`
`WORLD INTELLECTUAL PROPERTY ORGANIZATION
`International Bureau
`
`
`
`INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`
`(51) International Patent Classification 7 :
`
`(11) International Publication Number:
`
`WO 00/42992
`
`A61K 9/70
`
`(43) International Publication Date:
`
`27 July 2000 (27.07.00)
`
`(81) Designated States: AE, AL, AM, AT, AU, AZ, BA, BB, BG,
`BR, BY, CA, CH, CN, CR, CU, CZ, DE, DK, DM, EE,
`ES, FI, 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, TI‘, 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, 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, TG).
`
`Published
`
`Without international search report and to be republished
`upon receipt of that report.
`
`(21) International Application Number:
`
`PCT/US99/31327
`
`(22) International Filing Date:
`
`30 December 1999 (30.12.99)
`
`(30) Priority Data:
`60/ 1 16,823
`09/43 4,878
`
`21 January 1999 (2l.01.99)
`5 November 1999 (05.1 1.99)
`
`US
`US
`
`(71) 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-
`ster Point, Glen Cove, ME 04846-0088 (US). BURANA-
`CHOKPAISAN, 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; Lavipharm Laboratories, Inc., Suite
`6, 131 Ethel Road West, Piscataway, NJ 08854 (US).
`
`(74) Agent: STRIMPEL, Harriet, M.; Bromberg & Sunstein LLP,
`125 Summer Street, Boston, MA 021l0—1618 (US).
`
`(54) Title: COMPOSITIONS AND METHODS FOR MUCOSAL DELIVERY
`
`DOSEHLMZO
`
`SINGLEDOSEFILMZO
`
`CONTAINER SNAP 170
`
`UD CLOSURE 17b\,\
`
`BI.ISTER CARD 16
`
`CONTAINER BODY 17c
`
`— ROI.L'IYPE DISPENSER 18
`
`‘\
`
`_ in
`PERFORATED FILM STRIP 19
`
`(57) Abstract
`
`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 slidenafil citrate, nicotine, hydromorphone, oxybutynine or estradiol are used as active agents.
`
`TEVA EXHIBIT 1005
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC
`
`TEVA EXHIBIT 1005
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC
`
`
`
`FOR THE PURPOSES OF INFORMATION ONLY
`
`Codes used to identify States party to the PCT on the front pages of pamphlets publishing international applications under the PCT.
`
`Albania
`Armenia
`Austria
`Australia
`Azerbaijan
`Bosnia and Herzegovina
`Barbados
`Belgium
`Burkina Faso
`Bulgaria
`Benin
`Brazil
`Belarus
`Canada
`Central African Republic
`Congo
`Switzerland
`Cote d‘Ivoire
`Cameroon
`China
`Cuba
`Czech Republic
`Germany
`Denmark
`Estonia
`
`ES
`FI
`FR
`GA
`GB
`GE
`GH
`GN
`GR
`HU
`IE
`IL
`IS
`IT
`JP
`KE
`KG
`KP
`
`KR
`KZ
`LC
`LI
`LK
`LR
`
`Spain
`Finland
`France
`Gabon
`United Kingdom
`Georgia
`Ghana
`Guinea
`Greece
`Hungary
`Ireland
`Israel
`Iceland
`Italy
`Japan
`Kenya
`Kyrgyzstan
`Democratic People's
`Republic of Korea
`Republic of Korea
`Kazakstan
`Saint Lucia
`Liechtenstein
`Sri Lanka
`Liberia
`
`LS
`LT
`LU
`LV
`MC
`MD
`MG
`MK
`
`ML
`MN
`MR
`MW
`MX
`NE
`NL
`NO
`NZ
`PL
`PT
`RO
`RU
`SD
`SE
`SG
`
`Lesotho
`Lithuania
`Luxembourg
`Latvia
`Monaco
`Republic of Moldova
`Madagascar
`The former Yugoslav
`Republic of Macedonia
`Mali
`Mongolia
`Mauritania
`Malawi
`Mexico
`Niger
`Netherlands
`Norway
`New Zealand
`Poland
`Portugal
`Romania
`Russian Federation
`Sudan
`Sweden
`Singapore
`
`SI
`SK
`SN
`SZ
`TD
`TG
`TJ
`TM
`TR
`TT
`UA
`UG
`US
`UZ
`VN
`YU
`ZW
`
`Slovenia
`Slovakia
`Senegal
`Swaziland
`Chad
`Togo
`Tajikistan
`Turkmenistan
`Turkey
`Trinidad and Tobago
`Ukraine
`Uganda
`United States of America
`Uzbekistan
`Viet Nam
`Yugoslavia
`Zimbabwe
`
`TEVA EXHIBIT 1005
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC
`
`TEVA EXHIBIT 1005
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC
`
`
`
`WO 00/42992
`
`PCT/US99/31327
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`COMPOSITIONS AND METHODS FOR MUCOSAL DELIVERY
`
`Technical Description
`
`The present invention is directed to a device and method for administering agents
`
`in a dissolving film configuration.
`
`Background to the Invention
`
`Many pharmaceutical dosage forms are administrated orally in the form of solid
`
`shaped articles such as tablets, pills, Caplets and capsules that retain their shape under
`
`moderate pressure. Generally these dosage forms are designed to be swallowed whole or
`
`chewed to deliver the medication with adequate amounts of liquid. Some patients,
`
`particularly pediatric and geriatric patients, have difficulty swallowing or chewing solid
`
`dosage forms. Certain patients such as children or animals resist taking medication, and
`
`may try to hide a solid pill in order to spit it out later.
`
`In addition, many pediatric and
`
`geriatric patients are unwilling to take a solid dosage form because the active agent is
`
`difficult to swallow or is retained in the pharynx or gullet even when liquids are
`
`consumed with the dosage unit. Furthermore, the availability of liquids at the time of
`
`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
`
`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
`
`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 mucosal tissues in order to
`
`accelerate onset of the therapeutic effect.
`
`Many active agents are poorly absorbed, even after they are dispersed in the
`
`stomach. because of low solubility or slow dissolution rate in the gastric fluids. Tablets
`
`may be formulated so as to be quick dissolving. These tablets are commonly placed on
`
`the tongue and disintegrate rapidly in the oral cavity. However, these dosage units are
`
`-1-
`
`TEVA EXH.B.T1005
`SUBSTITUTE SHEET (RULE 26)
`TEVA PHARMACEUTICALS USA, INC. v. IVIONOSOL RX, LLC
`
`TEVA EXHIBIT 1005
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC
`
`
`
`WO 00/42992
`
`PCT/US99/31327
`
`not fixed to a mucosal surface and may move around in the mouth. Consequently, they
`do not overcome a risk associated with choking or gagging that occurs with subjects
`having limited control of their swallowing reflexes. However, once placed in the mouth,
`
`these tablets dissolve rapidly in the saliva to provide a liquid formulation which is then
`
`swallowed. Quick dissolving tablets may be formed from a particulate support matrix
`
`containing the therapeutic agent. where the 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 shearforrn matrices which are substantially amorphous sugar
`formed when crystalline sugar is subjected to heat and shear (WO 95/07194; WO
`
`10
`
`95/35293). Other methods of forming quick dissolving tablets include wet granulation
`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 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”
`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 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
`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 deteriorate 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.
`
`15
`
`25
`
`30
`
`-2-
`
`TEVA EXH,B,T10o5
`SUBSTITUTE SHEET (RULE 26)
`TEVA PHARMACEUTICALS USA, INC. v. IVIONOSOL RX, LLC
`
`TEVA EXHIBIT 1005
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC
`
`
`
`WO 00/42992
`
`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
`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
`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;
`EPO 381194; CA—PS l—2633l; 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
`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.( 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.).
`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.
`
`Summagg of the Invention
`
`In an
`A novel dosage unit and its method of manufacture and use is provided.
`embodiment, the dosage unit includes a water—soluble hydrocolloid, mucosal surface-
`
`coat—forming film, such film including an effective dose of an active agent.
`
`-3-
`
`10
`
`15
`
`20
`
`25
`
`30
`
`TEVA EXH,B,T 1005
`SUBSTITUTE SHEET (RULE 26)
`TEVA PHARMACEUTICALS USA, INC. V. IVIONOSOL RX, LLC
`
`TEVA EXHIBIT 1005
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC
`
`
`
`WO 00/42992
`
`PCT/US99/31327
`
`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
`agent, a water soluble inert filler, a preservative, a buffering agent, a coloring agent, a
`permeation enhancer, and a stabilizer. The film may further include an active agent
`selected from the group consisting of a therapeutic agent, a dietary supplement and a
`hygiene aid. Embodiments of the invention utilize effective amounts of sildenafil citrate.
`
`nicotine, hydromorphone , oxybutynine or estradiol as active agents in the dosage unit.
`The active agent may be encapsulated within a second polymer having dissolution
`properties that are different from those of the hydrocolloid. More than one active agent
`may be included in the film. In an embodiment of the invention, the emulsifier may have
`a concentration of 0.1-10%w. The water inert filler may include a concentration range of
`0.5-50% and the preservative may include a concentration range of 0.01-10%. A
`
`mucosal adhesion enhancer such as starch graft copolymer may be included in the
`
`dosage unit.
`
`In embodiments of the invention, the dosage unit may further include any of the
`following features: a dry film thickness in the range of 1-20 mil, more particularly less
`than 10 mils, a dry tack value of less than 3.5g, more particular less than 2 g, a wet tack
`value of greater than 35g, a tensile strength greater than l500psi, a modulus in the range
`of 235,000-300,000 psi, a tear propagation resistance in the range 0.00lN—lN. a
`disintegration time in a range from I-300 seconds, a dissolution time in a range from I0-
`600 seconds, and a percentage elongation less than 20%.
`
`l0
`
`15
`
`20
`
`25
`
`In embodiments of the invention, methods are provided for making a dosage
`unit, that include in one embodiment, dissolving a hydrocolloid in a solvent so as to form
`
`a substantially homogeneous preparation: adding to the hydrocolloid preparation, an
`active agent and at least one reagent selected from the group consisting of an emulsifier,
`a plasticizer, a taste modifier, a water soluble inert filler, a coloring agent, a preservative.
`a permeation enhancer, a stabilizer and a buffering agent to form a coatable mixture; and
`forming a mucosal surface-coat forming film from the mixture for packaging as a dosage
`unit. The method may further include the step of coating the mixture onto a backing
`film.
`In a further embodiment, the reagents including: a hydrocolloid, an active agent,
`
`30
`
`-4-
`
`TEVA EXHW 1005
`SUBSTITUTE SHEET (RULE 26)
`TEVA PHARMACEUTICALS USA, INC. V. IVIONOSOL RX, LLC
`
`TEVA EXHIBIT 1005
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC
`
`
`
`WO 00/42992
`
`PCT/US99/31327
`
`and at least one reagent selected from the group consisting of an emulsifier, a plasticizer.
`a taste modifier. a water soluble inert filler, a coloring agent, a preservative, a
`
`permeation enhancer, a stabilizer, and a buffering agent. may be combined in any order
`in a vessel having a heating source and a mechanical mixing device,
`the combined
`
`ingredients being mixed during and after the addition of the ingredients to the vessel, an
`
`10
`
`15
`
`20
`
`In an embodiment of the invention, a method is provided for administering an
`active agent to a subject, that includes obtaining a water-soluble hydrocolloid, mucosal
`surface—coat-forming film, such film including an effective dose of an active agent; and
`placing the film on a mucosal surface coat forming film in the subject; so as to release
`the active agent.
`
`In a further embodiment of the invention, a dosage unit is provided that includes
`a water soluble hydrocolloid and an effective dose of sildenafil citrate in a mucosal-
`
`surface contacting film. More particularly, an effective dose of sildenafil citrate is
`
`formed into a solid dispersion with xylitol for treating erectile dysfunction. The
`sildenafil/xylitol 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
`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
`sildenafil in the solid dispersion is at least 20 mg/ml, more particularly about 50mg/ml.
`More particularly, the film may be capable of completely dissolution at the oral mucosal
`surface within 10-600 seconds.
`
`Brief Description of the Figures
`
`Figure 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.
`
`30
`
`Figure 2 illustrates one manufacturing process for the dosage unit. (8) is the
`
`-5-
`
`TEVA EXH,B,T1005
`SUBSTITUTE SHEET (RULE 26)
`TEVA PHARMACEUTICALS USA, INC. v. IVIONOSOL RX, LLC
`
`TEVA EXHIBIT 1005
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC
`
`
`
`WO 00/42992
`
`PCT/US99/31327
`
`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
`
`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
`
`delivery system as a function of thickness.-— - —- is disintegration time and -- 0 -- is
`
`dissolving time.
`
`Figure 5 shows the release profiles of -- V -— nicotine, —- V -- oxybutynin,
`-- 0 -- hydromorphone and -- 0 -- estradiol.
`
`Figure 6 shows the pharmacokinetics in six subjects after administration of a
`
`dissolving film sildenafil formulation and after administration of the commercial tablet
`
`containing the same dosage of sildenafil. Sildenafil film -- 0 -- Viagra -- v -.
`
`Detailed Description of Invention
`
`Delivery of active agents in solid form via the mouth causes problems to patients
`who may choke on the dosage unit. This effect is caused at least in part by the mobility
`of the dosage unit within the mouth. We have developed a new class of dosage units
`which are not mobile in the mouth because on contact with the moist mucosal surface,
`
`the film becomes a coating that adheres to the mucosal surface and then disintegrates and
`dissolves over a time frame controlled in the design of the dosage. The dosage unit, in
`an 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 mucosal surface,
`the
`
`mucosal surface-coat-forrning 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.
`
`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
`
`10
`
`15
`
`20
`
`25
`
`30
`
`-6-
`
`TEVA EXH,B,T 1005
`SUBSTITUTE SHEET (RULE 26)
`TEVA PHARMACEUTICALS USA, INC. V. IVIONOSOL RX, LLC
`
`TEVA EXHIBIT 1005
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC
`
`
`
`WO 00/42992
`
`PCT/US99/31327
`
`film. the concentration of the active agent, the solubility of the agent at the mucosal
`
`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
`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
`
`15
`
`mucosal surface can be controlled by the dissolution rate of the film. A dissolving film
`will release the active agent and this in turn will cause the active agent to be swallowed
`
`20
`
`25
`
`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
`
`governing the release of an active agent at the mucosal surface is the manner in which
`
`the agent is dispersed in the film. For example, the agent may be dispersed as colloidal
`
`particles or microencapsulated within the film or alternatively may be mixed throughout
`the film as a reagent during casting.
`
`The dosage unit of the invention may be used as a vehicle for delivering a wide
`
`range of active agents. For example, the active agent may be a small molecule, a protein,
`a nucleic acid including antisense molecules or other biological or synthetic molecules.
`
`The term "mucosal surface-coat-forrning" as applied to a film as used in this
`
`description and in the following claims unless specified otherwise , means a film that
`
`coats the mucosal surface on contact, and may not thereafter be manually recovered or
`
`moved from the contact site: and subsequently disintegrates and dissolves so as to
`
`release the active agent. It should be noted that for purposes of the description of the
`
`30
`
`invention and the claims,
`
`“mucosal surface” refers to any moist surface of the body. This includes the surfaces
`
`identified in Figure 1. It further includes a wound surface where lymph fluid bathes the
`
`-7-
`
`TEVA EXH,B,T1005
`SUBSTITUTE SHEET (RULE 26)
`TEVA PHARMACEUTICALS USA, INC. v. IVIONOSOL RX, LLC
`
`TEVA EXHIBIT 1005
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC
`
`
`
`WO 00/42992
`
`PCT/US99/31327
`
`tissue surface.
`
`Embodiments of the present invention include a process, composition and
`method of use for a quick dissolving film for local and systemic delivery of
`
`10
`
`15
`
`20
`
`25
`
`30
`
`may be applied to any mucosal surface as deemed appropriate for the systemic or local
`delivery of an active agent including vaginal, rectal, and ocular surfaces. For purposes of
`oral delivery, the films may be applied on lingual, sub-lingual, buccal, gingival, and
`palatal surfaces (Figure 1).
`
`For vaginal delivery of such agents as contraceptive agents including nonoxynol
`or anti—infectives including antifungal agents, antibacterial agents and anti-viral agents,
`or fragrant or hygiene agents; the film should be non-sticky when removed from the
`
`packaging but should have mucoadhesive properties when applied in the vagina.
`Although films containing active agents for use in the vagina have been used, they
`appear to have some significant drawbacks most particularly the lack of adhesive
`
`properties at the mucosal surface. This makes these films impractical to administer. (US
`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
`
`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
`
`-3-
`
`TEVA EXH,B,T 1005
`SUBSTITUTE SHEET (RULE 26)
`TEVA PHARMACEUTICALS USA, INC. v. IVIONOSOL RX, LLC
`
`TEVA EXHIBIT 1005
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC
`
`
`
`WO 00/42992
`
`PCT/US99/31327
`
`cavity for treatment or modification of the oral environment: for example, for
`
`periodontal disease treatment 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 specific application of the
`
`invention, the disintegration time and the dissolution time can be controlled within a
`
`prescribed range by adjustment of the formulation and the thickness of the film.
`
`In some
`
`cases, it is desirable for release of the active agent to occur after dissolution of the film.
`
`For these applications, the active agent may be encapsulated in a material with
`
`dissolution properties that are different from those of the hydrocolloid. Encapsulation of
`
`the active agent also may be utilized to achieve masking of taste for active agents that are
`
`bitter. In some cases, two or more different active agents may be included in the film.
`
`An example where multiple active agents frequently are administered is cold
`
`medications, which often contain several active agents.
`
`“Coating solution” is defined here and in the claims as a viscous and
`
`homogeneous mixture of hydrocolloids, active agents and other additives in a solvent.
`
`The coating solution is treated according to the method of the invention to form a film.
`
`“Subject” is defined here and in the claims as a human or animal species.
`
`“Thickness” is defined here and in the claims by measurements in mil (a mil =
`
`10
`
`15
`
`20
`
`one thousandth of an inch) determined when a film is placed between two microscopic
`slides.
`
`25
`
`“Permeation enhancer” as defined here and in the claims is a natural or synthetic
`
`molecule which facilitates the absorption of an active agent through a mucosal surface.
`
`“Enzyme inhibitor” as defined here and in the claims is a natural or synthetic
`
`molecule which inhibits enzymatic metabolism of an active agent in the saliva or in a
`mucosal tissue.
`
`30
`
`“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-
`
`TEVA EXH,B,T1005
`SUBSTITUTE SHEET (RULE 26)
`TEVA PHARMACEUTICALS USA, INC. v. IVIONOSOL RX, LLC
`
`TEVA EXHIBIT 1005
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC
`
`
`
`WO 00/42992
`
`PCT/US99/31327
`
`the dry weight of the film.
`
`“The hydration rate” is defined here and in the claims as the speed of absorbing
`
`water at 25°C. and 75% relative humidity in 24 hours.
`
`“Percentage of swelling” is defined here as a percentage of the initial volume that
`
`In an embodiment of the invention, the percentage of
`is increased before dissolving.
`swelling is less than 10% in 60 seconds.
`
`Taste modifying agents include flavoring agents, sweetening agents and taste
`
`masking agents and are exemplified by: the essential oils or water soluble extracts of
`
`menthol, wintergreen, peppermint, sweet mint, spearmint, vanillin, cherry, chocolate,
`
`cinnamon, clove, lemon, orange, raspberry, rose, spice, violet, herbal, fruit, strawberry,
`
`grape, pineapple, peach, kiwi, papaya, mango, coconut, apple, coffee, plum, watermelon,
`
`nuts, durean, green tea, grapefruit, banana, butter, camomile, sugar, dextrose, lactose,
`
`mannitol. sucrose, xylitol, malitol, acesulfame potassium, talin, glycyrrhizin, sucralose,
`
`aspartame, saccharin, sodium saccharin, sodium cyclamate and honey.
`
`Emulsifying agents include solubilizers and wetting agents and are exemplified
`
`by polyvinyl alcohol, sorbitan esters, cyclodextnns, benzyl benzoate, glyceryl
`
`monostearate, polyoxyethylene alkyl ethers, polyoxyethylene stearates, poloxamer,
`
`polyoxyethylene Castor oil derivatives, hydrogenated vegetable oils, bile salts,
`
`polysorbates and ethanol.
`
`Plasticizers may include glycerin, sorbitol, propylene glycol, polyethylene glycol,
`
`triacetin. triethyl citrate (TEC), acetyl triethyl citrate (ATEC) and other citrate esters.
`
`Active agents (for human and veterinary applications) include therapeutic agents.
`
`nutritional supplements and hygiene aids. The therapeutic agents are exemplified by
`
`analgesics, a-adrenergic receptor blockers, anti-Alzheimer’s disease medication,
`
`antianginal, antianxiety, antiariythmics, antiarthritics, antibiotics,
`
`anticoagulants/thrombolytics, anticonvulsants/anti—Parkinson medication, anti-
`
`depressants, anti-diabetics, anti-diarrheal. anti-epileptics, anti—fungal. anti-gout, anti-
`
`heartworrn medication for dogs, anti—histamines, anti-hypertensives, anti—inflammatories,
`
`anti—infectives, antimigraines, anti—nasuants/anti—emetics, anti-neoplastics/anti-tumor
`
`active agents. anti—pruitics, anti-psychotics, anti-pyretics, anti—spasmodics, anti—virals,
`
`bronchial dilators/anti-asthmatics. calcium antagonists, cardiac agents. cardiotonics,
`
`central nervous system actives, contraceptives, coronary vasodilators. cough/cold
`
`-10-
`
`10
`
`15
`
`20
`
`25
`
`30
`
`TEVA EXH,B,T 1005
`SUBSTITUTE SHEET (RULE 26)
`TEVA PHARMACEUTICALS USA, INC. V. IVIONOSOL RX, LLC
`
`TEVA EXHIBIT 1005
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC
`
`
`
`WO 00/42992
`
`PCT/US99/31327
`
`remedies. dietary supplements. including vitamins and minerals. diuretics, fertility active
`agents. flea control agents for animals (Iverrnectin), H3 receptor antagonists, herbal
`
`actives. hormones, hypoglycemics, hypolipidemics. muscle relaxants, ovulation
`
`stimulators, peptide active agents, polypeptide active agents, proteins such as insulin.
`
`calcitonin, LHRH and the like. Sedatives and hypnotics, sexual dysfunction active
`
`agents, sleep aids, smoking cessation aids, steroids and steroidals, tranquilizers,
`
`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
`
`treatment of osteoporosis, hormone replacement, treatment of periodontal disease,
`
`antiseptics. corticosteroids, non steroidal anti-inflammatory agents. antiviral agents and
`vaccines.
`
`Water soluble inert fillers include mannitol, xylitol, sucrose, lactose,
`
`maltodextrin, dextran, dextrin, modified starches, dextrose, sorbitol, and dextrates. The
`
`water soluble inert fillers may be used in embodiments of the invention as inert caniers
`
`to form a high water soluble dispersion with active agents.
`
`Buffering agents include acidulants and alkalizing agents exemplified by citric
`acid, fumaric acid, lactic acid, tartaric acid, malic acid, as well as sodium citrate, sodium
`
`bicarbonate and carbonate, sodium or potassium phosphate and magnesium oxide.
`
`Coloring agents may include FD & C coloring agents, natural coloring agents,
`and natural juice concentrates. pigments such as titanium oxide. silicon dioxide and zinc
`oxide.
`
`Stabilizers as used here and in the claims, include anti-oxidants, chelating agents.
`and enzyme inhibitors as exemplified by ascorbic acid, vitamin E, butyla