Note: Descriptions are shown in the official language in which they were submitted.
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FILM DOSAGE FORM WITH EXTENDED RELEASE
MUCOADHESIVE PARTICLES
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This
application is a claims benefit of priority of U.S. Patent Application No.
15/588,897, filed May 8, 2017, and which are hereby incorporated by reference
in its entirety.
FIELD OF THE DISCLOSURE
[0002] This
disclosure relates generally to controlled release oral dosage forms,
especially those oral film dosage forms releasing an active agent over a
sustained period of
time.
BACKGROUND OF THE DISCLOSURE
[0003] Film
dosage forms that provide extended release of an active agent have been
known. Such film dosage forms are known to comprise at least two layers, which
include at
least one mucoadhesive layer to facilitate adhesion of the dosage form to
mucosa for an
extended period, and a layer that acts as a diffusion barrier that prevents or
restricts loss of the
active agent from the dosage form to saliva in the oral cavity and ultimately
to the
gastrointestinal tract. The active agent can be located in the mucoadhesive
layer or in a third,
reservoir layer between the mucoadhesive layer and the diffusion barrier
layer. Such multiple
layer film dosage forms require preparation of multiple formulations, casting
of multiple film
layers, and combining the multiple layers into a composite, such as by casting
one layer on
another layer, or using a lamination process. As a result, multiple layer film
dosage forms for
achieving sustained release of an active agent for local delivery in the
buccal cavity can be
difficult and expensive to produce. Multiple-layer, sustained-release film
oral dosage forms
can also be annoying to some patients, as the film dosage form must be
retained in the oral
cavity for an extended period, all the while providing a palpable sensation
that many patients
find undesirable. In addition, swelling of the mucoadhesive film, may also
present an important
source of discomfort to the patient.
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[0004] It has
been suggested that mucoadhesive particles can be incorporated into oral
dosage forms such as capsules, cachets, pills, tablets, lozenges, powders,
granules, syrups or
liquid suspensions to facilitate transport of an active agent across mucosal
barriers.
[0005] It has
also been suggested that mucoadhesive particles can be incorporated into
ophthalmic suspensions or administered rectally, parenterally,
intracisternally, intravaginally,
intranasally, intraperitoneally, topically, buccally or in an oral or nasal
spray.
SUMMARY OF THE DISCLOSURE
[0006] The
disclosed dosage forms facilitate controlled (e.g., sustained) release of an
active agent for local delivery in the buccal cavity, and transport through
oral mucosa, while
avoiding the discomfort associated with long lasting mucoadhesive films or
tablets that must
typically reside on the oral mucosa during the period of controlled release.
Controlled release
of an active agent for local action in the buccal cavity in accordance with
the disclosed dosage
form is achieved by providing a dosage form in which mucoadhesive particles of
a small size
(e.g., from several nanometers to several micrometers), which contain the
active agent, are
dispersed in a disintegrating film. Upon administration in the oral cavity,
the film disintegrates
(e.g., within an acceptable period of time) and releases the mucoadhesive
particles, some of
which will contact the oral mucosa and immediately become tenaciously bound to
the mucosa.
The active agent can be released from the mucoadhesive particles over a
prolonged period of
time as the mucoadhesive material slowly dissolves or erodes.
[0007] In
certain disclosed embodiments, the mucoadhesive particles are comprised of
a mucoadhesive, non-biodegradable polymer such as polyacrylic acid or a
copolymer of maleic
anhydride and a methylvinyl ether, maleic acid and a methylvinyl ether or
polymethacrylates-
based copolymers.
[0008] In
certain disclosed embodiments, the mucoadhesive particles are comprised of
a mucoadhesive biodegradable polymer such as poly-(D,L-lactide-co-glycolide).
[0009] In
certain disclosed embodiments, the mucoadhesive particles are made of an
oil particle with a polymer material located at the interface of the oil
particle or surrounding it.
This oil particle, containing the active agent, is also comprised of an oil
base, one or more
surfactants, a permeation enhancer, and an antioxidant.
[0010] The
disclosed dosage forms include those having a single layer comprising the
active agent-containing mucoadhesive particles dispersed in a disintegrating
film.
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[0011] The disclosed dosage forms can comprise at least two layers,
including at least
one layer formed from mucoadhesive particles dispersed in a distinguishing
film and at least
one layer formed from a mucoadhesive, non-mucoadhesive or controlled release
composition.
[0012] The disclosed dosage forms may comprise a single active agent that
is present
in only the mucoadhesive particles or in both the mucoadhesive particles and
in any of a free
form dispersed in the disintegrating film, in a granular, enterically coated,
or other controlled
release form that is dispersed in the disintegrating film along with the
mucoadhesive particles
or that is dispersed in a different film of a multiple layer dosage form.
[0013] The disclosed dosage forms providing transport of an agent for local
delivery
in a buccal cavity of a subject for a sustained period of time, may comprise a
disintegrable film
matrix; and mucoadhesive particles dispersed in the disintegrable film, the
particles comprising
a mucoadhesive material exhibiting adhesivity to the mucosa in the buccal
cavity and/or to the
gastrointestinal tract and at least a first active agent, wherein the
disintegratable film has a
disintegrating time within which 90% of the film is disintegrated, and wherein
the
mucoadhesive particles have a modulated erosion time within which 90% of the
mucoadhesive
material encapsulating the active agent is dissolved in the buccal fluid.
[0014] The disclosed dosage forms may deliver active agent locally in the
buccal cavity
for the topical treatment of a disease arising in the oral cavity.
[0015] The disclosed dosage forms may comprise active agents capable of
being
absorbed transmucosally such as active agents that are permeable to the buccal
mucosa.
Buccally permeable active agent are generally small molecules which are
soluble and
permeable. Buccally permeable active agent are generally classified as class I
active agents
according to the Biopharmaceutical Classification System.
[0016] The disclosed dosage form may also comprise nonpermeable active
agents or
active agents that are only permeable over a prolonged period of time. These
active agents are
thus preferably administered with a permeation or penetration enhancer.
However, since the
oral film matrix quickly disintegrates, a penetration enhancer dispersed in
the film matrix
would simply be swallowed with little effect other than possibly promoting
some penetration
of active agent comprised in the film matrix but not (or to very little
extent) the active agent
comprised within the mucoadhesive particles. For the penetration enhancer to
increase
permeation of active agent encapsulated in the mucoadhesive particles, the
permeation
enhancer can be included in the mucoadhesive particles. Disclosed is an oral
film dosage form
providing transport of an agent for delivery in the buccal cavity for buccal
absorption, the oral
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film dosage form comprising a disintegrable film and mucoadhesive particles
comprising
mucoadhesive material encapsulating an active agent and a penetration
enhancer.
[0017] The disclosed dosage forms providing transport of an agent for local
delivery
in a buccal cavity of a subject for at least two different agents for a
sustained period of time,
may comprise a disintegrable film matrix, first mucoadhesive particles
dispersed in the
disintegrable film, the first mucoadhesive particles comprising a mucoadhesive
material
exhibiting adhesivity to mucosa in the buccal cavity and a first active agent
that is released
over a sustained period and second mucoadhesive particles dispersed in the
disintegrable film,
the second mucoadhesive particles comprising a mucoadhesive material that is
different from
the first mucoadhesive material, exhibiting adhesivity to mucosa in the buccal
cavity that is
different from the first mucoadhesive particles and a second active agent that
is released over
a sustained period from the second mucoadhesive particles, wherein the first
mucoadhesive
particles have a first erosion time within which at least 90% of the
mucoadhesive material is
dissolved or dispersed and the second mucoadhesive particles have a second
erosion time
within which 90% of the mucoadhesive material is dissolved or dispersed, and
wherein the first
90% erosion time is different from the second 90% erosion time.
[0018] These and other features, advantages and objects of the various
embodiments
will be better understood with reference to the following specification and
claims.
DETAILED DESCRIPTION OF THE DISCLOSED EMBODIMENTS
[0019] The disclosed orally administrable dosage forms can be used to
provide
sustained release of an agent that is delivered for local action anywhere in
the buccal cavity or
under the tongue. The dosage forms can be employed in a variety of treatments
in which release
of a particular active agent in the buccal cavity or under the tongue over a
prolonged period of
time provides a beneficial effect. Examples include treatment of gingivitis,
buccal ulcers,
canker sores, SjOgren's syndrome, oral mucositis, and Behcet's disease.
[0020] According to certain embodiment, the sustained release dosage forms
are also
suitable for active agents with low permeation capability. Increasing the
residence time of the
active agent within the oral cavity through the mucoadhesion of the particles,
particularly with
mucoadhesive particles having an erosion time greater than that of
mucoadhesive oral film,
allows active agents having low permeation to be permeable to the buccal
mucosa and exhibit
improved transmucosal absorption. An example of active agents requiring
increased residence
time is tetrahydrocannabinol and its derivatives such as dronabinol.
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[0021]
Sustained release delivery of an agent for local delivery in the buccal cavity
is
achieved with a dosage form that is essentially imperceptible to the patient.
Rather than leaving
a mucoadhesive film or patch of substantial size on the oral mucosa during the
duration of the
extended treatment, the active agent is released from mucoadhesive particles
that are adhered
to oral mucosa and are of a size that is essentially unnoticeable to the
patient. The term
"particle" refers to a nanoscopic (1 to 1000 nm) or microscopic (1 to 1000
micrometers) solid
or semi-solid aggregate structures. The particles can be spherical or non-
spherical (e.g.,
ellipsoidal or rod-like) structures, with hollow or solid core, such as solid
spheres, micelles,
vesicles, liposomes or lamellaes. For example, it is possible to employ known
techniques to
form mucoadhesive particles comprising a mucoadhesive material and an active
agent that have
a particle size range from a few nanometers (e.g., 5 nm, 10 nm, 50 nm, 100 nm)
to a few
micrometers (e.g.,1 p.m, 100 p.m, 200 p.m, 300 p.m, 500 p.m).
[0022] The
term "bioadhesion" and "bioadhesivity" generally mean a material that
tends to adhere to living tissue to facilitate prolonged retention at a site
of application. A
mucoadhesive material is a bioadhesive material that can interact with mucus
or a mucosal
surface and thereby provide prolonged retention of a drug at a mucosal surface
as compared
with a simple liquid or powder system that does not include a bioadhesive
material.
[0023] In
order to reduce patient discomfort and facilitate rapid adhesion or
bioadhesion between the mucoadhesive particles and oral mucosa (e.g., buccal
mucosa), the
mucoadhesive particles are distributed in a disintegrating film. In certain
embodiments, the
film disintegrates completely without leaving a noticeable residue. As the
film disintegrates,
the mucoadhesive particles are released, with those contacting oral mucosa
immediately and
tenaciously bonding to the mucosa.
[0024] In the
case where particular areas of the buccal mucosa are targeted for
treatment, the dosage form can be placed immediately adjacent or in contact
with the targeted
mucosa. For example, a dosage form used to treat a canker sore on buccal
mucosa can be
positioned directly on the sore to promote disintegration of the film and
adhesion of the residual
mucoadhesive particles.
[0025] The
term "disintegrating" and variations thereof generally refers to the ability
of the film dosage forms to break up into particles and/or dissolve within an
acceptable period
of time (e.g., within less than 5 minutes, within 4 minutes, within 3 minutes,
within 2 minutes,
or within 1 minute or within 15 to 30 seconds of being administered, (i.e.,
placed in the oral
cavity of a subject). A "disintegrating time within which 90% of the film is
disintegrated"
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("90% disintegration") means that time at which the largest part of a film
submerged in a
simulated saliva solution comprises 10% of the weight of the original film
before it is contacted
with the simulated saliva (an aqueous solution buffered to a pH of about 6.7
to 7.4).
[0026]
Disintegrating films suitable for use in preparing the disclosed dosage forms
are
typically comprised of at least one water soluble polymer. In certain
embodiments, the
disintegrating film does not include insoluble polymers or other materials
that can leave a
gritty, unpleasant residue. Surfactants, polyalcohols, and or plasticizers may
be incorporated
into the disintegrating film to facilitate or enhance wettability and
disintegration of the film.
[0027] Water
soluble polymers that can be employed in the disclosed films include
water soluble cellulose derivatives, including hydroxypropylmethyl cellulose,
hydroxyethyl
cellulose, hydroxypropyl cellulose; polyvinyl pyrrolidone (PVP); copovidone (a
copolymer of
1-vinyl-2-pyrrolidone and vinyl acetate); other copolymers of vinyl
pyrrolidone; other
polymers or copolymers of substituted vinyl pyrrolidone; derivatives of
polyvinyl pyrrolidone;
polyethylene oxide, carboxymethyl cellulose; polyvinyl alcohol; natural gums,
including
xanthan, tragacanth, guar, acacia and arabic gums; and water soluble
polyacrylates.
Combinations of these water soluble polymers or other water soluble polymers
can also be
used. Examples of substituted vinyl pyrrolidones include N-vinyl-3-methyl-2-
pyrrolidone, N-
viny1-4-methy1-2-pyrrolidone, N-vinyl-5-methy1-2-pyrrolidone, N-viny1-5,5-
dimethy1-2-
pyrrolidone, N-vinyl-3,3,5-trimethy1-2-pyrrolidone and others. Examples of
monomers that
can be copolymerized with vinyl pyrrolidone or substituted vinyl pyrrolidones
include vinyl
aromatic monomers such as styrene, and acrylate or methacrylate monomers such
as methyl
methacrylate and 2-dimethylaminoethyl methacrylate.
[0028] The
terms "surfactant" and "polyalcohol" are intended to have their ordinary
meanings. Specifically, the term "surfactant" is intended to mean an
amphophilic compound
that lowers the surface tension of a liquid, the interfacial tension between
two liquids, or the
interfacial tension between a liquid and a solid. Examples of surfactants that
can be used in a
disintegrating film of an oral dosage form are known and include polyoxy-
ethylene sorbitan
fatty acid esters, an a-hydro-co-hydroxypoly (oxyethylene) poly (oxypropylene)
poly(oxyethylene) block copolymer, a polyoxyethylene allyl ether, a
polyoxyethylene or a
castor oil derivative. Combinations of surfactants can be used. The term
"polyalcohol" means
a sugar alcohol, which is a hydrogenated form of a carbohydrate having a
carbonyl group that
has been reduced to a primary or secondary hydroxyl group. Polyalcohols are
also
distinguishable based on their chemical formula. Polyalcohols have the general
formula
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H(HCH0).+11-1, whereas sugars have the general formula H(HCH0). HCO. Common
examples of polyalcohols or sugar alcohols that can be used from the disclosed
films include
glycol, glycerol, erythritol, threitol, arabitol, xylitol, ribitol, mannitol,
sorbitol, galactitol,
fucitol, iditol, inositol, volemitol, isomalt, maltitol, lactitol, maltotritol
and maltotetraitol.
[0029] The
term "penetration enhancer" as used herein to describe and claim the
invention refers to a substance that can increase buccal permeation of an
active ingredient by
enabling a transcellular route for transportation of the drug through the
buccal epithelium.
Certain non-limiting examples of pharmaceutically acceptable penetration
enhancers include
benzalkonium chloride, cetylpyridinium chloride, cyclodextrins, dextran
sulfate, lauric
acid/propylene glycol, menthol, oleic acid, oleic acid derivatives,
polyoxyethylene,
polysorbates (such as Polysorbate 80), sodium EDTA, sodium lauryl sulfate,
sodium salicylate.
[0030] In
certain embodiments, the disclosed films may include a plasticizer. The term
"plasticizer" refers to a component that reduces the glass-transition
temperature of the film
forming polymers (e.g., the water soluble polymer or water soluble polymers in
the film). The
plasticizer increases the flexibility, enhances elasticity and reduces
brittleness of the film.
Examples of plasticizers that can be used in the disclosed film oral dosage
forms include
polyethylene glycol, triacetin, triethyl citrate, tributyl citrate, acetyl
tributyl citrate, acetyl
triethyl citrate, trioctyl citrate, acetyl trioctyl citrate, trihexyl citrate,
dibutyl sebacate, glycerol
etc. Plasticizer may be added in an amount up to 25% of the total mass of the
film oral dosage
form, such as from 0.5% to 25%, 1% to 20%, 2% to 15% or 5% to 10%.
[0031]
Optionally, an active agent can be incorporated into the disintegrating film
in
an immediate release form (i.e., a form that is not incorporated into
sustained release
mucoadhesive particles), such as in a free particulate form or immediate
release granular form.
The agent incorporated into the disintegrating film in an immediate release
form can be the
same agent as in the mucoadhesive particles or a different agent.
[0032] The
term "agent" and "active agent" refer to any agent that is being administered
orally to a subject and includes pharmaceutically active agents,
nutraceutically active agents,
flavoring agents, and breath freshening agents. Examples of pharmaceutically
active agents
include ACE-inhibitors, antianginal drugs, anti-arrhythmics, anti-asthmatics,
anti-
cholesterolemics, analgesics, anesthetics, anti-convulsants, anti-depressants,
anti-diabetic
agents, anti-diarrhea preparations, antidotes, anti-histamines, anti-
hypertensive drugs, anti-
inflammatory agents, anti-lipid agents, anti-manics, anti-nauseants, anti-
stroke agents, anti-
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thyroid preparations, anti-tumor drugs, anti-viral agents, acne drugs,
alkaloids, amino acid
preparations, anti-tussives, anti-uricemic drugs, anti-viral drugs, anabolic
preparations,
systemic and non-systemic anti-infective agents, anti-fungal agents, anti-
neoplastics, anti-
parkinsonian agents, anti-rheumatic agents, appetite stimulants, biological
response modifiers,
blood modifiers, bone metabolism regulators, cardiovascular agents, central
nervous system
stimulates, cholinesterase inhibitors, contraceptives, decongestants, dietary
supplements,
dopamine receptor agonists, endometriosis management agents, enzymes, erectile
dysfunction
therapies such as sildenafil citrate, tadalafil, and vardenafil, fertility
agents, gastrointestinal
agents, homeopathic remedies, hormones, hypercalcemia and hypocalcemia
management
agents, immunomodulators, immunosuppressives, anti-migraine preparations such
as
rizatriptan, eletriptan and zolmitriptan, motion sickness treatments, muscle
relaxants, obesity
management agents, osteoporosis preparations, oxytocics, parasympatholytics,
parasympathomimetics, prostaglandins, psychotherapeutic agents, respiratory
agents,
sedatives such as lorazepam or diazepam, smoking cessation aids such as
bromocryptine or
nicotine, sympatholytics, tremor preparations, urinary tract agents,
vasodilators, laxatives,
antacids, ion exchange resins, anti-pyretics, appetite suppressants,
expectorants, anti-anxiety
agents such as alprazolam, anti-ulcer agents, anti-inflammatory substances,
coronary dilators,
cerebral dilators, peripheral vasodilators, psycho-tropics, stimulants, anti-
hypertensive drugs,
vasoconstrictors, antibiotics, tranquilizers, anti-psychotics, anti-tumor
drugs, anti-coagulants,
anti-thrombotic drugs, hypnotics, anti-emetics, anti-nauseants, anti-
convulsants,
neuromuscular drugs, hyper- and hypo-glycemic agents, thyroid and anti-thyroid
preparations,
diuretics, anti-spasmodics, terine relaxants, anti-obesity drugs,
erythropoietic drugs, anti-
astmatics, cough suppressants, mucolytics, DNA and genetic modifying drugs,
and
combinations thereof Examples of nutraceutically active agents include various
dietary
supplements, vitamins, minerals, herbs and nutrients. Breath freshening agents
include, for
example, spearmint oil, cinnamon oil, peppermint oil, clove oil, menthol, etc.
[0033] The
total amount of agent(s) that can be incorporated in the disintegrating films
disclosed herein is generally from 0.01% to 80% by total weight of the film,
such as 1% to
60%, 2% to 50%, or 5% to 40% by total weight of the film.
[0034] The
term "matrix" or "film matrix" refers to the polymer component or mixture
of polymers, which creates the film forming matrix supporting the API within
the oral film
dosage form. The mucoadhesive particles are dispersed within the film matrix.
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[0035] The
disclosed oral film dosage form may have various weight ratios of
film/particles. The film/particles weight ratios may vary depending on the
active agent. The
film/particles weight ratio is typically in the range of from about 1 to about
100 preferably in
the range of from about 5 to about 75 and more preferably in the range of from
about 10 to
about 50. In other words, the disclosed oral film dosage forms have a film
matrix that is about
1 to about 100 times, preferably about 5 to about 75 times, and more
preferably about 10 to
about 50 times the weight of the particles.
[0036]
Examples of mucoadhesive materials that can be used to prepare the
mucoadhesive particles include poly(ethylene oxide), polyvinyl pyrrolidone,
poly(acrylic acid)
derivatives (e.g., commercially available Carbopol0), polycarbophil polymers,
polyoxyalkylene ethers, polymethacrylates, polymethacrylates-based copolymers
(e.g.,
commercially available Eudragit0), biodegradable polymers such as poly(D,L-
lactide-co-
glycolide) (e.g., commercially available Resomer0), anionic biopolymers such
as hyaluronic
acid, or sodium carboxymethylcellulose, cationic biopolymers such as chitosan
or poly(L-
lysine) and other cellulose derivatives. Other mucoadhesive polymers that can
be used include
methyl vinyl ether-maleic acid, a mixed salt of sodium/calcium methyl vinyl
ether-maleic acid,
methyl vinyl ether-maleic anhydride, and half esters (monoethyl; monobutyl and
isopropyl
ester) of methyl vinyl ether-maleic anhydride copolymers (e.g., commercially
available
Gantrez0).
[0037]
Additional suitable mucoadhesive materials may be chosen from the group
consisting of alginate, pectin, hyaluronic acid (and esters thereof), agar
agarose, dextran,
ovalbumin, collagen casein and copolymers of glycolide-based monomers.
[0038] The
agent incorporated into the mucoadhesive particles can be any of the
previously listed active agents that can optionally be added, along with the
mucoadhesive
particles, to the disintegrating film in immediate release form or in a
controlled release form
that is not incorporated into a mucoadhesive.
[0039]
Examples of agents that can be beneficially employed in the mucoadhesive
particles are those for treating fungal or bacterial infections, gingivitis,
buccal ulcers, canker
sores, SjOgren's syndrome, oral mucositis, Behcet's disease or other
conditions that can be
beneficially treated from long exposure or controlled release (e.g., sustained
release) of an
agent for local delivery in the buccal cavity. Systemic treatments where there
is a pronounced
food effect or the bioavailability of the active product or for active
products that need to be
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absorbed in the upper gastrointestinal tract could also benefit from use of
the disclosed dosage
forms.
[0040]
Particular categories of agents that can be incorporated into the mucoadhesive
particles include antimicrobial agents including antibacterial agents and/or
antifungal agents,
such as triclosan, chlorhexidine, doxycycline, tetracycline, minocycline,
neomycin,
caspofungin, miconazole, micafungin, and anidulafungin; topical analgesic
agents such as
benzydamine, amlexanox, lidocaine and diclofenac; corticosteroid anti-
inflammation agents
such as hydrocortisone, beclomethasone dipropionate, clobetasol, betamethasone
sodium
phosphate, and dexamethasone; agents for modulating immune response such as
prednisolone,
colchicines, pentoxifylline, azothioprine, thalidomide, dapsone,
mycophenolate, mofetil,
adalimunab, vitamin B12, clofazimine, fevamizole, montelukast, and sulodexide;
and disease
modifying antirheumatic agents, such as methotrexate and hydroxychloroquine.
These and
other agents can be used alone or in combination, either incorporated into the
disintegrating
film in an immediate release form or non-mucoadhesive controlled release form,
in the
mucoadhesive particles, or both.
[0041] As a
specific example, for the treatment of canker sores, an antimicrobial agent
and a topical analgesic agent may be used together in the mucoadhesive
particles to provide
simultaneous treatment and relief from pain. Alternatively, or in addition,
the topical analgesic
agent can be incorporated as an immediate release agent in the disintegrating
film. As another
example, Sjogren's disease can be treated with a combination of cevimeline
and/or pilocarpine,
and optionally with a corticosteroid anti-inflammatory agent and/or a disease-
modifying anti-
rheumatic agent, which optional agents can be added in a free form to the
film, to the
mucoadhesive particles, or both to the mucoadhesive particles and in free form
to the film.
[0042]
According to certain embodiments, the disclosed oral film dosage form,
comprises particles that are mucoadhesive. Mucoadhesive particles as opposed
to
mucoadhesive film or tablet, may allow the film to be quickly disintegrated
and/or dissolved
and swallowed while the mucoadhesive particles remain in the buccal cavity,
preferably
adhered to the oral mucosa, thus removing discomfort generally felt from
administration of
known mucoadhesive dosage forms in which the entire film adheres to the mucosa
for a
prolonged period of time (residence time).
[0043]
According to certain embodiments of the present disclosure, the disclosed oral
film dosage form may be suitable for both buccal and enteral delivery. The
delivery of the API
will thus vary depending on the method of administration of the oral film
dosage form. This
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innovative mucoadhesive dosage form thus potentially allows two alternative
routes of
administration using a single oral dosage form. In such an embodiment, the
delivery of the
API will be dependent on the method of administration of the oral film dosage
form.
[0044]
According to certain embodiments, the oral film dosage form may be
administered for buccal delivery. When administered for buccal delivery of the
active agent,
the film is administered to the patient in a way that promotes film
disintegration in close
proximity to the oral mucosa. For instance, the film administered for buccal
delivery may be
given to a patient with the indication of being positioned against the oral
mucosa inside the
cheeks or under the tongue (administered sublingually). Therefore, once
disintegrated, the
mucoadhesive particles adhere to the mucosa and remain there for a specific
residence time.
The residence time of the mucoadhesive particles being substantially affected
by their
dissolution rate (also referred to as the erosion time), the quantity of
saliva present in the mouth,
and the size of the mucoadhesive particles. The faster the dissolution of the
mucoadhesive
particle the shorter the residence time and conversely, the longer the
dissolution time, the
greater the residence time. The extent to which the active agent is released
from the particles
may be modulated by the use of various mucoadhesive or polymer materials
generally having
distinct mucoadhesive properties or distinct viscosity and solubility, hence
having different
dissolution rates in saliva and consequently, different residence times. The
term "erosion time
within which 90% of the mucoadhesive material is dissolved" (or "90% erosion
time") refers
to the time in which 90% of the weight of the mucoadhesive particles are
dissolved after being
submerged in simulated saliva (buffered to a pH of about 6.7 to 7.4). Such 90%
erosion time
is expected to be representative of, and approximately equal to the residence
time or 90%
erosion time in the buccal cavity of a human subject in the absence of food
consumption and
rinsing.
[0045] For
certain embodiments, it may be desired to have an oral film dosage form
wherein two active agents are retained (and respectively released) for
different periods of time.
[0046] Where
the disclosed oral dosage form is used for local delivery, according to
such certain embodiments, the mucoadhesive particles containing the active
agent have the
potential to alleviate the symptoms or provide other therapeutic effect over a
longer period of
time than other known systemic administration techniques for the same active
agent. The
increased residence time of the active agent in the oral cavity may
continuously dispense (or
release) the active agent locally over an extended period of time. In
addition, the disclosed oral
film may continuously dispense (or release) active agents without the
discomfort usually felt
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from comparable mucoadhesive dosage forms (films or tablets) where the dosage
form itself is
mucoadhesive. The presently disclosed dosage form having mucoadhesive
particles as opposed
to having a mucoadhesive matrix typically allows adherence of the particles to
the mucosa
without being an inconvenience for the patient.
[0047]
According to certain embodiments, the oral film dosage form may be
administered for enteral delivery. In such embodiment, the oral film is
administered in a way
that promotes quick disintegration of the film followed by swallowing of the
mucoadhesive
particles. For instance, the oral film may be positioned on the tongue where
the disintegrating
film will be swallowed and the mucoadhesive particles contained therein will
be delivered to
the stomach thus potentially adhering to the enteral mucosa. Additional
indications could
include the intake of water shortly after administration of the film on the
tongue to promote
swallowing of the mucoadhesive particles destined for enteral delivery.
[0048]
Contrary to known mucoadhesive oral dosage forms, the disclosed oral dosage
forms in certain embodiments can be suitable for both buccal and enteral
delivery depending
on the prescribing information and its mode of administration. The
mucoadhesive particles of
the presently described oral dosage forms are delivered via the film matrix
which by design
disintegrates in the oral cavity upon contact with saliva. It is thus possible
to modulate the
administration of the active agent contained within the mucoadhesive particle
depending on
the ailment or disease in need of treatment. The disclosed oral dosage forms
may thus be used
for treating both local disease, such as disease located in a patient's mouth
as well as treatment
of disease systemically wherein the active agent is administered to the
patient enterally and/or
buccally and reaches the bloodstream.
[0049]
According to certain other embodiments, the disclosed oral dosage form is
designed for administration of active agents both buccally and enterally. In
such embodiment,
the oral dosage form is administered to a patient with specific prescribing
information to have
a portion of the film positioned on either the buccal or sublingual mucosa and
another portion
of the same film dosage form positioned on the tongue for disintegration and
quick swallowing
of the disintegrated film portion. Similarly, the prescribing information may
require the patient
to take two distinct oral films each being applied against a different portion
of the oral cavity.
For instance, a first oral film may be applied sublingually while the second
oral film is applied
against the mucosa or where enteral absorption is desired the second film is
positioned on the
tongue for quick dissolution and swallowing of the mucoadhesive particles.
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[0050]
Alternatively, according to certain other embodiments where the oral dosage
form is designed for both buccal and enteral delivery, the oral film may
comprise two forms of
the active agent, a first form positioned in the film via the use of
mucoadhesive particles and a
second form disposed in the film without the use of mucoadhesive particles. In
such
embodiments, disintegration of the film leaves both the first and second form
of active, with
and without mucoadhesive particles, dispersed in the saliva. The suspended
mucoadhesive
particles would generally adhere to the mucosa whereas the remaining active
which is dispersed
in the film matrix in a non-mucoadhesive format would generally be swallowed
and reach the
bloodstream via the typical enteral delivery route. Quick disintegration of
the film and
comparatively quick swallowing of the suspended active agent may also affect
absorption of
the active agent, thus favoring quicker absorption of the non mucoadhesive
active agent.
[0051]
According to some other embodiments, the oral dosage form is designed for the
treatment of both local and systemic administration. As such, the oral dosage
form allows quick
administration of the active agent transmucosally bypassing the first pass
mechanism while the
remaining mucoadhesive particles (the swallowed particles) are administered
enterally.
[0052] Based
on the type of material used a wide range of erosion times may be
achieved (few minutes up to few days, for instance, from about 300 seconds to
about 3 to 5
days). In addition, it is possible to tune or modulate the overall physical
properties of the
polymer-drug matrix by controlling the relevant parameters such as polymer
molecular weight
(10 kDa up to 5000 kDa), ratio of monomers or comonomers (25:75, 50:50; 75:25)
and drug
concentration (0.1 to 20%) to achieve a desired dosage and release interval
depending upon the
drug type or active agent used.
[0053]
Examples of biodegradable materials that can be used to create mucoadhesive
particles with tunable erosion or dissolving time include polysaccharides
(starch,
chitosan/chitin, gums, pectins), proteins (gelatin, collagen, casein),
polyhydroxyalkanoates
(PHA), polyhydroxybutyrate (PHB), polyhydroxybutyrate co-hydroxyvalerate
(PHBV),
polylactides (polylactic acid (PLA), polylactic-co-glycolic acid (PLGA),
polycaprolactones
(polyesters PCL).
[0054] The
residence time of the mucoadhesive particles is affected by several
parameters. These parameters may be used for modulation of the residence time
of
mucoadhesive particles and thus affect the extended release profile of the
active agent. For a
define mucoadhesive material, the size of mucoadhesive particles and molecular
size and/or
molecular weight of the mucoadhesive material directly affect the mucoadhesive
particles
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erosion time and are important parameters used to modulate the residence time
of the
mucoadhesive particles in the oral cavity and/or in the GIT. The larger the
mucoadhesive
particles, the longer they will generally adhere to the mucosa and thus the
longer the buccal
and/or GIT residence time. Conversely, the smaller the mucoadhesive particles
the faster they
will dissolve and the smaller their buccal or enteral residence time will be.
Other factors, such
as food consumption and rinsing of the mouth may affect the residence time of
the
mucoadhesive particles particularly the residence time in the buccal cavity.
[0055]
According to certain embodiments, having mucoadhesive particles as opposed
to having a mucoadhesive film matrix generally allows the active agent to be
released over a
longer period of time compared with the same active agent being delivered
through known
mucoadhesive oral films where the film matrix itself is mucoadhesive. The
limited size of the
particles compared to an entire film matrix also allows the particles to
adhere to the oral mucosa
for a greater period of time (residence time of the active in the oral cavity)
when compared to
known mucoadhesive films.
[0056]
According to certain embodiments, the mucoadhesive particles have an erosion
time within which 90% of the mucoadhesive material is dissolved that is
typically from five to
five thousand times the disintegrating time within which 90% of the film is
disintegrated.
[0057]
According to certain embodiments, the oral film dosage form is used to deliver
orally active agents that are permeable to the buccal mucosa. Transmucosal
absorption of the
active agent is generally affected by the permeation of the active agent
through the mucosa and
by the erosion time of the mucoadhesive particles which in most cases is
directly related to the
rate of release of the active agent.
[0058] Active
agents which are permeable through the oral or buccal mucosa are
generally low molecular weight, neutral molecules, generally classified as
class I according to
Biopharmaceutics Classification System (BCS). BCS is a system to differentiate
the drugs on
the basis of their solubility and permeability. This system restricts the
prediction using the
parameters solubility and intestinal permeability. The solubility
classification is based on a
United States Pharmacopoeia (USP) aperture. Class one molecules are highly
soluble and
highly permeable however, enteral permeation is not indicative that the
molecule will be
buccally permeable. Other factors such as molecule size and the charge of the
molecule may
affect its permeation.
[0059] In such
embodiments, as the film disintegrates the mucoadhesive particles will
adhere to the buccal mucosa. The retention time in the buccal cavity will
depend on the time
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required by the mucoadhesive particles to erode (erosion time). During
retention in the buccal
cavity, the active agent can diffuse into the mucosa or be released by
erosion. Released active
agent is, to a significant extent, absorbed transmucosally through penetration
of the buccal
mucosa.
[0060]
According to certain embodiments, the oral film dosage form is used to deliver
an active agent that has low permeation to the buccal mucosa.
[0061]
According to an aspect of the disclosure, the microparticles may be passively
targeted to antigen-presenting cells (APCs) in mucosal membranes such as
macrophages and
dendritic cells. The ability of APCs to phagocytose particulates is dependent
on the particle
size. In particular, about 1.0 to about 10.0 p.m diameter microspheres are
optimally taken up
by APCs.
[0062]
According to certain embodiments, the disclosed oral film dosage form is
designed to administer active agents capable of transmucosal absorption
through the buccal
mucosa. In such embodiments, the mucoadhesive particles allow the active agent
to be
absorbed through the oral mucosa over a prolonged period of time. This
extended release of
the active agent is permitted via the longer residence time of the particles
in the oral cavity.
According to this embodiment, extended release and absorption is dependent on
the ability of
the active agent to traverse the mucosa and be absorbed transmucosally. The
disclosed oral
dosage form for providing transport of an agent for local delivery in a buccal
cavity of a subject
for a sustained period of time, comprises a disintegrable film and
mucoadhesive particles
dispersed in the disintegrable film, the particles comprising a mucoadhesive
material exhibiting
adhesivity to mucosa in the buccal cavity and at least a first active agent
capable of being
absorbed transmucosally.
[0063]
According to certain embodiments, the disclosed oral film dosage form is
designed to enhance transbuccal administration of an active agent which is
weakly permeable
to the buccal mucosa. In such embodiments, a penetration enhancer is employed,
preferably a
penetration enhancer that is administered conjointly or simultaneously
available with the active
agent. Adding a penetration enhancer to a film matrix will only potentially
improve the
penetration of active agent which is instantly released with the
disintegration of the matrix (not
the active contained in the mucoadhesive particles). Penetration enhancer
available instantly
following the disintegration of the matrix will thus not significantly improve
the permeation of
the active agent released over a sustained period of time. In other words, the
active agent
contained in the mucoadhesive particles will not benefit from an immediate
release (at the time
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of the disintegration of the film matrix) of the penetration enhancer. In
accordance with these
certain embodiments, enhanced transbuccal delivery of an active agent is
achieved by
incorporating a penetration enhancer, along with the active agent, within the
mucoadhesive
particles.
[0064] The
oral dosage form according to these embodiments will be made by a process
that differs from the other embodiments in that the permeation enhancer will
be added to the
mucoadhesive particles. One way to include the penetration enhancer in the
mucoadhesive
particles is by adding the penetration enhancer to a liquid phase in which the
active agent is
dissolved and which is used in the preparation of the mucoadhesive particles
(such as by solvent
displacement technique or emulsification technique, described herein). Using
this process, both
the active agent and the permeation enhancer will be encapsulated in the
mucoadhesive
material thus creating the mucoadhesive particles.
[0065] Similar
to embodiments previously described, certain embodiments comprising
more than one active agent may include a combination of active agents which
are buccally
permeable to different degrees. For instance, embodiments of the oral film
dosage form may
comprise a first active agent that is permeable to the buccal mucosa and a
second active that is
not permeable to the buccal mucosa. Transbuccal delivery of the second active
agent can be
enhanced with a penetration enhancer. The penetration enhancer can be added to
the same
portion of the film where the second active is. For example, in an oral film
where a first active
agent having low permeation to buccal mucosa is instantly released, a
penetration enhancer
and the first active agent can be added to the film matrix for instant
delivery as the film matrix
disintegrates while a second active agent can remain in the mucoadhesive
particles for delivery
over a prolonged period of time. Conversely, for an oral film where the non or
weakly
permeable active agent is administered over a prolonged period of time, a
first active agent (the
permeable one) will be added to the film matrix for delivery instantly as the
film disintegrates
in the buccal cavity while a second active will be encapsulated in the
mucoadhesive material
with a penetration enhancer.
[0066] Other
embodiments could also comprise a plurality of active agents that are not
permeable or only weakly permeable. In such embodiments, all active agents can
be
administered with a penetration enhancer. As such, a penetration enhancer
could be added to
both the film matrix and the mucoadhesive particles.
[0067]
According to some embodiments, the mucoadhesive particles may have
residence times lasting from about 5 min to a few days (e.g., 2 to 3 days),
depending on the
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size of the mucoadhesion particles and the mucoadhesive materials used. The
erosion time and
thus the residence time of the mucoadhesive particles is related to the
molecular weight and
other physical and/or chemical properties of the mucoadhesive material.
[0068] The
disclosed oral film dosage form systems comprise a disintegrating matrix
and mucoadhesive particles containing the active agent. The present system may
thus be
modulated for various residence times according to the desired treatment and
the active agent
effectiveness. The residence time in the oral cavity of the mucoadhesive
particle will be
modulated by various parameters such as size of the mucoadhesive particles,
the materials used
in the mucoadhesive particles, and pH of the medium.
[0069] In some
embodiments, the particles are formed using precipitation techniques,
followed by coating of the particles with a block copolymer. Precipitation
techniques (e.g.,
microprecipitation techniques, nanoprecipitation techniques) may involve
forming a first
solution comprising the polymeric material (or other hydrophobic material) and
a solvent,
wherein the polymeric material is substantially soluble in the solvent. The
solution may be
added to a second solution comprising another solvent in which the polymeric
material is
substantially insoluble, thereby forming a plurality of particles comprising
the polymeric
material. In some cases, one or more surfactants, and/or bioactive agents may
be present in the
first and/or second solution.
[0070] In an
exemplary embodiment, a method of forming the particles includes using
a poly(ethylene glycol)-vitamin E conjugate (hereinafter "PEG-VitE conjugate"
or "VP5k").
The PEG-VitE conjugate can act as a surfactant, may aid in stabilizing the
particles, and/or
may aid in encapsulating the particle material. In some cases, a method for
forming a plurality
of particles using PEG-VitE comprises forming a solution comprising a
hydrophobic polymeric
material (or other hydrophobic material), and adding the solution to a solvent
in which the
hydrophobic material is substantially insoluble. The PEG-VitE conjugate may be
present in the
solution comprising the hydrophobic material and/or the solvent to which the
solution is
present. Upon addition of the solution comprising the hydrophobic material to
the solvent, a
plurality of particles form, which are stabilized by the PEG-VitE conjugate.
The PEG-VitE
conjugate may be present in the solvent or solution at about 0.1%, 0.5%, 1.0%,
1.5%, 1.65%,
2%, 3%, 4%, 5%, 10%, 20% weight percent, or greater. Examples of solvents that
may be
suitable in this method include, but are not limited to, acetonitrile,
benzene, p-cresol, toluene,
xylene, mesitylene, diethyl ether, glycol, petroleum ether, hexane,
cyclohexane, pentane,
dichloromethane (methylene chloride), chloroform, carbon tetrachloride,
dioxane,
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tetrahydrofuran (THF), dimethyl sulfoxide, dimethylformamide, hexamethyl-
phosphoric
triamide, ethyl acetate, pyridine, triethylamine, nicotine, mixtures thereof,
or the like.
[0071] Another
technique that may be used for preparing the mucoadhesive particles is
a solvent displacement technique.
[0072] Solvent
displacement method is based on spontaneous emulsification of an
organic internal phase (i.e., acetone, ethanol, or butyl alcohol alone or as a
mixture), also
referred to as the solvent phase, into an aqueous (mainly water) or
hydroalcoholic external
phase (alcohol/water mixture).
[0073] The
solvent phase is a solution of a polymer (e.g., Eudragit0 family
(polymethacrylates-based copolymers), Resomer0 family (such as poly(D,L-
lactide-co-
glycolide), or Gantrez0 family (copolymer of maleic anhydride)) and the active
substance
(e.g., antifungal, antibacterial, gingival treatments, buccal ulcer
treatments, canker sore
treatments) in an organic solvent miscible with water.
[0074] The
polymer and the active substance are dissolved in a water-miscible solvent
of intermediate polarity, leading to precipitation of the particles. This
phase is transferred into
a stirred aqueous or hydroalcoholic solution optionally in the presence of a
stabilizing
surfactant. Polymer deposition on the interface between the water and the
organic solvent,
caused by fast diffusion of the solvent, leads to the instantaneous formation
of a colloidal
suspension.
[0075] It is
possible to use either two organic phases or two aqueous phases or mixtures
thereof as long as solubility, insolubility and miscibility conditions are
satisfied. Regarding
particle preparation, the organic phase is mixed with the stirred aqueous
phase in one shot,
stepwise, dropwise or other controlled addition. The organic solvent is
removed from the
system using evaporation under reduced pressure.
[0076]
Alternatively, the mucoadhesive particles can be prepared by single or
multiple
emulsification techniques. The organic inner phase is a solution of the
polymer in the presence
or absence of the active substance in an organic solvent system (e.g., ethyl
acetate, isobutyl
acetate, methyl ethyl ketone (MEK), dichloromethane (DCM), or ethyl formate
alone or in
combination) partially miscible or non-miscible with the outer phase (water or
silicone oil).
The outer phase can be saturated with an organic solvent. It is possible for
some active
substances to be dissolved first in an aqueous phase and then emulsified in an
organic partially
miscible solvent phase to form the first microemulsion droplet, and then
emulsified within the
outer phase. The outer phase comprises the dispersion of a stabilizing agent
(e.g., polyvinyl
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alcohol (PVA), polysorbates) or sodium lauryl sulfate prepared by using
solvent-saturated
phase.
[0077]
Optionally, a cross-linking agent can be used during the production of the
mucoadhesive particles to improve their stability and extend the residence
time. Examples of
cross-linking agents that may be suitable for use in the invention include,
but are not limited
to, acetate salts such as magnesium or calcium acetate, carbodiimide and
diamine compounds
or their derivatives.
[0078] For
both techniques, the mucoadhesive particles are formed instantaneously
with a size range between 100 nm and 100 p.m depending on the operating
conditions. The
operating conditions can be varied to obtain specific particle compositions,
morphologies and
sizes, and improve the local extended residence time.
[0079] The two
methods allow active substance loading ranges between 0.5-20% and
entrapment efficiencies ranges between 50-99.9%.
Production of antimicrobial dru2 loaded Gantrez AN mucoadhesive particles
[0080] Solvent
displacement method: 20 mg of antimicrobial drug are dissolved in 5
ml of Gantrez AN/organic phase solution at 2% w/v. The mucoadhesive particles
are produced
by the addition of 20 ml of hydroalcoholic solution (1:1) under stirring for
10 min at 4 C. The
alcohol is removed under reduced pressure using a rotavapor. The aqueous
suspension of drug
loaded Gantrez particles are collected and used in the formulation of water
soluble films.
[0081] Emulsification method: 20 mg of antimicrobial drug are dissolved in 5
ml of Gantrez
AN/MEK solution at 2% w/v. The organic phase (0) is emulsified in an
aqueous/PVA solution
(W) using a high speed homogenizer for 5 min. to achieve an oil-in-water
emulsion system. If
necessary, the organic solvent is removed by extraction/evaporation or
filtration technique.
The drug loaded Gantrez particles are collected and used in the formulation of
water soluble
films.
Production of Film Oral Dosa2e Form
[0082] The mucoadhesive particles, sweetener, flavor and a pore former are
combined in water
and stirred until a homogeneous dispersion (wet-blend) is obtained.
Polyethylene oxide is then
added gradually to the wet blend and mixed until the polyethylene oxide is
completely
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dissolved. The wet blend is then coated on support liner and dried in an oven
until the moisture
level reaches less than 5%. The obtained product is cut and packaged.
[0083] Conventional mixing techniques can be employed for dispersing the
mucoadhesive
particles and other optional active agents into the film composition, which
typically comprises
a suitable solvent, and contains any optional ingredients such as
plasticizers, polyalcohols, and
surfactants. The film composition containing the mucoadhesive particles and
any optional
active agents present in either a free, immediate release form, or in a non-
mucoadhesive
controlled release form can be cast and dried to form a film using known
processes.
Production of THC/CBD Film Oral Dosa2e Form
[0084] A mucoadhesive particle containing as an active agent a cannabis
extract, cannabis oil,
tetrahydrocannabinol (THC), THC complexated with cyclodextrin (CD),
cannabidiol (CBD),
or a THC/CBD combination of variable composition, is prepared by an
emulsification
technique.
[0085] The active cannabinoid agent is added to the oil phase containing an
oil base, one or
more surfactants, and an antioxidant. The aqueous phase is comprised of an
emulsifier, one or
more surfactants, an antibacterial, a flavoring agent, and a mucoadhesive
polymer. Both phases
are mixed together using a high-speed homogenizer to achieve an oil-in-water
emulsion blend
system.
[0086] A mucoadhesive polymer or a combination of mucoadhesive polymers is
added to the
oil-in-water emulsion blend until complete dissolution of the polymers. The
blend is coated on
a liner and dried in an oven at a temperature below 60 C. The obtained film is
then cut and
packaged.
[0087] In certain embodiments, the disclosed particles may include an oil
base. The term "oil
base" refers to the main component of the oil particle, found in the highest
amount. The other
components would be dissolved or dispersed in this oil base. Examples of this
oil base include
fats and oils of different melting points, such as soybean oil, sesame oil,
coconut oil, sunflower
oil, cocoa butter, palm oil, palm kernel oil, carnauba wax, beeswax, or
paraffin wax.
[0088] A flavoring agent is used to modify and enhance the taste of the
resultant film.
Flavoring oils and oleoresins might be added to the oil phase. Examples of
these are natural
essential oils like peppermint oil, cinnamon oil, eucalyptus oil, orange oil,
spearmint oil, or
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lemon oil. Synthetic flavoring substances, such as vanillin, DL-menthol,
eugenol, or limonene,
can be added to either the oil or the aqueous phase depending on their
solubility.
[0089] Example of emulsification procedure: 0.7 g of THC are dissolved into 10
g of soybean
oil, together with 0.01 g of a-tocopherol and 4 g of oleic acid.
Simultaneously, 1.4 g of
poloxamer 188, 0.7 g of soy lecithin, 1.6 g of polyethylene glycol, 0.2 g of
methylparaben, 0.4
g of DL-menthol, and 3 g of hydroxypropyl cellulose are dissolved or dispersed
in 100 mL of
water. The oil phase is emulsified in the aqueous phase by using a high-speed
homogenizer for
min to achieve an oil-in-water emulsion.
[0090] Example of emulsification procedure: 0.6 g of THC are dissolved into 8
g of coconut
oil, together with 0.01 g of butylated hydroxytoluene and 3.4 g of oleic acid.
Simultaneously,
1.1 g of poloxamer 407, 0.6 g of soy lecithin, 2.6 g of glycerol, 1.5 g of
sucralose, 0.2 g of
methylparaben, and 3 g of hydroxypropyl cellulose are dissolved or dispersed
in 100 mL of
water. The oil phase is emulsified in the aqueous phase by using a high-speed
homogenizer for
5 min to achieve an oil-in-water emulsion.
[0091] Example of emulsification procedure: 0.7 g of cannabis oil is added to
10 g of melted
cocoa butter. Also, 0.01 g of butylated hydroxytoluene, 0.7 g of soy lecithin,
and 1 g of
peppermint oil are added to the oil base. Simultaneously, 2.6 g of glycerol,
1.5 g of sucralose,
and 0.2 g of methylparaben are dissolved or dispersed in 100 mL of water, also
warmed up to
60 C. The oil phase is emulsified in the aqueous phase by using a high-speed
homogenizer for
5 min to achieve an oil-in-water emulsion.
[0092] Example of emulsification procedure: 0.7 g of THC and 4.3 g of
cyclodextrin (CD) are
mixed in 7 ml of ethanol to form a THC/CD complex. The complex in ethanol is
dispersed in
g of soybean oil, together with 0.01 g of a-tocopherol and 4 g of oleic acid.
Simultaneously,
1.4 g of poloxamer 188, 0.7 g of soy lecithin, 1.6 g of glycerol, 0.2 g of
methylparaben, 0.4 g
of DL-menthol, and 3 g of hydroxypropyl cellulose are dissolved or dispersed
in 100 mL of
water. The oil phase is emulsified in the aqueous phase by using a high-speed
homogenizer for
5 min to achieve an oil-in-water emulsion.
[0093] The resultant emulsion is mixed with 20 g of a high molecular weight
hydroxypropyl
cellulose until the polymer completely dissolve. The blend is coated on a
liner and dried in an
oven at 40 C.
[0094] According to one embodiment, the oral film dosage form comprises THC,
CBD or a
combination thereof encapsulated within mucoadhesive particles. According to
other
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embodiments, the oral film dosage form comprises a first active (either THC,
CBD or a
combination of cannabinoids) and a second non cannabinoid active, wherein at
least one of the
first and second active is comprised within mucoadhesive particle.
[0095] According to one embodiment, the oral film comprises mucoadhesive
particle having a
microencapsulated THC-cyclodextrin complex or cannabinoid-cyclodextrin
complex.
According to one embodiment, the complex is gamma-cyclodextrin-THC.
[0096] According to one embodiment, the process for making a cannabinoid oral
film
comprises the steps of blending cannabinoid emulsion with high molecular
weight cellulose,
coating the blend as a thin sheet on a liner and drying the coated blend at a
temperature below
60 C or preferably at a temperature below about 40 C.
[0097] The above description is considered that of the preferred embodiment(s)
only.
Modifications of these embodiments will occur to those skilled in the art and
to those who
make or use the illustrated embodiments. Therefore, it is understood that the
embodiment(s)
described above are merely exemplary and not intended to limit the scope of
this disclosure,
which is defined by the following claims as interpreted according to the
principles of patent
law, including the doctrine of equivalents.
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