Exhibit 1013
`
`U.S. Patent No. 6,730,325 (“the ‘325 Patent”)
`
`

`
`(12) United States Patent
`Devane et al.
`
`US006730325B2
`(10) Patent No.:
`US 6,730,325 B2
`(45) Date of Patent:
`*May 4, 2004
`
`(54) MULTIPARTICULATE MODIFIED RELEASE
`COMPOSITION
`(75) Inventors: John G. Devane, Athlone (IE); Paul
`g?icgglzgEgl’Eghan M‘ M‘
`(73) Assignee: Elan Corporation, plc, Dublin (IE)
`( * ) Notice:
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U50 154(9) by 0 days-
`
`'
`
`'
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`.
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`Thls Patent 15 Sublect to a termmal dls'
`Clalmer'
`(21) Appl. No.: 09/850,425
`(22) Filed:
`May 7, 2001
`.
`.
`.
`(65)
`Pnor Pubhcatlon Data
`US 2002/0054907 A1 May 9, 2002
`Related US. Application Data
`.
`.
`.
`(63) ggélémrlllgalogiftf $311225); 31;;
`ai?gl??g??g)? 5%
`applijcation NO: PCT/[359972567327 ?led on NOV_ 1’ 1999_
`(60) Provisional application No. 60/106,726, ?led on Nov. 2,
`1998~
`(51) Int. c1.7 ................................................ .. A61K 9/14
`(52) U S C]
`42 4 / 489 424/464 424/490
`424/497 424/465 424/468 424/469 424/456
`’ 424/451’_ 424/472’_ 424/48,;
`’
`(58) Field of Semi;
`445264/
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`’
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`’
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`’ 490’
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`(56)
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`References Clted
`U.S. PATENT DOCUMENTS
`4’728’512 A
`5/1988 Mehta et a1‘
`4,794,001 A 12/1988 Mehta et al.
`4,888,178 A 12/1989 Rotini et al.
`4,904,476 A
`2/1990 Mehta et al.
`
`
`
`
`
`Plasma concentration (nglm)
`
`EP
`W0
`W0
`
`a
`
`a
`
`e a e a.
`
`5,158,177 A 10/1992 Abramowitz et al.
`5,445,829 A
`8/1995 Paradissis et a1.
`5,639,476 A
`6/1997 Oshlack et al.
`2 1i;
`54mg? ‘it ‘I1
`6,228,398 B1 * 5/2001 Devane et al. ............ .. 424/484
`FOREIGN PATENT DOCUMENTS
`0 274 734
`7/1988
`W0 9703672
`2/1997
`WO 98/14168
`4/1998
`OTHER PUBLICATIONS
`Shah et al., J. Cont. Rel. (1989) 9:169—175.
`Giumchedi et al., Int. J. Pharm (1991) 77:177—181.
`Conte et al., Drug. Del. Ina’. Pharm. (1989) 15:2583—2596.
`* cited by examiner
`Primary Examiner—Thurman K. Page
`Assistant Examiner—Rachel M. Bennett
`(74) Attorney, Agent, or Firm—Synnestvedt & Lechner
`LLP
`ABSTRACT
`(57)
`The invention relates to a multiparticulate modi?ed release
`composition that in operation delivers an active ingredient in
`a pulsed or bimodal manner. The multiparticulate modi?ed
`release composition comprises an immediate release com
`ponent and a modi?ed release component; the immediate
`release Component Comprising a ?rst Population of active
`ingredient containing particles and the modi?ed release
`component comprising a second population of active ingre
`dient containing particles coated With a controlled release
`coating; Wherein the combination of the immediate release
`and modi?ed release c0II1ponents in Operation deliver the
`active ingredient in a pulsed or a bimodal manner. The
`invention also relates to a solid oral dosage form containing
`such a multiparticulate modi?ed release composition. The
`plasma pro?le achieved by the multiparticulate modi?ed
`release composition is advantageous in reducing patient
`tolerance to the active ingredient and in increasing patient
`compliance by reducing dosage frequency.
`
`28 Claims, 1 Drawing Sheet
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`Time (h)
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`

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`U.S. Patent
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`May 4, 2004
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`US 6,730,325 B2
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`_\ mSmE
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`(LU/5U) uonenueouoo ewse|d
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`US 6,730,325 B2
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`1
`MULTIPARTICULATE MODIFIED RELEASE
`COMPOSITION
`This application is a continuation of 09/566,636 ?led
`May. 08, 2000 now US. Pat. 6,228,398, Which is a continu
`ation of PCT/US99/25 632 ?led Nov. 01, 1999, Which is a
`claims bene?ts of 60/106,726 ?led Nov. 02, 1998.
`FIELD OF THE INVENTION
`The present invention relates to a multiparticulate modi
`?ed release composition. In particular the present invention
`relates to a multiparticulate modi?ed release composition
`that in operation delivers an active ingredient in a pulsatile
`manner. The present invention further relates to solid oral
`dosage forms containing such a multiparticulate controlled
`release composition.
`DESCRIPTION OF THE PRIOR ART
`The plasma pro?le associated With the administration of
`a drug compound may be described as a “pulsatile pro?le”
`in Which pulses of high active ingredient concentration,
`interspersed With loW concentration troughs, are observed. A
`pulsatile pro?le containing tWo peaks may be described as
`“bimodal”. Similarly, a composition or a dosage form Which
`produces such a pro?le upon administration may be said to
`exhibit “pulsed release” of the active ingredient.
`Conventional frequent dosage regimes in Which an imme
`diate release (IR) dosage form is administered at periodic
`intervals typically gives rise to a pulsatile plasma pro?le. In
`this case, a peak in the plasma drug concentration is
`observed after administration of each IR dose With troughs
`(regions of loW drug concentration) developing betWeen
`consecutive administration time points. Such dosage
`regimes (and their resultant pulsatile plasma pro?les) have
`particular pharmacological and therapeutic effects associ
`ated With them. For example, the Wash out period provided
`by the fall off of the plasma concentration of the active
`ingredient betWeen peaks has been thought to be a contrib
`uting factor in reducing or preventing patient tolerance to
`various types of drugs.
`Many controlled release drug formulations are aimed at
`producing a Zero-order release of the drug compound.
`Indeed, it is often a speci?c object of these formulations to
`minimise the peak-to-trough variation in drug plasma levels
`associated With conventional frequent dosage regimes.
`HoWever, some of the therapeutic and pharmacological
`effects intrinsic in a pulsatile system may be lost or dimin
`ished as a result of the constant or nearly constant plasma
`levels achieved by Zero-order release drug delivery systems.
`Thus, a modi?ed release composition or formulation Which
`substantially mimics the release of frequent IR dosage
`regimes, While reducing the need for frequent dosing, is
`desirable.
`Atypical example of a drug Which may produce tolerance
`in patients is methylphenidate. Methylphenidate, or
`ot-phenyl-2-piperidine acetic acid methyl ester, is a stimu
`lant affecting the central nervous and respiratory systems
`and is primarily used in the treatment of attention de?cit
`disorder. After absorption from the gastrointestinal tract
`(GIT), drug effects persist for 3—6 hours after oral admin
`istration of conventional IR tablets or up to about 8 hours
`after oral administration of extended release formulations.
`The total dosage is typically in the range of 5—30 mg per day,
`in exceptional cases rising to 60 mg/day. Under conventional
`dosage regimes, methylphenidate is given tWice daily, typi
`cally With one dose given before breakfast and a second dose
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`given before lunch. The last daily dose is preferably given
`several hours before retiring. Adverse effects associated With
`methylphenidate treatment include insomnia and the devel
`opment of patient tolerance.
`WO 98/14168 (AlZa Corp.) teaches a dosage form and a
`method of administering methylphenidate in a sustained and
`constantly ascending rate. The dosage form disclosed com
`prises a plurality of beads comprising a hydrogel matrix With
`increasing amounts of the active ingredient therein, coated
`With varying amounts of a release rate controlling material.
`Appropriate combinations of the active ingredient dose and
`the number and thickness coating layers can be selected to
`give an ascending release pro?le in Which the plasma
`concentration of the active ingredient continually increases
`over a given period of time. In contrast to the present
`invention, an object of W0 98/ 14168 is to provide a dosage
`form to speci?cally avoid uneven blood levels (characterised
`by peaks and troughs) associated With conventional treat
`ments using immediate release dosage formulations.
`WO 97/03672 (Chiroscience Ltd.) discloses that meth
`ylphenidate exhibits a therapeutic effect When administered
`in the form of a racemic mixture or in the form of a single
`isomer (such as the RR d-threo enantiomer). Further, WO
`97/03763 (Chiroscience Ltd.) discloses a sustained release
`formulation containing dtmp. This disclosure teaches the use
`of a composition comprising a coating through Which the
`dtmp passes in order to attain sustained release and achieve
`serum levels (of the active ingredient) of at least 50% cmwc
`over a period of at least 8 hours. Thus, this formulation does
`not deliver the active ingredient in a pulsatile manner.
`Shah et al., J. Cont. Rel. (1989) 91169-175 discloses that
`certain types of hydroxypropyl methylcellulose ethers com
`pressed into a solid dosage form With a therapeutic agent
`may give a bimodal release pro?le. HoWever, it Was noted
`that While polymers from one supplier yielded a bimodal
`pro?le, the same polymers With almost identical product
`speci?cations obtained from a different source gave non
`bimodal release pro?les.
`Giunchedi et al., Int. J. Pharm (1991) 77:177-181 dis
`closes the use of a hydrophilic matrix multiple-unit formu
`lation for the pulsed release of ketoprofen. Giunchedi et al.
`teach that ketoprofen is rapidly eliminated from the blood
`after dosing (plasma half-life 1—3 hours) and consecutive
`pulses of drug may be more bene?cial than constant release
`for some treatments. The multiple-unit formulation dis
`closed comprises four identical hydrophilic matrix tablets
`placed in a gelatin capsule. Although the in vivo studies
`shoW tWo peaks in the plasma pro?le there is no Well de?ned
`Wash out period and the variation betWeen the peak and
`trough plasma levels is small.
`Conte et al., Drug Dev. Ind. Pharm, (1989) 15:2583-2596
`and EP 0 274 734 (Pharmidea Srl) teach the use of a three
`layer tablet for delivery of ibuprofen in consecutive pulses.
`The three layer tablet is made up of a ?rst layer containing
`the active ingredient, a barrier layer (the second layer) of
`semi-permeable material Which is interposed betWeen the
`?rst layer and a third layer containing an additional amount
`of active ingredient. The barrier layer and the third layer are
`housed in an impermeable casing. The ?rst layer dissolves
`upon contact With a dissolving ?uid While the third layer is
`only available after dissolution or rupture of the barrier
`layer. In such a tablet the ?rst portion of active ingredient
`must be released instantly. This approach also requires the
`provision of a semi-permeable layer betWeen the ?rst and
`third layers in order to control the relative rates of delivery
`of the tWo portions of active ingredient. Additionally, rup
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`ture of the semi-permeable layer leads to uncontrolled
`dumping of the second portion of the active ingredient
`Which may not be desirable.
`US. Pat. No. 5,158,777
`R. Squibb & Sons Inc.)
`discloses a formulation comprising captopril Within an
`enteric or delayed release coated pH stable core combined
`With additional captopril Which is available for immediate
`release following administration. In order to form the pH
`stable core, chelating agents such as disodium edetate or
`surfactants such as polysorbate 80 are used either alone or in
`combination With a buffering agent. The compositions have
`an amount of captopril available for immediate release
`folloWing oral administration and an additional amount of
`pH stabilised captopril available for release in the colon.
`US. Pat. No. 4,728,512, US. 4,794,001 and US. 4,904,
`476 (American Home Products Corp.) relate to preparations
`providing three distinct releases. The preparation contains
`three groups of spheroids containing an active medicinal
`substance: the ?rst group of spheroids is uncoated and
`rapidly disintegrates upon ingestion to release an initial dose
`of medicinal substance; the second group of spheroids is
`coated With a pH sensitive coat to provide a second dose;
`and the third group of spheroids is coated With a pH
`independent coat to provide to third dose. The preparation is
`designed to provide repeated release of medicinal substances
`Which are extensively metabolised presystemically or have
`relatively short elimination half-lives.
`US. Pat. No. 5,837,284 (Mehta et al) discloses a meth
`ylphenidate dosage form having immediate release and
`delayed release particles. The delayed release is provided by
`the use of ammonio methacrylate pH independent polymers
`combined With certain ?llers.
`Accordingly, it is an object of the present invention to
`provide a multiparticulate modi?ed release composition
`containing an active ingredient Which in operation produces
`a plasma pro?le substantially similar to the plasma pro?le
`produced by the administration of tWo or more IR dosage
`forms given sequentially.
`It is a further object of the invention to provide a multi
`particulate modi?ed release composition Which in operation
`delivers an active ingredient in a pulsatile manner.
`Another object of the invention is to provide a multipar
`ticulate modi?ed release composition Which substantially
`mimics the pharmacological and therapeutic effects pro
`duced by the administration of tWo or more IR dosage forms
`given sequentially.
`Another object of the present invention is to provide a
`multiparticulate modi?ed release composition Which sub
`stantially reduces or eliminates the development of patient
`tolerance to the active ingredient of the composition.
`Another object of the invention is to provide a multipar
`ticulate modi?ed release composition in Which a ?rst portion
`of the active ingredient is released immediately upon admin
`istration and a second portion of the active ingredient is
`released rapidly after an initial delay period in a bimodal
`manner.
`Another object of the invention is to provide a multipar
`ticulate modi?ed release composition capable of releasing
`the active ingredient in a bimodal or multi-modal manner in
`Which a ?rst portion of the active ingredient is released
`either immediately or after a delay time to provide a pulse
`of drug release and one or more additional portions of the
`active ingredient are released each after a respective lag time
`to provide additional pulses of drug release.
`Another object of the invention is to provide solid oral
`dosage forms comprising a multiparticulate modi?ed release
`composition of the present invention.
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`US 6,730,325 B2
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`Other objects of the invention include provision of a once
`daily dosage form of methylphenidate Which, in operation,
`produces a plasma pro?le substantially similar to the plasma
`pro?le produced by the administration of tWo immediate
`release dosage forms given sequentially and a method for
`treatment of attention de?cit disorder based on administra
`tion of such a dosage form.
`BRIEF DESCRIPTION OF THE INVENTION
`The above objects are realised by a multiparticulate
`modi?ed release composition having a ?rst component
`comprising a ?rst population of active ingredient-containing
`particles and a second component comprising a second
`population of active ingredient-containing particles. The
`active ingredient contained in the ?rst and second compo
`nents can be the same or different and active ingredient
`containing particles of the second component are coated
`With a modi?ed release coating. Alternatively or
`additionally, the second population of active ingredient
`containing particles further ‘comprises a modi?ed release
`matrix material. FolloWing oral delivery, the composition in
`operation delivers the active ingredient or active ingredients
`in a pulsatile manner.
`In a preferred embodiment of a multiparticulate modi?ed
`release composition according to the invention the ?rst
`component is an immediate release component.
`The modi?ed release coating applied to the second popu
`lation of active ingredient containing particles causes a lag
`time betWeen the release of active ingredient from the ?rst
`population of active ingredient containing particles and the
`release of active ingredient from the second population of
`active ingredient containing particles. Similarly, the pres
`ence of a modi?ed release matrix material in the second
`population of active ingredient containing particles causes a
`lag time betWeen the release of active ingredient from the
`?rst population of active ingredient containing particles and
`the release of active ingredient from the second population
`of active ingredient containing particles. The duration of the
`lag time may be varied by altering the composition and/or
`the amount of the modi?ed release coating and/or altering
`the composition and/or amount of modi?ed release matrix
`material utilised. Thus, the duration of the lag time can be
`designed to mimic a desired plasma pro?le.
`Because the plasma pro?le produced by the multiparticu
`late modi?ed release composition upon administration is
`substantially similar to the plasma pro?le produced by the
`administration of tWo or more IR dosage forms given
`sequentially, the multiparticulate controlled release compo
`sition of the present invention is particularly useful for
`administering active ingredients for Which patient tolerance
`may be problematical. This multiparticulate modi?ed
`release composition is therefore advantageous for reducing
`or minimising the development of patient tolerance to the
`active ingredient in the composition.
`In a preferred embodiment of the present invention, the
`active ingredient is methylphenidate and the composition in
`operation delivers the active ingredient in a bimodal or
`pulsed manner. Such a composition in operation produces a
`plasma pro?le Which substantially mimics that obtained by
`the sequential administration of tWo IR doses as, for
`instance, in a typical methylphenidate treatment regime.
`The present invention also provides solid oral dosage
`forms comprising a composition according to the invention.
`The present invention further provides a method of treat
`ing an animal, particularly a human in need of treatment
`utilising the active ingredient, comprising administering a
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`therapeutically effective amount of a composition or solid
`oral dosage form according to the invention to provide
`pulsed or bimodal administration of the active ingredient
`Advantages of the present invention include reducing the
`dosing frequency required by conventional multiple IR
`dosage regimes While still maintaining the bene?ts derived
`from a pulsatile plasma pro?le. This reduced dosing fre
`quency is particularly advantageous in the case of children
`in that it eliminates the need for dosing during the middle of
`the school day Which can be both disruptive and embarrass
`ing for the patient. It is also advantageous in terms of patient
`compliance to have a formulation Which may be adminis
`tered at reduced frequency. The reduction in dosage fre
`quency made possible by utilising the present invention
`Would contribute to reducing health care costs by reducing
`the amount of time spent by health care Workers on the
`administration of drugs. In the case of methylphenidate, and
`other controlled substances, the use of a once-daily formu
`lation (in place of multiple IR doses) reduces or eliminates
`the need for the storage of controlled substances on the
`premises of schools or other institutions.
`DESCRIPTION OF THE DRAWINGS
`FIG. 1 shoWs methylphenidate plasma pro?les folloWing
`oral administration of the folloWing three formulations to
`human volunteers: A—20 mg methylphenidate formulation
`having an immediate release component comprising par
`ticles containing a total of 10 mg methylphenidate
`(according to Table 1 (ii)) and a modi?ed release component
`comprising particles containing a total of 10 mg meth
`ylphenidate (according to Table 2 (viii); IR particles coated
`to a 30% Weight gain); B—20 mg methylphenidate formu
`lation having an immediate release component comprising
`particles containing a total 10 mg methylphenidate
`(according to Table 1 (ii)) and a modi?ed release component
`comprising particles containing a total of 10 mg meth
`ylphenidate (according to Table 2 (vii); IR particles coated
`to a 30% Weight gain); and Control—tWo doses of 10 mg
`Ritalin® Hydrochloride (IR) tablets administered at times 0
`and 4 hours (total of 20 mg methylphenidate administered).
`DETAILED DESCRIPTION OF THE
`INVENTION
`The term “particulate” as used herein refers to a state of
`matter Which is characterised by the presence of discrete
`particles, pellets, beads or granules irrespective of their siZe,
`shape or morphology. The tern “multiparticulate” as used
`herein means a plurality of discrete, or aggregated, particles,
`pellets, beads, granules or mixture thereof irrespective of
`their siZe, shape or morphology.
`The term “modi?ed release” as used herein in relation to
`the composition according to the invention or a coating or
`coating material or used in any other context means release
`Which is not immediate release and is taken to encompass
`controlled release, sustained release and delayed release.
`The term “time delay” as used herein refers to the duration
`of time betWeen administration of the composition and the
`release of the active ingredient from a particular component.
`The term “lag time” as used herein refers to the time
`betWeen delivery of active ingredient from one component
`and the subsequent delivery of active ingredient from
`another component.
`The invention Will be described in detail With respect to
`methylphenidate as a speci?c example of an active ingredi
`ent particularly suited to formulation in a multiparticulate
`modi?ed release composition according to the present
`invention.
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`US 6,730,325 B2
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`The multiparticulate modi?ed release composition of the
`invention may have more than tWo active ingredient
`containing components. In this case the release of active
`ingredient from the second and subsequent components is
`modi?ed such that there is a lag time betWeen the release of
`active ingredient from the ?rst component and each subse
`quent component. The number of pulses in the pro?le arising
`from such a composition in operation Will depend on the
`number of active ingredient containing components in the
`composition. A composition containing three active
`ingredient-containing components Will give rise to three
`pulses in the pro?le.
`Any active ingredient for Which it is useful to combine the
`advantages of a pulsatile plasma pro?le With a reduced
`frequency dosage regime may be used in practice of the
`present invention. Particularly useful in the practice of the
`invention include active ingredients Whose pharmacological
`and/or therapeutic effects bene?t from having a Wash-out
`period betWeen plasma concentration peaks, such as those
`active ingredients susceptible to the development of patient
`tolerance. Example active ingredients include but are not
`limited to peptides or proteins, hormones, analgesics, anti
`migraine agents, anti-coagulant agents, narcotic antagonists,
`chelating agents, anti-anginal agents, chemotherapy agents,
`sedatives, anti-neoplastics, prostaglandins and antidiuretic
`agents, drug compounds acting on the central nervous sys
`tem such as cerebral stimulants, for example methylpheni
`date; pain management active ingredients; alkaloids such as
`opiates, for example morphine; cardiovascular drugs, such
`as nitrates; and agents for treating rheumatic conditions. It is
`further appreciated that the present invention may be used to
`deliver a number of drugs including, but not limited to,
`peptides, proteins or hormones such as insulin, calcitonin,
`calcitonin gene regulating protein, atrial natriuretic protein,
`colony stimulating factor, betaseron, erythropoietin (EPO),
`interferons such as ot,[3 or y interferon, somatropin,
`somatotropin, somastostatin, insulin-like groWth factor
`(somatomedins), luteiniZing hormone releasing hormone
`(LHRH), tissue plasminogen activator (TPA), groWth hor
`mone releasing hormone (GHRH), oxytocin, estradiol,
`groWth hormones, leuprolide acetate, factor VIII, interleu
`kins such as interleukin-2, and analogues thereof; analgesics
`such as fentanyl, sufentanil, butorphanol, buprenorphine,
`levorphanol, morphine, hydromorphone, hydrocodone,
`oxymorphone, methadone, lidocaine, bupivacaine,
`diclofenac, naproxen, paverin, and analogues thereof; anti
`migraine agents such as sumatriptan, ergot alkaloids, and
`analogues thereof; anti-coagulant agents such as heparin,
`hirudin, and analogues thereof; anti-emetic agents such as
`scopolamine, ondansetron, domperidone, metoclopramide,
`and analogues thereof; cardiovascular agents, anti
`hypertensive agents and vasodilators such as diltiaZem,
`clonidine, nifedipine, verapamil, isosorbide-5-mononitrate,
`organic nitrates, agents used in treatment of heart disorders,
`and analogues thereof; sedatives such as benZodiaZepines,
`phenothioZines, and analogues thereof; chelating agents
`such as deferoxamine, and analogues thereof; anti-diuretic
`agents such as desmopressin, vasopressin, and analogues
`thereof; anti-anginal agents such as nitroglycerine, and ana
`logues thereof; anti-neoplastics such as ?uorouracil,
`bleomycin, and analogues thereof; prostaglandins and ana
`logues thereof; and chemotherapy agents such as vincristine,
`and analogues thereof.
`The active ingredient in each component may be the same
`or different. For example, a composition in Which the ?rst
`component contains a ?rst active ingredient and the second
`component comprises a second active ingredient may be
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`7
`desirable for combination therapies. Indeed, tWo or more
`active ingredients may be incorporated into the same com
`ponent When the active ingredients are compatible With each
`other. A drug compound present in one component of the
`composition may be accompanied by, for example, an
`enhancer compound or a sensitiser compound in another
`component of the composition, in order to modify the
`bioavailability or therapeutic effect of the drug compound.
`As used herein, the term “enhancer” refers to a compound
`Which is capable of enhancing the absorption and/or bio
`availability of an active ingredient by promoting net trans
`port across the GIT in an animal, such as a human. Enhanc
`ers include but are not limited to medium chain fatty acids;
`salts, esters, ethers and derivatives thereof, including glyc
`erides and triglycerides; non-ionic surfactants such as those
`that can be prepared by reacting ethylene oxide With a fatty
`acid, a fatty alcohol, an alkylphenol or a sorbitan or glycerol
`fatty acid ester; cytochrome P450 inhibitors, P-glycoprotein
`inhibitors and the like; and mixtures of tWo or more of these
`agents.
`The proportion of active ingredient contained in each
`component may be the same or different depending on the
`desired dosing regime. The active ingredient may be present,
`in the ?rst component individually or in combination With
`the active ingredient (or active ingredients) in the second
`component, in any amount sufficient to elicit a therapeutic
`response. The active ingredient (or active ingredients), When
`applicable, may be present either in the form of one sub
`stantially optically pure enantiomer or as a mixture, racemic
`or otherWise, of enantiomers. The active ingredient is pref
`erably present in a composition in an amount of from
`0.1—500 mg, preferably in the amount of from 1—100 mg.
`When the active ingredient is methylphenidate, it is prefer
`ably present in the ?rst component in an amount of from
`0.5—60 mg; more preferably the active ingredient is present
`in the ?rst component in an amount of from 2.5—30 mg. The
`active ingredient is present in the subsequent components in
`an amount Within a similar range to that described for the
`?rst component.
`The time release characteristics for the release of the
`active ingredient from each of the components may be
`varied by modifying the composition of each component,
`including modifying any of the excipients or coatings Which
`may be present. In particular the release of the active may be
`controlled by changing the composition and/or the amount
`of the modi?ed release coating on the particles, if such a
`coating is present. If more than one modi?ed release com
`ponent is present, the modi?ed release coating for each of
`these components may be the same or different. Similarly,
`When modi?ed release is facilitated by the inclusion of a
`modi?ed release matrix material, release of the active ingre
`dient may be controlled by the choice and amount of
`modi?ed release matrix material utilised. The modi?ed
`release coating may be present, in each component, in any
`amount that is suf?cient to yield the desired delay time for
`each particular component. The modi?ed release coating
`may be preset, in each component, in any amount that is
`sufficient to yield the desired time lag betWeen components.
`The lag time or delay time for the release of the active
`ingredient from each component may also be varied by
`modifying the composition of each of the components,
`including modifying any excipients and coatings Which may
`be present. For example the ?rst component may be an
`immediate release component Wherein the active ingredient
`is released substantially immediately upon administration.
`Alternatively, the ?rst component may be, for example, a
`time-delayed immediate release component in Which the
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`US 6,730,325 B2
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`8
`active ingredient is released substantially immediately after
`a time delay. The second component may be, for example,
`a time-delayed immediate release component as just
`described or, alternatively, a time-delayed sustained release
`or extended release component in Which the active ingredi
`ent is released in a controlled fashion over an extended
`period of time.
`As Will be appreciated by those skilled in the art, the exact
`nature of the plasma concentration curve Will be in?uenced
`by the combination of all of these factors just described. In
`particular, the lag time betWeen the delivery (and thus also
`the on-set of action) of the active ingredient in each com
`ponent may be controlled by varying the composition and
`coating (if present) of each of the components. Thus by
`variation of the composition of each component (including
`the amount and nature of the active ingredient(s)) and by
`variation of the lag time, numerous release and plasma
`pro?les may be obtained. Depending on the duration of the
`lag time betWeen the release of active ingredient from each
`component and the nature of the release from each compo
`nent (i.e. immediate release, sustained release etc.), the
`pulses in the plasma pro?le may be Well separated and
`clearly de?ned peaks (eg when the lag time is long) or the
`pulses may be superimposed to a degree (eg in When the lag
`time is short).
`In a preferred embodiment, the multiparticulate modi?ed
`release composition according to the present invention has
`an immediate release component and at least one modi?ed
`release component, the immediate release component com
`prising a ?rst population of active ingredient containing
`particles and the modi?ed release components comprising
`second and subsequent populations of active ingredient
`containing particles. The second and subsequent modi?ed
`release components may comprise a controlled release coat
`ing. Additionally or alternatively, the second and subsequent
`modi?ed release components may comprise a modi?ed
`release matrix material. In operation, administration of such
`a multiparticulate modi?ed release composition having, for
`example, a single modi?ed release component results in
`characteristic pulsatile plasma concentration levels of the
`active ingredient in Which the immediate release component
`of the composition gives rise to a ?rst peak in the plasma
`pro?le and the modi?ed release component gives rise to a
`second peak in the plasma pro?le. Embodiments of the
`invention comprising more than one modi?ed release com
`ponent give rise to further peaks in the plasma pro?le.
`Such a plasma pro?le produced from the administration of
`a single dosage unit is advantageous When it is desirable to
`deliver tWo (or more) pulses of active ingredient Without the
`need for administration of tWo (or more) dosage units.
`Additionally, in the case of some disorders it is particularly
`useful to have such a bimodal plasma pro?le. For example,
`a typical methylphenidate treatment regime consists of
`administration of tWo doses of an immediate release dosage
`formulation given four hours apart. This type of regime has
`been found to be therapeutically effective and is Widely
`used. The plasma pro?le produced by such an administ