111111
`
`1111111111111111111111111111111111111111111111111111111111111
`US0084 75832B2
`
`c12) United States Patent
`Myers et al.
`
`(10) Patent No.:
`(45) Date of Patent:
`
`US 8,475,832 B2
`Jul. 2, 2013
`
`(54) SUBLINGUAL AND BUCCAL FILM
`COMPOSITIONS
`
`(75)
`
`Inventors: Garry L. Myers, Kingsport, TN (US);
`Samuel D. Hilbert, Jonesboro, TN (US);
`Bill J. Boone, Johnson City, TN (US); B.
`Arlie Bogue, New Carlisle, IN (US);
`Pradeep Sanghvi, Schererville, IN (US);
`Madhusudan Hariharan, Munster, IN
`(US)
`
`(73) Assignee: RB Pharmaceuticals Limited, Slough
`(GB)
`
`( *) Notice:
`
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 231 days.
`
`(21) Appl. No.: 12/537,571
`
`(22) Filed:
`
`Aug. 7, 2009
`
`(65)
`
`(51)
`
`(52)
`
`Prior Publication Data
`
`US 2011/0033541 Al
`
`Feb. 10,2011
`
`Int. Cl.
`A61F 13100
`A61K9/14
`A61K 31144
`U.S. Cl.
`USPC ........... 424/435; 424/422; 424/434; 424/484;
`514/282
`
`(2006.01)
`(2006.01)
`(2006.01)
`
`(58) Field of Classification Search
`None
`See application file for complete search history.
`
`(56)
`
`References Cited
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`(Continued)
`
`Primary Examiner- Janet Epps-Smith
`(74) Attorney, Agent, or Firm- Hoffmann & Baron, LLP
`
`(57)
`
`ABSTRACT
`
`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(cid:173)
`dence while providing sufficient buccal adhesion of the dos(cid:173)
`age form.
`
`19 Claims, No Drawings
`
`TEVA EXHIBIT 1001
`TEVA PHARMACEUTICALS USA, INC. V. RB PHARMACEUTICALS LTD.
`
`

`
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`topical films produced by hot melt extrusion," Journal of Controlled
`Release, 70: 341-351 (200 1 ).
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`dated Apr. 11,2011.
`
`TEVA EXHIBIT 1001
`TEVA PHARMACEUTICALS USA, INC. V. RB PHARMACEUTICALS LTD.
`
`

`
`US 8,475,832 B2
`Page 3
`
`Written Opinion of the International Searing Authority for Interna(cid:173)
`tionalApplication No. PCT/US2010/044488 dated Apr. 11,2011.
`Abeer M. Al-Ghananeem eta!., "Effect of pH on Sublingual Absorp(cid:173)
`tion ofOxycodone Hydrochloride." AAPS PharmSciTech 2006; 7(1)
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`Mahmood eta!., "A limited sampling method for the estimation of
`AUC and Cmax of carbamazepine and carbamazepine epoxide fol(cid:173)
`lowing a single and multiple dose of a sustained-release product." BrJ
`Clin Pharrnacol1998; 45: pp. 241-246.
`* cited by examiner
`
`TEVA EXHIBIT 1001
`TEVA PHARMACEUTICALS USA, INC. V. RB PHARMACEUTICALS LTD.
`
`

`
`US 8,475,832 B2
`
`1
`SUBLINGUAL AND BUCCAL FILM
`COMPOSITIONS
`
`2
`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
`
`The present invention relates to compositions, methods of
`manufacture, products and methods of use relating to films
`containing therapeutic actives. The invention more particu(cid:173)
`larly relates to self-supporting film dosage forms which pro(cid:173)
`vide a therapeutically effective dosage, essentially matching
`that of currently-marketed tablets containing the same active.
`Such compositions are particularly useful for treating nar(cid:173)
`cotic dependence while providing sufficient buccal adhesion
`of the dosage form.
`
`BACKGROUND OF THE RELATED
`TECHNOLOGY
`
`15
`
`In one embodiment of the present invention, there is pro(cid:173)
`vided a film dosage composition including: a polymeric car(cid:173)
`rier matrix; a therapeutically effective amount of buprenor(cid:173)
`phine or a pharmaceutically acceptable salt thereof, a
`10 therapeutically effective amount of naloxone or a pharmaceu(cid:173)
`tically 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.
`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 pharma-
`20 ceutically acceptable salt thereof; and a buffer in an amount
`sufficient to inhibit the absorption of the naloxone when
`administered orally.
`In still other embodiments, there may be provided a film
`dosage composition including: a polymeric carrier matrix; a
`25 therapeutically effective amount ofbuprenorphine or a phar(cid:173)
`maceutically acceptable salt thereof, a therapeutically effec(cid:173)
`tive amount of naloxone or a pharmaceutically acceptable salt
`thereof; and a buffering system; where the buffering system
`includes a buffer capacity sufficient to maintain the ionization
`30 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(cid:173)
`ceutically acceptable salt thereof, and a buffer in an amount to
`40 provide a pH of the composition of a value sufficient 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(cid:173)
`vided a process offorming a film dosage composition includ-
`45 ing 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(cid:173)
`cally effective amount of naloxone or a pharmaceutically
`50 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(cid:173)
`tion.
`In another embodiment, there is provided a film dosage
`composition including a therapeutically sufficient amount of
`buprenorphine or a pharmaceutically acceptable salt thereof
`and a therapeutically sufficient amount of naloxone or a phar(cid:173)
`maceutically acceptable salt thereof, the film dosage compo-
`60 sition 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 provide an
`orally dissolving film formulation including buprenorphine
`65 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
`
`35
`
`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(cid:173)
`tially different due to differing absorption of the charged and
`uncharged species. These factors represent some of the chal(cid:173)
`lenges in appropriately co-administering therapeutic agents.
`Co-administration of therapeutic agents has many applica(cid:173)
`tions. Among such areas of treatment include treating indi(cid:173)
`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(cid:173)
`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(cid:173)
`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(cid:173)
`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(cid:173)
`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 55
`for abuse. In some instances, the patient who has been pro(cid:173)
`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 film
`dosage form that provides the desired absorption levels of the
`agonist and antagonist, while providing an adhesive effect in
`
`TEVA EXHIBIT 1001
`TEVA PHARMACEUTICALS USA, INC. V. RB PHARMACEUTICALS LTD.
`
`

`
`US 8,475,832 B2
`
`3
`plasma profile having a Cmax of between about 41.04 pg/ml
`to about 323.75 pg/ml for naloxone.
`
`DETAILED DESCRIPTION OF THE PREFERRED
`EMBODIMENTS
`
`Definitions
`
`As used herein, the term Cmax refers to the mean maxi(cid:173)
`mum plasma concentration after administration of the com(cid:173)
`position to a human subject. As also used herein, the term
`AUC refers to the mean area under the plasma concentration(cid:173)
`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(cid:173)
`tration of the currently available Suboxone® tablet. An "opti(cid:173)
`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 ofbuprenorphine may be
`about 7.43 to about 59.46 hr*ng/ml at dosages offrom 2-16 25
`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(cid:173)
`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 of0.5 mg to 4.0 mg ranges
`from 32.5 to 260 pg/ml, and an AUC of naloxone for dosage
`of0.5 mg to 4.0 mg ranges from 90.55 to 724.4 hr*pg/ml. It 45
`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 50
`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(cid:173)
`lent product would have a Cmax of buprenorphine in the
`range of0.624-0.975 ng/ml, and anAUC value ofbuprenor- 55
`phine of 5.431-8.486 hr*ng/ml.
`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 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 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 lami(cid:173)
`nated films.
`
`4
`Oral dissolving films generally fall into three main classes:
`fast dissolving, moderate dissolving and slow dissolving. Fast
`dissolving films generally dissolve in about 1 second to about
`30 seconds in the mouth. Moderate dissolving 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 oflow molecular
`weight hydrophilic polymers (i.e., polymers having a
`molecular weight between about 1,000 to 9,000, or polymers
`10 having a molecular weight up to 200,000). In contrast, slow
`dissolving films generally have high molecular weight poly(cid:173)
`mers (i.e., having a molecular weight in the millions).
`Moderate dissolving films tend to fall in between the fast
`and slow dissolving films. Moderate dissolving films dissolve
`15 rather quickly, but also have a good level of mucoadhesion.
`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
`20 moderate dissolving films 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 film is not easily removable once it is placed in
`the oral cavity of the user.
`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 of providing a physiologi(cid:173)
`cal response or activity in the body of the user. The films
`30 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
`35 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 nee-
`40 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(cid:173)
`tion relates to the treatment of opioid dependence in an indi(cid:173)
`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(cid:173)
`bination ofbuprenorphine (an opioid agonist) and naloxone
`(an opioid antagonist). Therefore, the present invention pro(cid:173)
`vides a method of treating narcotic dependence by providing
`an orally dissolvable film dosage, which provides a
`bioequivalent effect to Suboxone®. The film dosage prefer(cid:173)
`ably provides buccal adhesion while it is in the user's mouth,
`60 rendering it difficult to remove after placement.
`The film dosage composition preferably includes a poly(cid:173)
`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
`65 removed and it should form a gel like structure when admin(cid:173)
`istered. The orally consumable films are preferably moderate(cid:173)
`dissolving in the oral cavity and particularly suitable for
`
`TEVA EXHIBIT 1001
`TEVA PHARMACEUTICALS USA, INC. V. RB PHARMACEUTICALS LTD.
`
`

`
`US 8,475,832 B2
`
`5
`delivery of actives, although both fast and sustained release
`compositions are also among the various embodiments con(cid:173)
`templated.
`The films used in the pharmaceutical products may be
`produced by a combination of at least one polymer and a 5
`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(cid:173)
`bination thereof. In some embodiments, the solvent may be a
`non-polar organic solvent, such as methylene chloride. The 10
`film may be prepared by utilizing a selected casting or depo(cid:173)
`sition method and a controlled drying process. For example,
`the film may be prepared through controlled drying pro(cid:173)
`cesses, which include application of heat and/or radiation
`energy to the wet film matrix to form a visco-elastic structure, 15
`thereby controlling the uniformity of content of the 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
`A1, the contents of which are incorporated herein by refer- 20
`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 A1, the contents of
`which are incorporated herein by reference in their entirety. 25
`The polymer included in the films may be water-soluble,
`water-swellable, water-insoluble, or a combination of one or
`more either water-soluble, water-swellable or water-in(cid:173)
`soluble polymers. The polymer may include cellulose or a
`cellulose derivative. Specific examples of useful water- 30
`soluble polymers include, but are not limited to, polyethylene
`oxide, pullulan, hydroxypropylmethyl cellulose, hydroxy(cid:173)
`ethyl cellulose, hydroxypropyl cellulose, polyvinyl pyrroli(cid:173)
`done, carboxymethyl cellulose, polyvinyl alcohol, sodium
`alginate, polyethylene glycol, xanthan gum, tragancanth 35
`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(cid:173)
`ited to, ethyl cellulose, hydroxypropyl ethyl cellulose, cellu- 40
`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 45
`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- 50
`soluble or water-swellable at room temperature and other
`temperatures, such as temperatures exceeding room tempera(cid:173)
`ture. Moreover, the materials may be water-soluble or water(cid:173)
`swellable at pressures less than atmospheric pressure. Desir(cid:173)
`ably, the water-soluble polymers are water-soluble or water- 55
`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(cid:173)
`ficiently water-soluble to be dissolvable upon contact with 60
`bodily fluids.
`Other polymers useful for incorporation into the films
`include biodegradable polymers, copolymers, block poly(cid:173)
`mers and combinations thereof. It is understood that the term
`"biodegradable" is intended to include materials that chemi- 65
`cally degrade, as opposed to materials that physically break
`apart (i.e., bioerodable materials). Among the known useful
`
`6
`polymers or polymer classes which meet the above criteria
`are: poly(glycolic acid) (PGA), poly(lactic acid) (PLA), poly(cid:173)
`dioxanes, polyoxalates, poly( a-esters), polyanl!ydrides,
`polyacetates,
`polycaprolactones,
`poly( orthoesters ),
`polyamino acids, polyaminocarbonates, polyurethanes, poly(cid:173)
`carbonates, polyamides, poly(alkyl cyanoacrylates), and
`mixtures and copolymers thereof. Additional useful polymers
`include, stereopolymers ofL- 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(cid:173)
`mers, copolymers of polyurethane and (poly(lactic acid),
`copolymers of polyurethane and poly(lactic acid), copoly(cid:173)
`mers of a-amino acids, copolymers of a-amino acids and
`caproic acid, copolymers of a-benzyl glutamate and polyeth(cid:173)
`ylene glycol, copolymers of succinate and poly(glycols),
`polyphosphazene, polyhydroxy-alkanoates and mixtures
`thereof. Binary and ternary systems are contemplated.
`Other specific polymers useful include those marketed
`under the Medisorb and Biodel trademarks. The Medisorb
`materials are marketed by the Dupont Company of Wilming(cid:173)
`ton, Del. and are generically identified as a "lactide/glycolide
`co-polymer" containing "propanoic acid, 2-hydroxy-poly(cid:173)
`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°-175° C.); lactide/glycolide 100 L,
`believed to be 1 00% glycolide having a melting point within
`the range of 437°-455° F. (225°-235° 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°-175°
`C.); and lactide/glycolide 50/50, believed to be a copolymer
`of 50% lactide and 50% glycolide with a melting point within
`the range of338°-347° F. (170°-175° C.).
`The Biodel materials represent a family of various polyan(cid:173)
`hydrides which differ chemically.
`Although a variety of different polymers may be used, it is
`desired to select polymers that provide mucoadhesive prop(cid:173)
`erties 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 compo(cid:173)
`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 film. In other
`embodiments, however, it may be desirable to use combina(cid:173)
`tions of water-soluble polymers and polymers that are water(cid:173)
`swellable, water-insoluble and/or biodegradable, as provided
`above. The inclusion of one or more polymers that are water(cid:173)
`swellab