PCT
`INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`WO 00/42992
`
`WORLD INTELLECTUAL PROPERTY ORGANIZATION
`lntema1ional Bureau
`
`(51) International Patent Classification 7 :
`A61K 9no
`
`(ll) International Publication Number:
`
`A2
`
`(43) International Publication Date:
`
`27 July 2000 (27.07.00)
`
`(8 1) Designated States: AE, AL, AM, AT, AU, AZ, BA, BB, BG,
`BR, BY, CA, CH, CN, CR, CU, CZ, DE, DK, DM, EE,
`ES, Fl, GB, GD, GE, GH, GM, HR, HU, ID, 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, SG, SI, SK, SL, TJ, TM, TR, TT, TZ, UA, UG,
`UZ, VN, YU, ZA, ZW, ARIPO patent (GH, GM, KE, LS,
`MW, SD, SL, SZ, TZ, UG, ZW), Eurasian patent (AM, AZ,
`BY, KG, KZ, MD, RU, TJ, TM), European patent (AT, BE,
`CH, CY, DE, DK, ES, Ff, PR, GB, GR, IE, IT, LU, MC,
`NL, PT, SE), OAPT patent (BF, BJ, CF, CG, Cl, CM, GA,
`GN, GW, ML, MR, NE, SN, TD, TG).
`
`Published
`Without imernational search report and to be republished
`upon receipt of that reporl.
`
`(21) International Application Number:
`
`PCT/US99/3 t 327
`
`(22) International Filing Date:
`
`30 December 1999 (30.12.99)
`
`(30) Priority Data:
`60/ 116,823
`09/434,878
`
`21 January 1999 (21.01.99)
`5 November 1999 (05.11.99)
`
`us
`us
`
`(7 1) Applicant: LAVIPHARM LABORATORIES, INC. [US/US];
`Suite 6, 131 Ethel Road West, Piscataway, NJ 08854 (US).
`
`(72) Inventors: CHEN, Li-Lan, H.; 3906 Victory Court, Edison,
`NJ 08817 (US). PFISTER, William, R.; 16 Saxony Lane,
`Robbinsville, NJ 08691 (US). RENN, Donald, W.; 4 Brew(cid:173)
`ster Point, Glen Cove, ME 04846--0088 (US). BURANA(cid:173)
`CHOKPA!SAN, Thitiwan; 4 Stout Court, Lawrenceville, NJ
`08648 (US). OSBORNE, James; Lavipharm Laboratories,
`Inc., Suite 6, 131 Ethel Road West, Piscataway, NJ 08854
`(US). TAN, Hock, Seng; 25 Jaime Court, Old Bridge, NJ
`08857 (US). TAO, Li; Lavipharrn Laboratories, Inc., Suite
`6, 131 Ethel Road West, Piscataway, NJ 08854 (US).
`
`(74) Agent: STRIMPEL, HarTiet, M.; Bromberg & Sunstein LLP,
`125 Summer Street, Boston, MA 02110-1618 (US).
`
`(54) Title: COMPOSITIONS AND METHODS FOR MUCOSAL DELIVERY
`
`SIHGtE DOSE FILM 20
`
`SINGLE DOSE F1lM 20
`
`CONTMIR SNAP 170
`LIO CLOSURE 17b~ ::-"\.
`
`fW-31 fW1 m
`~~~
`fw.31 rEitt @) fE:il
`~~~8
`
`1£AT srJL£D POUOf 15
`
`BllS1ER CARO 16
`
`cow.HR 800f 17c
`
`PERFORATED FllM STRIP 19
`
`(57) Abstract
`
`A dosage unit comprising a water~soluble hydrocolloid and a mucosa! surface-coat-forming film, such film including an effective
`dose of active agent. In the dosage un it slidenafil citrate, nicotine, hydromorphone, oxybutynine or estradiol are used as active agents.
`
`Par Pharm., Inc., et al.
`Exhibit 1006
`Page 001
`
`

`

`Codes used to identify States party to the PCT on the front pages of pamphlets publishing intemational applications under the PCT.
`
`FOR THE PURPOSES OF INFORMATION ONLY
`
`AL
`AM
`AT
`AU
`AZ
`BA
`86
`BJ::
`BF
`BC
`BJ
`BR
`BY
`CA
`CF
`cc
`CH
`Cl
`CM
`CN
`cu
`CZ
`DE
`OK
`EE
`
`Albania
`Annenia
`Austria
`Aus1ralia
`Azerbaijan
`Botnia and Hcn.egovina
`Barbados
`Belgium
`Burkina Paso
`Bulgaria
`Benin
`Brazil
`Belarus
`Canada
`Central African Republic
`Coo go
`Swi1urland
`C~e d"lvoire
`Cameroon
`China
`Cuba
`Cicch Republic
`Oennany
`Denmark
`Es1onia
`
`ES
`H
`FR
`CA
`GB
`GE
`GH
`GN
`GR
`HU
`IE
`IL
`IS
`IT
`JP
`KK
`KC
`KP
`
`KR
`KZ
`LC
`LI
`LK
`LR
`
`Spain
`Finland
`France
`Gabon
`United Kingdom
`Georgia
`Ghana
`Guinea
`Greece
`Hungary
`Ireland
`brae I
`Iceland
`Italy
`Japan
`Kenya
`Kyrgyutan
`Democraiic People"s
`Republic of Korea
`Republic or Korea
`Kazakstan
`Saint Lucia
`Liechtenstein
`Sri Lanka
`Liberia
`
`LS
`LT
`LU
`LV
`MC
`MO
`MG
`MK
`
`ML
`MN
`MR
`MW
`MX
`NE
`NL
`NO
`NZ
`Pl.
`PT
`RO
`RU
`so
`SE
`SG
`
`Leso1ho
`Lilhuania
`Luxembourg
`U11via
`Monaco
`Republic or Moldova
`Madagascar
`·111c ronncr Yugoslav
`Republic or M:xedonia
`Mali
`Mongolia
`Mauri1ania
`Malawi
`Mexico
`Niger
`Nethcrlandt
`Norway
`New Zealand
`Poland
`Ponugal
`Romania
`Russian Federal ion
`Sudan
`Sweden
`Singll{lOre
`
`SI
`SK
`SN
`sz
`TO
`TG
`TJ
`TM
`TR
`TT
`UA
`UG
`us
`UZ
`VN
`YU
`zw
`
`Slovenia
`Slovakia
`Senegal
`Swaziland
`Chad
`Togo
`Tajiki$1an
`Turkmenistan
`Turkey
`Trinidad and Tobago
`Ubaine
`Uganda
`United States or America
`Uzbekistan
`Viet Nam
`Yugotlavia
`Zimbabwe
`
`Par Pharm., Inc., et al.
`Exhibit 1006
`Page 002
`
`

`

`WO 00/42992
`
`PCT/US99/31327
`
`COMPOSmONS AND METHODS FOR MUCOSAL DELIVERY
`
`Technical Description
`
`5
`
`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
`
`10 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
`
`15
`
`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
`
`administering medications may be limited for certain patients and may be restricted for
`
`certain diseases and/or treatments. Chewable tablets provide some advantages over the
`
`20
`
`conventional 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.
`
`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
`
`25
`
`from these dosage forms occurs in the gastrointestinal (GI) tract, after the agent has
`
`separated from the dosage form and dissolved in the gastric fluids. For some active
`
`agents. it is desirable to achieve absorption through the oral mucosa! tissues in order to
`
`accelerate onset of the therapeutic effect.
`
`Many acti ve agents are poorly absorbed, even after they are dispersed in the
`
`30
`
`stomach. because of low solubil ity 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
`
`- l -
`
`SUBSTITUTE SHEET (RULE 26)
`
`Par Pharm., Inc., et al.
`Exhibit 1006
`Page 003
`
`

`

`WO 00/42992
`
`PCT /US99/3 1327
`
`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
`
`5
`
`swallowed. Quick dissolving tablets may be formed from a particulate suppon matrix
`
`containing the therapeutic agent. where the particulate support matrix is a protein (US
`
`5,807,576, US 5,635,210, US 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 manufactured from shearlorm matrices which are substantially amorphous sugar
`
`10
`
`formed when crystalline sugar is subjected to heat and shear (WO 95/07194; WO
`
`95/35293). Other methods of forming quick dissolving tablets include wet granulation
`
`methods (EP 0627 218) and dry granulation methods (EP 0124027 Al) and by freeze(cid:173)
`
`drying techniques (EP 0084705A2). Generally, quick dissolving tablets are formed
`
`using complex multi-step manufacturing processes. In addition, these tablets may have
`
`15
`
`poor mechanical strength, are fragile and friable and have insufficient holding capacity
`
`for active ingredients (US 5,720,974) and may be difficult to store and handle.
`
`Therapeutic compounds are sometimes provided as powders 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"
`
`20
`
`and unpleasant taste in the mouth. In the elderly, powders may cause choking and
`
`discomfon 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 geriatric 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
`
`25
`
`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
`
`30
`
`accurately and administer easily. Liquid formulations deteriorate rapidl y upon exposure
`
`to heat or atmosphere and consequently have a relatively shon shelf life. Furthermore.
`
`liquid formulations require a relatively large volume and are bulky to store.
`
`- 2 -
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`SUBSTITUTE SHEET (RULE 26)
`
`Par Pharm., Inc., et al.
`Exhibit 1006
`Page 004
`
`

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`WO 00/42992
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`PCT/US99/31327
`
`In addition to solid and liquid dosage forms. rapidly dissolving buccal/oral
`
`delivery systems have been developed. These systems are commonly freeze dried
`
`preparations which are more expensive to manufacture as compared to tablets (US
`
`5,648,093). Furthermore, freeze dried preparations are brittle and fragile when handled
`
`5
`
`and must be kept in dry conditions to avoid disintegration. The instability of freeze(cid:173)
`
`dried preparations has been reduced somewhat by the addition of mannitol (US
`
`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 (US 4,876,092: EP 0200508;
`
`10 EPO 381194; CA-PS 1-26331; DE 2449865.5; 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 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
`
`15
`
`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
`
`20
`
`traditional oral dosages because they target the oral mucosa. These formu lations include
`
`dosage units containing 75%-90% polyethylene glycol that melt at body temperature, m
`
`the mouth.( US 5,004.601 and 5.135,752) Other formulations include liquid forms,
`
`lozenges or tablets that are administered sublingually or by a sweetened matrix on a
`
`stick. (US 5,770,606. Streisand et al. and Zhang et al., Christie et al., Sasaki et al.).
`
`25 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 delivery systems.
`
`Summary of the Invention
`
`30
`
`A novel dosage unit and its method of manufacture and use is provided. In an
`
`embodiment, the dosage unit includes a water-soluble hydrocolloid, mucosa! surface(cid:173)
`
`coat-forming film, such film including an effective dose of an active agent.
`
`- 3 -
`
`SUBSTITUTE SHEET (RULE 26)
`
`Par Pharm., Inc., et al.
`Exhibit 1006
`Page 005
`
`

`

`WO 00/42992
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`PCT/US99/31327
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`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
`
`exemplified 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
`
`5
`
`agent. a water soluble inert filler, a preservative. a buffeting 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 effective amounts of sildenafil citrate.
`
`nicotine, hydromorphone, oxybutynine or estradiol as active agents in the dosage unit.
`
`10 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. l-10%w. The water inert filler may include a concentration range of
`
`0.5-50% and the preservative may include a concentration range of 0.01-10%. A
`
`15 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 3.5g, more particular less than 2 g, a wet tack
`
`20
`
`value of greater than 35g, a tensile strength greater than lSOOpsi , a modulus in the range
`
`of 35,000-300,000 psi, a tear propagation resistance in the range O.OOlN-lN. a
`
`disintegration time in a range from l -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
`
`25
`
`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 buffeting agent to form a coatable mixture: and
`
`30
`
`forming a mucosa! 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.
`
`- 4 -
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`SUBSTITUTE SHEET (RULE 26)
`
`Par Pharm., Inc., et al.
`Exhibit 1006
`Page 006
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`

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`WO 00/42992
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`PCT/US99/31327
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`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
`
`5
`
`ingredients being mixed during and after the addition of the ingredients to the vessel, an
`
`effective amount of heat being applied for melting a substantial 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, mucosa!
`
`10
`
`surface-coat-forming film, such film including an effective dose of an active agent; and
`
`placing the film on a mucosa! 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-
`
`15
`
`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 dispersion may be mixed with at least one reagent 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
`
`20
`
`dispersion of sildenafil and xylitol may arise at a ratio of 9 parts sildenafil to one part
`
`xylitol. According to embodiments of the invention directed to a dosage unit and method
`
`of making a dosage unit suitable for erectile dysfunction. the water solubility of
`
`si ldenafil in the solid dispersion is at least 20 mg/ml . more particularly about SOmg/ml.
`
`More particularly, the film may be capable of completely dissolution at the oral mucosa)
`
`25
`
`surface within 10-600 seconds.
`
`Brief Description of the Figures
`
`Figure l 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;
`
`30
`
`(5) is the lingual; (6) is the sublingual: (7) is the lower lip.
`
`Figure 2 illustrates one manufacturing process for the dosage unit. (8) is the
`
`- 5 -
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`SUBSTITUTE SHEET (RULE 26)
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`Par Pharm., Inc., et al.
`Exhibit 1006
`Page 007
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`

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`WO 00/42992
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`PCT/US99/31327
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`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.
`
`Figure 3 shows examples of packaging and dispensing devices for the intraoral
`
`5
`
`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.
`
`Figure 4 demonstrates the disintegration and dissolution time of the intraoral
`
`lO
`
`delivery system as a function of thkkness.-- • -- is disintegration time and -- o -- is
`
`dissolving time.
`
`Figure 5 shows the release profiles of -- " -- nicotine, -- " -- oxybutynin,
`
`-- • -- hydromorphone and -- o -- estradiol.
`
`Figure 6 shows the pharmacokinetics in six subjects after administration of a
`
`15
`
`dissolving film sildenafil formulation and after administration of the commercial tablet
`
`containing the same dosage of sildenafi l. Sildenafi l film -- o -- Viagra -
`
`<:J - .
`
`Detailed Description of Invention
`
`Delivery of active agents in solid form via the mouth causes problems to patients
`
`20 who may choke on the dosage unit. This effect is caused at least in part by the mobility
`
`of 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 mucosa! surface,
`
`the film becomes a coating that adheres to the mucosa! surface and then disintegrates and
`
`dissolves over a time frame controlled in the design of the dosage. The dosage unit, in
`
`25
`
`an embodiment 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 mucosa! surface, the
`
`mucosa! surface-coat-forming film hydrates substantially immediately 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.
`
`30
`
`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
`
`- 6 -
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`SUBSTITUTE SHEET (RULE 26)
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`Par Pharm., Inc., et al.
`Exhibit 1006
`Page 008
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`WO 00/42992
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`PCT/US99/31327
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`film. the concentration of the active agent. the solubility of the agent at the mucosa!
`
`surface and how the agent is dispersed throughout the film. The thickness of the film is a
`
`factor in determining the rate of dissolution. A thick film will dissolve more slowly than
`
`an otherwise similar thin film. A thick film may be desirable for its holding capacity for
`
`5
`
`active agents that are required in high dosages. Although the surface area of a film 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 filler for purposes of increasing the solubility
`
`of the agent when released from the film thereby enhancing bioavailability of the active
`
`10
`
`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
`
`mucosa) surface can be controlled by the dissolution rate of the film. A dissolving film
`
`15 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 mucosa!
`
`surface will give rise to increased uptake by the mucosal surface. A further parameter
`
`governing the release of an active agent at the mucosa] surface is the manner in which
`
`the agent is dispersed in the film. For example. the agent may be dispersed as colloidal
`
`20
`
`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 biological or synthetic molecules.
`
`25
`
`The term "mucosa! 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 mucosa] 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. lt should be noted that for purposes of the description of the
`
`30
`
`invention and the claims,
`
`"mucosa! surface" refers to any moist surface of the body. This includes the surfaces
`
`identified in Figure l. It further includes a wound surface where lymph fluid bathes the
`
`- 7 -
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`SUBSTITUTE SHEET (RULE 26)
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`Par Pharm., Inc., et al.
`Exhibit 1006
`Page 009
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`

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`WO 00/42992
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`tissue surface.
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`PCT/US99/31327
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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 fil m for local and systemic delivery of
`
`pharmaceutical agents to a mucosa! surface in a subject. In the following text, specific
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`5
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`reference may be made to the oral cavity by way of example. However, it is not intended
`
`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 mucosa! surface as deemed appropriate for the systemic or local
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`deb very of an active agent including vaginal, rectal, and ocular surfaces. For purposes of
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`oral delivery, the films may be applied on lingual, sub-lingual, buccal, gingival. and
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`10
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`palatal surfaces (Figure l ).
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`For vaginal delivery of such agents as contraceptive agents including nonoxynol
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`or anti-infectives including anti fungal 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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`15 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 mucosa! surface. This makes these films impractical to administer. (US
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`5,380 ,529; 5,595,980 and 5,529,782).
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`Embodiments of the invention provide improved dosage forms to deliver active
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`20
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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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`25
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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 active agents and
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`other active agents that will dissolve and completely release their contents on a moist
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`30 mucosa! 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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`- 8 -
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`SUBSTITUTE SHEET (RULE 26)
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`Par Pharm., Inc., et al.
`Exhibit 1006
`Page 010
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`WO 00/42992
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`PCT/US99/31327
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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: 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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`5
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`cavity; a dosage fonn 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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`swallowing. Depending on the optimal program for a specific application of the
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`10
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`invention, the disintegration time and the dissolution time can be controlled within a
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`prescribed range by adjustment of the formulation and the thickness of the film. In some
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`cases. it is desirable for release of the active agent to occur after dissolution of the film.
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`For these applications, the active agent may be encapsulated in a material with
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`dissolution properties that are different from those of the hydrocolloid. Encapsulation of
`
`15
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`the active agent also may be utilized to achieve masking of taste for active agents that are
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`bitter. In some cases, two or more different active agents may be included in the film.
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`An example where multiple active agents frequently are administered is cold
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`medications, which often contain several active agents.
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`"Coating solution" is defined here and in the claims as a viscous and
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`20
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`homogeneous mixture of hydrocolloids, active agents and other additives in a solvent.
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`The coaung solution is treated according to the method of the invention to form a film.
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`"Subject" is defined here and in the claims as a human or animal species.
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`"Thickness" is defined here and in the claims by measurements in mil (a mil =
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`one thousandth of an inch) determined when a film is placed between two microscopic
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`25
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`slides.
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`"Penneation enhancer" as defined here and in the claims is a natural or synthetic
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`molecule which facilitates the absorption of an active agent through a mucosal surface.
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`"Enzyme inhibitor" as defined here and in the claims is a natural or synthetic
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`molecule which inhibits enzymatic metabolism of an active agent in the saliva or in a
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`30 mucosa! tissue.
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`"Water Content" is defined here and in the claims as % residual water content per
`
`unit dose as measured according to the Karl Fisher method and expressed as percent of
`
`- 9 -
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`SUBSTITUTE SHEET (RULE 26)
`
`Par Pharm., Inc., et al.
`Exhibit 1006
`Page 011
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`

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`W000/42992
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`PCT/US99/31327
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`the dry weight of the film.
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`"The hydration rate" is defined here and in the claims as the speed of absorbing
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`water at 25°C. and 75% relative humidity in 24 hours.
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`"Percentage of swelling" is defined here as a percentage of che initial volume chat
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`5
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`is increased before dissolving. In an embodiment of the invention. che percentage of
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`swelling is less than 10% in 60 seconds.
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`Taste modifying agents include flavoring agents. sweetening agents and taste
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`masking agents and are exemplified by: the essential oils or water soluble extracts of
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`menthol. wincergreen, peppermint, sweet mint, spearmint, vanillin, cherry, chocolate,
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`10
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`cinnamon, clove, lemon, orange, raspberry, rose, spice, violet, herbal, fruit, strawberry,
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`grape, pineapple, peach, kiwi, papaya, mango, coconut, apple, coffee. plum. watermelon,
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`nuts, durean, green tea, grapefruit, banana, butter, camomile, sugar. dextrose, lactose,
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`mannitol. sucrose, xylitol, malitol, acesulfame potassium, talin, glycyrrhizin, sucralose,
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`aspartame, saccharin, sodjum saccharin, sodium cyclamate and honey.
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`15
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`Emulsifying agents include solubilizers and wetting agents and are exemplified
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`by polyvinyl alcohol, sorbitan esters, cyclodextrins, benzyl benzoate, glyceryl
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`monostearate, polyoxyethylene alkyl ethers, polyoxyethylene stearates, poloxamer,
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`polyoxyethylene castor oil derivatives, hydrogenated vegetable oils, bile salts,
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`polysorbates and ethanol.
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`20
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`Plasticizers may include glycerin. sorbitol, propylene glycol, polyethylene glycol,
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`triacetin. triethyl citrate (TEC), acetyl triethyl citrate (A TEC) and other citrate esters.
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`Active agents (for human and veterinary applications) include therapeutic agents.
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`nutritional supplements and hygiene aids. The therapeutic agents are exemplified by
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`analgesics. a-adrenergic receptor blockers, anti-Alzheimer's disease medication,
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`25
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`antianginal. antianxiety, antiarrythmics, antianhritics, antibiotics,
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`anticoagulants/thrombolytics, anticonvulsants/anti-Parkinson medication. anti(cid:173)
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`depressants, anti-diabetics, anti-diarrheal. anti-epileptics, anti-fungal. anti-gout, anti(cid:173)
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`heartworm medication for dogs, anti-histamines, anti-hypertensives, anti-inflammatories,
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`anti-infectives, antimigraines, anti-nasuants/anti-emetics, anti-neoplastics/anti-tumor
`
`30
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`active agents. anti-pruitics, anti-psychotics. anti-pyretics. anti -spasmodics, anti-virals,
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`bronchial dilators/anti-asthmatics. calcium ancagonists, cardiac agents. cardiotonics,
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`central nervous system actives. contraceptives. coronary vasodilators. cough/cold
`
`- lO -
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`SUBSTITUTE SHEET (RULE 26)
`
`Par Pharm., Inc., et al.
`Exhibit 1006
`Page 012
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`WO 00/42992
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`PCT/US99/31327
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`remedies. dietary supplements. including vitamins and minerals. diuretics, fertility active
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`agents. flea control agents for animals (lvermectin), H1 receptor antagonists, herbal
`actives. hormones, hypoglycemics. hypolipidemics. muscle relaxants, ovulation
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`stimulators, peptide active agents, polypeptide active agents, proteins such as insulin.
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`5
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`calcitonin, LHRH and the like. Sedatives and hypnotics, sexual dysfunction active
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`agents. sleep aids. smoking cessation aids. steroids and steroidals, tranquilizers,
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`laxatives, ophthalmic preparations. nutritional supplements, breath fresheners, breath
`
`deodorants, saliva substitutes, antigingivitis agents. anti-cavity agents. anti-plaque
`
`agents. diagnostic indicators, and local anesthetics. Also included are active agents for
`
`10
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`treatment of osteoporosis, hormone replacement, treatment of periodontal disease,
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`antiseptics. corticosteroids, non steroidal anti-inflammatory agents. antiviral agents and
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`vaccines.
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`Water soluble inert fillers include mannitol, xylitol, sucrose, lactose,
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`maltodextrin , dextran, dextrin, modified starche