O
`Unlted States Patent
`
`[19]
`
`|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
`
`U8006159498A
`
`[11} Patent Number:
`
`6,159,498
`
`Tapolsky et a1.
`
`[45] Date of Patent:
`
`Dec. 12, 2000
`
`[54] BIOEROI)ABLE FILM FOR DELIVERY 011‘
`pHARMACEUTICAL COMPOUNDS 011‘
`MUCOSAL SURFACES
`
`,
`
`-
`
`,
`
`-
`
`’
`‘
`’
`['13] Assignee: Vimtex Corporation, The Woodlands,
`Tcx-
`
`'
`
`'21] AWL Na; 091144327
`
`[22]
`
`Filed:
`
`Sep. 1, 1998
`
`Related U.S. Application Data
`
`[(13] Continualion of application No. 081734519, Oct. 18, 1996,
`pm, No_ 5,300,832,
`‘ 7
`Int. (,1.
`
`[51]
`
`.......................... ..
`
`AfilK 47138;
`A61M 37100
`
`4,889,720
`4,894,232
`4,900,554
`4,906,463
`4,915,948
`
`5,1 159,189
`“
`
`5,081,158
`5,116,621
`5,131,129
`5,192,802
`5,196,202
`5,298,258
`5,314,915
`5,332,516
`514921749
`5,466,465
`5,505,956
`5:780:04?
`
`1011991
`'
`( E
`
`
`
`................................. .. 4241443
`1211989 Konishi
`111990 Reul el :11.
`4241439
`211990 Yanagibashi er al
`4241448
`311990 Clear)1 c1 al.
`424178
`411990 (iallopo el al.
`4241435
`
`
`
`604131.17
`
`
`
`(filento et al.
`.......... ..
`ggglgéfiizal‘"
`5141781
`111992 Pomerantz ..
`4241445
`511992 Oji et :1].
`4241435
`811992 Kuroya e1 :11.
`311993 Rancher
`................................ .. 5141535
`311993 Konishi
`................................. .. 4241448
`311994 Akemi el al.
`4241484
`511994 Reneher
`5141535
`"111994 Mantcllc .
`_________ ,. 4241443
`1011995 R9991?“
`----- -- 4241434
`1111995 Royds er a1.
`4241449
`411996 Kim (:1 al. ......................... .. 4241443
`7,11998 Kamiya el al‘ I
`
`........................... 4241449; 4241448; 4241434
`[52] U.S. C1.
`[58]
`Field of Search ................................... .. 4241449, 448,
`424-14-34-
`
`[56]
`
`References Cited
`
`U.S‘ PATENT DOCUMENTS
`
`FOREIGN PATENT DOCUMENTS
`005041“)
`411982
`1;,“ roman pm 01},
`,
`0250187
`12119871
`European Pat. Off. .
`0381194
`811990 European Pat. Off. .
`0181546
`“111997
`European Pat. 011.
`.
`2491098
`'111982
`France .
`2582942
`1211986 France.
`
`811981
`Japan'
`551100714
`1011985
`Japan.
`0159604
`“988 Jam”
`0262422
`prinmry Exmnmer_fldward J_ webman
`Arromey, Agem, or Finn—Morrison & 1’0ersler LLP
`[5'1]
`ABSTRACT
`
`The present invention relates to water—soluble, bioerodable
`pharmaceulieal delivery device for applicalion lo mueosal
`surfaces. The device comprises an adhesive layer and a
`non-adhesive backing layer, and [he pharmaceutical may be
`-
`-
`-
`,
`-
`-
`Egrégcjdfi‘cghg Tgebmtclg‘iméuggs: :figfiggn’(1:3;
`.
`I
`.
`‘
`I
`’.
`MW“? and P1090110“ ‘0 “1° ma‘mcn‘ 511°
`
`27 Claims, N0 Drawings
`
`Dr. Reddy’s - EX1012
`
`Page 1
`
`1061170
`211972 Eles
`3,640,741
`
` 3,996,934 1211976 Zafi'aroni . 1281268
`
`4,226,848 1011981] Nagaietal.
`.............................. 424119
`4,250,163
`211981 Nagai 81 ill.
`............................ .. 424114
`4,285,934
`811981 Tmnell
`..
`‘
`4,286,592
`911981 Chand ruseka ran
`4,292,299
`911981 Suzuki
`424116
`. 4241148
`4,381,296
`411983 'l‘innell
`4,517,113
`511985 Kizawa el :11.
`.. 424116
`4,518,121
`511985 Dhabhar et a].
`. 5231120
`4,512,832
`211986 Kigasawa ct al.
`........ .. 424119
`13:: gfirf‘cid‘f‘ 11- 1-"
`--------
`,
`,
`,
`.
`enra lea.
`.
`1211987 Susukie: al.
`........................... 1281156
`4,715,369
`4,133,387Ir
`111988 Sakamoto e1 :11.
`.
`4,740,385
`411988 Yukimatsu el al.
`4241435
`4,765,983
`811988 'l‘akayanagi CE 81.
`. 4241434
`4,867,910
`911989 Newsham et al.
`...................... .. 424181
`
`
`
`.
`
`Dr. Reddy's - EX1012
`Page 1
`
`

`

`
`
`6,159,498
`
`1
`BIOERODABLE FILM FOR DELIVERY OF
`PHARMACEUTICAL COMPOUNDS ()F
`MUCOSAI. SURFACES
`
`This is a continuation of application Ser. No. 08t734,519
`filed Oct. 18, 1996, now US. 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 treatment site.
`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 mucosal tissue, and eating, drinking, and speak-
`ing movements are some of the problems that have limited
`the effectiveness and residence time of pharmaceutical earn
`riers.
`
`Bioadhesive carriers are known in the art and include gels,
`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 include the 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 of the 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 US.
`Pat. Nos. 5,314,915; 5,298,258; and 5,642,749. The gels
`described in these 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. 4,894,32 and 4,518,721
`describe denture adhesive pastes. The "('21 Patent describes
`a combination of sodium carboxymethyl cellulose and poly-
`ethylene oxide in polyethylene glycol.
`Pastes have also been used as film protectants and as drug
`delivery systems. One such example having film forming
`
`in
`
`15
`
`25
`
`30
`
`35
`
`40
`
`45
`
`5f]
`
`55
`
`60
`
`65
`
`2
`and adhesive properties is the product commercialized under
`the name 0rabase®-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 US. 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 lime. Bioad-
`hesive tablets are also described in U .8. 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 claimed cellulosic 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 liexible and therefore have a
`
`decreased foreign body sensation, is described in US. 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 methyl 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 Patent relates 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—6095;
`water-insoluble ethylene oxide, 040% 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 adhesive film 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
`
`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, 3 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 tissues all 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 peeled off of the
`site of application.
`
`SUMMARY OF THE INVENTION
`
`invention relates to a novel water-soluble
`'lhe 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 ofuse. 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 lilm disk
`having an adhesive layer and a backing layer, both water-
`soluble, having the pharmaceutical in 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,
`hydroxypropylmcthyl cellulose, polyvinyl alcohol, polyeth—
`ylene glycol, polyethylene oxide, or ethylene oxide-
`propylene oxide co—polymers, alone or in combination.
`Methods for 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.
`
`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 treatment site, 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 solubilizalion in aqueous solution
`or bodily fluids such as saliva, and the slow, natural disso-
`
`if]
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`15
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`25
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`30
`
`35
`
`40
`
`45
`
`5f]
`
`55
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`60
`
`65
`
`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 of bodily fluids such as saliva to wash away the gel
`from the treatment site,
`the present
`invention olIers an
`increased residence time because of its lilmy consistency
`and components. Atypical residence 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 aflinity 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 physical state of the device. While a gel
`or solution will readily mix with saliva andt’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
`eiIective drug delivery to the treatment site. Although bio-
`adhesive tablets do oifer 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 advantages ol‘an etl‘ective 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 of the 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 away the 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
`
`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, including its
`crystallinin 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 included in either layer,
`although preferably,
`it is included in the adhesive layer,
`which is closest to the treatment site and which will have a
`slower dissolution 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-
`ylmelhyl celluIOse, 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 102 to 10" and more prefer-
`ably in the range 103 to 105, while in the case of hydrox—
`ypropyl cellulose,
`the average molecular weight
`(Mw
`obtained from size exclusion chromatography
`measurements) is in the range 50x103 to 1.5x106, and more
`preferably between 80x103 to 5x105. The film-forming,
`polymer may he 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 (PVI’), 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,
`
`if]
`
`15
`
`25
`
`30
`
`35
`
`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 may result 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 mucosa] 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 ofdifferent grades ofthe same polymer is preferred.
`The use of a combination of at
`least
`two bioadhesive
`polymers maximizes the adhesion capabilities of the device,
`although use of a single bioadhesive polymer is efiective 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 FAA,
`NaCMC, and PVI’, some examples are provided below.
`Preferred combinations include FAA and NaCMC, NaCMC
`and PVP, or FAA and PVP, and also 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, polyvinylalcoho], 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 corn prises 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
`102 to 106, and more preferably in the range 103 to 105,
`while in the case of hydroxypropyl cellulose, the average
`molecular weight (Mw obtained from size exclusion chro-
`matography measurements) is in the range of 50x103 to
`l.5><10‘i and more preferably from 80x10q to 5x105.
`Combinations of dilIerent polymers or similar polymers
`with definite molecular weight characteristics may he 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 3A of hydroxyethyl cellu-
`lose and lit of hydroxypropyl cellulose; 1/5 of low molecular
`weight hydroxyethyl cellulose and Vs of medium molecular
`weight hydroxyethyl cellulose; and % of low molecular
`weight hydroxyethyl cellulose and 1/6 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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`6,159,498
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`7
`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 and ercsslinking 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 incorporated in the adhesive
`layer, the backing layer, or both. Pharmaceuticals which may
`be used, either alone or in combination,
`include anti-
`inllammatory analgesic agents, steroidal anti-inflammatory
`agents, antihistamines, local anesthetics, bactericides and
`disinfectants, vasoconstrictors, hemostatics, chemothera-
`peutic drugs. antibiotics, keratolyties, cauterizing agents,
`and antiviral drugs.
`Examples of anti—inflammatory analgesic agents include
`acetaminophen, methyl salicylate, monoglycol salicylale,
`aspirin, mefenamic acid,
`llufenamic acid,
`indomethacin,
`diclofenac, alclot‘enac, 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, predonisolonc, dexamethasone, triamcino—
`lone acetonide, fluocinolone acetonide, hydrocortisone
`acetate, predonisolone acetate, methylpredonisolone, dex-
`amethasone acetate, betamethasone, betamethasonc
`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,
`lidoeainc
`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. dycloninc hydrochloride,
`60:.
`
`Examples of bactericides and disinfectants include
`thimerosal, phenol, thymol, benzalkcnium chloride, benze-
`thonium chloride, chlorhexidine, povidone iode, cetylpyri-
`dinium chloride, eugenol, trimethylammonium bromide, etc.
`Examples of vasoconstrictors include naphaxoline nitrate,
`tetrahydrozoline hydrochloride, oxymetazoline
`hydrochloride, phenylephrine hydrochloride,
`tramamline
`hydrochloride, etc. Examples of hemostatics include
`thrombin, phytonadione, protamine sulfate, aminocaproic
`acid,
`tranexamic acid, carbazochrome, carbaxochrome
`sodium sulfanate, rutin, hesperidin, etc.
`Examples of chemotherapeutic drugs include sull‘amine,
`sulfathiazole, sulfadiazine, homosulfamine, sulfisoxamle,
`sulfisomidine, sulfamethimle, nitrol'urazone, etc. Examples
`of antibiotics include penicillin, meticillin, oxacillin,
`
`5
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`10
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`25
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`30
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`35
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`8
`lincomycin,
`cefalotin, cel‘alordin, erythromcycin,
`tetracycline, chlortetracycline, oxytetracycline, metacycline,
`chloramphenico], 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 and silver 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 000]
`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% of the final weight of the 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 known in the
`art. In one embodiment, the components are 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 content in the film may be
`the result of either or both layers. The solvent may also be
`used as a plasticizer or dissolution—rate—rnodifying 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 ofeaeh other may be cut into
`any type of shape, for application to the mucosal tissue.
`Some shapes include disks, ellipses, squares, rectangles, and
`parallepipedes.
`treating mu cosal surfaces, surrounding
`Methods for
`tissues, and bodily fluids for localized and systemic drug
`delivery are also provided. In one embodiment, the method
`comprises applying an adherent film of the invention to the
`t