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`
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`Bibliographic data: WO2004028509 (A1) ― 2004-04-08
`
`SUSTAINED RELEASED DELIVERY OF AMPHETAMINE SALTS
`
`Inventor(s):
`
`Applicant(s):
`
`Classification:
`
`Application
`number:
`
`Priority
`number(s):
`
`Also
`published as:
`
`COUCH RICHARD A [US]; BURNSIDE BETH [US]; CHANG RONG-
`KUN [US] + (COUCH, RICHARD, A, ; BURNSIDE, BETH, ; CHANG,
`RONG-KUN)
`
`SHIRE LAB INC [US]; COUCH RICHARD A [US]; BURNSIDE
`BETH [US]; CHANG RONG-KUN [US] + (SHIRE LABORATORIES,
`INC, ; COUCH, RICHARD, A, ; BURNSIDE, BETH, ; CHANG, RONG-
`KUN)
`- international:A61K31/137; A61K31/205; A61K9/22; A61K9/50;
`A61K9/54; A61K; (IPC1-7): A61K31/137; A61K9/22;
`A61K9/54
`A61K31/137; A61K31/205; A61K9/5015;
`A61K9/5026; A61K9/5047
`WO2003US29757 20030924 Global Dossier
`
`- cooperative:
`
`US20030353073 20030129 ; US20020412799P 20020924
`
`AP2030 (A) AT495731 (T) AU2003272619 (A1)
`AU2003272619 (B2) BR0314486 (A) CA2499546 (A1)
`CA2499546 (C) CN1684668 (A) CN1684668 (B) CR7766 (A)
`CY1112335 (T1) DK1542660 (T3) EA018082 (B1)
`EA200500530 (A1) ECSP055702 (A) EP1542660 (A1)
`EP1542660 (B1) ES2360046 (T3) HK1075828 (A1)
`HRP20050356 (A2)
`IL167470 (A)
`IS2814 (B) IS7818 (A)
`JP2006503071 (A) KR20050084589 (A) MA27469 (A1)
`MXPA05003129 (A) NO20051986 (A) NO336938 (B1)
`NZ539216 (A) OA13075 (A) PL375991 (A1) SI1542660 (T1)
`US2004059002 (A1) US2005158384 (A1) US6913768 (B2)
`ZA200502406 (B)
`less
`
`Abstract of WO2004028509 (A1)
`
`3/22/2018, 2:21 PM
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`Page 1
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`SHIRE EX. 2051
`KVK v. SHIRE
`IPR2018-00290
`
`

`

`(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`
`(19) World Intellectual Property
`Organization
`International Bureau
`
`(43) International Publication Date
`
`8 April 2004 (08.04.2004)
`
` (10) International Publication Number
`
`WO 2004/028509 A1
`
`(51) International Patent Classification7:
`31/137, 9/54
`
`A61K 9/22,
`
`(21) International Application Number:
`PCT/US2003/029757
`
`(22) International Filing Date:
`24 September 2003 (24.09.2003)
`
`(25) Filing Language:
`
`(26) Publication Language:
`
`English
`
`English
`
`(30) Priority Data:
`60/412,799
`10/353 ,073
`
`24 September 2002 (24.09.2002)
`29 January 2003 (29.01.2003)
`
`US
`US
`
`(63) Related by continuation (CON) or continuation-in-part
`(CIP) to earlier application:
`US
`Filed on
`
`10/353,073 (CIP)
`29 January 2003 (29.01.2003)
`
`(71) Applicant (for all designated States except US): SHIRE
`LABORATORIES, INC.
`[US/US]; 1550 East Gude
`Drive, Rockville, MD 20850 (US).
`
`(72) Inventors; and
`(75) Inventors/Applicants (for US only): COUCH, Richard,
`A. [US/US]; 5509 Center Street, Chevy Chase, MD 20815
`(US). BURNSIDE, Beth [US/US]; 5404 Huntington
`PKWY, Bethesda, MD 20814 (US). CHANG, Rong-Kun
`[US/US]; 13607 Pine View Lane, Rockville, MD 20850
`(US).
`
`(74) Agents: ZELANO, Anthony, J. et al.; Millen, White, Ze—
`lano & Branigan, P.C., Arlington Courthouse Plaza 1, Suite
`1400, 2200 Clarendon Boulevard, Arlington, VA 22201
`(US).
`
`(81) Designated States (national): AE, AG, AL, AM, AT, AU,
`AZ, BA, BB, BG, BR, BY, BZ, CA, CH, CN, CO, CR, CU,
`CZ, DE, DK, DM, DZ, EC, EE, EG, ES, FI, GB, GD, GE,
`
`[Continued on next page]
`
`(54) Title: SUSTAINED RELEASED DELIVERY OF AMPHETAMINE SALTS
`
`LLl C
`
`(57) Abstract: A pharmaceutical composi—
`tion comprises a once—a—day sustained release
`formulation of at least one amphetamine salt
`which provides mean plasma concentration
`profile aspects in human ADHD patients
`which are substantially the same as
`that
`provided by ADDERALL XR® type pulsatile
`formulations.
`
`*ADDERALL XR" 20 mg qd
`
`*ADDERALL" 10 mg bid
`
`LEVOAMPHETAMINE
`
`«ah-ADDERALL xm 20 mg qd
`
`MADDERALU 10 mg bid
`
` D EXT ROAMPHETAMINE
`
`043 12
`
`15
`
`20
`24
`28
`TM (HOURS)
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`32
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`35 40 44 48
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`Page 2
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`M (h
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`M D
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`.4.41:U1
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`MEANPLASMACCNCENTRAIIONS0FCEXTROANDLEVOMlPl‘El’Al-ANE(fig/mL) U.
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`W02004/028509A1|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||IIIIH
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`Page 2
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`WO 2004/028509 A1
`
`GH, GM, HR, HU, ID, IL, IN, IS, JP, KE, KG, KP, KR,
`KZ, LC, LK, LR, LS, LT, LU, LV, MA, MD, MG, MK,
`MN, MW, MX, MZ, NI, NO, NZ, OM, PG, PH, PL, PT,
`RO, RU, SC, SD, SE, SG, SK, SL, SY, TJ, TM, TN, TR,
`TT, TZ, UA, UG, US, UZ, VC, VN, YU, ZA, ZM, ZW.
`
`ES, FT, FR, GB, GR, HU, IE, IT, LU, MC, NL, PT, RO,
`SE, SI, SK, TR), OAPI patent (BF, BJ, CF, CG, CI, CM,
`GA, GN, GQ, GW, ML, MR, NE, SN, TD, TG).
`
`Published:
`
`— with international search report
`
`(84) Designated States (regional): ARIPO patent (GH, GM,
`KE, LS, MW, MZ, SD, SL, SZ, TZ, UG, ZM, ZW),
`Eurasian patent (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM),
`European patent (AT, BE, BG, CH, CY, CZ, DE, DK, EE,
`
`For two—letter codes and other abbreviations, refer to the ”Guid—
`ance Notes on Codes and Abbreviations ” appearing at the begin—
`ning of each regular issue of the PCT Gazette.
`
`Page 3
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`Page 3
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`WO 2004/028509
`
`PCT/US2003/029757
`
`Sustained Release Delivery of Amphetamine Salts
`
`Described herein are compositions fer 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 ofpatients having ADI—ID (attention deficit. hyperactivity disorder), but
`
`other disease states can also be treated. The sustained-release forms of one or more
`
`amphetamines and/or 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 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 profile achieved by pulsatile release
`forniulations of the same amphetamines and/or amphetamine 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 profile (the plasma concentration profile being distinguished from the
`release profile) typically exhibits first order or biphasic or sigmoidal characteristics.
`Particularly preferably, the SR formulations according to the invention exhibit a
`single dose in vivo plasma concentration profile substantially the same as that shown in
`
`Figure l. The latter shows the substantially smooth mean (over about 20 patients) plasma
`
`concentration curves achieved for both the dextr‘oamphetamine and. levoamphetamine
`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.
`
`.
`
`By substantially the same “profile” 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 1: 20% of each other, or even closer, e.g., i 10%, j; 5%, i 2%, etc,, which
`
`parameters are entirely conventionally defined and determined. See,le.g., Fundamentals
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`Page 4
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`Page 4
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`W0 2004/028509
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`mm-
`
`a“ “it its;qwszogggqygsn;3
`
`..
`
`;
`
`..: N:::L> “my ”my. ._.
`
`of Clinical Pharmacokinetics.
`
`J.G. Wagner, Drug Intelligence Publications,
`
`Inc.,
`
`Hamilton, Illinois, 1975; Guidance for Industfl. Bioavailabilitv and Bioeguivalence
`
`Studies for Orallv Administered Drug Products-General Considerations. FDA. CDER.
`
`October 2000. For Fig. 1, AUG (time zero to infinity) is 556.6 ng hr/mL and Cr,12m is 28.0
`
`ng/mL for d—amphetamine and 205.1 ng hr/mL and 8.7, ng/mL, respectively, for l-
`
`arnphetamine. 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, :
`20%) matching initial rising slope, post-peak curve shapes, Tmax 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 closes), 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.
`
`In another independent embodiment, the fast SR formulations of this invention,
`
`for the ADDERALL XR® 20 mgdose of Figure 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 closes, e.g., those mentioned above, the slopes vary directly (linearly) proportionally
`
`to dose.
`
`The formulations of WO 00/2305 5 (whose entire disclosure is incorporated by
`
`reference herein), e.g., that for ADDERALL XR®, 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 profile substantially the same as that of Example
`
`Page 5
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`Page 5
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`W0 ”04/028509
`
`12‘: 51—» "is w:— -.
`a“: r z; ecPCT/Uszqgg/Qggjslg; 3:2?
`
`5 (combination of Examples 1 and 2) of WO 00/23055, despite the latter’s disclosure
`that conventional sustained release formulation technology was not suitable for
`‘
`
`amphetamines. (Note that the plasma profile of Example 5 shown in Fig. 7 of WO
`00/23 055 is not a mean profile, as is that of Fig. 1 ofthis application, but rather is one
`from a single individual.)
`The SR formulations of this invention will be effective to treat, e.g., ADI-ID, 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.
`Preferred salts are those in the commercial product ADDERALL XR®, i.e.,
`
`dextroamphetamine sulfate, dextroamphetamine saccharate, amphetamine aspartate
`
`monohydrate and amphetamine sulfate. However, the invention is not limited to these
`specific amphetamine salts. Other amphetamines and amphetamine salts and mixtures
`thereof can be used in a sustained—release delivery system to achieve the plasma
`
`concentration profiles ofthe invention. For example, amphetamine base, chemical and
`chiral derivatives thereof and other amphetamine saltsican 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 amphetamine 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‘c'oated with "a coating
`which allows the release of the amphetamine salts there through over time, such as a
`
`pharmaceutically acceptable water-insoluble fihn former alone or with a dissolution
`
`regulating agent. In addition, by combining the immediate-release beads with the
`
`sustained-release heads, a biphasic release profile can be achieved. Other methods for
`providing sustained-release of a drug, including thdse further discussed below, are known
`and can be used to piovide a sustained-release delivery iwhich 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
`
`U.)
`
`Page 6
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`Page 6
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`WO 2004/028509
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`PCT/US2003/029757
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`achieve a first order, biphasic, sigmoidal etc. release profile to achieve 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 conventional;
`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 combination ofpolymers 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 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
`
`complete dosages of pharmaceutically 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:
`
`,
`
`0
`
`0 ,
`
`0
`
`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 relatively high
`
`concentration mix of amphetamine and polymer, coated with weaker
`
`concentration mix of amphetamine and polymer, coated with polymer,
`
`Page 7
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`Page 7
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`

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`WO 2004/028509
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`PCT/US2003/029757
`
`I
`
`..
`
`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 and/or different rates of
`
`release of amphetamine.
`
`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 conventional. See e.g., WO 00/23055.
`
`‘ 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 conventional
`
`adjustments, e. g., involving identities of polymers 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), dissolution 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
`ADDERALL XR® and differences compensated byfully conventional formulation and
`
`-
`
`dissolution profile adjustments such as but not limited to those mentioned.
`
`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 propiogate, ethyl cellulose, fatty acids and
`
`their esters, alkyl alcohols, waxes, zein (prolamine from corn), and aqueous polymeric
`
`Page 8
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`Page 8
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`WO 2004/028509
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`PCT/US2003/029757
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`dispersions such as Eudragit RS and RL3OD, Eudragit NE3OD, Aquacoat, Surelease,
`
`Kollicoat SRBOD, and cellulose acetate latex.
`
`Methods of manufacturing cores include:
`
`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.
`lb. High-Shear Granulation - Drug(s) and other additives are dry-mixed and then
`
`the mixture is wetted by addition of a bindersolution 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.
`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 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 fluidized bed apparatus 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, 0r aloue.
`
`Typical excipients to be added to a capsule formulation include, but are not limited to:' J
`
`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.
`
`Page 9
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`WO 2004/028509
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`PCT/US2003/029757
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`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 filler/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 (AVICBL.RTM.), soy polysaccharide (EMCAOSOYRTMJ,
`
`pre-gelatinized starches (STARCHRTM. 1500, NATIONALRTM. 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 25-5 0% (w/w).
`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-Dl-SOL.RTM.), sodium starch glycolate
`
`(EXPLOTAB.RTM., PRIMOJEL.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 540% (w/w).
`
`Lubricants are also optionally added to assure proper tableting, and these can
`
`include, but are not limited to: magnesium stearate, calcium .stearate, ’stearic acid,
`polyethylene glycol, leucine, glyceryl- behanate, and hydrogenated vegetable oil. These
`lubricants are preferably present in amounts from O.l-lO% (w/w), with a more preferred
`range of 03—10% (w/w).
`‘
`(
`
`Tablets are formed, for example, as follows. The particles are introduced into a
`blender along with AVICEL.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.
`
`‘
`
`Various enteric materials, e.g., cellulose acetate phthalate, hydroxypropyl
`
`methylcellulose phthalate, polyvinyl acetate phthalate, and the EUDRAGITRTM. 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 conventionally
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`Page 10
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`WO 2004/028509
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`PCT/US2003/029757
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`employable 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
`
`products that are not pH sensitive. Examples of such coating products include the neutral
`methacrylic acid esters With a small portion of trimethylammonioethyl methacrylate
`
`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. NEBOD and EUDRAGITRTM. NESO; and
`
`other pH independent coating products.
`
`‘
`
`A conventional protective coating layer may also be applied immediately outside I
`
`the core, either a drug-containing matrix core or a drug—layered core, by conventional
`
`coating techniques such as pan coating or fluid 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, polyvinylpyrrolidone/vinyl acetate copolymer, ethyl cellulose
`aqueous dispersions (AQUACOATRTNL, SURELEASE.RTM.), EUDRAGITRTM. RL
`
`30D, OPADRYRTM. and the like. The suggested coating levels are from 1 to 6%,
`preferably 2-4% (w/w).
`I
`
`An overcoating layer can further optionally be applied to the composition of the
`
`present invention. OPADRY.RTM., OPADRYJIRTM. (Colorcon) and corresponding
`
`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 ofprotective or color
`
`coating are froml to 6%, preferably 23% (w/w).
`
`Many ingredients can be incorporated into the overcoating formula, for example
`
`to provide a quicker (immediate) release, such as plasticizers: acetyltriethyl citrate,
`
`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 silicate, and the like.
`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
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`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 byzconventional coating techniques such as pan coatingor
`fluid 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, cellulose acetate
`
`propionate, ethyl cellulose, fatty acids and their esters, waxes, zein, and aqueous polymer
`dispersionssuch as EUDRAGITRTM. RS and RL 30D, EUDRAGITRTM. NE 30D,
`
`AQUACOAT.RTM., SURELEASE.RTM., cellulose acetate latex. The combination of
`
`the above'pnolyme'rs and hydrophilic polymers such as hydroxyethyl cellulose,
`hydroxypropyl cellulose (KLUCELRTM, Hercules Corp), hydroxypropyl
`methylcellulose (METHOCELRTIVL, Dow Chemical. Corp), polyvinylpyrrolidone can
`
`also be used.
`
`Principles of sustained release formulation 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 Pharmaceutical Dosage Forms: Tablets, volume 3, edited by HA.
`
`‘
`
`Lieberman, L. Lachman, and IE. Schwartz, Marcel Dekker, Inc., 1991; RJ. Campbell
`
`and G.L. Sackett, chapter 3: “Film coating,” in Pharmaceutical Unit Operations: Coating,
`edited by K.E. Avis, AJ. Shukla, and R.K. Chang, Interpharm PreSS, Inc., 1999, whose
`disclosures are entirely incorporated by reference herein.
`‘
`This invention also relates to use of the SR formulations to treat indications other
`
`than ADI-ID at dosages and in regimens analogous to those described herein. These
`include but are not limited to Alzheimer’s disease and other memory disorders,
`fibromyalgia, chronic fatigue, depression,.obsessive compulsive disorder, alone or in
`combination with a SSRI; oppositional defiant disorder (ODD), with or without ADHD
`
`and with or without 'guanfacine or welbutrin; anxiety, with or without ADHD and alone
`
`or in combination with an anxiolytic or SSRI; resistant depression; stroke rehabilitation;
`Parkinson’s disease; mood disorder; schizophrenia; Huntington’s disorder; dementia, e.g.
`
`AIDS dementia and frontal lobe dementia; movement disfunction; apathy; fatigue; Pick’s
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`disease; sleep disorders, e.g., narcolepsy, cataplexy, sleep paralysis and hypnagogic
`
`hallucinations; etc.
`
`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 belformulated 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 occitr, 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 apatient.
`These other therapeutic agents include e.g., for Alzheimer’s: Reminyl, Cognex,
`
`Aricept, Exelon, Alcatinol, Neotrop in, Eldepryl, Estrogen, Clioquinol,
`Ibuprofen, and Ginko Bilboa; for ADI-ID: methylphenidate (e.g., Ritalin), Dexedrine,
`Adderall, Cylert, clonidine, guanfacine, etc; for depression: Prozac, Zoloft, Paxil,
`
`Reboxetine, Wellbutrin, Olanzapine, F1uoxetine,.Elavil, Totranil, Parnelor, Nardil,
`Parnate, Desyrel, and Effexor; for mood disorder: Thorazine, Haldol, Navane, Mellaril,
`
`Clozaril, Risperdal, Zyprexa, Clozapine, Risperidone,‘and Olanzapine; for fatigue:
`
`benzodiazapines, Anaprox, Naprosen, Prozac, Zoloft, Paxil, Effexor, and Desyrel; for
`
`fibromyalgia: Dilantin, Carbatrol, Epitol, Tegretol, Depacon, Depakote, Norpramin,
`
`1
`
`‘ Aventyl, Pamelor, Elavil, Enovil, Adapin, Sinequan, Zonalon, and non-steroidal.
`inflammatory drugs; for oppositional defiant disorder (ODD): clonidine, Risperidone, and
`
`Zyprexa; for apathy: Amisulpride, Olanzapine, Visperidone, Quetiapine, Clozapine, and
`Zotepinei; for Parkinson’s disease: Levodopa, Parlodel, Permax, and MIRAPEX; for
`schizophrenia: 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, Modafiml and Ritalin; for
`cataplexy: Xyrem; for hallucinations: 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,
`
`Tegretol, Anafranil, Norpramine, Adapin, Sinequan, Tofranil, Epitol, Janirnire, Parnelor,
`
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`Ventyl, Aventyl, Surmontil etc; selective serotonin reuptake inhibitors (SSRIS) including
`
`Prozac, Luvox, Serzone, Paxil, Zoloft, Effexor, etc, benzodiazepines, including Xanax,
`Librium, Klonopin, Valium, Zetran, Valrelease, Dalmane, Ativan, Alzapam, Serax,
`Halcion, etc, monamine oxidase inhibitors including Aurorix, Manerix, Nardil, Parnate,
`. etc.
`
`The entire disclosures of all applications, patents and publication, cited above, and
`
`below, are hereby incorporated by reference.
`
`Examples
`
`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.
`
`SR Coated Beads
`
`Example 1
`
`Mixed amphetamine salts loaded beads (MASL)
`
`500 gram
`
`Ethyl cellulose (Ethocel N-lo, Dow Chemical)
`
`15.46 gram
`
`Ethyl acetate
`
`_ 515 gram
`
`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 approximately
`twenty minutes and recovered to give a product of 97 % by weight MASL beads and 3%
`by weight ethyl cellulose coating.
`'
`7
`
`Example 2
`
`_
`
`Mixed amphetamine salts loaded beads
`
`500 grams
`
`Ethyl cellulose (Ethocel N~10, Dow Chemical)
`
`37.78 grams
`
`Hydroxypropyl cellulose (Klucel LF, Aqualon)
`
`8.70 grams
`
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`Methylene chloride
`
`744 grams
`
`Methanol
`
`186 grams
`
`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’lO 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
`Icellulose/hydroxypropyl cellulose coating.
`
`Example 3
`
`Mixed amphetamine salts loaded beads
`
`500 gram
`
`Surelease (Ethyl cellulose~based dispersion, Colorcon) 173.92 grams
`
`Water
`
`43 .48 grams
`
`Surelease (173.92 grams) wasdiluted with 43.48. grams of water. Into a Wurster ‘
`1
`column (Verset-Glatt, Glatt Air Techniques) was charged 500 grams ofMASL beads
`which were then coated with the coating mixture under conditions of 60°C inlet
`
`temperature, spray pressure 1 bar, and spray rate 6 grams/min. The line was rinsed with
`
`water 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 coating.
`1
`
`Example 4
`
`Mixed amphetamine salts loaded beads
`
`500 grams
`
`Eudragit RS3 0D
`
`111249 grams
`
`Triethyl citrate _
`
`10.03 grams
`
`Water
`
`115 .94 grams
`
`Triethyl citrate was mixed into Eudragit RS30D for 30 min. The plasticized Eudragit
`
`RS3 OD was diluted with water and filtered through a 60-mesh screen. Into a Wurster
`
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`column was charged 500 grams of M