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`PCTIUS94/09305
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`- 11 -
`
`concentrations to contribute a continuous pleasant smell to the exhalant
`
`breath sufficient to mask bad breath odor.
`Preferred water soluble adhesives may be permeable to certain mint
`
`odorant components; that is, certain of the mint odorant components may by
`diffusion pass into and through the adhesive.layer, to the mucosal surface
`
`5
`
`onto which the adhesive layer is affixed. Because some mint odorant
`
`components may be irritating to the mucosa or may cause an unpleasant
`
`local numbing effect on the mucosa when present in higher amounts, it may
`
`be desirable to avoid delivery of the odorant to the underlying mucosa. This
`
`10
`
`can be accomplished according to the invention by interposing an additional
`
`water-soluble layer, poorly permeable to the odorant components, between
`
`the odorant-containing layer and the adhesive layer, to substantially prevent
`
`movement of the odorant components into the adhesive layer.
`Any of a variety of odorants may be delivered according to the
`
`15
`
`invention, and any of various mint odorants, as described below, may be
`
`particularly desirable.
`
`Because the device according to the invention remains affixed to a
`
`surface of the oral cavity during use, no conscious effort by the· user is
`required to hold the device in place, and the likelihood that it may be
`
`20
`
`swallowed or spit out of the mouth during use is diminished. As the device
`has a thin profile, and conforms smoothly to the surface of the oral cavity, it
`
`is not mechanically annoying and does not interfere with speech or with
`
`ingestion of foods or fluids.
`
`25 Disclosure of the Invention
`
`Water-Soluble Pressure-Sensitive Adhesives
`In one general aspect, the invention features a water-soluble pressure(cid:173)
`
`sensitive adhesive including a water-soluble polymer that is made tacky (that
`
`30
`
`is, it is rendered pressure-sensitive) at room temperature by addition of a
`
`water-soluble plasticizer that is miscible with the polymer. Suitable
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`DRL - EXHIBIT 1002
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`

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`W095/05416
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`PCT!US94/09305
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`- 12-
`
`polymers are characterized as being solid at room temperature (that is, as
`
`having a glass transition temperature T(g), or melting point T(m), higher
`
`than about 25 °C, and more preferably higher than about 30 °C, and lower
`
`than about 120 °C, and more preferably lower than about 100 °C); and
`
`5
`
`having a hydrophilicity as measured by water uptake greater than about
`25 %. Suitable plasticizers are characterized as being liquid at room
`temperature and having a boiling point higher than about 80 °C.
`
`Suitable polymers include polysaccharides such as for example
`
`cellulose-type materials and natural gums, polypeptides, and water-soluble
`
`10
`
`synthetic polymers. Particular examples of such suitable polymers which
`
`are GRAS certified include poly(vinyl pyrrolidone) ("PVP"), poly(vinyl
`
`alcohol) ("PVA "), hydroxy propyl cellulose ("HPC"), poly( ethylene oxide)
`("PEO"), poly( acrylic acid) ("PAA "), polyacrylates such as Carbopol 934
`
`(B.F. Goodrich), starch and starch derivatives, polysaccharides, sodium
`
`15
`
`carboxymethyl cellulose ("Na-CMC"), xanthan gum, karaya gum, and
`
`gelatin, among others. Suitable plasticizers include, for example and
`
`particularly for oral-mucosal contact and other use in the oral cavity,
`glycerin, sorbitol, any of the glycols, polysorbate 80, triethyl citrate, acetyl
`triethyl citrate, and tributyl citrate.
`In some embodiments for oral mucosal contact and for skin contact, a
`
`water-soluble pressure-sensitive adhesive according to the invention includes
`
`PVP (about 95- 40 weight %) and, optionally, HPC (up to about 50
`weight %) as a polymer; and glycerin as a plasticizer (about 5 - 35
`weight %). Optionally, any balance (up to about 30 weight %) can be made
`up by water. By way of illustration, such compositions adhere
`
`instantaneously (within less than five seconds) to oral mucosal surfaces and
`
`to oral cavity prostheses or other devices of the poly(methyl methacrylate)
`
`("PMMA ") type, as well as to human skin.
`
`20
`
`25
`
`In other embodiments for oral mucosal contact and for skin contact, a
`
`30 water-soluble pressure-sensitive adhesive according to the invention includes
`
`as a polymer HPC (about 0 - 50 weight %) and, optionally, (up to about 50
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`DRL - EXHIBIT 1002
`DRL828
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`

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`W095/05416
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`PCTIUS94/09305
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`- 13-
`
`weight%) one or more ofPVP, PYA, PEO, starch, polysucrose or other
`polysaccharide, xanthan gum, or karaya gum; and glycerin as a plasticizer
`(about 11 - 60 weight % and, preferably about 30 - 50 weight % for PVP(cid:173)
`
`or HPC-containing adhesive compositions). In these formulations, the HPC
`
`5
`
`preferably has a molecular weight between about 60 k and about 1, 000 k,
`
`and more preferably between about 100 k and about 300 k.
`In another general aspect, the invention features a water-soluble
`
`pressure-sensitive adhesive film made up of a water-soluble polymer that is
`
`made tacky (that is, it is rendered pressure-sensitive) at room temperature by
`
`10
`
`addition of a water-soluble plasticizer that is miscible with the polymer.
`
`In preferred embodiments the thickness of the film is in the range of
`about 5- 20 mils, and is shaped to fit and to conform generally to a mucosal
`surface-contacting portion of a dental prosthesis such as a dental plate.
`
`Preferred water-soluble pressure-sensitive adhesive films according to the
`
`15
`
`invention are very flexible, and are therefore capable of conforming to and
`
`adhering to contoured surfaces such as the gum or the roof of the mouth.
`Such a film can be used as a denture adhesive, that can adhere to oral
`
`mucosal surfaces and to dental prosthesis for an extended period, typically of
`
`20
`
`more than about 5 hours. The film can be used as part of a system for
`delivery of substances through the oral mucosa (as a buccal transmucosal
`patch), or for delivery of substances into the oral cavity itself.
`Device Having a Water-Soluble Pressure-Sensitive Adhesive
`for Emplacement in a Mucosa-Lined Body Cavity
`
`In another general aspect, the invention features a laminated device
`
`25
`
`for controlled release of one or more substances within a mucosa-lined body
`
`cavity, having an adhesive layer by means of which the device can be
`
`affixed within the body cavity.
`
`In some embodiments the mucoadhesive layer is water-soluble,
`
`constructed in some embodiments of a water-soluble moistenable
`
`30 mucoadhesive, and in some embodiments of a water-soluble pressure(cid:173)
`
`sensitive mucoadhesive; in some embodiments the adhesive adheres to a
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`DRL - EXHIBIT 1002
`DRL829
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`

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`W095/05416
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`PCT!US94/09305
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`- 14-
`
`variety of materials, such as polymers, that can be used in construction of
`
`devices for emplacement on a
`
`mucosal surface or within a body cavity that has a mucosal lining; or it is
`
`mucoadhesive and additionally adheres to such materials. Preferably the
`
`5
`
`water-soluble pressure-sensitive adhesive requires no moistening prior to
`contact with the mucosal or the polymer surface. For placement within the
`
`oral cavity, for example, the adhesive preferably is made from materials
`
`generally regarded as safe ("GRAS-certi:fied"), or national formulary ("NF(cid:173)
`
`certi:fied"), and therefore safe for oral use or for ingestion.
`
`10
`
`Preferred water-soluble pressure-sensitive adhesives for use in the
`
`adhesive layer of the invention are those according to the invention, as
`
`disclosed above under the heading "Water-Soluble Pressure-Sensitive
`
`Adhesives", and as described in further detail hereafter. Accordingly they
`
`include a water-soluble polymer that is rendered tacky (that is, it is rendered
`
`15
`
`pressure-sensitive) at room temperature by addition of a water-soluble
`
`plasticizer that is miscible with the polymer.
`In some embodiments for oral mucosal contact, a water-soluble
`
`pressure-sensitive adhesive according to the invention includes PVP ( ab01~t
`95 - 65 weight %) and, optionally, HPC (up to about 50 weight %) as a
`polymer; and glycerin as a plasticizer (about 5- 35 weight %). Optionally,
`any balance (up to about 30 weight%) can be made up by water. By way
`
`20
`
`of illustration, such compositions adhere well to oral mucosal surfaces and to
`
`oral cavity prostheses or other devices of the poly(methyl methacrylate)
`("PMMA ") type.
`
`25
`
`In other embodiments for oral mucosal contact a water-soluble
`
`pressure-sensitive adhesive according to the invention includes as a polymer
`HPC (about 100- 50 weight %) and, optionally, (up to about 50 weight %)
`
`one or more of PVP, PV A, PEO, starch, polysucrose or other
`polysaccharide, xanthan gum, or karaya gum; and glycerin as a plasticizer
`(about 5 - 35 weight %). In these formulations, the HPC preferably has a
`
`30
`
`molecular weight between about 60 k and about 1,000 k, and more
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`wo 95/05416
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`
`preferably between about I 00 k and about 300 k.
`pressure-sensitive adhesive layer may take the form of a film which
`
`The water-soluble
`
`preferably is about 5-10 mils thick. Preferred water-soluble pressure(cid:173)
`sensitive adhesive films according to the invention are very flexible, and are
`
`5
`
`therefore capable of conforming to and adhering to contoured surfaces such
`
`as the gum or the roof of the mouth.
`
`In preferred embodiments the device includes at least one water(cid:173)
`
`soluble polymer layer in addition to the water-soluble pressure-sensitive
`adhesive layer. This water soluble polymer layer is a hydrophobic material
`
`10
`
`that will not dissolve in cold water (below about 40 °C) and has little or no
`
`tendency to hydrate with water. The material may further be hot water
`
`dispersible and may have non-tacky surface properties upon moistening.
`
`Examples of suitable GRAS-certified materials include but are not limited to
`
`monoglycerides, triglycerides, waxes such as paraffin, fatty acids, fatty
`
`15
`
`alcohols and mixtures thereof. In a particular embodiment, sorbitan
`
`monostearate (SPAN 60) with hydroxypropyl cellulose (HPC LF) is useful.
`
`The pressure-sensitive adhesive layer and, in some embodiments, one
`
`or more of the polymer layers in the device according to the invention are
`
`fully water-soluble, and are thus fully soluble in secretions present in
`20 mucous-lined body cavities. Consequently, the pressure-sensitive adhesive
`layer and the water-soluble polymer layers eventually dissolve completely
`
`within the body cavity in which the device is placed, and the material of the
`
`dissolved layers is flushed away with the fluid secretions of the cavity or, in
`
`the case of use in the oral cavity, passes on to the alimentary canal.
`
`25
`
`According to the invention, the adhesive serves to keep the device in
`
`place within the body cavity, and release of the substance or substances is
`
`controlled by the particular arrangement of layers.
`Device for Controlled Release of Substance
`within a Mucosa-Lined Body Cavity
`
`30
`
`In a further general aspect, the invention features a device for .
`
`emplacement within a mucosa-lined body cavity of a subject, the device
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`DRL - EXHIBIT 1002
`DRL831
`
`

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`W095/05416
`
`PCTnJS94/09305
`
`.
`including a portion made of a water-soluble pressure sensitive adhesive
`
`- 16-
`
`composition. A surface of the water-soluble pressure sensitive adhesive
`
`portion forms a basal surface of the device which, when the device is in use,
`
`5
`
`is affixed to a surface of the body cavity.
`The adhesive compositions providing. an adhesive surface of the
`device of the invention are pressure-sensitive; that is, the adhesive surface of
`
`the device requires no wetting prior to contacting it with the body cavity
`
`surface to which it is to be affixed.
`
`The adhesive compositions are fully water-soluble, and are thus fully
`
`10
`
`soluble in secretions present in mucous-lined body cavities. Consequently,
`the adhesive eventually dissolves completely within the body cavity in which
`
`the device is placed, and is flushed away with the fluid secretions of the
`cavity or, in the case of use in the oral cavity, passes on to the alimentary
`canal. For placement within the oral cavity, for example, the adhesive
`
`15
`
`preferably is made from materials generally regarded as safe ("GRAS(cid:173)
`
`certified"), or national formulary ("NF-certified"), and therefore safe for
`
`oral use or for ingestion.
`
`Preferred water-soluble pressure-sensitive adhesives for use in the
`
`20
`
`adhesive layer of the invention are those according to the invention, as
`disClosed above under the heading "Water-Soluble Pressure-Sensitive
`Adhesives", and as described in further detail hereafter. Accordingly they
`
`include a water-soluble polymer that is rendered tacky (that is, it is rendered
`
`pressure-sensitive) at room temperature by addition of a water-soluble
`
`plasticizer that is miscible with the polymer.
`
`25
`
`In some embodiments the device is emplaced within the body cavity
`
`by contacting the adhesive surface with a mucosal surface within the body
`
`cavity or with a surface of a prosthesis that is employed within the body
`
`cavity, and for such embodiments the water-soluble pressure sensitive
`adhesive composition preferably includes PVP (about 95- 40 weight %)
`
`30
`
`and, optionally, HPC (up to about 50 weight %) as a polymer; and glycerin
`
`as a plasticizer (about 5 - 35 weight %). Optionally, any balance (up to
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`DRL - EXHIBIT 1002
`DRL832
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`

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`wo 95/05416
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`- 17-
`
`about 30 weight %) can be made up by water. By way of illustration, such
`
`compositions adhere instantaneously (within less than five seconds) to
`
`mucosal surfaces as well as to surfaces of prostheses or other devices of the
`poly(methyl methacrylate) ("PMMA ")type.
`
`5
`
`In other embodiments, a water-soluble pressure-sensitive adhesive
`
`according to the invention includes as a polymer HPC (about 0- 50
`
`weight %) and, optionally, (up to about 50 weight %) one or more of PVP,
`
`PV A, PEO, starch, polysucrose or other polysaccharide, xanthan gum, or
`karaya gum; and glycerin as a plasticizer (about 11 - 60 weight % and,
`preferably about 30 - 50 weight % for PVP- or HPC-containing adhesive
`
`10
`
`compositions). In these formulations, the HPC preferably has a molecular
`
`weight between about 60 k and about 1,000 k, and more preferably between
`
`about 100 k and about 300 k.
`
`In some embodiments the device is a
`
`device for delivery of one or more substances into the body cavity or across
`
`15
`
`the mucosa. Typically the device has a laminated structure, and the water(cid:173)
`
`soluble pressure sensitive portion is a basal layer of the device.
`Conveniently, the water-soluble pressure sensitive adhe.sive portion of such a
`
`device is constructed as a film made up of an adhesive composition as
`
`described above. In preferred embodiments the film has a thickness in the
`
`20
`
`range about 5 - 20 mils, and is shaped to fit and to conform generally to the
`
`surface to which the device is intended to be attached for use. Preferred
`
`water-soluble pressure-sensitive adhesive films according to the invention are
`
`very flexible, and are therefore capable of conforming to and adhering to
`
`contoured surfaces such as the gum or the roof of the mouth ..
`In some embodiments the device when in place within the body cavity
`
`25
`
`provides a protective barrier for the area of the mucosal surface to which it
`
`is affixed which is covered by the device. The barrier may protect the
`
`underlying mucosal surface from mechanical abrasion or erosion, for
`example, or, for example, it may serve to protectively isolate the underlying
`
`30 mucosal surface from some substance in the fluid of the milieu of the body
`
`cavity.
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`
`Where the device is a laminated device for delivery of an active
`
`agent, and includes an upper active-containing layer laminated to an adhesive
`
`layer, or where the device provides a protective barrier, and includes an
`
`upper barrier layer laminated to an adhesive layer, the upper layer is
`
`5
`
`preferably constructed of a hydrophobic polymer material that will not
`dissolve in cold water (below about 40 °C) and has little or no tendency to
`
`hydrate with water. The material may further be hot water dispersible and
`
`may have non-tacky surface properties upon moistening. Examples of
`
`suitable GRAS-certified materials include but are not limited to
`
`10 monoglycerides, triglycerides, waxes such as paraffin, fatty acids, fatty
`
`alcohols and mixtures thereof.
`
`The rate of release of the active substance within the oral cavity
`
`depends to at least some extent upon the rate of dissolution or dispersion of
`
`the polymer of the active layer in situ, which in tum varies substantially
`according to the molecular weight of the principal polymer component: a
`
`15
`
`given polymer type dissolves or disperses more slowly at higher molecular
`
`weights than at lower molecular weights. In some embodiments the active(cid:173)
`
`containing layer includes a polymer such as hydroxypropyl cellulose, and
`
`may additionally include a plasticizer such as glycerin. In a particular
`
`20
`
`embodiment, hydroxypropyl cellulose (HPC Klucel LF), having a molecular
`
`weight of 80,000, with glycerin as a plasticizer, is useful.
`
`Long-Lasting Mucoadhesive Device for Temporary
`Relief of Sore Throat and Cough
`
`In yet another general aspect, the invention features a layered
`
`25
`
`composite mucoadhesive device for delivery of an active substance into the
`
`oral cavity, having an active-containing layer that includes the active
`
`substance dispersed or dissolved in a water soluble polymer, and a water
`
`soluble adhesive layer.
`
`In some embodiments the active-containing water soluble polymer
`
`30
`
`layer is a hydrophobic material that will not dissolve in cold water (below
`
`about 40 o C) and has little or no tendency to hydrate with water. The
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`DRL - EXHIBIT 1002
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`

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`wo 95/05416
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`- 19-
`
`material may further be hot water dispersible and may have non-tacky
`
`surface properties upon moistening. As noted above examples of suitable
`GRAS-certified materials include but are not limited to monoglycerides,
`
`triglycerides, waxes such as paraffin, fatty acids, fatty alcohols and mixtures
`thereof.
`
`5
`
`Also as noted above, the rate of release of the active substance within
`
`the oral cavity depends to at least some extent upon the rate of dissolution or
`dispersion of the polymer of the active layer in situ, which in turn varies
`
`substantially according to the molecular weight of the principal polymer
`component; a desired release rate can be specified by choice of the polymer
`
`10
`
`or polymer combination.
`
`In some embodiments the adhesive for use in the adhesive layer of the
`
`invention is a water-soluble pressure-sensitive adhesive according to the
`
`invention, as disclosed above under the heading "Water-Soluble Pressure-
`
`15
`
`Sensitive Adhesives", and as described in further detail hereafter.
`
`Accordingly such adhesives include a water-soluble polymer that is rendered
`
`tacky (that is, it is rendered pressure-sensitive) at room temperature by
`
`addition of a water-soluble plasticizer that is miscible with the polymer.
`
`Additional ingredients, such as, for example, deodorants or
`reodorants or flavorants, may be delivered along with the active substance as
`
`20
`
`the active-containing layer disperses within the oral cavity. Such additional
`
`ingredients include, for example, sweeteners such as aspartame, and breath
`
`fresheners such as menthol.
`
`In another general aspect the invention features a method for
`
`25
`
`administering a substance over an extended time period for relief of sore
`
`throat or cough. The method involves dissolving or dispersing the substance
`
`in a laminated water soluble device that has a water soluble pressure
`
`sensitive adhesive layer. The device is affixed to the mucosal surface of the
`
`oral cavity.
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`DRL - EXHIBIT 1002
`DRL835
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`

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`W095/05416
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`PCTIUS94/09305
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`-20-
`
`Long-Lasting Mucoadhesive Device for Administration
`of Breath-Freshening Agent
`
`In still another general aspect, the invention features a laminated
`composite device for administering an odorant into the oral cavity over an
`extended time. The device has at least two layers, including a basal layer
`
`5
`
`constructed of a water soluble pressure sensitive mucoadhesive polymer
`
`composition; and an odorant-containing water soluble polymer layer.
`
`In some embodiments the basal adhesive layer is mucoadhesive and
`
`additionally adheres to a variety of materials, such as polymers, that can be
`
`10
`
`used in construction of devices for emplacement on an oral mucosal surface
`
`or within the oral cavity. The basal adhesive layer preferably is constructed
`of a water soluble pressure sensitive adhesive that requires no moistening
`prior to contact with the mucosal or the polymer surface. The adhesive
`
`preferably is made from materials generally regarded as safe ("GRAS-
`
`15
`
`certified"), or national formulary ("NF-certified"), and therefore safe for
`
`oral use or for ingestion.
`
`Preferred water-soluble pressure-sensitive adhesives for use in the
`
`adhesive layer of the invention are those disclosed above under the heading
`"Water-Soluble Pressure-Sensitive Adhesives", and described in further
`detail hereafter. Accordingly such adhesives include a water-soluble
`
`20
`
`polymer that is rendered tacky (that is, it is rendered pressure-sensitive) at
`
`room temperature by addition of a water-soluble plasticizer that is miscible
`
`with the polymer.
`
`In some embodiments the odorant containing layer includes a polymer
`
`25
`
`such as a hydroxypropyl cellulose, and in a particular embodiment may
`
`additionally include a plasticizer such as glycerin. The rate of release of the
`
`odorant within the oral cavity can be specified by selection of particular
`polymer or polymer combinations, as noted generally above under the
`
`heading "Device for Controlled Release of Substance within a Mucosa-Lined
`
`30
`
`Body Cavity". In a particular embodiment, a hydroxypropyl cellulose (HPC
`
`Klucel GF), having a molecular weight of 300,000, is useful.
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`wo 95/05416
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`PCT/US94/09305
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`-21-
`
`The water soluble odorant containing layer may take the form of a
`
`film which preferably is about 20 - 30 mils thick. Suitable slow-dissolving
`
`polymers such as HPC are typically not sufficiently flexible to conform with
`
`the irregularly curved surfaces of the oral cavity or of oral or dental
`
`5
`
`prostheses, and addition of a plasticizer to the polymer or polymer mixture
`
`of films would be required for these applications. Suitable plasticizers can
`
`include glycerin, for example.
`
`In some embodiments the odorant is an essential oil of a plant
`
`material, or a refined fraction of an essential oil, or a combination of the
`
`10
`
`chief aromatic constituents of an essential oil. Preferably the odorant is a
`
`mint odorant. We have discovered that, surprisingly, the essential oils that
`
`are commonly used as flavorings, particularly oil of wintergreen, oil of
`
`peppermint, and oil of spearmint, are themselves effective as plasticizers.
`
`For breath freshener devices for delivering a mint odorant, therefore, the
`
`15
`
`odorant containing layer therefore can consist of the polymer and the mint
`
`odorant (and, optionally, a sweetener and a preservative), without any
`
`requirement for a plasticizer other than the mint odorant.
`
`Accordingly, in another aspect the invention features a laminated
`
`composite device for administering a mint odorant into the oral cavity over
`
`20
`
`an extended time, comprising a basal layer constructed of a water soluble
`pressure sensitive mucoadhesive composition and an upper layer containing a
`
`water soluble polymer, such as a HPC,. and a mint oil.
`
`Extended delivery of odorant can be obtained according to the
`
`invention from devices whose composite thickness is 35 mils or less. The
`
`25
`
`devices according to the invention are very flexible, and are therefore
`
`capable of conforming to and adhering to contoured surfaces such as the
`
`gum or the roof of the mouth. Breath freshening devices according to the
`
`invention can deliver a mint odorant such as a peppermint continuously over
`
`a period of up to two hours or longer from a single device, and can provide
`
`30
`
`breath freshening for even greater periods of time.
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`-22-
`
`Description of Preferred Embodiments
`Preferred embodiments of the invention will now be described,
`
`beginning with a brief description of the drawings.
`
`5
`
`Brief Description of the Drawings
`Fig. 1 is a sketch in sectional view showing a device of the invention
`configured to provide delivery of one or more substances at two different
`
`rates.
`
`Fig. 2 is a sketch in sectional view showing a device of the invention
`
`10
`
`configured to provide delayed-onset delivery of one or more substances.
`
`Fig. 3 is a sketch in sectional view showing a device of the invention
`
`configured to provide delivery of one or more substances in a sequence of
`
`pulses.
`Fig. 4 is a sketch in sectional view showing a device of the invention
`
`15
`
`configured to provide delayed-onset delivery of one or more substances
`
`while minimizing diffusion of the substance(s) at the edges of the device.
`
`Figs. 5 through 7 are rough hypothetical plots showing quantity of an
`
`active substance released by devices of the invention configured on the plans
`
`shown in Figs. 1 through 3, respectively.
`
`20
`
`Fig. 8 is a sketch in transverse sectional view showing a bilaminate
`
`device according to the invention.
`Fig. 9 is a sketch in transverse sectional view showing a trilaminate
`
`device according to the invention.
`
`Fig. 10 is a plot of data showing the cumulative release of Dyclonine
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`25
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`HCl into water from a mucoadhesive disc according to the invention, and
`from a Sucrets® lozenge.
`
`Fig. 11 is a plot of data comparing release of benzocaine into distilled
`
`water from mucoadhesive discs according to the invention, having different
`
`molecular weight polymers in the active-containing layer.
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`30
`
`Fig. 12 is a sketch in sectional view showing another embodiment of
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`a device according to the invention.
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`DRL - EXHIBIT 1002
`DRL838
`
`

`
`wo 95/05416
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`PCTIUS94/09305
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`-23-
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`Fig. 13 is a sketch in sectional view showing another embodiment of
`
`a device according to the invention.
`Fig. 14 is a graph comparing tack characteristics, on a PMMA
`
`surface, of dry and of moistened adhesive films according to the invention
`
`5
`
`with tack characteristics of conventional films.
`
`Fig. 15 is a graph comparing adhesion characteristics, on a PMMA
`
`surface, of dry and of moistened adhesive films according to the invention
`
`with adhesion characteristics of conventional films.
`
`Fig. 16 is a graph comparing elastic moduli of HPC films, illustrating
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`10
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`the plasticizing effect of mint odorants.
`
`Fig. 17 is a graph comparing menthol release over time from a breath
`
`freshening device according to the invention and from a conventional
`commercially marketed "breath mint" (Certs®).
`
`As will be appreciated, the drawings are not made to scale, and, in
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`15
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`particular, no attempt has been made to represent relative thicknesses of the
`
`layers proportionately, and the thicknesses of the various layers are
`
`exaggerated for clarity of presentation.
`
`Modes of Carrying out the .invention
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`20
`
`Water-Soluble Pressure-Sensitive Adhesives
`
`1.
`
`Preparation of a water-soluble pressure-sensitive adhesive
`
`composition made up of PVP and glycerin.
`
`A solution of poly( vinyl pyrrolidone) ("PVP": Kollidon®, obtained
`from BASF) and glycerin was first prepared in isopropyl alcohol ("IPA "),in
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`25
`
`the following proportion by weight: 15 parts PVP, 6 parts glycerin, and 79
`
`parts IPA. The solution was coated on a polyester release liner and allowed
`
`to dry at room temperature for 15 hours to permit evaporation of the IP A.
`The resulting dry film is both pressure-sensitive and water-soluble.
`
`30
`
`Measurements of tack were made using a TA.XT2 Texture Analyzer
`
`(Texture Technologies Corp.) together with an XT.RA Dimension software
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`DRL - EXHIBIT 1002
`DRL839
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`

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`wo 95/05416
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`PCTIUS94/09305
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`-24-
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`package (Stable Micro Systems, Ltd.), as follows. A sample of the film on
`
`a release liner is mounted upon a block, and a probe is moved at a fixed
`
`speed against the adhesive surface of the film, distorting the film to a fixed
`
`penetration depth, where the probe is permitted to dwell for a fixed time.
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`5
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`The probe is then withdrawn from the film, at a fixed speed, and the peak
`
`force required to detach the probe from the film surface is measured as a
`
`measure of tack.
`
`Measured tack of samples of a PVP-glycerin film prepared as
`described above and having 5 mils thickness was 1820 g/ cm2, using a probe
`
`10
`
`diameter of 0.80 em, a penetration depth of 0.1 mm, a penetration rate of
`
`1.0 mm/sec, a dwell time of 10 sec, and a withdrawal rate of 5.0 mm/sec.
`
`Typical tack values for adhesives used in transdermal devices, for example,
`are about 1000- 2000 g/cm2 •
`
`Measurements of water solubility were made by submersion of a
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`15
`
`sample of the film in water at 21 °C, stirring the water, and determining the
`
`time required for apparent complete dissolution of the film.
`
`The total measured dissolution time of samples of a PVP-glycerin film
`
`prepared as described above and having 5 mils thickness was about 10
`
`minutes.
`
`2.
`
`Preparation of a water-soluble pressure-sensitive
`
`20
`
`adhesive composition made up of HPC, PVP and glycerin.
`
`Hydroxy propyl cellulose ("HPC"), PVP and glycerin were first
`
`blended in the proportion, by weight, of 4 parts HPC, 2 parts PVP, and 2
`
`parts glycerin. The resulting mixture was pressed in a heated Carver
`
`laboratory press at 200 °F to a thickness about 35 mils. The resulting film
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`25
`
`was flexible, translucent and tacky at room temperature.
`
`3.
`
`Preparation of dental prosthesis adhesive film.
`
`A water-soluble pressure-sensitive adhesive film made as described
`
`above can be die-cut in a shape that conforms to that portion of the dental
`
`prosthesis that closely fits the mucosal surface of the mouth, such as the part
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`30
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`of the dental plate that fits against the palate. The shaped film pieces can be
`
`packaged dry. For use, the dry film is pressed onto the appropriate surface
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`DRL - EXHIBIT 1002
`DRL840
`
`

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`W095/05416
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`PCTIUS94/09305
`
`-25-
`
`of the dental prosthesis so that it adheres. Then the dental prosthesis with
`
`the adhesive affixed is inserted into the correct position in the mouth and
`
`pressed against the mucosal surface until adhesion is achieved.
`The following Example is intended to illustrate but not to limit the
`
`5
`
`invention.
`
`Example I
`
`Breath Freshening Device
`
`A dissolvable mucoadhesive device capable of releasing a flavor into
`
`the oral cavity was constructed as follows: A solution was made up by co-
`
`lO
`
`dissolving 15.4 grams of polyvinyl pyrrolidone PVP (K90) and 6.0 grams of
`
`glycerin in 80 grams of isopropanol (IPA). The resulting solution was
`
`coated at a thickness of 30 mils onto a polyester release liner and allowed to
`dry for 15 hours at room temperature. The resulting dry film was tacky at
`room temperature and had a final thickness of -about 5 mils. A second
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`15
`
`solution containing 43 grams of IP A, 42 grams of water, 15 grams of HPC
`
`EF, 2.5 grams of peppermint oil and 3.0 grams of Nutrasweet™ brand
`sweetener containing aspartame was prepared by mixing all the components
`
`until fully dissolved. The solution was then coated at a thickness of 50 mils
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`20
`
`onto a polyester release liner. The film was allowed to dry at room
`temperature for 15 hours to a final thickness of about 5 mils.
`The two dry films were laminated together. Discs having a diameter
`
`of about 1.2 em were cut from the laminate. The discs were tested in vivo
`
`by adhering a single disc to the upper palate of three volunteers. The discs
`
`adhered well to the mucosal surface and upon hydration with saliva
`
`25
`
`immediately began releasing peppermint oil and aspartame as noticed by
`
`taste. The total time of dissolution in the mouth was about 10 minutes,
`
`during which time a pleasant, refreshing mint flavor was perceived.
`
`Device Having a Water-Soluble Pressure-Sensitive Adhesive
`for Emplacement in a Mucosa-Lined Body Cavity
`1. Water-soluble pressure-sensitive adhesive layer.
`
`30
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`DRL - EXHIBIT 1002
`DRL841
`
`

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`wo 95/05416
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`PCTIUS94/09305
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`-26-
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`The preferred water-soluble pressure-sensitive ad