`Intematronal Bureau
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`
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`INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
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`(5|) International Patent Classification 7 =
`A61K 9no
`
`(11) International Publication Number:
`(43) International Publication Date:
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`WO 00142992
`27 July 2000 (27.07.00)
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`(21) International Application Number:
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`PCT/US99/31327
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`(22) International Filing Date:
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`30 December 1999 (30.12.99)
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`(30) Priority Data:
`60/ 1 16.823
`09/434,878
`
`21 January 1999 (21.01.99)
`5 November 1999 (05.11.99)
`
`US
`US
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`(71) Applicant: LAVIPHARM LABORATORIES. INC. [US/US]:
`Suite 6. 131 Ethel Road West. Piscataway, NJ 08854 (US).
`
`(81) Designated States: AE, AL. AM. AT. AU. AZ. BA. BB. BG.
`BR. BY. CA. CH. CN. CR. U. CZ. DE. DK. DM. EB.
`ES. FI. GB, GD. GE. GH. GM. HR. HU. 1D, IL. IN. IS. JP.
`KE. KG. KP. KR. KZ. LC. LK. LR. LS. LT. LU. LV. MA.
`MD. MG. MK. MN. MW. MX. NO. NZ. PL. PT, RO. RU.
`SD. SE. 86. SI. SK, SL. TJ. TM. 11!. TI‘. Tl. UA. UG.
`UZ. VN. YU. ZA. ZW. ARIPO patent (GI-1. GM. KE, LS.
`MW. SD. S
`SZ. TZ, UG. ZW). Eurasian patent (AM. AZ.
`BY. KG. KZ. MD. RU. TJ. TM). European patent (AT, BE.
`CH. CY. DE. DK. ES. FI. FR. GB. GR. IE, IT, LU. MC.
`NL. PT. SE). OAPI patent (BF. BJ. CF. CG. CI. CM. GA.
`GN. GW. ML. MR. NE, SN. TD. TO).
`
`(72) Inventors: CHEN. Li—Lan. H.; 3906 Victory Court. Edison.
`NJ 088|7 (US). PFISTER. William. R.; 16 Saxony lane. Published
`Robbinsville. NJ 08691 (US). RENN. Donald, W.: 4 Brew-
`Without international search report and to be republished
`stcr Point. Glen Cove. ME 04846-0088 (US). BURANA-
`upon receipt of that report.
`CHOKPAISAN, 'l'hitiwan; 4 Stout Court. Lawrencevilie. NJ
`08648 (US). OSBORNE, James; Lavipharm Laboratories.
`inc.. Suite 6. I31 Ethel Road West. Piscataway. NJ 08854
`(US). TAN. Hock. Song; 25 Jaime Court. Old Bridge. NJ
`08857 (US). TAO. Li; Lavipharrn Laboratories. 1nc.. Suite
`6.
`I31 Ethel Road West. Piscataway. NJ 08854 (US).
`
`(74) Agent: STRIMPEL. Harriet. M.; Bromberg & Sunstein LLP.
`IZS Summer Street. Boston. MA 02110—1618 (US).
`
`(54) Title: COMPOSITIONS AND METHODS FOR MUCOSAL DELIVERY
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`WWW:
`\ mmnxn—
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`‘L
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`’3;
`momma
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`"
`“ '3
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`mam: FILMS!" 19
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`(51) Abstract
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`A dosage unit comprising a water—soluble hydrocolloid and a mucosal surface-coat—forming film. such film including an effective
`dose of active agent.
`in the dosage unit siidenatil citrate. nicotine. hydromorphone. oxybutynine or estradiol are used as active agents.
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`Dr- Reddy's - EX1006
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`Page 1
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`FOR THE PURPOSES 0F INFORJM NON ONLY
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`Codes used to identify States party to the PCI‘ on the front pages of pamphlets publishing international applications under the PCT.
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`EEififiSEdfiida‘éifififia
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`Tithe;
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`Trimmide
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`UM
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`Anal:th
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`Dania and Renegade:
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`Belgium
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`Bettina I‘m
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`Salaam
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`Benin
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`Brazil
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`Mann
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`Canada
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`Central arrim Republic
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`Conan
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`Switzerland
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`can d'Ivolle
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`Czech Republle
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`Gummy
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`Estonia
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`Al.
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`Republic of Moldova
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`The form Yugoslav
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`Malawi
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`Nice:
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`Norway
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`Noam
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`Roland
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`WI
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`Mania
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`Russian Few-mien
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`Sudan
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`Sweden
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`Slngapore
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`saosszaazfiaaiifii
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`Page 2
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`W0 W42992
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`PCTRJS99131327
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`COMPOSITIONS AND METHODS FOR MUCOSAL DELIVERY
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`Tet:
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`The present invention is directed to a device and method for administering agents
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`in a dissolving film configuration.
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`Backggggnd t9 the Inventign
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`Many pharmaceutical dosage forms are administrated orally in the form of solid
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`shaped articles such as tablets. pills. caplets and capsules that retain their shape under
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`moderate pressure. Generally these dosage forms are designed to be swallowed whole or
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`chewed to deliver the medication with adequate amounts of liquid. Some patients.
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`particularly pediatric and geriatric patients. have difficulty swallowing or chewing solid
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`dosage forms. Certain patients such as children or animals resist taking medication. and
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`may try to hide a solid pill in order to spit it cut later. In addition. many pediatric and
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`geriatric patients are unwilling to take a solid dosage form because the active agent is
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`difficult to swallow or is retained in the pharynx or gullet even when liquids are
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`consumed with the dosage unit. Furthermore. the availability of liquids at the time of
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`administering medications may be limited for certain patients and may be restricted for
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`certain diseases andfor treatments. Chewable tablets provide some advantages over the
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`conventional tablets. However. they are not suitable for children wearing braces and the
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`taste of the medication may be unpleasant and difficult to mask in a chewable tablet. At
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`the same time, water may be still required for the administration of chewable tablets.
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`In addition. the standard oral dosage forms. such as tablets, pills. caplets. and
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`capsules. are designed for short residence time in the mouth. Absorption of the agent
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`from these dosage forms occurs in the gastrointestinal (GI) tract. after the agent has
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`separated from the dosage form and dissolved in the gastric fluids. For some active
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`agents. it is desirable to achieve absorption through the oral mucosal tissues in order to
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`accelerate onset of the therapeutic effect.
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`Many active agents are poorly absorbed. even after they are dispersed in the
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`stomach. because of low solubility or slow dissolution rate in the gastric fluids. Tablets
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`may be formulated so as to be quick dissolving. These tablets are commonly placed on
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`the tongue and disintegrate rapidly in the oral cavity. However. these dosage units are
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`-1-
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`SUBSTITUTE SHEET (RULE 26)
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`Page 3
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`Page 3
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`W0 00.342992
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`PCTHJS9981327
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`not fixed to a mucosal surface and may move around in the mouth. Consequently. they
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`do not overcome a risk associated with choking or gagging that occurs with subjects
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`having limited control of their swallowing reflexes. However. once placed in the mouth.
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`these tablets dissolve rapidly in the saliva to provide a liquid formulation which is then
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`swallowed. Quick dissolving tablets may be formed from a particulate support matrix
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`containing the therapeutic agent. where the particulate support matrix is a protein (US
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`5.807.576. US 5,635,210. US 5,595,761). Alternatively. the tablet may be formed from
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`a laminate with several layers and an outer coating (JP 100535518). Tablets have also
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`been manufactured from shearform matrices which are substantially amorphous sugar
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`formed when crystalline sugar is subjected to heat and shear (WO 95(07194; W0
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`9585293). Other methods of forming quick dissolving tablets include wet granulation
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`methods (EP 0627 218) and dry granulation methods (EP 0124027Al) and by freeze-
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`drying techniques (EP 0084705A2). Generally. quick dissolving tablets are formed
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`using complex multi-step manufacturing processes.
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`in addition. these tablets may have
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`poor mechanical strength. are fragile and friable and have insufficient holding capacity
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`for active ingredients (US 5320.974) and may be difficult to store and handle.
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`Therapeutic compounds are sometimes provided as powders or granules which
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`may be difficult to swallow and cause unpleasant sensations in the mouth. Furthermore.
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`many quick dissolving tablets contain particulates (>25 microns) which leave a “gritty”
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`and unpleasant mate in the mouth. In the elderly, powders may cause choking and
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`discomfort associated with trapping of granules in dentures. Powders and granules are
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`generally packaged in a sealed pouch which requires tearing before use. This causes
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`problems for geriatric patients and those suffering from arthritis in the fingers as well as
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`for children. Consequently, problems of spillage of the contents arise in this group of
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`patients. Furthermore. these oral preparations should be taken with water which for
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`certain patients are incanvenient and may cause reduced patient compliance.
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`Liquid. syrups or suspensions are an alternative to solid dosage forms and are
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`considered desirable for pediatric and geriatric patients who have problems in
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`swallowing tablets. However, these dosage forms are often difficult to measure
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`accurately and adminismr easily- Liquid formulations deteriorate rapidly upon exposure
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`to heat or atmosphere and consequently have a relatively short shelf life. Furthermore.
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`liquid formulations require a relatively large volume and are bulky to store.
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`SUBSTITUTE SHEET (RULE 26)
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`Page 4
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`Page 4
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`W0 00MI992
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`PCTIUS993 1327
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`In addition to solid and liquid dosage forms. rapidly dissolving buccalforal
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`delivery systems have been developed. These systems are commonly freeze dried
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`preparations which are more expensive to manufacture as compared to tablets (US
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`5.648.093). Fumber-more. freeze dried preparations are brittle and fragile when handled
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`and must be kept in dry conditions to avoid disintegration. The instability of freeze-
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`dried preparations has been reduced somewhat by the addition of mannitol (US
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`4,946,684). W0 9820862 reports a film that is formed according to a method that does
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`not utilize freeZe drying and avoids problems described in the art such as rigidity of the
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`films. delayed softening and poor solubility in the mouth (US 4,876,092; EP 0200508:
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`EPO 381194; CA-PS 1-26331; DE 24498655; DE 3630603; EP 0452446 and EP
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`0219762). However. the film described in W0 9820862 relies on the use of at least two
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`different non-ionic surfactants to achieve inunediate wettability.
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`it is desirable that a dosage unit should provide a non~invasive, effective and
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`economic means to deliver an active agent to the target site. Where the target site is the
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`plasma. additional issues arise concerning the rate of delivery of the active agent to that
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`site as measured by bioavailability. For many types of active agent. fast onset of the
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`therapeutic effect is desirable. Traditional oral dosages, such as tablets. are limited in
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`onset time by the rate of absorption in the gastrointestinal tract. Formulations have
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`been developed which. when applied in the mouth. lead to faster onset that the
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`traditional oral dosages because they target the oral mucosa. TheSe formulations include
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`dosage units containing 75%—90% polyethylene glycol that melt at body temperature, in
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`the mouth.( US 5.004.60l and 5.135.752) Other formulations include liquid forms.
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`lozenges or tablets that are administered sublingually or by a sweetened matrix on a
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`stick. (US 5.7?0,606. Streisand et a1. and Zhang et al.. Christie et al.. Sasaki et al.).
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`Whereas the above references address the delivery route. they do not address the
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`problems of bioavailability that arise from poor solubility or low dissolution rate.
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`A delivery device that addresses the above limitations would represent a
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`desirable improvement on existing delivery systems.
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`Sammy 9f the Invention
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`A novel dosage unit and its method of manufacture and use is provided.
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`In an
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`embodiment. the dosage unit inciudes a water-soluble hydrocolloid. mucosal surface-
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`coat—forming film, such film including an effective dose of an active agent.
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`SUBSTITUTE SHEET (RULE 26)
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`Page 5
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`Page 5
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`In an embodiment of the invention. the hydrooolloid includes a polymer selected from
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`the group consisting of a natural. semi-natural and synthetic biopolymer being
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`exemplified by a polysaccharide and a polypeptide.
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`In addition to the hydrocolloid. the
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`film may further include one or more of an emulsifier. a plasticizer. a taste modifying
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`agent. a water soluble inert tiller. a preservative. a buffering agent. a Coloring agent. a
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`permeation enhancer. and a stabilizer. The film may further include an active agent
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`selected from the group consisting of a therapeutic agent. a dietary supplement and a
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`hygiene aid. Embodiments of the invention utilize effective amounts of sildenafil citrate.
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`nicotine, hydromorphone . oxybutynine or estradiol as active agents in the dosage unit.
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`The active agent may be encapsulated within a second polymer having dissolution
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`properties that are different from those of the hydrocolloid. More than one active agent
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`may be included in the film. In an embodiment of the invention. the emulsifier may have
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`a concentration of 0.1-10%w. The water inert filler may include a concentration range of
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`05—50% and the preservative may include a concentration range of {101-1095. A
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`mucosa] adhesion enhancer such as starch graft copolymer may be included in the
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`dosage unit.
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`In embodiments of the invention. the dosage unit may further include any of the
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`following features: a dry film thickness in the range of 1-20 mil. more particularly less
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`than 10 mils. a dry tack value of less than 3.5g, more particular less than 2 g. a wet tack
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`value of greater than 35g, a tensile strength greater than lSOOpsi, a modulus in the range
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`of 35.000—300.000 psi. a tear propagation resistance in the range 0.001N-1N. a
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`disintegration time in a range from 1-300 seconds. a dissolution time in a range from 10-
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`600 seconds. and a percentage elongation less than 20%.
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`In embodiments of the invention. methods are provided for making a dosage
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`unit. that include in one embodiment. dissolving a hydrocolloid in a solvent so as to form
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`a subStantially homogeneous preparation: adding to the hydrocolloid preparation. an
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`acrive agent and at least one reagent Selected from the group Consisting of an emulsifier.
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`a plasticizer. a taste modifier. a water soluble inert filler. a coloring agent. a preservatiVe.
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`a permeation enhancer. a stabilizer and a buffering agent to form a coatable mixture: and
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`30
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`forming a mucosai surface-coat forming film from the mixture for packaging as a dosage
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`unit. The method may further include the step of coating the mixture onto a backing
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`film. In a further embodiment. the reagents including: a hydrocolloid. an active agent.
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`-4-
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`Page 6
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`Page 6
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`W0 00MZ992
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`and at least one reagent selected from the group consisting of an emulsifier. a plasticizer.
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`a taste modifier. a water soluble inert filler. a coloring agent. a preservative. a
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`permeation enhancer. :1 stabilizer. and a buffering agent. may be combined in any order
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`in a vessel having a heating source and a mechanical mixing device. the combined
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`ingredients being mirted during and after the addition of the ingredients to the vessel. an
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`effective amount of heat being applied for melting a substantial portion of the mixture.
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`The mixture may then be formed into a film in a dry extrusion process.
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`In an embodiment of the invention. a method is provided for administering an
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`active agent to a subject. that includes obtaining a water~soluble hydrocolloid, mucosa]
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`10
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`surface-coat-forming film. such film including an effective dose of an active agent: and
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`placing the film on a mucosal surface coat forming film in the subject: so as to release
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`the active agent.
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`In a further embodiment of the invention. a dosage unit is provided that includes
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`a water soluble hydrooolloid and an effective dose of sildenafil citrate in a mucosal-
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`surface contacting film. More particularly, an effective dose of sildenafil citrate is
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`formed into a solid dispersion with xylitol for treating erectile dysfunction. The
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`sildenafilfxylitol dispersion may be mixed with at least one reagent selected from the
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`group consisting of an emulsifier. a plasticizar. a taste modifier. a coloring agent. a
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`preservative, a permeation enhancer, a stabilizer and a buffering agent. The solid
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`20
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`dispersion. of sildenafil and xylitol may arise at a ratio of 9 parts sildenafil to one part
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`xylitol. According to embodiments of the invention directed to a dosage unit and method
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`of making a dosage unit suitable for erectile dysfunction. the water solubility of
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`sildenafil in the solid dispersion is at least 20 mglml. more particularly about 50mglml.
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`More particularly, the film may be capable of completely diesolution at the oral mucosal
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`surface within 10—600 seconds.
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`'ef
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`f th Fi
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`Figure 1 shows possible application sites in the oral cavity for the inventive
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`dosage unit. (1) is the upper lip: (2) is the gingiva: (3) is the hard palate: (4) is the cheek;
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`(5) is the lingual: (6) is the sublingual: (7) is the lower lip.
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`Figure 2 illusu'ates one manufacturing process for the dosage unit. (8) is the
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`-5-
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`Page 7
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`Page 7
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`W0 00!42992
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`PCTfUS99f31327
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`mixing and degassing tank: (9) is the coating siot with thickness controller. (10) is the
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`polyester backing belt: (11) is the drying oven with aeration controller: (12} is the
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`intraoral film: (13) is the die cutting and (14) is the intraoral unit dose.
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`Figure 3 shews examples of packaging and dispensing devices for the intraoral
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`delivery system. (15) is a heat sealed single pouch: (16) is a multi—unit blister card: (I?)
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`is a multi-unit diSpensing pack. 17(3) the container snap and 17(b) the lid closure: (18) is
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`a multi-unit toll-type dispenser cylinder. (19) is a perforated film strip; and (20) is a
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`single dose film.
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`Figure 4 demonstrates the disintegration and disaolution time of the intraoral
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`delivery system as a function of thickness.-— - -- is disintegration time and -— 0 -- is
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`Figure 5 shows the release profiles of -— t -- nicotine. - v - oxybutynin.
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`-- - —- hydromorphone and — 0 -— estradiol.
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`Figure 6 shows the pharmacokinetics in six subjects after administration of a
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`dissolving film sildenafil formulation and after administration of the commercial tablet
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`containing the SMe dosage of sildenafil. Sildenafil film -— O - Viagra —- v -.
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`Dgtaiigd Description 9f lgvgntign
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`Delivery of active agents in solid form via the mouth causes problems to patients
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`who may choke on the dosage unit. This effect is caused at least in part by the mobility
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`of the dosage unit within the mouth. We have developed a new class of dosage units
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`which are not mobile in the month because on contact with the moist mucosal surface.
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`the film becomes a coating that adheres to the mucosal surface and then disintegrates and
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`dissolves over a time frame controlled in the design of the dosage. The dosage unit. in
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`25
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`an embodiment of the invention, is in the form of a flexible, non-tacky, dry conveniently
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`packaged film. Once removed from the package and placed on a mucosal surface.
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`the
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`mucosal surface-coat-forming film hydrates substantially immediately to form a coating
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`on the moist surface of the mucous membrane and then disintegrates and diSSolves to
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`release the active agent from the film.
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`The dosage unit may release the active agent over a period of time that is
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`determined by a number of different factors. These factors include the dimensions of the
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`W0 W429”
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`PCTIUS99131 32?
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`film. the concentration of the active agent. the solubility of the agent at the mucosal
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`surface and how the agent is dispersed throughout the film. The thickness of the film is a
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`factor in determining the rate of dissolution. A thick film will dissolve more slowly than
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`an otherwise similar thin film. A thick film may be desirable for its holding capacity for
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`active agents that are required in high dasages. Although the surface area of a film can
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`be adjusted up to about 5 square centimeters. increased thickness may also be desirable
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`for purposes of achieving effective active agent dosages. The active agent can form a
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`solid dispersion with a water soluble inert filler for purposes of increasing the solubility
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`of the agent when released from the film thereby enhancing bioavailability of the active
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`agent. This is exemplified here by sildenafil which is incorporated in a film with a water
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`soluble inert filler. for example. xylitol. which has been found here to enhance the
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`bioavailability of this agent. Solubilizing agents that are well known in the art may be
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`included in the film. The extent of uptake of the active agent from the dosage unit at the
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`mucosal surface can be controlled by the dissolution rate of the film. A dissolving film
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`will release the active agent and this in turn will cause the active agent to be swallowed
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`and taken up in the GI tract. In contrast. slow release of the active agent at the mucosal
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`surface will give rise to increased uptake by the mucosal surface. A further parameter
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`governing the release of an active agent at the mucosal surface is the manner in which
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`the agent is dispersed in the film. For example. the agent may be diSpersed as colloidal
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`particles or micrOencapsulated within the film or alternatively may be mixed throughout
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`the film as a reagent during casting.
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`The dosage unit of the invention may be used as a vehicle for delivering a wide
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`range of active agents. For example. the active agent may be a small molecule. a protein.
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`a nucleic acid including antisense molecules or other biological or synthetic molecules.
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`The term "mucosal surface-coat-forming“ as applied to a film as used in this
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`description and in the following claims unless specified otherwise . means a film that
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`coats the mucosal surface on contact. and may not thereafter be manually recovered or
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`moved from the contact site: and subsequently disintegrates and dissolves so as to
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`release the active agent. It should be noted that for purposes of the description of the
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`invention and the claims.
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`“mucosal surface" refers to any moist surface of the body. This includes the surfaces
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`identified in F1 gure I. It further includes a wound surface where lymph fluid bathes the
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`-7-
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`SUBSTITUTE SHEET (RULE 26)
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`Page 9
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`Page 9
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`W0 00.342992
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`tissue surface.
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`PCT{U89931321r
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`Embodiments of the present invention include a process. composition and
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`method of use for a quick dissolving film for local and systemic delivery of
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`pharmaceutical agents to a mucosa] surface in a subject. In the following text. specific
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`reference may be made to the oral cavity by way of example. However. it is not intended
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`to limit the scope of the invention to the oral cavity. The dosage unit of the invention
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`may be applied to any mucosal surface as deemed appropriate for the systemic or local
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`delivery of an active agent including vaginal, rectal. and ocular surfaces. For purpoaes of
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`oral delivery, the films may be applied on lingual. sub-lingual. buccal. gingival. and
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`palatal surfaces (Figure 1).
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`For vaginal delivery of such agents as contraceptive agents including nonoxynol
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`or anti-infectives including antifungal agents. antibacterial agents and anti~viral agents.
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`or fragrant or hygiene agents; the film should be non-sticky when removed from the
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`packaging but should have mucoadhesive properties when applied in the vagina.
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`Although films containing active agents for use in the vagina have been used. they
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`appear to have some significant drawbacks most particularly the lack of adhesive
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`properties at the mucosal surface. This makes these films impractical to administer. (US
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`5.380.529; 5.595.930 and 5.529.782).
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`Embodiments of the invention provide improved dosage forms to deliver active
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`agents that are appropriate for all age groups and that physician. parents. patients and
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`family members can administer easily. These dosage forms are economical to prepare
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`and have an extended shelf life. They are easy to handle and non-tacky before
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`administration so as to avoid disintegration prior to use and are conveniently packaged
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`for shelf life. ease of storage and distribution. The dosage form may be administered to
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`the subject by placing the film on a mucous surface. at which time the film becomes a
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`mucoadhesive coating, characterized by the property that it can no longer exist in an
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`independent form and is subsequently dispersed in solution.
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`Embodiments of the invention provide a delivery system for acrive agents and
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`other active agents that will dissolve and completely release their contents on a moist
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`mucosal surface -for example in the oral cavity. The release of the active agent occurs
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`without mastication or the need for intake of water. With particular reference to the oral
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`cavity. an embodiment of the invention provides active agents that remain in the oral
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`SUBSTITUTE SHEET (RULE 26)
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`Page 10
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`Page 10
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`Page 11
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`WO 00142992
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`PCTIUS99131327
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`cavity for treatment or modification of the oral environment: for example. for
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`periodontal disease treatment or breath-odor control. Furthermore, embodiments of the
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`invention further provide improvements that include:
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`improved organoleptic properties
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`(smell and taste). and texture and feel of dosage forms intended to be placed in the oral
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`cavity; a dosage form which “melts” in the mouth and leaves a smooth pleasant after feel
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`following dissolution: and a prolonged retention of the active agent in the mouth
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`following dissolution of the quick dissolving dosage form to extend the residence time of
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`the active agent cleared from the mouth by the production of saliva and subsequent
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`swallo