(12) United States Patent
`Chen et al.
`
`(10) Patent N0.:
`
`(45) Date of Patent:
`
`US 6,552,024 B1
`Apr. 22, 2003
`
`US006552024B1
`
`COMPOSITIONS AND METHODS FOR
`MUCOSAL DELIVERY
`
`Inventors: Li-Lan H. Chen, Edison; William R.
`Pfister, Robbinsville, both of NJ (US);
`Donald W. Renn, Glen Cove, ME
`(US); Thitiwan Buranachokpaisan,
`Milltown, NJ (US); James Osborne,
`Princeton Junction, NJ (US); Hock
`Seng Tan, Old Bridge, NJ (US); Li
`Tao, Edison, NJ (US)
`
`Lavipharm Laboratories Inc.,
`Hightstown, NJ (US)
`
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 0 days.
`
`Appl. No.: 09/434,878
`
`Filed:
`
`NOV. 5, 1999
`
`Related U.S. Application Data
`Provisional application No. 60/116,823, filed 011 Jail. 21,
`1999.
`
`Int. Cl.7 ...................... .. A61K 31/495; A61K 9/00;
`A61K 9/14; A61K 9/70; A61K 31/24; A61K 31/44;
`A61K 31/50; A61K 31/505; A61K 31/56
`................ .. 514/252.16; 424/400; 424/443;
`U.S. Cl.
`424/444; 424/484; 424/485; 424/486; 424/487;
`424/488; 514/182; 514/258; 514/289; 514/343;
`514/534
`Field of Search ............................... .. 424/400, 443,
`424/444, 484, 485, 486, 487, 488; 514/182,
`252.16, 258, 289, 343, 534
`
`References Cited
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`>>CI>>>>>>>>>>>3>>>>>>>>C1>>>CI>>
`
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`424/452
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`424/435
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`424/441
`5/1992 McCarty ................... .. 424/435
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`
`5,166,202 A
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`
`................ .. 514/220
`11/1992 Schweizer
`11/1992 Kuroya et al.
`.............. .. 524/37
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`514/221
`
`(List continued on next page.)
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`
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`OTHER PUBLICATIONS
`
`JP 04363332 A Patent Abstract, Dec. 16, 1992, Toru et al.
`JP 08291051 A Patent Abstract, Nov. 5, 1996, Tatara et al.
`JP 09216816 A Patent Abstract, Aug. 19, 1997, Nakamichi
`et al.
`
`JP 09309821 Patent Abstract, Dec. 2, 1997, Nakamichi et al.
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`
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`PCT/JP92/01631—Translation, Intrabuccally Disintegrat-
`ing Preparation and Production Thereof
`
`(List continued on next page.)
`
`Primary Examiner—Jose’ G. Dees
`Assistant Examiner—Frank Choi
`
`(74) Attorney, Agent, or Firm—Dechert; Thomas S. Deibert
`
`(57)
`
`ABSTRACT
`
`Mucosal surface-coat-forming film dosage units containing
`a Water-soluble hydrocolloid, an effective dose of an active
`agent and a mucosal adhesion enhancer; wherein the active
`agent is encapsulated within a polymer which is chemically
`or physically distinct from the hydocolloid; wherein the
`mucosal adhcsion cnhanccr is a starch graft copolymcr;
`wherein the film exhibits a dry tack value of less than 3.5 g,
`a Wet tack of greater than 35 g, a gelation temperature that
`is greater than 70° C. for a 2% polymer solution, a dry film
`thickness of less than 20 mil, a water content of 0.5 to 10%,
`a tensile strength greater than 1500 psi, a modulus in the
`range of 35,000 to 300,000 psi, a % elongation of less than
`20%, a tear probagation resistance of 0.001 to 1 N, and a
`dissolution time in the range of 1 to 600 seconds upon
`application to an oral mucosal surface.
`
`51 Claims, 6 Drawing Sheets
`
`TEVA EXHIBIT 1025
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`
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`

`
`US 6,552,024 B1
`Page 2
`
`U.S. PATENT DOCUMENTS
`
`5,223,264
`5,229,130
`5,229,164
`5,244,668
`5,288,497
`5,346,701
`5,378,473
`5,413,792
`5,430,029
`5 .466,464
`5,472,704
`5,474,783
`5,501,861
`5,529,789
`5,558,880
`5,567,439
`5,569,466
`5,576,014
`5,595,761
`5,629,003
`5,635,210
`5,648,093
`5,650,192
`5,662,920
`5,700,478
`5,716,928
`5,720,974
`5,731,339
`5,770,606
`5,807,576
`5,948,430
`
`>>>>>>>>>>>>>>>>>>>>3>>>C1>>>>>>>>
`
`6/1993 Wehling et al. ........... .. 424/466
`7/1993 Sharma et al.
`424/449
`7/1993 Pins et al.
`.. 264/510
`9/1993 Snipes ........ ..
`424/435
`2/1994 Stanley et al.
`424/440
`9/1994 Heiber et al.
`............. .. 424/435
`1/1995 Sharma et al.
`424/449
`5/1995 Ninomiya et al.
`424/434
`7/1995 Biella et al.
`514/220
`11/1995 Masaki et al.
`424/434
`12/1995 Santus et al.
`424/435
`12/1995 Miranda et al.
`424/448
`3/1996
`.. 424/464
`6/1996
`424/473
`9/1996
`424/484
`10/1996
`424/486
`10/1996 Tanner et al.
`424/452
`11/1996 Mizumoto et al.
`424/435
`1/1997 Allen, Jr. et al.
`424/484
`5/1997 Horstmann et al.
`424/401
`6/1997 Allen, Jr. ct al.
`424/465
`7/1997 Gole et al.
`..... ..
`424/484
`7/1997 Britton et al.
`427/2.19
`9/1997 Santus . . . . . . . . . . . . .
`. . . .. 424/435
`12/1997 Biegajski et al.
`424/434
`2/1998 Benet et al.
`514/11
`..
`2/1998 Makino et al.
`.. 424/464
`3/1998 Lowrey ............ ..
`514/400
`6/1998 El—Rashidy et al.
`514/284
`9/1998 Allen, Jr. et al.
`.. 424/465
`9/1999 Zerbe et al.
`..........
`424/435
`OTHER PUBLICATIONS
`
`.
`
`.
`
`..
`
`.
`
`Alderman, D., A Review of Cellulose Ethers in Hydrophilic
`Matrices for Oral Controlled-Release Dosage Forms, Int. J.
`Pharm. tech & Prod. Mfr, 5 (3) 1-9, 1984.
`Ahuja, A. et al., Mucoadhesive Drug Delivery Systems,
`Drug Development and Industrial Pharmacy, 23 (5),
`489-515, 1997.
`Brewster, D. et al., The systemic bioavailability of buprenor-
`phinc by various routes of administration, J. Pharm. Phar-
`macol., 33, 500-506, 1981.
`
`Christie, J. et al., Dose—Titration, Multicenter Study of Oral
`Transmucosal Fentanyl Citrate for the Treatment of Break-
`through Pain in Cancer Patients Using Transdermal Fentanyl
`for Persistent Pain, Journal of Clinical Oncology, vol. 16,
`No. 10, 3238-3256, Oct., 1998.
`
`Feely, et al., The influence of polymeric excipients on drug
`release from hydoxypropylmethylcellulose matrices, Inter-
`national Journal of Pharmaceutics, 44, 131-139, 1988.
`
`Gandhi et al., Oral cavity as a site for bioadhesive drug
`delivery, Advanced Drug Delivery Reviews, 13, 43-74,
`1994.
`
`Harris et al, Drug Delivery via the Mucous Membranes of
`the Oral Cavity, Journal of Pharmaceutical Sciences, vol.
`81, No. 1, 1-10, Jan., 1992.
`
`Ponchel, G., Formulation of oral mucosal drug delivery
`systems for the systemic delivery of bioactive materials,
`Advanced Drug Delivery Reviews, 13, 75-87, 1994.
`
`Rathbone, M. et al., The oral cavity as a site for systemic
`drug dclivcry, Advanced Drug Delivery Reviews, 13, 1-22,
`1994.
`
`Russell, W. et al., Pharmacokinetics of a New Sublingual
`Formulation of Temazepam, European Journal of Clinical
`Pharmacology, 35, 437-439, 1988.
`
`Sasaki et al., Kinetics of Buccal Absorption of Propafenone
`Single Oral Loading Dose in Healthy Humans, Gen. Phar-
`mac., vol. 331, No. 4, 589-591, 1998.
`
`Streisand, et al., Oral Transmucosal Etomidate in Volun-
`teers, Anesthesiology, 88, 899-95, 1998.
`
`Yamanouchi, In Pursuit of New Drug Delivery Technolo-
`gies, Annual Report 1996, http://WWw.yamanouchi.com/eg/
`ar96/ar06.html.
`
`Zhang, J. et al., Buccal Absorption of Etomidate from a
`Solid Formulation in Dogs, Anesth. Analg., 86, 1116-22,
`1998.
`
`* cited by examiner
`
`TEVA EXHIBIT 1025
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC
`
`RBP_TEVA05017750
`
`TEVA EXHIBIT 1025
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC
`
`

`
`U.S. Patent
`
`Apr. 22, 2003
`
`Sheet 1 of 6
`
`US 6,552,024 B1
`
`GINGIVA 2
`
`HARD PALATE 3
`
`CHEEK 4
`
`SUBUNGUAL 6
`
`UPPER UP I
`
`LOWER LIP 7
`
`FIG.1
`
`TEVA EXHIBIT 1025
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`

`
`U.S. Patent
`
`Apr. 22, 2003
`
`Sheet 2 of 6
`
`US 6,552,024 B1
`
`
`
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`TEVA EXHIBIT 1025
`TEVA PHARMACEUTICALS USA, INC. v. MONOSOL RX, LLC
`
`RBP_TEVA05017752
`
`TEVA EXHIBIT 1025
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`
`

`
`U.S. Patent
`
`Apr. 22, 2003
`
`6f03t6B_h__S
`
`US 6,552,024 B1
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`TEVA EXHIBIT 1025
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`
`

`
`U.S. Patent
`
`Apr. 22, 2003
`
`Sheet 4 of 6
`
`US 6,552,024 B1
`
`
`
`THICKNESS(mil) FIG.4
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`TEVA EXHIBIT 1025
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`

`
`U.S. Patent
`
`Apr. 22, 2003
`
`Sheet 5 of 6
`
`US 6,552,024 B1
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`RBP_TEVA05017755
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`

`
`U.S. Patent
`
`Apr. 22, 2003
`
`Sheet 6 of 6
`
`US 6,552,024 B1
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`

`
`US 6,552,024 B1
`
`1
`COMPOSITIONS AND METHODS FOR
`MUCOSAL DELIVERY
`
`RELATED APPLICATIONS
`
`This application gains priority fron1 Provisional Applica-
`tion No. 60/116,823 filed Jan. 21, 1999.
`
`TECHNICAL DESCRIPTION
`
`The present invention is directed to a device and method
`for administering agents in a dissolving film configuration.
`
`BACKGROUND TO THE INVENTION
`
`Many pharmaceutical dosage forms are administrated
`orally in the form of solid shaped articles such as tablets,
`pills, caplets and capsules that retain their shape under
`moderate pressure. Generally these dosage forms are
`designed to be swallowed whole or chewed to deliver the
`medication with adequate amounts of liquid. Some patients,
`particularly pediatric and geriatric patients, have difficulty
`swallowing or chewing solid dosage forms. Certain patients
`such as children or animals resist taking medication, and
`may try to hide a solid pill in order to spit it out later. In
`addition, many pediatric and geriatric patients are unwilling
`to take a solid dosage form because the active agent is
`difficult to swallow or is retained in the pharynx or gullet
`even when liquids are consumed with the dosage unit.
`Furthermore, the availability of liquids at the time of admin-
`istering medications may be limited for certain patients and
`may be restricted for certain diseases and/or treatments.
`Chewable tablets provide some advantages over the con-
`ventional tablets. However, they are not suitable for children
`wearing braces and the taste of the medication may be
`unpleasant and difficult to mask in a chewable tablet. At the
`same time, water may be still required for the administration
`of chewable tablets.
`
`the standard oral dosage forms, such as
`In addition,
`tablets, pills, caplets, and capsules, are designed for short
`residence time in the mouth. Absorption of the agent from
`these dosage forms occurs in the gastrointestinal (GI) tract,
`after the agent has separated fron1 the dosage forn1 and
`dissolved in the gastric fluids. For some active agents, it is
`desirable to achieve absorption through the oral mucosal
`tissues in order to accelerate onset of the therapeutic effect.
`Many active agents are poorly absorbed, even after they
`are dispersed in the stomach, because of low solubility or
`slow dissolution rate in the gastric fluids. Tablets may be
`formulated so as to be quick dissolving. These tablets are
`commonly placed on the tongue and disintegrate rapidly in
`the oral cavity. However, these dosage units are not fixed to
`a mucosal surface and may move around in the mouth.
`Consequently, they do not overcome a risk associated with
`choking or gagging that occurs with subjects having limited
`control of their swallowing reflexes. However, once placed
`in the mouth, these tablets dissolve rapidly in the saliva to
`provide a liquid formulation which is then swallowed. Quick
`dissolving tablets may be formed from a particulate support
`matrix containing the therapeutic agent, where the particu-
`late support matrix is a protein (U.S. Pat. Nos. 5,807,576,
`5,635,210, 5,595,761). Alternatively,
`the tablet may be
`formed from a laminate with several layers and an outer
`coating (JP 100535518). Tablets have also been manufac-
`tured from shearform matrices which are substantially am or-
`phous sugar formed when crystalline sugar is subjected to
`heat and shear (WO 95/07194; WO 95/35293). Other meth-
`ods of forming quick dissolving tablets include wet granu-
`
`2
`lation methods (EP 0627 218) and dry granulation methods
`(EP 0124027A1) and by freeze-drying techniques (EP
`0084705A2). Generally, quick dissolving tablets are formed
`using complex multi-step manufacturing processes.
`In
`addition, these tablets may have poor mechanical strength,
`are fragile and friable and have insufficient holding capacity
`for active ingredients (U.S. Pat. No. 5,720,974) and may be
`difficult to store and handle.
`
`Therapeutic compounds are sometimes provided as pow-
`ders or granules which may be difficult to swallow and cause
`unpleasant sensations in the mouth. Furthermore, many
`quick dissolving tablets contain particulates (>25 microns)
`which leave a “gritty” and unpleasant taste in the mouth. In
`the elderly, powdcrs may cause choking and discomfort
`associated with trapping of granules in dentures. Powders
`and granules are generally packaged in a sealed pouch which
`requires tearing before use. This causes problems for geri-
`atric patients and those suffering from arthritis in the fingers
`as well as for children. Consequently, problems of spillage
`of the contents arise in this group of patients. Furthermore,
`these oral preparations should be taken with water which for
`certain patients are inconvenient and may cause reduced
`patient compliance.
`Liquid, syrups or suspensions are an alternative to solid
`dosage forms and are considered desirable for pediatric and
`geriatric patients who have problems in swallowing tablets.
`However, these dosage forms are often difficult to measure
`accurately and administer easily. Liquid formulations dete-
`riorate rapidly upon exposure to heat or atmosphere and
`consequently have a relatively short shelf life. Furthermore,
`liquid formulations require a relatively large volume and are
`bulky to store.
`In addition to solid and liquid dosage forms, rapidly
`dissolving buccal/oral delivery systems have been devel-
`oped. These systems are commonly freeze dried prepara-
`tions which are more expensive to manufacture as compared
`to tablets (U.S. Pat. No. 5,648,093). Furthermore, freeze
`dried preparations are brittle and fragile when handled and
`must be kept in dry conditions to avoid disintegration. The
`instability of freeze-dried preparations has been reduced
`somewhat by the addition of mannitol (U.S. Pat. No. 4,946,
`684). WO 9820862 reports a film that is formed according
`to a method that does not utilize freeze drying and avoids
`problems described in the art such as rigidity of the films,
`delayed softening and poor solubility in the mouth (U.S. Pat.
`No. 4,876,092; EP 0200508; EPO 381194; CA-PS 1-26331;
`DE 24498655; DE 3630603; EP 0452446 and EP 0219762).
`However, the film described in WO 9820862 relies on the
`use of at least two different non-ionic surfactants to achieve
`immcdiatc wettability.
`It is desirable that a dosage unit should provide a non-
`invasive, effective and economic means to deliver an active
`agent to the target site. Where the target site is the plasma,
`additional issues arise concerning the rate of delivery of the
`active agent to that site as measured by bioavailability. For
`many types of active agent, fast onset of the therapeutic
`effect is desirable. Traditional oral dosages, such as tablets,
`are limited in onset time by the rate of absorption in the
`gastro-intestinal tract. Formulations have been developed
`which, when applied in the mouth, lead to faster onset that
`the traditional oral dosages because they target the oral
`mucosa. These formulations include dosage units containing
`75%—90% polyethylene glycol
`that melt at body
`temperature,
`in the mouth.(U.S. Pat. No. 5,004,601 and
`5,135,752) Other formulations include liquid forms, loz-
`enges or tablets that are administered sublingually or by a
`sweetened matrix on a stick.
`(U.S. Pat. No. 5,770,606,
`
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`

`
`US 6,552,024 B1
`
`3
`Streisand et al. and Zhang et al., Christie et al., Sasaki et al.).
`Whereas the above references address the delivery route,
`they do not address the problems of bioavailability that arise
`from poor solubility or low dissolution rate.
`A delivery device that addresses the above limitations
`would represent a desirable improvement on existing deliv-
`ery systems.
`
`SUMMARY OF THE INVENTION
`
`A novel dosage unit and its method of manufacture and
`use is provided. In an embodiment, the dosage unit includes
`a water-soluble hydrocolloid, mucosal surface-coat-forming
`film, such film including an effective dose of an active agent.
`In an embodiment of the invention,
`the hydrocolloid
`includes a polymer selected from the group consisting of a
`natural, semi-natural and synthetic biopolymer being exem-
`plified by a polysaccharide and a polypeptide. In addition to
`the hydrocolloid, the film may further include one or more
`of an emulsifier, a plasticizer, a taste modifying agent, a
`water soluble inert filler, a preservative, a buffering agent, a
`coloring agent, a permeation enhancer, and a stabilizer. The
`film may further include an active agent selected from the
`group consisting of a therapeutic agent, a dietary supplement
`and a hygiene aid. Embodiments of the invention utilize
`eifective amounts of sildenafil citrate, nicotine,
`hydromorphone, oxybutynine or estradiol as active agents in
`the dosage unit. The active agent may be encapsulated
`within a second polymer having dissolution properties that
`are different from those of the hydrocolloid. More than one
`active agent may be included in the film. In an embodiment
`of the invention, the emulsifier may have a concentration of
`0.1—10% W. The water inert filler may include a concentra-
`tion range of 0.5-50% and the preservative may include a
`concentration range of 0.01—10%. A mucosal adhesion
`enhancer such as starch graft copolymer may be included in
`the dosage unit.
`In embodiments of the invention, the dosage unit may
`further include any of the following features: a dry film
`thickness in the range of 1-20 mil, more particularly less
`than 10 mils, a dry tack value of less than 3.5 g, more
`particular less than 2 g, a wet tack value of greater than 35
`g, a tensile strength greater than 1500 psi, a modulus in the
`range of 35,000-300,000 psi, a tear propagation resistance
`in the range 0.0001N—1 N, a disintegration time in a range
`from 1-300 seconds, a dissolution time in a range from
`10-600 seconds, and a percentage elongation less than 20%.
`In embodiments of the invention, methods are provided
`for making a dosage unit, that include in one embodiment,
`dissolving a hydrocolloid in a solvent so as to form a
`substantially homogeneous preparation; adding to the
`hydrocolloid preparation, an active agent and at least one
`reagent selected from the group consisting of an emulsifier,
`a plasticizer, a taste modifier, a water soluble inert filler, a
`coloring agent, a preservative, a permeation enhancer, a
`stabilizer and a buffering agent to form a coatable mixture;
`and forming a mucosal surface-coat forming film from the
`mixture for packaging as a dosage unit. The method may
`further include the step of coating the mixture onto a backing
`film. In a further embodiment,
`the reagents including: a
`hydrocolloid, an active agent, and at
`least one reagent
`selected from the group consisting of an emulsifier, a
`plasticizer, a taste modifier, a water soluble inert filler, a
`coloring agent, a preservative, a permeation enhancer, a
`stabilizer, and a buffering agent, may be combined in any
`order in a vessel having a heating source and a mechanical
`mixing device, the combined ingredients being mixed dur-
`
`4
`ing and after the addition of the ingredients to the vessel, an
`effective amount of heat being applied for melting a sub-
`stantial portion of the mixture. The mixture may then be
`formed into a film in a dry extrusion process.
`In an embodiment of the invention, a method is provided
`for administering an active agent to a subject, that includes
`obtaining a water-soluble hydrocolloid, mucosal surface-
`coat—forming film, such film including an effective dose of
`an active agent; and placing the film on a mucosal surface
`coat forming film in the subject; so as to release the active
`agent.
`In a further embodiment of the invention, a dosage unit is
`provided that includes a water soluble hydrocolloid and an
`effective dose of sildenafil citrate in a mucosal-surface
`contacting film. More particularly, an effective dose of
`sildenafil citrate is formed into a solid dispersion with xylitol
`for treating erectile dysfunction. The sildenafil/xylitol dis-
`persion may be mixed with at least one re agent selected from
`the group consisting of an emulsifier, a plasticizer, a taste
`modifier, a coloring agent, a preservative, a permeation
`enhancer, a stabilizer and a buffering agent. The solid
`dispersion of sildenafil and xylitol may arise at a ratio of 9
`parts sildenafil to one part xylitol. According to embodi-
`ments of the invention directed to a dosage 11nit and method
`of making a dosage unit suitable for erectile dysfunction, the
`water solubility of sildenafil in the solid dispersion is at least
`20 mg/ml, more particularly about 50 mg/ml. More
`particularly, the film may be capable of completely disso-
`lution at the oral mucosal surface within 10-600 seconds.
`
`BRIEF DESCRIPTION OF THE DRAWINGS
`
`FIG. 1 shows possible application sites in the oral cavity
`for the inventive dosage unit. (1) is the upper lip; (2) is the
`gingiva; (3) is the hard palate; (4) is the cheek; (5) is the
`lingual; (6) is the sublingual; (7) is the lower lip.
`FIG. 2 illustrates one manufacturing process for the
`dosage unit. (8) is the mixing and degassing tank; (9) is the
`coating slot with thickness controller; (10) is the polyester
`backing belt; (11) is the drying oven with aeration controller;
`(12) is the intraoral film; (13) is the die cutting and (14) is
`the intraoral unit dose.
`
`FIG. 3 shows examples of packaging and dispensing
`devices for the intraoral delivery system. (15) is a heat
`sealed single pouch; (16) is a multi-unit blister card; (17) is
`a multi-unit dispensing pack, 17(a) the container snap and
`17(b) the lid closure; (18) is a multi-unit roll-type dispenser
`cylinder; (19) is a perforated film strip; and (20) is a single
`dose film.
`
`FIG. 4 demonstrates the disintegration and dissolution
`time of the intraoral delivery system as a function of
`thickness. ——o—— is disintegration time and ——o—— is dis-
`solving time.
`FIG. 5 shows the release profiles of ——v—— nicotine,
`——v—— oxybutynin, ——o—— hydromorphone and
`——o—— estradiol.
`
`FIG. 6 shows the pharmacokinetics in six subjects after
`administration of a dissolving film sildenafil formulation
`and after administration of the commercial tablet containing
`the same dosage of sildenafil. Sildenafil film --o-- Viagra
`--V--.
`
`DETAILED DESCRIPTION OF INVENTION
`
`Delivery of active agents in solid form via the mouth
`causes problems to patients who may choke on the dosage
`unit. This effect is caused at least in part by the mobility of
`
`TEVA EXHIBIT 1025
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC
`
`RBP_TEVA05017758
`
`TEVA EXHIBIT 1025
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC
`
`

`
`,_
`3
`
`US 6,552,024 B1
`
`the dosage unit within the mouth. We have developed a new
`class of dosage units which are not mobile in the mouth
`because on contact with the moist mucosal surface, the film
`becomes a coating that adheres to the mucosal surface and
`then disintegrates and dissolves over a time frame controlled
`in the design of the dosage. The dosage unit, in an embodi-
`ment of the invention, is in the form of a flexible, non-tacky,
`dry conveniently packaged film. Once removed from the
`package and placed on a mucosal surface,
`the mucosal
`surface-coat-forming film hydrates substantially immedi-
`ately to form a coating on the moist surface of the mucous
`membrane and then disintegrates and dissolves to release the
`active agent from the film.
`The dosage unit may release the active agent over a period
`of time that is determined by a number of different factors.
`These factors include the dimensions of the film, the con-
`centration of the active agent, the solubility of the agent at
`the mucosal surface and how the agent is dispersed through-
`out
`the film. The thickness of the film is a factor in
`determining the rate of dissolution. Athick film will dissolve
`more slowly than an otherwise similar thin film. Athick film
`may be desirable for its holding capacity for active agents
`that are required in high dosages. Although the surface area
`of a film can be adjusted 11p to about 5 square centimeters,
`increased thickness may also be desirable for purposes of
`achieving effective active agent dosages. The active agent
`can form a solid dispersion with a water soluble inert filler
`for purposes of increasing the solubility of the agent when
`released from the film thereby enhancing bioavailability of
`the active agent. This is exemplified here by sildenafil which
`is incorporated in a film with a water soluble inert filler, for
`example, xylitol, which has been found here to enhance the
`bioavailability of this agent. Solubilizing agents that are well
`known in the art may be included in the film. The extent of
`uptake of the active agent from the dosage unit at
`the
`mucosal surface can be controlled by the dissolution rate of
`the film. A dissolving film will release the active agent and
`this in turn will cause the active agent to be swallowed and
`taken up in the GI tract. In contrast, slow release of the active
`agent at
`the mucosal surface will give rise to increased
`uptake by the mucosal surface. A further parameter govern-
`ing the release of an active agent at the mucosal surface is
`the manner in which the agent is dispersed in the film. For
`example, the agent may be dispersed as colloidal particles or
`microencapsulated within the film or alternatively may be
`mixed throughout the film as a reagent during casting.
`The dosage unit of the invention may be used as a vehicle
`for delivering a wide range of active agents. For example,
`the active agent may be a small molecule, a protein, a
`nucleic acid including antisense molecules or other biologi-
`cal or synthetic molecules.
`The term “mucosal surface—coat—forming” as applied to a
`film as used in this description and in the following claims
`unless specified otherwise , means a film that coats the
`mucosal surface on contact, and may not
`thereafter be
`manually recovered or moved from the contact site; and
`subsequently disintegrates and dissolves so as to release the
`active agent. It should be noted that for purposes of the
`description of the invention and the claims, “mucosal sur-
`face” refers to any moist surface of the body. This includes
`the surfaces identified in FIG. 1. It further includes a wound
`
`surface where lymph fluid bathes the tissue surface.
`Embodiments of the present invention include a process,
`composition and method of use for a quick dissolving film
`for local and systemic delivery of pharmaceutical agents to
`a mucosal surface in a subject. In the following text, specific
`reference may be made to the oral cavity by way of example.
`
`6
`the scope of the
`intended to limit
`is not
`it
`However,
`invention to the oral cavity. The dosage unit of the invention
`may be applied to any mucosal surface as deemed appro-
`priate for the systemic or local delivery of an active agent
`including vaginal, rectal, and ocular surfaces. For purposes
`of oral delivery,
`the films may be applied on lingual,
`sub-lingual, buccal, gingival, and palatal surfaces (FIG. 1).
`For vaginal delivery of such agents as contraceptive
`agents including nonoxynol or anti-infectives including anti-
`fungal agents, antibacterial agents and anti-viral agents, or
`fragrant or hygiene agents; the film should be non-sticky
`when removed from the packaging but should have mucoad-
`hesive properties when applied in the vagina. Although films
`containing active agents for use in the vagina have been
`used, they appear to have some significant drawbacks most
`particularly the lack of adhesive properties at the mucosal
`surface. This makes these films impractical to administer.
`(U.S. Pat. Nos. 5,380,529; 5,595,980 and 5,529,782).
`Embodiments of the invention provide improved dosage
`forms to deliver active agents that are appropriate for all age
`groups and that physician, parents, patients and family
`members can administer easily. These dosage forms are
`economical to prepare and have an extended shelf life. They
`are easy to handle and non-tacky before administration so as
`to avoid disintegration prior to use and are conveniently
`packaged for shelf life, ease of storage and distribution. The
`dosage form may be administered to the subject by placing
`the film on a mucous surface, at which time the film becomes
`a mucoadhesive coating, characterized by the property that
`it can no longer exist
`in an independent form and is
`subsequently dispersed in solution.
`Embodiments of the invention provide a delivery system
`for active agents and other active agents that will dissolve
`and completely release their contents on a moist mucosal
`surface—for example in the oral cavity. The release of the
`active agent occurs without mastication or the need for
`intake of water. With particular reference to the oral cavity,
`an embodiment of the invention provides active agents that
`remain in the oral cavity for treatment or modification of the
`oral environment; for example, for periodontal disease treat-
`ment or breath-odor control. Furthermore, embodiments of
`the invention further provide improvements that include:
`improved organoleptic properties (smell and taste), and
`texture and feel of dosage forms intended to be placed in the
`oral cavity; a dosage form which “melts” in the mouth and
`leaves a smooth pleasant after feel following dissolution;
`and a prolonged retention of the active agent in the mouth
`following dissolution of the quick dissolving dosage form to
`extend the residence time of the active agent cleared from
`the mouth by the production of saliva and subsequent
`swallowing. Depending on the optimal program for a spe-
`cific application of the invention, the disintegration time and
`the dissolution time can be controlled within a prescribed
`range by adjustment of the formulation and the thickness of
`the film. In some cases, it is desirable for release of the active
`agent
`to occur after dissolution of the film. For these
`applications,
`the active agent may be encapsulated in a
`material with dissolution properties that are different from
`those of the hydrocolloid. Encapsulation of the active agent
`also may be utilized to achieve masking of taste for active
`agents that are bitter. In some cases, two or more different
`active agents may be included in the film. An example where
`multiple active agents frequently ar