U.S. patent application number 10/607766 was filed with the patent office on 2004-12-30 for soft tablet containing high molecular weight cellulosics.
Invention is credited to Parikh, Nick, Wynn, David.
Application Number | 20040265372 10/607766 |
Document ID | / |
Family ID | 33418719 |
Filed Date | 2004-12-30 |
United States Patent
Application |
20040265372 |
Kind Code |
A1 |
Wynn, David ; et
al. |
December 30, 2004 |
Soft tablet containing high molecular weight cellulosics
Abstract
The invention relates to an immediate release tablet capable of
being chewed or disintegrated in the oral cavity, which comprises a
pharmaceutically active ingredient having an optional tastemasking
coating, and a matrix comprising hydroxyalkylcellulose having a
weight average molecular weight of from about 60,000 to about
5,000,000. The tablet possesses exceptionally good mouthfeel and
stability.
Inventors: |
Wynn, David; (Abington,
PA) ; Parikh, Nick; (Long Valley, NJ) |
Correspondence
Address: |
PHILIP S. JOHNSON
JOHNSON & JOHNSON
ONE JOHNSON & JOHNSON PLAZA
NEW BRUNSWICK
NJ
08933-7003
US
|
Family ID: |
33418719 |
Appl. No.: |
10/607766 |
Filed: |
June 27, 2003 |
Current U.S.
Class: |
424/464 ;
514/165; 514/406; 514/629; 514/651 |
Current CPC
Class: |
A61K 9/2054 20130101;
A61P 29/00 20180101; A61K 9/0056 20130101; A61K 9/2081
20130101 |
Class at
Publication: |
424/464 ;
514/165; 514/406; 514/629; 514/651 |
International
Class: |
A61K 031/60; A61K
031/415; A61K 031/16; A61K 009/50; A61K 009/20 |
Claims
We claim:
1. An immediate release dosage form capable of being chewed or
disintegrated in the oral cavity prior to swallowing, comprised 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 a
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.
2. The dosage form of claim 1, wherein the hydroxyalkylcellulose is
a hydroxypropylcellulose having a weight average molecular weight
of from about 140,000 to about 1,150,000.
3. The dosage form of claim 1, wherein the hydroxyalkylcellulose is
a hydroxypropylmethylcellulose having a viscosity of from about
3,000 mPa.S to about 150,000 mPa.s in a 2% aqueous solution.
4. The dosage form of claim 1, wherein the matrix further comprises
a water-disintegratable, compressible carbohydrate selected from
the group consisting of dextrose monohydrate, mannitol, sorbitol,
xylitol, and mixtures thereof.
5. The dosage form of claim 1, wherein the pharmaceutically active
ingredient is 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.
6. The dosage form of claim 1, wherein the pharmaceutically active
ingredient is selected from the group consisting of
pseudoephedrine, phenylpropanolamine, chlorpheniramine,
dextromethorphan, diphenhydramine, astemizole, terfenadine,
fexofenadine, loratadine, cetirizine, mixtures thereof and
pharmaceutically acceptable salts, esters, isomers, and mixtures
thereof.
7. The dosage form of claim 1, wherein the dosage form is a
tablet.
8. The dosage form of claim 1, wherein the dosage form is comprised
of, based upon the total weight of the dosage form, a. from greater
than about 0.25 percent and less than about 70 percent of the
coated particles comprising the pharmaceutically active ingredient,
said coated particles comprising, based upon the total weight of
the coated particles, from greater than about 1 percent and less
than about 50 percent of the taste masking coating; and b. from
greater than about 0.5 percent and less than about 10 percent of
the hydroxyalkylcellulose in the matrix.
9. The dosage form of claim 8, wherein the taste masking coating is
comprised of: a) at least one solubilizable polymer; and b) at
least one insoluble film forming polymer.
10. The dosage form of claim 9, wherein the solubilizable polymer
is selected from the group consisting of enteric polymers, reverse
enteric polymers, water soluble polymers, and mixtures and
copolymers thereof.
11. The dosage form of claim 10, wherein the enteric polymers are
selected from the group consisting of shellac, hydroxypropyl
methylcellulose phthalate, hydroxypropyl methylcellulose acetate
succinate, cellulose acetate phthalate, polyvinylacetate phthalate,
polymethacrylate-based polymers and mixtures and copolymers
thereof.
12. The dosage form of claim 10, wherein the enteric polymers are
selected from the group consisting of hydroxypropyl methylcellulose
phthalate, hydroxypropyl methylcellulose acetate succinate,
cellulose acetate phthalate, polyvinylacetate phthalate, and
mixtures thereof.
13. The dosage form of claim 10, wherein the reverse enteric
polymers are methylaminoethyl-methacrylate and/or neutral
methacrylic acid esters.
14. The dosage form of claim 10, wherein the water soluble polymers
are selected from the group consisting of
hydroxypropylmethylcellulose, hydroxypropylcellulose,
hydroxyethylcellulose, methylcellulose, polyvinyl pyrrolidone,
polyethylene glycol, polyvinyl alcohols, sodium
carboxymethylcellulose, and mixtures thereof.
15. The dosage form of claim 10 wherein the insoluble polymers are
selected from the group consisting of cellulose acetate, cellulose
acetate butyrate, cellulose triacetate, ethylcellulose, neutral
ester co-polymer of ethyl acylate and methyl methacrylate,
poly(ethyl acrylate, methyl methacrylate, trimethylammonioethyl
methacrylate chloride) in a ratio of 1:2:0.1, and mixtures and
copolymers thereof.
16. The dosage form of claim 9, wherein the taste masking coating
is comprised of: a. a first polymer selected from the group
consisting of cellulose acetate and/or cellulose acetate butyrate;
and b. a second polymer selected from the group consisting of
enteric polymers, reverse enteric polymers, water soluble polymers,
and mixtures and copolymers thereof, wherein the weight ratio of
the second polymer to the first polymer is within the range of
about 5:95 to about 80:20.
17. The dosage form of claim 9, wherein the hydroxyalkylcellulose
is selected from the group consisting of hydroxymethylcellulose,
hydroxyethylcellulose, hydroxypropylcellulose,
hydroxyethylmethylcellulos- e, hydroxypropylmethylcellulose, and
mixtures thereof.
18. The dosage form of claim 9, wherein the hydroxyalkylcellulose
is hydroxypropylcellulose and/or hydroxypropylmethylcellulose.
19. The dosage form of claim 9, wherein the dosage form is a tablet
of manufactured by a direct compression or dry granulation
process.
20. The dosage form of claim 9, wherein said dosage form meets USP
dissolution requirements for immediate release forms of said
pharmaceutically active ingredient.
21. The dosage form of claim 9, which has a moisture content of not
more than about 5 percent as measured by weight loss on drying at
105 degrees Celsius.
22. 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.
23. The immediate release dosage form of claim 22, wherein the
matrix further comprises a water-disintegratable, compressible
carbohydrate selected from the group consisting of dextrose
monohydrate, mannitol, sorbitol, xylitol, and mixtures thereof.
Description
BACKGROUND OF THE INVENTION
[0001] 1. Field of the Invention
[0002] 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.
[0003] 2. Background of the Invention
[0004] 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.
[0005] 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., U.S. Pat. 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.
[0006] Alternative texture masking agents include polyalkylene
glycols. For instance, U.S. Pat. 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.
[0007] 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.
[0008] U.S. Pat. No. 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 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.
[0009] 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
[0010] This invention relates to 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
[0011] a. a plurality of particles comprising a pharmaceutically
active ingredient, said particles having a particle size of about
150 .mu.m to about 400 .mu.m; and
[0012] 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.
[0013] This invention further relates to 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
[0014] a. a plurality of particles comprising a pharmaceutically
active ingredient; and
[0015] 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,
[0016] wherein the pharmaceutically active ingredient is coated
with a taste masking coating.
DETAILED DESCRIPTION OF THE INVENTION
[0017] 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, 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 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.
[0018] 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.
[0019] 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/orb) 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.
[0020] 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.
[0021] 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.
[0022] 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
relaxants, osteoporosis preparations, polydimethylsiloxanes,
respiratory agents, sleep aids, urinary tract agents and mixtures
thereof.
[0023] 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 clarithromycin, amoxicillin,
tetracycline, and metronidazole; antidiarrheals, such as
diphenoxylate and loperamide; glycopyrrolate; antiemetics, such as
ondansetron, analgesics, such as mesalamine.
[0024] 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.
[0025] 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.
[0026] 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.
[0027] Examples of suitable polydimethylsiloxanes, which include,
but are not limited to dimethicone and simethicone, are those
disclosed in U.S. Pat. Nos. 4,906,478, 5,275,822, and 6,103,260,
the contents of each is expressly incorporated herein by reference.
As used herein, the term "simethicone" refers to the broader class
of polydimethylsiloxanes, including but not limited to simethicone
and dimethicone.
[0028] 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.
[0029] 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.
[0030] 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 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.
[0031] 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 masked
active ingredients may also be employed.
[0032] Suitable taste masking coatings are described in, for
example, U.S. Pat. Nos. 6,471,991, 4,851,226, 5,075,114, and
5,489,436, which are all incorporated by reference herein.
[0033] 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 methylcelluiose,
hydroxypropyl cellulose, hydroxyethyl cellulose, and mixtures
thereof.
[0034] 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).
[0035] 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 Pharma GmbH under the tradename,
"EUDRAGIT L" polymers. Combinations of enteric polymers may also be
used.
[0036] 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.
[0037] 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, "EUDRAGIT.TM. 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.
[0038] 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.
[0039] 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.
[0040] Other examples of suitable taste masking coatings are
provided in the following table:
1 COAT POLYMER POLYMER SYSTEM LEVEL.sup.1 RATIO.sup.2 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 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
.sup.1percent by weight of the coated particle in a dried state
.sup.2by 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) EUDRAGIT .TM. E 100 -
methylaminoethyl-methacrylate and neutral methacrylic acid esters
available from Rohm Pharma GmbH, Germany.
[0041] 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
surfactant is present in an amount, based upon the total weight of
the taste masking coating layer, from about 2% to about 10%.
[0042] 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.
[0043] 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.
[0044] 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), which is hereby
incorporated by reference.
[0045] 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.
[0046] 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.
[0047] 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.
[0048] 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.
[0049] 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 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.
[0050] 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.
[0051] 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.
[0052] "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.
[0053] 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.RTM. H(CS) and "Klucel.RTM. M".
[0054] 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.
[0055] 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.
[0056] 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 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.
[0057] 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.
[0058] 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, (3.sup.rd Ed. 1986), which is incorporated by reference
herein.
[0059] 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.
[0060] 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/cm.sup.2), i.e.,
e.g., from about 1 kp/cm.sup.2 to 8 kp/cm.sup.2 or from about 2
kp/cm.sup.2 to 6 kp/cm.sup.2. 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/cm.sup.2,
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, 2.sup.nd
ed., Marcel Dekker Inc., 1990, pp. 213-217, 327-329, which is
incorporated by reference herein.
[0061] 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.
[0062] The dosage form of the present invention typically has a
moisture content of not more than about 5 percent, as measured by
weight loss on drying at 105.degree. C. in a moisture analyzer,
such as that available from Arizona Instruments under the
tradename, "Computrac Max 2000."
[0063] 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.
[0064] 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
[0065] 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,
[0066] Cellulose acetate . . . 43%
[0067] HPMCP-50* . . . 53%
[0068] Polysorbate-80 . . . 4%
[0069] *available from Shin-Etsu, Inc.
Example 2
Preparation of Coated Active Ingredient
[0070] Preparation of Ibuprofen Pre-Mixture: Ibuprofen USP powder
was combined with colloidal silicon dioxide and microcrystalline
cellulose to form the following ibuprofen pre-mixture:
2 Component Weight Percent* Colloidal silicon dioxide 0.27%
microcrystalline cellulose** 1.04% Ibuprofen USP 98.71% *based upon
total weight of Ibuprofen pre-mixture **available from FMC
Biopolymer under the tradename, "Avicel"
[0071] Preparation of Granulation solution: A simethicone emulsion
available from Dow Corning Company under the tradename, "30%
Simethicone Emulsion USP Q7-2587" was added to an 8% solids
hydroxypropylmethylcellul- ose aqueous solution under ambient
conditions to form the following granulating solution:
3 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"
[0072] Preparation of Ibuprofen Granules: The ibuprofen mixture was
then granulated to a larger particle sizes of approximately 206
.mu.m by first spraying the granulating solution thereon at a rate
of about 1200 g/min under product temperature conditions of about
19.degree. 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.degree. C.
[0073] The final dried, ibuprofen granules had the following
formulation
4 Component Weight Percent* Ibuprofen 95.7%
hydroxypropylmethylcellulose 3.01% colloidal silicon dioxide 0.25%
microcrystalline cellulose 1.00% simethicone emulsion 0.04%
[0074] The resulting ibuprofen granules were then coated with the
taste-masking solution described in Example 1 at a rate of bout 375
g/min in a Wurster fluid bed coating unit under product temperature
conditions of about 29.degree. 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.
Example 3
Production of Hydroxyalkylcellulose Tablet and Mouthfeel Evaluation
Thereof
[0075] 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.
5TABLE A Mg/ Ingredient Tradename Supplier 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 5.00 0.63 stearate
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
[0076] Preparation of Tablets:
[0077] 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.
[0078] The mannitol was then sieved through a 40 mesh screen and
added to the blend.
[0079] The coated ibuprofen was then sieved through a 20 mesh
screen and added to the blend.
[0080] The resulting blend was then manually blended in a plastic
blender until the mixture was homogenous.
[0081] 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.
[0082] This procedure was repeated, but with the omission of the
high molecular weight hydroxypropylmethylcellulose ingredient.
[0083] 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 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.
* * * * *