I|||||||||||||||||||||ll||||||||||||||l|||||||||||||||||||||||||||||||||||||||||||||||l|||
`
`US 200401 9T405A1
`
`(19; United States
`(12) Patent AppliC3ti0fl PllbliC3ti0Il
`Devane et al.
`
`(10) Pub. No.: US 2004/0197405 A1
`(43) Pub. Date:
`Oct. 7, 2004
`
`(54) MU LTIPARTICULATE MODIFIED RELEASE
`COMPOSITION
`
`(60) Provisional application No. (){l,I'1(l6,7'26, filed on Nov.
`2, 1998.
`
`(75)
`
`Inventors: John C. Devane, Athlone (IE); Paul
`Stark, Alhlone (Ii.-E); Niall M.M.
`Fanning, Atlilone (IE); Gnrvtnder
`Slngll Rel-(Ill, Suwanee, GA (US)
`
`Publication Classification
`
`Int. Clf’ ............................. .. A6]I( W26; /\f:.|K W14
`(SI)
`(52) U.S. CI.
`............................................................ .. 424/9469
`
`Correspondence Address:
`SYNNES"l‘VEDT & LF.CHNF.R, LL!‘
`2600 ARAMARK TOWER
`1101 MARKET STREICT
`l’Hll..Al)ELl’I-IIA, PA 191072950
`
`U3) Assignee: Elan Corporation, plc, Dublin (IE)
`
`(21) Appl. No.:
`
`10,827,689
`
`(22)
`
`Filed:
`
`Apr. 19, 2004
`
`Rciated U.S. Application Data
`
`(63)
`
`l(];’354,483. Illed on
`(Tonlirtuation of application No.
`Jan. 30, 2003, which is a continuation of application
`No. 10..*'33l,754, filed on Dec. 30, 2002, which is a
`continuation of application No. 09_!8S0,425, filed on
`May 7, 2001, now Pat. No. 6,730,325, which is a
`continuation ol’ application No. {l9,t'566,()36. filed on
`May 8, 3000, now Pat. No. 6,228,398, which is a
`continuation ol‘ application No.
`I’(.'l't'US99.t25632,
`filed on Nov. 1, 1999.
`
`(57)
`
`ABSTRACT
`
`The invention relates to a multiparticulate modified release
`composition that in operation delivers an active ingredient in
`a pulsed or bimodal manner. The rnultipartieulate rnoditied
`release composition comprises an immediate release eom~
`ponent and a modified release component; the immediate
`release component comprising a first population of active
`ingredient containing particles and the modified release
`component comprising it second population of active ingre-
`dient containing particles coated with a controlled release
`coating; wherein the CIIll'|'Il_‘Jil'IaT.i(l1'! of the immediate release
`and modified release cortlponents 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 mulliparticttlale modified release composition. The
`plasma profile achieved by the multiparliculale modified
`release composition is advantageous in reducing patient
`tolerance to the active ingredient and in increasing patient
`compliance by reducing dosage l"reqi.tency.
`
`
`
`
`
`Plasmaconcentration(ngfmj
`
`
`
`Amerigen Ex. 1026, p. 1
`Amerigen Ex. 1026, p. 1
`
`

`
`Patent Application Publication Oct. 7, 2004
`
`US 2004/0197405 A1
`
`Time(h)
`
`
`
`Figure‘If
`
`:u::}
`
`in
`
`1"
`' N
`co '
`11'
`(wfiiu) uog1enua:_auo9'eu.Ise]d
`
`Amerigen Ex. 1026, p. 2
`Amerigen Ex. 1026, p. 2
`
`

`
`US 2004/0197405 A1
`
`Oct. 7, 2004
`
`MUI.'l‘IPAR’l"ICUI.A'l'E MODIl“IF.D RELEASE
`COMPOSITION
`
`FIELD OF TIIE INVIENTION
`
`[0001] The present invention relates to a multiparticulate
`modified release composition.
`in particular the present
`invention relates to a mu ltiparticulate modified release com-
`position that in operation delivers an active ingredient in a
`pulsatile manner. The present
`invention further relates to
`solid oral dosage forms containing such a multiparticutate
`controlled release composition.
`
`DESCRIPTION 01-‘ ’I'I-IE PRIOR ART
`
`[0002] The plasma profile associated with the administra-
`tion of a drug compound may be described as a "pulsatile
`profile” in which pulses of high active ingredient concen-
`tration,
`interspersed with low concentration troughs. are
`observed. A pulsatile profile containing two peaks may be
`described as “bimodal". Similarly, a composition or a dos-
`age form which produces such a profile upon administration
`may be said to exhibit “pulsed release" of the active ingre-
`dient.
`
`[0003] Conventional frequent dosage regimes in which an
`immediate release (IR) dosage form is administered at
`periodic intervals typically gives rise to a pulsatile plasma
`profile. In this case, a peak in the plasma drug concentration
`is observed after administration of each [R dose with troughs
`(regions of low drug concentration) developing between
`consecutive
`administration time points. Such dosage
`regimes (and their resultant pulsatile plasma profiles) 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.
`
`[0004] Many controlled release drug formulations are
`aimed at producing a zero-order release of the drug com-
`pound. Indeed, it is often a specific object of these fonTtu-
`lations to minimize the peak-to-trough variation in drug
`plasma levels associated with conventional frequent dosage
`regimes. However, some of the therapeutic and pharmaco-
`logical efiects intrinsic in a pulsatile system may be lost or
`diminished as a result of the constant or nearly constant
`plasma levels achieved by zero-order release drug delivery
`systems. Thus, a modified release composition or formula-
`tion which substantially mimics the release of frequent IR
`dosage regimes. while reducing the need for frequent dos-
`ing, is desirable.
`
`[0005] A typical example of a drug which may produce
`tolerance in patients is methylphenidate. Methylphenidate,
`or .alpha.—phenyl—2—piperidine acetic acid methyl ester, is a
`stimulant affecting the central nervous and respiratory sys-
`tems and is primarily used in the treatment of attention
`deficit disorder. After absorption from the gastrointestinal
`tract (GIT). drug etfects persist for 3-6 hours after oral
`administration of conventional IR tablets or up to about 8
`hours after oral administration of extended release formu-
`
`lations. The total dosage is typically in the range of 5-30 mg
`per day, in exceptional cases rising to 60 mgfday. Under
`conventional dosage regimes,
`rnethylphenidate is given
`twice daily, typically with one dose given before breakfast
`
`and a second dose given before lunch. The last daily dose is
`preferably given several hours before retiring. Adverse
`effects associated with mcthylphenidate treatment include
`insomnia and the development of patient tolerance.
`
`[0006] W0 98;’ 14168 (Alza Corp.) teaches a dosage form
`and a method of administering methylphenidate in a sus-
`tained and constantly ascending rate. The dosage form
`disclosed comprises a plurality of beads comprising a hydro-
`gel 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 profile in which
`the plasma concentration ofthe active ingredient continually
`increases over a given period of time. In contrast
`to the
`present invention, an object of WO 98214168 is to provide
`a dosage form to specifically avoid uneven blood levels
`(characterized by peaks and troughs) associated with con-
`ventional treatments using immediate release dosage formu-
`lations.
`
`[0007] W0 97t036'r'2 (Chiroscience Ltd.) discloses that
`methylphenidate exhibits a therapeutic el1‘ect when admin-
`istered in the form of a racemic mixture or in the form of a
`single isomer (such as the RR d—threo enantiomer). Further,
`W() 97f()3'}'63 (Chiroscience Ltd.) discloses a sustained
`release formulation containing dtmp. 'l'his 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 (ofthe active ingredient) of at least
`50% c.sub.rnax over a period of at least 8 hours. Thus, this
`forrnulation does not deliver the active ingredient
`in a
`pulsatile mariner.
`
`[0008] Shah ct al.,.l (font. Rel. (1939) 9:169-175 discloses
`that certain types of hydroxypropyl methylcellulose ethers
`compressed into a solid dosage fortn with a therapeutic
`agent may give a bimodal release profile. However, it was
`noted that while polymers from one supplier yielded a
`bimodal profile, the same polymers with almost identical
`product specifications obtained from a diifcrent source gave
`non-bimodal release profiles.
`
`[0009] Giunchedi et al., Int. J. Pharm (1991) 77:17?-181
`discloses the use of a hydrophilic matrix multiple-unit
`formulation for the pulsed release of ketoprofen. Giunchedi
`et al. teach that ketoprofen is rapidly eliminated from the
`blood after dosing (plasma half-life l-3 hours) and consecu-
`tive pulses of drug may be more beneficial than constant
`release for some treatments. The multiple-unit formulation
`disclosed comprises four identical hydrophilic matrix tablets
`placed in a gelatin capsule. Although the in vivo studies
`show two peaks in the plasma profile there is no well defined
`wash out period and the variation between the peak and
`trough plasma levels is small.
`
`(1989)
`Ind. Pharm,
`[0010] Come et al., Drug Dev.
`15:2583-2596 and EP (1 274 734 (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
`lirst layer containing the active ingredient, a barrier layer
`(the second layer) of semi-permeable material which is
`interposed between the first layer and a third layer contain-
`ing an additional amount of active ingredient. The barrier
`layer and the third layer are housed in an irnpenrteable
`casing. The first layer dissolves upon contact with a dis-
`
`Amerigen Ex. 1026, p. 3
`Amerigen Ex. 1026, p. 3
`
`

`
`US 2004/0197405 A1
`
`Oct. 7, 2004
`
`solving fluid while the third layer is only available after
`dissolution or rupture of the barrier layer. In such a tablet the
`first portion of active ingredient must be released instantly.
`This approach also requires the provision of a seI'ni-pe1'I11e-
`able layer between the first and third layers in order to
`control the relative rates of delivery of the two portions of
`active ingredient. Additionally, rupture of the semi-perme-
`able layer leads to uncontrolled dumping of the second
`portion of the active ingredient which may not be desirable.
`
`[0011] U.S. Pat. No. 5,158,777 (E. 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 [ollowing 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 oonipositions have
`an amount of captopril available for
`immediate release
`following oral administration and an additional amount of
`pH stabilized captopril available for release in the colon.
`
`[0012] US. Pat. Nos. 4328,51 2, 4,794,001 and 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 first group of spheroids is uncoatcd and
`rapidly disintegrates upon ingestion to release an initial dose
`of medicinal substance; the second group of spheroids is
`coated with a pH sensitive coal 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 metabolized presystcmically or have
`relatively short elimination hall"-lives.
`
`[0013] US. Pat. No. 5,837,284 (Mehta et at) discloses a
`methylphenidate dosage form having immediate release and
`delayed release particles. The delayed release is provided by
`the use of arnmonio mcthacrytate pH independent polymers
`combined with certain fillers.
`
`[0014] Accordingly, it is an object of the present invention
`to provide a multiparticulate modified release composition
`containing an active ingredient which in operation produces
`a plasma profile substantially similar to the plasma profile
`produced by the administration of two or more IR dosage
`forms given sequentially.
`
`It is a further object of the invention to provide a
`[0015]
`multiparticulate modified release composition which in
`operation delivers an active ingredient in a pulsatile manner.
`
`[0016] Another object of the invention is to provide a
`multiparticulate modified release composition which sub-
`stantially mimics the pharmacological and therapeutic
`ellects prodttced by the administration ol‘ two or more IR
`dosage fonns given sequentially.
`
`[0017] Another object of the present invention is to pro-
`vide a multiparticulate modified release composition which
`substantially reduces or eliminates the development of
`patient tolerance to the active ingredient of the composition.
`
`[0018] Another object of the invention is to provide a
`multiparticulate modified release composition in which a
`first portion of the active ingredient is released immediately
`
`upon administration and a second portion ot the active
`ingredient is released rapidly after an initial delay period in
`a bimodal manner.
`
`[0019] Another object of the invention is to provide a
`multiparticulate modified release composition capable of
`releasing the active ingredient in a bimodal or multi-modal
`manner in which a first 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.
`
`[0020] Another object of the invention is to provide solid
`oral dosage forms comprising a multiparticulate modified
`release composition of the present invention.
`
`[0021] Other objects of the invention include provision of
`a once daily dosage form of rnethylphenidate which,
`in
`operation, produces a plasma profile substantially similar to
`the plasma profile produced by the administration of two
`immediate release dosage forms given sequentially and a
`method for treatment of attention deficit disorder based on
`
`administration of such a dosage form.
`
`BRIEF DI3SCRlP'I'I()N OF THE INVENTION
`
`[0022] The above objects are realized by a multiparticulate
`modified release composition having a first component
`comprising a first 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 first and second compo-
`nents can be the same or different and active ingredient~
`containing particles of the second component are coated
`with a modified release coating. Alternatively or addition-
`ally, the second population of active ingredient containing
`particles further comprises a modified release matrix mate-
`rial. 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
`[0023]
`modified release composition according to the invention the
`first component is an immediate release component.
`
`[0024] The modified release coating applied to the second
`population of active ingredient containing particles causes a
`lag time between the release of active ingredient from the
`first 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 modified release matrix material in the second
`population of active ingredient containing particles causes a
`lag time between the release of active ingredient from the
`first 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 andfor
`the amount of the modified release coating andlor altering
`the composition andfor amount of modified release matrix
`material utilized. Thus, the duration of the lag time can be
`designed to mimic a desired plasma profile.
`
`[0025] Because the plasma profile produced by the mul~
`tiparticulate mortified release composition upon administra-
`tion is substantially similar to the plasma profile produced
`by the adrninistration of two or more [R dosage fonns given
`
`Amerigen Ex. 1026, p. 4
`Amerigen Ex. 1026, p. 4
`
`

`
`US 2004/0197405 A1
`
`Oct. 7, 2004
`
`sequentially, the multiparticulatc controlled release compo-
`sition of the present
`invention is particularly useful for
`administering active ingredients for which patient tolerance
`may be problematical. This multiparticulatc modified
`release cornposition is therefore advantageous for reducing
`or minimizing the development of patient tolerance to the
`active ingredient in the composition.
`
`In a preferred embodimentof the present invention,
`[0026]
`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 profile which substantially mimics that obtained by
`the sequential administration of two IR doses as,
`for
`instance, in a typical methylphenidate treatment regime.
`
`invention also provides solid oral
`[0027] The present
`dosage forms comprising a composition according to the
`invention.
`
`[0028] The present invention further provides a method of
`treating an animal, particularly a human in need of treatment
`utilizing the active ingredient, comprising administering a
`therapeutically elfective amount of a composition or solid
`oral dosage form according to the invention to provide
`pulsed or bimodal administration of the active ingredient.
`
`[0029] Advantages of the present invention include reduc-
`ing the dosing frequency required by conventional multiple
`IR dosage regimes while still maintaining the benefits
`derived from a pulsatile plasma profile. This reduced dosing
`frequency is particularly advantageous in the case of chil-
`dren in that it eliminates the need for dosing during the
`middle of the school day which can be both disruptive and
`embarrassing for the patient. It is also advantageous in terms
`of patient compliance to have a formulation which may be
`administered at reduced frequency. The reduction in dosage
`frequency made possible by utilizing 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 mcthylphenidate, 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.
`
`lJl3S(.'RIP'I'l()N 0!’ TIIIE DRAWINGS
`
`[0030] FIG. 1 shows methylphenirlate plasma profiles
`following oral administration of the following three formu-
`lations to human volunteers: A—2U mg methylphenidate
`formulation having an immediate release component com-
`prising particles containing a total of IO mg methylphenidate
`(according to Table 1 (ii}) and a modified 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—2U mg methylphenidate t'om1u-
`lation having an immediate release component comprising
`particles containing a total 10 mg methylphenidate (accord-
`ing to Table 1
`(ii)) and a modified 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® I-Iydrochloride (IR) tablets administered at times 0
`and 4 hours (total of 20 mg methylphenidate administered).
`
`DETAILED DESCRIPTION OF THE
`INVENTION
`
`[0031] The term “particulate” as used herein refers to a
`state, of matter which is characterized by the presence of
`discrete particles, pellets, beads or granules irrespective of
`their size, shape or morphology. The term “multiparticulate"
`as used herein means a plurality of discrete, or aggregated,
`particles, pellets, beads, granules or mixture thereof irre-
`spective of their size, shape or morphology.
`
`[0032] The term “modified 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.
`
`[0033] 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.
`
`[0034] The term "lag time" as used herein refers to the
`time between delivery of active ingredient from one com-
`ponent and the subsequent delivery of active ingredient from
`another component.
`
`[0035] The invention will be described in detail with
`respect to methylphenidate as a specific example of an active
`ingredient particularly suited to formulation in a multipar-
`ticulate modified release composition according to the
`present invention.
`
`[0036] The multiparticulatc modified 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
`modified such that there is :1 lag time between the release of
`active ingredient from the first component and each subse-
`quent componcnt. The number of pulses in the profile 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 ingre-
`dient-containing components will give rise to three pulses in
`the profile.
`
`to
`is useful
`[0037] Any active ingredient for which it
`combine the advantages of a puisalile plasma profile 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 pharmaco-
`logical andfor therapeutic effects benefit
`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, anticoagulant agents, narcotic antago-
`nists, chclating agents, anti-anginal agents, chemotherapy
`agents,
`sedatives,
`anti-neoplastics, prostaglandins
`and
`antidiuretic agents, drug compounds acting on the central
`nervous system such as cerebral stimulants. for example
`methylphenidate; pain management active ingredients; alka-
`loids such as opiates, for example morphine; cardiovascular
`drugs, such as nitrates; and agents for treating rheumatic
`conditions. It is further appreciated that the present inven-
`tion may be used to deliver a number of drugs including. but
`not
`limited to, peptides, proteins or hormones such as
`
`Amerigen Ex. 1026, p. 5
`Amerigen Ex. 1026, p. 5
`
`

`
`US 2004/0197405 A1
`
`Oct. 7, 2004
`
`insulin, calcitonin, calcitonin gene regulating protein, atrial
`natriuretic protein, colony stimulating factor, betaseron,
`erythropoictin (EPO), interferons such as alpha., beta. or
`gamma. interferon, somatropin, somatotropin, som'r1stosta-
`tin, insulin-like growth factor (somatomedins), luteinizing
`hormone releasing hormone (LHRH), tissue plasminogen
`activator
`(TPA), growth hormone
`releasing hormone
`(GHRI-l), oxytocin, estradiol, growth hormones, leuprolide
`acetate, factor VIII, interleukins such as interleukin-2, and
`analogues thereof; analgesics such as fentanyl,sufentanil,
`butorphanol, buprenorphine, levorphanul, morphine, hydro-
`murphone,
`hydrocodone,
`oxymorphone, methadone,
`lidoeainc, 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, dornperidone,
`metoclopramide, and analogues
`thereof; cardiovascular
`agenLs, anti-hypertensive agents and vasodilators such as
`diltiazem, clonidine, nifedipine, verapamil,
`isosorbidc-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, vaso-
`pressin, and analogues thereof; anti-anginal agents such as
`nitroglycerine, and analogues thereof; anti-neoplastics such
`as fluorou racil, bleomycin, and analogues thereof; prostag-
`landins and analogues thereof; and chemotherapy agents
`such as vincristine, and analogues thereof.
`
`[0038] The active ingredient in each component may be
`the saute or different. For example, a composition in which
`the first component contains a first active ingredient and the
`second component comprises a second active ingredient
`may be desirable for combination therapies. Indeed, two or
`more active ingredients may be incorporated into the same
`component when the active ingredients are compatible with
`each other. Adrug compound present in one component of
`the composition may be accompanied by, for example, an
`enhancer compound or a scnsitizer compound in another
`component of the composition,
`in order to modify the
`bioavailability or therapeutic effect of the drug compound.
`
`the term “enhancer“ refers to a
`[0039] As used herein,
`compound which is capable of enhancing the absorption
`andior hioavailability of an active ingredient by promoting
`net transport across the GIT in an animal, such as a human.
`Enhancers include but are not limited to medium chain fatty
`acids; salts, esters, et hers and derivatives thereof, including
`glyceridcs 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-gly-
`coproteirt inhibitors and the like; and mixtures of two or
`more of these agents.
`
`[0040] 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 lirst component individually or in combina-
`tion 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 ingre-
`dients), when applicable, may be present either in the form
`of one substantially optically pure enantiomer or as it
`
`mixture, racemic or otherwise, of enantiomers. The active
`ingredient
`is preferably present
`in a composition in an
`amount of from 01-500 mg, preferably in the amount of
`from 1-100 mg. When the active ingredient is methy1pherii-
`date, it is preferably present in the first component in an
`amount of from 05-60 mg; more preferably the active
`ingredient is present in the first component in an amount of
`from 25-30 mg. The active ingredient
`is present
`in the
`subsequent components in an amount within a similar range
`to that described for the first component.
`
`[0041] 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 ofthe excipients or coatings which
`may be present. In particular the release of the active may be
`controlled by changing the composition andfor the amount
`of the modified release coating on the particles, if such a
`coating is present. If more than one modified release com-
`ponent is present, the modified release coating for each of
`these components may be the same or dilferent. Similarly,
`when modified release is facilitated by the inclusion of a
`modified release matrix material, release of the active ingre-
`dient may be controlled by the choice and amount of
`modified release matrix material utilized. The modified
`release coating may be present, in each component, in any
`amount that is sufficient to yield the desired delay time for
`each particular component. The modified release coating
`may be preset, in each component. in any amount that is
`sutlicicnt to yield the desired time lag between components.
`
`[0042] 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 first component may he an
`immediate release component wherein the active ingredient
`is released substantially immediately upon administration.
`Alternatively, the first component may be, for example, a
`time~delayed immediate release component
`in which the
`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.
`
`[0043] As will be appreciated by those skilled in the art,
`the exact nature of the plasma concentration curve will be
`influenced 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 component may be controlled by varying the com-
`position 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 profiles 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
`component (i,e. immediate release, sustained release etc.),
`the pulses in the plasma profile may be well separated and
`clearly defined peaks (c.g. when the lag time is long) or the
`pulses may be superimposed to a degree (e.g. in when the lag
`time is short).
`
`Amerigen Ex. 1026, p. 6
`Amerigen Ex. 1026, p. 6
`
`

`
`US 2004/0197405 A1
`
`Oct. 7, 2004
`
`the multiparticulate
`In a preferred embodiment,
`[0044]
`modified release composition according to the present
`invention has an immediate release component and at least
`one modified release component,
`the immediate release
`component comprising a first population of active ingredient
`containing particles and the modified release components
`comprising second and subsequent populations of active
`ingredient containing particles. The second and subsequent
`modified release components may comprise a controlled
`release coating. Additionally or alternatively, the second and
`subsequent modified release components may comprise a
`rrlodified release matrix material. In operation, administra-
`tion of such a multiparticulate modified release composition
`having. for example, a single modified release component
`results in characteristic pulsatile plasma concentration levels
`of the active ingredient
`in which the immediate release
`component ofthe composition gives rise to a first peak in the
`plasma profile and the modified release component gives
`rise to a second peak in the plasma profile. l_".mbodirnents of
`the invention comprising more than one modified release
`component give rise to further peaks in the plasma profile.
`[0045] Such a plasma profile produced from the adminis-
`tration 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 profile.
`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 elfective and
`is widely used. The plasma profile produced by such an
`administration regime is illustrated by the “Control” curve in
`FIG.
`I. As previously mentioned,
`the development of
`patient tolerance is an adverse et‘1'ect sometimes associated
`with methylphenidate treatments.
`It
`is believed that
`the
`trough in the plasma profile between the two peak plasma
`concentrations is advantageous in reducing the development
`of patient tolerance by providing a period of wash out of the
`active ingredient.