Note: Descriptions are shown in the official language in which they were submitted.
CA 02945770 2016-10-19
POWDER COATING COMPOSITIONS FOR COATING PHARMACEUTICAL
PELLETS
FIELD
The present disclosure relates to powder coating compositions for coating
pharmaceutical pellets.
BACKGROUND
Orally administered pharmaceutical products such as tablets are typically
coated for many different reasons, including anyone or combination of moisture
protection, delayed release of the medicinally active component, targeted drug
delivery, extended release, taste masking, taste modification, and aesthetic
appeal,
to mention a few reasons.
Tablets have been coated using pan coaters in which the tablet cores to the
coating are typically sprayed in either powder or liquid form, or a
combination of
=
both. Electrostatic powder coating is a relatively new film coating technique
for the
manufacture of coated tablets to achieve a wide range of functions such as
modified release, moisture protection, aesthetics and taste masking functions.
It is
an environmental friendly and cost effective method that can potentially
replace the
existing aqueous and solvent coating methods. Electrostatic powder coating
using
a pan coating apparatus was introduced in United States Patent Publication No.
2007/0128274.
In addition to tablets, another orally administered pharmaceutical product is
made of pellets which are much smaller than tablets. These smaller pellets can
be
1
CA 02945770 2016-10-19
orally administered in pre-set dosage amounts such as pellets in filled hard
gelatin
capsules, or they can be compressed together with additional excipients to
form
larger tablets such that these tablets are made from the smaller pellets.
Typically,
the administration of oral pellets provide significant clinical benefits such
as
consistent bioavailability of modified release products and patient safety
benefits
compared to monolithic tablets such as reduction of dose dumping of extended
released formulations. It would be very advantageous to be able to coat these
individual pellets but for the coated pellets to be viable the resulting
coating must
be uniform and coating the entire pellet surface.
The inventors have noted that the same formulations used for powder
coating of tablets alone are not adequate for multi-particulate (pellet)
coating. Due
to the increased surface area and reduced bulk density of the much smaller
pellets
compared to the larger tablets, the agglomeration tendency of pellets is
increased
during the coating process. The larger specific area associated with the
smaller
pellets provides a more favorable environment for pellets to adhere together
and
their lower bulk density prevents the agglomerated pellets from separating
from
each other, thereby resulting in unevenly coated pellets.
One of the reasons for agglomeration during coating is due to polymer film
stickiness associated with the polymers used to form the coatings. For
example,
coating of oral pharmaceutical products is commonly conducted using a liquid
coating process where a coating film is produced by concurrent deposition and
drying of polymeric coating material. The film coat is generally non-sticky
when it
is not wet and the product temperature is not too high. However, since the
glass
2
CA 02945770 2016-10-19
transition temperature of the coating material is lowered in the presence of
plasticiser(s) and solvent, the coat surface can become sticky if the solvent
is not
evaporated quickly or the coating temperature is too high relative to the
glass
transition temperature. This results in product agglomeration if the product
is over
wetted due to insufficient product movement in the coating pan and/or
excessive
spray rate of coating material and high coating temperature. In powder
coating, the
glass transition temperature of the coating material is also decreased to
facilitate
film forming. An excessive reduction of the glass transition temperature
increases
the tackiness of the film coating causing agglomeration. The agglomeration is
3.13 particularly problematic for pellets versus tablets as the pellets
have a much
smaller inertia to break off from each other.
Another reason of agglomeration of solid oral products in coating is the
presence of electrostatic charge. Electrostatic charged surfaces attract much
stronger than non-charged surfaces because of the stronger electrostatic force
of
charged units than the non-specific van der Waal force of the non-charged
units.
This is particularly problematic for the much smaller pellets than it is for
the much
larger tablets since much lighter pellets when charged up can
electrostatically bind
to oppositely charged pellets which results in stronger bonding than
associated
with lower surface area to volume tablets.
As noted above, agglomeration must be avoided to produce a quality film in
coating of pellets. Agglomeration causes coating surface defects, coating
dissolution failure, and in-vivo performance issues. Agglomeration of tablets
and
pellets in pharmaceutical film coating is a common cause of product
manufacturing
3
CA 02945770 2016-10-19
failures and inter- and intra-batch-to-batch variations in product performance
such
as bioavailability and absorption characteristics.
Therefore, the formulations used for powder coating of small pellets must
include not only the functional constituents which give the resulting coat
with
desired pharmaceutical properties, but also must include constituents which
facilitate the production of uniform coatings on the pellets during the powder
coating process.
Thus, it would be very advantageous to provide formulations for
electrostatic spray powder coating of pellets which avoid the aforementioned
limitations.
SUMMARY
The present disclosure provides powder coating compositions for
pharmaceutical pellets which include one or more film forming polymers in
powder
form present in the composition in a range from about 1 to about 95 % w/w. The
compositions include one or more plasticizers in powder or liquid form present
in
the composition in quantity to lower the glass transition temperature of the
coating
composition to a temperature in a range from about 30 to 100 C. The
compositions
also include one or more flow enhancing agents in powder form present in the
composition in a range from about 0.1 to about 25 % w/w.
The one or more film forming polymers may be present in the composition
in a range from about 10 to about 70 % w/w.
4
CA 02945770 2016-10-19
The one or more flow enhancing agents may be present in the composition
in a range from about 0.25 to about 20 % w/w.
The one or more flow enhancing agents may be present in the composition
in a range from about 0.5 to about 3 % w/w.
The composition may further include one or more one anti-static agents in
powder or liquid form present in the composition in a range from about 0.1 to
about
95 % w/w.
The one or more anti-static agents may be present in the composition in a
range from about 1 to about 50 % w/w.
The one or more plasticizers may include any one or combination of
glycerol, propylene glycol, PEG 200 to 8000 grades, triacetin, diethyl
phthalate
(DEP), dibutyl phthalate (DBP), tributyl citrate (TBC), triethyl citrate(TEC),
leyl
alcohol, castor oil, fractionated coconut oil, acetylated monoglycerides,
glycerol
monostearate. Plasticizers may also include low molecular weight polymers,
oligomers, copolymers, oils, small organic molecules, low molecular weight
polyols
having aliphatic hydroxyls, ester-type plasticizers, glycol ethers,
poly(propylene
glycol), multi-block polymers, single block polymers, low molecular weight
poly(ethylene glycol) and citrate ester-type plasticizers.
The one or more plasticizers may include any one or combination of
ethylene glycol, 1,2-butylene glycol, 2,3-butylene glycol, styrene glycol,
diethylene
glycol, triethylene glycol, tetraethylene glycol and other poly(ethylene
glycol)
compounds, monopropylene glycol monoisopropyl ether, propylene glycol
monoethyl ether, ethylene glycol monoethyl ether, diethylene glycol monoethyl
5
CA 02945770 2016-10-19
ether, sorbitol lactate, ethyl lactate, butyl lactate, ethyl glycolate,
dibutyl sebacate,
acetyltributylcitrate, acetyl triethyl citrate and allyl glycolate.
The one or more anti-static agents may include common salts, carbon black,
magnesium stearate, fumed silicate, magnesium trisilicate, glycerol
monostearate,
Kaolin, talc and a liquid plasticizer. The liquid plasticizer may include any
one or
combination of PEG 200 to 600, propylene glycol, glycerin, and triacetin. The
common salts may include any one or combination of sodium chloride, calcium
chloride, magnesium hydroxide, sodium carbonate, sodium bicarbonate, sodium
phosphate, sodium citrate, sodium acetate, potassium acetate, potassium
citrate,
potassium chloride, and magnesium sulfate.
The plasticizer may be selected to lower the glass transition temperature of
the coating composition to a temperature in a range from about 45 to 70 C.
The one or more flow enhancing agents may include any one or
combination of calcium stearate, colloidal silicon dioxide, hydrogenate castor
oil
and microcrystalline cellulose, funnaric acid, glycerol behanate, glycerol
monostearate, glycerol palmitostearate, leucine, magnesium stearate, medium
chain triglyceride, myristic acid, palmitic acid, poloxamer, polyethylene
glycol,
potassium benzoate, sodium benzoate, sodium lauryl sulfate, sodium stearyl
fumarate, starch, stearic acid, talc, hydrogenated vegetable oil and zinc
stearate.
The one or more film forming polymers may be selected to exhibit any one
or combination of a moisture barrier, immediate release, flavoring, taste
modifying,
and taste masking, and wherein the film forming polymer includes any one or
combination of methylcellulose, hydroxyethyl cellulose, hydroxypropyl
cellulose
6
CA 02945770 2016-10-19
(HPC), hydroxylpropyl methyl cellulose (HPMC), polyethylene glycol, propylene
glycol, polaxamer and povidone, polyvinyl alcohol based composition such as
Opadry AMB, Aminoalkyl methacrylate copolymers.
The one or more film forming polymers may be selected to exhibit extended
release and includes any one or combination of cellulose ether derivative,
acrylic
resin, a copolymer of acrylic acid and methacrylic acid esters with quaternary
ammonium groups, a copolymer of acrylic acid and methacrylic acid esters,
ethyl
=
cellulose, and poly(meth)acrylate polymers that are not soluble in digestive
fluids.
The one or more film forming polymers may be selected to exhibit extended
release and includes any one or combination of polyethylene oxide (PEO),
ethylene oxide- propylene oxide co-polymers, polyethylene-polypropylene glycol
(e.g. poloxamer), carbomer, polyvinyl pyrrolidone (PVP), polyvinyl alcohol
(PVA),
hydroxyalkyl celluloses such as hydroxypropyl cellulose (HPC), hydroxypropyl
methylcellulose, sodium carboxymethyl cellulose, methylcellulose, hydroxyethyl
methylcellulose, hydroxypropyl methylcellulose, polyacrylates such as
carbomer,
polyacrylamides, alginic acid and its derivatives, starch and starch
derivatives,
gelatin that are soluble in digestive fluids.
The poly(meth)acrylate polymers that are not soluble in digestive fluids may
include any one or combination of Eudragit RS polymers, Eudragit RL
polymers,
and EUDRAGIT NE polymers.
The one or more film forming polymers may be selected to exhibit delayed
release include any one or combination of cellulose acetate phthalate,
cellulose
acetate trimaletate, hydroxyl propyl methylcellulose phthalate, polyvinyl
acetate
7
CA 02945770 2016-10-19
phthalate, acrylic polymers, polyvinyl acetaldiethylamino acetate,
hydroxypropyl
methylcellulose acetate succinate, cellulose acetate trimellitate, shellac,
methacrylic acid copolymers, methacrylic copolymers with carboxylic acid
groups.
The methacrylic copolymers with carboxylic acid groups may include
Eudragit L30D, Eudragit L100, Eudragit FS30D, Eudragit SI00, Acryl-EZE .
A further understanding of the functional and advantageous aspects of the
present disclosure can be realized by reference to the following detailed
description and drawings.
BRIEF DESCRIPTION OF THE DRAWINGS
Embodiments disclosed herein will be more fully understood from the
following detailed description thereof taken in connection with the
accompanying
drawings, which form a part of this application, and in which:
Figure 1 is an example dissolution profile of coated pellets with taste-
masking film forming polymer powder;
Figure 2 is an example dissolution profile of coated pellets with extended-
release film forming polymer powder; and
Figure 3 is an example dissolution profile of coated pellets with delayed film
forming polymer powder.
DETAILED DESCRIPTION
Various embodiments and aspects of the disclosure will be described with
reference to details discussed below. The following description and drawings
are
8
CA 02945770 2016-10-19
illustrative of the disclosure and are not to be construed as limiting the
disclosure.
Numerous specific details are described to provide a thorough understanding of
various embodiments of the present disclosure. However, in certain instances,
well-known or conventional details are not described in order to provide a
concise
discussion of embodiments of the present disclosure.
As used herein, the terms, "comprises" and "comprising" are to be
construed as being inclusive and open ended, and not exclusive. Specifically,
when used in the specification and claims, the terms, "comprises" and
"comprising"
and variations thereof' mean the specified features, steps or components are
included. These terms are not to be interpreted to exclude the presence of
other
features, steps or components.
As used herein, the term "exemplary" means "serving as an example,
instance, or illustration," and should not be construed as preferred or
advantageous over other configurations disclosed herein.
As used herein, the terms "about" and "approximately" are meant to cover
variations that may exist in the upper and lower limits of the ranges of
values, such
as variations in properties, parameters, and dimensions. In one non-limiting
example, the terms "about" and "approximately" mean plus or minus 10 percent
or
less.
As used herein the phrases pellets, beads and spheroids (hereinafter
pellets) are interchangeable terms as used herein to refer to small spherical
or
close to spherical single particles or agglomerations of fine powders or
granules of
pharmaceutical ingredients. It will be noted pellets may not be spherical but
could
9
CA 02945770 2016-10-19
have other shapes, such as but not limited to cylindrical, cubical etc.
Pellets can be
coated or uncoated, depending on its end usage. The pellet size ranges for
commercially available pharmaceutical uncoated pellets is typically in the
range
from about 100 to about 2000 pm (0.10 to 2.00 mm). As used herein, pellets
have
sizes in a range from about 50 to about 3,000 pm (microns) (0.30 to 3.00 mm),
with a preferable size range being from about 100 to about 2,000 pm. Uncoated
pellets are prepared using a variety of palletisation methods including, but
not
limited to, wet granulation, extrusion/spheronization, hot melt extrusion,
fluidbed
layering, or powder layering methods.
Defined quantities of coated or uncoated pellets are filled into capsules or
compressed into tablets along with pharmaceutically acceptable excipients to
produce a dosage unit for oral administration. Pellets can also be
administered
directly or dispersed in a liquid as an oral suspension for oral
administration. The
use of pellets is not limited to oral administration. For example, pellets can
be
mixed with a semisolid based composition, such as, but not limited to creams,
for
use as a topical product.
In contrast, pharmaceutical tablets for humans have sizes in a range from
about 5 mm to about 25 mm in the longest dimension of round, oblong, oval or
any
other shapes.
As used herein the phrase "film forming polymers" refer to polymers that
produce a physical, continuous film upon curing when used as a coating
material
for powder coating. The continuous film may or not may not contain a
plasticizer.
Film forming polymers together with other pharmaceutical agents are used to
CA 02945770 2016-10-19
produce functional, cosmetic or a combination thereof, film coats for
pharmaceutical products. One or more film forming polymer coatings can provide
one or a combination of, but not limited to, the following characteristics: 1)
moisture
protection, e.g. moisture protective film coating of a tablet or pellets; 2)
delayed
release characteristics, e.g. enteric film coating so that a drug will not be
released
in the stomach before it reaches the upper intestine; 3) targeted drug
delivery, e.g.
a delayed pH sensitive film coating of a tablet or pellets to colonic delivery
of a
drug so that the drug will start releasing in the lower Cl tract; 4) extended
release,
e.g. a sustained release film coating of a tablet or pellets to provide
prolonged
drug released at a constant rate for a period of time after drug
administration
where product is typically taken once or twice daily instead several times a
day; 5)
taste masking to prevent dissolution in the mouth, and similarly taste
modifying
agents in the coating; and 6)10w dose coating, e.g. a small amount (low dose)
of
drug substance is embedded in the polymer coating of a low dose product. The
present disclosure provides compositions used to improve content uniformity of
low dose products.
As used herein the phrase "plasticizer" refers to additives that soften a
polymer by lowering its glass transition temperature or reducing its
crystallinity or
melting temperature. For powder coatings, an appropriate level of a
plasticizer
allows the polymer/plasticizer material to coalesce to form a continuous
polymeric
film at a defined time and temperature. Plasticizers also refer to additives
for
polymers for imparting desired viscosity, flexibility, plasticity and any
other physical
properties to produce a suitable coating film that can withstand the
mechanical
11
=
CA 02945770 2016-10-19
handling forces in the film coating process, product transfer, and packaging
and
transportation.
As used herein the phrase "anti-static agents" refers to additives that help
eliminate electrostatic charges generated on a surface of pellets or tablets.
One
mechanism of charge elimination is obtained by increasing the conductivity of
the
surface in the presence of an electro-conducting anti-static agent. Another
charge
elimination mechanism is the use of a hygroscopic anti-static agent so that
the
surface moisture on pellet or tablet enhances charge dispersion. Anti-static
agents
prevent powder particle adhesion to each other and to non-electrical bonded or
poorly bonded surfaces.
As used herein the phrase "flow enhancing agents" refers to additives that
improve the flowability of powders. A suitable flow enhancing agent enables
effective bulk powder transfer to the electrostatic spray gun during powder
coating
process.
The present compositions have been developed to provide compositions
that exhibit the required film forming and processing characteristics for
uniform and
non-agglomerating film coating of pellets. The inventors have surprisingly
found,
that a combination of excipients with the following functional properties
produce
well-formed (coated) pellets using electrostatic powder coating processes.
These
functional properties include film forming polymers for the intended release
characteristics, plasticizers for optimal film forming temperature, anti-
static agents
for charge distribution, and flow aids for metering powders for coating.
12
CA 02945770 2016-10-19
One surprising finding of these powder coatings is that the powder coating
formulations can be prepared in a pan coater. Because of the difficulties in
coating
pellets compared to tablets, the liquid coating of pellets are generally
produced
using a fluidbed with Wurster inserts, see United States Patent No. 3,241,520
(Wruster 1966) which shows a bottom sprayed fluidized bed with a Wurster
insert.
Film Forming Polymers
Film forming polymers that can achieve, immediate release, flavoring or
taste modifying/masking or moisture barrier include, but are not limited to,
any one
or combination of methylcellulose, hydroxyethyl cellulose, hydroxypropyl
cellulose
(H PC), hydroxylpropyl methyl cellulose (HPMC), polyethylene glycol, propylene
glycol, polaxamer and povidone, polyvinyl alcohol based composition such as
Opadry AMB, Aminoalkyl methacrylate copolymers such as Eudragit E.
Coating polymers that could achieve extended release include, but not limit
to a cellulose ether derivative, an acrylic resin, a copolymer of acrylic acid
and
methacrylic acid esters with quaternary ammonium groups, a copolymer of
acrylic
acid and methacrylic acid esters or a combination of any thereof, or it can
include
ethyl cellulose, cellulose acetate, poly(meth)acrylates polymers that are not
soluble
in digestive fluids such as Eudragit RS and RL polymers with alkaline groups
and
EUDRAGIT NE polymers with neutral groups.
Coating polymers that exhibit extended release include water soluble
polymers such as, but not limit to, polyethylene oxide (PEO), ethylene oxide-
propylene oxide co-polymers, polyethylene-polypropylene glycol (e.g.
poloxamer),
13
CA 02945770 2016-10-19
carbonner, polycarbophil, chitosan, polyvinyl pyrrolidone (PVP), polyvinyl
alcohol
(PVA), hydroxyalkyl celluloses such as hydroxypropyl cellulose (H PC),
hydroxyethyl cellulose, hydroxymethyl cellulose and hydroxypropyl
methylcellulose,
sodium carboxymethyl cellulose, methylcellulose, hydroxyethyl methylcellulose,
hydroxypropyl methylcellulose, polyacrylates such as carbomer,
polyacrylamides,
polymethacrylamides, polyphosphazines, polyoxazolidines,
polyhydroxyalkylcarboxylic acids, alginic acid and its derivatives such as
carrageenate alginates, ammonium alginate and sodium alginate, starch and
starch derivatives, polysaccharides, carboxypolymethylene, polyethylene
glycol,
natural gums such as gum guar, gum acacia, gum tragacanth, karaya gum and
gum xanthan, povidone, gelatin or the like. Coating polymers that could
achieve
delayed release include, but are not limited to, any one or combination of
cellulose
acetate phthalate, cellulose acetate trimaletate, hydroxyl propyl
methylcellulose
phthalate, polyvinyl acetate phthalate, acrylic polymers, polyvinyl
acetaldiethylamino acetate, hydroxypropyl methylcellulose acetate succinate,
cellulose acetate trimellitate, shellac, methacrylic acid copolymers,
methacrylic
copolymers with carboxylic acid groups (such as Eudragit L30D, Eudragit
L100,
Eudragit FS300, Eudragit SI00, Acryl-EZE ).
It will be appreciated by those skilled in the art that multiple coats may be
applied to the pellets with each coat selected to have a pre-determined
functionality as set out above with respect to the film forming polymers.
14
=
=
CA 02945770 2016-10-19
Plasticizers
Both liquid and solid plasticizers can be used to achieve the target glass
transition temperature for powder coating, and may be present in the
composition
in quantity to lower the glass transition temperature of the coating
composition to
broadly in the temperature range from about 30 to 100 C and more preferably
from
45 to 70 C. It has been surprisingly found that the liquid plasticizers have
multiple
functions in the present pellet coatings. The functions of the plasticizers
used
include: 1) lowering the glass transition temperature (i.e., increase in
molecular
mobility) of the film forming polymer(s) to produce satisfactory functional or
cosmetic coating for oral pharmaceutical formulations; 2) increased adhesion
of
the film forming powder to the pellet substrate; and 3) increasing the
electrical
conductivity on spraying the substrate surface during coating. Thus the
surface
plasticizer also acts as an anti-static agent before it is incorporated into
coating
polymer matrix to produce a polymer film.
The plasticizers can be incorporated with the chain of the main formulation
of the film forming coating powder, as a result, the free volume between
polymer
chains can be increased and the glass transition temperature of the polymer
powder can be reduced dramatically. When the plasticizer is comprised of
liquid
polymers or polymer solutions, a certain amount of the plasticizer on the
surface of
the pellets can also decrease the electrical resistance of the pellets
dramatically so
that the adhesion of charged coating powder and the coating uniformity and
efficiency is improved. Furthermore, a certain amount of liquid plasticizer or
CA 02945770 2016-10-19
plasticizer solution can provide a strong capillary force between particles
and allow
polymer sintering and film formation to occur.
Plasticizers suitable for use in the present coating formulations include, but
are not limited to, glycerol, propylene glycol, PEG 200-600 grades, triacetin,
diethyl
phthalate (DEP), dibutyl phthalate (DBP) and tributyl citrate (TBC), triethyl
citrate(TEC), castor oil, fractionated coconut oil, acetylated monoglycerides
and
glycerol monostearate.
Plasticizers suitable for use in the present invention also include, but are
not limited to, low molecular weight polymers, oligomers, copolymers, oils,
small
organic molecules, low molecular weight polyols having aliphatic hydroxyls,
ester-
type plasticizers, glycol ethers, poly(propylene glycol), multi-block
polymers, single
block polymers, and citrate ester-type plasticizers. Such plasticizers can
also
include ethylene glycol, 1,2- butylene glycol, 2,3-butylene glycol, styrene
glycol,
diethylene glycol, triethylene glycol, tetraethylene glycol and other
poly(ethylene
glycol) compounds, monopropylene glycol monoisopropyl ether, propylene glycol
monoethyl ether, ethylene glycol monoethyl ether, diethylene glycol monoethyl
ether, sorbitol lactate, ethyl lactate, butyl lactate, ethyl glycolate,
dibutyl sebacate,
acetyltributylcitrate, acetyl triethyl citrate, tributyl citrate and ally'
glycolate.
Anti-static agents
The one or more anti-static agents may include common salts, carbon black,
magnesium stearate, fumed silicate, magnesium trisilicate, glycerol
monostearate,
Kaolin, talc and a liquid plasticizer. The liquid plasticizer may include any
one or
16
CA 02945770 2016-10-19
combination of PEG 200 to 600, propylene glycol, glycerin, and triacetin. The
common salts may include, but are not limited to, any one or combination of
sodium chloride, calcium chloride, magnesium hydroxide, sodium carbonate,
sodium bicarbonate, sodium phosphate, sodium citrate, sodium acetate,
potassium
acetate, potassium citrate, potassium chloride, and magnesium sulfate. The
anti-
static agents may be present in the composition in a range from about 0.1 to
about
95 % w/w, and more preferably in a range from about 1 to about 50 % w/w.
Flow enhancing agents
The one or more flow enhancing agents may include any one or
combination of calcium stearate, colloidal silicon dioxide, hydrogenate castor
oil
and microcrystalline cellulose, fumaric acid, glycerol behanate, glycerol
monostearate, glycerol palmitostearate, leucine, magnesium stearate, medium
chain triglyceride, myristic acid, palmitic acid, poloxamer, polyethylene
glycol,
potassium benzoate, sodium benzoate, sodium lauryl sulfate, sodium stearyl
fumarate, starch, stearic acid, talc, hydrogenated vegetable oil and zinc
stearate.
The one or more flow enhancing agents in powder form may be present in
the composition in a range from about 0.1 to about 25 % w/w, and more
preferably
from about 0.25 to about 20 % w/w. In embodiments the one or more flow
enhancing agents is present in the composition in a range from about 0.5 to
about
3 % w/w.
Several non-limiting examples are given below.
17
CA 02945770 2016-10-19
EXAMPLES
In the present examples, piroxicam pellets were used as the model drug
coating pellets to demonstrate the effectiveness of the electrostatic powder
coating
compositions provided in the present disclosure. Three different classes of
functional pharmaceutical polymers compositions containing Eudragit EPO,
Eudragit RS/RL, Acryl-EZE , were selected to achieve taste masking, extended
release and delayed release, respectively.
EXAMPLE 1
Dry powder coating of piroxicam pellets with a taste masking coating
(Eudragit EPO)
This example demonstrates the dry powder coating of piroxicam pellets
using a coating composition (Table 1) containing Eudragit EPO (a cationic
copolymer based on dimethylaminoethyl methacrylate, butyl methacrylate, and
methyl methacrylate), a pH sensitive polymer that is soluble in gastric juice
up to
pH 5.0, swellable and permeable above pH 5.0, and a liquid plasticizer,
polyethylene glycol 400 (PEG 400, EMD Chemicals Inc. Ontario, Canada), is used
to increase the adhesion between the coating powder and the piroxicam pellets.
Talc is used as the anti-static agent and colloidal silicon dioxide is used as
the flow
enhancing agent.
18
CA 02945770 2016-10-19
Preparation Of The Coating Powder
The coating powder was prepared using a blade grind mill for about 25
seconds following the composition shown in Table 1. Eudragit EPO and
colloidal
silicon dioxide (AEROSIL 200 Pharma) were donated by Evonik Degussa
Corporation (Germany). Talc was purchased from Mallinckrodt Baker Inc.
(Canada).
Table 1 Composition of taste masking coating powder*
Formulation Composition (% w/w)
Eudragit EPO 10.0
Talc 89.0
Colloidal silicon dioxide(nano level) 0.5
Pigment(FD&C Yellow No.6) 0.5
*The plasticizer, PEG 400, is included in the coating composition by spraying
onto
the coating pellets. The particle size (volume mean diameter) D[4,3] of the
above
used Eudragit EPO and Talc powder are 13.3pm and 28.9pm, respectively.
1) Powder coating process
40 g piroxicam pellets were loaded into the rotatable drum of a rotary powder
coating apparatus and was pre-heated to 40 C at a rotating speed of 20 rpm.
Then
the rotation speed of the drum was increased to 70 rpm and the temperature was
19
CA 02945770 2016-10-19
maintained at 40 C. Liquid plasticizer (PEG 400) was sprayed on to the
particles
from an atomizing spraying nozzle at a flow rate of 0.25 g/min for 35 seconds.
1.5
g coating materials were immediately deposited to the coating particles after
plasticizer spraying. The plasticizer spraying and coating materials
deposition cycle
was repeated after about 15 mins 3 times until the target coating level was
achieved. The particles were cured at 40 C and a rotating speed of 20 rpm for
2
hours.
2) Dissolution Test
The coated piroxicam pellets was visually examined in phosphate buffer
solution (PBS) at pH 6.8. No dissolution was observed and the film coat was
intact
for up to 10 minutes. The dissolution profile of coated piroxicam pellets in
0.1 N
HCI solution (pH=1.2) was obtained using an USP dissolution apparatus
(Apparatus 2) at 37 C and a rotation speed of 100 rpm. The dissolution samples
were assayed using a UV-Vis spectrophotometer at a wavelength of 334 nm. The
PBS and rapid dissolution in 0.1N HCI results shown in Figure 1 indicate that
the
coated pellets exhibit taste masking behavior, i.e. little or no dissolution
upon
swallowing and rapid dissolution when the product reaches the stomach.
=
20
CA 02945770 2016-10-19
EXAMPLE 2
Dry powder coated piroxicam pellets with extended release coating
(Eudragit RS/RL)
This example demonstrate the dry powder coating of piroxicam pellets using
a coating composition (Table 2) containing Eudragit RS (a low permeability
copolymer of ethyl acrylate, methyl methacrylate and a low content of
methacrylic
acid ester with quaternary ammonium groups.) and Eudragit RL(a high
premeabillity copolymer of ethyl acrylate, methyl methacrylate and a low
content of
methacrylic acid ester with quaternary ammonium groups.), two pH independent
polymers that are commonly used for extended release coating. A liquid
plasticizer,
triethyl citrate (TEC, Caledon Laboratories Ltd. Ontario, Canada), is also
used to
increase the adhesion between the coating powder and the piroxicam pellets and
to decrease the Tg of the Eudragit RS/RL from 63-65 to around 35 C. Talc is
used as the anti-static agent and colloidal silicon dioxide is used as the
flow
enhancing agent.
1) Preparation Of The Coating Powder
The coating powder was prepared using a blade grind mill for about 25
seconds following the composition shown in
2) Formulation Composition (%w/w)
21
=
CA 02945770 2016-10-19
Eudragit RS 40.0
Eudragit RL 40.0
Talc 19.0
Colloidal silicon dioxide (nano level) 0.5
Pigment( FD&C Blue number 1) 0.5
Table 2. Eudragit RS and Eudragit RL and colloidal silicon dioxide
(AEROSIL 200 Pharma) were donated by Evonik Degussa Corporation
(Germany). Talc was purchased from Mallinckrodt Baker Inc. (Canada).
3) Formulation Composition (`Yow/w)
Eudragit RS 40.0
Eudragit RL 40.0
Talc 19.0
Colloidal silicon dioxide (nano level) 0.5
Pigment( FD&C Blue number 1) 0.5
22
CA 02945770 2016-10-19
Table 2 Composition of extended release coating powder*
*A liquid plasticizer, TEC, is included in the coating composition by spraying
onto
the coating pellets.
The particle size (volume mean diameter) D[4,3] of the above used Eudragit
RS,
Eudragit RL and Talc were 47.7pm, 40.8pm and 28.9 pm, respectively.
4) Powder Coating Process
40 g piroxicam pellets were loaded into the rotatable drum of a rotary powder
coating apparatus and was pre-heated to 50 C at a rotating speed of 20 rpm.
Then
the rotation speed of the drum was increased to 70 rpm and the temperature was
maintained at 50 C. Liquid plasticizer (TEC) was sprayed on to the particles
from
an atomizing spraying nozzle at a flow rate of 0.25 g/min for 35 seconds. 1.5
g
coating materials were immediately deposited to the coating particles after
plasticizer spraying. The plasticizer spraying and coating materials
deposition cycle
was repeated after about 15 mins 6 times until the target coating level was
achieved. The particles were cured at 50 C and a rotating speed of 20 rpm for
2
hours.
5) Dissolution test
The dissolution profile of coated piroxicam pellets in pH=7.0 phosphate buffer
solution was obtained using an USP dissolution apparatus (Apparatus 2) at 37 C
and a rotation speed of 50 rpm. The dissolution samples were assayed using a
UV-Vis spectrophotometer at a wavelength of 354 nm. Figure 2 is the
dissolution
profile of the coated piroxicam pellets with Eudragit RS/RL which
demonstrated
23
CA 02945770 2016-10-19
the expected extended release function of the coated formulation.
EXAMPLE 3
Dry powder coated piroxicam pellets with delayed release coating (Acryl-
EZE`)
This example demonstrates the dry powder coating of piroxicann pellets using
a enteric coating composition (Table 3) containing Acryl-EZE (contains
Eudragit
L100-55, an anionic copolymer based on methacrylic acid and ethyl acrylate
provided by Colorcon Inc. USA), a formulated coating pH sensitive coating
powder
that is soluble in water at a pH above 5.5.
A liquid plasticizer, polyethylene glycol 400 (PEG 400, EMD Chemicals Inc.
Ontario, Canada), is used to increase the adhesion between the coating powder
and the piroxicann pellets and to decrease the Tg of the Acryl-EZE from 133 C
to
50-55 C. The plasticizer also serves as an anti-static agent.
1) Preparation Of The Coating Powder
The coating powder was prepared using a blade grind mill for about 25
seconds following the composition shown in Table 3.
Table 3 Composition of delayed release coating materials*
Formulation Composition (% w/w)
24
CA 02945770 2016-10-19
Acryl-EZE 99.5
pigment (FD&C Blue number 1) 0.5
*The plasticizer, PEG 400, is included in the coating composition by spraying
onto
the coating pellets. The particle size (volume mean diameter) D[4,3] of the
above
used Acryl-EZE was 20.5pm.
2) Powder coating process
40 g piroxicam pellets were loaded into the rotatable drum of a rotary
powder coating apparatus and was pre-heated to 50 C at a rotating speed of 20
rpm. Then the rotation speed of the drum was increased to 70 rpm and the
temperature was maintained at 50 C. Liquid plasticizer (PEG 400) was sprayed
on
to the particles from a atomizing spraying nozzle at a flow rate of 0.25 g/min
for 35
seconds. 1.5 g coating materials were immediately deposited to the coating
particles after plasticizer spraying. The plasticizer spraying and coating
materials
deposition cycle was repeated after about 15 mins for several times (4 times
for
coating level of 13.25 % w/w; 7 times for 21.93 % w/w) until the target
coating level
=
was achieved. The particles were cured at 50 C and a rotating speed of 20 rpm
for
2 hours.
3) Dissolution test
The dissolution profile of coated piroxicam pellets was obtained in 0.1 N
(pH=1.2) HCI solution for 2 hours (acid stage) and in pH=6.8 phosphate buffer
solution after the acid stage using an USP dissolution apparatus at 37 C and
at a
CA 02945770 2016-10-19
rotation speed of 100 rpm. The dissolution samples were assayed using a UV-Vis
spectrophotometer at a wavelength of 334 nm (acid stage samples) and 353 nm
(buffer stage samples).
The delayed release profiles of the coated pellets at coating level of 13.25
and
21.93 % w/w are shown in Figure 3. In both cases, the results met and exceeded
the requirements of the acid resistance test of percent release of not more
than
10% released in 0.1 N HCI in 2 hours.
All of the formulation compositions can be made and executed without
undue experimentation in light of the present disclosure. While the
formulation
compositions, methods of this disclosure have been described in terms of
preferred embodiments, it will be apparent to those of skill in the art that
variations
may be applied to the formulation compositions, and/or apparatus and/or
methods
and in the steps or in the sequence of steps of the methods described herein.
More specifically, it will be apparent that certain agents that are chemically
or
physiologically related may be substituted for the agents described herein
while
the same or similar results would be achieved. All such similar substitutes
and
modifications apparent to those skilled in the art.
26
