(12) IN'I'ERNA'I'IONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`
`(19) World Intellectual Property Organization A 0
`International Bureau
`
`ma
`
`PCT
`
`||I|||||||||||||||||||||||||||||||||||||ll|||||||||I|||||||||||||||||||||I|I||||I|||I||
`
`(10) International Publication Number
`WO 2008/040534 A2
`
`(43) International Publication Date
`10 April 2008 (10-04-2008)
`
`(51) International Patent Classification:
`A6IK 9/70 (2006.01)
`A6IK 31/445 (2006.01)
`
`(DE). GALF'E'I'I‘I, Paolo [IT/IT]; Via Canturina Vecchia
`34/b, 22070 Senna Comasco (CO) (IT).
`
`9” "'‘°''”‘‘“°“'‘' APP"°""°“ N'"“"°"
`PCT/EP2007/008579
`
`(22) International Filing Date: 2 October 2007 (02.10.2007)
`
`(25) Filing Language:
`
`(26) Publication Language:
`
`Engfish
`
`English
`
`(30) Pl'l0l'it)' Data:
`60/848,965
`
`2 October 2006 (02.10.2006) US
`
`(71) Applicants (for all designated States except US):
`LABTEC GESELLSCIIAFI‘ FER TECHNODOGIS-
`CHE FORSCHUNG UND ENTWICKLUNG MB“
`[DE/DE]; Raiffeisenstrasse 3a, 40754 Langenfeld (DE).
`APR APPLIED PHARMA RESEARCH S.A. [CH/CH];
`via Com.’ 5' CM828 Balema (CH).
`
`(74) Agent: LEISSLER-GERSTL, Gabriele; Hoefer & Part-
`ner, Pilge1sheimerStmsse 20, 31543 Miinchen (DE).
`(81) Designated States (unless otherwise indicated. for every
`kind ofnativnal Protection available): AE. AG. AL. AM.
`AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, CA, CH,
`
`CN, co, CR, CU, cz, DE, DK, DM, DO, DZ, EC,EE, EG,
`ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL,
`IN, IS, JP, KE, KG, KM, KN, KP, Ifli, KZ, LA, LC, LK,
`LR, LS, LT, LU, LY, MA, MD, ME, MG, MK, MN, MW,
`MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PG, PH, PL,
`pr’ R0, RS, RU, SC, 31), SE, SG’ SK, 314, SM, 3v. SY,
`TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA,
`ZM, Zw.
`
`_
`_
`_
`(84) Designated States (unless otherwlse lndlcated, for every
`’“"" "f ’‘’$’‘‘’"“’ 1”“""“""" ""“""”"’)‘ ARIPO (BW* 6"’
`GM’ K5’ ‘is’ M“’- MZ= NA= SD~ 51*’ Szv T2’ UG, 2“
`zw), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM),
`European (AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, Fl,
`
`FR, GB, GR, HU, 115, IS, IT, LT, LU, LV, MC, MT, NL, PL,
`(72) 1m,m°,s; and
`P'1‘»R°« 3Ev31~SK~TR>s0AP1(BF~BJ= CF»CG»C1s CM»
`(75) Inventors/Applicants (for us only): LEICHS, Chrls-
`GA~GN~GQsGW~M1~ MR» NE: SN» TD~TG)-
`tian [DE/DE]; Liesendahler Weg 22A, 51399 Burscheid
`Published:
`(DE). BREITENBACH, Armlu [DE/DE]; Widdauener
`Strasse 35, 51371 Leverkusen (DE). LEHRKE, Ingo — without international seamh repon‘ and to be republished
`[DEIDE]; Emst-Wilhelm-Nay-Strasse 9, 50935 K6ln
`upon receipt of that report
`
`(54) Title: NON-MUCOADHESIVE FILM DOSAGE FORMS
`
`Dluolutlon protllu Dude ndutron: comparison tablet V: out dluolvtng
`tablet vo Rnpldtllm
`
`time [min]
`
`——o-—-Zofrano Im 9 Film telnet
`-0-—zolrnnO Imp zydho Lingual
`-0-— Ondenutron am 9 hpldfiln
`-x—-Zotnnoavlo zydho Llngunl
`—l—0mlInutron 4m 9 mpldfilln
`
`3 5 3 §
`
`
`
`2008/040534A2|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
`
`(57) Abstract: Orally disintegrating film dosage forms for delivering active pharmaceutical agents. methods of formulating the
`dosage forms to retard absorption through the oral mucosa, and methods of using the dosage forms for the treatment of various
`medical conditions are provided.
`
`DRL - EXHIBIT 1007
`
`DRL001
`
`DRL - EXHIBIT 1007
`DRL001
`
`

`
`
`WO 2008/040534
`
`
`
`PCT/EP2007/008579
`
`
`
`
`
`
`
`
`NON-MUCOADHESIVE FILM DOSAGE FORMS
`
`
`
`
`
`
`
`RELATIONSHIP TO PRIOR APPLICATIONS
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`This application claims priority to U.S. Provisional Application No. 60/848,965, filed
`
`
`
`
`
`October 2, 2006 (now abandoned).
`
`
`
`
`
`
`FIELD OF THE INVENTION
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`The present invention relates to orally disintegrating film dosage forms for delivering
`
`
`
`
`
`
`
`
`
`
`
`
`
`active pharmaceutical agents, methods of formulating the dosage forms to promote
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`gastrointestinal absorption comparable to immediate release solid oral dosage forms, and to
`
`
`
`
`
`
`
`
`
`
`
`
`
`methods of using the dosage forms for the treatment of various medical conditions.
`
`
`
`
`
`
`BACKGROUND OF THE INVENTION
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Orally administered film strip dosage forms have been recently developed for the
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`pharmaceutical industry, and are currently used for the sale of several popular over-the-
`
`
`counter dru
`
`
`8 P
`
`
`
`
`
`
`
`
`
`
`roducts, includin Listerine® breath stri s, Triaminic® thin stri s active a ent
`8
`P
`P
`8
`
`
`
`
`
`
`
`
`
`
`
`
`
`= diphenhydramine HCl), and Sudafed PETM quick dissolve strips (active ingredient =
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`phenylephrine HCl). The absolute bioavailability of diphenhydramine when ingested orally is
`
`
`
`
`
`
`
`
`
`
`
`
`
`approximately 61%, and the time to maximum serum concentration is about 3-4 hours.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Phenylephrine is subject to extensive presystemic metabolism in the gut wall, such that the
`
`
`
`
`
`
`
`
`
`
`
`
`
`absolute bioavailability of phenylephrine when ingested orally is approximately 40% relative
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`to intravenous dosing, and peak plasma concentrations are achieved in about 1-2 hours.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`In addition, several manufacturers have proposed formulations that could be used to
`
`
`
`
`
`
`
`
`
`
`
`deliver prescription drugs. The vast majority of these formulations are “mucoadhesive”
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`formulations designed for adhesion of the dosage form to mucosal tissue in the mouth, and
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`transmission of the drug from the dosage form through the mucosal tissue into the systemic
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`circulation. As described in U.S. Patent No. 6,750,921 to Kim et al., film-forming agents
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`have been used to manufacture drug delivery formulations for percutaneous or transderrnal
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`application, but these necessarily involve an adhesive composition to retain the agent in situ
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`long enough to cause sustained release of the active ingredient. Bioerodible films are
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`described in Tapolsky et al., U.S. Patent No. 5,800,832. The films have an adhesive layer and
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`a non-adhesive backing layer and are intended to adhere to the mucosal surface. Biegajski et
`
`
`
`DRL - EXHIBIT 1007
`
`DRL002
`
`
`
`DRL - EXHIBIT 1007
`DRL002
`
`

`
`
`WO 2008/040534
`
`
`
`PCT/EP2007/008579
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`al., U.S. Patent No. 5,700,478, describes a water-soluble pressure-sensitive mucoadhesive
`
`
`
`
`
`
`
`
`
`suitable for use in a mucosa]-lined body cavity.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`The purported advantage of these mucoadhesive films resides in their ability to bypass
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`the gastrointestinal tract, and barriers in the gastrointestinal tract to drug absorption such as
`
`
`
`
`
`
`
`
`
`
`
`first pass metabolism and decomposition of the active ingredient
`
`
`
`
`
`
`in the stomach. An
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`additional advantage for these dosage forms, when compared to tablets, capsules and other
`
`
`
`
`
`
`
`
`dosage forms that must be swallowed,
`
`
`
`
`
`
`
`
`
`is that some patient populations have difficulty
`
`
`
`
`
`
`
`
`
`swallowing, such as children and the elderly.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Until now the prior art has been focused principally on improving the delivery profile
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`of a given pharmaceutical agent with this dosage form, by increasing its rate of dissolution or
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`absorption, or bypassing metabolic processes that reduce the bioavailability of the drug. The
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`prior art has not appreciated that an innovator’s drug product, be it a tablet, capsule, or other
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`oral dosage form, has already proven itself effective through rigorous clinical testing, and that
`
`
`
`
`
`
`
`
`
`
`
`
`
`the innovator’s product may already provide the optimum bioavailability of pharmaceutical
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`agent. What is needed is a film product that mimics the pharmacokinetics of an innovator’s
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`product, and that follows the same metabolic and bioabsorption pathways as the innovator’s
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`product, to ensure that the dosage form achieves the proven clinical efficacy of the innovator
`
`
`
`product.
`
`
`
`
`
`
`OBJECTS OF THE INVENTION
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Accordingly, it is an object of the present invention to provide non-mucoadhesive
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`orally disintegrating film dosage forms that mimic the pharmacokinetic profile of orally
`
`
`
`
`
`
`
`
`administered drug products such as
`
`
`tablets, capsules,
`
`
`
`
`
`
`liquid suspensions, and orally
`
`
`
`
`
`dissolving/dispersing tablet (ODT).
`
`
`
`
`
`
`
`
`
`
`
`
`
`Another object of the invention is to provide non-mucoadhesive orally disintegrating
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`film dosage forms that follow the same metabolic and bioabsorption pathways through the
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`gastrointestinal tract as existing orally administered drugs, such as tablets, capsules, liquid
`
`
`
`
`
`
`
`
`suspensions, and orally dissolving/dispersing tablet (ODT).
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Still another object of the present invention is to provide methods of formulating and
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`testing non-mucoadhesive orally disintegrating film dosage forms so that they follow the
`
`
`
`
`
`
`
`
`
`
`
`
`
`same metabolic and bioabsorption pathways, and obtain the same pharmacokinetic profiles,
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`as existing orally administered drugs such as tablets, capsules, liquid suspensions, and orally
`
`
`
`
`
`dissolving/dispersing tablet (ODT).
`
`
`
`
`
`DRL - EXHIBIT 1007
`
`DRL003
`
`
`
`DRL - EXHIBIT 1007
`DRL003
`
`

`
`
`WO 2008/040534
`
`
`
`PCT/EP2007/008579
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Another object of the present invention is to provide methods of treatment using the
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`film dosage forms of the present invention, and methods that promote bioequivalence to
`
`
`
`
`
`
`
`
`
`
`
`
`orally administered drug products such as tablets, capsules, liquid suspensions, and orally
`
`
`
`
`
`dissolving/dispersing tablet (ODT).
`
`
`
`
`
`
`
`
`Yet another object of the present
`
`
`
`
`
`invention is
`
`
`
`
`
`to provide techniques and
`
`
`
`
`
`
`
`
`
`
`
`
`methodologies for retarding the absorption of drugs from orally disintegrating films through
`
`
`
`
`
`the oral mucosa.
`
`
`
`
`
`
`SUMMARY OF THE INVENTION
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`The present invention provides film dosage forms that are formulated or administered
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`for gastrointestinal absorption of the active pharmaceutical agent, and that are bioequivalent
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`to and interchangeable with existing orally administered drug products. These film dosage
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`forms are non-mucoadhesive; they quickly disintegrate in the mouth when exposed to saliva;
`
`
`
`
`
`
`
`
`
`
`
`
`
`and they are absorbed predominantly through the gastrointestinal tract. Most importantly,
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`these dosage forms are specially formulated to meet exacting bioavailability requirements, or
`
`
`
`
`
`
`
`
`
`
`
`
`to be bioequivalent to existing orally administered dosage forms.
`
`Therefore,
`
`
`
`
`in a
`
`
`
`
`first principal
`
`
`
`embodiment,
`
`
`
`the
`
`
`
`
`
`
`invention provides a non-
`
`
`
`
`
`
`
`
`
`
`
`
`
`mucoadhesive orally disintegrating film, able to disintegrate upon contact with saliva in the
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`buccal cavity within about sixty seconds, comprising a defined amount of an active
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`pharmaceutical agent, a hydrophilic binder and a water-soluble diluent, wherein: (a) said film
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`is formulated for delivery of said active agent through the gastrointestinal tract when applied
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`to the tongue; (b) said film comprises from about 0.05% to about 50% (w/w) of said active
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`pharmaceutical agent, based on the total weight of the formulation; and (c) said film is
`
`
`
`
`
`
`
`
`
`
`
`
`bioequivalent to an immediate release tablet or or orally dissolving/dispersing tablet (ODT)
`
`
`
`
`
`
`
`
`
`
`
`
`that comprises said active pharmaceutical agent in said defined amount.
`
`
`
`
`
`
`
`
`
`
`
`
`
`In one embodiment, the immediate release tablet or orally dissolving/dispersing tablet
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`(ODT) is characterized by slow or delayed bioavailability (i.e. a “slowly bioavailable drug”).
`
`
`
`
`
`
`
`
`
`
`
`
`
`The inventors have developed orally disintegrating film dosage forms which, it is believed,
`
`
`
`
`
`
`will unexpectedly be bioequivalent
`
`
`
`
`
`
`
`
`to these conventional “slowly bioavailable drugs,”
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`without any substantial modification of the release characteristics from the film dosage form,
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`as long as the film can disintegrate when placed on the tongue within about sixty seconds.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Thus, for example, the immediate release dosage form can be characterized by:
`
`
`
`DRL - EXHIBIT 1007
`
`DRL004
`
`
`
`DRL - EXHIBIT 1007
`DRL004
`
`

`
`
`WO 2008/040534
`
`
`
`PCT/EP2007/008579
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`a Tmax (i.e. time to maximum plasma concentration) of greater than about 1.5
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`hours, 2.0 hours, 2.5 hours, 3.0 hours, 3.5 hours, 4.0 hours, 4.5 hours or even 5.0
`
`hours;
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`a disintegration time of greater than about 10 or 20 minutes, but less than about 90
`
`
`
`or 60 minutes;
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`a 90% dissolution time of greater than about 10 or 20 minutes, but less than about
`
`
`
`
`
`90 or 60 minutes; and/or
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`a film coating that delays the release and absorption of active ingredient from the
`
`
`dosage form.
`
`
`Of course,
`
`
`
`
`
`
`
`
`
`
`
`
`the invention could also be practiced with drugs having other
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`pharmacokinetic profiles, and in other embodiments the Tm“ of the drug is less than 3.0, 2.5,
`
`
`
`
`
`
`
`
`
`2.0, 1.5 or 1.0 hours.
`
`
`
`In another embodiment,
`
`
`
`
`
`
`
`
`
`
`
`
`the film strip of the present invention, or the immediate
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`release dosage form, can be defined by its pharmacokinetics, and in one embodiment, the film
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`strip or immediate release dosage form has an absolute bioavailability of greater than 65%,
`
`
`
`
`
`
`
`
`
`
`
`75%, 85% or even 95% when administered orally.
`
`
`
`
`
`
`
`In another embodiment, the film strip or
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`immediate release dosage form has an absolute bioavailability that is greater than about 45%,
`
`
`
`
`
`
`
`
`
`
`50%, or 55%, and peak plasma concentrations (Cmax)
`
`
`
`
`
`
`
`
`
`
`in less than 3.0, 2.5 or 2.0 hours.
`
`
`
`
`
`
`
`
`
`
`Finally, because the film dosage form is
`
`
`
`
`
`
`specially formulated or administered for
`
`
`
`
`
`
`
`
`
`
`
`
`gastrointestinal absorption, the film dosage form has a comparable absolute bioavailability or
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Tmax as an immediate release tablet or capsule or orally dissolving/dispersing tablet (ODT)
`
`
`
`
`
`
`
`
`
`
`
`
`that comprises the same amount of active pharmaceutical agent.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`The films themselves, and the methods of using the films, are characterized by a
`
`
`
`
`
`
`
`
`
`
`
`
`
`number of features that ensure their bioequivalence to a comparable immediate release tablet
`
`
`
`
`
`
`
`
`
`
`or capsule or orally dissolving/dispersing tablet (ODT), including:
`
`
`
`
`
`I
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`the films may be engineered or used so that the active pharmaceutical agent is
`
`
`
`
`
`
`
`
`
`swallowed and absorbed predominantly or entirely through the gastrointestinal
`
`
`
`
`
`
`
`
`
`tract, instead of being absorbed through the oral mucosa;
`
`
`
`
`
`
`
`
`
`
`
`
`
`if necessary, the films or active pharmaceutical agents may be formulated so that
`
`
`
`
`
`
`
`
`
`
`
`absorption of active pharmaceutical agent through the oral mucosa is retarded;
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`the films are typically designed for rapid disintegration when taken orally, and are
`
`
`
`
`
`
`
`
`
`
`
`
`most often swallowed in less than thirty or sixty seconds after administration;
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`the films are usually applied directly onto the tongue to promote mixing with the
`
`
`
`
`
`
`
`
`
`
`
`saliva and subsequent swallowing of the active ingredient, and thereby discourage
`
`
`
`mucosal absorption; and
`
`
`
`
`
`
`
`
`
`
`
`
`
`water could be aditionally swallowed within about thirty or sixty seconds after
`
`
`
`
`
`
`
`
`
`
`
`
`
`administration of the film, to further promote swallowing of the active agent and
`
`
`gastrointestinal absorption.
`
`
`
`DRL - EXHIBIT 1007
`
`DRL005
`
`
`
`DRL - EXHIBIT 1007
`DRL005
`
`

`
`
`WO 2008/040534
`
`
`
`PCT/EP2007/008579
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`A particularly preferred drug of the present invention is a donepezil film strip, which
`
`
`
`demonstrates
`
`
`
`bioequivalence
`
`
`
`
`to
`
`existing
`
`
`
`immediate
`
`
`
`release
`
`
`
`
`
`tablets of donepezil
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`hydrochloride, and which exhibits a peak plasma concentration of donepezil in from about
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`three to about four hours. Another preferred drug is an ondansetron film strip, which is
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`characterized by an absolute bioavailability of ondansetron of from about 45% to about 75%,
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`and which is formulated as a base to retard absorption through the oral mucosa.
`
`
`
`Other
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`preferred drugs are set forth in the detailed description of invention and examples which
`
`
`
`
`follow.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Additional advantages of the invention will be set forth in part in the description
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`which follows, and in part will be obvious from the description, or may be learned by practice
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`of the invention. The advantages of the invention will be realized and attained by means of
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`the elements and combinations particularly pointed out in the appended claims. It is to be
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`understood that both the foregoing general description and the following detailed description
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`are exemplary and explanatory only and are not restrictive of the invention, as claimed.
`
`
`
`
`
`
`DESCRIPTION OF THE FIGURES
`
`
`
`
`Figure 1
`
`
`
`
`
`
`
`
`
`is a comparison of dissolution profiles over
`
`
`
`
`
`time comparing three
`
`
`
`
`
`
`
`
`
`
`
`commercially available formulations of ondansetron with two ondansetron RapidFilm
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`formulations, as described in Table 4. The upper line at 1 minute is Zofran® 4 mg Zydis®
`
`Lingual;
`
`
`
`
`
`
`the second line at
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`1 minute is Zofran® 8 mg Zydis® Lingual; the third line is
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`ondansetron 8 mg RapidFilm; the fourth line is ondansetron 4 mg RapidFilm; the bottom line
`
`
`
`
`
`
`
`is Zofran® 8 mg Filmtablet.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Figure 2 depicts mean (FIG 2A) and log mean (FIG 2B) drug plasma concentration
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`profiles versus time for 8 mg ondansetron RapidFilm investigational product versus Zofran®
`
`
`
`
`
`
`
`
`
`
`
`
`8 mg Lingual orally disintegrating tablets, as described in Table 6.
`
`
`
`
`
`
`
`
`
`
`
`
`Figure 3 is a comparison of dissolution profiles over time comparing commercially
`
`
`
`
`
`
`
`
`available donepezil hydrochloride immediate release tablets,
`
`
`
`
`commercially available
`
`
`
`
`
`
`
`
`
`
`
`donepezil hydrochloride orally disintegrating tablets, and four donepezil hydrochloride
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`RapidFilm formulations, as described in Tables 9-14. The top line at 3 minutes is RapidFilm
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`prototype F; the second line at 3 minutes is Aricept® film tablets; the third line at 3 minutes is
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`RapidFilm prototype E; the fourth line at 3 minutes is RapidFilm prototype A; the fifth line at
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`3 minutes is Aricept® ODT; the bottom line at 3 minutes is RapidFilm prototype C.
`
`
`
`DRL - EXHIBIT 1007
`
`DRL006
`
`
`
`DRL - EXHIBIT 1007
`DRL006
`
`

`
`
`WO 2008/040534
`
`
`
`PCT/EP2007/008579
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Figure 4 is a stacking x-ray diffraction pattern for three samples — (1) ondansetron
`
`
`
`
`
`
`base Form B polymorph,
`
`
`
`
`
`
`
`
`
`
`
`(2) RapidFilm comprising 4 mg of ondansetron having the
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`formulation of Table 4 and stored at 40 °C, and (3) RapidFilm comprising 4 mg of
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`ondansetron having the formulation of Table 4 (OND 013 OD), and stored at 60 °C
`
`
`
`(84201506).
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Figure 5 is a DSC heating curve for donepezil HCI Form I.
`
`
`
`
`
`
`
`
`
`
`
`
`Figure 6 is an X-ray diffraction pattern for donepezil HCl Form 1.
`
`
`
`
`
`
`
`
`
`
`
`
`
`Figure 7 is an X-ray diffraction pattern for ondansetron base Form B.
`
`
`
`
`
`DETAILED DESCRIPTION OF THE INVENTION
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`The present invention may be understood more readily by reference to the following
`
`
`
`
`
`
`
`
`
`
`
`
`detailed description of preferred embodiments of the invention and the Examples included
`
`
`
`therein.
`
`
`
`
`
`
`Definitions and Use of Terms
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`As used in this specification and in the claims which follow, the singular forms “a,”
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`“an” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for
`
`
`
`
`
`
`
`
`
`
`
`
`
`example, reference to “an ingredient” includes mixtures of ingredients, reference to “an active
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`pharmaceutical agent” includes more than one active pharmaceutical agent, and the like.
`
`
`
`
`
`
`
`
`
`
`
`
`The term “disintegrate” has its usual and customary meaning in the pharmaceutical
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`arts, as described in <70l> of the U.S. Pharmacopoeia (2005 USP/NF) for uncoated tablets,
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`using a basket rack assembly operating at 30 cycles per minute through a distance of 5.5 cm,
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`in a disintegration medium at 37 °C. When disintegration requirements are discussed herein,
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`they are preferably met under the foregoing testing conditions, at a pH of 4.0 or 6.8. A film
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`or other dosage form is said to be “disintegrated” if it is completely disintegrated, a state in
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`which any residue of the unit remaining on the screen of the test apparatus, or in the mouth, is
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`a soft mass having no palpably film core, or fragments of a tablet coating or capsule shell.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Disintegration thus does not imply complete dissolution of the dosage unit or even the active
`
`
`
`
`
`
`
`
`
`
`
`
`
`constituent, although a dissolved dosage unit would typically be completely disintegrated.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`When reference to Ph. Eur. 2.9.1 (disintegration) is made herein, it will be understood that the
`
`
`
`
`
`
`
`
`
`
`
`
`
`disintegration conditions described above under <701> USP can also be employed.
`
`
`
`The
`
`
`
`
`
`
`term “dissolution” also has
`
`
`
`
`
`its usual
`
`
`
`
`
`and customary meaning in the
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`pharmaceutical arts, as described in <711> and <724> of the U.S. Pharmacopoeia (2005
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`USP/NF). Therefore, a film is said to be “dissolved” if, upon testing by the method of U.S.
`
`
`
`
`
`DRL - EXHIBIT 1007
`
`DRL007
`
`
`
`DRL - EXHIBIT 1007
`DRL007
`
`

`
`
`WO 2008/040534
`
`
`
`PCT/EP2007/008579
`
`
`
`
`
`
`
`Pharmacopoeia (2005 USP/NF),
`
`
`
`
`
`
`
`
`
`
`
`the amount of active agent dissolved in the dissolution
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`medium exceeds a predetermined percentage. When dissolution conditions are given, it will
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`be understood that stirring preferably occurs in 0.lN hydrochloric acid buffer (pH=2), or at
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`pH l.2, pH 4.0 or 6.8, at 37° C, using the paddle method at 50 rpm in a type II dissolution
`
`
`
`apparatus.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`The term “immediate release,” when used in this document, refers to a dosage form
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`that allows the drug to dissolve in the gastrointestinal contents, with no intention of delaying
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`or prolonging the dissolution or absorption of the drug. The term includes tablets, capsules,
`
`
`
`
`
`
`
`
`
`
`
`
`
`liquid suspensions, orally disintegrating/dispersing tablet (ODT), and other dosage forms
`
`
`
`
`
`
`
`
`
`
`
`intended for immediate release of active ingredient upon administration (preferably oral
`
`
`
`administration).
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`In contrast, a “modified release” dosage form is a dosage form whose drug
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`release characteristics of time course and/or location are chosen to accomplish therapeutic or
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`convenience objectives not offered by conventional dosage forms such as a solution or
`
`
`
`0
`
`
`
`
`
`
`
`
`
`
`
`
`immediate release dosage form. Modified release solid oral dosage forms include both
`
`
`
`
`
`
`
`
`delayed and extended release drug products.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`An “immediate release” dosage form as used herein preferably refers to a dosage form
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`adapted to release at least 80% or 90% of an active pharmaceutical ingredient in 60 minutes
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`or less when measured in a type II dissolution apparatus (as described in <71 l> and <724> of
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`the U.S. Pharmacopoeia (2005 USP/NF)), in 0.lN hydrochloric acid buffer (pH=2), or at pH
`
`
`
`
`
`
`
`
`
`
`
`1.2, pH 4.0 or 6.8, at 37° C.
`
`
`
`
`
`
`
`
`
`
`
`
`In a preferred embodiment, at least 80%, 90% or 100% is
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`dissolved in no more than 45 or 30 minutes. Stirring preferably occurs using the paddle
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`method at 50 rpm. Finally, it will be understood that when reference to Ph. Eur. 2.9.3 (paddle
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`over disc) is made herein, the foregoing dissolution conditions under <71 1> and <724> of the
`
`
`
`
`
`
`
`
`
`
`U.S. Pharmacopoeia (2005 USP/NF) can be applied.
`
`
`
`
`
`
`
`
`
`
`
`
`An immediate release solid oral dosage form is considered “rapidly dissolving” when
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`not less than 80% of the label amount of the drug substance dissolves (i.e. releases) within 15
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`minutes in each of the following media: (1) pH 1.2, (2) pH 4.0, and (3) pH 6.8, in accordance
`
`
`
`
`
`with Q6 ICH-guideline.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`A “orally dissolving or orally dispersible tablet” (“ODT”) refers to an uncoated tablet
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`intended to be placed in the mouth where it can disperse rapidly before being swallowed, as
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`described in Eur. Ph. 5.0. An ODT disintegrates within three minutes when tested according
`
`
`
`
`
`
`
`
`to the disintegration testing described herein.
`
`
`
`
`
`DRL - EXHIBIT 1007
`
`DRL008
`
`
`
`DRL - EXHIBIT 1007
`DRL008
`
`

`
`
`WO 2008/040534
`
`
`
`PCT/EP2007/008579
`
`
`
`
`
`
`
`
`
`The term “non-mucoadhesive” means that
`
`
`
`
`
`
`
`
`
`
`the dosage form is not designed for
`
`
`
`
`
`
`
`
`
`
`administration of the active pharmaceutical agent through the oral mucosa.
`
`
`
`
`
`I.e. the dosage
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`form is not designed to adhere to the mucosal surfaces of the buccal cavity as an intact film or
`
`
`
`
`
`
`disintegrated film residue.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Unless specified otherwise, the term “wt. %” as used herein with reference to the final
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`product (i.e., the film, as opposed to the formulation used to create it), denotes the percentage
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`of the total dry weight contributed by the subject ingredient. This theoretical value can differ
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`from the experimental value, because in practice, the film typically retains some of the water
`
`
`
`
`
`
`
`and/or ethanol used in preparation.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`When doses are given for a drug and its salt, it will be understood that the calculated
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`dose is based on the molecular weight of the active pharmaceutical ingredient, which includes
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`the cationic and anionic species in the case of a salt, and just the base when the active
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`principle is not present as a salt. In addition, when reference is made to the salt of a drug and
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`pharmaceutically acceptable salts thereof, it will be understood that salts of the base form of
`
`
`
`
`
`
`
`the base drug are intended.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`When ranges are given by specifying the lower end of a range separately from the
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`upper end of the range, it will be understood that the range can be defined by selectively
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`combining any one of the lower end variables with any one of the upper end variables that is
`
`
`mathematically possible.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`When used herein the term “about” or “ca.” will compensate for variability allowed
`
`
`
`
`for
`
`
`
`in the pharmaceutical
`
`
`
`
`
`industry and inherent
`
`
`
`
`
`in pharmaceutical products,
`
`
`
`
`
`such as
`
`
`
`
`
`
`
`
`
`
`
`differences in product strength due to manufacturing variation and time-induced product
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`degradation. The term allows for any variation which in the practice of pharmaceuticals
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`would allow the product being evaluated to be considered bioequivalent to the recited
`
`
`
`
`
`
`strength of a claimed product.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`The term “absolute bioavailability” refers to the availability of the active drug in
`
`
`
`
`
`
`
`
`
`
`systemic circulation after non-intravenous administration (i.e., after oral, rectal, transdermal,
`
`
`
`
`subcutaneous administration).
`
`
`
`
`
`
`
`
`
`
`
`
`In order to determine absolute bioavailability of a drug, a
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`pharmacokinetic study must be done to obtain a plasma drug concentration versus time plot
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`for the drug after both intravenous (IV) and non-intravenous administration. The absolute
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`bioavailability is the dose-corrected area under curve (AUC) non-intravenous divided by
`
`
`AUC intravenous.
`
`
`
`
`
`DRL - EXHIBIT 1007
`
`DRL009
`
`
`
`DRL - EXHIBIT 1007
`DRL009
`
`

`
`
`WO 2008/040534
`
`
`
`PCT/EP2007/008579
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`When pharmacokinetic parameters are given herein (i.e. Tmax, absolute bioavailability,
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`etc.), it will be understood that they can refer to the mean, median, or individual observed
`
`
`
`
`
`
`
`
`
`
`
`
`
`pharmacokinetics, and that mean pharmacokinetics are intended when claimed unless stated
`
`
`
`
`
`to the contrary.
`
`
`
`Discussion
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`As discussed above, the invention provides a physiologically acceptable film that is
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`particularly well adapted to disintegrate rapidly when placed on the tongue of a patient, and to
`
`
`
`
`
`
`
`
`
`
`
`
`facilitate gastrointestinal absorption of the pharmaceutically active agent. The film and active
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`agent need not dissolve entirely in the mouth, and preferably the film is not entirely dissolved.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`When tested according to Ph. Eur. 2.9.3, paddle over disc, the film preferably dissolves (at
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`least 80% or 100% active agent release) within about 15, 10 or 5 minutes, when tested at pH
`
`
`
`
`
`
`
`1.2, 4.0 or 6.8.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`The film may also be characterized by the time it takes to disintegrate completely, and
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`it preferably disintegrates to a soft residue within about 10, 20, 30 or 60 seconds of
`
`
`
`
`
`
`
`administration, after which it
`
`
`is swallowed.
`
`
`
`
`
`
`
`These disintegration times are preferably
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`observed in the oral cavity when the film is administered, as well as when tested for
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`disintegration using the method described i