I|||||||||||||||||||||||||||||||||||||||||||
`
`US0089064l3B2
`
`(12) United States Patent
`Chang et al.
`
`(10) Patent No.:
`
`(45; Date of Patent:
`
`US 8,906,413 B2
`Dec. 9, 2014
`
`(54) DRUG I’()RMUl.ATIO-.\'S HAVING REl)U(TED
`ABUSE POTENTIAL
`
`(56)
`
`References Cited
`
`U,S. PATENT DOCUMENTS
`
`(7S}
`
`Inventors: Rong—Kun Chang. Rockville. MD (US):
`Richard A. Couch. Chevy Chase. MD
`(US): Beth A. Burnside. Bethesda. MD
`(US)
`
`(73) Assignee: Supernus Pharmaceuticals, Inc..
`Rockvillc. Ml) (US)
`
`( "‘ J Notice:
`
`Subject to any disclaimer, the term oftiijs
`patent is extended or adjusted under 35
`U.S.(.‘. l54(b)by [073 days.
`
`FP
`
`3.079.303 A
`3.383.283 A “‘
`4.070.494 A
`4.401.679 A
`4.451933 .-\
`4.834.965 A
`S.t62.34t A
`5.236.714 A
`
`2r'l963 Raff et al.
`5-“I968 Brindamour ................ .. 4243490
`l.-'19‘.-‘S
`I-Iollineister etal.
`3"l983 Portoghese
`7.-‘I984 Gordon ct al.
`5.-‘I939 Martanictal.
`ll.-‘I992 Cook
`3.-"I993 Lee elal.
`
`
`
`SI4-'31?
`424-"449
`
`((.‘o11tintIi.'d]
`
`FOREIGN PATENT DOCUMENTS
`
`I52004
`l 382 331 Al
`OTHER PUBLICATIONS
`
`(21) Appl.No.:
`
`llJ:’435.,597
`
`(22)
`
`Filed:
`
`May 12, 2003
`
`(65)
`
`Prior Publication Data
`
`US 20()4!0228802 Al
`
`Nov. 18. 2004
`
`(51)
`
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`
`Int. Cl.
`/t6IK 9.190
`.46IK 9/50
`Acsrx 9,/70
`A6IK 31/00
`.461K 9/28
`(52) U.S. Cl.
`(‘PC ........... .. A6IK 9./7061' (2013.01): .46IK 9/’5078
`(2013.01); AISIK 9/205 (2013.01); /t6l'K 9/2013
`(2013.01): A6111’ 9/7069 (201301 ); A6IK
`31/00 (2013.01); .46l'K 9/2846 (201301 ): AGIK
`9/5084 (20I3.0J); A6l'K 9./2018 (2013.01)
`4241489: 424/451; 4243464: 424:"-’-190
`
`USPC.‘
`
`(58) Field of Classification Search
`CFC
`A6lK 9:’l6'.": A6lK 9a"l676: AGIK 95078:
`AGIK ‘M5073:
`.’\6lK 310-185
`See application tile for complete search history.
`
`Non—Fina.l Ollice Action mailed on Apr. 7. 2009 in [.'.S. Appl. No.
`ll."2 50.309.
`1 l pages.
`Matsehiner et :1]. “Characterization of ion pair fonnation between
`erytlumnycin and ii pophil ic counter ions." Pharlnazie. I 995. vol. 50.
`pp. 452-454.
`
`(Continued)
`
`Primary E.\'o‘.m:'ncr — Lakslltni Cljamlavajjala
`(74) A.-‘!orm:_1'.Agent. 0rFt'rm — Foley & Lardner LLP: Sunjt
`Talapatra
`
`ABS'l‘RAC'l‘
`(57)
`Drug forntulations ltaving reduced abuse potential which
`contain one or more of (1) a bittering agent. (2) a bright
`deterrent/‘indicator dye and (3) fine insoluble panicttlate mat-
`ter. The bittering agent and dye are in a Form wltieh does 11ot
`afl'ect proper administration of tl1e drug, but the bittering
`agent creates a bitter side effect when the dosage form is
`cnlshed or chemically extracted a11d nasally. orally. buccally
`or sublingually administered and the dye produces a bright
`color when crushed and contacted. The line insoluble particu-
`late matter hinders extraction oi‘ the drug from the dosage
`lbrtn and. when crushed. can deter intravenous injection
`because of the presetiee of the insoluble particles or hinder
`injection by blocking an intravenous needle. The bright color
`of the dye. when extracted. also has a psychologically deter-
`rent effect on intravenous abusers.
`
`23 Claims, 1 Drawing Sheet
`
`Mun Ulasolutlon Profiles tor Exam rile‘-I 4. 5. and 8
`
`‘IUD
`
`Pucant
`
`Dissolved E _._ Example 4
`
`- -
`|
`-35- Example GB
`_._Exan1p|e6A
`T...‘
`
`
`
`14‘I2 16 Z0
`22
`N
`I5
`
`—»4— Example 5
`
`—
`- —
`
`Amerigen Ex. 1028, p. 1
`Amerigen Ex. 1028, p. 1
`
`

`
`US 8,906,413 B2
`Page 2
`
`(56)
`
`References Cited
`
`US. PATENT DOCUMENTS
`
`9,1999 Nm-|1ng¢1a[,
`5_953_45g _.\
`9.-2000 Seiiers eta].
`5.124.232 A
`132009 Skinhoj
`5'1 5959; A
`22900]
`J In
`t
`l.
`6.187.341 Bl‘
`srznm P:1crT::::t :1.
`6.228.863 131
`6-27?-384 B1 W01 Kaikom
`-"r'l4I'250 B2:
`[M2006 O5hl“°k"tal'
`7.214.385 B2
`502007 Gruber
`2003-0064099 Al *
`4-‘Z003 Ushlack er al-
`200330064122 Al
`4.52003 Goldberg er al.
`20030091635 Al
`102003 Baichwal ct al.
`
`............ .. 514.-227.5
`
`4243480
`..
`.. 514.232
`
`-- W400
`4243090
`42445]
`424.='465
`
`OTHER PUBLICATIONS
`Ran er al.. “Effect of Sodium Lauryl Sulfate on the Release of
`Rilhmpicin frmn guar gum MaLrix." indian Jo1m1.1l 01' Pharmaceuti-
`ca] Sciences. Sep.-Oct. 2000. pp. 404-406.
`Wells el 91.. “lF.II'ect ol’ Anionic Surfaclarlls on 01: Release of
`Chlorphcnmmnc Mamie ff0_m an IWL f1°1°r03°1=°0l=5 Matrix-."
`Pgglggvclomnentmd 1l']d1lSLl'l3l Pharlnacy. l992.vo]. l8.I\o.2.pp.
`,
`Z
`'
`,
`‘_ _
`.
`.
`“}“‘°5§°’“‘l*" °‘ 1"
`“f"“';:-3 °"“”‘:."". “"]'[’},,"r:"’g”g."-"‘_““°}
`’J.°e’£'33Zi.3‘.‘IZ’£.?.§Z3°§.§"E1.i?"§Ii§o§’,L.o‘I.°i32.‘E,’§‘§{¢§I’ii??he.;oa.e‘f1ch..°§o‘§.:
`and it's adsorption to small and middle size molecules" 1.
`Micmem,ap5u]aIiOn_ 1995‘ VOL 13‘ 1\'o_5‘pp_5g5_5l4_
`1-'ina] (Jffice Action in us. Appl. No. 11.-'25o,3o9 dated Scp. 24.
`2012.
`
`200650083690 Al
`
`40006 Chang
`
`* cilcd by examiner
`
`Amerigen Ex. 1028, p. 2
`Amerigen Ex. 1028, p. 2
`
`

`
`US. Patent
`
`Dec. 9, 2014
`
`US 8,906,413 B2
`
`
`
`
`
`mucu.m.vmu_nEnxmgo.moEoE=2.=_o$_n.Ems.
`
`
`
`mmm._aEmxm.Ix!mwEEmxmIxl
`
`
`
`.3m_n_Emxm_lol
`
`wmEEmxwIol
`
`mmonS
`w_.E.2Sm
`
`
`
`__E..__o£oE_._.
`
`panqossgg ;ua:uad
`
`Amerigen Ex. 1028, p. 3
`Amerigen Ex. 1028, p. 3
`
`

`
`US 3,906,411 3 B2
`
`1
`DRUG FORMULATIONS HAVING REDUCED
`ABUSE P0'l‘El\"I'lAL
`
`FIELD OF THE INV"EN'l'ION
`
`This invention relates to dosage forms ofprescription psy-
`choactive drug. liirmulations having El reduced potential for
`abuse and to methods of reducing the potential for abuse of
`dosage forms of prescription psychoactive drugs.
`
`IE]
`
`BACKGROUND OF 'l'liE INVENTION
`
`Prescription psychoactive drugs can help patients manage
`chronic or severe pain, restore emotional or behavioral hal-
`anee, control sleep disorders. or fight obesity. When such
`prescription medications are abused. however. the conse-
`quences, including addiction. can be dangerous. even deadly.
`The risks associated with abuse o fthree classes ofcoinmonly
`abused prescription drugs. i.e._. opioids; central nervous sys-
`tem (CNS) depressants. including sedatives and tranquilizers;
`and stimulants. are well documented.
`Opioids include morphine, codeine. and related drugs such
`as oxycodone (Percodan and OxyContin)_. hydrocodone (Vi-
`codin), and meperidine {I)emerol) and are connnonly pre-
`scribed to relieve pain. Taken as prescribed. opioids can be
`used to manage pain ellectiveiy without‘ unwanted side
`ellects. Chronic use of opioids can result in tolerance. wliich
`means that users must take higher doses to achieve the same
`efl'ects. Long-term use also can lead to physical dependence
`and addiction. W"1thdrawal can occur when an individual dis-
`continues use ofthe drugs. Withdrawal symptoms can include
`restlessness. muscle and bone pain. insonmia_. diarrhea, vom-
`iting, cold Flashes with goose humps. and involuntary leg
`movements. Individuals who are addicted to opioids are more
`likely to overdose on the drugs. which could be fatal.
`Among the most conmionly prescribed CNS depressants
`are barbiturates. such as inephobarbital (Mebaral) and pen-
`tobarbital sodium (Nembutal). which are prescribed to treat
`anxiety. tension, and sleep disorders: and benzodiazepines.
`such as diazepam (Valium) and alprazolam (Xanax). which
`typically are prescribed to treat anxiety. acute stress reactions.
`and panic attacks. Other benzodiazepines, such as triazolarn
`(I-Ialcion) and estazolam {ProSom). are prescribed for short-
`term treatment of sleep disorders. Although the various
`classes ol'C‘NS depressants work di lferently, they all produce
`a benelicial drowsy or calming effect in individuals sul'fering
`from sleep disorders or anxiety. However. if one uses these
`drugs over a long period of time. the body will develop
`tolerance. and larger doses will be needed to achieve the
`initial ellects. In addition, continued use can lead to physical
`dependence and. when use is reduced or stopped. withdrawal.
`Both barbiturates and benzodiazepines have the potential For
`abuse and should be used only as prescribed. As with opioids.
`an overdose of these drugs can be fatal.
`Stimulants increase heart rate, blood pressure and 1netabo—
`lism. provide feelings of exhilaration and energy. and
`increase mental alertness. Stimulants such as methy1pheni-
`date
`(Ritalin)
`and dextroamphetamine
`{Adderall
`and
`Dexedrine) are prescribed for the treatment of narcolepsy,
`attention-deficitfltypetactivity disorder. and depression that
`has not responded to other treatments. They also may be used
`for short—term treatment of obesity. Individuals may become
`addicted to the sense of well—being and enhanced energy that
`stimulants can generate. Taking. high doses of stimulants
`repeatedly over a shor1 time. however. can lead to feelings of
`
`3U
`
`35
`
`4t":
`
`45
`
`50
`
`55
`
`60
`
`2
`
`taking l1igl1 doses of
`hostility or paranoia. Additionally.
`stimulants may result in dangerously high body temperatures
`and an irregular heartbeat.
`Abuse potential ofthese three classes of drugs is of major
`concern. This is specially true for opioids and stimulants and
`hence they are classified by the Drug Iitlforceinent Agency
`(DEA) as Schedule II drugs [substances that have a high
`potential for abuse with severe liability to cause psychic or
`physical dependence. but have some approved medical use).
`Various dosage forms of psychoactive d.rugs for medical
`use are available or possible. These include capsules. tablets,
`transdermal patches and liquid suspensions. For example_.
`methylphenidate (Ritalin) is available in oral. tablet and
`extended-release tablet dosage forms. Ikxtroamphetarnine
`(Adderall)
`is available in imrnediate-release tablet and
`extended-release capsule dosage forms. Metliylphenidate.
`aniplietamine. fentanyl. 3-methyl fentanyl. morphine. eter-
`phi ne. etc. can be incorporated into transdcrmal patches. A
`Fentanyl patch (Duragesic) is already in the marketplace and
`a methylpbenidate patch [Methypatch) is under FDA review.
`Liquid suspensions of drugs in innnediate release and sus-
`tained release lorms are also possible. A sustained release
`system can be formulated by using drug ion-exchange com-
`plex particles with a further coating of ethyl cellulose. The
`ion-exchange teclmology makes reliable liquid controlled-
`release possible for many ionic drugs. which include amphet-
`amine, methylpheiiidate, hydrocodonc, codeine. morphine,
`and the like.
`
`These various dosage forms provide valuable medical bett-
`efits when properly taken or administered. but also have a
`high potential for abuse. For example, sustained release dos-
`age forms are abused by crushing or chewing and then swal-
`lowing or snorting or by mixing or dissolving in water or the
`like and then ‘injecting. 'I'1'a1'Ls dermal patches can be chewed to
`provide a quick onset via buccal. sublingual. or oral absorp-
`tion of the controlled substances. In addition, a significant
`drug residue after normal administration of the patches is
`quite common. Such residue can be extracted and concen-
`trated for abuse. Liquid suspensions can be similarly concen-
`trated and abused.
`
`It view ofthese problems. new and improved dosage forms
`of psychoactive drugs having decreased abuse potential are
`desired. Several approaches to reducing the abuse potential of
`dosage forms of drugs can be found in 1J.S. patents. These
`include. for example. the incorporation of an opioid antago-
`nist into a dosage form (US. Pat. Nos. 4.401.672. 4.457.933.
`5,162.3-=11. 5,236,714, 6.277.384 and 6.228.863). the use of
`cytochronie P450 2D6 enzymt: inhibitor (US. Pat. No. 6.124.
`282). and the incorporation of a water solublergelable mate-
`rial into a dosage form (U.S. Pat. No. 4.070.494). I-lowever.
`these approaches still are far from ideal in terms of the elTec-
`tiveness of deterring someone from abusing the medication
`by snorting or improper oral administration
`
`Ol3Jl.i(_"l' 0]" ll ill INVF.N'I"ION
`
`It is an object of the present invention to reduce the poten-
`tial tor abuse o fdo sage l'o rms o fpsychoactive drugs and other
`drugs of abuse and to provide dosage fomis of psychoactive
`drugs having a reduced potential ior abuse. More particularly,
`it is an object of the present invention to provide oral dosage
`forms of opioids. CNS depressants a11d stimulants that have
`increased effectiveness in deterring abuse by snortingJinject-
`ing or the like.
`
`Amerigen Ex. 1028, p. 4
`Amerigen Ex. 1028, p. 4
`
`

`
`3
`SUMMARY OF THE INVENTION
`
`US 3,906,411 3 B2
`
`4
`
`According to the present invention dosage forms of psy-
`choactive drugs. which have reduced abuse potential are pro-
`vided by adding one or more of the following to the dosage
`forms:
`
`[I ) a bittering agent i11 a form which does not create a bitter
`taste when a dosage form ofthe drttg is properly admin-
`istered. but which creates a bitter side effect when the
`dosage forrn is crushed or chemically extracted for nasal
`(snorting). oral. buccal or sublingual administration:
`(2) a bright deterretttfittdicator dye in a form which does
`not create color when a dosage form of Lhc drug is
`properly administered. bttt which colors or stains the
`nose. 111outl1 or hands when the dosage form is crushed
`or cliemically extracted: and
`(3)
`fine insoluble particulate matter which does not
`adversely affect the human body when a dosage form of
`the drug is properly administered. bill which hinders
`extraction of the drug from the dosage form and can
`deter intravenous injection because of the presence of
`the insoluble particles or hinder injection by blocking
`the intravenous needle.
`
`BRIEF DESCRIPTION OF THE DRAWING
`
`The drawing is a graph showing the mean dissolution pro-
`files of the drug formulations prepared in Examples 4. 5 and
`6.
`
`DE'l‘AILliI) l3XPI.ANA'l‘I()N O1"-' 'l‘l-ll£
`lNV'EN'I'ION
`
`The psychoactive drug (Le. a drug that alfocts the central
`nervous system] of the dosage fonn ofthe present invention is
`not particularly limited insofar as the drug is approved for
`medical use in dosage form and has a potential for abuse. The
`drug includes opioids. central nerve system (CNS) depres-
`sants and stimulants such as. for example. drugs sold com-
`tnercially uttder the trademarks Adderall XR. Matadate C‘ D.
`Kadian. Oramorph SR. MS Contin. Oxycontin and the like.
`The bittering agent andfor indicator dye to be incorporated
`into the dosage forms of the present invention is used in a
`form which does not exhibit its deterrent efiect when a dosage
`form of the drug is properly administered, but exhibits a
`deterrent eifect when the dosage form is chewed. crushed or
`chemically extracted for nasal (snorting), oral. buccal or sub-
`lingual administration. The bittering agent andfor indicator
`dye can be incorporated i11to granules. beads. or mini-tablets
`which can be sttbsequently coated with a suitable barrier
`coating to prevent against leakage of the bittering agent and
`indicator dye and to minimize or prevent absorption of the
`bittering agent and indicator dye under nomtal dosage admin-
`istration conditions. These granulesfbeadsftnini-tablets can
`be encapsulated orcotnpressed with the drug ofinterest or can
`be used as coating substrates for drug layering and fttrther
`enterict'sustained—release coatings.
`The sizes of the granules. beads and mini-tablets is not
`limited as long as the granules can be incorporated into the
`dosage forms of the invention. Typically. the granules and
`beads have a size ofS0 pin to 4000 tun. The mini-tablets have
`a size which is typically significantly smaller than common
`tablets {<9/32 inch diameter). When granules. beads or mini-
`tablets containing a bittering agent and.r’or a dye indicator and
`not containing a drug are encapsulated with granules. beads
`or mini-tablets containing an active pharmaceutical ingredi-
`ent (A131). the granules, beads or mini-tablets are preferably
`
`.3
`
`10
`
`3h
`
`35
`
`4t":
`
`45
`
`50
`
`55
`
`60
`
`ofthe sa111e size to make it diflicult for the respective beads to
`be distinguished and separated.
`Altematively. the bittering agent andfor indicator dye can
`be incorporated directly into a drug formulation and the
`resultant formulation incorporated into granules. beads, or
`mini-tablets. Subsequently. a barrier coating is applied to
`ensure against leakage ofthe bittering agent and indicator dye
`under normal dosage administration conditions. The resultant
`coated granules. beads or tnini-ta blets ofthe drttg formulation
`are thereafter encapsulated or compressed into tablets.
`When used in a transdermal patch fonnulation. the bitter-
`ing agent andfor indicator dye can be used in the fonn of the
`above—described granules. beads. or mini—tablets coated with
`a suitable barrier coating. The bittcring agent can also be
`added directly to the transdermal drug formulation.
`The bittering agent useful in the present invention includes
`any pltarmaceutically acceptable bitter substance that creates
`a bitter taste or side eflixt when administered nasally
`(snorted). orally. bucally or sublingually. Such agents
`include. but are not litnited to. sucrose octaacetate, denato—
`nium saccharide. denatoniunt benzoate. caffeine. quinine (or
`a quinine salt such as quinine sulfate), bitter orange peel oil.
`and other botanical extract ingredients, such as pepper extract
`(Cubeb}. capsicum, and the like. The preferred bittering
`agents are sucrose octaacetate. denatonium saccharide and
`denatonium bcnzoatc because they are inexpensive. show an
`unusually pronounced bitter tasting effect at low concentra-
`tions and are essentially non-toxic in the low concentrations
`used in the drug fonnulations of the invention.
`Sucrose octaacetate is a USPINF material and is an
`
`intensely bitter compound and has been used in the industry
`as a bittering agent or a denaturant for alcohol. Denatoniunt
`benzoate is the chemical name for Bitrex. an exceptionally
`biner substance, which has been added to appropriate home
`care products. Denatoniunt saccharide is reportedly four
`times more bitter than dcnatonitun benzoate. When a product
`contains sucrose octaacetate. denatonium benzoate or dena-
`tonium saccharide. it has such an intensely nasty taste it is
`practically impossible for a person to ingest it.
`The bittering agent is used in an amount of from 0.0] to
`10% by weight and, preferably. 0.1 to 4% by weight and, most
`preferably. 0.1 to 0.5% by weight based on the weight ofa
`dosage form of the pharmaceutical formulation into which
`the agent is incorporated.
`The indicator dye useful in the invention includes any dye
`that is pharmaceutically acceptable attd that
`is capable of
`providing an intense. bright color on the nose. mouth and
`hands after a pharmaceutical formttlation containing the dye
`is crushed or dissolved. The bright color also can have a
`psychologically deterrent effect on intravenous abusers. Such
`dyes include. but are not limited to allura red. amaranth,
`brilliant bltte. canthaxanthin. carrnine. carmoisine. carotene,
`curcumin. erythrosine. green S. indigo cartnine. iron oxide
`black. iron oxide red. iron oxide yellow. patent blue. pltloxine
`O. ponceau 4R. qttinoline yellow. riboflavin. sunset yellow.
`tartrazine.
`titanium dioxide. vegetable carbon black. and
`other natural colors such as annatto, beet, black carrot. black
`currant.
`caramel.
`camtine.
`carmine lake. chlorophyll.
`cocltineal. elderberry. grapcskinfgrape juice. malt. paprika.
`red cabbage. turmeric. and anthocyanins. Riboflavin is a pre-
`fen'ed indicator because it can also be used as a tracing agent
`for easy urine detection of drug abusers.
`The amount ofthe dye indicator used in the dosage form of
`the pharmaceutical fonnulation will vary with the particular
`dye used but. typically. the dye indicator is used in an amount
`of 0.01 to 20% by weight and. preferably, 0.1 to 10% by
`
`Amerigen Ex. 1028, p. 5
`Amerigen Ex. 1028, p. 5
`
`

`
`5
`
`US 3,906,411 3 B2
`
`6
`
`weight, and, most preferably. 0.1 to 5% by weight. based on
`tl1e weight of a dosage form of the phannaceutical formula-
`tion.
`
`The granules. beads. mini-tablets and tablets of the bitter-
`ing agent andfor dye indicator and of the drug formulations
`containing the bittering agent andfor dye indicator can be
`made by various known pharmaceutical processes, such as
`roller compacting. and solutioitfslurrylpowder layering in a
`fluid bed or other appropriate coating equipment. and com-
`pressing in a tablet press. lit a particularly preferred embodi-
`ment. core seeds such as non-pareil seeds are coated with a
`layer of the bittering agent andfor dye indicator and a barrier
`coating is applied to the layered core seeds.
`The barrier coating applied to the granules. beads or mini-
`tablets containing the bittering agent andlor dye indicator or
`to granules. beads, mini-tablets or tablets of drug formula-
`tions containing the bittering agent andfor dye indicator to
`minimize or prevent leakage of the agent and dye and to
`minimize absorption of the agent and dye under normal cort-
`ditions of dosage administration can be a protective coating.
`enteric coating or sustained release coating or various com-
`binations ofthese coatings. In a preferred embodiment. gran-
`ttles, beads or mini-tablets containing the bittering agent and!
`or dye indicator and not containing the drttg are coated with a
`non-dissolving phannaccutically acceptable polymer coating
`which does not dissolve or release under conditions existing
`in the G} tract. With such a coating. the bittering agent andfor
`dye indicator is not released in the human body when properly
`administered and is released only when a drug formulation
`including the granules, beads or mini-tablets coated with the
`non-dissolving coating is crushed for non-prescribed pur-
`poses.
`The barrier coating may be applied by conventional coat-
`ing tcclutiques such as pan coating or lluid bed coating using
`solutions of polymers ir1 water or suitable organic solvents or
`by using aqueous polymer dispersions.
`Materials useful as a protective coating are well-known in
`the art and include, for example. cellulose derivatives such as
`hydroxycthyl cellulose. hydnoxypropyl cellulose. hydrox-
`ypropyl
`tnethylcellulose. polyvinylpyrrolidone.
`polyvi-
`nylpyrrolidonelvinyl acetate copolymer. and pH dependent
`cationic polymers soluble in gastric fluid up to pH 5.0 such as
`those sold under the trademarks EUDRAGIT E 100 and
`
`EUDRAGIT EPO. The suggested coating levels are from 1 to
`6%, preferably 2-4% (wlw).
`The enteric coating layer can be any pl--1-sensitive polymer.
`which dissolves at a pl-I greater than 4.5. after a certain
`delayed time. or after the coated unit passes through the
`stomach. The preferred delay time is in the range of two to six
`hours. Suitable enteric polymers include cellulose acetate
`phthalate. cellulose acetate trimellitate. hydroxypropyl meth-
`ylcellnlose phthalate. polyvinyl acetate phthalate, carboxym-
`ethylethylcellu lose. and co-polymerized methacrylic acid!
`methacryl ic acid methyl esters such as. for instance. materials
`sold under the trademarks EUDRAGIT L100. EU DR.'\Gl'l‘
`L100-55. EUDRAGIT L 30 D~55 or EUDRAGIT S100 or
`
`similar compounds used to obtain enteric coatings. The sug-
`gested coating levels are from 1
`to 6%, preferably 2—4%
`(wfw).
`The enteric polymers can be modified by mixing with other
`known coating products that are not pH sensitive to provide
`sustained controlled release. lixarnples of such coating prod-
`ucts include the neutral methacrylic acid esters with a small
`portion of trintethylanunonioethyl methacrylate chloride,
`sold currently under the trademarks EUDRAGIT RL 30 D,
`IiUl)RA(}l‘l' RL P0. l-£1Jl.'JRAGl’l‘ Rt, 100. l-.iUI'Jl{A(iI’t‘ RS
`30 D and other pl-I independent coating products.
`
`10
`
`3o
`
`35
`
`4t":
`
`45
`
`50
`
`55
`
`60
`
`The pharrnaceutically acceptable ooating that does not dis-
`solve in the GI tract
`includes cellulose acetate. cellulose
`acetate butyrate. cellulose acetate propionate. ethyl cellulose.
`poly[ethyl acrylate), poly[methyl methacrylate). and poly(t-
`ritnethylammonioethylmethacrylate chloride). Suitable coat-
`ing levels are those that prevent premature leakage of the
`bittc-ringjcoloring (dye) agent and depend on the coating
`used. Coating levels range. for example, from ] to 60% (wlw).
`An overcoating layer can further optionally be applied to
`the composition of the present
`invent ion. Ol-"ADRY®.
`OPADRY lltfit (sold by Colorcon} and corresponding. color
`and colorless grades from (Tolorcon can be used to protect the
`pellets from being tacky and to provide color to the product.
`Additiolially, Kollicoat IR (sold by HASP) with or witliotlt
`colorants and opacifiers can be used as an overcoating layer.
`The suggested levels ofprotective or color coating are from 1
`to 6%, preferably 2-3% (w/w}.
`In an alternative embodiment. insoluble particulate matter
`is used in the phanuaceutical formulat ions to hinder drug
`abusers from extracting the drug from the dosage units. to
`deter drug abusers. because olithe insoluble paniculate mat-
`ters, from injecting the formulations intravenously. and to
`hinder the injection because ofneedle blocking. Suitable fine
`solid particulate materials include, bill are not limited to_.
`Noveoniv AA-l polycarbophil, Etlioceltffii Fl’. methacrylic
`acid copolymer {e.g.. F.udragit!Ri L100-55. Eudragitiiit S100).
`microcrystalline cellttlose (e.g.. Aviceltfil Pl] 102). sodium
`starch glycolate. crospovidonc, croscarmellose sodium. tal-
`cum, and silicon dioxide. The size of the particles is selected
`such that the particles are easily suspended in the extraction
`media to hinder the extraction and block a needle while inject-
`ing. The usual particle size is from 1 pm to 150 um and.
`preferably. from 1 pm to 50 tun.
`The insoluble fine particles can be included in the deterrent
`granules beads or mini-tablets that contain the bittcrirtg a ent
`andlor the dye indicator with or without the drttg of interest.
`Alternatively. the insoluble fine particles can be encapsulated
`or compressed with the drug-containing granules. beads or
`mini-tablets.
`
`The water-insoluble agent is used in an amount of from 5 to
`80% by weight and, preferably, from S to 40" u by weight. and,
`most preferable, from 5 to 10% by weight. based on the
`weight of a dosage form of tlie pharmaceutical formulation
`into which the agent is incorporated.
`
`EXAMPLES
`
`The following examples are presented to illustrate embodi-
`ments of the invention. The invention. however. is not limited
`to these embodiments but. instead, includes all those embodi-
`ments within the spirit and scope of the intended claims.
`
`Example 1
`
`The formulation in Table l is used to layer a bittering agent
`(sucrose octaacetate) and an indicator dye (tartrazine) onto
`sugar spheres. Nonpareil seeds (30335 mesh, Paulaur Corp.
`NJ). 6.8 kg are put into a Glatt GPCG— 15 fluid bed processor
`with a 9" Wurster column and fluidized at 60° C. The coating
`system containing sucrose octaacetate. tartraziue, and l-IPMC
`E5 Premium (Dow Chemical} as a binder is sprayed onto the
`seed under suitable conditions. Almost no agglomeration and
`no lines is observed with a yield of at least 98%. Subse-
`quently, a barrier coat is applied onto the sucrose octaacetate
`and tartrazine loaded beads to ensure no leakage of the bit-
`tering agent and tartra zine dye illld to minimize the absorption
`of these agents in the gastrointestinal tract.
`
`Amerigen Ex. 1028, p. 6
`Amerigen Ex. 1028, p. 6
`
`

`
`US 8,906,411 3 B2
`
`7
`
`The procedure described above can be used to prepare
`beads loaded with either sucrose octaacetate or tarnazine and
`
`other bittering agents and other dyes can be substituted for the
`sucrose octaacetate and tarlrazine.
`
`TAl3I..l7. 1
`
`Ingredients
`
`Non-pareil seeds
`Sucrose octrtacetale
`Tartrztzine
`Metliocel ® E5 Premium
`W:lter
`
`Amotmt I[°/u}
`
`89.4
`5.0
`5.ti
`0.6
`"
`
`‘lcnitwcd d1.!t'll'|_E, proocssirlg
`
`Example 2
`
`The formulation in Table 2 is used to coat the beads from
`Example 1 with Euclragitffii E100 and subsequently with
`Eudragit® FS30D. 3.6 kg of beads (contain sucrose oetaac—
`etate and tartrazine) are loaded into a fluid bed processor with
`a Wurster column equipped with an l-IS nozrile ((jl’(‘(i-l5.
`Glatt Air'l’echniques). The Eudragititit E100 spray suspension
`is prepared by dispersing talc and dissolving the Eudragittls
`13100 in the organic solvent system (acetone: isopropyl alco-
`hol 50:50). Under suitable fluidiralion conditions, the coating
`system is sprayed onto tl1e fluidized pellets. Subsequently. a
`coating dispersion is prepared by dispersing triethyl citrate.
`talc and EUDRAGIT<E'= FS 30D into water and mixing for at
`least 30 minutes. Under suitable liuidization conditions. the
`coating dispersion is sprayed onto the fluidized Eudragitikl
`E100 coated beads. The spraying is continued until the tar-
`geted coating level is achieved (20 pm). The coated beads are
`dried at 30-35 C. for 5 minutes before stopping the process.
`Tale is added to the Eudragit'-R3 FS30D coated beads to mini-
`tni ze the static charge and to prevent the agglomeration of the
`beads. The enteric coated beads are tested in acidic medium
`and no leakage of the bitter agent and coloring agent is
`observed. The beads from this example can be encapsulated
`with sustained-release beads.
`irnmediate—release beads.
`delayed-release beads. or the combination of any of these
`types of beads. Also. the beads from the Example 2 can be
`compressed with sustained-release or immediate-release
`matrix tablet formulation to reduce the abuse potential.
`
`TABLE 2
`
`Ingredient
`
`Amotutt t 94:}
`
`Beads containing sucrose
`oct.'i.'1ccl:ttt: a.tId l:I.I’tra'I.i|1t:
`Eurlragit L35 E100
`Acetone
`lsopropyl alcohol
`E.tnir;tgit EBJ FSSUD
`Triethyl citrate
`Water
`'t':i1i:""
`
`‘removed dtrriiig pmccssirig
`
`63.0
`
`5.0
`"
`“‘
`26.34
`0.'lt3
`"
`t’a_u
`
`Example 3
`
`The formulation in TABLE 3 is used to layer mixed
`amphetamine salts onto sugar spheres. Nonpareil seeds (30!
`35 mesh, Paulaur Corp.. NJ), 6.8 kg are put into a Glatt
`(iP(_'(}-I 5 [inid bed processor with a 9" Wm-ster column and
`fluidized at 60° C. The suspension of mixed amphetamine
`
`1U
`
`3U
`
`35
`
`4t":
`
`45
`
`50
`
`55
`
`60
`
`65
`
`8
`salts with 1% HPMC E5 Premium (Dow Chemical}. sucrose
`octaacetate and tartrazine is sprayed onto the seed under
`suitable conditions. Almost no agglomeration and no fines are
`observed with a yield of at least 98%. The drug-loaded cores
`are coated with enteric and sustained release coatings.
`
`’l’Al3I..l.i 3
`
`Ingredients
`
`Amount t%I
`
`Nonpareil seed
`mixed atttphetaniine salts
`METHOCEL LE) ES Premium
`Sucrose oet:tzIr:e1aIe
`'1':1rtm.?.ir|t.:
`Water
`
`S2.t;tLJ
`11.40
`t'i.t3U
`3.0
`3.0
`‘
`
`'rcrntwcd din-mg processing
`
`Example 4
`
`The formulation in Table 4 is used to coat the beads coated
`
`with mixed amphetamine salts from lixamplc 3 with the
`liUl)RAGI‘l‘n‘li) 1. 3013-55 (Rohm Phat-ma, Gerniany) coating
`dispersion. 3.6 kg of amphetamine heads are loaded into a
`fluid bed processor with a Wurster column equipped with an
`HS no:r.;I.le (GPCG-l5. Glatt Air Techniques). The coating
`dispersion is prepared by dispersing triethyl citrate. talc and
`EUDRAGITIE L 30D—55 into water and mixing for at least 30
`minutes. Under suitable llttidization conditions. the coating
`dispersion is sprayed onto the fluidized mixed amphetamine
`salt loaded (MASL) beads. The spraying is continued until
`the targeted coating level is achieved (20 tun). The beads are
`further coated with 0PADRY=T'§' beige to prevent agglomera-
`tion during storage. The enteric coated amphetamine pellets
`are tested at different pH buffers by a USP paddle method.
`The drug content is analymd using [II-’l.,C. The mean disso-
`lution profile for the pellets is shown in the drawing. The
`results show that the enteric coating delays the drug release
`from the coated beads until alier exposure to pH 6 or higher.
`
`TABLE 4
`
`lngredieiits
`
`.-'\lIlnlI.l':l 1%]
`
`Ampitetanline beads from Example 3
`EIJDR.-\G1T CS5 L 30D-55
`'l‘rieLii_yl citr.-tte
`Talc
`O1’ADl{‘i' ® beige
`Water
`
`68.10
`2438
`252
`létil
`.?.t:
`"
`
`‘rcmovetl during processing
`
`Example 5
`
`The lormulation in Table 5 is used to coat the anipltetamine
`beads from I-Example 3 with F,lJl)RAGITlRi FSSOI) (Rohm
`Pharrna. Germany] coating dispersion. The amphetamine
`beads (3.6 kg) are loaded in a fluid bed processor with a
`Wurster colutrut (GPGC—15. Glatt ). The coating dispersion is
`prepared
`by
`dispersing
`triethyl
`citrate.
`talc
`and
`EIll)I{A('il'l'~1§= 1"S30[) into water and mixing for at least 30
`minutes. Under suitable fltiidization conditions. the coating
`dispersion is sprayed onto the fluidized amphetamine beads.
`The spraying is continued until the targeted coating level is
`achieved. The coated beads are dried at 30—35° C . for 5 min-
`
`utes before stopping the proeess. The enteric coated amphet-
`amine beads are tested using a USP paddle method at differ-
`ent pl-l buffers. The drug content is analyzed using I-IPL('.‘.
`
`Amerigen Ex. 1028, p. 7
`Amerigen Ex. 1028, p. 7
`
`

`
`9
`
`10
`
`US 8,906,411 3 B2
`
`The mean dissolution profile for the beads is shown in the
`drawing. The enteric coating delays the drug release from the
`coated beads for several hours until the pH value reaches 6.8
`or higher.
`
`TABI..li 5
`
`release beads obtained from Example 7. the delayed-release
`beads (beads from Example 7 further coated with enter-ic
`material). the sustained-release beads (beads from Example 7
`further coated with sustained-release material