(19) l • I Canadian
`
`Intellectual Property
`Office
`
`Office de la Propriete
`lntellectuelle
`du Canada
`
`An Agency of
`Industry Canada
`
`Un organisme
`d'lndustrie Canada
`
`(11) CA 2 467 490
`(40) 05.06.2003
`(43) 05.06.2003
`
`(13) A 1
`
`(12)
`
`(21) 2 467 490
`
`(22) 04.11.2002
`
`(51) Int. Cl. 1
`
`:
`
`A61 K 47/38 , A61 K 47/02,
`A61K 47/10, A61K 47/36,
`A61 K 31/495
`
`(85) 28.05.2004
`
`(86) PCT/I802/004612
`
`60/334,652 us 30.11.2001
`
`PFIZER PRODUCTS INC.,
`Eastern Point Road, GROTON, XX (US).
`
`87 WO03/045437
`WATERMAN, KENNETH CRAIG (US).
`QUAN, ERNEST SHING (US).
`SMITH, SCOTT WENDELL (US).
`AM ENDE, MARY TANYA (US).
`ROY, MICHAEL CHRISTOPHER (US).
`
`MOSES, SARA KRISTEN (US).
`
`(74)
`
`SMART & BIGGAR
`
`COMPOSITIONS PHARMACEUTIQUES DE 5,7, 14-TRIAZA TETRACYCLO[10.3.1 .0(2, 11 ).0(4,9)]-HEXADECA-
`2(11 )3,5, 7,9-PENTAENE
`PHARMACEUTICAL COMPOSITIONS OF 5,7,14-TRIAZATETRACYCLO[10.3.1 .0(2,11).0(4,9)]-HEXADECA-2(11 )
`3,5,7,9-PENTAENE
`
`(30)
`
`(71)
`
`(72)
`
`(54)
`
`(54)
`
`(57)
`
`is directed to controlled(cid:173)
`The present invention
`release (CR) oral pharmaceutical dosage forms of 5,8,
`14-triazatetracyclo[10.3.1.02, 11.04,9]-
`hexadeca-2(11
`),
`3,5,7,9-pentaene, 1, and pharmaceutically acceptable
`salts
`thereof, and methods of using them to reduce
`nicotine addiction or aiding
`in
`the cessation or
`lessening of tobacco use while reducing nausea as an
`adverse
`effect. The present invention also relates to
`an
`immediate-release (IR)
`low
`dosage composition
`having
`a
`stable
`formulation with
`uniform
`drug
`distribution and potency.
`
`Apotex Exhibit 1008.001
`
`

`

`l • I Office de la Propriete
`
`lntellectuelle
`du Canada
`Un organisme
`d'lndustrie Canada
`
`Canadian
`Intellectual Property
`Office
`An agency of
`Industry Canada
`
`(86) Date de depot PCT/PCT Filing Date: 2002/11/04
`(87) Date publication PCT/PCT Publication Date: 2003/06/05
`(85) Entree phase nationale/National Entry: 2004/05/28
`(86) N° demande PCT/PCT Application No.: 1B 2002/004612
`(87) N° publication PCT/PCT Publication No.: 2003/045437
`(30) Priorite/Priority: 2001/11/30 (60/334,652) US
`
`CA 2467 490 A 1 2003/06/05
`(21) 2 467 490
`c12J DEMANDE DE BREVET CANADIEN
`CANADIAN PATENT APPLICATION
`r13J A 1
`
`(51 ) Cllnt. 7 /Int.CL 7 A61 K 47/38 , A61 K 31/495, A6 1 K 47/36,
`A61K47/10, A61 K 47/02
`(71 ) Demandeur/Applicant:
`PFIZER PRODUCTS INC., US
`(72) lnventeurs/lnventors:
`AM EN DE, MARY TANYA, US;
`ROY, MICHAEL CHRISTOPHER, US;
`SMITH, SCOTT WENDE LL, US;
`WATERMAN, KENNETH CRAIG, US;
`MOSES, SARA KRISTEN , US;
`QUAN, ERNEST SHING, US
`(74) Agent: SMART & BIGGAR
`
`(54) Titre: COMPOSITIONS PHARMACEUTIQUES DE 5,7, 14-TRIAZATETRACYCLO[10.3.1 0(2, 11) 0(4,9)]-HEXADECA-
`2(11)3,5,7,9-PENTAENE
`(54) Title: PHARMACEUTICAL COMPOSITIONS OF 5,7, 14-TRIAZATETRACYCLO[10.3. 1 0(2, 11) 0(4,9)]-HEXADECA-
`2(11 )3,5,7,9-PENTAENE
`
`NH
`
`(1)
`
`(57) Abrege/Abstract:
`(CR) oral pharmaceutical dosage
`to controlled-release
`is directed
`The present
`invention
`forms of 5,8, 14-
`triazatetracyclo[10.3 1 02 11 .04·9]-hexadeca-2(11 ),3,5,7,9-pentaene, 1, and pharmaceutically acceptable salts thereof, and
`methods of using them to reduce nicotine addiction or aiding in the cessation or lessening of tobacco use while reducing nausea
`as an adverse effect. The present invention also relates to an immediate-release (IR) low dosage composition having a stable
`formulation with uniform drug distribution and potency
`
`dl+I
`ana a J1ttp://opic.gc.ca · Ottawa-Hull KI A OC9 · http ://cipo.gc.ca
`C
`
`OPIC · CIPO 19 1
`
`0 P I C
`
`C IP O
`
`Apotex Exhibit 1008.002
`
`

`

`CA 02467490 2004-05-28
`
`(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`
`(19) World Intellectual Property Organization
`International Bureau
`
`1111111111111111 IIIIII 111111111111111 IIIIIIIIII IIIII IIIII 1111111111111111111111111111
`
`(43) International Publication Date
`5 June 2003 (05.06.2003)
`
`PCT
`
`(10) International Publication Number
`WO 03/045437 Al
`
`(51) International Patent Classification 7:
`47/36, 47/02, 47/10, 31/495
`
`A61K 47/38,
`
`(21) International Application Number:
`
`PCT/1B02/04612
`
`Sara, Kristen [US/US]; Pfizer Global Research and De(cid:173)
`velopment, Eastern Point Road, Groton, CT 06340 (US).
`Q UAN, Ernest, Shing l US/US J; Pfizer Global Research
`a nd Development, Eastern P oint Road, Groton , CT 0fi340
`(US).
`
`(22) International Filing Date:
`4 November 2002 (04.11.2002)
`
`(74) Agents: LUMB, J., Trevor ct al.; Pfizer Inc., 201 Tabor
`Road, Morris Plains, NJ 07950 (US).
`
`(25) Filing Language:
`
`(26) Publication Language:
`
`English
`
`English
`
`(30) Priority Data:
`60/334.652
`
`30 November 2001 (30.11.2001) US
`
`(71) Applicant (for all designated States except US): PFIZER
`PRODUCTS INC. flJS/lJS]; Eastern Point Road, Groton,
`CT 06340 (US).
`
`(72) Inventors; and
`(75) Inventors/Applicants (for US onl:r~: AM ENDE, Mary,
`Tanya lUS/USJ; Pfizer Global Research and Develop(cid:173)
`ment, Eastern Point Road, Groton, CT 06340 ( US). ROY,
`Michael, Christopher [US/US]; Pti zer Glohal Research
`and Development , Tiastern P oint Road, Groton, CT 0 6340
`(US). SMITH, Scott, Wendell [US/US] ; Pfizer Global
`Research and Development, 10777 Science Center Drive,
`San Diego, CA 92121 (US). WATERMAN, Kenneth,
`Craig [US/US]; Pfizer Global Research and Dcvclopmcnl,
`Eastern Point Road, Groton, CT 06340 (US). MOSES,
`
`--
`--=
`
`(81) Designated States (national) : AE, AG, AL, AM, AT, AU,
`AZ, BA, BB, BG, BR, BY, BZ, CA, CH, CN, CO , CR, CU,
`CZ, DE, DK, DM, DZ, EC, 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, M A, MD, M G, M K, MN, l\,1W,
`MX, MZ, NO, NZ, OM, PH, PL, fYl', RO, RU, S D, SH, SG,
`SI, SK, SL , TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ,
`VN, YU, ZA, ZM, ZW.
`
`(84) Designated States (regional): ARIPO paLcnt (GH, GM,
`KE, LS, l\,1W, MZ, SD, SL, SZ, TZ, UG, ZM, ZW),
`Eurasian pate nt (AM, AL, BY, KG, KZ, MD, RU, TJ, TM),
`European patent (AT, BE, BG, CII, CY, CZ, DE, DK, EE,
`TIS, fi'f, T7R , GR, GR , m, TT, LU , MC, NL, PT, SE , SK,
`TR), OAPI patent (Br, BJ, CP, CG, CI, CM, GA, G N, GQ,
`GW, ML, tvlR, NE, SN, TD, TG).
`
`Published:
`-
`with international search report
`
`For two-letter codes and other abbreviations, refer to the "Guid(cid:173)
`ance Notes on Codes and Abbreviations" appearing at the begin(cid:173)
`ning of each regular issue of the PCT Gazette.
`
`== --iiiiiiiiiiiiii
`
`t--, (54) Title:
`PHARMACElJTICAL C OMPOSITIONS OF 5 ,7,14 -TRIAZATETRJ\CYCL O[l0.3. l.0(2,ll).0(4 ,9)]-HEX-
`~ ADECA-2(11)3,5,7,9-PENTAENE
`"" i
`
`-~-
`
`NH
`
`(I)
`
`---~-
`
`N
`
`....._
`(
`~
`O ~
`0
`N
`>
`
`(57) Abstract: The present invention is directed to controlled-re lease
`(CR)
`oral
`pharmaceutica l
`dosage
`forms
`of
`5,8,14-triazatetra-
`cyclo[l0.3. 1.02,11_04·9]-hexadeca-2(11
`),3,5,7,9-pentaene,
`1,
`and
`pharmaceutically acceptable salts thereof, and methods of using them to
`reduce nicotine addiction or aiding in the cessation or lessening of tobacco use
`while reducing nausea as an adverse effect. T he present invention also rela tes
`;;-,,- to an immcdiatc-rclcasc (IR) low dosage composition having a stable formulation with uniform drug distribution and potency.
`
`Apotex Exhibit 1008.003
`
`

`

`WO 03/045437
`
`PCT/IB02/04612
`
`CA 02467490 2004-05-28
`
`PHARMACEUTICAL COMPOSITIONS OF 5,7,14-TRIAZATETRACYCLO'l0 . 3.1.0 (2 , 1 1 ) .0
`(4,9) !- HEXADECA-2(11)3,5,7,9-PENTAENE
`
`The present invention is directed to controlled-release (CR) oral pharmaceutical
`11.04
`9]-hexadeca-2(11),3,5,7,9-pentaene, 1,
`dosage forms of 5,8, 14-triazatetracyclo[10.3.1.02
`•
`•
`
`5
`
`and related compounds, and methods of using them to reduce nicotine addiction or aiding in
`
`the cessation or lessening of tobacco use while reducing nausea as an adverse effect. The
`
`present invention also relates to an immediate-release (IR) low dosage composition having a
`
`stable formulation with uniform drug distribution and potency.
`
`10
`
`1
`BACKGROUND OF THE INVENTION
`Compound 1, also known as 7,8,9, 1O-tetrahydro-6,10-methano-6H-pyrazino[2,3-h][3](cid:173)
`
`benzazepine, binds to neuronal nicotinic acetylcholine specific receptor sites and are useful in
`
`modulating cholinergic function. Accordingly, this compound is useful in the treatment of
`
`15
`
`inflammatory bowel disease (including but not
`
`limited
`
`to ulcerative colitis, pyoderma
`
`gangrenosum and Crohn's disease), irritable bowel syndrome, spastic dystonia, chronic pain,
`
`acute pain, celiac sprue, pouchitis, vasoconstriction, anxiety, panic disorder, depression, bipolar
`
`disorder, autism, sleep disorders, jet lag, amyotrophic lateral sclerosis (ALS), cognitive
`
`dysfunction, hypertension, bulimia, anorexia, obesity, cardiac arrhythmias, gastric acid
`
`20
`
`hypersecretion, ulcers, pheochromocytoma, progressive supranuclear palsy, chemical
`
`dependencies and addictions @&, dependencies on, or addictions to nicotine (and/or tobacco
`
`products), alcohol, benzodiazepines, barbiturates, opioids or cocaine), headache, migraine,
`
`stroke,
`
`traumatic brain
`
`injury (TBI), obsessive-compulsive disorder (OCD), psychosis,
`
`Huntington's chorea, tardive dyskinesia, hyperkinesia, dyslexia, schizophrenia, multi-infarct
`
`25
`
`dementia, age-related cognitive decline, epilepsy, including petit mal absence epilepsy, senile
`dementia of the Alzheimer's type (AD), Parkinson's disease (PD), attention deficit hyperactivity
`disorder (ADHD) and Tourette's Syndrome.
`
`Compound 1 and pharmaceutically acceptable acid addition salts thereof are referred
`
`to in International Patent Publication WO 99/35131, published July 15, 1999, which is
`
`30
`
`incorporated herein by reference in its entirety.
`
`Whereas immediate release (IR) dosage forms of the aforementioned compound,
`
`that is, dosage forms designed to provide the drug in a dissolved form upon swallowing in
`
`less than about 30 minutes, provide therapeutically useful levels of drug in the blood and
`brain, it has been observed that there is a significant level of nausea in patients, especially at
`doses sufficiently high to be therapeutically useful for some patients. Since nausea can lead
`
`35
`
`SUBSTITUTE SHEET (RULE 26)
`
`Apotex Exhibit 1008.004
`
`

`

`WO 03/045437
`
`PCT/IB02/04612
`
`CA 0 2467490 2004-05-28
`
`-2-
`
`to poor patient compliance with a dosing regimen, there Is a need to provide 1 in a form that
`reduces the incidence of nausea.
`Accordingly, the present invention provides CR dosage forms of 1 that reduce or
`eliminate nausea while maintaining a therapeutic level of the drug in the blood and central
`nervous system (CNS). While examples exist in the art suggesting that CR dosage forms
`may in some cases provide for a reduction in such side effects as nausea (e.g., oxycodone (J,
`R. Caldwell, et al., J. of Rheumatology.1999, 26, 862-869), venlafaxine (R. Entsuah and R.
`Chitra, Psychopharmaco/ogy Bulletin, 1997, 33, 671-676) and paroxetine (R. N. Golden, et
`al., J. Cl/n. Psychiatry, 2002, 63, 577-584), counter examples also exist .which indicate that
`CR dosage forms are sometimes no better than immediate release dosage forms for the
`reduction of nausea, and therefore teach away from the utility of the CR form as a means of
`reducing side effects. Examples of this teaching away include morphine sulfate (T. D. Walsh,
`et al., J. Clin. Oncology, 1992, 15, 268-272), hydromorphone (H. Hays, et al., Cancer, 1994,
`74, 1808-1816), dihydrocodeine tartrate (G. Xu, et al., Zhongguo Yaowu Yilaixing Zazhi,
`1999, 8, 52-57) and carbidopa/levodopa {G. Block, et al., European Neurology, 1997, 37, 23-
`27). In addition, in many cases, CR dosage forms result in reduction in bioavailability
`compared to the IR dosage form, necessitating an increase in dose or even making the use of
`a CR dosage form infeasible. It therefore remains impossible to predict a priori which· drugs
`showing nausea will actually benefit from CR do~age forms. Moreover, the rate at which the
`drug is made available, that is, its dissolution rate, can range considerably from slightly slower
`than the IR dosage form to deliver over an extended period (up to about 24 hours). The
`inventors have discovered that for 1, CR dosage forms with a certain range of delivery rates
`will provide therapeutic blood and CNS drug levels while reducing the incidence of nausea
`when compared to the IR dosage form. The inventors have also discovered specific preferred
`ways of formulating 1 to achieve the desired drug administration rates. The inventors have
`also discovered preferred dosing regimens that provide therapeutic drug levels while
`maintaining low levels of nausea.
`The high potency of compound 1 as a nicotinic receptor ligand allows the use of low
`dosage strengths for· administration. For ease of handling, manufacturing and patient
`convenience, low dosage strength drugs are often formulated at high dilution with excipients.
`In the preparation and storage of such dilute formulations, however, unique challenges are
`Introduced. First, the high dilution can enable excipients or even excipient impurities to cause
`significant drug degradation during storage. Examples of excipient properties that may
`impact drug degradation include moisture content and mobility of moisture (see J.T.
`Carstensen, Drug Stability: Principles and Practices, 2nd Ed, Marcel Dekker, NY, 1995, 449-
`452)., and excipient acidity affecting local pH microenvironments (see K. Waterman et al.,
`Pharm Dev. Tech., 2002, 7(2), 113-146). Examples of excipient impurities that affect drug
`
`5
`
`10
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`15
`
`20
`
`25
`
`30
`
`35
`
`Apotex Exhibit 1008.005
`
`

`

`WO 03/045437
`
`PCT/IB02/04612
`
`CA 0 2 467490 2 004-05-2 8
`
`-3-
`
`degradation include trace metals, peroxides, and formic acid (see K. Waterman, et al., Pharm.
`Dev. Tech., 2002, 7(1 ), 1-32). Although consideration of the chemical structure and
`identification of reactive moieties therein can be used to theorize potential degradation
`pathways, it remains impossible to predict a priori whether a particular excipient will form an
`acceptably stable formulation with a given drug. Moreover, 1 has been observed to react with
`It therefore remains a need to provide
`many common exclpients and excipient impurities.
`excipient and excipient combinations which can provide acceptable formulations (for such
`properties as tableting) while providing suitable stability for 1. The inventors have discovered
`specific preferred ways of formulating 1 to achieve the desired stablllty. More specifically for
`a film coated tablet, the inventors have discovered specific formulations and processes to
`achieve the desired stability.
`A second issue sometimes seen with potent drugs prepared at high dilution is
`variability in potency due to segregation and adhesion to equipment during manufacturing.
`This Issue has been found to be a problem with formulations of 1. One method recently
`reported for achieving a uniform drug distribution in a blend of a low dose drug makes use of
`a carrier excipien~ lactose, to form an ordered mixture with a micronized drug (L. Wu, et al.,
`AAPS PharmSc!Tech, 2000, 1(3), article 26). Although one can effectively implement a
`manual brushing step to recover active ingredient segregated by fluidization or adhered to the
`metal surfaces in small scale equipment, a manual brushing step is neither efficient not
`desirable in a production scale environment. Liquid processes can minimize the drug loss
`issues during drug product manufacturing; however, compounds that undergo form changes
`(e.g. polymorph, hydrate, or solvate changes) make liquid processes very difficult to perform
`while maintaining drug Ingredient stability (physical and chemical). - Although many
`techniques have been used to solve these general problems, it remains impossible to predict
`which particular techniques will be effective for a given set of drugs and excipients.
`Therefore, because of the high dilution necessary with 1, there is a need for a process
`suitable for commercialization of 1 whereby adequate potency uniformity from dosage form
`(e.g., tablet) to dosage form and lot to lot can be maintained. The inventors have also
`discovered preferred ways of processing formulations of 1 to achieve the desired uniform
`drug potency and uniform drug distribution.
`SUMMARY OF THE INVENTION
`The present invention relates to certain controlled-release (CR) pharmaceutical
`dosage forms of 1 or pharmaceutically acceptable salts thereof, to a subject in need thereof,
`said CR dosage form comprising the compound, or pharmaceutically acceptable salt thereof,
`and a means for delivering the compound, or pharmaceutically acceptable salt thereof, to said
`subject at a rate of less than about 6 mgA/hour (where mgA refers to milligrams of actlve drug
`in equivalence to the free base), whereby at least about 0.1 mgA of the compound, or
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`Apotex Exhibit 1008.006
`
`

`

`WO 03/045437
`
`PCT/IB02/04612
`
`CA 0 2467490 2004-05-28
`
`-4-
`
`In certain
`pharmaceutically •acceptable salt thereof, Is administered over a 24 hour period.
`subjects, it may be advantageous, after administration of the CR dosage form in a series of
`doses, to administer an immediate release (IR) dosage form comprising the compound, or
`pharmaceutically acceptable salt thereof, as described herein.
`In particular, the present invention relates to methods of treatment using CR
`pharmaceutical dosage forms of 1 that result In a reduction in nausea as an adverse effect.
`Such CR dosage forms are characterized by providing drug in the gastrointestinal (GI) tract in
`a dissolved form at a rate ranging from about 0.03 mgA/hr to about 6 mgA/hr; more preferably
`from about 0.06 mgA/hr to about 3 mgAlhr; and most preferably from about 0.10 mgA/hr to
`about 1 mgA/hr. The present invention also provides for CR dosage forms which achieve a
`reduction In the average maximum blood concentration of the drug (Cmax) upon the first
`administration of the dosage to a subject by between 10 and 80% of the average Cmax for an
`Immediate release bolus initial administration; more preferably, between 30 and 70%. The
`present Invention also provides for dosage forms which Increase the time It takes to achieve
`In particular, it has been found that an
`this maximum blood level concentration, T max•
`Increase of the average T max by 50% compared to the average found for an immediate
`release bolus results in a reduction in nausea. The present invention also provides for a
`dosage form whereby the release rate of 1 as determined by a USP type II dissolution method
`results in a release rate of less than 6 mgA/hr and such that the time for dissolution of 50%
`w/w of said drug is between 1 and 15 hours; more preferably between 2 and 1 O hours.
`The present Invention also provides for pharmaceutical compositions to achieve
`these deliver;y rates. In particular, the present invention relates to dosage forms of 1 which
`comprise such means of delivery as hydrophilic matrlxes, hydrophobic matrixes, coated CR
`tablets and multlpartlculates, buccal systems, transdermal systems, suppositories and depot
`systems. Among the coated tablets, a partlcular1y preferred dosage form is an asymmetric
`membrane technology system (as described in U.S. Patent Nos. 5,612,059 and 5,698,220, the
`contents of which are hereby incorporated herein by reference).
`The present invention further provides such a controlled release dosage form which is
`a combination delayed plus sustained release form exhibiting a delay period of up to eight
`hours prior to the onset of sustained release, wherein the pentaene is released at a rate of not
`more than about 0.1 mgA/hr during the delay period and wherein the delay period is
`controlled temporally or spatially by position in the gastrointestinal tract.
`It is also the purpose of the present invention to provide for the reduction in nausea
`when compound 1 Is dosed to patients by beginning a course of treatment with the CR
`dosage form, followed by a course of treatment with an IR dosage form.
`As used herein, the term "controlled-release" (CR) refers to dosage forms which
`slowly release or deliver the drug to the patient at a rate such that at least some of the drug is
`
`5
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`10
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`15
`
`20
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`-_25
`
`30
`
`35
`
`Apotex Exhibit 1008.007
`
`

`

`WO 03/045437
`
`PCT/IB02/04612
`
`CA 0 2 467490 2 004-05-2 8
`
`-5-
`
`unavailable in the first hour. A CR system can provide the drug at a constant rate (zero
`order), at a steadily decreasing rate (first order) or an uneven or pulsatile rate. The drug
`delivery can also involve a lag time In initial drug release. This lag can be temporal or be
`related to the position of the drug in the body. For example, a CR dosage form may be
`prepared by exploiting an enteric coating where drug is released upon reaching the pH of the
`intestine after oral administration.
`Jn the present invention, a suitable CR dosage form of 1 can be identified by one or
`both of two methods:
`(1 )The first method Involves measuring the behavior of the drug in the dosage form
`by sampling and analyzing blood after initial administration of the drug to a subject
`(generating a pharmacokinetic profile). Initial administration refers to drug administered to a
`subject either for the first time, or with at least four days since a previous dosing of any form
`It has been found that of particular Importance in reducing nausea with 1 are the
`of 1.
`maximum blood level of 1 reached after initial administration of the drug (Cmax) and the time it
`takes to reach that maximum (T max), In measuring both Cmax and T max, it will be recognized by
`those skilled in the art that there is significant variability between dosings and between
`subjects. To achieve an adequate comparison in Cmax and T max and thereby to determine if a
`given dosage form will achieve the desired reduction in nausea, it Is necessary to measure
`these parameters for at least 1 O subjects In a cross-over experiment (i.e., each subject
`receives both dosage forms, IR and CR) with at least 7 days between experimental legs. In
`particular, it has been found that an average initial Cmax reduction to achieve a value of 10 to
`80% of that achieved with an average initial IR bolus administration is needed for nausea
`reduction; more preferred ls between 30 and 70%. For T max, an increase in the average initial
`T max for a CR dosage form compared to an IR bolus should be at least 50% (I.e., 1.5 times the
`number of hours for the average CR dosage vs. the average IR bolus dosage) .
`. (2) The second method of analyzing the CR dosage form to determine if it will reduce
`nausea involves an in vitro test. The inventors have found that generating a plot of percent of
`1 dissolved vs. time is best used to determine the time required for 50% of the drug to be
`dissolved. The data needed for generation of this plot is obtained using a standard USP
`(United States Pharmacopoeia) Type II dlssolution apparatus (50 rpm; 500 mL of 0.01 N
`hydrochloric acid; 37°C) such as a Hanson model SRS. Analysis of samples is accomplished
`using reverse phase HPLC. It has been found that nausea is reduced when the dosage form
`shows 50% w/w of the total dose is dissolved between about 1 and 15 hours; more preferably
`between 2 and 10 hours.
`Accordingly, the present invention further relates to immediate-release dosage forms
`suitable for administration to a subject that result in stable dosage forms with uniform drug
`distribution and potency, comprising a core containing a compound of the formula 1, or a
`
`5
`
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`15
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`35
`
`Apotex Exhibit 1008.008
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`

`

`WO 03/045437
`
`PCT/IB02/04612
`
`CA 0 2 467490 2 004-05-2 8
`
`-6-
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`pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable substantially
`reducing carbohydrate--free diluent. The invention specifically provides such an immediate(cid:173)
`release dosage form, wherein the IR dosage form comprises either the L-tartrate or citrate salt
`9J-hexadeca-2(11 ),3,5;7,9-pentaene.
`11.04
`of 5,8, 14-triazatetra-cyclo{10.3.1.02
`'
`'
`than
`less
`As used herein, "substantially reducing carbohydrate-free" means
`approximately 20 w/w% of a reducing sugar (including, but not limited to, lactose). Preferably,
`dosage forms prepared In accordance with the present Invention will contain less than 1 0
`w/w% of a reducing sugar, and more preferably, less than 5 w/w%.
`The immediate release dosage form of the invention may further comprise a glidant,
`dlsintegrant and/or a lubricant. The present invention also relates to processes for the
`production of these immediate release dosage forms.
`The immediate release dosage form of the invention may further comprise a film
`coating. The present invention also relates to processes for production of these film coated
`immediate release dosage forms.
`The present Invention also provides a formulation suitable for film coating of
`immediate release dosage forms of 1 wherein the polymeric · binder for such coatings
`comprises substantially a cetlulosic polymer. A particularly preferred cellulosic polymer is
`further comprises an opacifier
`This coating
`hydroxypropyl methylcellulose (HPMC).
`(particularly titanium dioxide), plasticizer and/or glidant, all of which contain less than about
`20% w/w reducing carbohydrates. Particularly preferred coating formulations comprise
`HPMC, titanium dioxide, and triacetin or PEG.
`The present invention also provides for methods that produce good potency and
`content uniformity in blends as described herein. These methods include the process of
`geometric dilution of drug with excipients prior to tableting. These methods also Include the
`use of moderate shear blending. The preferred blending process uses a "bin blender";
`however, other blenders which produce similar shears are also usable.
`The dlsclosed methods of treatment using CR pharmaceuttcal dosage forms of 1 that
`result in a reduction in nausea as an adverse effect are characterized by providing drug in the
`gastrointestinal (GI) tract In a dissolved form at a rate ranging from about 0.03 mgA/hr to
`about 8 mgA/hr; more preferably from about 0.06 mgA/hr to about 3 mgA/hr; and most
`preferably from about 0.10 mgA/hr to about 1 mgA/hr.
`In particular, the present Invention provides a method for reducing nicotine addiction
`or aiding In the cessation or lessening of tobacco use in a subject, comprising administering
`to said subject an amount of either the controlled release _dosage form or the immediate-
`release dosage form of 1 that is effective in reducing nicotine addiction or aiding in the
`cessation or lessening of tobacco use. The invention specifically provides such a method,
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`35
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`Apotex Exhibit 1008.009
`
`

`

`WO 03/045437
`
`PCT/IB02/04612
`
`CA 02467490 2004-05-28
`
`-7-
`
`wherein the CR or IR dosage form comprises either the L-tartrate or citrate salt of 5,8, 14-
`11.04
`triazatetra-cyclo[10.3.1.02
`9]-hexadeca-2(11 ),3,5,7,9-pentaene.
`•
`•
`The present invention further provides a method for treating a disorder or condition
`selected from Inflammatory bowel disease, ulcerative colitis, pyoderma gangrenosum,
`Crohn's disease, irritable bowel syndrome, spastic dystonia, chronic pain, acute pain, celiac
`sprue, pouchitis, vasoconstriction, anxiety, panic disorder, depression, bipolar disorder,
`autism, sleep disorders, jet lag, amyotrophic lateral sclerosis {ALS), cognitive dysfunction,
`hypertension, bulimia, anorexia, obesity, cardiac arrythmias, gastric acid hypersecretion,
`ulcers, pheochromocytoma, progressive supranuclear palsy, chemical dependencies and
`tobacco products, alcohol,
`to, nicotine,
`addictions; dependencies on, or addictions
`benzodiazepines, barbiturates, oploids or cocaine; headache, stroke, traumatic brain injury
`tardive
`(TBI), obsessive-compulsive disorder (OCD), psychosis, Huntington's Chorea,
`dyskinesia, hyperkinesia, dyslexia, schizophrenia, multi-infarct dementia, age related
`cognitive decline, epilepsy, petit mal absence epilepsy, senile dementia of the Alzheimer"s
`type (AD), Parkinson's disease (PD), attention deficit hyperactivity disorder (ADHD) and
`Tourette's Syndrome in a subject in need of such treatment, comprising administering to the
`subject an amount of either the controlled release dosage form or the immediate-release
`that is effective in treating such disorder or condition. The invention
`dosage form of 1
`specifically provides such a method, wherein the CR or IR dosage form comprises either the L-
`11.04•~-hexadeca-2(11 ),3,5,7,9-
`tartrate or citrate salt of 5,8, 14-triazatetra-cyclo[10.3.1.02
`•
`pentaene.
`The present invention also provides for pharmaceutical compositions to achieve
`these administration rates. In particular, the present invention relates to dosage forms of 1
`· which comprise such means of administration as hydrophilic matrixes, hydrophobic matrixes,
`forms,
`controlled dosage
`systems, multiparticulates, permeable-coating
`osmotic
`suppositories, buccal systems, transdermal systems and l~plantable systems. Among the
`is an asymmetric membrane
`osmotic systems, a particularly preferred dosage form
`technology system (as described.in U.S. Patent Nos. 5,612,059 and 5,698,220, the contents of
`which are incorporated herein by reference).
`The present invention also provides for methods of administration which result in the
`reduction in nausea as an adverse effect when compound 1 is dosed to patients by beginning
`a course of treatment with the CR dosage form, followed by a course of treatment with an IR
`dosage form.
`As used herein, an "immediate-release" (IR) dosage form · refers to a dosage form
`which when taken orally substantially provides the drug In a form available to be absorbed
`within about one hour.
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`Apotex Exhibit 1008.010
`
`

`

`WO 03/045437
`
`PCT/IB02/04612
`
`CA 0 2467490 2004-05-28
`
`-8-
`
`A "matrix" system refers to a particular CR dosage form where the drug is admixed
`with excipients, often In compressed or extruded form, such that the release of the drug from
`the dosage form is controlled by a combination of erosion and diffusion. Erosional control of
`drug delivery Involves the slow removal of the matrix material by the GI fluids to gradually
`expose and release the drug from the matrix. Diffusional control of drug delivery involves
`In
`diffusion of soluble drug through the network of matrix excipients in a controlled fashion.
`practice, many matrix dosage forms involve some degree of combination of the two
`mechanisms.
`A "hydrophilic matrix" is a matrix CR dosage form where water-soluble or water-
`swell able polymers form a network containing the drug. The rate that drug diffuses to the
`surface of the dosage form and the rate that the matrix falls apart control the rate that drug Is
`made available to the GI system.
`A "hydrophobic matrix" is a matrix CR dosage form where water-insoluble or only
`partially water-soluble materials slow the rate that a drug is exposed to the fluid environment
`of the GI system, thereby controlling the rate drug is available for absorption:
`A "permeable coating" CR system refers to various coatings on tablets or particulates
`that act as barriers to drug leaving a tablet or to water reaching the drug. These coatings
`include enteric coatings which become permeable as the pH increases when a dosage form
`exits the stomach. Examples of such coatings include Eudraglts 111 sold by Rohm GmbH
`Pharma Polymers (Darmstadt, Germany) and cellulose acetate hydrogen phthalate (CAP}
`sold by Eastman Chemical {Kingsport, TN). One group of such coated CR systems includes
`osmotic systems. Such CR dosage forms involve a semi-permeable membrane surrounding a
`drug core containing sufficient osmotic pressure to drive water across the membrane in the GI
`system. The osmotic pressure can then force drug out of the core through preformed or in
`situ produced holes or pores in the coating. Such systems often involve the addition of
`agents (osmagents) designed to Increase the osmotic pressure 1n the core. A review
`describing such systems is found in G. Santus and R. W. Baker, J. Control. Rel., 1995, 35, 1-
`21 .
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`"Asymmetric membrane technology," AMT, describes a particular osmotic CR system
`30 where the coating is made porous by a phase separation process during the coating
`operation as described in U.S. Patent Nos 5,612,059 and 5,698,220, the contents of which are
`hereby Incorporated herein by reference.
`uTransdermal delivery systems" are drug delivery devices designed to provide
`systemic drug to a patient through the skin. Such systems commonly involve a layer of
`35 material containing drug on a backing with an adhesive to attach the materia