`Chen et al.
`
`(10) Patent N0.:
`(45) Date 0f Patent:
`
`US 6,552,024 B1
`Apr. 22, 2003
`
`US006552024B1
`
`(54) COMPOSITIONS AND METHODS FOR
`MUCOSAL DELIVERY
`
`(75) Inventors: Li-Lan H. Chen, Edison; William R.
`P?ster, Robbinsville, both Of NJ (US);
`Donald W; Rem‘, Glen C°Ve> ME
`(US); Thltlwan Buranachokpalsan,
`MilltoWn, NJ (US); James Osborne,
`
`Princeton Junction, NJ (US); Hock Seng Tan, Old Bridge, NJ (US); Li
`
`Tao’ Edlson’ NJ (Us)
`.
`.
`,
`(73) Assrgnee: Lavlpharm Laboratories Inc.,
`HighISIOWH, NJ (Us)
`
`_
`( * ) Notice:
`
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 0 days,
`
`(21) APPl- N91 09/434,878
`(22) Filed:
`NOV- 5’ 1999
`
`5,166,202 A 11/1992 SchWeiZer ................ .. 514/220
`5,166,233 A 11/1992 Kuroya et al. .............. .. 524/37
`5,198,436 A
`3/1993 Ellinwood, Jr. et al.
`514/221
`L. t
`t.
`d
`t
`( 15 CO“ “me on “X Page“)
`FOREIGN PATENT DOCUMENTS
`
`CA
`
`EP
`EP
`EP
`EP
`EP
`EP
`EP
`EP
`EP
`W0
`W0
`W0
`W0
`
`1263312
`
`11/1989
`
`2; 136022 0 124 027 A1 11/1984
`
`
`0 200 508 A2 10/1986
`0 124 027 B1
`6 1990
`0 371 466 A1
`62990
`0 404 490 A1 12/1990
`0 553 777 A2
`53/1993
`0 586 034 A2
`3/1994
`0 627 218 A1 12/1994
`0 711 547 A1
`5/1996
`WO 93/23017
`11/1993
`WO 95/01782
`1/1995
`WO 95/20377
`8/1995
`WO 95/34293
`12/1995
`
`Related US. Application Data
`(60) lggvgisional application NO- 60/116,823. ?led on Jan- 21,
`'
`(51) Int. Cl.7 ...................... .. A61K 31/495; A61K 9/00;
`A61K 9/14; A61K 9/70; A61K 31/24; A61K 31/44;
`(52) U S C] A61K 3l?gagizlgilgf1:43:36
`424/444; 424/484; 424/485; 424/486; 424/487;
`
`OTHER PUBLICATIONS
`JP 04363332 A Patent Abstract, Dec. 16, 1992, Toru 61 al.
`JP 08291051 A Patent Abstract, Nov. 5, 1996, Tatara et al.
`JP 09216816 A patent Abstract, Aug 19, 1997, Nakamichi
`et a1_
`JP 09309821 Patent Abstract, Dec. 2, 1997, Nakamichi 61 al.
`JP 09309822 Patent Abstract, Dec. 2, 1997, Nakamrchr et al.
`
`514/534
`(58) Field Of Search ............................... .. 424/400, 443,
`424/444, 484, 485, 486, 487, 488; 514/182,
`252-16, 258, 289, 343, 534
`_
`References Clted
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`(56)
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`JP 62081432APatent Abstract, Apr. 14, 1987, Morohoshi et
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`JP 62135417 APatent Abstract, Jun. 18, 1987, Tatara et al.
`JP 63310818 A Patent Abstract, Dec. 19, 1998, Tatara 61 al.
`PCT/JP92/01631—Translation, Intrabuccally Disintegrat
`ing Preparation and Production Thereof
`
`U'S' PATENT DOCUMENTS
`
`(List continued on neXt page.)
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`4,029,757 A
`4,029,758 A
`
`6/1977 Mlodozeniec et al. .... .. 424/452
`6/1977 Mlodozeniec et al. .... .. 424/452
`
`Primary Examiner—]ose’ G, Dees
`
`
`
`A 4,059,686 A 11/1977 Tanaka et al. . . . . . . . . . . . . . . . . . . . . . . . . . ..
`
`
`
`4,128,445 A 12/1978 SturZenegger et al.
`4,136,145 A
`1/1979 Fuchs et al. ....... ..
`4,136,162 A
`1/1979 Fuchs et al.
`4,414,198 A 11/1983 Michaelson . . . . . . .
`4,572,832 A
`2/ 1986 Kigasawa et al
`4,680,323 A
`7/1987 LOWeY - - - - - - - - - - - - -
`
`,
`
`,
`
`e e a.
`
`gotrltlertetlaL
`2
`4,777,046 A 10/1988 Iwakura et al.
`4,876,092 A 10/1989 Mizobuchietal. ..
`4,900,552 A
`2/1990 Sanvordeker et al.
`4,935,243 A
`6/1990 Borkan et a1_ _
`4,946,684 A
`8/1990 Blank et al.
`4,950,664 A
`8/1990 Goldberg ........ ..
`4,983,385 A * 1/1991 Hasegawa et al-
`5,004,601 A
`4/1991 SI1_iPes - - - - - - - - - - - - - -
`2
`gal
`""
`5,073,374 A 12/1991 McCarty ............ ..
`5,077,053 A 12/1991 Kuncewitch et al.
`
`,
`
`,
`
`anvor e er e a.
`
`. . . .. 424/19
`
`156/64
`264/164
`.. 424/443
`. . . .. 424/44
`424/19
`- - - ~~ 524/43
`
`424/435
`424/435
`424/422
`424/441
`424/441
`514/219
`514/772-4
`- - - ~~ 424/78
`
`424/435
`424/441
`
`-
`
`-
`
`-
`
`-
`
`
`
`Examiner_Frank (74) Attorney) Agent) 0,. Firm_DeChert; Thomas S_ Deibert
`
`(57)
`
`ABSTRACT
`
`Mucosal surface-coat-forming ?lm 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 physllcaclilg qlstmcthfrom the hy‘tiocinold’?wherelm th‘gf
`“1560531 E ?elslon £18m“? 1S 2‘; arlc g3 Capo ynslen
`W “mm 6 m "X 1 “S a TV ‘ac "*1 {1e 0 655‘ an 3- g’
`a Wet tack of greater than 35 g, a gelatron temperature that
`is greater than 70° C- for a 2% Polymer Solution, a dry ?lm
`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
`dlssfluttlon tnme “1 tlhe rangel of f1 to 600 Seconds upon
`app lea 10“ 0 an Ora mucosa sur “6'
`
`5,112,616 A
`5,135,752 A
`
`5/1992 McCarty ................... .. 424/435
`8/1992 Snipes ...................... .. 424/435
`
`51 Claims, 6 Drawing Sheets
`
`DRL - EXHIBIT 1032
`DRL001
`
`
`
`US 6,552,024 B1
`Page 2
`
`US. PATENT DOCUMENTS
`
`6/1993 Wehling et al. ........... .. 424/466
`5,223,264 A
`7/1993 Sharma et al. .
`424/449
`5,229,130 A
`7/1993 Pins et al.
`264/510
`5,229,164 A
`9/1993 Snipes ........ ..
`424/435
`5,244,668 A
`2/1994 Stanley et al. .
`424/440
`5,288,497 A
`9/1994 Heiber et al. ............. .. 424/435
`5,346,701 A
`1/1995 Sharma et al. ............ .. 424/449
`5,378,473 A
`5/1995 Ninomiya et al.
`424/434
`5,413,792 A
`7/1995 Biella et al. .... ..
`514/220
`5,430,029 A
`5,466,464 A 11/1995 Masaki et al. .
`424/434
`5,472,704 A 12/1995 Santus et al. ............. .. 424/435
`5,474,783 A 12/1995 Miranda et al. .......... .. 424/448
`5,501,861 A
`3/1996 Makino et al.
`424/464
`5,529,789 A
`6/1996 Lo ............. ..
`424/473
`5,558,880 A
`9/1996 Gole et al.
`424/484
`5,567,439 A 10/1996 Myers et al. ..
`424/486
`5,569,466 A 10/1996 Tanner et al.
`424/452
`5,576,014 A 11/1996 MiZumoto et al.
`424/435
`5,595,761 A
`1/1997 Allen, Jr. et al.
`424/484
`5,629,003 A
`5/1997 Horstmann et al. ..
`424/401
`5,635,210 A
`6/1997 Allen, Jr. et al.
`424/465
`5,648,093 A
`7/1997 Gole et al. ...... ..
`424/484
`5,650,192 A
`7/1997 Britton et al. .
`.. 427/2.19
`5,662,920 A
`9/1997 Santus ............ ..
`424/435
`5,700,478 A 12/1997 Biegajski et al. .
`424/434
`5,716,928 A
`2/1998 Benet et al. . . . . . .
`. . . .. 514/11
`5,720,974 A
`2/1998 Makino et al.
`424/464
`5,731,339 A
`3/1998 LOWrey ............. ..
`514/400
`5,770,606 A
`6/1998 El-Rashidy et al. .
`514/284
`5,807,576 A
`9/1998 Allen, Jr. et al.
`424/465
`5,948,430 A
`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
`phine 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 in?uence of polymeric eXcipients on drug
`release from hydoXypropylmethylcellulose matrices, Inter
`national Journal ofPharmaceutics, 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 delivery, 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
`
`DRL - EXHIBIT 1032
`DRL002
`
`
`
`U.S. Patent
`
`Apr. 22, 2003
`
`Sheet 1 0f 6
`
`US 6,552,024 B1
`
`UPPER UP 1
`
`LOWER LIP 7
`
`HARD PALATE 3
`
`CHEEK 4
`SUBLINGUAL 6
`
`DRL - EXHIBIT 1032
`DRL003
`
`
`
`U.S. Patent
`
`Apr. 22, 2003
`
`Sheet 2 0f 6
`
`US 6,552,024 B1
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`U.S. Patent
`
`Apr. 22, 2003
`
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`US 6,552,024 B1
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`DRL - EXHIBIT 1032
`DRL005
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`
`
`U.S. Patent
`
`Apr. 22, 2003
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`Sheet 4 0f 6
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`US 6,552,024 B1
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`U.S. Patent
`
`Apr. 22, 2003
`
`Sheet 5 of 6
`
`US 6,552,024 B1
`
`ESTRADIOL—¥—NICOTINE—-V—OXYBUTYNIN
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`DRL - EXHIBIT 1032
`DRL007
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`
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`U.S. Patent
`
`Apr. 22, 2003
`
`Sheet 6 6f 6
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`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 from Provisional Applica
`tion No. 60/116,823 ?led Jan. 21, 1999.
`
`TECHNICAL DESCRIPTION
`
`The present invention is directed to a device and method
`for administering agents in a dissolving ?lm con?guration.
`
`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 dif?culty
`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
`dif?cult 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 dif?cult to mask in a cheWable tablet. At the
`same time, Water may be still required for the administration
`of cheWable tablets.
`In addition, the standard oral dosage forms, such as
`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 from the dosage form and
`dissolved in the gastric ?uids. 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 ?uids. 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 ?xed 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 re?exes. 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 (US. 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 amor
`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
`
`15
`
`25
`
`35
`
`45
`
`55
`
`65
`
`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 (US. Pat. No. 5,720,974) and may be
`dif?cult 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, poWders 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 ?ngers
`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 (US. 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 (US. Pat. No. 4,946,
`684). WO 9820862 reports a ?lm 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 ?lms,
`delayed softening and poor solubility in the mouth (US. Pat.
`No. 4,876,092; EP 0200508; EPO 381194; CA-PS 1-26331;
`DE 24498655; DE 3630603; EP 0452446 and EP 0219762).
`HoWever, the ?lm described in WO 9820862 relies on the
`use of at least tWo different non-ionic surfactants to achieve
`immediate 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. (US. Pat. No. 5,770,606,
`
`DRL - EXHIBIT 1032
`DRL009
`
`
`
`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
`?lm, such ?lm 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
`pli?ed by a polysaccharide and a polypeptide. In addition to
`the hydrocolloid, the ?lm may further include one or more
`of an emulsi?er, a plasticiZer, a taste modifying agent, a
`Water soluble inert ?ller, a preservative, a buffering agent, a
`coloring agent, a permeation enhancer, and a stabiliZer. The
`?lm 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
`effective amounts of sildena?l 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 ?lm. In an embodiment
`of the invention, the emulsi?er may have a concentration of
`0.1—10% W. The Water inert ?ller 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 ?lm
`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—1N, 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 emulsi?er,
`a plasticiZer, a taste modi?er, a Water soluble inert ?ller, 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 ?lm from the
`mixture for packaging as a dosage unit. The method may
`further include the step of coating the mixture onto a backing
`?lm. In a further embodiment, the reagents including: a
`hydrocolloid, an active agent, and at least one reagent
`selected from the group consisting of an emulsi?er, a
`plasticiZer, a taste modi?er, a Water soluble inert ?ller, 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 ?lm 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 ?lm, such ?lm including an effective dose of
`an active agent; and placing the ?lm on a mucosal surface
`coat forming ?lm 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 sildena?l citrate in a mucosal-surface
`contacting ?lm. More particularly, an effective dose of
`sildena?l citrate is formed into a solid dispersion With xylitol
`for treating erectile dysfunction. The sildena?l/xylitol dis
`persion may be mixed With at least one reagent selected from
`the group consisting of an emulsi?er, a plasticiZer, a taste
`modi?er, a coloring agent, a preservative, a permeation
`enhancer, a stabiliZer and a buffering agent. The solid
`dispersion of sildena?l and xylitol may arise at a ratio of 9
`parts sildena?l to one part xylitol. According to embodi
`ments of the invention directed to a dosage unit and method
`of making a dosage unit suitable for erectile dysfunction, the
`Water solubility of sildena?l in the solid dispersion is at least
`20 mg/ml, more particularly about 50 mg/ml. More
`particularly, the ?lm 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 ?lm; (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 ?lm strip; and (20) is a single
`dose ?lm.
`FIG. 4 demonstrates the disintegration and dissolution
`time of the intraoral delivery system as a function of
`thickness. ——0—— is disintegration time and ——o—— is dis
`solving time.
`FIG. 5 shoWs the release pro?les of -—v—— nicotine,
`——v—— oxybutynin, ——0—— hydromorphone and
`——o—— estradiol.
`FIG. 6 shoWs the pharmacokinetics in six subjects after
`administration of a dissolving ?lm sildena?l formulation
`and after administration of the commercial tablet containing
`the same dosage of sildena?l. Sildena?l ?lm ——O—— Viagra
`"v".
`
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`DETAILED DESCRIPTION OF INVENTION
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`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
`
`DRL - EXHIBIT 1032
`DRL010
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`
`
`US 6,552,024 B1
`
`5
`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 ?lm
`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 ?exible, non-tacky,
`dry conveniently packaged ?lm. Once removed from the
`package and placed on a mucosal surface, the mucosal
`surface-coat-forming ?lm 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 ?lm.
`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 ?lm, 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 ?lm. The thickness of the ?lm is a factor in
`determining the rate of dissolution. Athick ?lm Will dissolve
`more sloWly than an otherWise similar thin ?lm. A thick ?lm
`may be desirable for its holding capacity for active agents
`that are required in high dosages. Although the surface area
`of a ?lm can be adjusted up 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 ?ller
`for purposes of increasing the solubility of the agent When
`released from the ?lm thereby enhancing bioavailability of
`the active agent. This is exempli?ed here by sildena?l Which
`is incorporated in a ?lm With a Water soluble inert ?ller, 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 ?lm. 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 ?lm. A dissolving ?lm 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 ?lm. For
`example, the agent may be dispersed as colloidal particles or
`microencapsulated Within the ?lm or alternatively may be
`mixed throughout the ?lm 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
`?lm as used in this description and in the folloWing claims
`unless speci?ed otherWise , means a ?lm 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 identi?ed in FIG. 1. It further includes a Wound
`surface Where lymph ?uid bathes the tissue surface.
`Embodiments of the present invention include a process,
`composition and method of use for a quick dissolving ?lm
`for local and systemic delivery of pharmaceutical agents to
`a mucosal surface in a subject. In the folloWing text, speci?c
`reference may be made to the oral cavity by Way of example.
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`6
`HoWever, it is not intended to limit the scope of the
`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 ?lms 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 ?lm should be non-sticky
`When removed from the packaging but should have mucoad
`hesive properties When applied in the vagina. Although ?lms
`containing active agents for use in the vagina have been
`used, they appear to have some signi?cant draWbacks most
`particularly the lack of adhesive properties at the mucosal
`surface. This makes these ?lms impractical to administer.
`(US. 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 ?lm on a mucous surface, at Which time the ?lm 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 modi?cation 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
`ci?c 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 ?lm. In some cases, it is desirable for release of the active
`agent to occur after dissolution of the ?lm. 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 ?lm. An example Where
`multiple active agents frequently are administered is cold
`medications, Which often contain several active agents.
`“Coating