(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`
`(19) World Intellectual Property
`Organization
`International Bureau
`
`(43) International Publication Date
`12 February 2004 (12.02.2004)
`
` (10) International Publication Number
`
`WO 2004/012741 A1
`
`(51) International Patent Classification7:
`9/22, 9/30, A6lP 25/08, 25/00, 25/18
`
`A61K 31/53,
`
`(21) International Application Number:
`PCT/EP2003/008368
`
`(22) International Filing Date:
`
`28 July 2003 (28.07.2003)
`
`(25) Filing Language:
`
`(26) Publication Language:
`
`English
`
`English
`
`(30) Priority Data:
`0217--93.6
`0217--92.8
`0313801.3
`
`29 July 2002 (29.07.2002)
`29 July 2002 (29.07.2002)
`13 June 2003 (13.06.2003)
`
`GB
`GB
`GB
`
`(71) Applicant (for all designated States except US): GLAXO
`GROUP LIMITED [GB/GB]; Glaxo Wellcome House,
`Berkeley Avenue, Greenford, Middlesex UB6 ONN (GB).
`
`(72) Inventors; and
`(75) Inventors/Applicants (for US only): BUXTON, Ian,
`Richard [GB/CA]; GlaxoSmithKline, 7333 Mississauga
`Road North, Mississauga, Ontario L5N 6L4 (CA). CUR-
`RIE, Robin [US/US]; GlaxoSmithKline, Five Moore
`Drive, Research Triangle Park, North Carolina, NC 27709
`(US). DELA-CRUZ, Myrna, A. [CA/CA]; GlaxoSmithK-
`line, 7333 Mississauga Road North, Mississauga, Ontario
`L5N 6L4 (CA). GOODSON, Gary, Wayne [US/US];
`GlaxoSmithKline, Five Moore Drive, Research Triangle
`Park, North Carolina, NC 27709 (US). KAROLAK,
`Wlodzimierz [CA/CA]; GlaxoSmithKline, 7333 Missis-
`sauga Road North, Mississauga, Ontario L5N 6L4 (CA).
`MALEKI, lvlehran [CA/CA]; GlaxoSmithKline, 7333
`Mississauga Road North, Mississauga, Ontario L5N 6L4
`(CA). IYER, Vijay, Mohan [CA/CA]; GlaxoSmithKline,
`7333 Mississauga Road North, Mississauga, Ontario L5N
`6L4 (CA). MUPPIRALA, Gopal [US/US]; Care of Glax-
`oSmithKline, Five Moore Drive, Research Triangle Drive,
`North Carolina, NC 27709 (US). PARR, Alan, Frank
`
`[US/US]; GlaxoSmithKline, Five Moore Drive, Research
`Triangle Park, North Carolina, NC 27709 (US). SIDHU,
`Jagdev, Singh [AU/GB]; GlaxoSmithKline, New Fron-
`tiers Science Park South, Third Avenue, Harlow, Essex
`CM19 5AW (GB). STAGNER, Robert, Allen [US/US];
`GlaxoSmithKline, Five Moore Drive, Research Triangle
`Park, North Carolina, NC 27709 (US). VIJAY-KUMAR,
`Akunuri, Venkata [IN/CA]; GlaxoSmithKline, 7333
`Mississauga Road North, Mississauga, Ontario L5N 6L4
`(CA).
`
`(74) Agent: HOCKLEY, Sian, Catherine; GlaxoSmithKline,
`Corporate Intellectual Property CN925.1, 980 Great West
`Road, Brentford, Middlesex TW8 9GS (GB).
`
`(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, ES, FI, GB, GD, GE, 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.
`
`(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,
`ES, FI, 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
`before the expiration of the time limit for amending the
`claims and to be republished in the event of receipt of
`amendments
`
`For two—letter codes and other abbreviations, refer to the "Guid-
`ance Notes on Codes andAbbreviations ” appearing at the begin-
`ning of each regular issue of the PCT Gazette.
`
`V-It
`
`(54) Title: SUSTAINED RELEASE FORMULATIONS COMPRISING LAMOTRIGINE
`
`(57) Abstract: A sustained release formulation of lamotrigine or a pharmaceutically acceptable derivative thereof and methods of
`treatment and uses thereof.
`
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`IPR2015-00410
`Petitioners' Ex. 1011
`Page 1
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`SUSTAINED RELEASE FORMULATIONS COMPRISING LAMOTRIGINE
`
`This invention relates to a novel method of treatment using lamotrigine and novel
`
`formulations, in particular tablet formulations, for use in such methods.
`Lamotrigine, 3,5-diamino-6—(2,3-dichlorophenyl)~l,2,4—triazine is disclosed in US
`4,602,017 and EP0021 121. Products comprising lamotrigine are marketed under the trade name
`LAMICTALTM by the GlaxoSmithKline group of companies. Such products are particularly
`effective for treatment of CNS disorders, particularly epilepsy; pain; oedema; multiple sclerosis
`
`and psychiatric indications including bipolar disorder.
`Various tablet formulations of lamotiigine have been approved for marketing, for
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`instance, conventional compressed instant release (IR) tablets comprising 25 mg, 50mg, 100 mg,
`150 mg or 200 mg of active ingredient. These are administered once, twice or three times daily.
`For lamotrigine, added to an antiepileptic drug regime containing valproic acid, titration begins at
`25 mg every other day for weeks 1 and 2 and increased to 25 mg every day for weeks 3 and 4.
`After this initial period the maintenance dose of 100 to 400 mg/day can be achieved by increasing
`the dose by 25 to 50 mg/day. If lamotrigine is added to enzyme-inducing antiepileptic drugs
`(EDXEDS) without valproic acid the dose is 50 mg/day for weeks 1 and 2 and 100 mg/day in 2
`divided doses thereafter. To achieve the maintenance dose of 300 to 500 mg/day in 2 divided
`
`doses, doses may be increased by 100 mg/day every 1 to 2 weeks. These regimens provide a
`
`therapeutic amount of lamotiigine.
`In addition, W092/13527 (The Wellcome Foundation Limited) describes tablet
`formulations comprising water dispersible tablets comprising lamoirigine and a dispersing agent
`where the dispersing agent is a swellable clay such as a smectite and is generally present Within
`the granules of the tablet to provide a tablet which is capable of dispersing in water Within 3
`minutes to provide a dispersion which will pass through a 710 um sieve. The tablet can be
`optionally film coated in which case the dispersion time is less than 5 minutes. Chewable
`dispersible tablets which may be swallowed whole, chewed or dispersed in a small amount of
`water are marketed comprising 2mg, 5mg, 25 mg or 100 mg of active ingredient. These are
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`generally administered to paediatric patients.
`W096/17611 (The Wellcome Foundation Limited) discloses pharmaceutical
`
`compositions comprising
`
`a) 0.5 to 50% by weight of lamotrigine;
`
`b) from 15 to 50% by weight lactose;
`
`c) from 15 to 50% by Weight of starch;
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`d) from 0.5 to 50% crystalline cellulose; and
`e) 5 to 15% by weight of polyvinylpyrrolidoneg
`and which is in the form of a free flowing powder having the following properties:
`
`(i) no granules having a particle size of greater than 850nm,
`(ii) at least 90% by weight having a particle size of 75 to 850 um,
`(iii) the granules disintegrate Within 30 minutes according to the Disintegration Test of
`The Pharmacopoeia of Japan, 12th edition and
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`(iv) at least 90% by weight of lamotrigine dissolves within 30 minutes when the granules
`are subjected to the Dissolution Test, method 2 (paddle method) of The Pharmacopoeia of
`
`Japan 12th edition 1991.
`Lamotrigine is rapidly and completely absorbed after oral administration with negligible
`first pass metabolism. The absolute bioavailability is about 98%, which is not affected by food.
`The chewable dispersible tablets were found to be equivalent to the lamotrigine
`compressed IR tablets whether they were administered as dispersed in water, chewed and
`swallowed or swallowed as whole in terms of rate and extent of absorption.
`Other drugs available on the market for the treatment of epilepsy are, but not limited to,
`carbamazepine (Tegretol TM), Valproate (Depakote TM), tiagabine (Gabitril TM), levetiracetam
`(Keppra TM), gabapentin (Neurontin TM) and phenytoin (Dilantin TM). Carbamazepine is
`available as an instant release tablet, a time releasing chewable tablet (Carbatrol; extended release
`beads) or Tegretol-XR an osmotic pump tablet, and a liquid to be administered by mouth.
`Valproate is available as an instant release tablet and a suspension. In the US Valproate is also
`available as Depakote a delayed release (coated) tablet which contains sodium Valproate +
`Valproate in 1:1 formulation and also Depakote ER an extended release form). Gabapentin,
`tiagabine and levetiracetam are available as instant release tablets. Dilantin is available in a
`'kapseal' that modifies release.
`Existing marketed tablet formulations of lamotrigine provide immediate release of the
`active ingredients once the tablet reaches the stomach. The peak plasma concentrations occur
`anywhere from 1.4 to 4.8 hours following drug administration. The disadvantage is that the
`plasma concentration (pharmacokinetic profile (PK)) achieved with conventional tablets is
`cyclical, with peaks occurring after administration followed by troughs occurring before the next
`administration of drug, see Figure (1).
`In particular for the treatment of epilepsy it is speculated that the troughs may lead to
`breakthrough seizures and the peak plasma concentration may result in some adverse events (AE)
`occurring in some patients or alternatively the rate of increase in plasma concentration in the
`initial stages before the peak plasma concentration is achieved may also effect the AE profile.
`Until recently, it was not known where, in the gastrointestinal tract, lamotrigine is
`absorbed. In carrying out a regional absorption study it has recently been discovered that the
`extent of absorption of lamotrigine is consistent when the drug is delivered to any point in the
`gastrointestinal tract between the stomach and the ascending colon. The extent of absorption is
`also equivalent whether the drug is delivered as a solid or as a solution.
`Accordingly, in a first aspect, the invention comprises a sustained release formulation of
`lamotrigine or a pharmaceutically acceptable derivative thereof.
`A further aspect of the present invention provides for a method of treating CNS disorders,
`which comprises orally administering to a patient a therapeutically effective amount of
`lamotrigine or a pharmaceutically acceptable derivative thereof in the form of a sustained release
`formulation.
`
`A further aspect ofthe present invention provides for a method of treating CNS disorders,
`which comprises orally administering to a patient a therapeutically effective amount of
`lamotrigine or a pharmaceutically acceptable derivative thereof, in the form of a sustained release
`formulation wherein the lamotrigine or a pharmaceutically acceptable derivative thereof is
`released approximately 2 to 20 hours after administration, preferably 6 to 16 hours after
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`administration and more preferably 10 to 15 hours, alternatively 10 to 14 hours after
`administration.
`
`When used herein the term "CNS disorder" includes epilepsy; pain; oedema, multiple
`
`sclerosis, schizophrenia and psychiatric conditions including bipolar disorder, preferably
`epilepsy; pain; oedema, and psychiatric conditions including bipolar disorder, particularly
`
`epilepsy, pain and bipolar disorder.
`When used herein the term "pain" includes acute pain such as musculoskeletal pain, post
`operative pain and surgical pain, chronic pain such as chronic inflammatory pain (e.g. rheumatoid
`arthritis and osteoarthritis), neuropathic pain (e.g. post herpetic neuralgia, trigeminal neuralgia,
`sympathetically maintained pain and pain associated with diabetic neuropathy) and pain
`associated with cancer and fibromyalgia or pain associated with migraine.
`Schizophrenia is a serious psychiatric disease that affects 1% of the world's population.
`Onset of the disorder occurs typically in the late teens or early 20's and in approximately 80% of
`cases becomes a lifelong condition. Furthermore, schizophrenia is associated with significant
`mortality, with 40% ofpatients attempting suicide within 10 years of the onset of this disorder.
`The disorder was rated as the 5m leading cause of disability in the US in a joint World Health
`
`Organisation — World Bank study in 1996 (Murray and Lopez, 1996).
`The clinical presentation of schizophrenia can include positive symptoms, such as
`hallucinations, delusions, or thought disorder, and negative symptoms such as apathy, avolition,
`
`or poverty of speech.
`The treatment of schizophrenia relies on the use of anti-dopaminergic drugs following the
`original discovery in the 1950's of the efficacy and mechanism of action of chlorpromazine.
`Chlorpromazine and other so-called "typical" antipsychotic drugs are still in common use today,
`though due to their association with motor side-effects, they are increasingly replaced by the
`newer "atypical" antipsychotics, such as clozapine (Clozarilm), olanzapine (zyprexam) or
`risperidone (Risperdalm). These newer drugs have a mixed pharmacology which includes
`dopamine D2 receptor antagonism and antagonism of the 5-HT2a receptor. Despite efficacy and
`relative safety of these newer drugs, a significant proportion of patients fail to respond to
`treatment and of those that do, many do not achieve a clinically meaningful improvement in
`
`global functioning and quality of life.
`In some patients, episodes of maj or depression, mania, or mixed mania can occur
`alongside symptoms of schizophrenia. The distinction between schizophrenia and mood disorder
`is then somewhat blurred and a diagnosis of schizoaffective disorder is often used. Treatment of
`
`schizoaffective disorder typically requires a combination of an antipsychotic, an antidepressant, a
`mood stabiliser, and anxiolytic drugs. Although positive psychotic symptoms can usually be
`controlled, negative symptoms and affective symptoms are poorly treated by current medications.
`Despite 40 years of development there remains a significant unmet need for treatment for
`patients with the chronic debilitating disorder schizophrenia.
`Multiple sclerosis (MS) is an autoimmune disease which is a progressive disease of the
`central nervous system (CNS) in which patches of myelin (the protective covering of nerve fibres)
`in the brain and spinal cord are destroyed by the body's own immune system. This destruction
`leads to scarring and damage to the underlying nerve fibres and may manifest itself in a variety of
`symptoms, depending on the parts of the brain and spinal cord that are affected. Spinal cord
`damage may result in tingling or numbness as well as heavy and/or Weak feeling in the
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`extremities. Damage in the brain may result in muscle weakness, fatigue, unsteady gain,
`numbness, slurred speech, impaired vision, vertigo and the like. Leandri et al (J Neurol(2000)
`247:556-55 8 reported that lamotrigine had been used in the treatment of trigeminal neuralgia
`secondary to multiple sclerosis.
`A further aspect of the invention is the use of lamotrigine or a pharmaceutically
`acceptable derivative thereof in the treatment of multiple sclerosis.
`A further aspect of the invention is a method of treatment of multiple scelrosis which
`comprises orally administering to a patient a therapeutically effective amount of lamotrigine or a
`pharmaceutically acceptable derivative thereof.
`A further aspect of the invention is the use lamotrigine or a pharmaceutically acceptable
`derivative thereof in the manufacture of a medicament for the treatment of multiple sclerosis.
`When used herein the term "pharmaceutically acceptable derivative" means a salt, ester or
`salt of such ester which upon administration to the recipient such a human is capable of providing
`(directly or indirectly) lamotrigine or an active metabolite thereof. Preferred salts are inorganic
`acid salts such as hydrochloride, hydrobromide, phosphate or organic acid salts such as acetate,
`fumarate, xinafoate, tartrate, succinate or glutarate.
`The term "treatment" as used herein includes the treatment of established disorders and
`
`also includes the prophylaxis thereof. This is particularly relevant for epilepsy wherein
`medication may treat seizures or prevent future seizures from occurring.
`As used herein, the term “sustained release" refers to the gradual but continuous release
`over any extended period of lamotrigine after oral ingestion e.g. 2-20 hours preferably between 6
`to 16 hours, and more preferably between 10 and 15 hours, alternatively 10 and 14 hours and
`which starts when the formulation reaches the stomach and starts to disintegrate/dissolve/erode.
`The release will continue over a period of time and may continue throughout the small intestine
`and after the formulation reaches the large intestine.
`A finther aspect of the invention provides a method of treating CNS disorders which
`comprises orally administering to a patient a therapeutically effective amount of lamotrigine in
`the form of a sustained release formulation wherein substantially all the lamotrigine is released
`from the formulation in the 2 to 20 hours after administration, preferably 6 to 16 hours after
`administration and more preferably 10 to 15, alternatively 10 to 14 hours after administration.
`A further aspect of the invention provides a sustained release formulation of lamotrigine
`or a phannaceutically acceptable derivative thereof, wherein substantially all the lamotrigine or a
`pharmaceutically acceptable derivative thereof is released from the formulation 2 to 20 hours
`after administration, preferably 6 to 16 hours after administration and more preferably 10 to 15,
`alternatively 10 to 14 hours after administration.
`When used herein "substantially all" means more than 85%, preferably more than 90%.
`Administration of lamotrigine over this time period delivers it gradually to the sites Where
`lamotrigine is readily absorbed but with a slower rise in serum concentrations and reduced post-
`dosing peaks to mitigate closing related adverse events (AE's) yet provide sufficient minimum
`plasma/serum concentrations (Cmin) to maintain efficacy. A formulation which achieves an area
`under the curve (AUC) equivalent to the conventional instant/immediate release (IR) tablet (90%
`confidence interval (CI) for the geometric least squares (GLS) mean ratio should fall within the
`range 80-125% compared to the reference IR product) is termed "bioequivalent".
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`Alternatively the sustained release formulation would not be deemed by the Food and
`Drug Administration (FDA) as bioequivalent to the IR tablets if the points estimate and the
`associated 90% Confidence Interval for Cmax will not fall Within the limit of 80 - 125% relative
`to the IR product with the AUC remaining within the 80-125% range compared with the reference
`1R product.
`Suitably the formulations are formulated such that the release of the‘ active substance is
`predominantly in the stomach, small intestine and into the colon.
`In a further aspect, the invention provides a method of treating CNS disorders, which
`comprises orally administering to a patient a therapeutically effective amount of lamotrigine or a
`pharmaceutically acceptable derivative thereof in the form of a sustained release formulation
`wherein the lamotrigine or a pharmaceutically acceptable derivative is present in the range of l to
`
`500 mg, preferably 25 to 400 mg.
`Preferably the sustained release formulation comprises an amount of lamotrigine or a
`pharmaceutically acceptable derivative selected from 25mg, 50mg, 100mg, 200mg or 400mg.
`Preferably the sustained release formulation is administered in a dosage regimen which is
`sufficient to maintain control over the disorder.
`
`Preferably the dosage regimen is once a day.
`An advantage of sustained release formulations is increased patient compliance.
`Socio-economic factors do not influence compliance: non—compliance is just as likely in
`wealthy, well educated, and healthy patients as it is in patient outside these categories. In most
`cases, epilepsy is a life-long disease that requires consistent and adequate antiepileptic drug
`‘(AED) blood levels to maximize seizure control. Further, it is generally accepted that each
`additional seizure may increase the risk of recurrence and worsen the overall prognosis.
`Therefore, primary treatment objectives for patients with epilepsy are maintenance of adequate
`AED levels and prevention of subsequent seizures. Compliance with the prescribed dosing
`regimen is essential for the maintenance of therapeutic blood levels.
`Patients with epilepsy often are treated with polypharmacy. Patients with severe or
`reficactory epilepsy frequently require the co-administration oftwo or more AEDS to achieve
`adequate seizure control. Also, it is not unusual for patients to have other concurrent chronic
`medical conditions such as depression, heart conditions or diabetes that also require adherence to
`
`daily dosing regimens.
`The treatment of bipolar disorder is currently recommended as once a day but the present
`formulation provides a lower rise in plasma concentration of the drug and thereby it is expected
`that this provides beneficial effects for the patient.
`The availability of a once a day tablet for the treatment of pain would be a significant
`advantage, pain is a continuous disease state, therefore a sustained release formulation would
`provide pain reliefby providing a Cmax at the appropriate point in the day or night depending
`when the patient's pain is most debilitating.
`Preferably the formulation provides about a 10 to 40%, alternatively a 10 to 20%
`reduction in Cmax over the Cmax obtained in the same patient on an IR dose if administered once
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`daily.
`
`Preferably the formulation provides a time to Cmax (tmax) of 8 to 24 hours post dose,
`
`alternatively 10 to 16 hours post close.
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`Preferably the formulation provides a rate of increase to tmax of less than 50% of an
`individual IR dose.
`
`The formulation may provide at 24 hours post dose a mean minimum serum
`concentration (Cmin) of at least 80 to 125% compared to the same IR dose in the same patient, or
`a (Cmin) higher that the IR dose and/or outside the range 80 to 125% compared to the same IR
`dose.
`
`Preferably the formulation provides a fluctuation index (Cmax-Cmin/Cave) in the range
`of0.lS to 0.45.
`
`At present some patients, when administered the conventional IR tablets, experience CNS
`adverse event (AE‘s) such as dizziness, ataxia, diplopia and rash.
`With the IR formulation the rate of AE‘s is for example, 31 to 38 % dizziness, 10 to 22%
`ataxia and 24 to 28 % diplopia. Without wishing to be bound by theory it is believed by the
`applicants that some of these adverse events relate to peak plasma levels or the rate of increase in
`plasma concentration afier administration and before the peak plasma concentration is achieved.
`The risk of rash and of serious rash may be related to the initial dose or the rate of dose escalation
`of lamotrigine, and the development of a formulation that lowers the peak level during titration
`
`may lessen the risk of these adverse events.
`A further aspect of the invention is a method of treating CNS disorders, which comprises
`orally administering to a patient a therapeutically effective amount of lamotrigine or a
`pharmaceutically acceptable derivative thereof in the form of a sustained release formulation,
`wherein a reduction in the AE's profile is achieved.
`Preferably the reduction in the AE‘s profile is a reduction in the rate of an adverse event
`of at least one side effect selected from dizziness, ataxia, diplopia or rash.
`Preferably the reduction in the AE‘s profile is a reduction in the rate of an adverse event
`of at least one side effect by 10%, preferably 20% more preferably 30%.
`A further aspect of the invention is a method of reducing the incidence of at least one
`adverse event associated with the administration of lamotrigine or a pharmaceutically acceptable
`derivative thereof, which method comprises orally administering to a patient a therapeutically
`effective amount of lamotrigine or a pharmaceutically acceptable derivative in the form of a
`sustained release formulation.
`Preferably the adverse event is at least one of dizziness, ataxia, diplopia or rash.
`A further aspect of the invention is a method of treating epilepsy comprising orally
`administering to a patient a therapeutically effective amount of lamotrigine or a pharmaccutically
`acceptable derivative thereof in the form of a sustained release formulation.
`A further aspect of the invention is the use of lamotrigine or a pharmaceutically
`acceptable derivative thereof in the treatment of CNS disorders for manufacture of a sustained
`release formulation as a means of treating epilepsy and reducing the rate of adverse events.
`A further aspect of the invention is the use of lamotrigine or a pharmaceutically
`acceptable derivative thereof for manufacture of a sustained release formulation for the treatment
`of CNS disorders.
`
`A further aspect of the invention is the use of lamotrigine or a pharmaceutically
`acceptable derivative thereof for manufacture of a sustained release formulation for the treatment
`of CNS disorders by any method described herein.
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`A further aspect of the invention is the use of lamotrigine or a pharmaceutically
`acceptable derivative thereof for the treatment of CNS disorders.
`The dosage in a sustained release formulation intended to be swallowed whole where the
`dosage form integrity is essential for controlling the rate of release may conveniently be provided
`as a number of swallow tablets or capsules, for instance two, three or four. In cases where the
`release is achieved from a number of discrete particles, beads or granules, the dosage form need
`not be swallowed intact as long as the beads or particles themselves remain intact.
`The dosage in a sustained release formulation may be also provided as a single tablet.
`Preferably, a sustained release formulation of the present invention has an in vitro
`dissolution profile in which 40 to 65%, preferably 45 to 65%, more preferably 45 to 55% of the
`lamotrigine content is dissolved between 3 to 8 hours, more preferably between 4 to 6 hours; and
`that 90% of lamotrigine is dissolved between 6 and 16 hours, preferably between 10 to 15
`alternatively 10 to 14 hours. In comparison, a conventional, immediate release lamotrigine tablet
`dissolves 80% within 30 minutes. The dissolution profile may be measured in a standard
`dissolution assay, for instance <724> Dissolution Test, Apparatus l or 2 or 3 or 4, provided in
`USP 24, 2000 and updated in subsequent supplements, at 37.0 :1: O.5°C, using dilute hydrochloric
`acid or other suitable media (500-3000 ml) and a rotation speed of 50 — 100 rpm.
`The sustained release formulation may provides an in viva "Area Under the Curve"
`(AUC) value which is equivalent to that of the existing instant release IR tablet, for instance at
`least 80%, preferably at least 90% to 110%, more preferably about 100%, but not exceeding
`125% of that of the corresponding dosage of lamotrigine taken as a conventional (immediate
`release) formulation, over the same dosage period, thereby maximising the absorption of
`lamotrigine from the sustained release formulation.
`The pharmacokinetic profile for a dosage of the present invention may be readily
`determined fi'om a single dosage bioavailability study in human volunteers. Plasma
`concentrations of lamotrigine may then be readily determined in blood samples taken from
`patients according to procedures well known and documented in the art.
`The person skilled in the art will appreciate that a therapeutically effective amount will
`depend on the patient‘s age, size, severity of disease and other medication.
`Preferred sustained release formulations are fiinctional coated tablets or caplets, or tinie-
`release tablets or caplets matrices containing wax or polymer, or osmotic pump devices or
`combinations thereof. They can also be controlled release beads, granules, spheroids that are
`contained within a capsule or administered from a sachet or other unit dose powder device.
`Representative sustained release formulations include a tablet, including swallow tablets,
`a capsule, granules or a sachet, typically a swallow tablet, which may or may not be coated.
`A further aspect of the invention is a formulation comprising lamotrigine or a
`pharrnaceutically acceptable derivative thereofand a release retarding excipient, which allows for
`sustained release of lamotrigine or a pharmaceutically acceptable derivative thereof. Suitable
`release retarding excipients include release-retarding polymers which may be swellable or not in
`contact with water or aqueous media such as the stomach contents; polymeric materials which
`fonn a gel on contact with water or aqueous media; polymeric materials which have both swelling
`and gelling characteristics in contact with water or aqueous media and pH sensitive polymers, for
`instance polymers based upon methacrylic acid copolymers such as the Eudragit (trade mark)
`
`10
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`15
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`25
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`IPR2015-00410
`Petitioners' Ex. 1011
`Page 8
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`WO 2004/012741
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`PCT/EP2003/008368
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`polymers, for example Eudragit L (trade mark) which may be used either alone or with a
`plasticiser.
`These sustained release formulations are often referred to in the art, as "matrix
`formulations" where by the drug is incorporated into a hydrated polymer matrix system and is
`released via diffusing or erosion, for example W098/47491 and US 5,242,627.
`Release retarding polymers which may be swellable or not include, inter alia, cross-
`linked sodium carboxymethylcellulose, cross-linked hydroxypropylcellulose,
`hydroxyethylcellulose, high-molecular weight hydroxypropylmethylcellulose,
`carboxyrnethylarnide, potassium methacrylatedivinylbenzene c0—polymer,
`polymethylmethacrylate, cross-linked polyvinylpyrrolidone, hydroxyethyl cellulose high-
`molecular weight polyvinylalcohols etc.
`Release retarding gellable polymers include methylcellulose, carboxymethylcellulose,
`low-molecular weight hydroxypropylmethylcellulose, hydroxyethyl cellulose, low-molecular
`weight polyvinylalcohols, polyoxyethyleneglycols, non-cross linked polyvinylpyrrolidone,
`xanthan gum etc.
`Release retarding polymers simultaneously possessing swelling and gelling properties
`include medium—viscosity hydroxypropylmethylcellulose and medium-viscosity
`
`polyvinylalcohols.
`Preferably the release retarding polymer used has a molecular weight in the range 5 to 95
`thousand, more preferably in the range 10 to 50 thousand.
`A preferred release—retarding polymer is one of the available grades of
`hydroxypropylmethyl cellulose or hydroxyethyl cellulose.
`Examples of polymers which may be used include Methocel K4M (Trade Mark),
`Methocel ESM (Trade Mark), Methocel E50 (Trade Mark), Methocel E4M (Trade Mark),
`Methocel EIOOM (Trade Mark), Methocel K15M (Trade Mark), Methocel Kl 00M (Trade Mark)
`and Methocel KIOOLV (Trade Mark), POLYOX WSR N-80 or mixtures thereof. Alternatively
`examples ofpolymers which may be used include Methocel K4M (Trade Mark), Methocel E5
`(Trade Mark), Methocel E50 (Trade Mark), Methocel E4M (Trade Mark), Methocel Kl5M
`(Trade Mark), Methocel Kl OOLV (Trade Mark), POLYOX WSR N—8O or mixtures thereof.
`Other known release-retarding polymers which may be incorporated include
`hydrocolloids such as natural or synthetic gums, cellulose derivatives other than those listed
`above, carbohydrate-based substances such as acacia, gum tragacanth, locust bean gum, guar
`gum, agar, pectin, carageenin, soluble and insoluble alginates, carboxypolymethylene, casein,
`zein, and the like, and proteinaceous substances such as gelatine.
`Preferably the release-retarding polymer is Methocel E4M Grade, POLYOX WSR N-80,
`Methocel Kl OOLV.
`
`The sustained release formulation may also include diluents/compression aid such as
`lactose, microcrystalline cellulose, dicalcium phosphate, sucrose, mannitol, xylitol; starches, and
`lubricants such as magnesium stearate, sodium stearyl fumarate and stearic acid. The sustained
`release formulation may further comprise disintegrants, such as cross-linked polyvinylpyrrolidone
`(CLPVP) and sodium starch glycollate; binders such as povidone (polyviny1pyrrolidone); flow
`aids such as silicon dioxide or talc. Typically, the sustained release formulation comprises from
`about 2.5 to 80% by weight of lam