(12; United States Patent
`Couch et al.
`
`(10) Patent N0.:
`(45) Date of Patent:
`
`US 6,913,768 B2
`Jul. 5, 2005
`
`US006913768B2
`
`(54) SUSTAINED RELEASE DELIVERY OF
`AMPHETAMINE SALTS
`
`(75)
`
`Inventors: Richard A. Couch, Bryn Mawr, PA
`(US); Beth A. Burnside, Bethesda, MI)
`(US); Rong-Kun Chang, Rockville,
`MD (US)
`
`(73) Assignee: Shire Ialmmtories, lne., Ruckville,
`MD (US)
`
`( ‘ ) Notice:
`
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`USC. 154(b) by 115 days.
`
`(21) Appl. No.: 10,353,073
`
`(22)
`
`Filed:
`
`.Ian. 29, 2003
`
`(65)
`
`Prior Publication Data
`
`US 2'U04r'U'05U'[|(l2 A1 Mar. 25, 21.104
`
`(60)
`
`Related U.S. Application Data
`Provisional application No. 611141239‘), filed on Sep. 24,
`2002.
`
`(51)
`
`Int. CL?
`
`A6lK 9,116; A61K 9120;
`/\6lK 9,122; AGIK 9148; A6lK 9114
`4241490; 4241489; 4241494;
`(52) U.. . Cl.
`4241495; 4241484; 4241486; 424,464; 4241468;
`4241451; 4241457
`4241490, 489,
`(58) Field o1'Seareh
`4241494, 495, 484, 486, 464, 468, 451,
`457
`
`(56)
`
`References Cited
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`
`El’
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`US 6,034,101, 312000, Gupta el al. (withdrawn)
`Walia et al., Preliminary Evaluation of an Aqueous Wax,
`Emulsion for
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`I-’han'n. Dev.
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`Banker et al., Modern Pharmaceutics, eds., Marcel Dekker,
`lnc., New York, p. 350 (1996).
`
`(Continued)
`
`I'hurman K. Page
`Primm'y Exanrimsr
`/l.s'.sfsIam Exaim'm-rr—Humera N. Sheikh
`
`(74) /trrorrtey,
`Branigan, P.C.
`
`/tgem‘, or F.".m:—Mi1len, White, Zelano,
`
`(57)
`
`ABSTRACT
`
`A phannaceulical com position comprises a once-a-day sus-
`tained release formulation of at least one amphetamine salt
`which provides mean plasma concentration profile aspects in
`human ADIID patients which are substantially the same as
`that provided by /\DI)l_".R/\l,.L XR® type pulsalile formu-
`lations.
`
`37 Claims, 13 Drawing Sheets
`
`—°—A|3I|JERAl_LXR' 2:: mg ml
`—-—ADL:Esm.L* 1n mg mu
`
`LEVOAloFHE|'NIINE
`
`—“—AlJlJERALLJ(R' EU mg ml
`——
`--ADDERALL‘ 1o mu met
`
`Min
`
`NID
`
`
`
`
`
`E-N1|PLASI|Al‘0E'lTR.nl'EDN5G'|Iflfl'mN|lJl.B'Oo'll-‘l'ETNIIt'ITBIIIJ
`
`U‘!Eh- DEKTROJIMH-lETAMNE
`
`a
`
`4 a121s2n242a323aqn444'a
`Tliflflflfi
`
`Amerigen Ex. 1023, p. 1
`Amerigen Ex. 1023, p.
`1
`
`

`
`US 6,913,768 B2
`Page 2
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`WO 99151209
`WO (10123055
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`WO 00135450
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`
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`412000
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`011 IER PUl3l.IC/\'1'I()NS
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`Gazzaniga et al., “Time—Dcpendent oral Delivery Systems
`for Colon Targeting,” S.'l'.P. Pharma Sciences 5(l):83—88
`(1995).
`Walia et al., "Preliminary Evaluation ol‘/\n Aqueous Wax
`Emulsion for Controlled—Relcase Coating,” Pharmaceutical
`Development and Technology, 3(1):103—113 (1998).
`Gazzaniga et al., “Oral Chronotopic Drug Delivery Systems:
`Achievement of Time A1‘td10r Site Specificity,” Eur. J.
`Pharm. Biopharm, 40(4):246—250 (1994).
`Pozzi et al., “The Time Clock System: A New Oral Dosage
`form for Fast and Complete release 0d Drug After a Prede-
`termined Lag Time,” Journal of Controlled Release,
`31:99—1U8 (1994).
`Wilding et al., "Gastrointestinal Transit and Systemic
`Absorption of Captopril From A Pulsec|—Release Formula-
`tion,” Pharmaceutical Research, 9 (5):654—657(l992).
`
`Xin Xu et al., “Programmable Drug Delivery [From An
`Erodible Association Polymer System," Pharmaceutical
`Research, 10(8):1144—1152 (1993).
`Come et al., “Press—C0ated tablets for Tin:|e—Programmec|
`Release of Drugs,” Biomaterials, 14(13):1017—1023 (1993).
`R. Gurny et al., Pulsatile Drug Delivery Current Applica-
`tions and Future Trends, pp. 112-134, (1993).
`Adderall XR, Package Insert, ()ct. 2001.
`Dexedrine, Spansule Capsules, Package Insert, Physicians’
`Desk Reference 1997.
`
`Adderatl, Package Insert, May 1996, Physicians’ Desk Ref-
`erence 1997.
`
`K. S. Patrick et al., “Phanrtacology of Methylphenidate,
`Amphetamine Enanliumers and Pemoline in Attention-
`Deficit
`.
`.
`. ” Human Psychopharmaeology, vol. 12, pp.
`527—546, 1.997.
`Lisa H. Brauer et al., “Acute Tolerance to Subjective but Not
`Cardiovascular Effects of d—/-\rnphetan1ine in Normal,
`Healthy Men," Journal of Clinical Psychopharmacology,
`vol. 16, No. 1, pp. 72-76, 1996.
`William P. Melega et al., “Pharmacokinetic and Pharmaco-
`dynamic Analysis of the Actions of D—Ampl:tetamine and
`D—Methamphetamine on the Dopamine Terminal,” The
`Joumal of Phannaoology and Experimental Therapeutics,
`vol., 274, No. 1, pp, 90—96, 1995.
`Peter Clausing et al., “Amphetamine Levels in Brain
`Microclialysate, Caudate1Putamen, Substantia Nigra and
`Plasma After Dosage That Produces Either Behavioral .
`.
`. ”
`The Journal of Pharmacology and Experimental Therapeu-
`tics, vol. 274, No. 2, pp. 6144521, 1995.
`S.I3. Sparher et al., “/Xmphetarrline Cumulation and Toler-
`ance Development: Concurrent and Opposing Phenomena,”
`Pharmacology Biochemistry & Behavior, vol. 20, pp,
`415424, 1984.
`
`Burt Angrist et al., “Early Pharrnacokinetics and Clinical
`E1Tects of Oral 1)~—Amphetamine in Normal Subjects,” Biol
`Psychiatry, vol. 22, pp. 1357—1368, 1987..
`Gerald L. Brown et al., Plasma Levels of d—Amphctamine in
`Hyperactive Children, PSYCHOPHARMACOLOGY, vol.
`62, pp. 133-140, 1979.
`Suk Han Wan et al., “Kinetics, Salivary Excretion of
`Amphetaniine Isorrters, and Effect of Urinary plI,” Clin.
`Pharmacol. Thcr., pp. 585~590, May 1978.
`Gerald L. Brown et al., “Plasma d—A1:nphetamine Absorp-
`tion and Elimination in Hyperactive Children," Psychophar—
`macology Bulletin, vol. 14, No. 3, pp. 33-35, 1978.
`Excerpts from Feb. 2, 2005 Deposition of Beth A. Bumside
`in S1111!’ 1'.abora1oric.s' hic 1’ Burr Labora1r)r£es,
`Ir1c.,
`03—CV—1219 and 03—CV—6632 (PKC), SDNY, pp. 1, 2 and
`143-150.
`
`Excerpts from Feb. 3, 2005 Deposition of Beth A Bu rnsicle
`in S1111!’ 1'.abom.t‘r)rr'£s
`Inc 1’
`fmpax 1'.r1bora!()rr'e.s' Inc,
`03—(_'V—1l64 (GMS), D.l)elaware, pp. 1—5 and 190-197.
`
`‘ cited by examiner
`
`Amerigen Ex. 1023, p. 2
`Amerigen Ex. 1023, p. 2
`
`

`
`US. Patent
`
`Jul. 5, 2005
`
`Sheet 1 of 13
`
`US 6,913,768 B2
`
`Figure 1
`
`LA.) 3
`
`
`
`l'u'IE.5-NPLASMACCNCENTRATIONSOFDEXTROANDLEVO.«flMP|-ETJ1MNE[ng.I‘mL]
`
`
`
`
`
`DEXTROJlMF’HETAM|NE
`
`—°—AD DERALL KR’ 2D mg qcl
`
`—-—ADDER.aLL* 10 mg mu
`
`LEVOAMPHEFAMINE
`
`--°-—-ADDERALL XR‘ 20 mg qd
`
`---+--A|ZIDERALL"1[J mg bid
`
`l'\.J LT1
`
`h.'l I3
`
`_.\. E
`
`mE
`
`D
`
`4
`
`8
`
`‘l21B2D2428323E4D444B
`
`TIli.IE[HOUREj
`
`Amerigen Ex. 1023, p. 3
`Amerigen Ex. 1023, p. 3
`
`

`
`US. Patent
`
`Jul. 5,2005
`
`Sheet 2 M13
`
`US 6,913,768 B2
`
`Figure 2. Mean CGIS-P total scores for ITT population.
`
`0 *Baseline (previous med)
`
`Week 1 (Adderall xR"“)
`
`Week 3 (Adderall xR"""‘)
`
`Week 7 (Adderall xR“")
`
`
`
`8-h CGIS-P {N=2911)
`
`12-h CGIS-P (N=2909)
`
`'P<0.0001 vs baseline. Note: 3 lower score indicates better response to treatment
`
`Amerigen Ex. 1023, p. 4
`Amerigen Ex. 1023, p. 4
`
`

`
`US. Patent
`
`Jul. 5, 2005
`
`Sheet 3 of 13
`
`US 6,913,768 B2
`
`Figure 3. CG! Improvement scores at week 7.
`
`Percent
`
`Improved - very much improved and much improved; No change xminimaily
`impmved and no change; Worse s= minimally warse and very much worse.
`
`Amerigen Ex. 1023, p. 5
`Amerigen Ex. 1023, p. 5
`
`

`
`US. Patent
`
`Jul. 5, 2005
`
`Sheet 4 of 13
`
`US 6,913,768 B2
`
`Figure 4. PedsQL total score.
`
`as
`
`In Baseiéne (previous mad)
`Week ? (Addams! XR**")
`
`80
`
`Percent
`
`?S
`
`70
`
`55 60
`
`.o<o.m1 Week ‘.7 vs basenne, one sample t test.
`
`Amerigen Ex. 1023, p. 6
`Amerigen Ex. 1023, p. 6
`
`

`
`U.S. Patent
`
`Jul. 5, 2005
`
`Sheet 5 of 13
`
`US 6,913,768 B2
`
`Figure 5. Parent Satisfaction Survey:
`"Overall, I am satisfied with my child taking this medication."
`
`Stron gly
`
`ag reei
`
`ag ree
`
`disagree,
`
`_
`
`S'[rang|y1|
`
`disagree‘
`
`52%
`
`6.0%
`
`24%
`
`4.6%
`
`1
`
`lo.”
`
`1-5%
`
`182°/o
`
`497"
`5299/
`
`37.5%
`
`172%
`
`‘
`I
`
`r- Baseli-I_':.=_. (previous mad)
`
`Week 7 (Adderall
`
`||
`
`fimu
`
`I
`
`\
`
`Amerigen Ex. 1023, p. 7
`Amerigen Ex. 1023, p. 7
`
`

`
`US. Patent
`
`Jul. 5, 2005
`
`Sheet 6 of 13
`
`US 6,913,768 B2
`
`Figure 6. Physician Preference Survey:
`"Overall, which ofthe two medications do you prefer?"
`
`S New medicafion {Adderafl KR‘)
`Previous medication
`W Equai prefaeemoe
`
`Percent 8 -
`
`.§!_o_‘_'aj'
`_
`_.
`:.:_.._...
`
`MPH ‘TID+
`U Adderauqb Adderail 8113+ MPH mmqn
`M2875
`nx1392
`n=16B
`nu-:3‘?
`
`Conceta
`n==350
`
`Previous Medications
`
`MPH: Methxflphen iclate.
`
`Amerigen Ex. 1023, p. 8
`Amerigen Ex. 1023, p. 8
`
`

`
`£0
`
`ii‘:
`
`'6
`
`
`
`DEXTROANPI-IETNoIIEPIAHMCONDENTRA"l1ON(l'ufn1)E.
`
`U.S. Patent
`
`Jul. 5, 2005
`
`Sheet 7 of 13
`
`US 6,913,768 B2
`
`50
`
`SUB-J EST 6
`
`—o—
`
`—i--
`
`FED
`
`FAST
`
`19
`
`
`
`a1216:n242n:2:s-wuuifi
`
`TIMERIJURS)
`
`FIG.
`
`7
`
`Amerigen Ex. 1023, p. 9
`Amerigen Ex. 1023, p. 9
`
`

`
`U.S. Patent
`
`Jul. 5, 2005
`
`Sheet 3 of 13
`
`US 6,913,768 B2
`
`SUBJECT 11
`
`
`
` mflEPLASDMCDNGENTRA'|10N(m!ml.) I3
`
`E’
`
`nqltaillzuz-ozlaaasinu-45$:
`
`'|'INE{H9LF3,
`
`‘FIG. S
`
`Amerigen Ex. 1023, p. 10
`Amerigen Ex. 1023, p. 10
`
`

`
`US. Patent
`
`Jul. 5, 2005
`
`Sheet 9 of 13
`
`US 6,913,768 B2
`
`1&0
`
`SUBJECT 20
`
` E
`
`EunevommemamemamBONcEN1flAT1DN(i1g1mll1.‘.'.1
`
`°n¢I1:1e:m2423:z:a-caucus:
`
`1'1L£(HGL$}
`
`F1G.9
`
`Amerigen Ex. 1023, p. 11
`Amerigen Ex. 1023, p. 11
`
`

`
`U.S. Patent
`
`Jul. 5, 2005
`
`Sheet 10 of 13
`
`US 6,913,768 B2
`
`
`
`
`
`usvonmnmwmerusmooncemmmnu(narmu
`
`15.
`
`Fa
`
`ii]
`
`SUBJECT 13
`
`-0-THTB FED (2lJI!'Igl..OT5flX!7BA}
`
`--—‘I'R'rI= I-'As'r (znmg.:.a1'nano7aA}
`
`a4a1z1smu:a::z:a-u:u-us:
`
`nmsmouas)
`
`FIG, $0
`
`Amerigen Ex. 1023, p. 12
`Amerigen Ex. 1023, p. 12
`
`

`
`U.S. Patent
`
`Jul. 5,2005
`
`Sheet 11 of 13
`
`US 6,913,768 B2
`
`SUEJ ECT 8
`
`
`
`namemouevommermmemamaCONCENTRATIONSmml!
`
`c
`
`2
`
`+
`
`5
`
`l1u1z141|i 1339323‘
`
`TIIAEIHOURS)
`
`315.
`
`.1].
`
`Amerigen Ex. 1023, p. 13
`Amerigen Ex. 1023, p. 13
`
`

`
`U.S. Patent
`
`Jul. 5, 2005
`
`Sheet 12 of 13
`
`US 6,913,768 B2
`
`SIEJECT ‘I1
`
`D2-6801lI‘l2'I41§‘I\l2lI21:-G
`
`TlME{HDlJl-'15)
`
`FIG. 12
`
`Amerigen Ex. 1023, p. 14
`Amerigen Ex. 1023, p. 14
`
`

`
`US. Patent
`
`Jul. 5,2005
`
`Sheet 13 of 13
`
`US 6,913,768 B2
`
`Figure 13. Visit schedule and monitoring.
`
` weeks 1 and 3: Vitals, #65.
`
`{ZGIS-P, CGH.
`
`
`
`wee!-< I
`
` Optional 8-week Safely Extension Vitals, AEs assessed at weeks 11 and 15. ECGa'iweek 15.
`
`Week -2
`
`Week. {J
`
`Treatment: Adderali KR" was Initiated the day after the baseline visit according to the dose conversion paradigm outlined in Table
`1. The dose could be increased as clinically warranted based on [he (3.61 and CGIS-P: decrease in dose was allowed based on
`saieiyrtolerahilily.
`
`Amerigen Ex. 1023, p. 15
`Amerigen Ex. 1023, p. 15
`
`

`
`US 6,913,768 B2
`
`1
`SUSTAINED RELEASE DELIVERY OF
`AMPHETAMINE SALTS
`
`This application claims the benefit of U.S. application
`Ser. No. 6{l.r’412,799 filed on Sep. 24, ZUIE.
`Described herein are compositions for providing an
`orally administrable sustained release (SR) form of one or
`more amphetamines andfor amphetamine salts. Also
`described are methods for administering the sustained
`release form of one or more amphetamine salts to a patient
`in need thereof. Preferably, the methods are carried out for
`treatment of patients having /\DIII) (attention deficit hyper-
`activity disorder), but other disease states can aLso be
`treated. The sustained—release forms of one or more amphet-
`amines andfor amphetamine salts according to the invention
`are preferably formulated to provide an in vivo plasma
`concentration profile (i.e., measured by total concentration
`of the amphetamines andfor amphetamine salts (often with
`separate tracking of d—and l—isomers) in the patients’ blood
`plasma) which is substantially equivalent to the in vivo
`plasma concentration profile achieved by pulsatile release
`formulations of the same amphetamines andfor amphet-
`amine salts when administered to a patient, e.g.,
`those
`achieved by /\I)I)l£RAI.I. XR®, Shire US Inc., whose FD/1
`package insert and labeling are entirely incorporated by
`reference herein. Further preferably, this sustained release
`profile (the plasma concentration profile being distinguished
`from the release profile) typically exhibits first order or
`biphasic or sigmoidal characteristics.
`Particularly preferably, the SR fonTIulations according to
`the invention exhibit a single (lose in vivo plasma concen-
`tration profile substantially the same as that shown in FIG.
`1. The latter shows the substantially smooth mean (over
`about 20 patients) plasma concentration curves achieved for
`both the dextroarnphetan'Iine and levoamphetarnine salts in
`ADDERALL XR®. (The overall mean plasma concentra-
`tion curve for total amphetamine level is simply the sum of
`the two curves shown in FIG. 1). Because the formulations
`of this invention achieve substantially the san1e mean
`plasma concentration curves, they can be termed fast sus-
`tained release formulations, with regard to the initial rising
`slopes involved.
`By substantially the same “prof1le" herein is meant that
`two curves have substantially the same AUC (area under the
`curve) and (l,M_Y, e.g., these parameters for each curve are
`220% of each other, or even closer, e.g. 210%, 15%, 12%,
`etc., which parameters are entirely conventionally defined
`and determined. See, e.g., Fundwrtenfais of Ci"r'm'cai" I’."mr-
`macokirtetics. .I. (J. Wagner, Drug Intelligence Publications,
`Inc., Hamilton, III., 1975; Guidance for Ir.rdtt.s'tr3; B£oarvaii—
`ability and Bis-equivalence Studies for Orafly/tdrttirti.stered
`Drug Produc.-‘s—GeneraI Considerations, FDA, CDE-R. Octo-
`ber 2[l'[)D. For FIG. 1, AUC (time zero to infinity) is 556.6 ng
`hr,/mI.. and (TM,_, is 28.0 ngJ'ml_ for d-amphetamine and 205.1
`ng hrfmL and 8.7 ngfmL, respectively, for l—amphetamine.
`Of course, plasma curves achieved by this invention can
`follow even more closely the course of a target curve such
`as that shown in FIG. I, e.g., substantially (e.g, 120%)
`matching initial rising slope, post-peak curve shapes, ’l',,m_,.
`values,
`(7.1 hr for d—amphetamine and 7.4 hr
`for
`1—amphetamine for FIG. 1), etc. Whereas FIG. 1 shows data
`for 20 mg tablets (i.e., two 10 mg pulsatile doses),
`the
`plasma curves (and e.g., AUC and (.',,m,) corresponding to
`other daily doses such as 10, 30, 40, 50, 60, 7'0, 80, 90 mg
`will be essentially linearly proportional to those shown in
`FIG. 1, corresponding to the involved dosage.
`In another independent embodiment, the fast SR formu-
`lations of this invention, for the AI)Dl.3R/\I.I. ){® 20 mg
`
`Ln
`
`"I0
`
`20
`
`|-J J1
`_
`
`30
`
`35
`
`40
`
`umum
`
`60
`
`2
`
`dose of FIG. 1, exhibit plasma concentration curves having
`initial (e.g., from 2 hours after administration to 4 hours after
`administration) slopes of about 3.7 to about 11.4 ngf(n:tL hr)
`for dextroa mphetamines and about 1.4 to about 3 ngf(mL hr)
`for levoamphetamines, preferably, about 4 to about 8 nga’(mI.
`hr) and about 1.5 to about 2.2 ng;’(mI. hr), respectively. The
`precise slope for a given individual will vary according to
`usual factors, including whether the patient has eaten or not.
`For other doses, e.g., those mentioned above, the slopes vary
`directly (linearly) proportionally to dose.
`The formulations of ‘W0 00,=’23(l55 (whose entire disclo-
`sure is incorporated by reference herein), e.g.,
`that
`for
`ADDERALL X®, achieve a two—folc|
`release of active
`amphetamine salts, one an immediate release dosage form
`and the other a delayed release dosage form. Typically, the
`lag time between the immediate release (release upon
`administration) and delayed release forms is 2-6 hours,
`preferably about 3 to about 5 hours, more preferably about
`3 to about 4 hours, and typically about four hours. In one
`embodiment, the fast sustained release formulations of this
`invention are used to provide a mean plasma concentration
`profile substantially the same as that of Example 5
`(combination of Examples 1 and 2) of WC) 00,=’23U55,
`despite the latter’s disclosure that conventional sustained
`release fonnulation technology was not suitable for amphet-
`amines. (Note that the plasma profile of Example 5 shown
`in FIG. 7 of WO 00123055 is not a mean profile, as is that
`of FIG. 1 of this application, but rather is one from a single
`individual.)
`The SR formulations of this invention will be effective to
`treat, e.g., ADHD, in the same manner as ADDERALD®
`XR. For example, they will be eifective to treat ADHD in the
`unexpectedly good manner established in the data reported
`in Example 10. They will also be elfective to treat /\I)III)
`with low incidence of side effects,
`including substance
`abuse, addiction, tolerance, tachyphylaxis, etc.
`Preferred salts are those in the commercial product
`Al)DI:‘.R/\I.I. XR®, i.e., dextroamphetamine sulfate, dex-
`troamphetamine saccharate, amphetamine aspartate mono-
`hydrate and amphetamine sulfate. However, the invention is
`not
`limited to these specific amphetamine salts. Other
`amphetamines and amphetamine salLs and mixtures thereof
`can be used in a sustained-release delivery system to achieve
`the plasma concentration profiles of the invention. For
`example, amphetamine base, chemical and chiral derivatives
`thereof and other amphetamine salts can be used.
`Preferred in vivo plasma concentration profiles of the
`amphetamine salts can be accomplished by providing a solid
`dosage form of the amphetamine salts which is capable of
`providing a sustained release of the one or more amphet-
`amine salts over a time period of, for example, from 8-12
`hours, or longer, preferably, 10-12 hours. For example, the
`amphetamine salts can be provided in a core which is ooated
`with a coating which allows the release of the amphetamine
`salts there through over time, such as a pharmaceutically
`acceptable water-insoluble film fonner alone or with a
`dissolution regulating agent. In addition, by combining the
`immediate-release beads with the sustained-release beads, a
`biphasic release profile can be achieved. Other methods for
`providing sustained—release of a drug, including those fur-
`ther discussed below, are known and can be used to provide
`a sustained-release delivery which results in the above-
`discussed in vivo plasma concentration profile.
`Suitable sustained—release systems, include SR coatings,
`e.g., on beads, SR matrices (i.e., no coatings needed), SR
`osmotic systems, etc. whereby amphetamine salts achieve a
`first order, biphasic, sigmoidal etc. release profile to achieve
`
`Amerigen Ex. 1023, p. 16
`Amerigen Ex. 1023, p. 16
`
`

`
`3
`
`4
`
`US 6,913,768 B2
`
`the plasma profile equivalent of pulsatile release systems of
`the same drugs as discussed above. Matching to the desired
`target plasma concentration profile using SR is conven-
`tional.
`Sustained-release beads can be prepared by coating con-
`ventional drug-containing cores with a water-insoluble
`polymer, or a combination of water—insoluble polymers, or a
`combination of water—insoluble and water—soluble polymers.
`This is usually not a combination of layers, but a combina-
`tion of polymers in a single coating. The resultant beads (or
`tiny tablets) can then be placed in a capsule. ()ther than
`beads in a capsule shell, tablets in a capsule shell (e.g., one
`irnmediate—release tablet and one delayed, sustained release
`tablet in a capsule shell, to provide an overall sustained
`release} also can be used to attain the desired plasma profile.
`Various polymeric materials can be used to achieve the
`type of pattern of release needed to result
`in the desired
`plasma concentration profile, for example, so as to increase
`the fast rate of delivery over the first 4 to 8 hours of delivery.
`For example, a multiple dosage form {e.g., as discussed
`below) of the present invention can deliver rapid and com-
`plete dosages of pharmaceuticatly active amphetamine salts
`to achieve the desired plasma profile of the drug in a
`recipient over the course of about 8-12 hours with a single
`oral administration. In so doing, the levels of drug in blood
`plasma of the pharmaceutically active amphetamine salts
`will reach a peak fairly rapidly, for example, over the course
`of about 8 hours or less as desired, which then slowly
`decreases over the course of, for example, the next 12 or
`more hours. The desired plasma concentration profile can
`thus be achieved using a fast sustained—release once daily
`dosage of the amphetamine salts.
`Examples of useful bead constructions for sustained-
`release include the following:
`Sugar core, coated with amphetamine, coated with
`polymer,
`Sugar core, coated with amphetamine, coated with mix of
`amphetamine and polymer, coated with polymer,
`Sugar core, coated with amphetamine, coated with rela-
`tively high concentration mix of amphetamine and
`polymer, Coated with weaker concentration mix of
`amphetamine and polymer, coated with polymer,
`Bead containing amphetamine, coated with polymer,
`Bead containing amphetamine, coated with mix of
`amphetamine and polymer, coated with polymer,
`Bead containing amphetamine, coated with relatively
`high concentration mix of amphetamine and polymer,
`coated with weaker concentration mix of amphetamine
`and polymer, coated with polymer, and
`Tablet or capsule containing multiple types of beads as
`described above having differing timing of release of
`amphetamine andfor dilferent
`rates of release of
`amphetamine.
`As mentioned, SR matrix beads can also be used, ie, not
`having any needed layers to achieve sustained release. The
`components used in such matrices are chosen from conven-
`tional SR polymers.
`In another construct,
`there can be
`included in the formulation, along with the layered beads or
`matrix beads, immediate release formulations which provide
`one way to achieve a desired initial
`fast release. Such
`immediate release formulations are fully conventional. See
`e.g., W0 UW23055.
`Details of using the foregoing constructs and others to
`achieve a desired plasma profile as discussed above are fully
`conventional and can be determined by those of skill in the
`art with at most a few routine parametric experiments, and
`
`Lu
`
`'10
`
`20
`
`I-J 'J|
`
`30
`
`35
`
`40
`
`umum
`
`60
`
`conventional adjustments. e.g., involving identities of poly-
`mers and mixtures thereof, relative amounts of components,
`coating thicknesses, bead diameters, number of layers and
`compositions thereof, etc. Thus, for example, for a given
`construct (e.g., one of those in the examples herein), disso-
`lution profiles can be determined and in vivo plasma profiles
`measured. The latter can then conventionally be compared to
`the target plasma profile {e.g., that of AI)I)ERAl.[. XR®)
`and differences compensated by fully conventional formu-
`lation and dissolution profile adjustments such as but not
`limited to those mentioned.
`Suitable materials which can be used in the SR formula-
`tions of this invention are well known and include but are
`
`not limited to polyvinyl acetate, cellulose acetate, cellulose
`acetate butyrate, cellulose acetate propionate, ethyl
`cellulose, fatty acids and their esters, alkyl alcohols, waxes,
`zein (prolamine from corn), and aqueous polymeric disper-
`sions such as IE.udragit® RS and RI .30I), E.udragit® NE30D,
`/\quacoat®, Surelease®, Kollicoat® SI-130D, and cellulose
`acetate latex.
`
`G
`
`Methods of manufacturing cores include:
`a. Extrusion—Spheronization——the drug(s} and other addi-
`tives are granulated with the addition of a binder
`solution. The wet mass is passed through an extruder
`equipped with a certain size screen. The extrudates are
`spheronized ir1 a maru merizer. The resulting pellets are
`dried and sieved for further applications.
`b. Iligh-Shear Granulation—I)rug(s} and other additives
`are dry-mixed and then the mixture is wetted by
`addition of a binder solution in a high shear—granulatorf
`mixer. The granules are kneaded after wetting by the
`combined action of mixing and milling. The resulting
`granules or pellets are dried and sieved for further
`applications.
`. Solution or Suspension Layering—A drug(s) solution
`or dispersion with or without a binder is sprayed onto
`starting seeds with a certain particle size in a fluidized
`bed processor or other suitable equipment. The drug
`thus is coated on the surface of the starting seeds. The
`drug—loaded pellets are dried for further applications.
`For purposes of the present invention, the core particles,
`preferably, have a diameter in the range of about 500-1500
`microns (micrometers); more preferably 100-800 microns.
`These particles can then be coated in a lluidized bed appa-
`ratus with an alternating sequence of selected coating layers.
`The composition, preferably in the bead forms described
`above, can be incorporated into hard gelatin capsules, either
`with additional excipients, or alone. Typical excipienls to be
`added to a capsule formulation include, but are not limited
`to:
`fillers such as microcrystalline cellulose, soy
`polysaccharides, calcium phosphate dihydrate, calcium
`sulfate, lactose, sucrose, sorbitol, or any other inert filler. In
`addition,
`there can be flow aids such as fumed silicon
`dioxide, silica gel, magnesium stearate, calcium stearate or
`any other material imparting flow to powders. A lubricant
`can further be added if necessary by using, for example,
`polyethylene glycol, leucine, glyceryl behenate, magnesium
`stearate or calcium stearate.
`The composition may also be incorporated into a tablet, in
`particular by incorporation into a tablet matrix, which rap-
`idly disperses the particles after ingestion.
`In order to
`incorporate these particles into such a tablet, a fillerfbinder
`must be added to a tablet that can accept the particles, but
`will not allow their destruction during the tableting process.
`Materials that are suitable for this purpose include, but are
`not limited to, microcrystalline cellulose {/\VI(_‘liI.®}. soy
`polysaccharide (l3MCOS()Y®), pre-gelatiniaoed starches
`
`Amerigen Ex. 1023, p. 17
`Amerigen Ex. 1023, p. 17
`
`

`
`US 6,913,768 B2
`
`5
`(S't‘AR(?Il® 15110, N/\'I‘l()N/\t.® 1551), and polyethylene
`glycols (CARBOWAX®). The materials are preferably
`present hi the range of 5—75% (wfw), with a more preferred
`range of 25—50% (wfw).
`In addition, disintegranLs are optionally added in order to
`disperse the beads once the tablet
`is ingested. Suitable
`disintegrants include, but are not limited to: cross—tinked
`sodium carboxymethyl cellulose (AC—Dl—SOL®), sodium
`starch glycolate (l_iXl’I..()'l'/\B®, I-’RlMOJl_il.®}, and cross-
`linked polyvinylpolypyrrolidine (Plasone-XL). These mate-
`rials are prelierably present in the rate of 53-15% (wlw), with
`a more preferred range of 5—10% (wfw).
`Lubricants are also optionally added to assure proper
`tableting, and these can include, but are not
`limited to:
`magnesium stearate, calcium stearate, stearic acid, polyeth-
`ylene glycol, leucine, glyceryl behanate, and hydrogenated
`vegetable oil. These lubricants are preferably present
`in
`amounts from 01-10% {wfw), with a more preferred range
`ot‘ {l.3—3.0% (wfw).
`Tablets are formed, for example, as follows. The particles
`are introduce into a blender along with AVlCEL®, disinte-
`grants and lubricant, mixed for a set number of minutes to
`provide a homogeneous blend which is then put
`in the
`hopper of a tablet press with which tablets are compressed.
`The compression force used is adequate to form a tablet;
`however, not enough to fracture the beads or coatings.
`Various enteric materials, e.g., cellulose acetate phthalate,
`hydroxypropyl methylcellulose phthalate, polyvinyl acetate
`phthalate, and the EUDR/\GI'l‘® acrylic polymers, can be
`used as gastroresistant, enterosoluble coatings for drug
`release in the intestine when desired. The enteric materials,
`which are soluble at higher pH values, are frequently used
`for colon-specific delivery systems and are entirely conven-
`tionally em ployable in the SR systems of this invention. The
`enteric polymers used in this invention can also be modified
`conventionally by mixing with other known coating prod-
`ucts that are not pH sensitive. Examples of such coating
`products include the neutral methacrylic acid esters with a
`small portion ol‘
`trimethylan1l'I1onioethyl methacrylate
`chloride, sold currently under
`the trade names
`EUDRAGIT® and EUDRAGIT® RL; a neutral ester dis-
`persion without any functional groups, sold under the trade
`names l_7.UI)R/-\(}IT® NI330l) and I-_iUDRAGIT® NE3tl; an
`other pll independent coating products.
`A conventional protective coating layer may also be
`applied immediately outside the core, either
`a drug-
`containing matrix core or a drug-layered core, by conven-
`tional coating techniques such as pan coating or lluid bed
`coating using solutions of polymers in water or suitable
`organic solvents or by using aqueous polymer dispersions.
`Suitable materials for the protective layer include cellulose
`derivatives such as hydroxyethyl cellulose, hydroxypropyl
`cellulose, hydroxypropyl methylcellulose,
`polyvinylpyrrolidone, polyvinylpyrrolidonefvinyl acetate
`copolymer, ethyl cellulose aqueous dispersions
`(I\()U/\C()/\T®, SURl.".lJ:l/-\Sl_i.®), L*lUl)RAGI'l'® RI.30l),
`()PADRY® and the like. The suggested coating levels are
`from 1 to 6%, preferably 2—4% {w,tw).
`An overcoating layer can further optionally be applied to
`the composition of the present
`invention. OPADRY®,
`OP/\I)RYIl® {(.'olorcon) and corresponding color and col-
`orless grades lrom Colorcon can be used to protect the
`pellets fron:t being tacky and provide colors to the product.
`The suggested levels of protective or color coating are from
`1 to 6%, preferably 2—3% (wfw).
`Many ingredients can be incorporated into the overcoat-
`ing formula, for example to provide a quicker (immediate)
`
`Ln
`
`ll]
`
`20
`
`6
`release, such as plasticizers: acelyltriethyl citrate, triethyl
`citrate, acetyltributyl citrate, dibutylsebacate, triacetin, poly-
`ethylene glycols, propylene glycol and the others;
`lubri-
`cants:
`talc, colloidal silica dioxide, magnesium stearate,
`calcium stearate, titanium dioxide, magnesium silicate, and
`the like.
`Optionally modifying components of a protective layer
`which can be use over the enteric or other coatings include
`a water penetration barrier layer (semi-permeable polymer)
`which can be successively coated after the enteric or other
`coating to reduce the water penetration rate through the
`enteric coating layer and thus increase the lag time of the
`drug release. Sustained—release coatings commonly known
`to one skilled in the art can be used for this purpose by
`conventional coating techniques such as pan coating or lluid
`bed coating using solutions of polymers in water or suitable
`organic solvents or by using aqueous polymer dispersions.
`For example, the following materials can be used, but not
`limited to: cellulose acetate, cellulose acetate butyrate, cel-
`lulose acetate propionate, ethyl cellulose, fatty acids and
`their esters, waxes, zein, and aqueous polymer dispersions
`such as EUDRAGIT® RS and RL 30D, EUDRAGITGI) NE
`3'[lD,
`/\(JUACOAT®, SURI3I.I_C/\Sl5.®, cellulose acetate
`latex. The combination of the above polymers and hydro-
`|-J Jr
`_ philic polymers such as hydroxyethyl cellulose, hydroxypro-
`pyl cellulose ('KLUCEL®, Hercules Corp), hydroxypropyl
`methylcellulose (METHOCED®, Dow Chemical Corp.),
`polyvinylpyrrolidone can also be used.
`Principles of sustained release liormulation technology
`applicable to this invention, including the exemplary modes
`mentioned herein, are disclosed, e.g., in R. K. Chang and J.
`R. Robinson, chapter 4: "Sustained Drug Release from
`Tablets and Particles Through Coating,” in I’imrmocezJtr'cat'
`Dosage Fr)rm.s‘.'
`’1E.-bters, volume 3, edited by It. A.
`Lieberman, L. Lachman,