(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`
`(19) World Intellectual Property Organization
`International Bureau
`
`(43) International Publication Date
`27 February 2003 (27.02.2003)
`
` (10) International Publication Number
`
`WO 03/015748 A2
`
`(51) International Patent Classification7:
`
`A61K 9/00
`
`(21) International Application Number:
`
`PCT/USO2/26083
`
`(22) International Filing Date: 16 August 2002 (16.08.2002)
`
`(25) Filing Language:
`
`(26) Publication Language:
`
`English
`
`English
`
`(30) Priority Data:
`09/931,319
`
`16 August 2001 (16.08.2001)
`
`US
`
`(71) Applicant (for all designated States except US): ACCESS
`PHARMACEUTICALS, INC. [US/US]; 2600 Stemmons
`Freeway, Ste. 176, Dallas, TX 75207 (US).
`
`(72) Inventors; and
`(7S) Inventors/Applicants (for US only): MORO, Daniel,
`G. [US/US]; 3355 Blackburn, Dallas, TX 75204 (US).
`CALLAHAN, Howard [US/US]; 8400 Stephanie Drive,
`North Richland Hills, TX 76180 (US). NOWOTNIK,
`David, P. [US/US]; 1405 Bellefonte Lane, Colleyville, TX
`76034 (US).
`
`(81) Designated States (national): AE, AG, AL, AM, AT, AU,
`AZ, BA, BB, BG, BR, BY, BZ, CA, CH, CN, CO, CR, CU,
`CZ, DE, DK, DM, DZ, EC, EE, ES, Fl, GB, GD, GE, GH,
`GM, HR, HU, ID, IL, IN, IS, JP, KE, KG, KP, KR, KZ, LC,
`LK, LR, LS, LT, LU, LV, MA, MD, MG, MK, MN, MW,
`MX, MZ, NO, NZ, OM, PH, PL, PT, RO, RU, SD, SE, SG,
`SI, SK, SL, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ,
`VC, VN, YU, ZA, ZM, ZW.
`
`(84) Designated States (regional): ARIPO patent (GH, GM,
`KE, LS, MW, MZ, SD, SL, SZ, TZ, UG, ZM, ZW),
`Eurasian patent (AM, AZ, BY, KG, KZ, MD, RU, Tl, TM),
`European patent (AT, BE, BG, CH, CY, CZ, DE, DK, EE,
`ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE, SK,
`TR), OAPI patent (BF, BJ, CF, CG, CI, CM, GA, GN, GQ,
`GW, ML, MR, NE, SN, TD, TG).
`
`Declaration under Rule 4.17:
`
`ofinventorship (Rule 4.1 7(iv)) for US only
`
`Published:
`
`without international search report and to be republished
`upon receipt of that report
`
`(74) Agent: HODGINS, Daniel, S.; Jackson Walker LLP, 112
`E. Pecan, Suite 2100, San Antonio, TX 78205 (US).
`
`For two-letter codes and other abbreviations, refer to the " Juid-
`ance Notes on Codes andAbbreviations ” appearing at the begin-
`ning ofeach regular issue ofthe PCT Gazette.
`
`015748A2
`
`(54) Title: MUCOADHESIVE ERODIBLE DRUG DELIVERY DEVICE FOR CONTROLLED ADMINISTRATION OF PHAR—
`MACEUTlCALS AND OTHER ACTIVE COMPOUNDS
`
`\ (57) Abstract: The present invention relates to a layered pharmaceutical delivery device for the administration of pharmaceuticals
`or other active compounds to mucosal surfaces. The device may also be used by itself without the incorporation of a therapeutic.
`03
`The device of the present invention consists of a water—soluble adhesive layer, a non—adhesive, bioerodible backing layer and one
`O or more pharmaceuticals if desired in either or both layers. Upon application, the device adheres to the mucosal surface, providing
`protection to the treatment site and localized drug delivery. The "Residence Time", the length of time the device remains on the
`B
`mucosal surface before complete erosion, can be easily regulated by modifications of the backing layer.
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`MUCOADHESIVE ERODIBLE DRUG DELIVERY DEVICE FOR
`
`CONTROLLEDADMINISTRATION OF PHARMACEUTICALS
`
`AND OTHER ACTIVE COMPOUNDS
`
`FIELD OF THE INVENTION
`
`[01]
`
`The present
`
`invention relates to a bioerodible pharmaceutical carrier
`
`device that adheres to mucosal surfaces for the localized and systemic, controlled
`
`delivery of pharmaceuticals or other active compounds and/or the protection of the
`
`underlying treatment site.
`
`BACKGROUND OF THE INVENTION
`
`[02]
`
`The localized treatment of body tissues, diseases and wounds requires that
`
`a particular pharmaceutical be administered and maintained at the treatment site for a
`
`therapeutically effective period of time. The topical treatment of wet, mucosal surfaces
`
`has been problematic, since natural bodily fluids can rapidly wash away a topically
`
`applied active compound before the appropriate therapeutic action to the underlying
`
`surface can occur. In the mouth, saliva, the natural replacement of the mucosal tissue, and
`
`the actions of eating, speaking and drinking are just some of the problems that have
`
`limited the usefulness of a variety ofpharmaceutical carrier devices.
`
`[03] Gels, pastes, tablets and films have been developed as bioadhesive carriers
`
`and are well known in the art. These types of products, however, do not exhibit all of the
`
`major characteristics required for an efficient and patient acceptable pharmaceutical
`
`delivery device for mucosal treatment. The important characteristics include, water
`
`erodability, ease of handling and application to the treatment site, comfort with minimal
`
`foreign body sensation, rapid adhesion, prolonged residence time for the protection of the
`
`treatment site and/or the delivery of a pharmaceutical or other active compound, and ease
`
`-2-
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`of removal from the underlying mucosal surface by natural erosion or dissolution of the
`
`delivery device at the treatment site.
`
`[04]
`
`Bioadhesive gels used especially in the oral mucosal cavity are known in
`
`the art.
`
`For example, U.S. Patent No. 5,192,802 describes a bioadhesive teething gel
`
`composed of a mixture of sodium carboxymethyl cellulose and xanthan gum. This gel
`
`composition may have potential use in the treatment of canker sores, fever blisters and
`
`hemorrhoids. However, these types of gel systems have limited residence times, since
`
`bodily fluids such as saliva will quickly wash ogels away fiom the treatment site. Other
`
`bioadhesive gels described in U.S. Pat. Nos.5,314,915; 5,298,258 and 5,642,749 use an
`
`aqueous or oily medium and different types of bioadhesive and gelling materials, but still
`
`suffer from the inherent limitation of all gel products. Another type of bioadhesive
`
`products known in the art is denture adhesive pastes. These products, however, were
`
`developed primarily for their adhesive properties only, and not to protect tissue or deliver
`
`pharmaceuticals to the underlying mucosal surface. However, active compounds such as
`
`local anesthetics may be formulated with the paste for the relief of sore gums. Denture
`
`adhesive pastes are described in U.S. Pat. Nos. 4,894,232 and 4,5518,721. In the ‘721
`
`patent, the combination of sodium carboxymethyl cellulose and polyethylene oxide in
`
`polyethylene glycol is used to provide a bioadhesive composition. Muccadhesive pastes
`
`have also been used as protective films and drug delivery systems. Orabase®-B, a
`
`commercialized paste product that has both film forming and adhesive properties, is used
`
`for the relief of mouth sores. This product does provide numbing of the treatment site, but
`
`the residence time is minimum due to the quick dissolution by saliva. This product
`
`contains guar gum, sodium carboxymethyl cellulose, tragacanth gum and pectin.
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`[05]
`
`Bioadhesive tablets are described in US. Patent No. 4,915,948. A xanthan
`
`gum or pectin in combination with an adhesion enhancing material such as a polyol is the
`
`water-soluble bioadhesive used in this device. Although the residence time is greatly
`
`enhanced, these tablets are not user friendly, especially when used in the oral cavity, due
`
`to their unpleasant feeling, solidity, bulkiness and slow dissolution time. Also, solid
`
`devices cannot readily adhere to curved surfaces, especially crevices Within the oral
`
`cavity. Bioadhesive tablets described in US. Patent Nos. 4,226,848; 4,292,299, and
`
`4,250,163 are single or bilayer devices having an average thickness of 0.2 to 2.5 mm.
`
`These devices are less bulky, but have limited residence times. They are composed of a
`
`non-adhesive material such as cellulose ether, a bioadhesive ingredient such as
`
`polyacrylic acid, sodium carboxymethyl cellulose, or polyvinylpyrrolidone, and a binder
`
`for tableting purposes. The cellulose derivatives used in these devices may or may not be
`
`water—soluble. The bilayer devices described in the ‘299 patent contain methyl cellulose,
`
`hydroxypropyl cellulose and hydroxypropylmethyl cellulose. Bandages and bioadhesive
`
`laminated films are also known in the art. The films as described in US. Patent Nos.
`
`3,996,934 and 4,286,592 are thinner, more flexible and therefore elicit a decreased
`
`foreign body sensation. The laminated fihns are usually composed of an adhesive layer, a
`
`reservoir layer and a backing layer and are designed to deliver drugs through the skin or
`
`mucosa. These films are typically not water soluble, thus they are not dissolved or
`
`washed away by bodily fluids and must be removed after the prescribed treatment time.
`
`[06]
`
`Fihn delivery systems for use on mucosal surfaces are also known in the
`
`art. These types of systems, which are water-insoluble and usually in the form of a
`
`laminated, extruded or composite fihn, are described in US. Patent Nos. 4,517,173; 4,
`
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`572, 832; 4,713, 243; 4,900,554 and 5,137, 729. The ‘173 patent relates to a membrane-
`
`adhering film composed of at
`
`least
`
`three layers,
`
`including a layer containing a
`
`pharmaceutical, a layer with limited water solubility, and an intermediate layer. The
`
`pharmaceutical
`
`layer contains a drug and a cellulose derivative selected from
`
`hydroxypropyl cellulose, methyl cellulose, and hydroxypropylmethyl cellulose. The layer
`
`having limited water solubility consists of a combination of one or more cellulose
`
`derivatives and a hydrophobic fatty acid, and the intermediate layer is made of cellulose
`
`derivatives. The ‘832 patent describes a soft film for buccal delivery. The fihn is
`
`composed of a water soluble protein, a polyol, and a polyhydric alcohol such as cellulose
`
`and polysaccharides and coloring and flavoring agents. The ‘243 patent relates to a single
`
`or multi-layered bioadhesive thin fihn made from 40—95% water soluble hydroxypropyl
`
`cellulose, 5-0% water-insoluble ethylene oxide, 0-10% water-insoluble ethyl cellulose,
`
`propyl cellulose, polyethylene or polypropylene and a medicament. These films are three-
`
`layered laminates and are composed of a bioadhesive layer, a reservoir layer, and a non
`
`water-soluble outer protective layer. The ‘729 patent teaches a soft, adhesive film for use
`
`on oral mucosa. The film is comprised of a mixture of vinyl acetate non water-soluble
`
`homopolyrner, an acrylic acid polymer, a cellulose derivative and a systemic drug.
`
`[07]
`
`In the ‘554 patent, the device is designed for use in the oral cavity and is
`
`composed of an adhesive layer including a mixture of an acrylic acid polymer, a water-
`
`insoluble cellulose derivative, a water-insoluble or sparingly soluble backing layer, and a
`
`pharmaceutical. The adhesive layer contains the active ingredient and upon application to
`
`the treatment site, the drug is delivered to the underlying mucosal surface. This patent
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`also teaches that all three of the aforementioned components are required to attain an
`
`appropriate adhesive device suitable for mucosal treatment and drug delivery.
`
`[08]
`
`Finally, water soluble films for the delivery of pharmaceutical compounds
`
`are also known in the art. U.S. Patent Nos.
`
`5,800,832 and 6,159,498 describe a
`
`bioerodible, water soluble pharmaceutical device to treat mucosal surfaces. These bilayer
`
`devices are composed of an adhesive layer and a non-adhesive backing layer, and the
`
`pharmaceutical may be contained in either or both layers.
`
`[09]
`
`The composition of the adhesive layer comprises polyacrylic acid, sodium
`
`carboxyrnethyl cellulose, and polyvinyl pyrrolidone, alone or in combination thereof. In
`
`addition to these mucoadhesive polymers, film forming polymers such as hydroxyethyl
`
`cellulose and hydroxypropyl cellulose are present. This layer can also contain a
`
`pharmaceutical compound. The backing layer of these devices comprises only film-
`
`forming polymers,
`
`such as hydroxyethyl cellulose, hydroxypropyl cellulose and
`
`hydroxypropylrnethyl cellulose. These polymers are known to exhibit low bioadhesion
`
`and are approved for use in a variety of pharmaceutical applications. The residence time
`
`is claimed to be regulated by only variations of the backing layer. To increase the
`
`residence time, the components of the backing layer can be crosslinked with glyoxal
`
`solution, rendering the polymers less water soluble, and therefore, slower to dissolve,
`
`while being exposed to bodily fluids like saliva. A second approach is to change the
`
`composition of the backing layer by using a mixture of different and higher molecular
`
`weight polymers from the same family of hydroxyethyl and hydroxypropyl celluloses.
`
`These alterations to the backing layer are easy to accomplish. However, they do not
`
`provide a consistent, controllable and reproducible residence time for the final device. In
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`addition, in order to produce this device under the teachings of these inventions, it is
`
`required to cast the mucoadhesive layer and/or backing layer preferably onto a hard and
`
`non-porous surface. Then, each layer is dried yielding a laminated film. The casting
`
`surface therefore becomes an integral part of the device or must be carefully removed
`
`from the laminated film prior to cutting to the desired shape and subsequent packaging.
`
`The removal of such a non-flexible film would be difficult to accomplish without
`
`stretching or breaking the material. The associated manufacturing processes to produce
`
`such a device are complicated and therefore may not commercially viable or cost
`
`effective.
`
`SUMMARY OF THE INVENTION
`
`[10]
`
`One object of this invention is to provide a novel, versatile, water-
`
`erodible, pharmaceutical carrier device for use on mucosal surfaces. Another object of
`
`this invention is to provide a pharmaceutical carrier device for use on mucosal surfaces
`
`capable of providing a wide range of Residence Times for a multitude of active
`
`compounds through formulation alterations of the erodible backing layer. Another object
`
`of this invention is to provide a water-credible device that can be used without an active
`
`ingredient to provide protection of mucosal surfaces. A fithher object of this invention is
`
`to provide a cost-effective, commercially viable and scaleable pharmaceutical carrier
`
`device for use on mucosal surfaces using simple manufacturing processes.
`
`[11]
`
`The device is applied to mucosal surfaces and provides protection of the
`
`application site while delivering pharmaceuticals to treat specific diseases or disorders.
`
`The device causes minimum discomfort,
`
`is easy to use and provides an effective
`
`Residence Time that can be tailored to deliver therapeutics over different time intervals.
`
`In one embodiment, the device comprises a mucoadhesive multi-layered film that is
`
`-7-
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`water-soluble and bioerodible. In another embodiment,
`
`the pharmaceutical delivery
`
`device comprises a multi-layered film having an adhesive layer and a coated, precast
`
`backing layer containing a pharmaceutical or other active compound in either or both
`
`layers. The film may be cut or fabricated into any desired shape, such as a disc, square,
`
`oval, parallelepiped, etc.,
`
`that provides convenience for use in application and/or
`
`treatment. The adhesive layer of the device is water soluble and the backing layer is
`
`bioerodible. The adhesive layer comprises a film-forming polymer such as hydroxyethyl
`
`cellulose,
`
`hydroxypropyl
`
`cellulose,
`
`hydroxypropylmethyl
`
`cellulose,
`
`or
`
`hydroxyethylmethyl cellulose, alone or in combination, and a bicadhesive polymer such
`
`as polyacrylic acid, polyvinyl pyrrolidone, sodium carboxymethyl cellulose, tragacanth
`
`gum, sodium alginate, or any other known naturally occurring or synthetic mucoadhesive
`
`polymer alone, or in combination. The non-adhesive backing layer is a premade film
`
`alone or in combination with other layers. The precast film is comprised of hydroxyethyl
`
`cellulose, hydroxypropyl cellulose, hydroxyethylmethyl cellulose, hydroxypropyhnethyl
`
`cellulose, polyvinyl alcohol, polyethylene glycol, polyethylene oxide, ethylene oxide-
`
`pr0pylene oxide co-polymers, or other water soluble film-forming polymer, alone or in
`
`combination thereof. The precast film may also include plasticizers or other excipients
`
`required to enhance the fihn forming properties of the polymer and to impart flexibilty to
`
`the final, muti-layered device. The non-adhesive backing layer is further modified to
`
`render it water erodible instead of water soluble. For definition purpose, water erodible
`
`means a material or substance that does not dissolve in water or bodily fluids in total,
`
`however will disintegrate and completely break apart upon exposure to water or bodily
`
`fluids. This is accomplished by coating the backing layer film with a more hydrophobic
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`polymer selected from a group of Eudragit® and/or ethyl cellulose and methyl cellulose
`
`polymers that are approved by the FDA for use in pharmaceutical applications. Other
`
`hydrophobic polymers known to those skilled in the art may also be used. The
`
`hydrophobic coating layer can be applied first to the premade film by conventional
`
`coating techniques and then the reverse, uncoated side can be used as the support on
`
`which the mucoadhesive polymer solution is cast to a desired thickness. The type and
`
`amount of hydrophobic polymer used will provide a wide and controlled range of
`
`Residence Times for the layered film device. In addition, using the modified, precast,
`
`erodible backing layer can eliminate the need to use a rigid support material such as a
`
`polyethylene film like ”Mylar” or other non-porous material as the casting surface on
`
`which both the adhesive layer and backing layer are produced. This rigid casting surface
`
`is no longer an integral component of the layered device, which from a safety and
`
`production point of view, is extremely desirable.
`
`[12]
`
`In another embodiment, the devices of the current invention can also be
`
`produced using a non-rigid, non-porous surface other than a polyethylene film as the
`
`casting and support material. Coated paper is preferred but other materials known to
`
`those skilled in the art are also acceptable. In this process, the hydrophobic layer can be
`
`first applied to the support paper, then the precast film is laminated to the hydrophobic
`
`layer under pressure using a roller and a polymeric solution that will bind both materials
`
`together after solvent drying, and finally the mucoadhesive solution is coated onto the
`
`composite layers and dried to remove the coating solvent. The incorporation of the
`
`plasticized precast film between these layers imparts significant overall flexibility to the
`
`final device. It is also preferred to use a polymeric solution to bind the mucoadhesive
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`layer to the precast laminated film upon drying. The resulting muti-layered device is then
`
`peeled from the carrier paper and cut into the desired shape.
`
`[13]
`
`In the preferred embodiment,
`
`the mucoadhesive coating solution or
`
`suspension, with or without an active ingredient, is first coated onto a carrier release
`
`paper and subsequently dried using a standard oven. A precast, water soluble plasticized
`
`film coated with the appropriate hydrophobic composition that provides the desired
`
`Residence Time is laminated to the dried adhesive film using a polymeric laminating
`
`solution, roller and pressure, and the multilayered device is then dried in a standard oven.
`
`The multilayered film may be then separated from the paper, cut into a desired shape and
`
`packaged, or the multilayered film and the release paper can be cut into a desired shape
`
`and packaged. With the latter example, the release paper will be an integral part of the
`
`final device and must be removed prior to application of the mucoadhesive side of the
`
`patch onto a mucosal surface. Since a rigid casting support material like “Mylar” is not
`
`being used, the potential for injury to the patient is also eliminated. It is apparent to, those
`
`skilled in the art that variations in the coating sequences and coating processes in addition
`
`to manufacturing conditions such as temperature, humidity, carrier release paper and
`
`drying time can have a major effect on the quality, reproducibility and cost-effectiveness
`
`of the final device.
`
`It
`
`is understood that other known processes for producing
`
`multilayered patches, in addition to the aforementioned casting processes, can be used to
`
`produce devices outlined in this invention disclosure.
`
`DETAILED DESCRIPTION OF THE INVENTION
`
`[14]
`
`In the present invention, a unique bioerodible pharmaceutical layered
`
`device that adheres to mucosal surfaces is provided. The present invention is most
`
`applicable to the treatment of body tissues, diseases, or wounds that may have moist
`
`-10-
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`surfaces and that are susceptible to bodily fluids, such as the mouth, vagina, anus, or
`
`other types of mucosal surfaces. Pharmaceuticals or other active compounds can be
`
`incorporated in the device, if desired, and upon application and adherence to the specific
`
`mucosal site, protection of the underlying tissue results. Concomitantly, pharmaceuticals
`
`are delivered to the treatment site, the surrounding tissues and other bodily fluids for a
`
`prolonged period of time. The device provides an appropriate, controlled residence time
`
`for effective drug delivery at the treatment site. The residence time is easily tailored to
`
`provide a range from minutes to hours, dependent upon the type of drug used and the
`
`therapeutic indication. In one embodiment, the pharmaceutical delivery device comprises
`
`a layered film patch having a water soluble adhesive layer and a water erodible backing
`
`layer, having a pharmaceutical in either or both layers.
`
`[15]
`
`The present
`
`invention offers advantages with respect
`
`to increased
`
`residence time over bioadhesive gels and pastes known in the art. Paste and gel products
`
`such as Orajel, Orabase, and Kanka have short residence times in the order of minutes.
`
`This is a result of limited or poor adhesion. Upon application of a gel product to the
`
`mucosal surface, the mucoadhesive components do not instantaneously penetrate the
`
`lipophilic surface of the mucosa. Instead, these hydrophilic components quickly mix with
`
`saliva or other bodily fluids and therefore are removed from the application site resulting
`
`in a minimal residence time. A similar mechanism of action can be expected to occur
`
`with paste products, however to a slightly lesser extent. This is due to the higher viscosity
`
`and greater hydrophobicity of the paste causing a slower erosion process to occur. The
`
`multilayered film of the present invention provides for immediate adhesion to the
`
`mucosal surface due to the combination of mucoadhesive polymers within water-soluble
`
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`film-forming polymers, and its thin, flexible solid form. A solid device will dissolve or
`
`erode more slowly than a gel or paste device due to dissolution kinetics.
`
`[16]
`
`Bioadhesive tablets known in the art also have serious limitations,
`
`primarily due to their bulkiness and rigidity causing an unpleasant sensation and
`
`discomfort after application to the oral cavity. These tablets provide effective residence
`
`times, but because they are an order of magnitude larger than the device in the present
`
`invention, the preferred application site is on the upper gingival or sublingual area. This
`
`site is suitable for systemic delivery of an active compound, but may not be satisfactory
`
`for localized, unidirectional delivery. The device of the present invention offers both
`
`local and systemic delivery with an effective and controlled residence time and minimal
`
`discomfort and ease of application as a result of its thinner, more flexible configuration.
`
`[17]
`
`Finally,
`
`film systems known in the art
`
`that are used to deliver
`
`pharmaceuticals also have other limitations. These films, unlike the pharmaceutical
`
`device of the present invention, are occlusive and water insoluble and are fabricated to be
`
`removed after treatment of a mucosal surface. Removal of a non-erodible device may
`
`cause some damage to the mucosa, or may damage healing mucosa when the device is
`
`used to cover a lesion. The pharmaceutical device of the present invention is designed to
`
`be water erodible, and therefore does not require removal. Once applied to a mucosal
`
`surface, water absorption softens the device, and over time, the device slowly erodes
`
`away delivering a specific pharmaceutical to the treatment site.
`
`[18]
`
`In one embodiment, the present invention is composed of a multi—layered
`
`film having an adhesive layer, a precast, non-adhesive, water soluble backing layer, and a
`
`hydrophobic coating layer. The hydrophobic coating layer renders the backing layer
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`water-erodible and provides a wide range of predictable and controlled residence times.
`
`The adhesive layer is water soluble and the backing layer is water erodible. All
`
`components used to manufacture the device are FDA approved materials. The
`
`pharmaceutical or other active agent may be included in either layer, but is preferably
`
`incorporated in the adhesive layer. This layer is in direct contact with the treatment site
`
`and the active compound will be released at a rate related to the dissolution of the
`
`adhesive layer. The backing layer will control the rate at which the adhesive layer
`
`hydrates, therefore will affect the rate of dissolution of the adhesive layer.
`
`[19]
`
`In one preferred manufacturing embodiment,
`
`the multilayered film is
`
`produced by first coating a canier release paper with the mucoadhesive coating solution
`
`at a known thickness and then dried using a conventional oven to produce the adhesive
`
`layer. The adhesive layer must remain adhered to the carrier release paper during this
`
`processing step, since fin'ther coatings will be applied on top of it to produce the final
`
`mutilayered product. However, after the final mutilayered film is produced,
`
`the
`
`composition must release without damage from the carrier paper prior to cutting into a
`
`preferred shape. It is obvious to one skilled in the art that these unique adhesion
`
`properties are a fimction of the type of mucoadhesive polymers used, the manufacturing
`
`conditions, the environmental conditions and the type of carrier substrate used. A precast
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`water soluble film that has been previously coated with a hydrophobic polymer is then
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`laminated to the dry adhesive. The lamination is maximized by pressing the films
`
`together using a roller with slight pressure after wetting the precast film with a polymeric
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`solution that can bind both layers together after drying. The polymeric, binding solution
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`must be compatible with both the precast film and the components of the adhesive film.
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`In the preferred embodiment, an alcoholic solution, or an alcoholic/water solution of
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`polyvinylpyrrolidone at a concentration between 1-3 0%, and more preferably 5-20%, will
`
`provide a good lamination. It is understood by one skilled in the art that a wide variety of
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`polymers with different molecular weights can be used to bind layers together. The
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`choice of the most appropriate polymer to use alone or in combination will be related to
`
`the type of mucoadhesive polymers in the adhesive layer, the composition of the precast
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`film and the active compound present if any in either layer. The polymers used to bind
`
`must also be safe and approved by the FDA. It‘is also understood that multilayered films
`
`produced using different coating sequences and processing alterations from those
`
`outlined above would fall within the scope ofthis invention.
`
`[20]
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`The adhesive layer may comprise at least one film-forming water-soluble
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`polymer,
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`typically selected from a family of cellulose polymers (the “film-forming
`
`polymer”) and at least one or more polymers known in the art for its bioadhesive property
`
`(the “bioadhesive polymer”). The film-forming polymer may comprise hydroxyethyl
`
`cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, hydroxyethylmethyl
`
`cellulose, alone or in combination thereof. The molecular weight of the film-forming
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`polymer is in the range of 102 to 106, and more preferably between 103 to 105. The film-
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`forming polymer may be crosslinked and/or the adhesive layer plasticized to alter the
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`dissolution characteristics. The bioadhesive polymer contained in the adhesive layer may
`
`comprise polyacrylic acid(PAA), which may or may not be partially crosslinked, sodium
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`carboxymethyl cellulose(NaCMC), polyvinylpyrrolidone(PVP), tragacanth gum, sodium
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`alginate or any other known naturally occurring or synthetic mucoadhesive polymer
`
`alone, or in combination thereof. These bioadhesive polymers are preferred because they
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`exhibit good instantaneous mucoadhesive properties in the dry, film state. In the case of
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`sodium carboxymethyl cellulose,
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`typical average molecular weights range between
`
`50,000 and 700,000 Daltons, and preferably between 60,000 to 500,000 Daltons, 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
`
`Daltons, preferably between 10,000 and 100,000 Daltons.
`
`In some instances,
`
`the
`
`combination of some grades of polyvinyl pyrrolidone with polyacrylic acid may result in
`
`precipitation, causing a non-homogeneous adhesive layer to result and a potentially less
`
`than optimum mucoadhesive property. Such combinations of polyacrylic acid and
`
`polyvinyl pyrrolidone should be avoided.
`
`[21]
`
`The chemical nature of the bioadhesive polymers used in the present
`
`invention, including chain, side groups and crosslinking agents, generates interactions
`
`between the mucosal constituents and the polymer or polymers, such as physical
`
`entanglement, Van der Waals forces, and hydrogen bonding. Since the mucosal surface
`
`differs from one individual to another and changes naturally over time, the use of a
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`combination of at least two bioadhesive polymers and/or the use of a combination of
`
`different grades of the same polymer will provide maximum adhesion of the device for a
`
`Wide range of different mucosal surfaces. However, the use of a single mucoadhesive
`
`polymer is effective as well. The ratio of bioadhesive polymer to film-forming polymer in
`
`the adhesive layer can be varied and depends upon the type and amount of
`
`pharmaceutical or other active ingredient used and other factors. However, the content of
`
`combined components in the adhesive layer is between 5 and 95% by weight, preferably ,
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`between 10 and 80% by weight. In terms of weight percent of the different bioadhesive
`
`polymers PAA, NaCMC, PVP, Tragacanth, and Sodium Alginate, some examples are
`
`detailed later. Preferred combinations include FAA and NaCMC, NaCMC and PVP, FAA
`
`and PVP, Tragacanth, Sodium Alginate, NaCMC and PVP, and also include the use of
`
`different molecular weight grades of the same polymer.
`
`[22]
`
`The non-adhesive backing layer is a premade film comprised of a water-
`
`soluble,
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`film-forming pharmaceutically acceptable polymer such as hydroxyethyl
`
`cellulose, hydroxypropyl cellulose, hydroxyethylmethyl cellulose, hydroxypropylmethyl
`
`cellulose, polyvinyl alcohol, polyethylene glycol, polyethylene oxide, ethylene oxide-
`
`propylene oxide co-polymers, or other water soluble film-forming polymers, alone or in
`
`combination thereof. The non-adhesive backing layer is further modified to render it
`
`water erodible instead of water soluble. This is accomplished by incorporating or coating
`
`the backing layer film with a more hydrophobic polymer selected from a group of FDA
`
`approved Eudragit polymers, ethyl cellulose and methyl cellulose polymers that are
`
`approved for use in other pharmaceutical dosage forms. Other hydrophobic polymers
`
`may be used, alone or in combination with other hydrophobic or hydrophilic polymers,
`
`provided that the layer derived from these polymers or combination of polymers erodes
`
`in a moist environment. The precast backing layer fihn can be precoated in advance with
`
`the hydrophobic coating solution or can be applied to the layered device as the final
`
`coating step. In one embodiment, the application of an erodible layer to the precast film
`
`allows the backing layer to act as the support layer if desired on which the adhesive
`
`solution can be cast without dissolving the