Note: Descriptions are shown in the official language in which they were submitted.
CA 02520986 1999-09-23
PHYSIOLOGICAL COMPATIBLE FILM
This application is a divisional of Canadian Application No. 2,339,353 filed
September 23, 1999.
SPECIFICATION
FIELD OF INVENTION
The invention relates to a method of preparing a physiologically compatible
film
adapted to dissolve in a human mouth. The film is used to deliver
pharmaceutical agents.
BACKGROUND OF THE INVENTION
In a more perfect world, people would thoroughly cleanse their mouths after
each
meal as part of their routine oral hygienic practices. Unfortunately, several
factors
conspire to prevent widespread compliance with this basic requirement of a
good oral
cleaning regimen.
Oral cleansing can be difficult or inconvenient at times, depending on the
nature
of the cleansing and the situation in which the cleansing must occur.
Brushing, flossing,
cleaning your tongue and gargling using a variety of devices and compositions
well-suited for the privacy of one's home are common oral care practices.
However, the
devices and compositions used in oral cleansing practices are less convenient
to use away
from home, where bathroom facilities might be scarce, unavailable or
unsanitary.
As brushing, flossing, cleaning your tongue and gargling in public are not
considered to be socially acceptable behaviors in many, if not all cultures, a
variety of
CA 02520986 1999-09-23
less obtrusive oral cleansing products have been developed. These include
breath-
freshening gums and lozenges. Although gums and lozenges have been formulated
to
achieve a variety of beneficial effects, they are not always socially
acceptable. For
example, gum is expressly banned from certain institutions, such as schools as
well as
in certain countries, such as Singapore. Gums and mints are used over extended
periods of time, and they require an amount of sucking or chewing action on
the part
of the consumer, which can be distracting, tedious and undesirable.
Another portable oral cleansing product is a mouthspray. Like a mouthwash, a
mouthspray can provide the consumer with a quick burst of strong breath-
freshening
action, which might be overwhelming in an extended-consumption product like
gum
or lozenges. On the other hand, mouthsprays are obtrusive. Spraying a
mouthspray
typically generates a noise, which undesirably draws the attention of the
public to the
consumer. Moreover, mouthsprays are typically packaged in relatively expensive
and
complex metal canisters, which can clog in use and are not environmentally
friendly.
Furthermore, misdirecting the spray not only wastes the product, but can
result in
irritated eyes, a sticky face and/or stained clothing.
It has been proposed to use an edible film as a vehicle for unobtrusively
delivering breath-freshening agents. See JP 5-236885. This Japanese patent
application does not, however, teach the inclusion of antimicrobial agents in
the film,
using the film to decrease the amount of undesirable bacteria within the oral
cavity, or
stimulating saliva. Furthermore, this patent application does not disclose
employing
2
CA 02520986 1999-09-23
its film for purposes other than breath freshening or within cavities other
than the
mouth.
U.S. Patent No. 5,518,902 to Ozaki et al. (Hayashibara) discloses high
pullulan
content products, such as edible films, dentifrices and pharmaceuticals
(column 3,
lines 44-56 and Example B-8). The products can include a variety of
ingredients in
addition to pullulan, such as other polysaccharides, polyhydric alcohols,
antiseptics
and flavor-imparting agents (column 4, line 58 to column 5, line 11). None of
the
essential oils, such as thymol, eucalyptol, methyl salicylate or menthol, are
mentioned
as suitable ingredients.
U.S. Patent No. 5,411,945 to Ozaki et al. (Hayashibara) discloses a pullulan
binder and products produced therewith, including edible films (Example B-2).
The
products can include a variety of ingredients in addition to pullulan, such as
other
polysaccharides, antibacterial agents, flavor-imparting agents and
pharmaceutically
active substances (column 4, lines 5-15). None of the essential oils are
mentioned as
suitable ingredients.
U.S. Patent No. 4,851,394 to Kubodera discloses glucomannan/polyhydric
alcohol edible films, which can comprise pullulan (column 3, line 59 to column
4, line
21). The films are contrasted with existing pullulan-based films, which are
said to
lack resistance to water (column 1, lines 40-44). None of the essential oils
are
mentioned as suitable ingredients.
U.S. Patent No. 3,784,390 Hijiya et at. discloses pullulan films and their use
in
3
CA 02520986 1999-09-23
coating and packing materials for foods, pharmaceuticals and other oxygen
sensitive
materials. All of the examples in this patent teach mixing pullulan in hot
water.
U.S. Patent No. 4,623,394 Nakamura et al. discloses a gradually disintegrable
molded article that can be a film made with pullulan. The articles contain a
particular
heteromannan, which can be locust bean gum.
U.S. Patent No. 4,562,020 Hijiya et al. discloses a process for producing a
self-
supporting film of a glucan, which can be pullulan.
Japanese Patent Document JP5-1198 discloses films made of polyvinyl alcohol
and at least one of carrageenan, water-soluble cellulose alpha-starch and
water-soluble
polysaccharides.
WO 99/17753 discloses rapidly dissolving films for delivery of drugs to be
adsorbed in the digestive tract.
WO 98/26780 discloses a flat, foil, paper or wafer type presentation for the
application and release of active substances in the buccal cavity. The
specific active
ingredient disclosed in WO 98/26780 is buprenorphine.
WO 98/20862 discloses a film for use in the oral cavity that can contain a
cosmetic or pharmaceutical active substance.
WO 98/26763 discloses a flat, foil, paper or wafer like presentation for
release
of active substances into the buccal cavity. The particular active disclosed
is
apomorphine.
Despite the existence of rapidly dissolving orally consumable films in the
prior
4
CA 02520986 1999-09-23
art, there is still room for improvement in such films, and in processes for
making them.
SUMMARY OF THE INVENTION
The invention is directed to a rapidly dissolvable film which acts as a
vehicle for
administering a pharmaceutically active agent orally, through a mucous
membrane or an
open wound of a patient and to a method of preparing same.
In particular, the invention comprises a method for preparing a
physiologically
compatible film, said method comprising:
a) mixing a water soluble polymer and at least one stabilizing agent
to provide a film-forming mixture;
b) dissolving water-soluble ingredients in water to provide an
aqueous solution;
c) combining said film-forming mixture and said aqueous solution
to provide a hydrated polymer gel;
d) mixing oils to form an oil mixture that comprises at least two
essential oils selected from the group consisting of thymol, methyl
salicylate, eucalyptol, and menthol;
e) adding said oil mixture to said hydrated polymer gel and mixing
to provide a uniform gel;
f) casting the uniform gel on a substrate; and
g) drying the cast gel to provide said film that adheres to and
dissolves in a consumer's mouth.
In a preferred embodiment, the invention comprises a consumable film adapted
to dissolve in the mouth of a consumer, wherein said film comprises a single
layer
including pullulan and at least one pharmaceutical agent.
5
CA 02520986 1999-09-23
BRIEF DESCRIPTION OF THE DRAWINGS
Fig. I is a photograph of an agar plate spread with Streptococcus mutans,
ATCC 25175, and exposed to a film according to the present invention that
contains
0.391 mg of essential oils.
Fig. 2 is a photograph of an agar plate spread with Streptococcus mutans,
ATCC 25175, and exposed to drops of an essential oil mixture containing 0.391
mg of
essential oils per drop.
DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS
Description of Oral Care Film Compositions
A related embodiment of the invention is a physiologically acceptable film
that
is particularly well adapted to adhere to and dissolve in a mouth of a
consumer to deliver
an antimicrobial agent that kills germs that cause halitosis, dental plaque
and gingivitis.
Thus, the film can be an effective tool in the prevention and treatment of
halitosis, dental
plaque accumulation, dental tartar accumulation and gingivitis. This film
preferably
comprises pullulan, thymol, methyl salicylate, eucalyptol and menthol.
LISTERINE brand mouthwash is, perhaps, the most well-known example of an
antiseptic oral composition that has proven effective in killing microbes in
the oral
6
CA 02520986 1999-09-23
cavity that are responsible for plaque, gingivitis and bad breath. LISTERINE
brand
mouthwash achieves its antimicrobial effect through a combination of essential
oils
that penetrate and kill the microorganisms. These essential oils include
precisely
balanced amounts of thymol, methyl salicylate, menthol and eucalyptol
(hereinafter
"the essential oils") in a hydro alcoholic solution. Many bad breath bacteria
live in
pits or fissure on the surface of the tongue. Listerine Antiseptic mouthwash
reduces
bad breath because of high concentrations of antimicrobial agents in a liquid
medium
that can easily penetrate into these pits and fissures. This would not be
possible with a
solid dosage form containing low amounts of these antimicrobial ingredients.
However, the preferred consumable film of the invention captures a significant
portion
of the hygienic benefits and the consumer appeal of LISTERINEO brand
mouthwash,
in a more portable and unobtrusively consumed fornm.
It was a significant challenge to maintain the essential oil interaction and
relatively high oil content of LISTERINE brand mouthwash in a film. However,
the
inventors have overcome this challenge in providing the film of the invention.
A further aspect of this invention is that while the amounts of LISTERINE
essential oils are relatively high for incorporation in a film, the film
according to the
present invention still delivers a lower total amount of essential oils per
unit dose
when compared to that of LISTERINE mouthwash. Yet the film suprisingly
provides antimicrobial efficacy in the oral cavity. The inventors theorize
that the
preferred film forming ingredient, pullulan, forms a thin layer on the oral
surfaces
7
CA 02520986 1999-09-23
entrapping the small amount of essential oils which are capable of penetrating
into the
pits and fissures of the oral cavity to provide sustained antimicrobial
efficacy.
Although the inventors are presently unaware of any other breath-freshening
consumable film that provides antimicrobial efficacy, they are aware of a
consumable
film disclosed in JP 5-236885, which is said to possess breath-freshening
activity, but
is not described as possessing any ingredients having significant
antimicrobial activity.
Moreover, JP 5-236885 teaches that its film should contain flavor and extract
in
amounts of 5 to 7 wt %, with the flavor being added as an oil (the essential
oils are not
disclosed), whereas the film of the invention preferably has an oil content of
at least
about 10 wt %, more preferably about 15 wt % to about 30 wt %, most preferably
about 15 wt % to about 25 wt %. Except as otherwise noted in the examples, the
amounts of oils and other ingredients in the film are wt% after the film
formulation
has been dried to create the film.
The amounts of the specific essential oils used in the film compositions can
vary as long as they are in amounts sufficient to provide antimicrobial
efficacy.
Generally the amount of thymol, methyl salicylate and eucalypto! is from about
0.01 to
about 4 wt % of the film composition, preferably about 0.50 to about 3.0 wt %
and
even more preferably from about 0.70 to about 2.0 wt % of the film. Menthol
can be
added from about 0.01 to about 15 wt % of the composition, preferably about
2.0 to
about 10 wt % and even more preferably from about 3 to about 9 wt % of the
film.
The amounts added can be readily determined to those skilled in the art and
can
8
CA 02520986 1999-09-23
exceed these amounts as long as the total oil content does not create sticking
or other
processing problems. In certain embodiments, the essential oils are combined
in
amounts synergistically effective to kill the plaque-producing germs that
cause dental
plaque, gingivitis and bad breath.
A major difficulty in formulating a film having such a relatively high oil
content is that simply increasing the amount of oil in the film without
determining the
precise proportions of the many other ingredients typically results in a film
that is too
moist and therefore difficult to handle or process. The inventors have
discovered how
to provide a high oil content film that is moist enough so that it is not
brittle, but is not
so moist that it feels undesirably slimy or significantly adheres to adjacent
films.
Thus, a non-self-adhering film according to the invention can be stored in
contact with
another such film (e.g., in a stack), or can be wound about itself (e.g.,
around a spool),
without having to place a non-stick agent (e.g., a plastic film, paper or
other support)
between adjacent portions of film.
The film-forming agent used in the films according to the present invention
can
be selected from the group consisting of pullulan, hydroxypropylmethyl
cellulose,
hydroxyethyl cellulose, hydroxypropyl cellulose, polyvinyl pyrrolidone,
carboxymethyl
cellulose, polyvinyl alcohol, sodium alginate, polyethylene glycol, xanthan
gum,
tragacanth gum, guar gum, acacia gum, arabic gum, polyacrylic acid,
methylmethacrylate copolymer, carboxyvinyl polymer. amylose, high amylose
starch,
hydroxypropylated high amylose starch, dextrin, pectin, chitin, chitosan,
levan,
9
CA 02520986 1999-09-23
elsinan, collagen, gelatin. zein, gluten, soy protein isolate. whey protein
isolate, casein
and mixtures thereof. A preferred film former is pullulan, in amounts ranging
from
about 0.01 to about 99 wt %, preferably about 30 to about 80 wt %, more
preferably
from about 45 to about 70 wt % of the film and even more preferably from about
60 to
about 65 wt % of the film.
The film of the invention preferably comprises pullulan as a film-forming
agent
and the essential oils as antimicrobial/flavoring agents, and can further
comprise
water, additional antimicrobial agents, additional film-forming agents,
plasticizing
agents. additional flavoring agents, sulfur precipitating agents, saliva
stimulating
agents, cooling agents, surfactants, stabilizing agents, emulsifying agents,
thickening
agents, binding agents, coloring agents, sweeteners, fragrances, and the like.
Due to the relatively high oil content in the oral care film, it is preferable
to
avoid substantial amounts of humectant in the film (and more preferable to
have no
humectant in the film), so as to avoid producing an overly moist, self-
adhering film.
In particular, it is preferred to fonnulate the film with a plasticizing agent
other than
glycerin, which is also a humectant, and with a sweetener other than sorbitol,
which is
a mild humectant.
Sulfur precipitating agents that reduce oral malodor can also be added to the
oral care films according to the present invention. These agents bind with,
and
inactivate, the volatile sulfur compounds that cause a large percentage of
oral malodor.
Sulfur precipitating agents useful in the present invention include metal
salts such as
CA 02520986 1999-09-23
copper salts and zinc salts. Preferred salts include copper gluconate, zinc
citrate and
zinc gluconate. The amount of sulfur precipitating agent is from about 0.01 to
about 2
wt %, preferably about.15 wt % to about 1.5 wt %, even more preferably about
.25 wt
% to about 1.0 wt % of the film.
Saliva stimulating agents can also be added to the oral care films according
to the
present invention. Useful saliva stimulating agents are those disclosed in
U.S. Patent No.
4,820,506. Saliva stimulating agents include food acids such as citric,
lactic, malic, succinic,
ascorbic, adipic, fumaric and tartaric acids. Preferred food acids are citric,
malic and ascorbic
acids. The amount of saliva stimulating agents in the film is from about 0.0 i
to about 12 wt
%, preferably about 1 wt % to about 10 wt %, even more preferably about 2.5 wt
% to about
6 wt %.
Preferred plasticizing agents include triacetin in amounts ranging from about
0
to about 20 wt %, preferably about 0 to about 2 wt %. Other suitable
plasticizing
agents include monoacetin and diacetin.
Preferred cooling agents include monomenthyl succinate, in amounts ranging
from about 0.001 to about 2.0 wt %, preferably about 0.2 to about 0.4 wt %. A
monomenthyl succinate containing cooling agent is available from Mane, Inc.
Other
suitable cooling agents include WS3TM, WS23TM, UltracoolTMII and the like.
Preferred surfactants include mono and diglycerides of fatty acids and
polyoxyethylene
sorbitol esters, such as, AtmosTM 300 and PolysorbateTM 80. The
11
CA 02520986 1999-09-23
surfactant can be added in amounts ranging from about 0.5 to about 15 wt %,
preferably about I to about 5 wt % of the film. Other suitable surfactants
include
pluronic acid, sodium lauryl sulfate, and the like.
Preferred stabilizing agents include xanthan gum, locust bean gum and
carrageenan, in amounts ranging from about 0 to about 10 wt %, preferably
about 0.1
to about 2 wt % of the film. Other suitable stabilizing agents include guar
gum and the
like.
Preferred emulsifying agents include triethanolamine stearate, quaternary
ammonium compounds, acacia, gelatin, lecithin, bentonite, veegum, and the
like, in
amounts ranging from about 0 to about 5 wt %, preferably about 0.01 to about
0.7 wt
% of the film.
Preferred thickening agents include methylcellulose, carboxyl methylcellulose,
and the like, in amounts ranging from about 0 to about 20 wt %, preferably
about 0.01
to about 5 wt %.
Preferred binding agents include starch, in amounts ranging from about 0 to
about 10 wt %, preferably about 0.01 to about 2 wt % of the film.
Suitable sweeteners that can be included are those well known in the art,
including both natural and artificial sweeteners. Suitable sweeteners include,
e.g.:
A. water-soluble sweetening agents such as monosaccharides,
disaccharides and polysaccharides such as xylose, ribose, glucose (dextrose),
mannose,
galactose, fructose (levulose), sucrose (sugar), maltose, invert sugar (a
mixture of
12
CA 02520986 1999-09-23
fructose and glucose derived from sucrose), partially hydrolyzed starch, cocn
syrup
solids, dihydrochalcones, monellin, steviosides, and glycyrrhizin;
B. water-soluble artificial sweeteners such as the soluble saccharin
salts, i.e., sodium or calcium saccharin salts, cyclamate salts, the sodium,
ammonium
or calcium salt of 3,4-dihydro-6-methyl-1,2,3-oxathiazine-4-one-2, 2-dioxide,
the
potassium salt of 3,4-dihydro-6-methyl-1,2,3-oxathiazine-4-one-2,2-dioxide
(acesulfameTM-K), the free acid form of saccharin, and the like;
C. dipeptide based sweeteners, such as L-aspartic acid derived
sweeteners, such as L-aspartyl-L-phenylalanine methyl ester (aspartameTM) and
materials
described in U.S. Pat. No. 3,492,131, L-
alpha-aspartyl-N-(2,2,4,4--tetramethyl-3-thietanyl)-D-alaninamide hydrate,
methyl
esters of L-aspartyl-L-phenylglycerin and L-asparryl-L-2,5,dihydrophenyl-
glycine,
L-aspartyl-2,5-dihydro- L-phenylalanine, L-aspartyl-L-(1-cyclohexyen)-alanine,
and
the like;
D. water-soluble sweeteners derived from naturally occurring
water-soluble sweeteners, such as a chlorinated derivative of ordinary sugar
(sucrose),
known, for example, under the product description of sucralose; and
E. protein based sweeteners such as thaumatoccous danielli
(ThaumatinTM I and II).
In general, an effective amount of auxiliary sweetener is utilized to provide
the
level of sweetness desired for a particular composition, and this amount will
vary with
13
CA 02520986 1999-09-23
the sweetener selected. This amount will normally be 0.01 % to about 10 % by
weight
of the composition when using an easily extractable sweetener. T'lte water-
soluble
sweeteners described in category A above, are usually used in amounts of about
0.01
to about 10 wt %, and preferably in amounts of about 2 to about 5 wt %. Some
of the
sweeteners in category A (e.g., glycyrrhizin) can be used in amounts set forth
for
categories B-E below due to the sweeteners' known sweetening ability. In
contrast,
the sweeteners described in categories B-E are generally used in amounts of
about
0.01 to about 10 wt %, with about 2 to about 8 wt % being preferred and about
3 to
about 6 wt % being most preferred. These amounts may be used to achieve a
desired
level of sweetness independent from the flavor level achieved from any
optional flavor
oils used. Of course, sweeteners need not be added to films intended for non-
oral
administration.
The flavorings that can be used include those known to the skilled artisan,
such
as natural and artificial flavors. These flavorings may be chosen from
synthetic flavor
oils and flavoring aromatics, and/or oils, oleo resins and extracts derived
from plants,
leaves, flowers, fruits and so forth, and combinations thereof. Representative
flavor
oils include: spearmint oil, cinnamon oil, peppermint oil, clove oil, bay oil,
thyme oil,
cedar leaf oil, oil of nutmeg, oil of sage, and oil of bitter almonds. Also
useful are
artificial, natural or synthetic fruit flavors such as vanilla, chocolate,
coffee, cocoa and
citrus oil, including lemon, orange, grape, lime and grapefruit and fruit
essences
including apple, pear, peach, strawberry, raspberry, cherry, plum, pineapple,
apricot
14
CA 02520986 1999-09-23
and so forth. These flavorings can be used individually or in admixture.
Commonly
used flavors include mints such as peppermint. artificial vanilla, cinnamon
derivatives,
and various fruit flavors, whether employed individually or in admixture.
Flavorings
such as aldehydes and esters including cinnamyl acetate, cinnamaldehyde,
citral,
diethylacetal, dihydrocarvyl acetate, eugenyl formate, p-methylanisole, and so
forth
may also be used. Generally, any flavoring or food additive, such as those
described in
Chemicals Used in Food Processing, publication 1274 by the National Academy of
Sciences, pages 63-258, may be used. Further examples of aldehyde flavorings
include, but are not limited to acetaldehyde (apple); benzaldehyde (cherry,
almond);
cinnamic aldehyde (cinnamon); citral, i.e., alpha citral (lemon, lime); neral,
i.e. beta
citral (lemon, lime); decanal (orange, lemon); ethyl vanillin (vanilla,
cream);
heliotropine, i.e., piperonal (vanilla, cream); vanillin (vanilla, cream);
aipha-amyl
cinnamaldehyde (spicy fruity flavors); butyraldehyde (butter, cheese);
valeraldehyde
(butter, cheese); citronellal (modifies, many types); decanal (citrus fruits);
aldehyde
C-8 (citrus fruits); aldehyde C-9 (citrus fruits); aldehyde C-12 (citrus
fruits); 2-ethyl
butyraldehyde (berry fruits); hexenal, i.e. trans-2 (berry fruits); tolyl
aidehyde (cherry,
almond); veratraldehyde (vanilla); 2,6-dimethyl- 5-heptenal, i.e. melonal
(melon);
2-6-dimethyloctanal (green fruit); and 2-dodecenal (citrus, mandarin); cherry;
grape;
mixtures thereof; and the like.
The amount of flavoring employed is normally a matter of preference subject to
such factors as flavor type, individual flavor, and strength desired. Thus,
the amount
CA 02520986 1999-09-23
may be varied in order to obtain the result desired in the final product. Such
variations
are within the capabilities of those skilled in the art without the need for
undue
experimentation. In general, amounts of about 0.1 to about 30 wt % are useable
with
amounts of about 2 to about 25 wt % being preferred and amounts from about 8
to
about 10 wt % are more preferred.
The compositions of this invention can also contain coloring agents or
colorants. The coloring agents are used in amounts effective to produce the
desired
color. The coloring agents useful in the present invention, include pigments
such as
titanium dioxide, which may be incorporated in amounts of up to about 5 wt %,
and
preferably less than about I wt %. Colorants can also include natural food
colors and
dyes suitable for food, drug and cosmetic applications. These colorants are
known as
FD&C dyes and lakes. The materials acceptable for the foregoing spectrum of
use are
preferably water-soluble, and include FD&C Blue No. 2, which is the disodium
salt of
5,5-indigotindisulfonic acid. Similarly, the dye known as Green No. 3
comprises a
triphenylmethane dye and is the monosodium salt of 4-[4-N-ethyl-p-
sulfobenzylamino)
diphenyl-methyleneJ-[ 1-N-ethyI-N-p-sulfoniurn benzyl)-2,5-cyclo-
hexadienimineJ. A
full recitation of all FD&C and D&C dyes and their corresponding chemical
structures
may be found in the Kirk-Othmer Encyclopedia of Chemical Technology, Volume 5,
Pages 857-884.
Antimicrobial Efficacy of Oral Care Films
The preferred embodiment of the oral care film composition according to the
16
CA 02520986 1999-09-23
present invention contains the essential oils used in Listerine mouthwash to
provide
antimicrobial efficacy. The films are shaped and sized to be placed in the
oral cavity.
The film adheres to a surface in the mouth, usually the roof of the mouth or
the
tongue, and quickly dissolves. The amount of essential oils in one individual
film that
is a preferred size for placing in the mouth is significantly lower than that
in the
recommended amount, 20m1, of Listerine mouthwash.
In a preferred formula according to the present invention, the amount of
thymol
and eucalyptol in the film is about 70 times less than in the mouthwash. The
amount
of methyl salicylate in the film is about 46 times less than in the mouthwash.
The
amount of menthol in the film is about 2.8 times less than in the mouthwash.
These
figures are based on comparing a 20 ml dose of liquid mouthwash with a 0.0358
gram
film.
The inventors have unexpectedly found that the film provides sustained
antimicrobial efficacy at these low amounts of oils. The inventors believe
that the
efficacy of the essential oils is enhanced by the creation of a layer of
pullulan in the
oral cavity that holds the essential oils. This is unexpected because pullulan
is water-
soluble and the film dissolves very quickly.
The extended antimicrobial activity is shown in the following experiments.
The purpose of these experiments was to determine the antibacterial efficacy
of
an application of a breath film on tongue malodor microorganisms thirty, sixty
or
ninety minutes after use. The thirty minute study also tested the efficacy of
using two
17
CA 02520986 1999-09-23
films. Subjects' baseline oral malodor microbial recoverable counts were
determined
by plating the microorganisms recovered from a tongue swab on a selective agar
medium. The test product was dispensed and subjects dissolved one or two
breath
films on their tongue. Subjects remained on the premises and retumed for a
second
tongue swab thirty, sixty or ninety minutes after placement of the test
product on their
tongue. After a forty-eight hour washout period, subjects returned for a no
treatment
control.
The thirty minute single film use group showed a reduction in mean log
malodor microbial counts compared to the control group. The data was
borderline
statistically significant (p=0.052). The difference between the one film group
and the
no treatment control group represented a 42.7% reduction in malodor microbial
colony
counts.
Statistically significant malodor microbial reduction was also observed with
the
two film use group. A 79.6% reduction in malodor microbial colony counts was
obtained (p<O.OO l ).
Statistically significant malodor microbial reduction was observed sixty
minutes after use of a single breath film. A 69.8% reduction in malodor
microbial
colony counts was obtained (p=0.002).
Significant malodor reduction was also observed ninety minutes after use of a
single breath film. A 69.1% reduction in malodor microbial colony counts was
obtained (p=0.006).
18
CA 02520986 1999-09-23
The data from these studies support the following conclusions: (i) Pullulan
polymer-based breath film containing essential oils is an effective
antibacterial
composition against oral malodor causing bacteria and (2) significant in vivo
bacterial
reductions were achieved at thirty, sixty and ninety minutes post use.
Experimental Procedures
The procedures used in these antimicrobial studies were as follows. The
subject were required to refrain from all oral hygiene procedures (e.g.,
toothbrushing,
oral lavage) eating or drinking any food, beverage or confectionery products
from
midnight prior to the study and until the study was completed on each test
day.
Subjects refrained from smoking on mornings prior to the odor evaluations.
In vivo Germ Kill Assay
1. Materials
Test tubes containing 10 ml of sterile 0.01 % peptone
Sterile Swabs
OOPS IIIT"' Agar (B.-F. Turng, G.E. Minah, and W.A. Falkler. Development of
an Agar Medium for Detection of Oral H2S-producing Organisms. J Dent Res
76 IADR Abstracts 1997.):
Columbia Agar Base (Catalogue # DF0792-17-3) 44 grams
Distilled Water 1 liter
Lead Acetatea (Sigma L3396) 0.2 grams
Hemin Solutionb (Sigma H-1652) 2 ml
19
CA 02520986 1999-09-23
Glutathione' (Sigma G4251TM) 1.2 grams
Forty-four grams of Columbia Blood Agar Base was suspended in 1 liter
distilled water and boiled to dissolve completely. The media was sterilized at
121-124 C for 15 minutes.
Dissolved 0.2 grams of lead acetate in 1 ml of distilled H20 and filter
sterilized.
Added after autoclaving the base media.
b Dissolved 50 mg of hemin in 1 ml of iN NaOH; qs'd to 100 ml with distilled
HZO.
Filter sterilized. Added 2 ml per liter of OOPS III after autoclaving base
media.
' Dissolved 1.2 grams of glutathione in 10 ml of distilled H20. Filter
sterilized.
Added after autoclaving base media.
2. Procedure
a. All media were prereduced in an anaerobic chamber overnight. Plates were
loosely wrapped in plastic bags to prevent excessive drying.
b. Panelists refrained from oral hygiene, eating and drinking from midnight
prior
to the assay and until the assay was complete. Twelve panelists were used for
the sixty and ninety minute experiments. Eighteen panelists were used for the
thirty minute experiments.
c. Each panelist swabbed the right side of his tongue by placing the swab at
the
midpoint of the tongue and swiping forward to the tip. The swab was placed in
a tube of peptone.
d. The panelist received a film treatment, either a single or double film.
Panelists
CA 02520986 1999-09-23
placed the breath film on the left side of their tongue covering the tongue
from
the midpoint to the tip and allowed the film to dissolve with the mouth
slightly
open for thirty seconds to prevent the film from sticking to the palate.
e. After thirty or sixty minutes, panelists swabbed the left side of the
tongue by
placing the swab at the midpoint of the tongue and swiping forward to the tip.
The swab was placed in a tube of peptone.
f. The tubes of peptone were vortexed vigorously for 10 seconds, and serial
dilutions were made. The l0 dilution was plated in duplicate on OOPS III
Agar using a Spiral Biotech Autoplate 4000TM (Bethesda, MD). All plates were
identified with the subject's initials, assay date, sampling time station, and
replicate number.
g. The plates were incubated in an anaerobic chamber at 35-37 C for 7 days to
permit full development of colonies without overgrowth.
h. After a 48 hour wash out period, panelists retumed for the no treatment
control.
No film was applied, and steps (e) through (g) were followed as described
above.
i. After a 48 hour wash out period, the sixty minute panelists returned for
another
single film application. Steps (a) through (h) were followed, with the
exception
that panelists returned after 90 min in step e.
j. The dark-pigmented colonies (H2S-producing organisms) were counted as
whole plate counts by hand under appropriate magnification or by Segment
21
CA 02520986 1999-09-23
counts using a Spiral BiotechTM counting template. The appropriate code was
entered on the data sheet to permit interpretation of the counts. The CFU's
counted were converted to CFU/ml by dividing by the appropriate exponential
volume constant listed in Table A and multiplying by 1000. This value was
then multiplied by the dilution factor of the plate (10 ).
Table A. Exponential Volume Constants for Segment Pairs
Last Counted Segment Exponential Volume Constant
8 1.214
9 2.968
5.500
11 9.157
12 14.482
13 25.015
Total Plate 50.030
The film used in the in vivo germ kill tests was Example 19 as described in
Table 2. The films used in the study were approximately 22mm x 32mm, between
10 about 0.00 13 and 0.0015 inches thick and weighed between about 35 to about
37 mg.
The enhanced activity of the essential oil containing pullulan film is also
shown
in Figures 1 and 2. Figure 1 is a photograph of an agar plate spread with
Streptococcus mutans, ATCC # 25175, to which a piece of an essential oil
pullulan
22
CA 02520986 1999-09-23
film according to the present invention was added. The piece of film delivered
approximately .391 mg of essential oils using Example 15 listed below.
Figure 2 is a photograph of an agar plate spread with Streptococcus mutans,
ATCC # 25175 to which drops of essential oils have been added. The drops were
148
ul in volume and contained 0.391 mg of essential oils. The percentages of each
essential oil in the drop are 2.200% menthol, 0.186% eucalyptol, 0.186% methyl
salicylate and 0.1300% thymol in a hydro alcohol solution.
The area or zone of inhibition around the film in Figure 1 is much larger than
the dimensions of the film. This is due to the presence of pullulan because
the oils in
the pullulan film were spread by the pullulan, diffused outward and did not
wash away
after repeated rinses. In contrast, the essential oils in Figure 2 did not
diffuse away
from the droplet, remained as a circle and easily washed off after 1-2 rinses.
This
shows that the antimicrobial efficacy of the essential oils is enhanced by the
presence
of pullulan.
Methods For Preparing Essential Oil Containing Films
Methods for preparing 6lms according to the invention are capable of
encapsulating the oil ingredients within the film-forming matrix and
maintaining the
integrity of the film, even when the film contains oils in amounts of 10 wt %
or more.
In certain methods for preparing films according to the invention, the film-
forming ingredients are mixed and hydrated with water separately from the
water-
soluble ingredients, which are mixed in aqueous solution separately from the
organic
23
CA 02520986 2006-06-29
ingredients and surfactants. In these methods, the final formulation is
preferably
produced by mixing the film-forming phase with the aqueous phase, then mixing
in
TM TM
the organic phase, which includes surfactants, such as Polysorbate 80 and
Atmos 300.
This mass is mixed until emulsified. In other embodiments, the aqueous and
film
forming phases are combined into a single phase by dissolving the water
soluble
ingredients in the water and then adding the gums to hydrate. The organic
phase is
then added to this single aqueous phase.
The resulting formulation is cast on a suitable substrate and dried to form a
film. The film is preferably air-dried or dried under warm air and cut to a
desired
dimension, packaged and stored. The film can contain from about 0.1 % to about
10
wt % moisture, preferably from about 3 % to about 8 wt % moisture, even more
preferably from about 4 to about 7 wt % moisture.
The film-forming phase can include pullulan and stabilizing agents such as
xanthan gum, locust bean gum and carrageenan. These ingredients are mixed and
then
hydrated in water for about 30 to about 48 hours to form a gel. The water is
preferably
heated to a temperature of about 25 to about 45 C to promote hydration. The
amount
of water is about 40 to 80 % of the gel. The resulting hydrated gel is then
chilled to a
temperature of about 20 to about 30 C for about I to about 48 hours. The
water is
preferably deionized.
The aqueous phase can include ingredients such as coloring agent(s), copper
gluconate and sweetener. The water is preferably deionized and the amount of
water
24
CA 02520986 1999-09-23
used is about 5 to about 80 wt % of the final gel mixture.
If sodium saccharin and copper gluconate are both ingredients in the
formulation, it is preferable to dissolve them separately in solution to avoid
precipitation.
In a preferred method of producing essential oil containing films according to
the invention, it is possible to hydrate the film-forming ingredients and
combine all of
the ingredients without heating. The preferred method of producing films
comprises
dissolving the water-soluble ingredients in water to form an aqueous mixture;
mixing
the film-forming ingredients in powder form to form a powder mixture; adding
the
powder mixture to the aqueous mixture to form a hydrated polymer gel; stirring
the
hydrated polymer at room temperature for about 30 minutes to about 48 hours;
mixing
the cooling agent, thymol and menthol in the flavor oil to form an oil
mixture; adding
methyl salicylate; eucalyptol and surfactants to the oil mixture; adding the
oil mixture
to the hydrated polymer gel and mixing until uniform; deaerating the film
until air
bubbles are removed, casting the uniform mixture on a suitable substrate; and
drying
the cast mixture to form a film.
The preferred method for making an essential oil containing film hydrates the
film-forming ingredients without heating the water. Heating the ingredients
increases
energy costs in the manufacturing process. Moreover, heating results in
undesirable
losses of volatile ingredients to evaporation, which also affects the germ
killing
activity of the composition due to the loss of essential oils. Further, mixing
the oils in
CA 02520986 1999-09-23
two steps minimizes the amount of flavor lost.
While not wishing to be bound by any theories, it is believed that the film-
forming ingredients can be hydrated and mixed without heating due to an ionic
effect
known as the Donnan equilibrium. Hydrating the film-forming agents in the
presence
of electrolytes in solution effectively lowers the viscosity of the polymer
gel being
formed, thus increasing the efficiency of the hydrating process. The water-
soluble
ingredients of the formulation provide the electrolytes, which are dissolved
in the
hydration solution prior to addition of the film-forming ingredients. High-
shear
mixing also accelerates hydration, which delumps the powders, providing
greater
surface area for water contact. In addition, local heating effects, generated
in the shear
regions, provide energy for hydration without substantially raising the
temperature of
the mass.
It is preferable to avoid adding both copper gluconate and saccharin at the
same
time to the aqueous solution, as a precipitate will form. Thus, it is
preferred to
combine sweeteners other than saccharin with copper gluconate.
Description of Film Compositions That Deliver Pharmaceutical Agents
A second embodiment of the invention is a fast dissolving film that includes
at
least one physiologically acceptable, pharmaceutically active agent. The
expression
"physiologically acceptable" as used herein is intended to encompass
compounds,
which upon administration to a patient, are adequately tolerated without
causing undue
negative side effects. The expression encompasses edible compounds.
26
CA 02520986 1999-09-23
The expression "pharmaceutically active agents" as used herein is intended to
encompass agents other than foods, which promote a structural and/or
functional
change in and/or on bodies to which they have been administered. These agents
are
not particularly limited; however, they should be physiologically acceptable
and
compatible with the film. Suitable pharmaceutically active agents include, but
are not
limited to:
A. antimicrobial agents, such as triclosan, cetyl pyridium chloride,
domiphen bromide, quatemary ammonium salts, zinc compounds, sanguinarine,
fluorides, alexidine, octonidine, EDTA, and the like,
B. non-steroidal anti-inflammatory drugs, such as aspirin,
acetaminophen, ibuprofen, ketoprofen, diflunisal, fenoprofen calcium,
naproxen,
tolmetin sodium, indomethacin, and the like,
C. anti-tussives, such as benzonatate, caramiphen edisylate, menthol,
dextromethorphan hydrobromide, chlophedianol hydrochloride, and the like,
D. decongestants, such as pseudoephedrine hydrochloride,
phenylepherine, phenylpropanolamine, pseudoephedrine sulfate, and the like,
E. anti-histamines, such as brompheniramine maleate,
chlorpheniramine maleate, carbinoxamine maleate, clemastine fumarate,
dexchlorpheniramine maleate, diphenhydramine hydrochloride, diphenylpyraline
hydrochloride, azatadine meleate, diphenhydramine citrate, doxylamine
succinate,
promethazine hydrochloride, pyrilamine maleate, tripelennamine citrate,
triprolidine
27
CA 02520986 1999-09-23
hydrochloride, acrivastine, loratadine, brompheniramine, dexbrompheniramine,
and
the like,
F. expectorants, such as guaifenesin, ipecac, potassium iodide,
terpin hydrate, and the like,
G. anti-diarrheals, such a loperamide, and the like,
H. H2 -antagonists, such as famotidine, ranitidine, and the like; and
I. proton pump inhibitors, such as omeprazole, lansoprazole, and
the like,
J. general nonselective CNS depressants, such as aliphatic alcohols,
barbiturates and the like,
K. general nonselective CNS stimulants such as caffeine, nicotine,
strychnine, picrotoxin, pentylenetetrazol and the like,
L. drugs that selectively modify CNS function such as
phenyhydantoin, phenobarbital, primidone, carbamazepine, ethosuximide,
methsuximide, phensuximide, trimethadione, diazepam, benzodiazepines,
phenacemide, pheneturide, acetazolamide, sulthiame, bromide, and the like,
M. antiparkinsonism drugs such as levodopa, amantadine and the
like,
N. narcotic-analgesics such as morphine, heroin, hydromorphone,
metopon, oxymorphone, levorphanol, codeine, hydrocodone, xycodone, nalorphine,
naloxone, naltrexone and the like,
28
CA 02520986 1999-09-23
0. analgesic-antipyretics such as salycilates, phenylbutazone,
indomethacin, phenacetin and the like,
P. psychopharmacological drugs such as chlorpromazine,
methotrimeprazine, haloperidol, clozapine, reserpine, imipramine,
tranylcypromine,
phenelzine, lithium and the like.
The amount of medicament that can be used in the rapidly dissolving films,
according to the present invention, is dependent upon the dose needed to
provide an
effective amount of the medicament. Examples of doses for specific medicaments
that
can be delivered per one strip of rapidly dissolving oral film are reviewed in
Table 1.
TABLE I
MEDICAMENT DOSE
Chlo heniramine Maleate 4 mg.
Brompheniramine Maleate 4 mg.
Dexchlorpheniramine 2 m .
Dexbrompheniramine 2 mg.
Triprolidine Hydrochloride 2.5 mg.
Acrivastine 8 mg.
Azatadine Maleate I m .
Loratidine 10 m .
Phen le hrine Hydrochloride 10 m.
Dextromethorphan Hydrochloride 10-20 mg.
Ketoprofen 12.5 mg.
Sumatri tan Succinate 35 - 70 mg.
Zolmitriptan 2.5 mg.
Loperamide 2 mg.
Famotidine 10 m .
Nicotine 2 mg.
Di henh dramine Hydrochloride 25 mg.
Pseudoephedrine Hydrochloride 30 mg.
29
CA 02520986 1999-09-23
The ingredients used to make the pharmaceutical containing films are similar
to
those used to make oral care films. Specifically, the plasticizing agents,
cooling
agents, surfactants, stabilizing agents, emulsifiers, thickening agents,
binding agents,
film formers, sweeteners, flavors and colors described above can also be used
in all of
the films according to the present invention.
The films that deliver a pharmaceutical agent can also include a triglyceride.
Examples of triglycerides include vegetable oils such as com oil, sunflower
oil, peanut
oil, olive oil, canola oil, soybean oil and mixtures thereof. A preferred
triglyceride is
olive oil. The triglyceride is added to the film in amounts from about 0.1 wt
% to
about 12 wt %, preferably in a range from about 0.5 wt % to about 9 wt %, of
the film.
The films that contain pharmaceutical agents also can include a preservative.
The preservative is added in amounts from about 0.001 wt % to about 5 wt %,
preferably from about 0.01 wt % to about 1 wt % of the film. Preferred
preservatives
include sodium benzoate and potassium sorbate.
The pharmaceutical agent containing films can also include a polyethylene
oxide compound. The molecular weight of the polyethylene oxide compound ranges
from about 50,000 to about 6,000,000. A preferred polyethylene oxide compound
is
N-10T"' available from Union Carbide Corporation. The polyethylene oxide
compound is
added in amounts from about 0.1 wt % to about 5 wt %, preferably from about
0.2 wt
% to about 4.0 wt % of the film.
The pharmaceutical agent containing films can also include propylene glycol.
CA 02520986 1999-09-23
The propylene glycol is added in amounts from about I wt % to about 20 wt %,
preferably from about 5 wt % to about 15 wt % of the film.
The active ingredient used in the film can be coated to mask the taste of the
active ingredient or to prevent the active ingredient from numbing the tongue
or other
surfaces in the oral cavity. The coatings that can be used are known to those
skilled in
the art. These include polymers such, as Eudragit E, cellulosics, such as
ethylcellulose, and the like.
An additional way to mask the taste of the active ingredient is by using an
ion
exchange resin such as Amberlite RP-69TM, available from Rohm and Haas, and
Dow XYS-
40010.OOTM, available from the Dow Chemical Co.
Examples
The invention will be illustrated in more detail with reference to the
following
Examples, but it should be understood that the present invention is not deemed
to be
limited thereto.
Preparation Method I
The following method was used to prepare the films of Examples 1-13.
A. The film-forming ingredients (e.g., xanthan gum, locust bean gum,
carrageenan and pullulan) other than Polysorbate 80 and Atmos 300 are mixed
and
hydrated in hot purified water to form a gel and stored in a refrigerator
ovemight at a
temperature of approximately 4 C to form preparation A.
B. The coloring agent(s), copper gluconate and sweetener are added to and
31
CA 02520986 1999-09-23
dissolved in purified water to form preparation B.
C. Preparation B is added to preparation A and mixed well to form
preparation C.
D. The flavoring agent and the oils (e.g., cooling agent, thymol, methyl
salicylate, eucalyptol and menthol) are mixed to form preparation D.
E. The polysorbate 80 and Atmos 300 are added to preparation D and
mixed well to form preparation E.
F. Preparation E is added to preparation C and mixed well to form
preparation F.
Preparation F is poured on a mold and cast to form a film of a desired
thickness
at room temperature. The FIm is dried under warm air and cut to a desired
dimension,
packaged and stored.
Preparation Method II
Examples 14-18 were prepared using a preferred method, which comprised the
following steps:
A. dissolve copper gluconate, acesulfame K. aspartame, glycerin,
sorbitol and dye in purified water to form an aqueous mixture;
B. mix pullulan, xanthan gum, locust bean gum and carrageenan
together in powder form to form a powder mixture;
C. add the powder mixture from step B to the aqueous mixture from
step A to form a hydrated polymer gel;
32
CA 02520986 1999-09-23
D. stir the hydrated polymer from step C at slow speed (about 50-
100 RPM) overnight at room temperature;
E. mix and dissolve cooling agent, thymol and menthol in the flavor
oil;
F. add methyl salicylate, eucalyptol, Polysorbate 80 and Atmos 300
to the oil mixture from step E;
G. add the oil mixture from step F to the hydrated polymer gel from
step D and mix until uniform;
H. cast the uniform mixture from step G on a suitable backing; and
I. dry the cast mixture to form a film.
Example 1
Example 1 produced a film according to the invention having a blue-green tint,
a mint odor and a refreshing mint taste.
Examples 2-4
Examples 2-4 contain sorbitol, glycerin or both. These examples yielded
products that easily broke off pieces, or were too moist and/or self-adhering.
However
they did produce films that rapidly dissolved in the oral cavity with a
refreshing mint
taste.
Examples 5-6
Examples 5 and 6 removed glycerin and sorbitol. The resultant films did not
stick together during processing and packaging and were more moisture stable
over a
33
CA 02520986 1999-09-23
long time frame.
Examples 7-9
Examples 7-9 were produced to determine the effect of Avicel on genm
killing activity. While Examples 7-9 produced more acceptable films from a
processing and handling perspective, they had diminished antimicrobial
activity
relative to films without Avicel , such as Example 8.
Examples 10-15
Examples 10 - 15 varied the amounts of aspartame and menthol to alter the
sweetness and coolness of the film.
Example 16
Example 16 was prepared by replacing the sorbitol replaced with maltitol,
which has less humectant properties. The resultant film was less sticky during
processing and long term storage.
Example 17
Example 17 is prepared in which pullulan is replaced with another film former,
polyvinyl pyrrolidone, to produce films according to the invention.
Example 18
Example 18 is prepared in which pullulan is partially replaced with another
film
former, konjac gum, to produce films according to the invention.
Example 19
Example 19 represents a film containing a salivary stimulant, citric acid.
34
CA 02520986 1999-09-23
Example 20
Example 20 is the film composition used in the antimicrobial efficacy studies
described above.
The formulas for examples 1- 20 are summarized in Table 2. The amounts in
these examples are presented as the actual weight (grams) or w/w %. These
formulas
create the solution/gel that is cast and dried into a film. The actual amount
of each
ingredient in the finished, dried film depends upon the amount of relative
moisture
removed during drying.
Table 2
In1;ledient Ex. 1 2 3 4 5 6 7 8 9
wMr A wt (9) wt (9) 'M (9) wt (9) wt (9) wt (9) wt (9) Wt (9)
Xanthan Gum, Food Grade 0.1070 11.60 12.60 11.60
Xanthan Gum 1% solutlon 3.85 3.85 3.85 3.85 3.85
Locust Bean Gum, Clarified 0.2150 23.40 25.40 23.40
Locust Bean Gum (1% 7.70 7.70 7.70 7.70 7.70
solution)
Pol in I Pyrrolidone
Konjac Gum
Carra eenan 1.0730 116.60 126.10 116.60
Carra eenan (5% solution) 7.70 7.70 7.70 7,70 7.70
500.00 500.00
Avicel
Puilulan 51.5780 5604.00 6513.00 5949.00
Pullulan (25% sol 74 74 74 74 74 N
Thymol NF 0.4070 0.146 0.146 0.146 40.70 40.70 40.70 0
Methyl Sali late NF 0.4210 0.151 0.151 0.151 58.50 58.50 58.50 01O0
Eucal tol 0.5850 0.21 0.21 0.21 42.10 42.10 42.10 O1
Menthol USP 5,8830 2.23 2.11 2.11 588.00 588.00 588.00 ~
Mint flavor 8.3640 2 3.0 3,0 836.00 836.00 836.00
Citric Acid
Co er luconate 1.1150 0.275 0.41 0.14 112.00 112.00 112.00 ~
Purifred water, USP/EP 22.32 2 10.22 12.22 8.0 8.0 2230.00 2230.00 2230.00
Sod. saccharin USP granulate 6.6910 1.8 1.4 1.4 2.0 2.4 W
Sodium saccharin 609.00 609.00 609.00
Acesutfame=K
Aspartame
Cooling agent 0.05 0.05 0.05 13.90 13.90 13.90
Maltitol
Sorbilol (crystalline) 64,30 64.30 64.30
Sorbitol 70% sol. 4 4.0
GI cerin 2 2.0 136.00 136.00 136.00
Polysorbate 80 NF/EP 0.5580 0.3 0.2 0.2 0.2 0.2 112.00 112.00 112.00
Almos 300 0.5580 112.00 112.00 112.00
Atlas 3000 0.3 0.2 0,2 0.2 0.2
Ni Set C Starch 77.0
FDBC Green 0 3 0.0084 0.3 0,3 0.3 0,3 0.3 0.84 0.84 0.84
D&C Yellow #10
Table nt.
ln redient 10 11 12 13 14 15 16 17 18 19 20
~' -- - wt (9) wt (9) wt (9) wt (9) w!w /a wMr96 wiw% w/w96 w/wQA whv96 wNv46
Xanthan Gum, Food Grade 0.0385 0.0385 0.0385 0.0385 0.0342 0.0342 0.0342 0.04
0.04 0.34 0.0342
Xanthan Gum 1 % sofution
Locust Bean Gum, Clarified 0.077 0.077 0.077 0.077 0.0684 0.0684 0.0684 0.07
0.07 0.68 0.0684
Locust Bean Gum (1%
solution)
Poi n l Pyrrolidone 16.5
Kon ac Gum 5.0
Carrageenan 0.385 0.385 0.385 0.385 0.342 0.342 0.342 0.34 0.34 .34 0.342
Carrageenan (5% solution)
Avicel
Pullulan 18.5 18.5 18,5 18.5 16.43 16.43 16.43 11.0 16.34 16.43 0
Pullulan (25% sol
cn
Th oi NF 0.146 0.146 0.146 0.146 0.130 0.13 0.13 0.13 0.13 0.129 0.13
Meth i Sali iate NF 0.21 0.21 0.21 0.21 0.186 0.186 0.186 0.186 0.186 0.185
0.18
Eucalyptol 0.21 0.21 0.21 0.21 0.186 0.186 0.186 0.186 0.186 0.185 0.18 00
Menthol USP 2.11 1.95 2.36 2.36 2.096 2.520 2.096 2.096 2.096 2.084 2.096
Mint flavor 3.0 3.0 3.0 3.0 2.664 2.344 2.664 2.664 2.664 2.849 2.0
Citric Acid 2.5
Copper gluconate 0.4 0.4 0.4 0.4 0.355 0,355 0.355 0.35 0.35 0.353 0.355
Purified water USP/EP 84.25 84.25 84.25 84.25 74.81 74.63 74.81 75 75 74.39
72.2168 1O
Sod. saccharin USP rv
ranulale
Sodium saccharin
Acesulfame-K 0.5 0.5 0.5 0.5 0.444 0.444 0.444 0.45 0.45 .04420 0.444
Aspartame 1.30 1.60 1.30 1.60 1.421 1,421 1.421 1.4 1.4 1.413 1.421
Cooling agent 0.10 0.10 0.10 0.10 0.089 0.089 0.089 0.089 0.089 0.088 0.89
Maltitol 2.80
Sorbitol C stalline
Sorbitol 70% sol. 0.199
Glycerin 0.418
Polysorbate 80 NF/EP 0.4 0.4 0.4 0.4 0.355 0.355 0.355 0.355 0.355 0.353 0.355
Atmos 300 0.355 .0355 0.355 0.355 0.355 0.353 0.355
Atlas 3000 0.4 0.4 0.4 0.4
Hi Set C Starch
FD&C Green 0 3 0.003 0.003 0.003 0.003 0.0026 0,0026 0.0026 0.0026 0.0026
D&C Yellow 010
CA 02520986 1999-09-23
The following examples are films according to the second embodiment of the
present invention, in which the rapidly dissolving film contains a
pharmaceutical
agent. Examples 21A-21E, listed in Table 3, are medicament containing rapidly
dissolvable oral film formulas. The amounts in Table 3 are in milligrams.
TABLE 3
Exam le Number 21A 21 B 21C 21 D 21E
Dextromethorphan HBr 7.500
Phen le herine HCI 10.0000 10.0000
Chlo heniramine Maleate 4.0000
Lo ramide HCI 2.0000
Nicotine 2.0000
Xanthan Gum 0.0818 0.0818 0.0818 0.0818 0.0818
Locust Bean Gum 0.0954 0.0954 0.0954 0.0954 0.0954
Carrageenan 0.4088 0.4088 0.4088 0.4088 0.4088
Pullulan 21.8036 21.8036 21.8036 21.8036 21.8036
Sodium Benzoate 0.0954 0.0954 0.0954 0.0954 0.0954
Acesuifame Potassium Salt 0.6814 0.6814 0.6814 0.6814 0.6814
As artame NF 1.9078 1.9078 1.9078 1.9078 1.9078
Purified Water = ' ' ' '
Cooling agent 0.1363 0.1363 0.1363 0.1363 0.1363
Menthol 2.7255 2.7255 2.7255 2.7255 2.7255
Polysorbate 80 NF 0.4770 0.4770 0.4770 0.4770 0.4770
Atmos 300 0.4770 0.4770 0.4770 0.4770 0.4770
Pro lene Glycol 4.0882 4.0882 4.0882 4.0882 4.0882
Olive Oil 0.6814 0.6814 0.6814 0.6814 0.6814
Titanium Dioxide 0.3407 0.3407 0.3407 0.3407 0.3407
Total Dose Weight 41.5000 44.0000 48.0000 36.0000 36.0000
"Calculated assuming complete evaporation of water from the films after drying
Table 4 summarizes additional films according to the present invention. The
amounts in Table 4 are % w/w prior to drying.
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CA 02520986 1999-09-23
Tab1e 4
Examples 22A 228 22C 22D 22E 22F 22G 22H 221
Xanthan Gum .03 .03 .06 .03 .03 .03 .06 .06 .06
Locust Bean .07 .07 .07 .07 .07 .07 .07 .07 .07
Gum
Carrageenan 0.3 0.3 0.3 0.3 0.3 0.3 0.3 0.3 0.3
Pullulan 16.0 16.0 16.0 16.0 16.0 16.0 16.0 16.0 16.0
Sodium 0.1 0.1 0.1 .07 .07 .07 .07 .07 0.7
Benzoate
Acesutfame 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5
Potassium
Aspartame 1.4 1.4 1.4 1.4 1.4 1.4 1.4 1.4 1.4
Water qs100 qs100 qs100 Os100 qslOO qs100 qslOO qs1O0 OslOO
Cool I n g agent 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1
Menthol 2.0 2.0 2.0 1.3 2.0 2.0 2.0 2.0 2.0
Polysorbate 80 0.35 0.35 0.35 0.35 0.35 0.35 0.35 0.35 0.35
Atmos 300 0.35 0.35 0.35 0.35 0.35 0.35 0.35 0.35 0.35
Propylene 1.0 1.0 1.0 1.0 1.0 1.0 3.0 3.0 3.0
Glycol
Peg 1450 3.10 = - -
Olive Oil 1-2 2.0 2.0 .5-2 - .5
POIyOX N-10 - - - 1.0
Tttanium 0.25 0.25 0.25 0.25 - 0.25 0.25
Dioxide
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CA 02520986 1999-09-23
Example 22A was used to make films containing a) 7.5 mg of
dextromethorphan hydrobromide, b) 2.5 mg of tripolidine, c) 4.0 mg of
chlorpheniramine maleate and d) 12.5 mg of diphenhydramine hydrochloride.
Example 22B was used to make a film containing 10 mg of dextrometorphan
hydrobromide.
Example 22C was used to make a film containing 10 mg of dextromethorphan
hydrobromide.
Example 22D was used to make a film containing a) 10 mg of phenylepherine
hydrochloride, b) 10 mg of phenylepherine hydrochloride and 4 mg of
chlorpheniramine maleate and c) 10 mg of dextromethorphan hydrobromide.
Example 22E was used to make a film containing 7.5 mg dextromethorphan
hydrobromide.
Example 22F was used to make a film containing 20 mg of coated
dextromethorphan hydrobromide to provide a 7.5 mg dose.
Example 22G was used to make a film containing a) 7.5 mg dextromethorphan
hydrobromide, b) 10 mg phenylepherine hydrochloride and c) 10 mg
phenylepherine
hydrochloride and 4 mg chlorpheniramine maleate.
Example 22H was used to make a film containing 15 mg of dextromethorphan
hydrobromide.
Example 221 was used to make a film containing 15 mg of dextromethorphan
CA 02520986 1999-09-23
hydrobromide.
Processes For Making Pharmecutical Containing Films
Example 22A was made using the following procedure.
1. Add the sodium benzoate and sweeteners to water.
2. Mix the locust bean gum, xanthan gum and carrageenan together.
3. Add the gum mixture to the mixture of step 1 and mix until dissolved.
4. Mix the active ingredient with either water or propylene glycol. Heat if
needed.
5. Add the remaining ingredients to the mixture of step 4 or mix the
remaining ingredients in a separate mixture.
6. Add the mixtures of step 4 and step 5 to the mixture of step 3. Cast and
dry to make a film and cut to a size to achieve the desired dose.
Examples 22B-22E were made using the following procedure.
l. Add the sodium benzoate to water heated to 50 C. Mix to dissolve.
2. Separately, add the Peg 1450, titanium dioxide and active ingredient to
the mixture of step 1, mixing with each addition.
3. Mix the locust bean gum, xanthan gum and carrageenan together.
4. Add the gums to the mixture of step 2 and mix until dissolve.
5. Add the remaining ingredients together with heat if needed.
6. Add the mixture of steps 4 and 5 together. Cast and dry to make a film
and cut to a size to achieve the desired dose.
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CA 02520986 1999-09-23
Examples 22F - 221 were made in the same manner as Examples 20B - 20E,
except the active was dispersed right before the film was cast.
While the invention has been described in detail and with reference to
specific
examples thereof, it will be apparent to one skilled in the art that various
changes and
modifications can be made therein without departing from the spirit and scope
thereof.
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