Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
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GRANULAR, FREE-FLOWING PHARMACEUTICAL COMPOSITION, AND
STRAW-LIKE DOSAGE FORM FOR ORAL ADMINISTRATION THEREOF
Field of the Invention
This invention relates to granular, free-flowing,
pleasant tasting pharmaceutical compositions for or-al
administration, and also to straw-like dosage forms for
administering same. These forms permit a more convenient
and reliable way of administering a wide variety of
medicaments and nutrients to those having difficulty in
using other types of oral dosage forms.
Background of the Invention
Orally administered medicaments exist in many forms
such as liquid solutions, emulsions, suspensions,
capsules and tablets. Caplet and tablet forms are
generally intended to be swallowed whole. Therefore, the
often disagreeable taste of the medicament need not be
taken into account when formulating such medicine, except
in preventing any uripleasant taste while the medicine is
in the mouth. This can be accomplished by placing a thin
and quickly dissolving coating on the tablet, by using
the gelatin capsule form, or by firmly compressing a
tablet during manufacture so as to prevent its
disintegration while in the mouth.
A common problem with chewable tablet forms is the
often disagreeable taste of the active ingredient which
manifests itself during chewing. In some cases, the
taste of the medicament in a tablet can be overpowered by
adding flavoring ingredients to the tablet so that when
it is chewed, the taste of the medicament is simply
overpowered. This has been done, for example, with
children's aspirin, where the dosage is small enough so
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that the amount of flavoring agents needed to mask the
taste of the medicament is not so great that the tablet
becomes unreasonably large.
A different approach is taken with a commercially
available children's size tablet of acetaminophen, where
the acetaminophen is present in granules coated with
polymers such as ethyl cellulose, or cellulose acetate
and polyvinyl pyrrolidone. While the tablet is in the
mouth, a significant proportion of the acetaminophen
remains shielded by the coating and thus does not
contribute to taste, despite some breakage of the polymer
coating upon compression of the tablet during
manufacture, and additional breakage of the coating
during chewing. The acetaminophen becomes bioavailable
from the granules where the coating is broken, and from
permeation through the coating. This phenomenon is due
to the fact that ethylcellulose films are water-
permeable, and combination films, such as cellulose
acetate and polyvinyl pyrrolidone, contain one soluble
component which dissolves in the gastrointestinal tract,
rendering the film permeable to water and dissolved
active components.
Despite the existing ability to mask unpleasant
medicament taste in tablets and capsules, a need still
exists for a more convenient way of administering these
medicaments to those such as the very young and very old,
who often have difficulty swallowing these types of
-30 dosage forms. Even among the broader population, a great
many people report difficulty in swallowing tablets and
capsules.
For pediatric medicines, the use of liquid and
chewable dosage forms predominates until children reach
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approximately 10-12 years of age. These dosages do not
address all the needs of children in this age group. For
example, problems with liquid dosage forms include
uncertainty of delivered dose, limited stability after
reconstitution (as seen with antibiotics), and poor
.taste. As for older patients, many require medicine
tablets to be crushed because of swallowing difficulties.
Indeed, the National Hospital Discharge Survey indicates
that there is a 67% incidence of a discharge diagnosis of
dysphagia among patients over age 65 (Department af
Health and Human Services, National Center for Health
Statistics (1989)). This incidence is almost five times
higher than that seen among younger patients.
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Sumraary of the Invention
This invention provides a dry, granular, free-
flowing, stable pharmaceutical composition for oral
administration comprising particles of medicament or
nutrient coated with a suitable taste-masking agent, a
salivation-inducing agent, and a pharmaceutically
acceptable carrier.
This invention also provides a dosage form =for
oral administration comprising a closed, moisture-
resistant, straw-like container having therein a single
unit dose of the instant pharmaceutical composition,
and having an opening means for permitting the dry oral
administration ther.eof.
Finally,,this invention provides a dosage form for
oral administration comprising a closed, moisture-
resistant, non-straw-like container having therein a
single unit dose of the instant pharmaceutical
composition, and having an opening means for permitting
the dry oral administration thereof.
4
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=74'374-4
According to one aspect of the present invention,
there is provided a dosage form for oral administration
comprising: a closed, moisture resistant, straw-like
container having therein a single unit dose of a
pharmaceutical composition comprising a dry, granular, free
flowing stable pharmaceutical composition for oral
administration, said pharmaceutical composition comprising
particles of medicament or nutrient coated with a suitable
taste masking agent; particles of a salivation inducing
agent in an amount sufficient to permit dry oral
administration without any intake of water or other liquid;
and particles of a pharmaceutically acceptable carrier, said
container having an opening means for permitting the dry
oral administration thereof.
According to another aspect of the present
invention, there is provided a dosage form for oral
administration comprising: a closed, moisture resistant,
non-straw-like container having therein a single unit dosage
of a pharmaceutical composition consisting essentially of a
dry, granular, free flowing stable pharmaceutical
composition for oral administration, said pharmaceutical
composition comprising particles of medicament or nutrient
coated with a suitable polymeric taste masking agent;
particles of a salivation inducing agent in an amount
sufficient to permit dry oral administration without any
intake of water or other liquid; and particles of a
pharmaceutically acceptable carrier, said container having
an opening means for permitting the dry oral administration
thereof.
According to still another aspect of the present
invention, there is provided a dosage form for oral
administration comprising: a closed, moisture-resistant,
non-straw-like container having therein a single unit dose
4a
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.74374-4
of a pharmaceutical composition consisting essentially of a
dry, granular, free-flowing pharmaceutical composition for
oral administration, said pharmaceutical composition
comprising particles of a pharmaceutically effective amount
of acetaminophen coated with a suitable polymeric taste-
masking agent; particles of citric acid in an amount
sufficient to permit dry oral administration without any
intake of water or other liquid; particles of mannitol at a
level of from about 30 to about 60% by weight, and particles
of a sweetener, and having an opening means for permitting
the dry oral administration thereof.
According to yet another aspect of the present
invention, there is provided a dosage form for oral
administration comprising a closed, moisture resistant
container having a drinking straw shape and having therein a
single unit dose of a pharmaceutical composition comprising
a dry, granular, free flowing stable pharmaceutical
composition for oral administration, said pharmaceutical
composition comprising: a) particles of acetaminophen coated
with a suitable taste masking agent; b) particles of an
edible carboxylic acid selected from the group consisting of
citric acid, malic acid, fumaric acid, benzoic acid, sorbic
acid, adipic acid, and mixtures thereof in an amount
sufficient to permit dry oral administration without any
intake of water or other liquid; and c) particles of a
pharmaceutically acceptable carrier, said container having
an opening means for permitting the dry oral administration
thereof and wherein the pharmaceutical composition has a
total water content of less than about 10% by weight.
4b
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Brief Description of the Figures
Figure 1 shows examples of the instant dosage forms,
i.e., a straw dosage form, a pouch dosage form, and a
blister pack dosage form.
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Detailed Description of the Invention
This invention provides dry, granular, free-flowing,
stable, pleasant tasting pharmaceutical compositions for
oral administration. The invention also provides dosage
forms employing both straw-like and non-straw-like
containers for administering same. These forms are a
convenient and reliable way of administering a wide
variety of medicaments and nutrients to those having
difficulty using other types of oral dosage forms,:
especially tablets and capsules.
More specifically, this invention provides a dry,
granular, free-flowing, stable pharmaceutical
composition for oral administration comprising
particles of medicament or nutrient coated with a
suitable taste-masking agent, a salivation-inducing
agent, and a pharmaceutically acceptable carrier.
In one embodiment, the instant dry composition has
a total water content of less than 10% by weight. In
the preferred embodiment, the instant dry composition
has a total water content of less than 3% by weight.
As used herein, the term "stable" shall mean physically
as well as chemically stable. This term is well
understood in the art and includes, but is not limited
' to, having a shelf life of at least about two years.
The medicament or nutrient used in this invention
can be any medicament or nutrient suitable for:oral
administration. The types of medicaments envisioned
for use in this invention include, without limitation,
analgesics, antacids, antibiotics, decongestants,
antitussives, expectorants, local anaesthetics,
antihistamines, sympathomimetics, laxatives, and
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antidiarrheals. The types of nurients envisioned for
use in this invention include, without limitation,
minerals such as iron, and vitamins such as B6, B12,
thiamin and folic acid.
Numerous analgesics are known in the art and
include, by way of example, acetaminophen, acetyl
salicylic acid, indomethacin and optically,active
isomers or racemates of ibuprofen, naproxen,
flurbiprofen, carprofen, tiaprofenic acid, cicloprofen,
ketoprofen, ketorolac, etodolac, indomethacin,
sulindac, fenoprofen, diclofenac, piroxicam,
benzydomine, nabumetone, their pharmaceutically
acceptable salts and mixtures thereof. In the
preferred embodiment, the analgesic is acetaminophen.
Decongestants for use in the present invention
include, for example, pseudoephedrine,
phenylpropanolamine, phenylephrine and ephedrine, their
pharmaceutically acceptable salts, and mixtures
thereof. Antitussives for use in this invention=
include, for example, dextromethorphan, chlophedianol,
carbetapentane, caramiphen, noscapine, diphenhydramine,
codeine, hydrocodone, hydromorphone, fominoben,
benzonatate, their pharmaceutically acceptable salts,
and mixtures thereof. Expectorants (also known as
mucolytic agents) useful in this invention include, for
example, glyceryl guaiacolate, guaifenesin, terpin
hydrate, ammonium chloride, N-acetylcysteine and
-30 bromhexine, ambroxol, their pharmaceutically acceptable
salts, and mixtures thereof. Local anaesthetics useful
in this invention include, for example,
hexylresorcinol, dyclonine, benzocaine, phenol, their
pharmaceutically acceptable salts, and mixtures
thereof.
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Antihistamines useful in the present invention
include, for example, chlorpheniramine,
brompheniramine, diphenhydramine, dexchlorpheniramine,
dexbromphreniramine, triprolidine, azatadine,
doxylamine, tripelennamine, cyproheptadine,
hydroxyzine, carbinoxamine, phenindamine,
bromodiphenhydramine, pyrilamine, their
pharmaceutically acceptable salts and mixtures thereof,
as well as the non-sedating antihistamines such as
acrivastine, AHR-11325, astemizole, azatadine,
azelastine, cetirizine, ebastine, ketotifen,
lodoxamide, loratidine, levocabastine, mequitazine,
oxatomide, setastine, tazifylline, temelastine, and
terfenadine, their pharmaceutically acceptable salts
and mixtures thereof.
Sympathomimetics suitable for use in this
invention include, for example, pseudoephedrine,
phenylpropanolamine, pharmaceutically acceptable salts
thereof (e.g., pseudoephedrine hydrochloride), and
mixtures thereof. Laxatives which can be used in the
present invention include, for example, sennosides A
and B. Suitable antidiarrheals include, for example,
loperamide and pharmaceutically acceptable salts
thereof (e.g., loperamide HC1).
As used herein, the term "pharmaceutically
acceptable salts" refers to salts prepared from
pharmaceutically acceptable non-toxic bases including
inorganic bases and organic bases. Salts deriv6d from
inorganic bases include sodium, potassium, lithium,
ammonia, calcium, magnesium, ferrous, zinc, manganous,
aluminum, ferric, manganic salts and the like. Salts
derived from pharmaceutically acceptable organic
non-toxic bases include salts of primary, secondary,
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tertiary and quaternary amines, substituted amines
including naturally occurring substituted amines,
cyclic amines and basic ion exchange resins such as
triethylamine, tripropylamine, 2-dimethylaminoethanol,
2-diethylaminoethanol, amino acids generally and
lysine, arginine and histidine specifically, caffeine,
procaine, N-ethylpiperidine, hydrabamine, choline-,
betaine, ethylenediamine,, glucosamine, methylglycamine,
theobromine, purines, piperazine, piperidine, polyamine
resins and the like.
All of these medicaments, as well as their
acceptable dosage ranges, are described in U.S. Patent
Nos. 4,783,465 and 4,619,934. Additional antitussives,
expectorants, antihistamines, sympathomimetics,
laxatives, antidiarrheals and analgesics suitable for
use in the present invention'are described in
Remington's Pharmaceutical Sciences (Mack Publishing
Co., Easton, PA, 18th ed., Chapters 39, 42, 43, 58 and
59 (1990)).
Methods of coating medicament and nutrient
particles used in this invention with taste-masking
agents are well known and commercially available in the
pharmaceutical industry. Such methods are taught, for
example, in U.S. Patent Nos. 5,489,436, 5,260,072,
5, 215, 755, 5, 489, 436, 5, 460, 825, and 4, 851, 224. These
taste-masking agents include, for example, ethyl
cellulose ("EC"); cellulose acetate ("CA"); cellulose
-30 acetate butyrate ("CAB"); polymethacrylates such as
dimethylaminoethyl methacrylate and neutral methacrylic
acid ester (Eudragito E-100); hydroxypropyl cellulose
("HPC"); hydroxyethyl cellulose ("HEC"); and
hydroxypropyl methyl cellulose ("HPMC").
Alternatively, medicament particles that are already
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taste-masked can be purchased commercially. For
example, taste-masked acetaminophen particles are
commercially available from Eurand America, Inc. (845
Center Drive, Vandalia, OH 45377), and taste-masked
pseudoephedrine ("PE") and chiorpheniramine maleate
("CPM") particles are available from Particle Dynamics,
Inc. (2503 South Hanley Road, St. Louis, MO 63144).
Pharmaceutically acceptable carriers are generally
water-disintegratable carbohydrates which are described
in Lieberman et al., Pharmaceutical Dosage Forms
(Marcel Dekker, Inc., New York, 2 Ed. Vol. 1, pp. 205-
209 (1990)). Preferred carriers include dextrose,
sucrose, lactose, maltose, xylose, maltodextrins,
dextrates, mannitol, sorbitol, and xylitol.
One or more salivation-inducing agents are
appropriate for the proper ingestion of the instant
pharmaceutical composition, given its dry, granular
nature. Such agents are routinely used in the art, and
are usually carboxylic acids. In one embodiment, the
salivation-inducing agent is an edible carboxylic acid
such as citric acid, malic acid, fumaric acid, benzoic
acid, sorbic acid, or adipic acid. Preferably,
anhydrous carboxylic acids are used. The use of
carboxylic acids in specific formulations is shown in
the Examples section below.
In order to enhance its taste, mouth-feel and
other physical properties, the instant pharmaceutical
composition ideally includes components additional to
the medicament, salivation-inducing agent, and carrier.
Thus, in one embodiment, the pharmaceutical composition
further comprises one or more of a soothing agent, a
sweetener, and a flavoring agent. In the-preferred
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embodiment, the composition comprises all of these
additional components.
Soothing agents create a "cooling" sensation in
the mouth due to their negative heat of hydration.
These are widely used in the art and include, for
=example, mannitol, sorbitol, and xylitol. Suitable
sweeteners include, for example, aspartame, sucralose,
saccharine, cyclamate, acesulfame potassium, manitol,
sorbitol, and xylitol. Suitable flavoring agents
include, for example, fruit flavoring (e.g. lemon
flavor) and cream flavoring. A more extensive list of
soothing agents, sweeteners, and flavoring agents is
provided in Handbook of Pharmaceutical Excipients, 2nd
ed. (American Pharmaceutical Association, Washington,
D.C. (1994)).
In one embodiment, the pharmaceutical composition
comprises coated acetaminophen particles, citric acid,
mannitol, a sweetener, and lemon flavoring.
Additional, more specific embodiments of this
composition are provided in the Examples section below.
In another embodiment, the coated particles of the
instant pharmaceutical composition comprise a plurality
of medicaments and/or nutrients. Here, two
possibilities exist, i.e., (i) the composition has one
type of coated particle containing a plurality of
medicaments and/or nutrients, and (ii) the composition
has more than one type of coated particle, each type
containing a one or more medicaments and/or nutrients.
In one example, the composition comprises coated
acetaminophen particles and coated particles of either
chlorpheniramine maleate or pseudoepheddrine (Descote ,
Particle Dynamics, Inc.).
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This invention also provides two dosage forms for
oral administration. The first form comprises a
closed, moisture-resistant, straw-like container having
therein a single unit dose of the instant
pharmaceutical composition, and having an opening means
for permitting the dry oral administration thereof.
'The second form comprises a closed, moisture-resistant,
non-straw-like container having therein a single unit
dose of the instant pharmaceutical composition, and
having an opening means for permitting the dry oral
administration thereof. As used herein, "dry oral
administration" means oral administration that does not
require the concomitant intake of water or other
liquid. In the preferred embodiment of the instant
dosage forms, the coated medicament is acetaminophen,
whose single unit dosages include, for example, 50 mg,
80 mg, 160 mg, 300 mg, 325 mg, 500 mg and 1000 mg.
As used herein, the term "straw-like container"
means any container having a cylindrical shape whose
length is greater than its width. The dimensions of
the straw-like container used in this invention can
vary widely. In one embodiment, its dimensions are
those of an ordinary drinking straw, e.g., having a
length of about 200 mm and a width of about 6 mm. The
straw-like container can be made from any non-toxic
moisture-resistant material such as plastic (e.g.
polyethylene) or wax-coated paper. Finally, the
opening means on the straw-like container includes, for
example, an end that is opened by tearing, or by
removing a cap (via twisting or otherwise). Once open,
the contents of the container are simply emptied
directly into the user's mouth. The straw-like
container used in this invention is intended to
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function like the straw-like container used in the
PIXIE STICKTM children's granular candy dispenser.
As used herein, the term "non-straw-like
container" means any container that does not have a
cylindrical shape whose length is greater than its
width. As with the straw-like container, the
dimensions of the non-straw-like container used in this
invention can vary widely. For example, the non-straw-
like container can be a "blister pack", which is--a
widely used type of pharmaceutical container typically
made from polymers such as polyvinyl chloride,
polyvinylidine chloride ("PVDC") and
polychlorotrifluoroethylene ("Aclar*"). Alternatively,
the non-straw-like container can be oblong and non-
cylindrically shaped, oblong and having only a portion
which is cylindrically shaped, or cylindrically shaped
wherein the width is greater than the length.
Moreover, non-straw-like container can be a pouch, such
as a foil/foil pouch, a foil/paper pouch, or a
paper/paper pouch. As with the straw-like container,
the non-straw-like container can be made from any non-
toxic moisture-resistant material such as plastic or
wax-coated paper, and the opening means includes, for
example, an end which is opened by tearing, or by
removing a cap.
In one embodiment (and in the case of straw dosage
forms the preferred embodiment), the instant dosage
forms are packaged, along with a desiccant, within an
outer, child-resistant container. Child-resistant
containers (which meet the requirements of the Poison
Prevention Packaging Act of 1970 (16 C.F.R. 1700, et
seq.)) and their methods of manufacture are standard in
the art. Ideally, within each outer container is a
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plurality of individual dosage forms to be administered
either on an "as needed" basis, or periodically over a
prescribed length of time. An example of the former
"as needed" scenario is the use of analgesics, such as
acetaminophen, for pain relief. An example of the
latter "periodic" scenario is the use of
antihistamines, such as brompheniramine, for relief of
symptoms of seasonal allergies.
This invention will be better understood by
reference to the Examples that follow, but those skilled
in the art will readily appreciate that they are only
illustrative of the invention as described more fully in
the claims which follow thereafter. In addition, various
publications are cited throughout this application. The
disclosure of these publications is hereby incorporated
by reference into this application to describe more fully
the state of the art to which this invention pertains.
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Example 1
TYLENOL (Acetaminophen) Granules - I
Ingredient Unit Weight Weight
Mg Percent
Encapsulated Acetaminophen* 1075.3 59.74
Citric Acid USP (Anhydrous 20.0 1.11
Powder)
Aspartame NF (Powder) 46.0 2.55
Alpine Cream Flavor Power 6.6 0.37
Natural and Artificial Lemon
Juice Flavor 6.6 0.37
Mannitol (Granular) 645.5 35.86
Total 1800.0 100.00
*Equivalent to 1,000 mg of acetaminophen.
Physicals Actual
Mesh Size % Retained
Particle Size 20 0.1%
Analysis .30 2.0%
40 16.0%
60 62.9%
80 11.8%
100 2.5%
Pan 4.8%
Bulk Density 0.60g/mL
Tap Density 0.74 g/mL at 250 taps
0.74 g/mL at 500 taps
Note: the following acronyms are used in the Examples.
"NF" means National Formulary.
"USP" means United States Pharmacopeia.
"JP" means Japan Pharmacopeia.
"JPE" means Japan Pharmaceutical Excipient.
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Example 2
TYLENOL (Acetaminophen) Granules - I2
Ingredient Unit Weight Weight
Mg Percent
Encapsulated Acetaminophen* 1070.1 58.48
Fumaric Acid NF (Powder) 60.0 3.28
Aspartame NF (Powder) 46.0 2.51
Alpine Cream Flavor 6.6 0.36
Natural and Artificial 6.6 0.36
Lemon Juice Flavor
Mannitol (Granular) 640.7 35.01
Total 1830.0 100.00
*Equivalent to 1,000 mg of acetaminophen.
Physicals Actual
Mesh Size % Retained
Particle Size Analysis 20 0.2%
30 1.8%
40 13.2%
60 63.4%
80 10.2%
100 7.0%
Pan 4.1%
Bulk Density 0.63g/mL
Tap Density 0.80g/mL at 50 taps
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Example 3
TYLENOL (Acetaminophen) Granules - III
Ingredient Unit Max. Daily Weight
Weight Dose (mg) Percent
(mg) ($)
JP Mannitol 358.70 1076.10 51.24
JP Citric Acid Anhydrous 3.70 11.10 0.53
Lemon Juice Flavor 2.30 6.90 0.33
JP Magnesium Stearate 2.00 6.00 0.28
JP Acetaminophen 300.00 900.00 '42.86
JPE Ethylcellulose 33.30 99.90 4.76
Total Weight 700.00 2100.00 100.00
Physicals Actual
Mesh Size % Retained
Particle Size 20 0%
Analysis 35 1.8%
200 97.6%
Pan 0.6%
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Example 4
Sore Throat Granules
Ingredient Unit Weight
Weight Percent
Mg
Encapsulated Acetaminophen* 571.4 56.95
Citric Acid USP (Anhydrous 7.0 0.7
Powder)
Aspartame NF (Powder) 15.0 1.5
Prosweet Power 4.0 6.4
Artificial Cherry Flavor 2.5 0.25
Mixed Berry Flavor 1.0 0.1
Mannitol (Granular) 399.1 39.8
Dyclonine HC1 3.0 0.3
Total 1003.0 100.0
*Equivalent to 500 mg of acetaminophen.
18
