OA18467A - Extended release pharmaceutical compositions of levetiracetam - Google Patents

Extended release pharmaceutical compositions of levetiracetam Download PDF

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Publication number
OA18467A
OA18467A OA1201700446 OA18467A OA 18467 A OA18467 A OA 18467A OA 1201700446 OA1201700446 OA 1201700446 OA 18467 A OA18467 A OA 18467A
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Prior art keywords
pharmaceutical composition
extended release
cognitive impairment
levetiracetam
tablet
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OA1201700446
Inventor
Michela Gallagher
Sharon Rozenzweig-Lipson
Elsie Melsopp
Jack Lawrence James
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Agenbio, Inc
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Publication of OA18467A publication Critical patent/OA18467A/en

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Abstract

This invention relates to novel extended release pharmaceutical compositions of levetiracetam and preparations and characterizations thereof. This invention further relates to using these extended release pharmaceutical compositions of levetiracetam for the treatment of cognitive impairment associated with central nervous system (CNS) disorders in a subject in need or at risk thereof.

Description

EXTENDED RELEASE PHARMACEUTICAL COMPOSITIONS OF LEVETIRACETAM [0001] This application claims priority and benefit from U.S. Provisional Patent
Application 62/165,812, filed May 22,2015, and U.S. Non-Provlsional Patent Application 15/160,424, filed May 20,2016, the contents and disclosures of which arc incorporated herein by reference in their entlrcty.
Field of the Invention |0002] This invention relates to novel extended release pharmaceutical compositions oflevetiracetam and préparations and characterizations thereof. This invention further relates to using these extended release pharmaceutical compositions of levetiracetam for the treatment of cognitive impairment associated with central nervous system (CNS) disorders in a subject în need or at risk thereof.
Background of the Invention [0003| Cognitive ability may décliné as a normal conséquence ofaging or as a conséquence of a CNS disorder.
[0004[ For example, a signîficant population of elderly adults expériences a décline in cognitive ability that excecds what Is typical in normal aging. Such agerelated loss of cognitive function is characterized cllnlcally by progressive loss of memory, cognitîon, reasoning, andjudgment. Mild Cognitive Impairment (MCI), Age-Associated Memory Impairment (AAMI), Age-Related Cognitive Décliné (ARCD) or similar clinical groupings are among those related to such age-related lossofcognitive function. Accordingtosomeestimâtes, there are morethan !6 million people with AAMI In the U.S. alone (Barker et al., 1995), and MCI is estimated to aflect 5.5 - 7 million ln the U.S. over the âge of 65 (Plassman et al, 2008).
[0005] Cognitive impairment is also associated with other central nervous system 30 (CNS) disorders, such as dementia, Aizhetmer's Disease(AD)l prodrome! AD, post
I traumatic stress disorder (PTSD), schizophrenîa, bipolar disorder (e.g., mania), amyotrophie latéral sclerosîs (ALS), can c cr-t h crapy-related cognitive impainnent, mental retardation, Parkinson’s disease (PD), autism, compulsive behavior, and substance addiction.
[0006] There is, therefore, a need for effective treatment of cognitive impairment associated with central nervous System (CNS) disordcrs and to improve cognitive function in patients diagnosed with, for cxamplc, age-reiated cognitive impainnent, MCI, amnestic MCI, AAMI, ARCD, dementia, Alzhcimcr’s Disease (AD), prodromal AD, post traumatic stress disorder (PTSD), schizophrenîa, bipolar disorder (e.g., mania), amyotrophie latéral scie rosi s, canccr-therapy-related cognitive impainnent, mental retardation, Parkînson’s disease (PD), autism, compulsive behavior, and substance addiction, and similar central nervous system (CNS) disordcrs associated with cognitive impairment or et risk of developing them.
[0007] Levetiracetam is a widely used antiepüeptic drug. Its International Union of Pure and Applied Chcmistry (IUPAC) name is (2S)-2-(2-oxopyrrolidin-l-yl) butanamide) and its chemical structure is shown in Fonnula I.
[0008] Levetiracetam is indicated as adjunctive therapy in the treatment of partial onset seizures, or myoclonie seizures, or primary generaiîzed tonic-clonlc seizures. it Îs recommended that such treatments should be initiated with a daily dose of 1000 mg/day. Additional dosing Incréments may be given to a maximum recommended daily dose of3000 mg. Levetiracetam is currently available as immédiate and extended release formulations for oral administration. Extended release dosage form of levetiracetam Is available in strengths of500 mg, 750 mg,
and 1000 mg for once daily usage. Immédiate release dosage form of levetiracetam îs available In strengths of250 mg, 500 mg, 750 mg, and 1000 mg for twlce daily usage.
|0009] International Application Nos. PCT/US09/05647, PCT/US12/24556, and
PCT/US 14/29170 disciose that levetlracetam, when administered et a dose lower than the therapeutic doses for treating epilepsy, can treat cognitive Impairment associated with central nervous system (CNS) dlsorders in a subject in need or at risk thereof.
[0010] The currently commercially available extended release dosage forms of levetlracetam comprise 500 mg, 750 mg, and 1000 mg of levetlracetam. Such extended release dosage forms are not suitable for treating cognitive Impairment. There Is, therefore, a need for novel extended release compositions of levetiracetam for treating cognitive impairment (5 Summary of the Invention [0011 [ In one aspect the présent invention provides an extended release pharmaceutical composition comprising: a) 220 mg of levetiracetam; b) 280 mg-350 mgofhydroxypropyl methylcellulose; c) 1.2 m g-1.4 mgof colloïdal silicon dioxide; d) 92.8 mg-I 19.2 mgofsiiicifîed microcrystailine celiuiose; and 20 e) 6.0 mg-6.7 mg of magnésium stéarate. In another aspect the présent invention provides an extended release pharmaceutical composition comprising: a) 220 mg of levetiracetam; b) 280 mgofhydroxypropyl methylcellulose; c) 12 mgof colloïdal silicon dioxide; d) 92.8 mg of silicified microcrystailine cellulose; and e) 6.0 mg of magnésium stéarate. In another aspect the présent Invention provides an 25 extended release pharmaceutical composition comprising: a) 220 mg of levetiracetam; b) 3473 mgofhydroxypropyl methylcellulose; c) 1.4 mg of colloïdal silicon dioxide; d) 119.2 mgofsiiicified microcrystailine cellulose; and e) 6.7 mg of magnésium stéarate. In certain embodiments of these aspects of the invention, the hydroxypropyl methylcellulose is Methocel™ K15M CR or
Methocel™ K100M Premium CR. In certain embodiments of these aspects of the invention, the hydroxypropyl methylcellulose Is Methocel™ K15M CR. In certain embodiments of these aspects of the invention, the sitlcified microcrystalline cellulose is ProSolv™ HD90.
]0012] In another aspect, the present invention provides an extended release pharmaceutical composition comprising: a) 190 mg of levetiracctam; b) 300 mg of hydroxypropyl methylcellulose; c) 12 m g of colloïdal silicon dioxide; d) 102.8 mg of sîlicified microcrystalline cellulose; and e) 6 mg of magnésium stéarate. In another aspect, the present invention provides an extended release pharmaceutical composition comprising: a) 190 mgoflevetiracetam; b) 300 mgof hydroxypropyl 10 methylcellulose; c) 1.2 mgof colloïdal silicon dioxide; d) 102.8 mgof anhydrous dicalcium phosphate; and e) 6 mg of magnésium stéarate. In certain embodiments of these aspects of the Invention, the hydroxypropyl methylcellulose Is Methocel™ KI5M CR or Methocel™ ΚΙ00Μ Premium CR. In certain embodiments of these aspects ofthe invention, the hydroxypropyl methylcellulose is Methocel™ K15M 15 CR. In certain embodiments of these aspects of the invention, the sllicified microcrystalline cellulose Is ProSolv™ HD90.
[0013] In certain embodiments ofthe Invention, the extended release pharmaceutical composition ofthe invention is formulated for once daily administration.
[0014] ln certain embodiments of the invention, the extended release pharmaceutical composition ofthe invention Is formulated for one-unit-dosageform-once-daiiy administration.
[0015] In certain embodiments ofthe Invention, the extended release pharmaceutical composition ofthe invention Is in the form ofa tablet ln some 25 embodiments, the extended release pharmaceutical composition ofthe invention Is in a tablet form and Is formulated for one-tablet-once-daily administration.
i [0016] ln certain embodiments of the invention, the extended release pharmaceutical composition of the invention is formulated for oral administration.
[0017] In certain embodiments of the invention, the extended release pharmaceutical composition of the invention does not comprise a hydrophobie rate controlling polymer.
[0018] ln certain embodiments of the Invention, the extended relcase pharmaceutical composition of the Invention does not comprise a functional coating.
[0019| ln another aspect, this invention provides methods of improving cognitlon in a subject su fie ring from cognitive impairment or at risk thereof by administering the extended release pharmaceutical compositions of the invention. In certain 10 embodiments, the subject suffers from cognitive impairment associated with a central nervous system (CNS) disorder, oral riskthereof. In certain embodiments, the cognitive impairment is associated with age-rclated cognitive Impairment In certain embodiments, the age-rclated cognitive impairment Is Mild Cognitive Impairment In certain embodiments, the Mild Cognitive Impairment is amnestic 15 Mild Cognitive Impairment ln certain embodiments, the cognitive impairment 1s associated with dementia, Alzheimcr’s disease, schizophrcnia, amyotrophie latéral sclerosis, post trau marie stress disorder, cancer therapy, bipolar disorder mental retardation, Parkinson’s disease, autlsm, compulsive behavior, or substance addiction.
[0020] In another aspect this invention provides methods of treating mild cognitive impairment due to Alzheimcr's disease in a human subject in need thereof by administering the extended release pharmaceutical compositions ofthe invention.
|0021] ln anotheraspect, this invention provides methods of treating amnestic miid cognitive impairment due to Alzheimer’s disease in a human subject ln need thereofby administering the extended release pharmaceutical compositions ofthe Invention.
[0022] In another aspect, this invention provides methods of slowing the progression of mild cognitive impairment due to Alzheimer’s disease in a human
subject ln need thereof by administering the extended release pharmaceutical compositions ofthe invention.
[0023] In another aspect, this Invention provides methods of slowing the progression of amnestic mild cognitive împalrment due to Al2heimer*s disease ln a 5 human subject in need thereof by administering the extended rciease pharmaceutical compositions ofthe Invention.
Brief Description ofthe Drawings [0024] Figure 1 is a flow diagram ofone embodiment ofa process for manufacturing extended release compositions of Ievetiracetam (e.gi, 190 mg and 10 220 mg tablets listed in Tables 1 and 3).
[0025] Figure 2 shows the mean concentrations of different Ievetiracetam formulations in plasma following oral administration to male dogs. The tested Ievetiracetam formulations are: an immédiate release 250 mg Ievetiracetam (LEV-IR) tablet being administered as 250 mg oral BID (twice daily) regimen 15 (total dose of 500 mg); an extended release 500 mg Ievetiracetam tablet (LEV-XR) being administered as n single oral dose of 500 mg; the 190 mg Tabiets A, B, and C of Table 1 being administered as single oral doses of 190 mg. Plasma pharmacokinetic samples are collected at pre-dose (f.e., 0), 025,03,1,2,4,6,8, 12,13 (LEV-IR 250 mg BID only), 18,24, and 48 hours post dose. For LEV-IR 20 250 mg BID, the 12-hour blood sample is coiiected just prior to administration of the second dose.
[0026] Figure 3 shows the mean concentrations ofdifferent Ievetiracetam formulations In plasma following oral administration to male dogs. The tested ievetiracetam formulations are: on extended release 500 mg Ievetiracetam tablet 25 (LEV-XR) being administered as a single ora! dose of 500 mg; the 220 mg Tablets
D and E of Table 3 being administered as single oral doses of220 mg.
[0027] Figure 4 shows the mean Ievetiracetam concentration-tîme profiles after administration ofthe 190 mg Tablet A ofTable 1 under Fasted Conditions (Group
1/Treatment A: Al) and the 190 mg Tablet A af Table 1 under Fed Conditions (Group 1/Treatment B: Bl).
[0028] Figure 5 shows the mean levetlracetam concentratlon-time profiles after administration ofthe 220 mg Tablet D afTable 3 under Fasted Conditions (Group 5 2/Treatment A: A2) and the 220 mg Tabîet D of Table 3 under Fed Conditions (Group 2/Treatment B: B2).
[0029] Figure 6 shows the effective plasma level ranges based on Agcd-lmpaired rat studies and phase II study in aMCI patients. The acceptable range goal for the Phase 1 food effect study ofthe extended release formulations is established based 10 on the effective plasma level range în aged-impalred rats and ln aMCI patients, Le., between 1.9 and 4.4 pg/ml. The preferred range goal for the Phase 1 food effect study ofthe extended release formulations is established based on the effective plasma levé! range in aMCI patients, Le., between 2.9 and 4.4 pg/ml.
|0030] Figure 7 shows the steady state modeling ofthe PK profile ofthe 190 mg 15 Tablet A af Table 1, indicating that this tablet meets the acceptable range goal. Le., between 1.9 and 4.4 gg/ml.
J0031 ] Figure 8 shows the steady state modeüng ofthe PK profile ofthe 220 mg Tablet D of Table 3, indicating that this tablet meets the preferred range goal, Le., between 2.9 and 4.4 pg/ml.
[0032] Figure 9 is a flow diagram ofanother embodiment ofa process far manufacturing extended release compositions of levetiracetam (e.g., 190 mgand 220 mg tablets listed In Tables 1 and 3).
Detailed Description of the Invention [0033] This invention provides novel extended release pharmaceutical compositions oflevetiracetam. This invention also provides methods ofusing these extended release pharmaceutical compositions of levetiracetam for treating cognitive impairmentor improving cognitive function associated with central nervous system (CNS) disorders in a subject in need or at risk thereof. This
invention also provides using these extended release pharmaceutical compositions of levetiracctam in the manufacture of médicaments for treating cognitive impairment or improving cognitive function associated with central nervous system (CNS) disorders in a subject In need or at risk thereof.
[0034] In order that the invention herein described may b e fully understood, the following details description Is set fbrth.
[0035] Unless otherwise defined herein, scientific and technical terms used in this application shall hâve the meanings that are commonly understood by those of ordinary skill in the art to which this invention bclongs. Generally, nomenclature 10 used ln connection with, and techniques of, cell and tissue culture, molecular biology, cell biology, cancer biology, neurobîology, neurochemistry, vlrology, Immunology, mlcrobiology, genetics, protein and nucleic acid chemlstry, chcmistry, and pharmacology described herein, are those well known and commonly used in the art Each embodiment ofthe inventions described herein 15 may be taken alone or in combination with one or more other embodiments ofthe inventions.
[0036] The methods and techn i ques o f the présent invention are general ly performed, unless otherwise indicated, according to conventional methods well known in the art and as described in various general and more spécifie référencés 20 that are cited and discussed throughout this spécification. See, e.g. “Principles of
Neural Science**, McGraw-Hill Medical, New York, N.Y. (2000); Motulsky, “Intuitive Biostatlstics, Oxford University Press, Inc. (1995); Lodish et aL “Molecular Cell Biology, 4th ed”, W. H. Freeman & Co., New York (2000); Griffiths et al„ “Introduction to Genetic Analysis, 7lh ed, W. H. Freeman & 25 Co., N.Y. ( 1999); Gilbert et al., “Devclopmental Biology, 6th ed”, Sinauer Associâtes, Inc„ Sunderiand, MA (2000).
[0037] Chemistry terms used herein are used according to conventional usage In the art, as exemplified by “The McGraw-Hill Dlctionary of Chemical Terms”, Parker S„ Ed., McGraw-Hill, San Francisco, C.A. (1985).
(0038] Al! ofthe above, and any other publications, patents and published patent applications referred to in this application are specifically încorporated by reference herein. tn case of conflict, the présent spécification, including its spécifie définitions, will control.
S (0039) Throughout this spécification, the word “comprise” or variations such as “comprises” or “comprising” will be understood to impiy the inclusion of a stated Integer (or components) or group of integers (or components), but not the exc lus ion o f any other integer (or components) or group o f integers (or components).
(0040( The singular forms “a, “an,” and “the” include the plurals unless the context clearly dictâtes otherwise.
(0041) The term “including” îs used to mean “including but not iimited to”. “Including” and “including but not iimited to” are used interchangeably.
[0042] In order to further define the invention, the following terms and définitions arc provided herein.
Définitions (0043] The term “extended release, ““extended release form”, or “extended release dosage form” is widely recognized in the art of pharmaceutical sciences as Systems that maintalns therapeutîc blood or plasma or tissue levels ofa drug for an 20 extended period. An extended release dosage form potentially provides greater ' effecti veness in the treatment of chronic diseases or conditions; greater convenience; reduccs side effects and provides higher levels of patient compliance or therapeutîc performance due to a simpli fied dosage schedule, compared with those ofimmediate-release drugs. Extended release pharmaceutical products arc 25 formulated to release the active ingrédient graduaily and predictably over an extended time period, such as a 24-hour period.
[0044] The term “extended release”, “extended release form”, or “extended release dosage form” is used herein to refer to a controlled release of ievetiracetam
from a dosage form to an environment over (throughout or during) an extended period oftime, e.g., twenty-four hours. An extended release dosage form will release drug at substantially constant rate over an extended period of time or a substantially constant amount of drug will be released incrémental ly over an 5 extended period of time. The term “extended release” used herein includes the terms “controlled release”, “prolonged release, “sustained release”, “slow release”, or “modified release” as these terms are used in the pharmaceutical sciences.
(0045] The term “active ingrédient” “active pharmaceutical ingrédient” or “API” 10 as used herein is defined as a substance which has a therapeutic effect, such as levetiracetam.
[0046] A “patient, “subject”, or “individual” are used interchangeabiy and refer to either a human or a non-human animal. These tenus include mammals, such as humans, primates, iivestock animais (Including bovines, porcines, etc.), companlon 15 animais (e.g., canines, felines, etc.) and rodents (e.g., mice and rats).
[0047] “Cognitive fonction” or “cognitive status” refera to any higher order Intellectual brain process or brain state, respectively, involved In leaming and/or memory including, but not limited to, attention, information acquisition, Information processing, working memory, short-tenu memoiy, long-tenu memory, 20 anterograde memory, rétrograde memory, memory retrieval, discrimination leaming, decision-making, inhibitory response control, attentional set-shifting, delayed reinforcement leaming, reversai leaming, the temporal intégration of voluntary behavîor, and expressing an interest In one’s surroundings and self-care, speed of processing, reasonlng and problem solving and social cognition.
[0048] In humans, cognitive fonction may be measured, for example and without limitation, by measuring neuronal injury, measuring change in Entorhinal Cortex thickness using structural MRI (e.g., for measuring neuronal injury); the clinical global impression of change scale (CiBIC-pius scale); the Mini Mental State Exam (MMSE); the Neuropsychiatrie Inventory (NPI); the Clinical Dementia Rating
Scale (CDR) (global, memory box); the Cambridge Neuropsychoiogîcal Test
Automated Battery (CANTAB); the Sandoz Clinical Assessment-Geriatric (SCAG); the Buschke Sélective Reminding Test (Buschke and Fuld, 1974); the Verbal Pal red Associâtes subtest; the Logical Memory subtest; the Visual Reproduction sublest of the Wechsler Memory Scale-Revised (WMS-R) (Wechsler, 1997); the Benton Visual Rétention Test; or the explicit 3-altemative forced choice task; or MATRICS consensus neuropsychologîcal test battery; or ADAS-Cog 13 item-scale; Wechsler Logical Memory 1 and II; BSP-O;
Neuropsychologîcal tests (Trails A and B, BNT, SR, CFT, R-O, Paired-assocîates), other MRI measures, DTI, resting IMR1, and the GDS. See Folstein et al., J 10 Psychiatrie Res 12: 189-98, (1975); Robbins et aU Dementta5:266-81, (1994);
Rey, L’examen clinique en psychologie, (1964); Kluger et al., J Geriatr Psychlatry Neurol 12:168-79, (!999); Marquis étal2002 and MasuretaL 1994. Also see Buchanan, R.W., Keefe, R.S.E., Umbricht, D^ Green, M.F., Laughren, T., and Manier, S.R. (2011), The FDA-NIMH-MATRICS guidelines for clinical trial i 5 design of cognitive-enhancing drugs: what do we know 5 years later? Schizophr.
Bull. 37, 1209-1217.
[0049] In animal mode! Systems, cognitive function may be measured ln various conventional ways known In the art, including using a Morris Water Maze (MWM), Barnes circular maze, elevated radial arm maze, T maze or any other 20 mazes in which the animais use spatial information. Cognitive function can be assessed by reversai leaming, extradimensional set shîftîng, conditional discrimination leaming and assessments ofrcward cxpectancy. Other tests known În the art may also be used to ossess cognitive function, such as nove! object recognitio n and odor recogn i lion tasks.
[0050] Cognitive function may also be measured using imaging techniques such as Positron Emission Tomography (PET), functional magnetic résonance imaging (IMRI), Single Photon Emission Computed Tomography (SPECT), or any other imaging technique that allows one to measure brain function. In animais, cognitive Function may also be measured with electrophysiological techniques.
[0051] “Promoting” cognitive function refers to afTecting impaired cognitive function so that it more closeiy resembles the function ofa normal, unimpaired
subject. Cognitive function may be promoted to any détectable degree, but ln humans preferably Is promoted sufïicicntly to allow an impaired subject to cany out daily activities of normal life a level of pnoficiency as close as possible to a normal, unimpaired subject or an agc-matched normal, unimpaired subject [0052] ln some cases, “promoting” cognitive function in a subject affected by age-related cognitive refers to afTectîng impaired cognitive function so that it more closely resembles the function of an aged-matched normal, unimpaired subject, or the function ofa young aduit subject Cognitive function of that subject may be promoted to any détectable degree, but in humans preferably Is promoted sufïÏcicntiy to allow an impaired subject to carry out daily activities of normal üfe at a level of proficiency as close as possible to a normal, unimpaired subject or a young adult subject or an age-matched normal, unimpaired subject [0053] “Preservîng cognitive function refera to affecting normal or impaired cognitive function such that it does not décliné or does not fait below that observed 15 in the subject upon firat présentation or diagnosis, or deiays such décliné.
[0054] “Im pro vin g” cognitive function includes promoting cognitive function and/or preservîng cognitive function in a subject [0055] “Cognitive impairment refera to cognitive function in subjects that is not as robust as that expected in a normal, unimpaired subject ln some cases, cognitive function is reduced by about 5%, about 10%, about 30%, or more, compared to cognitive fonction expected in a normal, unimpaired subject ln some cases, “cognitive impairment” in subjects affected by aged-rciated cognitive impairment refera to cognitive fonction in subjects that is not as robust as that expected ln an aged-matched normal, unimpaired subject or the fonction of a young adult subject (/.e. subjects with mean scores for a given âge in a cognitive test).
[0056] “Treating” a condition or patient refera to taking steps to obtain bénéficiai or desired results, including clinical results. Bénéficiai or desired clinical results include, but are not limited to, improvîng cognitive fonction, deiaying or slowing the progression of cognitive impairment, reducing the rate ofdeciineof cognitive
function, preventing or slowing the progression ofthe disease or disorder, or alleviation, amelioration, or slowing the progression, of one or more symptoms associated of cognitive împairment associated with CNS disorders, such as âge* related cognitive Impairment, Mild Cognitive Impairment (MCI), amnestlc MCI, 5 dementia, Alzheimer’s Disease (AD), prodromal AD, PTSD, schizophrcnla or blpolar disorder (in particular, mania), amyotrophie latéral sclerosls (ALS) or cancer lherapy*related cognitive Impairment Treating age-related cognitive Impairment further comprises slowing the conversion of age-related cognitive impairment (including, but not limited to MCI, ARCD and AAMI) into dementia 10 (e.g., AD).
[0057] “Treating cognitive Impaîrment” refers to taking steps to improve cognitive function ln a subject with cognitive impairment so that the subject’s performance in one or more cognitive tests Is Improved to any détectable degree, or Is prevented from further décliné. Preferably, that subject's cognitive function, 15 after treatment of cognitive Impairment, more closely resembles the function of a normal, unimpaired subject Treatment ofcognitive Impairment In humans may improve cognitive function to any détectable degree, but Is preferably Improved suffîclently to allow the impaired subject to cany out daily actlvitles of normal life at the same level of proficlency as a normal, unimpaired subject ln some cases, 20 “treating cognitive Impairment” refers to taking steps to Improve cognitive function ln a subject with cognitive impairment so that the subject’s performance in one or more cognitive tests Is Improved to any détectable degree, or Is prevented from further décliné. Preferably, that subject’s cognitive function, after treatment of cognitive impairment, more closely resembles the function of a normal, unimpaired subject ln some cases, “treating cognitive impairment in a subject affectlng by age-related cognitive impairment refers to takings steps to improve cognitive function In the subject $o that the subject’s cognitive function, after treatment of cognitive impairment, more closely resembles the fonction of an agematched normal, unimpaired subject, or the fonction of a young adult subject. In 30 some cases, “treating cognitive Impairment” in a subject refers to taking steps to delay or slow the progression of cognitive impairment in a subject with cognitive impairment. In some cases, “treating cognitive impairment” in a subject refera to
taking steps to reduce the rate of décliné of cognitive fonction In a subject with cognitive impairment.
[0058] The term “agent” is used herein to dénoté a chemical compound (such as an organic or inorganic compound, a mixture of chemical compounds), a biological 5 macromolecule (such as a nucleic acid, an antibody, including parts thereof as well bs human ized, chimeric and human antibodies and monoclonal antibodies, a protein or portion thereof, e.g., a peptide, a lipld, a carbohydrate), or an cxtract made from biological materials such as bacteria, plants, fongi, or animal (particularly mammalian) cells or (issues. Agents include, for example, agents î 0 whîch are known with respect to structure, and those which are not known with respect to structure.
Description of Compositions of the Invention |00591 This invention provides extended release compositions of levetiracetam.
The compositions of this invention can be used for Improving cognttlon in patients 15 who suffer from cognitive impairment associated with central nervous system (CNS) disorders in a subject ln need orat risk thereof. The compositions of this invention is administered once a day (le., once every 24 hours) for improving cognltlon.
[0060] In one aspect, the invention provides extended release pharmaceutical 20 compositions comprising: a) 220 mg of levetiracetam; b) 280 mg to 350 mg of hydroxypropyl methylcellulose (or hypromcllose); c) 12 mg to 1.4 mgof colloïdal silicon dioxide; d) 92.8 mg-l 192 mgofsilicified microcrystaiiinc cellulose; and e) 6.0 mg to 6.7 mg of magnésium stéarate, ln some embodiments, the hydroxypropyl methylcellulose (or hypromeüose) is Methocei™ K ISM CR. In 25 some embodiments, the hydroxypropyl mcthyiceiluiose (or hypromeilose) Is Methocei™ K100M Premium CR. In some embodiments, the silicified microcrystalline cellulose Is ProSolv™ HD90. In some embodiments, the magnésium stéarate Is HyQual®. In some embodiments, the extended release pharmaceutical composition is in a solid form. In some embodiments, the extended release pharmaceutical composition is ln the form of a tablet or capsule.
[0061J In another aspect, the invention provides extended release pharmaceutical compositions comprising: a) 220 mg of ievetiracetam; b) 280 mg of hydroxypropyl methylcellulose (or hypromellose); c) 12 mg of colloïdal silicon dioxide; d) 92.8 mg of silicified microcrystalline cellulose; and e) 6.0 mg of magnésium stéarate.
In some embodiments, the hydroxypropyl methylcellulose (or hypromellose) is Methocel™ KI5M CFL In some embodiments, the hydroxypropyl methylcellulose (or hypromellose) is Methocel™ K100M Premium CR. In some embodiments, the silicified microcrystalline cellulose is ProSolv™ HD90. In some embodiments, the magnésium stéarate is HyQual®. In some embodiments, the extended release 10 pharmaceutical composition Is in a solid form. In some embodiments, the extended release pharmaceutical composition is in the form of a tablet or capsule.
[0062] In another aspect, the invention provides extended release pharmaceutical compositions comprising: a) 220 mg of Ievetiracetam; b) 347.5 mg of hydroxypropyl methylcellulose (or hypromellose); c) 1.4 mg ofcolloidal silicon 15 dioxide; d) 1192 mg of silicified microcrystalline cellulose; and e) 6.7 mg of magnésium stéarate. In some embodiments, the hydroxypropyl methylcellulose (or hypromellose) is Methocel™ K15M CR. In some embodiments, the hydroxypropyl methylcellulose (or hypromellose) is Methocel™ K100M Premium CR. In some embodiments, the silicified microcrystalline cellulose is ProSolv™ 20 HD90. In some embodiments, the magnésium stéarate is HyQual®. In some embodiments, the extended release pharmaceutical composition is in a solid form. In some embodiments, the extended release pharmaceutical composition Is in the form of a tablet or capsule.
[0063] In another aspect the Invention provides extended release pharmaceutical 25 compositions comprising: a) 220 mg of Ievetiracetam; b) 280 mg of hydroxypropyl methylcellulose (or hypromellose) Methocel™ KI5M CR; c) 12 mg of colloïdal silicon dioxide; d) 92.8 mgof silicified microcrystalline cellulose ProSolv™
HD90; and e) 6.0 mg of magnésium stéarate (e.g., HyQual®). fn some embodiments, the extended release pharmaceutical composition is în a solid form.
ln some embodiments, the extended release pharmaceutical composition is in the form of a tablet or capsule.
J0064] In another aspect, the invention provides extended release pharmaceutical compositions comprising: a) 220 mg of levetiracetam; b) 3473 mg of hydroxypropyl methylcellulose (or hypromellose) Methocel™ KI5M CR; c) 1.4 mg of colloïdal silïcon dioxide; d) 119.2 mg of silicified microcrystalline cellulose 5 ProSolv™ HD90; and e) 6.7 mg of magnésium stéarate (e.g., HyQua!®). In some embodiments, the extended release pharmaceutical composition is in a solid form. In some embodiments, the extended release pharmaceutical composition is in the form of a tablet or capsule.
|0065] In another aspect, the invention provides extended release pharmaceutical 10 compositions comprising: a) 190 mg of levetiracetam; b) 300 mg of hydroxypropyl methylcellulose (or hypromellose); c) 1.2 mg of colloïdal silïcon dioxide; d) 102.8 mg of silicified microcrystalline cellulose; and e) 6 mg of magnésium stéarate, [n some embodiments, the hydroxypropyl methylcellulose (or hypromellose) is Methocel™ KI5M CR. In some embodiments, the hydroxypropyl methylcellulose 15 (or hypromellose) is Methocel™ ΚΙ00Μ Premium CR. In some embodiments, the silicified microcrystalline cellulose 1s ProSolv™ HD90. In some embodiments, the magnésium stéarate is HyQual®. In some embodiments, the extended release pharmaceutical composition is în a solid form. In some embodiments, the extended release pharmaceutical composition Is in the form of a tablet or capsule.
J0066] In another aspect, the invention provides extended release pharmaceutical compositions comprising: a) 190 mg of levetiracetam; b) 300 mg of hydroxypropyl methylcellulose (or hypromellose); c) U mg of colloïdal silïcon dioxide; d) 102.8 mg of anhydrous dicalcium phosphate; and e) 6 mg of magnésium stéarate. In some embodiments, the hydroxypropyl methylcellulose (or hypromellose) is
Methocel™ Kl5M CR. In some embodiments, the hydroxypropyl methylcellulose (or hypromellose) is Methocel™ K100M Premium CR. In some embodiments, the magnésium stéarate is HyQual®. In some embodiments, the extended release pharmaceutical composition is in a solid form. In some embodiments, the extended release pharmaceutical composition is in the form of a tablet or capsule.
]0067] In another aspect, the invention provides extended release pharmaceutical compositions comprising: a) 190 mg of levetiracetam; b) 300 mgof hydroxypropyl
methylcellulose (or hypromellose) Methocel™ K15M CR; c) 12 mgof colloïdal siücon dioxide; d) 102.8 mg of silîcified microcrystalline cellulose ProSolv™ HD90; and e) 6 mg of magnésium stéarate (e.g., HyQual®). In some embodiments, the extended release pharmaceutical composition is in a solid form.
In some embodiments, the extended release pharmaceutical composition Is in the form of a tablet or capsule.
[0068] In another aspect, the invention provides extended release pharmaceutical compositions comprising: a) 190 mg of levetiracetam; b) 300 mg ofhydroxypropyl methylcellulose (or hypromellose) Methocel™ K100M Premium CR; c) 12 mg of 10 colloïdal silicon dioxide; d) 102.8 mg of silici fïed microcrystalline cellulose
ProSolv™ HD90; and e) 6 mg of magnésium stéarate (e.g., HyQual®). In some embodiments, the extended release pharmaceutical composition is in a solid form. In some embodiments, the extended release pharmaceutical composition is in the form ofa tablet or capsule.
[0069] In another aspect, the invention provides extended release pharmaceutical compositions comprising: a) 190 mgof levetiracetam; b) 300 mg ofhydroxypropyl methylcellulose (or hypromellose) Methocel™ Kl00M Premium CR; c) 12 mg of colloïdal silicon dioxide; d) 102.8 mg of anhydrous dicalcium phosphate; and e) 6 mgofmagnésium stéarate (e.g., HyQual®). In someembodiments, the extended release pharmaceutical composition is In a solid form. tn some embodiments, the extended release pharmaceutical composition is in the form ofa tablet or capsule.
[0070] In another aspect, the invention provides extended release pharmaceutical compositions comprising 100-350 mg of levetiracetam, a matrix-forming polymer, a glidant, a diluent, and a lubricant. In some embodiments, the matrix-forming 25 polymer Is water soluble. In some embodiments, the diluent is water soluble. In some embodiments, the amount of levetiracetam in the extended release pharmaceutical compositions Is 125-250 mg oflevetiracetam. In some embodiments, the percentage ofthe matrix-forming polymer in the extended release pharmaceutical compositions 1s any range between 45% w/w-70% w/w, such as 45%, 46%, 47%, 48%, 49%, 50%, 55%, 60%, 65%, or 70% w/w.
|0071] In another aspect, the invention provides extended release pharmaceutical compositions comprising: a) 30-40% w/w (e.g., 31.7-36.7%w/w) of levetiracetam;
b) 45-55% w/w (e.g., 46.7-50%w/w) of hydroxypropyl methylcellulose (or hypromellose); c) 0.01-5% w/w of colloïdal silicon dioxide (e.g., 02% w/w); d)
15-20% w/w ( 15.5-17.1%w/w) of silicified microcrystalline cellulose; and e) 0.01 5% w/w of magnésium stéarate (e.g., 0.96-1% w/w). In some embodiments, the hydroxypropyl methylcellulose (or hypromellose) îs Methocel™ K15M CR. In some embodiments, the hydroxypropyl methylcellulose (or hypromellose) Is Methocel™ ΚΙ00Μ Premium CR. In some embodiments, the silicified microcrystalline cellulose îs ProSolv™ HD90. In some embodiments, the magnésium stéarate is HyQual®. In some embodiments, the extended release pharmaceutical composition is in a solid form. In some embodiments, the extended release pharmaceutical composition is in the form ofa tablet or capsule. In some embodiments, the total weight ofthe extended release pharmaceutical composition is 250 mg -1000 mg. In a particular embodiment, the total weight of the extended release pharmaceutical composition Is 600 mg. In some embodiments, the extended release composition comprises 125-250 mg of levetiracetam.
[0072( ln another aspect, the invention provides extended release pharmaceutical compositions comprising: a) 36.7% w/w of levetiracetam; b) 46.7% w/w of hydroxypropyl methylcellulose (or hypromellose); c) 0.2% w/w of colloïdal silicon dioxide; d) 15.5% w/w of silicified microcrystalline cellulose; and e) 1% w/w of magnésium stéarate, ln some embodiments, the hydroxypropyl methylcellulose (or hypromcüose) Is Methocel™ KI5M CR. In some embodiments, the hydroxypropyl methylcellulose (or hypromellose) Is Methocel™ ΚΙ00Μ Premium CR. In some embodiments, the silicified microcrystalline cellulose is ProSolv™ HD90. In some embodiments, the magnésium stéarate is HyQual®. In some embodiments, the extended release pharmaceutical composition is in a solid form. ln some embodiments, the extended release pharmaceutical composition is in the form ofa tablet or capsule, ln some embodiments, the total weight of the extended release pharmaceutical composition Is 250 mg -1000 mg. In a particular embodiment, the total weight ofthe extended release pharmaceutical composition • w is 600 mg. tn some embodiments, the extended release composition comprises 125-250 mg of levetiracetam.
[0073| In another aspect, the invention provîdes extended release pharmaceutical compositions comprising: a) 31.7% w/wof levetiracetam; b) 50% w/w of hydroxypropyl methylcellulose (or hypromellose); c) 0.2% w/w mg of colloïdal silicon dioxide; d) 17.1% w/w of sl I ici fied microcrystalline cellulose; and e) 0.96% w/w of magnésium stéarate, ln some embodiments, the hydroxypropyl methylcellulose (or hypromellose) is Methocel™ K15M CR. ln some embodiments, the hydroxypropyl methylcellulose (or hypromellose) is Methocel™
Kl DOM Premium CR. In some embodiments, the silicified microcrystalline cellulose Is ProSolv™ HD90. In some embodiments, the magnésium stéarate is HyQual®. In some embodiments, the extended release pharmaceutical composition is in a solid form. In some embodiments, the extended release pharmaceutical composition is in the form of a tablet or capsule, ln some embodiments, the total weight of the extended release pharmaceutical composition is 250 mg - 1000 mg. In a particular embodiment, the total weight of the extended release pharmaceutical composition is 695 mg. In some embodiments, the extended release composition comprises 125-250 mg of levetiracetam.
[0074] In another aspect, the invention provides extended release pharmaceutical compositions comprising: a) 36.7% w/w of levetiracetam; b) 46.7% w/w of hydroxypropyl methylcellulose (or hypromellose) Methocel™ K15M CR; c)0.2% w/w of colloïdal silicon dioxide; d) 15.5% w/w of silicified microcrystalline cellulose ProSolv™ HD90; and e) 1% w/w of magnésium stéarate (e.g., HyQual®). tn some embodiments, the extended release pharmaceutical composition (s in a solid form. tn some embodiments, the extended release pharmaceutical composition is in the form of a tablet or capsule, tn some embodiments, the total weight ofthe extended release pharmaceutical composition is 250 mg -1000 mg. tn a particular embodiment, the total weight ofthe extended release pharmaceutical composition Is 600 mg. In some embodiments, the extended release composition comprises 125-250 mg of levetiracetam.
[0075] In another aspect, the Invention provides extended release pharmaceutical compositions comprising: a) 31.7% w/w of levetiracetam; b) 50% w/w of hydroxypropyl methylcellulose (or hypromellose) Methocel™ KI5M CR; c) 02% w/w of colloïdal silicon dioxide; d) 17.1% w/w ofsilicified microcrystailine cellulose ProSoiv™ HD90; and e) 0.96% w/w of magnésium stéarate (e.g.,
HyQuai®). In some embodiments, the extended release pharmaceutical composition Is in a solid form. In some embodiments, the extended release pharmaceutical composition is in the form of a tablct or capsule. ïn some
Is 250 mg-1000 mg. In a particularembodiment, the total weight ofthe extended release pharmaceutical composition is 695 mg. In some embodiments, the extended release composition comprises 125*250 mg of levetiracetam.
[0076] In another aspect, the Invention provides extended release pharmaceutical compositions comprising: a) 31.7% w/w of levetiracetam; b) 50% w/wof hydroxypropyl methylcellulose (or hypromellose); c) 02% w/w of colloïdal silicon dioxide; d) 17.1% w/w ofsilicified microcrystailine cellulose; and e) 1% w/w of magnésium stéarate. In some embodiments, the hydroxypropyl methylcellulose (or hypromellose) is Methocel™ K15M CR. In some embodiments, the hydroxypropyl methylcellulose (or hypromellose) is Methocel™ Kl 00M Premium
CR. In some embodiments, the sllicified mlcrocrystalline cellulose Is ProSoiv™ HD90. In some embodiments, the magnésium stéarate is HyQuai®. In some embodiments, the extended release pharmaceutical composition is in a solid form. In some embodiments, the extended release pharmaceutical composition is in the form ofa tablet or capsule. In some embodiments, thé total weight ofthe extended release pharmaceutical composition îs 250 mg —1000 mg. In a particular embodiment, the total weight ofthe extended release pharmaceutical composition Is 600 mg. In some embodiments, the extended release composition comprises 125*250 mg of levetiracetam.
[0077] In another aspect, the invention provides extended release pharmaceutical compositions comprising: a) 31.7% w/w of levetiracetam; b) 50% w/w of hydroxypropyl methylcellulose (or hypromellose); c) 02% w/w of colloïdal silicon
dioxide; d) 17.1% w/w of anhydrous dîcalcîum phosphate; and e) 1% w/w of magnésium stéarate, ln some embodiments, the hydroxypropyl methylcellulose (or hypromellose) is Methocel™ K15M CR. In some embodiments, the hydroxypropyl methylcellulose (or hypromellose) is Methocel™ K100M Premium
CR. In some embodiments, the magnésium stéarate is HyQunl®. In some embodiments, the extended release pharmaceutical composition is in a solid form. ln some embodiments, the extended release pharmaceutical composition is in the form of a tablet or capsule, ln some embodiments, the total weight of the extended release pharmaceutical composition îs 250 mg -1000 mg. In a particular embodiment, the total weight of the extended release pharmaceutical composition is 600 mg. ln some embodiments, the extended release composition comprises 125 -250 mg of levetiracetam.
[0078] ln another aspect, the invention provides extended release pharmaceutical compositions comprising: a) 31.7% w/w of levetiracetam; b) 50% w/w of hydroxypropyl methylcellulose (or hypromellose) Methocel™ Kl 5M CR; c) 0.2% w/w of colloïdal silicon dioxide; d) 17.1% w/w of silicified mlcrocrystalllne cellulose ProSolv™ HD90; and e) 1% w/w of magnésium stéarate (e.g., HyQual®). ln some embodiments, the extended release pharmaceutical composition is în a solid form. ln some embodiments, the extended release pharmaceutical composition Is in the fbrm of a tablet or capsule, ln some embodiments, the total weight of the extended release pharmaceutical composition is 250 mg —1000 mg. ln a particular embodiment, the total weight of the extended release pharmaceutical composition is 600 mg. ln some embodiments, the extended release composition comprises 125 *250 mg of levetiracetam.
[0079] ln another aspect, the invention provides extended release pharmaceutical compositions comprising: a) 31.7% w/w of levetiracetam; b) 50% w/w of hydroxypropyl methylcellulose (or hypromellose) Methocel™ K100M Premium CR; c) 0.2% w/w of colloïdal silicon dioxide; d) 17.1 % w/w of silicified microcrystalline cellulose ProSolv™ HD90; and e) 1% w/w of magnésium stéarate (e.g., HyQual®). ln some embodiments, the extended release pharmaceutical composition is in a solid form. In some embodiments, the extended release
pharmaceutical composition is in the form of a tablet or capsule. In some embodiments, the total weight of the extended release pharmaceutical composition is 250 mg -1000 mg. In a particular embodiment, the total weight of the extended release pharmaceutical composition is 600 mg. In some embodiments, the extended release composition comprises 125-250 mg of levetiracetam.
[0080] In another aspect, the invention provides extended release pharmaceutical compositions comprising: a) 31.7% w/w of levetiracetam; b) 50% w/w of hydroxypropyl methylcellulose (or hypromellose) Methocel™ ΚΙ00Μ Premium CR; c) 0.2% w/w of colloïdal silicon dioxide; d) 17.1% w/w ofanhydrous dicalcium phosphate; and e) 1% w/w of magnésium stéarate HyQual®. In some embodiments, the extended release pharmaceutical composition Is in a solid form. In some embodiments, the extended release pharmaceutical composition is !n the form of a tablet or capsule. In some embodiments, the total weight of the extended release pharmaceutical composition is 250 mg -1000 mg. In a particular embodiment, the total weight ofthe extended release pharmaceutical composition is 600 mg. In some embodiments, the extended release composition comprises 125-250 mgof levetiracetam.
|0081] In some embodiments, the invention uses hydroxypropyl methylcellulose (or hypromellose) as a rate control! in g polymer or a matrix forming polymer in the 20 extended release compositions. In some embodiments, hydroxypropyl methylcellulose (or hypromellose) can be used together with other rate controlHng polymère or matrix forming polymère In the compositions of this invention. In some embodiments, hydroxypropyl methylcellulose can be replaced b y other rate controlHng polymère or matrix forming polymère In the compositions of this 25 invention. In some embodiments, the rate controllîng polymère or matrix forming polymère that can replace hydroxypropyl methylcellulose or be used together with hydroxypropyl methylcellulose hâve similar properties or characteristics as hydroxypropyl methylcellulose. Examples of these rate controllîng polymère or matrix forming polymère include, without being Iimited to, cellulose, non-cellulose 30 polysaccharide, polyvinyl polymer, hydrogel, monolithic polymer, or mixtures thereof. In some embodiments, hydroxypropyl methylcellulose, hydroxyethyl
cellulose, hydroxypropyl cellulose, methylcellulose, sodium carboxymethyl cellulose, sodium alginate, carbomer, xanthan gum, guar gum, locust bean gum, carob gum, arable gum, sterculla gum, polyvinyl pyrrolîdone, polyvinyl acetate, polyvinyl alcohol, polyethylene oxide, or a mixture thereof can be used as a rate 5 controlling polymer or matrix forming polymer ln the compositions of the invention. In some embodiments, the hydroxypropyl methylcellulose (or hypromeilose) in the compositions ofthe présent invention may be selected from the group consisting of Methocel™ K4M, KJ5M, K100M, E4M, EIOM, K4M CR, KI5M CR, ΚΙ00Μ CR, E4M CR, EIOM CR, K4M Premium, K15M Premium, 10 K100M Premium, E4M Premium, EIOM Premium, K4M Premium CR,KI5M
Premium CR, KIOOM Premium CR, E4M Premium CR, EIOM Premium CR, and KIOO Premium LV.
]0082] In some embodiments, the Invention uses colloidal silicon dioxide as a glidant in the extendcd release compositions, ln some embodiments, colloïdal 15 silicon dioxide can be used together with other glidants in the compositions of this invention. In some embodiments, colloïdal silicon dioxide can be replaced by other glidants in the compositions of thîs invention. In some embodiments, the glidant that can replace colloïdal silicon dioxide or that can be used together with colloidal silicon dioxide hâve similar properties or characteristics as colloïdal 20 silicon dioxide. Examples ofthese glidants include, without being limited to, comstarch, talc, calcium silicate, magnésium silicate, aluminum silicate, silicon hydrogel or a mixture thereof.
[0083] In some embodiments, the invention uses silicified microcrystalline cellulose as a diluent in the extended release compositions. In some embodiments, 25 silicified microcrystalline cellulose can be used together with other dîiuents in the compositions of this invention. In some embodiments, silicified microcrystalline cellulose can be replaced by other diluents in the compositions of this invention, ln some embodiments, the diluent that can replace silicified microcrystaliine cellulose or that can be used together with silicified microcrystaliine cellulose hâve 30 similar properties or characteristics as silicified microcrystaliine cellulose, such as water solubility. Examples ofthese diluents (or water soluble diluents) include.
without being limited to, mîcrocrystalline cellulose, lactose, mannitol, xylitol, dextrose, sucrose, sorbitol, compressible sugar, powdered cellulose, comstarch, pregelatinized starch, dextrate, dextran, dextrin, dextrose, maltodextrin, calcium carbonate, polyethylene oxide, and a mixture thereof.
[0084J I some embodiments, the Invention uses magnésium stéarate as a lubrîcant in the extended release compositions. In some embodiments, magnésium stéarate can be used together with other lubricants in the compositions of this invention. In some embodiments, magnésium stéarate can be replaced by other lubricants in the compositions ofthis invention. In some embodiments, the i 0 lubrîcant that can replace magnésium stéarate or that can be used together with magnésium stéarate hâve similar properties or characteristics as magnésium stéarate. Examples ofthese lubricants include, without being limited to, calcium stéarate, sodium stcaryl fumerate, glyceryl paimitostearate, glyceryl stéarate, minerai oil, stearic acid, zinc stéarate and a mixture thereof.
J 5 [0085] The compositions described herein can further contain pharmaceutically acceptable excipient(s) and may contain other agents that serve to enhance and/or complément the effectiveness of the ievetîracetam, or to enhance or improve the extended release profile or pharmacokinetic profile of the ievetiracetam.
[0086] In some embodiments, the pharmaceutical composition ofthe présent
Invention is the formulations in Table 1. In one embodiment, the pharmaceutical composition of the présent invention is the J90 mgTablet A formulation.
[0087] In some embodiments, the pharmaceutical composition ofthe présent invention is the formulations in Table 3. In one embodiment the pharmaceutical composition ofthe présent invention is the 220 mg Tablet D formulation.
[0088] In some embodiments, the extended release Ievetîracetam compositions are formulated for once daily administration. For example, the extended release compositions comprise 190 mg of Ievetîracetam and provide a daily dosage of 190 mg when administered once a day (/.e„ every twenty-four hours). The extended release compositions comprise 220 mg o f Ievetîracetam and provide a daily dosage of220 mg when administered once a day (Le., every twenty-four hours). In some • 25 embodiments, the extended release levetiracetam compositions are formulated for one-unit-dosage-form-once-daily administration, ln some embodiments, the extended release levetiracetam compositions are formulated for one-tablet-oncedaily administration. For exemple, subjects who sufTer from cognitive impairment 5 will take the extended release composition ofthe invention (e.g., Tablets A, B, and C in Table 1 or Tablets D and E in Table 3) one-tablet-once-a-day. Each tablet is an extended release dosage form comprising 190 mg or 220 mg of levetiracetam.
(0089] In some embodiments, the extended release levetiracetam compositions are administered ln the moming.
[0090] ln some embodiments, the extended release levetiracetam compositions are ln a solid form, for example, tablets, capsules, mini-tablets, mini tablets in a capsule, dragrees, pllls, lozcnges, granules, films or dissolvable films. In some embodiments, the compositions ofthe présent invention are in the form ofa tablet. ln some embodiments, the tablet is a homogencous mixture.
[0091] In some embodiments, the extended release levetiracetam compositions are formulated for oral administration, ln some embodiments, the extended release pharmaceutical compositions are formulated in a solid form for oral administration, ln some embodiments, the extended release levetiracetam compositions arc oral tablets. ln some embodiments, the extended release levetiracetam compositions are oral capsules, ln some embodiments, the extended release levetiracetam compositions are formulated for injection or sublingual administration, ln some embodiments, the extended release levetiracetam compositions are formulated for administration in the form of a patch or a pump.
[0092] In some embodiments, the pharmaceutical compositions ofthe invention 25 do not comprise a hydrophobie rate controlling polymer.
|0093] ln some embodiments, the pharmaceutical compositions ofthe invention do not comprise a functional coating.
Description of Methods of the Invention
[0094] The methods of this invention comprise administration of the extended release compositions of levetiracetam for treating cognitive impairment associated with central nervous system (CNS) disordcrs in a subject in need or at risk thereof, including, without limitation, subjects having or at risk for age-related cognitive 5 impairment, Mild Cognitive Impairment (MCI), amnestic MCI (aMCl), Age*
Associated Memory Impairment (AA MI), Age Related Cognitive Décliné (ARCD), dementia, Alzheimer’s Disease (AD), prodromal AD, post traumatic stress disorder (PTSD), schizophrénie, bipolar disorder, amyotrophie latéral sclerosis (ALS), cancer-therapy-rclated cognitive Impairment, mental retardation, 10 Parkinson’s disease (PD), autism, compulsive behavior, and substance addiction.
[0095] In some embodiments, treatment comprises Improving cognitive function in patients suffering from or at risk for cognitive impairment associated with a CNS disorder, such as age-related cognitive impairment, Mild Cognitive Impairment (MCI), amnestic MCI (aMCI), Age-Associated Memory Impairment 15 (AAMI), Age Related Cognitive Décliné (ARCD), dementia, Alzheimer’s
Disease(AD), prodromal AD, post traumatic stress disorder (PTSD), schizophrénie, bîpolar disorder, amyotrophie latéral sclerosis (ALS), cancertherapy-related cognitive impairment, mental retardation, Parkinson’s disease (PD), autism, compulsive behavior, and substance addiction. In certain 20 embodiments, treatment comprises slowing or delaying the progression ofthe CNS disorder. In certain embodiments, treatment comprises preventing, slowing, or delaying the progression of cognitive impairment associated with the CNS disorder. In certain embodiments, treatment comprises reducing the rate of décliné of cognitive function associated with the CNS disorder. In certain embodiments,· treatment comprises alleviation, amelioration or slowing the progression, of one or more symptoms associated whh the CNS disorder, such as cognitive impairment.
Methods of Assesslng Cognitive Impairment [0096] Animal models serve as an important resource for developing and evaluating treatments for cognitive impairment associated with CNS disorders.
Features that characterize cognitive impairment în animal models typically extend to cognitive impairment in humans. Efïicacy in such animal models is, thus,
expected to be prédictive ofefficacy in humans. The extent ofcognitive impairment in an animai model fora CNS disorder, and the efficacy of a method of treatment for said CNS disorder may be tested and conflrmed with the use of a variety of cognitive tests.
[0097] A Radiai Arm Maze (RAM) behavioral task 1s one example of a cognitive test, specifically testing spacial memory (Chappeli et al. Neuropharmacology 37: 481*487,1998). The RAM apparatus consista of, e.g., eight equldistantly spaced arms. A maze arm projects from each facet of a center platform. A food well is located at the distal end of each arm. Food is used as a reward. Blocks can be positioned to prevent entry to any arm. Numerous extra maze eues surrounding the apparatus may also be provided. After habituation and traînlng phases, spatial memory ofthe subjects may be tested in the RAM under control or test compoundtreated conditions. As a part ofthe test, subjects are pretreated before trials with a vehicle control or one of a range of dosages of the test compound. At the beglnnïng of each trial, a subset of the arms of the eight-arm maze 1s blocked.
Subjects are allowed to obtain food on the unbiocked arms to which access is permitted during this Initial “information phase” of the trial. Subjects are then removed from the maze for a delay period, e.g., a 60 second delay, a 15 minute delay, a one-hour delay, a two-hour delay, a six hour delay, a 24 hour delay, or longer) between the information phase and the subséquent “rétention test, during which the barrière on the maze are removed, thus allowing access to ail eight arms. After the delay period, subjects are placed back onto the center platform (with the barrière to the previously blocked arms removed) and allowed to obtain the remaining food rewards during this rétention test phase of the triai. The identity and configuration of the blocked arms vary across trials. The number of “errore” the subjects make during the rétention test phase Is tracked. An error occurs in the trial if the subjects entered an arm from which food had already been retrieved ln the pre-delay component of the trial, or if it re-visits an arm in the post-delay session that had already been visïted. A fewer number oferrore would indicate better spatial memory. The number oferrore made by the test subject, under various test compound treatment régimes, can then be compared for efficacy ofthe test compound ln treating cognitive impairment associated with CNS disorders.
[0098] Another cognitive test that may be used to assess the effects of a test compound on the cognitive Impaîrment of a CNS disorder model animai is the Morris water maze. A water maze is a pool surrounded with a novel set of patterns relative to the maze. The traînîng protocol for the water maze may be based on a 5 modified water maze task that has been shown to be hlppocampal-dcpendcnt (de
Hoz et al., £ur. J. NeuroscL, 22:745-54,2005; Steeie and Morris, Hippocampus 9:118-36, 1999). The subject is trained to iocate a submerged escape piatform hidden undemeath the surface ofthe pool. During the training trial, a subject is released in the maze (pool) from random starting positions around the perimeter of 10 the pool. The starting position varies from trial to trial. If the subject does not
Iocate the escape piatform within a set time, the expérimenter guides and places the subject on the piatform to “teach” the location ofthe piatform. After a delay period following the last training trial, a rétention test In the absence of the escape piatform is given to assess spatial memory. The subject*s level of preference for 15 the location of the (now absent) escape piatform, as measured by, e.g., the time spent ln that location or the number of crossîngs of that location made by the mouse, indicates better spatial memory, Le., treatment of cognitive ImpairmenL The preference for the location of the escape piatform under different treatment conditions, can then be compared for efficacy ofthe test compound in treating 20 cognitive impairment associated with CNS disorders.
[0099] There are various tests known ln the art for assessing cognitive function in humans, for example and without limitation, the clinîcal global impression of change scale (CIBIC-plus scale); the Mini Mental State Exam (MMSE); the Neuropsychiatrie Inventory (NPI); the Clinical Démenti a Rating Scale (CDR); the 25 Cambridge Neuropsychological Test Automated Battery (CANTAB); the Sandoz
C linical Assessmcnt-Geriatric (SCAG), the Buschke Sélective Reminding Test (Buschke and Fuld, 1974); the Verbal Paired Associâtes subtest; the Logical Memory subtest; the Visual Reproduction subtest ofthe Wechsler Memory ScaleRevised (WMS-R) (Wechsler, 1997); the Benton Visual Rétention Test, or 30 M ATR1CS consensus neuropsychological test battery which includes tests of working memory, speed of processing, attention, verbal leamïng, visual Icaming, reasoning and problem solvlng and social cognition. See Foistein et al„ J
Psychiatrie Res 12:189-98,(1975); Robbins et al, Dementia 5:266-81, (1994); Rey, L’examen clinique en psychologie, (1964); Kluger étal, J Geriatr Psychiafry Neurol 12:168-79, (1999); Marquis et al, 2002 and Masur et al, 1994, or MATRICS consensus neuropsychologîcal test battery which includes tests of working memory, speed of processing, attention, verbal leaming, vlsual leaming, reasoning and problem solving and social cognitlon. Another example ofa cognitive test in humans is the cxplicit 3-altemative forced choice task. In this test, subjccts arc presented with color photographs of common objecta consisting of a mix of three types of Image pairs: similar pairs, identical pairs and unrelated foils.
The second of the pair of similar objecta is refencd to as the “lurc”. These image pairs are fully randomizcd and presented Individually as a sériés of images, Subjccts are instructed to make a judgment as to whether the objecta seen are new, old or similar. A “similar” response to the présentation of a Jure stimulus indicates successfol memory retrieval by the subject By contrast, calling the lurc stimulus 15 “old” or “n ew indicates that correct mémo ry retrieval does not occu r.
[0100] In addition to assesslng cognitive performance, the progression of agerclated cognitive impairment and dementia, as wel! as the conversion ofagerelated cognitive impairment into dementia, may be monîtorcd by assessing surrogate changes in the brain ofthe subject Surrogate changes Include, without 20 limitation, changes in régional brain volumes, perforant path dégradation, and changes seen în brain function through resting state fMRI (R-fMRJ) and fluorodeoxyglucose positron émission tomography (FDG-PET). Examples of régional brain volumes useful in monitoring the progression of age-rclated cognitive impairment and dementia Include réduction of hippocampal volume and 25 réduction in volume or thickness of entorhinal cortex. These volumes may be measured in a subject by, for example, MRI. Alsen et al·, Alzheimer’s & Dementia 6:239-246 (2010). Perforant path dégradation has been shown to be linked to âge, as wel) as reduced cognitive fonction. For example, older adults with more perforant path dégradation tend to perform worse in hîppocampus30 dépendent memory tests. Perforant path dégradation may be monîtorcd in subjects through ultrahigh-resolution diffusion tensor imaging (DTI). Yassa et a), PNAS 107:12687-12691 (2010). Resting-state fMRI (R-fMRI) involves Imaging the
brain during rest, and recordîng large-amplitude spontaneous low-frequency (<0.l Hz) fluctuations in the fMRI signal that are temporal ly correlated across functionally related areas. Seed-based functional connectivity, independent component analyses, and/or frequenc y-domain analyses ofthe signais are used to reveal functional connectivity between brain areas, particularly those areas whose connectivity increase or decrease with âge, as well as the extent of cognitive impainnent and/or dementia. FDG-PET uses the uptake of FDG as a measure of régional metabolîc activity in the brain. Décliné of FDG uptake in régions such as the posterior ctngulated cortex, temporoparietal cortex, and prefrontal association 10 cortex has been shown to relate to the extent of cognitive décliné and dementia.
Aisen et al., Alzheimer’s & Dementia 6:239-246 (2010), Herholz et al., Neuroimage 17:302-316(2002).
Age-Related Cognitive Impairment [0101] This invention provides methods for treating age-relatcd cognitive impairment or the risk thereof using the extended release Ievetiracetam compositions ofthe invention. In certain embodiments, treatment comprises improving cognitive function in patients with age-related cognitive impairment. tn certain embodiments, treatment comprises siowing or delaying the progression of age-rciated cognitive impairment. tn certain embodiments, treatment comprises reducing the rate of décliné of cognitive function associated with age-related cognitive Impairment In certain embodiments, treatment comprises preventing or siowing the progression, of age-relatcd cognitive impairment In certain embodiments, treatment comprises alleviation, amelioration or siowing the progression, of one or more symptoms associated with age-related cognitive impairment In certain embodiments, treatment of age-related cognitive impairment comprises siowing the conversion of age-related cognitive impairment (including, but not limited to MCI, ARCD and AAMI) into dementia (e.g., AD). The methods and compositions may be used for human patients in clinical applications in the treating age-reiated cognitive impairment in conditions such as 30 MCI, ARCD and AAMI or for the risk thereof. The dose of the composition and dosage interva! for the method is, as described herein, one that is safe and efficacïous în those applications.
[0102] ln some embodiments, a subject to be treated by the methods and compositions of this invention exhlbits age-related cognitive impairment or is at risk ofsuch impairment In some embodiments, the age-related cognitive impairment includes, without limitation, Age-Associated Memory Impairment (AAMI), Mild Cognitive Impairment (MCI) and Age-related Cognitive Décliné (ARCD).
[0103] Animal modela serve as an Important resouree for developing and evaluating treatments for such age-related cognitive impairments. Features that characterize age-related cognitive impairment in animal modela typically extend to age-related cognitive impairment in humans. Efficacy În such animal models la, thus, expected to be prédictive of efficacy in humans.
[0104] Various animai models ofage-related cognitive Impairment are known in 15 the art For example, extensive behavioral characterization has identified a naturally occurring form of cognitive impairment in an outbred strain of aged Long-Evans rats (Charles River Laboratories; Gallaghcr et al., Behav. Neurosci.
107:618-626, (1993)). ln a behavioral assessment with the Morris Water Mazc (MWM), rats leam and remember the location of an escape piatform guided by a 20 configuration of spatial eues surrounding the maze. The cognitive basis of performance is tested ln probe trials using measures ofthe anlmal’s spatial biaa in searching for the location of the escape piatform. Aged rats in the study population hâve no difïïculty swimming to a visible piatform, but an age-dependent impairment is detected when the piatform is camouflaged, requiring the use of 25 spatial information. Performance for individual aged rats in the outbred LongEvans strain varies greatly. For example, a proportion of those rats perform on a par with young adults. However, approximately 40-50% fait outside the range of young performance. This variability among aged rats reflects reliable individuel différences. Thus, within the aged population some animais are cognitively impaired and designated aged-impaired (Al) and other animais are not impaired and are designated aged-unlmpaîred (AU). See, e.g., Colombo et al., Proc. Naîl.
• »
Acad. Sci. 94:14195-14199, (1997); Gallagher and Burwcll.AeuroA/o/. Aging 10:691-708, (1989); Gallagherc/oZ. Behav. Neurosci. 107:618-626,(1993);
Rapp and Gailagher, Proc. Natl. Acad. Sci. 93:9926-9930, (1996); Nicolle et al.t Neuroscience 14'. 741-756, (1996); Nicolle étal., J. Neurosci. 19:9604-9610, ( 1999); International Patent Publication W02007/019312 and International Patent
Publication WO 2004/048551. Such an animal model of age-related cognitive impairment may bc used to assay the effectlveness of the methods and compositions this invention in treating age-related cognitive impairment [0105] The efficacy of the methods and compositions of this invention in treating age-related cognitive impairment may be assessed using a variety of cognitive tests, Including the Morris water maze and the radial arm maze, as dîscussed above.
Dementia [0106] This invention aiso provides methods for treating dementia using the extended release levetiracetam compositions ofthe invention, in certain embodiments, treatment comprises improving cognitive fonction in patients with dementia. In certain embodiments, treatment comprises slowing or delaying the progression of dementia. in certain embodiments, treatment comprises reducing the rate of décliné of cognitive fonction associated with dementia. In certain embodiments, treatment comprises preventing or siowing the progression, of dementia, (n certain embodiments, treatment comprises alleviation, amelioration, or slowing the progression of one or more symptoms associated with dementia. in certain embodiments, the symptom to be treated is cognitive impairment. In certain embodiments, the dementia is Àl2heimer*s disease (AD), vascular dementia, dementia with Lewy bodies, or frontotemporal dementia. The methods and compositions may be used for human patients in ciinical applications in treating dementia. The dose of the composition and dosage interval for the method is, as described herein, one that is safe and efïicacious in those applications.
[0107] Animal modeis serve as an important resource for developing and evaluating treatments for dementia. Features that characterize dementia in animal • » models typicai !y extend to dementia in humans. Thus, efficacy in such anima! models is expected to be prédictive of efficacy in humans. Various animai models ofdementia are known ln the art, such as the PDAPP, Tg2576, APP23, TgCRND8, J20, hPS2 Tg. and APP + PS 1 transgenic mice. Sankaranarayanan, Curr. Top.
Médicinal Chem. 6:609-627,2006; Kobayashi et al. Genes Brain Behav. 4:173196. 2005; Ashe and Zahns, Neuron. 66:631-45,2010. Such animal models of dementia may be used to assay the effect! veness ofthe methods and compositions ofthis invention ofthe invention in treating dementia.
(0108] The efficacy ofthe methods and compositions ofthis invention întreating dementia, or cognitive impairment associated with dementia, may be assessed In animais models ofdementia, as weil as human subjects with dementia, using a variety of cognitive tests known in the art, as discussed above.
Post Traumatic Stress Disorder [0109] This invention aiso provides methods for treating post traumatlc stress ! 5 disorder (PTSD) using the extended release levetiracetam compositions ofthe invention, ln certain embodiments, treatment comprises improving cognitive function in patients with PTSD. In certain embodiments, treatment comprises slowing or delaying the progression of PTSD. In certain embodiments, treatment comprises reducing the rate of décliné of cognitive fonction associated with PTSD.
In certain embodiments, treatment comprises preventing or slowing the progression, of PTSD. ln certain embodiments, treatment comprises alleviatlon, amelioration, or slowing the progression of one or more symptoms associated with PTSD. ‘In certain embodiments, the symptom to be treated Is cognitive Impairment. The methods and compositions may be used for human patients in clintcai applications in treating PTSD. The dose of the composition and dosage interval for the method is, as described herein, one that is safe and efficacîous in those applications.
[0110] Patients with PTSD (and, to a lesscr degree trauma-exposed patients without PTSD) hâve smaller hippocampe! volumes (Woon et a!., Prog. Neuro3 0 Psychopharm. & Biological Psych. 34, I ! 81 -1 ! 8 8; Wang et al, Arch. Gen.
Psychlatry 67:296-303,2010). PTSD is also associated with impaired cognitive performance. Older lndividuals with PTSD hâve greater déclinés In cognitive performance relative to contre! patients (Yehuda et al., Bio. Psych. 60:714-721, 2006) and hâve a greater likelihood of developing dementia (Yaffe etal.,Arch.
Gen. Psych. 678:608-613,2010).
[0111] Animal models serve as an Important resource for developing and evaluatîng treatments for PTSD. Features that characterize PTSD în animal models typically extend to PTSD in humans. Thus, efticacy In such animal models is expected to be prédictive ofefficacy In humans. Various animal models of
PTSD are known în the art [0112] One rat model of PTSD is Tlme-dependent sensîtization (TDS). TDS involves exposure of the animal to a severe ly stressful event followed by a situatfonal reminder ofthe prîor stress. The following is an example ofTDS. Rats are placed in a rcstrainer, then placed in a swim tank and made to swlm for a period of time, e.g., 20 min. Following this, each rat is then Immediately exposed to a gaseous anesthetic until loss ofconsciousness, and finally dried. The animais are left undisturbed for a number of days, e.g, one week. The rats are then exposed to a “restress session consisting of an Initial stressor, e.g., a swimming session In the swim tank (Liberzon et a!., Psychoneuroendocrlnology 22; 443-453, 20 1997; Harvery et al., Psychopharmacology 175:494-502,2004). TDS results in an cnhancement of the acoustic startie response (ASR) in the rat, which is comparable to the exaggerated acoustic startie that is a prominent symptom of PTSD (Khan and Liberzon, Psychopharmacology 172:225-229,2004). Such animal models of PTSD may be used to assay the effectiveness of the methods and compositions of 25 this invention of the invention in treating PTSD.
[0113] The efticacy ofthe methods and compositions ofthis Invention in treating
PTSD, or cognitive impairment associated with PTSD, may also be assessed in animais models of PTSD, as well as human subjects with PTSD, using a variety of cognitive tests known in the art, as discussed above.
Schizophrénie
[0114] This invention provides methods for treating schizophrenia or bipolar disorder (in particular, mania) using the extended release levetiracetam co mpositions o f the invention. In certain embodi mcnts, treatment com prises improving cognitive function in patients with schizophrenia. In certain embodiments, treatment comprises slowïng or delaying the progression of schizophrenia. In certain embodiments, treatment comprises reducing the rate of décliné of cognitive function associated with schizophrenia. In certain embodiments, treatment comprises preventing or slowing the progression of schizophrenia or bipoiar disorder (in particular, mania). Schizophrenia ls characterized by a wîde spectrum of psychopathology, including positive symptoms such as aberrant or distorted mental représentations (e.g., hallucinations, delustons), négative symptoms characterized by diminution of motivation and adaptive goal-directed action (e.g., anhedonîa, affective flattening, avolition), and cognitive impairment ln certain embodiments, treatment comprises alieviation, amelioration or slowing the progression of one or more positive and/or négative symptoms, as well as cognitive impairment associated with schizophrenia. Further, there are a number ofother psychiatrie diseases such as schizotypical and schizoaffective disorder, other acute- and chronic psychoses and bipolar disorder (in particular, mania), which hâve an overlappîng symptomatology with schizophrenia. In some embodiments, treatment comprises aileviation, amelioration or slowing the progression of one or more symptoms, as well as cognitive impairment, associated with bipolardisorder (in particular, mania). The methods and compositions may be used for human patients in clinical applications in treating schizophrenia or bipolar disorder (În particular, mania), pie dose of the composition and dosage interval for the method is, as described herein, one that is safe and eflîcacious in those applications.
[0115] Cognitive impairments are associated with schizophrenia. They précédé the onset of psychosis and are présent tn ποη-aflfected relatives. The cognitive impairments associated with schizophrenia constitute a good predîctor for functional outcome and are a core feature of the disorder. Cognitive features in schizophrenia reflect dysfonction in frontal cortical and hippocampal circuits.
Patients with schizophrenia also présent hippocampal pathologies such as • 36 réductions in hippocampal volume, réductions in neuronal size and dysfonctional hyperactivity. An imbalance in excitation and inhibition in these brain régions has also been documented In schizophrénie patients suggesting that drugs targeting inhibitory mechanisms could be therapeutic. See, e.g., Guidottl et al.,
Psychopharmacology 180:19 i -205,2005; Zierhut, Psych. Res. Neurolmag. 183:187-194,2010; Wood et al., Neuroimage 52:62-63,2010; Vinkers étal.. Expert Opin. Investig. Drugs 19:1217-1233,2009; Young et al., Pharmacol. Ther. 122:150-202,2009.
[0116] Animal modela serve as an important resource for developing and evaluating treatments for schizophrénie. Features that characterize schlzophrenia In animai models typically extend to schizophrénie in humans. Thus, efïicacy in such animai models is expected to be prédictive ofcfFicacy In humans. Various animai models of schizophrénie are known in the art [0117] One animal model ofschizophrenia is protracted treatment with méthionine. Methionîne-treated mice exhiblt déficient expression of GAD67 in frontal cortex and hippocampus, similar to those reported in the brain of postmortem schlzophrcnia patients. They also exhibit propulse inhibition of startle and social interaction déficits (Tremonlizzo et al., PNAS, 99: 17095-17100, 2002). Another animal model of schizophrénie Is methylaoxymethanoi acetate (MAMytreatment In rats. Prégnant female rats are administered MAM (20 mg/kg, intraperitoneal) on gcstatlonai day 17. MAM-treatmcnt recapitulate a pathodevelopmental process to schizophronia-like phenotypes in the ofTspring, including anatomical changes, behavioral déficits and altered neuronal information processîng. More specifically, MAM-treated rats display a decreased density of parvalbumin-positive GABAcrgic intemeurons in portions of the prefrontal cortex and hîppocampus. In behavioral tests, MAM-treated rats display reduced latent inhibition. Latent Inhibition is a behavioral phenomenon where there is reduced leaming about a stimulus to which there has been prior exposure with any conséquence. This tendency to disregard previously benign stimuli, and reduce the 30 formation of association with such stimuil is believed to prevent sensory overload.
Low latent inhibition is indicative of psychosis. Latent inhibition may be tested în
rats in the following manner. Rats are divided into two groups. One group is preexposed to a tone over multiple triais. The other group has no tone présentation. Both groups are then exposed to an auditory fcar conditioning procedure, in which the same tone is presented concurrently with a noxious stimulus, e.g. an electric 5 shock to the foot Subsequently, both groups are presented with the tone, and the rats* change in locomotor activity during tone présentation is monitored. After the fear conditioning the rats respond to the tone présentation by strongly reducing locomotor activity. However, the group that has been exposed to the tone before the conditioning period dlsplays robust latent inhibition: the suppression of 10 locomotor activity in response to tone présentation is reduced. MAM-treated rats, by contrast show impaired latent inhibition. That is, exposure to the tone previous to the fcar conditioning procedure has no sîgnificant effect in suppressing the fcar conditioning. (see Lodge et al., J. Neuroscî., 29:2344-2354,2009) Such animal models of schizophrenia may be used to assay the effectiveness ofthe methods and 15 compositions ofthe invention in treating schizophrenia or bipolar disorder (ln particular, mania).
[01181 MAM-trcatcd rats display a significantly enhanced locomotor response (oraberrant locomotor activity) to low dose D-amphetamine administration. The MAM-treatcd rats also display a sîgnifîcantly greater number of spontaneously 20 firîng ventral tegmental dopamine (DA) neurons. These results are believed to be a conséquence of excessive hlppocampal activity because in MAM-treated rats, the ventral hippocampus (vHipp) inactivation (e.g., by intra-vHipp administration ofa sodium channel blocker, tetrodotoxin (τιΧ), to MAM rats) completely reversed the elevated DA neuron population activity and also normallzed the augmented 25 amphetamlne-induced locomotor behavior. The corrélation ofhlppocampal dysfonction and the hyper-responsivity ofthe DA system is believed to underlie the augmented response to amphétamine in MAM-treatcd animais and psychosis in schizophrenia patients. See Lodge D. J. et al. Neurobiology of Disease (2007), 27(42), 11424-11430. The use of MAM-treated rats in the above study may be 30 suitable for use to assay the effectiveness of the methods and compositions of the présent invention in treating schizophrenia or bipolar disorder (in particular, mania). For example, the methods and compositions of this invention maybe • 38 evaluated, using MAM-treated animais, for their effects on the central hippocampus (vHtpp) régulation, on the elevated DA neuron population activity and on the hyperactive locomotor response to amphétamine in the MAM-treated animais.
[0119| In MAM-treated rats, hippocampal (HPC) dysfonction leads to dopamine system hyperactivïty. A benzodiazepine-positive aliosteric modulator (PAM), sélective for the a5 subunit ofthe OABAa receptor, SH-053-2’F-R-CHj. is tested for its effects on the output ofthe hippocampal (HPC). The effect ofSH-053-2*FR-CHj on the hyperactive locomotor response to amphétamine in MAM-treated animais Is also examined. The aSGABAAR PAM reduces the number of spontaneously active DA neurons in the ventral tegmcntal area (VTA) of MAM rats to levels observed in saline-treated rats (control group), both when administered systemically and when directly înfosed into the ventral HPC. Moreover, HPC neurons in both saiine-treated and MAM-treated animais show diminished cortical-evoked responses following the aSGABAAR PAM treatment. ln addition, the increased locomotor response to amphétamine observed In MAMtreated rats Is reduced following the qSGABAaR PAM treatment See Giü K. M et al. Neuropsychopharmacology (2011), 1-9. The use of MAM-treated rats in the above study may bc suitable for use In the présent Invention to assay the effectiveness of the methods and compositions of the invention in treating schlzophrenia or bipolar disorder (in particular, mania). For example, the methods and compositions of this invention maybc evaluated, using MAM-treated animais, for their effects on the output of the hippocampal (HPC) and on the hyperactive locomotor response to amphétamine ln the MAM-treated animais.
10120] Administration of MAM to prégnant rats on embryonic day 15 (E15) severely impairs spatial memory or the abllity to learn the spatial location of four items on an eight-arm radial maze ln the ofispring. In addition, embryonic day 17 (E17) MAM-treated rats are able to reach the level of performance of control rats at the Initial stages of train ing, but are unabie to process and retrieve spatial
Information when a 30-mtn delay is interposed, indicating a significant impairment in worklng memory. See Gourevîtch R. et al. (2004). Behav. Pharmacol, 15,28718467
292. Such animal modeis of schizophrenia may be used to assay the efTectiveness of the methods and compositions ofthe invention în treating schizophrenia or bipolar disorder (în particular, mania).
[0121] Apomorphine-lnduced climbing (A1C) and stéréotype (AIS) în mice is another animal model useful ln this invention. Agents are administered to mice at a desired dose level (e.g., via intraperitoneal administration). Subsequently, e.g., thirty minutes later, experimental mice are challenges with apomorphine (e.g., with 1 mg/kg sc). Five minutes after the apomorphine injection, the snlffing-lickinggnawing syndrome (stereotyped behavîor) and climbing behavîor induced by apomorphine are scored and recorded for each animal. Readings can be repeated every 5 min during a 30-min test session. Scores for each animal are totaled over the 30-min test session for each syndrome (stereotyped behavîor and climbing). If an effect reached at least of 50% inhibition, and ID50 value (95% confidence interval) Is calculated using a noniinear least squares calculation with inverse prédiction. Mean climbing and stéréotypé scores can be expressed as a percent of control values observed ln vchible treated (e.g., saline-treated) mice that receive apomorphine. See Grauer S. M. et al. Pjychopharmacology (2009) 204, 37-48. This mice mode) may be used to assay the efTectiveness of the methods and compositions of the invention in treating schizophrenia or bipolar disorder (in particular, mania).
[0122] The efficacy ofthe methods and compositions ofthis Invention in treating schizophrenia may also be assessed in animal modeis of schizophrenia or bipolar disorder (in particular, mania), as well as human subjects with schizophrenia, using a variety of cognitive tests known in the art, as discussed above.
Amyotrophie Latéral Sclerosis (ALS) [0123] This invention additionally provides methods for treating ALS using the extended release levetiracetam compositions of the invention. In certain embodiments, treatment comprises improving cognitive fonction in patients with
ALS. In certain embodiments, treatment comprises slowing or delayîng the progression of ALS. ln certain embodiments, treatment comprises reducing the
rate of décliné of cognitive fonction associated with ALS. In certain embodiments, treatment comprises preventing or slowing the progression, of ALS. In certain embodiments, treatment comprises alleviation, amelioration or slowing the progression, of one or more symptoms associated with ALS. In certain embodiments, the symptom to be treated is cognitive impairment. The methods and compositions may be used for human patients In clinical applications in treating ALS. The dose ofthe composition and dosage interval for the method is, as described herein, one that is safe and efïïcacious in those applications.
[0124] In addition to the degeneration of motor neurons, ALS is characterized by 10 neuronal degeneration in the entcrhinal cortex and hippocampus, memory déficits, and neuronal hyperexcltability in different brain areas such as the cortex.
[0125] The efficacy ofthe methods and compositions ofthis invention in treating ALS, or cognitive impairment associated with ALS, may also be assessed in animal models of ALS, as well as human subjects with ALS, using a variety of 15 cognitive tests known in the art, as discussed above.
Cancer therapy-reiated cognitive impairment [0126] This invention additionaily provides methods for treating cancer therapyreiated cognitive impairment using the extended release ievetiracctam compositions ofthe Invention. In certain embodiments, treatment comprises 20 improving cognitive fonction in patients with cancer therapy-reiated cognitive impairment In certain embodiments, treatment comprises slowing or delaying the progression of cancer therapy-reiated cognitive impairment. In certain embodiments, treatment comprises reducing the rate of décliné of cognitive fonction associated with cancer therapy-reiated cognitive impairment. In certain 25 embodiments, treatment comprises preventing or slowing the progression, of cancer therapy-reiated cognitive impairment In certain embodiments, treatment comprises alleviation, amelioration or slowing the progression, of one or more symptoms associated with cancer therapy-reiated cognitive impairment The methods and compositions may be used for human patients in clinical applications in treating cancer therapy-reiated cognitive impairment The dose ofthe
composition and dosage interva! for the method is, as described herein, one that is safe and efïïcacious in those applications.
[0127] Thérapies that are used ln cancer treatment, including chemotherapy, radiation, or combinations thereof, can cause cognitive impairment in patients, in 5 such functions as memory, ieaming and attention. Cytotoxîcity and other adverse side-effects on the brain of cancer thérapies are the basis for this form of cognitive impairment, which can persist for décades. (Dietrich et al., Oncologist 13:128595,2008; Soussaln et al., Lancet 374:1639-51,2009).
[0128] Cognitive impairment following cancer thérapies reflects dysfonction in frontal cortical and hippocompai circuits that are essential for normal cognition. ln animal models, exposure to either chemotherapy or radiation adversely affects performance on tests of cognition specificaîly dépendent on these brain Systems, especially the hippocampus (Kim et al., J. Radîat. Res. 49:517-526,2008; Yang et al., Neurobiol. Leaming and Mem. 93:487-494,2010). Thus, drugs targeting these cortical and hippocampal Systems could be neuroprotective in patients receiving cancer thérapies and cfficacious in treating symptoms of cognitive Impairment that may last beyond the interventions used as cancer thérapies.
[0129] Animal models serve as an important resource for developing and evaluatîng treatments for cancer therapy-related cognitive Impairment Features 20 that characterize cancer therapy-rclatcd cognitive impairment in animal models typically extend to cancer therapy-reiated cognitive impaîrment in humans. Thus, efiicacy in such animal models is expected to be prédictive of eftîcacy in humans.
»
Various animal models of cancer therapy-reiated cognitive impairment are known in the art [0130] Examples ofanimal modeisofcancer therapy-related cognitive impairment include treating animais with anti-neoplastic agents such as cyclophosphamide (CYP) or with radiation, e.g., MCo gamma-rays. (Kim et al., J.
Radiat. Res. 49:517-526,2008; Yang et al., Neurobiol. Leaming andMem.
93:487-494,20iO). The cognitive fonction of animal models of cancer therapy30 related cognitive impairment may then be tested with cognitive tests to assay the
efTcctiveness ofthe methods and compositions ofthe invention in treating cancer therapy-related cognitive impairment. The efficacy ofthe methods and compositions of this invention in treating cancer therapy-related cognitive impairment, as well as human subjects with cancer therapy-related cognitive 5 impairment, using a variety of cognitive tests known in the art, as discussed above.
Parkinson’s disease (PD) [0131] Parkinson’s disease (PD) is a neurological disorder characterized by a decrease of voiuntary movements. The affiicted patient has réduction ofmotor activity and slower voiuntary movements compared to the normal individual. Tire 10 patient has characteristic “mask” face, a tcndcncy to hurry while walking, bent over posture and general ized weakness οΓ the muscles. There is a typical “leadpipe rigidity of passive movements. Another important feature of the discase is the tremor of the extremilies occurring at rest and dccreasing during movements.
[0132| Parkinson’s disease, the etiology of which is unknown, belongs to a group ofthe mostcommon movement disorders named parkinsonism. which affects approximately one person per one thousand. These other disorders grouped under the name of parkinsonism may resuit from viral Infection, syphilis, arteriosclerosis and trauma and exposure to toxic chemicals and narcotlcs. Nonethcless, It is belleved that the inappropriate loss of synaptic stability may lead to the disniption 20 of neuronal circuits and tobraln diseuses. Whether as the rcsult of genetics. drug use, the aging process. viral infections, or other various causes, dysfonction ln neuronal communication is considered the underlying cause for many neurologie diseases, such as PD (Myrrhe van Spronscn and Casper C. Hoogenraad, Curr. Neurol. Neurosci. Rep. 2010. 10,207-214).
[0133| Regardless ofthe cause ofthe discase, the main pathologie feature is degeneration of dopamînergic cells in basal ganglia, especlally ln substantia nigra.
Due to prématuré death ofthe dopamine containing neurons in substantia nigra, (lie largest structure ofthe basal ganglla, the striatum, will hâve reduced input from substantia nigra resulting in decreased dopamine release. The understonding ofthe underlying pathology led to the introduction of the first successful treatment which
can alleviate Parkinson’s disease. Virtually ail approaches to the therapy of the disease are based on dopamine replacement. Drugs currently used in the treatment can be converted into dopamine after crosslng the blood brain barrier. or they can boost the synthesis ofdopamîne and reduce its breakdown. Unfortunatcly, the main 5 pathologie event, degeneration ofthe cells ln substantia nigra, is not helped. The disease continues to progrcss and frequently after a certain length of lime, dopamine replacement treatment will lose its efTectivencss.
[0134] This invention provides methods for treating PD using the extended release levetiracetam composition ofthe invention, in certain embodiments, 10 treatmentcomprisespreventingorslowingtheprogressionofPD. Incertain embodiments, treatment comprises alleviation, amelioration, or slowing lhe progression of one or more symptoms associated with PD. In certain embodiments, the symptom to be treated is cognitive impairment. For example, methods and compositions ofthe dîsclosure can be used to Improve the motor/ccgnitive impairments symptomatic of Parkinson’s disease. Morcover, methods and compositions of the dîsclosure may bc useful for treating the memory impairment symptomatic of Parkinson’s disease.
[0135] There are a number of animal models for PD. Exempiary anima! models for PD include the reserpine model, the melhamphétamine model, the 6* hydroxydopamine (6-OHDA) model, the !-methyl-4-pheny!-l,23,6tetrahydropyridinc (MPTP) model, the paraquat (PQ)-Maneb model, the rotenone model, the 3-nitrotyrosîne model and genetic models using transgenic mice. Transgenic models include mice that over express α-synuclein, express human mutant forms ofa -synuclein, or mice that express LRKK2 mutations. See review of these models by Ranjita B. et al. (Ranjita B. et al. BloEssays 2002,24,308-318).
Additions! information regarding these animal models is readily available from Jackson Labo raton es (see also http://research.jax.org/grs/parkinsons.htmlX as well as in numerous publications disclosing the use of these vaiidated models.
[0136] The efficacy ofthe methods and compositions ofthis Invention in treating 30 PD, or cognitive impairment associated with PD, may be assessed in any of the
above animal models of PD, as weii as human subjects with PD, using a variety of cognitive tests known in the art, as discussed above.
Autism (01371 “Autism, as used herein. refers to an autism spectrum disorder characterized by a neural development disorder leading to impaired social interaction and communication by restricted and répétitive behavior. “Autism Spectrum Disorder” refers to a group of developmental disabilities that includes: autism: Asperger syndrome; pervasive developmental disorder not otherwise specified (PDD-NOS or atypical autism); Rett syndrome; and chiidhood disintegrati ve disorder.
[0138( Autism is a neurodeveiopmental disorder characterized by dysfonction in three core behavioral dimensions: repetitive behaviors. social déficits, and cognitive déficits. The repetitive behavior domain invoives compulsive behaviors. unusuai attachmcnts to objects. rigid adhérence to routines or rituals. and repetitive 15 motor mannerisms such as stereotypics and self* stimuîatory behaviors. The social déficit dimension invoives déficits in reciprocal social interactions, lackofeye contact, dîminished ability to carry on conversation, and impaired daily interaction skills. The cognitive déficits cnn include language abnormalities. Autism is a disabling neuro logical disorder that affects thousands of Americans and encompasses a number ofsubtypes, with various putative causes and few documcnted ameliorative treatments. The disorders of the autlstic spectrum may be présent at birth, or may hâve later onset, for cxamplc. at âges two or three. There are no clear eut biological markers for autism. Diagnosis ofthe disorder is made by considering the degree to which the chiid matches the behavioral syndrome, which is characterized by poor communicative abilitîcs. pccuiiaritics in social and cognitive capacltîes. and maladaptive behavioral patterns. The dysfonction in neuronal communication is considered one of the underlyîng causes for autism (Myrrhe van Spronscn and Caspcr C. Hoogenraad, Curr. Neurol. Nenrosci. Rep. 2010, 10,207-214).
[0139] This Invention provides methods for treating autism using the extended release Ievetiracetam composition ofthe invention, ln certain embodiments, treatment comprises preventing or siowing the progression of autism. In certain embodiments, treatment comprises allevlation, amelioration, or siowing the progression of one or more symptoms associated with autism. In certain embodiments, the symptom to be treated is cognitive déficit. For example, methods and compositions ofthe disclosure can be used to improvc the motor/cognitive déficits symptomatic of autism.
Mental retardation [0140| Mental retardation is a gencralized disorder characterized by significantly impaired cognitive function and déficits in adaptive bchaviors. Mental retardation is often defined as an Intelligence Quotient (IQ) score of less than 70. Inbom causes are among many underlying causes for mental retardation. The dysfonction in neuronal communication is also considered onc ofthe underlying causes for mental redardation (Myrrhe van Spronsen and Casper C. Hoogenraad. Curr, Neurol, Neitroscl. Rep. 2010,10,207-214).
[0141] In some instances, mental retardation includes, but are not limited to, Down syndrome, velocariofacial syndrome, fêtai alcohol syndrome, Fragile X syndrome, Klinefelter’s syndrome, neurofîbromatosis, congénital hypothyroidism.
Williams syndrome, phenyîketonuria (PKU), Smith-Lemli-Opitz syndrome, Prader-Willi syndrome, Phelan-McDermid syndrome, Mowat-Wilson syndrome, cillopathy, Lowe syndrome and siderium type X-linked mental retardation. Down syndrome is a disorder that includes a combination of blrth defects. including some degree of mental retardation, charactcristic facial features and, often, heurt dcfccts, 25 increased infections, problems with vision and hearing. and other health problems. Fragile X syndrome is a prévalent form of Inherited mental retardation, occurring with a frequency of I in 4,000 males and I in 8,000 females. The syndrome is also characterized by developmental delay, hyperactivity. attention déficit disorder, and autistic-likc beltavior. There Is no effective treatment for fragile X syndrome.
|0142] The présent invention contemplâtes the treatment of mild mental retardation, modernte mental retardation, severe mental retardation, proround mental retardation, and mental retardation severity unspecifted. Such mental retardation may be, but is not required to be. associated with chromosomal changes, (for example Down Syndrome duc to trisomy 2 i ), heredity, pregnancy and périnatal problems. and other severe mental disorders. This Invention provides methods for treating mental retardation using the extended release levetiracetam composition of the invention, ln certain embodiments, treatment comprises preventing or slowing the progression ofmental retardation, ln certain embodiments, treatment comprises alleviation, amelioration, or slowing the progression of one or more symptoms associated with mental retardation, ln certain embodiments, the symptom to be treated is cognitive deficit/impairment. For example, methods and compositions ofthe disclosure can bc used to improve the motor/cognitive impairments symptomatic of mental retardation.
(0143] Several animal models hâve been developed for mental retardation. For example, a knockout mouse model has been developed for Fragile X syndrome. Fragile X syndrome Is a common form of mental retardation causcd by the absence of the FMRI protein, FMRP. Two homologs of FMRP hâve been identified, FXRIP and FXR2P. FXR2P shows high expression in braîn and testis, like
FMRP. Both Fxr2 and Fmrl knockout mice, and Fmrl/Fxr2 double knockout mice are believed to be useful models for mental retardation such as Fragile X syndrome. Sec, Bontekoe C. J. M. et al. Hum. Mol. Genet. 2002, 11 (5): 487-498. The efficacy of the methods and compositions of this invention (n treating mental retardation, or cognitive deficit/impairment associated with mental retardation, may be assessed in the these mouse models and other animal models developed for mental retardation, as well as human subjects with mental retardation, using a variety of cognitive tests known in the art, as discussed above.
[0144] Obsessive compulsive disorder (“OC D“) is a mental condition that is most commonly characterized by intrusive, répétitive unwanted thoughts (obsessions) resulting in compulsive behaviors and mental acts that an individual • 47 feels driven to perform (compulsion). Current epidemiological data indicates that OCD is the fourth most common mental disorder in the United States. Some studies suggest the prevalence of OCD is between one and three percent although the prevalence of clînically recognized OCD is much lower. suggesting that many 5 individuals with the disorder may not bc diagnosed. Patients with OCD are often diagnosed by a psychologist, psychiatrist, or psychoanalyst according to the Diagnostic and Statistical Manual of Mental Disorders, 4th édition text révision (DSM-FV-TR) (2000) diagnostic criteria that include characteristics of obsessions and compulsions. Characteristics ofobsession include: (I) récurrent and persistent 10 thoughts. impulses, or images that are experienced as intrusive and that cause marked anxiety or distress; (2) the thoughts, impulses, or images are not slmply excessive worries about real-life problème; and (3) the person attempts to Ignore or suppress such thoughts. impulses, or images, or to neutralize them with some other thought or action. The person recognizes that the obsessional thoughts, impulses, 15 or images are a product of his or hcr own mind, and are not based in reality.
Characteristics of compulsion include: (I) répétitive behaviors or mentnl acts that the person feels driven to perform ln response to an obsession, or according to rulcs that must bc applied rigidly; (2) the behaviors or mental acts are almed at preventing or reducing distress or preventing some dreaded event or situation;
however, these behaviors or mental acts are not actualiy connected to the issue, or they are excessive.
[0145 J Individuals with OCD typically perform tasks (or compulsion) to seek relief from obsession-related anxiety. Répétitive behaviors such us handwashing, count i ne. checking, or clearing are often performed with the hape of preventing 25 obsessive thoughts or making them go away. Performing these ‘Tituals, however, only provides temporary relief. People with OCD may also bc diagnosed with a spectrum of other mental disorders, such as gcneraüzed anxiety disorder. anorexia nervosa. parie attack. or schizophrenia.
[0146] The dysfunction in neuronal communication is considered one ofthe underiying causes for obsession disorder (Myrrhe van Spronsen and Caspcr C.
lloogenraad, Cuit. Neurol. NeuroscL Rep. 2010.10.207*214), Studies suggest • 41 that OCD may be related to abnormal levels ofa neuro transmitter called serotonin. The first-lïne treatment of OCD consists ofbehavioral therapy, cognitive therapy, and médications. Médications for treatment Include serotonin reuptake Inhibitors (SRIs) such as paroxetine (Scroxat™, Paxil®. Xetanor™, ParoMerck™,
Rexctin™), scrtralinc (Zoloft®, Stimuloton™), fluoxetinc (Prozac®, Bioxetin™), escitalopram (Lexapro®), and fluvoxamine (Luvox®) as well as the trtcycl ic antidepressants, in particular clomipraminc (Anafranil®). Benzodiazépines arc also used in treatment. As much as 40 to 60% of the patients, however, fait to adequately rcspond to the SRI therapy and an even greater proportion of patients fait to expérience complété remission of their symptoms.
(0147] This invention provides methods for treating OCD using the extended release levetiracetam composition ofthe invention. In certain embodiments, treatment comprises preventing or slowing the progression of OCD. In certain embodiments, treatment comprises alleviation, amelioration, or siowing the progression of one or more symptoms associated with OCD, In certain embodiments, the symptom to be treated Is cognitive déficit. For example, methods and compositions ofthe disclosure can be used to treat the cognitive déficits in OCD, and/or to improve cognitive function in patients with OCD. A quinpirole-sensitized rat mode! has been developed for OCD. The compulsive chccking behavior ofthe quinpirole-sensitized rats is subject to interruption, which is an attribute characteristic ofOCD compulsions. The efticacy ofthe methods and compositions ofthis invention in treating OCD, or cognitive déficits associated with OCD, may be assessed in this rat model and other animal models developed for OCD, as well as human subjects with OCD, using a variety of cognitive tests known in the art, as discussed above.
Substance addiction [0148] Substance addiction (e.g., drug substance addiction, alcohol substance addiction) is a mental disorder. The substance addiction is not triggered instantaneously upon exposure to substnacc ofabuse. Ralher, it invoives multiple, complex neural adaptations that develop with dï fferent time courses ranging from hours to days to months (Kauer J. A. Nat. Rev. Nettroscl. 2007. 8. 844-858). The
path to substance addiction generally begtns with the voluntary use of onc or more controlled substances, such as narcotïcs, barbiturates, methamphetamines, alcohol, nicotine, and any of a variety of other such controlled substances. Over time, with extended use of the controlled substances), the voluntary ability to obstain from 5 the controlled subs tance (s) is compromised duc to the effects of proionged use on brain fonction, and thus on bchavïor. As such, substance addiction generally is characterized by compulsive substance craving, seeking and use that persist even In the face of négative conséquences. The cravings may represent changes in the underlying ncurobiology of the patient which likcly must be addressed in a 10 meaningfol way i f recovery is to be obtained. Substance addiction îs also characterized in many cases by withdrawa! symptoms, which for some substances arc life threatenLng (e.g., alcohol, barbiturates) and in others can resuit in substantial morbidity (which may include nausea, vomiting. fever, dizziness, and profose sweating), dîstress. and decreased ability to obtain recovery. For cxample.
alcohoiism, also known as alcohol dependence, is one such substance addiction. Alcoholism is primarily characterized by four symptoms, which include cravings, loss of control, physical dependence and tolérance. These symptoms also may characterize substance addictions to other controlled substances. The craving for alcohol, as well ns other controlled substances, oflcn is as strong as the need for 20 food or water. Thus, an alcoholic may continue to drink despi te scrious family, health and/or legal ramifications.
[0149] Recent work exploring the effects of abusing alcohol, central stimulants, and optâtes on the central nervous system (CNS) hâve demonstrated a variety of adverse effects related to mental health, including substance-induced impairments 25 i n cognitîon. Sec, Nybcrg F. Cognitive Impairments In Drug Addicts, Chapler 9. In several laboratories and ciinics substantial damages of brain fonction are seen to resuit from these drugs. Among the harmfol effects of the abusing drugs on brain are those contributing to acceierated obsolescence. An observation that has received spécial attention during recent years is that chronic drug usera display 30 pronounced impairment In brain areas associated with executive and memory fonction. A remarked neuroadaptation caused by addictive drugs, such a3 alcohol, central stimulants and opiates involves diminished neurogenesis In the subgranular
zone (SGZ) ofthe hippocampus. Indecd, it has been proposed that decreased adult neurogenesis in the SGZ could modify the hippocampe! function In such a way that it contributes to relapse and a maintained addictive behavior. It also mises the possibility that decreased neurogenesis may contribute to cognitive déficits clicited 5 by these abusing drugs.
(01501 This invention provides methods for treating substance addiction using the extended release levetiracetam composition of the invention. In certain embodiments, treatment comprises preventing or slowing the progression of substance addiction. In certain embodiments, treatment comprises alleviation, i 0 amelioration, or slowing the progression of one or more symptoms associated with substance addiction. In certain embodiments, the symptom to be treated is cognitive impairment. For example, methods and compositions of the disclosure can be used to treat the cognitive impairment and/or to improve cognitive function In patients with substance addiction.
(0151] Several animal models bave been deveioped to study substance addiction.
For example, a genetically selected Marchiglan Sardinian alcohol-p referring (msP) rat models is deveioped to study the neurobiology of alcoholism. See, Ciccocioppo R. et al. Substance addiction Blology 2006,11,339-355. The efficacy ofthe methods and compositions of this invention in treating substance addiction, or cognitive impairment associated with substance addiction, may aiso be assessed in animal models of substance addiction, as weil as human subjects with substance addiction, using a variety of cognitive tests known in the art, as discussed above.
[0152] Appropriate methods o fadmi nistering the extend ed release composit ions of the invention will also dépend, for example, on the âge of the subject, whether 25 the subject is active or inactive at the time of administering, whether the subject is cognitively impaired at the time of administering, or the extent ofthe impairment In some embodiments, the extended release levetiracetam composition of the invention is administered orally, e.g., to a subject by ingestion. In some embodiments, the orally administered composition 1$ administered using a device 30 for extended release.
(0153] It will be understood by one of ordinary skill in the art that the compositions and methods described herein may be adapted and modified as is appropriate for the application being addressed and that the compositions and methods described herein may be employed In other suitable applications, and that 5 such other additions and modifications will not départ from the scope hereof.
[0154] This invention will be better understood from the Experimental Details which follow. However, one skilled in the art will readily appreciate that the spécifie methods and results discussed are merely illustrative of the Invention as described more fully in the embodiments which follow thereafter.
Examines
Example 1: A process for making extended release compositions comprising 190 mg of levetiracetam
Table 1
Ingrédient Functionality Tablet A (Mg/Tablei Tablet B t) (Mg/Table Tablet C !t)(Mg/Tablet)
Levetiracetam Base API 190.0 190.0 190.0
Hypromellose (Methocel™ K ISM CR) Matrix Former 300.0 - •
Hypromellose (Methocel™ K100M Premium CR) Matrix Former 300.0 300.0
Colloïdal Silïcon Dioxide Glidant 1.2 U 12
Silicified Microcrystalline Diluent 102.8 102.8 -
Cellulose ProSolv™ HD90
Encompress, Anhydrous dicalcîum phosphate Diluent • • 102.8
Magnésium Stéarate Lubricant 6.0 6.0 6.0
Total 600 600 600
[0155] Three extended release tablets A, B, and C comprising 190 mg of levetiracetam as shown In Table 1 are manufactured following the process exemplifled in the flow diagram of Figure 1. The process exemplified in the flow 15 diagram of Figure 9 could also be used. tn brief, Silicified Microcrystalline
Cellulose ProSolv™ SMCC HD90 (or Encompress, Anhydrous dîcalcium
phosphate) Îs sifted through deagglomerate #30 U.S. mesh sieve, and then blended with Colloïdal Silicon Dioxide (16 qt V-shell blender; 75 rev ± 5 rev). The biended sample then goes through Round 1601 Impeller (2AO24R screen). 190 mg of levetiracetam and hypromellose 2208 (Methocel™ K15M Premium CR) (or
Methocel™ K10OM Premium CR) are also sifted through deagglomerate #30 U.S. mesh sieve, and then blended în a I Siant Cône Biender (250 rev ± 5 rev) with the ground Silicified Microcrystailine Cellulose ProSolv™ HD90 and Colloïdal Silicon Dioxide. This blended sample then goes through Round 1601 Impeller (2A024R screen) and then is blended In a 1 ft* Siant Cône Blender (125 rev ± 5 rev) 10 with sieved Magnésium Stéarate (HyQual®) (sleved through deagglomerate #30 U.S. mesh sieve). The blended samples are compressed into tablets. Optionally, the tablets are further film coated with a hypromcllose-based (HPMC-based) coating, such as Opadry* complété film coating system.
Example 2: Dissolution profile of extended release compositions comprising
190 me of levetiracetam [0156] Table 2 below shows the dissolution profile for the 190 mg levetiracetam extended release Tablet A of Table 1.
Table 2
Test Results (Time: Percentages of dissolution)
Dissolution lhr.29% 3hr:51% ' 12 hr. 92%
When extended release Tablet A is placed in variety of EtOH concentrations in
0.1 N HCL, no dose dumping is observed.
Example 3; A process for maklng extended release compositions comprising
220 mg of levetiracetam
Table 3
Ingrédient Functionality Tablet D Tablet E (Mg/Tablet) (Mg/Tablet)
Levetiracetam API 220.0 220.0
Hypromeliose(Methocei™ Matrix Former K ISM CR) 280.0 3473
Colloidal Silicon Dioxide Glidant 1.2 1.4
Silicified Microcrystaliine Cellulose ProSolv™ HD 90 Diluent 92.8 1192
Magnésium Stéarate Lubricant 6.0 6.7
Total 600 695
[0157] Two extended release tablets D and E comprising 220 mg of levetiracetam as shown în Table 3 are manufactured following the process excmplifled in the flow diagram of Figure 1. The process exemplified ln the flow diagram of Figure
9 could also be used. In brief Silicified Microcrystaliine Cellulose ProSolv™
SMCC HD90 (or Encompress, Anhydrous dicalcium phosphate) is sifted through deagglomerate #30 U.S. mesh sieve, and then blended with Colloidal Silicon Dioxide (16 qt V-shc!l blender, 75 rev ± 5 rev). The blended sample then goes through Round 1601 Impeller (2A024R screen). 220 mgof levetiracetam and hypromellose 2208 (Mcthocel™ KI5M Premium CR) (or Methocel™ K100M Premium CR) are also sifted through deagglomerate #30 U.S. mesh sieve, and then blended in a Ift3 Slant Cône Blender (250 rev ± 5 rev) with the ground Silicified Microcrystaliine Cellulose ProSolv™ HD90 and Colloïdal Silicon Dioxide. This blended sample then goes through Round 1601 Impeller (2A024R screen) and then isblended în a Ift3 SlantCône Blender (125 rev± 5 rev) with sieved Magnésium
Stéarate (HyQuai®) (sieved through deagglomerate #30 U.S. mesh sieve). The blended samples are compressed into tablets. Optionally, the tablets are further film coated with a hypromellose-based (HPMC-based) coating, such as Opadry* complété film coating system.
Example 4; Dissolution Profile of Extended Release Compositions Comprising
220 me Of Levetiracetam [0158] Table 4 below shows the dissolution profile for the 220 mg Ievetîracetam extended release Tablet D of Table 3.
Table 4
Test Results (Time: Percentages of dissolution)
Dissolution l hn 28% 3hn49% 12 hn 91%
When extended release Tablet D is placed in variety of EtOH concentrations în 0.1N HCL, no dose dumping is observed.
Examnle 5: Evaluation of extended release compositions of 190 mg levetiracetam on pharmacokinetic^ in does
Overview [0159] The purpose of this study is to collcct samples for investigating the pharmacokinetics ofnovel extended release formulations of levetiracetam (190 mg) in male dogs following oral administration. Table 1 provides a description of the three formulations utilized In this study (190 mg Tablets A, B, and C).
Animais [0160] Thîrty non-naïve male purebred beagle dogs from the Covance Stock colony are used in these studies. The animais are acclimated to study conditions for approximately three days prior to dose administration. At dosing, the animais weîgh 8.4 to 12.8 kg and are l to 2 years of âge. Ali animais are housed in Individual, stainless steel cages during acclimation and the test period, except during periods of commingling in accordance with Covance SOPs. Certifîed Harlan Teklad 2021,21% Protein Dog Diet is provided ad libitum unless otherwise specified for dose administration. Water is provided fresh daily, ad libitum. Environmental contrais for the animal room are set to maintain a température of 68 to 79°F, a relative humidîty of 50 £ 20%, and a 12-hour light/ 12-hour dark cycle.
As necessary, the 12-hour dark cycle is intemipted to accommodate study procedures.
Studv Design [0161] Five groups of dogs (N“6 per group) are utilized in this study. An immédiate release 250 mg levetiracetam (LEV IR) tablet is administered as a 250 mg oral B1D regimen (a total dose of 500). An extended release 500 mg levetiracetam tablet (LEV XR) is administered as a single oral dose of500 mg. Tablets A, B, and C are administered as single oral doses of 190 mg. Plasma pharmacokinetîc samples are collected at pre-dose, 0.25,0.5,1,2,4,6,8,12,13 (collecting only LEV IR), 18,24, and 48 hours post dose. For LEV IR, the 12hour blood sample is collected just prior to administration ofthe second dose.
Tabte 5: Overview of Study Design
Group Number of Test Dose Target Dose
Male Article Route Level
Animais (mg/tablet)
1 6 LEV-IR Oral Tablet 250
2 6 LEV-XR Oral Tablet 500
3 6 Tablet A Oral Tablet 190
4 6 Tablet B Oral Tablet 190
5 6 Tablet C Oral Tablet 190
IR immédiate release. XR Extended release.
Notes: Animais in Group I receive two 250 mg tablets, approximately 12 hours apart (500 mg total dose). Animais ln Groups 2 through 5 receive a single tablet ftnatvtical Methods [0162] Sample analysis Is performed using a Covance-owned generic method and analog internai standard. The method Is adjusted as appropriate for the spécifie test article used on study. Data collection and chromatographie interprétation is performed in Analyst and the Laboratory Information Management System (L1MS) used on study is Watson.
Absorption and Plasma Levels
[0163] LEV IR vs, LEV XR: LEV IR is administered as a 250 mg oral BID regimen (total daily dose of500 mg). LEV XR is administered as a single oral dose of 500 mg. Based on mean plasma Cm» and AUCo-inf, the overall exposurc of dogs to levetiracetam 1s similar with both formulations (Figure 2, Table 6). The plasma Thu Îs carlier with the IR formulation (range 025 - 2.00 h; mean l.00 h) than with the XR formulation (range 2.00 — 4.00 h; mean 333 h). The apparent élimination half-life of levetiracetam ln plasma averages 3.50 ±0273 h and 423 ± 0390 h with the LEV IR and LEV XR formulations, respectively.
[0164J 190 me Tablets A. B. and C: 190 mg Tablets A, B, and C of Table 1 are 10 administered as single oral doses of 190 mg. Oie highest exposurc to levetiracetam is achieved with Tablet A (Figure 2, Table 6); plasma Cmu and AUCo-m averaged 8650 ± 1440 ng/mL and 90000 ± 27200 ng*h/mL, respectively.
The plasma Tm» generally range from 2.00 to 4.00 hours. Hie apparent élimination half-life of levetiracetam in plasma average 4.15 ± 126h.
Table 6: Pharmacokinetic parameters ln plasma collected from male dogs , followiag oral administration of levetiracetam
LAAirml, Number Oroup (ng/mL) _ .C—flD___ ((ng/mLymi) T (h) — AUC«__AUCmrf- _AUCmP ((IpigônLymg) --<IA-J
(h ngOnL) (hntfail)
250 m» BID (LEV-IR)
112313 1 29200 514 0.50 247000 247000 493 332
113624 1 23200 46.4 025 237000 237000 474 3.45
113626 1 J1400 621 025 302000 302000 604 3.44
IIJ64S l 38100 762 200 277000 277000 554 3.15
113627 l 24300 4S.6 200 210000 210000 560 3.13
113614 1 24300 49 0 1,00 214000 214000 421 3.12
Mon 2S5OO S69 1.00 239000 239000 519 J30
SD 3710 11.4 0122 32400 32400 641 0273
500 ma (LEV - XR)
113637 2 36900 73.1 400 211000 211000 43« 3.73
113643 2 25000 500 200 265000 265000 531 5.19
I13646 2 31600 632 400 302000 302000 604 4.16
112513 2 35400 701 2.00 317000 317000 634 3.74
113631 2 24900 49.1 4.00 230000 230000 460 469
113615 2 44300 116 4.00 217000 217000 574 3.19
Mean 33000 66.0 333 270000 270000 540 423
SD 7490 150 103 39600 39600 79.1 0390
190 mg (Tablet A3
112417 3 9900 511 2.00 122000 122000 644 3.51
113636 3 10100 532 4.00 toiooo 101000 571 3.94
113616 3 7740 40.7 2.00 125000 NR NR NR
113613 3 7310 31.5 200 53100 53100 210 6 36
113611 3 7000 361 200 75600 75600 391 323
112516 3 9120 51.7 400 90600 90600 477 3 69
Man 1650 453 167 95900 90000 474 4.15
SD 1440 7.51 103 21200 27200 143 126
AUCm Ara aad*r Um pluaia aanuntteMlaM ram ap la lb* lui uapUag lima wllli meuenàla «aaceatritiom.
AUC*w Ara aadar lb* plaie· caaorwlratioa*ti»r cana ap ta laflalry.
AUCaa/D Doit adjaalcd ara aader tfea pluu* aMalratiaa-llua ara ap ta laflalty.
C_ Mulmam ptaaaa aacntmJM.
C__/D Dm* adlulad Baihaa» pluma coacaatrall··.
h llaar*.
IR ImaHdlala nlaaHL
NR Nal rtporlcd.
SD Suadard drrtada*.
Τ,μ Ttaa la aiaitaia· caacMtratl··.
tu, Oburvrd H «hutte· hair-HTe,
XR Ealaadad rata» [0165] The highest overall exposure of Ievetiracetam in dogs is achieved with the LEV XR and. LEV tR formulations. Of the 190 mg Tablets A, B, and C, the highest overall exposure of Ievetiracetam ln dogs is achieved with the 190 mg
Tablet A. Based on the mean dose-adjustcd plasma Cm» and AUC^w values, the Ievetiracetam exposure achieved with the 190 mg Tabict A is approximately 69% and 88%, respectively, ofthe exposure achieved with the LEV XR formulation, and 80% and 91%, respectively, of the exposure achieved with lhe LEV IR formulation.
i0 Example 6; Evaluation of extended release compositions of 220 mg Icvetiracetnm on nharmacokinetics In dogs
Overvievv [0166] The purpose ofthis study is to collect samples for Investigating the pharmacokinetics of nove! extended release formulations of levetiracetam (220 mg) in male dogs following oral administration. Table 3 provides a description of 5 the two formulations utilized in this study (220 mg Tablets D and E).
Animais [0167] Eighteen non-naïve male purebred beagie dogs from the Covance Stock colony are used in these studies. The animais are acciimated to study conditions for approximately three days prior to dose administration. At dosing, the animais 10 weigh 7.6to 11.7 kg and areapproximately l yearofage. Ail animais are housed in individual, stainless steel cages during accllmation and the test period, except during periods of commingiing in accordance with Covance SOPs. Certifled Harlan Teklad 2021,21% Protein Dog Dlet is provided ad libitum unless otherwise specified for dose administration. Water Is provided fresh daiiy, ad libitum.
Environmental controls for the animal room are set to maintain a température of 68 to 79°F, a relative humidity of 50 ± 20%, and a 12-hour light/!2-hour dark cycle. As necessary, the 12-hour dark cycle is interrupted to accommodate study procedures.
Studv Design [0168] Three groups ofdogs (N”6 per group) are utilized in this study, LEV XR is administered as a single oral dose of 500 mg. 220 mg Tablets D and E are administered as single oral doses of220 mg. Plasma pharmacokinetlc samples are collected at pre-dose(Le.,0), 0.25,0.5,1,2,4,6,8,12,18,24, and 48 hourspost dose. See Table 7.
Table 7: Overvlew of Study Design
Group Number of Test Dose Target Dose
Male Article Route Level
Animais (mg/tablet)
1 6 LEV-XR Oral Tablet 500
2 6 Tablet D Oral Tablet 220
3 6 Tablet E Oral Tablet 220
XR Extended Release. Note: Animais received a single tablet.
Analvtlcal Methods [0169] Sample analysis is performed using a Covance-owned generic method and analog interna! standard. The method Is adjusted as appropriate for the spécifie 5 test article used on study. Data collection and chromatographie interprétation are performed in Anaiyst and the Laboratory information Management System (LIMS) used on study is Watson.
Absorption and Plasma Levels [0170] LEV-XR Is administered as a single oral tabiet dose of500 mg; the 220 mg Tablets D and E are each administered as single oral tablet doses of220 mg. Based on mean dose-adjusted plasma Cmax and AUCo-ι, the overall exposure of dogs to levetiracetam is similar with the LEV-XR and the 220 mg Tablet D formulations (Figure 3, Table 8).
LEV XR vs 220 mg Tablets * 15 [0171] The plasma Cra and AUCo-inf for the 220 mg Tablet D average 10900±
2540 ng/mL and 110000 ± 23000 ng’h/mL, respectively. The plasma Tmu generally ranges from 2.00 to 6.00 hours. The apparent élimination half-ilfe of levetiracetam in plasma averages 4.41 ± 0.06 h. The mean dose-adjusted plasma Gnu values are 46.6 ± 7.37 and 49.3 ±113 ng/mL for the LEV-XR and the 220 mg Tablet D respectively. The dose-adjusted plasma AUCm values are 452 ±67.2 and 499 ± 104 ng*h/mL for the LEV-XR and the 220 mg Tablet D, respectively.
[0172] The plasma T««x is similar for LEV XR and the 220 mg Tablet D (LEVXR: range 1.0-3.6 h; mean 1,6 h; the 220 mg Tablet D: range 2.0-6.0 h; mean 2.7 h). The apparent élimination half-life of levetiracetam in plasma averages 5.16 ± 1.44 h and 4.41 ± 0.614 h with the LEV-XR and the 220 mg Tablet D formulations, respectively.
Table 8. Pharmacokinetic parameters ln plasma collected from maie dogs following oral administration of Levetiracetam
Croup Dom («n> Subjrct Ne. (ap/taL) C_/D (nt/mLymp TH W AUCm (nrVmL) AUC^/D (•t*h/inLym| AlCfcw (nrh/mL) *vt (6)
SnOmatLEV- W
1 500 1136)7 13600 512 10 159000 511 159000 J 75
t 500 113451 13700 474 36 101000 402 201000 717
1 500 113459 21400 576 10 163000 516 263000 521
1 500 113641 19500 390 10 192000 344 192000 635
1 500 113642 I9IOO 3tl 10 195000 190 196000 501
1 500 113647 13100 441 10 247000 494 247000 344
N 6 6 6 6 6 6 6
Mua 11300 446 16 226000 451 226OCO 516
SO 3410 7.17 1.1 15500 672 33400 144
evs 151 lit 661 141 14 9 141 110
220 ma fTahlet DI
1 220 113700 15300 695 60 142000 645 142000 445
1 220 113114 10400 471 10 lotooo 491 lotooo 3 91
1 220 II3II7 11400 511 10 130000 591 NR NR
1 220 113112 10000 45 5 20 104000 475 104000 3 74
1 120 114110 10500 477 20 94100 437 96200 527
1 220 114111 7520 342 10 79000 359 79000 450
N 6 6 6 6 6 5 5
Mcm (0900 493 17 110000 499 106000 441
SO 2540 115 16 23000 104 13200 0614
CV% 234 13 4 611 209 201 219 139
AUCm An· uodâ ih< plan· concâïâüiKiMim cum up ia lha laat lampiinl ixa* wuh maaûnbïûûûâcainÎonaT
AUCw AUCa^D
C—
C^JD CVS h
N NR
SO T— lu
An· ied« lh« piat·· amcmitntiaHMMnm * u> iafliuiy
Dom adjoud ma tmda Ib* plana concaimainadinM nm lip w iafmlry Madmtm ptaana cnnatntioa.
Dom adpiaiel ajumum plan· cancsitnno·.
CocfflcicM of nrado·.
Houn.
Number oTpnnuli·
Not npcelcd due to tH^cdacd lermbal phue.
Standard dem nu.
Tiare la maabnan coaccntmtc·.
ObMmd riixuruaoe lut f-liCt.
[0173] Based on the mean dose-adjusted plasma Cmu and AUQm values, the levetiracetam exposure achieved with the 220 mg Tablet D formulation is approximately 107% and 110%, respectively, of the exposure achieved with the LEV-XR formulation.
• 61
Example 7î Phase I food effect study of extended release compositions of 19(1 me and 220 ms levetiracetam |0174] This examplc describes a two-group, single-dose, two-period, two-way crossover, food-efTect study of two extended release levetiracetam formulations, ie., the 190 mg Tablet A ofTable I and the 220 mg Tablet D ofTable 3.
Objective
I0175J The objective ofthis study is to assess the effect offood on the rate and extent of absorption of two extended release levetiracetam formulations, Le., the 190 mg Tablet A ofTable 1 and the 220 mg Tablet D ofTable 3.
i 0 (0176] Steady state formulation goals: The preferred range goal is cstablished based on aMCI phase II human study: between 2.9 and 4.4 pg/mL. The acceptable range goal Is established based on Aged-Impalred (AI) rats and aMCI phase II human study: between 1.9 and 4.4 pg/mL. Sec Figure 6.
Study Design [0177] This Is an open label, randomized, two-group, single-dose, two-period crossover, food-efTect study. Flfty-slx (56) healthy subjects arc cnrolled. Subjects who successfully complété the screening process check into the research center the evening before first dose. Subjects who continue to meet incîuslon/exclusion criteria the moming of dose are assigned a subject number, based on the order In which they successfuily complété the required screening process and procedures. Dosing days arc separated by a washout period of at least 7 days.
]0178] Subjects are randomly assigned to one oftwo groups:
Group I: Subjects (n 28) received extended-release Tablet A ofTable 1 (190 mg).
Treatment A : Tablet A
Dose * 1 x 190 mg tablet, oraliy administered under fasted conditions
Treatment B: Tablet A
62 Dose 1 x 190 mg tablet, orally administered under fed conditions
Group 2: Subjects (n - 28) received extended-release Tablet D of Table 3
(220 mg). Treatment A: Tablet D Dose - 1 x 220 mg tablet, orally administered under fasted conditions
Treatment B: Tablet D Dose ” 1 x 220 mg tablet, orally administered under fed conditions
[0179] Fed treatment Following an ovemight fast of at least 10 hours, subjects began consuming a Food and Drug Administration (FDA) standard high-calorie, high-fat breakfast meal 30 minutes prior to administration of the study drug.
[0180] Fasted treatment Subjects are dosed after an ovemight fast ofat least
10 hours.
|01811 Each drug administration is separated by a washout period ofat least 7 days.
[0182] Each dose ls orally administered along with approximately 240 mL (8 fl. oz.) of room température water. After dosing, no food is allowed until
4 hours postdose. Except for the 240 mL ofroom temperature water provided with the dose, no water mlght be consumed for 1 hour prior through 1 hour after dose. Water consumption followed the guldelines în Section 5.42. With the exception of the FDA standard high-calorie, high-fat breakfast meal scrved during the fed treatment period, meals arc the same and scheduled at approximately the same times relative ta dose for each study period.
[0183] Subjects who wlthdraw from the study arc not rcplaced.
Clinical Procedures Summary
|0184] During each study period, 6 mL blood samples are obtained prior to each dosing and following each dose at selected times through 24 hours post-dose. A total of34 pharmacokinetic blood samples are to be collccted from each subject, 17 samples in each study period. In addition, blood is drawn and urine is collected 5 for clinical laboratory testîng at screening and study exit
J0185] In each study period, subjects are admitted to the study unit in the evening prior to lhe scheduled dose. Subjects are confined to the research center during each study period until completion of the 24-hour blood collection and other study procedures.
Procedures for Collecting Samples for Pharmacokinetic Analysis (0186) Blood samples (1x6 mL) are collected in vacutainer tubes contaîning KiEDTA as a preservative at pre-dose (0) and at 1.0,2.0,3.0,4.0,4.5,5.0,5.5,6.0, 6.5,7.0,8.0,9.0,10,12,18, and 24 hours after dosing.
Bioanalytlcal Su m mary {0187] Plasma samples are analyzed for levetiracetam using a validated
LC-MS-MS procedure. The method is validated fora range of 0.0500 to 30.0 pg/mL for levetiracetam, based on the analysis of0.200 mL of human EDTA plasma. Data are stored in Watson Laboratory Information Management System (LIMS; Version 72.0.03, Thenno Fisher Scientific).
Pharmacokinetic Analysis (0188] Data are analyzed by noncompartmental methods ln WinNonlin. Concentratîon-tîme data that are below the limit of quantification (BLQ) are treated as zéro in lhe data summarization and descriptive statistics. In the pharmacokinetic analysis, BLQ concentrations are treated as zéro from time-zero 25 up to the time at which the first quantifiable concentration is observed; embedded and/or terminal BLQ concentrations are treated as “missing. Actual sample times are used for ail pharmacokinetic and statistical analyses.
• « [0189] The following pharmacokinetic parameters are calculated: peak concentration in plasma (Cm»), time to peak concentration (Tmn), élimination rate constant (λ2), terminal half-life (T1/2), area under the concentratlon-time curve from timc-zero to the time of the last quantifiable concentration (AUCiast), and area under the plasma concentration time curve from time-zero extrapolated to infinity (AÜCinr). Additionally, Cmx, AUCts, and AUCmrare dose-normalized.
[0190] Analysis ofvariance (ANOVA) and the Schuirmann's two one-sided t-test procedures at the 5% signiflcance level are applied to the log-transformed pharmacokinetic exposure parameters, Cm™, AUCu*. and AUCm*. The ! 0 90% confidence interval for the ratio of the géométrie means (Test/Reference) is calculated. A lack of food effect is declared ifthe lower and upper confidence intervals of the log-transformed parameters are within 80% to 125% (190 mg Tablet A Fed vs. 190 mg Tablet A Fasted; 220 mg Tablet D Fed vs. 220 mg Tablet D Fasted). Additionally, the dose-normalized Cm», AUCt*, and AUCmrare compared within fasted and fed conditions to détermine dose-proportionality.
Dose-proportionality is concluded if the lower and upper confidence intervals of the dose-normalized, log-transformed parameters are within 80% to 125% (220 mg Tablet D Fasted vs. 190 mg Tablet A Fasted; 220 m g Tablet D Fed vs. 190 mg Tablet A Fed)
Results [0191] Data from 55 subjects for Group 1 and 54 subjects for Group 2 are included in the pharmacokinetic and statistlcal analyses. Mean concentration-time data are shown in Tables 9 and 10 and in Figures 4 and 5. Results of the pharmacokinetic and statistlcal analyses are shown below in Tables 9-15.
Conclusions
Food-Effect:
[0192] The 90% confidence intervals for the log-transformed exposure parameters C™, AUCuu, and AUCinrare within the 80% to 125% range for the
190 mg and 220 mg doses. The presence of food does not alter the pharmacokinetics ofthe 190 mg and 220 mg levetiracetam doses.
Dose Proportion al itv:
[0193] The 90% confidence intervals for the dose-normal ized log-trans formed exposure parameters Cm«x/D, AUCiet/D, and AUCmt/D are within the 80% to 125% range for fed and fasted conditions. Levetiracetam exposure, as measured by Cmax/D, AUCiui/D, and AUCin(/D, increase proportionately from 190 mg (Tablet A) to 220 mg (Tablet D).
Steady State Modeline [0194] AccordingtothesteadystatemodelingofPKprofile forthe 190mg
Tablet A, it meets the acceptable range goal. Le., between 1.9 and 4.4 pg/ml. See Figure 7.
[0195] According to the steady state modeling of PK profile for the 220 mg Tablet D, it meets the preferred range goal. Le., between 2.9 and 4.4 pg/ml. See 15 FigureS.
Table 9: Levetiracetam Concentration-Time Data after Administration of Extended-Relcasc Tablet A, 190 mg under Fastcd Conditions (Group I/Treatment A) and Extended-Relcase Tablet A, 190 mg under Fed Conditions (Group Ι/Treatment B)
Time (h) n Group 1/Treatment A: 190 mg Tablet A, Fasted Group 1/Treatment B: 190 mg Tablet A, Fed
Mean (pg/mL) SD (pg/mL) CV (%) n Mean (pg/mL) SD (pg/mL) CV (%)
0.00 28 0,00 0.00 NC 27 0.00 0.00 NC
1.00 28 1.46 0.450 30.76 27 0.665 035! 52.82
2.00 28 1.96 0335 27.21 27 1.41 0.454 3220
3.00 28 2.11 0348 25.93 27 1.86 0391 21.03
4.00 28 2.15 0.569 2633 27 2.19 0.443 2025
4.50 28 2.16 0349 25.42 27 227 0.469 20.70
5.00 28 2.11 0308 24.08 27 2.34 0300 2135
530 28 2.08 0.497 23.91 27 2.34 0319 22.15
6.00 28 2.06 0.445 21.61 27 2.38 0314 2138
6.50 28 2.02 0.445 22.07 27 239 0316 2137
7.00 28 1.99 0.437 21.97 27 236 0.472 20.04
8.00 28 1.94 0.451 2320 27 234 0317 22.13
9.00 28 1.86 0.440 23.64 27 230 0343 23.64
10.00 28 1.81 0464 2538 27 224 0368 25.41
12.00 28 1.65 0.402 24.42 27 1.98 0.471 23.74
18.00 28 123 0339 27.62 27 124 0306 24.63
24.00 28 0.888 0272 30.68 27 0.783 0212 27.07
32.00 28 0.431 0.140 3232 27 0342 0.0991 29.00
48.00 27 0.112 0.0517 4622 27 0.0798 0.0442 5539
Note: Plasma samples onalyzed using a bioanalytical method with a validated range 0.0500 to 30.0 pg/mL; concentrations reported in pg/mL to 3 significant figures; concentrations below limit of quantification set to zéro (0.00 pg/mL) in the data summarization
NC ·* Not calculated
Table 10: Levetiracetam Concentration-TIme Data after Administration of Extended-Release Tablet D, 220 mg under Fasted Conditions (Group 2/Treatment A) and Extended-Release Tablet D, 220 mg under Fed Conditions (Group 2/Treatment B)
Time (h) n Group 2/Treatment A: 220 mg Tablet D, Fasted Group 2/Treatment B: 220 mg Tablet D, Fed
Mean (pg/mL) SD (pg/mL) cv (%) n Mean (pg/mL) SD (itg/mL) CV (%)
0.00 26 0.00 0.00 NC 28 0.00 0.00 NC
1.00 26 1.94 0.619 31.91 28 0.911 0.681 74.77
2.00 26 2.53 0.645 2533 28 1.61 0.636 39.41
3.00 26 2.80 0.618 22.08 28 2.16 0360 25.89
4.00 26 2.86 0396 20.83 28 2.49 0358 2236
430 26 2.83 0353 1937 28 2.65 0306 19.07
5.00 26 2.73 0301 18.33 28 2.78 0.454 1635
5.50 26 2.70 0.499 18.47 28 2.87 0.474 16.49
6.00 26 2.64 0.487 18.44 28 2.93 0.448 1532
6.50 26 2.58 0.444 17.23 28 2.94 0332 18.07
7.00 26 2.48 0.444 17.88 28 2.96 0.471 15.92
8.00 26 2.41 0.444 18.44 28 2.88 0.456 15.82
9.00 26 236 0.428 18.93 28 2.83 0323 18.47
10.00 26 2.22 0.409 18.45 28 2.74 0.587 21.45
12.00 26 2.04 0382 18.68 28 2.45 0.678 27.69
18.00 26 1.43 0399 20.95 28 1.44 0373 25.90
24.00 26 0.998 0.243 2439 28 0.873 0361 29.87
32.00 26 0.472 0.138 29.17 28 0382 0.139 36.41
48.00 26 0.116 0.0442 38.18 28 0.0913 0.0557 61.00
Note: Plasma samples analyzcd using a bloanalytlcal method with a validated range
0.0500 to 30.0 pg/mL; concentrations reported in pg/mL to 3 significant figures; concentrations below limit of quantification set to zéro (0.00 pg/mL) in the data summarization NC Not calculated
Table 11: Pharmacokinetic Parameters of Levetiracetam
Parameter Group t/Treatment A: Group 1/Treatment B: 190 mg Tablet A, Fed
n 90 mg Tablet A, Fasted
Mean SD CV% n Mean SD CV%
Tmtut (h) 28 439 2.05 46.71 27 6.93 1.97 2830
Cmu (pg/mL) 28 231 0.505 21.83 27 233 0328 20.86
Cmax/D 27 0.0133 0.00278 20.86
(pg/mL/mg) 1 AUCto 28 0.0122 0.00266 21.83 27 46.53 9.352 20.10
(h*pg/mL) AUClast/D 28 46.40 11.44 24.66 27 02449 0.04922 20.10
(h* pg/mL/mg) 28 0.2442 0.06024 24.66
AUCinf (h*pg/mL) 28 47.93 11.63 24.25 27 47.81 9.451 19.77
AUCintfD (h* pg/mL/mg) 28 0.2523 0.06119 2425 27 02516 0.04974 19.77
AUCem»p (%) 28 329 232 76.75 27 2.72 1.40 5137
Xr(h’) 28 0.0873 0.0114 13.11 27 0.0911 0.0096 1030
Ti/2(h) 28 8.09 1.17 1430 27 7.70 0.88 1139
T|a« (H) 28 46.82 4.19 8.94 27 45.64 5.80 12.70
Clou (pg/mL) 28 0.125 0.0661 52.74 27 0.115 0.0605 52.46
Group 2/Treatment A: Group 2/Τιτπ tirent bl
Parameter 220 mg Tablet D, Fasted 220 mg Tablet D, Fed
n Mean SD CV% n Mean SD cv%
Tnu (h) 26 4.04 125 30.91 28 6.64 1.83 2735
Cm» (pg/mL) Cmax/D 26 3.02 0369 18.88 28 3.16 0.623 19.73
(pg/mL/mg) AUCiut 26 0.0137 0.00259 18.88 28 0.0143 0.00283 19.73
(h*pg/mL) AUClast/D 26 5633 10.42 18.49 28 5527 10.35 18.72
(h*pg/mL/mg) AUCuif 26 02560 0.04734 18.49 28 02512 0.04702 18.72
(h*pg/mL) 26 57.68 10.67 1830 28 56.63 1033 1839
AUCinf/D (h*pg/mL/mg) 26 0.2622 0.04850 1830 28 02574 0.04784 1839
AUCÉxtmp(%) 26 235 1.10 47.03 28 2.42 1.19 48.97
λ. (h1) 26 0.0905 0.0123 13.63 28 0.0933 0.0126 1330
Tin (h) 26 7.81 1.14 1439 28 7.56 1.0! 1332
Tu*(h) 26 48.01 0.06 0.13 28 45.73 5.71 12.48
Ckst (pg/mL) 26 0.116 0.0442 38.18 28 0.124 0.0640 51.46
Table 12: Statistical Analysis ofthe Natural Log-Transformed Systemic Exposure
Parameters of Levetiracetam Comparing Extended-Release Tablet A, 190 mg under Fed Conditions (Treatment B l ) to Extended-Release Tablet A, 190 mg under Fasted Conditions (Treatment A1) in Group 1
Dépendent Variable Géométrie Mean* Test Ref Ratio (%) (Test/Ref) 90% Cl* Lower Upper Power ANOVA CV%
In(CtMc) ln(AUCi»t) In(AUChr) 2.4777 22968 45.6972 45.6427 46.9703 47.0059 107.88 100.12 99.92 10332 112.63 95.44 105.02 9538 104.68 1.0000 929 1.0000 1031 1.0000 10.02
· Géométrie Mean for 190 mg Tablet A, Fed (Test-Bl) and 190 mg Tablet A, Fasted (Ref-Al) based on Least Squares Mean of log-transformed parameter values b Ratio(%) ° Géométrie Mean (TestyGeomctric Mean (Ref) ' 90% Confidence Intenral
Table 13: Statistical Analysis of the Natural Log-Transformed Systemic Exposure Parameters of Levetiracetam Comparing Extended-Release Tablet D, 220 mg under Fed Conditions (Treatment B2) to Extended-Release Tablet D, 220 mg under Fasted Conditions (Treatment A2) in Group 2
Dépendent Variable Géométrie Mean* Ratio (%)h (Test/Ref) 90% a* Power ANOVA CV%
Test Ref Lower Upper
In(Cmai) 3.1117 2.9660 104.91 10032 109.72 1.0000 9.43
ln(AUCi«i) 543598 55.6286 98.08 94.03 10230 1.0000 8.86
In(AUCi.r) 55.9406 56.9747 98.18 9421 10233 1.0000 8.71
· Géométrie Mean for 220 mg Tablet D, Fed (Test-B2) and 220 mg Tablet D, Fasted (Ref-A2) based on Least Squares Mean of log-transformed parameter values k Ratio(%) - Géométrie Mean (TestyGeometric Mean (Ref) e 90% Confidence Interval
Table 14: Statistical Analysis ofthe Natural Log-Transformed Systemic Exposure
Dose-Normalizcd Parameters of Levetiracetam Comparing Extended-Release
Tablet D, 220 mg under Fasted Conditions (Treatment A2) to Extended-Release
Tablet A, 190 mg under Fasted Conditions (Treatment Al)
Dépendent Variable Géométrie Mean* Twt Ref Ratio (%)b (Test/Rei) 90% cr Lower Upper Power ANOVA CV%
ln(C«tn/D) ln(AUChii/D) ln(AUCi»rZD) 0.0135 0.0119 02518 0.2371 02579 02452 11339 10622 105.17 102.88 124.98 95.98 11734 9521 116.16 0.9825 2138 0.9754 22.49 0.9789 22.07
• Géométrie M lean for 190 mg Tablet A, Fasted (Test-A2) and 220 mg Tablet D,
Fasted (Ref-Al) based on Least Squares Mean oflog-tran s formed parameter values b Ratlo(%) ” Géométrie Mean (Test)/Geometric Mean (Ref) c 90% Confidence Interval
Table 15: Statistical Analysis ofthe Natural Log-Transformed Systemic Exposure Dose-Normalized Parameters of Levetiracetam Comparing Extended-Release Tablet D, 220 mg under Fed Conditions (Treatment B2) to Extended-Release Tablet 1¼ 190 mg under Fed Conditions (Treatment B l)
Dépendent Variable Géométrie Mean* Ratio (%)b (Test/Rel) 90% CI* Power ANOVA CV%
Test Ref Lower Upper
In(Cnu«/D) 0.0141 0.0130 108.14 98.72 118.47 0.9906 20.41
ln(AUCiui/D) 02472 02404 102.82 9449 111.89 0.9959 18.87
in(AUCiat/D) 02534 02472 10231 9432 111.42 0.9965 18.61
1 Géométrie Mean for 220 mg Tablet D, Fasted (Tcst-B2) and 220 mg Tablet D,
Fasted (Ref-Bl) based on Least Squares Mean oflog-tran s formed parameter values b Ratio(%) - Géométrie Mean (Test)/Geomctric Mean (Ref) * 90% Confidence Interval

Claims (24)

  1. WHAT IS CLAIMED:
    ]. An extended release pharmaceutical composition comprising:
    a) 220 mg of levetiracetam;
    b) 280 mg-350 mg of hydroxypropyl methylcellulose;
    c) 12 mg-1.4 mg of colloïdal silicon dioxide;
    d) 92.8 mg-l 192 mg of silicified microcrystalline cellulose; and
    e) 6.0 mg-45.7 mgofmagnésium stéarate.
  2. 2. An extended release pharmaceutical composition comprising:
    a) 220 mg of levetiracetam;
    b) 280 mg of hydroxypropyl methylcellulose;
    c) 12 mg ofcolloidal silicon dioxide;
    d) 92.8 mg of silicified microcrystalline cellulose;
    and
    e) 6.0 mg of magnésium stéarate.
  3. 3. An extended release pharmaceutical composition comprising:
    a) 220 mgof levetiracetam;
    b) 347.5 mg of hydroxypropyl methylcellulose;
    c) 1.4 mg ofcolloidal silicon dioxide;
    d) 1192 mg of silicified microcrystalline cellulose;
    and
    e) 6.7 mg of magnésium stéarate.
  4. 4. The pharmaceutical composition of any one of claims 1-3, wherein the hydroxypropyl methylcellulose is Methocel™ K15M CR or Methocel™ K100M Premium CR-
  5. 5 5. The pharmaceutical composition of any one of claims 1*4, wherein the hydroxypropyl methylcellulose is Methocel™ K15M CR, and/or wherein the silicified mtcrocrystalline cellulose is ProSolv™ HD90.
  6. 6. An extended release pharmaceutical composition comprising:
    a) 190 mgof levetiracetam;
    10 b) 300 mg of hydroxypropyl methylcellulose;
    c) 12 mg of colloïdal silicon dioxide;
    d) 102.8 mg of silicified microcrystalline cellulose;
    and
    e) 6 mg of magnésium stéarate.
    IS
  7. 7. An extended release pharmaceutical composition comprising:
    a) 190 mgof levetiracetam;
    b) 300 mg of hydroxypropyl methylcellulose;
    c) 12 mg of colloïdal siiicon dioxide;
    d) 102.8 mg of anhydrous dicaicium phosphate;
    20 and
    e) 6 mgof magnésium stéarate.
  8. 8. The pharmaceutical composition of claim 6 or 7, wherein the hydroxypropyl methylcellulose Is Methocel™ K ISM CR or Methocel™ ΚΙ00Μ Premium CR.
  9. 9. The pharmaceutical composition of any one of claims 6-7, wherein the hydroxypropyl methylcellulose is Methocel™ K15M CR and/or wherein the silicified microcrystalline cellulose is ProSolv™ HD90.
  10. 10. The pharmaceutical composition of any one ofclaims i-9, wherein the composition is formulated for once daily administration, and/or wherein the composition is formulated for one-unlt-dosage-form-once-daily administration.
  11. 11. The pharmaceutical composition ofany one ofciaims 1-10, wherein the composition is ln the form ofa tablet.
  12. 12. The pharmaceutical composition ofclaim 11, wherein the composition is formulated for one-tablet-once*daily administration.
  13. 13. The pharmaceutical composition of any one of claims 1-12, wherein the composition u formulated for oral administration, and/or wherein the composition does not comprise a hydrophobie rate controlling polymer.
  14. 14. The pharmaceutical composition ofany one ofciaims 1-12. wherein the composition does not comprise a functional coating.
  15. 15. A pharmaceutical composition of any one of claims 1—14 for use in a method of improving cognition in a subject suflering from cognitive impairment or at risk thereof.
  16. 16. The pharmaceutical composition for use of claim 15, wherein the subject sufîers from cognitive Impairment associated with a central nervous system (CNS) disorder, or at risk thereof.
  17. 17. The pharmaceutical composition for use of claim 15 or 16, wherein the cognitive impairment is associated with agc-rclatcd cognitive impairment.
  18. 18. The pharmaceutical composition for use of claim 17, wherein the age-reiated cognitive Impairment is Mild Cognitive Impairment
  19. 19. The pharmaceutical composition for use of claim 18 wherein the Miid Cognitive Impairment is amnestic Mild Cognitive Impairment
  20. 20. The pharmaceutical composition for use of claim 15 or 16, wherein the cognitive Impairment Is associated with dementia, Alzheimer’s disease, schizophrénie, amyotrophie latéral sclerosîs, post traumatîc stress disorder, cancer therapy, bipolar disorder mental retardation, Parkinson’s disease, autisrn, compulsive behavior, or substance addiction.
  21. 21. A pharmaceutical composition of any onc ofclaims 1-14 for use In a method of treating mild cognitive impairment due to Alzheimer's disease in a human subject in need thereof.
  22. 22. A pharmaceutical composition of any one of claims 1-14 for use in a method of treating amnestic mild cognitive impairment due to Alzheimer's disease in a human subject in need thereof.
  23. 23. A pharmaceutical composition ofany one ofclaims 1-14 for use in a method of slowing the progression of mild cognitive impairment due to Alzheimer's disease in a human subject in need thereof.
  24. 24. A pharmaceutical composition of any one of claims 1-14 for use in a method of slowing the progression of amnestic mild cognitive impairment due to Alzheimer's disease in a human subject in need thereof.
OA1201700446 2015-05-22 2016-05-20 Extended release pharmaceutical compositions of levetiracetam OA18467A (en)

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US15/160,424 2016-05-20

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