.
`
`(12) Ulllted States Patent
`Myers et al.
`
`(10) Patent N0.:
`(45) Date of Patent:
`
`US 8,475,832 B2
`Jul. 2, 2013
`
`US008475832B2
`
`(54) SUBLINGUAL AND BUCCAL FILM
`COMPOSITIONS
`
`_
`(75) IIWBIIIOFSI Garry L- Myerss K111851300s TN (Us);
`Samuel D. Hilbert, Jonesboro, TN (US);
`Bill J. Boone, Johnson City, TN (03); B.
`Arlie B0 ue New Carlisle IN (US)'
`g ’
`_
`’_
`’
`PradeeP sallglwls 30119491311119s IN (US);
`Madhusudan Hariharan, Munster, IN
`(Us)
`
`-
`_
`.
`.
`.
`(73) Ass1gnee. RB Pharmaceuticals Limited, Slough
`(GB)
`
`( * ) Notice:
`
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U80 1546’) by 231 days‘
`
`(21) APP1-NO-I 12/537571
`
`(22) Filed:
`
`Aug. 7, 2009
`
`65
`(
`)
`
`P bl' t- D t
`P '
`nor “ m ‘on a a
`US 2011/0033541A1
`Feb. 10, 2011
`
`(51) Int. Cl.
`A61F13/00
`A61K 9/14
`A61K 31/44
`U s
`'
`'
`
`'
`
`(2006-01)
`(2006.01)
`(2006.01)
`
`9
`
`a
`
`el
`
`et
`
`.
`
`lsiuztlilki 621M
`2 lg;
`4,302,465 A 11/1981 Ekenstam et a1.
`4,307,075 A 12/1981 Martin
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`4,406,708 A
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`3/1984 Graham
`4,460,562 A
`7/1984 Keith et a1.
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`
`5
`
`a
`
`eVIle e
`
`.
`
`. . . . . . . . . ..
`
`514/282
`
`
`
`A 4,849,246 A
`
`
`
`et 7/1989 Schmidt
`
`(58) Field of Classi?cation Search
`None
`hh. t
`1 t
`?l f
`t.
`1.
`S
`ee app 1ca 1on e or comp e e searc
`1s ory.
`
`(56)
`
`References Cited
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`
`Primary Examiner * Janet Epps-Smith
`(74) Attorney, Agent, or Firm * Hoffmann & Baron, LLP
`
`ABSTRACT
`(57)
`The present invention relates to products and methods for
`-
`-
`-
`-
`treatment of narcot1c dependence 1n a user. The 1nvent1on
`_
`_
`more part1cularly relates to self-supportlng dosage forms
`which provide an active agent for treating narcotic depen
`dence While providing su?icient buccal adhesion of the dos
`age form
`'
`
`19 Claims, N0 Drawings
`
`Page 1
`
`

`

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`
`Page 2
`
`

`

`US 8,475,832 B2
`Page 3
`
`Written Opinion of the International Searing Authority for Interna-
`tional Application No. PCT?JS20l0/044488 dated Apr. 11, 2011.
`
`Abeer M. Al-Ghananeem et al., “Effect ofpH on Sublingual Absorp-
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`
`* Cited by examiner
`
`Page 3
`
`

`

`US 8,475,832 B2
`
`1
`SUBLINGUAL AND BUCCAL FILM
`COMPOSITIONS
`
`2
`the mouth, rendering it dif?cult to remove once placed in the
`mouth, thereby making abuse of the agonist dif?cult.
`
`FIELD OF THE INVENTION
`
`SUMMARY OF THE INVENTION
`
`The present invention relates to compositions, methods of
`manufacture, products and methods of use relating to ?lms
`containing therapeutic actives. The invention more particu
`larly relates to self-supporting ?lm dosage forms Which pro
`vide a therapeutically effective dosage, essentially matching
`that of currently-marketed tablets containing the same active.
`Such compositions are particularly useful for treating nar
`cotic dependence While providing suf?cient buccal adhesion
`of the dosage form.
`
`BACKGROUND OF THE RELATED
`TECHNOLOGY
`
`Oral administration of tWo therapeutic actives in a single
`dosage form can be complex if the intention is to have one
`active absorbed into the body and the other active remain
`substantially unabsorbed. For example, one active may be
`relatively soluble in the mouth at one pH, and the other active
`may be relatively insoluble at the same pH. Moreover, the
`absorption kinetics of each therapeutic agent may be substan
`tially different due to differing absorption of the charged and
`uncharged species. These factors represent some of the chal
`lenges in appropriately co-administering therapeutic agents.
`Co-administration of therapeutic agents has many applica
`tions. Among such areas of treatment include treating indi
`viduals Who suffer from narcotic dependence. Such individu
`als have a tendency to suffer from serious physical
`dependence on the narcotic, resulting in potentially danger
`ous WithdraWal effects When the narcotic is not administered
`to the individual. In order to help individuals addicted to
`narcotics, it is knoWn to provide a reduced level of a drug,
`Which provides an effect of satisfying the body’s urge for the
`narcotic, but does not provide the “high” that is provided by
`the misuse of the narcotic. The drug provided may be an
`agonist or a partial agonist, Which provides a reduced sensa
`tion and may help loWer dependence on the drug. HoWever,
`even though these drugs provide only a loW level of euphoric
`effect, they are capable of being abused by the individuals
`parenterally. In such cases, it is desirable to provide a com
`bination of the drug With a second drug, Which may decrease
`the likelihood of diversion and abuse of the ?rst drug. For
`example, it is knoWn to provide a dosage of an antagonist in
`combination With the agonist or partial agonist. The narcotic
`antagonist binds to a receptor in the brain to block the recep
`tor, thus reducing the effect of the agonist.
`One such combination of drugs has been marketed under
`the trade name Suboxone® as an orally ingestible tablet.
`HoWever, such combinations in tablet form have the potential
`for abuse. In some instances, the patient Who has been pro
`vided the drug may store the tablet in his mouth Without
`sWalloWing the tablet, then later extract the agonist from the
`tablet and inject the drug into an individual’ s body. Although
`certain antagonists (such as highly Water-soluble antagonists)
`may be used to help reduce the ability to separate the agonist,
`the potential for abuse still exists. It is desired to provide a
`dosage that cannot be easily removed from the mouth once it
`has been administered.
`There is currently a need for an orally dissolvable ?lm
`dosage form that provides the desired absorption levels of the
`agonist and antagonist, While providing an adhesive effect in
`
`20
`
`25
`
`30
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`In one embodiment of the present invention, there is pro
`vided a ?lm dosage composition including: a polymeric car
`rier matrix; a therapeutically effective amount of buprenor
`phine or a pharmaceutically acceptable salt thereof, a
`therapeutically effective amount of naloxone or a pharmaceu
`tically acceptable salt thereof; and a buffer in an amount to
`provide a pH of the composition of a value su?icient to
`optimiZe absorption of the buprenorphine.
`In another embodiment of the present invention, there is
`provided a ?lm dosage composition including: a polymeric
`carrier matrix; a therapeutically effective amount of
`buprenorphine or a pharmaceutically acceptable salt thereof,
`a therapeutically effective amount of naloxone or a pharma
`ceutically acceptable salt thereof; and a buffer in an amount
`suf?cient to inhibit the absorption of the naloxone When
`administered orally.
`In still other embodiments, there may be provided a ?lm
`dosage composition including: a polymeric carrier matrix; a
`therapeutically effective amount of buprenorphine or a phar
`maceutically acceptable salt thereof, a therapeutically effec
`tive amount of naloxone or a pharmaceutically acceptable salt
`thereof; and a buffering system; Where the buffering system
`includes a buffer capacity su?icient to maintain the ioniZation
`of naloxone during the time Which the composition is in the
`oral cavity of a user.
`In another embodiment of the invention, there is provided
`a method of treating narcotic dependence of a user, including
`the steps of: providing a composition including: a polymeric
`carrier matrix; a therapeutically effective amount of
`buprenorphine or a pharmaceutically acceptable salt thereof,
`a therapeutically effective amount of naloxone or a pharma
`ceutically acceptable salt thereof, and a buffer in an amount to
`provide a pH of the composition of a value su?icient to
`optimiZe absorption of the buprenorphine; and administering
`the composition to the oral cavity of a user.
`In still another embodiment of the invention, there is pro
`vided a process of forming a ?lm dosage composition includ
`ing the steps of: casting a ?lm-forming composition, the
`?lm-forming composition including: a polymeric carrier
`matrix; a therapeutically effective amount of buprenorphine
`or a pharmaceutically acceptable salt thereof, a therapeuti
`cally effective amount of naloxone or a pharmaceutically
`acceptable salt thereof, and a buffer in an amount to provide
`a pH of the composition of a value su?icient to optimiZe
`absorption of the buprenorphine and drying the ?lm-forming
`composition to form a self-supporting ?lm dosage composi
`tion.
`In another embodiment, there is provided a ?lm dosage
`composition including a therapeutically suf?cient amount of
`buprenorphine or a pharmaceutically acceptable salt thereof
`and a therapeutically suf?cient amount of naloxone or a phar
`maceutically acceptable salt thereof, the ?lm dosage compo
`sition having a bioequivalent release pro?le as compared to a
`Suboxone® tablet containing about 2 times the amount of
`buprenorphine or a pharmaceutically acceptable salt thereof.
`Still other embodiments of the present invention provide an
`orally dissolving ?lm formulation including buprenorphine
`and naloxone, Where the formulation provides an in-vivo
`plasma pro?le having a Cmax of betWeen about 0.624 ng/ml
`and about 5.638 ng/ml for buprenorphine and an in-vivo
`
`Page 4
`
`

`

`US 8,475,832 B2
`
`3
`plasma pro?le having a Cmax of between about 41.04 pg/ml
`to about 323.75 pg/ml for naloxone.
`
`DETAILED DESCRIPTION OF THE PREFERRED
`EMBODIMENTS
`
`De?nitions
`
`As used herein, the term Cmax refers to the mean maxi
`mum plasma concentration after administration of the com
`position to a human subject. As also used herein, the term
`AUC refers to the mean area under the plasma concentration
`time curve value after administration of the compositions
`formed herein. As Will be set forth in more detail beloW, the
`term “optimizing the absorption” does not refer to reaching
`the maximum absorption of the composition, and rather refers
`to reaching the optimum level of absorption at a pH of about
`2 to about 4. The “optimum” absorption may be, for example,
`a level that provides a bioequivalent absorption as adminis
`tration of the currently available Suboxone® tablet. An “opti
`mum” Cmax of buprenorphine is about 0.67 to about 5.36
`mg/ml at dosages of from 2-16 mg buprenorphine at a given
`pH. Similarly, an “optimum” AUC of buprenorphine may be
`about 7.43 to about 59.46 hr*ng/ml at dosages of from 2-16
`mg buprenorphine at a given pH. As Will be described in more
`detail beloW, it has been surprisingly discovered that the
`absorption of one particular agonist, buprenorphine, can pro
`vide an optimum absorption at a pH of about 2-4 as Well as
`about 5.5-6.5. Thus, one may “optimize” the absorption of
`buprenorphine by providing a pH of about 2-4 or about 5.5
`6.5.
`“Maximizing the absorption” refers to the maximum in
`vivo absorption values achieved at a pH of about 4 to about 9.
`The term “local pH” refers to the pH of the region of the
`carrier matrix immediately surrounding the active agent as
`the matrix hydrates and/or dissolves, for example, in the
`mouth of the user.
`By “inhibiting” the absorption of an active, it is meant
`achieving as complete an ionization state of the active as
`possible, such that little to none of the active is measurably
`absorbable. For example, at a pH of 3-3.5, the Cmax of an
`active such as naloxone for dosage of 0.5 mg to 4.0 mg ranges
`from 32.5 to 260 pg/ml, and an AUC of naloxone for dosage
`of 0.5 mg to 4.0 mg ranges from 90.55 to 724.4 hr*pg/ml. It
`is understood that at a pH loWer than 3.0, further ionization
`Would be expected and thus result in loWer absorption.
`The term “bioequivalent” means obtaining 80% to 125% of
`the Cmax and AUC values for a given active in a different
`product. For example, assuming Cmax and AUC values of
`buprenorphine for a commercially-available Suboxone® tab
`let (containing 2 mg buprenorphine and 0.5 mg naloxone) are
`0.780 ng/ml and 6.789 hr*ng/ml, respectively, a bioequiva
`lent product Would have a Cmax of buprenorphine in the
`range of 0624-0975 ng/ml, and an AUC value of buprenor
`phine of 5431-8486 hr*ng/ml.
`It Will be understood that the term “?lm” includes thin ?lms
`and sheets, in any shape, including rectangular, square, or
`other desired shape. The ?lms described herein may be any
`desired thickness and size such that it may be placed into the
`oral cavity of the user. For example, the ?lms may have a
`relatively thin thickness of from about 0.1 to about 10 mils, or
`they may have a someWhat thicker thickness of from about 10
`to about 30 mils. For some ?lms, the thickness may be even
`larger, i.e., greater than about 30 mils. Films may be in a
`single layer or they may be multi-layered, including lami
`nated ?lms.
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`Oral dissolving ?lms generally fall into three main classes:
`fast dissolving, moderate dissolving and sloW dissolving. Fast
`dissolving ?lms generally dissolve in about 1 second to about
`30 seconds in the mouth. Moderate dissolving ?lms generally
`dissolve in about 1 to about 30 minutes in the mouth, and sloW
`dissolving ?lms generally dissolve in more than 30 minutes in
`the mouth. Fast dissolving ?lms may consist of loW molecular
`Weight hydrophilic polymers (i.e., polymers having a
`molecular Weight betWeen about 1,000 to 9,000, or polymers
`having a molecular Weight up to 200,000). In contrast, sloW
`dissolving ?lms generally have high molecular Weight poly
`mers (i.e., having a molecular Weight in the millions).
`Moderate dissolving ?lms tend to fall in betWeen the fast
`and sloW dissolving ?lms. Moderate dissolving ?lms dissolve
`rather quickly, but also have a good level of mucoadhesion.
`Moderate dissolving ?lms are also ?exible, quickly Wettable,
`and are typically non-irritating to the user. For the instant
`invention, it is preferable to use ?lms that fall betWeen the
`categories of fast dissolving and moderate dissolving. Such
`moderate dissolving ?lms provide a quick enough dissolution
`rate, most desirably betWeen about 1 minute and about 20
`minutes, While providing an acceptable mucoadhesion level
`such that the ?lm is not easily removable once it is placed in
`the oral cavity of the user.
`Inventive ?lms described herein may include one or more
`agonists or partial agonists used for the treatment of drug
`addiction. As used herein, the term “agonist” refers to a
`chemical substance that is capable of providing a physiologi
`cal response or activity in the body of the user. The ?lms
`described herein may further include one or more antagonists.
`As used herein, the term “antagonist” refers to any chemical
`substance that acts Within the body of the user to reduce the
`physiological activity of another chemical substance. In some
`embodiments, an antagonist used herein may act to reduce
`and/or block the physiological activity of the agonist. The
`actives may be Water- soluble, or they may be Water-insoluble.
`As used herein, the term “Water-soluble” refers to substances
`that are at least partially dissolvable in a solvent, including but
`not limited to Water. The term “Water-soluble” does not nec
`essarily mean that the substance is 100% dissolvable in the
`solvent. The term “Water-insoluble” refers to substances that
`are not dissolvable in a solvent, including but not limited to
`Water. Solvents may include Water, or alternatively may
`include other polar solvents by themselves or in combination
`With Water.
`Inventive Films
`The present invention relates to methods of treating nar
`cotic dependence in an individual. More desirably, the inven
`tion relates to the treatment of opioid dependence in an indi
`vidual, While using a formulation and delivery that hinders
`misuse of the narcotic. Currently, treatment of opioid depen
`dence is aided by administration of Suboxone®, Which is an
`orally dissolvable tablet. This tablet Which provides a com
`bination of buprenorphine (an opioid agonist) and naloxone
`(an opioid antagonist). Therefore, the present invention pro
`vides a method of treating narcotic dependence by providing
`an orally dissolvable ?lm dosage, Which provides a
`bioequivalent effect to Suboxone®. The ?lm dosage prefer
`ably provides buccal adhesion While it is in the user’ s mouth,
`rendering it dif?cult to remove after placement.
`The ?lm dosage composition preferably includes a poly
`meric carrier matrix. Any desired polymeric carrier matrix
`may be used, provided that it is orally dissolvable. Desirably,
`the dosage should have enough bioadhesion to not be easily
`removed and it should form a gel like structure When admin
`istered. The orally consumable ?lms are preferably moderate
`dissolving in the oral cavity and particularly suitable for
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`Page 5
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`US 8,475,832 B2
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`5
`delivery of actives, although both fast and sustained release
`compositions are also among the various embodiments con
`templated.
`The ?lms used in the pharmaceutical products may be
`produced by a combination of at least one polymer and a
`solvent, optionally including other ?llers known in the art.
`The solvent may be Water, a polar organic solvent including,
`but not limited to, ethanol, isopropanol, acetone, or any com
`bination thereof. In some embodiments, the solvent may be a
`non-polar organic solvent, such as methylene chloride. The
`?lm may be prepared by utiliZing a selected casting or depo
`sition method and a controlled drying process. For example,
`the ?lm may be prepared through controlled drying pro
`cesses, Which include application of heat and/or radiation
`energy to the Wet ?lm matrix to form a visco-elastic structure,
`thereby controlling the uniformity of content of the ?lm. Such
`processes are described in more detail in commonly assigned
`US. application Ser. No. 10/074,272, ?led on Feb. 14, 2002,
`and published as US. Patent Publication No. 2003/0107149
`Al, the contents of Which are incorporated herein by refer
`ence in their entirety. Alternatively, the ?lms may be extruded
`as described in commonly assigned US. application Ser. No.
`10/856,176, ?led on May 28, 2004, and published as US.
`Patent Publication No. 2005/0037055 Al, the contents of
`Which are incorporated herein by reference in their entirety.
`The polymer included in the ?lms may be Water-soluble,
`Water-sWellable, Water-insoluble, or a combination of one or
`more either Water-soluble, Water-sWellable or Water-in
`soluble polymers. The polymer may include cellulose or a
`cellulose derivative. Speci?c examples of useful Water
`soluble polymers include, but are not limited to, polyethylene
`oxide, pullulan, hydroxypropylmethyl cellulose, hydroxy
`ethyl cellulose, hydroxypropyl cellulose, polyvinyl pyrroli
`done, carboxymethyl cellulose, polyvinyl alcohol, sodium
`alginate, polyethylene glycol, xanthan gum, tragancanth
`gum, guar gum, acacia gum, arabic gum, polyacrylic acid,
`methylmethacrylate copolymer, carboxyvinyl copolymers,
`starch, gelatin, and combinations thereof. Speci?c examples
`of useful Water-insoluble polymers include, but are not lim
`ited to, ethyl cellulose, hydroxypropyl ethyl cellulose, cellu
`lose acetate phthalate, hydroxypropyl methyl cellulose
`phthalate and combinations thereof. For higher dosages, it
`may be desirable to incorporate a polymer that provides a
`high level of viscosity as compared to loWer dosages.
`As used herein the phrase “Water-soluble polymer” and
`variants thereof refer to a polymer that is at least partially
`soluble in Water, and desirably fully or predominantly soluble
`in Water, or absorbs Water. Polymers that absorb Water are
`often referred to as being Water-sWellable polymers. The
`materials useful With the present invention may be Water
`soluble or Water-sWellable at room temperature and other
`temperatures, such as temperatures exceeding room tempera
`ture. Moreover, the materials may be Water-soluble or Water
`sWellable at pressures less than atmospheric pressure. Desir
`ably, the Water-soluble polymers are Water-soluble or Water
`sWellable having at least 20 percent by Weight Water uptake.
`Water-sWellable polymers having a 25 or greater percent by
`Weight Water uptake are also useful. In some embodiments,
`?lms formed from such Water-soluble polymers may be suf
`?ciently Water-soluble to be dissolvable upon contact With
`bodily ?uids.
`Other polymers useful for incorporation into the ?lms
`include biodegradable polymers, copolymers, block poly
`mers and combinations thereof. It is understood that the term
`“biodegradable” is intended to include materials that chemi
`cally degrade, as opposed to materials that physically break
`apart (i.e., bioerodable materials). Among the knoWn useful
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`polymers or polymer classes Which meet the above criteria
`are: poly(glycolic acid) (PGA), poly(lactic acid) (PLA), poly
`dioxanes, polyoxalates, poly(ot-esters), polyanhydrides,
`polyacetates,
`polycaprolactones,
`poly(orthoesters),
`polyamino acids, polyaminocarbonates, polyurethanes, poly
`carbonates, polyamides, poly(alkyl cyanoacrylates), and
`mixtures and copolymers thereof. Additional useful polymers
`include, stereopolymers of L- and D-lactic acid, copolymers
`of bis(p-carboxyphenoxy)propane acid and sebacic acid,
`sebacic acid copolymers, copolymers of caprolactone, poly
`(lactic acid)/poly(glycolic acid)/polyethyleneglycol copoly
`mers, copolymers of polyurethane and (poly(lactic acid),
`copolymers of polyurethane and poly(lactic acid), copoly
`mers of ot-amino acids, copolymers of ot-amino acids and
`caproic acid, copolymers of (x-benZyl glutamate and polyeth
`ylene glycol, copolymers of succinate and poly(glycols),
`polyphosphaZene, polyhydroxy-alkanoates and mixtures
`thereof. Binary and ternary systems are contemplated.
`Other speci?c polymers useful include those marketed
`under the Medisorb and Biodel trademarks. The Medisorb
`materials are marketed by the Dupont Company of Wilming
`ton, Del. and are generically identi?ed as a “lactide/glycolide
`co-polymer” containing “propanoic acid, 2-hydroxy-poly
`mer With hydroxy-polymer With hydroxyacetic acid.” Four
`such polymers include lactide/glycolide 100 L, believed to be
`100% lactide having a melting point Within the range of
`338°-347° F. (170°-175o C.); lactide/glycolide 100 L,
`believed to be 100% glycolide having a melting point Within
`the range of 437°-455o F. (225°-235o C.); lactide/glycolide
`85/15, believed to be 85% lactide and 15% glycolide With a
`melting point Within the range of 338°-347° F. (170°-175o
`C.); and lactide/glycolide 50/50, believed to be a copolymer
`of 50% lactide and 50% glycolide With a melting point Within
`the range of 338°-347° F. (170°-175o C.).
`The Biodel materials represent a family of various polyan
`hydrides Which differ chemically.
`Although a variety of different polymers may be used, it is
`desired to select polymers that provide mucoadhesive prop
`erties to the ?lm, as Well as a desired dissolution and/or
`disintegration rate. In particular, the time period for Which it
`is desired to maintain the ?lm in contact With the mucosal
`tissue depends on the type of active contained in the compo
`sition. Some actives may only require a feW minutes for
`delivery through the mucosal tissue, Whereas other actives
`may require up to several hours or even longer. Accordingly,
`in some embodiments, one or more Water-soluble polymers,
`as described above, may be used to form the ?lm. In other
`embodiments, hoWever, it may be desirable to use combina
`tions of Water-soluble polymers and polymers that are Water
`sWellable, Water-insoluble and/or biodegradable, as provided
`above. The inclusion of one or more polymers that are Water
`sWellable, Water-insoluble and/ or biodegradable may provide
`?lms With sloWer dissolution or disintegration rates than ?lms
`formed from Water-soluble polymers alone. As such, the ?lm
`may adhere to the mucosal tissue for longer periods or time,
`such as up to several hours, Which may be desirable for
`delivery of certain active components.
`Desirably, the individual ?lm dosage has a small siZe,
`Which is betWeen about 0.5-1 inch by about 0.5-1 inch. Most
`preferably, the ?lm dosage is about 0.75 inches><0.5 inches.
`The ?lm dosage should have good adhesion When placed in
`the buccal cavity or in the sublingual region of the user.
`Further, the ?lm dosage should disperse and dissolve at a
`moderate rate, most desirably dispersing Within about 1
`minute and dissolving Within about 3 minutes. In some
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`US 8,475,832 B2
`
`7
`embodiments the ?lm dosage may be capable of dispersing
`and dissolving at a rate of betWeen about 1 to about 1.5
`minutes.
`For instance, in some embodiments, the ?lms may include
`polyethylene oxide alone or in combination With a second
`polymer component. The second polymer may be another
`Water-soluble polymer, a Water-sWellable polymer, a Water
`insoluble polymer, a biodegradable polymer or any c