TOHUTUTIMULERUNTUS009750747B2 (12 ) United States Patent ( 10 ) Patent No

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TOHUTUTIMULERUNTUS009750747B2 (12 ) United States Patent ( 10 ) Patent No. : US 9 , 750 ,747 B2 Soares Da Silva ( 45 ) Date of Patent : Sep . 5, 2017

(54 ) TREATMENTS INVOLVING WO 2009 /054743 4 / 2009 Wo 2009 /082039 A1 7 /2009 ESLICARBAZEPINE ACETATE OR WO 2011 /014084 2 / 2011 (54 ) ESLICCARBAESLICARBAZEPINE WO 2011 /031176 3 / 2011 ( 75 ) Inventor: Patricio Manuel Vieira Araujo Soares WO 2012 / 091593 7 / 2012 Da Silva , São Mamede do Coronado (PT ) OTHER PUBLICATIONS Almeida et al . , Pharmacokinetics, Efficacy , and Tolerability of ( 73 ) Assignee: BAIL -PORTELA & CA , S . A . , São Eslicarbazepine Acetate in Children and Adolescents With Epilepsy , Mamede do Coronado (PT ) 2008 , J Clin Pharmacol 48 ( 8 ) : 966 - 977 . * International Search Report dated Oct. 29 , 2012 from International Application No . PCT/ PT2012 /000031 , pp . 1 - 4 . ( * ) Notice : Subject to any disclaimer , the term of this Karceski, Steven et al. Treatment of epilepsy in adults : expert patent is extended or adjusted under 35 opinion , 2005 . Science Direct, Epilepsy & Behavior 7 , 2005 , pp . U . S . C . 154 ( b ) by 0 days. S1 - S64 . Sierra -Paredes , German et al . Anticonvulsant effect of (21 ) Appl. No. : 14 /240 , 847 eslicarbazepine acetate (BIA 2 -093 ) on seizures induced by microperfusion of picrotoxin in the hippocampus of freely moving rats . Epilepsy & Behavior 72 , 2006 , pp . 140 - 163 . (22 ) PCT Filed : Aug . 24 , 2012 McCabe , Paul H . New anti -epileptic drugs for the 21st century . Expert Opinion on Pharmacotherapy, 2000 , pp . 1465 -6566 . ( 86 ) PCT No .: PCT/ PT2012 /000031 Sierra - Paredes , German et al . Effect of eslixarbazephine acetate (BIA 2 - 093 ) on latrunculin A - induced seizures and extracellular § 371 ( C ) ( 1 ) , amino acid concentrations in the rat hippocampus. Epilepsy ( 2 ), (4 ) Date : Jul. 10 , 2014 Research , 2007 , 77 , pp . 36 - 43 . Garnett , William R . Antiepileptic Drug Treatment : Outcomes and ( 87 ) PCT Pub . No . : WO2013 / 032351 Adherence . Supplement to Pharmacotherapy, 2000 , vol. 20 , No. 8 , pp . 1918 - 1995 . PCT Pub . Date : Mar. 7 , 2013 Almeida, Luis et al . Eslicarbazepine Acetate . The Treatment of Epilepsy, Chapter 38 , 3rd Edition , EDS , 2009 , pp . 485 - 498 . (65 ) Prior Publication Data Liu , Lige et al. The Mechanism of Carbamazepine Aggravation of Absence Seizures . JPET, Aug . 8 , 2006 , 319 : 1 - 38 . US 2014 /0315821 A1 Oct . 23 , 2014 Zheng , Thomas et al. Oxcarbazepine , not its active metabolite , potentiates GABAA activation and aggravates absence seizures. Related U .S . Application Data Epilepsia , 2009 , 50 ( 1) : 83 - 87 . Bialer , Meir et al . Key factors in the discovery and development of (60 ) Provisional application No .61 / 527 ,887 , filed on Aug . new antiepileptic drugs . Nature Review , Jan . 2010 , vol . 9 , pp . 68 -82 . 26 , 2011 . Ambrosio , Antonio F . et al . Inhibition of glutamate release by BIA 2 -093 and BIA 2 -024 , two novel derivatives of carbamazepine , due (51 ) Int . Cl. to blockade of sodium but not calcium channels . Biochemical A61K 31 / 55 ( 2006 .01 ) Pharmacology , 2001 (61 ) : 1271 - 1275 . A61K 31/ 195 ( 2006 .01 ) McCormack , Paul L . et al. Eslicarbazepine Acetate , Adis Drug Profile , CNS Drugs, 2009 , 23 ( 1 ) : 71 - 79 . A61K 31 /4166 ( 2006 . 01 ) Cretin , Benjamin et al . Adjunctive antiepileptic drugs in adult A6IK 31/ 4535 ( 2006 .01 ) epilepsy : how the first add -on could be last. Expert Opinion A61K 31/ 515 ( 2006 .01 ) Pharmacotherapy , 2010 , 11 ( 7 ) : 1053 - 1067 . A61K 45 /06 ( 2006 . 01 ) Mestre , Tiago et al . Eslicarbazepinee acetate: a new option for the (52 ) U .S . CI. treatment of focal epilepsy. Expert Opinion Invest . Drugs, 2009 , CPC ...... A61K 31 /55 (2013 . 01 ) ; A61K 31/ 195 18 ( 2 ) : 221 - 229 . ( 2013 . 01) ; A61K 31/ 4166 ( 2013 .01 ); A61K Gelisse, Philippe et al. Worsening of Seizures by Oxcarbazepine in 31/ 4535 (2013 . 01 ) ; A61K 31/ 515 ( 2013 .01 ) ; Juvenile Idiopathic Generalized Epilepsies . Epilepsia , 2004 , 45 ( 1) : A61K 45/ 06 (2013 . 01 ) 1282 - 1286 . (58 ) Field of Classification Search (Continued ) None See application file for complete search history . Primary Examiner — John Ulm (74 ) Attorney , Agent, or Firm — MH2 Technology Law ( 56 ) References Cited Group , LLP U . S . PATENT DOCUMENTS (57 ) ABSTRACT The invention provides a drug selected from eslicarbazepine 2010 /0297181 A1 11 / 2010 Hanada et al. acetate and eslicarbazepine , for use in treating or preventing FOREIGN PATENT DOCUMENTS a disorder selected from epilepsy, affective disorders , schizoaffective disorders , bipolar disorders , neuropathic EP 1767638 A2 3 / 2007 pain and neuropathic pain related disorders, attention disor WO 97 / 02250 1 / 1997 WO 2004 / 071152 8 / 2004 ders , anxiety disorders, sensorimotor disorders, vestibular WO 2006 / 120501 11 / 2006 disorders, and fibromyalgia , in a patient suffering from or WO 2006 / 121363 11/ 2006 susceptible to absence seizures . WO 2007 / 094694 8 / 2007 WO 2008 / 088233 7 / 2008 19 Claims, 3 Drawing Sheets US 9 , 750 ,747 B2 Page 2

References Cited Elger et al. Efficacy and safety of eslicarbazepine acetate as add -on ( 56 ) treatment in patients with partialonset seizures: pooled analysis of three double -blind phase III clinical studies , Epilepsia , 49 ( suppl. OTHER PUBLICATIONS 7 ) : 1 - 498 , 2008 , pp . 1 and 128 - 429 . Elger et al, Efficacy and safety of eslicarbazepine acetate as add -on CHMP Assessment Report for Zebinix (International treatment in adults with refractory partial - onset seizures: BIA - 2093 Nonproprietary Name: eslicarbazepine acetate Procedure No. 301 study, Epilepsia , 50 ( Suppl . 4 ) : 2 - 262, 2009 , pp . 1 and 71 . EMEA/ H /C /000988 , Feb . 19 , 2009 , pp . 1 - 80 . Fuseau et al , Population pharmacokinetics of eslicarbazepine Benes , Jan et al . 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S1 , pp . 148 - 149 . hyponatraemia secondary to carbamazepine and oxcarbazepine” , Harvey et al. , “ Relationship between eslicarbazepine exposure and Rev Neural, 2015 , vol. 61 , pp . 47 -48 with English translation ( 6 efficacy of eslicarbazepine acetate adjunctive therapy” , Epilepsy pages ) . Currents , Jan . /Feb . 2015 , vol. 15 , No. s1, p . 149 . Sperling et al. , “ Conversion to Monotherapy with Eslicarbazepine Penovich et al. , “ Relationship between eslicarbazepine exposure Acetate in Adults with Partial- Onset Seizures - Results of a North and safety endpoints for eslicarbazepine acetate adjunctive American Study ” , American Academy of Neurology 2014 Annual therapy ” , Epilepsy Currents , Jan . / Feb . 2015 , vol. 15 , No . sl , p . 150 . Meeting , Apr. 26 -May 3 , 2014 , Philadelphia , PA , 2 pages . Abou - Khalil et al. , " Eslicarbazepine acetate monotherapy : A popu Anastassopoulos et al ., “ Impact of Seizure Frequency Reduction on lation pharmacokinetic analysis ” , Epilepsy Currents , Jan ./ Feb . Health -Related Quality of Life Among Clinical Trial Subjects with 2015 , vol. 15 , No. sl , pp . 150 - 151 . Refractory Partial- Onset Seizures : A Pooled Analysis of Phase III Benbadis et al. , “ Lack of Exacerbation of partial -onset seizures Clinical Trials of Eslicarbazepine Acetate” , American Academy of during adjunctive treatment with eslicarbazepine acetate: A pooled Neurology 2014 Annual Meeting , Apr. 26 -May 3 , 2014 , Philadel analysis of three phase III controlled trials” , Epilepsy Currents , phia , PA , 3 pages . Jan . /Feb . 2015 , vol . 15 , No . sl , p . 151 US 9 , 750 ,747 B2 Page 12

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Meeting Abstract Database. AESnet .org . https: / / www .aesnet . org Juan Jose Poza - Aldea , “ A proposal for a model to replace annual _ meeting / abstracts/ copyright, Abstract 3 .273 , 2015 , 2 pages . carbamazepine or oxcarbazepine by eslicarbazepine acetate in clini Constantino et al. , “ Markers of bone turnover and lipid metabolism cal practice” , Rev Neural. , 2016 , vol. 63 , No . 5 , pp . 219 -223 with during eslicarbazepine acetate ( ESL ) monotherapy, in patients tak English abstract. ing or not taking enzyme - inducing antiepileptic drugs ( EIAEDS ) at Brigo et al. , “ A common reference -based indirect comparison baseline (BL ) ” , AES 2015 Annual Meeting Abstract Database . meta - analysis of eslicarbazepine versus lacosamide as add on AESnet .org . https: / /www .aesnet .org / annual _ meeting / abstracts/ treatments for focal epilepsy ” , Epilepsy Research , 2016 , vol. 127 , copyright, Abstract 3 .254 , 2015 , 5 pages. pp . 12 - 18 . 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6 : 6 - 5 4 3 Log (compound ] M US 9 , 750 , 747 B2 TREATMENTS INVOLVING enhanced activity at the GABA , receptor and aggravation of ESLICARBAZEPINE ACETATE OR absence seizures ( Zheng T et al, Epilepsia , 50 ( 1 ) : 83 -87 , ESLICARBAZEPINE 2009) . Given that oxcarbazepine and carbamazepine aggravate FIELD OF THE INVENTION 5 absence seizures , it was therefore expected that other mem bers of the carboxamide dibenzazepine family , such as The invention relates to new therapeutic techniques eslicarbazepine acetate should not be used to treat patients involving eslicarbazepine acetate or eslicarbazepine . who suffer from absence seizures . This is explained , for example , in the standard clinicians ' reference book “ The BACKGROUND OF THE INVENTION 10 Treatment of Epilepsy ” , 3rd edition , eds. Shorvon , Perucca & Engel , Chapter 38 ( Almeida , L et al) ( 2009 ) , which An epileptic seizure is defined as a clinical event associ- explains on page 497 that, based on the fact that eslicarba zepine acetate is structurally related to oxcarbazepine and ated with a transient, hypersynchronous neuronal discharge . carbamazepine, eslicarbazepine acetate may be expected to The seizure represents only the symptom of a potential 15 be potentially aggravating on some primary seizure types , underlying brain pathology and not the actual disease. particularly myoclonic and absence seizures . Epilepsy , in contradistinction to seizures , is a chronic dis Shorvon et al also explain at page 485 that the efficacy order characterised by recurrent seizures . Epilepsy affects spectrum of eslicarbazepine acetate is restricted to partial approximately 1 % of the population . epilepsies. Thus , there is no expectation in the art that Partial - onset seizures are a variety of epilepticpuc seizureseizure 20 eslicarbazepieslicarbazepine acetate would have any effect in treating which affect only a part of the brain at onset. The seizure primary generalized seizures , such as absence seizures and often remains localized , but may spread more widely primary generalized tonic clonic seizures . Many of the throughout the brain . Partial seizures are generally divided animal models which have historically been used to test into simple partial seizures , complex partial seizures and antiepileptogenic properties of compounds are unable to partial seizures secondarily generalised . 25 distinguish between efficacy against primary generalized In contrast, absence seizures , also known as petit mal seizures and secondary generalized seizures . Further , many seizures , are a form of generalized seizure , which affects the of the animal models may give results which are not directly whole of the brain , producing abnormal electrical activity applicable to the treatment of primary generalized seizures throughout both hemispheres and , typically, loss of con - in human patients . sciousness . Absence seizures are brief , generalized epileptic 30 Primary generalized tonic clonic seizures in particular are seizures with two characteristic features : ( 1 ) impairment of not well understood , and their mechanism differs from that consciousness (absence ) and ( 2 ) particular spike -and - slow of secondary generalized tonic clonic seizures . Thus , whilst wave discharges as measured by electroencephalography off label use of drugs licensed exclusively for treating partial ( EEG ) . The clinical manifestations of absence seizure may seizures has been reported in some secondary generalized vary significantly among patients , and their etiology is not 35 seizures, such use has not been reported in primary gener well defined or understood . Absence seizures generally alized seizures . occur more frequently in children than adults . Other variet ies of generalized seizures include tonic - clonic seizures SUMMARY OF THE INVENTION ( grand mal ) , e .g . primary generalized tonic clonic seizures, myoclonic seizures, atonic seizures, clonic seizures and 40 Eslicarbazepine acetate is metabolized in vivo in humans tonic seizures. to the active metabolite , eslicarbazepine ( ( S ) - 10 -hydroxy Eslicarbazepine acetate ( ( S ) - 10 -acetoxy - 10 , 11 - dihydro - 10 , 11 - dihydro - 5H - dibenz [ b , f | azepine - 5 -carboxamide ), with 5H -dibenz [ b , f ]azepine - 5 - carboxamide ) is a potent voltage - R -licarbazepine and OXC as minor metabolites. Details can gated sodium channel blocker described , e . g . , in WO - A - 97 / be found in “ The Treatment of Epilepsy ” , 3rd edition , eds . 02250 , WO - A - 2006 / 121363 , WO - A - 2007 /094694 , WO - A - 45 Shorvon , Perucca & Engel, Chapter 38 ( Almeida , L et al) 2008 /088233 , WO - A -2009 / 054743 , WO - A -2011 / 014084 , (2009 ) , the contents of which are incorporated herein by and WO - A - 2011 /031176 , the contents of which applications reference . are incorporated herein by reference . Eslicarbazepine Oxcarbazepine is also known to be metabolized in vivo in acetate has been approved by the European Medicines humans to eslicarbazepine and R - licarbazepine in a ratio of Agency (EMA ) for adjunctive therapy for partial -onset 50 approximately 4 : 1. seizures , with or without secondary generalization , in adults It has now surprisingly been found that , contrary to the with epilepsy. general understanding in the art , eslicarbazepine acetate and Eslicarbazepine acetate is one of several drugs in the eslicarbazepine do not in fact aggravate absence seizures . carboxamide dibenzazepine family . Other drugs in this fam Rather , they have antiepileptogenic activity in preventing or ily include oxcarbazepine ( 10 , 11 - dihydro - 10 -oxo -5H - 55 reducing the incidence of absence seizures. dibenz [ b , f ]azepine - 5 -carboxamide , OXC ) and carbam - Thus, it is a finding of the present invention that unlike azepine (5H -dibenzo [b ,f ] azepine - 5 -carboxamide , CBZ ) . oxcarbazepine and carbamazepine , eslicarbazepine is essen Drugs in the carboxamide dibenzazepine family are used tially devoid of effects upon GABA , receptor currents . It is to treat partial -onset seizures . However , drugs in this class another finding of the present invention that eslicarbazepine , are known to aggravate general seizures , specifically 60 in contrast to R -licarbazepine , oxcarbazepine and carbam absence seizures . Such aggravation of absence seizures is azepine, effectively inhibits high and low affinity inward mediated via enhanced activity at the gamma amino butyric currents in T - type calcium channels . Transcriptional induc acid (GABAA ) receptor. Thus, Liu et al (J Pharmacol Exp t ion of T- type calcium channels is a critical step in epilep Ther 319 :790 -798 ) explains that the activity of carbam - togenesis and neuronal vulnerability , so this finding dem azepine in aggravating absence seizures arises from the 65 onstrates that eslicarbazepine and eslicarbazepine acetate activity of the drug in enhancing activity at the GABA will have antiepileptogenic effects and will be effective in receptor. Similarly , oxcarbazepine has also been linked with preventing or reducing the incidence of absence seizures . US 9 , 750 , 747 B2 Advantageously , therefore , the findings of the present bamazepine (CBZ ), bicucculine and midazolam in Ltk cells invention allow treatment of epilepsy , affective disorders, using a whole - cell patch - clamp technique . schizoaffective disorders , bipolar disorders , neuropathic FIG . 2 shows representative current traces for eslicarba pain and neuropathic pain related disorders , attention disor- zepine, R - licarbazepine , oxcarbazepine (OXC ) and carbam ders , anxiety disorders , sensorimotor disorders , vestibular 5 azepine (CBZ ) and mibefradil at the high affinity ( top ) and disorders , and fibromyalgia with eslicarbazepine or eslicar - low affinity (bottom ) binding sites for hCa 3 .2 calcium bazepine acetate in patients susceptible to absence seizures . channels stably expressed in HEK cells using a whole -cell The epilepsy is typically partial onset seizures . patch -clamp technique . In a first embodiment, the present invention therefore F IG . 3 shows Inhibition dose -response curves for the provides a drug selected from eslicarbazepine acetate and blockade of hCa 3 . 2 currents by eslicarbazepine , R - licarba eslicarbazepine , for use in treating or preventing a disorder zepine , CBZ , OXC and mibefradil in HEK cells using a selected from epilepsy such as partialonset seizures , affec whole -cell patch - clamp technique. tive disorders , schizoaffective disorders , bipolar disorders , neuropathic pain and neuropathic pain related disorders, 15 . DETAILED DESCRIPTION OF THE attention disorders, anxiety disorders , sensorimotor disor INVENTION ders , vestibular disorders , and fibromyalgia , in a patient suffering from or susceptible to absence seizures. As used herein , the words “ treatment” and “ treating ” are In a second embodiment, the present invention provides a to be understood as embracing treatment and /or amelioration pharmaceutical composition for use in treating or preventing 20 and /or prevention of or reduction in aggravation /worsening a disorder as defined herein , in a patient as defined herein , of symptoms of a disease or condition as well as treatment which pharmaceutical composition comprises a pharmaceu - of the cause of the disease or condition , and may include tically acceptable carrier and , as active principle , a drug as reversing , reducing, or arresting the symptoms, clinical defined herein . signs , and underlying pathology of a condition in manner to In a third embodiment, the present invention provides use 25 improve or stabilise a subject' s condition . of a drug as defined herein , or a pharmaceutical composition Reference to " prevention ” and “ preventing ” a disease as defined herein , in the manufacture of a medicament for embraces prophylaxis and / or inhibition of the disease . The use in treating or preventing a disorder as defined herein , in term " preventing ” is art -recognized , and when used in a patient as defined herein . relation to a condition , such as a local recurrence ( e . g . , pain ), In a fourth embodiment, the present invention provides a 30 a disease such as cancer , a syndrome complex such as method of treating or preventing a disorder as defined epilepsy or pain or any other medical condition , is well herein , in a patient as defined herein , which method com understood in the art , and includes administration of a prises administering to said patient a safe and effective composition which reduces the frequency of, or delays the amount of a drug as defined herein , or a pharmaceutical composition as defined herein . onset of, symptoms of a medical condition in a subject In a fifth embodiment, the present invention provides a relative to a subject which does not receive the composition . method of treating or preventing a disorder as defined Thus , prevention of epilepsy includes , for example , delaying herein , which method comprises ( a ) selecting a patient as the onset or reducing the number incidence ) , frequency , defined herein , and (b ) administering to said patient a safe severity or duration of seizures, such as absence or partial and effective amount of a drug as definedfined herein ,. or a 4040 onsetof seizures, in a population of patients receiving a pro pharmaceutical composition as defined herein . phylactic treatment relative to a control population untreated In a sixth embodiment, the present invention provides a with eslicarbazepine or eslicarbazepine acetate , e . g ., by a drug selected from eslicarbazepine acetate and eslicarba - statistically and / or clinically significant amount. Prevention zepine , for use in treating or preventing , such as delaying the of pain , such as fibromyalgia , neuropathic pain or neuro onset or reducing the incidence , severity or duration of 45 pathic pain related disorders includes, for example , reducing absence seizures . the magnitude of, or alternatively delaying , pain sensations In a seventh embodiment, the present invention provides experienced by subjects in a treated population versus a a pharmaceutical composition for use in preventing or control population untreated with eslicarbazepine or eslicar reducing the incidence of absence seizures , which pharma - bazepine acetate. Prevention of bipolar disorders includes , ceutical composition comprises a pharmaceutically accept- 50 for example , reducing the number of manic , hypomanic , able carrier and , as active principle , a drug as defined herein . cyclothymic , psychotic or depressive episodes in a treated In an eighth embodiment , the present invention provides population versus a control population untreated with esli use of a drug as defined herein , or a pharmaceutical com - carbazepine or eslicarbazepine acetate . position as defined herein , in the manufacture of a medica Typically , the patient is a human patient. ment for use in preventing or reducing the incidence of 55 Affective disorders include depression , pre -menstrual absence seizures. dysphoric disorder, post -partum depression , post -meno In a ninth embodiment, the present invention provides a pausal depression , anorexia nervosa, bulimia nervosa , and method of preventing or reducing the incidence of absence neurodegeneration - related depressive symptoms. seizures in a patient, which method comprises administering Schizoaffective disorders include schizodepressive syn to said patient a safe and effective amount of a drug as 60 dromes , schizophrenia , extreme psychotic states , schizom defined herein , or a pharmaceutical composition as defined anic syndromes, dysphoric and aggressive behavior, epi herein . sodic dyscontrol or intermittent explosive disorder, and borderline personality disorder. DESCRIPTION OF THE FIGURES Bipolar disorders include bipolar disorder and unstable 65 bipolar disorder with rapid fluctuations ( rapid cyclers ), FIG . 1 shows representative current traces at alß2y2 manic - depressive disorders , acute mania , mood episodes , GABA receptors for eslicarbazepine , R - licarbazepine , car - and manic and hypomanic episodes. US 9 ,750 ,747 B2 Attention disorders include attention deficit hyperactivity years old , preferably under about 18 years old , more pref disorders (attention deficit disorders ) and other attention erably under about 17 years old , even more preferably under disorders such as autism . about 16 years old , even more preferably under about 15 Anxiety disorders include conditions social anxiety dis years old , even more preferably under about 14 years old , for orders , post - traumatic stress disorder , panic , obsessive -com - 5 example , from about 2 to about 13 years old , from about 9 pulsive disorder , alcoholism , drug withdrawal syndromes , to about 13 years old , from about 10 to about 15 years old , and cravings . from about 4 to about 8 years old , or from about 5 to about Neuropathic pain and neuropathic pain -related disorders 7 years old . Thus, typically , the patient has not yet reached are described in . WO - A - 2007094694 and include neuro - puberty . pathic pain and associated hyperalgesia , including trigemi- 10 Patients susceptible to absence seizures will typically nal , herpetic , post -herpetic and tabetic neuralgia , diabetic have been diagnosed as suffering from absence seizures. neuropathic pain , migraines , tension - type headaches, Patients susceptible to absence seizure will more typically causalgia , and deafferentation syndromes such as brachial have previously suffered from at least one seizure such as an plexus avulsion . absence seizure , myclonic seizure or tonic - clonic seizure , Sensorimotor disorders include restless legs syndrome, 15 preferably an absence seizure . spasticity , hemifacial spasm , nocturnal paroxysmal dysto - Patients susceptible to absence seizures may have a nia , brain ischemia associated motor and sensitive deficits , family history of epilepsy and / or may already have experi Parkinson ' s disease and parkinsonian disorders, antipsy - enced other seizures types prior to experiencing absence chotic - induced motor deficits, tardive dyskinesia , episodic seizures, for example generalized tonic -clonic seizures nocturnal wandering , and myotonia . 20 (which may often be experienced on awakening ) or myo Vestibular disorders include tinnitus or other inner ear / clonic seizures. Thus, typically , the patient has a family cochlear excitability related diseases, such as neuronal loss , history of epilepsy . Therefore patients susceptible to absence hearing loss , sudden deafness, vertigo , and Meniere ' s dis seizures , and in particular atypical absence seizures , may ease . show interictal abnormalities on electro - encephalogram Fibromyalgia is a well- known disorder , and is described 25 (EEG ), and may have previously experienced multiple types in , for example , WO - A -2011 / 014084 . of seizure , and may show cognitive abnormalities or mental Typically , the disorder is epilepsy, particularly partial retardation . onset seizures. Partial- onset seizures are a well -known dis - Particular genetic abnormalities may be present in order typically associated with epilepsy . Partial seizures may patients susceptible to absence seizures , for example , the also be referred to as focal or localized seizures . Partial 30 y -aminobutyric acid (GABA ) , receptor y - 2 subunit mutation seizures include simple partial seizures and complex partial R43Q . Thus, typically, the patient has the R430 mutation in seizures. Partial- onset seizures may present with or without the y - aminobutyric acid (GABA ) , receptor y - 2 subunit . secondary generalization . Patients susceptible to absence seizures may or may not be Typically , the disorder is partial onset seizure, neuropathic photosensitive . pain , a neuropathic pain -related disorder or fibromyalgia . 35 Idiopathic generalized epilepsies which present with Typically, the drug is eslicarbazepine acetate . absence seizures include childhood (or infantile ) absence Preferably , the drug is eslicarbazepine acetate , and the epilepsy , juvenile absence epilepsy , myoclonic absence epi disorder is partialonset seizures. lepsy, juvenile myoclonic epilepsy and Lennox -Gastaut syn Absence seizures are a well -known type of seizure, more drome. Other proposed generalized epilepsies associated commonly occurring in females. Typically , therefore, the 40 with absence seizures include perioral myoclonus with patient is female . Absence seizures are generally divided absences , Jeavons syndrome ( eyelid myoclonus with into typical and atypical absence seizures . absences ) and idiopathic generalised epilepsy with phantom Typical absence seizures usually occur in patients having absences . Thus , typically , the patient is suffering from or idiopathic generalised epilepsies and an EEG of patients susceptible to childhood absence epilepsy, juvenile absence having typical absence seizures shows fast > 2 . 5 Hz gener - 45 epilepsy , myoclonic absence epilepsy , juvenile myoclonic alised spike -wave discharges, for example greater than epilepsy , Lennox -Gastaut syndrome, perioral myoclonus about 3 Hz . Cognitive impairment is not often seen with with absences, Jeavons syndrome or idiopathic generalised typical absence seizures. epilepsy with phantom absences. Preferably, the patient is Atypical absence seizures typically occur only in children suffering from or susceptible to childhood absence epilepsy, suffering from severe symptomatic or cryptogenic epilep - 50 juvenile absence epilepsy , myoclonic absence epilepsy , sies, who usually also present with learning difficulties. Such juvenile myoclonic epilepsy or Lennox -Gastaut syndrome. patients typically also suffer from frequent seizures of other Primary generalized tonic clonic seizures are a well types such as atonic , tonic and myoclonic . Onset and ter - known type of seizure , which like absence seizures affect the mination of an atypical absence seizure is not so abrupt as whole brain . Primary generalized tonic clonic seizures in typical absence seizures, and changes in tone are more 55 involve two phases , the tonic phase and the clonic phase . In pronounced . EEG of patients having atypical absence sei- the tonic phase , patients typically display a rigid contracture Zures usually shows slow < 2 . 5 Hz spike and slow wave of muscles , including respiratory muscles. The tonic phase patterns, for example from about 1 to about 2 Hz. The is usually brief. In the clonic phase, patients typically discharge experienced in an atypical seizure is heteroge - display rhythmic shaking . The clonic phase is usually longer neous , often asymmetrical and may include irregular spike 60 than the tonic phase . Together, a generalized tonic clonic and slow wave complexes , fast and other paroxysmal activ seizure is also called a grand mat seizure . ity . Background interictal EEG is usually abnormal. Primary generalized tonic clonic seizures are idiopathic , Children and adolescents are more susceptible to absence i . e . they occur without any apparent cause and are typically seizures than adults . Many children who suffer from absence not preceded by a partial seizure . Primary generalized tonic seizures grow out of them as they get older . Typically , 65 clonic seizures may present on awakening . therefore , the patient susceptible to absence seizures is a The drugs for use in the present invention may be admin child or adolescent. Typically , the patient is under about 20 istered as monotherapy treatment for the indication or with US 9 , 750 , 747 B2 other drug ( s ) as adjunct therapy for the indication , as zepine acetate and eslicarbazepine for part of one of these described in more detail below . In the case of adjunct drugs, an antiepileptic effect may still be achieved without therapy , the drugs for use in the present invention may be aggravating absence seizures. administered simultaneously or sequentially with the other Eslicarbazepine acetate and eslicarbazepine may also be drug (s ) , for example in fixed dose combination or in separate 5 used in combination with another drug (adjunct therapy ) doses . which is effective against epilepsy such as partialonset isteredThe drugsby any for suitable use in theroute present to provide invention a therapeutic may be admin effect - seizures, affective disorders , schizoaffective disorders , bipo against partial -onset seizures , neuropathic pain or fibro lar disorders , neuropathic pain and neuropathic pain related myalgia . Thus , they can be administered orally , for example 10 disorders, attention disorders , anxiety disorders, sensorimo as tablets , capsules , caplets , troches, lozenges , aqueous or tor disorders, vestibular disorders, and fibromyalgia . Such oily suspensions, dispersible powders or granules. The drugs drugs will be well known to the skilled person . In the case may also be administered parenterally, whether subcutane of epilepsy ( such as partial onset seizure ), clorazepate , ously , intravenously , intramuscularly , intrasternally , trans clonazepam , ethosuximide , felbamate , fosphenytoin , lacos dermally or by infusion techniques. The drugs may alsoIso behe 15is amideam , lamotrigine, levetiracetam , primidone, topiramate , administered as suppositories . valproate semisodium , valproic acid , and zonisamide are all Typically, the drugs are for oral administration . approved by the FDA , for treating epilepsy , but are not In one embodiment, the drugs are administered as a tablet counterindicated against absence seizures . However, eslicar In another embodiment, the drugs are administered as a bazepine acetate and eslicarbazepine may also be adminis suspension . This embodiment is explained further in WO - A - 20 tered as monotherapy for the indication . 2011/ 031176 , the content of which is incorporated herein by In a second embodiment, the present invention provides a reference . pharmaceutical composition for use in treating or preventing In a further embodiment, the drugs are administered as a a disorder as defined herein , in a patient as defined herein , granule or sprinkle formulation . This embodiment is which pharmaceutical composition comprises a pharmaceu explained further in WO - A - 2012 /091593 , the content of 25 tically acceptable carrier and as active principle , a drug as which is incorporated herein by reference . defined herein . The drugs for use in the present invention may be admin - Said pharmaceutical composition typically contains at istered once a day , or more than once a day , for example two , least 50 wt % of a drug as defined herein . More typically , it three or four times a day. Typically , the drugs are for once contains at least 80 wt % of a drug as defined herein . daily administration . This is explained further in WO - A - 30 Preferred pharmaceutical compositions are sterile and pyro 2006 / 121363 , the content of which is incorporated herein by gen free . reference . Eslicarbazepine acetate and eslicarbazepine are typically Dosages will vary depending on , e . g ., the individual, the formulated for administration with a pharmaceutically mode and frequency of administration , and the nature and acceptable carrier or diluent. For example , solid oral forms severity of the condition to be treated . A clinician having 35 may contain , together with the active compound , diluents , ordinary skill in the art can readily determine and prescribe e . g . lactose , dextrose, saccharose , cellulose , corn starch or the effective amount required . potato starch ; lubricants , e. g . silica, talc , stearic acid , mag Typical doses for a patient will range from 1 mg per nesium or calcium stearate , and / or polyethylene glycols ; kilogram to 50 mg per kilogram of body weight per day , binding agents ; e . g . starches, arabic gums, gelatin , methyl preferably 5 mg per kilogram to 45 mg per kilogram of body 40 cellulose , povidone , carboxymethylcellulose or polyvinyl weight per day , more preferably 10 mg per kilogram to 40 pyrrolidone ; disaggregating agents , e . g. starch , alginic acid , mg per kilogram of body weight per day, even more pref- alginates , croscarmellose soldium or sodium starch glyco erably 5 , 10 , 15 , 20 , 25 or 30 mg per kilogram of body late ; effervescing mixtures; dyestuffs ; sweeteners ; wetting weight per day . A typical daily oral dose of the drugs is from agents , such as lecithin , polysorbates , laurylsulphates ; and , 100 mg to 1 . 200 mg per day , preferably from 200 mg to 800 45 in general, non toxic and pharmacologically inactive sub mg per day, more preferably from 400 to 600 mg per day. stances used in pharmaceutical formulations. Such pharma EMA approved dosages of eslicarbazepine acetate for ceutical preparations may be manufactured in any known adjunctive therapy for partialonset seizures , with or without manner , for example , by means of mixing , granulating , secondary generalisation , in adults with epilepsy are 400 tableting , sugar coating , or film coating processes. mg, 800 mg , or 1200 mg daily . 50 Liquid dispersions for oral administration may be syrups , Eslicarbazepine acetate and eslicarbazepine are particu - emulsions and suspensions. The syrups may contain as larly effective adjuncts for use with other drugs . The findings carriers , for example , saccharose or saccharose with glyc of the present invention mean that eslicarbazepine acetate erine and / or mannitol and / or sorbitol. and eslicarbazepine are particularly advantageous for use in Suspensions and emulsions may contain as carrier, for treating or preventing a disorder selected from epilepsy such 55 example a natural gum , xanthan gum , agar, sodium alginate , as partial -onset seizures, affective disorders , schizoaffective pectin , methylcellulose , carboxymethylcellulose , or polyvi disorders, bipolar disorders, neuropathic pain and neuro - nyl alcohol. The suspension or solutions for intramuscular pathic pain related disorders , attention disorders , anxiety injections may contain , together with the active compound , disorders, sensorimotor disorders , vestibular disorders , and a pharmaceutically acceptable carrier , e .g . sterile water, fibromyalgia in a patient susceptible to absence seizures who 60 olive oil, ethyl oleate , glycols , e . g . propylene glycol, a is being treated with a drug which may cause or aggravate wetting agent, for example polyoxyethylene stearate, an their absence seizures . Thus, for example , in the case of antimicrobial agent, such as methylparaben or propylpara epilepsy (such as partial onset seizure ), a patient may be ben , and if desired , a suitable amount of lidocaine hydro receiving a second antiepileptic drug which may cause or chloride . aggravate absence seizures, for example carbamazepine , 65 Solutions for injection or infusion may contain as a oxcarbazepine , vigabatrin , tiagabine , phenytoin , phenobar- carrier, for example , sterile water or preferably they may be bital, gabapentin , or pregabalin . By substituting eslicarba - in the form of sterile , aqueous, isotonic saline solutions. US 9 , 750 , 747 B2 10 Typically , the pharmaceutical composition is in the form affective disorders, schizoaffective disorders, bipolar disor of a tablet, granule ( sprinkle ) formulation ( i. e . for sprinkling ders, neuropathic pain and neuropathic pain related disor on food ) or suspension . Suitable suspensions are described ders , attention disorders , anxiety disorders , sensorimotor in WO - A - 2011031176 . disorders, vestibular disorders, and fibromyalgia . In the case In a third embodiment, the present invention provides use 5 of epilepsy , the additional medicament is typically chosen of a drug as defined herein , or a pharmaceutical composition from clorazepate , clonazepam , ethosuximide , felbamate , as defined herein , in the manufacture of a medicament for fosphenytoin , lacosamide , lamotrigine, levetiracetam , use in treating or preventing a disorder as defined herein , in primidone , topiramate , valproate semisodium , valproic acid , a patient as defined herein . and zonisamide . However, the drug may also be adminis Typically , in this embodiment , the medicament is for 10 tered as monotherapy for the indication . coadministration with a second drug which may cause or As discussed above, eslicarbazepine acetate and eslicar aggravate absence seizures , for example carbamazepine , bazepine have advantageous antiepileptogenic properties oxcarbazepine , vigabatrin , tiagabine , phenytoin , phenobar - which make them effective in preventing or reducing the bital , gabapentin , or pregabalin . incidence of absence seizures . Typically , in this embodiment, the medicament is for 15 In a sixth embodiment, therefore , the present invention coadministration with one or more additional medications provides a drug selected from eslicarbazepine acetate and ( adjunct therapy ) for treatment of epilepsy such as partial eslicarbazepine , for use in preventing or reducing the inci onset seizures, affective disorders , schizoaffective disorders , dence of absence seizures. Typically the drug provides bipolar disorders , neuropathic pain and neuropathic pain control of absence seizures , even when complicated by other related disorders , attention disorders , anxiety disorders , sen - 20 seizure types , for example by reducing the frequency and / or sorimotor disorders , vestibular disorders , and fibromyalgia . severity of absence seizures. In the case of epilepsy ( such as partial onset seizure ) , the Typically , the drug is eslicarbazepine acetate. additional medicament is typically chosen from clorazepate , Typically , the drug is for use in treating a patient who is clonazepam , ethosuximide , felbamate , fosphenytoin , lacos - suffering from or susceptible to absence seizures, as defined amide , lamotrigine, levetiracetam , primidone, topiramate , 25 herein . valproate semisodium , valproic acid , and zonisamide . How - Typical dosages of the drug are as defined above . ever , the medicament may also be administered as mono Typically, in this embodiment, the drug is for coadmin therapy for the indication . istration with one or more additional medications ( adjunct In a fourth embodiment, the present invention provides a therapy for treatment of absence seizures . Such medications method of treating or preventing a disorder as defined 30 are well -known to the skilled person , and include sodium herein , in a patient as defined herein , which method com - valproate , valproic acid , ethosuximide and lamotrigine . prises administering to said patient a safe and effective However , the drug may also be administered as mono amount of a drug as defined herein , or a pharmaceutical therapy for the indication . composition as defined herein . In a seventh embodiment, the present invention provides Typically , in this embodiment, the drug is coadministered 35 a pharmaceutical composition for use in preventing or with a second drug which may cause or aggravate absence reducing the incidence of absence seizures , which pharma seizures, for example carbamazepine , oxcarbazepine , ceutical composition comprises a pharmaceutically accept vigabatrin , tiagabine , phenytoin , phenobarbital , gabapentin , able carrier and , as active principle , a drug as defined herein . or pregabalin . Typical pharmaceutical compositions and pharmaceuti Typically , in this embodiment, the drug is coadministered 40 cally acceptable carriers are as defined herein . with one or more additional medications ( adjunct therapy ) In an eighth embodiment , the present invention provides for treatment of epilepsy such as partial - onset seizures , use of a drug as defined herein , or a pharmaceutical com affective disorders , schizoaffective disorders, bipolar disor- position as defined herein , in the manufacture of a medica ders, neuropathic pain and neuropathic pain related disor- ment for use in preventing or reducing the incidence of ders , attention disorders , anxiety disorders , sensorimotor 45 absence seizures . disorders, vestibular disorders , and fibromyalgia . In the case Typically , the medicament is for use in preventing or of epilepsy ( such as partial onset seizure ), the additional reducing the incidence of absence seizures in a patient who medicament is typically chosen from clorazepate , clonaze - is suffering from or susceptible to absence seizures , as pam , ethosuximide , felbamate , fosphenytoin , lacosamide , defined herein . lamotrigine , levetiracetam , primidone , topiramate , valproate 50 Typically in this embodiment, the medicament is for semisodium , valproic acid , and zonisamide . However , the coadministration with one or more additional medications drug may also be administered as monotherapy for the (adjunct therapy ) for treatment of absence seizures, as indication . defined herein . However , the medicament may also be In a fifth embodiment, the present invention provides a administered as monotherapy for the indication . method of treating or preventing a disorder as defined 55 In a ninth embodiment, the present invention provides a herein , which method comprises ( a ) selecting a patient as method of preventing or reducing the incidence of absence defined herein , and ( b ) administering to said patient a safe seizures in a patient , which method comprises administering and effective amount of a drug as defined herein , or a to said patient a safe and effective amount of a drug as pharmaceutical composition as defined herein . defined herein , or a pharmaceutical composition as defined Typically , in this embodiment, the drug is coadministered 60 herein . with a second drug which may cause or aggravate absence Typically , the patient is a patient suffering from or sus seizures , for example carbamazepine , oxcarbazepine , ceptible to absence seizures , as defined herein . vigabatrin , tiagabine , phenytoin , phenobarbital , gabapentin , Typically in this embodiment, the drug is coadministered or pregabalin . with one or more additional medications (adjunct therapy ) Typically , in this embodiment, the drug is coadministered 65 for treatment of absence seizures, as defined herein . How with one or more additional medications ( adjunct therapy ) ever, the drug may also be administered as monotherapy for for treatment of epilepsy such as partialonset seizures, the indication . US 9 , 750 , 747 B2 12 The antiepileptogenic properties of eslicarbazepine In a fourteenth embodiment the present invention pro acetate and eslicarbazepine also make them effective in vides a drug selected from eslicarbazepine acetate and preventing or reducing the incidence of primary generalized eslicarbazepine , for use in preventing or reducing the inci tonic clonic seizures . dence of both absence seizures and primary generalized In a tenth embodiment the present invention provides a 5 tonic clonic seizures . drug selected from eslicarbazepine acetate and eslicarba - Typically the drug provides control of both absence zepine, for use in preventing or reducing the incidence of seizures and primary generalized tonic clonic seizures, even when complicated by other seizure types, for example by primary generalized tonic clonic seizures. reducing the frequency and /or severity of absence seizures Typically the drug provides control of primary generalOr 10 and /or primary generalized tonic clonic seizures . ized tonic clonic seizures, even when complicated by other Typically , the drug is eslicarbazepine acetate. seizure types , for example by reducing the frequency and /or Typically , the drug is for use in treating a patient who is severity of primary generalized tonic clonic seizures. suffering from or susceptible to absence seizures and / or Typically , the drug is eslicarbazepine acetate . primary generalized tonic clonic seizures , as defined herein . typicallyTypically , the drug is for use in treatingtreating a patient who is 1515 . TupicalTypical dosages ofof the drug are as defined above . suffering from or susceptible to primary generalized tonic Typically , in this embodiment, the drug is for coadmin clonic seizures , as defined herein . istration with one or more additional medications ( adjunct Typical dosages of the drug are as defined above. therapy ) for treatment of absence seizures and / or primary Typically , in this embodiment, the drug is for coadmin generalized tonic clonic seizures. Such medications are istration with one or more additional medications (adjunct 20 well -known to the skilled person , and include sodium val therapy ) for treatment of primary generalized tonic clonic proate , valproic acid , ethosuximide , lamotrigine , topiramate , seizures. Such medications are well -known to the skilled zonisamide, levetiracetam and rufinamide . Preferably agents person , and include sodium valproate , valproic acid , etho - for coadministration are sodium valproate , valproic acid , suximide, lamotrigine , topiramate , zonisamide , levetirac - ethosuximide and lamotrigine. However, the drug may also etam and rufinamide . Preferably agents for coadministration 25 be administered as monotherapy for the indication . are sodium valproate , valproic acid , ethosuximide and lam - In a fifteenth embodiment, the present invention provides otrigine. However , the drug may also be administered as a pharmaceutical composition for use in preventing or monotherapy for the indication . reducing the incidence of both absence seizures and primary In an eleventh embodiment , the present invention pro - generalized tonic clonic seizures , which pharmaceutical vides a pharmaceutical composition for use in preventing or 30 composition comprises a pharmaceutically acceptable car reducing the incidence of primary generalized tonic clonic rier and , as active principle , a drug as defined herein . seizures, which pharmaceutical composition comprises a Typical pharmaceutical compositions and pharmaceuti pharmaceutically acceptable carrier and , as active principle , cally acceptable carriers are as defined herein . a drug as defined herein . In a sixteenth embodiment, the present invention provides Typical pharmaceutical compositions and pharmaceuti - 35 use of a drug as defined herein , or a pharmaceutical com cally acceptable carriers are as defined herein . position as defined herein , in the manufacture of a medica In a twelfth embodiment, the present invention provides ment for use in preventing or reducing the incidence of both use of a drug as defined herein , or a pharmaceutical com absence seizures and primary generalized tonic clonic sei position as defined herein , in the manufacture of a medica - zures . ment for use in preventing or reducing the incidence of 40 Typically , the medicament is for use in preventing or primary generalized tonic clonic seizures. reducing the incidence of absence seizures and /or primary Typically , the medicament is for use in preventing or generalized tonic clonic seizures in a patient who is suffering reducing the incidence of primary generalized tonic clonic from or susceptible to absence seizures and / or primary seizures in a patient who is suffering from or susceptible to generalized tonic clonic seizures, as defined herein . primary generalized tonic clonic seizures , as defined herein . 45 Typically in this embodiment, the medicament is for Typically in this embodiment, the medicament is for coadministration with one or more additional medications coadministration with one or more additional medications (adjunct therapy ) for treatment of absence seizures and /or ( adjunct therapy ) for treatment of primary generalized tonic primary generalized tonic clonic seizures , as defined herein . clonic seizures , as defined herein . However, the medicament However , the medicament may also be administered as may also be administered as monotherapy for the indication . 50 monotherapy for the indication . In a thirteenth embodiment, the present invention pro - In a seventeenth embodiment, the present invention pro vides a method of preventing or reducing the incidence of vides a method of preventing or reducing the incidence of primary generalized tonic clonic seizures , in a patient , which both absence seizures and primary generalized tonic clonic method comprises administering to said patient a safe and seizures, in a patient , which method comprises administer effective amount of a drug as defined herein , or a pharma - 55 ing to said patient a safe and effective amount of a drug as ceutical composition as defined herein . defined herein , or a pharmaceutical composition as defined Typically , the patient is a patient suffering from or sus herein . ceptible to primary generalized tonic clonic seizures, as Typically , the patient is a patient suffering from or sus defined herein . ceptible to absence seizures and / or primary generalized Typically in this embodiment, the drug is coadministered 60 tonic clonic seizures , as defined herein . with one or more additional medications (adjunct therapy ) Typically in this embodiment, the drug is coadministered for treatment of primary generalized tonic clonic seizures , as with one or more additional medications (adjunct therapy ) defined herein . However, the drug may also be administered for treatment of absence seizures and /or primary generalized as monotherapy for the indication . tonic clonic seizures, as defined herein . However , the drug The treatments described herein are also effective in 65 may also be administered as monotherapy for the indication . treating patients who are suffering from both absence sei The following non - limiting Examples illustrate the inven zures and primary generalized tonic clonic seizures . tion . US 9 , 750 , 747 B2 13 14 EXAMPLES in medium without antibiotics or antimycotics . Cells were tested 24 -48 hours following induction of transgene expres Example 1 sion with dexamethasone . Cells were continuously perfused with bath solution Carbamazepine (CBZ ) aggravates absence seizures in 5 (NaCl 137 mM , KCl 4 mM , CaCl, 1 . 8 mM , MgCl , 1 mM , ‘ generalized absence epilepsy rats from . Strasbourg' . One D -Glucose 10 mM HEPES 10 mM , pH 7 . 4 ) . The whole - cell putative mechanism for the aggravation is through its patch clamp recordings from transfected Ltk cells (voltage reported potentiation of GABA , currents . A study was clamped at a holding potential of - 80 mV) were made using carried out to determine the effect of eslicarbazepine , R -li - a EPC - 7 , HEKA Electronics amplifier. GABA inward -cur carbazepine and carbamazepine on sub - maximal GABA 10 rents were measured upon application of 1 or 2 uM GABA currents in Ltk cells stably expressing alß2y2, c2ß2y2 , to patch - clamped cells (at an EC5 ) . Eslicarbazepine, R - li a3b2y2 or a5B2y2 GABA - receptors. The whole - cell patch carbazepine , carbamazepine , midazolam (positive allosteric clamp technique was used to investigate the effects of the modulator of the GABA , receptor ) or bicuculline (negative test compounds on GABAA receptors. allosteric modulator of the GABA , receptor) were applied Used Ltk cells were stably transfected with recombinant 15 by perfusion with GABA . GABA , cDNAs: alß2y2 , a2ß2y2 , a3b2y2 or a5b2y2 SigmaPlot 8 .02 was used to calculate the means : SEM of ( B 'SYS GmbH , Switzerland ) . Cells were maintained in a relative peak ' current blockade for each test item . Analysis of humidified atmosphere (95 % relative humidity ) with 5 % Variance (ANOVA ) with post test multisample comparison CO2 and were grown in D -MEM / F - 12 (1x , liquid , with (Dunnett ) was conducted with GraphPad Prism 4 Software. GlutaMax 1 ) supplemented with 9 % foetal bovine serum 20 The effect of eslicarbazepine and R - licarbazepine on and 0 . 9 % Penicillin / Streptomycin solution (Gibco BRL ) . GABA inward current stimulation measured on Ltk cells For the electrophysiological experiments cells were culti stably transfected with alß2y2 , a2B2y2 , a3B2y2 or a5b2y2 vated , at a density that enabled single cells to be measured , GABA receptors is shown in the following table . TABLE 1 Current stimulation ( % alß2y2 Q2B2y2 A3B2y2 a58292

Compound (UM ) Mean SEM ? Mean SEM n Mean SEM n Mean SEM n | Vehicle 108 . 11 + 3 . 40 96 . 95 + 1 . 275 101 . 25 1 . 92 5 95 . 40 + 0 . 53 Eslicarbazepine 50 103. 3 + 1 . 96 ??? 91 . 58 + 2 .695 95 .61 1 4 .75 5 oho 95 . 18 + 2 . 18 100 95 .92 + 0 .83 97 .04 + 2 .65 97 . 93 + 4 . 22 oh 93 . 89 + 0 . 60 250 97 . 82 + 1 .13 ???? 88 . 56 + 3 . 24 * * 96 .44 + 2 . 16 93 . 52 + 1 . 75 500 99 . 39 + 0 . 80 89 . 80 + 4 .01 91. 63 + 5 . 56 oh 89 .65 + 3 . 44

R -Licarbazepine 50 99 . 85 + 1 . 18 ???? 96 . 48 + 2 . 11 99 .53 = 2 .65 h 96 . 13 + 0 . 57

100 92 .53 + 4 .53 97 .03 = 2 . 27 100 .38 + 1 . 56 ? 94 . 09 + 1. 27 250 ? 91 .73 + 4 .69 ?? 93 .79 + 3 . 09 102. 94 + 3. 34 97 .24 + 1. 58 500 95 . 83 + 6 .63 87 . 75 + 1 .94 * 97 . 35 + 2 .91 ? 92 . 25 + 1 . 29 Midazolam 184 .81 + 32 .93 * na na na ?? ? uuuuuuuuuu Bicucculline na 27 .85 + 3 . 21 34. 16 + 3 .995 39 .65 + 4 . 34 5 Vehicle was 0 . 2 % DMSO for alß2y2 and 0 . 4 % for all the other GABA receptors . * Significantly different from vehicle ( P < 0 .01 ) . uuuuuuuuuu * * Significantly different from vehicle (P < 0 .05 ) The effect of carbamazepine and bicucculline on GABA 45 inward current stimulation measured on Ltk cells stably transfected with alß2y2 , a2B2y2 , a3b2y2 or a5B2y2 GABA receptors is shown in the following table . TABLE 2 Current stimulation ( % ) alß2y2 a2B2y2 __ a3B2y2 a58242 Compound (UM ) Mean + SEM n Mean + SEM Ó Mean + SEM n Mean + SEM n 1 1 Vehicle 96 . 19 = 3 . 71 11 97 .58 3 .59 10 100 . 29 + 5 .92 o 95 . 25 + 4 .61 o Carbamazepine 50 104 . 30 5 . 02 97 .94 + 3 . 34 5 93. 32 + 4 . 07 o 103 .82 + 1 . 50 o 100 117 . 38 + 4 . 94 111. 36 + 2 . 65 112 . 76 5 . 40 o 103. 83 + 4 . 53 o 250 115 . 68 + 5 .31 109 .03 + 7 .61 131. 06 + 9 . 39 o 93 . 59 + 4 . 30 o 500 132 .42 + 5 . 31 * 103 .60 + 7 .61 120 . 27 + 11 .81 o 80 . 65 + 5 . 86 o 1000 150 . 26 + 15 . 48 * 104 . 18 2 .66 166 .66 21. 00 * 63. 01 + 4 . 50 * Bicuccullin 0 . 1 70 .48 = 3 . 19 * * 62 . 71 + 2 .57 * 66 . 06 + 3 .05 60 . 16 + 3 . 45 * 24 .28 + 1. 70 * 16 . 40 2 . 24 * 25 . 82 + 5 . 11 * Jio 10 . 26 + 1 . 77 Jio 8 .23 = 1 . 01 * 2 . 15 + 1 .09 * 10 .45 + 1 . 39 * 5 5 . 87 + 2 .47 * 0 . 35 + 0 . 49 * 1 . 87 + 1 . 40 * uuuuuuuu 3 .07 + 1 .42 * 1 .68 + 0 . 73 * Vehicle was 0 . 4 % DMSO . aaaaaaaaa * Significantly different from vehicle ( P < 0 . 01 ) . * * Significantly different from vehicle ( P < 0 .05 ) US 9 ,750 ,747 B2 15 16 Representative current traces at alß2y2 GABA receptors reference compounds valproic acid ( 1 mM ) or mibefradil for eslicarbazepine , R - licarbazepine , carbamazepine ( CBZ ) , ( 0 .01 - 10 uM ) . Vehicle was either bath solution or 0 . 2 % bicucculine and midazolam are shown as FIG . 1 . DMSO . Eslicarbazepine and R - licarbazepine , in contrast to car SigmaPlot 8 .02 was used to calculate the means + SEM of bamazepine , can be seen to be devoid of effects upon 5 relative peak current blockade for each compound . Analysis sub -maximal GABA currents . of variance (ANOVA ) with post test multisample compari son (Dunnett ) was conducted with GraphPad Prism 4 Soft Example 2 ware. IC50 were calculated with the equation : T - type channels are critically important in controlling the 10 excitability of the postsynaptic compartment of neurons, both in normal and epileptic neurons (Huguenard JR . ( 1996 ) current peak , relative = ( 100 - yl ) ( y1 - y2 ) Annu Rev Physiol 58 , 329 - 348 ) . Aberrant bursting is seen in yl + + y2 + - - VI CA1 hippocampal neurons from epileptic animals that is (v1 + 1 + 1010 ( [Logicsa Log /C50 ( 1 ) - x140X ]- H1 ) )+ (v2 + 1 + 1010123ics ([ Log / C50 ( 2 ) -, XX182 ]. H2 ) – yl mediated by increased expression of T - type Ca2 + channels ( Sanabria E R G , Su H , Yaari Y . ( 2001) J Physiol 532 , 13 205- 216 ). Transcriptional induction of T -type calcium chan where 1 refers to the high affinity fit and 2 to the low affinity nels (Ca 3 . 2 ) is a critical step in epileptogenesis and neu fit . X is the compound concentration , yl/ y2 is the remaining ronal vulnerability (Su H , Sochivko D , Becker A , Chen J, peak current amplitude , IC50 ( 1 )/ IC50 ( 2 ) is the concentra Jiang Y Yaari Y , Beck H . ( 2002 ) J Neurosci, 22 , 3645 - 3655 ) . tion of drug at half maximal inhibition and H1/ H2 is the Hill A study was carried out to determine the effect of esli - 20 coefficient for the fit . carbazepine . R - licarbazepine , oxcarbazepine (OXC ) and The effect of eslicarbazepine , R - licarbazepine , carbam carbamazepine (CBZ ) on human T -type calcium channels azepine ( CBZ ), oxcarbazepine (OXC ) and mibefradil on hCa 3 .2 currents recorded from stably transfected HEK 293 calcium peak currents on HEK 293 cells expressing the cells . The whole - cell patch - clamp technique was used to hCa 3 . 2 channels is shown in the following table . TABLE 3 Relative current amplitude ( % ) Concentration eslicarbazepine R - licarbazepine ??z Mean + SEM n Mean + SEM Mean + SEM OXC Mibefradil n 0 . 01 84 .72 + 3 . 20 5 57. 32 + 3. 97 * 5 86 . 99 = 1 . 56 98 .42 + 1 . 33 99 .10 + 0 .57 81. 61 + 1 . 31 92. 43 + 1 . 41 98 .04 + 0 .63 19 . 11 + 2 . 58 * 5 76 .21 + 1 .61 * 88 .21 + 1 .03 * buu 94 .82 + 0 . 93 71. 22 + 2 . 40 * Obau9 82 . 92 + 1 . 29 * 92. 83 2. 76 9. 13 2. 31 * 5 oüoWROO 87 . 58 + 2 . 94 uuuuu 30 73 . 04 + 1 .64 * 5 78 .21 + 2 . 14 * 90 . 14 + 1 .98 5 50 61. 44 + 4 . 96 * 4 . 73. 86 + 3 . 78 * 76 . 53 + 5 .48 100 54 .68 + 6 . 35 * 4 71. 61 + 1 .68 * 69 . 98 + 4 .47 250 46 . 92 + 6 .64 * 4 64. 52 + 3 . 05 * 59 .47 = 6 . 06 * 500 51. 83 + 4 . 77 * 8 58 .10 + 2 . 74 * wVAAA 45 . 66 + 7 .45 * 1000 45 . 48 4 . 94 * 4 39 . 37 + 5 . 33 * aaaaa Control values obtained with vehicle were 97 . 35 + 1 . 28 ( n = 8 ) . Remaining current obtained with 10 mM valproic acid was 65 . 15 = 2 . 05 % ( n = 8 ) . * Significantly different from control ( P < 0 .01 ) . 45 investigate the effects of eslicarbazepine, R - licarbazepine , Representative current traces for eslicarbazepine , R - licar oxcarbazepine and carbamazepine on hCa 3 . 2 calcium bazepine , oxcarbazepine and carbamazepine and mibefradil channels stably expressed in HEK cells . at the high affinity ( top ) and low affinity (bottom ) binding HEK 293 obtained from European Collection of Animal 50 sites are shown as FIG . 2 . Cell Culture Cells were maintained in a humidified atmo - Inhibition dose - response curves for the blockade of sphere (95 % relative humidity ) with 5 % CO2 and were hCa 3 . 2 currents by eslicarbazepine, R - licarbazepine, CBZ , grown in D -MEMF - 12 ( 1x liquid with GlutaMax I , Gibco OXC and mibefradil is shown as FIG . 3 . BRL ) supplemented with 9 % foetal bovine serum (Gibco - IC values were determined as follows from inhibition BRL ) , 0 . 9 % Penicillin / Streptomycin solution (Gibco BRL ) 55 curves for eslicarbazepine . R - licarbazepine , carbamazepine and 100 ug /ml Geneticin . Cells were stably transfected with (CBZ ) , oxcarbazepine (OXC ) and mibefradil . hCa 3 .2 cDNA . Cells were continuously perfused with bath solution TABLE 4 (NaCl 137 mM , KC1 4 mM , CaC1, 1 . 8 mM , MgCl, 10 mm , D -Glucose 10 mM HEPES 10 mM , pH 7 . 4 ) . Calcium inward 60 hCa. 3 . 2 currents were measured upon depolarization of the cell ICS ( UM ) membrane to - 25 mV for 50 ms from a holding potential of High Low - 80 mV. This voltage protocol was run at intervals of 10 s Compounds affinity affinity until stabilization of evoked hCa 3 . 2 currents . Once control Eslicarbazepine 0 . 43 62 .61 recordings were accomplished , cells were perfused with 65 R - licarbazepine 6 . 54 883 . 10 bath solution containing eslicarbazepine , R - licarbazepine , ??z 27 . 10 711 . 20 oxcarbazepine or carbamazepine ( 0 . 3 to 1000 uM ) or the US 9 , 750 , 747 B2 17 18 TABLE 4 -continued deficiency . Sequential electrocorticographic ( ECOG ) and prolonged video ECOG recordings from chroni hCa, 3. 2 cally implanted electrodes were performed on ICso (UM ) SSADH /, SSADH + ), and SSADH + / + mice from High Low 5 postnatal day ( P ) 10 to ( P ) 21 . Spontaneous , recur Compounds affinity affinity rent absence -like seizures appeared in the SSADH / OXC nc nc during the second week of life and evolved into Mibefradil 0 . 14 nc generalized convulsive seizures late in the third week of life that were associated with an explosive onset nc - not calculated 10 of status epilepticus which was lethal . The seizures It can be seen that eslicarbazepine , R - licarbazepine and in SSADH null mice were consistent with typical carbamazepine dose dependently inhibited hCa , 3. 2 calcium absence seizures in rodent with 7 Hz spike - and -wave peak currents ( Table 3 and FIG . 2 ) . The inhibition curves discharge (SWD ) recorded from thalamocortical cir were best fitted with a two site binding model and a constant 15 cuitry . Cortez et al ( 2004 ) Pharmacology, Biochem remaining current amplitude . A block ofhigh affinity occurs istry & Behaviour 79 :547 -553 . with an IC50 of 0 .43 uM , 6 .54 or 27 . 10 uM for eslicarba ( c ) Stargazer Mouse model . zepine, R - licarbazepine and carbamazepine, respectively The stargazer ( stg ) mutant mouse harbors a transposon ( table of IC50 values above and FIG . 3 ) . A further block insertion in the second intron of the calcium channel occurs at higher concentrations of the test items, with an 20 y2 subunit ( cacng2 ) locus, disrupting transcription of IC50 of 62. 61 uM for eslicarbazepine , 883 . 10 uM for R - li the gene . The stg mouse has proved to be an excep carbazepine and 711. 20 uM for carbamazepine ( table of IC50 tionally informative mutant, exhibiting several dis values above and FIG . 3 ) . Oxcarbazepine , up to 30 uM , was orders including spontaneous absence seizure , cer devoid of effect on hCa 3 . 2 currents . ebellar ataxia , and head tossing . Ryu et al ( 2008 ) (Regarding the reference compounds , 1 mM valproic acid 25 Journal of Neurochemistry 104 : 1260 - 1270 blocked calcium peak currents by 66 .15 + 2 .05 (n = 8 cells ) ( d ) C3H /He mouse model and mibefradil dose dependently inhibited hCa 3 . 2 calcium The inbred mouse strain C3H /He exhibits spontaneous peak currents with an IC50 of 143. 7 nM . ) absence seizures characterized by spike and wave The obtained data demonstrates that eslicarbazepine , in discharges (SWD ) on the electroencephalogram con contrast to R - licarbazepine, carbamazepine and oxcarba - 30 comitant with behavioural arrest . Tokuda et a (2009 ) zepine, effectively inhibits high and low affinity hCa 3 . 2 Genes, Brain & Behaviour 8 : 283 - 289 inward currents . Results show that eslicarbazepine acetate and eslicarba zepine are effective in controlling seizures in these models . Example 3 35 Example 4 Following oral administration of oxcarbazepine, eslicar bazepine acetate , eslicarbazepine and R - licarbazepine in Clinical trial study : A randomised double - blind , placebo rats , all compounds result in oxcarbazepine . Therefore to controlled , trial assesses the efficacy and safety of adjunctive test the effects of oral administration of eslicarbazepine eslicarbazepine acetate in primary generalised tonic clonic acetate , mice models are used . 40 seizure ( PGTCS ) in human patients in accordance with Administration of eslicarbazepine and eslicarbazepine established methods. acetate in the following models is tested : Methods: Men and women are selected for trial according ( a ) Absence seizure induced by y -butyrolactone to standard inclusion criteria in the field including the Absence seizure arises from aberrant thalamocortical. following : Oscillatory burst firing of thalamocortical neurons 45 Subject is male or female and aged 6 -65 years . induces spike and wave discharges (SWDs ) , and the Subject has 3 PGTCS over the two months before generation of this firing results from Ca2 + influx into screening and during the eight weeks Baseline Period the thalamocortical neurons via low - threshold cal with at least one seizure in each one month period . cium channels . y -Hydroxybutyric acid (GHB ) as PGTCS must occur in the context of Idiopathic Gen well as various y -aminobutyric acid GABA receptor 50 eralized Epilepsy ( IGE ) and may be accompanied by agonists are reported to induce absence seizures . other primary generalized seizures , provided these are GHB has been proposed as a neurotransmitter/ neu also consistent with a diagnosis of IGE . romodulator that acts via its own receptor . The Subject is taking a stable regimen of one or two other systemic injection ofGHB into mice elicits rhythmic Antiepileptic Drugs (AEDs ) for at least two weeks 3 Hz SWD , the EEG hallmark of absence seizures , 55 prior to Visit 1 (start of the Baseline Period ) . and represents a well established and widely used Subject has a clinical diagnosis of any type of idiopathic pharmacological model of this nonconvulsive epi generalized epilepsy which has PGTCS ( and which lepsy . Ryu et al (2007 ) Journal of Neurochemistry, may be accompanied by other generalized seizure 102 :646 -656 types) , according to the International League Against (b ) Succinic semialdehyde dehydrogenase deficiency 60 Epilepsy ( ILAE ) Classification of Epileptic Seizures The succinic semialdehyde dehydrogenase (SSADH ) ( 1981 ) and the ILAE Classification of Epilepsies and null mouse represents a viable animal model for Epileptic Syndromes ( 1989 ). Diagnosis should have human SSADH deficiency and is characterised by been established by clinical history , electroencephalo markedly elevated levels of both GHB and GABA in gram ( EEG ) and computed tomography /magnetic reso brain , blood , and urine . GHB is known to induce 65 nance imaging (CT /MRI ) of the brain consistent with absence -like seizures and absence seizures have idiopathic generalized epilepsy . CT /MRI scan should been reported to occur in children with SSADH have been performed within five years of the screening US 9 , 750 , 747 B2 19 20 visit or, if not available from this period , should be childhood absence epilepsy , juvenile absence epilepsy , performed in the Baseline Period . myoclonic absence epilepsy , juvenile myoclonic epi EEG should have been performed within one year of the lepsy , Lennox Gastaut syndrome, perioral myoclonus screening visit or, if not available from this period , with absences, Jeavons syndrome and idiopathic gen should be performed in the Baseline Period . eralized epilepsy with phantom absences . Subject has a body weight 220 kg . 9 . The method according to claim 1 , wherein the patient Patients may be excluded from trial in accordance with is receiving a second drug which may cause or aggravate known exclusion criteria in the field . absence seizures. Patients selected for trial are randomised to treatment sequences comprising eslicarbazepine acetate at effective 10 10 . The method according to claim 9 , wherein the second dosage and placebo administered by conventional means . drug is selected from the group consisting of: Trial endpoints assessed clinical criteria are as follows: calcarbamazepine , Oxcarbazepine , vigabatrin , tiagabine , time to withdrawal after randomisation ; phenytoin , phenobarbital , gabapentin , and pregabalin . time to first, second , or other seizure after randomisation 11 . The method according to claim 1 , wherein the esli (time to first seizure after randomisation allows deter - 15 carbazepine acetate is administered orally . mination of the proportion of patients at different time 12 . The method according to claim 1 , wherein the esli points who remain seizure free ) ; carbazepine acetate is administered once daily . time to achieving remission ( e . g . at six months, one year , 13. The method according to claim 1 , wherein the patient or two years ) ; receives one or more additionalmedications for treatment of change in seizure severity ; 20 partialonset seizures . change in seizure frequency ; 14 . The method according to claim 13 , wherein the percentage response to treatment ( response defined as a additional medication is selected from the group consisting 50 % or greater reduction in seizure frequency ) ; of: change in seizure- free interval; clorazepate , clonazepam , ethosuximide, felbamate , fos change in seizure duration ; 2525 phenytoin , lacosamide , lamotrigine , levetiracetam , change in seizure pattern ; primidone , topiramate , valproate semisodium , valproic change in functional capacity ; and acid , and zonisamide . patient- related quality of life . 15 . The method according to claim 1 , wherein the esli carbazepine acetate is administered to the patient as an CONCLUSION º adjunct therapy . Treatment with eslicarbazepine acetate in patients suffer 16 . A method of treating partial - onset seizures in a patient ing from or susceptible to PGTCS leads to improved clinical who is suffering from or susceptible to absence seizures, effects indicating usefulness of eslicarbazepine acetate which method comprises : adjunct or monotherapy in treating PGTCS . 35 administering to said patient a safe and effective amount The invention claimed is : of a pharmaceutical composition , which comprises a 1 . A method of treating partial -onset seizures in a patient pharmaceutically acceptable carrier and a safe and who is suffering from or susceptible to absence seizures, effective amount of eslicarbazepine acetate as an active which method comprises : ingredient. administering to said patient a safe and effective amount 40 17 . The method according to claim 16 , wherein the of eslicarbazepine acetate . pharmaceutical composition is in the form of a tablet, a 2 . The method according to claim 1 , wherein the patient suspension or a sprinkle formulation . is female . 18 . A method of treating partial onset seizures, which 3 . The method according to claim 1 , wherein the patient method comprises: is under sixteen years of age . 45 ( a ) selecting a patient who is suffering from or susceptible 4 . The method according to claim 1 , wherein the patient to absence seizures ; and has not reached puberty . ( b ) administering to said patient a safe and effective 5 . The method according to claim 1 , wherein the patient amount of eslicarbazepine acetate , or a pharmaceutical has previously suffered from at least one seizure selected composition , which comprises a pharmaceutically from the group consisting of absence seizure , myoclonic 50 acceptable carrier and a safe and effective amount of seizure and tonic - clonic seizure . eslicarbazepine acetate as an active ingredient. 6 . The method according to claim 1 , wherein the patient 19 . A method of reducing the incidence of absence has a family history of epilepsy . seizures in a patient, which method comprises administering 7. The method according to claim 1, wherein the patient to said patient a safe and effective amount of eslicarbazepine has the R43Q mutation in the y - aminobutyric acid (GABA ) A 55 acetate , or a pharmaceutical composition , which comprises receptor y - 2 subunit. a pharmaceutically acceptable carrier and a safe and effec 8 . The method according to claim 1 , wherein the patient tive amount of eslicarbazepine acetate as an active ingredi is suffering from or susceptible to at least one disease or ent. syndrome selected from the group consisting of: * * * * *