(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`
`(19) World Intellectual Property Organization
`International Bureau
`
`(43) International Publication Date
`10 April 2008 (10.04.2008)
`
`peT
`
`(51) International Patent Classification:
`A61K 9170 (2006.01)
`A61K 311445 (2006.01)
`
`(21) International Application Number:
`PCTlEP2007/008579
`
`(22) International Filing Date: 2 October 2007 (02.10.2007)
`
`(25) Filing Language:
`
`(26) Publication Language:
`
`English
`
`English
`
`(30) Priority Data:
`60/848,965
`
`2 October 2006 (02.10.2006) US
`
`(71) Applicants (jor all designated States except US):
`LABTEC GESELLSCHAFT FUR TECHNOLOGIS(cid:173)
`CHE FORSCHUNG UND ENTWICKLUNG MBH
`[DEIDE]; Raiffeisenstrasse 3a, 40764 Langenfeld (DE).
`APR APPLIED PHARMA RESEARCH S.A. [CHICH];
`Via Corti, 5, CH-6828 Balema (CH).
`
`(72) Inventors; and
`(75) InventorslApplicants (jor US only): LEICHS, Chris(cid:173)
`tian [DEIDE]; Liesendahler Weg 22A, 51399 Burscheid
`(DE). BREITENBACH, Armin [DEIDE]; Widdauener
`Strasse 35, 51371 Leverkusen (DE). LEHRKE, Ingo
`[DEIDE]; Emst-Wilhelm-Nay-Strasse 9, 50935 K51n
`
`11111111111111111111111111111111111111111111111111111111111111111111111111111111111111111111111
`
`(10) International Publication Number
`WO 2008/040534 A2
`(DE). GALFETTI, Paolo [ITIlT]; Via Canturina Vecchia
`34/b, 22070 Senna Comasco (CO) (IT).
`(74) Agent: LEISSLER-GERSTL, Gabriele; Hoefer & Part(cid:173)
`ner, Pilgersheimer Strasse 20, 81543 Miinchen (DE).
`(81) Designated States (unless otherwise indicated, for every
`kind of national 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, Fl, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, lL,
`IN, IS, JP, KE, KG, KM, KN, KP, KR, 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,
`PT, RO, RS, RU, SC, SD, SE, SG, SK, SL, SM, SV, SY,
`TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA,
`ZM, zw.
`(84) Designated States (unless otherwise indicated, for every
`kind of regional protection available): ARIPO (BW, GH,
`GM, KE, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM,
`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, IE, IS, IT, LT, LU, LV, MC, MT, NL, PL,
`PT, RO, SE, SI, SK, TR), OAPI (BF, BJ, CF, CG, CI, CM,
`GA, GN, GQ, GW, ML, MR, NE, SN, TD, TG).
`Published:
`without international search report and to be republished
`upon receipt of that report
`
`--------------------------------------------------------------------------------------
`(54) Title: NON-MUCOADHESNE FlLM DOSAGE FORMS
`
`Dissolution profiles Ondandestron: comparison tablet vs oral dissolving
`tablet vs Rapldfilm
`
`-
`
`/
`
`/ -
`
`/
`
`__ Zofran® Bm 9 Film labial
`_
`Zofran® Bm 9 Zydla® Lingual
`
`I--
`
`110
`
`90
`
`70
`
`Gi
`.a
`.!!
`E
`,g
`1§
`- 050
`e E
`'" e
`c
`3i
`30
`Ii
`" c
`0
`';/t.
`
`10
`
`-10
`
`-iiiiiiii
`
`iiiiiiii
`
`- -
`
`-
`_
`
`--
`
`!!!!!!!!
`iiiiiiii
`
`iiiiiiii ----
`
`tim a [min)
`
`~ medical conditions are provided.
`
`-
`r
`/ /
`II
`/
`II
`/
`f ~ --.-Ondanaatron Bmg RapldFilm
`.... ------
`,
`
`2
`
`4
`
`8
`
`~ Zofran® 4m 9 Zydla® Lingual
`_Ondanaetron 4mg RapldFilm
`10
`B
`
`I--
`
`I--
`1
`
`~
`~
`In
`Q
`~
`Q -.....
`QO
`Q
`Q
`o (57) Abstract: Orally disintegrating film dosage forms for delivering active pharmaceutical agents, methods of formulating the
`M
`> dosage forms to retard absorption through the oral mucosa, and methods of using the dosage forms for the treatment of various
`
`Page 1
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`WO 2008/040534
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`peT IEP2007 1008579
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`NON-MUCOADHESIVE FILM DOSAGE FORMS
`
`RELA TIONSHIP TO PRlOR 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(cid:173)
`
`counter drug products, including Listerine® breath strips, Triaminic® thin strips (active agent
`
`= diphenhydramine HCI), and Sudafed PE™ quick dissolve strips (active ingredient =
`
`phenylephrine HCI). 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 pre systemic 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 aI., film-forming agents
`
`have been used to manufacture drug delivery formulations for percutaneous or transdermal
`
`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 aI., 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
`
`Page 2
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`WO 2008/040534
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`peT IEP2007 1008579
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`al., U.S. Patent No. 5,700,478, describes a water-soluble pressure-sensitive mucoadhesive
`
`suitable for use in a mucosal-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 (DDT).
`
`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).
`
`2
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`Page 3
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`WO 2008/040534
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`peT IEP2007 1008579
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`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(cid:173)
`
`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:
`
`3
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`WO 2008/040534
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`peT IEP2007 1008579
`
`•
`
`•
`
`•
`
`•
`
`a T max (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 T max 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.
`is specially formulated or administered for
`Finally, because the film dosage form
`
`gastrointestinal absorption, the film dosage form has a comparable absolute bioavailability or
`
`T max 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:
`
`•
`
`•
`
`•
`
`•
`
`•
`
`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.
`
`4
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`WO 2008/040534
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`peT IEP2007 1008579
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`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.
`
`5
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`WO 2008/040534
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`peT IEP2007 1008579
`
`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 (aND 013 aD), 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 HCI Form I.
`
`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 <701> of the U.S. Pharmacopoeia (2005 USPINF) 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 m
`
`the
`
`pharmaceutical arts, as described in <711> and <724> of the U.S. Pharmacopoeia (2005
`
`USPINF). Therefore, a film is said to be "dissolved" if, upon testing by the method of U.S.
`
`6
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`WO 2008/040534
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`peT IEP2007 1008579
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`Pharmacopoeia (2005 USPINF), the amount of active agent dissolved in the dissolution
`
`medium exceeds a predetennined percentage. When dissolution conditions are given, it will
`
`be understood that stirring preferably occurs in 0.1 N hydrochloric acid buffer (pH=2), or at
`
`pH 1.2, pH 4.0 or 6.8, at 37° C, using the paddle method at 50 rpm in a type II dissolution
`
`apparatus.
`
`The tenn "immediate release," when used in this document, refers to a dosage fonn
`
`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 tenn includes tablets, capsules,
`
`liquid suspensions, orally disintegrating/dispersing tablet (ODT), and other dosage fonns
`
`intended for immediate release of active ingredient upon administration (preferably oral
`
`administration). In contrast, a "modified release" dosage fonn is a dosage fonn whose drug
`
`release characteristics of time course and/or location are chosen to accomplish therapeutic or
`
`convenience objectives not offered by conventional dosage fonns such as a solution or
`
`immediate release dosage fonn. Modified release solid oral dosage fonns include both
`
`delayed and extended release drug products.
`
`An "immediate release" dosage fonn as used herein preferably refers to a dosage fonn
`
`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 <711> and <724> of
`
`the U.S. Pharmacopoeia (2005 USPINF)), in O.1N 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 <711> and <724> of the
`
`U.S. Pharmacopoeia (2005 USPINF) can be applied.
`
`An immediate release solid oral dosage fonn is considered "rapidly dissolving" when
`
`not less than 80% of the label amount of the drug substance dissolves (Le. 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.
`
`7
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`peT IEP2007 1008579
`
`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 anyone of the lower end variables with anyone 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.
`
`8
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`peT IEP2007 1008579
`
`When pharmacokinetic parameters are given herein (i.e. T max, 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
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`As discussed above, the invention provides a physiologically acceptable film that is
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`particularly well adapted to disintegrate rapidly when placed on the tongue of a patient, and to
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`facilitate gastrointestinal absorption of the pharmaceutically active agent. The film and active
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`agent need not dissolve entirely in the mouth, and preferably the film is not entirely dissolved.
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`When tested according to Ph. Eur. 2.9.3, paddle over disc, the film preferably dissolves (at
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`least 80% or 100% active agent release) within about 15, 10 or 5 minutes, when tested at pH
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`1.2, 4.0 or 6.8.
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`The film may also be characterized by the time it takes to disintegrate completely, and
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`it preferably disintegrates to a soft residue within about 10, 20, 30 or 60 seconds of
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`administration, after which it is swallowed. These disintegration times are preferably
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`observed in the oral cavity when the film is administered, as well as when tested for
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`disintegration using the method described in Ph. Eur. 2.9.1. The prompt disintegration and
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`swallowing of the film helps to assure gastrointestinal absorption of the dosage form. The
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`film is not of the conventional mucoadhesive type, designed to deliver active agent
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`transmucosally.
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`In one embodiment, the film is defined by its long T max, and in various embodiments,
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`the film has a T max of greater than about 3.0, 3.5, 4.0, 4.5, or 5.0 hours. Alternatively or in
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`addition, the film can be defined by the absolute bioavailability (i.e. total extent of
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`absorption) of the active ingredient and, in various embodiments, the film has an absolute
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`bioavailability that is greater than about 45%, 55%, 65%, 75%, 85% or even 95%. In still
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`another embodiment, the film is defined by the rate or extent of absorption of active agent
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`into the bloodstream, in addition or alternatively to the absolute bioavailability of the active
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`agent. For example, the film can be defined by T max (i.e. time to maximum concentration of
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`the active agent in plasma) and, in various embodiments, the film has a T max less than about
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`3.0, 2.5, 2.0 or even 1.5 or 1.0 hours. Alternatively or in addition, the film can be defined by
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`an absolute bioavailability greater than about 45%, 50%, or 55%.
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`Therefore, in another embodiment the invention provides a non-mucoadhesive orally
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`disintegrating film, able to disintegrate upon contact with saliva in the buccal cavity within
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`WO 2008/040534
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`peT IEP2007 1008579
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`about sixty seconds, comprising a defined amount of an active pharmaceutical agent, or a
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`pharmaceutically acceptable salt thereof, a hydrophilic binder and a water-soluble diluent,
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`wherein: (a) said film is formulated for delivery of said active agent through the
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`gastrointestinal tract when applied to the tongue; (b) said film comprises from about 0.05% to
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`about 50% (w/w) of said active pharmaceutical agent, based on the total weight of the
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`formulation; and (c) said film
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`is characterized by one or more of the following
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`pharmacokinetic parameters: (i) a T max of greater than about 4.5 hours; (ii) an absolute
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`bioavailability of greater than 65%, and optionally a T max greater than about 1.5 hours; or (iii)
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`a T max ofless than about 3.0 hours, and an absolute bioavailability greater than about 45%.
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`In another embodiment, the invention is defined by its bioequivalence to an immediate
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`release dosage tablet or capsule or orally dissolving/dispersing tablet (ODT) that contains the
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`same amount of active pharmaceutical agent. In particular, the invention provides a non(cid:173)
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`mucoadhesive orally disintegrating film, able to disintegrate upon contact with saliva in the
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`buccal cavity within about sixty seconds, comprising a defined amount of an active
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`pharmaceutical agent, or a pharmaceutically acceptable salt thereof, a hydrophilic binder and
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`a water-soluble diluent, wherein: (a) said film is formulated for delivery of said active agent
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`through the gastrointestinal tract when applied to the tongue; (b) said film comprises from
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`about 0.05% to about 50% (w/w) of said active pharmaceutical agent, based on the total
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`weight of the formulation; and (c) said film is bioequivalent to an immediate release tablet or
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`capsule or orally dissolving/dispersing
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`tablet
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`(ODT)
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`that comprises said active
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`pharmaceutical agent or a pharmaceutically acceptable salt thereof in said defined amount
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`(i.e. a "reference product").
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`The reference product can be defined by various pharmacokinetic or physical
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`properties. For example, the reference product could be characterized by its absolute
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`bioavailability, and preferably the absolute bioavailability is greater than about 65%, 75%,
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`85% or even 95% when administered orally, and/or a T max greater than about or 4.5 hours.
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`The reference product could also be characterized by its T max and/or absolute bioavailability,
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`i.e. a T max less than about 3.0, 2.5, 2.0 or even 1.5 or 1.0 hours, and/or an absolute
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`bioavailability greater than about 45%, 50%, or 55%.
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`Alternatively, the reference product could be characterized by its disintegration time
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`which, in various embodiments could exceed 5, 10, 20, 30, 40 or 45 minutes, when tested
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`according to Ph. Eur. 2.9.1, and preferably would be less than 60, 75 or 90 minutes. The
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`reference product could also be defined by its dissolution time. Dissolution times for the
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`comparative reference products of the present invention, when tested according to Ph. Eur.
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`2.9.3, based on the time it takes to dissolve 75, 80, 85, 90 or 95 wt.% of the drug substance,
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`when tested at pH 1.2,4.0 and/or 6.8, are preferably greater than about 5, 10,20,30,40 or 45
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`minutes, and less than about 90, 75 or 60 minutes. In a preferred embodiment, the dissolution
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`profile for the reference product is in accordance with the following specification: not less
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`than 70, 80, 90 or 95% dissolved after 60 minutes when tested according to Ph. Eur. 2.9.3
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`(paddle over disc).
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`In one embodiment, the reference product is a capsule, optionally
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`characterized by a gelatin shell. In another embodiment, the reference product is a tablet,
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`optionally characterized by a film or enteric coating. In another embodiment, the reference
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`product is a orally dissolving/dispersing tablet (ODT).
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`The film can also be characterized by various physical characteristics, including its
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`structure, size and shape. For example, in one embodiment, the film is a single layer
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`homogeneous film. In another embodiment, the film has a weight of from about 30 to about
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`150 milligrams, preferably from about 40 to about 120 milligrams. The film may vary in
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`thickness anywhere from about 10 to about 200 microns, and preferably does not exceed 8 or
`7 cm2 in surface area.
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`The invention also provides various methods of treatment, based on the particular
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`active agent involved, that rely on one or more of several defining characteristics, including
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`the placement of the dosage form on the tongue, swallowing the dosage form within ten,
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`twenty, thirty, forty-five or sixty seconds, and swallowing the dosage form with or without
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`water. In yet another embodiment, therefore, the invention provides a method of treatment
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`comprising: (a) providing a non-mucoadhesive orally disintegrating film, able to disintegrate
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`upon contact with saliva in the buccal cavity within about sixty seconds, comprising a defined
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`amount of an active pharmaceutical agent, or a pharmaceutically acceptable salt thereof, a
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`hydrophilic binder and a water-soluble diluent: (b) placing s