PCT
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`WORLD INTELLECTUAL PROPERTY ORGANIZATION
`International Bureau
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`(22) International Filing Date:
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`30 December 1999 (30.12.99)
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`INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`(51) International Patent Classification 7 :
`(11) International Publication Number:
`WO 00/42992
`AG1K 9/70
`(43) International Publication Date:
`27 July 2000 (27.07.00)
`
`dose of active agent. In the dosage unit slidenafil citrate, nicotine, hydromorphone, oxybutynineor estradiol are used as active agents.
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`(21) International Application Number: PCT/US99/31327|(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, 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, 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).
`
`(30) Priority Data:
`60/116,823
`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).
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`(72) Inventors: CHEN, Li-—Lan, H.; 3906 Victory Court, Edison,
`NJ 08817 (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
`ster Point, Glen Cove, ME 04846-0088 (US). BURANA-
`upon receipt of that report.
`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 SummerStreet, Boston, MA 02110-1618 (US).
`
`(54) Title) COMPOSITIONS AND METHODS FOR MUCOSAL DELIVERY
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`CONTAINER SNAP 170
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`(57) 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
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`WO 00/42992
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`PCT/US99/31327
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`COMPOSITIONS AND METHODS FOR MUCOSAL DELIVERY
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`Technical Description
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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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`Backgroundto the Invention
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`Many pharmaceutical dosage forms are administrated orally in the form ofsolid
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`shapedarticles such astablets, pills, caplets and capsulesthat retain their shape under
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`moderate pressure. Generally these dosage formsare designed to be swallowed whole or
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`chewedto deliver the medication with adequate amountsofliquid. Somepatients,
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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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`maytry to hideasolid pill in orderto spit it out later. In addition, many pediatric and
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`geriatric patients are unwilling to take a solid dosage form becausetheactive agent is
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`difficult to swallow oris retained in the pharynx or gullet even whenliquids 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 maybelimited for certain patients and mayberestricted for
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`certain diseases and/or treatments. Chewable tablets provide some advantages over the
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`conventional tablets. However, they are notsuitable for children wearing braces and the
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`taste of the medication may be unpleasantand difficult to mask in a chewabletablet. At
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`the same time, water maybestill required for the administration of chewabletablets.
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`In addition, the standard oral dosage forms,suchas 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 formsoccurs in the gastrointestinal (GI) tract, after the agent has
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`separated from the dosage form anddissolved in the gastric fluids. For someactive
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`agents.it is desirable to achieve absorption throughthe oral mucosal tissues in order to
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`accelerate onset of the therapeutic effect.
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`Manyactive 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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`wile
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`SUBSTITUTE SHEET (RULE26)
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`Page 3
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`Page 3
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`WO 00/42992
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`PCT/US99/31327
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`not fixed to a mucosal surface and may move aroundin the mouth. Consequently, they
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`do not overcomea 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 whichis 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 whencrystalline sugar is subjected to heat and shear (WO 95/07194; WO
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`95/35293). Other methods of forming quick dissolving tablets include wet granulation
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`methods (EP 0627 218) and dry granulation methods (EP 0124027A1) and byfreeze-
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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 mechanicalstrength, are fragile and friable and haveinsufficient holding capacity
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`for active ingredients (US 5,720,974) and maybe difficult to store and handle.
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`Therapeutic compounds are sometimes provided as powders or granules which
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`maybe difficult to swallow and cause unpleasantsensations 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 unpleasanttaste in the mouth.
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`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 whichrequires tearing before use. This causes
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`problemsforgeriatric patients and those suffering from arthritis in the fingers as well as
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`for children. Consequently, problemsofspillage 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 inconvenient and may cause reduced patient compliance.
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`Liquid, syrups or suspensionsare an alternative to solid dosage forms and are
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`considered desirable for pediatric and geriatric patients who have problemsin
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`swallowing tablets. However, these dosage formsare often difficult to measure
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`accurately and administer easily. Liquid formulations deteriorate rapidly upon exposure
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`to heat or atmosphere and consequently havea relatively short shelf life. Furthermore,
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`liquid formulations require a relatively large volume andare bulky to store.
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`SUBSTITUTE SHEET (RULE26)
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`Page 4
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`Page 4
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`WO 00/42992
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`PCT/US99/31327
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`In addition to solid and liquid dosage forms,rapidly dissolving buccal/oral
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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 comparedto tablets (US
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`5,648,093). Furthermore, freeze dried preparationsare brittle and fragile when handled
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`and mustbe kept in dry conditionsto avoid disintegration. Theinstability of freeze-
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`dried preparations has been reduced somewhatbythe addition of mannitol (US
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`4,946,684). WO 9820862 reports a film that is formed according to a method that does
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`not utilize freeze drying and avoids problemsdescribedin the art such as rigidity of the
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`films, delayed softening and poorsolubility in the mouth (US 4,876,092; EP 0200508;
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`EPO 381194; CA-PS 1-26331; DE 2449865.5; DE 3630603; EP 0452446 and EP
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`0219762). However, the film described in WO 9820862relies on the use ofat least two
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`different non-ionic surfactants to achieve immediate wettability.
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`It is desirable that a dosage unit should provide a non-invasive, effective and
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`economic meansto deliver an active agentto the target site. Where the targetsite is the
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`plasma,additionalissues arise concerning the rate of delivery of the active agentto that
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`site as measuredby 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 timeby the rate of absorptionin the gastro-intestinal tract. Formulations have
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`been developed which, when applied in the mouth, lead to faster onsetthat the
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`traditional oral dosages because theytarget the oral mucosa. These formulationsinclude
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`dosage units containing 75%-90% polyethylene glycol that melt at body temperature, in
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`the mouth.( US 5,004,601 and 5,135,752) Other formulations includeliquid forms,
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`lozengesortablets that are administered sublingually or by a sweetened matrix on a
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`stick, (US 5,770,606, Streisand etal. and Zhanget al., Christie et al., Sasaki et al.).
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`Whereasthe above references address the delivery route, they do not address the
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`problemsof bioavailability that arise from poorsolubility or low dissolution rate.
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`A delivery device that addresses the above limitations would represent a
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`desirable improvementon existing delivery systems.
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`Summaryof 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 includes 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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`In an embodimentof the invention, the hydrocolloid 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 filler, a preservative, a buffering agent, a coloring agent, a
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`permeation enhancer, and a stabilizer. The film mayfurther include an active agent
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`selected from the group consisting of a therapeutic agent, a dietary supplementand 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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`Theactive agent may be encapsulated within a second polymerhavingdissolution
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`properties that are different from those of the hydrocolloid. More than one active agent
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`maybeincludedin the film. In an embodimentof the invention, the emulsifier may have
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`a concentration of 0.1-10%w. The waterinert filler may include a concentration range of
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`0.5-50% and the preservative may include a concentration range of 0.01-10%. A
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`mucosal adhesion enhancersuchas starch graft copolymer maybe included in the
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`dosage unit.
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`In embodimentsof 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 |50Opsi, a modulus in the range
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`of 35,000-300,000 psi, a tear propagation resistance in the range 0.001N-IN. 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 homogeneouspreparation: adding to the hydrocolloid preparation, an
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`active agentandat 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 agentto form a coatable mixture: and
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`forming a mucosal surface-coat forming film from the mixture for packaging as a dosage
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`unit. The method mayfurther include the step of coating the mixture onto a backing
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`film.
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`In a further embodiment, the reagents including: a hydrocolloid, an active agent.
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`a
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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.
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`a taste modifier. a water soluble inert filler, a coloring agent, a preservative. a
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`permeation enhancer,a stabilizer, and a buffering agent. may be combinedin any order
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`in a vessel having a heating source and a mechanical mixing device,
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`the combined
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`ingredients being mixed during andafter 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 formedintoafilm in a dry extrusion process.
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`In an embodimentof 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, mucosal
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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 embodimentof the invention, a dosage unit is provided that includes
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`a water soluble hydrocolloid and an effective dose of sildenafil citrate in a mucosal-
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`ee)
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`surface contacting film. More particularly, an effective dose of sildenafil citrate is
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`formedinto a solid dispersion with xylitol for treating erectile dysfunction. The
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`sildenafil/xylitol dispersion may be mixed withat least one reagent selected from the
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`group consisting of an emulsifier, a plasticizer, a taste modifier, a coloring agent, a
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`preservative, a permeation enhancer,a stabilizer and a buffering agent. Thesolid
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`20
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`dispersionofsildenafil and xylitol mayarise 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 watersolubility of
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`sildenafil in the solid dispersion is at least 20 mg/ml, more particularly about 5Omg/ml.
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`More particularly, the film may be capable of completely dissolution at the oral mucosal
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`surface within 10-600 seconds.
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`Brief Description of the Figures
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`Figure | showspossible applicationsites in the oral cavity for the inventive
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`dosage unit. (1) is the upperlip: (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 lowerlip.
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`Figure 2 illustrates one manufacturing process for the dosage unit. (8) is the
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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
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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 shows 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; (17)
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`is a multi-unit dispensing pack, 17(a) the container snap and 17(b)the lid closure; (18) is
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`a multi-unit roll-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 anddissolution timeof the intraoral
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`delivery system as a function of thickness.-- * -- is disintegration time and-- © -- is
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`dissolving time.
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`Figure 5 showsthe release profiles of -- ¥ -- nicotine, -- v -- oxybutynin,
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`-- *-- hydromorphoneand-- © -- estradiol.
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`Figure 6 shows the pharmacokinetics in six subjects after administration of a
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`dissolvingfilm sildenafil formulation and after administration of the commercialtablet
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`containing the same dosageofsildenafil. Sildenafil film -- 9 -- Viagra -- 9 -.
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`Detailed Description of Invention
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`Delivery of active agents in solid form via the mouth causes problemsto patients
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`who maychokeon 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 mouth because on contact with the moist mucosalsurface,
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`the film becomesa 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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`an embodimentof the invention,is in the form ofa flexible, non-tacky, dry conveniently
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`packaged film. Once removed from the package and placed on a mucosalsurface, the
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`mucosalsurface-coat-forming film hydrates substantially immediately to form a coating
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`on the moist surface of the mucous membraneandthen disintegrates and dissolves to
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`release the active agent from thefilm.
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`The dosage unit may release the active agent over a period oftimethatis
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`determined by a numberofdifferent factors. These factors include the dimensionsofthe
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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 mucosal
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`surface and how the agentis dispersed throughoutthe film. The thicknessofthe film ts a
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`factor in determiningtherate of dissolution. A thick film will dissolve more slowly than
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`an otherwise similar thin film. A thick film may be desirableforits holding capacity for
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`active agents that are required in high dosages. Although the surface area ofa film can
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`be adjusted up to about 5 square centimeters. increased thickness mayalso 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 purposesof 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 knownin the art may be
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`includedin the film. The extentof uptakeof the active agent from the dosage unit at the
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`mucosal surface can be controlled by the dissolutionrate of the film. A dissolving film
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`will release the active agent andthis in turn will cause the active agent to be swallowed
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`and taken upin the GItract. 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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`governingthe release of an active agent at the mucosalsurface is the manner in which
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`the agent is dispersed in the film. For example, the agent maybe 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 maybe usedas 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 moleculesor other biological or synthetic molecules.
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`The term "mucosalsurface-coat-forming”"as appliedto a film as used in this
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`description andin the following claims unless specified otherwise , means a film that
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`coats the mucosalsurface on contact, and maynot 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 purposesof 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 Figure 1, It further includes a wound surface where lymphfluid bathes the
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`lissue surface.
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`PCT/US99/31327
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`Embodimentsof the present invention include a process, composition and
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`methodof use for a quick dissolving film for local and systemic delivery of
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`pharmaceutical agents to a mucosal surface in a subject.
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`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 scopeof the inventionto 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 orlocal
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`delivery of an active agentincluding 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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`palatal surfaces (Figure 1).
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`Forvaginal 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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`Althoughfilms containing active agents for use in the vagina have been used, they
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`appear to have somesignificant drawbacks mostparticularly 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; 5,595,980 and 5,529,782).
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`Embodiments of the invention provide improved dosage formsto 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 economicalto 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 shelflife, ease of storage and distribution. The dosage form may be administered to
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`the subject by placing the film on a mucoussurface, at which time the film becomesa
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`mucoadhesive coating, characterized bythe property thatit can no longer exist in an
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`independent form and is subsequently dispersed in solution.
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`Embodimentsof 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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`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 referenceto the oral
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`cavity, an embodimentofthe invention providesactive agents that remain in the oral
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`cavity for treatment or modification of the oral environment: for example, for
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`periodontal disease treatmentor breath-odor control. Furthermore, embodimentsof the
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`invention further provide improvementsthat include:
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`improved organoleptic properties
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`(smell and taste), and texture and feel of dosage formsintendedto be placed in the oral
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`cavity; a dosage form which “melts” in the mouth and leaves a smoothpleasantafterfeel
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`following dissolution; and a prolongedretention ofthe 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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`invention, the disintegration time and the dissolution