(19) United States
`
`(12; Patent Application Publication (10) Pub. No.: US 2007/0264323 A1
`Shojaei et at.
`(43) Pub. Date:
`NOV. 15, 2007
`
`US 20070264323A1
`
`(54) CONTROLLED DOSE DRUG DELIVERY
`SYSTEM
`
`Publication Classification
`
`(75)
`
`lnvenlorsz Amir Slmjaei. Phoenixville. PA (US):
`Stephanie Read. Philadelphia, PA (US):
`Richard A_ Couch Bryn Mawr‘ PA
`(US); Paul Hodgkins, Exton. PA (US)
`(.‘0n'espundem.:e Address:
`DARBY &-. DARBY P.(.'.
`P_0, BOX 770
`(_'[-lurch st“-ct station
`New York! NY 10003_0770 (US)
`
`(73)
`
`__:\55[gn.;¢_-; S[|[RE [‘|J(_“ [-‘]m-L-mm-_ KY
`
`(21) App], No;
`
`11,883,056
`
`(22)
`
`Filed:
`
`May l2. 2'[|l}6
`
`[5l)
`
`Int. (fl.
`/l6IK 31/337
`
`(2006.01)
`
`(2006'(“)
`A611 9/48
`(200601)
`A61K‘ 9/24
`(52) U.S. CI.
`........................... 4241'-151: 424.1472: 5143649
`(57)
`ABS.l.RAC.l.
`A multiple pulsed dose drug delivery system for pharma-
`ceulieally active amphetamine salts, comprising a pharma-
`ceutically active amphetamine salt covered with an imme-
`diate—re]e-ase
`coating and a
`pharmaceutically
`active
`amphetamine salt covered with an enteric cnaling wherein
`the immediate release coating and the enterie coating pm-
`vide For multiple pulsed dose delivery of the phamiaeeuti-
`Cally active anlplietainine salt. The product can be coniposed
`01' either one or a number of beads in a dosage form.
`including either (3t:l])SlllC_. tablet. or sachet method lhr admin-
`istering the heads.
`
`Amerigen Ex. 1038, p. 1
`Amerigen Ex. 1038, p.
`1
`
`

`
`Patent Application Publication Nov. 15, 2007 Sheet 1 of 10
`
`US 2007;"0264323 Al
`
`F|G.1
`
`120
`
`110
`
`100
`
`9|]
`
`1D
`
`
`
`PercentDissolved
`
`50
`
`40
`
`30
`
`20
`
`U
`
`2
`
`4
`
`B
`
`8
`Time (hours)
`
`10
`
`12
`
`14
`
`15
`
`Amerigen Ex. 1038, p. 2
`Amerigen Ex. 1038, p. 2
`
`

`
`Patent Application Publication Nov. 15, 2007 Sheet 2 of 10
`
`US 2007;'0264323 Al
`
`F|G.2
`
`Protective coating
`
`Sureiease coating
`
`Drug layered
`
`core
`
`Eudragit FS-30D
`coating
`
`FIG. 3
`
`SPD465 Sustained Release Capsule
`
`Immediate-Release
`Bead (IR)
`
`Delayed-Release
`Bead 1 (DR1}
`
`Drug layer
`
`Overcoatin I
`
`
`
`
`Drug layer
`Overcoating
`
`Delayed-release
`polymer
`
`Delayed Release
`Bead 2 [DR2}
`Delayed-release
`polymer
`
`
`
`Core '
`
`Overcoatlng
`
`33.3%
`
`33.3%
`
`33.3%
`
`Sustained-release
`P°‘W“°'
`
`QD (morning}—b
`
`—>TID dosing profile
`
`Amerigen Ex. 1038, p. 3
`Amerigen Ex. 1038, p. 3
`
`

`
`Patent Application Publication Nov. 15, 2007 Sheet 3 of 10
`
`US 2007;"0264323 Al
`
`FIG.-4
`
`Dissolution Profile of SPD-I65 1 2.5mg Capsules Lonll AIJ3552A
`
`100
`
`on
`
`
`
`
`
`PercentDissolvad{"23}
`
`G 3
`
`83
`
`eca:2‘.N vh-
`
`_.”I
`
`14
`
`an
`
`an
`
`-8 4:
`
`Time {hr}
`
`F|G.5
`Dissolution Profile of SPD465 25mg Capsules Lot# A035-WA
`
`_
`
`838
`PercentDissolved(56) S
`
`
`
`
`
`MD
`
`O
`
`. NI J‘-
`
`05
`
`W
`
`_ 0
`
`12
`
`14
`
`Time [l1I‘}
`
`Amerigen Ex. 1038, p. 4
`Amerigen Ex. 1038, p. 4
`
`

`
`Patent Application Publication NOV. 15, 2007 Sheet 4 of 10
`
`US 2007;"0264323 A]
`
`F|G.6
`
`Dissolution Profile of SPDIIBE 3?.5rI1g Capsules Lotti AlJ3549B
`
`100
`
`QD
`
`
`
`PercentDissolvedPMinG)DD
`
`20
`
`F|G.7
`
`Dissolution Profile nf SPD-165 SD:-ng Capsules Lnt# AD‘.-15363
`
`100
`
`
`
`
`
`PercentDissolved(“M
`
`30
`
`60
`
`40
`
`20
`
`Amerigen Ex. 1038, p. 5
`Amerigen Ex. 1038, p. 5
`
`

`
`Patent Application Publication NOV. 15, 2007 Sheet 5 of 10
`
`US 2007;"0264323 A]
`
`FlG.8
`
`100
`
`33
`
`80
`60
`
`E’
`:3
`.2
`9 40
`‘E0
`2
`II‘!
`n.
`
`20
`
`O
`
`012 3
`
`.
`
`4
`
`5
`
`6
`
`?'
`
`8 910111213141516
`
`'l'in1a(hr)
`
`F|G.9
`
`i —o— SPD4-65 315 mg
`—®— ADDERALL xR“" 25 mg
`+ Mixed Amphetamine salts 12.5 mg
`
`
`
`d-AmphetamineMeanPlasma
`
`Concentration
`
`(ng.’mL)
`
`Amerigen Ex. 1038, p. 6
`Amerigen Ex. 1038, p. 6
`
`

`
`Patent Application Publication Nov. 15, 2007 Sheet 6 of 10
`
`US 2007;"0264323 Al
`
`FIG. 10
`
`-—o- ADDERAL1. XR‘’ 25 mg
`+ Mixed Amphetamine salts 12.5 mg
`+ SPD465 37.5 mg
`
`
`
`Concentration(nglmL)
`
`0
`
`1 0
`
`20
`
`30
`
`40
`
`50
`
`60
`
`Time (hr)
`
`FIG. 11
`
`25
`
`-
`
`
`
`
`
`Meand-AmphetaminePlasma
`
`
`
`Concentration(ngfmL)
`
`ll ——I—- Single Dose (Day 1)
`-—En—- Multiple Dose (Day 7)
`
`20
`
`En‘
`
`Time (hr)
`
`Amerigen Ex. 1038, p. 7
`Amerigen Ex. 1038, p. 7
`
`

`
`Patent Application Publication NOV. 15, 2007 Sheet 7 of 10
`
`US 2007;"0264323 A]
`
`
`
`
`
`Meand-AmphetaminePlasma
`
`FIG. 12
`
`-1- 12.5 mg (Day 7}
`—El— 25 mg (Day 7)
`-0- 50 mg {Day 7)
`—v— 75 mg {Day ?]
`
`
`
`Concentration(ng!mL)
`
`‘I60
`
`140
`
`120
`
`100
`
`80
`
`60
`
`40
`
`20 .
`
`0
`
`250
`
`“E3
`
`Individual Values
`0
`In Mean
`
`200
`
`--A~-- Power Model Regression Line
`
`150
`
`100
`
`50
`
`Dose (mg)
`
`Amerigen Ex. 1038, p. 8
`Amerigen Ex. 1038, p. 8
`
`3 E E
`
`’-v
`35E
`
`Ui
`
`nEE
`
`.59to:
`D.
`
`E4
`
`:
`
`

`
`Patent Application Publication Nov. 15, 2007 Sheet 8 of 10
`
`US 2007;"0264323 Al
`
`FIG. 14
`
`5000
`
`---
`
`--
`
`--—
`
`--— --
`
`
`
`0
`
`O
`8
`
`.
`
`g
`
`8
`
`0
`
`'1'
`50
`
`"*
`
`1 " I
`60
`
`-"1
`70
`
`-
`
`80
`
`3-
`__E_
`tn
`
`4000
`
`1
`Individual l/aJue0
`0
`-I Mean
`‘
`"A"
`Power Model Regression Line
`
`
`3000
`
`2000
`
`1000
`
`0
`
`0
`
`P‘
`
`3 -'
`10
`
`“I
`20
`
`‘‘'I‘'‘'
`
`I—'*-‘ "" 1
`30
`40
`
`Dose (mg)
`
`FIG. 15
`
`<54:
`E“
`(3;
`2|
`
`<‘
`
`E
`01
`-§-
`
`¢1
`
`.-5
`
`
`
`
`
`MeanI-AmphetaminePlasma
`
`10
`
`
`
`Concentration(ng!mL)
`
`-0- Single Dose {Day 1)
`
`-3- Multiple Dose [Day 7]
`
`0
`
`4
`
`3
`
`12
`
`16
`
`20
`
`24
`
`Amerigen Ex. 1038, p. 9
`Amerigen Ex. 1038, p. 9
`
`

`
`Patent Application Publication Nov. 15, 2007 Sheet 9 of 10
`
`US 2007;"0264323 A]
`
`FIG. 16
`
`
`
`
`
`MeanI-AmphetaminePlasma
`
`
`
`Concentration(ng!mL)
`
`
`
`I-AmphetamineC,m(ng!mL)
`
`60
`
`5D
`
`40
`
`30
`
`20
`
`'10
`
`100
`
`30
`
`-—I—- 12.5 mg (Day?)
`-5- 25 mg (Day 7)
`-9- 50 mg (Day?)
`—fi—-
`
`75 mg (Day?)
`
`.___I
`
`I
`
`3
`
`_‘.—
`
`|"'jI—T"|"“'jI'j|:"l"j"
`
`12
`
`'16
`
`20
`
`24
`
`Time (hr)
`
`FIG. 17
`
`Individual Values
`0
`- Mean
`
`A
`
`Power Model Regression Line
`
`CI
`
`
`
`Dose (mg)
`
`Amerigen Ex. 1038, p. 10
`Amerigen Ex. 1038, p. 10
`
`

`
`Patent Application Publication Nov. 15, 2007 Sheet 10 of 10
`
`US 2007;’0264323 A]
`
`0
`
`0 8
`
`—"E
`
`Q
`
`60
`
`70
`
`8'0
`
`Amerigen Ex. 1038, p. 11
`Amerigen Ex. 1038, p. 11
`
`1800
`
`1600
`
`1400
`
`1200
`
`1000
`
`800
`
`600
`
`400
`
`200
`
`Individual Values
`0
`- Mean
`
`
`
`'-A-- Power Model Regression Line
`
`E
`
`"'5'
`O
`
`O
`
`5'0
`
`_
`
`‘I'D
`
`I
`
`20
`
`3:0
`
`40
`
`Dose (mg)
`
`
`
`
`
`I-AmphetamineAUCm_24}(hr*ngfmL)
`
`

`
`US 2007/0264323 A1
`
`Nov. 15, 2007
`
`(f()N'I‘R()I.l.EI') DOSE DRUG DELIVERY SYSTEM
`
`BACKGROUND OF THE INVENT]ON
`
`[0001] Traditionally. d.rug delivery systems have focused
`on constantJ'sustained drug output with the objective of
`minimizing peaks and valleys of drug concentrations in the
`body to optimize drug eflicacy and reduce adverse ellocts.
`Reduced dosing frequency and i111proved patient compliance
`can also be expected for constant;’susIained release drug
`delivery systems, compared to immediate release prepara-
`tions. I lowever, liir certain drugs. sustained release delivery
`is not suitable and is affected by Ll1e following factors:
`
`such as
`lnetabolism: Some drugs,
`l-'irst pass
`[0002]
`[5—blockers. [5—estradiol, and salicylamide. undergo extensive
`first pass metabolism and require fast drug input to saturate
`metabolizing enzymes in order to minimize pre-systemic
`metabolism. Thus. a constant.I"sustained oral n1etl1od of
`delivery would result in reduced oral bioavailability.
`
`release drug
`tolerance: Continuous
`[0003] Biological
`plasma profiles are ofien accompanied by a decline in the
`pharmacotherapeutic eflect of the drug. e.g., biologcal
`tolerance of transdemial nitroglycerin.
`
`[0004] Clirouopllamlacology and circadian rhythms: Cir-
`cadian rhythms in certain physiological liinctions are well
`established.
`It has been recognized that a symptom or
`disease onset can occur during specific time periods of the
`24 hour day, e.g., asthma and angina pectoris attacks are
`most frequently in the moming hours (l.,en1mer. 13. J Con-
`trolled Release. 1991; 16:63-74; Lemmer B, Pulsatile Drug
`Delivery: Current Applications and Future Trends (R Gur-
`ney, II 17. Junginger, N A Peppeas, eds.) 1993; ll-24).
`
`[0005] Local therapeutic need: For the treatment of local
`disorders such as inilanunatory bowel disease. the delivery
`of compounds to the site of inllanunation with no loss due
`to absorption in the small intestine is highly desirable to
`achieve the therapeutic efl'ect and to minimize side eifects.
`
`[0006] Gastric irritation or drug instability in gastric fluid:
`For compounds with gastric irritation or chemical instability
`in gastric Iluid. the use of a sustained release preparation
`may exacerbate gastric irritation and chemical instability in
`gastric fluid.
`
`[0007] Drug absorption ditferences i11 various gastrointes-
`tinal segments: In general. drug absorption is moderately
`slow in Lhe stomach, rapid in the small intestine, and sharply
`declining in the large intestine. ('ornpensation for changing
`absorption characteristics in the gastrointestinal tract may be
`important for some drugs. For example. it is rational for a
`delivery system to pump out the drug much faster when the
`system reaches the distal segment of the intestine. to avoid
`the entombment of the drug in the feces.
`
`[0003] Pulsed dose delivery systetns, prepared as either
`single unit or multiple unit formulations. and which are
`capable of releasing the drug after a predetermined time.
`have been st1td.ied to address the aforementioned proble -
`atic areas for sustained release preparations. These same
`factors are also problematic in pulsed dose formulation
`development. For example. gastrointestinal
`transit
`times
`vary not only Troln patient to patient but also within patients
`as a result of food intake. stress, and illness; thus a single-
`unit pulsed—release system may exhibit higher variability
`compared to a multiple unit system. Additionally, drug
`layering or core making for multiple unit systems is a
`time-consuming and hard-to-optimize process. Particularly
`
`challenging for fonnulation scientists has been overcoming
`two conflicting hurdles for pulsatile formulation develop-
`ment. i.e.. lag time and rapid release.
`
`[0009] Various enteric materials. e.g.. cellulose acetate
`phthalate. hydroxypropyl methylcellulose phthalate. polyvi-
`nyl acetate phthalate. and the li1ll')RA(il'l‘~1§3- acrylic poly-
`mers, have been used as gastroresistant, enterosoluble coat-
`ings for single drug pulse release in the intestine (Xu X and
`Lee P. Phann Res. 1993:
`l0(8):1]44—ll52). The enteric
`materials, which are soluble at higher pIl values, are fre-
`quently used for colon-specific delivery systems. Due to
`their pH+:lependent attributes and the uncertainty of gastric
`retention time.
`in—vivo performance as well as inter— and
`intra-subject variability are major issues for using e11teric
`coated systems as a time-controlled release of drugs.
`
`[0010] A retarding, swellable hydmphilic coating has been
`used for oral delayed release systems (Ga'z'.7.aniga et al., lint’
`J Pharm Biopl1arm. 1994: 40(4):246—250_: Gazzaniga et al..
`S.T.P. Pharma Sciences. 1996; 5(l):83—88). It was demon-
`strated that lag time was linearly correlated with coating
`weight gain and drug release was pll independent.
`
`Ilydroxypropyl methylcellulose barriers with erod-
`[0011]
`ible andfor gellable characteristics formed using press coat-
`ing technology for tablet dosage tonns have been described
`to achieve time—programmed release of drugs (Conte et al..
`Biomaterials. 1993; l4(l3): 1017-I023). l3ar‘rierTorn1ulation
`variables (such as grade ofhydroxypropyl methylcellulose,
`water—soluble and water—insoluble excipients) significantly
`altered the lag time and the release rate from the center
`(.‘(]]'CS.
`
`[0012] Special grades of hydroxypropyl methylcellulose.
`e.g.. Ml'i'l”()I_.USl'.i® GOSH. 90SIl (Sllin-litsu Ltd, Japan),
`and Ml7.'l'[I()('_'lZl;C|§3 l*'4M [Dow Chemical Company, USA)
`have been used as a hydrophilic matrix material to achieve
`bimodal drug release for several drugs. i.e.. aspirin. ibupro-
`fen. a11d adinamlam (WC) 87i'()(l044). liimodal release is
`characteri“/_ed by a rapid initial release, followed by a period
`of constant release. and then by a second rapid drug release.
`
`[0013] Tablets of capsules coated with a hydrophobic
`wax—surfactant layer. made from an aqueous dispersion of
`carnauba wax.
`beeswax.
`polyoxyethylene
`sorbitau
`monooleate, and hydroxypropyl methylcellulose have been
`used for rapid drug release after a predetermined lag time.
`However. even though a two—hour lag time was achieved for
`the model drug theophylline at a higher coating level (60%).
`three hours were required for a complete release of tl1eo-
`phylline after the lag time. [Walia et al.. Phann Dev Tech.
`1998; 3(1):10?--113)
`
`[0014] A sustained-release d.rug delivery system is
`described in U.S. Pat. No. 4.871.549. When this system is
`placed into dissolution medium or the gastrointestinal tract,
`water intlux and the volume expansion of tlie swelling agent
`cause the explosion of the water penneable membrane. The
`drug thus releases alter a predetennined time period.
`
`[0015] The ()R()S0§' push-pull system (Alva Company)
`has been developed for pulsatile delivery of water—soluble
`and water—insoluble drugs (Theeuwes. Drug Dev Ind Pharm.
`i983; 9(7):l33l-i357: Theeuwes F. Novel Drug Delivery
`and its Therapeutic Application (1..
`l-' Prescott and W S
`Niinmos eds.) 1989; 323-340), e.g. the OROS—CT® system
`and is based on the swelling properties of an osmotic core
`compartment which provides a pll-independent, ti1ne-con-
`trolled drug release.
`
`Amerigen Ex. 1038, p. 12
`Amerigen Ex. 1038, p. 12
`
`

`
`US 2007/0264323 A1
`
`Nov. 15, 2007
`
`[0016] The l-’IJI.SINC./\P-IR} dosage form releases its drug
`content at either a predetermined time or at a specific site
`(e.g.. colon) in the gastrointestinal tract (W0 90f09168). The
`drug l‘ormulation is contained within a water—insoluble cap-
`sule body and is sealed will] a hydrogel plug. tJpon oral
`administration. the capsule cap dissolves in the gastric juice
`and the hydrogel plug swells. .At a controlled and predeter-
`mined time point.
`tl1e swollen plug is ejected fron1 the
`PUI..SlNCAl-’® dosage ‘form a11d the encapsulated drug is
`released. A pulsatile capsule system containing captopril
`with release after a nominal 5—hr period was found to
`perform. reproducible in dissolution and gamma scit1tigra-
`phy studies. However, i11 tl1e majority of subjects. no inca-
`surable amounts of the drug were observed in the blood.
`possibly due to instability ofthe drug in the distal intestine.
`(Wilding et al.. Pharm Res. l992:9(5):654-657)
`
`[0017] AlJI)l'iI{.!\I.I,-lI{l- is an immediate release co1nposi-
`tion. which includes a mixture of lbur amphetamine salts:
`dextroamphetamine sulfate, dextroamphetamine saccharate,
`amphetamine aspartate monohydrate and amphetamine sul-
`fate. This combination of atnphetamines is i11d.icated for the
`treatment of Attention Deficit Ilyperactivity Disorder in
`children from 3-10 years of age.
`
`[0018] One disadvantage of immediate release-only treat-
`ments for children is that two separate doses are adminis-
`tered, one in the moming and one approximately 4-6 hours
`later, commonly away from home under other than parental
`supervision. This requires a second treatment. which is
`time-consuming, inconvenient and may be problematic for
`those children l1avi.ng difliculties in swallowing tablet for-
`mulations. Al)l)|iR.’\l..I. XIICE-‘ met the need for a dosage
`form. which can be administered once.
`in place of the two
`oral doses which are needed using the conventional drug
`delivery formulations of the prior art. See U.S. Pat. Nos.
`6,322,819 and 6.605.300; co-pending Reissue application
`Ser. Nos. ll.I"09l.0l0 and lli'O9l.0l l.
`
`[0019] There are currently tw'o medications (Z\l.)|)l‘iRA[.I..,
`XR® and STRATTERAT”) approved by the U.S. Food a11d
`Drug Administration (FDA) for the treatment of ADHD in
`adults. _/\l)l)l3RAI.[. XR-ll§-‘
`is a mixed amphetamine salts
`medication. STR/\'l'l‘liRA"'*"'
`is an atomoxetine {a norepi-
`nephrine reuptake inhibitor) medication. Long acting sti1nu—
`lant preparations, such as ADDERALL XR® and CON-
`CI.7.I{TA® (methylphenidate). are designed to provide a
`duration of effect up to 12 hours. Ilowever. clinicians have
`noted that a proportion of patients treated with these for-
`mulations require additional treatment with a short—acting
`stimulant to extend the daily therapeutic elfect. For patients
`taking lo11g-acting stimulant fonllttlatiolts who require dura-
`tion of clinical benefit beyond 10-12 hours, clinicians have
`augmented the moming long-acting forn1ulation_. typically at
`8-10 hours post-dose, with a dose of the sa111e immediate-
`release (IR) medication. Typically. the dose of the IR 111edi-
`cation is smaller than the long-acting dose. This augmenta-
`tion strategy is most relevant to the “longer day demands" of
`adult and adolescents. rather than school age, pediatric
`patients.
`
`[0020] Thus, a need exists for a once-daily. long-acting
`oral composition that provides elfective treatment of./\l)l ll).
`without supplementation,
`for patients with longer day
`demands (e.g., 14-16 awake hours).
`
`SUMMARY OI" 'l‘IIl--l lN\r’l'iN'I'I()N
`
`long-acting
`a
`invention provides
`[0021] The present
`amphetamine pharmaceutical composition, which includes
`
`an immediate release component. a delayed pulsed release
`component and a sustained release component. to meet the
`therapeutic needs for ADHD patients with longerday
`demands. The present invention fills the need for once-daily
`longer-day treatment of _/\|:)ll[) by providing an amphet-
`amine phannaceutical composition that is bioequivalent to
`an equal dosage of ADDERALL XRIEJ followed by an IR
`a1npl1eta111ine composition 8 hours later.
`
`[0022] The addition of a second delayed pulsed release
`formulation. having a lag time of about 8 hours, to AI)I)lIER-
`ALI. XR¢I§‘e cannot, as one might expect, meet the recognized
`need for a oncedaily long-acting amphetamine composition
`that meets a patient’s longer day requirements (i.e.. a once-
`daily amphetamine composition that
`is bioequivalent
`to
`A[)l)|.iRAl..I.. XR~'Rl- plus an immediate release amphetamine
`composition administered 8 hours later). A delayed pulsed
`formulation having a lag time of about 8 hours would be
`unsuitable because it would release the active agent in the
`distal gastrointestillal
`tract
`[the
`colon),
`resulting in
`decreased absorption of the active agent.
`
`it has been discovered that a sus-
`[0023] Unexpectedly,
`tained release formulation administered in combination with
`immediate release and delayed pulsed release components
`similar to those present in ADDERALL XRITKJ can mimic the
`bioavailahility of an equivalent total amphetamine dosage
`provided by Al)|)l*'.RA[.I.. XRCRJ followed by an immediate
`release amphetamine composition 8 hours later. However.
`the “usual” or “typical" construction for a sustained release
`formulation is not suitable. Typically. a sustained release
`formulation is constructed with a delayed release coating
`overlaying a sustained release coating. Such a usual or
`typical sustained release construction results in a Tmax that
`is too early after administration to a patient to result in a
`composition that meets the longerday requirements for the
`treatment of ADHD. For example. the dissolution profiles
`for a typical sustained release formulation (P130149-124)
`and a sustained release formulation of the present invention
`(PD014-9-120) are illustrated in FIG. 1. PDOI4-9-124 l1as a
`typical sustained release formulation construction. wherein
`the immediate release bead of [Example I (see lixamples 1
`and 2.
`infra)
`is coated with a sustained release coating
`(SURELEASE®). the sustained release coating is coated
`with a delayed release coating (EUDRAGITIEJ FS30 D). and
`the delayed release coating is coated with a protective layer
`(()PAl')RY®). I-‘D0149-I20 is an embodiment ofa sustained
`release formulation of the present invention. PDOI4-9-120
`has a construction wherein the immediate release bead of
`
`is coated with a delayed release coating
`lixample 1
`[l£[Jl)R.’\(}I'l\l§i'
`l"S30 D).
`the delayed release coating is
`coated with a protective coating {OPADRY®). and the
`protective coating is coated with a sustained release coating
`(SIJRl5I.I.i./\Sl"l’-E). As illustrated in 1'' 1G. ]. P130149-I20
`provides a later Tmax relative to a typically-oonstructed
`sustained release formulation. PD0l49—l24.
`
`[0024] According to the present invention. an atypical,
`counter-intuitive
`construction for
`a
`sustained release
`amphetamine formulation_. when administered in combina-
`tion with an immediate release formulation and a delayed
`pulsed release forrnulalion, is bioeqttivalent to Al)l)l ‘IR./\l ,I.
`Xli-{I0 followed by an immediate release amphetamine for-
`mulation administered 8 hours later. A sustained release
`
`formulation of the present invention comprises at least one
`amphetamine salt layered onto. or incorporated into. a core:
`a delayed release coating layered onto the a111pl1etamine
`core; a sustained release coating layered onto the delayed
`
`Amerigen Ex. 1038, p. 13
`Amerigen Ex. 1038, p. 13
`
`

`
`US 2007/0264323 A1
`
`Nov. 15, 2007
`
`release coating: and. optionally. a protective coating. See
`FIG. 2. In a preferred embodintent,
`the delayed release
`component is pH dependent.
`
`release component. and a sustained release component. In
`embodiments of the invention. delayed pulsed release andfor
`sustained release can be provided by a11 enteric coating.
`
`[0025] A sustained release pharmaceutical formulation of
`the present
`invention can comprise about 10% to about
`150% of the amphetamine dosage of the immediate release
`mixed amphetamine salt composition andfor an extended
`release mixed amphetamine salt composition. For example.
`the sustained release formulation can be administered. in the
`
`same or different dosage forms. with the IR and delayed
`pulsed release components of Al)l)l?.RAI.I. XRJIJ in an
`amphetamine dosage ratio of l:l:l (e.g.. 10 mg inunediate
`release amphetamine. 10 mg delayed pulsed release amphet-
`amine. l0 mg sustained release amphetamine). Thus. in this
`example, the sustained release composition comprises abottt
`33% of the total amphetamine dose. In another example. a
`patient with ADIII) and insomnia can be administered a
`reduced amount of the sustained release composition. e.g._.
`10 mg immediate release amphetamine. 10 mg delayed
`pulsed release amphetamine, and 5 mg sustained release
`amphetamine (the sustained release cot11positio11 comprises
`20% of the total amphetamine close). Thus. according to the
`present invention_. a clinician can adjust the sustained release
`formulation dosage to meet
`the needs of an individual
`patient suffering frot11 Al)l II).
`
`[0026] The pharmaceutical composition of the present
`invention. comprising an immediate release amphetamine
`conlponent. a delayed pulsed release amphetamine con1po-
`nent and a sustained release amphetamine component. deliv-
`ers. in a single dose. mixed amphetamine salts to a patient
`with a pharmacokinetic profile similar to a 2-dose treatment
`with a cttrrently available commercial extended release
`conlposition (i.e., ADI )li'.RJ\I .1. XRIW) plus an immediate
`release composition administered about eight hours after the
`ADDERALL XR*-ED. See. for example. FIG. 9. This sin1ilar—
`ity in bioeqtlivalence is surprising because it would be
`expected that some part of the drttg delivered by the delayed
`release components ofcompositions ofthe present invention
`(i.e.. the delayed pulsed release andfor the sustained release
`components) would be lost (i.e.. not absorbed) in the colon.
`’['l1eI-‘DA package insert and labeling forAI)l)lERAI .1. XRfR'
`(Shire US. Inc.) are hereby incorporated by reference in their
`entirety.
`
`[0027] Preferred a111pl1etamit1e salts are those i11 Al)l)|-£R-
`ALL XR<E>. i.e.. dextroamphetzunine sulfate. dextroamphet—
`amine saccharate. amphetamine aspartate monohydrate and
`amphetamine sulfate. Ilowever, the invention is not limited
`to these salts. Other amphetamines and amphetamine salts
`can be used in the pharmaceutical compositions of the
`present
`invention including.
`for exzunple. zunphetamine
`base, chemical and chiral derivatives thereof; other amphet-
`amine salts; and mixtures of the foregoing.
`
`[0028] The three components comprising the extended
`release amphetamine composition of the invention release
`doses of the active ingredients at varying, pre-determined
`times to provide for filll day treatment (i.e.. about 14 hours
`to about 16 hours) of conditions such as ADHD. A treatment
`for ADHD. which can be delivered in a single dosage is
`especially beneficial to adolescents and adults who typically
`have longer daily waking hours compared to children.
`
`[0029] The compositions of the present invention CI.‘Jl'I1-
`prise an immediate release component. a delayed pulsed
`
`In a particular embodiment. the immediate release
`[0030]
`component, delayed pulsed release component and sustained
`release component each contain equal alnotmts of active
`ingredient.
`
`In one embodiment, the immediate release, delayed
`[003 1]
`pulsed release and sustained release components of the
`composition are present on the same core.
`In another
`embodiment.
`the immediate release and delayed pulsed
`release components are present on different cores.
`In a
`litrtlter embodiment, the delayed pttlsed release a11d sus-
`tained release components are present on different cores. In
`a preferred embodiment.
`the immediate release, delayed
`pulsed release and sustained release components are present
`on different cores. See FIG. 3.
`
`In yet another embodiment. the amphetamine salt
`[0032]
`is coated onto a core. In a further embodiment, the amphet-
`amine salt is incorporated into a core.
`
`It is contemplated that compositions of the present
`[0033]
`invention can include a combination of the hereinabove
`referred to cores (one or more cores that
`include three
`components on the same core. one or more cores that include
`two of the three components on the core. and one or more
`cores that include one of the three components on the core).
`
`invention. a
`In an embodiment of the present
`[0034]
`phamiaceutical composition is provided in which there is
`immediate release of drttg, a delayed pulsed release of drug,
`and a sustained release of drug. and wherein the drug
`includes one or more amphetamine salts and mixtures
`thereof.
`In a preferred embodiment.
`the delayed pulsed
`release of drug begins about one hour after oral administra-
`tion ofthe composition to a patient in the fasted state and the
`sustained release of drug begins about four hours to about
`six hours after oral administration to a patient in the fasted
`state.
`
`[0035] Surprisingly. amphetamine salt pharmaceutical
`compositions of the present
`invention deliver about
`bioequivalent drug levels to a patient in either a fasted state
`or fed state. Thus. an amphetamine salt composition accord-
`ing to the present invention does not exhibit a food effect.
`This is surprising because it would be expected that some of
`the drug delivered by delayed release would be released
`earlier in the presence of food (especially fatty food) dtte to
`the increase in gastric pH that accompanies the ingestion of
`food.
`
`[0036] A pharmaceutical composition according to the
`present invention includes:
`
`(a) an immediate release bead comprising an
`[0037]
`amphetamine salt;
`
`(b) a first delayed release bead comprising an
`[0038]
`amphetamine salt: and
`
`(c) a second delayed release bead comprising an
`[0039]
`amphetamine salt;
`
`wherein the first delayed release bead provides pulsed
`release of the mixed amphetamine salt and the second
`delayed release bead provides sustained release of the
`mixed amphetamine salt.
`
`Amerigen Ex. 1038, p. 14
`Amerigen Ex. 1038, p. 14
`
`

`
`US 2007/0264323 A1
`
`Nov. 15, 2007
`
`the present
`[0040] A phannaceutical composition ol’
`invention provides a patient with at least about 14 hours to
`about 16 hours of etfective therapy for Attention Deficit
`Hyperactivity Disorder (ADI ID).
`
`[0053] The present invention encompasses methods for
`treating ADHD. which cotnprise administering the amphet-
`amine salt pharmaceutical composition of the present inven-
`tion to a patient suflerilig ‘front AI')Il|).
`
`In an embodiment of the invention. the d—amphet—
`[0041]
`amine (Emu alter administration of a 37.5 1ng amphetamine
`pharmaceutical composition to a human patient is about 50
`ngi"ml.
`
`In another embodiment. the d-amphetamine area
`[0042]
`under the curve from ti111e 0 to tl1e last measured time
`{AUC,,_lm) after administration of a 37.5 mg amphetamine
`pharmaceutical composition to a human patient is about
`1058 ng-hrfml.
`
`Further. according to an embodiment of the present
`[0043]
`invention. the d-amphetamine area under the curve from
`time 0 to time infinity (AlJ(_'n_im-) after administration of a
`37.5 mg an1pl1etamit1e pharmaceutical composition to a
`human patient is about 1085 ng-hrfml.
`
`[11 an embodiment. the present invention provides
`[0044]
`a phannaceutical composition, wherein the d—amphetan1ine
`max
`T
`is about 8.2 hours after administration of a 37.5 mg
`ampl1etan1i11e phartnaceutical composition to a human
`patient.
`
`the l—amphetamine
`In a particular embodiment.
`[0045]
`C
`alter administration of a 37.5 lng amphetamine phar-
`llliiéiiiietllical composition to a human patient
`is about
`l5
`ng.r‘ml.
`
`I11 a further embodiment, the l-amphetamine area
`[0046]
`under the curve from time 0 to the last measured time
`(AUC0_1m,,] after administration of a 37.5 mg amphetamine
`pharmaceutical composition to a human patient is about 354
`ng-hrfml.
`
`In another embodiment. the l—amphetan1ine area
`[0047]
`under l.l1e curve from time 0 to time infinity (AtJ(TO_inr) after
`administration of a 37.5 mg amphetamine pharmaceutical
`composition to a human patient is about 373 ng-hri"ml.
`
`1’urther. in an embodiment of the present invention.
`[0048]
`the l-an1pl1etat11it1e 'l‘max is about 8.4 hours after adn1inistra-
`tion ofa 37.5 mg amphetamine phannaceutical composition
`to a human patient.
`
`In a fiirther embodiment, a protective layer is
`[0049]
`provided over at
`least one enteric coating.
`In another
`embodiment. a protective layer is provided between the
`amphetamine salt and at least one enteric coating. A pro-
`tective layer can also be provided over the sustained release
`coating according to the present invention.
`
`In a particular embodiment. the amphetamine salt
`[0050]
`is selected from the group consisting ofdextroamphetamine
`sulfate. dextroamphetamine saecharate. amphetamine aspar-
`tate monohydrate. amphetamine sulfate. and mixtures
`thereol‘.
`
`In a more particular en1bodiment_. the amphetamine
`[0051]
`salt is a tnixlure of dextroamphetamine sulfate. dextroan1-
`phetamine saccharate. amphetamine aspartate monohydrate,
`and amphetamine sulfate.
`
`[11 an aspect of the present invention. the pharma-
`[0052]
`cetltical composition does t1ot exhibit a food ellect.
`
`[0054] The delayed pulsed release and sustained release
`components retard or delay the release of the phannaceuti-
`cally active ingredjentfs] for a speeilied time period (“lag
`time”) until a predetermined time. For example. a delayed
`pulsed release component having an enteric coating layer
`retards or delays the release of the pharmaceutical active or
`drug [or a lag time.
`then releases the drug rapidly and
`completely. i.e.. a pulsed release. In one embodiment of a
`delayed pulsed release. the entire dose is released within
`about 30-60 ntinutes following a lag time after administra-
`tion of the composition.
`[11 anol.l1er example, a sustained
`release component having an enteric release coating retards
`or delays the release of the pharmaceutical active or drug for
`a lag time and then the release of the drug is sustained (i.e..
`release of the entire dose takes greater than about 60
`minutes).
`
`[0055] The delay or lag time will take into consideration
`factors such as transit
`times.
`food ellects.
`inflammatory
`bowel disease, use of antacids or other metlicamcnts. wllich
`can alter the pH of the GI tract.
`
`[0056] According to the present invention. the lag titne for
`the delayed pulsed release component can be pH dependent
`or pH independent. In an embodiment of the invention. the
`lag time for the delayed pulsed release component is only
`time-dependem. i.e., [111 independent. In a preferred embodi-
`ment. the lag titne is pIl dependent.
`
`[0057] According to the present invention. a lag tin1e can
`be about 1 hour to about 14 hours. Multiple dose formula-
`tions can have more than one lag time. In a preferred
`embodiment. the delayed pulsed release component has a
`lag time of about 60 mintttes and the sustained release
`component has a lag time of about 4 to about 6 hours.
`
`ln one aspect. the present invention is directed to a
`[0058]
`composition that provides for enteric release of at least one
`phannaceutically active amphetamine salt. including at least
`one pharmaceutically active amphetamine salt that is coated
`with an enteric coating wherein (J) the enteric release
`coating l1as a defined minimum thickness andfor (2) there is
`a protective layer between the at least one pharmaceutically
`active amphetamine salt and the enteric release coating
`andfor (3) there is a protective layer over the enteric release
`coating.
`
`In attempting to provide for delayed pulsed release
`[0059]
`of an amphetamine salt. applicants found that use ol‘ an
`enteric release coating as generally practiced in the art did
`t1ot provide the desired release prolile. Using the typi