(12) United States Patent
`Smith et al.
`
`US006194000B1
`US 6,194,000 B1
`Feb. 27, 2001
`
`(10) Patent N0.:
`(45) Date of Patent:
`
`(56)
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`4,859,461 * 8/1989 Chow et al. ......................... .. 424/79
`4,859,462 * 8/1989 Chow et al. .
`..
`5,084,278 * 1/1992 Mehta ................................ .. 424/441
`5,352,683
`10/1994 Mayer et al. .
`5,502,058
`3/1996 Mayer .
`5,834,479
`11/1998 Mayer et al. .
`5,840,731
`11/1998 Mayer et al. .
`
`OTHER PUBLICATIONS
`
`Chapman, C.R. et al., “Pain Measurement: an Overview”,
`Pain, 22 (1985) pp. 1—31.
`Hawthorn, Jan et al., “Management of Cancer Pain: Inter
`national Training for Cancer Nurses”, developed by Glaxo
`Wellcome in collaboration with The International Society of
`Nurses in Cancer Care, 1996, 6 pp.
`
`* cited by examiner
`
`Primary Examiner—James M. Spear
`(74) Attorney, Agent, or Firm—Cohen, Pontani, Lieberman
`& Pavane
`
`(57)
`
`ABSTRACT
`
`Disclosed is a method for the therapeutic treatment of pain
`related to wind up in a human or animal. The method of the
`invention is practiced by administering to the subject an
`effective amount of an analgesic pharmaceutical composi
`tion which includes a NMDA receptor antagonist in an
`immediate release form combined with an NMDA receptor
`antagonist in a sustained release form. The immediate
`release form and sustained release forn are present in suf
`?cient amounts to diminsh or abolish wind up.
`
`48 Claims, 2 Drawing Sheets
`
`(54)
`
`ANALGESIC IMMEDIATE AND
`CONTROLLED RELEASE
`PHARMACEUTICAL COMPOSITION
`
`(75) Inventors: Ian Keith Smith, Blair Athol; Grant
`Wayne Heinicke, Fairview Park, both
`of (AU)
`
`(73) Assignee: EH. Faulding & Co., Limited,
`Underdale (AU)
`
`( * ) Notice:
`
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 0 days.
`
`(21)
`(22)
`
`Appl. No.: 09/062,060
`Filed:
`Apr. 17, 1998
`
`Related US. Application Data
`
`(63) Continuation of application No. PCT/AU96/00658, ?led on
`Oct. 8, 1996.
`Foreign Application Priority Data
`
`(30)
`oct. 19, 1995
`
`(AU) ...................................................... .. 6057
`
`(51) Int. Cl.7 ............................. .. A61K 9/14; A61K 9/20;
`A61K 9/22; A61K 9/24; A61K 9/54
`(52) US. Cl. ........................ .. 424/458; 424/422; 424/423;
`424/436; 424/449; 424/451; 424/455; 424/457;
`424/464; 424/465; 424/468; 424/472; 424/473;
`424/489; 424/490; 424/483; 424/484; 424/485;
`424/486; 424/487; 424/488; 514/770; 514/772.2;
`514/772.3; 514/773; 514/777; 514/781;
`514/782; 514/783; 514/784; 514/785; 514/786;
`514/787
`Field of Search ................................... .. 424/464, 468,
`424/490, 422, 423, 436, 449, 451, 457,
`458, 483, 473, 455, 489, 472, 465, 484,
`485, 486, 487, 488
`
`(58)
`
`PEROEN TAGE
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`Page 1
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`U.S. Patent
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`Feb. 27, 2001
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`Sheet 1 0f 2
`
`US 6,194,000 B1
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`Page 2
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`U.S. Patent
`
`Feb. 27, 2001
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`Sheet 2 0f 2
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`US 6,194,000 B1
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`IPR2015-00410
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`Page 3
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`US 6,194,000 B1
`
`1
`ANALGESIC IMMEDIATE AND
`CONTROLLED RELEASE
`PHARMACEUTICAL COMPOSITION
`
`This application is a continuation of PCT/AU96/00658
`?led Oct. 18, 1996.
`The present invention relates to pharmaceutical compo
`sitions and is particularly concerned With pharmaceutical
`compositions containing N-methyl-D-aspartate (NMDA)
`receptor antagonists and their use in the treatment of pain.
`
`BACKGROUND OF THE INVENTION
`The amino acid glutamate is an excitatory neurotransmit
`ter that is an agonist at many post-synaptic terminals of the
`central nervous system. The glutamate receptor complex is
`termed the NMDA receptor and is a potential target for
`therapeutic drugs. This receptor incorporates an ion channel
`complex Which is novel because it is gated by both dual
`ligand binding (glutamate and glycine) and membrane volt
`age. Because of the novel requirements for activation, it is
`believed that the NMDA receptor complex plays only a
`minor role in routine synaptic transmission. HoWever, the
`receptor complex may be activated folloWing repeated affer
`ent stimuli as occurs during trauma such as surgery.
`Repeated stimuli cause a temporal summation of C-?bre
`mediated responses of dorsal horn nociceptive neurones; this
`phenomenon, increased output to a constant input, is knoWn
`as Wind-up.
`Studies indicate that activation of the NMDA receptor
`complex in the spinal dorsal horn leads to increased spon
`taneous neural discharge, expanded receptive ?elds and
`exaggerated responses to afferent input. These neural
`mechanisms may be expressed physically as hyperalgesia
`(increased pain sensation) and allodynia (pain arising from
`a stimulus that is not normally painful).
`Opioids, through their ability to inhibit release of primary
`afferent neurotransmitters or to inhibit interneurons early in
`nociceptive pathWays, initially reduce or block C-?bre
`inputs to the deeper dorsal horn nociceptive neurones.
`HoWever, as the peripheral stimulation continues, Wind-up
`breaks through the input inhibition and the neurones start to
`respond. Thus at moderate doses, opioids delay the onset of
`Wind-up Without inhibiting the process itself.
`By contrast, NMDA receptor antagonists have no effect
`on the initial inputs to the cells but diminish or abolish
`Wind-up and convert the potentiated response to a normal
`response.
`We have found that a particularly effective composition
`for the administration of an NMDA receptor antagonist to
`diminish or abolish Wind up is one providing both imme
`diate release of an NMDA receptor antagonist and controlled
`or sustained release of an NMDA receptor antagonist.
`NMDA antagonist receptors have also been indicated to
`be effective in the treatment of Huntington’s disease, amyo
`trophic lateral sclerosis (ALS), AIDS-related dementia,
`AlZheimer’s disease, schiZophrenia, motoneurone diseases
`and CNS and brain injuries resulting from a number of
`causes including stroke, trauma and neurosurgery.
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`THE INVENTION
`In accordance With one aspect of the present invention
`there is provided a pharmaceutical composition for the
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`2
`administration of an NMDA receptor antagonist to a human
`or animal subject, the composition including an NMDA
`receptor antagonist in an immediate release form in asso
`ciation With an NMDA receptor antagonist in a controlled
`release form.
`The same NMDA receptor antagonist may be used in both
`the immediate and controlled release forms or they may be
`different NMDA receptor antagonists.
`The composition of the invention is suitable for the
`treatment of chronic or acute pain, for example to be
`administered pre-operatively.
`Accordingly, the present invention further provides a
`method for the therapeutic or prophylactic treatment of pain
`in a human or animal subject, the method including admin
`istering to the subject, a composition in accordance With the
`present invention. The method of the invention may be used
`to treat chronic or acute pain.
`The composition of the invention may be used in the
`pre-emptive treatment of pain. The various features of
`novelty Which characteriZe the invention are pointed out
`With particularity in the claims next to and form a part of the
`speci?cation. For a better understanding of the invention, its
`operative advantages and speci?c objects obtained by its
`use, reference should be had to the accompanying draWings
`and descriptive matter in Which there is illustrated and
`described in the preferred embodiment of the invention.
`Preferably the NMDA receptor antagonist may be
`selected from a morphinan such as dextromethorphan and
`dextrorphan, ketamine, amantadine, memantine, eliprodil,
`ifenprodil, diZocilpine, remacemide, iamotrigine, riluZole,
`aptiganel, phencyclidine, ?upirtine, celfotel, felbamate,
`spermine, spermidine, levemopamil, a pharmaceutically
`acceptable salt or ester thereof, or a metabolic precursor of
`any of the foregoing.
`The formulation may include sufficient NMDA receptor
`antagonist to provide from about 1—5000 mg/day, typically
`1—1000 mg/day and preferably about 100—800 mg/day of the
`active ingredient. The composition includes an NMDA
`receptor antagonist in an immediate release form in asso
`ciation With a NMDA receptor antagonist in a controlled
`release form. The composition may include an amount of
`NMDA receptor antagonist in the immediate release form of
`approximately 5% to 90% of the total NMDA receptor
`antagonist, preferably 10% to 60%. An immediate release
`NMDA receptor antagonist content of about 15% to 50% is
`particularly preferred. The controlled release form of the
`NMDA receptor antagonist may constitute the remainder of
`the active ingredients.
`The composition of the invention may be in a form
`suitable for oral or rectal administration or for administra
`tion by transdermal, intravenous, intramuscular,
`subcutaneous, intrathecal, epidural or intracerebroventricu
`lar means.
`The composition of the invention may or may not be in a
`single dosage form. Preferably the composition is in a single
`dose form.
`The composition may be formulated as an oral dosage
`form such as a tablet, capsule, a liquid, poWder, granule or
`suspension, an injectable solution, a suppository, implant or
`transdermal patch.
`
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`US 6,194,000 B1
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`Preferably the NMDA receptor antagonist is dex
`tromethorphan (DM) or a pharmaceutically acceptable salt
`thereof. Preferably the dextromethorphan is in the form of
`dextromethorphan hydrobromide.
`The oral form of the pharmaceutical compositions of the
`invention may be selected from:
`1) liquids, for example, suspensions, reconstitutable
`poWders, elixirs, oils, solutions,or emulsions;
`2) confectionery, for example, cheWing gums, lozenges or
`candy bars;
`3) poWders, for example, drug poWder, prilled material,
`coated actives or granulated materials;
`4) capsules, for example, soft gelatin, hard gelatin
`containing, pellets, poWders, tablets, granulates,
`liquids, or combinations of these; said capsules may or
`may not be coated;
`5) tablets, for example, disintegrating, cheWable
`effervescent, matrix, osmotic pumps, prepared by
`multi-layering, contain coated poWders in tablets, tab
`lets in tablets, pellets in tablets etc, said tablets may or
`may not be coated.
`The oral pharmaceutical composition of the invention
`may be in the form of a “taste-masked” or “taste-neutral”
`form.
`The method of manufacture, components and quantities
`of components used, depend on the particular pharmaceu
`tical composition being considered.
`A suitable immediate release (IR) form of the NMDA
`30
`receptor antagonist may simply be particles of the antagonist
`or particles of the antagonist admixed With soluble compo
`nents for example, sugars (eg sucrose, lactose, fructose,
`mannitol etc.), polymers (eg polyethylene glycol, hydrox
`ypropyl cellulose, hydroxypropyl methyl cellulose, etc),
`surfactants (sodium lauryl sulphate, chremophor, tWeens,
`spans, pluronics, and the like), insoluble components
`(microcrystalline cellulose, Ca3 (PO4)2, talc, fumed silica,
`i.e. aerosil® and the like), coating material (examples of
`suitable coating materials are polyethylene glycol, hydrox
`ypropyl methyl cellulose, Wax, fatty acids, etc.), dispersions
`in suitable material (examples are Wax, polymers, pharma
`ceutically acceptable oils, soluble agents etc) or combina
`tions of the above. These mixtures may be prepared by
`blending, mixing, dissolution and evaporation, or by using
`suspensions etc. These mixtures may be deposited on inert
`cores, Wet massed and extruded, granulated, spray dried, etc.
`These mixtures or processed mixtures may be used in
`suspensions, ?lled into capsules, tabletted, ?lled into
`sachets, used in confectionery and so on.
`The controlled release may be a sustained release or
`delayed/modi?ed release.
`A controlled-release dosage form as de?ned in US Phar
`macopeia XXII includes extended release dosage forms
`Which alloW at least a tWofold reduction in dosing frequency
`as compared to the drug presented as a conventional dosage
`form and delayed release dosage forms Which release the
`drug at a time other than promptly after administration.
`A core used herein the description contains the active
`ingredient and other carriers and excipients, ?llers, stablis
`ing agents, binders, core seeds or colorants. The active
`component may be present in amounts of approximately 0.1
`to 95% by Weight based on the Weight of the total core
`element. Preferably the active components is present in
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`amounts of 10 to 80% by Weight based on the Weight of the
`total core element. The core may be 200 to 1700;! in
`diameter.
`A pellet is a coated core, the coating being any suitable
`coating.
`Preferably, the controlled release component is a sus
`tained (or extended) release form.
`A suitable sustained release (SR) form of the NMDA
`receptor antagonist may be a matrix tablet composition.
`Suitable matrix forming materials are Waxes (eg. carnauba,
`bees Wax, paraf?n Wax, ceresine, shellac Wax, fatty acids,
`fatty alcohols), oils, hardened oils or fats (eg. hardened
`rapeseed oil, castor oil, beef talloW, palm dil, soya bean oil),
`polymers (eg. hydroxypropyl cellulose,
`polyvinylpyrrolidone, hydroxypropyl methyl cellulose,
`polyethylene glycol) and other excipients knoWn to those
`familiar With the art. Other suitable matrix tabletting mate
`rials are microcrystalline cellulose, poWdered cellulose,
`hydroxypropyl cellulose, ethyl cellulose, With other carriers,
`?llers, and excipients knoWn to those familiar With the art.
`SR tablets may contain granulates, coated poWders, pellets,
`or be multi-layered and the ?nished tablet may be coated or
`uncoated.
`Suitable coating materials to prepare SR products are any
`pharmaceutically acceptable polymer such as ethyl
`cellulose, cellulose acetate butyrate, cellulose acetates, poly
`methacrylates containing quaternary ammonium groups or
`other pharmaceutically acceptable polymers, polyethylene
`glycol, hydroxypropyl cellulose, hydroxypropyl methyl
`cellulose, polyvinylpyrrolidone, polyvinyl alcohol, and
`monomeric materials such as sugars including lactose,
`sucrose, fructose and mannitol, salts including sodium
`chloride, potassium chloride and derivatives, organic acids
`including fumaric acid, succinic acid, lactic acid and tartaric
`acid and mixtures thereof, enteric polymers including
`hydroxypropyl cellulose, hydroxypropyl methyl cellulose,
`polyvinyl acetate phthalate, cellulose acetate phthalate, cel
`lulose acetate trimellitate, shellac, Zein, and polymethacry
`lates containing carboxyl groups. These polymers may be
`applied as solutions or latexes. Other barriers may be used
`such as Waxes.
`The coating composition may or may not be plasticised
`according to the properties of the coating blend such as the
`glass transition temperature of the main component or
`mixture of components or the solvent used for applying the
`coating compositions. Suitable plasticises can be added from
`0 to 50% by Weight of the coating composition and at least
`one may be selected from diethyl phthalate, citrate esters,
`polyethylene glycol, glycerol, acetylated glycerides, castor
`oil and the like.
`Cores containing active may be coated directly to produce
`a SR dose, or tablets or capsules containing active may be
`coated.
`Asuitable SR form of NMDA receptor antagonist may be
`an osmotic pump, or combinations of the above.
`These IR or SR forms may be made by prilling, spray
`drying, pan coating, melt granulation, granulation, Wurster
`coating, tangential coating, top spray, tabletting, extruding,
`coacervation and the like.
`The particle siZes of the IR and SR components in the
`dosage form depends on the technology used. The particle
`
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`Page 5
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`

`US 6,194,000 B1
`
`5
`sizes component range from submicron to 500 pm for
`powder technologies (mixtures, spray drying, dispersions
`etc), 5—1700 pm for coating technologies (Wurster, top spray,
`bottom spray, spray drying, extrusion, layering etc), to 1—40
`mm for tabletting technologies.
`The IR and SR forms of the NMDA receptor antagonist
`are then combined into a single dosage such that the amount
`of NMDA receptor antagonist in the composition of the
`invention is in the range of about 1—5000 mg typically, 1 mg
`to 1000 mg, and preferably 100 mg to 800 mg. The com
`position including an NMDA receptor antagonist in an
`immediate release form in association With a NMDA recep
`tor antagonist in a controlled release form may include an
`amount of NMDA receptor antagonist in the immediate
`release form of approximately 5% to 90% of the composi
`tion of the invention, preferably 10% to 60%. An immediate
`release NMDA receptor antagonist content of about 15% to
`50% is particularly preferred. The controlled release form of
`the NMDA receptor antagonist may constitute the remainder
`of the active ingredient.
`As a result, the ?nal composition provides an amount of
`NMDA receptor antagonist for immediate release folloWing
`administration and an additional amount of NMDA receptor
`antagonist for sustained release. The SR component is
`preferably aimed at reducing the dosage interval from 3 to
`6 times daily to 1 or 2 times daily.
`The composition of the invention may exhibit more than
`one peak in the plasma concentration/time curve in any one
`dosing interval depending on the particular NMDA receptor
`antagonist(s) used, the relative amounts of the IR and SR
`components, and the dissolution properties of the SR com
`ponent.
`The folloWing non-limiting examples illustrate the uses of
`the components listed above in producing a composition in
`accordance With the invention.
`Where the composition of the invention is in the form of
`a pellet product, the peltets may be presented in a sachet,
`capsule or tablet. The non limiting examples beloW
`describes pellet (particle siZes 200—1700 pm) in a capsule.
`All the quoted ranges are % W/W.
`A plurality of elements containing the active ingredients
`(cores) are prepared by extrusion/marumerisation, or layer
`ing the active (or blend of active With other excipients) onto
`inert carriers by various processes. The cores themselves
`could be IR or SR depending on the materials and method
`of manufacture. The cores may contain the drug at the
`required potency according to the particular NMDA dose
`(mg), required siZe and presentation, and subsequent pro
`cesses (coating etc.) The cores may contain drugs in the
`range 0.1—100% depending on the required dose, potency,
`manufacturing method, and properties.
`An extruded core Would typically include a carrier such as
`microcrystalline cellulose in the range 5—99.9%, a binder
`such as hydroxypropyl cellulose in the range 0—50%, a ?ller
`such as lactose in the range 0—50% and other excipients. An
`extruded core may only contain drug and binder.
`An extruded core With SR properties Would typically
`contain a sWelling/gelling polymer such as hydroxypropyl
`cellulose in the range 0—50% or a hydrophobic material such
`as cetylalcohol in the range 10—90% With the drug. Alayered
`core Would contain an inert carrier such as a sugar sphere in
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`the range 10—90% With a binder in the range 0.1—50% With
`the drug. The core may or may not contain ?llers, solubi
`lisers and other additives. The binder may be chosen to
`achieve IR (hydroxypropyl cellulose, hydroxypropyl methyl
`cellulose etc), or SR (ethyl cellulose, cellulose acetate
`butyrate etc), or delayed/modi?ed release (ie enteric binding
`materials such as hydroxypropyl methyl cellulose phthalate,
`polyvinyl acetate phthalate etc).
`Aportion of the ?nal dosage form may be IR cores made
`by the above described processes. Alternatively the IR cores
`may be coated With a rapidly disintegrating or dissolving
`coat for aesthetic, handling, or stability purposes. Suitable
`materials are polyvinylpyrrolidone, hydroxypropyl
`cellulose, hydroxypropyl methyl cellulose, polyethylene
`glycol, polymethacrylates containing free amino groups,
`each may be With or Without plasticisers, and With or Without
`an antitack agent or ?ller. An addition of about 3% of the
`Weight of the core as coating material is generally regarded
`as providing a continuous coat for this siZe range.
`The SR portion of the dose may be provided by a SR core
`as described above, a SR core Which is further modi?ed by
`overcoating, or an IR core Which is modi?ed by overcoating.
`The IR and SR NMDA receptor antagonist need not be the
`same active, nor are the IR or SR components of a dose
`themselves limited to just one active.
`A typical coating composition for making the SR com
`ponent Would contain an insoluble matrix polymer in
`amounts approximately 15—85% by Weight of the coating
`composition and a Water soluble material in an amount of
`approximately 15—85% by Weight of the coating composi
`tion. Optionally an enteric polymer in amounts from 0 to
`100% by Weight of the coating composition may be used or
`included. Suitable insoluble matrix polymers include ethyl
`cellulose, cellulose acetate butyrate, cellulose acetates, poly
`methacrylates containing quaternary ammonium groups or
`other pharmaceutically acceptable polymers. Suitable Water
`soluble materials include polymers such as polyethylene
`glycol, hydroxypropyl cellulose, hydroxypropyl methyl
`cellulose, polyvinylpyrrolidone, polyvinyl alcohol, and
`monomeric materials such as sugars (eg lactose, sucrose,
`fructose, mannitol and the like), salts (eg. sodium chloride,
`potassium chloride and the like), organic acids (eg. fumaric
`acid, succinic acid, lactic acid, tartaric acid and the like) and
`mixtures thereof. Suitable enteric polymers include hydrox
`ypropyl methyl cellulose, acetate succinate, hydroxypropyl
`methyl cellulose, phthalate, polyvinyl acetate phthalate,
`cellulose acetate phthalate, cellulose acetate trimellitate,
`shellac, Zein, polymethacrylates containing carboxyl groups,
`and the like.
`The coating composition may or may not be plasticised
`according to the properties of the coating blend such as the
`glass transition temperature of the main component or
`mixture of components or the solvent used for applying the
`coating compositions. Suitable plasticisers can be added
`from 0 to 50% by Weight of the coating composition and at
`least one may be selected from diethyl phthalate, citrate
`esters, polyethylene glycol, glycerol, acetylated glycerides,
`acetylated citrate esters, dibutylsebacate, castor oil and the
`like.
`The coating composition may or may not include a ?ller.
`The ?ller may comprise 0 to approximately 200% by Weight
`
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`US 6,194,000 B1
`
`7
`based on the total Weight of the coating composition and
`may be an insoluble material such as silicon dioxide, tita
`nium dioxide, talc, kaolin, alumina, starch, poWdered
`cellulose, MCC, polacrilin potassium, and the like.
`The coating composition may be applied as a solution or
`latex in organic solvents or aqueous solvents or mixtures
`thereof. Where solutions are applied the solvent is present in
`amounts from approximate by 25—99% by Weight preferably
`85—97% by Weight based on the total Weight of dissolved
`solids. Suitable solvents are Water, loWer alcohol, loWer
`chlorinated hydrocarbons, ketones or mixtures thereof.
`Where latexes are applied, the solvent is present in
`amounts from approximately 25—97% by Weight, preferably
`60—97% based on the quantity of polymeric material in the
`latex. The solvent may be predominantly Water.
`Asuitable tablet formulation may be of a sWelling/gelling
`polymer such as L-hydroxypropyl cellulose admixed With a
`?ller such as MCC and the drug. The tablet excipients may
`or may not be processed ie. spray dried together, prior to use
`in tabletting. The mixture may be compressed directly, or
`granulated prior to compression. Matrix tablets of this type
`often exhibit a rapid initial release until the polymers sWell
`and gel, Which induces SR for the remainder of the drug.
`The quantity of IR and duration of SR can be varied by
`altering the quantities of the excipients used. If the IR
`component is not large enough, a quantity of drug can be
`included in a rapidly dissolving outer coat of polymers such
`as PEG or hydroxypropyl methyl cellulose. Atypical matrix
`tablet Would contain the sWelling/gelling polymer in
`amounts from approximately 15 to 70% by Weight based on
`the total Weight of the tablet and ?ller in amounts from
`approximately 15 to 70% by Weight based on the total
`Weight of the tablet. Additional ?llers may be included in
`amounts from approximately 0—60% by Weight based on the
`total Weight of the tablet. These may be soluble materials
`such as lactose, mannitol, sorbitol and the like, or insoluble
`materials such as tribasic calcium phosphate poWdered
`cellulose or any of the various starches (corn, Wheat, potato
`etc.) Additionally, the tablets may contain a lubricant in an
`amount from 0—8% by Weight based on the total Weight of
`the tablet. Lubricants may be selected from metal stearates,
`stearic acid, hydrogenated oils, such as soya bean oil or
`castor oil, sodium stearyl fumarate, polytetra?uoroethylene,
`talc and the like. The tablets may be coated for aesthetic,
`handling or stability purposes, or to increase the quantity of
`the IR portion of the drug. In this latter case the drug is
`dissolved or suspended in the coating solution and sprayed
`onto the tablets until the desired quantity of drug has been
`added. Suitable coating materials include polyethylene
`glycol, hydroxypropyl methyl cellulose, hydroxypropyl
`cellulose, polyvinyl alcohol, polyvinylpyrrolidone, sugar,
`Waxes, or mixtures of these. The material may be added to
`any desired thickness but Weight gains in the range 1—20%
`are typical, preferably 2—10%, more preferably 2—5%. The
`coat may or may not be plasticised. A plasticiser may be
`present in amounts from about 0—50% by Weight based on
`the total Weight of the tablet of the coating material.
`Examples of plasticisers are diethyl phthalate, citrate esters,
`acetylated citrate esters, polyethylene glycol, glycerol,
`dibutylsebacate, acetylated monoglycerides, castor oil and
`the like).
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`55
`
`60
`
`65
`
`8
`The coating composition may include an antitack agent
`such as talc, kaolin, titanium dioxide, silicon dioxide,
`alumina, starch, polacrilin potassium, microcrystalline cel
`lulose or the like).
`The coating materials may be applied to the drug
`particles, processed drug particles (ie. cores, granules),
`?nished tablets, or ?nished capsules.
`The coating composition may or may not include a ?ller.
`The ?ller may comprise 0 to approximately 200% by Weight
`based on the total Weight of the coating composition and
`may be an insoluble material such as silicon dioxide, tita
`nium dioxide, talc, kaolin, alumina, starch, poWdered
`cellulose, microcrystalline cellulose, polacrilin potassium.
`The coat may contain other ingredients such as dyes and
`Waxes.
`The coat may be applied as a solution or suspension from
`aqueous or organic solvents solution concentration in equip
`ment familiar to these skilled in the art. The coating com
`position may be applied as a solution or latex in organic
`solvents or aqueous solvents or mixtures thereof. Where
`solutions are applied the solvent is present in amounts from
`approximate by 25—99% by Weight preferably 85—97% by
`Weight based on the total Weight of dissolved solids. Suitable
`solvents are Water, loWer alcohols, loWer chlorinated
`hydrocarbons, keton es, or mixtures thereof. Where latexes
`are applied, the solvent is present in amounts from approxi
`mately 25—97% by Weight, preferably 60—97% based on the
`quantity of polymeric material in the latex. The solvent may
`be predominantly Water.
`Alternatively the SR component of a tablet may be
`provided in the form of SR pellets and the IR component
`may be included in the body of the tablet. Such a tablet
`disintegrates to release the IR drug and the SR pellets.
`Pellets may be present in amounts from 1—60% by Weight of
`the tablet, preferably 5—50% more preferably 5 40%. Suit
`able matrix materials for tablets of this type are microcrys
`talline cellulose, starches and the like.
`The immediate release form of the NMDA receptor
`antagonist may be presented in a fast dissolving dosage
`form. The immediate release form may be in the form of a
`solid or molecular dispersion of the active Within a polymer
`matrix. The polymer matrix may be selected from biologi
`cally acceptable polymer such as a cellulose ether, for
`example ethyl cellulose, or cellulose ester, for example
`cellulose acetate butyrate etc. The immediate release form
`may simply be particles of the antagonist or the antagonist
`deposited on a core containing the antagonist.
`The composition of the invention, Where it is in a tablet
`or like form, may include the tWo forms of the NMDA
`receptor antagonist as separate components, for example, in
`a multi-layer tablet, Wherein one or more layer include the
`NMDA receptor antagonist in an immediate release form
`With one or more layers of the NMDA receptor antagonist in
`a controlled release form. Alternatively the composition of
`the invention may be in the form of a tablet Wherein the
`immediate release forms the shell and the controlled release
`form constitutes the core.
`Alternatively, the tWo forms of the NMDA receptor
`antagonist may be dispersed throughout the tablet.
`The composition of the invention may be produced by
`providing a core containing the NMDA receptor antagonist
`
`IPR2015-00410
`Petitioners' Ex. 1024
`Page 7
`
`

`

`US 6,194,000 B1
`
`9
`controlled release component coated With an enteric or
`delayed release coating. The core can be in the form of beads
`compressed to a tablet. The coated core may then be
`compressed into tablets along With a poWder mixture con
`taining additional NMDA receptor antagonist or ?lled in
`combination With uncoated NMDA receptor antagonist into
`a capsule shell. As a result, the ?nal composition provides an
`amount of NMDA receptor antagonist for immediate release
`folloWing administration and an additional amount of
`NMDA receptor antagonist for controlled release.
`The controlled release form of the NMDA receptor
`antagonist is such as to provide sustained release of the
`antagonist. Preferably the controlled or sustained release
`form provides a therapeutic effect over a period greater than
`about 6 hours. More preferably the sustained therapeutic
`effect is greater than about 8 hours. A sustained therapeutic
`effect period of 8 to 24 hours being especially preferred. The
`SR component of the controlled release composition is
`aimed at reducing the dosage interval from 3 to 6 times daily
`to 1 to 2 times daily.
`The controlled release form of the antagonist may be
`coated beads or granules of the NMDA receptor antagonist.
`The coated antagonist may be combined With uncoated or
`lightly coated antagonist to provide a composition of the
`present invention. The term “lightly coated” as used in the
`description means a rapidly disintegrating coating for
`aesthetic, handling or stability purposes. These then may be
`?lled into capsules or formed into tablets. Microencapsula
`tion may also be used to produce the controlled release form
`of the NMDA receptor antagonist.
`The coating or matrix material may be any suitable
`material. The coating or matrix material may be a polymer
`or a Wax. The Wax may be selected from any suitable Wax
`or Wax-like material including natural oil and fat and hard
`ened oils such as hardened rapeseed oil, hardened castor oil,
`hardened beef talloW, palm oils and the like; Waxes such as
`camauba Wax, bees Wax, paraf?n Wax, ceresine Wax, shellac
`Wax or a fatty acid.
`The present invention