Note: Descriptions are shown in the official language in which they were submitted.
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' WO 99/24020 PCT/US98/23263
A PROCESS FOR MAKING A FREE-FLOWING, DUST-FREE, COLD WATER
DISPERSIBLE, EDIBLE, FILM-COATING COMPOSITION
The present invention concerns an improved edible film-coating composition
and its method of manufacture. The improved compositions are free-flowing,
dust-free and
cold water_dispersible. Such compositions are useful in pharmaceutical,
confectionery and
food applications.
The use of dry, edible, film-coating compositions in applications such as
to coating pharmaceutical tablets is well known in the art. By mixing a dry
polymer powder with
pigment particles and by grinding the mixture to obtain a dry polymer-pigment
composition
as a fine powder, the problem of shipping pigment dispersions containing
aqueous or non-
aqueous solvents is reduced, although not eliminated. However, when this fine
polymer
pigment mixture is stirred into water and dispersed, the polymer makes lumps
and "fish
is eyes" because it agglomerates, resulting in a non-uniform dispersion.
Unless the dispersion
is left to solvate for a considerable period of time, for example, overnight,
the coating is
lumpy and not uniform.
To improve the uniformity of the dispersion, U.S. Patent 4,543,370 discloses
a method of making a dry-powder, edible, film-coating composition by mixing a
powder of a
2o film-forming polymer and powdered pigment particles in a blender to form a
polymer-pigment
mix, adding a plasticizes to the blender containing the polymer-pigment mix,
and mixing until
the combined mix is thoroughly blended. Optionally, surfactants can be added
with the
plasticizes. Such compositions disperse in water at room temperature and form
usable
dispersions an hour after mixing. However, such dry powders are stilt dusty
and not easily
z5 transferred. In addition, the various components, such as the pigments, are
susceptible to
segregation.
In order to provide a composition which dissolves more quickly in cold water,
flows more freely, and avoids the dust hazards associated with powders, U.S.
Patent
4,816,298 discloses a method of making a granular, edible, film-coating
composition by
3 o extruding a thermally moldable polymer and plasticizes at elevated
temperatures, that is,
>_70°C, cooling to solidify the extrudate and comminuting the extruded
material to form a
granulated product. Optionally, pigments and surfactants may be added to the
granules or
to the blend before extrusion. Unfortunately, the diameter of the strands
produced by this
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extrusion process are of necessity relatively large, for example, 1/8 inch
(3.175 millimeters),
and the pellets produced are quite friable:
It would be highly desirable to formulate an edible film-coating composition
which readily disperses in cold water and which eliminates the segregation of
the
components while remaining dust-free and free-flowing.
By mixing all of the ingredients of the film-coating compositiori~together
with
an appropriate amount of water to form an, aqueous polymer blend, extruding
the polymer
blend, drying the extrudate and cutting the strands of extruded polymer blend,
an improved
granular film-coating composition is prepared. The film-coating composition is
readily
so dispersible in water, is dust-free and is free-flowing. Furthermore, the
blended ingredients
are relatively immune to segregation from the dry formulation.
One aspect of the present invention concerns a process for making an
improved, granular, cold-water dispersible, edible film-coating composition
for use in
pharmaceuticals, confectionery and food which comprises (a) mixing a film-
forming polymer
ss with water and a plasticizer to obtain an extrudable polymer blend having a
content of from
20 to 60 weight percent water, (b) extruding the polymer blend to obtain wet
strands of
polymer blend, {c) drying the strands of polymer blend to remove most of the
water and (d)
cutting the strands of dried polymer blend into pellets.
In another aspect, the present invention concerns the improved, granular,
2o cold water dispersible, edible film-coating composition obtainable from the
process of the
present invention.
In still another aspect, the present invention concerns a method of making a
coating dispersion for use in pharmaceutical, confectionery and food
applications which
comprises dispersing the granular, cold water dispersible, edible film coating
composition
25 obtainable from the process of the present invention into water without
agglomeration to
form a coating dispersion adapted for use as a film coating for tablets.
The present invention is a process for making an improved granular, cold
water dispersible, edible film-coating composition. The process involves the
steps of (a)
mixing a film-forming polymer with water and a plasticizer to obtain an
extrudable polymer
3 o blend, (b) extruding the polymer blend into wet strands and (c) drying the
wet strands to
remove most of the water and (d) cutting the, strands of polymer blend into
pellets. In
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addition to the film-forming polymer, plasticizer and water, various other
ingredients such as
pigments and colorants, surfactants and wetting agents, excipients and
diluents, and
detackifiers can be incorporated into the polymer blend.
The film-forming polymers that may be used in this invention are soluble
s either in water or in the plasticizer and are acceptable for human
consumption. Such fiim-
forming polymers include cellulosics, vinyl polymers such as polyvinyl
pyrrolidone, acrylics
such as dimethylaminoethyl methacrylate-methacrylic acid ester copolymer, and
carbohydrate polymers such as maftodextrins or polydextroses. Preferred film-
forming
polymers are cellulose ethers that are water soluble. Some typical examples of
cellulose
to ethers that are water-soluble and are particularly useful in the invention
are methylcellulose,
methylethyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose,
and
hydroxyethyl methylcellulose. Mixtures of these cellulose ethers cara also be
used. Most
preferred cellulose ethers are methylcellulose and hydroxypropyl
methyicellulose.
The viscosity and the substitution of the cellulose ethers preferred in the
15 invention are not critical as long as the cellulose ether is water-soluble.
For example,
methylcellulose with a 2 percent aqueous viscosity of 3 to 200,000 mPa~s
(millipascal-
seconds) can be used. The methoxy substitution of the methylcellulose can vary
from 10
percent to 50 percent by weight. The hydroxypropyl substitution can vary from
0 percent to
40 percent by weight. The hydroxyethyl substitution can vary from 0 percent to
45 percent
2o by weight.
Exemplary of the polymer plasticizer for use in the film-coating compositions
of the invention are polyethylene glycol, for example, polyethylene glycol
having a molecular
weight of 200 to 8000, glycerin, propylene glycol, glycerin triacetate,
acetylated
monoglyceride, diethyl phthalate and mineral oil.
2s The polymer plasticizer, which softens the polymer and makes it less
brittle,
may be a liquid or a solid plasticizer; a preferred plasticizer is a liquid
such as polyethylene
glycol 400.
Pigment dispersions typically used in pharmaceutical formulations, such as
aluminum-lake pigments, and colorants, such as dyes, may be added to the
blend.
s o Likewise, excipients or detackifiers such as sugars or starches may be
added to the blend.
Surfactants, such as dioctylsodium sulfosuccinates or sodium lauryl sulphate,
may optionally
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be added before or after the extrusion or milling to reduce surface tension of
water in contact
with the granules and increase the wetting of the particles.
Typically, the polymer blend to be extruded is from 40 to 70 weight percent
film-forming polymer, 20 to 60 weight percent water and 1 to 20 weight percent
plasticizes.
The addition of pigments, surfactants and other additives is optional.
Typically, the polymer
blend comprises from 0 to 0.3 weight percent surfactant, O to 30 weight
percent pigment or
colorant, and 0 to 40 weight percent other additives such as excipients,
diluents,
detackifiers, surfactants and wetting agents.
In a typical extrusion of a polymer or polymer blend, the polymer is wetted,
to forced through a die and cooled to solidify the extruded strands prior to
milling. In the
present invention, the polymer blend contains water so that it will flow under
pressure. The
water content of the polymer blend is only important in that it should neither
be so low that
excessive pressure is required to extrude it nor so high that the extruded
strands fail to
maintain their shape after extrusion. Generally, this calls for a water
content of from 20 to
is 60 weight percent of the polymer blend.
By conventional means, the plasticizes, film-forming polymer and water are
mixed to form a homogeneous blend. This can be done at the inlet of an
extruder or in an
external mixing device. Preferably, the blend is premixed and is slowly added
to the
extruder.
2o In general, the shape and size of the orifices fix the cross-sectional
shape and
size of the extrudate. Although any shape of orifice will suffice, that is,
circle, triangle,
square, or rectangle, it is preferred that the extrusion of the polymer blend
be through
equiaxial orifices. Equiaxial orifices are orifices that have approximately
equal dimensions in
all directions.
2 s The size of the orifices, that is, cross-sectional area, should be small
enough
so that the final product particle size is not so large that excessive time is
required for
dissolution. On the other hand, the cross-sectional area of the orifice should
not be so small
that an excessive amount of energy must be exerted to press the polymer blend
through the
orifices. Generally, the orifices are of 4.5x10-9 m2 to 4.5x10-5 m2.
Preferably, the orifices
3 o have a cross-sectional area of 9.9x10-8 m2 to 2.0x10-5 m2. Most
preferably, the orifices
have a cross-sectional area of 5x10'8 m2 to 2x10-7 m2.
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The polymer blend to be extruded is temperature sensitive in that at elevated
temperatures it expels water and solidifies. When the blend solidifies, it no
longer flows
under pressure and cannot be extruded. For this reason, the temperature of the
polymer
blend during extrusion is maintained so that the polymer blend remains
hydrated. While
s temperatures of up to 65°C or 70°C give acceptable results,
typically the temperature is
maintained below 40°C. Similarly, at low temperatures the water freezes
and the polymer
blend solidifies. While temperatures of down to 10°C are acceptable,
typically the
temperature is maintained above 20°C. Ambient temperature is preferred.
The extrusion can be done with any device that applies sufficient pressure to
so push the polymer blend through the extrusion orifices at a temperature
which keeps the
polymer blend hydrated. For example, a positive displacement extruder, such as
one
employing a positive displacement piston or a gear pump, can be used. Positive
displacement extruders are highly preferred in this invention because they are
energy
efficient and can extrude the polymer blend without unduly increasing its
temperature.
15 Another example of typical extrusion equipment is a screw-type extruder
which advances
the polymer blend by means of a screw rotating inside a cylinder. Screw-type
extruders are
not as energy efficient as positive displacement extruders and convert much of
the energy to
heat. This causes the temperature of the blend to increase and dehydration to
occur. Thus,
when a screw-type extruder is used, it is generally necessary to use a cooling
device to keep
2o the hydrated cellulose ether temperature below 40°C.
The elongated extrudate is the polymer blend that has been pressed through
the extrusion orifices. Generally, the elongated extrudate is in the form of
long narrow
strands. The strands of extrudate have a uniform cross-sectional area that is
approximately
the same as the extrusion orifices described above.
2s Normally, the extrudate is cooled in order to provide a solidified or
hardened
product. In the present invention since cooling does not harden the polymers
at these water
levels, the extrudate is dried to remove most of the water and to give a
hardened product.
The drying of the elongated extrudate can be accomplished with standard drying
equipment
and methods known in the art. Typical dryers include belt dryers and steam
tube dryers.
3o Belt dryers are preferred because there is a large surface area upon which
the polymer
blend strands can be spread.
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Preferably, the extruded strands are dried to a moisture content such that the
strands are sufficiently brittle to be cut. Generally, the polymer blend
strands are dried to a
moisture content of less than 10 percent.
In order to reduce the strands of polymer blend into smaller particles, it is
necessary to cut the strands. The cutting can be accomplished by using
standard
equipment known in the art. Typical cutting devices are air-swept impact
mills, ball mills,
hammer mills, knife grinders, and disk mills. In most cases, the size of the
extrusion orifice
is selected to fix two of the dimensions of the polymer blend. Therefore, it
is only necessary
to cut the strands to shorten the length. Typically, the extrudate is cut to a
length/diameter
io ratio of 0.5 to 10. Preferably, the extrudate is cut to a length/diameter
ratio of 1 to 4. This is
preferably done in an air-swept impact mill because the other mills, that is,
ball mills, have a
tendency to overmill the product into fine particles that are dusty.
In..addition, an air-swept
impact mill will dry the extrudate, if necessary, by blowing hot air across
the mill. Thus, if a
hot air mill is used, it may only be necessary to dry the extruded strands to
a moisture
is content of 25 percent before feeding them to the hot air mill.
The granular film-coating composition that results can be added to cold water
under agitation to form a coating solution. The solution can be used in a
conventional
coating operation, for example, spraying the solution directly onto a tablet
bed in a coater.
The composition may be used to coat pharmaceuticals, foods and food
supplements to
2o protect, color, harden, make more palatable, and mask the taste of solid
dosage forms.
In a typical example of the process, the film-forming polymer is agitated in a
high shear mixer/granulator. Plasticizer and optional ingredients such as
pigment, colorant
or surfactant are conveniently added to water and sprayed onto the film-
forming polymer
under agitation to form a wet polymer blend. Dry ingredients, such as some
excipients and
2 s detackifiers can be dry blended with the film-forming polymer before
spraying with the
aqueous solution of plasticizer. The polymer blend is then extruded through a
die face using
a piston pump. The wet strands are dried and cut with an air swept impact mill
to form a
free-flowing, non-dusty composition.
The following examples illustrate the invention.
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example 1 - Clear Coating_I ormuj~t~ ion
METHOCEL* E5 Premium, a film-forming polymer consisting of an
hydroxypropyi methylcellulose (having a 2 percent aqueous viscosity of 3.75-
7.0 mPa~s at
20°C, a methoxy substitution of 28-30 percent and a hydroxypropyl
substitution of 7-12
percent), (1260.8 grams (g)) was charged into a 10 liter (L) high speed
mixer/granulator and
agitated at a rate of 300 revolutions per minute (rpm) for the main impeller
and_ 1500 rpm for
the side chopper blades. While maintaining the agitation rate, a solution of
124.8 g of
polyethylene glycol 400 in 1275 g of water was sprayed onto the film-forming
polymer. The
wetted polymer blend was extruded through circular die openings having a cross-
sectional
to area of 1.46x10-7 m2. The extruded strands were dried and then milled using
an Alpine 100
UPZ mill equipped with a short track without screen.
*a trademark of The Dow Chemical Company
Example 2 - Yellow Coating Formulation
The procedure of Example 1 was repeated using the following ingredients:
METHOCEL E5 Premium 1260.8 g
polyethylene glycol 400 124.8 g
Yellow OPASPRAY** Liquid Color Conc. 116.8 g
water 969.9 g
The yellow colorant was added to the solution of the plasticizer and water
before spraying onto the film-forming polymer. After extrusion, drying and
milling, a dust-
free, free-flowing granular composition was obtained from which the colorant
would not
segregate.
**a trademark of Colorcon, Inc.
Example 3 - Blue Coatin~~ Formulation
The procedure of Example 2 was repeated using the following ingredients:
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METHOCEL E5 Premium 1260.8
g
polyethylene glycol 400 124.8 g
Blue OPASPRAY Liquid Color 127.4 g
Conc.
water 1000.0
g
Example 4 - Red CoatinaFormulation
The procedure of Example 2 was repeated using the following ingredients:
METHOCEL E5 Premium 884.5 g
MALTODEXTRINE*** 2774 402.0 g
polyethylene glycol 400 124.8 g
Red OPASPRAY Liquid Color Conc. 105.1 g
water 469.0 g
s The MALTODEXTRIN 2774 was dry blended with the METHOCEL E5 Premium in the
high
shear granulator prior to spraying with the aqueous mixture of plasticizer and
colorant. A
CoMil model 197-S mill was used instead of the Alpine 100 UPZ mill.
***a trademark of National Starch Company
Example 5 - Tablet-Coatinct Solution
to A 10 percent tablet coating solution was prepared by quickly adding the
formulations of Examples 1-4 into moderately agitated water at 23°C.
The pellets quickly
dispersed and went into solution within 20 to 30 minutes.
_g_
