U.S. patent application number 14/522795 was filed with the patent office on 2015-04-23 for disintegrable oral films.
The applicant listed for this patent is Novartis AG. Invention is credited to Christopher Edward FANKHAUSER, Stephan MEYER, Greg SLOMINSKI.
Application Number | 20150111928 14/522795 |
Document ID | / |
Family ID | 38372253 |
Filed Date | 2015-04-23 |
United States Patent
Application |
20150111928 |
Kind Code |
A1 |
FANKHAUSER; Christopher Edward ;
et al. |
April 23, 2015 |
Disintegrable Oral Films
Abstract
A water soluble film that is disintegrable in the oral cavity to
deliver an active agent is provided. The disintegrable film
includes at least one water soluble polymer and an active agent.
Also provided are methods for preparing the disintegrable oral film
and for using the disintegrable film to administer an effective
dosage of an active agent into the oral cavity for absorption
through the oral mucosa. According to certain embodiments, the
disintegrable film includes at least one water soluble polymer and
a nicotine active.
Inventors: |
FANKHAUSER; Christopher Edward;
(Eagle, NE) ; SLOMINSKI; Greg; (Elmwwod, NE)
; MEYER; Stephan; (Geneve, CH) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Novartis AG |
Basel |
|
CH |
|
|
Family ID: |
38372253 |
Appl. No.: |
14/522795 |
Filed: |
October 24, 2014 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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13329390 |
Dec 19, 2011 |
8871243 |
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14522795 |
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11675822 |
Feb 16, 2007 |
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13329390 |
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60774592 |
Feb 17, 2006 |
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Current U.S.
Class: |
514/343 |
Current CPC
Class: |
A61K 9/006 20130101;
A61K 47/36 20130101; A61K 47/10 20130101; A61K 47/38 20130101; A61P
25/34 20180101; A61K 9/0056 20130101; A61K 9/7007 20130101; A61K
31/465 20130101 |
Class at
Publication: |
514/343 |
International
Class: |
A61K 31/465 20060101
A61K031/465; A61K 47/36 20060101 A61K047/36; A61K 47/10 20060101
A61K047/10; A61K 47/38 20060101 A61K047/38; A61K 9/70 20060101
A61K009/70; A61K 9/00 20060101 A61K009/00 |
Claims
1-31. (canceled)
32. A disintegrable oral film having high mucoadhesivity to the
oral mucosa and slow disintegration rate, comprising: (a) at least
45 weight percent of at least one water soluble film forming
polymer, based on the total weight of the dry film; (b) an active
agent; and optionally (c) one or more compounds selected from the
group consisting of taste-modifying agents, bioadhesive agents,
coloring agents, stabilizing agents, inert fillers, emulsifying
agents, permeation enhancers, plasticizers, and preservatives;
wherein component (c) is not a pH adjusting agent or buffering
agent, and wherein said oral film maintains at least partial
integrity and active agent release capability after in vitro
exposure to artificial human saliva solution for at least 15
minutes.
33. The disintegrable oral film of claim 32, wherein said
disintegrable oral film comprises from about 45 to about 90 weight
percent of said at least one water soluble polymer, based on the
total weight of the dry film.
34. The disintegrable oral film of claim 32, wherein said
disintegrable oral film comprises a mixture of two different water
soluble film forming polymers.
35. The disintegrable oral film of claim 34, wherein said
disintegrable oral film comprises a mixture of a polyalkylene oxide
and a cellulose polymer.
36. The disintegrable oral film of claim 35, wherein said
polyalkylene oxide is polyethylene oxide and said cellulose polymer
is hydroxypropyl methylcellulose.
37. The disintegrable oral film of claim 36, wherein said ratio of
polyethylene oxide to hydroxypropyl methylcellulose in the film is
from about 1:2 to about 1:5.
38. The disintegrable oral film of claim 37, wherein said ratio of
polyethylene oxide to hydroxypropyl methylcellulose in the film is
about 1:2.
39. The disintegrable oral film of claim 37, wherein said ratio of
polyethylene oxide to hydroxypropyl methylcellulose in the film is
about 1:3.
40. The disintegrable oral film of claim 37, wherein said ratio of
polyethylene oxide to hydroxypropyl methylcellulose in the film is
about 1:4.
41. The disintegrable oral film of claim 37, wherein said ratio of
polyethylene oxide to hydroxypropyl methylcellulose in the film is
about 1:5.
42. The disintegrable oral film of claim 32 which additionally
comprises a gum.
43. The disintegrable oral film of claim 42 which comprises
hydroxypropyl methylcellulose and xanthan gum.
44. The disintegrable oral film of claim 42 which comprises
hydroypropyl methylcellulose and arabic gum.
45. The disintegrable oral film of claim 32, wherein said active
agent is a nicotine active.
46. A disintegrable oral film for delivery of nicotine comprising:
(a) a mixture of a polyalkylene oxide and a cellulose polymer,
wherein the ratio of said polyalkylene oxide to said cellulose
polymer present in said film is about 1:2 to about 1:5; (b) a
nicotine active; and optionally (c) one or more compounds selected
from the group consisting of taste-modifying agents, bioadhesive
agents, coloring agents, stabilizing agents, inert fillers,
emulsifying agents, permeation enhancers, plasticizers, and
preservatives; wherein component (c) is not a pH adjusting agent or
buffering agent.
47. The disintegrable oral film of claim 46, wherein said
polyalkylene oxide is polyethylene oxide said cellulose polymer is
hydroxypropyl methylcellulose.
48. The disintegrable oral film of claim 47, wherein said ratio of
polyethylene oxide to hydroxypropyl methylcellulose in the film is
about 1:2.
49. The disintegrable oral film of claim 47, wherein said ratio of
polyethylene oxide to hydroxypropyl methylcellulose in the film is
about 1:3.
50. The disintegrable oral film of claim 47, wherein said ratio of
polyethylene oxide to hydroxypropyl methylcellulose in the film is
about 1:4.
51. The disintegrable oral film of claim 47, wherein said ratio of
polyethylene oxide to hydroxypropyl methylcellulose in the film is
about 1:5.
52. The disintegrable oral film of claim 46 wherein said film
maintains at least partial integrity and active agent release
capability after in vitro exposure to artificial human saliva
solution for at least 15 minutes.
53. A dry oral film having high mucoadhesivity to the oral mucosa
and slow disintegration rate, comprising: (a) at least 45 weight
percent of at least one water soluble film forming polymer, based
on the total weight of the dry film; and (b) an active agent;
wherein said dry oral film maintains at least partial integrity and
active agent release capability after in vitro exposure to
artificial human saliva solution for at least 15 minutes, and
wherein said dry oral film does not contain a buffer or pH
adjusting agent.
54. A method of administering an active agent comprising: providing
a dry oral film of claim 53; and introducing said dry oral film
into the oral cavity.
Description
[0001] This application claims the benefit of U.S. Provisional
Application No. 60/774,592, filed Feb. 17, 2006.
[0002] The present invention relates to disintegrable oral films
for the delivery and release of an active agent into the oral
cavity. According to certain embodiments, the invention relates to
a slow disintegrating oral film containing a nicotine active for
delivery and release into the oral cavity. The slow disintegrating
oral film maximizes the absorption of the nicotine active through
the oral mucosa to alleviate cravings for nicotine.
BACKGROUND
[0003] Smoking of tobacco products, such as cigarettes, cigars, and
pipe tobacco, presents serious health risks to the tobacco user.
Additionally, the use of smoke-less tobacco products, such as
chewing tobacco (both short and broad leaf tobacco) and snuff, can
also result in serious health risks to the user.
[0004] While the serious health risks associated with the use of
tobacco products are well documented and widely publicized, many
habitual users are unable to quit using the tobacco products. The
inability to quit using tobacco products can be primarily
attributed to the fact that the user has developed a dependence on
the nicotine that is present in the tobacco products. The
dependence on nicotine manifests itself as nicotine cravings.
Accordingly, a nicotine addicted tobacco user must continually use
tobacco products to replenish the amount of nicotine in the blood,
thereby satisfying the nicotine craving.
[0005] In order to successfully quit using tobacco products, the
nicotine addicted tobacco user must overcome the nicotine cravings,
thereby diminishing the desire to use tobacco products. Certain
nicotine replacement therapies have been developed to assist the
habitual tobacco user to quit using tobacco products. These
nicotine replacement therapies attempt to temporarily replace some
of the nicotine in the blood that is lost when a habitual user
quits using tobacco products.
[0006] Nicotine replacement therapies have been developed and are
provided in a variety of product forms. Such nicotine replacement
products include, for example, nicotine containing gums, nicotine
containing inhalers, nicotine containing transdermal patches,
nicotine containing lozenges, and nicotine containing lollipops.
Nicotine containing gums, lozenges and patches have enjoyed
substantial commercial success.
[0007] One commercially available nicotine containing gum product
is available under the trademark NICORETTE. The nicotine containing
gums are generally supplied as individual pieces of chewable gum.
The user removes an individual piece of the nicotine containing gum
from the package and places it into the oral cavity. While the user
is chewing the gum, nicotine is released from the gum and is
absorbed by the oral mucosa. The nicotine containing gums, however,
must be used at regular intervals in order to maintain steady
levels of nicotine in the blood.
[0008] Nicotine containing gums may be used to relieve acute
cravings experienced by a tobacco user that is attempting to quit
smoking or smoke-less tobacco product use. For example, a single
piece of gum may be self-administered by an individual in response
to an acute nicotine craving. Such use of the nicotine gum
typically results in an increase in blood nicotine levels to
counteract the nicotine cravings. The tobacco user must repeatedly
self-administer nicotine containing gums to maintain steady
nicotine levels in the blood.
[0009] Commercially available nicotine containing transdermal
patches include, for example, NICODERM, NICOTROL, and HABITROL. The
nicotine transdermal patches are generally supplied as a patch
having an adhesive backing covered by a release liner to protect
the adhesive. The user of the patch removes the release liner from
the patch to expose the adhesive backing. The adhesive backing is
then applied to a suitable location on the dermis of the user,
thereby adhering the patch to the user. Over time, nicotine is
released from the patch and diffuses through the dermis and into
the blood. The nicotine containing transdermal patches are useful
for maintaining relatively steady blood level concentrations over
time by providing the user with a substantially continuous infusion
of nicotine while the patch is being worn.
[0010] Nicotine containing lozenges may be utilized in a similar
manner as nicotine containing gums to provide relief from acute
nicotine cravings. Commercially available nicotine containing
lozenges include, for example, those lozenges sold under the
trademarks COMMITS, STOPPERS, NIQUITIN, and NICOTINELLS. Similar to
the nicotine containing gums, a tobacco user, instead of choosing
to use a tobacco product, may self-administer a nicotine containing
lozenge to alleviate a nicotine craving.
[0011] While commercially available nicotine replacement products
provide some level of alleviation of both steady and acute tobacco
cravings, there is still an ongoing need to provide more effective
craving relief and to assist the tobacco user in quitting use of
the tobacco products.
[0012] Films for delivering a pharmacologically or cosmetically
active agent via the oral cavity have been developed. The films
generally comprise water soluble films that disintegrate in the
oral cavity and release the active agent that is incorporated the
film. Nicotine has been incorporated into water soluble films,
which upon disintegration of the film, releases nicotine into the
oral cavity. The prior art has focused on water soluble thin films
for achieving rapid disintegration or dissolution in the oral
cavity, in order to alleviate acute nicotine cravings. For these
rapidly disintegrating films, studies estimate that systemic
absorption of the nicotine active is merely 25% of the total amount
of the nicotine active initially present in the oral film dosage
unit. This low level of absorption of the nicotine active through
the oral mucosa can be directly attributed to the rapid
disintegration of the oral film, which does not permit sufficient
time for mucosal permeation. Thus, the vast majority of the
nicotine active present in the oral film is simply swallowed.
[0013] The prior art nicotine containing oral films, however, do
not address the difficulty associated with maximizing absorption of
the nicotine active through the oral mucosa. Thus, there remains a
need in the art for a slower disintegrating oral film that
disintegrates at a rate that maximizes the absorption of the
nicotine active through the oral mucosa, which thereby effectively
delivers a dose of nicotine active to a user in a sufficient amount
to reduce or eliminate nicotine cravings associated with the
cessation of tobacco usage.
SUMMARY
[0014] An oral film for delivering and releasing an active agent
into the oral cavity is provided. The composition of the oral film
provides a mucoadhesive film having a delayed or slow
disintegration and release of active agent from the film. The rate
of disintegration of the film and release of the active agent from
the film within the conditions of the oral cavity maximizes the
absorption of the active agent through the oral mucosa.
[0015] According to certain embodiments, said oral film comprises
at least about 45 weight percent of at least one water soluble film
forming polymer, based on the weight of the dry film, and an active
agent.
[0016] According to other embodiments, the oral film comprises a
mixture of a polyalkylene oxide and a cellulose polymer, wherein
the ratio of said polyalkylene oxide to said cellulose polymer
present in said film is about 1:2 to about 1:5, and an active
agent.
[0017] According to further embodiments, the oral film comprises at
least one water soluble film forming polymer and an active agent,
wherein said oral film maintains at least partial integrity and
active agent release capability after in vitro exposure to
artificial human saliva solution for at least 15 minutes.
[0018] A method for preparing a slow disintegrating oral film from
at least one water soluble film forming polymer and an active agent
is provided.
[0019] According to certain embodiments, the method for preparing a
slow disintegrating oral film comprises mixing together at least
one water soluble film forming polymer, an active agent and a
solvent to form a mixture; and forming a film from the mixture,
wherein said film comprises at least 45 weight percent of said at
least one water soluble film forming polymer, based on the total
weight of the dry film.
[0020] According to other embodiments, the method for preparing a
slow disintegrating oral film comprises mixing together at least
one polyalkylene oxide polymer, at least one cellulose polymer, and
an active agent to form a mixture; and forming a film from the
mixture, wherein the ratio of said polyalkylene oxide polymer to
said cellulose polymer present in said dry film is about 1:2 to
about 1:5 (wt/wt).
[0021] According to further embodiments, the method for preparing a
slow disintegrating oral film comprises mixing together at least
one water soluble film forming polymer and an active agent to form
a mixture; and forming a film from the mixture, wherein said oral
film maintains at least partial integrity and active agent release
capability after in vitro exposure to artificial human saliva
solution for at least 15 minutes.
[0022] A method of using a slow disintegrating oral film to
administer an effective amount of an active agent to the oral
cavity is further provided.
[0023] According to certain embodiments, the method of
administering an active agent comprises providing a slow
disintegrating oral film comprising least 45 weight percent of at
least one water soluble film forming polymer, based on the weight
of the dry film, and an active agent; and introducing said film
into the oral cavity.
[0024] According to other embodiments, the method of administering
an active agent comprises providing a slow disintegrating film
comprising a mixture of a polyalkylene oxide and a cellulose
polymer, wherein the ratio of said polyalkylene oxide to said
cellulose polymer present in said dry film is about 1:2 to about
1:5 (wt/wt), and an active agent; and introducing said film into
the oral cavity.
[0025] According to further embodiments, the method of
administering an active agent comprises providing a slow
disintegrating oral film comprising at least one water soluble film
forming polymer and an active agent, wherein said oral film
maintains at least partial integrity and active agent release
capability after in vitro exposure to artificial human saliva
solution for at least 15 minutes, and introducing said film into
the oral cavity.
BRIEF DESCRIPTION OF THE DRAWINGS
[0026] FIG. 1 is a graph showing the results of an in vitro release
of nicotine from three different oral film as compared to a release
of nicotine from a prior art film.
[0027] FIG. 2 is a graph showing the results of an in vitro mucosa
permeation test.
DETAILED DESCRIPTION
[0028] The invention relates to a slow disintegrating thin film for
delivering and releasing a cosmetically active agent, or
pharmacologically active agent to the oral cavity for absorption
through the oral mucosa. According to certain embodiments, the oral
film compositions for the delivery and release of an active agent
contains a nicotine active for delivery and release into the oral
cavity of an individual so that the nicotine active is absorbed
through the oral mucosa and directly enters the individual's
systemic circulation.
[0029] The dosage form may be a monolayer or multi-layer
mucoadhesive film, which comprises at least one water soluble film
forming polymer and an effective amount of an active agent. The
mucoadhesive film disintegrates when applied to the oral cavity to
release the active agent, which is then absorbed through the oral
mucosa and directly reaches systemic circulation.
[0030] According to certain embodiments, the oral film comprises at
least about 45 weight percent of one or more water soluble film
forming polymers, based on the total weight of the dry film. The
disintegrable thin film includes a pharmacologically active agent
that is compatible with the water soluble film forming polymer(s).
The active agent incorporated into the oral film is released upon
disintegration of the film and can be absorbed through the oral
mucosa. The composition of the disintegrable oral film is such that
the oral film has a disintegration time in the oral cavity of
greater than 30 seconds and as much as 15 or more minutes.
"Disintegration time" is the time in which the integral oral film
breaks down and is no longer recognized as an integral unit after
being brought into contact with saliva, water, or similar solvent.
The integral dosage unit maintains partial integrity and active
agent release capability for at least 15 minutes after exposure to
artificial human saliva solution.
[0031] The oral film comprises at least one water soluble film
forming polymer. Water soluble film forming polymers that are
suitable for use in the present invention include, but are not
limited to, cellulose, cellulose derivatives, polyalkylene oxides,
polyalkylene glycols, synthetically or naturally occurring gums,
acrylic acid polymers, acrylic acid copolymers, methacrylic acid
polymers, methacrylic acid copolymers, polyacrylamides,
carrageanan, pullunan, polyvinyl pyrrolidone, polyvinyl alcohol,
alginic acid, polyethylene glycol-polyvinyl alcohol copolymers,
salts of alginic acid, carboxyvinyl polymers, and mixtures
thereof.
[0032] Without limitation, suitable cellulose derivatives include
alkyl celluloses, such as methyl cellulose and ethyl cellulose,
substituted alkyl celluloses, such as hydroxyethyl cellulose,
hydroxypropyl cellulose, hydroxypropyl methylcellulose,
carboxymethyl cellulose, salts of substituted alkyl celluloses,
such as sodium carboxymethyl cellulose, and mixtures thereof.
[0033] Without limitation, suitable gums include xanthan gum,
tragacanth gum, guar gum, acacia gum, arabic gum, and mixtures
thereof.
[0034] The slow disintegrating oral film may comprise a mixture of
polyethylene oxide and hydroxypropyl methylcellulose as the water
soluble film forming polymers. The film forming polymers
polyethylene oxide and hydroxypropyl methylcellulose may be present
in the dry film in an amount greater than 45 weight percent, based
on the total weight of the dry oral film.
[0035] According to certain embodiments, the film forming polymers
polyethylene oxide and hydroxypropyl methylcellulose may be present
in the dry film in an amount from greater than 45 weight percent to
about 90 weight percent, based on the total weight of the dry oral
film. According to other embodiments, the film forming polymers
polyethylene oxide and hydroxypropyl methylcellulose may be present
in the dry film in an amount from greater than 45 weight percent to
about 75 weight percent, based on the total weight of the dry oral
film. According to further embodiments, the film forming polymers
polyethylene oxide and hydroxypropyl methylcellulose may be present
in the dry film in an amount from greater than 45 weight percent to
about 50 weight percent, based on the total weight of the dry oral
film.
[0036] According to certain embodiments, the disintegrable oral
film comprises a blend or mixture of a polyalkylene oxide, a
cellulose polymer and the active agent. The weight ratio of the
polyalkylene oxide to cellulose polymer in the dry film may be
about 1:2 to about 1:5.
[0037] According to certain illustrative embodiments, the
disintegrable oral film comprises a mixture of polyethylene oxide
and hydroxypropyl methylcellulose. Without limitation, a suitable
polyethylene oxide polymer for use in the oral film is commercially
available from The Dow Chemical Company under the trademark POLYOX.
POLYOX polyethylene oxide polymers are non-ionic, film forming
water soluble polymers that may be calendered, extruded, injection
molded or cast. The molecular weights of the POLYOX polyethylene
oxide polymers range from about 100,000 to about 8,000,000. Without
limitation, a particularly suitable POLYOX polymer that may used in
the oral film is POLYOX N-80. POLYOX N-80 has an approximate
molecular weight of 200,000 and a viscosity of about 65 to about
115 mPa/s (5% aqueous solution at 25.degree. C.).
[0038] Without limitation, suitable hydroxypropyl methylcellulose
polymers for use in the oral film are commercially available from
The Dow Chemical Company under the trademark METHOCEL. A
particularly suitable METHOCEL polymer that may used in the oral
film is METHOCEL E50. METHOCEL E50 is a hydroxypropyl
methylcellulose polymer having an approximate molecular weight of
30,000.
[0039] A special embodiment of the invention is characterized by a
disintegrable oral film comprising: at least 45 weight percent of
at least one water soluble film forming polymer, based on the total
weight of the dry film; and an active agent, wherein said
disintegrable oral film comprises a mixture of a polyalkylene
oxide, preferably polyethylene oxide, and a cellulose polymer,
preferably hydroxypropyl methylcellulose.
[0040] The oral film is used to deliver and release a wide variety
of active agents to the oral cavity. The term "active agents"
includes cosmetically or pharmacologically active agents which may
be delivered to the oral cavity. Non-limiting examples of suitable
active agents include tooth whitening materials, breath fresheners,
anti-cavity compounds, anti-calculus compounds, anti-anginals,
anti-anxiety, anti-oxidants, anti-convulsants, anti-diabetic
agents, anti-diarrheal agents, anti-epileptic agents,
anti-inflammatory agents, anti-psychotic agents, anti-pyretic
agents, anti-spasmodic agents, analgesics, antihistamines, local
anesthetics, anti-bacterial compounds, disinfectants,
vasoconstrictors, hemostatics, chemotherapeutics, antibiotics,
tooth desensitizing agents, anti-fungals, vasodilators,
anti-hypertensives, anti-migraine, anti-arrhythmics,
anti-asthmatics, anti-depressants, cardiac agents, calcium
antagonists, central nervous system actives, cold remedies, cough
remedies, decongestants, diuretics, nicotine, vaccines, peptides or
prodrugs, hormones, proton pump inhibitors, H2 receptor
antagonists, vitamins and other dietary and nutritional
supplements. The above list of active agents is merely provided to
illustrate the types of active agents which may be incorporated
into the oral film. It should be noted, however, that any other
compatible cosmetically or pharmacologically active agent or
combinations of agents may be included in the slow disintegrating
oral film.
[0041] The above list of active agents has been described in
connection with preparation of oral films for delivery of
cosmetically and pharmacologically active agents humans. However,
it is within the scope of the present invention to incorporate
cosmetically or pharmacologically active veterinary agents into the
slow disintegrating oral films for delivery to non-human
animals.
[0042] According to certain embodiments, the oral film comprises at
least one water soluble film forming polymer and a nicotine active
as the active agent. The term "nicotine active" refers free
nicotine base, nicotine derivatives, nicotine salts, salts of
nicotine derivatives, nicotine complexes, and combinations or
mixtures thereof. A variety of nicotine actives are well known in
the art and are commercially available.
[0043] Nicotine salts include any physiologically acceptable salt,
such as hydrochloride, dihydrochloride, sulfate, tartrate,
bitartrate, zinc chloride, salicylate, alginate, ascorbate,
benzoate, citrate, edetate, fumarate, lactate, maleate, oleate and
sorbate, formed by the interaction of nicotine and any acid.
Particularly useful nicotine salts include but are not limited to,
nicotine monotartrate, nicotine bitartrate, nicotine hydrochloride,
nicotine dihydrochloride, nicotine sulfate, nicotine zinc chloride
monohydrate, nicotine salicylate, and mixtures thereof.
[0044] Suitable nicotine complexes include, but are not limited to,
nicotine oils, nicotine complexed with cyclodextrin, nicotine
complexed with polymer resins, and combinations or mixtures
thereof.
[0045] The slow disintegrating oral films comprise at least one
nicotine active in an amount sufficient to reduce or alleviate
nicotine cravings. The phrase "at least one nicotine active" refers
to an oral film comprising one nicotine active, or a mixture of
more than one nicotine active. In certain embodiments, the amount
of nicotine active included in the oral film is from about 0.25 mg
to about 10 mg per dose unit.
[0046] According to certain embodiments, the amount of the nicotine
active included in the oral film is from about 0.25 to about 6 mg
per dose unit. According to other embodiments, the amount of
nicotine active included in the oral film is from about 0.25 to
about 4 mg per dosage unit. According to further embodiments, the
amount of nicotine active included in the oral film is from about 1
to about 3 mg per dosage unit.
[0047] The disintegrable oral films may contain one or more of the
following optional components: taste modifying agents, bioadhesive
agents, buffering agents, coloring agents, stabilizing agents,
inert fillers, emulsifying agents, permeation enhancers, pH
adjusting agents, plasticizers, and preservatives.
[0048] Without limitation, suitable taste modifying agents for use
in the disintegrable oral film include flavorants, sweeteners,
taste-masking agents, and mixtures thereof. Suitable taste
modifying agents include, but are not limited to, the essential
oils or water soluble extracts of menthol, wintergreen, peppermint,
sweet mint, spearmint, vanillin, cherry, butterscotch, chocolate,
cinnamon, clove, lemon, orange, raspberry, rose, spice, violet,
herbal, fruit, strawberry, grape, pineapple, peach, kiwi, papaya,
mango, coconut, apple, coffee, plum, watermelon, nuts, green tea,
grapefruit, banana, butter, chamomile, sugar, dextrose, lactose,
mannitol, sorbitol, sucrose, sucralose, xylitol, malitol,
aspartame, saccharin, sodium saccharin, sodium cyclamate,
acesulfame K, and honey.
[0049] Without limitation, suitable colorants for use in the
disintegrable oral film include pigments, dyes, natural food colors
that are suitable for food and drug applications, such as FD&C
coloring agents, and mixtures thereof.
[0050] Without limitation, suitable stabilizing agents for use in
the oral thin films include chelating agents. Chelating agents are
used to prevent oxidation of the disintegrable oral film. A
particularly useful chelating agent is ethylenediaminetetraacetic
acid (EDTA). Any chelating agents that can be incorporated into a
solid pharmaceutical preparation may be utilized in the oral
film.
[0051] The oral film compositions may optionally include one or
more water soluble inert fillers. Without limitation, suitable
water soluble inert fillers for use in the disintegrable oral film
include mannitol, xylitol, glucose, fructose, sucrose, sucralose,
lactose, trehalose, maltodextrin, dextran, dextrin, modified
starches, dextrose, sorbitol, dextrates, and mixtures thereof.
[0052] Without limitation, suitable emulsifying agents for use in
the disintegrable oral film include solubilizers, wetting agents,
and release modifiers. Suitable emulsifying agents include, but are
not limited to, castor oil derivatives, cetyl alcohol, ethanol,
hydrogenated vegetable oils, polyvinyl alcohol, simethicone,
sorbitan ester, glyceryl monostearate, polyoxyethylene alkyl
ethers, polyoxyethylene stearates, poloxamer, polysorbates, and
mixtures thereof.
[0053] The oral film compositions may optionally include at least
one plasticizer. Suitable plasticizers which may be included in the
film composition include, but are not limited to, alkylene glycols,
polyalkylene glycols, glycerol, triacetin, deacetylated
monoglyceride, diethyl salate, triethyl citrate, dibutyl sebacate,
polyethylene glycols, and the like, and mixtures thereof.
[0054] The oral films may also optionally include one or more
"permeation enhancers." A "permeation enhancer" is a natural or
synthetic compound which facilitates the absorption of an active
agent through a mucosal surface. The phrase "one or more" is
intended to mean that a single permeation enhancer, or combinations
or mixtures of more than one permeation enhancer, may be included
in the oral film.
[0055] The oral film composition may also include one or more
preservatives. Suitable preservative include, but are not limited
to, butylated hydroxyanisole (BHA), butylate hydroxytoluene (BHT),
ascorbic acid, tocopherol derivatives, citric acid, parabens,
derivatives of parabens, sorbic acid, salts of sorbic acid, sodium
benzoate, propionic acid, salts of propionic acid, acetic acid,
salts of acetic acid, and mixtures thereof.
[0056] Methods for preparing the disintegrable oral film are
described. According to certain embodiments, the method for
preparing a disintegrable oral film includes mixing together at
least one water soluble film forming polymer, an active agent, a
compatible solvent, and optionally any one or more of the above
described optional components to form a homogenous mixture. A film
is formed from the mixture of water soluble film forming
polymer(s), active agent and optional components to provide a
disintegrable oral film containing at least 45 percent by weight of
said water soluble polymer(s), based on the total weight of the dry
film.
[0057] According to other embodiments, the method for preparing a
disintegrable oral film includes mixing together at least one
polyalkylene oxide polymer, at least one cellulose polymer, an
active agent, a compatible solvent, and any optionally one or more
of the above described optional components to form a homogenous
mixture. A film is formed from this mixture. The water polymer
polymers are combined together to provide a ratio of said
polyalkylene oxide polymer to cellulose polymer in the dry film of
about 1:2 to about 1:5 (wt/wt).
[0058] The homogenous mixture of film components is degassed and
uniformly coated onto a casting substrate at a predetermined
thickness and then dried. Alternatively, the homogenous mixture may
be extruded to form a film on a casting substrate The dried film
prepared from casting or extrusion is cut into various sizes to
produce individual dosage units. The dried film may be cut by any
known cutting method, such as, for example, die cutting, knife
cutting, or machine cutting.
[0059] Methods of using the disintegrable film for administering an
effective dosage of an active agent to the oral cavity of an
individual is also provided. According to illustrative embodiments,
the method includes using the disintegrable film to administer an
effective dosage of nicotine to the oral cavity of an individual
who desires to stop using tobacco products.
[0060] The thin film dosage form is applied to the oral cavity and
adheres to a mucosal surface, such as the cheek, palate, or tongue
as soon as the individual closes his or her mouth. The film
disintegrates and releases the nicotine active for absorption
through the oral mucosa. For example, the active may be absorbed by
the sublingual or buccal mucosa. The oral film has a high
mucoadhesivity to the oral mucosa and slow disintegration rate.
Because of the high mucoadhesivity and slow disintegration rate,
the nicotine active is absorbed substantially at the point of
adhesion within the oral cavity. Because the nicotine active is
absorbed through the oral mucosa, the amount of nicotine active
that is swallowed is minimized. The release of nicotine from the
thin film occurs without mastication, such as chewing or sucking of
the film. There is virtually no risk that an individual will choke
or accidentally swallow the whole dosage form, which may occur with
nicotine-containing tablets, capsules or lozenges.
EXAMPLES
[0061] The following examples are set forth to further illustrate
the oral films and methods of preparation. The below examples,
however, should not be construed as limiting the present invention
in any manner.
Example 1
[0062] A single layer disintegrable oral film was produced by
preparing a casting solution and casting a thin film from the
casting solution. The oral film comprised a mixture of POLYOX N80
and METHOCEL E50 at a weight ratio of 1:2.
[0063] Preparation of the Casting Solution
[0064] 451 g of deionized water was placed into a stainless steel
pot and heated on a hot plate to 80.degree. C. with mixing. To the
water solution, 0.03 g of FD&C blue coloring agent, 23.55 g of
POLYOX N80 and 47.14 g of METHOCEL E50 and were added and was mixed
at a high mixing speed. The stainless steel pot was removed from
the hot plate and transferred to a water bath and cooled. Once the
mixture had cooled, the stainless steel pot was removed from the
water bath and placed into an ice bath and mixed. The stainless
steel pot was removed from the ice bath and a menthol solution
(10.56 g of menthol in ethanol), 7.54 g of glycerin, 1.95 g of
sucralose, 49.53 g of peppermint flavor, and ethyl alcohol was
added with mixing. A nicotine solution was prepared by adding 4.01
g of nicotine bitartrate to 20 ml of deionized water. The nicotine
bitartrate solution was added to the thin film casting
solution.
[0065] Casting the Thin Film
[0066] The casting solution was coated on a polyvinyl chloride
casting liner and was dried at a temperature of about 70.degree. C.
for about 4 minutes. The resulting disintegrable thin film
contained 1 mg of nicotine in 484 mm.sup.2. The table below
indicates the weight percent of each component in the dry film.
TABLE-US-00001 Ingredient % in Dry Film Polyox .TM. N-80 (Dow)
16.32 Methocel .TM. E50 (Dow) 32.67 MENTHOL 7.32 Nicotine
bitartrate 2.78 Glycerin 5.22 Peppermint Flavor 34.32 Sucralose
1.35 FD&C Blue 0.02
Example 2
[0067] A single layer disintegrable oral film was produced by
preparing a casting solution and casting a thin film from the
casting solution. The oral film comprised a mixture of POLYOX N80
and METHOCEL E50 at a ratio of 1:3.
[0068] Preparation of the Casting Solution
[0069] 300 g of deionized water was placed into a stainless steel
pot and heated on a hot plate to 80.degree. C. with mixing. To the
water solution, 0.02 g of FD&C blue coloring agent, 11.77 g of
POLYOX N80 and 35.30 g of METHOCEL E50 and were added and was mixed
at a high mixing speed. The stainless steel pot was removed from
the hot plate and transferred to a water bath and cooled. Once the
mixture had cooled, the stainless steel pot was removed from the
water bath and placed into an ice bath and mixed. The stainless
steel pot was removed from the ice bath and a menthol solution (7 g
of menthol in ethanol), 5 g of glycerin, 1.3 g of sucralose, 33 g
of peppermint flavor, and ethyl alcohol was added with mixing. A
nicotine solution was prepared by adding 6.63 g of nicotine
bitartratc to 30 ml of deionized water. The nicotine bitartrate
solution was added to the thin film casting solution.
[0070] Casting the Thin Film
[0071] The casting solution was coated on a siliconized casting
liner at a coating wet thickness of 0.62 mm, and was dried at a
temperature of about 70.degree. C. for about 4 minutes. The
resulting disintegrable thin film contained 1 mg of nicotine in 484
mm.sup.2. The table below indicates the weight percent of each
component in the dry film.
TABLE-US-00002 Ingredient % in Dry Film Polyox .TM. N-80 11.77
Methocel .TM. E50 35.3 Menthol 7 Nicotine bitartrate 6.63 Glycerin
5 Peppermint Flavor 33 Sucralose 1.3 FD&C Blue 0.02
Example 3
[0072] A single layer disintegrable oral film was produced by
preparing a casting solution and casting a thin film from the
casting solution. The oral film comprised a mixture of POLYOX N80
and METHOCEL E50 at a ratio of 1:4.
[0073] Preparation of the Casting Solution
[0074] 300 g of deionized water was placed into a stainless steel
pot and heated on a hot plate to 80.degree. C. with mixing. To the
water solution, 0.02 g of FD&C blue coloring agent, 9.41 g of
POLYOX N80 and 37.65 g of METHOCEL E50 and were added and was mixed
at a high mixing speed. The stainless steel pot was removed from
the hot plate and transferred to a water bath and cooled. Once the
mixture had cooled, the stainless steel pot was removed from the
water bath and placed into an ice bath and mixed. The stainless
steel pot was removed from the ice bath and a menthol solution (7 g
of menthol in ethanol), 5 g of glycerin, 1.3 g. of sucralose, 33 g
of peppermint flavor, and ethyl alcohol was added with mixing. A
nicotine solution was prepared by adding 6.63 g of nicotine
bitartrate to 30 ml of deionized water. The nicotine bitartrate
solution was added to the thin film casting solution.
[0075] Casting the Thin Film
[0076] The casting solution was coated on a siliconized casting
liner at a coating wet thickness of 0.62 mm, and was dried at a
temperature of about 70.degree. C. for about 4 minutes. The
resulting disintegrable thin film contained 1 mg of nicotine in 484
mm.sup.2. The table below indicates the weight percent of each
component in the dry film.
TABLE-US-00003 Ingredient % in Dry Film Polyox .TM. N-80 9.41
Methocel .TM. E50 37.65 Menthol 7 Nicotine bitartrate 6.63 Glycerin
5 Peppermint Flavor 33 Sucralose 1.3 FD&C Blue 0.02
Example 4
[0077] A single layer disintegrable oral film was produced by
preparing a casting solution and casting a thin film from the
casting solution. The oral film comprised a mixture of POLYOX N80
and METHOCEL E50 at a ratio of 1:5 (wt/wt).
[0078] Preparation of the Casting Solution
[0079] 300 g of deionized water was placed into a stainless steel
pot and heated on a hot plate to 80.degree. C. with mixing. To the
water solution, 0.02 g of FD&C blue coloring agent, 7.84 g of
POLYOX N80 and 39.22 g of METHOCEL E50 and were added and was mixed
at a high mixing speed. The stainless steel pot was removed from
the hot plate and transferred to a water bath and cooled. Once the
mixture had cooled, the stainless steel pot was removed from the
water bath and placed into an ice bath and mixed. The stainless
steel pot was removed from the ice bath and a menthol solution (7 g
of menthol in ethanol), 5 g of glycerin, 1.3 g of sucralose, 33 g
of peppermint flavor, and ethyl alcohol was added with mixing. A
nicotine solution was prepared by adding 6.63 g of nicotine
bitartrate to 30 ml of deionized water. The nicotine bitartrate
solution was added to the thin film casting solution.
[0080] Casting the Thin Film
[0081] The casting solution was coated on a siliconized casting
liner at a coating wet thickness of 0.585 mm, and was dried at a
temperature of about 70.degree. C. for about 4 minutes. The dry
coat weight of the film was 0.956 g. The resulting disintegrable
thin film contained 1 mg of nicotine in 484 mm.sup.2. The table
below indicates the weight percent of each component in the dry
film.
TABLE-US-00004 Ingredient % in Dry Film Polyox .TM. N-80 7.84
Methocel .TM. E50 39.22 MENTHOL 7 Nicotine bitartrate 6.63 Glycerin
5 Peppermint Flavor 33 Sucralose 1.3 FD&C Blue 0.02
Example 5
[0082] A single layer disintegrable oral film was produced by
preparing a casting solution and casting a thin film from the
casting solution. The oral film comprised a mixture of POLYOX N80
and METHOCEL E50 at a ratio of 1:2.
[0083] Preparation of the Casting Solution
[0084] 458 g of deionized water was placed into a stainless steel
pot and heated on a hot plate to 80.degree. C. with mixing. To the
water solution, 0.03 g of FD&C blue coloring agent, 23.58 g of
POLYOX N80 and 47.12 g of METHOCEL E50 and were added and was mixed
at a high mixing speed. The stainless steel pot was removed from
the hot plate and transferred to a water bath and cooled. Once the
mixture had cooled, the stainless steel pot was removed from the
water bath and placed into an ice bath and mixed. The stainless
steel pot was removed from the ice bath and a menthol solution
(10.57 g of menthol in ethanol), 7.52 g of glycerin, 1.95 g of
sucralose, 49.51 g of peppermint flavor, and ethyl alcohol was
added with mixing. A nicotine solution was prepared by adding 9.94
g of nicotine bitartrate to 30 ml of deionized water. The nicotine
bitartrate solution was added to the thin film casting
solution.
[0085] Casting the Thin Film
[0086] The casting solution was coated on a siliconized casting
liner at a coating wet thickness of 0.70 mm, and was dried at a
temperature of about 70.degree. C. for about 4 minutes. The dry
coat weight of the film was 1.034 g. The resulting disintegrable
thin film contained 1 mg of nicotine in 600 mm.sup.2. The table
below indicates the weight percent of each component in the dry
film.
TABLE-US-00005 Ingredient % in Dry Film Polyox .TM. N-80 15.7
Methocel .TM. E50 31.37 Menthol 7.04 Nicotine bitartrate 6.62
Glycerin 5.01 Peppermint Flavor 32.96 Sucralose 1.3 FD&C Blue
0.02
Examples 6-8
In Vitro Drug Release
[0087] A 1.54 cm.sup.2 size samples of oral films were placed on a
Franz cell with a teflon filter as a support. An artificial human
saliva solution was prepared from 0.19 g/L K.sub.2PO.sub.4, 2.38
g/L Na.sub.2HPO.sub.4 and 8 g/L of NaCl in water. Approximately 8
ml of artificial saliva solution buffered at pH 7.4 with HEPES 25
mM and maintained as 37.degree. C., was introduced into the test
Franz cell.
[0088] The experiment was started by placing the artificial saliva
in contact with the oral film. 1 ml samples of the artificial
saliva solution were taken every 30 seconds for 15 minutes. The
removed artificial saliva volume (1 ml) was replenished with fresh
artificial saliva solution after each sample. The quantities of
nicotine released by the oral film was determined by HPLC analysis
of the collected samples. A total of three measurements were made
per formulation. The results of the in vitro drug release
experiments are shown in FIG. 1.
Example 8
In Vitro Buccal Mucosa Permeation
[0089] In vitro buccal mucosa permeation studies were performed at
35.degree. C. in Franz cells using porcine buccal mucosa tissue.
Fresh porcine buccal mucosa tissue was obtained and frozen at
-80.degree. C. Immediately prior to use, the porcine buccal mucosa
tissue was dermatomed to a thickness of 0.8 mm.
[0090] Approximately 8 ml of artificial saliva solution buffered at
pH 7.4 with 25 mM HEPES was added to the Franz cell. A test sample
of the oral film was placed in the Franz cell. The porcine mucosal
tissue was placed in the Franz cell and was brought into contact
with the oral film. The experiment was started when the artificial
saliva solution was put into contact with the oral film. After 3
minutes, the artificial saliva solution was removed and the Franz
cell was washed with distilled water. 0.75 ml of fresh artificial
saliva solution and approximately 8 ml of phosphate buffered saline
(PBS) was added to the Franz cell. Samples of the solution were
withdrawn from the Franz cell at various time intervals, namely, 0,
0.5, 1, 2, 3 and 4 hours. The removed solution volume (1 ml) was
replenished with an equal amount of fresh solution after each
withdrawal. The quantities of nicotine released after 3 minutes and
permeating the mucosa were determined by HPLC of the collected
samples. The results of the in vitro buccal permeation experiments
are shown in FIG. 2.
Example 9
[0091] Additional thin film prototypes were prepared from
formulations (A), (B) and (C) comprising Methocel.TM. E50 and E5
grades of HPMC in fixed amounts; and the effect of a gum such as
xantham gum on in vitro disintegration time was evaluated.
TABLE-US-00006 (A) (B) (C) Methocel .TM. E50 6.60 6.60 6.60
Methocel .TM. E5 13.20 13.20 13.20 Xanthan Gum 0.00 2.00 4.00
(Xantural .RTM. 180, CP Kelko) Total dry weight 19.80 21.80
23.80
[0092] In vitro disintegration time. All three formulations, when
contacted with human saliva, were transformed into a bio-adhesive
gel within a few seconds. (A) disintegrated in a few seconds; (B)
in 4 minutes; and (C) in 8 minutes. Thus, the addition of xanthan
gum was found to lengthen time to disintegration. (B) is a
preferred formulation for delivering nicotine active to the oral
cavity.
Example 10
[0093] Thin film prototypes according to the invention can also be
prepared comprising hydroxypropyl methylcellulose as the film
forming polymer and arabic gum. For example, arabic gum can be
substituted for xantham gum in formulations (A), (B) and (C) above,
to provide similar disintegration profiles.
[0094] The disintegrable oral films are useful as a nicotine
replacement therapy. The oral films are useful as a means to reduce
or stop tobacco usage, such as stopping the smoking cigarettes,
cigars, pipe tobacco, stopping the use of smokeless chewing
tobacco. The oral films may be used concurrently with tobacco in
any planned tobacco reduction program. Thus, the present invention
also relates to methods of reducing tobacco usage, comprising
orally administering one or more of the orally dissolving films of
the present invention to a person in need of such reduction. In
general, the disintegrable oral films may be administered to an
individual as needed to prevent or reduce nicotine cravings, within
any recommended or permitted limits. The orally dissolving films
are typically administered such that the nicotine active is
primarily delivered transbuccally in the mouth.
[0095] While the present invention has been described above in
connection with the certain illustrative embodiments, it is to be
understood that other similar embodiments may be used or
modifications and additions may be made to the described
embodiments for performing the same function of the present
invention without deviating therefrom. Furthermore, all embodiments
disclosed are not necessarily in the alternative, as various
embodiments of the invention may be combined to provide the desired
characteristics. Variations can be made by one having ordinary
skill in the art without departing from the spirit and scope of the
invention. Therefore, the present invention should not be limited
to any single illustrative embodiment, but rather construed in
breadth and scope in accordance with the recitation of the attached
claims.
* * * * *