United States Patent [19]
`United States Patent [19]
`United States Patent [19]
`Schiraldi et al. (cid:9)
`Schiraldi et al. (cid:9)
`Schiraldi et al.
`
`[11] Patent Number: (cid:9)
`[11] Patent Number: (cid:9)
`[11] Patent Number:
`[45] Date of Patent: (cid:9)
`[45] Date of Patent: (cid:9)
`[45] Date of Patent:
`
`4,713,243
`4,713,243
`4,713,243
`Dec. 15, 1987
`Dec. 15, 1987
`Dec. 15, 1987
`
`[54] BIOADHESIVE EXTRUDED FILM FOR
`[54] BIOADHESIVE EXTRUDED FILM FOR
`[54] BIOADHESIVE EXTRUDED FILM FOR
`INTRA-ORAL DRUG DELIVERY AND
`INTRA-ORAL DRUG DELIVERY AND
`INTRA-ORAL DRUG DELIVERY AND
`PROCESS
`PROCESS
`PROCESS
`
`[75] Inventors: Michael T. Schiraldi, East
`[75] Inventors: Michael T. Schiraldi, East
`[75] Inventors: Michael T. Schiraldi, East
`Brunswick, N.J.; Martin M. Perl,
`Brunswick, N.J.; Martin M. Perl,
`g: :21; liq/Egg!’
`Brooklyn, N.Y.; Howard Rubin,
`Brooklyn, N.Y.; Howard Rubin,
`Rockaway, NJ.
`Rockaway, N.J.
`Rockaway, N.J.
`
`[73] Assignee; Johnson & Johnson products, Inc”
`[73] Assignee: Johnson & Johnson Products, Inc.,
`[73] Assignee: Johnson & Johnson Products, Inc.,
`New Brunswick, NJ‘
`New Brunswick, N.J.
`New Brunswick, N.J.
`
`[21] Appl. No.: 874,904
`[21] Appl. No.: 874,904
`[21] APPL Nod 874,904
`
`-
`
`[22] Filed
`[22] Filed: (cid:9)
`[22] Filed: (cid:9)
`'
`
`Jun 16 1986
`Jun. 16, 1986
`Jun. 16, 1986
`'
`’
`
`[51] Int. CI.4 (cid:9)
` AO1N 59/10; A61K 33/16
`[51] Int. CI.4 (cid:9)
` AO1N 59/10; A61K 33/16
`[51] Int. Cl.4 .................... .. A01N 59/10; A61K 33/16
`[52] U.S. Cl. (cid:9)
` 424/151; 424/449;
`[52] U.S. Cl. (cid:9)
` 424/151; 424/449;
`[52] U.S. Cl. .................................. .. 424/151; 424/449;
`424/435
`424/435
`424/435
`[58] Field of Search (cid:9)
` 424/21, 28, 449, 435,
`[58] Field of Search (cid:9)
` 424/21, 28, 449, 435,
`[58] Field of Search ................. .. 424/21, 28, 449, 435,
`424/ 151
`424/151
`424/151
`
`[56]
`[56]
`[56]
`
`References Cited
`References Cited
`References Cited
`U.S. PATENT DOCUMENTS
`U.S. PATENT DOCUMENTS
`U.S. PATENT DOCUMENTS
`4,292,299 9/1981 Suzuki et al. (cid:9)
` 424/16
`4,292,299 9/1981 Suzuki et al. (cid:9)
` 424/16
`4,292,299 9/1981 Suzuki et a1. ....................... .. 424/16
`4,421,738 12/1983 Yamigawa et al. (cid:9)
`4,421,738 12/1983 Yamigawa et al. (cid:9)
`4,421,738 12/1983 Yamigawa et a1.
`424/21
` 424/21
` 424/21
`4,517,173 5/1985 Kizawa et al. (cid:9)
` 424/16
`4,517,173 5/1985 Kizawa et al. (cid:9)
` 424/16
`4,517,173 5/1985 Kizawa et al. ...................... .. 424/16
`Primary Examiner-Peter F. Kulkosky
`Primary Examiner—Peter F. Kulkosky
`Primary Examiner—Peter F. Kulkosky
`[57]
`ABSTRACT
`[57]
`ABSTRACT
`[57]
`ABSTRACT
`A bioadhesive extruded single or multi-layered thin
`A bioadhesive extruded single or multi-layered thin
`A bioadhesive extruded single or multi-layered thin
`?lm, especially useful in intra-oral controlled-releasing
`film, especially useful in intra-oral controlled-releasing
`film, especially useful in intra-oral controlled-releasing
`delivery, having a water soluble or swellable polymer
`delivery, having a water soluble or swellable polymer
`delivery, having a water soluble or swellable polymer
`matrix bioadhesive layer which can adhere to a wet
`matrix bioadhesive layer which can adhere to a wet
`matrix bioadhesive layer which can adhere to a wet
`mucous surface and which bioadhesive layer consists
`mucous surface and which bioadhesive layer consists
`mucous surface and which bioadhesive layer consists
`essentially of 40-95% by weight of a hydroxypropyl
`essentially of 40-95% by weight of a hydroxypropyl
`essentially of 40-95% by weight of a hydroxypropyl
`cellulose, 5-60% of a homopolymer of ethylene oxide,
`cellulose, 5-60% of a homopolymer of ethylene oxide,
`cellulose, 5-60% of a homopolymer of ethylene oxide,
`0-10% of a water-insoluble polymer such as ethyl cellu-
`0-10% of a water-insoluble polymer such as ethyl cellu-
`0-10% of a water-insoluble polymer such as ethyl cellu
`lose, propyl cellulose, polyethylene and polypropylene,
`lose, propyl cellulose, polyethylene and polypropylene,
`lose, propyl cellulose, polyethylene and polypropylene,
`and 2-10% of a plasticizer, said ?lm having incorpo
`and 2-10% of a plasticizer, said film having incorpo-
`and 2-10% of a plasticizer, said film having incorpo-
`rated therein a medicament, e.g., anesthetics, analgesics,
`rated therein a medicament, e.g., anesthetics, analgesics,
`rated therein a medicament, e-g-, anesthetics, analgesics,
`anticaries agents, anti-inflammatories, antihistamines,
`anticaries agents, anti-inflammatories, antihistamines,
`antiearies agents, anti-in?ammatories, antihistamines,
`antibiotics, antibacterials, fungistats, etc.
`antibiotics, antibacterials, fungistats, etc.
`antibiotics, antibacterials, fungistats, etc.
`
`9 Claims, N0 Drawings
`9 Claims, No Drawings
`9 Claims, No Drawings
`
`Par Pharm., Inc., et al.
`Exhibit 1014
`Page 001
`
`(cid:9)
`(cid:9)
`

`

`1
`1
`1
`
`BIOADHESIVE EXTRUDED FILM FOR
`BIOADHESIVE EXTRUDED FILM FOR
`BIOADHESIVE EXTRUDED FILM FOR
`INTRA-ORAL DRUG DELIVERY AND PROCESS
`INTRA-ORAL DRUG DELIVERY AND PROCESS
`INTRA-ORAL DRUG DELIVERY AND PROCESS
`
`5
`5
`
`4,713,243
`4,713,243
`4,713,243
`2
`2
`2
`The prior art products and delivery systems de
`The prior art products and delivery systems de-
`The prior art products and delivery systems de-
`scribed above are useful but have the following disad
`scribed above are useful but have the following disad-
`scribed above are useful but have the following disad-
`vantages:
`vantages:
`vantages:
`Tablets, appliances, hollow ?bers are “bulky” in the
`Tablets, appliances, hollow fibers are "bulky" in the
`Tablets, appliances, hollow fibers are "bulky" in the
`mouth, are difficult to keep in place and inconve-
`mouth, are difficult to keep in place and inconve-
`mouth, are dif?cult to keep in place and inconve
`nient to apply.
`nient to apply.
`nient to apply.
`Ethyl cellulose and/or silicone films do not adhere to
`Ethyl cellulose and/or silicone films do not adhere to
`Ethyl cellulose and/or silicone ?lms do not adhere to
`mucosal tissue.
`mucosal tissue.
`mucosal tissue.
`Ointments (i.e., ORABASE*) have an unpleasant feel
`Ointments (i.e., ORABASE*) have an unpleasant feel
`Ointments (i.e., ORABASE*) have an unpleasant feel
`and do not last very long.
`and do not last very long.
`and do not last very long.
`Except for ORABASE*, all the foregoing systems
`Except for ORABASE*, all the foregoing systems
`Except for ORABASE*, all the foregoing systems
`require professional application to the tooth or
`require professional application to the tooth or
`require professional application to the tooth or
`periodontal pockets.
`periodontal pockets.
`periodontal pockets.
`The bioadhesive ?lm of the present invention alleviates
`The bioadhesive film of the present invention alleviates
`The bioadhesive film of the present invention alleviates
`many of the above problems. It may be applied easily by
`many of the above problems. It may be applied easily by
`many of the above problems. It may be applied easily by
`the consumer. It has very little or no mouthfeel, it has
`the consumer. It has very little or no mouthfeel, it has
`the consumer. It has very little or no mouthfeel, it has
`good adhesion to the mucosal tissues, and provides
`good adhesion to the mucosal tissues, and provides
`good adhesion to the mucosal tissues, and provides
`controlled release of the medicament.
`controlled release of the medicament.
`controlled release of the medicament.
`
`OBJECT OF THE INVENTION
`OBJECT OF THE INVENTION
`OBJECT OF THE INVENTION
`It is an object of this invention to provide an extruded
`It is an object of this invention to provide an extruded
`It is an object of this invention to provide an extruded‘
`film that is an effective and convenient intra-oral drug
`film that is an effective and convenient intra-oral drug
`?lm that is an effective and convenient intra-oral drug
`delivery system and method for applying and delivering
`delivery system and method for applying and delivering
`delivery system and method for applying and delivering
`controlled dosages of therapeutic agents into the oral
`controlled dosages of therapeutic agents into the oral
`controlled dosages of therapeutic agents into the oral
`cavity. This technology may also be extended for con
`25 cavity. This technology may also be extended for con-
`25 cavity. This technology may also be extended for con-
`trolled drug delivery in skin care, gynecological appli
`trolled drug delivery in skin care, gynecological appli-
`trolled drug delivery in skin care, gynecological appli-
`cations, wound care and like uses.
`cations, wound care and like uses.
`cations, wound care and like uses.
`
`BACKGROUND OF THE INVENTION
`BACKGROUND OF THE INVENTION
`BACKGROUND OF THE INVENTION
`1. Field of the Invention
`1. Field of the Invention
`1. Field of the Invention
`The present invention relates to a controlled-releas-
`The present invention relates to a controlled-releas-
`The present invention relates to a controlled-releas
`ing medicament-containing preparation for intra-oral
`ing medicament-containing preparation for intra-oral
`ing medicament-containing preparation for intra-oral
`use, and is more especially concerned with such a prep- 10
`use, and is more especially concerned with such a prep- 10
`use, and is more especially concerned with such a prep
`aration (and the process of using it) in the form of a very
`aration (and the process of using it) in the form of a very
`aration (and the process of using it) in the form of a very
`thin extruded thermoplastic film (which can be in single
`thin extruded thermoplastic film (which can be in single
`thin extruded thermoplastic ?lm (which can be in single
`layer or laminated multi-layer form) having at least one
`layer or laminated multi-layer form) having at least one
`‘ layer or laminated multi-layer form) having at least one
`bioadhesive layer containing 40-95% of a thermoplastic
`bioadhesive layer containing 40-95% of a thermoplastic
`bioadhesive layer containing 40-95% of a thermoplastic
`cellulose ether and 5—60% of a homopolymer of ethyl
`cellulose ether and 5-60% of a homopolymer of ethyl- 15
`cellulose ether and 5-60% of a homopolymer of ethyl- 15
`ene oxide which can adhere to the mucosa of the oral
`ene oxide which can adhere to the mucosa of the oral
`ene oxide which can adhere to the mucosa of the oral
`cavity. The extruded ?lm drug delivery system of the
`cavity. The extruded film drug delivery system of the
`cavity. The extruded film drug delivery system of the
`present invention, which has incorporated therein the
`present invention, which has incorporated therein the
`present invention, which has incorporated therein the
`medicament to be dispensed, is so thin and flexible when
`medicament to be dispensed, is so thin and flexible when
`medicament to be dispensed, is so thin and ?exible when
`20
`20
`wet as to be unobtrusive to the patient after it has been
`wet as to be unobtrusive to the patient after it has been
`wet as to be unobtrusive to the patient after it has been
`properly positioned and placed in the mouth.
`properly positioned and placed in the mouth.
`properly positioned and placed in the mouth.
`2. Description of the Prior Art
`2. Description of the Prior Art
`2. Description of the Prior Art
`Several systems have previously been described
`Several systems have previously been described
`Several systems have previously been described
`which pertain to the delivery of drugs into the oral
`which pertain to the delivery of drugs into the oral
`which pertain to the delivery of drugs into the oral
`cavity. These include:
`cavity. These include:
`cavity. These include:
`1. Treatment of periodontal disease with tetracycline,
`1. Treatment of periodontal disease with tetracycline,
`1. Treatment of periodontal disease with tetracycline,
`chlorhexidine or metronidazole loaded into hollow
`chlorhexidine or metronidazole loaded into hollow
`chlorhexidine or metronidazole loaded into hollow
`cellulose acetate fibers. These fibers are packed in the
`cellulose acetate fibers. These fibers are packed in the
`cellulose acetate ?bers. These ?bers are packed in the
`periodontal pockets and provide controlled release of
`periodontal pockets and provide controlled release of
`periodontal pockets and provide controlled release of
`30
`30
`the drug to the infected area.
`the drug to the infected area.
`the drug to the infected area.
`2. Cast ?lms containing ethyl cellulose/propylene gly
`2. Cast films containing ethyl cellulose/propylene gly-
`2. Cast films containing ethyl cellulose/propylene gly-
`col with chlorhexidine or metronidazole for treat-
`col with chlorhexidine or metronidazole for treat-
`col with chlorhexidine or metronidazole for treat
`ment of periodontal disease.
`ment of periodontal disease.
`ment of periodontal disease.
`3. An orthodontic appliance with a hydroxyethyl me-
`3. An orthodontic appliance with a hydroxyethyl me-
`3. An orthodontic appliance with a hydroxyethyl me
`thacrylate/ methyl methacrylate copolymer (HE
`thacrylate/methyl methacrylate copolymer (HE-
`thacrylate/methyl methacrylate copolymer (HE-
`MA/MMA) matrix. Sodium fluoride is incorporated
`MA/MMA) matrix. Sodium fluoride is incorporated
`MA/MMA) matrix. Sodium fluoride is incorporated
`into the HEMA/MMA matrix to provide sustained
`into the HEMA/MMA matrix to provide sustained
`into the HEMA/MMA matrix to provide sustained
`?uoride release and enhanced anticaries activity.
`fluoride release and enhanced anticaries activity.
`fluoride release and enhanced anticaries activity.
`HEMA/MMA with fluoride may also be attached to 40
`HEMA/MMA with fluoride may also be attached to 40
`HEMA/MMA with ?uoride may also be attached to
`the tooth in the form of a wafer-like tablet.
`the tooth in the form of a wafer-like tablet.
`the tooth in the form of a wafer-like tablet.
`4. Silicone/ethyl cellulose/polyethylene glycol ?lms
`4. Silicone/ethyl cellulose/polyethylene glycol films
`4. Silicone/ethyl cellulose/polyethylene glycol films
`containing sodium fluoride are applied as coatings on
`containing sodium fluoride are applied as coatings on
`containing sodium fluoride are applied as coatings on
`orthodontic bands or in chewing gum. Controlled
`orthodontic bands or in chewing gum. Controlled
`orthodontic bands or in chewing gum. Controlled
`release of fluoride and anticaries activity is claimed.
`release of fluoride and anticaries activity is claimed.
`release of ?uoride and anticaries activity is claimed.
`The above systems are discussed in the "The Compen-
`The above systems are discussed in the "The Compen-
`The above systems are discussed in the “The Compen
`dium of Continuing Education” Vol VI, No. 1, January
`dium of Continuing Education" Vol VI, No. 1, January
`dium of Continuing Education" Vol VI, No. 1, January
`1985 p. 27-36 review article "Controlled Drug Deliv-
`1985 p. 27-36 review article "Controlled Drug Deliv-
`1985 p. 27-36 review article “Controlled Drug Deliv
`ery: A New Means of Treatment of Dental Disease", by
`ery: A New Means of Treatment of Dental Disease", by
`ery: A New Means of Treatment of Dental Disease”, by
`J. Max Goodson, D.D.S., Ph.D. of the Forsyth Dental
`J. Max Goodson, D.D.S., Ph.D. of the Forsyth Dental
`J. Max Goodson, D.D.S., Ph.D. of the Forsyth Dental
`Center. Other systems, described in GB patent applica
`Center. Other systems, described in GB patent applica-
`Center. Other systems, described in GB patent applica-
`tion No. 2,042,888 and U.S. Pat. Nos.
`tion No. 2,042,888 and U.S. Pat. Nos.
`tion
`No.
`2,042,888
`and
`U.S.
`Pat.
`Nos.
`4,292,299/4,226,848 (Teijin Ltd., Japan), use combina-
`4,292,299/4,226,848 (Teijin Ltd., Japan), use combina-
`4,292,299/4,226,848 (T eijin Ltd., Japan), use combina
`tions of cellulosic and polyacrylate polymers. The pre
`tions of cellulosic and polyacrylate polymers. The pre-
`tions of cellulosic and polyacrylate polymers. The pre-
`ferred materials are hydroxypropyl cellulose ("Klucel")
`ferred materials are hydroxypropyl cellulose ("Klucel")
`ferred materials are hydroxypropyl cellulose (“Klucel”)
`and a copolymer of acrylic acid ("Carbopol") that is
`and a copolymer of acrylic acid ("Carbopol") that is
`and a copolymer of acrylic acid (“Carbopol”) that is
`administered in the form of thin tablets (discs), granules
`administered in the form of thin tablets (discs), granules
`administered in the form of thin tablets (discs), granules
`or powder. Other polymers that might be added are
`or powder. Other polymers that might be added are
`or powder. Other polymers that might be added are
`vinyl copolymers, polysaccharides, gelatin and colla
`vinyl copolymers, polysaccharides, gelatin and colla-
`vinyl copolymers, polysaccharides, gelatin and colla-
`gen. U.S. Pat. No. 4,517,173 (Nippon Soda Co. Ltd,
`gen. U.S. Pat. No. 4,517,173 (Nippon Soda Co. Ltd,
`gen. U.S. Pat. No. 4,517,173 (Nippon Soda Co. Ltd,
`Japan) uses various celluloses in a multi-layered non-
`Japan) uses various celluloses in a multi-layered non-
`Japan) uses various 'celluloses in a multi-layered non
`extruded cast film preparation.
`extruded cast film preparation.
`extruded cast ?lm preparation.
`Examples of prior art products currently on the mar-
`Examples of prior art products currently on the mar-
`Examples of prior art products currently on the mar
`ket include ointments such as ORABASE* with Benzo- 65
`ket include ointments such as ORABASE* with Benzo- 65
`ket include ointments such as ORABASE* with Benzo
`caine (Squibb), Kenalog* (Triamcinolone Acetonide) in
`caine (Squibb), Kenalog* (Triamcinolone Acetonide) in
`caine (Squibb), Kenalog* (Triamcinolone Acetonide) in
`ORABASE* (Squibb) and Mycostatin* (Nystatin) oint
`ORABASE* (Squibb) and Mycostatin* (Nystatin) oint-
`ORABASE* (Squibb) and Mycostatin* (Nystatin) oint-
`ment (Squibb).
`ment (Squibb).
`ment (Squibb).
`
`35
`35
`
`45
`45
`
`SUMMARY OF THE INVENTION
`SUMMARY OF THE INVENTION
`SUMMARY OF THE INVENTION
`The invention involves a pharmaceutically accept
`The invention involves a pharmaceutically accept-
`The invention involves a pharmaceutically accept-
`able controlled-releasing medicament-containing ex
`able controlled-releasing medicament-containing ex-
`able controlled-releasing medicament-containing ex-
`truded single or multi-layered thin ?lm, capable of ad
`truded single or multi-layered thin film, capable of ad-
`truded single or multi-layered thin film, capable of ad-
`hering to a wet mucous surface, comprising a water
`hering to a wet mucous surface, comprising a water
`hering to a wet mucous surface, comprising a water
`soluble or swellable polymer matrix bioadhesive layer
`soluble or swellable polymer matrix bioadhesive layer
`soluble or swellable polymer matrix bioadhesive layer
`which can adhere to a wet mucous surface and which
`which can adhere to a wet mucous surface and which
`which can adhere to a wet mucous surface and which
`bioadhesive layer consists essentially of 40-95% by
`bioadhesive layer consists essentially of 40-95% by
`bioadhesive layer consists essentially of 40-95% by
`weight of hydroxypropyl cellulose 5—60% of a homo
`weight of hydroxypropyl cellulose 5-60% of a homo-
`weight of hydroxypropyl cellulose 5-60% of a homo-
`polymer of ethylene oxide, 0-10% of a water-insoluble
`polymer of ethylene oxide, 0-10% of a water-insoluble
`polymer of ethylene oxide, 0-10% of a water-insoluble
`polymer selected from the group consisting of ethyl
`polymer selected from the group consisting of ethyl
`polymer selected from the group consisting of ethyl
`cellulose, propyl cellulose, polyethylene and polypro
`cellulose, propyl cellulose, polyethylene and polypro-
`cellulose, propyl cellulose, polyethylene and polypro-
`pylene, and 2-10% of a plasticizer, said ?lm having
`pylene, and 2-10% of a plasticizer, said film having
`pylene, and 2-10% of a plasticizer, said film having
`incorporated therein a pharmaceutically effective
`incorporated therein a pharmaceutically effective
`incorporated therein a pharmaceutically effective
`amount of said medicament.
`amount of said medicament.
`amount of said medicament.
`The present invention is directed to an extruded sin-
`The present invention is directed to an extruded sin-
`The present invention is directed to an extruded sin
`gle or multi-layered laminated thin (1-10 mils or
`gle or multi-layered laminated thin (1-10 mils or
`gle or multi-layered laminated thin (l-lO mils or
`0.025-O.25 mm) ?lm, composed of selected water solu
`0.025-0.25 mm) film, composed of selected water solu-
`0.025-0.25 mm) film, composed of selected water solu-
`ble and/or insoluble polymers. Various therapeutic
`ble and/or insoluble polymers. Various therapeutic
`ble and/or insoluble polymers. Various therapeutic
`agents are incorporated into the ?lm during manufac
`agents are incorporated into the film during manufac-
`agents are incorporated into the film during manufac-
`ture which are useful for treatment of oral disorders
`ture which are useful for treatment of oral disorders
`ture which are useful for treatment of oral disorders
`(i.e., denture discomfort, caries, periodontal disease,
`(i.e., denture discomfort, caries, periodontal disease,
`(i.e., denture discomfort, caries, periodontal disease,
`aphthous ulcers, etc.).
`aphthous ulcers, etc.).
`aphthous ulcers, etc.).
`The extruded film of the present invention must have
`The extruded film of the present invention must have
`The extruded ?lm of the present invention must have
`at least one bioadhesive layer, but may also have a reser-
`at least one bioadhesive layer, but may also have a reser-
`at least one bioadhesive layer, but may also have a reser
`voir layer and/or an outer protective barrier membrane
`voir layer and/or an outer protective barrier membrane
`voir layer and/ or an outer protective barrier membrane
`layer. The therapeutic agent may be incorporated into
`layer. The therapeutic agent may be incorporated into
`layer. The therapeutic agent may be incorporated into
`any or all of the layers. When properly formulated and
`any or all of the layers. When properly formulated and
`any or all of the layers. When properly formulated and
`fabricated, these films will adhere to wet mucosal sur-
`fabricated, these films will adhere to wet mucosal sur-
`fabricated, these ?lms will adhere to wet mucosal sur
`faces, provide a protective barrier for injured tissue and
`faces, provide a protective barrier for injured tissue and
`faces, provide a protective barrier for injured tissue and
`deliver controlled/sustained dosages of medication to
`deliver controlled/sustained dosages of medication to
`deliver controlled/sustained dosages of medication to
`60
`60
`the infected areas. The film may be designed for local-
`the infected areas. The film may be designed for local-
`60 the infected areas. The ?lm may be designed for local
`ized drug delivery (i.e., the periodontal pocket, an aph
`ized drug delivery (i.e., the periodontal pocket, an aph-
`ized drug delivery (i.e., the periodontal pocket, an aph-
`thous lesion), or may allow diffusion of the drug into the
`thous lesion), or may allow diffusion of the drug into the
`thous lesion), or may allow diffusion of the drug into the
`oral cavity.
`oral cavity.
`oral cavity.
`~
`An example of a non-localized system would be the
`An example of a non-localized system would be the
`An example of a non-localized system would be the
`delivery of sodium fluoride for caries prevention. A
`delivery of sodium fluoride for caries prevention. A
`delivery of sodium ?uoride for caries prevention. A
`single or laminated film with good adhesion to the tooth
`single or laminated film with good adhesion to the tooth
`single or laminated ?lm with good adhesion to the tooth
`or mucosal tissue may be employed in which the fluo-
`or mucosal tissue may be employed in which the fluo-
`or mucosal tissue may be employed in which the ?uo
`ride release rates may be controlled by varying film
`ride release rates may be controlled by varying film
`ride release rates may be controlled by varying ?lm
`
`50
`50
`
`55
`55
`
`Par Pharm., Inc., et al.
`Exhibit 1014
`Page 002
`
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`

`

`4,713,243
`4,713,243
`4,713,243
`4
`4
`4
`3
`3
`3
`then laminated together, so that the ?nal multi-layered
`then laminated together, so that the final multi-layered
`then laminated together, so that the final multi-layered
`solubilities and/or concentration of fluoride in a multi-
`solubilities and/or concentration of fluoride in a multi-
`solubilities and/or concentration of ?uoride in a multi
`film is still very thin. The films of the present invention
`film is still very thin. The films of the present invention
`?lm is still very thin. The ?lms of the present invention
`layered ?lm.
`layered film.
`layered film.
`can be made in thicknesses of only 1-10 mils or
`can be made in thicknesses of only 1-10 mils or
`An example of a localized application of medication
`An example of a localized application of medication
`can be made in thicknesses of only 1-10 mils or
`An example of a localized application of medication
`0.025-0.25 mm. The films are so thin that when placed
`0.025-0.25 mm. The films are so thin that when placed
`0.025-0.25 mm. The ?lms are so thin that when placed
`would be in the treatment of aphthous lesions. A lami-
`would be in the treatment of aphthous lesions. A lami-
`would be in the treatment of aphthous lesions. A lami
`in the mouth after they become wet they soon become
`in the mouth after they become wet they soon become
`in the mouth after they become wet they soon become
`nated two layer ?lm with benzocaine incorporated into
`nated two layer film with benzocaine incorporated into 5
`nated two layer film with benzocaine incorporated into 5
`unobtrusive, and hardly noticeable by most patients.
`unobtrusive, and hardly noticeable by most patients.
`unobtrusive, and hardly noticeable by most patients.
`the adhesive layer would directly contact the injured
`the adhesive layer would directly contact the injured
`the adhesive layer would directly contact the injured
`The film must always have a bioadhesive layer,
`The film must always have a bioadhesive layer,
`The ?lm must always have a bioadhesive layer,
`mucosa. The outer layer would consist of non-soluble/-
`mucosa. The outer layer would consist of non-soluble/-
`mucosa. The outer layer would consist of non-soluble/
`non-adhesive polymers that provide durability, protec
`which enables it to adhere to wet mucosal surfaces. The
`which enables it to adhere to wet mucosal surfaces. The
`which enables it to adhere to wet mucosal surfaces. The
`non-adhesive polymers that provide durability, protec-
`non-adhesive polymers that provide durability, protec-
`bioadhesive layer has 40-95% of hydroxypropyl cellu-
`bioadhesive layer has 40-95% of hydroxypropyl cellu-
`bioadhesive layer has 40-95% of hydroxypropyl cellu
`tion and directs the delivery of benzocaine toward the
`tion and directs the delivery of benzocaine toward the
`tion and directs the delivery of benzocaine toward the
`lose, 5-60% of a homopolymer of ethylene oxide and
`lose, 5-60% of a homopolymer of ethylene oxide and
`lose, 5-60% of a homopolymer of ethylene oxide and
`lesion. (cid:9)
`lesion. (cid:9)
`lesion.
`2-10% of a glycol plasticizer (all percents are % by
`2-10% of a glycol plasticizer (all percents are % by
`2-l0% of a glycol plasticizer (all percents are % by
`The film forming polymers that are useful in this
`The film forming polymers that are useful in this
`The ?lm forming polymers that are useful in this
`weight).
`weight).
`weight).
`invention are selected from pharmaceutical grade mate-
`invention are selected from pharmaceutical grade mate-
`invention are selected from pharmaceutical grade mate
`The Hydroxypropyl cellulose (HPC), useful for pur
`The Hydroxypropyl cellulose (HPC), useful for pur-
`The Hydroxypropyl cellulose (HPC), useful for pur-
`rials, or those that are considered generally regarded as
`rials, or those that are considered generally regarded as
`rials, or those that are considered generally regarded as
`poses of the present invention is commercially available
`poses of the present invention is commercially available
`poses of the present invention is commercially available
`safe (GRAS) as food additives. They include, hydroxy
`safe (GRAS) as food additives. They include, hydroxy-
`safe (GRAS) as food additives. They include, hydroxy-
`propyl cellulose, and polyethylene oxide homopoly
`from Hercules, Inc. (Wilmington, DE) under the trade
`from Hercules, Inc. (Wilmington, DE) under the trade-
`from Hercules, Inc. (Wilmington, DE) under the trade-
`propyl cellulose, and polyethylene oxide homopoly- 15
`propyl cellulose, and polyethylene oxide homopoly- 15
`5
`name KLUCEL*. Preferred grades include Klucel MF,
`name KLUCEL*. Preferred grades include Klucel MF,
`name KLUCEL". Preferred grades include Klucel MF,
`mers. Small amounts of other polymers, e.g., polyvinyl
`mers. Small amounts of other polymers, e.g., polyvinyl
`mers. Small amounts of other polymers, e.g., polyvinyl
`with a molecular weight around 600,000 and having a
`with a molecular weight around 600,000 and having a
`with a molecular weight around 600,000 and having a
`ether-maleic acid copolymers and the like may be used
`ether-maleic acid copolymers and the like may be used
`ether-maleic acid copolymers and the like may be used
`viscosity of 4,000-6,000 cps (Brookfield) in 2 percent
`viscosity of 4,000-6,000 cps (Brookfield) in 2 percent
`viscosity of 4,000—6,000 cps (Brook?eld) in 2 percent
`in small amounts as well, replacing a small portion of
`in small amounts as well, replacing a small portion of
`in small amounts as well, replacing a small portion of
`water solutions, or Klucel HF, having a molecular
`water solutions, or Klucel HF, having a molecular
`the other polymers. The above materials are either
`the other polymers. The above materials are either
`water solutions, or Klucel HF, having a molecular
`the other polymers. The above materials are either
`weight around 1,000,000 and viscosity of 1500-2500 cps
`weight around 1,000,000 and viscosity of 1500-2500 cps
`weight around 1,000,000 and viscosity of 1500-2500 cps
`water soluble of swellable and are most useful in the 20
`water soluble of swellable and are most useful in the 20
`water soluble of swellable and are most useful in the
`20
`in 1 percent water solution. In general, any HPC having
`in 1 percent water solution. In general, any HPC having
`bioadhesive layer of the ?lm. Various non-soluble poly
`' in 1 percent water solution. In general, any .HPC having
`bioadhesive layer of the film. Various non-soluble poly-
`bioadhesive layer of the film. Various non-soluble poly-
`a Molecular Weight above about 100,000 is useful for
`a Molecular Weight above about 100,000 is useful for
`a Molecular Weight above about 100,000 is useful for
`mers may also be incorporated for modification of the
`mers may also be incorporated for modification of the
`mers may also be incorporated for modification of the
`purposes of this invention.
`purposes of this invention.
`film's permeability properties, such as ethyl cellulose,
`film's permeability properties, such as ethyl cellulose,
`?lm’s permeability properties, such as ethyl cellulose,
`purposes of this invention.
`The homopolymer of ethylene oxide useful for pur
`The homopolymer of ethylene oxide useful for pur-
`The homopolymer of ethylene oxide useful for pur-
`propyl cellulose, polyethylene, polypropylene and car
`propyl cellulose, polyethylene, polypropylene and car-
`propyl cellulose, polyethylene, polypropylene and car-
`boxymethylcellulose (free acid). By varying the ratios
`poses of the present invention has a relatively high
`poses of the present invention has a relatively high
`poses of the present invention has a relatively high
`boxymethylcellulose (free acid). By varying the ratios 25
`boxymethylcellulose (free acid). By varying the ratios 25
`25
`molecular weight, i.e., above 100,000 and preferably
`molecular weight, i.e., above 100,000 and preferably
`molecular weight, i.e., above 100,000 and preferably
`of the above polymers both the solubility and the adhe
`of the above polymers both the solubility and the adhe-
`of the above polymers both the solubility and the adhe-
`above 3,000,000. Such polymers‘ are commercially
`above 3,000,000. Such polymers are commercially
`above 3,000,000. Such polymers are commercially
`sive properties of each layer of ?lm may be controlled.
`sive properties of each layer of film may be controlled.
`sive properties of each layer of film may be controlled.
`available from various sources. The Union Carbide
`available from various sources. The Union Carbide
`Therefore, dep