l|||||||||||||ll||l||||||||l||||||||||||||||||||||||||||l|||||||||||||||||||||||||||||||||
`
`US 20040059002A1
`
`(19) United States
`(12) Patent Application Publication (10) Pub. No.: US 2004/0059002 A1
`Couch et al.
`(43) Pub. Date:
`Mar. 25, 2004
`
`(54) SUSTAINED RELEASE DELIVERY OF
`AMPHETAMINE SALTS
`
`(75) Inventors: Richard A. Couch, Chevy Chase, MD
`(US); Beth Burnside, Bethesda, MD
`(US); Rong-Kun Chang, Rockville,
`MD (US)
`
`Correspondence Address;
`MILLEN, WHITE, ZELANO & BRANIGAN,
`RC,
`2200 CLARENDON BLVD.
`SUITE 1400
`ARLINGTON, VA 22201 (US)
`
`(73) Assignee; SHIRE LABORATORIES, INC”
`Rockville, MD
`
`(21) Appl, No;
`
`10/353,073
`
`(22) Filed:
`
`Jan. 29, 2003
`
`30
`
`Related US. Application Data
`
`(60) Provisional application No. 60/412,799, ?led on Sep.
`24, 2002.
`
`Publication Classi?cation
`
`(51) Int. Cl.7 .................... .. A61K 31/205; A61K 31/137
`
`(52) US. Cl. .......................................... .. 514/649; 514/554
`
`(57)
`
`ABSTRACT
`
`Apharmaceutical composition comprises a once-a-day sus
`tained release formulation of at least one amphetamine salt
`Which provides mean plasma concentration pro?le aspects in
`human ADHD patients Which are substantially the same as
`that provided by ADDERALL XR® type pulsatile formu
`lations.
`
`
`
`
`
`MEAN PLASMA CCNCENTRAHONS OF UEXTRO AND LEVOAMPFETAMNE (DQJ'IHL)
`
`
`
`
`
`D Bil-(T ROAMPH ETAMINE
`
`M-"ADDERALL XR" 20 Eng qd
`+ADDERALL" 10 mg bid
`
`LE'VOAMPHET AMINE
`
`- ——°——ADDERALL XFZ" 20 mg qd
`--~--ADDERALU* 10 mg bid
`
`m E
`
`l l
`
`T
`
`T
`
`T’
`
`*1
`
`I. 9
`
`‘I
`
`l’
`
`l
`
`1
`
`l
`
`1
`
`04812162024283235404445
`TIMEl?HOURS)
`
`KVK-TECH EXHIBIT 1023
`
`

`

`Patent Application Publication Mar. 25, 2004 Sheet 1 0f 12
`
`US 2004/0059002 A1
`
`Figure 1
`30
`
`h.) U1 i
`
`
`
`
`
`MEAN PLASMA CCNCEIWRATIONS 0F BEXTRO Alf-1D LEVOAMPFETAMNE (ngJmL)
`
`
`
`
`
`
`
`""FAEJDERALL HR" 20 Eng qd
`-+—ADDERALL‘° 10 mg bid
`
`LEV'OAMPHETAMINE
`
`'2 A» ADDERALL XR" 20 mg qd
`--»--ADDERALL* 10 mg bid
`
`...a. Q I
`
`m l ‘
`
`f
`
`4
`
`U
`
`T
`
`F
`
`F j
`
`I
`
`1
`
`l'
`
`T-
`
`T
`
`I
`
`B 121520242532 3640441115
`
`TINElfI'DURS
`
`'
`
`

`

`Patent Application Publication Mar. 25, 2004 Sheet 2 0f 12
`
`US 2004/0059002 A1
`
`Figure 2. Mean CGIS-P total scores for ITT population.
`
`*Baseline (previous med
`Week 1 (Adderail XRTM)
`Week 3 (Adderall XRTM)
`Week 7 (Adderall XRTM)
`
`Owomm
`
`B-h cessm (N=291I)
`
`12m CGIS‘P (M2909;
`
`I
`
`"M00001 vs baseline. Note: a lower score indicates better response to Ireatment
`
`

`

`Patent Application Publication Mar. 25, 2004 Sheet 3 0f 12
`
`US 2004/ 0059002 A1
`
`Figure 3. CGI lm provement scores at week 7.
`
`70
`60
`S0
`40
`3O
`20
`(1O
`
`Percent
`
`Improved - very much impmvcd and much improved; No mango -minima\ty
`Ry merge and very much worse.
`improved and no change; Worse = minimal
`
`

`

`Patent Application Publication Mar. 25, 2004 Sheet 4 0f 12
`
`US 2004/0059002 A1
`
`?gure 4. PedsQL totai score.
`
`:- Easeiine (previous med)
`Week ? {Adderali mm)
`
`85
`
`75
`
`Percent 70
`
`65
`
`P<0.000'l. Week 7 vs basc?nc, one sample 1: test.
`
`

`

`Patent Application Publication Mar. 25, 2004 Sheet 5 0f 12
`
`US 2004/0059002 A1
`
`Figure 5. Parent Satisfaction Survey:
`"Overall, 1 am satis?ed with my child taking this medication."
`
`Strongiyi
`agree
`
`Agree
`
`Somewhat
`agree
`
`Somewha?
`
`disagree
`
`_
`
`Disagree
`
`_
`
`V
`52%
`
`60%
`24%
`
`4.6%
`
`Strongiy 14% 7
`disagree
`1.5%
`
`182%
`
`49.7%
`
`52.9%
`
`37.5%
`
`172%
`
`_
`
`.i
`
`r' Baseiine (previous med)
`Week 7 (Adderail XRT")
`
`

`

`catlon Mar. 25, 2004 Sheet 6 0f 12
`'
`Patent Application Publi
`
`US 2004/00590 02 A1
`
`i- igure 6. Physician Preference Survey‘.
`"Overall, which of the two medications do you
`
`III New medication (Addaraii XR’")
`Previous medicauon
`Equal preferemce
`
`100
`
`Percent
`
`Mderail QD Addcraii 510+ MPH BID-i-Qi)
`n-876
`B11392
`0:163
`
`MPH 110+
`m-nr
`
`6:350
`
`Previcus Medications
`
`MPH: Meihyigriemdate.
`
`

`

`Patent Application Publication Mar. 25, 2004 Sheet 7 0f 12
`
`US 2004/0059002 A1
`
`
`
`DEXTROAMPHETAMINE PLASMA CONCENTRATION (nglmL)
`
`
`
`
`
`50’
`
`45
`
`40—
`
`u. (h l
`
`-A N
`U3 U1
`M D 1
`
`SUBJECTS
`
`-o-
`
`FED '
`
`—*—‘
`
`FAST
`
`TIME (HOURS)
`
`FIG. 7
`
`

`

`Patent Application Publication Mar. 25, 2004 Sheet 8 0f 12
`
`US 2004/0059002 A1
`
`
`
` W w SE35 ZOFEZMQZOO Saw/Dn- mZ_E<PwImE<OE.XwO
`
`
`
`
`
`SUBJECT 1 1
`
`0 m an m
`
`TIME (HOURS)
`
`FIG.
`
`

`

`Patent Application Publication Mar. 25, 2004 Sheet 9 0f 12
`
`US 2004/0059002 A1
`
`
`
`LAEVOAMPHETAMINE PLASMA CONCENTRATiON (nglmL)
`
`
`
`
`
`SUBJECT 20
`
`'—o—
`
`FED
`
`-.-'
`
`FAST
`
`1s.c
`
`12_5_
`
`7.5—
`
`5.0-1
`
`2.5
`
`0-0
`1
`I
`32
`2s
`24
`mi a 121$ 20
`TIME (HOURS)
`
`as 404448 52
`
`

`

`Patent Application Publication Mar. 25, 2004 Sheet 10 0f 12 US 2004/0059002 A1
`
`
`
`LAEVOAMPHETAMINE PLASMA CONCENTRATION (ng/mL)
`
`
`
`
`
`SUBJECT 13
`
`—<>—TRT B FED (20 mg LOT 980076A)
`
`~r- TRT F FAST (20 mg \LOTBSOQTEA)
`
`12.5-
`
`10.0
`
`‘n1a121s20242a>a23s40444as2
`TlME?-IDURS)
`
`‘FIG! l0
`
`

`

`Patent Application Publication Mar. 25, 2004 Sheet 11 0f 12
`
`US 2004/0059002 A1
`
`75
`
`SUBJECT 8
`
`
`
`
`
`DEXTRO AND LAEVOAMPHETAMINE PLASMA CONCENTRATIONS (ng/mL)
`
`
`
`
`
`
`
`O
`
`2
`
`4
`
`E
`
`8
`
`16
`
`1B
`
`20
`
`22
`
`24
`
`1D
`12
`14
`TIME (HOURS)
`
`‘FIG, .11
`
`

`

`Patent Application Publication Mar. 25, 2004 Sheet 12 0f 12 US 2004/0059002 A1
`
`SUBJECT 11
`
`
`
`
`
`DEXTRO AND LAEVOAMPHETAMINE PLASMA CONCENTRATIONS lnglmL)
`
`
`
`
`
`
`
`75
`
`70‘
`
`55-1
`
`60
`
`So-
`
`45
`
`4D
`
`35
`
`O
`
`O
`
`l
`
`2
`
`i
`
`4
`
`.
`
`I
`
`8
`
`|
`
`B
`
`-=>- DEXTRO
`
`—a-— LAEVO
`
`l
`
`\
`
`15
`
`l
`
`|
`
`1 B _ 2U
`
`22
`
`24
`
`l
`
`I
`
`10
`12
`14
`TIME (HOURS)
`
`FIG. 12
`
`

`

`US 2004/005 9002 A1
`
`Mar. 25, 2004
`
`SUSTAINED RELEASE DELIVERY OF
`AMPHETAMINE SALTS
`
`[0001] Described herein are compositions for providing an
`orally administrable sustained release (SR) form of one or
`more amphetamines and/or 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 ADHD (attention de?cit hyper
`activity disorder), but other disease states can also be
`treated. The sustained-release forms of one or more amphet
`amines and/or amphetamine salts according to the invention
`are preferably formulated to provide an in vivo plasma
`concentration pro?le (i.e., measured by total concentration
`of the amphetamines and/or 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 pro?le achieved by pulsatile release
`formulations of the same amphetamines and/or amphet
`amine salts When administered to a patient, e.g., those
`achieved by ADDERALL XR®, Shire US Inc., Whose FDA
`package insert and labeling are entirely incorporated by
`reference herein. Further preferably, this sustained release
`pro?le (the plasma concentration pro?le being distinguished
`from the release pro?le) typically exhibits ?rst order or
`biphasic or sigmoidal characteristics.
`[0002] Particularly preferably, the SR formulations
`according to the invention exhibit a single dose in vivo
`plasma concentration pro?le 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 dextroamphetamine and levoamphet
`amine salts in ADDERALL XR®. (The overall mean plasma
`concentration 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 same
`mean plasma concentration curves, they can be termed fast
`sustained release formulations, With regard to the initial
`rising slopes involved.
`[0003] By substantially the same “pro?le” herein is meant
`that tWo curves have substantially the same AUC (area under
`the curve) and CmaX, e.g., these parameters for each curve
`are 120% of each other, or even closer, eg 110%, 15%, 12%,
`etc., Which parameters are entirely conventionally de?ned
`and determined. See, e.g., Fundamentals of Clinical Phar
`macokinetics. J. G. Wagner, Drug Intelligence Publications,
`Inc., Hamilton, Ill., 1975; Guidance for Industry, Bioavail
`ability and Bioequivalence Studies for Orally Administered
`Drug Products-General Considerations, FDA, CDER. Octo
`ber 2000. For FIG. 1, AUC (time Zero to in?nity) is 556.6
`ng hr/mL and CrnaX is 28.0 ng/mL for d-amphetamine and
`205.1 ng hr/mL and 8.7 ng/mL, respectively, for l-amphet
`amine. 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. 1, e.g., substantially (e.g, 120%)
`matching initial rising slope, post-peak curve shapes, TrnaX
`values, (7.1 hr for d-amphetamine and 7.4 hr for 1-amphet
`amine 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 CmaX) corresponding to other
`daily doses such as 10, 30, 40, 50, 60, 70, 80, 90 mg Will be
`essentially linearly proportional to those shoWn in FIG. 1,
`corresponding to the involved dosage.
`
`[0004] In another independent embodiment, the fast SR
`formulations of this invention, for the ADDERALL X® 20
`mg 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
`ng/(mL hr) for dextroamphetamines and about 1.4 to about
`3 ng/(mL hr) for levoamphetamines, preferably, about 4 to
`about 8 ng/(mL hr) and about 1.5 to about 2.2 ng/(mL 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 men
`tioned above, the slopes vary directly (linearly) proportion
`ally to dose.
`
`[0005] The formulations of WO 00/23055 (Whose entire
`disclosure is incorporated by reference herein), e.g., that for
`ADDERALL X®, achieve a tWo-fold 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
`pro?le substantially the same as that of Example 5 (combi
`nation of Examples 1 and 2) of WO 00/23055, despite the
`latter’s disclosure that conventional sustained release for
`mulation technology Was not suitable for amphetamines.
`(Note that the plasma pro?le of Example 5 shoWn in FIG. 7
`of WO 00/23055 is not a mean pro?le, as is that of FIG. 1
`of this application, but rather is one from a single indi
`vidual.)
`[0006] The SR formulations of this invention Will be
`effective to treat, e.g., ADHD, in the same manner as
`ADDERALL® XR. For example, they Will be effective to
`treat ADHD in the unexpectedly good manner established in
`the data reported in Example 10. They Will also be effective
`to treat ADHD With loW incidence of side effects, including
`substance abuse, addiction, tolerance, tachyphylaxis, etc.
`
`[0007] Preferred salts are those in the commercial product
`ADDERALL XR®, i.e., dextroamphetamine sulfate, dex
`troamphetamine saccharate, amphetamine aspartate mono
`hydrate and amphetamine sulfate. HoWever, the invention is
`not limited to these speci?c amphetamine salts. Other
`amphetamines and amphetamine salts and mixtures thereof
`can be used in a sustained-release delivery system to achieve
`the plasma concentration pro?les of the invention. For
`example, amphetamine base, chemical and chiral derivatives
`thereof and other amphetamine salts can be used.
`
`[0008] Preferred in vivo plasma concentration pro?les 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 coated
`With a coating Which alloWs the release of the amphetamine
`salts there through over time, such as a pharmaceutically
`acceptable Water-insoluble ?lm former alone or With a
`dissolution regulating agent. In addition, by combining the
`immediate-release beads With the sustained-release beads, a
`biphasic release pro?le can be achieved. Other methods for
`
`

`

`US 2004/005 9002 A1
`
`Mar. 25, 2004
`
`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 pro?le.
`
`[0009] 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 ?rst order, biphasic, sigmoidal etc. release
`pro?le to achieve the plasma pro?le equivalent of pulsatile
`release systems of the same drugs as discussed above.
`Matching to the desired target plasma concentration pro?le
`using SR is conventional.
`[0010] Sustained-release beads can be prepared by coating
`conventional 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. Other than
`beads in a capsule shell, tablets in a capsule shell (e.g., one
`immediate-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 pro?le.
`
`[0011] Various polymeric materials can be used to achieve
`the type of pattern of release needed to result in the desired
`plasma concentration pro?le, for example, so as to increase
`the fast rate of delivery over the ?rst 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 pharmaceutically active amphetamine salts
`to achieve the desired plasma pro?le 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 pro?le can
`thus be achieved using a fast sustained-release once daily
`dosage of the amphetamine salts.
`
`[0012] Examples of useful bead constructions for sus
`tained-release include the folloWing:
`
`[0013] Sugar core, coated With amphetamine, coated
`With polymer,
`
`[0014] Sugar core, coated With amphetamine, coated
`With mix of amphetamine and polymer, coated With
`polymer,
`[0015] Sugar core, coated With amphetamine, coated
`With relatively high concentration mix of amphet
`amine and polymer, coated With Weaker concentra
`tion mix of amphetamine and polymer, coated With
`polymer,
`[0016] Bead containing amphetamine, coated With
`polymer,
`[0017] Bead containing amphetamine, coated With
`mix of amphetamine and polymer, coated With poly
`mer,
`[0018] 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
`
`[0019] Tablet or capsule containing multiple types of
`beads as described above having differing timing of
`release of amphetamine and/or different rates of
`release of amphetamine.
`
`[0020] As mentioned, SR matrix beads can also be used,
`i.e., not having any needed layers to achieve sustained
`release. The components used in such matrices are chosen
`from conventional 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 con
`ventional. See e.g., WO 00/23055.
`[0021] Details of using the foregoing constructs and others
`to achieve a desired plasma pro?le 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 conventional adjustments, e.g., involving identities of
`polymers and mixtures thereof, relative amounts of compo
`nents, 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 pro?les can be determined and in vivo plasma pro?les
`measured. The latter can then conventionally be compared to
`the target plasma pro?le (e.g., that of ADDERALL XR® and
`differences compensated by fully conventional formulation
`and dissolution pro?le adjustments such as but not limited to
`those mentioned.
`
`[0022] Suitable materials Which can be used in the SR
`formulations 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 Eudragit RS and RL30D, Eudragit NE30D,
`Aquacoat, Surelease, Kollicoat SR30D, and cellulose
`acetate latex.
`
`[0023] Methods of manufacturing cores include:
`
`[0024] a. Extrusion-SpheroniZation—the drug(s) and
`other additives 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 in a marumeriZer. The
`resulting pellets are dried and sieved for further
`applications.
`[0025] b. High-Shear Granulation—Drug(s) and
`other additives are dry-mixed and then the mixture is
`Wetted by addition of a binder solution in a high
`shear-granulator/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.
`
`[0026] c. 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 ?uidiZed bed processor or other
`suitable equipment. The drug thus is coated on the
`
`

`

`US 2004/005 9002 A1
`
`Mar. 25, 2004
`
`surface of the starting seeds. The drug-loaded pellets
`are dried for further applications.
`
`[0027] 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 ?uidized
`bed apparatus With an alternating sequence of selected
`coating layers.
`[0028] The composition, preferably in the bead forms
`described above, can be incorporated into hard gelatin
`capsules, either With additional eXcipients, or alone. Typical
`eXcipients to be added to a capsule formulation include, but
`are not limited to: ?llers such as microcrystalline cellulose,
`soy polysaccharides, calcium phosphate dihydrate, calcium
`sulfate, lactose, sucrose, sorbitol, or any other inert ?ller. In
`addition, there can be ?oW aids such as fumed silicon
`dioXide, silica gel, magnesium stearate, calcium stearate or
`any other material imparting ?oW to poWders. A lubricant
`can further be added if necessary by using, for eXample,
`polyethylene glycol, leucine, glyceryl behenate, magnesium
`stearate or calcium stearate.
`
`[0029] The composition may also be incorporated into a
`tablet, in particular by incorporation into a tablet matriX,
`Which rapidly disperses the particles after ingestion. In order
`to incorporate these particles into such a tablet, a ?ller/
`binder 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 (AVICEL
`.RTM.), soy polysaccharide (EMCOSOY.RTM.), pre-gela
`tiniZed starches (STARCHRTM. 1500, NAT IONAL.RTM.
`1551), and polyethylene glycols (CARBOWAX.RTM.). The
`materials are preferably present in the range of 5-75%
`(W/W), With a more preferred range of 25-50% (W/W).
`[0030] In addition, disintegrants are optionally added in
`order to disperse the beads once the tablet is ingested.
`Suitable disintegrants include, but are not limited to: cross
`linked sodium carboXymethyl cellulose (AC-DI-SOL
`.RTM.), sodium starch glycolate (EXPLOTAB.RTM., PRI
`MOJEL.RTM.), and cross-linked polyvinylpolypyrrolidone
`(Plasone-XL). These materials are preferably present in the
`rate of 3-15% (W/W), With a more preferred range of 5-10%
`(W/W).
`[0031] Lubricants are also optionally added to assure
`proper tableting, and these can include, but are not limited
`to: magnesium stearate, calcium stearate, stearic acid, poly
`ethylene glycol, leucine, glyceryl behanate, and hydroge
`nated vegetable oil. These lubricants are preferably present
`in amounts from 01-10% (W/W), With a more preferred
`range of 03-30% (W/W).
`[0032] Tablets are formed, for eXample, as folloWs. The
`particles are introduced into a blender along With AVICE
`L.RTM., disintegrants 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.
`[0033] Various enteric materials, e.g., cellulose acetate
`phthalate, hydroXypropyl methylcellulose phthalate, polyvi
`nyl acetate phthalate, and the EUDRAGITRTM. acrylic
`
`polymers, can be used as gastroresistant, enterosoluble coat
`ings for drug release in the intestine When desired. The
`enteric materials, Which are soluble at higher pH values, are
`frequently used for colon-speci?c delivery systems and are
`entirely conventionally employable in the SR systems of this
`invention. The enteric polymers used in this invention can
`also be modi?ed conventionally by miXing With other
`knoWn coating products that are not pH sensitive. Examples
`of such coating products include the neutral methacrylic acid
`esters With a small portion of trimethylammonioethyl meth
`acrylate chloride, sold currently under the trade names
`EUDRAGITRTM. and EUDRAGITRTM. RL; a neutral
`ester dispersion Without any functional groups, sold under
`the
`trade names EUDRAGITRTM. NE30D and
`EUDRAGITRTM. NE30; and other pH independent coating
`products.
`[0034] 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 ?uid 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, potyvinylpyrroli
`done, polyvinylpyrrolidone/vinyl acetate copolymer, ethyl
`cellulose aqueous dispersions (AQUACOAT.RTM., SURE
`LEASE.RTM.),
`EUDRAGITRTM.
`RL
`30D,
`OPADRYRTM. and the like. The suggested coating levels
`are from 1 to 6%, preferably 2-4% (W/W).
`
`[0035] An overcoating layer can further optionally be
`applied to the composition of the present invention.
`OPADRYRTM., OPADRY II.RTM. (Colorcon) and corre
`sponding color and colorless grades from Colorcon can be
`used to protect the pellets from being tacky and provide
`colors to the product. The suggested levels of protective or
`color coating are from 1 to 6%, preferably 2-3% (W/W).
`
`[0036] Many ingredients can be incorporated into the
`overcoating formula, for eXample to provide a quicker
`(immediate) release, such as plasticiZers: acetyltriethyl cit
`rate, triethyl citrate, acetyltributyl citrate, dibutylsebacate,
`triacetin, polyethylene glycols, propylene glycol and the
`others; lubricants: talc, colloidal silica dioXide, magnesium
`stearate, calcium stearate, titanium dioXide, magnesium sili
`cate, and the like.
`
`[0037] Optional modifying components of a protective
`layer Which can be used 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 ?uid
`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 EUDRAGITRTM. RS and RL 30D,
`EUDRAGITRTM. NE 30D, AQUACOAT.RTM., SURE
`
`

`

`US 2004/005 9002 A1
`
`Mar. 25, 2004
`
`LEASE.RTM., cellulose acetate latex. The combination of
`the above polymers and hydrophilic polymers such as
`hydroxyethyl
`cellulose,
`hydroxypropyl
`cellulose
`(KLUCEL.RTM., Hercules Corp.), hydroxypropyl methyl
`cellulose (METHOCEL.RTM., DoW Chemical Corp.), poly
`vinylpyrrolidone can also be used.
`
`[0038] Principles of sustained release formulation tech
`nology 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 Pharma
`ceutical Dosage Forms: Tablets, volume 3, edited by H. A.
`Lieberman, L. Lachman, and J. B. SchWartZ, Marcel Dekker,
`Inc., 1991; R. J. Campbell and G. L. Sackett, chapter 3:
`“Film coating,” in Pharmaceutical Unit Operations: Coat
`ing, edited by K. E. Avis, A. J. Shukla, and R. K. Chang,
`Interpharm Press, Inc., 1999, Whose disclosures are entirely
`incorporated by reference herein.
`
`[0039] This invention also relates to use of the SR formu
`lations to treat indications other than ADHD at dosages and
`in regimens analogous to those described herein. These
`include but are not limited to AlZheimer’s disease and other
`memory disorders, ?bromyalgia, chronic fatigue, depres
`sion, obsessive compulsive disorder, alone or in combina
`tion With a SSRI; oppositional de?ant disorder (ODD), With
`or Without ADHD and With or Without guanfacine or Wel
`butrin; anxiety, With or Without ADHD and alone or in
`combination With an anxiolytic or SSRI; resistant depres
`sion; stroke rehabilitation; Parkinson’s disease; mood dis
`order; schiZophrenia; Huntington’s disorder; dementia, e.g.
`AIDS dementia and frontal lobe dementia; movement dis
`function; apathy; fatigue; Pick’s disease; sleep disorders,
`e.g., narcolepsy, cataplexy, sleep paralysis and hypnagogic
`hallucinations; etc.
`
`[0040] The invention also relates to combinations of the
`SR formulations of this invention With other therapeutic
`agents, including all those useful for a given indication. The
`involved drugs can be formulated in the same dosage form
`as the SR dose of this invention or can be formulated
`separately, e.g., as conventionally used alone, in Which case,
`the drugs can be administered sequentially in any order or
`simultaneously. Typically, dosages can be in the same ranges
`as for each drug used separately or, Where synergistic effects
`occur, one or more of the combined drugs can be used in
`loWer dosages. Combinations encompass any Where the
`drugs are made bioavailable in a patient at the same time,
`including combinations coming into being in a patient.
`
`[0041] These other therapeutic agents include e.g., for
`AlZheimer’s: Reminyl, Cognex, Aricept, Exelon, Akatinol,
`Neotropin, Eldepryl, Estrogen, Clioquinol, Ibuprofen, and
`Ginko Bilboa; for ADHD: methylphenidate (e.g., Ritalin),
`Dexedrine, Adderall, Cylert, clonidine, guanfacine, etc; for
`depression: ProZac, Zoloft, Paxil, Reboxetine, Wellbutrin,
`OlanZapine, Fluoxetine, Elavil, Totranil, Pamelor, Nardil,
`Parnate, Desyrel, and Effexor; for mood disorder: ThoraZine,
`Haldol, Navane, Mellaril, CloZaril, Risperdal, Zyprexa,
`CloZapine, Risperidone, and OlanZapine; for fatigue: ben
`ZodiaZapines, Anaprox, Naprosen, ProZac, Zoloft, Paxil,
`Effexor, and Desyrel; for ?bromyalgia: Dilantin, Carbatrol,
`Epitol, Tegretol, Depacon, Depakote, Norpramin, Aventyl,
`Pamelor, Elavil, Enovil, Adapin, Sinequan, Zonalon, and
`non-steroidal in?ammatory drugs; for oppositional de?ant
`
`disorder (ODD): clonidine, Risperidone, and Zyprexa; for
`apathy: Amisulpride, OlanZapine, Visperidone, Quetiapine,
`CloZapine, and Zotepine; for Parkinson’s disease:
`Levodopa, Parlodel, Permax, and MIRAPEX; for schiZo
`phrenia: CloZapine, Zyprexa, Seroquel, and Risperdal; for
`Huntington’s disorder: haloperidal and clonZepam; for
`dementia: thioridaZine, haloperidal, Risperidone, Cognex,
`Aricept, and Exelon; for narcolepsy: Provigil, Dexedrine,
`Moda?nil and Ritalin; for cataplexy: Xyrem; for hallucina
`tions: CloZapine, Risperidone, Zyprexa, and Seroquel; for
`sleep paralysis: Perocet, Vicodin, and Lorcet; for obsessive
`compulsive disorder: Anafranil, ProZac, Zoloft, Paxil,
`Luvox; and for anxiety: Elavil, Asendin, Wellbutrin, Tegre
`tol, Anafranil, Norpramine, Adapin, Sinequan, Tofranil, Epi
`tol, J animire, Pamelor, Ventyl, Aventyl, Surmontil etc; selec
`tive serotonin reuptake inhibitors (SSRIs) including ProZac,
`Luvox, SerZone, Paxil, Zoloft, Effexor, etc., benZodiaZ
`epines, including Xanax, Librium, Klonopin, Valium, Zet
`ran, Valrelease, Dalmane, Ativan, AlZapam, Serax, Halcion,
`etc., monamine oxidase inhibitors including Aurorix, Man
`erix, Nardil, Parnate, etc.
`[0042] The entire disclosures of all applications, patents
`and publication, cited above, and beloW, are hereby incor
`porated by reference.
`
`EXAMPLES
`
`[0043] In the foregoing and in the folloWing examples, all
`temperatures are set forth uncorrected in degrees Celsius;
`and, unless otherWise indicated, all parts and percentages are
`by Weight.
`[0044] SR Coated Beads
`
`Example 1
`
`[0045]
`
`Mixed amphetamine salts loaded beads (MASL)
`Ethyl cellulose (Ethocel N-10, DoW Chemical)
`Ethyl acetate
`
`500 gram
`15.46 gram
`515 gram
`
`[0046] Ethyl cellulose (15.46 gram) Was dissolved in 515
`gram of ethyl acetate. Into a Wurster column Was charged
`500 grams of MASL beads Which Were then coated With the
`coating mixture under conditions of 40° C., spray pressure
`1 bar, and spray rate of 10 grams/min. The line Was rinsed
`With ethyl acetate and the pellets Were dried for approxi
`mately tWenty minutes and recovered to give a product of
`97% by Weight NTASL beads and 3% by Weight ethyl
`cellulose coating.
`
`Example 2
`
`[0047]
`
`Mixed amphetamine salts loaded beads
`Ethyl cellulose (Ethocel N-10, DoW Chemical)
`Hydroxypropyl cellulose (Klucel LF, Aqualon)
`Methylene chloride
`Methanol
`
`500 grams
`37.78 grams
`8.70 grams
`744 grams
`186 grams
`
`

`

`US 2004/005 9002 A1
`
`Mar. 25, 2004
`
`[0048] Ethyl cellulose (37.78 grams) and hydroxypropyl
`cellulose (8.70 grams) Were dissolved in a mixture of
`methylene chloride and methanol (4:1). Into a Wurster
`column Was charged 500 grams of MASL beads Which Were
`then coated With the coating mixture under conditions of 40°
`C., spray pressure 1 bar, and spray rate 10 grams/min. The
`line Was rinsed With methanol and the pellets Were dried for
`approximately tWenty minutes and recovered to give a
`product of 92% by Weight MASL beads and 8% by Weight
`ethyl cellulose/hydroxypropyl cellulose coating.
`
`Example 3
`
`[0049]
`
`a Wurster column under conditions of 30° C. inlet tempera
`ture, spray pressure 2 bar, and a spray rate of 10 grams/min.
`
`Example 6
`
`[0055]
`
`Mixed amphetamine salts loaded beads
`Eudragit L100
`Ethyl cellulose (Ethocel N-10, DoW Chemical)
`Triethyl citrate
`Acetone
`Methanol
`
`500 grams
`25.25 grams
`25.25 grams
`5.05 grams
`833.4 grams
`277.8 grams
`
`Mixed amphetamine