(19) United States
`(12) Patent Application Publication (10) Pub. No.: US 2014/0005218 A1
`(43) Pub. Date: Jan. 2, 2014
`
`Myers et al.
`
`US 20140005218A1
`
`(54) SUBLINGUAL AND BUCCAL FILM
`COMPOSITIONS
`
`(22)
`
`Filed:
`
`Aug. 12, 2013
`
`(71) ApplicantszGarry L- Myers, K111335130”: TN (US);
`Samuel D- Hilbert, Jonesboro, TN (US);
`Bill J- Boone: Johnson Cltys TN (US);
`Beuford A. Bogue, Valparaiso, IN (US);
`Pradeep Sanghvi, Dyer, IN (US);
`Madhusudan Hariharan, Munster, IN
`(US)
`
`(72)
`
`Inventors: Garry L. Myers, Kingsport, TN (US);
`Samuel D. Hilbert, Jonesboro, TN (US);
`Bill J. Boone, Johnson City, TN (US);
`Beuford A. Bogue, Valparaiso, IN (US);
`Pradeep Sanghvi, Dyer, IN (US);
`Madhusudan Hariharan, Munster, IN
`(US)
`
`(73) Assignee: RB Pharmaceuticals Limited, Slough
`(GB)
`
`(21) Appl. No.: 13/964,975
`
`Related US. Application Data
`
`(63) Continuation of application No. 13/923,749, filed on
`Jun. 21, 2013, which is a continuation of application
`No. 12/537,571, filed on Aug. 7, 2009, now Pat. No.
`8,475,832.
`
`Publication Classification
`
`(51)
`
`(2006.01)
`(2006.01)
`
`Int. Cl.
`A61K 9/00
`A61K 31/485
`(52) US. Cl.
`CPC ............... A61K 9/006 (2013.01); A61K 31/485
`(2013.01)
`USPC .......................................................... 514/282
`ABSTRACT
`(57)
`The present invention relates to products and methods for
`treatment of narcotic dependence in a user. The invention
`more particularly relates to self-supporting dosage forms
`which provide an active agent for treating narcotic depen-
`dence while providing sufiicient buccal adhesion of the dos-
`age form.
`
`BDSI, Inc. vs. RB Pharmaceuticals lelted
`Page 1
`
`|PR2014-OO325
`BDSI EXHIBIT 1036
`
`Page 1
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`

`

`US 2014/0005218 A1
`
`Jan. 2, 2014
`
`SUBLINGUAL AND BUCCAL FILM
`COMPOSITIONS
`
`CROSS-REFERENCE TO RELATED
`APPLICATION
`
`[0001] This application is a continuation of US. applica-
`tion Ser. No. 13/923,749, filed Jun. 21, 2013, which is a
`continuation of US. application Ser. No. 12/537,571 filed
`Aug. 7, 2009, now US. Pat. No. 8,475,832, issued Jul. 2,
`2013.
`
`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.
`
`[0006] There is currently a need for an orally dissolvable
`film dosage form that provides the desired absorption levels
`of the agonist and antagonist, while providing an adhesive
`effect in the mouth, rendering it difficult to remove once
`placed in the mouth, thereby making abuse of the agonist
`difficult.
`
`FIELD OF THE INVENTION
`
`SUMMARY OF THE INVENTION
`
`invention relates to compositions,
`[0002] The present
`methods of manufacture, products and methods of use relat-
`ing to films containing therapeutic actives. The invention
`more particularly relates to self-supporting film dosage forms
`which provide a therapeutically effective dosage, essentially
`matching that of currently-marketed tablets containing the
`same active. Such compositions are particularly useful for
`treating narcotic dependence while providing sufficient buc-
`cal adhesion of the dosage form.
`
`BACKGROUND OF THE RELATED
`TECHNOLOGY
`
`[0003] 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.
`[0004] Co-administration of therapeutic agents has many
`applications. Among such areas of treatment include treating
`individuals who suffer from narcotic dependence. Such indi-
`viduals 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 first 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.
`[0005] 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 provided 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.
`
`In one embodiment ofthe present invention, there is
`[0007]
`provided a film 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 to
`provide a pH of the composition of a value sufficient to
`optimize absorption of the buprenorphine.
`[0008]
`In another embodiment of the present invention,
`there is provided a film 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
`pharmaceutically acceptable salt thereof; and a buffer in an
`amount sufficient to inhibit the absorption of the naloxone
`when administered orally.
`[0009]
`In still other embodiments, there may be provided a
`film dosage 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 buffering system; where the
`buffering system includes a buffer capacity sufficient to main-
`tain the ionization of naloxone during the time which the
`composition is in the oral cavity of a user.
`[0010]
`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
`pharmaceutically acceptable salt thereof; and a buffer in an
`amount to provide a pH of the composition of a value suffi-
`cient
`to optimize absorption of the buprenorphine; and
`administering the composition to the oral cavity of a user.
`[001 1]
`In still another embodiment ofthe invention, there is
`provided a process of forming a film dosage composition
`including the steps of: casting a film-forming composition,
`the film-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 sufficient to optimize
`absorption of the buprenorphine and drying the film-forming
`composition to form a self-supporting film dosage composi-
`tion.
`
`In another embodiment, there is provided a film
`[0012]
`dosage composition including a therapeutically sufficient
`amount of buprenorphine or a pharmaceutically acceptable
`salt thereof and a therapeutically sufficient amount of nalox-
`
`Page 2
`
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`

`US 2014/0005218 A1
`
`Jan. 2, 2014
`
`one or a pharmaceutically acceptable salt thereof, the film
`dosage composition having a bioequivalent release profile 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
`[0013]
`provide an orally dissolving film formulation including
`buprenorphine and naloxone, where the formulation provides
`an in-vivo plasma profile having a Cmax of between about
`0.624 ng/ml and about 5.638 ng/ml for buprenorphine and an
`in-vivo plasma profile having a Cmax ofbetween about 41.04
`pg/ml to about 323.75 pg/ml for naloxone.
`
`DETAILED DESCRIPTION OF THE PREFERRED
`EMBODIMENTS
`
`Definitions
`
`[0014] As used herein, the term Cmax refers to the mean
`maximum plasma concentration after administration of the
`composition 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 ofthe 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 ofthe 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 maxi-
`[0015]
`mum in vivo absorption values achieved at a pH of about 4 to
`about 9.
`
`[0016] The term “local pH” refers to the pH ofthe 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.
`
`[0017] 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 ofthe 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.
`[0018] 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 Sub-
`oxone® tablet (containing 2 mg buprenorphine and 0.5 mg
`naloxone) are 0.780 ng/ml and 6.789 hr*ng/ml, respectively,
`a bioequivalent product would have a Cmax ofbuprenorphine
`
`in the range of 0624-0975 ng/ml, and an AUC value of
`buprenorphine of 5431-8486 hr*ng/ml.
`[0019]
`It will be understood that the term “film” includes
`thin films and sheets, in any shape, including rectangular,
`square, or other desired shape. The films 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 films
`may have a relatively thin thickness offrom 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 films, 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
`laminated films.
`
`[0020] Oral dissolving films generally fall into three main
`classes: fast dissolving, moderate dissolving and slow dis-
`solving. Fast dissolving films generally dissolve in about 1
`second to about 30 seconds in the mouth. Moderate dissolv-
`
`ing films generally dissolve in about 1 to about 30 minutes in
`the mouth, and slow dissolving films generally dissolve in
`more than 30 minutes in the mouth. Fast dissolving films 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 films generally have high
`molecular weight polymers (i.e., having a molecular weight
`in the millions).
`[0021] Moderate dissolving films tend to fall in between the
`fast and slow dissolving films. Moderate dissolving films
`dissolve rather quickly, but also have a good level ofmucoad-
`hesion. Moderate dissolving films are also flexible, quickly
`wettable, and are typically non-irritating to the user. For the
`instant invention, it is preferable to use films that fall between
`the categories of fast dissolving and moderate dissolving.
`Such moderate dissolving films provide a quick enough dis-
`solution rate, most desirably between about 1 minute and
`about 20 minutes, while providing an acceptable mucoadhe-
`sion level such that the film is not easily removable once it is
`placed in the oral cavity of the user.
`[0022]
`Inventive films 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 ofproviding a physiologi-
`cal response or activity in the body of the user. The films
`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
`
`[0023] The present invention relates to methods of treating
`narcotic dependence in an individual. More desirably, the
`invention relates to the treatment of opioid dependence in an
`
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`

`US 2014/0005218 A1
`
`Jan. 2, 2014
`
`individual, while using a formulation and delivery that hin-
`ders misuse of the narcotic. Currently, treatment of opioid
`dependence is aided by administration of Suboxone®, which
`is an orally dissolvable tablet. This tablet which provides a
`combination ofbuprenorphine (an opioid agonist) and nalox-
`one (an opioid antagonist). Therefore, the present invention
`provides a method of treating narcotic dependence by pro-
`viding an orally dissolvable film dosage, which provides a
`bioequivalent effect to Suboxone®. The film dosage prefer-
`ably provides buccal adhesion while it is in the user’s mouth,
`rendering it difficult to remove after placement.
`[0024] The film dosage composition preferably includes a
`polymeric 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
`administered. The orally consumable films are preferably
`moderate-dissolving in the oral cavity and particularly suit-
`able for delivery of actives, although both fast and sustained
`release compositions are also among the various embodi-
`ments contemplated.
`[0025] The films used in the pharmaceutical products may
`be produced by a combination of at least one polymer and a
`solvent, optionally including other fillers 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
`film may be prepared by utilizing a selected casting or depo-
`sition method and a controlled drying process. For example,
`the film may be prepared through controlled drying pro-
`cesses, which include application of heat and/or radiation
`energy to the wet film matrix to form a visco-elastic structure,
`thereby controlling the uniformity ofcontent ofthe film. Such
`processes are described in more detail in commonly assigned
`U.S. application Ser. No. 10/074,272, filed on Feb. 14, 2002,
`and published as U.S. Patent Publication No. 2003/0107149
`Al, the contents of which are incorporated herein by refer-
`ence in their entirety. Alternatively, the films may be extruded
`as described in commonly assigned U.S. application Ser. No.
`10/856,176, filed on May 28, 2004, and published as U.S.
`Patent Publication No. 2005/0037055 Al, the contents of
`which are incorporated herein by reference in their entirety.
`[0026] The polymer included in the films may be water-
`soluble, water-swellable, water-insoluble, or a combination
`ofone or more either water-soluble, water- swellable or water-
`insoluble polymers. The polymer may include cellulose or a
`cellulose derivative. Specific 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. Specific 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.
`[0027] 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,
`films formed from such water-soluble polymers may be suf-
`ficiently water-soluble to be dissolvable upon contact with
`bodily fluids.
`[0028] Other polymers useful for incorporation into the
`films include biodegradable polymers, copolymers, block
`polymers and combinations thereof. It is understood that the
`term “biodegradable” is intended to include materials that
`chemically degrade, as opposed to materials that physically
`break apart (i.e., bioerodable materials). Among the known
`useful polymers or polymer classes which meet the above
`criteria are: poly(glycolic acid) (PGA), poly(lactic acid)
`(PLA), polydioxanes, polyoxalates, poly(ot-esters), polyan-
`hydrides, 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 ot-benzyl glutamate and polyeth-
`ylene glycol, copolymers of succinate and poly(glycols),
`polyphosphazene, polyhydroxy-alkanoates and mixtures
`thereof. Binary and ternary systems are contemplated.
`[0029] Other specific polymers useful include those mar-
`keted under the Medisorb and Biodel trademarks. The Med-
`
`isorb materials are marketed by the Dupont Company of
`Wilmington, Del. and are generically identified as a “lactide/
`glycolide co-polymer” containing “propanoic acid, 2-hy-
`droxy-polymer 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°-1750 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% gly-
`colide 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.).
`[0030] The Biodel materials represent a family of various
`polyanhydrides which differ chemically.
`[0031] Although a variety of different polymers may be
`used, it is desired to select polymers that provide mucoadhe-
`sive properties to the film, as well as a desired dissolution
`and/or disintegration rate. In particular, the time period for
`which it is desired to maintain the film in contact with the
`
`mucosal tissue depends on the type of active contained in the
`composition. Some actives may only require a few minutes
`
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`
`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 film. 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/orbiodegradable may provide
`films with slower dissolution or disintegration rates than films
`formed from water- soluble polymers alone. As such, the film
`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.
`[0032] Desirably, the individual film dosage has a small
`size, which is between about 0.5-1 inch by about 0.5-1 inch.
`Most preferably, the film dosage is about 0.75 inches><0.5
`inches. The film dosage should have good adhesion when
`placed in the buccal cavity or in the sublingual region of the
`user. Further, the film dosage should disperse and dissolve at
`a moderate rate, most desirably dispersing within about 1
`minute and dissolving within about 3 minutes. In some
`embodiments the film 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 films may
`[0033]
`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
`combination thereof. Suitable water-soluble polymers
`include, without limitation, any of those provided above. In
`some embodiments, the water-soluble polymer may include
`hydrophilic cellulosic polymers, such as hydroxypropyl cel-
`lulose and/or hydroxypropylmethyl cellulose. In accordance
`with some embodiments, polyethylene oxide may range from
`about 20% to 100% by weight in the polymer component,
`more specifically about 30% to about 70% by weight, and
`even more specifically about 40% to about 60% by weight. In
`some embodiments, one or more water-swellable, water-in-
`soluble and/or biodegradable polymers also may be included
`in the polyethylene oxide-based film. Any of the water-
`swellable, water-insoluble or biodegradable polymers pro-
`vided above may be employed. The second polymer compo-
`nent may be employed in amounts of about 0% to about 80%
`by weight in the polymer component, more specifically about
`30% to about 70% by weight, and even more specifically
`about 40% to about 60% by weight.
`[0034] The molecular weight of the polyethylene oxide
`also may be varied. In some embodiments, high molecular
`weight polyethylene oxide, such as about 4 million, may be
`desired to increase mucoadhesivity of the film. In some other
`embodiments, the molecular weight may range from about
`100,000 to 900,000, more specifically from about 100,000 to
`600,000, and even more specifically from about 100,000 to
`300,000. In some embodiments, it may be desirable to com-
`bine high molecular weight (600,000 to 900,000) with low
`molecular weight (100,000 to 300,000) polyethylene oxide in
`the polymer component.
`[0035] A variety of optional components and fillers also
`may be added to the films. These may include, without limi-
`tation: surfactants; plasticizers; polyalcohols; anti-foaming
`agents, such as silicone-containing compounds, which pro-
`mote a smoother film surface by releasing oxygen from the
`
`film; thermo-setting gels such as pectin, carageenan, and
`gelatin, which help in maintaining the dispersion of compo-
`nents; inclusion compounds, such as cyclodextrins and caged
`molecules; coloring agents; and flavors. In some embodi-
`ments, more than one active components may be included in
`the film.
`
`[0036] Additives may be included in the films. Examples of
`classes of additives include excipients, lubricants, buffering
`agents,
`stabilizers, blowing agents, pigments, coloring
`agents, fillers, bulking agents, sweetening agents, flavoring
`agents, fragrances, release modifiers, adjuvants, plasticizers,
`flow accelerators, mold release agents, polyols, granulating
`agents, diluents, binders, buffers, absorbents, glidants, adhe-
`sives, anti-adherents, acidulants, softeners, resins, demul-
`cents, solvents, surfactants, emulsifiers, elastomers and mix-
`tures thereof. These additives may be added with the active
`ingredient(s).
`[0037] Useful additives include, for example, gelatin, veg-
`etable proteins such as sunflower protein, soybean proteins,
`cotton seed proteins, peanut proteins, grape seed proteins,
`whey proteins, whey protein isolates, blood proteins, egg
`proteins, acrylated proteins, water-soluble polysaccharides
`such as alginates, carrageenans, guar gum, agar-agar, xanthan
`gum, gellan gum, gum arabic and related gums (gum ghatti,
`gum karaya, gum tragancanth), pectin, water-soluble deriva-
`tives of cellulose: alkylcelluloses hydroxyalkylcelluloses and
`hydroxyalkylalkylcelluloses,
`such
`as methylcelulose,
`hydroxymethylcellulose, hydroxyethylcellulose, hydrox-
`ypropylcellulose,
`hydroxyethylmethylcellulose,
`hydrox-
`ypropylmethylcellulose, hydroxybutylmethylcellulose, cel-
`lulose esters and hydroxyalkylcellulose esters
`such as
`cellulose acetate phthalate (CAP), hydroxypropylmethylcel-
`lulose (HPMC); carboxyalkylcelluloses, carboxyalkylalkyl-
`celluloses, carboxyalkylcellulose esters such as carboxym-
`ethylcellulose and their alkali metal salts; water-soluble
`synthetic polymers such as polyacrylic acids and polyacrylic
`acid esters, polymethacrylic acids and polymethacrylic acid
`esters, polyvinylacetates, polyvinylalcohols, polyvinylac-
`etatephthalates (PVAP), polyvinylpyrrolidone (PVP), PVY/
`vinyl acetate copolymer, and polycrotonic acids; also suitable
`are phthalated gelatin, gelatin succinate, crosslinked gelatin,
`shellac, water-soluble chemical derivatives of starch, cationi-
`cally modified acrylates and methacrylates possessing, for
`example, a tertiary or quaternary amino group, such as the
`diethylaminoethyl group, which may be quaternized if
`desired; and other similar polymers.
`[0038]
`Such extenders may optionally be added in any
`desired amount desirably within the range ofup to about 80%,
`desirably about 3% to 50% and more desirably within the
`range of 3% to 20% based on the weight of all film compo-
`nents.
`
`Further additives may flow agents and opacifiers,
`[0039]
`such as the oxides ofmagnesium aluminum, silicon, titanium,
`etc. desirably in a concentration range of about 0.02% to
`about 3% by weight and desirably about 0.02% to about 1%
`based on the weight of all film components.
`[0040]
`Further examples of additives are plasticizers which
`include polyalkylene oxides, such as polyethylene glycols,
`polypropylene glycols, polyethylene-propylene glycols,
`organic plasticizers with low molecular weights, such as
`glycerol, glycerol monoacetate, diacetate or triacetate, triace-
`tin, polysorbate, cetyl alcohol, propylene glycol, sorbitol,
`sodium diethylsulfosuccinate, triethyl citrate, tributyl citrate,
`and the like, added in concentrations ranging from about
`
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`US 2014/0005218 A1
`
`Jan. 2, 2014
`
`0.5% to about 30%, and desirably ranging from about 0.5% to
`about 20% based on the weight of the polymer.
`[0041] There may further be added compounds to improve
`the texture properties of the starch material such as animal or
`vegetable fats, desirably in their hydrogenated form, espe-
`cially those which are solid at room temperature. These fats
`desirably have a melting point of 50° C. or higher. Preferred
`are tri-glycerides with C12-, C14-, C16-, C18-, C20- and C22-
`fatty acids. These fats can be added alone without adding
`extenders or plasticizers and can be advantageously added
`alone or together with mono- and/or di-glycerides or phos-
`phatides, especially lecithin. The mono- and di-glycerides are
`desirably derived from the types of fats described above, i.e.
`with C12-, C14-, C16-, C18-, C20- and CZZ-fatty acids.
`[0042] The total amounts used of the fats, mono-, di-glyc-
`erides and/or lecithins are up to about 5% and preferably
`within the range of about 0.5% to about 2% by weight of the
`total film composition.
`[0043]
`It further may be useful to add silicon dioxide, cal-
`cium silicate, or titanium dioxide in a concentration of about
`0.02% to about 1% by weight of the total composition. These
`compounds act as flow agents and opacifiers.
`[0044] Lecithin is one surface active agent for use in the
`films described herein. Lecithin may be included in the feed-
`stock in an amount of from about 0.25% to about 2.00% by
`weight. Other surface active agents, i.e. surfactants, include,
`but are not limited to, cetyl alcohol, sodium lauryl sulfate, the
`SpansTM and TweensTM which are commercially available
`from lCl Americas, Inc. Ethoxylated oils, including ethoxy-
`lated castor oils, such as Cremophor® EL which is commer-
`cially available from BASF, are also useful. CarbowaxTM is
`yet another modifier which is very useful in the present inven-
`tion. TweensTM or combinations of surface active agents may
`be used to achieve the desired hydrophilic-lipophilic balance
`(“HLB”). The present invention, however, does not require
`the use ofa surfactant and films or film-forming compositions
`ofthe present invention may be essentially free ofa surfactant
`while still providing the desirable uniformity features of the
`present invention.
`[0045] Other ingredients include binders which contribute
`to the ease of formation and general quality of the films.
`Non-limiting examples of binders include starches, pregela-
`tinize starches, gelatin, polyvinylpyrrolidone, methylcellu-
`lose, sodium carboxymethylcellulose, ethylcellulose, poly-
`acrylamides, polyvin