United States Patent
`Tapolsky et al.
`
`j19)
`
`[54]
`
`BIOERODABLE FILM FOR DELIVERY OF
`PHARMACEUTICAL COMPOUNDS OF
`MUCOSAL SURFACES
`
`[75]
`
`Inventors: Gilles H. Tapolsky; David W.
`Osborne, both of The Woodlands, ‘Tex.
`
`[73]
`
`Assignee: Virotex Corporation, The Woodlands,
`Tex.
`
`Appl. No.: 09/144,827
`
`Filed:
`
`Sep. 1, 1998
`
`[63]
`
`[51]
`
`[52]
`[58]
`
`[56]
`
`Related U.S. Application Data
`
`Continuation of application No. 08/734,519, Oct. 18, 1996,
`Pat, No, 5,800,832.
`
`Tint. C17 coccccceeccssseessseeesenee A61LK 9/70; AG1K 47/38;
`A61M 37/00
`WB2 Ce cesccsssssewascssszesrscens 424/449; 424/448; 424/434
`Field of Search .........c.ccccccccceceeseeeees 424/449, 448,
`424/434
`
`References Cited
`
`U.S, PATENT DOCUMENTS
`
`2/1972 EteS cssssssssesesseuseeeseneeseeeeee 106/170
`3,640,741
`12/1976 Zaffaroni
`...
`‘
`26
`3,996,934
`
`4,226,848 10/1980 Nagai et al. occ cee 424/19
`4,250,163
`2/1981 Nagai et al. occ 424/14
`4,285,934
`8/1981 Tinnell
`.........
`424/148
`
`4,286,592
`9/1981 Chandrasekaran
`128/260
`.........
`4,202,299
`9/1981 Suzuki
`424/16
`
`......
`4,381,296
`4/1983 Tinnell
`424/148
`
`4,517,173
`5/1985 Kizawaet al.
`424/16
`4,518,721
`5/1985 Dhabharet al.
`523/120
`4,572,832
`2/1986 Kigasawa et al.
`s.scsecseseresseeeees 424/19
`4,668,232
`5/1987 Cordes et al...
`cece 604/897
`4,713,243 12/1987 Schiraldi et al.
`. 424/151
`4,715,369 12/1987 Susuki et al.
`.......cccccccersessesere 128/156
`4,720,387
`1/1988 Sakamoto et al. .
`4,740,365
`4/1988 Yukimatsu et al. wo 424/435
`
`4,765,983
`8/1988 Takayanagi et al.
`. 424/434
`9/1989 Newsham et al... 424/81
`4,867,970
`
`.
`
`US006159498A
`(11) Patent Number:
`[45] Date of Patent:
`
`6,159,498
`Dec. 12, 2000
`
`
`
`......s.csscssersssssssrensnse 424/448
`12/1989 Komishii
`4,889,720
`1/1990 Reul et al.
`.........
`wv. 424/439
`4,894,232
`2/1990 Yanagibashi et al
`424/448
`4,900,554
`3/1990 Cleary et ab. cucccccceeseneees 424/78
`4,906,463
`4/1990 Gallopo etal. .......
`424/435
`4,915,948
`2/1991 Schull etal. .
`4,990,339
`604/307
`10/1991 Cilento et al. wu.
`5,059,189
`we 424/448
`11/1991 Berner et al.
`...
`5,064,654
`-» 514/781
`1/1992 Pomerantz ..
`5,081,157
`+ 514/781
`1/1992 Pomerantz ..
`5,081,158
`we 424/445
`5/1992 Ojiet al.
`.....
`5,116,621
`« 424/435
`8/1992 Kuroya et al.
`5,137,729
`3/1993 Rencher
`.2......c...cccceseeeeee 514/535
`5,192,802
`“3/1003: Konishi jcnniacuna 424/448
`S166908
`3/1994 Akemi et al.
`we 424/484
`5,298,258
`5/1994 Rencher......
`+ 514/535
`5,314,915
`7/1994 Mantelle ....ccccccsesssseessesensees 424/443
`5,332,576
`10/1995 Rencher
`........2.
`cece 424/484
`5,462,749
`11/1995 Roydset al.
`+» 424/449
`5,466,465
`4/1996 Bimet al.
`.....ccccessccsssssseseeenenes 424/448
`5,505,956
`7/1998 Kamiya et al.
`.
`5,780,047
`FOREIGN PATENT DOCUMENTS
`
`
`
`
`
`0050480
`0250187
`0381194
`0781546
`2497098
`2582942
`56/100714
`0159604
`0262422
`
`European Pat. Off. .
`4/1982
`European Pat. Off. .
`12/1987
`8/1990 European Pat. Off. .
`7/1997
`European Pat. Off. .
`7/1982
`France .
`12/1986
`France .
`8/1981
`Japan .
`10/1985
`Japan .
`4/1988
`Japan .
`
`Primary Examiner—Edward J. Webman
`Attorney, Agent, or Firm—Morrison & Foerster LLP
`ABSTRACT
`
`[57]
`
`The present invention relates to water-soluble, bioerodable
`pharmaceutical delivery device for application to mucosal
`surfaces. The device comprises an adhesive layer and a
`non-adhesive backing layer, and the pharmaceutical may be
`provided in either or both layers, Upon application,
`the
`device adheres to the mucosal surface, providing drug
`delivery and protection to the treatmentsite.
`
`27 Claims, No Drawings
`
`Dr. Reddy's - EX1012
`Page 1
`
`Dr. Reddy's - EX1012
`Page 1
`
`

`

`6,159,498
`
`1
`BIOERODABLE FILM FOR DELIVERY OF
`PHARMACEUTICAL COMPOUNDS OF
`MUCOSAL SURFACES
`
`This is a continuation of application Ser. No. 08/734,519
`filed Oct. 18, 1996, now U.S. Pat. No. 5,800,832.
`FIELD OF THE INVENTION
`
`The present invention relates generally to a bioerodable,
`water-soluble pharmaceutical carrier which adheres to
`mucosal surfaces for the localized delivery of pharmaceu-
`tical compounds and protection of the treatmentsite.
`BACKGROUND OF THE INVENTION
`
`The localized treatment of body tissues, diseases, and
`wounds requires that the particular pharmaceutical compo-
`nent be maintained at the site of treatment for an effective
`period of time. Given the tendency of natural bodily fluids
`to rapidly wash away topically applied pharmaceutical
`components, the topical treatment of wet mucosal tissues
`has been problematic. In the mouth, saliva, natural replace-
`ment of the mucosaltissue, and eating, drinking, and speak-
`ing movements are some of the problems that have limited
`the effectiveness and residence time of pharmaceutical car-
`riers.
`
`10
`
`15
`
`20
`
`25
`
`2
`and adhesive propertiesis the product commercialized under
`the name Orabase®-B, which is a thick gel or paste for the
`relief of mouth sores. Ingredients include guar gum, sodium
`carboxymethyl! cellulose, tragacanth gum, and pectin. Even
`though it does provide numbing to the area of application,
`the film forming behavior and bioadhesion do not last. Thus,
`this product has a limited residence time.
`Bioadhesive tablets are described in U.S. Pat. No. 4,915,
`948. The water-soluble bioadhesive material used in this
`device is a xanthan gum or a pectin combined with an
`adhesion enhancing material such as a polyol. Although
`residence time is improved with the use of bioadhesive
`tablets, they are not user friendly, especially when used in
`the oral cavity, given the unpleasant feelings associated with
`their solidity, bulkiness, and slow dissolution time. Bioad-
`hesive tablets are also described in U.S. Pat. Nos. 4,226,848;
`4,292,299; and 4,250,163, and are single layer or bilayer
`devices having an average thickness of 0.2 to 2.5 mm. The
`bioadhesive tablets described in these patents utilize a
`non-adhesive component such as cellulose ether, a bioad-
`hesive component such as polyacrylic acid, sodium car-
`boxymethyl cellulose, or polyvinylpyrrolidone, and a binder
`for tableting purposes. The cellulose derivatives may or may
`not be water-soluble. The claimedcellulosic materials in the
`*299 Patent are methyl cellulose, hydroxypropyl cellulose,
`and hydroxypropylmethyl cellulose.
`The use of bandages or bioadhesive laminated films,
`which are thinner and flexible and therefore have a
`
`decreased foreign body sensation, is described in U.S. Pat.
`Nos. 3,996,934 and 4,286,592. These products are used to
`deliver drugs through the skin or mucous. The laminated
`films usually include an adhesive layer, a reservoir layer, and
`a backing layer. Bioadhesive devices designed to release
`drug through the skin at a given rate and over a period of
`time are usually not water soluble, and are not dissolved or
`washed away by bodily fluids.
`In addition to film systems for the delivery of drug
`through the skin, film delivery systems for use on mucosal
`surfaces are also known. These types of systems, which are
`water-insoluble and usually in the form of laminated,
`extruded or composite films, are described in U.S. Pat. Nos.
`4,517,173; 4,572,832; 4,713,243; 4,900,554: and 5,137,729.
`The *173 Patent describes and claims a membrane-adhering
`film consisting of at least three layers, including a pharma-
`ceutical layer, a poor water soluble layer, and an interme-
`diate layer. The pharmaceutical layer includes the drug and
`a cellulose derivative selected from hydroxypropyl
`cellulose, methyl cellulose, and hydroxypropyl methy! cel-
`lulose. The poor water soluble layer is made by the combi-
`nation of one or more cellulose derivatives with a poor water
`soluble fatty acid, and the intermediate layer is made of
`cellulose derivatives. The *832 Patentrelates to a soft film
`for buccal delivery, made by the combined use of a water
`soluble protein, a polyol, and a polyhydric alcohol such as
`cellulose and polysaccharides, and also teaches the use of
`coloring or flavoring agents. The *243 Patent describes a
`single or multi-layered bioadhesive thin film made from
`40-95% water soluble hydroxypropyl cellulose, 5-60%
`water-insoluble ethylene oxide, 0-10% water-insoluble
`ethyl cellulose, propyl cellulose, polyethylene, or
`polypropylene, and a medicament. The films are three-
`layered laminates and include a bioadhesive layer, a reser-
`voir layer, and a non water-soluble outer protective layer.
`The *729 Patent teaches a soft adhesivefilm applicable to the
`oral mucosa containing a systemic drug and comprising a
`mixture of a vinyl acetate non water-soluble homopolymer,
`an acrylic acid polymer, and a cellulose derivative. Finally,
`
`Page 2
`
`Bioadhesive carriers are known in the art and includegels,
`pastes, tablets, and films. These products, however, may lack
`one or several of the preferred characteristic for an efficient
`and commercially acceptable pharmaceutical delivery
`device. Some characteristics which are preferred by users of
`bioadhesive carriers include water-erodability, ease of han-
`dling and application to the treatment site, and ease of
`comfort with minimal foreign body sensation. Other pre-
`ferred characteristics for an effective and user-friendly prod-
`uct for the treatment of mucosal surfaces includethe use of
`pharmaceutically approved components or materials; instan-
`taneous adhesion to mucosal surface upon application;
`increased residence time for the protection of the affected
`tissue or the delivery of the pharmaceutical component; and
`ease of removal ofthe delivery device from the affected
`tissue or natural dissolution of the delivery device at the
`delivery site.
`Bioadhesive gels which are used for application to
`mucosal tissues and especially the oral cavity are known in
`the art. For example, U.S. Pat. No. 5,192,802 describes a
`bioadhesive teething gel made from a blend of sodium
`carboxymethyl cellulose and xantham gum. The gel may
`also have potential use in the treatment of canker sores, fever
`blisters, and hemorrhoids. However, this type of pharma-
`ceutical carrier has a very limited residence time, given that
`body fluids such as saliva quickly wash it away from the
`treatment site. Bioadhesive gels are also described in U.S.
`Pat. Nos. 5,314,915; 5,298,258; and 5,642,749. The gels
`described in those patents use an aqueous or oily medium
`and different types of bioadhesive and gelling agents.
`Denture adhesive pastes are another type of bioadhesive
`product known in the art. However, these preparations are
`used primarily for their adhesive properties, to adhere den-
`tures to the gums,rather than for the protection of tissue or
`for the topical delivery of pharmaceuticals, although drugs
`such as local anesthetics may be used in the paste for the
`relief of sore gums. U.S. Pat. Nos. 4,894,232 and 4,518,721
`describe denture adhesive pastes. The *721 Patent describes
`a combination of sodium carboxymethyl cellulose and poly-
`ethylene oxide in polyethylene glycol.
`Pastes have also been used asfilm protectants and as drug
`delivery systems. One such example having film forming
`
`30
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`Page 2
`
`

`

`6,159,498
`
`3
`the °554 Patent describes a device for use in the oral cavity
`having an adhesive layer including a mixture of an acrylic
`acid polymer, a water-insoluble cellulose derivate, and a
`pharmaceutical preparation, and a water-insoluble or spar-
`ingly soluble backing layer. The adhesive layer contains the
`pharmaceutical, and upon application to the mucosal
`surface, delivers the drug. The 554 Patent also states that “it
`is impossible to achieve an adhesive device for application
`to body tissue without all three components, that is, acrylic
`acid polymer, water insoluble cellulose derivative and a
`water insoluble or sparingly soluble backing layer.”
`The previous examples of thin films to be applied in the
`oral cavity by adhesion onto the mucosal tissuesall utilize
`polymers which are water-insoluble by nature or which are
`made water-insoluble by crosslinking, and claim a long
`residence time. They are satisfactory but do not provide a
`water soluble device with good adhesive properties.
`Therefore, following application for an expected period of
`time and the release of an amount of drug, the thin films
`made by water insoluble polymers must be peeledoff of the
`site of application.
`
`SUMMARY OF THE INVENTION
`
`10
`
`15
`
`4
`In one
`to the delivery.
`lution of the film concomitant
`embodiment, the pharmaceutical delivery device comprises
`a bilayer film disk having an adhesive layer and a backing
`layer, both water-soluble, having the pharmaceutical
`in
`either or both layers.
`Unlike bioadhesive gels and pastes known in the art,
`which have a very limited residence time, given the ten-
`dency ofbodily fluids such as saliva to wash away the gel
`from the treatment site,
`the present
`invention offers an
`increased residence time because ofits filmy consistency
`and components. A typicalresidence time for an aqueous gel
`or paste, such as Orajel®, Orabase®, or Kanka® is a few
`minutes. This short residence time is a consequence of a
`limited or poor adhesion.
`In a typical aqueous gel,
`the
`mucoadhesive components are either in solution,
`suspension, or swollen, Once applied to the mucosal surface,
`however,
`the water based gel does not
`instantaneously
`penetrate the lipophilic mucosal surface. The composition
`and water affinity of these gels results in a tendency to
`quickly mix with the saliva, rapidly pulling away the dif-
`ferent components of the gel, and limiting the residence
`time. The same tendency is expected with pastes,
`the
`increase in viscosity only slightly delaying the timing. The
`present invention, by its solid form and its instantaneous
`adhesion to the mucosal surface, allows a lasting contact, a
`consequence of the entanglement of polymer chains and
`glycoproteins of the mucosal tissue which assures adhesion.
`Dissolution kinetics in the saliva and other aqueous media
`are influenced by the physicalstate of the device. While a gel
`or solution will readily mix with saliva and/or other bodily
`fluids, a solid form such as a crystalline, film, or precipitate
`of the same or similar composition is expected to dissolve
`more slowly.
`Also, unlike the bioadhesive tablets which are known in
`the art, the pharmaceutical device of the present invention
`minimizes the discomfort associated with application of a
`foreign substance for a period of time sufficient to provide
`effective drug delivery to the treatment site. Although bio-
`adhesive tablets do offer effective residence time, users of
`bioadhesive tablets experience unpleasant sensations due to
`their solidity, bulkiness, and slow dissolution time if
`erodable, especially when used in the oral cavity. Moreover,
`the typical thickness of bioadhesive tablets, which may or
`may not be water soluble, is a couple of millimeters, and
`because of their thickness, the preferred site of application
`is on the upper gingival area. This site is quite satisfactory
`for the systemic delivery of an active component, but may
`not be as satisfactory for local delivery. The device of the
`present invention offers the advantagesofan effective resi-
`dence time with minimal discomfort and ease of use, and is
`an appropriate vehicle for the local as well as systemic
`delivery of pharmaceutical, given its thinner, flexible form.
`Finally, unlike the film systems known in the art which are
`used to deliver pharmaceutical through the skin or mucous,
`the device ofthe present invention is made of water-soluble
`components and is bioerodable. The use of water-soluble
`components allows the device to dissolve over a period of
`time, with natural bodily fluids slowly dissolving and erod-
`ing awaythe carrier, while the pharmaceutical remains at the
`application site. Unlike bandages and other non-water-
`soluble film systems, the user of the present invention does
`not have to remove the device following treatment. Nor does
`the user experience the sensation of the presence of a foreign
`object at
`the mucosal surface or within the body cavity,
`given that upon application, water absorption softens the
`device, and over time, the device slowly dissolves or erodes
`away.
`
`Page 3
`
`invention relates to a novel water-soluble
`The present
`pharmaceutical carrier device for application to mucosal
`surfaces to provide protection of and delivery of pharma-
`ceutical to the site of application, surrounding tissues, and
`other bodily fluids, having an effective residence time, with
`minimal discomfort and ease of use. In one embodiment, the
`device includes a mucoadhesive bilayer film disk which is
`water-soluble and bioerodable.
`In one embodiment,
`the
`pharmaceutical delivery device comprises a bilayer film disk
`having an adhesive layer and a backing layer, both water-
`soluble, having the pharmaceuticalin either or both layers...
`The adhesive layer comprises a film forming polymer such
`as hydroxyethyl cellulose, hydroxyproyl cellulose, hydrox-
`ypropylmethyl cellulose, or hydroxyethyl methyl cellulose,
`alone or in combination, and a bioadhesive polymer such as
`polyacrylic acid, polyvinyl pyrrolidone, or sodium car-
`boxymethyl cellulose, alone or in combination. The non-
`adhesive backing layer comprises hydroxyethyl cellulose,
`hydroxypropyl cellulose, hydroxyethylmethyl cellulose,
`hydroxypropylmethy! cellulose, polyvinyl alcohol, polyeth-
`ylene glycol, polyethylene oxide, or ethylene oxide-
`propylene oxide co-polymers, alone or in combination.
`Methodsfor treating mucosal surfaces, surrounding tissues,
`and bodily fluids, by applying the bilayer film to the treat-
`ment site for drug delivery and protection of the site of
`application, are also provided.
`
`25
`
`30
`
`40
`
`45
`
`50
`
`DETAILED DESCRIPTION OF THE
`INVENTION
`
`In the present invention, a novel water soluble, bioerod-
`able pharmaceutical device which adheres to mucosal sur-
`faces is provided. The present invention finds particular use
`in the localized treatment of body tissues, diseases, or
`wounds which may have moist surfaces and which are
`susceptible to bodily fluids, such as the mouth, the vagina,
`or other types of mucosal surfaces. The device carries a
`pharmaceutical, and upon application and adherence to the
`mucosal surface, offers a layer of protection and delivers the
`pharmaceutical to the treatmentsite, the surrounding tissues,
`and other bodily fluids. The device provides an appropriate
`residence time for effective drug delivery at the treatment
`site, given the control of solubilization in aqueous solution
`or bodily fluids such as saliva, and the slow, natural disso-
`
`55
`
`60
`
`65
`
`Page 3
`
`

`

`6,159,498
`
`5
`The residence time of the device of the present invention
`depends on the dissolution rate of the water-soluble poly-
`mers used. The dissolution rate may be adjusted by mixing
`together chemically different polymers, such as hydroxy-
`ethyl cellulose and hydroxypropyl cellulose; by using dif-
`ferent molecular weight grades of the same polymer, such as
`mixing low and medium molecular weight hydroxyethyl
`cellulose; by using crosslinking agents such as glyoxal with
`polymers such as hydroxyethyl cellulose for partial
`crosslinking; or by post-treatment
`irradiation or curing,
`which may alter the physical state of the film, includingits
`crystallinity or phase transition, once obtained. These strat-
`egies might be employed alone or in combination in order to
`modify the dissolution kinetics of the device, without sup-
`pressing the water solubility characteristics of the compo-
`nent materials.
`
`the pharmaceutical delivery device
`Upon application,
`adheres to the mucosal surface and holds in place. Water
`absorption softens the device quickly, diminishing and
`eliminating the foreign body sensation. As the device rests
`on the mucosal surface, delivery of the drug is provided.
`Residence times may vary, depending on the formulation
`and materials used, but may be modulated between a few
`minutes to several hours. Residence times which may be
`achieved with this invention include 30 minutes to about 3
`or 4 hours. A preferred residence time for effective drug
`delivery is about 1 to 2 hours. In addition to providing drug
`delivery, once the device adheres to the mucosal surface,it
`also provides protection to the treatment site, acting as an
`erodable band aid.
`
`invention comprises a
`In one embodiment, the present
`
`film disk having two layers—an adhesive layer and a
`non-adhesive backing layer—which are both water soluble
`and made of pharmacologically-approved materials. The
`pharmaceutical component may be includedin eitherlayer,
`although preferably,
`it is included in the adhesive layer,
`which is closest to the treatment site and which will have a
`slowerdissolution time, given that the backing layer protects
`the interior, adhesive layer and will dissolve first.
`The adhesive layer may comprise at
`least one film-
`forming water-soluble polymer, usually a cellulose deriva-
`tive (the “film-forming polymer”) and at least one pharma-
`cologically acceptable polymer known for its bioadhesive
`capabilities (the “bioadhesive polymer’). The film forming
`polymer may comprise hydroxyethyl cellulose, hydroxypro-
`pyl cellulose, hydroxypropylmethyl cellulose, hydroxyeth-
`ylmethyl cellulose, or a combination thereof. Preferably, the
`film-forming polymer comprises hydroxyethyl cellulose.
`Preferably, in the case of hydroxyethyl cellulose, the average
`molecular weight (Mw estimated from intrinsic viscosity
`measurements) is in the range 10° to 10° and more prefer-
`ably in the range 10° to 10°, while in the case of hydrox-
`ypropyl cellulose,
`the average molecular weight
`(Mw
`obtained from size exclusion chromatography
`measurements)is in the range 50x10° to 1.5x10°, and more
`preferably between 80x10° to 5x10°. The film-forming,
`polymer may be crosslinked or plasticized in order to alter
`its dissolution kinetics.
`
`The bioadhesive polymer of the adhesive layer may
`comprise polyacrylic acid (PAA), which may or may not be
`partially crosslinked, sodium carboxymethyl cellulose
`(NaCMC), and polyvinylpyrrolidone (PVP), or combina-
`tions thereof. These bioadhesive polymers are preferred
`because they have good and instantaneous mucoadhesive
`properties in a dry, film state. In the case of sodium car-
`boxymethyl cellulose,
`typical average molecular weights
`comprise 50,000 to 700,000, and preferably 60,000 to 500,
`
`10
`
`15
`
`20
`
`25
`
`30
`
`;
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`6
`000, with a degree of substitution of 0.7. The substitution
`range varies between 0.5 and 1.5, and preferably between
`0.6 and 0.9. The polyvinyl pyrrolidone can be characterized
`according to its average molecular weight and comprises
`between 5,000 and 150,000, preferably between 10,000 and
`100,000. The simultaneous use of PAA with some grades of
`PVP mayresult in the precipitation of one or both compo-
`nents. This precipitation may not be ideal
`to obtain a
`homogenous layer and may slightly alter the overall adhe-
`sive properties of the device.
`The adhesion properties of the present invention are the
`result of the entanglement of polymer chains and interac-
`tions with glycoproteins of the mucosal surface. The chemi-
`cal nature of the bioadhesive polymers, including chain and
`side groups and crosslinking agents, generates interactions
`between the mucosal constituents and the polymer or
`polymers, such as physical entanglement, Van der Waals
`interactions, and hydrogen bonding. Given that the compo-
`sition of mucosal
`tissues differs from one individual
`to
`another and changes naturally over time,
`the use of a
`combination of bioadhesive polymers or the use of a com-
`bination of different grades of the same polymer is preferred.
`The use of a combination of at
`least
`two bioadhesive
`polymers maximizes the adhesion capabilities ofthe device,
`although use of a single bioadhesive polymerts effective as
`well.
`
`The ratio of the bioadhesive polymer to the film-forming
`polymer in the adhesive layer may vary, depending on the
`type of pharmaceutical and the amount of pharmaceutical to
`be used. However, the content of combined components in
`the adhesive layer is between 5 and 95% by weight, pref-
`erably between 10 and 80% by weight. In terms of weight
`percent of the different bioadhesive polymers PAA,
`NaCMC, and PVP, some examples are provided below.
`Preferred combinations include PAA and NaCMC, NaCMC
`and PVP, or PAA and PVP, andalso include the use of
`different grades of the same polymer.
`The non adhesive backing layer may comprise a water-
`soluble, film-forming pharmaceutically acceptable polymer
`such as hydroxyethyl cellulose, hydroxypropyl cellulose,
`hydroxypropylmethyl cellulose, hydroxyethylmethyl
`cellulose, polyvinylalcohol, polyethylene glycol, polyethyl-
`ene oxide, ethylene oxide-propylene oxide co-polymers, or
`a combination thereof. The backing, layer component may
`or may not be crosslinked. In one embodiment, the preferred
`backing layer component comprises hydroxyethyl cellulose
`or hydroxypropyl cellulose, and more preferably comprises
`hydroxyethyl! cellulose. Preferably, in the case of hydroxy-
`ethyl cellulose,
`the average molecular weight (Mw esti-
`mated from intrinsic viscosity measurements)is in the range
`10° to 10°, and more preferably in the range 10° to 10°,
`while in the case of hydroxypropyl cellulose, the average
`molecular weight (Mw obtained from size exclusion chro-
`matography measurements) is in the range of 50x10° to
`1.5x10° and more preferably from 80x10° to 5x10°.
`Combinations of different polymers or similar polymers
`with definite molecular weight characteristics may be used
`in order to achieve preferred film forming capabilities,
`mechanical properties, and kinetics of dissolution. Some
`combinations for use in the invention are provided in the
`examples below and may include %4 of hydroxyethyl cellu-
`lose and ¥4 of hydroxypropyl cellulose; 4 of low molecular
`weight hydroxyethyl cellulose and ¥s of medium molecular
`weight hydroxyethyl cellulose; and % of low molecular
`weight hydroxyethyl cellulose and % of high molecular
`weight hydroxyethyl cellulose. In order to modify the water
`dissolution kinetics of the backing layer without resulting in
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`a non-water soluble material, partial and limited crosslink-
`ing may be used. Crosslinking agents known in the art are
`appropriate for use in the invention and may include glyoxal,
`propylene glycol, glycerol, dihydroxy-polyethylene glycol
`of different sizes, and butylene glycol. The amount of
`crosslinking agent used may vary, depending on the particu-
`lar polymers andcrosslinking agent, but should not exceed
`5% molar equivalent of the polymeric material, and prefer-
`ably comprises 0 to 3% molar equivalent of the polymeric
`material. Dissolution characteristics may be adjusted to
`modify the residence time and the release profile of a drug
`when included in the backing layer.
`The pharmaceutical component of the present invention
`may comprise a single pharmaceutical or a combination of
`pharmaceuticals, which may be incorporatedin the adhesive
`layer, the backing layer, or both. Pharmaceuticals which may
`be used, either alone or in combination,
`include anti-
`inflammatory analgesic agents, steroidal anti-inflammatory
`agents, antihistamines, local anesthetics, bactericides and
`disinfectants, vasoconstrictors, hemostatics, chemothera-
`peutic drugs, antibiotics, keratolytics, cauterizing agents,
`and antiviral drugs.
`Examples of anti-inflammatory analgesic agents include
`acetaminophen, methyl salicylate, monoglycol salicylate,
`aspirin, mefenamic acid, flufenamic acid,
`indomethacin,
`diclofenac, alclofenac, diclofenac sodium,
`ibuprofen,
`ketoprofen, naproxen, pranoprofen, fenoprofen, sulindac,
`fenclofenac, clidanac, flurbiprofen, fentiazac, bufexarnac,
`piroxicam, phenylbutazone, oxyphenbutazone, clofezone,
`pentazocine, mepirizole,
`tiaramide hydrochloride, etc.
`Examples of steroidal anti-inflammatory agents include
`hydrocortisone, predonisolone, dexamethasone, triamcino-
`lone acetonide, fluocinolone acetonide, hydrocortisone
`acetate, predonisolone acetate, methylpredonisolone, dex-
`amethasone acetate, betamethasone, betamethasone ~
`valerate, flumetasone, fluorometholone, beclomethasone
`diproprionate, etc.
`Examples of antihistamines include diphenhydramine
`hydrochloride, diphenhydramine salicylate,
`diphenhydramine, chlorpheniramine hydrochloride, chlor-
`pheniramine maleate isothipendyl hydrochloride, tripelen-
`namine hydrochloride, promethazine hydrochloride, meth-
`dilazine hydrochloride, etc. Examples of local anesthetics
`include dibucaine hydrochloride, dibucaine,
`lidocaine
`hydrochloride,
`lidocaine,
`benzocaine,
`p-buthylaminobenzoic acid 2-(die-ethylamino) ethyl ester
`hydrochloride, procaine hydrochloride, tetracaine, tetracaine
`hydrochloride, chloroprocaine hydrochloride, oxyprocaine
`hydrochloride, mepivacaine, cocaine hydrochloride, piper-
`ocaine hydrochloride, dyclonine, dyclonine hydrochloride,
`etc.
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`Examples of bactericides and disinfectants include
`thimerosal, phenol, thymol, benzalkonium chloride, benze-
`thonium chloride, chlorhexidine, povidone iode, cetylpyri-
`dinium chloride, eugenol, trimethylammonium bromide,etc.
`Examples of vasoconstrictors include naphazoline nitrate,
`tetrahydrozoline hydrochloride, oxymetazoline
`hydrochloride, phenylephrine hydrochloride,
`tramazoline
`hydrochloride, etc. Examples of hemostatics include
`thrombin, phytonadione, protamine sulfate, aminocaproic
`acid,
`tranexamic acid, carbazochrome, carbaxochrome
`sodium sulfanate, rutin, hesperidin, ete.
`Examples of chemotherapeutic drugs include sulfamine,
`sulfathiazole, sulfadiazine, homosulfamine, sulfisoxazole,
`sulfisomidine, sulfamethizole, nitrofurazone, etc. Examples
`of antibiotics include penicillin, meticillin, oxacillin,
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`lincomycin,
`cefalotin, cefalordin, erythromeycin,
`tetracycline, chlortetracycline, oxytetracycline, metacycline,
`chloramphenicol, kanamycin, streptomycin, gentamicin,
`bacitracin, cycloserine, etc.
`Examples of keratolytics include salicylic acid, podophyl-
`lum resin, podolifox, and cantharidin. Examples of cauter-
`izing agents include the chloroacetic acids andsilver nitrate.
`Examples of antiviral drugs include protease inhibitors,
`thymadine kinase inhibitors, sugar or glycoprotein synthesis
`inhibitors, structural protein synthesis inhibitors, attachment
`and adsorption inhibitors, and nucleoside analogues such as
`acyclovir, penciclovir, valacyclovir, and ganciclovir.
`The amount of active pharmaceutical (s) to be used
`depends on the desired treatment strength, although
`preferably, the pharmaceutical component comprises 0.001
`to 30% by weight of the device, and more preferably
`between 0.005 and 20% by weight.
`Plasticizers, flavoring and coloring agents, and preserva-
`tives may also be included in the pharmaceutical delivery
`device of the present invention in the adhesive layer, the
`backing layer, or both. Preferably, these components com-
`prise no more than 1% ofthe final weight ofthe device, but
`the amount may vary depending on the drug or other
`components.
`The thickness of the device may vary, depending on the
`thickness of each of the layers. Preferably,
`the bilayer
`thickness ranges from 0.05 mm to 1 mm, and more prefer-
`ably from 0.1 to 0.5 mm. The thickness of each layer may
`vary from 10 to 90% of the overall thickness of the bilayer
`device, and preferably varies from 30 to 60%. Thus, the
`preferred thickness of each layer may vary from 0.01 mm to
`0.9 mm, and more preferably from 0.03 to 0.6 mm.
`The pharmaceutical delivery device of the present inven-
`tion may be prepared by numerous methods knownin the
`art. In one embodiment, the componentsare dissolved in the
`appropriate solvent or combination of solvents to prepare a
`solution. Solvents for use in the present
`invention may
`comprise water, methanol, ethanol, or low alkyl alcohols
`such as isopropyl alcohol, acetone, methyl ethyl cetone,
`heptane, or dichloroethane, alone or combination. The final
`solvent content or residual solvent contentin the film may be
`the result of either or both layers. The solvent may also be
`used as a plasticizer or dissolution-rate-modifying agent.
`Each solution is then coated onto a substrate. Eventually,
`one of the components might be in suspension. Each solu-
`tion is casted and processed into a thin film by techniques
`known in the art, such as by film dipping, film coating, film
`casting, spin coating, or spray drying using the appropriate
`substrate. The thin film is then dried. The drying step can be
`accomplished in any type of oven. However) the solvent
`residual depends on the drying procedure. The film layers
`may be filmed independently and then laminated together or
`may be filmed one on the top of the other.
`The film obtained after the two layers have been lami-
`nated together or coated on top of each other may be cut into
`any type of shape, for application to the mucosal tissue.
`Some shapesinclude disks,ellipses, squares, rectangles, and
`parallepipedes.
`treating mucosal surfaces, surrounding
`Methods for
`tissues, and bodily fluids for localized and systemic drug
`delivery are also provided. In one embodiment, the method
`comprise