United States Patent [191
`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
`PROCESS
`
`[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
`
`[51]
`[52]
`
`[58]
`
`Int. Cl.4 ...................... AOlN 59/10; A61K 33/16
`U.S. Cl ..................................... 424/151; 424/449;
`424/435
`Field of Search ................... 424/21, 28, 449, 435,
`424/151
`
`[56]
`
`References Cited
`U.S. PATENT DOCUMENTS
`4,292,299 9/1981 Suzuki et al. ......................... 424/16
`4,421,738 12/1983 Yamigawa et al. ................... 424/21
`4,517,173 5/1985 Kizawa et al. ........................ 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 homopolymer of ethylene oxide,
`0-10% of a water-insoluble polymer such as ethyl cellu(cid:173)
`lose, propyl cellulose, polyethylene and polypropylene,
`and 2-10% of a plasticizer, said film having incorpo(cid:173)
`rated therein a medicament, e.g., anesthetics, analgesics,
`anticaries agents, anti-inflammatories, antihistamines,
`antibiotics, antibacterials, fungistats, etc.
`
`9 Claims, No Drawings
`
`DRL - EXHIBIT 1004
`DRL001
`
`

`
`1
`
`4,713,243
`
`BIOADHESIVE EXTRUDED FILM FOR
`INTRA-ORAL DRUG DELIVERY AND PROCESS
`
`5
`
`25
`
`BACKGROUND OF THE INVENTION
`1. Field of the Invention
`The present invention relates to a controlled-releas(cid:173)
`ing medicament-containing preparation for intra-oral
`use, and is more especially concerned with such a prep- 10
`aration (and the process of using it) in the form of a very
`thin extruded thermoplastic film (which can be in 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 homopolymer of ethyl- 15
`ene oxide which can adhere to the mucosa of the oral
`cavity. The extruded film drug delivery system of the
`present invention, which has incorporated therein the
`medicament to be dispensed, is so thin and flexible when
`wet as to be unobtrusive to the patient after it has been 20
`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 30
`the drug to the infected area.
`2. Cast films containing ethyl cellulose/propylene gly(cid:173)
`col with chlorhexidine or metronidazole for treat(cid:173)
`ment of periodontal disease.
`3. An orthodontic appliance with a hydroxyethyl me- 35
`thacrylate/methyl methacrylate copolymer (HE(cid:173)
`MA/MMA) matrix. Sodium fluoride is incorporated
`into the HEMA/MMA matrix to provide sustained
`fluoride release and enhanced anticaries activity.
`HEMA/MMA with fluoride may also be attached to 40
`the tooth in the form of a wafer-like tablet.
`4. Silicone/ethyl cellulose/polyethylene glycol films
`containing sodium fluoride are applied as coatings on
`orthodontic bands or in chewing gum. Controlled
`release of fluoride and anticaries activity is claimed. 45
`The above systems are discussed in the "The Compen(cid:173)
`dium of Continuing Education" Vol VI, No. 1, January
`1985 p. 27-36 review article "Controlled Drug Deliv(cid:173)
`ery: A New Means of Treatment of Dental Disease", by
`J. Max Goodson, D.D.S., Ph.D. of the Forsyth Dental 50
`Center. Other systems, described in GB patent applica(cid:173)
`tion No.
`and U.S.
`Pat. Nos.
`2,042,888
`4,292,299/4,226,848 (Teijin Ltd., Japan), use combina(cid:173)
`tions of cellulosic and polyacrylate polymers. The pre-
`ferred materials are hydroxypropyl cellulose ("Klucel")
`and a copolymer of acrylic acid ("Carbopol") that is
`administered in the form of thin tablets (discs), granules
`or powder. Other polymers that might be added are
`vinyl copolymers, polysaccharides, gelatin and calla- 60
`gen. U.S. Pat. No. 4,517,173 (Nippon Soda Co. Ltd,
`Japan) uses various 'celluloses in a multi-layered non(cid:173)
`extruded cast film preparation.
`Examples of prior art products currently on the mar(cid:173)
`ket include ointments such as ORABASE* with Benzo- 65
`caine (Squibb), Kenalog* (Triamcinolone Acetonide) in
`ORABASE* (Squibb) and Mycostatin* (Nystatin) oint(cid:173)
`ment (Squibb).
`
`55
`
`2
`The prior art products and delivery systems de(cid:173)
`scribed above are useful but have the following disad(cid:173)
`vantages:
`Tablets, appliances, hollow fibers are "bulky" in the
`mouth, are difficult to keep in place and inconve(cid:173)
`nient to apply.
`Ethyl cellulose and/or silicone films do not adhere to
`mucosa! tissue.
`Ointments (i.e., ORABASE*) have an unpleasant feel
`and do not last 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
`many of the above problems. It may be applied easily by
`the consumer. It has very little or no mouthfeel, it has
`good adhesion to the mucosa! tissues, and provides
`controlled release of the medicament.
`
`OBJECT OF THE INVENTION
`It is an object of 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(cid:173)
`trolled drug delivery in skin care, gynecological appli(cid:173)
`cations, wound care and like uses.
`
`SUMMARY OF THE INVENTION
`The invention involves a pharmaceutically accept(cid:173)
`able controlled-releasing medicament-containing ex(cid:173)
`truded single or multi-layered thin film, capable of ad(cid:173)
`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(cid:173)
`polymer of ethylene oxide, 0-10% of a water-insoluble
`polymer selected from the group consisting of ethyl
`cellulose, propyl cellulose, polyethylene and polypro(cid:173)
`pylene, and 2-10% of a plasticizer, said film having
`incorporated
`therein a pharmaceutically effective
`amount of said medicament.
`The present invention is directed to an extruded sin(cid:173)
`gle or multi-layered laminated thin (1-10 mils or
`0.025-0.25 mm) film, composed of selected water solu(cid:173)
`ble and/or insoluble polymers. Various therapeutic
`agents are incorporated into the film during manufac(cid:173)
`ture which are useful for treatment of oral disorders
`(i.e., denture discomfort, caries, periodontal disease,
`aphthous ulcers, etc.).
`The extruded film of the present invention must have
`at least one bioadhesive layer, but may also have a reser(cid:173)
`voir layer and/or an outer protective barrier membrane
`layer. The therapeutic agent may be incorporated into
`any or all of the layers. When properly formulated and
`fabricated, these films will adhere to wet mucosa! sur(cid:173)
`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(cid:173)
`ized drug delivery (i.e., the periodontal pocket, an aph(cid:173)
`thous lesion), 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 adhesion to the tooth
`or mucosa! tissue may be employed in which the fluo(cid:173)
`ride release rates may be controlled by varying film
`
`DRL - EXHIBIT 1004
`DRL002
`
`

`
`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. The films 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 enables it to adhere to wet mucosa! surfaces. The
`bioadhesive layer has 40-95% of hydroxypropyl cellu-
`10 lose, 5-60% of a homopolymer of ethylene oxide and
`2-10% of a glycol plasticizer (all percents are % by
`weight).
`The Hydroxypropyl cellulose (HPC), useful for pur(cid:173)
`poses of the present invention is commercially available
`from Hercules, Inc. (Wilmington, DE) under the trade(cid:173)
`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 water solution. 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(cid:173)
`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(cid:173)
`table oils such as castor oil, 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.
`The preferred.plasticizer for use in the present inven(cid:173)
`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(cid:173)
`tion, minor amounts of other non-essential but custom- ·
`ary ingredients will often be used if desired, e.g., antiox(cid:173)
`idants, preservatives, flavors, colorants.
`
`3
`solubilities and/or concentration of fluoride in a multi(cid:173)
`layered film.
`An example of a localized application of medication
`would be in the treatment of aphthous lesions. A lami(cid:173)
`nated two layer film with benzocaine incorporated into 5
`the adhesive layer would directly contact the injured
`mucosa. The outer layer would consist of non-soluble/(cid:173)
`non-adhesive polymers that provide durability, protec(cid:173)
`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(cid:173)
`rials, or those that are considered generally regarded as
`safe (GRAS) as food additives. They include, hydroxy(cid:173)
`propyl cellulose, and polyethylene oxide homopoly- 15
`mers. Small amounts of other polymers, e.g., polyvinyl
`ether-maleic acid copolymers and the 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 20
`bioadhesive layer of the film. Various non-soluble poly(cid:173)
`mers may also be incorporated for modification of the
`film's permeability properties, such as ethyl cellulose,
`propyl cellulose, polyethylene, polypropylene and car(cid:173)
`boxymethylcellulose (free acid). By varying the ratios 25
`of the above polymers both the solubility and the adhe(cid:173)
`sive properties of each layer of film 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- 30
`tom design the film by selecting and blending various
`polymers. The final film product may also 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 35
`in the prior art discussed above may generally be deliv(cid:173)
`ered by the drug delivery system of the present inven(cid:173)
`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 40
`present invention. Preferred medicaments include:
`Anesthetics/ Analgesics-benzocaine, dyclonine HCl,
`phenol, aspirin, phenacetin, acetaminophen, potas(cid:173)
`sium nitrate, etc.
`Anticaries Agents-sodium fluoride, sodium mono- 45
`fluorophosphate, stannous fluoride, etc.
`Anti-inflammatories-hydrocortisone acetate, triamcino(cid:173)
`lone acetonide, dipotassium, glycyrrhizinate, etc.
`Antihistamines-chlorpheniramine maleate, ephedrine
`HCL, diphenhydramine HCL, etc.
`Antibiotics-i.e., tetracycline, doxycycline hyclate, me(cid:173)
`clocycline, minocycline, etc.
`Antibacterials-chlorhexidine, cetyl pyridinium chlo(cid:173)
`ride, benzethonium chloride, dequalinium chloride,
`silver sulfadiazene, phenol, thymol, hexedine, hexeti- 55
`dine, alexidine, etc.
`Fungistats-nystatin, miconazole, ketoconazole, etc.
`The above are illustrative examples of therapeutic
`agents that are used to treat oral disorders. The present
`invention is not to be limited to these specific materials 60
`especially where it is intended to deliver drug outside of
`the oral cavity e.g. to skin where other drugs may be
`desirable.
`The film of the present invention has the advantage of
`being an extruded film, rather than a cast film. When a 65
`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
`
`50
`
`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(cid:173)
`meters. For easy conversion, 4 mils is approximately
`equal to 0.1 mm.
`
`EXAMPLE 1
`. Triple Layered Laminate Containing Sodium Fluo(cid:173)
`ride for Anticaries Protection
`This three layered film laminate is comprised of a
`"bioadhesive" layer, a sodium fluoride "reservoir"
`
`DRL - EXHIBIT 1004
`DRL003
`
`

`
`5
`layer and, an "outer protective barrier membrane"
`layer, in which the composition and thickness of each
`layer are as shown below:
`
`4,713,243
`
`6
`-continued
`
`Die Zone I
`Die Zone 2
`Die Zone 3
`
`185
`185
`185
`
`Each layer is extruded separately with the first layer
`extruded as a "free film". Successive layers are extruded
`onto each other and laminated by passing them through
`heated stainless steel rollers.
`Test Results:
`In vitro fluoride ion release studies were conducted
`on samples of the above described triple laminate film
`measuring 0.5 cmX 1.25 cm (0.625 cm2) according to
`15 the following procedures:
`The test sample is adhered to a glass slide by prewet(cid:173)
`ting the film and placing the bioadhesive layer on the
`glass surface. The slide is then immersed in a beaker
`containing 100 ml of distilled water with continuous
`20 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.
`The results obtained indicated fluoride release rates in
`the order of 0.05-0.2 mgs/cm2/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
`30 use levels by modification of the film composition and
`construction.
`
`Outer
`Protective
`Barrier
`%w/w
`Bio-
`adhesive Reservoir Membrane
`Layer
`Layer
`Layer
`(!mil)
`(4 mils)
`(I mil)
`(0.025 mm)
`(0.025 mm)
`(0.1 mm)
`
`20.0
`
`24.0
`
`60.0
`
`30.0
`
`5.0
`
`3.0
`2.0
`
`59.0
`
`5.0
`
`69.6
`
`6.0
`
`100.0
`
`___Q:!_
`~
`100.0
`100.0
`
`Ingredients
`
`Polyethylene oxide
`homopolymer (Union
`Carbide-Polyox• WSR-301)
`Hydroxypropyl Cellulose
`(Hercules, Inc.-Kluce!• MF)
`Polyethylene (Allied
`Chemical-6A)
`(Low Density)
`Propylene Glycol, U.S.P.
`Polyethylene Glycol
`400 (Union Carbide)
`Ethyl Cellulose (Hercules,
`Inc.-NIOOF)
`Caprylic/Capric
`Triglyceride (PVO
`Incorporated-Neobee M-5)
`Sodium Fluoride, U.S.P.
`
`5
`
`10
`
`25
`
`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-5 (liquid plasticizers) are placed in a
`Patterson Kelley (PK) V-blender equipped with liq(cid:173)
`uid addition capabilities. The ingredients which are
`all powders are blended for approximately 10-15
`minutes while the liquid plasticizer is slowly added to 35
`the mix. Three separate powder blends are made, one
`for each layer.
`b. Extrusion Process-A standard Johnson 2-~ inch vi(cid:173)
`nyl/polyolefin extruder equipped with a single three
`stage screw was used to extrude the "powder blend". 40
`The temperature conditions for the water soluble
`powders are however quite different from those used
`for vinyls and polyolefins. The temperature (°C.)
`profile for the "reservoir" and "membrane layers" of
`the triple laminate was as follows:
`
`45
`
`EXAMPLE2
`Single Layer Adhesive Film Containing Hydrocorti(cid:173)
`sone Acetate (0.5%) As An Anti-Inflammatory Agent
`The composition of the film, which was 0.1 mm.
`thick, was as follows:
`
`Ingredients
`
`Ethylene Oxide Homopolymer
`(Polyox• WSR-301)
`Hydroxypropyl Cellulose
`(Kluce!• MF)
`Polyethylene (AC-6A)
`Propylene Glycol
`Polyethylene Glycol 400
`Butylated Hydroxy Toluene (BHT)
`FCC (preservative)
`Hydrocortisone Acetate
`
`%w/w
`59.4
`
`30.0
`
`5.0
`3.0
`2.0
`0.1
`
`0.5
`100.0
`
`Barrel Zone I
`100
`Barrel Zone 2
`125
`Barrel Zone 3
`135
`Barrel Zone 4
`145
`Barrel Zone 5
`160
`The powder blending process and extruder conditions
`Barrel Zone 6
`170
`used were the same as those described in Example I for
`Adapter
`180
`Die Zone I
`the "bioadhesive layer" of the sodium fluoride trilami-
`180
`Die Zone 2
`180
`55 nate. In vitro tests were performed on the above film
`Die Zone 3
`180
`- - - - - - - - - - - - - - - - - - - - - and demonstrated a prolonged drug release pattern.
`EXAMPLE 3
`Single Layer Adhesive Film Containing Triamcino(cid:173)
`lone Acetonide (0.1 % ) As An Anti-Inflammatory
`The composition of the film, which was 0.1 mm.
`thick, was as follows:
`
`50
`
`The films which had a width of 18 inches, were ex(cid:173)
`truded at approximately 20 feet/minute through a flat
`lipped die. The temperature profile for the "bioadhesive 60
`layer" was:
`
`Barrel Zone I
`Barrel Zone 2
`Barrel Zone 3
`Barrel Zone 4
`Barrel Zone 5
`Barrel Zone 6
`Adapter
`
`125
`140
`165
`170
`185
`185
`185
`
`65
`
`Ingredients
`
`Ethylene Oxide Homopolymer
`(Polyox WSR-301)
`Hydroxypropyl Cellulose
`(Klucel MF)
`
`% w/w
`
`59.9
`
`29.9
`
`DRL - EXHIBIT 1004
`DRL004
`
`

`
`7
`-continued
`
`Ingredients
`
`Polyethylene (AC-6A)
`Propylene Glycol
`Polyethylene Glycol 400
`BHT
`Triamcinolone Acetonide
`
`4, 713,243
`
`8
`-continued
`
`B.
`
`5
`
`Outer protective/barrier layer
`Hydroxypropyl Cellulose
`(Klucel* MF)
`Ethyl Cellulose
`Polyethylene Glycol 400
`
`%w/w
`5.0
`3.0
`2.0
`0.1
`_o_.1_
`100.0
`
`100.00
`
`78.00
`
`20.00
`_bQQ_
`100.00
`
`The powder blending process and extruder conditions 10
`used to make the film 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 adhesive films of any of Examples 15
`1-3 in place of the particular medicament used in said
`examples. These include Benzocaine (analgesic), Potas(cid:173)
`sium nitrate (analgesic), Silver sulfadiazene (antimicro(cid:173)
`bial),
`Chlorhexidine (antimicrobial), miconazole nitrate 20
`(antifungal), Benzethonium chloride (antimicrobial),
`Tetracycline (antibiotic) and other similar therapeutic
`compounds.
`
`Part A was extruded on a Johnson extruder 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)
`through separate die slots within a coextruder and lami(cid:173)
`nating the two layers together.
`
`EXAMPLE6
`Anesthetic Films with Phenol and Dyclonine HCI
`Four variations of a single layer bioadhesive film
`25 were made as shown below:
`
`EXAMPLE4
`Analgesic Films with Potassium Nitrate
`This example shows 5 variations of the film having
`different solubilities, resulting in different release rates.
`
`Ingredients
`
`Polyethylene oxide homo-
`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 HCI
`
`30
`
`35
`
`2
`
`4
`
`59.10
`
`54.00
`
`59.70
`
`58.20
`
`29.45
`
`26.91
`
`29.75
`
`29.00
`
`4.93
`2.96
`1.97
`0.09
`1.50
`
`4.50
`2.70
`1.80
`0.09
`
`10.00
`
`4.98
`2.99
`1.99
`0.09
`
`0.50
`
`4.85
`2.91
`1.94
`0.10
`
`3.00
`
`,Jngredients
`
`Polyethylene oxide
`homopolymer (Polyox•
`WSR-301)
`Hydroxypropyl Cell(cid:173)
`·ulose, N.F. (Klucel* HF)
`Hydroxypropyl Cell(cid:173)
`ulose, N.F. (Klucel* MF)
`·'Ethyl Cellulose
`'\Polyethylene Glycol 400
`;,,,l?.olyethylene Glycol 8000
`·Propylene Glycol, U.S.P.
`BHT, F.C.C.
`Potassium Nitrate, F.C.C.
`
`2
`
`23.75
`
`57.00
`
`%w/w
`3
`4
`55.00 55.00
`
`57.00
`
`68.30
`
`28.40 29.90
`
`22.40
`
`22.40
`
`1.90
`0.95
`
`0.10
`5.00
`
`4.75
`1.90
`
`2.85
`0.10
`5.00
`
`5.00
`2.00
`
`3.00
`0.10
`5.00
`
`12.50
`2.00
`
`12.50
`2.00
`
`40
`
`3.00
`0.10
`5.00
`
`3.00
`0.10
`3.00
`
`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.
`
`EXAMPLE7
`Silver Sulfadiazene Films-Antimicrobial
`Three different single-layered bioadhesive films con(cid:173)
`taining 1.0% 0.5% and 0.5% respectively of silver sul(cid:173)
`fadiazene (SSD) were prepared on a heated Carver
`laboratory press (designed to simulate extruded condi(cid:173)
`tions) as shown below.
`
`Ingredients
`
`Polyethylene oxide homopolymer
`(Polyox• WSR-301)
`Hydroxypropyl Cellulose·
`(Klucel• HF)
`Polyethylene (AC-6A)
`Propylene Glycol, U.S.P.
`Polyethylene Glycol 400
`BHT, F.C.C.
`Silver Sulfadiazine
`
`%w/w
`
`A
`
`60.00
`
`28.9
`
`5.0
`3.0
`2.0
`0.1
`_1_.o _
`100.0
`
`B
`60.00
`
`29.4
`
`5.0
`3.0
`2.0
`0.1
`_fil_
`100.0
`
`The above ingredients are blended in a Patterson-Kelly
`powder blender equipped with liquid addition capabili(cid:173)
`ties. The resulting powder blend is then extruded into
`film on a Killion or Johnson vinyl extruder using pro(cid:173)
`cessing procedures similar to those of the bioadhesive 50
`layer of Example I.
`
`45
`
`EXAMPLES
`Anesthetic Films with Benzocaine (Laminate)
`This is an example of a two-layer laminate. The pro- 55
`cessing conditions used were similar to those of the
`bioadhesive layer and outer protective barrier mem(cid:173)
`brane layer of Example I.
`
`60
`
`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
`--1.:92_
`
`65 Effects on wound repair and activity against Staphylo(cid:173)
`coccus aureus were evaluated in the guinea pig model.
`Full-thickness excisions were inoculated with 3.8X 105
`organisms, (Staph. aureus) and wound surface microbi-
`
`DRL - EXHIBIT 1004
`DRL005
`
`

`
`10
`9
`3. The extruded film of claim 2 having a thickness no
`ology samples taken 10 minutes and 24 hours after treat-
`greater than 0.25 millimeters.
`ment. Test films were placed on the wound and covered
`with BIOCLUSIVE* Transparent Dressings secured
`4. The extruded film of claim 1, in single layer form,
`which also contains up to 10% by weight of a non-solu-
`with elastic tape. Wound contraction was measured
`over an eight-day period using OPTOMAX* Comput- 5 ble polymer selected from the group consisting of ethyl
`er-Assisted Image Analysis. The three films tested were
`cellulose, polyethylene, polypropylene and carboxy-
`the following:
`methyl cellulose free acid.
`A. 1.0% Silver Sulfadiazene, 125° c.12 minutes/4 tons
`5. The extruded film of claim 1, in multi-layer lami-
`B. 0.5% Silver Sulfadiazene, 125 0 C./2 minutes/4 tons
`nated form, which is addition to the bioadhesive layer
`IO also contains a reservoir layer in which at least a major
`C. 0.5% Silver Sulfadiazene, 150° C./3 minutes/4 tons
`portion of the medicament is contained.
`SIL V ADENE Cream and an untreated occluded
`6. The extruded multi-layer film of claim 5 in which
`control. The results indicated that:
`the reservoir layer consists essentially of a polymer
`1. SIL V AD ENE* treated wounds significantly inhib-
`matrix comprised of both a water soluble or swellable
`ited full-thickness wound contraction.
`15 polymer and a non-water soluble polymer selected from
`2. Film A, B and C inhibited wound contraction relative
`the group consisting of ethyl cellulose, propyl cellulose,
`to that of BIOCLUSIVE* dressed wounds.
`polyethylene and polypropylene, and also hydroxypro-
`3. The three SSD films each permitted substantially
`pyl cellulose.
`faster wound contraction than that of wounds treated
`7. The extruded film of claim 1 in multi-layer lami-
`daily with SIL V AD ENE* cream.
`20 nated form, which in addition to the bioadhesive layer
`4. All films were very active against S. aureus 24 hours
`also contains an outer protective-barrier membrane
`after inoculation.
`layer.
`The films may be scaled up by using an extruder. This
`8. The extruded multi-layer film of claim 7 in which
`example demonstrates the feasibility of such a film to
`the outer protective-barrier membrane layer is thinner
`perform its intended purpose. Use of a press for larger 25 than the bioadhesive layer, and said outer protective
`bamer layer consists essentially of a polymer matrix of
`samples would result in a non-uniform and lower-qua!-
`ity film than an extruded film.
`a major proportion of a non-water-soluble polymer
`selected from the group consisting of ethyl cellulose,
`propyl cellulose, polyethylene and polypropylene, and
`Based on the above findings, the films were very
`effective antibacterial agents, while mildly inhibiting 30 a minor proportion of hydroxypropyl cellulose.
`wound contraction. They offer clinicians a convenient
`9. The extruded multi-layer film of claim 1 in the
`form of a triple layered laminate containing sodium
`and more effective delivery system for antimicrobials
`which can be place in wounds beneath any dressing or
`fluoride for anticaries protection having the following
`can be laminated to any acceptable dressing face.
`composition:
`What is claimed is:
`1. A pharmaceutically acceptable controlled-releas(cid:173)
`ing medicament-containing extruded single or multi(cid:173)
`layered thin film, capable of adhering to a wet mucous
`surface, comprising a water soluble or swellable poly(cid:173)
`mer matrix bioadhesive layer which can adhere to a wet 40
`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 homopolymer of ethylene oxide having a
`molecular weight from 3,000,000 to 5,000,000, 0-10% 45
`of a water-insoluble polymer selected from the group
`consisting of ethyl cellulose, propyl cellulose, polyeth(cid:173)
`ylene and polypropylene, and 2-10% of a plasticizer,
`said film having incorporated therein a pharmaceuti- 50
`cally effective amount of said medicament.
`2. The extruded film of claim 1, made in a form which
`is so thin and flexible when wet as to be unobtrusive to
`the patient when properly positioned and placed in the
`patients mouth.
`
`4,713,243
`
`35
`
`55
`
`60
`
`65
`
`Bio-
`adhesive
`Layer
`(0.1 mm)
`
`%w/w
`Reservoir
`Layer
`(0.025 mm)
`
`Outer
`Protective
`Barrier
`Membrane
`Layer
`(0.025 mm)
`
`20.0
`
`24.0
`
`59.0
`5.0
`
`16.0
`100.0
`
`69.6
`6.0
`
`0.4
`100.0
`
`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
`(MW400)
`Ethyl Cellulose
`Caprylic/Capric
`Triglyceride
`Sodium Fluoride
`
`60.0
`
`30.0
`
`5.0
`3.0
`2.0
`
`100.0
`
`* *
`
`* * *
`
`DRL - EXHIBIT 1004
`DRL006