United States Patent 1
`Schiraldi et al.
`
`(11] Patent Number:
`[45] Date of Patent:
`
`4,713,243
`Dec. 15, 1987
`
`[54] BIOADHESIVE EXTRUDED FILM FOR
`INTRA-ORAL DRUG DELIVERY AND
`Pp
`
`[75]
`
`Inventors: Michael T, Schiraldi, East
`Brunswick, N.J.; Martin M. Perl,
`Brooklyn, N.Y.; Howard Rubin,
`Rockaway, N.J.
`
`[73] Assignee:
`
`Johnson & Johnson Products,Inc.,
`New Brunswick, N.J.
`
`[21] Appl. No.: 874,904
`
`:
`
`[22] Filed:
`
`Jun. 16, 1986
`
`[St] nb CMF sc secccccaics AOIN 59/10; A6IK 33/16
`[52] US. C0. ceceeccetseeeeeeeeeeees 424/151; 424/449,
`424/435
`[58] Field of Search...............0. 424/21, 28, 449, 435,
`424/151
`
`[56]
`
`References Cited
`U.S. PATENT DOCUMENTS
`9/1981 Suzuki et al. ccs 424/16
`4,292,299
`
`wees 424/21
`4,421,738 12/1983 Yamigawaetal. ..
`4,517,173
`5/1985 Kizawa et aly scsssecssssesnseees 424/16
`:
`.
`Primary Examiner—Peter F. Kulkosky
`[57]
`ABSTRACT
`A bioadhesive extruded single or multi-layered thin
`film, especially useful in intra-oral controlled-releasing
`delivery, having a water soluble or swellable polymer
`matrix bioadhesive layer which can adhere to a wet
`mucous surface and which bioadhesive layer consists
`essentially of 40-95% by weight of a hydroxypropyl
`cellulose, 5-60% of a homopolymerof ethylene oxide,
`0-10% of a water-insoluble polymersuch as ethyl cellu-
`lose, propyl cellulose, polyethylene and polypropylene,
`and 2-10% ofa plasticizer, said film having incorpo-
`rated therein a medicament,e.g., anesthetics, analgesics,
`anticaries agents, anti-inflammatories, antihistamines,
`antibiotics, antibacterials, fungistats, etc.
`
`9 Claims, No Drawings
`
`Dr. Reddy's - EX1014
`Page 1
`
`Dr. Reddy's - EX1014
`Page 1
`
`

`

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

`

`__
`
`3
`solubilities and/or concentration of fluoride in a multi-
`layered film.
`An example ofa localized application of medication
`would be in the treatment of aphthouslesions. A lami-
`nated twolayer film with benzocaine incorporated into
`the adhesive layer would directly contact the injured
`mucosa. The outer layer would consist of non-soluble/-
`non-adhesive polymers that provide durability, protec-
`tion and directs the delivery of benzocaine toward the
`lesion.
`The film forming polymers that are useful in this
`invention are selected from pharmaceutical grade mate-
`rials, or those that are considered generally regarded as
`safe (GRAS)as food additives. They include, hydroxy-
`propyl cellulose, and polyethylene oxide homopoly-
`mers. Small amounts of other polymers, e.g., polyvinyl
`ether-maleic acid copolymers andthe like may be used
`in small amounts as well, replacing a small portion of
`the other polymers. The above materials are either
`water soluble of swellable and are most useful in the
`bioadhesivelayer of the film. Various non-soluble poly-
`mers may also be incorporated for modification of the
`film’s permeability properties, such as ethyl cellulose,
`propyl cellulose, polyethylene, polypropylene and car-
`boxymethylcellulose (free acid). By varying the ratios
`of the above polymers both the solubility and the adhe-
`sive properties of each layer offilm may be controlled.
`Therefore, depending on the desired delivery rate, the
`type of disorder to be treated, the area to be treated and
`the medication being administered it is possible to cus-
`tom design the film by selecting and blending various
`polymers. Thefinal film product mayalso be fabricated
`into flexible tapes of varied thickness and width, “spots”
`of different sizes and shapes or other pre-shaped forms.
`‘The medicaments and pharmaceutical agents set forth
`in the prior art discussed above may generally be deliv-
`ered by the drug delivery system of the present inven-
`tion. Usable medicaments are those which are capable
`of withstanding the heats and pressures generated in the
`extrusion process involved in making the film of the
`present invention. Preferred medicaments include:
`Anesthetics/Analgesics-benzocaine, dyclonine HCl,
`phenol, aspirin, phenacetin, acetaminophen, potas-
`sium nitrate, etc.
`sodium mono-
`Anticaries Agents-sodium fluoride,
`fluorophosphate, stannousfluoride, etc.
`Anti-inflammatories-hydrocortisone acetate, triamcino-
`lone acetonide, dipotassium, glycyrrhizinate,etc.
`Antihistamines-chlorpheniramine maleate, ephedrine
`HCL, diphenhydramine HCL, etc.
`Antibiotics-i.e., tetracycline, doxycycline hyclate, me-
`clocycline, minocycline,etc.
`Antibacterials-chlorhexidine, cetyl pyridinium chlo-
`ride, benzethonium chloride, dequalinium chloride,
`silver sulfadiazene, phenol, thymol, hexedine, hexeti-
`dine, alexidine, etc.
`Fungistats-nystatin, miconazole, ketoconazole,etc.
`The aboveare illustrative examples of therapeutic
`agents that are used to treat oral disorders. The present
`invention is not to be limited to these specific materials
`especially whereit is intended to deliver drug outside of
`the oral cavity e.g. to skin where other drugs may be
`desirable.
`Thefilm of the present invention has the advantage of
`being an extruded film, rather than a cast film. When a
`multi-layered film is involved, the different layers can
`be coextruded and then laminated together, or else each
`layer can be separately extruded one on the other, and
`
`—_ 5
`
`20
`
`25
`
`40
`
`45
`
`50
`
`60
`
`65
`
`4,713,243
`
`4
`then laminated together, so that the final multi-layered
`film is still very thin. The films of the present invention
`can be made in thicknesses of only 1-10 mils or
`0.025-0.25 mm. Thefilms are so thin that when placed
`in the mouth after they become wet they soon become
`unobtrusive, and hardly noticeable by most patients.
`The film must always have a bioadhesive layer,
`which enablesit to adhere to wet mucosalsurfaces. The
`bioadhesive layer has 40-95% of hydroxypropyl cellu-
`lose, 5-60% of a homopolymerof ethylene oxide and
`2-10% of a glycol plasticizer (all percents are % by
`weight).
`The Hydroxypropylcellulose (HPC), useful for pur-
`poses of the present invention is commercially available
`from Hercules, Inc. (Wilmington, DE) underthe trade-
`name KLUCEL"*. Preferred grades include Klucel MF,
`with a molecular weight around 600,000 and having a
`viscosity of 4,000-6,000 cps (Brookfield) in 2 percent
`water solutions, or Klucel HF, having a molecular
`weight around 1,000,000 and viscosity of 1500-2500 cps
`in 1 percent watersolution. In general, any HPC having
`a Molecular Weight above about 100,000 is useful for
`purposes of this invention.
`The homopolymer of ethylene oxide useful for pur-
`poses of the present invention has a relatively high
`molecular weight,
`i.e., above 100,000 and preferably
`above 3,000,000. Such polymers are commercially
`available from various sources. The Union Carbide
`Corporation material, ““Polyox WSR-301”, which has a
`molecular weight of approximately 4,000,000-5,000,000
`is most preferred for purposes of the present invention.
`The “plasticizer” useful for purposes of the present
`invention are selected from glycols such as propylene
`glycol and polyethylene glycol; polyhydric alcohols
`such as glycerin and sorbitol; glycerol esters such as
`glycerol
`triacetate;
`fatty acid triglycerides such as
`NEOBEE* M-5 and MYVEROLS*; mineral oil; vege-
`table oils such as castoroil, etc.
`For the uses for the present invention contemplated
`here, the plasticizer should be non-toxic. The purpose of
`the plasticizer is to improve polymer melt processing by
`reducing the polymer melt viscosity and to impart flexi-
`bility to the final product.
`Thepreferred plasticizer for use in the present inven-
`tion is either propylene glycol or polyethylene glycol
`(such as is available from Union Carbide Corporation as
`their series of Carbowaxes which runs from 200 to 600
`molecular weight, of which we prefer to use Carbowax
`400, which has a molecular weight of 400, average.
`In addition to the polymers and plasticizer which are
`required ingredients of the films of the present inven-
`tion, minor amounts of other non-essential but custom-'
`ary ingredients will often be used if desired, e.g., antiox-
`idants, preservatives, flavors, colorants.
`DETAILED DESCRIPTION
`
`The following examples will serve to illustrate the
`present invention in greater detail. The units shown in
`the examples are parts by weight. The thickness of the
`layers is expressed in either mils (0.001 inches) or milli-
`meters. For easy conversion, 4 mils is approximately
`equal to 0.1 mm.
`
`EXAMPLE1
`
`_ Triple Layered Laminate Containing Sodium Fluo-
`ride for Anticaries Protection
`This three layered film laminate is comprised of a
`“bioadhesive” layer, a sodium fluoride “reservoir”
`
`Page 3
`
`Page 3
`
`

`

`4,713,243
`
`6
`-continued
`
`Die Zone 1
`Die Zone 2
`Die Zone 3
`
`185
`185
`185
`
`5
`layer and, an “outer protective barrier membrane”
`layer, in which the composition and thickness of each
`layer are as shown below:
`
`Outer
`Protective
`Barrier
`% w/w
`Reservoir Membrane
`Layer
`Layer
`(1 mil)
`(1 mil)
`(0.025 mm)
`(0.025 mm)
`_
`-
`
`Ingredients
`Polyethylene oxide
`homopolymer (Union
`Carbide-Polyox* WSR-301)
`Hydroxypropy! Cellulose
`(Hercules, Inc.-Klucel* MF)
`Polyethylene (Allied
`Chemical-6A)
`(Low Density)
`Propylene Glycol, U.S.P.
`Polyethylene Glycol
`400 (Union Carbide)
`Ethyl Cellulose (Hercules,
`Inc.-NLOOF)
`Caprylic/Capric
`Triglyceride (PVO
`Incorporated-Neobee M-5)
`Sodium Fluoride, U.S.P.
`
`Bio-
`adhesive
`Layer
`(4 mils)
`(0..mm)
`60.0
`
`30.0
`
`5,0
`
`3.0
`2.0
`
`_
`
`_
`
`=
`100.0
`
`20.0
`
`24.0
`
`—
`
`-
`~
`
`59.0
`
`5.0
`
`16.0
`100.0
`
`—-
`
`-
`-
`
`69.6
`
`6.0
`
`0.4
`100.0
`
`The process used to make the above laminate was:
`a. Powder Blending-Each layer is made separately and
`all ingredients used therein except propylene glycol
`and Neobee M-S (liquid plasticizers) are placed in a
`Patterson Kelley (PK) V-blender equipped with liq-
`uid addition capabilities. The ingredients which are
`all powders are blended for approximately 10-15
`minutes while the liquid plasticizer is slowly added to
`the mix. Three separate powderblends are made, one
`for each layer.
`b. Extrusion Process-A standard Johnson 2-4 inch vi-
`nyl/polyolefin extruder equipped with a single three
`stage screw was usedto extrude the “powder blend”.
`The temperature conditions for the water soluble
`powders are howeverquite different from those used
`for vinyls and polyolefins. The temperature (°C.)
`profile for the “reservoir” and “membranelayers” of
`the triple laminate was as follows:
`
`Barrel Zone 1
`100
`Barrel Zone 2
`125
`Barrel Zone 3
`135
`Barrel Zone 4
`145
`Barrel Zone 5
`160
`Barrel Zone 6
`170
`Adapter
`180
`Die Zone 1
`180
`Die Zone 2
`180
`
`Die Zone 3 180
`
`Each layer is extruded separately with the first layer
`extruded as a “free film”. Successive layers are extruded
`onto each otherand laminated by passing them through
`heatedstainless steel rollers.
`Test Results:
`In vitro fluoride ion release studies were conducted
`on samples of the above describedtriple laminate film
`measuring 0.5 cm 1.25 cm (0.625 cm?) according to
`the following procedures:
`Thetest sample is adhered to a glass slide by prewet-
`ting the film and placing the bioadhesive layer on the
`glass surface. Theslide is then immersed in a beaker
`containing 100 ml of distilled water with continuous
`stirring, Five milliliter aliquots are withdrawn from the
`solution, at prescribed time intervals, and analyzed for’
`fluoride content with an Orion Ionanlyzer equipped
`with a fluoride specific electrode. Release rates are then
`calculated from the data.
`Theresults obtained indicated fluoriderelease rates in
`the order of 0.05-0.2 mgs/cm?/hr for 24 hours. This
`falls within the desired range for maintaining constant
`low levels of fluoride in the mouth and enhanced anti-
`caries activity. Release rates may be tailored to desired
`use levels by modification of the film composition and
`construction.
`
`EXAMPLE2
`
`Single Layer Adhesive Film Containing Hydrocorti-
`sone Acetate (0.5%) As An Anti-Inflammatory Agent
`The composition of the film, which was 0.1 mm.
`thick, was as follows:
`
`Ingredients
`% wiw
`Ethylene Oxide Homopolymer
`59.4
`(Polyox* WSR-301)
`Hydroxypropy! Cellulose
`(Klucel* MF)
`Polyethylene (AC-6A)
`Propylene Glycol
`Polyethylene Glycol 400
`Butylated Hydroxy Toluene (BHT)
`FCC(preservative)
`0.5
`Hydrocortisone Acetate
`100.0
`
`5.0
`3.0
`2.0
`0.1
`
`30.0
`
`The powder blending process and extruder conditions
`used were the sameas those described in Example I for
`the “bioadhesive layer” of the sodium fluoride trilami-
`nate. In vitro tests were performed on the abovefilm
`and demonstrated a prolonged drugrelease pattern.
`EXAMPLE3
`
`Ingredients
`Ethylene Oxide Homopolymer
`(Polyox WSR-301)
`Hydroxypropyl Cellulose
`(Klucel MF)
`
`To wiw
`39.9
`
`29.9
`
`20
`
`25
`
`35
`
`45
`
`50
`
`55
`
`65
`
`Page 4
`
`The films which had a width of 18 inches, were ex-
`truded at approximately 20 feet/minute throughaflat
`Single Layer Adhesive Film Containing Triamcino-
`lipped die. The temperatureprofile for the “bioadhesive
`lone Acetonide (0.1%) As An Anti-Inflammatory
`60
`layer” was:
`The composition of the film, which was 0.1 mm.
`thick, was as follows:
`
`Barrel Zone |
`125
`
`Barrel Zone 2
`140
`Barrel Zone 3
`165
`Barrel Zone 4
`170
`Barrel Zone 5
`185
`Barrel Zone 6
`185
`Adapter
`185
`
`Page 4
`
`

`

`4,713,243
`
`-continued
`
`Ingredients
`% w/w
`Polyethylene (AC-6A)
`5.0
`Propylene Glycol
`3.0
`Polyethylene Glycol 400
`2.0
`BHT
`0.1
`
`Triamcinolone Acetonide
`0.1
`100.0
`
`The powder blending process and extruder conditions
`used to make thefilm of this Example 3 were the same
`as those of the “bioadhesive layer” of Example I.
`Other desired active medicament ingredients may be
`incorporated into the adhesivefilms of any of Examples
`1-3 in place of the particular medicament used in said
`examples. These include Benzocaine(analgesic), Potas-
`sium nitrate (analgesic), Silver sulfadiazene (antimicro-
`bial),
`Chlorhexidine (antimicrobial), miconazole nitrate
`(antifungal), Benzethonium chloride (antimicrobial),
`Tetracycline (antibiotic) and other similar therapeutic
`compounds.
`
`EXAMPLE4
`
`_ 5
`
`25
`
`-continued
`
`100.00
`
`B.
`
`Quter protective/barrier layer
`Hydroxypropyl Cellulose
`(Klucel* MF)
`20.00
`Ethyl Cellulose
`2,00
`Polyethylene Glycol 400
`100.00
`
`78.00
`
`Part A was extruded on a Johnsonextruder followed by
`subsequent extrusion and lamination of Part B to A.
`Samples were applied to oral lesions, and provided
`profound anesthetic effects
`(lasting several hours)
`within minutes of application.
`The identical two-layer laminate may also be made
`by coextruding the inner medicated bioadhesive layer
`(Part A) and the outer protective barrier layer (Part B)
`throughseparate die slots within a coextruder and lami-
`nating the two layers together.
`EXAMPLE6
`
`Anesthetic Films with Phenol and Dyclonine HCl
`Four variations of a single layer bioadhesive film
`were made as shownbelow:
`
`
`Analgesic Films with Potassium Nitrate
`This example shows 5 variations of the film having
`Ii
`different solubilities, resulting in different release rates.
`Polyethylene oxide homo-
`59.10
`54.00
`59.70
`58.20
`polymer (Polyox* WSR-301)
`Hydroxypropyl Cellulose
`(Klucel HF)
`Ethyl!Cellulose
`Propylene Glycol, U.S.P.
`Polyethylene Glycol 400
`BHT,F.C.c.
`Phenol, U.S.P.
`Dyclonine HCl
`
`
`% wiw
`
`;
`
`Polyethylene oxide
`homopolymer (Polyox*
`WSR-301)
`‘Hydroxypropyl Cell-
`sulose, N.F. (Klucel* HF)
`‘Hydroxypropyl Cell-
`ulose, N.F. (Klucel* MF)
`“Ethyl Cellulose
`“Polyethylene Glycol 400
`_»Folyethylene Glycol 8000
`Propylene Glycol, U.S.P.
`BHT,F.C.C.
`Potassium Nitrate, F.C.C.
`
`23.75
`
`57.00
`
`55.00
`
`55.00
`
`57.00
`
`68.30 —
`
`_
`
`_
`
`=_
`
`_
`
`28.40
`
`29.90
`
`22.40
`
`22.40
`
`475
`-
`«61.90
`190
`095 —
`_
`2.85
`0.10
`08.10
`5.00
`5.00
`
`500
`62.00
`—
`3.00
`08.10
`5.00
`
`12.50
`2.00
`—
`3.00
`O10
`5.00
`
`12,50
`2.00
`Le
`3.00
`O10
`3.00
`
`The aboveingredients are blended in a Patterson-Kelly
`powder blender equipped with liquid addition capabili-
`ties. The resulting powder blend is then extruded into
`film on a Killion or Johnson vinyl extruder using pro-
`cessing procedures similar to those of the bioadhesive
`layer of Example I.
`
`EXAMPLE5
`
`Anesthetic Films with Benzocaine (Laminate)
`This is an example of a two-layer laminate. The pro-
`cessing conditions used were similar to those of the
`bioadhesive layer and outer protective barrier mem-
`brane layer of ExampleI.
`
`
`A.
`
`Inner medicated bioadhesive layer
`Polyoxyethylene Homopolymer
`(Polyox* WSR-301)
`Hydroxypropyl Cellulose, N.F.
`(Klucel* MF)
`Polyethylene (AC-6A)
`Propylene Glycol, U.S.P.
`Polyethylene Glycol 400
`BHT,F.C.c.
`Benzocaine, U.S.P.
`
`57.00
`
`28.40
`
`4.75
`2.85
`1.90
`0.10
`3.00
`
`30
`
`35
`
`29.45
`
`4.93
`2.96
`1.97
`0.09
`1.50
`=
`
`26.91
`
`4.50
`2.70
`1.80
`0.09
`_
`10,00
`
`29,75
`
`29.00
`
`4.98
`2.99
`1.99
`0.09
`ae
`0.50
`
`4.85
`251
`1.94
`0.10
`—
`3.00
`
`40
`
`45
`
`50
`
`55
`
`65
`
`Following the procedures for the bioadhesive layer of
`Example I, the powders were blended in P-K blender
`equipped with liquid addition capabilities. Resulting
`powders were extruded on a Killion laboratory-sized
`extruder.
`
`EXAMPLE 7
`
`Silver Sulfadiazene Films-Antimicrobial
`Three different single-layered bioadhesive films con-
`taining 1.0% 0.5% and 0.5% respectively ofsilver sul-
`fadiazene (SSD) were prepared on a heated Carver
`laboratory press (designed to simulate extruded condi-
`tions) as shown below.
`
`% wiw
`
`A
`60.00
`
`28.9
`
`Ingredients
`Polyethylene oxide homopolymer
`(Polyox* WSR-301)
`Hydroxypropyl Cellulose
`(Klucel* HF)
`Polyethylene (AC-6A)
`5.0
`5.0
`Propylene Glycol, U.S.P.
`3.0
`3.0
`Polyethylene Glycol 400
`2.0
`2.0
`BHT,F.C.c.
`0.1
`0.1
`
`Silver Sulfadiazine
`1.0
`0.5
`
`100.0 100.0
`
`B
`60.00
`
`29.4
`
`Effects on woundrepair and activity against StapAylo-
`coccus aureus were evaluated in the guinea pig model.
`Full-thickness excisions were inoculated with 3.8 x 105
`organisms, (Staph. aureus) and wound surface microbi-
`
`Page 5
`
`Page 5
`
`

`

`4,713,243
`
`10
`3. The extruded film of claim 2 having a thickness no
`greater than 0.25 millimeters.
`4. The extrudedfilm of claim 1, in single layer form,
`whichalso contains up to 10% by weight ofa non-solu-
`ble polymer selected from the group consisting ofethyl
`cellulose, polyethylene, polypropylene and carboxy-
`methyl cellulose free acid.
`5. The extruded film of claim 1, in multi-layer lami-
`nated form, which is addition to the bioadhesive layer
`also contains a reservoir layer in which at least a major
`portion of the medicamentis contained.
`6. The extruded multi-layer film of claim 5 in which
`the reservoir layer consists essentially of a polymer
`matrix comprised of both a water soluble or swellable
`polymer and a non-water soluble polymerselected from
`the group consisting of ethyl cellulose, propyl cellulose,
`polyethylene and polypropylene, and also hydroxypro-
`pyl cellulose.
`7. The extruded film of claim 1 in multi-layer lami-
`nated form, which in addition to the bioadhesive layer
`also contains an outer protective-barrier membrane
`layer.
`8. The extruded multi-layer film of claim 7 in which
`the outer protective-barrier membranelayer is thinner
`than the bioadhesive layer, and said outer protective
`barrier layer consists essentially of a polymer matrix of
`a major proportion of a non-water-soluble polymer
`selected from the group consisting of ethyl cellulose,
`propyl cellulose, polyethylene and polypropylene, and
`a minor proportion of hydroxypropylcellulose.
`9. The extruded multi-layer film of claim 1 in the
`form of a triple layered laminate containing sodium
`fluoride for anticaries protection having the following
`composition:
`
`Outer
`Protective
`Barrier
`% wiw
`Reservoir Membrane
`Layer
`Layer
`(0.025 mm)
`(0.025 mm)
`_
`=
`
`Bio-
`adhesive
`Layer
`(0.1 mm)
`60.0
`
`9
`ology samples taken 10 minutes and 24 hoursaftertreat-
`ment. Testfilms were placed on the wound and covered
`with BIOCLUSIVE* Transparent Dressings secured
`with elastic tape. Wound contraction was measured
`over an eight-day period using OPTOMAX* Comput-
`er-Assisted Image Analysis. The threefilms tested were
`the following:
`A. 1.0% Silver Sulfadiazene, 125° C./2 minutes/4 tons
`B. 0.5% Silver Sulfadiazene, 125° C./2 minutes/4 tons
`C. 0.5% Silver Sulfadiazene, 150° C./3 minutes/4 tons
`SILVADENE Cream and an untreated occluded
`control. The results indicated that:
`1. SILVADENE*treated woundssignificantly inhib-
`ited full-thickness wound contraction.
`2. Film A, B and C inhibited woundcontractionrelative
`to that of BIOCLUSIVE* dressed wounds.
`3. The three SSD films each permitted substantially
`faster wound contraction than that of wounds treated
`daily with SILVADENE*cream.
`4. All films were very active against S. aureus 24 hours
`after inoculation.
`The films may be scaled up by using an extruder. This
`example demonstrates the feasibility of such a film to
`perform its intended purpose. Use of a press for larger
`samples would result in a non-uniform and lower-qual-
`ity film than an extrudedfilm.
`Based on the above findings, the films were very
`effective antibacterial agents, while mildly inhibiting
`wound contraction. They offer clinicians a convenient
`and moreeffective delivery system for antimicrobials
`which can be place in wounds beneath any dressing or
`can be laminated to any acceptable dressing face.
`Whatis claimedis:
`1. A pharmaceutically acceptable controlled-releas-
`ing medicament-containing extruded single or multi-
`layered thin film, capable of adhering to a wet mucous
`surface, comprising a water soluble or swellable poly-
`mer matrix bioadhesive layer which can adhere to a wet
`mucous surface and which bioadhesive layer consists
`essentially of 40-95% by weight of a hydroxypropyl
`cellulose having a molecular weight above 100,000,
`5-60% of a homopolymerof ethylene oxide having a
`molecular weight from 3,000,000 to 5,000,000, 0-10%
`of a water-insoluble polymer selected from the group
`consisting of ethyl cellulose, propyl cellulose, polyeth-
`ylene and polypropylene, and 2-10% ofa plasticizer,
`said film having incorporated therein a pharmaceuti-
`cally effective amount of said medicament.
`2. The extrudedfilm of claim 1, madein a form which
`is so thin andflexible when wetas to be unobtrusive to
`the patient when properly positioned andplaced in the
`patients mouth.
`
`20
`
`30
`
`35
`
`45
`
`35
`
`60
`
`Ingredients
`Polyethylene oxide
`homopolymer
`(MW 3,000,000 minimum)
`Hydroxypropyl Cellulose
`(MW 1,000,000)
`Polyethylene (Low Density)
`Propylene Glycol, U.S.P.
`Polyethylene Glycol
`(MW 400)
`Ethyl Cellulose
`Caprylic/Capric
`Triglyceride
`0.4
`16.0
`—
`Sodium Fluoride
`
`
`100.0100.0 100.0
`
`30.0
`
`5.0
`3.0
`2.0
`
`-
`_
`
`20.0
`
`—
`_
`_
`
`59.0
`5.0
`
`24.0
`
`—,
`-
`=
`
`69.6
`6.0
`
`65
`
`Page 6
`
`Page 6
`
`