(12) Unlted States Patent
`Tapolsky et a].
`
`(10) Patent N0.:
`(45) Date of Patent:
`
`US 7,579,019 B2
`Aug. 25, 2009
`
`USOO7579019B2
`
`(54) PHARMACEUTICAL CARRIER DEVICE
`SUITABLE FOR DELIVERY OF
`PHARMACEUTICAL COMPOUNDS TO
`MUCOSAL SURFACES
`
`(75) Inventors: Gilles H. Tapolsky, The Woodlands, TX
`(Us). David w_ Osborne The
`Woog?ands TX (Us)
`’
`3
`(73) Assignee: Arius Two, Inc., Raleigh, NC (U S)
`
`( * ) Notice:
`
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 835 days.
`
`(21) App1.No.: 11/069,089
`
`(22) Filed:
`
`Mar. 1, 2005
`
`CA
`
`(65)
`
`Prior Publication Data
`US 2005/0147658 A1
`Ju1.7, 2005
`
`Related US. Application Data
`_
`_
`_
`_
`(60) Contlnuatlon of appllcatlon No. 09/ 684,682, ?led on
`Oct. 4, 2000, noW abandoned, Which is a division of
`application No. 09/069,703, ?led on Apr. 29, 1998,
`now abandoned, Which is a continuation-in-part of
`appllcatlon No. PCT/US97/18605, ?led on Oct. 16,
`1997
`'
`
`2/1981 Nagai et a1.
`4,250,163 A
`8/1981 Tinnell
`4,285,934 A
`9/1981 Chandrasekaram
`4,286,592 A
`9/1981 Suzuki
`4,292,299 A
`4/1983 Tinnell
`4,381,296 A
`5/1985 Kizawa et a1~
`4,517,173 A
`5/1985 Dhabhar et a1.
`4,518,721 A
`4,552,751 A 11/1985 Inaba et a1.
`4,572,832 A
`2/1986 Kigasawa et a1.
`4,594,240 A
`6/1986 Kawata et al'
`4,668,232 A
`5/1987 Cordes
`4,713,243 A 12/1987 SChlraldl et 31'
`4’713’246 A 12/1987 Begum et 31'
`
`(Continued)
`FOREIGN PATENT DOCUMENTS
`2169729
`4/2001
`
`d
`C t'
`( onmue )
`OTHER PUBLICATIONS
`
`The Merck Manual, http://WWW.merck.c0m/mmhe/secO6/ch078/
`ch078a.html?qt:pain&alt:sh, obtained online on Aprkl 9 2009*
`_
`(Commued)
`Primary ExaminerijohannR Richter
`Assistant ExamineriAbiga? Fisher
`74 A
`)1 Ag
`F' M c &E gl' hLLP
`Horne ,
`@712, 0r zrmi c arter
`n ls
`
`(51) Int- Cl-
`A61F 13/00
`
`(2006.01)
`
`57
`(
`)
`
`ABSTRACT
`
`A61K 9/14
`(2006.01)
`(52) us. Cl. ..................................... .. 424/435, 424/486
`(58) Field of Classi?cation Search ............... .. 424/435,
`42 4 / 48 6
`.
`.
`.
`see apphcanon ?le for complete searCh hlswry'
`References Cited
`
`(56)
`
`U.S. PATENT DOCUMENTS
`
`2/1972 Estes
`3,640,741 A
`3,996,934 A 12/1976 Zaffaroni
`4,226,848 A 10/1980 Nagaiet a1.
`
`_
`_
`_
`_
`The, Present mention relates to a pharmaceumal dehvery
`gemeéolr 8513110811011 Of? Pharmf‘lieupcall ‘0 mucgsal sur'
`ages. a: ivlce1 compnsgshan £211
`eslve ayelr an la non
`a eslve ac lng ayer, an t e p almaceutlca may e pro
`vided in either or both layers. Upon application, the device
`adheres to the mucosal surface, providing localized drug
`delivery and protection to the treatment site. The kinetics of
`erodability are easily adjusted by varying the number of lay
`ers and/or the components.
`
`7 Claims, 1 Drawing Sheet
`
`Page 1
`
`

`

`US 7,579,019 B2
`Page 2
`
`US. PATENT DOCUMENTS
`
`4’715’369 A 12/1987 Suzuki etaL
`4’720’387 A
`l/ 1988 SakamotoetaL
`4,740,365 A
`4/1988 Yukimatsu et al.
`4’755’386 A
`7/1988 Hsiao etal'
`4’764’378 A
`8/1988 KeithetaL
`4,765,983 A
`8/1988 Takayanagiet a1.
`4,784,858 A 11/1988 Ventouras
`4,857,336 A
`8/1989 Khannaetal.
`4,867,970 A
`9/1989 Newsham et a1.
`4,876,092 A 10/1989 Mizobuchi et a1.
`4,889,720 A 12/1989 Konishi
`4,894,232 A
`1/1990 116616131.
`4,900,552 A
`2/1990 Sanvordeker 6131.
`4,900,554 A
`2/1990 Yanagibashiet 31.
`4,906,463 A
`3/1990 Cleary 6161.
`4,915,948 A
`4/1990 Gallopo et a1.
`4,990,339 A
`2/1991 $011011 et a1.
`5,047,244 A
`9/1991 Sanvordekeretal.
`5,059,189 A 10/1991 (31161116 @131.
`5,064,654 A 11/1991 Berneretal,
`5,081,157 A
`1/1992 Pomerantz
`5,081,158 A
`1/1992 Pomerantz
`5,116,621 A
`5/1992 Oji @1211.
`5,137,729 A
`8/1992 Kuroyaetal.
`5,166,233 A 11/1992 Kuroyaetal.
`5,192,802 A
`3/1993 Rencher
`5,196,202 A
`3/1993 Konishi
`5,254,345 A 10/1993 Poganyet a1.
`5,254,346 A 10/1993 Tucker @1211.
`5,298,258 A
`3/1994 Akemi et a1.
`5,314,915 A
`5/1994 Rencher
`5,332,576 A
`7/1994 Mantelle
`5,346,701 A
`9/1994 Heiberetal.
`5,462,749 A 10/1995 Rencher
`5,466,465 A 11/1995 Royds @1211.
`5,505,956 A
`4/1996 Kim @1211.
`5,516,523 A
`5/1996 Heiberetal,
`5,540,930 A
`7/1996 Guyetal,
`5,599,554 A *
`2/1997 Majeti ...................... .. 424/448
`5,603,947 A *
`2/1997 Wong @1211. ............... .. 424/448
`5,679,714 A * 10/1997 Weg ......................... .. 514/647
`5,700,478 A 12/1997 Biegajski et a1.
`5,723,143 A
`3/1998 Jacques et a1.
`5,750,136 A
`5/1998 801101261211.
`5,780,047 A
`7/1998 Kamiya 61211.
`5’800’832 A
`9/1998 TapOlSky et 31'
`5’849’322 A 12/1998 Eben et 31'
`5,853,760 A 12/1998 Cremeretal.
`5,900,247 A
`5/ 1999 Rault et a1.
`
`9/1999 Zerbe et a1.
`5,948,430 A
`5,985,317 A 11/1999 Venkateshwaran et a1.
`6,159,498 A 12/2000 Tapolsky 61211.
`6,177,096 B1
`1/2001 Zerbeetal.
`6,284,262 B1
`9/2001 Place
`6,592,887 B2
`7/2003 Zerbe 61211.
`2005/0048102 A1
`3/2005 Tapolskyetal.
`
`FOREIGN PATENT DOCUMENTS
`
`EP
`EP
`EP
`EP
`EP
`EP
`EP
`EP
`EP
`FR
`FR
`GB
`GB
`JP
`JP
`JP
`JP
`JP
`JP
`JP
`JP
`JP
`JP
`JP
`JP
`JP
`JP
`JP
`JP
`JP
`JP
`W0
`W0
`W0
`W0
`
`4/1982
`0050 480
`10/1985
`0 159 604
`0159604 A2 10/1985
`0250187
`12/1987
`0262 422
`4/1988
`0275550 Al
`7/1988
`0381194
`8/1990
`0 654 261 A1
`5/1995
`0781546
`7/1997
`2497098
`7/1982
`2582942
`12/1986
`981372
`1/1965
`2108841
`5/1983
`56-100714
`8/1981
`58-079916
`5/1983
`60-116630
`6/1985
`62-178513
`2/1986
`61-280423
`12/1986
`62-022713
`1/1987
`62-056420
`3/1987
`62-13541?
`6/1987
`63-060924
`3/1988
`63-160649
`7/1988
`63-310818
`12/1988
`64-071812
`3/1989
`64-090121
`4/1989
`1-226823
`9/1989
`3-246220
`11/1991
`4-059723
`2/1992
`9-504810
`5/1997
`2001-508037
`6/2001
`WG-94/18925 A1
`9/1994
`WG-95/05416
`2/1995
`WO-95/05416 A2
`2/1995
`WO-9525544
`9/1995
`
`OTHER PUBLICATIONS
`Webster’s New World Dictionary (1988). V. Neufeldt ed. and DB.
`Guralink ed., Prentice Hall: NeWYork 3rd. College Ed., p. 505.
`
`* cited by examiner
`
`Page 2
`
`

`

`US. Patent
`U.S. Patent
`
`Aug. 25, 2009
`Aug. 25, 2009
`
`US 7,579,019 B2
`US 7,579,019 B2
`
`
`
`Page 3
`
`Page 3
`
`

`

`US 7,579,019 B2
`
`1
`PHARMACEUTICAL CARRIER DEVICE
`SUITABLE FOR DELIVERY OF
`PHARMACEUTICAL COMPOUNDS TO
`MUCOSAL SURFACES
`
`The instant application is a continuation of US. patent
`application Ser. No. 09/684,682, ?led Oct. 4, 2000, which is
`a divisional of US. patent application Ser. No. 09/069,703,
`?ledApr. 29, 1998 which is a continuation-in-part application
`of PCT/US97/18605, ?led Oct. 16, 1997, which is a PCT
`application claiming priority from Ser. No. 08/734,519, ?led
`Oct. 18, 1996, which applications are incorporated herein by
`reference.
`
`FIELD OF THE INVENTION
`
`The present invention relates generally to a water-erodable
`pharmaceutical carrier which adheres to mucosal surfaces for
`the localized delivery of pharmaceutical compounds and pro
`tection 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 ?uids to
`rapidly wash away topically applied pharmaceutical compo
`nents, the topical treatment of wet mucosal tissues has been
`problematic. In the mouth, saliva, natural replacement of the
`mucosal tissue, as well as, eating, drinking, and speaking
`movements are some of the problems that have limited the
`effectiveness and residence time of pharmaceutical carriers.
`Bioadhesive carriers are known in the art and include gels,
`pastes, tablets, and ?lms. These products, however, may lack
`one or several of the preferred characteristics for an e?icient
`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; ease of comfort;
`minimal foreign body sensation; and unidirectional, speci?c
`release into the mucosal tissue. Other preferred characteris
`tics for an effective and user-friendly product for the treat
`ment of muco sal surfaces include the use of pharrnaceutically
`approved components or materials; instantaneous 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 deliv
`ery device from the affected tissue or natural erosion 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, US. Pat. No. 5,192,802 describes a bioadhesive
`teething gel made from a blend of sodium carboxymethyl
`cellulose and xanthan gum. The gel may also have potential
`use in the treatment of canker sores, fever blisters, and hem
`orrhoids. However, this type of pharmaceutical carrier has a
`very limited residence time, given that body ?uids such as
`saliva quickly wash it away from the treatment site. Bioad
`hesive gels are also described in US. Pat. Nos. 5,314,915;
`5,298,258; and 5,642,749. The gels described in those patents
`use an aqueous or oily medium and different types of bioad
`hesive 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
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`2
`the topical delivery of is pharmaceuticals, although drugs
`such as local anesthetics may be used in the paste for the relief
`of sore gums. US. Pat. Nos. 4,894,232 and 4,518,721
`describe denture adhesive pastes. The ’721 patent describes a
`combination of sodium carboxymethyl cellulose and polyeth
`ylene oxide in polyethylene glycol.
`Pastes have also been used as ?lm protectants and as drug
`delivery systems. One such example having ?lm forming and
`adhesive properties is the product commercialized under the
`name Orabase®-B, which is a thick gel or paste for the relief
`of mouth sores. Ingredients include guar gum, sodium car
`boxymethyl cellulose, tragacanth gum, and pectin. Even
`though it does provide numbing to the area of application, the
`?lm 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 adhe
`sion 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 erosion time.
`Bioadhesive tablets are also described in US. 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 bioadhe
`sive component such as polyacrylic acid, sodium carboxym
`ethyl cellulose, or polyvinylpyrrolidone, and a binder for
`tableting purposes. The cellulose derivatives may or may not
`be water-erodable.
`The use of bandages or bioadhesive laminated ?lms, which
`are thinner and ?exible and therefore have a decreased for
`eign 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 ?lms 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 thus are not dissolved or washed away
`by bodily ?uids.
`In addition to ?lm systems for the delivery of drug through
`the skin, ?lm delivery systems foruse on mucosal surfaces are
`also known. These types of systems, which are water-in
`soluble and usually in the form of laminated, extruded or
`composite ?lms, are described in US. 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 ?lm con
`sisting of at least three layers, including a pharmaceutical
`layer, a poor water soluble layer, and an intermediate layer.
`The pharmaceutical layer includes the drug and a cellulose
`derivative selected from hydroxypropyl cellulose, methyl cel
`lulose, and hydroxypropyl methyl cellulose. The poor water
`soluble layer is made by the combination 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 ?lm 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 ?avoring agents. The
`’243 patent describes a single or multi-layered bioadhesive
`thin ?lm made from 40-95% water soluble hydroxypropyl
`cellulose, 5-60% water-insoluble ethylene oxide, 0-10%
`water-insoluble ethyl cellulose, propyl cellulose, polyethyl
`ene, or polypropylene, and a medicament. The ?lms are three
`layered laminates and include a bioadhesive layer, a reservoir
`
`Page 4
`
`

`

`US 7,579,019 B2
`
`3
`layer, and a non water-soluble outer protective layer. The ’729
`patent teaches a soft adhesive ?lm 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, the ’554
`patent describes a device for use in the oral cavity having an
`adhesive layer including a mixture of an acrylic acid polymer,
`a water-insoluble cellulose derivative, and a pharmaceutical
`preparation, and a water-insoluble or sparingly soluble back
`ing 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.”
`JP 56-100714 describes a preparation which comprises a
`coating layer and an active ingredient layer. The coating layer
`adheres to the mucosal membrane and is comprised of a
`cellulose ether or an acrylic acid polymer or salt. The active
`ingredient layer comprises an ointment base comprised of
`water-insoluble substances such as fats and oils, waxes,
`hydrocarbons, higher fatty acids, higher alcohols, polyhydric
`alcohols or glycerol esters. A surfactant and active ingredient
`are also present in the active ingredient layer. Thus, the active
`ingredient is mixed with an essentially non-water erodable
`substance. The previous examples of thin ?lms 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. Therefore, unfortunately, the above
`examples of thin ?lms do not provide a water erodable device
`with good adhesive properties. Therefore, upon release of the
`desired amount of drug, the thin ?lms of water insoluble
`polymers must be peeled off the site of application. Such
`peeling often removes tissue from the mucosal tissue and is
`painful to the patient. What is needed in the art is a water
`erodable pharmaceutical delivery device which provides
`good adhesion and localized delivery of a pharmaceutical
`with minimal discomfort to the patient.
`
`20
`
`25
`
`30
`
`35
`
`40
`
`SUMMARY OF THE INVENTION
`
`4
`lagen and derivatives, gelatin, albumin, polyaminoacids and
`derivatives, polyphosphazenes, polysaccharides and deriva
`tives, chitin, or chitosan, alone or in combination and a bio
`adhesive polymer such as polyacrylic acid, polyvinyl pyrroli
`done, or sodium carboxymethyl cellulose, alone or in
`combination.
`The non-adhesive backing layer(s) comprise(s) hydroxy
`ethyl cellulose, hydroxypropyl cellulose, hydroxyethylm
`ethyl cellulose, hydroxypropylmethyl cellulose, polyvinyl
`alcohol, polyethylene glycol, polyethylene oxide, or ethylene
`oxide-propylene oxide co-polymers, alone or in combination.
`In another embodiment of the invention, one or more of the
`layers of the device further comprise a component which acts
`to adjust the kinetics of the erodability and provide a conve
`nient manner of altering the release of the pharmaceutical and
`the lifespan of the device. A component which acts to adjust
`the kinetics of the erodability is a water-based emulsion of a
`polylactide, polyglycolide, lactide-glycolide copolymers,
`poly-e-caprolactone and derivatives, polyorthoesters and
`derivatives, polyanhydrides and derivatives, ethyl cellulose,
`vinyl acetate, cellulose acetate, and polyisobutylene, alone or
`in combination. Another component which acts to adjust the
`kinetics of the erodability is alkyl-glycol, propylene glycol,
`polyethyleneglycol, oleate, sebacate, stearate or esters of
`glycerol, or phthalate, alone or in combination.
`In another embodiment of the invention, the number of
`layers of the device further may be varied to adjust the kinet
`ics of the erodability and provide a convenient manner of
`altering the release of the pharmaceutical and the lifespan of
`the device.
`In a preferred embodiment, the backing layer comprises
`two or more layers with different erodibility kinetics.
`
`BRIEF DESCRIPTION OF THE DRAWINGS
`
`FIG. 1 is a three layered ?lm disk wherein layers 2 and 3 are
`bioadhesive layers and layer 1 is a backing layer.
`FIG. 2 is a three layered ?lm disk wherein two of the layers
`are bioadhesive layers and the other layer is a backing layer.
`The bioadhesive layer, layer 3, which will adhere to the
`mucosal tissue is of smaller surface area and encompassed by
`the second bioadhesive layer, layer 2, to provide unidirec
`tional delivery. Layer 1 is a backing layer.
`
`The present invention relates to a novel water-erodable
`pharmaceutical carrier device for application to mucosal sur
`faces to provide protection of and localized delivery of phar
`maceutical to the site of application, surrounding tissues, and
`other bodily ?uids such as blood or lymph, having an effective
`residence time, with minimal discomfort and ease of use. In
`one embodiment, the pharmaceutical delivery device
`includes a layered ?lm disk which is water-erodable. The
`device comprises a layered ?lm disk having an adhesive layer
`and a backing layer, both water-erodable, having the pharma
`ceutical in one or more of the layers.
`In another embodiment, the pharmaceutical delivery
`device further comprises a third layer between the ?rst adhe
`sive layer and the second backing layer. The third layer is a
`water-erodable adhesive layer which has a surface area suf
`?cient to encompass said ?rst adhesive layer and contact the
`mucosal surface. In this manner, localized delivery of a phar
`maceutical may be accomplished in a unidirectional manner
`toward the mucosal layer.
`The adhesive layer(s) comprise(s) a ?lm-forming polymer
`such as hydroxyethyl cellulose, hydroxypropyl cellulose,
`hydroxypropylmethyl cellulose, hydroxyethyl methyl cellu
`lose, polyvinyl alcohol, polyethylene glycol, polyethylene
`oxide, ethylene oxide-propylene oxide co-polymers, col
`
`45
`
`DETAILED DESCRIPTION OF THE INVENTION
`
`As used herein, the term “water-erodable” means that the
`component, device, layer, etc. erodes in water-based media
`such as saliva, over time. Such erosion in water may be due to
`factors such as dissolution, dispersion, friction, gravity, etc.
`As used herein, the term “kinetics of erodability” or “ero
`sion kinetics” refers to the timing of the release of pharma
`ceutical from the carrier device (release pro?le), as well as,
`the timing of the erosion of the device itself over time
`(lifespan or residence time of the device). As described
`herein, kinetics of erodability are based on factors such as
`type and amount of components in the device, thickness and
`number of layers in the device, and additives or excipients in
`the device. In a case in which all the components of the device
`are very water soluble, the kinetics of erodability will closely
`parallel the solubility kinetics.
`In the present invention, a novel water-erodable pharma
`ceutical device which adheres to mucosal surfaces is pro
`vided. The present invention ?nds particular use in the local
`ized treatment of body tissues, diseases, or wounds which
`may have moist surfaces and which are susceptible to bodily
`?uids, such as the mouth, the vagina, or other types of
`
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`60
`
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`Page 5
`
`

`

`US 7,579,019 B2
`
`5
`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 ?u
`ids. The device provides an appropriate residence time for
`effective drug delivery at the treatment site, given the control
`of erosion in aqueous solution or bodily ?uids such as saliva,
`and the slow, natural erosion of the ?lm concomitant or sub
`sequent to the delivery. In one embodiment, the pharmaceu
`tical delivery device comprises a layered ?lm disk having an
`adhesive layer and a backing layer, both water-erodable, hav
`ing 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 tendency of
`bodily ?uids such as saliva to wash away the gel from the
`treatment site, the present invention offers an increased resi
`dence time because of its ?lmy consistency and components.
`A typical 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 orpoor 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 af?nity of these gels results in a ten
`dency to quickly mix with the saliva, rapidly pulling away the
`different 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. Erosion kinetics
`in the saliva and other aqueous media are in?uenced by the
`physical state of the device. While a gel or solution will
`readily mix with saliva and/or otherbodily ?uids, a solid form
`of the same or similar composition, such as the ?lm of the
`present invention, dissolves/erodes more slowly.
`Also, unlike the bioadhesive tablets which are known in the
`art, the pharmaceutical device of the present invention mini
`mizes the discomfort associated with application of a foreign
`substance for a period of time su?icient to provide effective
`drug delivery to the treatment site. Often, users of the bioad
`hesive tablets of the prior art experience unpleasant sensa
`tions 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 applica
`tion is on the upper gingival area. This site is usually unsat
`isfactory for local delivery as the type of compounds to be
`delivered, their bioavailability, and pharmokinetics is limited.
`In contrast to tablets, the device of the present invention offers
`the advantages of an effective residence 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, ?exible form.
`Finally, unlike the ?lm 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-erodable
`components and thus is bioerodable. The use of water-erod
`able components allows the device to erode over a period of
`time, with natural bodily ?uids slowly dissolving or eroding
`away the carrier, while the pharmaceutical remains at the
`application site. Unlike bandages and other non-water-erod
`able ?lm systems, the user of the present invention does not
`have to remove the device following treatment. Nor does the
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`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.
`The residence time of the device of the present invention
`depends on the erosion rate of the water erodable polymers
`used in the formulation and their respective concentrations.
`The erosion rate may be adjusted, for example, by mixing
`together components with different solubility characteristics
`or chemically different polymers, such as hydroxyethyl cel
`lulose and hydroxypropyl cellulose; by using different
`molecular weight grades of the same polymer, such as mixing
`low and medium molecular weight hydroxyethyl cellulose;
`by using excipients or plasticizers of various lipophilic values
`or water solubility characteristics (including essentially
`insoluble components); by using water soluble organic and
`inorganic salts; 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 ?lm, including its
`crystallinity or phase transition, once obtained. These strate
`gies might be employed alone or in combination in order to
`modify the erosion kinetics of the device.
`Upon application, the pharmaceutical delivery device
`adheres to the mucosal surface and is held in place. Water
`absorption softens the device, thereby diminishing the for
`eign body sensation. As the device rests on the mucosal sur
`face, delivery of the drug occurs. Residence times may be
`adjusted over a wide range depending upon the desired timing
`of the delivery of the chosen pharmaceutical and the desired
`lifespan of the carrier. Generally, however, the residence time
`is modulated between about a few seconds to about a few
`days. Preferably, the residence time for mo st pharmaceuticals
`is adjusted from about 30 minutes to about 24 hours. More
`preferably, the residence time is adjusted from about 1 hour to
`about 8 hours. In addition to providing drug delivery, once the
`device adheres to the mucosal surface, it also provides pro
`tection to the treatment site, acting as an erodable bandage.
`In one embodiment, the present invention comprises a ?lm
`disc having an adhesive layer and a non-adhesive backing
`layer which can be comprised of components having a similar
`or different hydrophilicity. The pharmaceutical component
`may be included in either layer, although preferably, it is
`included in the adhesive layer, which is closest to the treat
`ment site and which will have a slower erosion time, given
`that the backing layer protects the interior, adhesive layer and
`will typically erode ?rst.
`The adhesive layer may comprise at least one ?lm-forming
`water-erodable polymer (the “?lm-forming polymer”) and at
`least one pharmacologically acceptable polymer known for
`its bioadhesive capabilities (the “bioadhesive polymer”). The
`?lm forming polymer may comprise hydroxyethyl cellulose,
`hydroxypropyl cellulose, hydroxypropylmethyl cellulose,
`hydroxyethyl methyl cellulose, polyvinyl alcohol, polyethyl
`ene glycol, polyethylene oxide, ethylene oxide-propylene
`oxide co-polymers, collagen and derivatives, gelatin, albu
`min, polyaminoacids and derivatives, polyphosphazenes,
`polysaccharides and derivatives, chitin and chitosan, alone or
`in combination. Preferably, the ?lm-forming polymer com
`prises hydroxyethyl cellulose and hydroxypropyl cellulose.
`Preferably, in the case of hydroxyethyl cellulose, the average
`molecular weight (Mw estimated 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
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`US 7,579,019 B2
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`7
`size exclusion chromatography measurements) is in the range
`50><103 to 1.5><106, and more preferably between 80><103 to
`5x105.
`The bioadhesive polymer of the adhesive layer may com
`prise polyacrylic acid (PAA), which may or may not be par
`tially
`crosslinked, sodium carboxymethyl cellulose
`(NaCMC), and polyvinylpyrrolidone (PVP), or combinations
`thereof. These bioadhesive polymers are preferred because
`they have good and instantaneous mucoadhesive properties in
`a dry, ?lm state. In the case of sodium carboxymethyl cellu
`lose, typical average molecular weights comprise 50,000 to
`700,000, and preferably 60,000 to 500,000, 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 components. This precipitation
`may not be ideal to obtain a homogenous layer and may
`slightly alter the overall adhesive properties of the device.
`While not wishing to bound to a particular theory, it is
`believed that the adhesion properties of the present invention
`are the result of the entanglement of polymer chains and
`interactions with glycoproteins of the mucosal surface. The
`chemical nature of the bioadhesive polymers, including chain
`and side groups and crosslinking agents, generates interac
`tions between the mucosal constituents and the polymer or
`polymers, such as physical entanglement, Van der Waals
`interactions, and hydrogen bonding. Given that the composi
`tion 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 combination of different
`grades of the same polymer is preferred. The use of a combi
`nation of at least two bioadhesive polymers maximizes the
`adhesion capabilities of the device, although use of a single
`bioadhesive polymer is effective as well.
`The ratio of the bioadhesive polymer to the ?lm-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 usually between 5 and 95% by weight,
`preferably between 10 and 80% by weight. In terms of weight
`percent of the different bioadhesive polymers PAA, NaCMC,
`and PVP, some examples are provided below and using the
`examples one skilled in the art will be able to readily adjust
`the percentages to obtain a pharmaceutical device having
`desired characteristics for a given application. Preferred com
`binations include PAA and NaCMC, NaCMC and PVP, or
`PAA and PVP, and also include the use of different grades of
`the same polymer.
`The non adhesive backing layer may comprise a water
`erodable, ?lm-forming pharmaceutically acceptable polymer
`such as hydroxyethyl cellulose, hydroxypropyl cellulose,
`hydroxypropylmethyl cellulose, hydroxyethylmethyl cellu
`lose, polyvinylalcohol, polyethylene glycol, polyethylene
`oxide, ethylene oxide-propylene oxide co-polymers, col
`lagen and derivatives, gelatin, albumin, polyaminoacids and
`derivatives, polyphosphazenes, polysaccharides and deriva
`tives, chitin and chitosan, alone or in combination. The back
`ing layer component may or may not be crosslinked depend
`ing on the desired erosion kinetics. In one embodiment, the
`preferred backing layer component comprises hydroxyethyl
`cellulose or hydroxypropyl cellulose, and more preferably
`comprises hydroxyethyl cellulose. Preferably, in the case of
`hydroxyethyl cellulose, the average molecular weight (Mw
`esti