
with the conventional, fine powder form of ll/lethocel'" (a trademark of The
Dow
Chemical Company) cellulose ether. As described above, even without the use of
an
25 encrusting agent, e.g., sucrose or maltodextrin, a suitable dispersion can
be achieved.
The following scheme illustrates processes for preparing the compositions
of the present invention.
35
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PROCESS SCHEME
(UHMW) HPMC
Alpine mill through a 0.4 mm screen or similar process
to attain the required particle size distribution
UHMW HPMC fluff or
pharmaceutically active ingredient
a) coat with an aqueous admix with
solution of encrusting agent dry powders
and then
b) dry, at about 120°C
formulated product
encrusted UHMW HPMC ~ optional
knife mill
to pass through
a 16 mesh screen optional disperse into
liquids
granulated derivativE
admix with
dry powder
formulated product
The compositions of the present invention, particularly the granulated
30 derivative described in Example 3 containing UHMW HPMC, provide exceptional
ease
of dispersion into water and aqueous liquids and excellent organoleptic
properties
therein, while minimizing the stir time necessary to achieve satisfactory
dispersion and
hydration. Further, the present compositions prolong the time before excessive
viscosity build occurs. This is especially important when Larger doses (e.g.,
5.0 g) of the
35 UHMW HPMC are desired or required for treatment.
The compositions of this invention are readily dispersible into a variety of
aqueous liquids, such as fruit juices, aqueous nectars and extracts (such as
apple)
orange and apricot). The compositions also mix well with other formulated dry-
mix
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powders (such as Tang'" brand orange drink mix, SIimFast'" and Horlicks) that
are
intended to be reconstituted with water or milk. The compositions are also
readily
dispersible into applesauce, instant set dry pudding mixes and tapioca, baked
good dry
mixes (such as cookies and muffins), granola bar compositions, and the like.
The Schultz patent (US-A-4,820,8'13, the disclosure of which is hereby
incorporated by reference) discloses one method of making finely powdered UHMW
HPMC which involves low impact grinding of UHMW HPMC. Although this method
could be used to produce the present fluff, he did not do so. The particle
size
distribution of the HPMC made was below 80 mesh. The purpose of his efforts
was to
obtain a very fine particle size to mimic the known methylcellulose products
while
maintaining high viscosity.
The compositions of the present invention having the UHMW HPMC
present, may be used to reduce serum cholesterol. To achieve this result, the
active
ingredient (UHMW HPMC) should be present at a level of about 1 to 8 g per
dose,
preferably from about 2.5 to about 5 g per dose, in the formulated product.
The total
number of doses administered per day will depend on the level of reduction
desired
for the particular patient. Typically, about 2 to 3 doses containing about 1
to 8 g each
are administered. Thus from about 2 to about 25 g per day is administered in
divided
doses.
ZO While not wishing to be bound by theory, it is believed that the
advantageous properties of the HPMC compositions of the present invention and
results obtained from their use are due to their particular particle size
distribution and
greater molecular weight) especially for the UHMW HPMC, i.e. its molecular
weight,
viscosity grade and dispersibility. Any procedure which enables these
requirements of
25 particle size distribution and molecular weight for the HPMC to be attained
is within
the scope of the present invention.
The invention will be further clarified by a consideration of the following
examples, which ate intended to be purely e~:emplary of the present invention.
35
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Example 1
UHMW HPMC fluff, 2.5 gram (g), milled through a 0.4 millimeter (mm)
bore screen on an Alpine mill, was mixed in a 70 ounce (oz) plastic cup with 2
level
tablespoons (30.8 g) of Tang'" brand dry powder orange drink mix. The
admixture
was accomplished simply by stirring with a spoon. A homogeneous
particulate/particulate dispersion in the form of a orange colored, dry powder
mix was
obtained.
To this dry powder mixture was added 8 oz (224 g) of cool (about
15°C) tap
water all at once, and the suspension was spoon stirred for about 1 minute. At
the end
of the stirring, a cool, smooth, palatable, pulpy textured orange drink
composition
was obtained.
With occasional stirring to test the viscosity of the dispersion formed, the
orange drink was consumed in portions over the subsequent 6 minutes at about
30
second intervals. The orange drink continued to be tasty, totally palatable
and free of
~5 objectionable stubs, dry-centered lumps or any other objectionable
particulate matter.
A composition having 2.5 g of UHMW HPMC in a liquid formulation form
was thus achieved without heating the liquid above the thermal gel point of
the
UHMW HPMC.
Example 2
UHMW HPMC fluff, 5.1 g, milled as described in Example 1, was mixed in a
oz plastic cup with 2 level tablespoons (28.6 g) of Tang'" brand dry powder
orange
drink mix. The admixture was easily accomplished by stirring with a spoon. An
homogeneous particulate/particulate dispersion in the form of a orange
colored, dry
powder mix was obtained.
25 To this dry powder mixture was added 225 g of cool (about 13°C) tap
water all at once, with spoon stirring. After 30 seconds of continued
stirring, an
homogeneous suspension with the texture of apricot nectar was obtained. This
suspension was thoroughly palatable and free of dry particles.
With continued stirring) after about 60 seconds from the time of water
30 addition, a thoroughly palatable orange drink mix was still extant. By 90
seconds, the
suspension was thickening. At 120 seconds, thickening was further advanced. At
180
seconds, a soft, spoonable, jam-textured gel had begun to form. At 210
seconds, a soft
gel was obtained which had the consistency of applesauce. ff a formulation to
be
consumed at this later stage is desired, the orange flavoring is replaced by
apple
3~ flavoring.
A composition having 5.1 g of UHMW HPMC in a fully suspended liquid
form was thus achieved without recourse to heating the liquid above the
thermal gel
point of the HPMC.
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Example 3
A sucrose encrusted UHMW HPMC (1:1 w/w sucrose: UHMW HPMC)
granulated derivative was prepared by wet-granulating one part by weight UHMW
HPMC fluff with a hot (above 50°C) aqueous solution of one part by
weight sucrose in
one part by weight of water. A moist, crumbly mass was obtained. The material
was
dried to a constant weight at about 120°C. The resulting dry granule
was then milled
and screened so that about 95% or more passed a 1.0 mm (US Standard No. 18)
screen.
The dry granulated derivative contains less than 1 % w/w residual moisture.
The assay
of UHMW HPMC fluff present in the dry granulate is 50% by weight. The settled
bulk
1p density of the dry granulate is about 0.43 glcc. The dry granulated
derivative is a
visually attractive, free-flowing, low dust granule that gives the dry
granulated
derivative excellent powder-flow and powder-spooning properties. This 1:1
sucrose
encrusted granulated derivative of UHMW HPtVIC fluff was used in about 5 to 10
g
quantities to make a variety of doses of variou s formulated products.
15 For example, the dry granulated derivative was readily dispersible directly
into a variety of liquid juices and beverages, such as fruit juices, aqueous
nectars and
extracts (such as apple, orange and apricot). It dispersed smoothly into
applesauce,
mixed well with formulated dry-mix powders (such as Tang'" brand orange drink
mix,
SIimFast'" and Horlicks that are intended to beg reconstituted with water or
milk), and
20 was readily usable by direct addition to a wide variety of baked good
recipes, instant
set dry pudding mixes, baked good dry mixes (such as cookies and muffins) and
granola bar compositions.
Example 4
The encrusting procedure of Example 3 was repeated using maltodextrin
Z5 in place of sucrose as the encrusting component. A sugar-free granulated
derivative
was obtained which was suitable for use either as is as a formulated product,
or in
admixture with additional dry powder ingredients to form other formulated
products.
Example 5
Sample A:
30 UHMW HPMC (400,000 cP viscosity grade), 2.53 g, which had been milled
through a 2.0 mm screen, was mixed with 30.f. g of Tang'" brand orange drink
mix.
This formulated product, 15.5 g, was placed in a 9 oz plastic cup and mixed
with a
plastic spoon. Mixing was difficult and incomplete in attempting to obtain a
uniform
dry mix. The fibrous UHMW HPMC tended to cling together in aggregates
resembling
35 white lichens. To the dry mix was added all at once 8 oz of cool water with
spoon
stirring. Many bubbles formed in the matrix and on top of the liquid as a
froth.
Stirring was continued for 1 minute. Many stubs appeared on the side of the
cup and
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spoon. The mouth feel of about 2 tbsp of the mixture was gritty and grainy,
and
particles of moistened but incompletely hydrated UHMW HPMC were obvious.
Sample B:
UHMW HPMC (400,000 cP viscosity grade), 2.50 g, which had been milled
through a 0.4 mm screen as described in Example 1, was mixed with 25.2 g of
Tang '"
brand dry powder orange drink mix, placed in a 9 oz plastic cup, and mixed
with a
plastic spoon. Admixture of the powders was easy using the spoon. The
aggregates of
UHMW HPMC disentangle on spoon mixing and disperse into the Tang'" brand
orange
drink mix. To the resulting homogeneous looking formulated product was added
all
at once 8 oz of cool water (about 10°C), and the mixture was stirred
with a spoon.
After 1 minute of mixing, the liquid showed some froth and only a few stubs as
wet
dots on the side of the glass, but no graininess in the mouth. Viscosity
buildup was
slow, with pulp-like particles of the UHMW HPMC suspended in the main body of
the
drink. The mixture was still totally acceptable for at least 5 more minutes
before
viscosity buildup was advanced.
Sample C:
Conventional, finely powdered HPMC (80,000 cP viscosity grade, ? 80%
less than 80 mesh), 2.5 g, was spoon mixed with 25.2 g of Tang'" brand dry
powder
orange drink mix in a 9 oz plastic cup. To the resulting homogeneous looking
powder
2o mix (formulated product) was added all at once 8 oz of cool water (about
10°C), and
the mixture was stirred with a spoon. After 1 minute of mixing, the liquid
showed
much froth, with many bubbles in suspension. Taste testing revealed no
graininess in
the mouth at one minute, but the viscosity was building up very quickly. In
less than 3
minutes the mixture was too viscous and too tacky to drink.
25 Sample D:
Sucrose encrusted (1:1 w/w) UHMW HPMC fluff (420,000 cP viscosity
grade), 5.2 g, which had been course milled through a 16 mesh screen, was
mixed with
25.2 g of Tang'" brand dry powder orange drink mix in a 9 oz plastic cup. The
two
powders were admixed easily with a plastic spoon. The resulting powder mix
30 appeared heterogeneous with some large white particles obvious against the
orange
background. To this formulated product was added all at once 8 oz of cool
water
(about 10°C), and the mixture was stirred with a spoon. No froth and no
stubs formed.
The liquid suspension looked like Tang'" with suspended pulp. At 1 minute, the
mouth feel was characteristic of pulp in Tang'". After 3 minutes total time,
the
35 suspension showed very slow viscosity buildup, with no tackiness. After S
minutes the
suspension was still not viscous, and the suspended pulp-like particles were
very soft.
At 7 minutes there was no appreciable difference in mouth feel. At 12 minutes,
the
pulp-like particles were gloppy and viscosity was building.
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Sample E:
Sucrose encrusted (1:1 w/w) UHNIW HPMC fluff (420,000 cP viscosity
grade, milled as described in Example 1), 5.1 g, which had been coarse milled
through
a 16 mm screen, was placed in a 9 oz plastic cup, with no additional
formulation
components. To the neat powder was added all at once 8 oz of cool water (about
10°C), and the mixture was stirred with a spoon. No froth or stubs
formed. At 1
minute, the suspension consisted of clear gel particles in water. There were
no foam
and no opaque gel particles (fish eyes) present. This stable, easily flowable
aqueous
dispersion persisted for at least 10 minutes. By 13 minutes, the dispersion
had the
consistency of mucous. At 25 minutes, a soft runny gel had formed.
Sample F:
When Sample E was carried out by pouring 5.0 g of the encrusted UHMW
HPMC granulated derivative into the water, similar results to Sample E were
obtained.
This shows the versatility of 1:1 Sucrose encrusted UHMW HPMC
granulated derivative as a formulated produca.
Example 6
When the encrusted UHMW HPN1C granulated derivative of Example 5,
Samples E and F, was used, this composition vas found to be very suitable both
for
further incorporation into final formulated products, and as a final
formulated
20 product in its own right. It is important that t:he granulated derivative
or formulated
product can be dispersed into either cool water (0-20°C), or warm water
or heated
beverages (40-50°C), with simple spoon stirring. Under these conditions
viscosity
buildup was slow, and grittiness was avoided. The granules of this granulated
derivative are large. The particle size distribution of the granulated
derivative was in
25 the range of about 75% larger than 40 mesh (420 pm) but smaller than 16
mesh (1200
Nm), and less than about 10% smaller than 80 mesh (180 Nm). Yet, when this
encrusted UHMW HPMC derivative was dispersed in water it rapidly formed
individual
gels which had a mouth feel characteristic of soft pulp particles. Suspensions
of these
gels retain acceptable viscosity for at least 4 rninutes (2.5 g UHMW HPMC
equivalent; 8
30 oz dispersing liquid).
Example 7
Sucrose encrusted (1:1 w/w) UHPJIW HPMC (420,000 cP viscosity grade, as
described in Example 6), 5.9 g, was stirred into a 4 oz cold (10°C)
applesauce alf at once.
A totally palatable applesauce suspension of the granulated derivative was
obtained.
35 The viscosity, taste, and texture of the applesauce suspension remained
stable and
appealing for at least 15 minutes.
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Example 8
UHMW HPMC fluff {420,000 cP viscosity grade, milled as described in
Example 1), 5.0 g, was admixed with 10.0 g JELL-O'" brand sugar-free instant
chocolate
fudge dry powder pudding mix in a 10 oz cup. This resulting formulated product
was
an homogeneous dry brown powder mix. To this powder mix was added all at once
6
oz (178 g) cold (12°C) 2% butterfat milk. The mixture was spoon stirred
for 2 minutes.
A thick, smooth pudding resulted which exhibited excellent mouth feel and
flavor.
Other embodiments of the invention will be apparent to those skilled in
the art from a consideration of this specification or practice of the
invention disclosed
herein. It is intended that the specification and examples be considered as
exemplary
only, with the true scope and spirit of the invention being indicated by the
following
claims.
20
30
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