U.S. patent application number 11/239974 was filed with the patent office on 2007-04-05 for oral compositions containing a salivation inducing agent.
Invention is credited to Ronni Robinson, David W. Wynn.
Application Number | 20070077300 11/239974 |
Document ID | / |
Family ID | 37902197 |
Filed Date | 2007-04-05 |
United States Patent
Application |
20070077300 |
Kind Code |
A1 |
Wynn; David W. ; et
al. |
April 5, 2007 |
Oral compositions containing a salivation inducing agent
Abstract
Oral dosage forms, and particles used therein, containing
salivation inducing agents are disclosed. The salivation agents may
be in the core of the dosage form and/or in coatings applied
thereto, or alternatively may be within particles and/or the matrix
of such dosage forms, in coatings applied to such particles, or on
the surface of such coated particles. The particles may be produced
into a tablet form, such as a chewable tablet form, that provides
for the immediate release of the active ingredient. Other oral
dosage forms include thin film strips, gummi, foam tabs, and
lozenges.
Inventors: |
Wynn; David W.; (Huntingdon
Valley, PA) ; Robinson; Ronni; (Ambler, PA) |
Correspondence
Address: |
PHILIP S. JOHNSON;JOHNSON & JOHNSON
ONE JOHNSON & JOHNSON PLAZA
NEW BRUNSWICK
NJ
08933-7003
US
|
Family ID: |
37902197 |
Appl. No.: |
11/239974 |
Filed: |
September 30, 2005 |
Current U.S.
Class: |
424/472 ;
424/773; 514/278; 514/397; 514/650 |
Current CPC
Class: |
A61K 9/0056 20130101;
A61K 9/2886 20130101; A61K 36/28 20130101; A61P 29/00 20180101;
A61K 31/4178 20130101; A61K 9/2068 20130101; A61K 9/7007 20130101;
A61K 9/2081 20130101; A61K 9/282 20130101; Y10S 514/96 20130101;
A61K 9/5078 20130101; A61K 31/4747 20130101; A61K 31/167 20130101;
Y10S 514/974 20130101; A61K 36/28 20130101; A61K 2300/00
20130101 |
Class at
Publication: |
424/472 ;
424/773; 514/278; 514/397; 514/650 |
International
Class: |
A61K 36/28 20060101
A61K036/28; A61K 31/4747 20060101 A61K031/4747; A61K 31/4178
20060101 A61K031/4178; A61K 31/137 20060101 A61K031/137; A61K 9/24
20060101 A61K009/24 |
Claims
1. An oral dosage form comprised of: a) a core; and b) a coating
substantially covering the core, wherein the coating contains,
based upon the total dry weight of the dosage form, from about 0.1
percent to about 10 percent of at least one salivation inducing
agent.
2. The oral dosage form of claim 1, wherein the salivation inducing
agent is selected from the group consisting of tasteless muscarinic
acetylcholine receptor agonists; N,N-disubstituted
phenylalkylamines wherein the alkyl has from about 1 to about 8
carbons; spirooxathiolane-quinuclidine; Heliopsis longpipes root;
cholinesterase inhibitors; and mixtures thereof.
3. The oral dosage form of claim 1, wherein the salivation inducing
agent is selected from the group consisting of pilocarpine;
N,N-disubstituted-2-phenylcyclopropylamines;
spirooxathiolane-quinuclidine; Heliopsis longpipes root;
cholinesterase inhibitors; and mixtures thereof.
4. The oral dosage form of claim 1 wherein the salivation inducing
agent has a salivation-inducing value of at least about 12%.
5. The oral dosage form of claim 1, wherein the active ingredient
is a nonsteroidal anti-inflammatory drug, acetaminophen,
pseudoephedrine, phenylpropanolamine, chlorpheniramine,
dextromethorphan, diphenhydramine, dimenhydrinate, meclizine,
famotidine, loperamide, ranitidine, cimetidine, astemizole,
loratadine, desloratadine, fexofenadine, cetirizine, antacids,
oxybutynin, methylphenidate, pharmaceutically acceptable salts
thereof, metabolites thereof, and mixtures thereof.
6. The oral dosage form of claim 1 which meets the USP dissolution
specification for immediate release tablets containing the
particular active ingredient.
7. A particle comprising, based upon the total dry weight of the
particle: a) a core containing an active ingredient; and b) a
texture masking coating layer substantially covering the core, and
c) from about 0.1% to about 25% of a salivation inducing agent
layer substantially covering the texture masking coating layer.
8. The particle of claim 7, wherein the salivation inducing agent
is selected from the group consisting of tasteless muscarinic
acetylcholine receptor agonists; N,N-disubstituted
phenylalkylamines wherein the alkyl has from about 1 to about 8
carbons; spirooxathiolane-quinnuclidine; Heliopsis longpipes root;
cholinesterase inhibitors; and mixtures thereof.
9. The particle of claim 8, wherein the salivation inducing agent
is pilocarpine; N,N-disubstituted-2-phenylcyclopropylamines;
spirooxathiolane-quinuclidine; Heliopsis longpipes root;
cholinesterase inhibitors; and mixtures thereof.
10. The particle of claim 7 wherein the salivation inducing agent
has a salivation-inducing value of at least about 12%.
11. The particle of claim 7, wherein the active ingredient is a
nonsteroidal anti-inflammatory drug, acetaminophen,
pseudoephedrine, phenylpropanolamine, chlorpheniramine,
dextromethorphan, diphenhydramine, dimenhydrinate, meclizine,
famotidine, loperamide, ranitidine, cimetidine, astemizole,
loratadine, desloratadine, fexofenadine, cetirizine, antacids,
oxybutynin, methylphenidate, pharmaceutically acceptable salts
thereof, metabolites thereof, and mixtures thereof.
12. The particle of claim 7, wherein the particle meets the USP
dissolution specification for immediate release tablets containing
the particular active ingredient.
13. A chewable tablet comprised of the particles of claim 7.
14. An oral dosage form comprised of, based upon the total dry
weight of the dosage form, from about 0.1% to about 10% of a
salivation inducing agent, wherein the dosage form is selected from
the group consisting of a chewable tablet, thin film strip, foam
tab, and gummi.
15. The oral dosage form of claim 14, wherein the salivation
inducing agent is selected from the group consisting of tasteless
muscarinic acetylcholine receptor agonists; N,N-disubstituted
phenylalkylamines wherein the alkyl has from about 1 to about 8
carbons; spirooxathiolane-quinnuclidine; Heliopsis longpipes root;
cholinesterase inhibitors; and mixtures thereof.
16. The oral dosage form of claim 15, wherein the salivation
inducing agent is selected from the group consisting of
pilocarpine; N,N-disubstituted-2-phenylcyclopropylamines;
spirooxathiolane-quinuclidine; Heliopsis longpipes root;
cholinesterase inhibitors; and mixtures thereof.
17. The oral dosage form of claim 14 wherein the salivation
inducing agent has a salivation-inducing value of at least about
12%.
18. The oral dosage form of claim 14, wherein the active ingredient
is a nonsteroidal anti-inflammatory drug, acetaminophen,
pseudoephedrine, phenylpropanolamine, chlorpheniramine,
dextromethorphan, diphenhydramine, dimenhydrinate, meclizine,
famotidine, loperamide, ranitidine, cimetidine, astemizole,
loratadine, desloratadine, fexofenadine, cetirizine, antacids,
oxybutynin, methylphenidate, pharmaceutically acceptable salts
thereof, metabolites thereof, and mixtures thereof.
19. The oral dosage form of claim 14, wherein the dosage form meets
the USP dissolution specification for immediate release tablets
containing the particular active ingredient.
20. A particle comprising, based upon the total dry weight of the
particle: a) a core containing an active ingredient; and b) a
coating substantially covering the core, said coating comprised of
from about 0.1% to about 25% of a salivation inducing agent.
21. The particle of claim 20, wherein the salivation inducing agent
is selected from the group consisting of tasteless muscarinic
acetylcholine receptor agonists; N,N-disubstituted
phenylalkylamines wherein the alkyl has from about 1 to about 8
carbons; spirooxathiolane-quinnuclidine; Heliopsis longpipes root;
cholinesterase inhibitors; and mixtures thereof.
22. The particle of claim 21, wherein the salivation inducing agent
is selected from the group consisting of pilocarpine;
N,N-disubstituted-2-phenylcyclopropylamines;
spirooxathiolane-quinuclidine; Heliopsis longpipes root;
cholinesterase inhibitors; and mixtures thereof.
23. The particle of claim 20, wherein the active ingredient is a
nonsteroidal anti-inflammatory drug, acetaminophen,
pseudoephedrine, phenylpropanolamine, chlorpheniramine,
dextromethorphan, diphenhydramine, dimenhydrinate, meclizine,
famotidine, loperamide, ranitidine, cimetidine, astemizole,
loratadine, desloratadine, fexofenadine, cetirizine, antacids,
oxybutynin, methylphenidate, pharmaceutically acceptable salts
thereof, metabolites thereof, and mixtures thereof.
24. A chewable tablet comprised of the particles of claim 20.
Description
FIELD OF THE INVENTION
[0001] This invention relates to oral compositions containing an
active ingredient and a salivation inducing agent. These
compositions may be used to make dosage forms that conveniently may
be administered without water.
BACKGROUND OF THE INVENTION
[0002] Pharmaceuticals intended for oral administration are
typically provided in solid form as tablets, capsules, pills,
lozenges, or granules. Tablets are swallowed whole, chewed in the
mouth, or dissolved in the oral cavity. Chewable tablets are
typically made from a mixture including active drug particles, and
other inactive ingredients (excipients), and are often employed for
the administration of pharmaceuticals where it is impractical to
provide a tablet for swallowing whole. With chewable tablets, the
act of chewing helps to break up the tablet particles as the tablet
disintegrates and may increase the rate of absorption by the
digestive tract. Chewable tablets are often utilized to improve
drug administration in pediatric and geriatric patients.
[0003] Various attempts have been made to enhance the texture of
drug particles in order to prevent their adhesion to the oral
mucosa upon ingestion. For example, WO88/06893 discloses an oral
composition comprised of an active substance and a gelling or
swelling agent capable of forming a viscous medium around the
particles in an aqueous carrier. Disadvantageously, such
compositions must be disintegrated in water to form a liquid
suspension before ingestion for purposes of facilitating the ease
of quickly swallowing the composition without chewing. U.S. Pat.
No. 6,709,678 has overcome the need to suspend the formulation in
an aqueous vehicle before administration by coating its particles
with a hydratable polymer and a salivation-promoting agent.
[0004] It would be desirable to have an oral dosage form that
effectively increases saliva production during ingestion, which
thereby obviates the need for consumption with water and thereby
improves the swallowability of such dosage forms.
SUMMARY OF THE INVENTION
[0005] The present invention provides for pharmaceutical
compositions as disclosed in the claims.
[0006] In accordance with this invention, various forms of
pharmaceutical formulations having an immediate release profile may
be made using a salivation inducing agent. The initiation of an
increased amount of saliva not only facilitates the swallowing of
the dosage form, but it also provides for convenient ingestion
without the need for water.
DETAILED DESCRIPTION OF THE INVENTION
[0007] It is believed that one skilled in the art can, based upon
the description herein, utilize the present invention to its
fullest extent. The following specific embodiments are to be
construed as merely illustrative, and not limitative of the
remainder of the disclosure in any way whatsoever.
[0008] Unless defined otherwise, all technical and scientific terms
used herein have the same meaning as commonly understood by one of
ordinary skill in the art to which the invention belongs. Also, all
publications, patent applications, patents, and other references
mentioned herein are incorporated by reference. As used herein, all
percentages are by weight unless otherwise specified.
[0009] Unless defined otherwise, all ranges provided herein also
explicitly include all range combinations that may be formed by all
numbers within the endpoints of the range.
[0010] As used herein, "injection molding" shall mean a process of
forming a dosage form in a desired shape and size wherein a
flowable material, which is in a fluid or flowable state form,
enters a mold, then is solidified in the mold via a change in
temperature (either positive or negative) before being removed
therefrom. By contrast, "compression," as used herein, shall mean a
process of forming a dosage form in a desired shape and size
wherein a material is compacted into a tablet between the surfaces
of punches via an increase in pressure before being removed
therefrom.
[0011] As used herein, an "exterior surface" of a portion is a
surface that comprises part of the exterior surface of the finished
dosage form.
[0012] As used herein, the term "substantially covers" or
"substantially continuous" means that the coating is generally
continuous and generally covers the entire surface of the core or
underlying layer, so that little to none of the active ingredient
or underlying layer is exposed.
[0013] As used herein, the term "salivation inducing agent" shall
mean a tasteless compound that has a salivation-inducing value of
at least about 10%, e.g. at least about 12% or at least about 16%
or at least about 18%, and which substantially excludes the
following water soluble components: a) water-soluble acids such as
tartaric acid, citric acid, malic acid, fumaric acid, and ascorbic
acid; b) water-soluble salts such as sodium or potassium chloride,
sodium or potassium hydrogen tartarate, sodium hydrogen citrate or
sodium ascorbate; and c) water-soluble substances having an osmotic
action such as glucose, fructose, sucrose, xylitol, mannitol;
sorbitol, maltitol and mixtures thereof. By "substantially
excludes," it means that the resulting formulation contains less
than about 0.1 percent, e.g. less than about 0.5 percent or less
than about 0.01 percent or less than 0.001 percent of such water
soluble components.
[0014] Examples of suitable salivation inducing agents include, but
are not limited to, those tasteless muscarinic acetylcholine
receptor agonists such as pilocarpine and the compound that is
commercially available from IFF under the tradename, "SN12011;"
sigma sigma binders such as arylalkylamines wherein the alkyl group
has from about 1 to about 8 carbons, i.e., e.g., N,N-disubstituted
phenylalkylamines wherein the alkyl has from about 1 to about 8
carbons and N,N disubstituted-2-phenylcyclopropylamines;
spirooxathiolane-quinnuclidine; Heliopsis longpipes root;
cholinesterase inhibitors; and mixtures thereof.
[0015] As used herein, "tasteless" shall mean the substantial
absent of or not substantially contributing to a sense of flavor,
sweetness, saltiness, bitterness or sourness.
[0016] As used herein, "salivation inducing value" is the amount of
additional saliva, expressed in percentage terms, secreted in the
mouth of a user who consumes a dosage form containing a compound
that may be a salivation inducing agent in accordance with the test
method set forth in Example 3, relative to the amount of saliva
secreted in the mouth of a user who similarly consumes a tablet
containing the same ingredients but without that compound, after a
period of about 30 seconds, e.g. after about 1 minute or about 3
minutes or about 5 minutes, after either swallowing the tablet or
removing the tablet from the user's mouth.
[0017] As used herein, "sweetness index" is a term used to describe
the level of sweetness of the dosage form relative to sucrose.
Sucrose, defined as the standard, has a sweetness index of 1. For
example, the sweetness indices of several known sweetener compounds
are listed below: TABLE-US-00001 Sorbitol 0.54-0.7 Dextrose 0.6
Mannitol 0.7 Sucrose 1.0 High Fructose Corn Syrup 55% 1.0 Xylitol
1.0 Fructose 1.2-1.7 Cyclamate 30 Aspartame 180 Acesulfame K 200
Saccharin 300 Sucralose 600 Talin 2000-3000
[0018] In one embodiment, the dosage form of the present invention
may be provided with a sweetness index less than about 0.6. The
addition of sweetening agent may increase the sweetness of the
dosage form to at least about 0.9, e.g. at least about 1.0, say at
least about 1.5, or at least about 2.0.
[0019] As used herein, the term "dosage form" applies to any
ingestible forms that are designed to be chewed or remain in the
mouth of a user, as opposed to those forms that are designed to be
immediately swallowed upon ingestion. Examples of suitable
ingestible forms include, but are not limited to solid, dosage
forms having a liquid, powder or solid core; chewable or oral
disintegrating tablets; thin strips; gummi tablets; foam tablet;
and coated particles having the salivation inducing agent in the
coating and/or granulation matrix. In one embodiment, dosage forms
are solid, semi-solid, or liquid compositions designed to contain a
specific pre-determined amount (i.e. dose) of a certain ingredient,
for example an active ingredient as defined below. Suitable dosage
forms may be pharmaceutical drug delivery systems, including those
for oral administration, buccal administration, or mucosal
delivery; or compositions for delivering minerals, vitamins and
other nutraceuticals, oral care agents, flavorants, and the like.
In one embodiment, the dosage forms of the present invention may be
considered to be solid; however, they may contain liquid or
semi-solid components. In another embodiment, the dosage form is an
orally administered system for delivering a pharmaceutical active
ingredient to the gastro-intestinal tract of a human. In yet
another embodiment, the dosage form is an orally administered
"placebo" system containing pharmaceutically inactive ingredients,
and the dosage form is designed to have the same appearance as a
particular pharmaceutically active dosage form, such as may be used
for control purposes in clinical studies to test, for example, the
safety and efficacy of a particular pharmaceutically active
ingredient. "Active ingredients," as used herein, includes, for
example, pharmaceuticals, minerals, vitamins and other
nutraceuticals, oral care agents, flavorants 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. Suitable oral care agents include breath fresheners, tooth
whiteners, antimicrobial agents, tooth mineralizers, tooth decay
inhibitors, topical anesthetics, mucoprotectants, and the like.
Suitable flavorants include menthol, peppermint, mint flavors,
fruit flavors, chocolate, vanilla, bubblegum flavors, coffee
flavors, liqueur flavors and combinations and the like. Examples of
suitable gastrointestinal agents include antacids such as calcium
carbonate, magnesium hydroxide, magnesium oxide, magnesium
carbonate, aluminum hydroxide, sodium bicarbonate,
dihydroxyaluminum sodium carbonate; 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, nizatidine; proton pump inhibitors such as omeprazole
or lansoprazole; 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. In one embodiment
of the invention, the active ingredient 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 ingredient may
be selected from analgesics, anti-inflammatories, and antipyretics:
e.g. non-steroidal anti-inflammatory drugs (NSAIDs), including
propionic acid derivatives: e.g. ibuprofen, naproxen, ketoprofen
and the like; acetic acid derivatives: e.g. indomethacin,
diclofenac, sulindac, tolmetin, and the like; fenamic acid
derivatives: e.g. mefanamic acid, meclofenamic acid, flufenamic
acid, and the like; biphenylcarbodylic acid derivatives: e.g.
diflunisal, flufenisal, and the like; and oxicams: e.g. piroxicam,
sudoxicam, isoxicam, meloxicam, and the like. In one embodiment,
the active ingredient is selected from propionic acid derivative
NSAID: e.g. ibuprofen, naproxen, flurbiprofen, fenbufen,
fenoprofen, indoprofen, ketoprofen, fluprofen, pirprofen,
carprofen, oxaprozin, pranoprofen, suprofen, and pharmaceutically
acceptable salts, derivatives, and combinations thereof. In another
embodiment of the invention, the active ingredient 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.
[0020] In another embodiment of the invention, the active
ingredient may be selected from pseudoephedrine, phenylepherine,
phenylpropanolamine, chlorpheniramine, dextromethorphan,
diphenhydramine, guaifenesin, astemizole, terfenadine,
fexofenadine, loratadine, desloratidine, doxilamine, norastemizole,
cetirizine, benzocaine, mixtures thereof and pharmaceutically
acceptable salts, esters, isomers, and mixtures thereof.
[0021] In another embodiment, the active ingredient may be
methylphenidate, modafinil and other active agents suitable for
attention deficit hyperactivity disorder or attention deficit
disorder; oxybutynin; sidenefil; and cyclobenzaprine.
[0022] 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.
[0023] The active ingredient or ingredients are present in the
dosage forms of the present invention 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,
the particular active ingredient being administered, the
bioavailability characteristics of the active ingredient, the
dosing regimen, the age and weight of the patient, and other
factors must be considered, as known in the art. In one embodiment,
the dosage form comprises at least about 85 weight percent of the
active ingredient. The active ingredient or ingredients may be
present in the dosage form in any form. For example, the active
ingredient may be dispersed at the molecular level, e.g. melted or
dissolved, within the dosage form, or may be in the form of
particles, which in turn may be coated or uncoated. If the active
ingredient is in form of particles, the particles (whether coated
or uncoated) typically have an average particle size of about 1
micron to about 2000 microns. In one embodiment, such particles are
crystals having an average particle size of about 1 micron to about
300 microns. In yet another embodiment, the particles are granules
or pellets having an average particle size of about 50 microns to
about 2000 microns, e.g. from about 50 microns to about 1000
microns or from about 100 microns to about 800 microns.
[0024] In certain embodiments in which modified release of the
active ingredient is desired, the active ingredient may optionally
be coated with a known release-modifying coating. This
advantageously provides an additional tool for modifying the
release profile of active ingredient from the dosage form. For
example, the dosage form may contain coated particles of one or
more active ingredients, in which the particle coating confers a
release modifying function, as is well known in the art. Examples
of suitable release modifying coatings for particles are described
in U.S. Pat. Nos. 4,173,626; 4,863,742; 4,980,170; 4,984,240;
5,286,497; 5,912,013; 6,270,805; and 6,322,819. Commercially
available modified release active ingredients may also be employed.
For example, acetaminophen particles, which are encapsulated with
release-modifying polymers by a coaccervation process, may be used
in the present invention. Such coaccervation-encapsulated
acetaminophen is commercially available from, for example, Eurand
America, Inc. or Circa Inc.
[0025] If the active ingredient has an objectionable taste, and the
dosage form is intended to be chewed or disintegrated in the mouth
prior to swallowing, the active ingredient may be coated with a
taste masking coating, as known in the art. Examples of suitable
taste masking coatings are described in, for example, U.S. Pat.
Nos. 4,851,226; 5,075,114; and 5,489,436. Suitable processes for
applying taste-masked coatings to dosage forms are known in the
art, and include but are not limited to, fluid bed coating,
coaccervation, complex coaccervation, spray drying and spray
congealing. Commercially available taste masked active ingredients
may also be employed. For example, acetaminophen particles, which
are encapsulated with ethylcellulose or other polymers by a
coaccervation process, may be used in the present invention. Such
coaccervation-encapsulated acetaminophen is commercially available
from Eurand America, Inc. or Circa Inc.
[0026] The active ingredient or ingredients are typically capable
of dissolution upon contact with a fluid such as water, stomach
acid, intestinal fluid or the like. In one embodiment, the
dissolution characteristics of the active ingredient meet USP
specifications for immediate release tablets containing the active
ingredient. In embodiments in which it is desired for the active
ingredient to be absorbed into the systemic circulation of an
animal, the active ingredient or ingredients should be capable of
dissolution upon contact with a fluid such as water, gastric fluid,
intestinal fluid or the like. In one embodiment, the dissolution
characteristics of the active ingredient meet USP specifications
for immediate release tablets containing the active ingredient. 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). In another embodiment, the dissolution characteristics
of the active ingredient may be modified: e.g. controlled,
sustained, extended, retarded, prolonged, or delayed.
[0027] The location of the salivation agent within the dosage form
is not critical, and will depend upon, for example, the type of
dosage form selected, active agent selected, processing steps
desired, and the like. For example, the salivation agent may be in
the core of a dosage form or in one or more coatings applied to the
core of the dosage form. In another embodiment, the salivation
agent may be in coatings for active ingredient granules and/or in
the granulation matrix therefor, which are then compacted or
extruded to yield a dosage form.
[0028] In addition to the active ingredient and the salivation
inducing agent, the dosage form may contain other optional
ingredients including, but are not limited to fillers, including
water soluble compressible carbohydrates such as sucrose, mannitol,
sorbitol, maltitol, xylitol, erythritol, lactose, isomalt,
lactitiol, dextrose, polydextrose, dextrose monohydrate, fructose,
maltose and mixtures thereof; conventional dry binders including
cellulose, cellulosic derivatives, polyvinyl pyrrolidone, starch,
modified starch, maltodextrin, and mixtures thereof, and in
particular microcrystalline cellulose, maltodextrin, and starch;
sweeteners including aspartame, acesulfame potassium, sucralose and
saccharin; disintegrants such as microcrystalline cellulose,
starch, sodium starch glycolate, crosslinked polyvinylpyrrolidone,
crosslinked carboxymethylcellulose; preservatives, flavors,
acidulants, antioxidants, glidants, surfactants, and coloring
agents.
[0029] The dosage forms of the present invention may be made by any
means known in the art. For example, 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. In embodiments wherein the
tablets are formed by the direct compression method, the desired
blend of active ingredients, salivation inducing agent, and
optional ingredients are blended, then a pre-determined volume of
particles 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.
[0030] One embodiment of the present invention is directed to a
dosage form having a core substantially covered with a coating,
wherein the coating is comprised of, based upon the total weight of
the coating, from about 0.01 percent to about 15 percent, for
example, from about 0.1 percent to about 5 percent of a salivation
inducing agent. Suitable ingredients for coatings and methods for
applying such coatings to tablet cores, such as, for example, via
dip coating, spray coating, or injection molding, are known in the
art and disclosed in, for example, United States Publication Nos.
20030072729, 0072731, and 0070584; and U.S. Pat. Nos. 4,820,524,
5,228,916; and 6,837,696.
[0031] Another embodiment of the present invention is directed to a
chewable dosage form having particles of active agents that are
optionally covered with a taste masking and/or texture masking
coating. Examples of suitable taste masking and/or texture masking
agents are known in the art and disclosed in, for example, U.S.
Pat. No. 4,851,226, U.S. Pat. No. 5,260,072 and U.S. Pat. No.
5,075,114. In this embodiment, the salivation inducing agent may be
present in the matrix in an amount, based upon the total dry weight
of the dosage form, from about 0.01 percent to about 10 percent,
e.g., from about 0.05 percent to about 5 percent. The salivation
inducing agent may also be within the granulated active agent
particle, and/or within the coating applied to the particles in an
amount, based upon the total dry weight of the coated particle,
from about 0.1 percent to about 25 percent, e.g., from about 0.1
percent to about 15 percent. In embodiments wherein the salivation
inducing agent is applied to a particle of an active ingredient
that has been previously coated with an initial coating taste
masking and/or texture masking coating, the dosage form contains,
based upon the total dry weight of the particle coated with an
initial coating as well as a salivation inducing agent coating,
from about 0.1 percent to about 25 percent, e.g., from about 0.1
percent to about 15 percent of a salivation inducing agent.
Suitable additional ingredients for chewable dosage forms and
methods for their manufacture are well known in the art and
disclosed in, for example, U.S. Pat. No. 6,277,409, U.S. Pat. No.
6,270,790, and U.S. Pat. No. 6,258,381. For example, the chewable
dosage form may contain an active ingredient, a salivation inducing
agent, a sweetener such as sucrose, and any of the above-mentioned
compressible carbohydrate including, but not limited to dextrose
monohydrate, lactose, mannitol and xylitol.
[0032] In embodiments wherein a chewable tablet is desired, the
degree of particle compaction is controlled so that the resulting
tablets are relatively soft, i.e. they have a hardness of up to
about 15 kiloponds per square centimeter (kp/cm.sup.2), e.g. from
about 1 kp/cm.sup.2 to about 10 kp/cm.sup.2 or from about 2
kp/cm.sup.2 to about 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
different size tablets, the breaking strength is normalized for the
area of the break (which may be approximated as the tablet diameter
times the 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
(hereinafter "Lieberman").
[0033] In another embodiment, the dosage form may be comprised of a
thin film strip containing, based upon the total dry weight of the
dosage form, from about 0.1 percent to about 10 percent, e.g., from
about 0.1 percent to about 5 percent of a salivation inducing
agent. Suitable ingredients for thin film strip dosage forms and
methods for their products are well known in the art and disclosed
in, for example, U.S. Pat. Nos. 6,177,096; 5,948,430; U.S. Pat. No.
6,596,298 and U.S. Pat. No. 6,419,903. As used herein, "thin film
strip" shall mean a dosage form that rapidly disintegrates in the
oral cavity subsequent to ingestion and that comprises at least one
water soluble polymer and optionally one active ingredient, wherein
the thickness of the dosage form is less than 200 microns.
[0034] In another embodiment, the dosage form may be comprised of a
gummi dosage form containing, based upon the total dry weight of
the dosage form, from about 0.1 percent to about 10 percent, e.g.,
from about 0.1 percent to about 5 percent of a salivation inducing
agent. Suitable ingredients for gummi dosage forms and methods for
their products are well known in the art and disclosed in, for
example, U.S. Pat. No. 6,432,442. As used herein, "gummi" dosage
forms shall mean an edible dosage form suitable for human
consumption having a gel-like matrix comprised of gelatin, one or
more hydrocolloids, and an optional active ingredient, such that
the dosage form is chewed and swallowed in less than 20 seconds.
Such gummi dosage forms may also optionally contain sweeteners,
adjuvants and flavorants such as those aforementioned.
[0035] In another embodiment, the dosage form may be comprised of a
foam tab dosage form containing, based upon the total weight of the
dry dosage form, from about 0.1 percent to about 10 percent, e.g.,
from about 0.1 percent to about 5 percent of a salivation inducing
agent. Suitable ingredients for foam tab dosage forms and methods
for their products are well known in the art and disclosed in, for
example, U.S. Pat. No. 6,090,401. As used herein, "foam tab" dosage
forms shall mean an edible dosage form suitable for human
consumption having a density less than 0.40 grams per cubic
centimeter comprising a polymeric foaming agent such as, for
example, hypromellose, a polysaccharide and optionally an active
ingredient. Such foam tab dosage forms may also optionally contain
sweeteners, adjuvants and flavorants such as those
aforementioned.
[0036] 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 Chewable Tablet without Salivary Inducing Agent
[0037] A blend for chewable tablets was prepared using the
materials described in Table 1. TABLE-US-00002 TABLE 1 Chewable
Tablet Formulation Ingredients Trade Name Manufacturer Mg/Tablet
Sucralose Powder NF Tate and Lyle 10.0 Dextrose Monohydrate NF
957.3 Crospovidone NF Polyplasdone International 16.7 XL-10
Specialty Products Magnesium Stearate NF 8.0 Peppermint Flavor
International 8.0 Flavors and Fragrances Total 1000.0
[0038] The dextrose monohydrate was screened through a 20 mesh
screen, then approximately half was added to a plastic bottle. The
sucralose powder, peppermint flavor, and crospovidone were screened
through a 50 mesh screen, then added to the plastic bottle. One
half of the remaining portion of dextrose monohydrate was screened
through the 50 mesh screen, then added to the plastic bottle. All
remaining, unscreened dextrose monohydrate was then added to the
plastic bottle. The components were blended end-over-end in the
plastic bottle for 3 minutes.
[0039] The magnesium stearate was then screened through a 50 mesh
screen and added to the bottle. The bottle was blended end-over-end
for an additional minute, then compressed to a hardness of
approximately 6.3 kiloponds on a rotary tablet press equipped with
5/8 inch round flat-faced beveled edge tooling.
Example 2
Preparation of Chewable Tablet Containing Salivary Inducing
Agent
[0040] A blend for chewable tablets containing a salivary inducing
agent was prepared using the materials described in Table 2 below:
TABLE-US-00003 TABLE 2 Chewable Tablet Formulation Ingredients
Trade Name Manufacturer Mg/Tablet Sucralose Powder NF Tate &
Lyle 10.0 Dextrose Monohydrate NF 956.3 Crospovidone NF
Polyplasdone International 16.7 XL-10 Specialty Products Magnesium
Stearate NF 8.0 Peppermint Flavor International 8.0 Flavors and
Fragrances Salivary Inducing Agent Succulence International 1.0
SN061022 Flavors and Fragrances Total 1000.0
[0041] The dextrose monohydrate was screened through a 20 mesh
screen, then approximately half was added to a plastic bottle. The
sucralose powder, peppermint flavor, crospovidone, and salivary
inducing agent were then screened through a 50 mesh screen and
added to the plastic bottle. One half of the remaining portion of
dextrose monohydrate was screened through the 50 mesh screen, then
added to the bottle. After all remaining dextrose monohydrate was
added to the plastic bottle, the components were blended
end-over-end in the plastic bottle for 3 minutes. After the
magnesium stearate was screened through a 50 mesh screen, it was
added to the bottle, which was blended end-over-end for an
additional minute. The blend was then compressed into tablets with
a hardness of approximately 6.3 kiloponds on a rotary tablet press
equipped with 5/8 inch round flat-faced beveled edge tooling.
Example 3
Method for Determining Salivation Inducing Agent
[0042] A panelist received a tablet, which was produced in
accordance with Example 1, and was instructed to chew the tablet
and to expectorate (instead of swallow) their saliva into a
graduated cylinder as they slowly swallowed the tablet. At
intervals of 30 seconds, two minutes, three minutes, and five
minutes after the tablet was swallowed, the amount of expectorated
saliva was measured. The panelist waits four hours, then repeats
the procedure with a second tablet, which was produced in
accordance with Example 2.
[0043] Ten additional, independent panelists repeated this
procedure. The results are set forth below in Tables 3 and 4.
TABLE-US-00004 TABLE 3 Amount of Expectorated Saliva 30 Seconds 2
Minutes 3 Minutes 5 Minutes 1.sup.st 2.sup.nd 1.sup.st 2.sup.nd
1.sup.st 2.sup.nd 1.sup.st 2.sup.nd Tablet Tablet Tablet Tablet
Tablet Tablet Tablet Tablet Panelist # (ml) (ml) (ml) (ml) (ml)
(ml) (ml) (ml) 1 0.5 0.5 1.5 1.4 2.0 2.0 3.0 3.5 2 1.1 1.3 2.6 3.6
3.3 4.4 4.4 7.3 3 0.2 1.0 1.6 2.1 2.6 2.4 3.5 2.9 4 0.6 0.8 1.0 1.2
0.3 1.0 1.0 1.5 5 1.4 1.8 1.8 3.7 3.8 4.8 5.6 8.4 6 0.4 0.9 1.3 2.5
2.2 3.0 4.4 4.8 7 0.3 0.5 0.5 0.9 0.8 1.0 0.9 1.0 8 0.5 0 2.0 2.3
2.5 2.7 3.5 3.5 9 0.8 1.0 1.8 1.9 2.1 2.8 3.0 3.5 10 1.5 1.0 3.5
2.5 4.7 4.2 7.2 7.0 11 12.0 <1 2.5 2.5 3.0 3.1 3.9 4.1
[0044] TABLE-US-00005 TABLE 4 Difference in Saliva Production
Difference in saliva production by second tablet relative to amount
of saliva produced by first tablet (%) Panelist 30 seconds 1 minute
3 minutes 5 minutes 1 0 -7.1 0 14.3 2 15 27.8 25.0 39.7 3 80 23.8
-8.3 -20.7 4 25 16.7 70.0 33.3 5 22 51.4 20.8 33.3 6 56 48.0 26.7
8.3 7 40 44.4 20.0 10.0 8 0 13.0 7.4 0 9 20 5.3 25.0 14.3 10 -50
-40.0 -11.9 -2.9 11 0 0.0 3.2 4.9 Average 18.92 16.66 16.17
12.24
[0045] This Example showed that 8 out of the 11 panelists had
increased saliva generation with second tablet, which contained a
salivation inducing agent, relative to the first tablet which did
not.
[0046] This Example also showed that the second tablet, which
contained the salivation inducing agent, generated an average in
excess of 18 percent more saliva than the amount generated by the
first tablet, when the saliva generated from each tablet was
measured 30 seconds after swallowing each respective tablet.
[0047] For dosage forms that are designed to remain in the mouth of
a user, such as a lozenge, this test can be modified so that the
user removes such dosage form from the mouth 30 seconds after
placing it therein. The amount of saliva produced can then be
measured for any interval after the dosage form is removed.
Example 4
Production of Thin-Film Dosage Form Containing Salivary Inducing
Agent
[0048] TABLE-US-00006 TABLE 5 Preparation of the Thin-Film Base
Percent Ingredients (w/w) mg/strip Acetaminophen 26.67 80.00
Hydroxypropylmethylcellulose (HPMC 5) cps) 62.68 188.04 Carrageenan
1.00 3.00 Propylene Glycol 7.00 21.00 Citric Acid USP (anhydrous)
0.75 2.25 Sodium Benzoate NF 0.30 0.90 Flavor NF 1.00 3.00
Sucralose Powder NF 0.50 1.50 Salivary Inducing Agent 0.10 0.30
Deionized (DI) Water* 0.00 -- TOTAL 100.0 300.0 *Deionized Water
removed upon drying.
[0049] The materials in the table above are processed into a thin
film using the following procedure.
[0050] For every 10.0 grams of total materials for the thin-film
mixture in Table A, 90.0 grams of DI water is required to create a
dispersion that contains approximately 10% solids. The water is
first heated to 85.degree. C. To prepare the thin-film dosage form,
the sodium benzoate, flavor, sucralose, salivary inducing agent and
citric acid are added to the DI water until dissolved using a lab
scale mixer at 500 RPM. The HPMC and carrageenan are then added
while mixing at 500 RPM. The acetaminophen is then added and
dispersed while mixing.
[0051] The mixture is then poured manually into preformed molds
designed to produce thin-film dosage forms having a thickness of
about 70 microns and a dry weight of approximately 300.0 mg under a
constant temperature of 10.degree. C. The thin-film dosage forms
are then removed from the molds and dried at 50.degree. C. and 40%
relative humidity until the water is substantially removed.
Example 5
Preparation of Coating Solution with Salivation Inducing Agent
[0052] A film coating solution is prepared by adding to a beaker
containing ethanol and purified water in a 50:50 weight ratio the
following solid ingredients in order and under ambient conditions:
hydroxypropylmethylcellulose (5 centipoise grade); polyethylene
glycol 8000; and talc. The finished solution contains 10.0% of
solids, relative to the total weight of the coating solution.
[0053] The salivary inducing agent is then added thereto and mixed
at 500 RPM for 1 hour under ambient conditions. The solution is
allowed to deaerate for a minimum of 2 hours prior to use. The
final coating solution contains the ingredients set forth below in
Table 6 in amounts based upon the weight percent of the final
coating solution: TABLE-US-00007 TABLE 6 Composition of Coating
Solution Component Weight Percent Polyethylene Glycol 8000 [60] . .
. 57.6% Hydroxypropylmethylcellulose 5 cps [40] . . . 38.4% Talc
2.0% Salivary Inducing Agent 2.0% Water Ethanol
Example 6
Preparation of Calcium Carbonate Granules Containing Salivary
Inducing Agent Coating
[0054] The coating solution in Example 5 is applied to 500.0 g of
calcium carbonate granules using a Glatt GPC-3 Wurster fluid bed
coating unit at a spray rate of about 10-15 g/min, an atomization
air pressure of about 2-2.5 bar, a product temperature of about
28-35.degree. C., and an inlet temperaure of about 45.degree. C.
until the granules were coated with a 10.0% Yes weight gain of the
coating solution. The resulting coated granules contain, based upon
the total dry weight of the coated granules, 0.2% of the salivary
inducing agent.
[0055] The granules are then formed into tablets via compression to
a hardness of approximately 6.3 kiloponds on a rotary tablet press
equipped with 5/8 inch round flat-faced beveled edge tooling.
Example 7
Lozenge Containinq Salivary Inducing Agent
[0056] A formulation for lozenges containing a salivary inducing
agent is prepared using the materials described in Table 7.
TABLE-US-00008 TABLE 7 Lozenge Formulation Ingredients Trade Name
Manufacturer Mg/Unit Corn Syrup NF 400.0 Sucrose NF Domino Sugar
Inc. 600.0 Red Dye # 40 NF 0.5 Citric Acid Powder NF 3.0 Cherry
Flavor International 1.0 Flavors and Fragrances Salivary Inducing
Succulence International 1.0 Agent Flavors and Fragrances Total
1005.5
[0057] For every 1000.0 g of mixture weighed from Table 7, 100.0 g
of deionized water will need to be added to process the
lozenges.
[0058] The corn syrup, sucrose and water are added to a pot, then
heated to a temperature of about 140.degree. C. with mixing. The
dye and citric acid are added thereto with mixing, then the
resulting solution is heated with stirring until it reaches
155.degree. C. The mixture is then removed from the heat, and
allowed to cool to 120.degree. C., at which point the flavor and
salivary inducing agent are added thereto with mixing.
[0059] The resulting mixture is then poured manually into preformed
molds to form lozenges and are removed therefrom after reaching
room temperature.
Example 8
Antacid Chewable Tablet Containing Salivary Inducing Agent
[0060] A blend for antacid chewable tablets containing a salivary
inducing agent are prepared using the materials described in Table
8. TABLE-US-00009 TABLE 8 Chewable Tablet Formulation Ingredients
Trade Name Manufacturer Mg/Tablet Sucralose Powder NF Tate &
Lyle 10.0 Dextrose Monohydrate NF 556.3 Calcium Carbonate USP 400.0
Crospovidone NF Polyplasdone International 16.7 XL-10 Specialty
Products Magnesium Stearate NF 8.0 Peppermint Flavor International
8.0 Flavors and Fragrances Salivary Inducing Succulence
International 1.0 Agent SN541850 Flavors and Fragrances Total
1000.0
The dextrose monohydrate and calcium carbonate are screened through
a 20 mesh screen, then approximately half are added to a plastic
bottle. The sucralose powder, peppermint flavor, crospovidone, and
salivary inducing agent are then screened through a 50 mesh screen
and added to the plastic bottle. One half of the remaining portion
of dextrose monohydrate is then screened through the 50 mesh
screen. All remaining dextrose monohydrate and calcium carbonate
are then added to the plastic bottle. The components are blended
end-over-end in the plastic bottle for 3 minutes. The magnesium
stearate is then screened through a 50 mesh screen and added to the
bottle, and blended end-over-end for an additional 1 minute.
[0061] The resulting blend is then compressed into tablets with a
hardness of approximately 6.2 kiloponds on a rotary tablet press
equipped with 5/8 inch round flat-faced beveled edge tooling.
* * * * *