Note: Descriptions are shown in the official language in which they were submitted.
CA 02472432 2004-06-25
SOFT TABLET CONTAINING
HIGH MOLECULAR WEIGHT CELLULOSICS
Background of the Invention
1. Field of the Invention
The present invention relates to an immediate release, chewable or
disintegrable tablet
comprising a blend of active ingredient and high molecular weight cellulosics,
having exceptionally
good mouthfeel and stability.
2. Background of the Invention
Pharmaceuticals intended for oral administration are typically provided in
solid dosage forms
such as, for example, tablets, capsules, pills, lozenges, or granules. Tablets
are swallowed whole,
chewed in the mouth, or dissolved in the oral cavity. Chewable or
disintegrable tablets are often
employed in the administration of pharmaceuticals where it is impractical to
provide a tablet for
swallowing whole, such as, for example, with pediatric and geriatric patients.
Workers in the field continue to try to improve the flavor and mouthfeel of
chewable tablets
and other comestibles by adding agents, such as gums, thereto. See, e.g.,
United States Patent No.
4,818,539 and WO 88/06893. In order to effectively texture mask such dosage
forms, it is necessary
to blend a high level of gum with the active agent. Disadvantageously, during
mastication such forms
become pasty and initially cause a significant drying phase in the mouth.
Alternative texture masking agents include polyalkylene glycols. For instance,
U.S. Patent
No. 4,882,154 discloses chewable dosage forms wherein the pharmaceutical
ingredient is pre-coated
with, for example, a polyalkylene glycol having a molecular weight of less
than 3700. Further, WO
00/30617 discloses a taste masked drug particle having an active inner core, a
polyethylene oxide
layer covering the core, and an outer taste masking layer. However, these
texture masking processes
disadvantageously require one or more coating steps, which not only makes them
less economical but
also increases production cycle time.
Another technique for texture masking an agent involves the blending of low-
viscosity
hydroxyalkylcellulose and high-viscosity hydroxyalkylcellulose with calcium
powder, then granulating
the blend into pelletizable granules in order to improve the mouth feel of the
resulting calcium-
containing dosage forms. See, e.g., Japanese Patent Application 5[1993]-
306229.
U. S. Patent Number 6,432,442 discloses the use of a gelatin matrix and an
optional
hydrocolloid as another technique for providing a soft, chewable delivery
system. Because these
"gummi" or confectionary systems also contain water in an amount of from about
10 to 30 percent by
MCP-5014 NP I
CA 02472432 2004-06-25
51394-1
weight of the final product, they disadvantageously possess
certain limitations with respect to shelf-life, packaging,
and storage conditions. Additionally, it is economically
more beneficial to produce other dosage forms such as, for
example, compressed tablets, due to their simplicity of
processing.
It would be desirable to have a chewable or
disintegrable, texture masked, immediate release dosage
form, and in particular a chewable or disintegrable
compressed tablet, that could be suitable for use with
active agents having large particle sizes, e.g. those in
excess of 100 microns.
Summary of the Invention
According to one aspect of the present invention,
there is provided an immediate release dosage form capable
of being chewed or disintegrated in the oral cavity prior to
swallowing, comprising, consisting of, and/or consisting
essentially of
a. a plurality of particles comprising a
pharmaceutically active ingredient, said particles having a
particle size of about 150 um to about 400 um; and
b. a matrix comprising, based upon the total
weight of the dosage form, from about 0.1 percent to about
percent of hydroxyalkylcellulose having a weight average
25 molecular weight of from about 60,000 to about 5,000,000
and/or a viscosity of from about 3,000 mPa=s to about
150,000 mPa=s in a 2% aqueous solution.
According to another aspect of the present
invention, there is provided an immediate release dosage
2
CA 02472432 2004-06-25
51394-1
form capable of being chewed or disintegrated in the oral
cavity prior to swallowing, comprising: a. a plurality of
particles comprising a pharmaceutically active ingredient,
said particles having a particle size of about 150 pm to
about 400 pm; and b. a matrix comprising, based upon the
total weight of the dosage form, from about 0.1 percent to
about 25 percent of hydroxyalkylcellulose having a weight
average molecular weight of from about 60,000 to about
5,000,000 and/or a viscosity of from about 3,000 mPa=s to
about 150,000 mPa=s in a 2% aqueous solution, wherein the
plurality of particles comprised of a pharmaceutically
active ingredient are substantially free of
hydroxyalkylcellulose having a weight average molecular
weight of from about 60,000 to about 5,000,000 and/or a
viscosity of from about 3,000 mPa=s to about 150,000 mPa=s
in a 2% aqueous solution.
According to still another aspect of the present
invention, there is provided an immediate release dosage
form capable of being chewed or disintegrated in the oral
cavity prior to swallowing, comprising, consisting of,
and/or consisting essentially of
a. a plurality of particles comprising a
pharmaceutically active ingredient; and
b. a matrix comprising, based upon the total
weight of the dosage form, from about 0.1 percent to about
25 percent of hydroxyalkylcellulose having a weight average
molecular weight of from about 60,000 to about 5,000,000
and/or a viscosity of from about 3,000 mPa=s to about
150,000 mPa=s in a 2% aqueous solution,
wherein the pharmaceutically active ingredient is coated
with a taste masking coating.
2a
CA 02472432 2004-06-25
51394-1
According to yet another aspect of the present
invention, there is provided an immediate release dosage
form capable of being chewed or disintegrated in the oral
cavity prior to swallowing, comprised of: a. a plurality of
coated particles comprising, based upon the total weight of
the dosage form, from greater than about 12 percent and less
than about 40 percent of a pharmaceutically active
ingredient selected from the group consisting of
acetaminophen, acetyl salicylic acid, ibuprofen, naproxen,
ketoprofen, flurbiprofen, diclofenac, cyclobenzaprine,
meloxicam, rofecoxib, celecoxib, and pharmaceutically
acceptable salts, esters, isomers, and mixtures thereof,
said coated particles further comprising, based upon the
total weight of the coated particles, from greater than
about 5 percent and less than about 30 percent of a taste
masking coating comprised of cellulose acetate,
hydroxymethylcellulose phthalate, and polysorbate-80 at a
ratio of 43:53:4, wherein the taste masking coating
substantially covers the active ingredient; and b. a matrix
comprising, based upon the total weight of the dosage form,
from about 0.5 percent to about 10.0 percent of
hydroxypropylmethylcellulose and/or hydroxypropylcellulose
having a weight average molecular weight of from about
60,000 to about 5,000,000 and/or a viscosity of from about
3,000 mPa=s to about 150,000 mPa=s in a 2% aqueous solution.
Detailed Description of the Invention
As used herein, the term "dosage form" applies to
any solid, semi-solid, or liquid composition designed to
contain a specific pre-determined amount or "dose" of a
certain ingredient, for example an active ingredient as
defined below. Dosage forms may include, but are not
limited to: a) pharmaceutical drug delivery systems,
2b
CA 02472432 2004-06-25
51394-1
including those for oral administration, buccal
administration, or mucosal delivery; or b) compositions for
delivering minerals, vitamins and other nutraceuticals, oral
care agents, flavorants, and the like. In one embodiment,
the solid dosage form is an orally administered system for
delivering a pharmaceutical active ingredient to the GI
tract of a mammal. The dosage forms of the present
invention are typically considered to be solid; however,
they may
2c
CA 02472432 2004-06-25
contain liquid or semi-solid components. Suitable "solid dosage forms" of the
present invention
include, but are not limited to, tablets, e.g. caplets; capsules; sachets; and
the like. One suitable solid
dosage form is a chewable or orally disintegratable tablet.
As used herein, the term "immediate release" shall mean that the dissolution
of the dosage
form conforms to USP specifications for immediate release tablets containing
the particular active
ingredient employed. For example, for acetaminophen tablets, USP 24 specifies
that in pH 5.8
phosphate buffer, using USP apparatus 2 (paddles) at 50 rpm, at least 80% of
the acetaminophen
contained in the dosage form is released therefrom within 30 minutes after
dosing, and for ibuprofen
tablets, USP 24 specifies that in pH 7.2 phosphate buffer, using USP apparatus
2 (paddles) at 50 rpm,
at least 80% of the ibuprofen contained in the dosage form is released
therefrom within 60 minutes
after dosing. See USP 24, 2000 Version, 19 - 20 and 856 (1999). The term,
"good mouth feel" shall
mean that the dosage form becomes a slippery, gel-like mass capable of
suspending gritty particles
during mastication.
By "high weight average molecular weight hydroxyalkylcellulose," it is meant a
hydroxyalkylcellulose having a) weight average molecular weight between about
60,000 to about
5,000,000, e.g. from about 140,000 to about 1,150,000; and/or b) a viscosity
between about 3,000
mPa.s to about 150,000 mPa.s in a 2% aqueous solution, e.g., from about 4,000
mPa.s to about
100,000 mPa.s in a 2% aqueous solution.
The dosage form of the present invention may be made from a composition
comprising one or
more active ingredients and, based upon the total weight of the dosage form,
from about 0.1 percent
to about 25.0 percent, e.g. from about 0. 5 percent to about 10.0 percent, of
a hydroxyalkylcellulose
having a high weight average molecular weight in the matrix.
The phrase "hydroxyalkylcellulose having a high weight average molecular
weight in the
matrix," as used herein, shall refer to such a hydroxyalkylcellulose that is
present in the final dosage
form but is not contained in the active ingredient powder or the granulated
active ingredient particles or
crystals per se. In one embodiment, the granulated active ingredient particles
are substantially free of
high weight average molecular weight hydroxyalkylcellulose. As used herein,
"substantially free of
high weight average molecular weight hydroxyalkylcellulose" shall mean that
the granulated particles
contain, based upon the total weight of the particles, less than about 1 %,
e.g., less than about 0.1 % or
less than about 0.01 % of high weight average molecular weight
hydroxyalkylcellulose.
Suitable active ingredients include pharmaceuticals, minerals, vitamins, other
nutraceuticals,
and mixtures thereof. Suitable pharmaceuticals include analgesics, anti-
inflammatory agents,
antiarthritics, anesthetics, antihistamines, antitussives, antibiotics, anti-
infective agents, antivirals,
anticoagulants, antidepressants, antidiabetic agents, antiemetics,
antiflatulents, antifungals,
antispasmodics, appetite suppressants, bronchodilators, cardiovascular agents,
central nervous
system agents, central nervous system stimulants, decongestants, diuretics,
expectorants,
gastrointestinal agents, migraine preparations, motion sickness products,
mucolytics, muscle
MCP-5014 NP 3
CA 02472432 2011-06-10
64160-598
relaxants, osteoporosis preparations, polydimethylsiloxanes, respiratory
agents, sleep aids, urinary
tract agents and mixtures thereof.
Examples of suitable gastrointestinal agents include stimulant laxatives, such
as bisacodyl,
cascara sagrada, danthron, senna, phenolphthalein, aloe, castor oil,
ricinoleic acid, and dehydrocholic
acid, and mixtures thereof; H2 receptor antagonists, such as famotadine,
ranitidine, cimetadine; proton
pump inhibitors; gastrointestinal cytoprotectives, such as sucraflate and
misoprostol; gastrointestinal
prokinetics, such as Prucalopride, antibiotics for H. pylori, such as
c.larithromycin, amoxicillin,
tetracycline, and metronidazole; antidiarrheals, such as diphenoxylate and
loperamide; glycopyrrolate;
antiemetics, such as ondansetron, analgesics, such as mesalarrtine.
to In one embodiment, the active agent may be selected from bisacodyl,
famotadine, ranitidine,
cimetidine, prucalopride, diphenoxylate, loperamide, lactase, mesalamine,
bismuth, antacids, and
pharmaceutically acceptable salts, esters, isomers, and mixtures thereof.
In another embodiment, the active agent may be selected from acetaminophen,
acetyl salicylic
acid, ibuprofen, naproxen, ketoprofen, flurbiprofen, diclofenac,
cyclobenzaprine, meloxicam, rofecoxib,
celecoxib, and pharmaceutically acceptable salts, esters, isomers, and
mixtures. thereof.
In another embodiment, the active agent may be selected from pseudoephedrine,
phenylpropanolamine, chlorpheniramine, dextromethorphan, diphenhydramine,.
astemizole,
terfenadine, fexofenadine, loratadine, cetirizine, mixtures thereof and
pharmaceutically acceptable
salts, esters, isomers, and mixtures thereof.
Examples of suitable polydimethylsiloxanes, which include, but are not limited
to dimethicone
and simethicone, are those disclosed in United States Patent Nos. 4,906,478,
5,275,822, and.
6,103,260. As used herein, the
term "simethicone"refers to the broader class of polydimethylsiloxanes,
including but not limited to
simethicone and dimethicone.
The active ingredient(s) are present in the dosage form in a therapeutically
effective amount,
which is an amount that produces the desired therapeutic response upon oral
administration and can
be readily determined by one skilled in the art. In determining such amounts,
it is well known in the art
that various factors must be considered that include, but are not limited to
the particular active
ingredient being administered, the bioavailability characteristics of the
active ingredient, the dose
regime, and the age and weight of the patient.
In one embodiment, the amount of active ingredient contained in the dosage
form is, based
upon the total weight of the dosage form, from about 0.25 percent to about 70
percent, e.g., from
about 0.5 percent to about 25 percent or from about 10 percent to about 50
percent.
The active ingredient can be in the form of a fine powder, granule, or large
crystal, and
typically has an average particle size from about 20 microns to about 1000
microns, e.g., from about
50 microns to about 700 microns or from about 100 microns to about 500
microns. In one
embodiment, one or more active ingredients are contained in particles having
an average size from
4
CA 02472432 2011-06-10
64160-598
about 150 to about 400 microns. The active ingredient may be in any form
within the particles, for
example as a fine powder dispersed throughout a matrix of inactive
ingredients, or in crystalline or
amorphous form, layered onto an inert seed particle.
If the active ingredient has an objectionable taste, a coated particle
containing the active
ingredient coated with a taste masking agent is employed. "Coated particle,"
as used herein, refers to
a solid active ingredient in the form of a crystal or particle, an agglomerate
of individual particles, or a
granuled particle, which has been encapsulated with a taste masking agent,
either by film coating
method known in the art or by other known processes such as coaccervation. For
example,
acetaminophen particles that have been encapsulated with ethylcellulose or
other polymers via
coaccervation may be used in the present invention. Such coaccervation-
encapsulated
acetaminophen may be purchased commercially from Eurand America, Inc.
Vandalia, Ohio, or from
Circa Inc., Dayton, Ohio. Other commercially available taste maskedactive
ingredients, may also be
employed.
Suitable taste masking coatings are described in, for example, U.S. Patent
Nos. 6.471,991,
4,851,226, 5,075,114, and 5,489,436.
Examples of suitable taste masking agents include, but are not limited to
cellulose acetate,
ethylcellulose, poly(ethyl acrylate, methyl methacrylate,
trimethylammonioethyl methacrylate chloride),
which is commercially available from Rohm Pharma under the tradename, "
EUDRAGIT",
hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl
cellulose, and mixtures thereof.
In certain embodiments, the taste masking agent may be comprised of a mixture
of a) at least
one solubilizable polymer selected from the group consisting of enteric
polymers, reverse enteric
polymers, water soluble polymers, and copolymers and mixtures thereof; and b)
and at least one
insoluble film forming polymer. "Solubilizable polymer" as used herein, shall
mean a polymer that
swells or dissolves in a certain medium and can be dispersed at the molecular
level to form a
homogeneous dispersion therein. The medium may resemble conditions that could
exist in the
gastrointestinal tract of a human. For example, the solubilizable polymer may
be soluble in a water
medium (e.g. water soluble polymers). Alternatively the solubilizable polymer
may be soluble in an
aqueous medium having a certain pH range, such as at a pH less than 5 (e.g.
reverse enteric
polymers) or such as at a pH of 5.5 or greater (e.g. enteric polymers).
The enteric polymer may be selected from any one of a variety of known enteric
polymers,
such as shellac, hydroxypropyl methylcellulose phthalate, hydroxypropyl
methylcellulose acetate
succinate, cellulose acetate phthalate , polyvinylacetate phthalate, ;and
polymethacrylate-based
polymers such as poly(methacrylic acid, methyl methacrylate) 1:2, which is
commercially available
from Rohm Pharma GmbH under the tradename, " EUDRAGIT S" polymers, and
poly(methacrylic
acid, methyl methacrylate) 1:1, which is commercially available from Rohm
Phamia GmbH under the
tradename, " EUDRAGIT L" polymers. Combinations of enteric polymers may also
be used.
* Trade-mark
5
CA 02472432 2004-06-25
In one embodiment, the enteric polymer is selected from non-acrylate
compounds, specifically
hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate
succinate, cellulose
acetate phthalate, and polyvinylacetate phthalate. Non-acrylates are preferred
because acrylate
polymers tend to become tacky and agglomerate at high temperature. Cellulose
polymers are more
heat stable than acrylate polymers. In addition, acrylate polymers are known
to have a characteristic,
slightly unpleasant taste, whereas cellulose polymers have a more neutral
taste profile.
Examples of suitable reverse enteric polymers include, but are not limited to
methylaminoethyl-methacrylate and neutral methacrylic acid esters available
from Rohm Pharma
GmbH, Germany under the tradename, "EUDRAGITN E 100."
Examples of suitable water soluble polymers include, but are not limited to
hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose,
methylcellulose,
polyvinyl pyrrolidone, polyethylene glycol, polyvinyl alcohols, and sodium
carboxymethylcellulose.
The insoluble film forming polymer may be selected from a number of known
compounds,
including cellulose acetate, cellulose acetate butyrate, cellulose triacetate,
ethylcellulose, neutral ester
co-polymer of ethyl acylate and methyl methacrylate, which is commercially
available from Rohm
Pharma under the tradename, "EUDRAGIT NE", and poly(ethyl acrylate, methyl
methacrylate,
trimethylammonioethyl methacrylate chloride) 1:2:0.1 , which is commercially
available from Rohm
Pharma under the tradename, " EUDRAGIT RS". One or more than one insoluble
film forming
polymer may be used. Preferably, the insoluble film forming polymer is
impermeable and does not
swell in an aqueous environment. More preferably, the insoluble film forming
polymer is selected from
cellulose acetate and ethylcellulose.
The weight ratio of solubilizable polymer to insoluble film forming polymer in
the polymeric
coating is preferably in the range of about 5:95 to about 80:20, more
preferably about 40:60 to about
70:30.
Other examples of suitable taste masking coatings are provided in the
following table:
POLYMER SYSTEM COAT LEVEL POLYMER RATIO
Cellulose acetate / PVP 5 - 60% 90/10 to 60/40
Cellulose acetate Butyrate/ PVP 5 - 60% 90/10 to 60/40
Cellulose acetate / HPC 5 - 60% 90/10 to 50/50
Cellulose acetate / HPMCP 5 - 60% 90/10 to 50/50
Cellulose acetate Butryate / HPC 5 - 60% 90/10 to 50/50
Cellulose acetate / EUDRAGIT E100 8 - 60% ALL RATIOS
Cellulose acetate Butryate / EUDRAGIT E 8- 60% ALL RATIOS
100
Ethyl cellulose / PVP 8 - 60% 90/10 to 60/40
Ethyl cellulose / HPC 8 - 60% 90/10 to 50/50
MCP-5014 NP 6
CA 02472432 2004-06-25
Ethyl cellulose / EUDRAGIT E 100 8 - 60% ALL RATIOS
HPC 10-60% NA
HEC 10 - 60% NA
EUDRAGIT E 100 10 - 60% NA
HPMC 10 - 60% NA
HEC / HPMC 10 - 60% ALL RATIOS
HPC / HPMC 10 - 60% ALL RATIOS
HEC / HPC 10-60% ALL RATIOS
2-vinyl pyridine styrene co-polymer 10-60% NA
CA/2-vps 8 - 60% ALL RATIOS
CAB/2-vps 8 - 60% ALL RATIOS
Ethyl cellulose / 2-vps 8 - 60% ALL RATIOS
Cellulose triacetate / PVP 8 - 60% 90/10 to 60/40
Cellulose triacetate / HPC 8 - 60% 90/10 to 50/50
Cellulose triacetate / EUDRAGIT E 100 8 - 60% ALL RATIOS
1 percent by weight of the coated particle in a dried state
2 by weight
PVP = polyvinylpyrrolidone
HPC - hydroxypropyl cellulose
HEC - hydroxylethyl cellulose
HPMC - hydroxypropylmethyl cellulose
CA - cellulose acetate
CAB - cellulose acetate butyrate
2 vps - 2 vinyl pyridine styrene
HPMCP - hypromellose pthalate (also known as hydroxypropylmethyl cellulose)
EUDRAGITT'" E 100 - methylaminoethyl- methacrylate and neutral methacrylic
acid esters
available from Rohm Pharma GmbH, Germany.
The taste masking polymers may also optionally be combined with a surfactant.
Suitable
surfactants include both ionic and non-ionic materials from both synthetic and
natural origins, including
but not limited to lecithin, glyceryl esters, sugar esters, polysorbates, mono
and diglycerides of fatty
acids, propylene glycol esters, sucrose fatty acid esters, polyoxyethylene
derivatives of sorbitan fatty
acid esters, and mixtures thereof. Examples of useful polysorbates include
sorbitan trioleate, sorbitan
monopalmitate, sorbitan monolaurate, propylene glycol monolaurate, glycerol
monostearate, diglycerol
monostearate, glycerol lactyl-palmitate. Lactic acid derivatives include
sodium stearoyl lactylate and
calcium stearoyl lactylate. When a surfactant is present in the taste masking
coating, the level of
MCP-5014 NP 7
CA 02472432 2011-06-10
64160-598
surfactant is present in an amount, based upon the total weight of the taste
masking coating layer,
from about 2% to about 10%.
In one embodiment, the dried taste masking coating comprises about 53 wt %
hydroxypropyl
methylcellulose phthalate ("hypromellose phthalate"), about 43 wt % cellulose
acetate, and about 4 wt
% polysorbate.
The taste masking coating may be coated directly onto the pure active
ingredient core or may
be coated on to a granulated particle core containing the active ingredient,
such that the core is
substantially covered. As used herein, "substantially covered" shall mean at
least about 95%, e.g.
about 99% of the exterior surface of the core is covered with the 'subject
coating.
The taste masking coating is preferably applied to the active ingredient, or a
granulated
particle containing the active ingredient, in the form of a solution using
conventional fluidized bed
technology, such as Wurster coating or rotor coating. These coating operations
are further described
in Leiberman, et al., 3 Pharmaceutical Dosage Forms 138 - 150 (1990),
A wide variety of organic solvents may be used to prepare the solution of the
taste masking
coating. Useful solvents include any of the pharmaceutically suitable organic
solvents such as
acetone, methanol, ethanol, isopropanol; aqueous solvents such as water, and
mixtures thereof.
Generally, the proportion of the taste masking coating in the solvent solution
will be within the range of
about 5 to about 20, e.g. from about 8 to about 15, weight percent, depending
on the solvent and other
similar considerations. One suitable solvent mixture includes acetone and
water at a ratio from about
85:15 to about 95:5.
When a fluidized bed coating operation is used, air, which may be heated,
passes through a
bed of the active ingredient solids to fluidize them, and the solution of the
taste masking composition is
sprayed onto the fluidized bed and thereby coats the active. The air passing
through the bed dried the
coating onto the active ingredient, so that a dry coated granule is obtained.
The thickness of the taste masking coating on the active ingredient-containing
core is typically
from about 1 micron to about 20 microns, e.g. from about 2 microns to about 15
microns or from about
4 to about 9 microns.
Particles coated with a taste masking coating, in a dried state, generally
contain the taste
masking coating in an amount, based upon the total weight of particle and the
taste masking coating,
from about 1 percent to about 50 percent, e.g. from about 15 percent to about
25 percent. The exact
proportions of the coating to the active ingredient can vary depending upon,
for example, the level of
tastemasking required and whether a sustained or immediate release of the
active ingredient is
desired. Increased amounts of the taste masking coating tend to provide a
sustained release effect
and enhanced taste masking.
In embodiments employing a granulated particle, such as a rotogranulated
particle, the active
ingredient will constitute from about 5 to about 90 weight percent of the
particle, with, the remainder
8
CA 02472432 2004-06-25
being the binder or filler. Suitable binders for the granulated particles
include polyvinyl pyrrolidone,
hydroxypropylmethyl cellulose, hydroxypropyl cellulose, and other
pharmaceutically acceptable
polymers. Fillers suitable for use in such granulated particles include
lactose, confectioner's sugar,
mannitol, dextrose, fructose, other pharmaceutically acceptable saccharide and
microcrystalline
cellulose.
According to the dosage form of the present invention, the active ingredient
may be combined
with a matrix comprising a high weight average molecular weight
hydroxyalkylcellulose, wherein the
high weight average molecular weight hydroxyalkylcellulose is present in the
matrix in an amount,
based upon the total weight of the dosage form, from about 0.1 percent to
about 25 percent, e.g. from
about 0.5 percent to about 10 percent. The average particle size of the high
weight average molecular
weight hydroxyalkylcellulose may vary from about 1 micron to about 500
microns, e.g., from about
150 microns to about 400 microns or from about 200 microns to about 300
microns.
For optimal dissolution results, it is preferable to employ such
hydroxyalkylcelluloses that have
average molecular weights in the lower end of the range of "high weight
average molecular weight"
hydroxyalkylcelluloses as defined herein, as well as to employ the lowest
level of such
hydroxyalkylcelluloses that may yield the desired mouthfeel for the selected
active ingredient.
"Hydroxyalkylcellulose," as used herein shall mean cellulose derivatives that
are substituted
with a hydroxyalkyl group, wherein the alkyl group contains from about 1 to
about 10 carbons.
Examples of suitable high molecular weight hydroxyalkylcelluloses include, but
are not limited to,
hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose,
hydroxyethylmethylcellulose,
hydroxypropylmethylcellulose, and the like. In one embodiment, the
hydroxyalkylcellulose is
hydroxypropylcellulose and/or hydroxypropylmethylcellulose.
Examples of suitable hydroxypropylmethylcelluloses include those available
from Dow
Chemical Corporation under the tradenames, "HPMC K4M," "HPMC K15M," and "HPMC
K100M."
Examples of suitable hydroxypropylcelluloses include those available from
Hercules, Inc. under the
tradenames, "Klucel H(CS) and "Klucel M".
The matrix may optionally contain other conventional, pharmaceutically
acceptable auxiliary
ingredients, such as fillers, conventional dry binders, sweeteners,
disintegrants, and lubricants such
as, for example, stearic acid, magnesium stearate, and mixtures thereof.
Suitable fillers include water-disintegratable, compressible carbohydrates
such as, for
example, sugars, sugar alcohols, starch hydrolysates, and mixtures thereof.
Examples of suitable
sugars include, but are not limited to dextrose, sucrose, maltose, and
lactose. Examples of suitable
sugar alcohols include, but are not limited to mannitol, sorbitol, maltitol,
xylitol, and erythritol.
Examples of suitable starch hydrolysates include, but are not limited to,
dextrins and maltodextrins.
In one embodiment, the water-disintegratable, compressible carbohydrate may be
selected
from dextrose monohydrate, mannitol, sorbitol, xylitol, and mixtures thereof.
In embodiments in which
a water-disintegratable compressible carbohydrate is employed as a filler, it
is typically present at a
MCP-5014 NP 9
CA 02472432 2011-06-10
64160-598
level from, based upon the total weight of the dosage form, from about 40 to
about 90 percent, e.g.
from about 50 to about 80 percent.
The matrix may also incorporate pharmaceutically acceptable adjuvants,
including, for
example, preservatives, flavors such as, for example, orange and/or vanilla,
acidulants, glidants,
surfactants, and coloring agents such as, for example, FD&C yellow. However,
the matrix preferably
comprises no more than, based upon the total weight of the dosage form, about
25 weight % of such
optional auxiliary ingredients.
The dosage form may be made in any manner, and for tablet dosage forms, a
variety of
tableting methods are known in the art. Conventional methods for tablet
production include direct
compression ("dry blending"), dry granulation followed by compression, and wet
granulation followed
by drying and compression. Other methods include the use of compacting roller
technology such as a
chilsonator or drop roller, or molding, casting, or extrusion technologies:
All of these methods are well
known in the art, and are described in detail in, for example, Lachman, et
al., The Theory and Practice
of Industrial Pharmacy, Chapter 11, (3d Ed. 1986),.
In the direct compression tableting method, a blend of the active ingredient,
which may
optionally be coated with a tastemasking coating, hydroxyalkylcellulose, and
any other appropriate
optional ingredients are directly compacted. After all ingredients are blended
together, a pre-
determined volume of particles from the blend is filled into a die cavity of a
rotary tablet press, which
continuously rotates as part of a "die table" from the filling position to a
compaction position. The
particles are compacted between an upper punch and a lower punch to an
ejection position, at which
the resulting tablet is pushed from the die cavity by the lower punch and
guided to an ejection chute by
a stationary "take-off bar.
In one embodiment, the tableting method is carried out such that the resulting
tablet is
relatively soft. The hardness of a "soft" tablet produced in accordance with
the present invention is up
to about 15 kiloponds per square centimeter (kp/cm2), i.e., e.g., from about 1
kp/cm2 to 8 kp/cm2 or
from about 2 kp/cmZ to 6 kp/cmZ. Hardness is a term used in the art to
describe the diametrical
breaking strength as measured by conventional pharmaceutical hardness testing
equipment, such as
a Schleuniger Hardness Tester. In order to compare values across differently-
sized tablets, the
breaking strength is normalized for the area of the break (which may be
approximated as tablet
diameter times thickness). This normalized value, expressed in kp/cm2, is
sometimes referred in the
art as "tablet tensile strength. " A general discussion of tablet hardness
testing is found in Leiberman
et al., Pharmaceutical Dosage Forms - Tablets, Volume 2, 2nd ed., Marcel
Dekker Inc., 1990, pp. 213
- 217, 327 - 329.
The tablet of the present invention advantageously has acceptable friability.
Friability levels
are typically less than about 2%, e.g. less than about 1%, or less than about
0.5%. A discussion of
tablet friability is presented in USP 23 (1995) <1216> p. 1981.
The dosage form of the present invention typically has a moisture content of
not more than
CA 02472432 2011-06-10
64160-598
about 5 percent, as measured by weight loss on drying at 105 C in a moisture
analyzer, such as that
available from Arizona Instruments under the tradename, "Computrac Max 2000."
We have unexpectedly found that the addition of high weight average molecular
weight
hydroxyalkylcellulose to the matrix results in a dosage form that delivers a
good mouthfeel through a
rapid viscosity build without an initial intense drying sensation of the mouth
and without a subsequent
excessive slimy or gummy feel during mastication. Although the increase in
viscosity will depend upon
several factors such as, for example, the amount and molecular weight of such
hydroxyalkylcellulose
used and the amount and type of active ingredient, generally the use of about
0.1 percent to about
25.0 percent of a 60,000 to about 5,000,000 MW hydroxyalkylcellulose based
upon the total weight of
the dosage form, will result in a viscosity increase during tablet mastication
that is similar to that
obtained using gums, but without the drying sensation and without the
subsequent excessive slimy or
gummy feel imparted by using conventional agents.
Specific embodiments of the present invention are illustrated by way of the
following
examples. This invention is not confined to the specific limitations set forth
in these examples, but
rather to the scope of the appended claims. Unless otherwise stated, the
percentages and ratios
given below are by weight.
Examples
Example 1: Preparation-of Tastemasking Coating Solution
A coating solution was prepared by dispersing cellulose acetate, hypromellose-
phthalate
(HPMCP-50), and polysorbate-80 in a solvent consisting of 90% acetone and 10%
water under
ambient conditions, so that the finished solution contained 10% of the coating
materials. The relative
amounts of coating materials were, based upon the total weight percent of the
final coating,
Cellulose acetate ........................ 43%
HPMCP-50* ................................53%
Polysorbate-80 ................ 4%
*available from Shin-Etsu, Inc.
Example 2: Preparation of Coated Active Ingredient
Preparation of Ibuprofen Pre-Mixture: Ibuprofen USP powder was combined with
colloidal
silicon dioxide and microcrystalline cellulose to form the following ibuprofen
pre-mixture:
Component Weight Percent*
Colloidal silicon dioxide 0.27%
microcrystalline cellulose ** 1.04%
Ibuprofen USP 98.71%
*based upon total weight of Ibuprofen pre-mixture
* Trade-mark
11
CA 02472432 2011-06-10
64160-598
** available from FMC Biopolymer under the tradename, "Avicel"
Preparation of Granulation solution: A simethicone emulsion available from Dow
Coming
Company under the tradename, " 30% Simethicone Emulsion USP Q7-2587" was added
to an 8%
solids hydroxypropylmethylcellulose aqueous solution under ambient. conditions
to form the following
granulating solution:
Component Weight Percent*
Simethicone emulsion 0.10%
Hydroxypropylmethylcellulose** 7.90%
Water 92.00%
* based upon total weight of granulating solution
** available from the Dow Chemical Company under the tradename, "E 15"
Preparation of Ibuprofen Granules: The ibuprofen mixture was then granulated
to a larger
particle sizes of approximately 206 pm by first spraying the granulating
solution thereon at a rate of
about 1200 g/min under product temperature conditions of about 19 C using a
Model GRG 600
fluid bed granulator available from Glatt, Inc. and then subsequently drying
the sprayed ibuprofen at a
product temperature of 23 C.
The final dried, ibuprofen granules had the following formulation
Component Weight Percent*
Ibuprofen 95.7%
hydroxypropylmethylcellulose. 3.01%
colloidal silicon dioxide 0.25%
microcrystalline cellulose 1.00%
simethicone emulsion 0.04%
The resulting ibuprofen granules were then coated with the taste-masking
solution described
in Example I at a rate of bout 375 g/min in a Wurster fluid bed coating unit
under product temperature
. conditions of about 29 C . The resulting coated ibuprofen granules
contained, based upon the total
dry weight of the ibuprofen granules and the tastemasking coating, about 25%
of the taste-masking
coating.
* Trade-mark
12
CA 02472432 2004-06-25
Example 3: Production of Hvdroxvalkvlcellulose tablet and Mouthfeel Evaluation
Thereof
A batch of tablets having the formulation set forth in Table A below was made
and then taste
tested for mouthfeel and texture during mastication.
Table A
In redient Tradename Supplier Ma/tablet %/batch
Flavor 10.64 1.33
Microcrystalline Cellulose Avicel 40.00 5.00
Mannitol 417.81 52.23
Sucralose McNEIL - 2.64 0.33
PPC, Inc.
Crospovidone - NF Polyplasdone ISP Corp. 8.00 1.00
Colorant 1.36 0.17
72% Coated Ibuprofen 278.55 34.82
Lubricant - magnesium stearate 5.00 0.63
Acidulant - citric acid 4.00 0.50
High MW hydroxypropyl- HPMC K4M Dow 32.00 4.00
methylcellulose Chemical
Corp.
TOTAL 800.00 100.0
= Ibuprofen particle coated with Cellulose acetate/Hydroxypropyl
Methylcellulose
Phthalate/Polysorbate 80 as prepared in accordance with Example 2
Preparation of tablets:
In one container, the colorant, flavor, sucralose NF, acidulant, high
molecular weight
hydroxypropylmethylcellulose) and crospovidone NF were sieved through a 40
mesh screen to form
an excipient blend.
The mannitol was then sieved through a 40 mesh screen and added to the blend.
The coated ibuprofen was then sieved through a 20 mesh screen and added to the
blend.
The resulting blend was then manually blended in a plastic blender until the
mixture was
homogenous.
The lubricant was then sieved through a 40 mesh screen, added to the total
resulting mixture,
and manually blended until the final mixture was homogenous. The final mixture
was then
compressed into 800 mg chewable tablets using 1/2" diameter flat faced tooling
to a thickness of
0.219" inches and a hardness of 5.2 kp. under ambient conditions.
This procedure was repeated, but with the omission of the high molecular
weight
hydroxypropylmethylcellulose ingredient.
Samples of the resulting tablets were evaluated by a laboratory panel in a
blinded study for
grittiness during mastication. The results of the evaluation demonstrated that
the high weight average
MCP-5014 NP 13
CA 02472432 2004-06-25
molecular weight hydroxyalkylcellulose -containing tablets had significantly
less of a grittiness feel in
the mouth in comparison to those tablets lacking the high weight average
molecular weight
hydroxyalkylcellulose.
MCP-5014 NP 14
