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`USOD6555136B2
`
`(12) Ulllted States Patent
`Midha
`
`(10) Patent No.:
`(45) Date of Patent:
`
`US 6,555,136 B2
`*Apr. 29, 2003
`
`(54)
`
`l’I-LARMACI-JUTICAI. l)()SA(;[-1 FORM FOR
`PULSATILE DEHVERY 0|."
`METHYLPHENIDATE
`.
`.
`Inventor: Kamal K. Midha, Hamilton (BM)
`(75)
`(73) Amignee: Pl1arn1aQuest, 1.m., Hamilton (BM)
`.
`.
`,
`.
`.
`.
`( * ) Notree:
`Subjcctte any cltsclzumcr, the term ofttuf
`patent
`15 extended or <'id]USl¢d under 3.‘:
`U-SL1 154(b) by U dflysv
`
`This patent
`Qlaimcr‘
`
`is subject to a terminal dis-
`
`1211 Am. Nos 091995353
`‘)3
`.~ ,
`.
`("“ m"d'
`((15)
`
`NW‘ 13’ 2001
`Prior Publication Data
`
`US 200210058061 A1 May 16,2002
`
`11.11993 Chen
`5,250,059 A
`4,(1<J*J4 Shclh el al.
`:‘3,3(Il_.3tJ4 A
`531994 Balahan el al.
`::_.308_.348 A
`31994 Wong
`:\,3l2_.39() A
`. u w
`.
`‘t.
`R i Shiv:
`Q
`g‘,’§;‘-‘cf'aj‘_"
`5,445,823 A
`8!i99S P
`lzi.
`5,456,679 A
`Li, al_
`10,1995
`5,4—,»2;:(,3 A
`12,1995 Chen
`5,493,255 A
`31199:; Wong
`5__49")_.9?9 A
`3,I'i9‘Jt‘J Wong el al.
`5,508,040 A
`4;'1996 Chen
`5,531,736 }\
`7;"19‘.3fi Wong Cl ill.
`5,?73.4?8 A
`61'1'FJ¢J8 Richards et al.
`2’§‘l%”;§i 2
`$332 i.§.:‘11?a°£."Ji
`5,859,249 A
`l,«’l9.‘J9 Scido el al.
`5,374,090 A
`21199-;- Baker ct al.
`5,.‘-314.129 A
`51’1‘J9‘J M3"?-k0P
`tS_,l5U_,3'?t‘) A
`I1,-'2UUU Kozikowski el al.
`6,21'?_.9U4 Bl
`412nm Midha et al.
`*
`6,340,476 BI
`11"2Ut')2 Midha et al.
`"
`[‘0RL‘IGN PAI'l;N'l‘ DOCUMLLNTS
`
`424(4r53
`424.-"4F)‘1J
`
`W0
`
`2’1998
`we 93’'U638°
`OTHER PUB]_]CATIONS
`,(,T]‘J’,”‘‘';.','‘‘ ‘”d(%"::°)=,;ARF1,°"il‘1“ ,1;‘3“““°“:§~l5]’ E3? ‘“‘;.LiE°“’-
`Sa 10-10 , "W."
`.‘3°"“"’°°
`.'“3'.‘t
`° .',“g °’ W
`Accommodatron ot Drjhcult In Vnru Iargcts,
`Jrmrnm’ of
`C0,m,0,,.m. R,,m_e 64_,63_.,58
`L
`"
`H
`* cited by examiner
`Page
`Prmtary 1I3xaminer—'I'hu‘rman
`Assisrrrnt E.mrniner—L111ana D1 Nola-Baron
`(74) Attorney, Agem, or Fr'rm—Dianne E. Reed; Karen
`Canaan; Reed & Asesoctates
`(3?)
`ABSTRACT
`
`'
`
`None! pharmaceutical dosage forms provide for pulsatilc
`tlcltvery of methyiphcnidette, 1.e., release encapsulated drug
`m spaced apart "pulses.
`lhc cloeage forms are comertsecl of
`first, second and optlonally lhlrd dosage unlts, wllh each
`dosage unit having a different drug release profile. The
`dosage lbrrns may comprise capsules housing Lttmpressed
`tablets or drug-containing heads or particles. or may corn-
`prise a single tablet with the first second and dptionallv third
`,
`.
`,
`,
`.
`’
`.
`:
`,
`,
`dosage uratts utaclhrd rehprjsenélng an Integral
`age! C::SLl'ClL
`segment I erco.
`et 0 s 0 treatment usmgt 1.. p arma-
`ct-:u11ca1 do:-:.age forms are provrded as well.
`
`45 Claims, No Drawings
`
`Amerigen Ex. 1029, p. 1
`Amerigen Ex. 1029, p. 1
`
`Related U'S' Application Dam
`(53) Continuation of application No. (IJ_f544f-'32. filed on Apr. 6,
`2mr_:_. now Pat. No. -5_.34D_.4'1‘n.
`filed on Apr. 6,
`]l’5(;\JSiDDaI application No.
`rjn1’12?.934_.
`(60)
`A6lK 9,126
`Int. C1?
`(51)
`4241469 474(451- 494145o-
`(57) US Cl
`’
`'
`‘ "
`’ '
`‘
`“
`'
`'
`'
`4241457; 424E458; 4241459; 4241453; 42-‘I-E4-64;
`424E465; 42419168; 42413474; 42-’t-I475; 424-I481;
`424E482
`446i4’:2§’
`’ 469’ 41;; 47,; 481’ 487’
`‘
`‘
`‘
`‘
`*
`"
`
`‘ '
`
`’
`
`(58) Fleld of
`
`(56)
`
`References Cited
`U.S. PATENT DOCUMENTS
`
`4}62.,‘85,, A
`4_;113_24-,~ A
`4?—;2g,_-,l3 A
`4,TTi‘__tl49 A
`4,874,388 A
`4.957-494 A
`4»°71-3"5 A
`5-‘Dfl-‘088 A
`5,110,597 A
`5:204:11“ A
`5,m,,_.,.46 A
`_;’221,2-,;3 A
`."I,23(>,68(J A
`:3_.2t'>(l__()68 A
`
`12,1986 Deters EHL
`12,1193-,» 5,,k,,m,,,D at ,,|_
`3,1933 Mom N A],
`ltI;'l988 Magrudcr ct al.
`IUIIFJSQ Wong at a].
`91’1‘»‘90 W003 N a|-
`W199” Kflanishi 9‘ 31'
`511991 WW3 5' “L
`511992 Wong ctal.
`4J,w,J_, Edgrm eEa|_
`5,1993 Babb“ elall
`6,1993 Ijnkwilz A ,,I_
`8;'l903 Wong ct al.
`1Ul¢J93 (Then
`
`

`
`US 6,555,136 B2
`
`1
`PHARMACEUTICAL DOSAGE FORM FOR
`PULSATILE l)I'lI.IVF.RY (IF
`ME'l‘l-IYLPHlilNI[)A'l‘l<I
`
`C ROSS—REFERENC E TO RELATED
`APl’LICA'l‘IONS
`
`This is a continuation of U.S. Ser. No. 09l544,?32, filed
`Apr. 6, 2000, now U.S. Pat. No. 6,340,476, which claims
`priority under 35 U.S.C. §ll9(e)(l) to U.S. Provisional
`Patent Application Serial No. 60! 121984, filed Apr. 6, 1999.
`The disclosures of the aforementioned patent applications
`are incorporated by reference in their entireties.
`The present invention relates generally to drug delivery,
`and more specifically relates to novel pharmaceutical dosage
`forms that provide pulsatile delivery of methylphenidate.
`The invention additionally relates to methods for adminis-
`tering methylphcnidate using the novel dosage forms.
`
`lll
`
`15
`
`BACKGROUND
`
`Pharmaceutical dosage forms are known which provide a
`variety of drug release profiles, including immediate release,
`sustained release, and delayed release. That
`is,
`it may be
`desirable, for a particular drug, to prevent drug release after
`drug administration until a certain amount of time has _
`passed (so-called “timed release"), to provide substantially
`continuous release over a predetermined time period {so-
`called "sustained release") or to provide release immediately
`following drug administration (i.e., "immediate release”).
`For some types of drugs, it is preferred to release the drug
`in "pulses," wherein a single dosage form provides for an
`initial dose of drug followed by a release-free interval, after
`which a second dose of drug is released, followed by one or
`more additional
`release-free intervals and drug release
`"pulses." Pulsatile drug delivery is useful, for example,with
`active agents that have short half-lives and must be admin-
`istered two or three times daily, with active agents that are
`extensively metabolized presystemically, and with active
`agents which lose the desired therapeutic effect when con-
`stant blood levels are maintained. These types of agents have
`pharmacokinetic-pharmacodynamie relationships that are
`best described by a clockwise “hysteresis loop." A drug
`dosage form that provides a pulsatile drug release profile is
`also useful for minimizing the abuse potential of eertain
`types of drugs, i,e., drugs for which tolerance, addiction and
`deliberate overdose can be problematic.
`Because a precise and effective pulsatile drug delivery
`system is dillicult to formulate and manufacture, there are
`few such dosage forms that have been commercialized.
`There are, however, several patents and literature references
`pertaining to pulsatile drug delivery. See, for example, US.
`Pat. No. 5,413,777 to Sheth et al., directed to a pulsatile
`once-a-day delivery system for the administration of
`minocycline; US. Pat. No. 5,260,068 to Chen, directed to a
`rnultiparticulatc pulsatile dnig delivery system; U.S. Pat.
`No. 4,‘?T?,(}49 to Magruder et al., directed to an osmotic
`delivery system for constant release of a drug with inter-
`mittent release "pulses"; U.S. Pat. No. 5,391,381 to Wong et
`al., directed to a drug dispenser for delivering individual
`drugaeontaining units in a “pulsatile" manner; PCT Publi-
`cation No. W0 9882424, pertaining to pulsatile delivery of
`diltiazem hydrochloride; U.S. Pat. Nos. 5,472,708 and
`5,260,069 to Chen; Ishino et al. (1992) “Design and Prepa-
`ration of Pulsatile Release Tablet as a New Oral Drug
`Delivery System,” Clicrn. Pitnrrir. Bull’. 4-0(l l):3036—304l;
`Cohen et al. (1994), "Pulsatile Release from Microencap-
`sulated Liposomes,” J. Iiposortte Res. 349-360; and Gaz-
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`2
`zaniga et al. (1994), "Chronotopic Drug Delivery Systems
`for Pulsatile andfor Site-Specific Release,” 31“. Proc. Int‘.
`Symp. Controlled Release Bioact. Maren, pp. 744-745.
`The present
`invention is directed in part
`to a rtovel
`pulsatile drug delivery system which is straightforward to
`manufacture and provides precisely timed drug release
`“pulses" at desired intervals.
`Methylphenidate hydrochloride (I'I(_'l), the hydrochloride
`salt of 0'.-phenyl-2-piperidine-acetic acid methyl ester
`(available commercially as Ritalin®), is a central nervous
`system stimulant that is used in the treatment of Attention
`Deficit Disorder ("ADD"), a commonly diagnosed nervous
`system illness in children that
`is characterized by both
`distractability and impulsivity. Methylphenidate HCl is also
`used to treat a related disorder, Attention Deficit Hyperac-
`tivity Disorder ("ADIID”), in which symptoms of hyperac-
`tivity are present along with the symptoms of ADD. The
`drug is additionally used in the symptomatic treatment of
`narcolepsy, depression, and the cognitive decline associated
`with Acquired Immunodeficiency Syndrome (‘'AIDS’’) or
`AIDS-related conditions, as well as for mood elevation,
`particularly in terminally ill patients with diseases such as
`cancer. Methylphenidate exists as four distinct isomers, as
`follows:
`
`"d~tl'It'eo"
` H
`
`171
`
`OO;(‘t-t_.
`
`CD3C‘H3
`"d—er_vtl1ro"
`
`N
`t-l
`
`.
`
`Eo,crt_,
`"I—erytltro"
`
`The drug as used in therapy is a racemic mixture of the d-
`and l-threo enantiomers, which have been acknowledged as
`more active than the crythro pair.
`Because of its potential for tolerance (loss of clinical
`eflicacy when constant blood levels are maintained), short-
`half lite and potential
`for abuse, methylphenidate is a
`primary candidate for use in conjunction with the drug
`delivery systems of the invention.
`Accordingly, the present invention provides novel phar-
`maceutical dosage forms for the administration of meth-
`ylphenidate in its conventional form,
`i.e., as a racemic
`mixture of the d—threo and l—threo enantiomers. The novel
`dosage forms provide for pulsatile drug release,
`thereby
`maximizing eflicacy (i.e., the loss of clinical etficacy over
`time), reducing the potential for abuse or noncompliance.
`The invention thus represents a significant advance in the
`art, particularly in the administration of drugs such as
`methylphenidate that have short half—lives, tend to be exten-
`sively metabolized presysternically, have pharmacokinetic-
`pharrnacodynamic relationships which are best described by
`positive (clockwise) hysteresis loops (hence resulting in
`tolerance when constant blood levels are maintained), or are
`likely candidates for drug abuse. No art of which applicants
`are aware describes pulsatile drug delivery systems as now
`provided herein.
`To the best of applicants’ knowledge, the pharmaceutical
`dosage forms of the invention are previously unknown and
`completely unsuggested by the art.
`
`Amerigen Ex. 1029, p. 2
`Amerigen Ex. 1029, p. 2
`
`

`
`US 6,555,136 B2
`
`3
`SUMMARY OF THE INVENTION
`
`it is a primary object of the invention to
`Accordingly,
`address the above-mentioned need in the art by providing a
`pharmaceutical dosage form for putsatile delivery of meth-
`ylphenidate.
`It
`is another object of the invention to provide such a
`dosage form comprising at
`least
`two individual drug-
`containing dosage units, each of which has a dillerent drug
`release profile.
`It
`is another object of the invention to provide such a
`dosage form wherein the dosage units are housed in a closed
`capsule.
`It is still another object of the invention to provide such
`a dosage form wherein the dosage units are compressed
`tablets.
`
`It is yet another object of the invention to provide such a
`dosage form wherein the dosage units are drug-containing
`particles or beads.
`It is a funher object of the invention to provide such a
`dosage form comprised of a single tablet of which the
`drug—containing dosage units represent integral but discrete
`segments.
`It is a further object of the invention to provide such a
`dosage form for administering methylphenidate optionally
`in combination with one or more other active agents such as
`CNS stimulants (including analeptic agents and
`psychostimulants), antidepressant drugs, antianxiety agents
`and the like.
`
`is an additional object of the invention to provide
`It
`methods for administering methylphenidate using the novel
`dosage forms.
`Additional objects, advantages and novel features of the
`invention will be set forth in part in the description which
`follows, and in pan will become apparent to those skilled in
`the art upon examination of the following, or may be learned
`by practice of the invention.
`DETAILED DESCRIPTION OF THE
`INVENTION
`
`Definitions and Nomenclature
`
`Before the present formulations and methods of use are
`disclosed and described. it is to be understood that unless
`otherwise indicated this invention is not limited to specific
`pharmacologically active agents. specific pharmaceutical
`carriers, or to particular administration regimens, as such
`may vary. It is also to be understood that the terminology
`used herein is for the purpose of describing particular
`embodiments only and is not intended to be limiting.
`It must be noted that, as used in the specification and the
`appended claims, the singular forms “a," "an" and “the"
`include plural referents unless the context clearly dictates
`otherwise. Thus, for example, reference to “an active agent"
`includes mixtures of active agents, reference to "a pharma-
`ceutical carrier” includes combinations of two or more
`carriers, and the like.
`In this specification and in the claims which follow,
`reference will be made to a number of terms which shall be
`defined to have the following meanings:
`“Optional” or “optionally” means that the subsequently
`described circumstance may or may not occur, so that the
`description includes instances where the circumstance
`occurs and instances where it does not.
`
`The terms "active agent," “drug" and “phannacologically
`active agent" are used interchangeably herein to refer to a
`
`ll!
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`chemical material or compound which. when administered
`to an organism (human or animal, generally human) induces
`a desired pharmacologic effect. In the context of the present
`invention, the tenns refer to a compound that is capable of
`being delivered orally.
`The term "methylphenidate” as used herein refers to a
`racemic mixture of d—threo methylphenidate and I—tl1reo
`methylphcnidate, also referred to herein as “d,l-
`Inethylphenidate."
`By the terms “effective amount" or "pharmaceutically
`effective amount" of an agent as provided herein are meant
`a nontoxic but sufficicnt amount of the agent to provide the
`desired therapeutic elfcct. The exact amount required will
`vary from subject to subject, depending on age, general
`condition of the subject, the severity of the condition being
`treated, and the particular active agent administered. and the
`like. Thus, it is not possible to specify an exact “effective
`amount." Ilowever, an appropriate “elIective" amount
`in
`any individual case may be determined by one of ordinary
`skill in the art using routine experimentation.
`By "pharmaceutically acceptable" carrier is meant a car-
`rier comprised of a material
`that
`is not biologically or
`otherwise undesirable, ie, the material may be administered
`to an individual along with the selected active agent without
`causing any undesirable biological effects or interacting in a
`deleterious manner with any of the other components of the
`pharmaceutical composition in which it
`is contained. 'Il'1e
`term "ca.rrier” is used generically herein to refer to any
`components present
`in the pharmaceutical
`formulations
`other than the active agent or agents, and thus includes
`diluents, binders, lubricants, disintegrants, fillers, coloring
`agents, wetting or emulsifying agents, pH bulfering agents.
`preservatives, and the like.
`Similarly, a “pharmaccutically acceptable” salt or a “phar-
`maceutically acceptable” ester of a compound as provided
`herein is a salt or ester which is not biologically or otherwise
`undesirable.
`In the chemical structures drawn herein, the use of bold
`and dashed lines to denote particular conformation of sub-
`stituents follows IUPAC convention. The symbols ""0." and
`"B" indicate the specific stereoehernical configuration of a
`substituent at an asymmetric carbon atom in a chemical
`structure as drawn. Thus "to," denoted by a broken line,
`indicates that
`the group in question is below the general
`plane of the molecule as drawn, and “B” denoted by a bold
`line, indicates that the group at the position in question is
`above the general plane of the molecule as drawn.
`“Pulsatile Release” Dosage Fonrts
`In a lirst embodiment, the invention features pharmaceu-
`tical dosage forms that provide for pulsatile delivery of
`rnethylphenidate. By “pulsatile” is meant that a plurality of
`dnig doses are released at spaced apart
`time intervals.
`Generally, upon ingestion of the dosage form, release of the
`i.nitial dose is substantially immediate, i.c., the lirst drug
`release “pulse" occurs within 1-2 hours of ingestion. This
`initial pulse is followed by a first time interval during which
`substantially no drug is released from the dosage form, after
`which a second dose is then released. Typically, the second
`dose is released on the order of 3—5 hours following inges-
`tion of the dosage form. Preferably, release of the second
`dose is followed by a second non-release interval, which is
`again followed by a “pulse" of drug release. Ideally, release
`of a third dose occurs on the order of 7-9 hours following
`ingestion. In a preferred embodiment herein, either two or
`three release pulses are provided. Ilowever, the invention is
`also intended to encompass dosage forms that provide more
`
`Amerigen Ex. 1029, p. 3
`Amerigen Ex. 1029, p. 3
`
`

`
`US 6,555,136 B2
`
`5
`than three pulses, with non-release intervals therebetween of
`approximately 2-6 hours, preferably 3-5 hours.
`The aforementioned pulsatile release profile is achieved
`with dosage forms that, in one embodiment, are closed and
`preferably sealed capsules housing two or more drug-
`containing “dosage units.” In a preferred embodiment, each
`dosage unit comprises a compressed or molded tablet,
`wherein each of the tablets within the capsule provides a
`different drug release profile. That
`is, for an exemplary
`dosage form, a lirst tablet releases drug substantially imme-
`diately following ingestion of the dosage form, while a
`second tablet in the capsule releases drug approximately 3—5
`hours following ingestion, and an optional third tablet pro-
`vides drug release after approximately 7-9 hours. While the
`dosage form will not generally include more than three
`tablets, dosage forms housing four or more tablets are within
`the scope of the present invention.
`In an alternative embodiment, each dosage unit comprises
`a drug-containing particle or bead (drug-containing "beads"
`refer to drug-coated inert supports, e.g., lactose beads coated
`with drug}. A first group of these particles or beads releases
`drug substantially immediately following ingestion of the
`dosage form, a second group releases drug approximately
`3-5 hours following ingestion, and an optional third group
`provides drug release after approximately 7-9 hours.
`In a further alternative embodiment, the individual dosage
`units are compacted in a single tablet. and represent integral
`but discrete segments thereof (e.g., layers). For example,
`drug-containing particles or drug—containing beads can be
`compressed together into a single tablet using conventional
`tabletting means.
`As will be appreciated by those skilled in the art and as
`described in the pertinent texts and literature, a number of
`methods are available for preparing drug—containing tablets
`or other dosage units which provide a variety of drug release
`profiles. Such methods include coating a drug or drugw
`containing composition, increasing the drug’s particle size,
`placing the drug within a matrix. and forming complexes of
`the drug with a suitable complexing agent.
`The delayed release dosage units in the present capsules
`can be prepared,
`for example, by coating a drug or a
`drug-containing composition with a selected membrane
`coating material. typically although not necessarily a poly-
`meric material. When a coating is used to provide delayed
`release dosage units, particularly preferred coating materials
`comprise bioerodible, gradually hydrolyzable andfor gradu-
`ally water-soluble polymers. The "coating weight," or rela-
`tive amount of coating material per dosage unit, generally
`dictates the time interval between ingestion and drug
`release.
`
`Suitable membrane coating materials for elfecting
`delayed release include, but are not limited to: eellule-sic
`polymers such as hydroxypropyl cellulose, hydroxyethyl
`cellulose, hyrlroxypropyl methyl cellulose, methyl cellulose,
`ethyl cellulose, cellulose acetate, cellulose acetate phthalate,
`cellulose acetate trimellitate, hydroxypropylmethyl cellu-
`lose phthalate, cellulose ester-ether phthalate, hydroxypro-
`pyleellulose phthalate, alkali salts of cellulose acetate
`phthalate, alkaline earth salts of cellulose acetate phthalate,
`hydroxypropylmethyl cellulose hexahydrophthalate, cellu-
`lose acetate hexahydrophthalate, and carboxymethylcellu-
`lose sodium; acrylic acid polymers and copolymers prefer-
`ably formed from acrylic acid, methacrylic acid, acrylic acid
`alkyl esters, metltacrylic acid alkyl esters, and the like, e.g.
`copolymers of acrylic acid, methacrylic acid, methyl
`acrylate. ethyl acrylate, methyl methacrylate andlor ethyl
`
`ill
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`6
`methacrylate, with a terpolymer of ethyl acrylate, methyl
`methacrylate and trimetbylammonioetbyl methacrylate
`chloride (sold under the tradename Eudragit RS) particularly
`preferred; vinyl polymers and copolymers such as polyvinyl
`pyrrolidone. polyvinyl acetate, polyvinylacetate phthaiate,
`vinylacetate crotonic acid copolymer, and ethylene-vinyl
`acetate copolymers; and shellac, ammoniated shellac,
`shellac-acelyl alcohol, and shellac n-btttyl stearate.
`In some cases, it may be desirable for the third tablet or
`bead or particle fraction to provide for release of the active
`agent in the colon, in which case polymeric or other mate-
`rials are used that enable drug release within the colon.
`These may be selected from the aforementioned list, or other
`materials may be used as will be known to those skilled in
`the art of phannaceutical formulation and drug delivery. For
`example, hydrooolloid gums may be effective to provide for
`colonic delivery, e.g., guar gum, locust gum, bena gum, gum
`tragacanth, and karaya gum (see, e.g., US. Pat. No. 5,656,
`294 to Friend). Other materials suitable for effecting colonic
`drug
`delivery
`include
`polysaccharides,
`mucopolysaccharides, and related compounds, eg, pectin,
`arahinogalactose, chitosan, chondroitin sulfate. dextran,
`galactomannan. and xylan.
`Combinations of dillerent coating materials may also be
`used to coat a single dosage unit.
`To bring about the desired pulsatile release profile for a
`dosage form comprised of encapsulated tablets,
`the first
`tablet is provided with little or no coating material,
`the
`second tablet
`is provided with sortie degree of coating
`material, the coating weight of a third tablet is still higher,
`and so on. Artalogously, for encapsulated dosage forms in
`which the drug-containing dosage units are beads or
`particles, a first fraction of beads or particles is provided
`with little or no coating material, a second fraction is
`provided with some degree of coating material. the coating
`weight of a third fraction is still higher, etc. For example,
`when the dosage form contains three tablets (or,
`analogously,
`three groups of drug-containing particles or
`beads),
`the lirst
`tablet, which releases drug substantially
`immediately, may have a total coating weight of less than
`about 10%, preferably less than about 8%. the second tablet
`may have a total coating weight in the range of approxi-
`mately 10% to 30%, preferably 15% to 25%, and the third
`tablet, if present, may have a total coating weight in the
`range of approximately 15% to 65%, preferably 20% to
`65%. The preferred coating weights for particular coating
`materials may be readily determined by those skilled in the
`art by evaluating individual release profiles for dosage units
`prepared with different quantities of various coating mate-
`rials.
`
`Alternatively, the delayed release dosage units, i.e., tab-
`lets or particles, may be formulated by dispersing the drug
`within a matrix of a suitable material such as an insoluble
`plastic, a hydrophilic polymer, or a fatty compound. The
`insoluble plastic matrices may be comprised of, for example,
`polyvinyl chloride or polyethylene. I-lydrophilic polymers
`useful for providing a matrix for a delayed release dosage
`unit include. but are not limited to, those described above as
`suitable coating materials. Fatty compounds for use as a
`matrix material
`include. but are not
`limited to, waxes
`generally (e.g., carnauba wax) and glyceryl lristearate. Once
`the active ingredient is mixed with the matrix material, the
`mixture can be compressed into tablets or processed into
`individual drug-containing particles.
`The individual dosage units may be provided with colored
`coatings, with a single color used to identify a tablet or head
`
`Amerigen Ex. 1029, p. 4
`Amerigen Ex. 1029, p. 4
`
`

`
`US 6,555,136 B2
`
`ill
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`15
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`30
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`35
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`40
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`7
`or particle fraction having a corresponding delayed release
`profile. That is, for example, a blue coating may be used for
`the immediate release tablet or bead or particle fraction, a
`red coating may be used for the "medium" release tablet or
`bead or panicle fraction, and the like. In this way, errors
`during manufacture can be easily avoided. The color is
`introduced by incorporating a pharmaceutically acceptable
`colorant
`into the coating during coating preparation. The
`colorant may be either natural or synthetic. Natural colora nts
`include pigments such as chlorophyll, anattencs, peta-
`carotene, alizarin, indigo, rutin, besperidin, quercitin, car-
`minic acid, and 6,6’-dibromoindigo. Synthetic colorants are
`dyes, including both acidic dyes and basic dyes, such as
`nitroso dyes, nitro dyes, azo dyes, oxazines,
`thiazines,
`pyrazolones, xamhenes,
`indigoids, anthraquinon-es,
`acridines, rosanilines, phthaleins, quinolines. c,g., a dye or
`pigment, during preparation of the coating solution.
`lior encapsulated tablets, the weight of each individual
`tablet in the capsule is typically in the range of about 10 mg
`to 150 mg, preferably in the range of about 25 mg to about
`[00 mg, and most preferably is in the range of about 40 mg
`to 80 mg. The individual tablets are prepared using conven-
`tional means. A preferred method for forming tablets herein
`is by direct compression of a powdered, crystalline or
`granular drugcontaining composition, alone or in cc-mbina~ _
`tion with diluents, binders, lubricants, disintegrants, colo-
`rants or the like. As an alternative to direct compression,
`compressed tablets can be prepared using wet-granulation or
`dry—granulation processes. Tablets may also be molded
`rather than compressed, starting with a moist material con-
`taining a suitable water—soluble lubricant. Preferred tablets
`herein are manufactured using compression rather than
`molding, however. Drug-containing particles or beads are
`also prepared using conventional means, typically from a
`fluid dispersion.
`Conventional coating procedures and equipment may
`then be used to coat
`the dosage units,
`i.e.,
`the drug-
`containing tablets, beads or particles. For example,
`a
`delayed release coating composition may be applied using a
`coating pan, an airlessspray technique, fluidized bed coating
`equipment, or the like. For detailed information concerning
`materials, equipment and processes for preparing tablets,
`beads, drug particles, and delayed release dosage forms,
`reference may be had to Plirrriitrrcettticnl Dosage Forms:
`lhblets, eds. Lieberman et al. (New York: Marcel Dekker,
`Inc., 1989), and to Ansel et al., Plrnnitnccrrticni Dosage
`Forms and Drug De.-'r't-cry Systems, 6”‘ Ed. (Media, Pa.:
`Williams & Wilkins. 1995).
`in the individual drug-
`Optional components present
`containing dosage units include, but are not
`limited to,
`diluents, binders,
`lubricants, disintcgrants, stabilizers,
`surfactants, coloring agents. and the like. Diluents. also
`termed “fillers," are typically necessary to increase the bulk
`of a tablet so that a practical size is provided for compres-
`sion. Suitable diluents include, for example, dicalcium phos-
`phate dihydrate, calcium sulfate, lactose, cellulose, kaolin,
`mannitol, sodium chloride, dry starch, hydrolyzed starches,
`silicon dioxide, titanium oxide, alumina, talc, microcrystal-
`line cellulose, and powdered sugar. Binders are used to
`impart cohesive qualities to a tablet formulation. and thus
`ensure that a tablet remains intact after compression. Suit-
`able binder materials include, but are not limited to, starch
`(including corn starch and pregelatinizicd starch), gelatin,
`sugars (including sucrose, glucose, dextrose,
`lactose and
`sorbitol), polyethylene glycol, waxes, natural and synthetic
`gums, e.g., acacia,
`tragacanth, sodium alginate,
`polyvinylpyrrolidone, eelluloses. and Veegu m, and synthetic
`
`45
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`50
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`55
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`60
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`65
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`8
`polymers such as polymethacrylates and polyvinylpyrroli-
`done. Lubricants are used to facilitate tablet manufacture;
`examples of suitable lubricants include, for example, mag-
`nesium stearate, calcium stearate, stearic acid, glyceryl
`behenate, and polyethylene glycol, and are preferably
`present at no more than approximately 1 wt. '56 relative to
`tablet weight. Disintegrants are used to facilitate tablet
`disintegration or “breakup” after administration, and are
`generally starches, clays, celluloses, algins, gums or
`crosslinked polymers. Stabilizers are used to inhibit or retard
`drug decomposition reactions which include, by way of
`example. oxidative reactions. Surfactants may be anionic,
`cationic, arnphoteric or nonionic surface active agents, with
`anionic surfactants preferred. Suitable anionic surfactants
`include, but are not limited to, those containing carboxylate,
`sulfonate and sulfate ions, associated with cations such as
`sodium, potassium and ammonium ions. Particularly pre-
`ferred surfactants include, but are not limited to: long alkyl
`chain sulfonatcs and alkyl aryl sulfonates such as sodium
`dodecylbenzene sulfonate; dia|.l(yl sodium sulfosuccinates,
`such as sodium bis-(2-ethylhcxyl)-sulfosuecinate; and alkyl
`sulfates such as sodium lauryl sulfate. If desired, the tablets
`may also contain minor amounts of nontoxic auxiliary
`substances such as wetting or emulsifying agents, pll buff-
`ering agents, preservatives, and the like.
`As noted earlier herein, the individual drug tablets, beads
`or particles are,
`in one embodiment, contained within a
`closed capsule. The capsule material may be either hard or
`soft, and as will be appreciated by those skilled in the art of
`pharmaceutical science, typically comprises a tasteless, eas-
`ily administered and water soluble compound such as
`gelatin, starch or cellulose. A preferred capsule material is
`gelatin. The capsules are preferably sealed, such as with
`gelatin bands or the like. See, for example, Remington: Hie
`Science and Practice of Phnrmrrcy. Nineteenth Edition
`(Easton, Pa.: Mack Publishing Co., 1995), which describes
`materials and methods for preparing encapsulated pharma-
`ceuticals designed to dissolve shortly after ingestion.
`The novel dosage forms are used to administer meth-
`ylphenidate in a pulsatile release manner. As noted earlier
`herein, the drug is administered as a racemic mixture of the
`rl-threo and 1-threo enantiorners. For administration of race-
`mic methylphenidate, a dosage form of the invention com-
`prises a
`total of approximately 2 mg to 100 mg
`methylphenidate, preferably 2 mg to 50 mg
`methylphenidate, divided among the individual dosage
`units. Optimally,
`the first and second dosage units each
`contain approximately 2 mg to 20 mg methylphenidate, and
`preferably, the first and second methylphenidate doses are
`approximately the same. The third tablet should contain a
`lower dose of methylpbenidate, preferably about half the
`dose in the first tablet. to avoid sleep disruption. Also. if an
`additional CNS stimulant such as d-amphetamine is incor-
`porated into the dosage form, it will be included in the first,
`immediate release dosage unit, will optionally be present in
`the second dosage unit, (and if present, at a lower dose than
`in the first dosage unit), and will not be included in the third
`dosage unit.
`it may be desirable to include one or more additional
`active agents in the dosage forms herein. These active agents
`may potentiatc certain effects of mcthylphcnidate, or vice
`versa. The additional active agent or agents may be com-
`bined with methylphenidate in a single dosage unit within
`the dosage form, or one or more dosage units within the
`dosage form may comprise the additional active agent
`without any methylphenidate. In the former case, the various
`active agents may be present as an admixture in a tablet, or
`
`Amerigen Ex. 1029, p. 5
`Amerigen Ex. 1029, p. 5
`
`

`
`US 6,555,136 B2
`
`9
`the agenLs may be physically segregated as in a bilayer
`tablet, a tablet having two or more active agent-containing
`coatings, or the like.
`Preferred additional active agents, i.e., active agents for
`co-administration with methylphenidate, are CNS stimu-
`lants (including analeptic agents and psy