NZ743322A

NZ743322A - Methods and compositions for the treatment of seizure-related disorders

Info

Publication number: NZ743322A
Application number: NZ743322A
Authority: NZ
Inventors: David Chernoff; Timothy J Fultz; Sangita Ghosh; Jack Nguyen; Gregory T Went
Original assignee: Adamas Pharmaceuticals Inc
Priority date: 2015-12-30
Filing date: 2016-12-30

Abstract

Compositions and methods are provided for administering a pharmaceutical composition to a human patient. Compositions are administered to a human patient orally, once daily, at a therapeutically effective dose. The pharmaceutical compositions comprise a drug selected from the group consisting of brivaracetam, divalproex, lacosamide, levetiracetam, oxcarbazepine, vigabatrin, and pharmaceutically acceptable salts of any of the foregoing, and at least one excipient. At least one of said at least one excipients modifies the release of said drug to provide an extended release form. The pharmaceutical composition have pharmacokinetic properties recited in the claims. varacetam, divalproex, lacosamide, levetiracetam, oxcarbazepine, vigabatrin, and pharmaceutically acceptable salts of any of the foregoing, and at least one excipient. At least one of said at least one excipients modifies the release of said drug to provide an extended release form. The pharmaceutical composition have pharmacokinetic properties recited in the claims.

Description

METHODS AND COMPOSITIONS FOR THE TREATMENT OF SEIZURE-RELATED DISORDERS REFERENCE This patent application claims the beneﬁt of US. Application Serial No. 62/273,187, ﬁled December 30, 2015, which is herein incorporated by reference in its entirety.

FIELD OF THE INVENTION The ﬁeld of the invention relates to extended e compositions of anti-epileptic compounds for the treatment of seizure-related disorders and methods of using same.

BACKGROUND Epilepsy and seizure-related disorders affect nearly 3 million people in the US annually, at an estimated annual cost of $17.6 billion in direct and indirect costs. 200,000 new cases of seizures are reported annually in the US, and approximately 10% of the American population will experience at least one seizure in their lifetime. Seizures dramatically affect the quality of life and activities of daily living, especially activities that occur during the day like cooking, cleaning, and driving.

Numerous nvulsant drugs exist in the market today to treat the ms or manage epilepsy and other seizure disorders, including lacosamide, lamotrigine, levetiracetam, topiramate, valproate, and zonisamide. These agents have modest or d efﬁcacy and only about one-third of patients respond to monotherapy.

Data on the distribution of seizures duIing the human sleep—wake cycle or on the al bution of seizures over the 24-hour day have been scarce and variable. Based on a large retrospective study in a tertiary sy and sleep center, 176 patients (76 children, 100 adults) had continuous electroencephalography (EEG) and video monitoring. More than 800 seizures were recorded. Signiﬁcantly more seizures occurred n 11 AM and 5 PM than at any other time of day, whereas signiﬁcantly fewer seizures were ed between 11 PM and 5 AM. The results suggest that seizures have a cy to occur in a diurnal pattern, characterized by a peak during midday and lower frequency in the ime (Hofstra et al., 2009). A once daily modiﬁed release formulation of an antiepileptic drug (AED) that has a PK proﬁle that is synchronous with the diurnal pattern of es could be clinically advantageous.

Improved therapeutics and methods for ent of these diseases and disorders are needed. Currently approved AEDs (both immediate and extended release forms) do not match the peak plasma concentrations to the times of highest seizure susceptibility, resulting in suboptimal seizure control. For instance, immediate release products with short half-lives (e. g. lacosamide and levetiracetam) are expected to have relatively low plasma trations throughout long periods of the day when there is a high seizure burden. Furthermore, currently approved AEDs with long half-lives are associated with safety concerns, including black box warnings (e.g. igine and zonisamide) and the risk of increased bleeding and xis (e. g. topiramate).

The ideal t for treating seizures should have demonstrated efficacy in reducing the frequency of seizures, be relatively well tolerated, and have a PK profile that is synchronous with the daily impact of seizures. Thus, a novel formulation for an AED that provides sustained and high plasma levels between 9 AM and 6 PM would provide better seizure control.

Additionally, many of the ed AEDs in clinical use have limiting side s which are related to the rapid rate in which the drug is absorbed into plasma, as opposed to the Cmax or AUC. By slowing the l release of the AED and decreasing the initial rate of rise of plasma concentration, it is possible to improve the tolerability of the AED without compromising the effectiveness of the drug. Furthermore, by slowing the initial rate of rise of plasma concentration and improving tolerability, it is possible to reduce or eliminate titration and administer higher strengths of the AED compared to existing commercial immediate release formulations, thereby providing greater efﬁcacy and better seizure control, Anti-Epileptic Drugs (AEDs) A large number of drugs have shown anti-epileptic activity, including, but not limited to, carbamazepine, divalproex sodium, eslicarbazepine acetate, ethotoin, ine, felbamate, gabapentin, lacosamide, lamotrigine, levetiracetam, oxcarbazepine, perampanel, phenytoin, pregabalin, primidone, tiagabine, topiramate, valproic acid, vigabatrin, and mide.

Lacosamide Lacosamide, also known as Racetamido—N—benzyl-3 -methoxypropionamide, is a functionalized amino acid with the molecular formula C13H18N20 3 and a molecular weight of 250.30. The chemical ure is: Lacosamide was ed for use in the US in 2008 by the FDA as adjunctive therapy in the ent of partial—onset seizures in ts with epilepsy aged 17 years and older. In 2014, lacosamide was approved for monotherapy in patients with partial onset seizures. It was also approved for use in the European Union in 2008. It is marketed as “Vimpat” (UCB ceuticals).

Lacosamide immediate release (“IR”) is currently available in the form of 50 mg, 100 mg, 150 mg, and 200 mg s for oral administration, as well as a 200 mg/20 mL solution for intravenous administration (“IV”). Typical oral dosages are 200-400 mg daily administered in two divided doses daily.

Lacosamide IR is completely absorbed after oral administration with negligible first-pass effect with a bioavailability of approximately 100%. The Tmax for an immediate release form is l to 4 hours for oral dosing, with an elimination half-life of approximately 13 hours. Steady state plasma concentrations are achieved after 3 days of twice-daily repeated administration.

Pharmacokinetics of mide are proportional to dose within a range of 100 to 800 mg with low inter- and intra-subject variability. Compared to lacosamide, the major metabolite, O— desmethyl metabolite, has a longer Tmax (0.5 to 12 hours) and elimination half-life (15 to 23 hours). rome P450 2C 19 (CYP2Cl9) a member of the cytochrome P450 mixed-function oxidase system, is involved in the metabolism of many antiepileptic drugs. There is no signiﬁcant effect of CYP2C 19 polymorphism on the pharmacokinetics of lacosamide. There are reports that there no clinically nt ences in the pharmacokinetics between CYP2C 19 poor lizers and extensive metabolizers, but concentrations and the amount excreted into urine of the O—desmethyl metabolite were about 70% reduced in the former as compared to the latter.

Lacosamide can be associated with a number of adverse side s. For example, lacosamide is implicated to increase the risks of suicidal ts and behavior. Users are warned that lacosamide may cause dizziness, headache, ataxia, somnolence, tremor, nystagmus, balance disorder, cardiac complications including cardiac rhythm and conduction abnormalities, atrial fibrillation and atrial ﬂutter, and syncope. Other adverse events associated with lacosamide at higher incidence than placebo in clinical trials include, but are not limited to, vertigo, diplopia, blurred vision, nausea, vomiting, diarrhea, fatigue, gait disturbance, asthenia, sion and us.

Adverse reactions in patients with partial-onset seizures ed in clinical trials include penia, anemia, cardiac palpitations, us, constipation, dehydration, dry mouth, oral hypoaesthesia, irritability, pyrexia, increased incidence of falls, muscle spasms, paresthesia, cognitive disorder, hypoaesthesia, dysarthria, disturbance in attention, cerebellar syndrome, confusion, mood disorders, and depressed mood. In tive therapy controlled clinical trials, the adverse reactions most commonly g to discontinuation were dizziness, ataxia, ng, diplopia, nausea, vertigo, and blurred vision, The most common e reactions in tive therapy controlled clinical trials include dizziness (31%), headache (13%), and diplopia (11%).

In a long term (up to ﬁve years exposure) open—label extension clinical trial to study long term safety and efﬁcacy of lacosamide, 10.7% of patients withdrew due to ent emergent adverse events (TEAEs). However, the authors noted that it was difficult to attribute the TEAES solely to lacosamide therapy due to trial design, length of study, and the use of concomitant AEDs, and/or the addition of new AEDs. TEAES reported included dizziness, headache, contusion, nausea, convulsion, nasopharyngitis, fall, vomiting, and diplopia. TEAES that most commonly resulted in discontinuation of lacosamide ent were dizziness and convulsion.

The lacosamide ition is described in US 5,378,729, RE38,551 (from US. Patent No. 5,773,475), and US 5,654,301. These patents, along with US 6,048,899 discuss the use of mide for treating CNS conditions. US 7,884,134 is directed to lacosamide sis. US 7,718,161 discusses the use of lacosamide for treating motor neuron disease. US 20070043120, 20070048372, US 20070197657, US 20080280835, US 56179, US 20120225119, and US 20100260716 are directed to the use of lacosamide for treatment, inhibition, ation or prevention of a number of ions including pain, non—inﬂammatory osteoarthritic pain, musculoskeletal pain associated with ﬁbromyalgia, muscle pain associated with myofascial pain syndrome, back pain, neck pain, and demyelination ions. US 201003 24144 is directed to methods for alleviating or treating myotonia. US 20140128377 is directed to methods of treating tive seizures and e clusters. US 20140066515 is directed to methods of ating or treating channelopathies using lacosamide. US 20140128378 is directed to methods of alleviating or treating epileptogenesis.

Other US applications, including US 20130251813 and US 20130251803 by Cawello et al., are based on the development of controlled release oral lacosamide formulations. US 19631 by Kulkarni et al., describes a modified release formulation of lacosamide with minimal Cmax to ijn peak to trough variation. These compositions are characterized as having a decreased Cmax and delayed Tmax, a decreased peak-trough ﬂuctuation (PTF), and an increased Cmm in comparison to [R formulations. WO 201 1/101863 (Roy) is based on extended release lacosamide compositions comprising modified release polymers.

Levetiracetam Levetiracetam, also known as (S)-alpha—ethyloxo-pyrrolidine ide, is an S—enantiomer of etiracetam and has the chemical ure CgH14N202 and a molecular weight of 170.209. The chemical structure is: Levetiracetam was approved by the FDA in 1999 as an adj unctive y for the treatment of partial onset seizures in adults. The FDA later extended the use to children four years of age and older in 2012, and to children one month of age or older in 2012, Levetiracetam is marketed as Keppra by UCB Pharmaceuticals.

Levetiracetam is approved for use in some regions as adjunctive y in the treatment of myoclonic seizures in adults and adolescents 12 years of age or older with juvenile myoclonic epilepsy, as adjunctive therapy in the treatment of primary generalized clonic seizures in patients with idiopathic generalized sy, and for partial onset seizures in adults and children as young as one moth of age.

Levetiracetam (immediate release) is marketed as Keppra IR is available as 250 mg, 500 mg, and 750 mg tablets, as well as 100 mg/ml oral solution. Typical closing is 500 mg twice daily, which can be increased with 1000 mg increments to 3000 mg/day.

Levetiracetam has a Tmax of approximately one hour in fasted subjects, which can be delayed by 1.5 hours by food. It has a plasma half-life of 6-8 hours, an AUC0.24 (ug*h/mL) of 300-350, and is excreted y mostly in an unmetabolized form at a rate of 0.6 mL/min/kg.

Adverse events associated with levetiracetam use include somnolence in 14.8% of patients (compared to 8% in patients taking a placebo). Approximately 45% of patients taking 4000 mg levetiracetam daily reported somnolence in one ated study.

Besides somnolence, other common adverse events associated with levetiracetam use include asthenia, , sis, psychotic depression, behavioral symptoms including aggression, ion, anger, y, apathy, depersonalization, depression, emotional lability, hostility, irritability, and suicidal behavior. Adverse events ed in pediatric patients include somnolence, fatigue and behavior alities.

An extended release formulation of levetiracetam is marketed as Keppra XR by UCB Pharmaceuticals. It is available as 500 mg and 750 mg tablets. Like the IR formulation, the Keppra XR doses are typically between 1000—3000 mg daily, but are taken as a single dose per day.

Adverse events associated with the XR formulation of levetiracetam at levels higher than in corresponding patients taking a placebo e suicidal behavior and on, ence, dizziness, depression, nervousness, fatigue, nausea, y, amnesia irritability, hostility, paresthesia, ataxia, o, emotional lability, and ia.

The levetiracetam composition is described US 4,837,223, US 4,943,639 and US 6,107,492. Extended release levetiracetam is described in US 7,858,122 and US 7,863,316 US 075 is ed to the methods for treating age-related cognitive function using levetiracetam.

Brivaracetam Brivaracetam (Briva) is the 4-n-propyl analog of levetiracetam. It is also known as (ZS)- 2-[(4R)—2—oxo—4—propylpyrrolidin—1—yl]butanamide. It has the chemical formula CUHZONZOZ, and has a molecular weight of 212.29. The chemical structure is: “517 In one clinical study, brivaracetam had a Tmax of approximately 2 hours and a plasma half-life of 7-8 hrs, Unlike levetiracetam, only a small fraction of the brivaracetam dose administered (5-8%) is unchanged in urine, the remaining drug appears to be excreted as metabolites, indicating lic clearance.

In clinical trials, dose-dependent AEs included sedation and decreased alertness. Another trial showed that somnolence, dizziness, and decreased attention, alertness, and motor control were dose—related in healthy adult males.

Brivaracetam synthesis, itions, and methods are described in US 6,911,461, US 6,713,635, Us 6,784,197, Us 7,358,276, and US 7,692,028, US 8,435,564 is based on the development of brivaracetam sustained release tablets, US 712 and US 50282 describe compositions covering brivaracetam granules coated for sustained release; US 20120040006 and US 20110091547 are directed to brivaracetam ned release solid dosage foirns, 20130039957 is directed to controlled release formulations of brivaracetam; US 81929 and US 20110275693 are directed to immediate release brivaracetam formulations, US 20110021786 is directed to stable brivaracetam aqueous solutions; US 20100240576 is directed to therapeutic compounds comprising, in some embodiments, lacosamide and a racetam selected from a group comprising levetiracetam, and brivaracetam.

W0 2006/131322 and US2009131508 are directed to methods for treating myoclonic epilepsies using brivaracetam—based nds.

Oxcarbazepine Oxcarbazepine, also known as 10,1l-dihydrooxo-5H-dibenz(b,f)azepine carboxamide is a structural derivative of the anti-epileptic agent carbamazepine. It has the chemical formula C15H12N202, and a molecular weight of 252.268 g/moli It is marketed under the name Trileptal. The al structure is: 0 NH2 Oxcarbazepine is metabolized by liver s into 10-monohydroxy metabolite (MHD), the active form of the drug, as well as small s of an ve metabolite, 10,11- dihydroxy lite (DHD). Although the precise mechanism of action is unknown, the drug is thought to act by blocking voltage-sensitive sodium channels, thereby stabilizing hyperexcited neural membranes, inhibiting repetitive neuronal firing, and ng propagation of synaptic firing onally, the drug is thought to modulation of high-voltage CA+2 channels and se potassium conductance, contributing to anti-epileptic activity.

Oxcarbazepine has a half-life of approximately 2 hours, while the metabolite (MDH) has a half-life of 9 hours. The Tmax is approximately 3 hours, the Cmax (ug/mL) of 2.72 for 600 mg IR BID, and an AUC0_24 mL) of 16.8 for 600 mg [R BID. Per the Trileptal label, oxcarbazepine and the MDH metabolite share similar bioavailability. No food effects are displayed with either oxcarbazepine or its metabolite.

Seven multicenter, randomized, controlled clinical trials established the effectiveness of Trileptal as adjunctive and monotherapy for partial seizures in adults, and as tive therapy in en aged 2-16 years. AEs identified in the clinical trials include cognitive symptoms including psychomotor slowing, difﬁculty with concentration, speech and language problems, somnolence and fatigue, and coordination abnormalities including ataxia and gait disturbances.

Patents covering Trileptal include US 7037525, covering methods of treatment using oxcarbazepine, and US 8119148, ng an oxcarbazepine suspension. Other patents directed WO 17569 to oxcarbazepine include US 3642775, covering the composition, and US 5863558, US 5876750, US 5906832, US 5955103, US 6210712, covering osmotic forms ofthe drug for release of active ingredient in the GI tract.

Divalproex sodium/ Valproic acid Divalproex sodium, is the sodium salt of valproic acid, which is also known as 2- propylpentanoic acid It has the chemical formula C8H1602, and the chemical structure: Sold under a number of brand names including Depakote, Convulex, Epilim, Valparin, Valpro, Vilapro, and Stavzor, roex dissociates into the valproate ion in the gastrointestinal tract. The mechanism of action is not fully characterized, but its anti-epileptic activity has been ated with increased GABA concentrations in the brain. Immediate release (IR) and extended release forms of the drugs are available. Divalproex sodium ER has a half-life of 16 :: 3 hours, a Tmax of 7.7 hours for 1000 mg ER, and an 4 (ug*h/mL) of 1970 for 1000 mg Adverse events associated with valproic acid y include abdominal pain, accidental injury, alopecia, amblyopia/blurred vision, amnesia, anorexia, asthenia, ataxia, back pain, bronchitis, constipation, depression, diarrhea, diplopia, dizziness, dyspepsia, dyspnea, ecchymosis, emotional lability, fever, ﬂu syndrome, headache, increased appetite, infection, insomnia, , nervousness, nystagmus, peripheral edema, pharyngitis, rash, is, somnolence, thinking abnormal, thrombocytopenia, tinnitus, , vomiting, weight gain, and weight loss.

US. Patents ed to divalproex sodium/valproic acid e US. 4,988,731, US. 326, US. 6,511,678, US. 6,528,090, US. 6,713,086, and US. 6,720,004.

Vigabatrin Vigabatrin, also known as (RS)—4-aminohex—5—enoic acid and as gamma—vinyl—GABA is a GABA analog. It has the chemical formula C6H11N02, and a molecular weight of 129.157 g/mol. It is marketed under the name Sabril. The chemical structure is: Vigabatrin irreversibly inhibits gamma-aminobutyric acid transaminase (GABA-T), the enzyme responsible for GABA lism. It has a Tm of 7.5 hrs at steady state, a Tmax of approximately 1 hour, a Cmax 61 (ug/mL) at steady state.

Vigabatrin is ted as monotherapy for pediatric ts one month to two years of age with infantile spasms for whom the potential beneﬁts outweigh the potential risk of vision loss, and as adj unctive n) therapy for adult patients with refractory complex l seizures (CPS) who have inadequately responded to l ative treatments and for whom the potential beneﬁts outweigh the risk of vision loss. Vigabatrin may cause permanent vision loss in a high percentage of patients. This effect may occur within weeks or sooner after starting treatment. It may also occur after months or years. The risk may increase with higher doses and prolonged use, but it may occur with any dose or length of use. Vision loss may continue to worsen after stopping vigabatrin. Commonly reported side effects of vigabatrin include confusion, fatigue, diplopia, weight gain, arthralgia, blurred vision, depression, cough, diarrhea, memory impairment, drowsiness, tremor, ataxia, abnormal gait, irritability, and pharyngolaryngeal pain. Other side effects e urinary tract infection, status epilepticus, pulmonary congestion, sed mood, muscle twitching, paresthesia, weakness, dysmenorrhea, eye pain, erectile dysfunction, sinus headache, abnormality in thinking, peripheral edema, nystagmus, lethargy, sedation, back pain, abnormal behavior, constipation, myalgia, fever, nervousness, vertigo, , chest pain, bronchitis, hyporeﬂexia, upper abdominal pain, che, thesia, sensory disturbance, peripheral neuropathy, malaise, increased appetite, bruise, and abnormal dreams.

SUMMARY OF THE INVENTION The inventors have found that certain AED pharmaceutical compounds may be formulated to provide more effective treatment of seizures, particularly partial onset seizures, and other indications for which these compounds are used. Generally, the invention relates to an extended release composition of an anti-epilepsy drug, that provides pharmacokinetic teristics as r deﬁned herein, and its use in a method of treating seizure-related disorders by administration as deﬁned herein.

In some embodiments, compositions of these AED ceutical compounds comprise an extended release form that, upon oral ingestion by a subject (or subjects) of a fasted, single dose, human pharmacokinetic study provides a Tmax that is greater than the Tmax provided by WO 17569 2016/069581 ingestion of an immediate release, oral form of the same pharmaceutical compound to a subject (or subjects) in the same or similar , single dose, human pharmacokinetic study. In some embodiments, compositions of these compounds comprise an extended release form that, upon oral dosing to a t of a fasted, single dose, human pharrnacokinetic study provides a Tmax that is greater than the Tmax provided by oral dosing of an immediate release, oral form of the same ceutical compound at the same strength to said subject in the same fasted, single dose, human pharrnacokinetic study, preferably the Tmax is 5 to 20 hours, more preferably, the Tmax is 10 to 20 hours, even more preferably, the Tmax is 12 to 20 hours, and most preferably, the Tmax is 14 to 20 hours. The plasma concentration s provided by compositions described herein are designed to achieve one or more of the following objectives: increased diurnal variation, peak steady state plasma concentration chronosynchronous with the need for therapy (i.e., higher concentration when seizures are most prevalent), reduced adverse events (including those adverse events which may lead to discontinuation or lower adherence), reduced dosing frequency, sed daily dose, increased efﬁcacy. In some ments, two or more of these objectives are achieved; in some embodiments, at least three of the ives are achieved.

Formulations may be designed for administration at speciﬁc times to achieve the entioned obj ectives, In some embodiments, the compositions may be ed to provide a reduced rate of rise in drug plasma concentration during the ﬁrst 2, 3, 4, 5, or 6 hours of administration as compared to a commercially available, oral, immediate release form of the same amount of the same active pharmaceutical ingredient, yet provide bioavailability comparable to that for a commercially available, oral, immediate release form of the same active ceutical ingredient (e.g., 80% to 125% of the AUCOM of the commercially available, oral, immediate release form of the same active ceutical ingredient), For example, an extended release composition of lacosamide may be designed (as exempliﬁed below) to release the drug much more slowly than an immediate release formulation; n such formulations may be administered in the evening, before bedtime, and upon multiple administrations, the steady state plasma concentration proﬁle will be characterized by a higher plasma concentration proﬁle during the daytime hours (and lower concentrations during the night) such that the peak concentrations are chronosynchronous with the peak seizure activity in a patient. Furthermore, such formulations enable a full day’s closing to be administered orally, once daily. In some embodiments, the total daily dose of the active pharmaceutical ingredient may be administered orally, once daily at a higher daily dose than lly employed for the same active pharmaceutical ingredient in an immediate release form in divided doses (e.g., BID, TID). In some embodiments, the once daily administration of the pharmaceutical composition provides a plasma concentration proﬁle of the active ceutical ingredient characterized by a diurnal variation that is increased such that the swing (i.e., (Cmam-Cmmyss)/Cmm,SS x 100%) is greater than 90%, 100%, 110%, or 120%.

In some ments, the AED drug is one or more members of the group consisting of brivaracetam, divalproex, lacosamide, levetiracetam, oxcarbazepine, trin, and pharmaceutically acceptable salts of brivaracetam, divalproex, lacosamide, levetiracetam, oxcarbazepine, and Vigabatrin.

Additionally, many of the approved AEDs in clinical use have limiting side s which are related to the rapid rate in which the drug is absorbed into plasma, as opposed to the Cmax or AUC. By slowing the initial release of the AED and decreasing the initial rate of rise of plasma concentration, it is possible to improve the bility of the AED without compromising the effectiveness of the drug. Furthermore, by slowing the initial rate of rise of plasma concentration and improving tolerability, it is possible to reduce or eliminate titration and ster higher strengths of the AED compared to ng commercial immediate release formulations, thereby providing greater efficacy and better seizure l. Some embodiments provide an anti-epileptic formulation that is administered once daily and has a pharmacokinetic proﬁle with diurnal variations, with a Tm between 4 and 15 hours, preferably between 4 and 12 hours. These embodiments include, but are not limited to, formulations of brivaracetam, divalproex sodium, valproic acid, felbamate, lacosamide, lamotrigine, levetiracetam, oxcarbazepine, alin, tiagabine, and Vigabatrin. Preferred are formulations of brivaracetam, divalproex sodium, valproic acid, lacosamide, levetiracetam, oxcarbazepine, pregabalin, tiagabine, and Vigabatrin. Most red are formulations of levetiracetam, brivaracetam, mide, oxcarbazepine and valproic acid for administration once daily.

Some embodiments described herein provide a method of administering a pharmaceutical composition to a human, comprising administering to a human orally, once daily, a therapeutically effective dose of a pharmaceutical composition sing (i) a drug selected from the group consisting of brivaracetam, divalproex, lacosamide, racetam, oxcarbazepine, Vigabatrin, and pharmaceutically acceptable salts thereof, and mixtures of any of the foregoing, and (ii) one or more excipients, wherein at least one of said one or more ents s the e of the drug to provide an extended e form. In some embodiments the pharmaceutical composition comprises one or more additional active ceutical ingredients. In a preferred embodiment, no other drugs are included in the pharmaceutical composition.

Some embodiments described herein provide a method of administering a pharmaceutical composition to a human, comprising administering to a human orally, once daily, a therapeutically effective dose of a pharmaceutical composition comprising (i) a drug WO 17569 selected from the group consisting of brivaracetam, lacosamide, levetiracetam, oxcarbazepine, and pharmaceutically acceptable salts thereof, and mixtures of any of the foregoing, and (ii) one or more excipients, wherein at least one of said one or more excipients modiﬁes the release of the drug to provide an ed release form.

Some embodiments described herein provide a method of administering a pharmaceutical composition to a human, comprising administering to a human orally, once daily, a therapeutically effective dose of a pharmaceutical composition comprising (i) a drug selected from the group consisting of lacosamide and pharmaceutically able salts f, and mixtures of any of the foregoing, and (ii) one or more excipients, wherein at least one of said one or more ents es the release of the drug to provide an extended release form.

Some aspects of any of the embodiments described herein provide a method of administering a pharmaceutical composition to a human, orally, once daily, wherein said ition comprises at least one or more excipients with es the release of the drug to provide a delayed release form.

Some aspects of any of the embodiments described herein provide a method of administering a ceutical composition to a human, , once daily, wherein said composition provides a dissolution profile characterized by at least two of the following: (i) release of less than 8% in 2 hours, (ii) release of less than 17% in 4 hours, (iii) release of less than 45% at 6 hours, and wherein the dissolution profile of said pharmaceutical composition is terized by release of at least 45% at 12 hours, wherein the dissolution is performed in a USP type 1 (basket) apparatus rotating at 100 rpm using 900 ml simulated c fluid (pH 1.2) at 37.0::0.5°C for 2 hours, followed by ution in the same apparatus and speed using 900 ml simulated intestinal ﬂuid (pH 6.8) at 37.0i0.5°C for the subsequent 4 hours, followed by dissolution in the same apparatus and speed using 900 ml phosphate buffer (pH 7.5) at 37.Od:05°C for the subsequent 18 hours. In a preferred aspect of this embodiment, all three of said release criteria are met. In a preferred aspect of this embodiment, the release of drug at 4 hours is less than 10%.

Some aspects of any of the embodiments bed herein provide a method of administering a pharmaceutical composition to a human, orally, once daily, n said composition provides a dissolution proﬁle characterized by at least three of the following: (i) less than 10% release at 1 hour, (ii) less than 15% release at 2 hours, (iii) less than 25% release at 4 hours, (iv) at least 35% release at 9 hours, (v) at least 65% release at 12 hours, wherein the dissolution is performed in a USP type 1 (basket) apparatus rotating at 100 rpm using 900 ml simulated gastric ﬂuid (pH 1.2) at 37,010.50C for 2 hours, followed by dissolution in the same apparatus and speed using 900 ml simulated intestinal ﬂuid (pH 6.8) at 37.0::O.5°C for the subsequent 4 hours, followed by dissolution in the same apparatus and speed using 900 ml phosphate buffer (pH 7.5) at 37.0::0.5°C for the subsequent 18 hours.

Some aspects of any of the embodiments described herein provide a method of administering a pharmaceutical composition to a human, orally, once daily, wherein said composition es a dissolution proﬁle characterized by a release at 2 hours of not more than 18%, and wherein the ution proﬁle of said pharmaceutical ition is characterized by release of at least 45% at 12 hours, wherein the dissolution is performed in a USP type 1 t) tus rotating at 100 rpm using 900 ml simulated gastric ﬂuid (pH 1.2) at 37.0i0.5°C for 2 hours, followed by dissolution in the same apparatus and speed using 900 ml simulated intestinal ﬂuid (pH 6.8) at 37.0::0.5°C for the subsequent 4 hours, followed by dissolution in the same apparatus and speed using 900 ml ate buffer (pH 7.5) at 37.0i0.5°C for the subsequent 18 hours. In a preferred aspect of this embodiment, all three of said release ia are met, In a preferred aspect of this embodiment, all three of said release criteria are met. In a preferred aspect, the release of drug at 2 hours is less than 12%. In a preferred aspect, the release of drug at 2 hours is less than 9%. In a preferred aspect, the release of drug at 2 hours is less than 6%. In a preferred aspect, the release of drug at 2 hours is less than 3% In a preferred aspect, the release of drug at 2 hours is less than 2%.

Some aspects of any of the embodiments described herein provide a method of administering a ceutical composition to a human, orally, once daily, wherein said composition provides a dissolution proﬁle characterized by a release at 4 hours of not more than %, and wherein the dissolution proﬁle of said pharmaceutical composition is characterized by release of at least 45% at 12 hours, wherein the dissolution is performed in a USP type 1 (basket) apparatus rotating at 100 rpm using 900 ml simulated gastric ﬂuid (pH 1.2) at 37.0::O.5°C for 2 hours, followed by ution in the same apparatus and speed using 900 ml simulated intestinal ﬂuid (pH 6.8) at 37.0i0.5°C for the subsequent 4 hours, followed by dissolution in the same apparatus and speed using 900 ml ate buffer (pH 7.5) at 37.0::O.5°C for the subsequent 18 hours. In a preferred aspect, the release of drug at 4 hours is less than 20%. In a preferred aspect, the release of drug at 4 hours is less than 15%. In a preferred aspect, the release of drug at 4 hours is less than 10%, In a red aspect, the release of drug at 4 hours is less than 7.5%. In a preferred aspect, the release of drug at 4 hours is less than 5%.

Some s of any of the embodiments described herein provide a method of administering a ceutical composition to a human, orally, once daily, n said composition provides a dissolution proﬁle characterized by a release at 6 hours of not more than %, and wherein the dissolution proﬁle of said pharmaceutical composition is characterized by release of at least 45% at 12 hours, wherein the dissolution is performed in a USP type 1 (basket) apparatus rotating at 100 rpm using 900 ml simulated gastric ﬂuid (pH 1.2) at 37.0i0.5°C for 2 hours, followed by dissolution in the same apparatus and speed using 900 ml simulated intestinal ﬂuid (pH 6.8) at 37.0::0.5°C for the subsequent 4 hours, followed by dissolution in the same tus and speed using 900 ml phosphate buffer (pH 7.5) at 37.0i0.5°C for the subsequent 18 hours. In a preferred aspect, the release of drug at 6 hours is less than 25%. In a red aspect, the release of drug at 6 hours is less than 20%. In a preferred aspect, the release of drug at 6 hours is less than 15%. In a preferred aspect, the release of drug at 4 hours is less than 12%. In a preferred aspect, the release of drug at 6 hours is less than 9%.

Some aspects of any of the embodiments described herein provide a method of stering a pharmaceutical composition to a human, orally, once daily, wherein said composition provides a dissolution profile characterized by a release at 9 hours of at least 35%, and wherein the ution profile of said pharmaceutical composition is characterized by release of at least 45% at 12 hours, wherein the dissolution is performed in a USP type 1 (basket) tus rotating at 100 rpm using 900 ml simulated gastric ﬂuid (pH 1.2) at 37.0ﬂ20.5°C for 2 hours, followed by dissolution in the same apparatus and speed using 900 ml simulated intestinal ﬂuid (pH 6.8) at 37.0::0.5°C for the subsequent 4 hours, followed by dissolution in the same apparatus and speed using 900 ml phosphate buffer (pH 7.5) at 37.0::O.5°C for the uent 18 hours. In a preferred , the release of drug at 9 hours is at least 40% and the release at 12 hours is at least 65%. In a red aspect, the release of drug at 9 hours is at least 45% and the release at 12 hours is at least 65%. In a red aspect, the release of drug at 9 hours is at least 50% and the release at 12 hours is at least 65%, Some aspects of any of the embodiments described herein provide a method of administering a pharmaceutical composition to a human, orally, once daily, n oral ingestion of a dose of said pharmaceutical composition by a subject of a fasted, single dose, human pharmacokinetic study provides a plasma concentration proﬁle for the drug of said pharmaceutical composition characterized by a Tmax of 5 to 20 hours. In a preferred aspect, said Tmax is 5 to 10 hours. In a red aspect, said Tmax is 8 to 20 hours. In a preferred aspect, said Tmax is 10 to 20 hours. In a preferred aspect, said Tmax is 10 to 14 hours. In a red aspect, said Tmax is 12 to 20 hours. In a more preferred aspect, said Tmax is 13 to 20 hours.

Some aspects of any of the ments described herein provide a method of administering a pharmaceutical composition to a human, orally, once daily, wherin oral ingestion of a dose of said pharmaceutical composition by a subject of a fasted, single dose, human acokinetic study provides a plasma concentration proﬁle for the drug of said pharmaceutical composition characterized by a Tlag of 0.25 to 9 hours. In a preferred aspect, said Tlag is 0.25 to 5 hours. In a preferred aspect, said Tlag is l to 9 hours. In a preferred aspect, said Tlag is 2 to 9 hours. In a preferred aspect, said Tlag is 3 to 8 hours. In a preferred aspect, said Tlag is 0.5 to 5 hours. In a preferred , said Tlag is 1 to 5 hours. In a preferred aspect, said Tlag is 2 to 5 hours.

Some aspects of any of the embodiments bed herein provide a method of administering a pharmaceutical ition to a human, orally, once daily, wherein oral ion of a dose of said pharmaceutical composition by a subject of a fasted, single dose, human phannacokinetic study provides a plasma concentration proﬁle for the drug of said pharmaceutical composition characterized by an AUC0.00 that es AUC equivalence to IR.

Some aspects of any of the embodiments bed herein provide a method of administering a pharmaceutical composition to a human, orally, once daily, wherein oral ion of a dose of said pharmaceutical composition by a subject of a fasted, single dose, human cokinetic study provides a plasma concentration proﬁle for the drug of said pharmaceutical composition terized by an AUCOm that is 100% to 150% of the AUCO.00 ined for an equivalent dose of the drug of said pharmaceutical composition in an immediate release form after ingestion by a subject of said fasted, single dose, human pharmacokinetic study.

Some aspects of any of the embodiments described herein provide a method of administering a pharmaceutical composition to a human, orally, once daily, wherein oral ingestion of a dose of said pharmaceutical composition by a subject of a fasted, single dose, human pharmacokinetic study provides a plasma concentration proﬁle for the drug of said pharmaceutical composition characterized by a dC/dt over the ﬁrst 1.4 hours after ingestion that is less than 10% of the dC/dt determined for an equivalent dose of the drug of said pharmaceutical composition in an immediate release form over the ﬁrst 1.4 hours after ingestion by a subject of said fasted, single dose, human pharmacokinetic study. In a preferred aspect, the dC/dt determined for said composition is less than 5% of the dC/dt ined for an equivalent dose of the drug of said ceutical composition in an immediate release form over the ﬁrst 1.4 hours after ingestion by a subject of said fasted, single dose, human pharmacokinetic study.

Some aspects of any of the embodiments described herein provide a method of administering a pharmaceutical composition to a human, orally, once daily, wherein oral ingestion of a dose of said pharmaceutical composition by a subject of a fasted, single dose, human pharmacokinetic study es a plasma tration proﬁle for the drug of said pharmaceutical composition characterized by a dC/dt over the ﬁrst 2 hours after ingestion that is less than 15% of the dC/dt determined for an equivalent dose of the drug of said pharmaceutical composition in an immediate release form over the ﬁrst 2 hours after ingestion by a subject of said fasted, single dose, human pharmacokinetic study. In a preferred aspect, the dC/dt determined for said composition is less than 10% of the dC/dt determined for an equivalent dose of the drug of said pharmaceutical composition in an immediate release form over the ﬁrst 2 hours after ingestion by a subject of said fasted, single dose, human pharmacokinetic study. In a preferred aspect, the dC/dt determined for said composition is less than 5% of the dC/dt determined for an equivalent dose of the drug of said pharmaceutical composition in an immediate e form over the ﬁrst 2 hours after ingestion by a subject of said fasted, single dose, human pharmacokinetic study.

Some aspects of any of the embodiments described herein provide a method of administering a pharmaceutical composition to a human, orally, once daily, wherein oral ingestion of a dose of said pharmaceutical composition by a subject of a fasted, single dose, human pharmacokinetic study provides a plasma concentration proﬁle for the drug of said pharmaceutical composition characterized by a dC/dt over the ﬁrst 3 hours after ingestion that is less than 25% of the dC/dt determined for an equivalent dose of the drug of said pharmaceutical composition in an immediate release form over the ﬁrst 3 hours after ingestion by a subject of said , single dose, human pharmacokinetic study. In a preferred aspect, the dC/dt determined for said ition is less than 20% of the dC/dt determined for an equivalent dose of the drug of said pharmaceutical composition in an immediate release form over the ﬁrst 3 hours after ion by a subject of said fasted, single dose, human pharmacokinetic study. In a preferred , the dC/dt ined for said composition is less than 10% of the dC/dt determined for an equivalent dose of the drug of said pharmaceutical composition in an immediate release form over the ﬁrst 3 hours after ingestion by a subject of said fasted, single dose, human pharmacokinetic study.

Some aspects of any of the embodiments described herein provide a method of administering a pharmaceutical composition to a human, orally, once daily, wherein oral ingestion of a dose of said pharmaceutical composition by a subject of a , single dose, human pharmacokinetic study es a plasma concentration proﬁle for the drug of said pharmaceutical composition characterized by a dC/dt over the ﬁrst 4 hours after ion that is less than 30% of the dC/dt ined for an equivalent dose of the drug of said pharmaceutical composition in an immediate release form over the ﬁrst 4 hours after ion by a subject of said fasted, single dose, human pharmacokinetic study. In a preferred aspect, the dC/dt determined for said composition is less than 20% of the dC/dt determined for an equivalent dose of the drug of said ceutical ition in an immediate release form over the ﬁrst 4 hours after ingestion by a subject of said fasted, single dose, human pharmacokinetic study. In a preferred aspect, the dC/dt determined for said composition is less than 10% of the dC/dt ined for an equivalent dose of the drug of said pharmaceutical ition in an immediate release form over the ﬁrst 4 hours after ingestion by a subject of said fasted, single dose, human pharmacokinetic study.

Some s of any of the embodiments described herein provide a method of administering a pharmaceutical ition to a human, , once daily, wherein oral ingestion of a dose of said ceutical composition by a subject of a , single dose, human pharmacokinetic study provides a plasma concentration proﬁle for the drug of said ceutical composition characterized by a dC/dt over the ﬁrst 2 hours after ingestion that is less than 1 ug/ml/hr. In a preferred aspect, said dC/dt over the ﬁrst 2 hours after ingestion is less than 0.6 ug/ml/hr. In a preferred aspect, said dC/dt over the ﬁrst 2 hours after ingestion is less than 0.45 ug/ml/hr. In a preferred aspect, said dC/dt over the ﬁrst 2 hours after ingestion is less than 0.3 ug/ml/hr. In a preferred aspect, said dC/dt over the ﬁrst 2 hours after ingestion is less than 0.1 ug/ml/hr.

Some aspects of any of the embodiments described herein provide a method of administering a pharmaceutical composition to a human, orally, once daily, wherein oral ion of a dose of said pharmaceutical composition by a subject of a fasted, single dose, human pharmacokinetic study provides a plasma concentration proﬁle for the drug of said pharmaceutical composition characterized by a dC/dt over the ﬁrst 3 hours after ingestion that is less than 08 ug/ml/hr. In a preferred aspect, said dC/dt over the ﬁrst 3 hours after ingestion is less than 0.6 ug/ml/hr. In a preferred , said dC/dt over the ﬁrst 3 hours after ingestion is less than 0.4 ug/ml/hr. In a preferred aspect, said dC/dt over the ﬁrst 3 hours after ingestion is less than 0.25 ug/ml/hr. In a preferred aspect, said dC/dt over the ﬁrst 3 hours after ingestion is less than 01 ug/ml/hr.

Some aspects of any of the embodiments described herein provide a method of administering a pharmaceutical composition to a human, orally, once daily, wherein oral ingestion of a dose of said pharmaceutical ition by a subject of a fasted, single dose, human pharmacokinetic study provides a plasma concentration proﬁle for the drug of said pharmaceutical ition characterized by a dC/dt over the ﬁrst 4 hours after ingestion that is less than 06 ug/ml/hr. In a preferred , said dC/dt over the ﬁrst 4 hours after ingestion is less than 0.5 ug/ml/hr. In a preferred aspect, said dC/dt over the ﬁrst 4 hours after ingestion is less than 04 ug/ml/hr. In a preferred aspect, said dC/dt over the ﬁrst 4 hours after ingestion is less than 0.25 ug/ml/hr. In a preferred aspect, said dC/dt over the ﬁrst 4 hours after ingestion is less than 01 ug/ml/hr.

Some aspects of any of the embodiments described herein provide a method of administering a pharmaceutical composition to a human, orally, once daily, wherein oral ingestion of a dose of said pharmaceutical composition by a subject of a fasted, single dose, human pharmacokinetic study provides a plasma concentration proﬁle for the drug of said pharmaceutical composition characterized by a dC/dt over the ﬁrst 2 hours after ingestion that is less than 2.2 ng/ml/hr per mg of the drug of said ceutical composition. In a preferred aspect, said dC/dt over the ﬁrst 2 hours after ingestion is less than 1.8 ng/ml/hr per mg of the drug of said pharmaceutical ition. In a preferred aspect, said dC/dt over the ﬁrst 2 hours after ingestion is less than 1.4 ng/ml/hr per mg of the drug of said pharmaceutical composition.

In a preferred aspect, said dC/dt over the ﬁrst 2 hours after ingestion is less than 1 ng/ml/hr per mg of the drug of said pharmaceutical composition. In a preferred aspect, said dC/dt over the ﬁrst 2 hours after ion is less than 0.5 ng/ml/hr per mg of the drug of said pharmaceutical composition.

Some aspects of any of the embodiments described herein provide a method of administering a pharmaceutical composition to a human, orally, once daily, n oral ingestion of a dose of said pharmaceutical composition by a subject of a fasted, single dose, human pharmacokinetic study provides a plasma concentration proﬁle for the drug of said pharmaceutical composition characterized by a dC/dt over the ﬁrst 3 hours after ingestion that is less than 2 ng/ml/hr per mg of the drug of said ceutical composition. In a preferred aspect, said dC/dt over the ﬁrst 3 hours after ingestion is less than 1.6 ng/ml/hr per mg of the drug of said pharmaceutical ition. In a preferred aspect, said dC/dt over the ﬁrst 3 hours after ingestion is less than 1.2 ng/ml/hr per mg of the drug of said pharmaceutical composition.

In a preferred , said dC/dt over the ﬁrst 3 hours after ingestion is less than 0.8 ng/ml/hr per mg of the drug of said pharmaceutical composition. In a preferred , said dC/dt over the ﬁrst 3 hours after ingestion is less than 0.4 ng/ml/hr per mg of the drug of said pharmaceutical composition Some aspects of any of the embodiments described herein provide a method of administering a ceutical composition to a human, orally, once daily, wherein oral ingestion of a dose of said ceutical composition by a subject of a fasted, single dose, human pharmacokinetic study provides a plasma concentration proﬁle for the drug of said pharmaceutical composition terized by a dC/dt over the ﬁrst 4 hours after ion that is less than 1.6 ng/ml/hr per mg of the drug of said pharmaceutical composition. In a preferred aspect, said dC/dt over the ﬁrst 4 hours after ingestion is less than 1.2 ng/ml/hr per mg of the drug of said pharmaceutical composition. In a preferred , said dC/dt over the ﬁrst 4 hours after ingestion is less than 0.8 ng/ml/hr per mg of the drug of said pharmaceutical composition.

In a preferred aspect, said dC/dt over the ﬁrst 4 hours after ingestion is less than 0.4 ng/ml/hr per mg of the drug of said pharmaceutical composition. In a preferred aspect, said dC/dt over the ﬁrst 4 hours after ingestion is less than 0.2 ng/ml/hr per mg of the drug of said ceutical composition.

Some aspects of any of the embodiments described herein provide a method of administering a pharmaceutical composition to a human, orally, once daily, wherein oral ingestion of a dose of said pharmaceutical composition by a subject of a fasted, single dose, human pharmacokinetic study provides a plasma concentration proﬁle for the drug of said pharmaceutical composition characterized by a pAUC0.4 that is less than 12% of AUCOQO determined for the drug of said pharmaceutical composition from said plasma concentration proﬁle. In a preferred aspect, said pAUC0-4 is less than 10% of AUC0.DO ined for the drug of said pharmaceutical composition from said plasma concentration . In a preferred , said pAUC0.4 is less than 8% of AUCWO determined for the drug of said pharmaceutical composition from said plasma concentration proﬁle. In a preferred aspect, said pAUCo.4 is less than 6% of AUC0.0O ined for the drug of said pharmaceutical composition from said plasma concentration proﬁle. In a preferred , said pAUC0-4 is less than 4% of AUC0.0O determined for the drug of said pharmaceutical composition from said plasma tration proﬁle. In a preferred aspect, said pAUC0.4 is less than 2% of AUC0.0O ined for the drug of said ceutical composition from said plasma concentration proﬁle. In a preferred aspect, said pAUC0.4 is less than 1% of AUC0.0O determined for the drug of said pharmaceutical composition from said plasma concentration proﬁle.

Some aspects of any of the embodiments described herein provide a method of administering a pharmaceutical ition to a human, orally, once daily, wherein oral ingestion of a dose of said pharmaceutical composition by a subject of a fasted, single dose, human pharmacokinetic study provides a plasma concentration proﬁle for the drug of said pharmaceutical composition characterized by a pAUC0-g that is less than 12% of AUC0.0O determined for the drug of said pharmaceutical composition from said plasma concentration proﬁle. In a preferred aspect, said pAUC0.g is less than 10% of AUC0.0O ined for the drug of said pharmaceutical composition from said plasma concentration proﬁle. In a preferred aspect, said pAUCM is less than 7.5% of AUC0.0O determined for the drug of said ceutical composition from said plasma concentration proﬁle. In a preferred aspect, said g is less than 5% of AUC0.0O determined for the drug of said pharmaceutical composition from said plasma concentration proﬁle. In a preferred aspect, said pAUC0-8 is less than 3% of AUC0.0O determined for the drug of said pharmaceutical composition from said plasma concentration proﬁle.

Some s of any of the embodiments described herein provide a method of administering a ceutical composition to a human, orally, once daily, wherein oral ingestion of a dose of said pharmaceutical composition by a subject of a fasted, single dose, human pharmacokinetic study provides a plasma concentration proﬁle for the drug of said pharmaceutical composition characterized by a pAUC4_g that is less than 14% of AUC0_OO determined for the drug of said pharmaceutical composition from said plasma concentration proﬁle. In a preferred aspect, said pAUC4.g is less than 12% of AUCO.00 determined for the drug of said pharmaceutical ition from said plasma concentration proﬁle. In a preferred aspect, said 3 is less than 10% of O ined for the drug of said pharmaceutical composition from said plasma concentration proﬁle. In a preferred aspect, said pAUC4.8 is less than 8% of AUCOIJO determined for the drug of said pharmaceutical composition from said plasma concentration proﬁle. In a preferred aspect, said pAUC4-g is less than 7% of AUCOI,O determined for the drug of said pharmaceutical ition from said plasma concentration proﬁle. In a preferred , said pAUC4.g is less than 6% of AUC0.0O determined for the drug of said pharmaceutical composition from said plasma concentration proﬁle. In a red aspect, said pAUC4.8 is less than 4% of AUCMO determined for the drug of said pharmaceutical composition from said plasma concentration proﬁle. In a preferred aspect, said pAUC4.g is less than 2.5% of AUCOm determined for the drug of said pharmaceutical composition from said plasma concentration proﬁle.

Some aspects of any of the embodiments described herein e a method of administering a pharmaceutical composition to a human, orally, once daily, wherein once daily oral dosing of said pharmaceutical ition to a subject of a fasted, human cokinetic study provides a steady state plasma tration proﬁle for the drug of said ceutical composition characterized by a Tum,SS that is 5 to 20 hours. In a preferred aspect, said Tmax,SS is 5 to 10 hours. In a preferred aspect, said Tmax,SS is 10 to 20 hours. In a preferred , said Tmax,SS is 12 to 20 hours. In a preferred aspect, said me’SS is 11 to 18 hours. In a preferred aspect, said Tmax,SS is 12 to 18 hours. In a preferred , said ngSS is 13 to 18 hours. In a preferred aspect, said Tmax)SS is 14 to 18 hours.

Some aspects of any of the embodiments described herein provide a method of administering a pharmaceutical ition to a human, orally, once daily, wherein once daily oral dosing of said pharmaceutical composition to a subject of a fasted, human pharmacokinetic study provides a steady state plasma concentration proﬁle for the drug of said pharmaceutical composition characterized by a Cmax,SS that is 12 to 36 ng/ml per mg of drug. In a preferred aspect, said Cmax,SS is 16 to 32 ng/ml per mg of drug. In a preferred aspect, said CumSS is 20 to 30 ng/ml per mg of drug In a preferred aspect, said Cmax,SS is 22 to 30 ng/ml per mg of drug. In a preferred aspect, said Cmax,ss is 23 to 30 ng/ml per mg of drug. In a preferred aspect, said Cmax,SS is 24 to 32 ng/ml per mg of drug.

Some aspects of any of the embodiments described herein provide a method of administering a pharmaceutical composition to a human, orally, once daily, wherein once daily oral dosing of said pharmaceutical composition to a subject of a fasted, human phannacokinetic study es a steady state plasma concentration proﬁle for the drug of said pharmaceutical composition characterized by a Cmin,ss that is 6 to 15 11ng per mg of drug, In a preferred aspect, said Cmin,ss is 8 to 125 ng/ml per mg of drug. In a red , said Cmin’ss is 9 to 12 ng/ml per mg of drug.

Some aspects of any of the embodiments described herein provide a method of administering a pharmaceutical composition to a human, orally, once daily, wherein once daily oral dosing of said pharmaceutical composition at a predetermined administration time to a subject of a fasted, human pharmacokinetic study provides a steady state plasma concentration proﬁle for the drug of said pharmaceutical composition characterized by a C-ave-day that is 20 to 100% greater than C-ave-night. In a preferred aspect, said steady state plasma concentration proﬁle for the drug of said pharmaceutical compositon is terized by a C—ave—day that is % to 100% greather than C—ave-night. In a preferred aspect, C—ave-day is determined from the steady state plasma concentration proﬁle over the period of 9 am to 6 pm and C-ave-night is determined from the steady state plasma concentration proﬁle over the period of 11 pm to 8 am and said predetermined time is 5 am. In a red aspect, day is determined from the steady state plasma concentration proﬁle over the period of 9 am to 6 pm and C-ave-night is determined from the steady state plasma concentration proﬁle over the period of 11 pm to 8 am and said predetermined time is 6 am. In a preferred aspect, C-ave-day is determined from the steady state plasma concentration proﬁle over the period of 9 am to 6 pm and C-ave-night is determined from the steady state plasma concentration proﬁle over the period of 11 pm to 8 am and said predetermined time is 7 am. In a preferred aspect, C-ave—day is determined from the steady state plasma concentration proﬁle over the period of 9 am to 6 pm and C-ave-night is determined from the steady state plasma tration proﬁle over the period of 11 pm to 8 am and said ermined time is 8 am. In a preferred aspect, C—ave—day is determined from the steady state plasma concentration proﬁle over the period of 9 am to 6 pm and C-ave-night is determined from the steady state plasma concentration proﬁle over the period of 11 pm to 8 am and said predetermined time is 8 pm. In a red aspect, C-ave—day is determined from the steady state plasma concentration proﬁle over the period of 9 am to 6 pm and night is determined from the steady state plasma tration proﬁle over the period of 11 pm to 8 am and said predetermined time is 9 pm. In a preferred aspect, C-ave—day is determined from the steady state plasma concentration proﬁle over the period of 9 am to 6 pm and C-ave-night is determined from the steady state plasma concentration proﬁle over the period of 11 pm to 8 am 2016/069581 and said predetermined time is 10 pm. In a preferred aspect, C-ave-day is determined from the steady state plasma concentration proﬁle over the period of 9 am to 6 pm and C-ave-night is determined from the steady state plasma concentration proﬁle over the period of 11 pm to 8 am and said predetermined time is 11 pm. In a preferred aspect, C-ave-day is determined from the steady state plasma concentration proﬁle over the period of 9 am to 6 pm and C-ave-night is determined from the steady state plasma concentration proﬁle over the period of 11 pm to 8 am and said predetermined time is 12 am. In a preferred aspect, C-ave-day is determined from the steady state plasma concentration proﬁle over the period of 9 am to 4 pm and C—ave-night is determined from the steady state plasma concentration proﬁle over the period of 11 pm to 8 am and said ermined time is 6 am. In a preferred aspect, C-ave-day is determined from the steady state plasma concentration proﬁle over the period of 9 am to 4 pm and C-ave—night is determined from the steady state plasma concentration proﬁle over the period of 11 pm to 8 am and said predetermined time is 10 pm. As used herein, 100%*((C-ave-day/C-ave-night) — 1) is equivalent to the percentage increase recited in this paragraph; for example a C—ave—day/C-ave— night ratio of 1.3 is equivalent to a 30% increase in C-ave—day from C-ave—night.

Some aspects of any of the embodiments bed herein provide a method of administering a pharmaceutical ition to a human, orally, once daily, wherein once daily oral dosing of said pharmaceutical ition at a ermined administration time to a subject of a fasted, human pharmacokinetic study provides a steady state plasma concentration proﬁle for the drug of said pharmaceutical composition characterized by a day that is 40 to 120% greater than C-ave-night. In a preferred aspect, C-ave-day is determined from the steady state plasma concentration proﬁle over the period of 9 am to 6 pm and C-ave-night is determined from the steady state plasma concentration proﬁle over the period of 11 pm to 8 am and said predetermined time is 5 am. In a preferred aspect, C-ave-day is determined from the steady state plasma concentration proﬁle over the period of 9 am to 6 pm and C-ave-night is determined from the steady state plasma concentration proﬁle over the period of 11 pm to 8 am and said predetermined time is 6 am. In a red aspect, C—ave-day is determined from the steady state plasma concentration proﬁle over the period of 9 am to 6 pm and C-ave-night is determined from the steady state plasma concentration proﬁle over the period of 11 pm to 8 am and said predetermined time is 7 am. In a preferred , C-ave-day is determined from the steady state plasma tration proﬁle over the period of 9 am to 6 pm and C-ave-night is determined from the steady state plasma concentration proﬁle over the period of 11 pm to 8 am and said predetermined time is 8 am. In a preferred aspect, day is ined from the steady state plasma concentration proﬁle over the period of 9 am to 6 pm and C-ave-night is determined from the steady state plasma concentration proﬁle over the period of 11 pm to 8 am and said predetermined time is 8 pm. In a preferred aspect, C-ave-day is determined from the steady state plasma concentration proﬁle over the period of 9 am to 6 pm and C-ave-night is determined from the steady state plasma tration proﬁle over the period of 11 pm to 8 am and said ermined time is 9 pm. In a red , C-ave—day is determined from the steady state plasma concentration proﬁle over the period of 9 am to 6 pm and C-ave-night is determined from the steady state plasma concentration proﬁle over the period of 11 pm to 8 am and said predetermined time is 10 pm. In a preferred aspect, C-ave-day is determined from the steady state plasma concentration proﬁle over the period of 9 am to 6 pm and C—ave-night is ined from the steady state plasma concentration proﬁle over the period of 11 pm to 8 am and said predetermined time is 11 pm. In a red aspect, C-ave-day is determined from the steady state plasma concentration proﬁle over the period of 9 am to 6 pm and C-ave-night is ined from the steady state plasma concentration proﬁle over the period of 11 pm to 8 am and said predetermined time is 12 am. In a red aspect, C-ave-day is determined from the steady state plasma concentration proﬁle over the period of 9 am to 4 pm and C—ave-night is determined from the steady state plasma concentration proﬁle over the period of 11 pm to 8 am and said predetermined time is 6 am. In a preferred aspect, C-ave-day is determined from the steady state plasma concentration proﬁle over the period of 9 am to 4 pm and C-ave—night is determined from the steady state plasma concentration proﬁle over the period of 11 pm to 8 am and said predetermined time is 10 pm. As used herein, 100%*((C-ave-day/C-ave-night) — 1) is equivalent to the percentage increase recited in this aph; for example a C—ave—day/C-ave— night ratio of 1.55 is equivalent to a 55% increase in C-ave-day from C-ave-night.

Some aspects of any of the embodiments bed herein provide a method of administering a pharmaceutical composition to a human, orally, once daily, wherein once daily oral dosing of said pharmaceutical composition to a subject of a fasted, human pharmacokinetic study provides a steady state plasma concentration proﬁle for the drug of said pharmaceutical composition characterized by a swing that is 40% to 200%. In a preferred aspect, said swing is 60% to 200%. In a preferred , said swing is 75% to 200%. In a preferred aspect, said swing is 80% to 180%. In a preferred aspect, said swing is 85% to 160%. In a preferred aspect, said swing is 80% to 150%. In a preferred aspect, said swing is 100% to 150%. In a preferred aspect, said swing is 50% to 100%.

Some aspects of any of the embodiments described herein e a method of administering a pharmaceutical composition to a human, orally, once daily, wherein once daily oral dosing of said pharmaceutical composition to a subject of a fasted, human pharmacokinetic study provides a steady state plasma concentration proﬁle for the drug of said pharmaceutical composition characterized by a PTF that is 50% to 100%. In a preferred aspect, said PTF is 50% to 90%. In a preferred aspect, said PTF is 55% to 85%. In a preferred aspect, said PTF is 60% to 80%. In a preferred aspect, said PTF is 45% to 85%. In a red aspect, said PTF is 40% to 80%.

Some s of any of the ments described herein e a method of stering a pharmaceutical composition to a human, , once daily, wherein said pharmaceutical composition ses a d e coating.

Some aspects of any of the embodiments described herein provide a method of administering a pharmaceutical composition to a human, orally, once daily, wherein the daily dose of the drug of said pharmaceutical composition is 50 mg to 900 mg. In a preferred aspect, the daily dose of the drug of said composition is 100 mg to 900 mg. In a preferred aspect, the daily dose of the drug of said composition is 150 mg to 900 mg. In a preferred aspect, the daily dose of the drug of said composition is 300 mg to 900 mg. In a preferred aspect, the daily dose of the drug of said composition is 200 mg to 850 mg, In a preferred aspect, the daily dose of the drug of said composition is 250 mg to 850 mg. In a preferred aspect, the daily dose of the drug of said ition is 300 mg to 850 mg. In a preferred aspect, the daily dose of the drug of said composition is 350 mg to 850 mg. In a preferred aspect, the daily dose of the drug of said composition is 400 mg to 850 mg. In a preferred aspect, the daily dose of the drug of said composition is 450 mg to 850 mg. In a preferred aspect, the daily dose of the drug of said composition is 500 mg to 850 mg. In a preferred aspect, the daily dose of the drug of said composition is 550 mg to 850 mg. In a preferred aspect, the daily dose of the drug of said composition is 600 mg to 850 mg. In a preferred aspect, the daily dose of the drug of said composition is 650 mg to 850 mg. In a preferred aspect, the daily dose of the drug of said composition is 400 mg to 800 mg. In a preferred aspect, the daily dose of the drug of said composition is 450 mg to 800 mg.

Some aspects of any of the embodiments described herein provide a method of administering a pharmaceutical composition to a human, orally, once daily, 0 to 4 hours before bedtime; preferably 0 to 3 hours before bedtime; more preferably 0 to 2 hours before bedtime.

Some aspects of any of the embodiments described herein provide a method of administering a pharmaceutical composition to a human, orally, once daily, at 8 pm, 9 pm, 10 pm, 11 pm, or 12 am; preferably at 8 pm 9 pm, 10 pm or 11 pm. In a preferred aspect the , , composition is administered at 10 pm. In a red aspect, the composition is administered at 11 pm. These administration times are examples of preferred predetermined administration times.

Some aspects of any of the embodiments bed herein provide a method of administering a pharmaceutical composition to a human, orally, once daily, 0 to 4 hours after waking for the day, preferably 0 to 3 hours after waking for the day, more preferably 0 to 2 hours after waking for the day.

Some aspects of any of the embodiments described herein provide a method of administering a pharmaceutical composition to a human, orally, once daily, at 5 am, 6 am, 7 am, 8 am, or 9 am; preferably at 6 am 7 am, or 8 am. In a preferred aspect the composition is administered at 6 am In a preferred , the composition is administered at 7 am. These administration times are es of preferred predetermined administration times Some embodiments described herein provide a pharmaceutical composition for oral administration to a human comprising (i) a drug selected from the group consisting of brivaracetam, divalproex, mide, levetiracetam, oxcarbazepine, vigabatrin, and pharmaceutically acceptable salts thereof, and mixtures of any of the ing, and (ii) one or more excipients, wherein at least one of said one or more excipients modiﬁes the release of the drug to provide an extended release form. In some embodiments the pharmaceutical ition comprises one or more additional active pharmaceutical ingredients. In a red embodiment, no other drugs are included in the pharmaceutical ition.

Some ments described herein provide a pharmaceutical composition for oral stration to a human comprising (i) a drug selected from the group consisting of brivaracetam, lacosamide, levetiracetam, oxcarbazepine, and pharmaceutically acceptable salts thereof, and mixtures of any of the ing, and (ii) one or more excipients, wherein at least one of said one or more excipients modiﬁes the release of the drug to provide an extended release form Some embodiments described herein e a pharmaceutical composition for oral administration to a human comprising (i) a drug selected from the group consisting of lacosamide and pharmaceutically acceptable salts thereof, and mixtures of any of the foregoing, and (ii) one or more excipients, wherein at least one of said one or more excipients modiﬁes the release of the drug to provide an extended release form.

Some aspects of any of the embodiments bed herein provide a pharmaceutical composition wherein said pharmaceutical composition comprises at least one or more excipients which modiﬁes the release of the drug to provide a delayed release form.

Some aspects of any of the embodiments described herein provide a pharmaceutical ition for oral administration to a human, wherein said composition provides a dissolution proﬁle characterized by at least two of the following: (i) e of less than 8% in 2 hours, (ii) release of less than 17% in 4 hours, (iii) release of less than 45% at 6 hours, and n the dissolution proﬁle of said pharmaceutical composition is characterized by release of at least 45% at 12 hours, wherein the dissolution is performed in a USP type 1 (basket) apparatus rotating at 2016/069581 100 rpm using 900 ml 0.1 N simulated gastric ﬂuid (pH 1.2) at 37.0::O.5°C for 2 hours, followed by dissolution in the same apparatus and speed using 900 ml simulated intestinal ﬂuid (pH 6.8) at 37.0::0.5°C for the uent 4 hours, followed by ution in the same apparatus and speed using 900 ml phosphate buffer (pH 7.5) at 37.0i0.5°C for the subsequent 18 hours. In a preferred aspect of this embodiment, all three of said release criteria are met. In a preferred aspect of this embodiment, the release of drug at 4 hours is less than 10%1 Some aspects of any of the embodiments described herein provide a pharmaceutical composition to a human, wherein said composition provides a dissolution proﬁle characterized by at least three of the following: (i) less than 10% release at 1 hour, (ii) less than 15% release at 2 hours, (iii) less than 25% release at 4 hours, (iv) at least 35% release at 9 hours, (v) at least 65% release at 12 hours, wherein the dissolution is performed in a USP type 1 t) apparatus rotating at 100 rpm using 900 ml simulated gastric fluid (pH 1.2) at 37.0i0.5°C for 2 hours, followed by dissolution in the same apparatus and speed using 900 ml simulated intestinal fluid (pH 6.8) at 37.0::O.5°C for the uent 4 hours, followed by dissolution in the same apparatus and speed using 900 ml phosphate buffer (pH 7.5) at 37.0i0.5°C for the subsequent 18 hours.

Some aspects of any of the embodiments bed herein provide a pharmaceutical composition for oral administration to a human, n oral ingestion of a dose of said pharmaceutical composition by a subject of a fasted, single dose, human pharmacokinetic study provides a plasma concentration proﬁle for the drug of said pharmaceutical composition characterized by a Tmax of 5 to 20 hours. In a preferred aspect, said Tmax is 5 to 10 hours. In a preferred , said Tmax is 8 to 20 hours. In a preferred aspect, said Tmax is 10 to 20 hours. In a preferred aspect, said Tmax is 10 to 14 hours. In a preferred aspect, said Tmax is 12 to 20 hours. In a more preferred aspect, said Tmax is 13 to 20 hours.

Some aspects of any of the embodiments bed herein provide a pharmaceutical composition for oral stration to a human, n oral ingestion of a dose of said pharmaceutical composition by a subject of a fasted, single dose, human pharmacokinetic study provides a plasma concentration proﬁle for the drug of said pharmaceutical composition characterized by a Tlag of 0.25 to 9 hours. In a preferred aspect, said Tlag is 0.25 to 5 hours. In a preferred aspect, said Trag is 1 to 9 hours. In a preferred aspect, said Tlag is 2 to 9 hours. In a preferred , said Tlag is 3 to 8 hours. In a preferred aspect, said Tlag is 0.5 to 5 hours. In a preferred aspect, said Tlag is 1 to 5 hours. In a red aspect, said Tlag is 2 to 5 hours.

Some aspects of any of the ments described herein provide a pharmaceutical composition for oral administration to a human, wherein oral ingestion of a dose of said pharmaceutical composition by a subject of a fasted, single dose, human pharmacokinetic study provides a plasma concentration proﬁle for the drug of said pharmaceutical composition characterized by an AUC0.0O provides AUC equivalence to IR.

Some s of any of the ments described herein provide a pharmaceutical composition for oral administration to a human, wherein oral ingestion of a dose of said pharmaceutical composition by a subject of a fasted, single dose, human pharmacokinetic study provides a plasma concentration proﬁle for the drug of said ceutical composition characterized by a dC/dt over the ﬁrst 1.4 hours after ingestion that is less than 10% of the dC/dt determined for an equivalent dose of the drug of said pharmaceutical composition in an immediate release form over the ﬁrst 1.4 hours after ingestion by a subject of said fasted, single dose, human cokinetic study. In a red aspect, the dC/dt determined for said composition is less than 5% of the dC/dt ined for an equivalent dose of the drug of said pharmaceutical composition in an immediate release form over the ﬁrst 1.4 hours after ingestion by a subject of said fasted, single dose, human pharmacokinetic study.

Some aspects of any of the embodiments described herein provide a pharmaceutical composition for oral administration to a human, n oral ingestion of a dose of said pharmaceutical ition by a subject of a fasted, single dose, human pharmacokinetic study es a plasma concentration proﬁle for the drug of said ceutical composition characterized by a dC/dt over the ﬁrst 2 hours after ingestion that is less than 15% of the dC/dt determined for an equivalent dose of the drug of said pharmaceutical composition in an immediate release form over the ﬁrst 2 hours after ingestion by a subject of said fasted, single dose, human pharmacokinetic study. In a preferred aspect, the dC/dt determined for said composition is less than 10% of the dC/dt determined for an equivalent dose of the drug of said pharmaceutical composition in an immediate release form over the ﬁrst 2 hours after ingestion by a subject of said fasted, single dose, human pharmacokinetic study. In a preferred aspect, the dC/dt ined for said composition is less than 5% of the dC/dt determined for an equivalent dose of the drug of said pharmaceutical composition in an immediate release form over the ﬁrst 2 hours after ingestion by a subject of said fasted, single dose, human pharmacokinetic study.

Some aspects of any of the embodiments described herein provide a pharmaceutical composition for oral administration to a human, wherein oral ingestion of a dose of said pharmaceutical composition by a subject of a fasted, single dose, human pharmacokinetic study provides a plasma concentration proﬁle for the drug of said pharmaceutical composition characterized by a dC/dt over the ﬁrst 3 hours after ingestion that is less than 25% of the dC/dt determined for an lent dose of the drug of said ceutical composition in an immediate release form over the ﬁrst 3 hours after ingestion by a subject of said fasted, single dose, human pharmacokinetic study. In a preferred aspect, the dC/dt determined for said ition is less than 20% of the dC/dt determined for an equivalent dose of the drug of said pharmaceutical ition in an immediate release form over the ﬁrst 3 hours after ingestion by a subject of said fasted, single dose, human pharmacokinetic study. In a preferred aspect, the dC/dt determined for said composition is less than 10% of the dC/dt determined for an equivalent dose of the drug of said pharmaceutical composition in an immediate release form over the ﬁrst 3 hours after ingestion by a subject of said fasted, single dose, human cokinetic study.

Some aspects of any of the embodiments described herein provide a ceutical composition for oral administration to a human, wherein oral ingestion of a dose of said pharmaceutical composition by a subject of a fasted, single dose, human pharmacokinetic study provides a plasma tration proﬁle for the drug of said pharmaceutical composition characterized by a dC/dt over the ﬁrst 4 hours after ingestion that is less than 30% of the dC/dt determined for an equivalent dose of the drug of said pharmaceutical composition in an immediate release form over the ﬁrst 4 hours after ingestion by a subject of said fasted, single dose, human pharmacokinetic study. In a preferred aspect, the dC/dt determined for said composition is less than 20% of the dC/dt determined for an equivalent dose of the drug of said pharmaceutical composition in an immediate release form over the ﬁrst 4 hours after ingestion by a subject of said fasted, single dose, human pharmacokinetic study. In a preferred , the dC/dt determined for said composition is less than 10% of the dC/dt determined for an lent dose of the drug of said pharmaceutical ition in an immediate release form over the ﬁrst 4 hours after ingestion by a subject of said , single dose, human pharmacokinetic study.

Some s of any of the embodiments described herein provide a pharmaceutical composition for oral administration to a human, wherein oral ingestion of a dose of said pharmaceutical composition by a subject of a fasted, single dose, human pharmacokinetic study provides a plasma concentration proﬁle for the drug of said pharmaceutical composition terized by a dC/dt over the ﬁrst 2 hours after ingestion that is less than 1 ug/ml/hr. In a preferred aspect, said dC/dt over the ﬁrst 2 hours after ion is less than 0.6 ug/ml/hr. In a preferred aspect, said dC/dt over the ﬁrst 2 hours after ingestion is less than 0.45 ug/ml/hr. In a preferred aspect, said dC/dt over the ﬁrst 2 hours after ingestion is less than 0.3 ug/ml/hr. In a preferred aspect, said dC/dt over the ﬁrst 2 hours after ingestion is less than 0.1 ug/ml/hr.

Some aspects of any of the embodiments described herein provide a pharmaceutical composition for oral administration to a human, wherein oral ingestion of a dose of said pharmaceutical composition by a t of a fasted, single dose, human pharmacokinetic study provides a plasma tration proﬁle for the drug of said pharmaceutical composition characterized by a dC/dt over the ﬁrst 3 hours after ingestion that is less than 0.8 ug/ml/hr. In a red aspect, said dC/dt over the ﬁrst 3 hours after ingestion is less than 0.6 ug/ml/hr. In a preferred aspect, said dC/dt over the ﬁrst 3 hours after ingestion is less than 0.4 ug/ml/hr. In a preferred aspect, said dC/dt over the ﬁrst 3 hours after ingestion is less than 0.25 hr. In a preferred aspect, said dC/dt over the ﬁrst 3 hours after ingestion is less than 0.1 ug/ml/hr, Some aspects of any of the ments described herein provide a pharmaceutical composition for oral administration to a human, n oral ingestion of a dose of said pharmaceutical composition by a subject of a fasted, single dose, human pharmacokinetic study provides a plasma concentration proﬁle for the drug of said pharmaceutical composition characterized by a dC/dt over the ﬁrst 4 hours after ion that is less than 0.6 ug/ml/hr. In a red aspect, said dC/dt over the ﬁrst 4 hours after ingestion is less than 0.5 ug/ml/hr. In a preferred , said dC/dt over the ﬁrst 4 hours after ingestion is less than 0.4 ug/ml/hr. In a preferred aspect, said dC/dt over the ﬁrst 4 hours after ingestion is less than 0.25 ug/ml/hr. In a preferred aspect, said dC/dt over the ﬁrst 4 hours after ingestion is less than 0.1 ug/ml/hr.

Some aspects of any of the embodiments described herein provide a pharmaceutical composition for oral administration to a human, wherein oral ion of a dose of said pharmaceutical composition by a subject of a fasted, single dose, human phannacokinetic study provides a plasma concentration proﬁle for the drug of said pharmaceutical composition characterized by a dC/dt over the ﬁrst 2 hours after ingestion that is less than 2.2 ng/ml/hr per mg of the drug of said pharmaceutical composition. In a preferred aspect, said dC/dt over the ﬁrst 2 hours after ingestion is less than 1.8 hr per mg of the drug of said pharmaceutical composition. In a preferred aspect, said dC/dt over the ﬁrst 2 hours after ingestion is less than 1.4 ng/ml/hr per mg of the drug of said ceutical composition. In a preferred aspect, said dC/dt over the ﬁrst 2 hours after ingestion is less than 1 ng/ml/hr per mg of the drug of said pharmaceutical composition. In a preferred , said dC/dt over the ﬁrst 2 hours after ingestion is less than 0.5 ng/ml/hr per mg of the drug of said pharmaceutical composition.

Some aspects of any of the embodiments described herein provide a pharmaceutical composition for oral administration to a human, wherein oral ingestion of a dose of said ceutical composition by a subject of a fasted, single dose, human pharrnacokinetic study provides a plasma concentration proﬁle for the drug of said pharmaceutical composition characterized by a dC/dt over the ﬁrst 3 hours after ingestion that is less than 2 ng/ml/hr per mg of the drug of said pharmaceutical composition. In a preferred aspect, said dC/dt over the ﬁrst 3 hours after ingestion is less than 1.6 ng/ml/hr per mg of the drug of said pharmaceutical composition. In a preferred aspect, said dC/dt over the ﬁrst 3 hours after ingestion is less than 1.2 hr per mg of the drug of said pharmaceutical composition. In a red aspect, said dC/dt over the ﬁrst 3 hours after ingestion is less than 0.8 ng/ml/hr per mg of the drug of said pharmaceutical ition. In a red aspect, said dC/dt over the ﬁrst 3 hours after ingestion is less than 0.4 hr per mg of the drug of said pharmaceutical composition.

Some aspects of any of the embodiments described herein provide a pharmaceutical composition for oral administration to a human, wherein oral ion of a dose of said ceutical composition by a subject of a fasted, single dose, human phannacokinetic study provides a plasma concentration proﬁle for the drug of said pharmaceutical composition characterized by a dC/dt over the ﬁrst 4 hours after ingestion that is less than 1.6 ng/ml/hr per mg of the drug of said pharmaceutical composition. In a preferred aspect, said dC/dt over the ﬁrst 4 hours after ingestion is less than 1.2 ng/ml/hr per mg of the drug of said pharmaceutical composition. In a preferred aspect, said dC/dt over the ﬁrst 4 hours after ingestion is less than 0.8 ng/ml/hr per mg of the drug of said pharmaceutical ition. In a preferred aspect, said dC/dt over the ﬁrst 4 hours after ingestion is less than 0.4 ng/ml/hr per mg of the drug of said pharmaceutical composition. In a preferred aspect, said dC/dt over the ﬁrst 4 hours after ingestion is less than 0.2 ng/ml/hr per mg of the drug of said pharmaceutical composition.

Some s of any of the embodiments described herein provide a pharmaceutical composition for oral administration to a human, n oral ingestion of a dose of said pharmaceutical composition by a subject of a fasted, single dose, human pharrnacokinetic study provides a plasma concentration proﬁle for the drug of said pharmaceutical composition characterized by a pAUC0.4 that is less than 12% of AUCM determined for the drug of said pharmaceutical composition from said plasma concentration proﬁle. In a preferred aspect, said pAUC0.4 is less than 10% of AUC0.DO determined for the drug of said pharmaceutical composition from said plasma concentration proﬁle. In a preferred aspect, said pAUC0_4 is less than 8% of AUC0.OO determined for the drug of said ceutical composition from said plasma tration proﬁle. In a preferred aspect, said pAUC0-4 is less than 6% of AUC0.QO determined for the drug of said pharmaceutical composition from said plasma concentration proﬁle. In a preferred aspect, said pAUC0.4 is less than 4% of AUC0.0O determined for the drug of said pharmaceutical composition from said plasma concentration proﬁle. In a preferred aspect, said pAUC0.4 is less than 2% of AUCo.00 determined for the drug of said pharmaceutical composition from said plasma concentration proﬁle. In a preferred aspect, said pAUCo.4 is less than 1% of AUC0.0O determined for the drug of said ceutical ition from said plasma concentration , Some aspects of any of the ments described herein provide a pharmaceutical ition for oral administration to a human, wherein oral ingestion of a dose of said pharmaceutical composition by a subject of a fasted, single dose, human pharrnacokinetic study provides a plasma concentration proﬁle for the drug of said pharmaceutical ition characterized by a pAUC0.g that is less than 12% of AUCM determined for the drug of said pharmaceutical composition from said plasma concentration proﬁle. In a preferred aspect, said pAUC0.g is less than 10% of AUCOQO determined for the drug of said pharmaceutical composition from said plasma tration proﬁle. In a preferred aspect, said pAUC0.g is less than 7.5% of AUC0.0O determined for the drug of said pharmaceutical composition from said plasma concentration proﬁle. In a preferred aspect, said pAUC0-3 is less than 5% of AUC0.0O determined for the drug of said pharmaceutical composition from said plasma concentration proﬁle. In a preferred aspect, said pAUC0-g is less than 3% of AUCOI>0 determined for the drug of said pharmaceutical composition from said plasma concentration proﬁle.

Some aspects of any of the embodiments described herein provide a pharmaceutical composition for oral administration to a human, wherein oral ingestion of a dose of said pharmaceutical composition by a subject of a , single dose, human pharmacokinetic study provides a plasma tration proﬁle for the drug of said pharmaceutical composition characterized by a pAUC4.g that is less than 14% of AUCOI>0 ined for the drug of said pharmaceutical composition from said plasma concentration proﬁle. In a preferred aspect, said pAUC4.g is less than 12% of AUCoao determined for the drug of said pharmaceutical ition from said plasma concentration proﬁle. In a preferred aspect, said pAUC4.g is less than 10% of AUCO.00 determined for the drug of said pharmaceutical composition from said plasma concentration proﬁle. In a preferred aspect, said pAUC4-g is less than 8% of AUCO.00 determined for the drug of said pharmaceutical composition from said plasma concentration proﬁle. In a preferred aspect, said pAUC4.g is less than 7% of AUCWO determined for the drug of said pharmaceutical composition from said plasma concentration . In a preferred aspect, said pAUC4.g is less than 6% of O ined for the drug of said pharmaceutical composition from said plasma concentration proﬁle. In a preferred aspect, said pAUC4.g is less than 4% of AUC0.0O determined for the drug of said pharmaceutical composition from said plasma concentration proﬁle. In a preferred aspect, said pAUC4-g is less than 2.5% of AUC0.OO determined for the drug of said ceutical composition from said plasma concentration proﬁle.

Some aspects of any of the embodiments described herein provide a ceutical ition for oral administration to a human, n once daily oral dosing of said ceutical composition to a subject of a fasted, human pharmacokinetic study provides a steady state plasma tration proﬁle for the drug of said pharmaceutical composition characterized by a Tmax,SS that is 5 to 20 hours. In a preferred aspect, said TumSS is 5 to 10 hours.

In a preferred aspect, said Imam is 10 to 20 hours. In a preferred aspect, said Tmax,SS is 12 to 20 hours. In a preferred aspect, said Tmax,SS is 11 to 18 hours. In a preferred aspect, said Tmax,SS is 12 to 18 hours. In a preferred aspect, said Tmax,SS is 13 to 18 hours. In a preferred aspect, said Tmax,SS is 14 to 18 hours. [01 10] Some aspects of any of the embodiments described herein provide a pharmaceutical composition for oral administration to a human, wherein once daily oral dosing of said pharmaceutical composition to a subject of a fasted, human pharmacokinetic study provides a steady state plasma tration profile for the drug of said pharmaceutical composition characterized by a Cmax,SS that is 12 to 36 ng/ml per mg of drug. In a preferred aspect, said Cmax’SS is 16 to 32 ng/ml per mg of drug. In a red aspect, said Cmax,SS is 20 to 30 ng/ml per mg of drug. In a preferred aspect, said Cmax,SS is 22 to 30 ng/ml per mg of drug. In a preferred aspect, said Cmax,SS is 23 to 30 ng/ml per mg of drug. In a preferred , said S is 24 to 32 ng/ml per mg of drug. [01 11] Some aspects of any of the embodiments described herein provide a pharmaceutical composition for oral administration to a human, wherein once daily oral dosing of said WmmememmMmmawWﬁdahmdmmmﬂmmmﬁmwmmemwﬂa steady state plasma concentration profile for the drug of said pharmaceutical composition dmmdamwbyaCMMJMHs6w15mmmpﬂngoﬂmg.mapmﬁnwawmanCmms is 8 to 12.5 ng/ml per mg of drug. In a preferred aspect, said Cmin,SS is 9 to 12 ng/ml per mg of Some aspects of any of the embodiments described herein provide a pharmaceutical composition for oral administration to a human, wherein once daily oral dosing of said MammaMmemmmMnmameufaﬁmﬂhmmnmmmmﬂmwcwwymWM6a steady state plasma concentration e for the drug of said pharmaceutical composition characterized by a swing that is 40% to 200%. In a red aspect, said swing is 60% to 200%.

In a preferred aspect, said swing is 75% to 200%. In a preferred aspect, said swing is 80% to 180%. In a preferred aspect, said swing is 85% to 160%. In a preferred aspect, said swing is 8m6m1m%.hamdﬂmdmmaﬁdeMgm1MMmoUm6hmpmﬁnwawman swing is 50% to 100%. Some s of any of the embodiments described herein e a pharmaceutical ition for oral administration to a human, wherein once daily oral dosing of said pharmaceutical composition to a subject of a fasted, human pharmacokinetic study provides a steady state plasma concentration proﬁle for the drug of said ceutical cmmmmmmdmmaﬂﬁaﬂwaPTmem5W6w1mﬂ8InamﬁﬂmdmmmthPTFm 50% to 90%. In a preferred aspect, said PTF is 55% to 85%. In a red aspect, said PTF is 60% to 80%. In a preferred aspect, said PTF is 45% to 85%. In a preferred aspect, said PTF is 40% to 80%.

Some aspects of any of the embodiments described herein provide a pharmaceutical composition for oral administration to a human comprising a delayed release coating.

Some aspects of any of the embodiments described herein provide a pharmaceutical composition for oral administration to a human, wherein the wherein the drug of said pharmaceutical ition is 50 mg to 900 mg. In a preferred aspect, the drug of said composition is 100 mg to 900 mg. In a preferred aspect, the drug of said composition is 150 mg to 900 mg. In a preferred aspect, the drug of said composition is 300 mg to 900 mg. In a preferred aspect, the drug of said composition is 200 mg to 850 mg. In a preferred aspect, the drug of said composition is 250 mg to 850 mg. In a preferred aspect, the drug of said composition is 300 mg to 850 mg. In a preferred aspect, the drug of said composition is 350 mg to 850 mg. In a preferred aspect, the drug of said composition is 400 mg to 850 mg, In a preferred aspect, the drug of said composition is 450 mg to 850 mg. In a preferred aspect, the drug of said composition is 500 mg to 850 mg. In a preferred , the drug of said ition is 550 mg to 850 mg. In a preferred aspect, the drug of said composition is 600 mg to 850 mg. In a red aspect, the drug of said composition is 650 mg to 850 mg, In a preferred aspect, the drug of said composition is 200 mg to 800 mg. In a preferred aspect, the drug of said ition is 225 mg to 800 mg. In a red aspect, the drug of said composition is 250 mg to 800 mg. In a preferred , the drug of said composition is 400 mg to 800 mg. In a preferred aspect, the drug of said composition is 450 mg to 800 mg, Some embodiments described herein provide a method of administering a pharmaceutical composition to a human, comprising stering to a human orally, once daily, a dose of the pharmaceutical compositions described herein comprising a drug selected from the group consisting of acetam, divalproex, lacosamide, racetam, oxcarbazepine, vigabatrin, and pharmaceutically acceptable salts thereof, and one or more ents, and mixtures of any of the foregoing, wherein at least one of said one or more ents modifies the release of the drug to provide an extended release form, and wherein administration of said pharmaceutical composition preferably es one or more of the following: a Tmax of 5 to 20 hours, an AUCOM of 80% to 125% of that for an equivalent dose of the drug in an immediate release form, and/or a dC/dt over the period of 0 to 1.4 hours after administration that is less than 10% of the dC/dt of an equivalent dose of the drug in an immediate release form over the same time period as determined from a single dose, fasted, human pharrnacokinetic study.

In some aspects of these embodiments, partial AUCs of the compositions are from 8 am to 10 am, 10 am to 12 pm, 12 pm to 2 pm, 2 pm to 4 pm, and 4 pm to 8 pm and are 80% to 125% of the partial AUCs for an equivalent total daily dose of the drug in an immediate release form of said drug administered in equal portions at 8 am and 8 pm.

In some embodiments, oral administration of said pharmaceutical composition to a subject of a fasted, single dose, human pharmaceutical composition provides a drug plasma concentration proﬁle characterized by one or both of the following: a pAUC0.4 for at least one active pharmaceutical ingredient of the composition that is less than 2%, 4%, 6%, 8%, 10%, or 12% of the AUCO-inff0r said active pharmaceutical ingredient of the composition (e. g. <4%), or a pAUC4.8 for at least one active pharmaceutical ingredient of the composition that is less than 3%, 5%, 7%, 9%, 12%, or 15% of the AUCO.jnff0r said active pharmaceutical ient of the composition(e.g. <7%). In preferred aspects the active pharmaceutical ingredient of the composition is selected from the group consisting of brivaracetam, lacosamide, and racetam. In more preferred aspects, the active pharmaceutical ingredient of the composition is lacosamide.

In some embodiments of the invention, the method is directed to orally stering, to a human once daily, a dose of said pharmaceutical ition consisting of a drug selected from the group consisting of brivaracetam, divalproex, lacosamide, levetiracetam, oxcarbazepine, vigabatrin, and pharmaceutically acceptable salts thereof, and one or more excipients, and mixtures of any of the foregoing, wherein at least one of said one or more excipients modiﬁes the release of the drug to provide an extended release form, and wherein administration of said pharmaceutical composition preferably provides one or more of the ing: a Tmax of 12 to 20 hours, AUC equivalence to IR, and/or a dC/dt over the period of O to 1.4 hours after stration that is less than 10% of the dC/dt of an equivalent dose of the drug in an immediate release form over the same time period as determined from a single dose, fasted, human pharmacokinetic study. [01 19] In other embodiments of the invention, the method of administering, to a human , once daily, a dose of said pharmaceutical composition ting of a drug selected from the group consisting of acetam, divalproex, lacosamide, racetam, oxcarbazepine, vigabatrin, and pharmaceutically acceptable salts thereof, and one or more excipients, wherein at least one of said one or more excipients modifies the release of the drug to provide an extended release form, wherein the dissolution profile of said pharmaceutical composition is characterized by 2 or more of the following: (i) release of less than 8% in 2 hours, (ii) e of less than 17% in 4 hours, (iii) release of less than 45% at 6 hours, and/or (iv) release of at least 45% at 12 hours; n the dissolution is typically performed in a USP type 1 (basket) apparatus rotating at 100 rpm using 900 ml 0.1 N HCl at 37 5°C for 2 hours followed by dissolution in the same apparatus and speed using 900 ml USP phosphate buffer pH 6.8 at 37.0::0.5°C, and wherein administration of said pharmaceutical composition provides one or more of the following: a Tmax of 12 to 20 hours, AUC equivalence to IR, and/or a dC/dt over the period of 0 to 1.4 hours after stration that is less than 10% of the dC/dt of an equivalent dose of the drug in an immediate release form over the same time period as determined from a single dose, fasted, human pharmacokinetic study.

In another embodiment of the invention, the pharmaceutical composition is administered 0 to 4 hours before bedtime, and said pharmaceutical composition comprising an AED selected from the group consisting of brivaracetam, divalproex, mide, levetiracetam, oxcarbazepine, vigabatrin, and pharmaceutically acceptable salts thereof, provides a Tmax of 12 to 20 hours, AUC equivalence to IR, and a dC/dt over the period of 0 to 1.4 hours after administration that is less than 10% of the dC/dt of an equivalent dose of the drug in an immediate release form over the same time period as determined from a single dose, fasted, human pharmacokinetic study.

In some embodiments of the invention, the method of administering a pharmaceutical composition to a human, comprising orally administering to a human, once daily, a dose of said ceutical composition consisting of a drug selected from the group consisting of brivaracetam, divalproex, lacosamide, racetam, azepine, vigabatrin, and pharmaceutically acceptable salts f, and one or more excipients, wherein at least one of said one or more excipients modifies the release of the drug to provide an extended release form, and wherein administration of said pharmaceutical composition provides a Tmax of 5 to 10 hours, AUC equivalence to IR, and a dC/dt over the period of 0 to 1.4 hours after administration that is less than 10% of the dC/dt of an equivalent dose of the drug in an immediate release form over the same time period as determined from a single dose, fasted, human pharmacokinetic study. In some aspects of this embodiment, the drug is administered 0 to 3 hours after waking for the day, ably between 5:00 am and 9:00 am.

Another embodiment is directed to a method of administering a pharmaceutical composition to a human, comprising administering to said human orally, once daily, a dose of said pharmaceutical composition consisting of a drug selected from the group ting of brivaracetam, mide, racetam, oxcarbazepine, divalproex, vigabatrin, and pharmaceutically acceptable salts thereof, and one or more excipients, wherein at least one of said one or more excipients modifies the release of the drug to provide an ed release form, and wherein administration of said ceutical ition provides a Tmax of 5 to 20 hours, AUC equivalence to IR, and a C-ave-day that is 20% to 100% greater than C-ave-night as determined from a fasted human pharmacokinetic study. In a preferred aspect of this embodiment, C—ave—day is the average plasma concentration at steady state determined over the period from 9 am to 6 pm and C-ave-night is the average plasma concentration at steady state ined over the period from 11 pm to 8 am. In a red aspect of this embodiment, the C-ave-day and night determinations are from a WinNonLin model or a GastroPlus model of the steady state plasma concentration proﬁle for a once daily orally administered ition of said drug. In r preferred aspect of this embodiment, the C-ave-day is 30%, 40%, 50%, 60% to 60%, 70%, 80%, 90%, or 100% greater than C—ave-nighti Some embodiments are directed to a method of administering a pharmaceutical composition to a human, comprising administering to said human orally, once daily, a dose of said pharmaceutical composition consisting of (i) a drug selected from the group consisting of brivaracetam, lacosamide, levetiracetam, oxcarbazepine, divalproex, Vigabatrin, and pharmaceutically acceptable salts thereof, and (ii) one or more ents, wherein at least one of said one or more excipients modiﬁes the release of the drug to provide an extended release form, and wherein stration of said pharmaceutical composition provides a) a Tmax of 12 to hours and b) AUC equivalence to IR, and a C—ave—day that is 20% to 100% greater than C— ave-night as determined from a fasted human pharmacokinetic study.

In some embodiments, administration of the pharmaceutical composition is 0 to 4 hours before bedtime and provides a Tmx of 12 to 20 hours as determined from a single dose, fasted, human cokinetic study. In some embodiments, the ceutical composition is administered once daily 0 to 4 hours before bedtime. In some aspects of these embodiments, the C—ave—day is 20 to 100% greater than the C—ave—night wherein C—ave—day is ined over the period from 9 am to 6 pm and C-ave-night is determined over the period from 11 pm to 8 am.

Some embodiments are directed to a method of administering a pharmaceutical composition to a human, comprising stering to said human orally, once daily, a dose of said pharmaceutical composition ting of (i) a drug selected from the group consisting of brivaracetam, lacosamide, levetiracetam, oxcarbazepine, divalproex, Vigabatrin, and pharmaceutically acceptable salts thereof, and (ii) one or more excipients, wherein at least one of said one or more excipients modiﬁes the release of the drug to e an extended e form, and wherein stration of said pharmaceutical composition provides a) a Tmax of 5 to hours and b) AUC equivalence to IR, and a C-ave—day that is 20% to 100% greater than C— ave—night as determined from a fasted human pharmacokinetic study.

Some embodiments are directed to a method of administering a pharmaceutical composition to a human, comprising administering to said human orally, once daily 0 to 3 hours after waking, a dose of said pharmaceutical composition consisting of (i) a drug selected from the group consisting of brivaracetam, lacosamide, levetiracetam, oxcarbazepine, divalproex, Vigabatrin, and pharmaceutically acceptable salts thereof, and (ii) one or more excipients, wherein at least one of said one or more excipients modiﬁes the release of the drug to provide an extended release form, and wherein administration of said pharmaceutical ition provides a) a Tmax of 5 to 10 hours; and b) AUC equivalence to IR, and a C-ave-day that is 20% to 100% greater than C-ave-night as determined from a fasted human pharmacokinetic study.

Some embodiments are directed to a method of administering a pharmaceutical composition to a human, comprising administering to said human orally, once daily, a dose of said pharmaceutical ition consisting of (i) a drug selected from the group consisting of acetam, lacosamide, levetiracetam, oxcarbazepine, roex, vigabatrin, and pharmaceutically acceptable salts thereof, and (ii) one or more excipients, wherein at least one of said one or more excipients modiﬁes the release of the drug to provide an extended release form, and wherein oral dosing of said composition to a subject of a fasted, single dose, human pharmacokinetic study es a plasma proﬁle characterized by one or more of the following elements: (i) a Tmax of 5 to 20 hours, (ii) AUC equivalence to IR, (iii) a dC/dt over the period of 0 to 2 hours that is less than 1 ug/ml/hr, (iv) a dC/dt over the period of 0—2 hours that is less than 2 ng/ml/hr per mg of drug, (v) a pAUC0_4 that is less than 4% of AUCOM for the drug, (vi) a pAUC4.8 that is less than 8% of AUCOM for the drug. In some embodiments, the plasma proﬁle is characterized by two or more of these elements. In some ments, the plasma proﬁle is terized by three or more of these elements. In some ments, the plasma proﬁle is characterized by four or more of these elements. In some of these embodiments, the plasma concentration proﬁle is terized by a Tmax of 12 to 20 hours. In some of these embodiments, the plasma concentration proﬁle is characterized by a Tmax of 5 to 10 hours.

Some embodiments are directed to a method of administering a pharmaceutical composition to a human, comprising administering to said human orally, once daily, a dose of said pharmaceutical composition consisting of (i) a drug selected from the group consisting of brivaracetam, lacosamide, levetiracetam, oxcarbazepine, divalproex, vigabatrin, and pharmaceutically acceptable salts f, and (ii) one or more excipients, wherein at least one of said one or more excipients modiﬁes the release of the drug to provide an extended release form, and wherein oral dosing of said composition to a t of a fasted, single dose, human pharmacokinetic study provides a plasma proﬁle characterized by one or more of the following elements: (i) a Tmax of 5 to 20 hours, (ii) AUC equivalence to IR, (iii) a dC/dt over the period of 0 to 2 hours that is less than 1 ug/ml/hr, (iv) a dC/dt over the period of 0-2 hours that is less than 2 ng/ml/hr per mg of drug, (v) a pAUC0.4 that is less than 4% of AUCOM for the drug, (vi) a pAUC4.g that is less than 8% of AUC0.mf for the drug, and (iii) one or more additional drugs selected from the group ting of brivaracetam, lacosamide, levetiracetam, azepine, divalproex, vigabatrin, and pharmaceutically acceptable salts thereof. In some embodiments, the plasma proﬁle is characterized by two or more of these elements. In some embodiments, the plasma proﬁle is characterized by three or more of these elements. In some embodiments, the plasma proﬁle is characterized by four or more of these elements. In some of these embodiments, the plasma concentration proﬁle is characterized by a Tmax of 12 to 20 hours. In some of these embodiments, the plasma concentration proﬁle is characterized by a Tmax of 5 to hours.

Some embodiments are directed to methods of stering a pharmaceutical composition to a human, comprising administering to said human orally, once daily, a dose of said pharmaceutical composition consisting of a drug selected from the group consisting of brivaracetam, lacosamide, racetam, oxcarbazepine, divalproex, Vigabatrin, and pharmaceutically acceptable salts f, and one or more excipients, wherein at least one of said one or more excipients modiﬁes the release of the drug to provide an extended release form, wherein the dissolution proﬁle of said pharmaceutical ition is less than 8% in 2 hours, less than 17% in 4 hours, less than 45% at 6 hours, and at least 45% at 12 hours, wherein the dissolution is performed in a USP type 1 (basket) tus rotating at 100 rpm using 900 ml 0.1 N HCl at 37.0::0.5°C for 2 hours followed by dissolution in the same apparatus and speed using 900 ml USP phosphate buffer pH 68 at 37.0i0.5°C, and wherein administration of said pharmaceutical composition provides a Tmax of 5 to 20 hours, AUC equivalence to IR, and a C- ave-day that is 20% to 100% greater than night as determined from a fasted human pharmacokinetic study.

Some embodiments are ed to methods of administering a pharmaceutical composition to a human, comprising administering to said human orally, once daily, a dose of said pharmaceutical composition consisting of a drug selected from the group consisting of brivaracetam, lacosamide, levetiracetam, oxcarbazepine, roex, Vigabatrin, and pharmaceutically acceptable salts thereof, and one or more excipients, wherein at least one of said one or more excipients modiﬁes the e of the drug to provide an extended release form, wherein the dissolution proﬁle of said pharmaceutical composition characterized by at least two of the following: (i) release of less than 8% in 2 hours, (ii) release of less than 17% in 4 hours, (iii) release of less than 45% at 6 hours, and wherein the ution proﬁle of said pharmaceutical ition is terized by release of at least 45% at 12 hours, wherein the dissolution is performed in a USP type 1 (basket) apparatus rotating at 100 rpm using 900 ml 0.1 N simulated gastric ﬂuid (pH 1.2) at 37.0::0.5°C for 2 hours, followed by dissolution in the same apparatus and speed using 900 ml simulated intestinal ﬂuid (pH 6.8) at 37.0i—0.5°C for the subsequent 4 hours, followed by dissolution in the same tus and speed using 900 m1 phosphate buffer (pH 7.5) at 0.5°C for the subsequent 18 hours, and wherein oral dosing of said pharmaceutical ition to a subject of a fasted, single dose, human cokinetic ﬁMymwamwmawmmmmmwmmemammﬁwbyMmﬂﬁ5m2MmmsMame aspects of this embodiment, said plasma concentration proﬁle provides AUC equivalence to IR.

In some aspects of this embodiment, said plasma concentration proﬁle is characterized by one or more of the following: (i) a dC/dt over the period of 0 to 2 hours that is less than 1 ug/ml/hr, (ii) a dC/dt over the period of 0-2 hours that is less than 2 ng/ml/hr per mg of drug, (iii) a pAUC0-4 that is less than 4% of AUCOM for the drug, (iv) a pAUC4.g that is less than 8% of AUCOM for the drug. In some aspects, the plasma proﬁle is characterized by two or more of these elements.

InmmeamMsﬂwphmmpmmemdmmamﬁwbymmmxmmedﬂmmdmmMsInmme embodiments, the drug is selected from the group consisting of brivaracetam, lacosamide, and levetiracetam, In some ments, the drug is lacosamide.

In some aspects of any of the previous embodiments, oral dosing of the composition to a subject of a fasted, human pharmacokinetic study provides a steady state plasma concentration proﬁle for once daily oral dosing characterized by one or more of the following: (i) a Tmax,SS of to 20 hours, (ii) a Tum)SS of 12 to 20 hours, (iii) a C-ave-day that is 20% to 100% greater than C-ave-night (iii) a swing of 70% to 200%, (iv) a swing of 75% to 160%, (v) a PTF of 50% to 100%, preferably .

In some aspects, the steady state plasma proﬁle is terized by two or more of these elements. In some aspects, the steady state plasma proﬁle is characterized by three or more of these elements. In some aspects, the C-ave-day is determined over the period from 9 am to 4 pm. In some aspects, the C—ave—day is determined over the period from 9 am to 6 pm. In some aspects, the C-ave-night is determined over the period from 11 pm to 8 am. In some aspects, the steady state plasma concentration proﬁle is adjusted to a predetermined amnmmﬁmmnﬁmempKWMeaC4wa¢wﬁmﬁs2W6mlOWGgmMﬂﬂmnmeCavemgm.

In some aspects, the steady state plasma concentration proﬁle is adjusted to a predetermined ammmmmmmﬁmempKwMeaCamdamMﬂs«WhoMm%gmmaﬂmnme0wmmgm, Some embodiments are directed to a method of administering a pharmaceutical composition to a human, comprising administering to said human orally, once daily, a dose of said ceutical ition ting of: a drug selected from the group ting of brivaracetam, lacosamide, levetiracetam, oxcarbazepine, divalproex, vigabatrin, and pharmaceutically acceptable salts thereof, and one or more excipients, wherein at least one of said one or more excipients modiﬁes the release of the drug to provide an extended e form, aMmemwmmwmmmﬁmMMmewwMMm%MMmmeanmﬁ5wﬁmwm an AUCO-inf of 80% to 125% of that for an equivalent dose of the drug in an immediate release form, wherein the l AUCs from 8 am to 10 am, 10 am to 12 pm, 12 pm to 2 pm, 2, pm to 4 pm, and 4 pm to 8 pm are 80% to 125% of the partial AUCs for an equivalent total daily dose of the drug in an immediate release form of said drug administered in equal portions at 8 am and 8 pm, and wherein C—ave-day that is 20% to 100% greater than C-ave-night as determined from a fasted human pharmacokinetic study.

Some embodiments are directed to a method of stering a pharmaceutical composition to a human, comprising administering to said human orally, once daily, a dose of said ceutical composition consisting of a drug selected from the group consisting of brivaracetam, lacosamide, levetiracetam, azepine, divalproex, Vigabatrin, and pharmaceutically acceptable salts thereof, and one or more excipients, wherein at least one of said one or more excipients modiﬁes the release of the drug to provide an extended release form, and wherein said pharmaceutical composition provides a plasma concentration proﬁle characterized by a Tmax of 5 to 20 hours and /or (i) an AUC0.4 for the drug of less than 2%, 4%, 6%, 8%, 10%, 12% (preferably less than 4%) of the AUCO-inf for said drug or (ii) an AUC4-8 for the drug of less than 3%, 5%, 7%, 9%, 12%, 15% rably less than 7%) of the AUCOM for said drug, wherein TmX and AUC values are determined from the plasma concentration for said drug upon oral administration of the pharmaceutical composition to a subject of a fasted, single dose human pharmacokinetic study. In some embodiments, the AUCOM for said drug of the composition is 80% to 125% of the AUCO.inf for said drug when administered in an oral, immediate release form to said subject of said fasted, single dose, human pharmacokinetic study.

In some embodiments, said drug is selected from the group consisting of brivaracetam, lacosamide, and levetiracetam. In some ments, said drug is lacosamide.

Another ment is a pharmaceutical composition consisting of a drug selected from the group consisting of brivaracetam, lacosamide, levetiracetam, oxcarbazepine, divalproex, Vigabatrin, and pharmaceutically acceptable salts thereof, and one or more ents, wherein at least one of said one or more ents modifies the release of the drug to provide an extended release form, and n stration of said pharmaceutical composition provides a Tm” of to 20 hours, AUC equivalence to IR, and a dC/dt over the period of 0 to 1.4 hours after administration that is less than 10% of the dC/dt of an equivalent dose of the drug in an immediate release form over the same time period as determined from a single dose, fasted, human pharmacokinetic study.

Another ment is a pharmaceutical composition consisting of a drug selected from the group consisting of brivaracetam, lacosamide, levetiracetam, oxcarbazepine, divalproex, Vigabatrin, and pharmaceutically acceptable salts thereof, and one or more excipients, wherein at least one of said one or more excipients modiﬁes the release of the drug to e an extended release form, and n administration of said pharmaceutical composition es a Tmax of 12 to 20 hours, AUC equivalence to IR, and a dC/dt over the period of 0 to 1.4 hours after stration that is less than 10% of the dC/dt of an equivalent dose of the drug in an immediate release form over the same time period as determined from a single dose, fasted, human pharmacokinetic study.

Additional embodiments provide a pharmaceutical composition consisting of a drug selected from the group consisting of brivaracetam, mide, levetiracetam, oxcarbazepine, divalproex, vigabatrin, and ceutically acceptable salts thereof, and one or more excipients, wherein at least one of said one or more excipients modiﬁes the e of the drug to provide an extended release form, and wherein administration of said pharmaceutical ition provides a Tmax of 5 to 20 hours, AUC equivalence to IR, and one or more of the following: (i) a dC/dt over the period of 0 to 2 hours after administration that is less than 5%, %, 15% of the dC/dt of an equivalent dose of the drug in an immediate release form over the same time period, (ii) a dC/dt over the period of 0 to 3 hours after administration that is less than %, 15%, 20% of the dC/dt of an equivalent dose of the drug in an immediate release form over the period of O to 3 hours after administration and (iii) a dC/dt over the period of 0 to 4 hours after stration that is less than 10%, 15%, 20%, 25%, 30% of the dC/dt of an equivalent dose of the drug in an immediate release form over the period of 0 to 4 hours after administration, wherein the dC/dt values are determined from a fasted, single dose, human pharmacokinetic study.

In a preferred aspect of this embodiment, the drug is selected from the group consisting of brivaracetam, lacosamide, racetam, and pharmaceutically acceptable salts f. In a more preferred aspect of this embodiment, the drug is lacosamide.

Another embodiment is a pharmaceutical composition consisting of a drug selected from the group consisting of lacosamide and pharmaceutically acceptable salts thereof, and one or more ents, wherein at least one of said one or more excipients modiﬁes the release of the drug to provide an extended release form, and n administration of said pharmaceutical composition provides a TmaX of 5 to 20 hours, and one or more of the following: (i) a dC/dt over the period of 0 to 2 hours after administration that is less than 0.5, 1.0, 1.5, 2.0 ng/ml/hr per mg of drug, (ii) a dC/dt over the period of 0 to 3 hours after administration that is less than 0.25, 0.5, 1.0, 1.5, 2.0 hr per mg of drug, (iii) a dC/dt over the period of 0 to 4 hours after administration that is less than 0.25, 0.50, 0.75, 1.00, 1,25, 1.50 ng/ml/hr per mg of drug, (iv) a dC/dt over the period of 0 to 2 hours after administration that is less than 0.2, 0,4, 0.6, 0.8 ug/ml/hr, (v) a dC/dt over the period of 0 to 3 hours after administration that is less than 0.2, 0.4, 0.6, 0.8 ug/ml/hr, (vi) a dC/dt over the period of 0 to 4 hours after administration that is less than 0.1, 0.2, 0.3, 0.4, 0.5, 0.6 ug/ml/hr, wherein Tmax and dC/dt values for the drug are determined from a fasted, oral, single dose, human pharmacokinetic study.

In some embodiments, stration of the pharmaceutical composition provides a Tmax of 5 to 10 hours as ined from a single dose, fasted, human pharmacokinetic study.

In another embodiment the pharmaceutical ition consisting of a drug selected from the group consisting of brivaracetam, lacosamide, levetiracetam, oxcarbazepine, divalproex, vigabatrin, and pharmaceutically acceptable salts thereof, and one or more excipients, wherein at least one of said one or more excipients modiﬁes the release of the drug to provide an extended release form, the pharmaceutical composition having a dissolution proﬁle of said pharmaceutical composition is less than 8% in 2 hours, less than 17% in 4 hours, less than 45% at 6 hours, and at least 45% at 12 hours, wherein the dissolution is performed in a USP type 1 (basket) apparatus ng at 100 rpm using 900 ml 0.1 N HCl at 37.0::0.5°C for 2 hours followed by dissolution in the same apparatus and speed using 900 ml USP phosphate buffer pH 6.8 at 37.0i0.50C, and n administration of said pharmaceutical composition provides a Tmax of 5 to 20 hours, AUC equivalence to IR, and a dC/dt over the period of 0 to 1.4 hours after administration that is less than 10% of the dC/dt of an lent dose of the drug in an immediate release form over the same time period as determined from a single dose, fasted, human pharmacokinetic study.

In some embodiments described herein, a pharmaceutical composition consists of a drug selected from the group consisting of brivaracetam, lacosamide, levetiracetam, oxcarbazepine, divalproex, vigabatrin, and pharmaceutically acceptable salts thereof, and one or more excipients, wherein at least one of said one or more excipients modiﬁes the release of the drug to provide an extended release form, and n administration of said pharmaceutical composition provides a Tmax of 5 to 20 hours and b) AUC equivalence to IR, wherein the partial AUCs from 8 am to 10 am, 10 am to 12 pm, 12 pm to 2 pm, 2, pm to 4 pm, and 4 pm to 8 pm are 80% to 125% of the partial AUCs for an equivalent total daily dose of the drug in an immediate release form of said drug administered in equal portions at 8 am and 8 pm, a dC/dt over the period of 0 to 1.4 hours after administration that is less than 10% of the dC/dt of an equivalent dose of the drug in an immediate release form over the same time period as determined from a single dose, fasted, human pharmacokinetic study.

In yet another ment, the pharmaceutical composition consists of a drug ed from the group ting of brivaracetam, mide, levetiracetam, oxcarbazepine, divalproex, vigabatrin, and pharmaceutically acceptable salts thereof, and one or more excipients, n at least one of said one or more excipients modifies the release of the drug to provide an extended release form, and wherein administration of said pharmaceutical composition es a) a Tmax of 5 to 20 hours and b) AUC equivalence to IR, and a C-ave-day that is 20% to 100% greater than C-ave-night as determined from a fasted human pharmacokinetic study.

In another embodiment, the pharmaceutical composition consists of a drug selected from the group consisting of brivaracetam, lacosamide, levetiracetam, oxcarbazepine, divalproex, Vigabatrin, and pharmaceutically acceptable salts thereof, and one or more excipients, wherein at least one of said one or more excipients modiﬁes the release of the drug to provide an ed release form, and wherein administration of said pharmaceutical composition provides a) a Tmax of 12 to 20 hours and b) AUC equivalence to IR, and a C—ave—day that is 20% to 100% greater than C-ave-night as determined from a fasted human phannacokinetic study.

In yet another embodiment, the pharmaceutical composition consists of a drug selected from the group consisting of acetam, mide, levetiracetam, oxcarbazepine, divalproex, Vigabatrin, and pharmaceutically acceptable salts thereof, and one or more excipients, wherein at least one of said one or more ents modiﬁes the release of the drug to provide an ed release form, and wherein administration of said pharmaceutical composition provides a) a Tmax of 5 to 10 hours and b) AUC lence to IR, and a C-ave—day that is 20% to 100% greater than C-ave-night as determined from a fasted human cokinetic study.

Another embodiment is directed to a the pharmaceutical composition consists of a drug selected from the group consisting of brivaracetam, lacosamide, levetiracetam, oxcarbazepine, divalproex, trin, and pharmaceutically acceptable salts thereof, and one or more excipients, wherein at least one of said one or more excipients modiﬁes the release of the drug to provide an extended release form, wherein the dissolution proﬁle of said pharmaceutical ition is less than 8% in 2 hours, less than 17% in 4 hours, less than 45% at 6 hours, and at least 45% at 12 hours, wherein the ution is performed in a USP type 1 (basket) apparatus rotating at 100 rpm using 900 ml 0.1 N HCl at 37.0:t0.5°C for 2 hours ed by dissolution in the same apparatus and speed using 900 ml USP phosphate buffer pH 6.8 at 37.0::0.5°C, and wherein administration of said pharmaceutical composition provides a) a Tmax of 5 to 20 hours, and b) an AUCO.inf of 80% to 125% of that for an lent dose of the drug in an immediate release form, and a C—ave-day that is 20% to 100% greater than C—ave—night as determined from a fasted human pharrnacokinetic study.

Some embodiments are directed to a pharmaceutical composition selected from a group consisting of a drug selected from the group consisting of brivaracetam, lacosamide, levetiracetam, azepine, divalproex, trin, and pharmaceutically acceptable salts thereof, and one or more excipients, wherein at least one of said one or more excipients modiﬁes the e of the drug to provide an extended release form, wherein administration of said pharmaceutical composition provides a Tmax of 5 to 20 hours and AUC equivalence to IR, wherein the partial AUCs from 8 am to 10 am, 10 am to 12 pm, 12 pm to 2 pm, 2, pm to 4 pm, and 4 pm to 8 pm are 80% to 125% of the partial AUCs for an equivalent total daily dose of the drug in an immediate release form of said drug administered in equal ns at 8 am and 8 pm and n a C-ave-day that is 20% to 100% r than C-ave—night as determined from a fasted human pharmacokinetic study.

Some embodiments are ed to a method of administering a pharmaceutical composition to a human, comprising administering to said human orally, once daily, a dose of said pharmaceutical composition consisting of (i) a drug selected from the group ting of brivaracetam, divalproex, lacosamide, levetiracetam, oxcarbazepine, vigabatrin, and pharmaceutically acceptable salts thereof, and (ii) at least one excipient, wherein at least one of said excipients s the release of the drug to provide an extended release form, and wherein administration of said pharmaceutical composition provides a) a TmaX of 5 to 20 hours and b) AUC equivalence to IR, and c) a dC/dt over the period of O to 1.4 hours after administration that is less than 10% of the dC/dt of an equivalent dose of the drug in an immediate release form over the same time period as determined from a single dose, fasted, human cokinetic study.

In some aspects of that embodiment, the administration of the pharmaceutical composition provides a Tmax of 12 to 20 hours as determined from a single dose, , human pharmacokinetic study.

In some aspects of that embodiment, the administration is 0 to 4 hours before bedtime.

In some aspects of that embodiment, stration of said ceutical composition provides a TmaX of 5 to 10 hours as determined from a single dose, fasted, human pharmacokinetic study. In some aspects of that embodiment, administration is 0 to 3 hours after waking.

In some embodiments of the invention providing a composition with a TmaX of 12 to 20 hours as determined from a single dose, fasted, human pharmacokinetic study, the dissolution proﬁle of the pharmaceutical composition is less than 8% in 2 hours, less than 17% in 4 hours, less than 45% at 6 hours, and at least 45% at 12 hours, wherein the dissolution is performed in a USP type 1 (basket) apparatus rotating at 100 rpm using 900 ml 0.1 N HCl at 37.0i0.5°C for 2 hours followed by dissolution in the same apparatus and speed using 900 ml USP phosphate buffer pH 6.8 at 37.010500 In some embodiments of the pharmaceutical composition consisting of (i) a drug selected from the group consisting of brivaracetam, roex, lacosamide, levetiracetam, oxcarbazepine, vigabatrin, and pharmaceutically acceptable salts thereof, and (ii) at least one ent, wherein at least one of said ents modiﬁes the release of the drug to provide an extended e form, and wherein administration of said pharmaceutical composition provides a) a Tmax of 5 to 20 hours and b) AUC equivalence to IR, and c) a dC/dt over the period of 0 to 1.4 hours after administration that is less than 10% of the dC/dt of an equivalent dose of the drug in an immediate release form over the same time period as determined from a single dose, fasted, human pharmacokinetic study, the partial AUCs from 8am to 10 am, 10 am to 12 pm, 12 pm to 2 pm, 2, pm to 4 pm, and 4 pm to 8 pm are 80% to 125% ofthe partial AUCs for an equivalent total daily dose of the drug in an immediate release form of said drug administered in equal portions at 8 am and 8 pm.

Some embodiments of the invention are directed to s of administering a pharmaceutical ition to a human, comprising administering to said human orally, once daily, a dose of said pharmaceutical composition consisting of (i) a drug selected from the group consisting of brivaracetam, lacosamide, levetiracetam, oxcarbazepine, divalproex, vigabatrin, and pharmaceutically acceptable salts thereof, and (ii) at least one excipient, n at least one of said excipients modiﬁes the release of the drug to e an extended e form, and wherein administration of said pharmaceutical composition provides a) a Tmax of 5 to 20 hours and b) AUC equivalence to IR, and a C—ave—day that is 20% to 100% greater than C—ave—night as determined from a fasted human pharmacokinetic study.

In some aspects of the above embodiment, the administration of said pharmaceutical composition provides a Tmax of 12 to 20 hours as determined from a single dose, fasted, human pharmacokinetic study. In some of these ments, administration is 0 to 4 hours before bedtime.

In other aspects of the above embodiment, administration of said pharmaceutical composition provides a Tmax of 5 to 10 hours as determined from a single dose, fasted, human pharmacokinetic study. In some of these embodiments, administration is 0 to 3 hours after waking.

Some embodiments of the invention are directed to a dose of a ceutical composition consisting of (i) a drug selected from the group consisting of brivaracetam, lacosamide, levetiracetam, oxcarbazepine, divalproex, vigabatrin, and pharmaceutically acceptable salts thereof, and (ii) at least one excipient, wherein at least one of said excipients modifies the release of the drug to provide an extended release form, and wherein administration of said pharmaceutical composition provides a) a Tmax of 5 to 20 hours and b) AUC equivalence to IR, and a C-ave-day that is 20% to 100% greater than C—ave—night as ined from a fasted human cokinetic study, wherein the dissolution profile of said ceutical composition is less than 8% in 2 hours, less than 17% in 4 hours, less than 45% at 6 hours, and at least 45% at 12 hours, wherein the dissolution is performed in a USP type 1 (basket) apparatus rotating at 100 rpm using 900 ml 0.1 N HCl at 37.0i0.5°C for 2 hours followed by ution in the same apparatus and speed using 900 ml USP phosphate buffer pH 6.8 at 37.0i0.5°C.

In some aspects of the above embodiment, the partial AUCs from 8am to 10 am, 10 am to 12 pm, 12 pm to 2 pm, 2, pm to 4 pm, and 4 pm to 8 pm are 80% to 125% of the partial AUCs for an equivalent total daily dose of the drug in an immediate release form of said drug stered in equal portions at 8 am and 8 pm.

Some embodiments of the invention are directed to a pharmaceutical composition ting of (i) a drug selected from the group consisting of brivaracetam, lacosamide, levetiracetam, oxcarbazepine, divalproex, vigabatrin, and pharmaceutically acceptable salts f, and (ii) at least one excipient, wherein at least one of said excipients modifies the release of the drug to provide an extended release form, and wherein administration of said ceutical composition provides a) a TmaX of 5 to 20 hours and b) AUC equivalence to IR, and c) a dC/dt over the period of 0 to 1.4 hours after stration that is less than 10% of the dC/dt of an lent dose of the drug in an immediate release form over the same time period as determined from a single dose, fasted, human pharmacokinetic study.

In some of these embodiments, the partial AUCs from 8am to 10 am, 10 am to 12 pm, 12 pm to 2 pm, 2, pm to 4 pm, and 4 pm to 8 pm are 80% to 125% ofthe partial AUCs for an lent total daily dose of the drug in an immediate release form of said drug administered in equal portions at 8 am and 8 pm.

In some aspects of the embodiment, administration of said pharmaceutical composition provides a TmaX of 12 to 20 hours or of 5 to 10 hours as determined from a single dose, fasted, human acokinetic study.

In some aspects of the embodiment, the dissolution proﬁle of said pharmaceutical composition is less than 8% in 2 hours, less than 17% in 4 hours, less than 45% at 6 hours, and at least 45% at 12 hours, wherein the dissolution is performed in a USP type 1 (basket) apparatus rotating at 100 rpm using 900 ml 0.1 N HCl at 37.0::0.5°C for 2 hours followed by dissolution in the same apparatus and speed using 900 ml USP phosphate buffer pH 6.8 at 37.0::0.5°C. In some of these embodiments, Some ments of the invention are directed to a pharmaceutical composition consisting of (i) a drug selected from the group consisting of brivaracetam, lacosamide, levetiracetam, oxcarbazepine, divalproex, vigabatrin, and pharmaceutically able salts thereof, and (ii) at least one excipient, wherein at least one of said excipients modiﬁes the release of the drug to provide an ed release form, and wherein administration of said pharmaceutical composition provides a) a Tmax of 5 to 20 hours and b) AUC equivalence to IR, and a C-ave—day that is 20% to 100% greater than C-ave-night as ined from a fasted human pharmacokinetic study. In some of these embodiments, the dissolution proﬁle of the pharmaceutical composition is less than 8% in 2 hours, less than 17% in 4 hours, less than 45% at 6 hours, and at least 45% at 12 hours, wherein the dissolution is performed in a USP type 1 (basket) apparatus rotating at 100 rpm using 900 ml 0.1 N HCl at 37.0i0150C for 2 hours followed by dissolution in the same apparatus and speed using 900 ml USP phosphate buffer pH 6.8 at 37.0:t0.50C.

In some embodiments of the ion, stration of said pharmaceutical composition provides a Tmax of 12 to 20 hours as determined from a single dose, fasted, human pharmacokinetic study. In other embodiments, the Tmax is 5 to 10 hours as determined from a single dose, fasted, human pharmacokinetic study.

In some aspects of the above embodiments, the pharmaceutical ition provides partial AUCs from 8am to 10 am, 10 am to 12 pm, 12 pm to 2 pm, 2, pm to 4 pm, and 4 pm to 8 pm are 80% to 125% of the partial AUCs for an equivalent total daily dose of the drug in an immediate e form of said drug administered in equal portions at 8 am and 8 pm.

In some of the embodiments of pharmaceutical compositions described in the preceding paragraphs, the drug is lacosamide.

In some method embodiments bed in the preceding paragraphs, the drug is lacosamide.

An ment of the invention is a method of administering a pharmaceutical composition to a human patient, comprising administering to the human patient , once daily, a therapeutically effective dose of the ceutical composition wherein the pharmaceutical composition comprises (i) a drug selected from the group consisting of brivaracetam, divalproex, lacosamide, levetiracetam, oxcarbazepine, vigabatrin, and pharmaceutically acceptable salts of any of the foregoing, and (ii) at least one excipient, n at least one of the at least one excipients modiﬁes the release of the drug to provide an extended release form wherein the pharmaceutical composition has a plasma concentration proﬁle for the drug characterized by a pAUC0.4 that is less than 4% of AUCOM for the drug as determined by dosing the ceutical composition to a subject of a fasted, single dose, human pharmacokinetic study. In some aspects of the embodiment, the drug is selected from the group ting of brivaracetam, lacosamide, levetiracetam, and ceutically acceptable salts of any of the foregoing. In some embodiments the drug is lacosamide. In some aspects of the embodiment, the pharmaceutical composition has a plasma concentration proﬁle for the drug characterized by a pAUC4.g that is less than 14% of AUCOM for the drug as determined by 2016/069581 dosing the pharmaceutical composition to a subject of a fasted, single dose, human pharmacokinetic study. In some embodiments, the therapeutically effective dose of is 300 to 900 mg, 400 to 800 mg, or 450 to 800 mg of the drug. In some embodiments ofthe invention, at least one of the at least one excipients modiﬁes the release of the drug to provide a delayed release form.

In some aspects of the embodiment pharmaceutical composition has a steady state plasma concentration proﬁle for said drug upon once daily dosing of said pharmaceutical composition characterized by a Tmax,SS of 10 to 20 hours, as determined by dosing said pharmaceutical composition to a subject of a fasted pharmacokinetic study. In some aspects of the embodiment, plasma concentration proﬁle for said drug is further characterized by an AUCO. inf that provides AUC equivalence to IR Another embodiment of the invention is directed to a method of administering a pharmaceutical composition to a human t, comprising administering to the human patient orally, once daily, a therapeutically effective dose of the pharmaceutical composition, wherein the pharmaceutical composition comprises (i) a drug selected from the group ting of acetam, divalproex, lacosamide, levetiracetam, oxcarbazepine, trin, and ceutically acceptable salts of any of the foregoing, and (ii) at least one excipient, wherein at least one of the at least one excipients s the release of the drug to provide an extended release form, wherein the pharmaceutical composition has a plasma concentration proﬁle for the drug characterized by a g that is less than 8% of AUCOM for the drug as determined by dosing pharmaceutical composition to a subject of a fasted, single dose, human pharmacokinetic study. In some s of the embodiment, the drug is selected from the group consisting of brivaracetam, lacosamide, levetiracetam, and pharmaceutically acceptable salts of any of the foregoing. In some embodiments of the method, the drug is lacosamide. In some aspects of the embodiment, the therapeutically effective dose is 300 to 900 mg, 400 to 800 mg, or 450 to 800 mg of said drug. In some embodiments of the method, at least one of said at least one excipients modiﬁes the release of said drug to provide a delayed release form. In some aspects of the embodiment, the said pharmaceutical composition has a steady state plasma concentration proﬁle for said drug upon once daily dosing of said pharmaceutical composition terized by a Tmax,SS of 10 to 20 hours, as determined by dosing said pharmaceutical composition to a subject of a fasted human pharmacokinetic study. In some aspects of the embodiment, said plasma tration proﬁle for said drug is further terized by an AUCO.[nf that provides AUC equivalence to IR Some embodiments of the invention are ed to a method of administering a pharmaceutical composition to a human patient, comprising administering to the human patient orally, once daily, a therapeutically effective dose of the pharmaceutical composition, wherein the pharmaceutical composition comprises (i) a drug selected from the group consisting of brivaracetam, divalproex, lacosamide, levetiracetam, oxcarbazepine, trin, and pharmaceutically acceptable salts of any of the foregoing, and (ii) at least one excipient, wherein at least one of the excipients modiﬁes the release of the drug to e an extended release form, wherein the pharmaceutical composition has a plasma concentration proﬁle for the drug characterized by a Tmax of 8 to 20 hours as ined by dosing the pharmaceutical composition to a t of a fasted, single dose, human pharmacokinetic study, and wherein said pharmaceutical ition has a steady state plasma concentration proﬁle for said drug upon once daily dosing of said pharmaceutical composition characterized by a swing of 40% to 200%, as determined by dosing said pharmaceutical composition to a t of a fasted human pharmacokinetic study.

In some aspects of the embodiment, the drug is selected from the group consisting of brivaracetam, lacosamide, levetiracetam, and pharmaceutically acceptable salts of any of the foregoing. In some embodiments of the method, the drug is lacosamide. In some aspects of the embodiment, the therapeutically effective dose is 300 to 900 mg, 400 to 800 mg, or 450 to 800 mg of said drug. In some embodiments of the method, at least one of said at least one excipients modiﬁes the release of said drug to provide a delayed release form. In some aspects of the embodiment, the pharmaceutical composition has a plasma concentration proﬁle for said drug characterized by a Tmax of 12 to 20 hours as determined by dosing said pharmaceutical composition to a subject of a fasted, single dose, human pharmacokinetic study. In other aspects of the embodiment, said pharmaceutical composition has a steady state plasma concentration proﬁle for said drug upon once daily dosing of said pharmaceutical composition characterized by a Tmax,SS of 10 to 20 hours, as determined by dosing said pharmaceutical composition to a t of a fasted pharmacokinetic study. In some aspects of the embodiment, said pharmaceutical composition has a steady state plasma concentration proﬁle for said drug upon once daily dosing of said pharmaceutical composition characterized by a swing of 50% to 100%, as determined by dosing said pharmaceutical ition to a subject of a fasted pharmacokinetic study. In some aspects of the embodiment, said pharmaceutical ition has a steady state plasma tration proﬁle for said drug upon once daily dosing of said pharmaceutical composition characterized by a swing of 60% to 200%, as determined by dosing said pharmaceutical composition to a subject of a fasted human pharmacokinetic study. In some aspects of the embodiment, said drug is further terized by an AUCO-mf that provides AUC equivalence to IR. Some embodiments of the ion are directed to a method of administering a pharmaceutical ition to a human patient, comprising administering to the human patient orally, once daily, a therapeutically effective dose of the pharmaceutical composition, wherein said pharmaceutical composition comprises (i) a drug selected from the group consisting of brivaracetam, divalproex, lacosamide, levetiracetam, oxcarbazepine, vigabatrin, and pharrnaceutically acceptable salts of any of the foregoing, and (ii) at least one excipient, wherein at least one of the at least one excipients modiﬁes the release of the drug to provide an extended release form, n the pharmaceutical composition has a plasma concentration proﬁle for the drug characterized by a T111le of 8 to 20 hours and a dC/dT of less than 2.2 ng/ml/hr per mg of the drug over the ﬁrst 2 hours after dosing, both as determined by dosing the pharmaceutical composition to a subject of a fasted, single dose, human cokinetic study.

In some aspects of the embodiment, the drug is selected from the group consisting of acetam, lacosamide, levetiracetam, and pharmaceutically acceptable salts of any of the foregoing. In some embodiments of the , the drug is lacosamide. In some aspects of the embodiment, the therapeutically effective dose is 300 to 900 mg, 400 to 800 mg, or 450 to 800 mg of drug. In some embodiments of the , at least one of said at least one excipients modiﬁes the release of said drug to provide a delayed release form. In some aspects of the ment, the pharmaceutical composition has a plasma concentration proﬁle for said drug characterized by a Tmax of 12 to 20 hours as determined by dosing said pharmaceutical composition to a subject of a fasted, single dose, human pharmacokinetic study. In other aspects of the embodiment, said pharmaceutical composition has a steady state plasma concentration proﬁle for said drug upon once daily dosing of said pharmaceutical composition characterized by a Tmax,SS of 10 to 20 hours, as determined by dosing said ceutical composition to a subject of a fasted human cokinetic study. In some aspects of the embodiment, the pharmaceutical composition has a plasma concentration proﬁle for said drug characterized by a dC/dT of less than 1.4 ng/ml/hr per mg of said drug over the ﬁrst 2 hours after dosing as determined by dosing said pharmaceutical composition to a subject of a fasted, single dose, human pharmacokinetic study. In some aspects of the ment, the pharmaceutical composition has a plasma concentration proﬁle for said drug characterized by a dC/dT of less than 1.0 ng/ml/hr per mg of said drug over the ﬁrst 2 hours after dosing as ined by dosing said pharmaceutical composition to a subject of a fasted, single dose, human pharmacokinetic study. In some s of the embodiment, said plasma concentration proﬁle for said drug is further characterized by an AUCO-inf that provides AUC equivalence to IR.

Some embodiments of the invention are directed to a method of administering a pharmaceutical composition to a human patient, comprising administering to e human patient orally, once daily, a therapeutically effective dose of pharmaceutical composition, n said pharmaceutical composition consists of (i) a drug selected from the group ting of brivaracetam, divalproex, lacosamide, levetiracetam, oxcarbazepine, vigabatrin, and ceutically acceptable salts of any of the foregoing, and (ii) at least one excipient, n at least one of said at least one excipients modiﬁes the release of said drug to provide an extended release form, wherein said pharmaceutical composition has a plasma concentration proﬁle for said drug characterized by a Tmax of 8 to 20 hours and a dC/dT of less than 1 ug/ml/hr over the ﬁrst 2 hours after dosing, both as determined by dosing said pharmaceutical composition to a subject of a fasted, single dose, human pharmacokinetic study. In some aspects of the embodiment, the drug is selected from the group consisting of brivaracetam, mide, racetam, and ceutically acceptable salts of any of the foregoing. In some embodiments of the method, the drug is lacosamide. In some aspects of the embodiment, the therapeutically effective dose is 300 to 900 mg, 400 to 800 mg, or 450 to 800 mg of said drug.

In some ments of the , at least one of said at least one ents modiﬁes the release of said drug to provide a delayed release form. In some aspects of the embodiment, the pharmaceutical composition has a plasma concentration proﬁle for said drug characterized by a Tmax of 12 to 20 hours as determined by dosing the pharmaceutical composition to a subject of a fasted, single dose, human pharmacokinetic study. In some aspects of the ment, said pharmaceutical composition has a steady state plasma concentration proﬁle for said drug upon once daily dosing of said pharmaceutical composition characterized by a Tmax,SS of 10 to 20 hours, as determined by dosing said pharmaceutical composition to a subject of a fasted human pharmacokinetic study. In some aspects of the embodiment, the pharmaceutical composition has a plasma concentration proﬁle for the drug characterized by a dC/dT of less than 0.6 ug/ml/hr over the ﬁrst 2 hours after dosing as determined by dosing the pharmaceutical composition to a subject of a fasted, single dose, human pharmacokinetic study. In some aspects of the embodiment, the pharmaceutical composition has a plasma concentration proﬁle for the drug characterized by a dC/dT of less than 0.3 hr over the ﬁrst 2 hours after dosing as determined by dosing the ceutical composition to a subject of a fasted, single dose, human pharmacokinetic study. In some aspects of the embodiment, wherein said plasma concentration proﬁle for said drug is further characterized by an AUCO.inf that provides AUC equivalence to IR.

Another embodiment of the invention is ed to a method of administering a pharmaceutical composition to a human patient, comprising administering to the human t orally, once daily, at a predetermined stration time, a therapeutically effective dose of the pharmaceutical composition, wherein the pharmaceutical composition comprises (i) a drug selected from the group consisting of brivaracetam, divalproex, lacosamide, levetiracetam, oxcarbazepine, vigabatrin, and pharmaceutically acceptable salts of any of the foregoing, and (ii) at least one ent, wherein at least one of the at least one excipients modiﬁes the release of the drug to e an extended release form, wherein the predetermined administration time is a time ined from a fasted, human pharmacokinetic study of the pharmaceutical composition and the predetermined time is a time at which once daily dosing of the pharmaceutical composition to a human subject of the pharmacokinetic study provides a C-ave-day that is 20% to 100% greater than C-ave-night, wherein C-ave-day is the average plasma concentration of the drug determined over the period from 9:00 am to 6:00 pm and C—ave-night is the average plasma concentration of the drug determined over the period from 11:00 pm to 8:00 am. In some aspects of the embodiment, the drug is selected from the group consisting of brivaracetam, lacosamide, levetiracetam, and ceutically acceptable salts of any of the foregoing. In some embodiments of the method, the drug is lacosamide. In some aspects of the embodiment, the therapeutically effective dose is 300 to 900 mg, 400 to 800 mg, or 450 to 800 mg of the drug. In some embodiments of the method, at least one of the at least one excipients modiﬁes the release of the drug to provide a delayed release form. In some aspects of the ment, the predetermined administration time is 0—4 hours before bedtime. In some aspects of the embodiment, the predetermined administration time is between 8 pm and 12 am. In some aspects of the embodiment, the predetermined administration time is 0—3 hours after waking: In some aspects of the embodiment, the predetermined stration time is between 5 am and 9 am. In some aspects of the embodiment, the predetermined time is a time at which once daily dosing of the pharmaceutical composition to a human subject of the pharmacokinetic study provides a steady state plasma concentration proﬁle characterized by a day that is 30% to 100% greater than C-ave-night, wherein C-ave-day is the average plasma concentration of the drug determined over the period from 9:00 am to 6:00 pm and C-ave-night is the average plasma concentration of the drug determined over the period from 11:00 pm to 8:00 am. In some aspects of the embodiment, the pharmaceutical composition has a plasma concentration proﬁle for the drug characterized by a TmaX of 8 to 20 hours as ined by dosing the pharmaceutical composition to a subject of a fasted, single dose, human pharmacokinetic study. In some aspects of the embodiment, the pharmaceutical composition has a plasma tration proﬁle for the drug characterized by a Tmax of 12 to 20 hours as determined by dosing the pharmaceutical composition to a subject of a fasted, single dose, human pharmacokinetic study. In some aspects of the embodiment, the pharmaceutical composition has a plasma tration proﬁle for the drug characterized by a Tmax of 5 to 10 hours as ined by dosing the ceutical composition to a subject of a , single dose, human pharmacokinetic study. In some aspects of the embodiment, said pharmaceutical composition has a steady state plasma tration proﬁle for said drug upon once daily dosing of said pharmaceutical composition characterized by a Tmax,SS of 10 to 20 hours, as determined by dosing said pharmaceutical composition to a subject of a fasted human pharmacokinetic study. In some aspects of the embodiment, said pharmaceutical composition has a plasma concentration proﬁle for said drug as determined by dosing said pharmaceutical ition to a t of a fasted, single dose, human pharmacokinetic study characterized by an nf for said drug_that provides AUC equivalence to 1R.Another embodiment of the invention is directed to a method of stering a pharmaceutical composition to a human patient, comprising administering to the human patient orally, once daily, a therapeutically effective dose of the pharmaceutical composition, wherein the pharmaceutical ition complises (i) a drug selected from the group consisting of brivaracetam, divalproex, lacosamide, levetiracetam, oxcarbazepine, vigabatrin, and pharmaceutically acceptable salts of any of the foregoing, and (ii) at least one excipient, n at least one of the at least one excipients modiﬁes the release of the drug to provide an extended release form, wherein the pharmaceutical composition has a dissolution proﬁle terized by three or more of the following: (a) less than 10% release at 1 hour, (b) less than 15% release at 2 hours, (c) less than 25% release at 4 hours, (d) at least 35% release at 9 hours, (e) at least 65% at 12 hours, wherein the dissolution is carried out in 900 mL simulated gastric ﬂuid (pH 1.2) at 37i0.5°C for the ﬁrst two hours, followed by 900 mL ted intestinal ﬂuid (pH 6.8) at 37i0.5°C for the subsequent four hours, followed by 900 mL phosphate buffer (pH 7.5) at 37i0.5°C for the subsequent 18 hours, wherein all dissolution is performed in a USP Apparatus 1 (Basket), with a rotational speed of 100 rpm, and wherein the pharmaceutical ition has a plasma concentration proﬁle for the drug characterized by a Tmax of 8 to 20 hours as determined by dosing the pharmaceutical composition to a subject of a fasted, single dose, human pharmacokinetic study. In some aspects of the embodiment, the drug is selected from the group consisting of brivaracetam, lacosamide, levetiracetam, and pharmaceutically acceptable salts of any of the ing. In some embodiments of the method, the drug is mide. In some aspects of the embodiment, the therapeutically effective dose is 300 to 900 mg, 400 to 800 mg, or 450 to 800 mg of the drug. In some embodiments of the method, at least one of the at least one excipients modiﬁes the release of the drug to provide a delayed release form. In some aspects of the embodiment, the pharmaceutical composition has a plasma concentration proﬁle for the drug characterized by a Tmax of 12 to 20 hours as determined by dosing the pharmaceutical composition to a subject of a fasted, single dose, human pharmacokinetic study.

In some aspects of the embodiment, said pharmaceutical composition has a steady state plasma concentration proﬁle for said drug upon once daily dosing of said pharmaceutical composition characterized by a Tmax,SS of 10 to 20 hours, as determined by dosing said pharmaceutical ition to a subject of a fasted human cokinetic study. In some embodiments, said plasma concentration proﬁle for said drug is further characterized by an AUCO.inf that provides AUC equivalence to IR.

Another embodiment of the invention is a ceutical composition for oral administration to a human, comprising (i) 50 mg to 900 mg of a drug selected from the group consisting of brivaracetam, divalproex, lacosamide, racetam, oxcarbazepine, vigabatrin, and pharmaceutically acceptable salts of any of the foregoing, and (ii) at least one excipient, wherein at least one of the at least one excipients s the release of the drug to provide an extended release form, wherein pharmaceutical composition has a plasma concentration proﬁle for the drug characterized by a pAUC0_4 that is less than 4% of AUCO.inf for the drug as determined by dosing the pharmaceutical composition to a subject of a fasted, single dose, human pharmacokinetic study by a pAUC0-4 that is less than 4% of AUCO.'mf for the drug of the plasma concentration . In some aspects of the embodiment, the pharmaceutical composition has a plasma concentration proﬁle for the drug characterized by a pAUC4-g that is less than 14% of AUCOM for the drug as determined by dosing the pharmaceutical composition to a subject of a fasted, single dose, human pharmacokinetic study. In some aspects of the embodiment, the drug is selected from the group consisting of brivaracetam, lacosamide, levetiracetam, and pharmaceutically acceptable salts of any of the foregoing. In some embodiments of the composition, the drug is lacosamide. In some aspects of the ment, the ition comprises 150 to 900 mg, 200 to 800 mg, 225 to 800, or 250 to 800 mg ofthe drug. In some embodiments of the composition, at least one of the at least one excipients modiﬁes the release of said drug to provide a delayed release form. In some aspects of the embodiment, wherein said pharmaceutical ition has a steady state plasma concentration proﬁle for said drug upon once daily dosing of said pharmaceutical composition characterized by a Tmax,SS of 10 to 20 hours, as determined by dosing said ceutical composition to a subject of a fasted human pharmacokinetic study. In some aspects of the embodiment, said plasma concentration proﬁle for said drug is r characterized by an AUC0.mf that provides AUC equivalence to IR.

Another embodiment of the invention is directed to a pharmaceutical composition for oral administration to a human, comprising (i) 50 mg to 900 mg of a drug selected from the group consisting of acetam, divalproex, lacosamide, racetam, oxcarbazepine, trin, and pharmaceutically acceptable salts of any of the ing, and (ii) at least one excipient, wherein at least one of the at least one excipients modiﬁes the release of the drug to provide an extended release form, wherein the pharmaceutical composition has a plasma concentration proﬁle for the drug characterized by a pAUC4.g that is less than 8% of AUCOM for the drug as determined by dosing the ceutical composition to a subject of a fasted, single dose, human pharmacokinetic study. In some aspects of the embodiment, the drug is selected from the group consisting of brivaracetam, lacosamide, levetiracetam, and pharmaceutically acceptable salts of any of the foregoing In some embodiments of the composition, the drug is lacosamide. In some aspects of the embodiment, the composition comprises 150 to 900 mg, 200 to 800 mg, 225 to 800 mg or 250 to 800 mg of the drug. In some embodiments of the composition, at least one of the at least one ents modiﬁes the release of the drug to provide a delayed release form. In some embodiments, said pharmaceutical ition has a steady state plasma concentration proﬁle for said drug upon once daily dosing of said pharmaceutical composition characterized by a Tum,SS of 10 to 20 hours, as ined by dosing said pharmaceutical composition to a subject of a fasted pharmacokinetic study.

In some of the above embodiments, said plasma concentration proﬁle for said drug is further characterized by an AUCO-inf that provides AUC equivalence to IR.

Another embodiment of the invention is directed to a ceutical composition for oral administration to a human, comprising (i) 50 mg to 900 mg of a drug selected from the group consisting of brivaracetam, divalproex, lacosamide, levetiracetam, oxcarbazepine, trin, and pharmaceutically acceptable salts of any of the foregoing, and (ii) at least one excipient, wherein at least one of the excipients modiﬁes the e of the drug to provide an extended release form, wherein the pharmaceutical ition has a plasma concentration proﬁle for the drug characterized by a Tmax of 8 to 20 hours as determined by dosing the pharmaceutical composition to a subject of a fasted, single dose, human cokinetic study, and wherein said pharmaceutical composition has a steady state plasma concentration proﬁle for said drug upon once daily dosing of said pharmaceutical composition characterized by a swing of 75% to 200%, as determined by dosing said pharmaceutical composition to a subject of a fasted human pharmacokinetic study. In some aspects of the embodiment, the drug is selected from the group consisting of brivaracetam, lacosamide, levetiracetam, and pharmaceutically acceptable salts of any of the foregoing. In some ments of the composition, the drug is lacosamide. In some aspects of the embodiment, the composition comprises 150 to 900 mg, 200 to 800 mg, 225 to 800 mg or 250 to 800 mg of the drug. In some embodiments of the composition, at least one of the at least one ents modiﬁes the release of drug to e a delayed e form. In some aspects of the embodiment, the ceutical composition has a plasma concentration proﬁle for said drug characterized by a Tmax of 12 to 20 hours as determined by dosing the pharmaceutical composition to a subject of a fasted, single dose, human pharmacokinetic study. In some embodiments, said pharmaceutical composition has a steady state plasma concentration proﬁle for said drug upon once daily dosing of said pharmaceutical composition characterized by a me,SS of 10 to 20 hours, as determined by 2016/069581 dosing said pharmaceutical composition to a subject of a fasted human pharmacokinetic study.

In some ments, said pharmaceutical composition has a steady state plasma concentration proﬁle for said drug upon once daily dosing of said pharmaceutical composition characterized by a swing of 50% to 100%, as determined by dosing said pharmaceutical composition to a subject of a fasted human pharmacokinetic study. In some embodiments, said pharmaceutical composition has a steady state plasma concentration proﬁle for said drug upon once daily dosing of said pharmaceutical composition characterized by a swing of 60% to 200%, as determined by dosing said pharmaceutical composition to a subject of a fasted human cokinetic In some aspects of the embodiment, said plasma tration proﬁle for said drug is further terized by an AUCOM that provides AUC equivalence to IR.

Yet another embodiment of the invention is directed to a pharmaceutical composition for oral administration to a human, comprising (i) 50 mg to 900 mg of a drug ed from the group consisting of brivaracetam, divalproeX, lacosamide, levetiracetam, oxcarbazepine, vigabatrin, and pharmaceutically acceptable salts of any of the foregoing, and (ii) at least one excipient, wherein at least one of the at least one ents modiﬁes the release of the drug to provide an extended release form, wherein the ceutical composition has a plasma concentration proﬁle for the drug characterized by a Tmax of 8 to 20 hours and a dC/dT of less than 2.2 ng/ml/hr per mg of the drug over the ﬁrst 2 hours after dosing, both as ined by dosing the pharmaceutical composition to a subject of a fasted, single dose, human cokinetic study. In some aspects of the embodiment, the drug is selected from the group consisting of brivaracetam, lacosamide, levetiracetam, and pharmaceutically acceptable salts of any of the foregoing. In some ments of the composition, the drug is lacosamide. In some aspects of the embodiment, the composition comprises 150 to 900 mg, 200 to 800 mg, 225 to 800 mg or 250 to 800 mg of the drug. In some embodiments of the composition, at least one of the at least one excipients modiﬁes the release of the drug to provide a delayed release form, In some aspects of the embodiment, the pharmaceutical composition has a plasma concentration proﬁle for the drug terized by a Tmax of 12 to 20 hours as determined by dosing the ceutical composition to a subject of a fasted, single dose, human pharmacokinetic study.

In some aspects of the embodiment, said pharmaceutical composition has a steady state plasma concentration proﬁle for said drug upon once daily dosing of said pharmaceutical composition characterized by a Tmax,ss of 10 to 20 hours, as determined by dosing said pharmaceutical composition to a subject of a fasted human pharmacokinetic study. In some aspects of the embodiment, the pharmaceutical composition has a plasma concentration proﬁle for the drug characterized by a dC/dT of less than 1.4 ng/ml/hr per mg of the drug over the ﬁrst 2 hours after dosing as determined by closing the pharmaceutical composition to a subject of a fasted, single dose, human pharmacokinetic study. In some s of the embodiment, the pharmaceutical composition has a plasma concentration proﬁle for the drug characterized by a dC/dT of less than 1.0 hr per mg of the drug over the ﬁrst 2 hours after dosing as determined by dosing the pharmaceutical composition to a subject of a fasted, single dose, human pharmacokinetic study. In some of these embodiments, said plasma concentration proﬁle for said drug is further characterized by an AUCO.inf that provides AUC equivalence to IR.

One embodiment of the invention is directed to a pharmaceutical composition for oral administration to a human, sing (i) 50 mg to 900 mg of a drug selected from the group consisting of brivaracetam, divalproex, lacosamide, levetiracetam, azepine, vigabatrin, and pharmaceutically acceptable salts of any of the foregoing, and (ii) at least one excipient, wherein at least one of the at least one excipients modiﬁes the release of the drug to provide an extended release form, wherein ceutical composition has a plasma concentration proﬁle for the drug characterized by a Tmax of 8 to 20 hours and a dC/dT of less than 1 ug/ml/hr over the ﬁrst 2 hours after , both as determined by dosing the ceutical composition to a t of a fasted, single dose, human pharmacokinetic study. In some embodiments of the invention, the drug is selected from the group consisting of brivaracetam, lacosamide, levetiracetam, and pharmaceutically acceptable salts of any of the foregoing. In some embodiments of the composition, the drug is lacosamide. In some aspects of the embodiment, the composition comprises 150 to 900 mg, 200 to 800 mg, 225 to 800 mg or 250 to 800 mg of the drug. In some embodiments of the composition, at least one of the at least one excipients modiﬁes the release of the drug to provide a delayed release form. In some embodiments, the pharmaceutical composition has a plasma concentration proﬁle for the drug characterized by a me of 12 to 20 hours as ined by dosing the pharmaceutical ition to a subject of a fasted, single dose, human pharmacokinetic study. In some embodiments, wherein said pharmaceutical composition has a steady state plasma concentration proﬁle for said drug upon once daily dosing of said ceutical ition characterized by a Tmax)SS of 10 to 20 hours, as determined by dosing said pharmaceutical composition to a subject of a fasted human pharmacokinetic study. In some embodiments, the pharmaceutical composition has a plasma concentration proﬁle for the drug characterized by a dC/dT of less than 0.6 ug/ml/hr over the ﬁrst 2 hours after dosing as determined by closing the pharmaceutical ition to a subject of a fasted, single dose, human pharmacokinetic study. In some aspects of the embodiment, the pharmaceutical composition has a plasma concentration proﬁle for the drug characterized by a dC/dT of less than 0.3 ug/ml/hr over the ﬁrst 2 hours after dosing as determined by dosing the pharmaceutical composition to a subject of a fasted, single dose, human pharmacokinetic study.

In some of these embodiments, said plasma concentration proﬁle for said drug is further characterized by an AUCOM that provides AUC equivalence to IR.

Another embodiment of the invention is directed to a pharmaceutical composition for oral administration to a human, comprising (i) 50 mg to 900 mg of a drug selected from the group consisting of brivaracetam, divalproex, lacosamide, racetam, oxcarbazepine, vigabatrin, and pharmaceutically acceptable salts of any of the ing, and (ii) at least one excipient, wherein at least one of the at least one excipients modiﬁes the release of the drug to provide an extended release form, n the ceutical composition has a dissolution proﬁle characterized by three or more of the following: (a) less than 10% e at 1 hour, (b) less than 15% release at 2 hours, (c) less than 25% release at 4 hours, ((1) at least 35% at 9 hours, (e) at least 65% at 12 hours, wherein the dissolution is d out in 900 mL ted gastric ﬂuid (pH 1.2) at 37i0.5°C for the ﬁrst two hours, ed by 900 mL simulated intestinal ﬂuid (pH 6.8) at 37::0.5°C for the subsequent four hours, followed by 900 mL phosphate buffer (pH 7.5) at 37i0.5°C for the subsequent 18 hours, wherein all dissolution is performed in a USP Apparatus 1 (Basket), with a rotational speed of 100 rpm, and n the pharmaceutical composition has a plasma concentration proﬁle for the drug characterized by a Tmax of 8 to 20 hours as determined by dosing the pharmaceutical composition to a subject of a fasted, single dose, human pharmacokinetic study. In some embodiments of the invention, the drug is selected from the group consisting of brivaracetam, lacosamide, levetiracetam, and pharmaceutically acceptable salts of any of the foregoing. In some embodiments of the composition, the drug is mide. In some s of the embodiment, the composition comprises 150 to 900 mg, 200 to 800 mg, 225 to 800 mg or 250 to 800 mg of the drug. In some embodiments ofthe composition, at least one of the at least one excipients modiﬁes the release of the drug to provide a delayed release form. In some aspects of the embodiment, the pharmaceutical composition has a plasma concentration proﬁle for the drug characterized by a Tmax of 12 to 20 hours as determined by dosing the pharmaceutical composition to a subject of a fasted, single dose, human pharrnacokinetic study. In some ments, wherein said pharmaceutical composition has a steady state plasma concentration proﬁle for said drug upon once daily dosing of said pharmaceutical composition as ined by closing said pharmaceutical composition characterized by a Tmax,SS of 10 to 20 hours, as determined by dosing said pharmaceutical composition to a subject of a fasted human pharmacokinetic study. In some aspects of the embodiment, said plasma concentration proﬁle for said drug is further characterized by an AUC0--mf that provides AUC equivalence to IR.

BRIEF DESCRIPTION OF THE S Figure 1A is a graph depicting the ution proﬁles of ER lacosamide formulations Fonnl,FOHn2,Fonn3,Fonn4,andFOHn4ti Figure 1B is a graph depicting the dissolution proﬁles ofER lacosamide formulations Form 2, Form 2.2, Form 2.4, Form 26, and Form 4.6.

Figure 1C is a graph depicting the dissolution proﬁles ofER lacosamide formulations Form 2, Form 4, Form 4.2, Form 4.4, and Form 4.6.

Figure 2A is a graph depicting the plasma proﬁles for single dose administration of mide fonnulations Fonn 1, Form 2, Form 3, Form 4, Form 4.6, and BID dosing of an [R lacosamide formulation simulated using GastroPlus, version 9.0 Figure 2B is a graph depicting the plasma proﬁles for single dose administration of 400 mg mide in formulations Form 2, Form 2.2, Form 2.4, Form 2.6, Form 4.6, and single dose administration of 400mg lacosamide in an IR form simulated using Plus, version 9.0.

Figure 2C is a graph depicting the plasma proﬁles for single dose administration of lacosamide formulations Form 2.4, Form 4, Form 4.2, Form 44, and Form 4.6 simulated using GastroPlus, version 9.0.

Figure 3A is a graph shown over the le dose time period of 0 to 144 hours showing the steady state plasma proﬁles for single dose (400 mg) administration of lacosamide mmwmmnﬁmnmedﬂyﬁSmmmemengMymLhmme3manNWm Hmmme4omemgMymleLRmn46mmemgMym“mmﬁmMMOmngdmmgQ am and 8 pm) of an IR lacosamide formulation simulated using GastroPlus, version 9.0.

Figure 3B is the same data as Figure 3A, limiting the X-axis scale to the 36 hour window beghnnngatSpnlondayS, Figure 3C is a graph depicting the steady state plasma proﬁles for single dose (400 mg) administration of lacosamide formulations Form 2, Form 2.2, Form 2.4, Form 26 each once nightly at 12am, and 200 mg BID dosing (8 am and 8 pm) of an [R lacosamide formulation simulated using Plus, n 9.0.

Figure 3D is a graph depicting the steady state plasma proﬁles for single dose (400 mg) administration of lacosamide formulations Form 4, Form 4.2, Form 4.4, Form 46 each once nightly at 10pm, and 200 mg B1D dosing (8 am and 8 pm) of an [R lacosamide formulation simulated using GastroPlus, version 9.0.

Figure 4 is a graph ing the administration of two controlled release mide compositions and an immediate release composition of lacosamide with dose titration.

Figure 5 is a graph depicting the dissolution proﬁles of Example 18.

Figure 6 is a graph depicting the plasma concentration proﬁles of the Example 19.

Figure 7A is a graph depicting steady state proﬁles of Formulation A administered at different times.

Figure 7 B is a graph depicting steady state proﬁles of Formulation B administered at different times.

Figure 7C is a graph depicting steady state proﬁles of Formulation C administered at different times.

Figure 7D is a graph depicting steady state s of Formulation D administered at different times.

Figure 8 is a graph depicting steady state proﬁles of Formulations A-D administered at speciﬁed times to provide meﬁs in the period of about 10 am to 2 pm.

Figure 9 is a chart ing the effect of the lacosamide dosing regimen on the performance of the test animals on the rotarod.

Figure 10 is a graph depicting the plasma concentration proﬁles of the study drugs of Example 21. lationl of the ﬁgure is the plasma tration proﬁle for Formulation A of Example 21; Formulation2 of the ﬁgure is the plasma concentration proﬁle for Formulation B of Example 21; Formulation3 of the ﬁgure is the plasma tration proﬁle for Formulation C of Example 21; Formulation4 of the ﬁgure is the plasma concentration proﬁle for Formulation D of Example 21; IR of the ﬁgure is the plasma concentration proﬁle for the IR lacosamide of Example 21.

DETAILED DESCRIPTION OF THE INVENTION The present invention provides compositions and methods for primary or adjunctive therapy for treating or preventing any disease or disorder for which an anti-epilepsy drug is prescribed, such as epilepsy, seizure—based ers including myoclonic seizures in nic epilepsy, primary generalized tonic-clonic es in patients with idiopathic lized epilepsy, partial onset seizures, status epilepticus, acute mania management, paroxysmal kinesigenic choreoathetosis, phasic spasticity in le sclerosis, Landau- er syndrome, migraine treatment or prophylaxis, pediatric ne, Meige syndrome, late—onset seizures in patients with Alzheimer's disease, anxiety disorders, severe myoclonic epilepsy of infancy, tardive dyskinesia, lumbar radiculopathy, late onset myoclonic epilepsy in Down syndrome, atypical pain syndromes, neuropathic pain, and Alzheimer's disease. In some embodiments, the present methods treat epilepsy. In some embodiments, the present methods treat e-based disorders, ary compositions include brivaracetam, divalproex sodium, mide, levetiracetam, oxcarbazepine, valproic acid, or vigabatrin in an extended release form.

Compositions of the invention also include, but are not limited to, formulations of brivaracetam, divalproex sodium, valproic acid, ate, lacosamide, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, tiagabine, and vigabatrin. Preferred are formulations of brivaracetam, divalproex sodium, valproic acid, lacosamide, levetiracetam, oxcarbazepine, pregabalin, ine, and vigabatrin, Most preferred are formulations of racetam, acetam, lacosamide, azepine and valproic acid for administration once daily.

Suitable AEDS for the compositions may be those with half-lives of 4 to 20 hours, preferably 6 to 18 hours, more preferably 7 to 17 hours. Suitable AEDs for the itions are lly well absorbed after oral administration in an immediate release form, e. g., the bioavailability of AEDs in immediate release compositions is greater than 70%, preferably greater than 80%, more ably greater than 90%, and even more ably greater than 95%. Suitable AEDs for the compositions when administered orally as immediate release compositions will typically provide a time to peak plasma concentration, Tmax, of less than 8 hours, preferably less than 6 hours, more preferably less than 5 hours.

In some embodiments, the ion provides an anti-epileptic formulation that is administered once daily and has a pharmacokinetic proﬁle with diurnal variations, with a Tm between 4 and 15 hours, preferably between 4 and 12 hours.

Some compositions described herein enable administration of a therapeutically effective amount of a selected AED. The therapeutically effective amount may be less than the amount typically ted for an immediate release form, e. g. 50% of the amount typically required when in an immediate release form. In another embodiment, the daily dose of an AED for a patient in need thereof will be able to, or equal to, the daily dose of an immediate release form of the same drug nce. In another embodiment, the daily dose of an AED for a patient in need thereof will be greater than the daily dose of an immediate release form of the same drug substance, e.g. 125%, 150%, 175%, 200%, 250% (eg. preferably 150 to 200%) of the amount of the same AED as ordinarily dosed to a patient on a daily basis. Due to the characteristics of the compositions, greater doses of a particular AED are well tolerated.

In some embodiments, the tolerability of the AED is improved relative to a comparable dose of an immediate release form of said AED. As used herein, unless expressly stated otherwise, improvement in tolerability means the reduction in nce and/or severity of adverse effects associated with the administration of a composition comprising the AED relative to the incidence and/or severity of adverse s associated with stration of the same dose of an immediate release form of said AED. In some embodiments, the improvement in tolerability may e reduced adverse effects associated with administration regimen of the compositions described herein. In some embodiments, the improvement in tolerability may include d adverse effects associated with the properties of the compositions described herein. Thus, reduction in the incidence and/or severity of adverse events may be accomplished with the methods and compositions described herein. In some embodiments, administration of a composition with the diurnal plasma concentration s described herein reduces the incidence and/or ty of sleep disturbances as compared to an IR form of the same AED at the same daily dose administered two or more times per day, In some embodiments, administration of a composition with the reduced dC/dt characteristics described herein reduces the incidence and/or severity of adverse effects as compared to an IR form of the same AED at thymeww.m“memmmeMJmnmmdemewmammuwanwmw immeewwMSWHMwaemwMHaMmmewmmmmhwdmbmambmHMVSMnIn some embodiments, the increased tolerability is associated with reduced incidence and/or severity of nervous system disorder adverse events such as dizziness, headache, , somnolence, tremor, mus, balance disorders, paresthesia, paresthesia oral, or memory impairment; in preferred embodiments, the increased tolerability is associated with reduced incidence and/or severity of dizziness; in preferred embodiments, the increased tolerability is associated with reduced incidence and/or severity of he; in preferred embodiments, the increased tolerability is associated with reduced incidence and/or ty of paresthesia or paresthesia oral. In some embodiments, the increased tolerability is associated with reduced nce and/or severity of vertigo. In some embodiments, the increased tolerability is associated with reduced incidence and/or severity of nausea. In some embodiments, the increased tolerability is associated with reduced incidence and/or severity of vomiting. In some embodiments, the sed tolerability is associated with reduced incidence and/or severity of lwm%m%MMdInwmemmwmwmsmammmmmmnndawmwemMaﬂwmawwm daily dose of the AED as compared to an immediate release form. In some embodiments, the improvement in tolerability associated with the diurnal proﬁle ing from administration of the compositions or the C—ave—day to C—ave—night ratio resulting from the predetermined administration time, enables the once daily administration, preferably at doses higher than those ed with immediate release forms of the same AED.

Anti—epileptic drugs suitable for the compositions and methods described herein include those stered in immediate e form at daily doses of up to 3000 mg, however drugs of wammﬂmmdTMcmmmMmmmewMMemmmmmmmmannommmg AED per day, 2500 mg AED per day, 2000 mg AED per day, 1500 mg AED per day, 1200 mg AED per day, preferably up to 1000 mg per day, more preferably up to 800 mg per day, even more preferably up to 600 mg per day, up to 500 mg per day, up to 400 mg per day, up to 300 mg per day, up to 250 mg per day, or up to 200 mg per day. ing upon the composition and the daily dose of drug, compositions may be administered in one or more unit dosage forms.

In some embodiments the composition of the invention is administered as one unit dosage form.

In some embodiments the ition of the invention is administered as two unit dosage forms. In some embodiments the composition of the invention is administered as three unit dosage forms. In some embodiments the composition of the ion is administered as four unit dosage forms. Compositions are administered orally once or twice per day, preferably once per day.

In ments comprising lacosamide or a pharmaceutically acceptable salt thereof as the AED, the daily dose of lacosamide or pharmaceutically acceptable salt thereof may be 200 to 900 mg per day, 250 to 850 mg per day, 300 to 800 mg per day, 350 to 800 mg per day, 400 to 800 mg per day, 450 to 800 mg per day, 500 to 800 mg per day, 350 to 750 mg per day, 400 to 750 mg per day, 450 to 750 mg per day, 500 to 750 mg per day, 350 to 700 mg per day, 400 to 700 mg per day, 450 to 700 mg per day, 500 to 700 mg per day, 350 to 650 mg per day, 400 to 650 mg per day, 450 to 650 mg per day, 500 to 650 mg per day, 350 to 600 mg per day, 400 to 600 mg per day, 450 to 600 mg per day, or 500 to 600 mg per day. In preferred s ofthis embodiment, the daily dose of lacosamide or pharmaceutically acceptable salt thereof may be 400 to 800 mg per day. In preferred aspects of this embodiment, the daily dose of lacosamide or pharmaceutically able salt thereof may be 450 to 800 mg per day. In red aspects of this embodiment, the daily dose of lacosamide or pharmaceutically acceptable salt thereof may be 450 to 700 mg per day. In red aspects of this embodiment, the compositions comprising lacosamide or pharmaceutically acceptable salts thereof are administered orally, once daily.

As used herein, references to lacosamide, levetiracetam, brivaracetam, oxcarbazepine, divalproex sodium, ic acid, vigabatrin and other AEDs are ed to encompass ceutically acceptable salts thereof, and, optionally, prodrugs or rphs thereof.

As used herein, except where speciﬁed as otherwise, “extended release” es “controlled release73 ccmodiﬁed release77 cc sustained release77 cctimed release”, “delayed release”, 7 7 7 and also mixtures of delayed release, immediate release, enteric coated, etc. with each of the above.

As used herein, except where speciﬁed as otherwise, “delayed release” compositions include dosage forms containing a delayed release coating over an immediate release and/or extended e composition.

As used herein, fasted, single dose human pharmacokinetic study means a fasted study in one or more healthy subjects to determine the pharmacokinetic characteristics of the composition being tested. The study may include a reference composition such as an oral, immediate release dosage form of the same drug substance typically with the same dose. Where WO 17569 a nce composition is ed, the study design may be a parallel or ver study design. Design parameters for such studies are well known an also included in various FDA guidances such as those referenced , including, but not d to the 2002 FDA Guidance: Waiver of In Vivo Bioavailability and Bioequivalence Studies for Immediate-Release Solid Oral Dosage Forms Based on a Biopharmaceutics Classiﬁcation System, and the 2003 ce for Industry: Bioavailability and Bioequivalence Studies for Orally Administered Drug Products — General Considerations. The output of such single dose human pharmacokinetic studies typically includes plasma concentration data for the drug substance (and active metabolites, if any) from blood s collected at times speciﬁed in the study protocol. These plasma concentration data may then be used to construct a plasma concentration proﬁle from which the pharmacokinetic parameters described herein may be determined, As used herein, except where speciﬁed as otherwise, “bioavailability” is 100% multiplied by the AUC0.0O for a drug in a composition (e.g., ‘Test’ formulation) divided by the AUC0.0O for an equivalent dose of the same drug in an immediate release form (e.g., ‘Reference’ formulation), both as determined from a fasted, single dose, human pharmacokinetic study. In preferred ments, the bioavailability of compositions described herein is “AUC equivalence to IR” which, as used herein, means that for an equivalent dose of the same drug, the 90% conﬁdence interval for the ratio (multiplied by 100%) of the geometric squares mean (“GLSM”) for the AUCOm for the drug of the composition to the GLSM for the AUCOm for the same drug in an immediate release oral form is between 80% to 125%, inclusive.

As used herein, except where speciﬁed as otherwise, “Tl/2”, the “elimination half-life”, “terminal-phase half-life33 LL 7 plasma half-life” and “pharmacokinetic half-life” refer to the half- life of the disappearance of drug from the plasma, As used herein, except where speciﬁed as ise, “Tmax” refers to the median Tmax observed from the subjects included in a bioavailability or bioequivalence study, It should be tood, however, the TmX determined from a simulation refers to a mean Tmax. Similarly, except where speciﬁed as otherwise, “Tmams” refers to the median Tmax,ss, when the formulation has been dosed to steady state, and the Tmax,SS determined from a simulation refers to a mean Tmams.

As used herein, except where speciﬁed as ise, “Tlag” is the time delay between drug administration and ﬁrst observed concentration above the limit of quantiﬁcation in plasma.

As used herein, except where speciﬁed as otherwise, “Cmm”, “Cmax”, “CmmSS”, “Cmam” and AUC values determined over various time periods each refer to mean values.

As used herein, except where speciﬁed as otherwise, ” is 100%*(Cmax,ss- Cmin,ss)/Cmin,ss~ As used herein, except where ed as otherwise, “PTF” is the peak trough ﬂuctuation for a speciﬁed drug in plasma at steady state. It is determined as 100%*(Cmax,ss- Cmin’SS)/(AUCtau,SS/tau), n AUCwu’SS is the steady state AUC over the dosing interval, tau.

As used herein, except where speciﬁed as otherwise, a subject of a human pharrnacokinetic study shall include one or more subjects of said human pharmacokinetic study. In cases where tau is 24 hours, AUCtau,SS is AUC0.24 at steady state.

As used herein, dC/dt over a speciﬁed time period is the change in mean plasma concentration of the drug substance from the beginning of the speciﬁed time period to the end of said speciﬁed time period divided by the length of the time period, determined from a plasma concentration proﬁle from a fasted, single dose, human pharrnacokinetic study (unless speciﬁed otherwise); the units for dC/dt are mass/volume/time such as ng/ml/hr. Where speciﬁed, the dC/dt values may be reported per dose; in these instances, the dC/dt values are divided by the dose to provide a dC/dt per mg of drug. Also in other instances, the dC/dt values are compared to those ined for a nce ition, lly an oral, immediate release form of the drug substance; in such cases, to minimize variability in the plasma concentration proﬁles from which the dC/dt values are determined, the extended release ition and the reference composition are each administered orally to subjects in a fasted, single dose, oral human pharmacokinetic study.

As used herein, the terms “C-ave—day” and “C-ave-night” are average plasma concentration values for the drug substance determined over speciﬁed time periods from a steady state plasma concentration proﬁle wherein administration of the composition is at a ermined time or within a speciﬁed time period such as once daily at 8:00 am.

In some embodiments, C-ave-day is the average AED plasma concentration determined within any four to twelve hour period between the hours of 5 am and 8 pm, such as the average AED plasma concentration determined within any four, ﬁve, six, seven, eight, nine, ten, eleven or twelve hour period between the hours of 5 am and 8 pm (e. g. a seven—hour period). In a preferred ment, C-ave-day is determined over the period from 9 am to 4 pm. In a preferred embodiment, C-ave-day is determined over the period from 9 am to 6 pm. In some ments, C—ave—night is the average AED plasma concentration determined within any four to twelve hour period between the hours of 8 pm and 9 am, such as the average AED plasma concentration as measured within any four, ﬁve, six, seven, eight, nine, ten, eleven or twelve hour period between the hours of 8 pm and 9 am (e.g. a nine-hour period). In a preferred embodiment, C-ave-night is determined over the period from 11 pm to 8 am. In a preferred ment, C-ave-night is determined over the period from 11 pm to 6 am.

The steady state plasma concentration proﬁle may be determined from (i) a multi—dose human cokinetic study of the pharmaceutical composition or from (ii) a multi-dose model based on a fasted, single-dose human pharmacokinetic study (prepared using WinNonlin version 5.3 or higher, or comparable ) or from (iii) a multi-dose simulation of the human pharrnacokinetics based on the dissolution proﬁles of the pharmaceutical composition prepared using GastroPlus version 9.0 or higher. Of these three, (ii) is a preferred .

As used , except where speciﬁed as otherwise, “about” refers to a value within % of the value shown. For example, a Tmax of about 10 hours would also include values from 9.0 to 11.0, unless speciﬁed otherwise.

As used herein, the transitional term “comprising” is inclusive or open-ended and does not exclude additional, unrecited elements or method steps. Thus, as used herein, “comprising” includes within its metes and bounds “consisting essentially” of and “consisting of,” as deﬁned herein. Accordingly, disclosure of embodiments and aspects “comprising” subject matter herein includes ments and aspects “consisting essentially of ’ and “consisting of,” the recited subject matter.

As used herein, the tional phrase “consisting ially of ’ limits the scope of a claim to the speciﬁed subject , materials or steps and those that do not materially affect the basic and novel characteristic(s).

As used herein, the transitional phrase “consisting of ’ limits the recited t matter to the speciﬁed matter, elements, steps, or ients, and excludes any subject , element, step, or ingredient not speciﬁed.

As used herein, except where speciﬁed as otherwise, a fractional AUC over a speciﬁed period of time is equivalent to a pAUC over the same period of time divided by AUCO-inf (i.e.

AUC0.w) or, for steady state calculations, AUC24 (i.e. AUC0-24), and multiplied by 100%, As used herein, single dose, fasted, human pharmacokinetic studies are clinical studies performed in accordance to the FDA Guidance nts i.e. 2002 FDA Guidance for Industry: Food Effect Bioavailability and Fed Bioequivalence Studies and/or analogous EMEA Guidelines. Such studies may be performed using either parallel or crossover designs, typically in y subjects. For fasted s, study drug is typically administered following an overnight fast of at least 10 hours; no food should be allowed for at least 4 hours post—dose, and water can be d as desired except for one hour before and after drug administration. Blood samples are taken at predetermined times (relative to dosing) and analyzed using validated s to determine the levels of drug (and active metabolites as appropriate).

As used herein, fasted human pharmacokinetic studies include both single dose, fasted, human pharmacokinetic studies and multiple dose, fasted, human pharmacokinetic studies.

Multiple dose, fasted, human pharmacokinetic studies are performed in accordance to the FDA Guidance documents and/or analogous EMEA Guidelines. cokinetic parameters for steady state values may be determined directly from multiple dose, fasted, human pharmacokinetic studies or may be conveniently determined by extrapolation of single dose data using standard methods or industry standard re such as WinNonlin version 5.3 or higher.

As used herein, chronosynchronous means that the therapeutic composition provides a therapeutically effective dose of the drug substance with increased exposure over time periods in which need is greater, such as during the peak periods of partial onset seizure activity, and less re at time in which the need is lower, such as during sleep s when partial onset seizure activity may be reduced. In this instance, exposure may be determined from partial AUCs at steady state or average plasma concentrations over speciﬁed time periods at steady state.

In some embodiments, the chronosynchronous proﬁle provides a therapeutically effective plasma concentration of the AED such as lacosamide at Cumss and a substantially higher plasma concentration at Tmax,ss to provide greater efﬁcacy at a time when the therapeutic need is greater, e. g. a time when seizure ty is more frequent or more pronounced. Preferably, the Cmin,ss is sufﬁcient to reduce the frequency and/or ty of seizures during the the time that the plasma concentration is lower. Preferably, the predetermined administration time selected as described herein provides for the Cmin,ss to occur during a period of reduced seizure activity as well as providing for the Cmax,SS to occur during a period of increased seizure activity. Some ments, the composition for use in the described methods is adapted for the generation of a diurnal proﬁle which, upon reaching steady state, provides a higher concentration during the waking hours of the day than the sleeping hours of the night. The compositions may be d for g administration, e.g. administration 0 to 4 hours before bedtime, or for morning administration by the methods provided herein. For example, a composition of an AED such as lacosamide may be formulated ing to the methods below to provide an extended release ation that upon once daily administration 0 to 4 hours before bedtime provides a steady state Cmm (Cmin,ss) during the night while the subject sleeps and a steady state Cmax ss) in the middle of the day, e.g., between the hours of 9 am and 3 pm. Such formulations may have a single dose median Tm1X of 11 to 20 hours and/or steady state Tmax between 11 and 18 hours.

In some embodiments, the Tmax for the composition, as determined from a single dose human pharrnacokinetic study in the fasted state, may be 11 to 20 hours, 11 to 18 hours, 11 to 16 hours, 12 to 20 hours, 12 to 18 hours, 12 to 16 hours, 13 to 20 hours, 13 to 18 hours, 13 to 16 hours, 14 to 20 hours, 14 to 18 hours, or 15 to 20 hours. In some embodiments, the steady state Tmax (Tmax,ss), as determined from a le dose fasted human pharmacokinetic study of 11 to 18 hours, 11 to 16 hours, 12 to 18 hours, 12 to 16 hours, 13 to 18 hours, 13 to 16 hours. In some embodiments, both Tmax and Tmax,SS are within the aforementioned ranges.

In some embodiments, the composition providing s at night and CumSS in the middle of the day steady are administered in the morning, typically between 0 and 1, 2, 3 hours after the subject awakes for the day’s activities. Such compositions may provide a Tmax, as determined from a single dose, fasted, human pharmacokinetic study of 3 to 5 hours In some embodiments of any of the above aspects, the steady state plasma concentration proﬁle ing multiple administrations to a human subject of the composition once daily is characterized by an average plasma concentration lacosamide concentration during the day (“C- ave-day”, deﬁned as the average day time plasma concentration for said drug as determined from a fasted, human PK study) that is 1.1 to 2.0 times the average plasma lacosamide tration during the night (“C-ave-night”, deﬁned as the average nighttime lacosamide plasma concentration as determine from a , human PK . In some embodiments, the ratio of C—ave—day/C-ave—night at steady state is within one of the ranges 1.2 to 2.0, 1.2 to 1.9, 1.3 to 1.9, 1.3 to 1.8, 1.3 to 1.7, 1.3 to 1.6, 1.4 to 2.0, 1.4 to 1.9, 1.4 to 1.8, 1.4 to 1.7, 1.5 to 2.0, 1.5 to 1.9, 1.5 to 1.8, 1.5 to 1.7, 1.6 to 2.0, or 1.6 to 1.9. In some embodiments, the ratio of C- ave—day/C-ave—night at steady state is 1.3, 1.35, 1.4, 1.45, 1.5, 1.55, 1.6, 1.65, 1.7, 1.75, 1.8, 1.85, or 1.9. In some embodiments, the C-ave-day is the average lacosamide plasma tration as ed between the hours of 5 am, 6 am, 7 am, 8 am or 9 am to the hours of 4 pm, 5 pm, 6 pm, 7 pm or 8 pm and the C—ave—night is the e lacosamide plasma concentration as measured between the hours of 8 pm, 9 pm, 10 pm or 11 pm to the hours of 5 am, 6 am, 7 am, 8 am or 9 am. In some embodiments, the C-ave-day is the average lacosamide plasma concentration as measured Within any four to twelve hour period between the hours of 5 am and 8 pm; and the C-ave-night is the average mide plasma concentration as ed within any four to twelve hour period between the hours of 8 pm and 9 am. In some embodiments, the C—ave—day is the average lacosamide plasma concentration as measured within any four, ﬁve, six, seven, eight, nine, ten, eleven or twelve hour period between the hours of 5 am and 8 pm, and the C-ave-night is the average lacosamide plasma concentration as measured within any four, ﬁve, six, seven, eight, nine, ten, eleven or twelve hour period between the hours of 8 pm and 9 am. In a preferred embodiment, the C-ave—day to C-ave-night ratio is 1.2 to 2.0, wherein C-ave-day is determined over the period from 9 am to 4 pm and C-ave-night is determined over the period from 11 pm to 8 am. In a more preferred embodiment, the C-ave-day to C-ave-night ratio is 1.2 to 1.8, wherein C-ave-day is determined over the period from 9 am to 4 pm and C-ave-night is determined over the period from 11 pm to 8 am.

In another preferred embodiment, the C-ave—day to C—ave-night ratio is 1.2 to 2.0, wherein C-ave-day is determined over the period from 9 am to 6 pm and C-ave-night is determined over the period from 11 pm to 8 am. In some embodiments, the C-ave-day and C- ght values are determined from steady state plasma tration proﬁles n the dosing time is at 8 am. In some embodiments, the C-ave-day and night values are determined from steady state plasma concentration proﬁles adjusted to a predetermined adminisistration time, wherein said predetermined administration time is a time for which the C- y and C-ave-night values provide the recited ratio. In a more preferred embodiment, the C—ave—day to C—ave—night ratio is 1.4 to 2.0, wherein C—ave—day is determined over the period from 9 am to 6 pm and C-ave-night is determined over the period from 11 pm to 8 am.

In some embodiments, the C-ave-day is about 20%, 25%, 35%, 45%, 60%, 80%, 100% higher than C—ave—night. In some embodiments, the C—ave—day is about 20% to about 80% higher than C-ave-night, preferably about 20% to about 50% higher than C-ave-night. In some embodiments, the C-ave-day and C-ave—night values are determined from steady state plasma concentration proﬁles wherein the dosing time is at 8 am. In some embodiments, the C—ave—day and C-ave-night values are determined from steady state plasma concentration proﬁles adjusted to a predetermined administration time, wherein said predetermined administration time is a time for which the C—ave—day is greater than C—ave—night by the recited percentage. In some embodiments, the C-ave-day is about 30% to 150% higher than C-ave-night. In some embodiments, the C-ave-day is about 40% to 130% higher than C-ave-night. In some embodiments, the C—ave—day is about 50% to 120% higher than C—ave—night. In come embodiments, the C-ave-day is about 50% to 110% higher than night. In some ments, the C-ave-day is about 50% to 100% higher than C-ave-night. In some embodiments, the C-ave-day is about 60% to 100% higher than the C—ave-night. In red embodiments the C-ave-day is determined over the period from 9 am to 4 pm, 5pm, 6pm, 7pm, ably over the period from 9am to 6 pm. In preferred embodiments, C-ave-night is determined over the period from 11 pm to 6 am, 7am, 8am, 9 am; ably over the period from 11 pm to 8 am.

In some embodiments of the invention, the composition is administered once daily at a predetermined administration time. In such embodiments, the predetermined stration time may be determined, based on a steady state plasma concentration proﬁle, to provide pharmacokinetic ters disclosed herein that are related to speciﬁc times of day, including C-ave-day, C-ave-night, and pAUCs at speciﬁc times of day. For example, the predetermined administration time providing a C-ave—day/C-ave-night ratio of 1.4 to 2.0 could be a time within 6 am to 9 am for a composition with a relatively short time to Tmax, alternatively the predetermined administration time could be a time with 8 pm to 11 pm for a composition WO 17569 providing a Tm”S of 12 to 14 hours. A steady state plasma concentration proﬁle of the drug of the composition may be determined as described herein. By adjusting the time of administration, also as described herein, the C-ave-day and C-ave-night values may be readily determined and a predetermined administration time which provides the pAUC values or C-ave-day to C-ave— night ratio or increase in day ve to C-ave-night may also be readily ined.

Certain compositions may provide diurnal variation that is insufﬁcient to meet these parameters, regardless of the time of administration; other compositions may provide sufﬁcient diurnal variation, but may provide pAUC values or C—ave—day or C—ave—night values meeting the requirements of the invention only if the predetermined administration times would require waking a patient to administer the compositions. In preferred embodiments, the predetermined administration time is a time during the normal waking hours of a t, such as 5 am, 6 am, 7 am, 8 am, 9 am, 10 am, 5 pm, 6 pm, 7 pm, 8 pm, 9 pm, 10 pm, 11pm, or 12 am. In one embodiment, administration of a single dose of the ition to a human subject provides a plasma concentration proﬁle characterized by: a fractional AUC from 0 to 4 hours that is less than 5%, and preferably less than 3% of AUC0-mf; a fractional AUC from 0 to 8 hours that is about 5 to 15%, and preferably about 8 to 12% of AUC0.mf, a fractional AUC from O to 12 hours that is about 10 to 40%, and preferably about 15 to 30% of AUCo.mf; a fractional AUC from 0 to 18 hours that is about 25 to 60%, and preferably about 30 to 50% of AUCo.mf; and a fractional AUC from 0 to 24 hours that is about 40 to 75%, and preferably about 50 to 70% of nf In another embodiment, a once daily oral administration of the composition to a human t provides a steady state plasma tration proﬁle characterized by: a fractional AUC from 0 to 4 hours that is about 2 to 25%, and preferably about 5 to 20% of AUC24; a fractional AUC from 0 to 8 hours that is about 15 to 50%, and preferably about 20 to 40% of AUC24; a fractional AUC from O to 12 hours that is about 30 to 70%, and preferably about 40 to 60% of AUC24: and a fractional AUC from O to 18 hours that is about 60 to 95%, and preferably about 75 to 90% of AUC24.

In some embodiments of any of the above aspects, a once daily oral administration of the composition to a human subject provides a steady state plasma concentration proﬁle characterized by: a fractional AUC from 0 to 8 hours that is about 15 to 40%, and preferably about 20 to 32% of AUC24; a fractional AUC from 8 to 16 hours that is about 30 to 50%, and preferably about 35 to 45% of AUC24; and a onal AUC from 16 to 24 hours that is about 20 to 35%, and preferably about 25 to 33% of AUC24.

In some embodiments of any of the above aspects, a once daily oral stration of the composition to a human subject provides a steady state plasma concentration proﬁle characterized by: a fractional AUC from 0 to t (where t is any two—hour increment post administration within a 24 hour period) that is between 80 to 125% of the corresponding fractional AUC from O to t of the immediate release formulation.

In some embodiments, a once daily oral administration of the composition to a human subject provides a steady state plasma concentration proﬁle terized by one or more of the following: (i) a fractional AUC from 8 AM to 10 AM that is between 80 to 125% of the ate e formulation, and preferably between 90 to 110% of the immediate release formulation; (ii) a fractional AUC from 10 AM to 12 noon that is between 80 to 125% of the immediate release formulation, and preferably between 90 to 110% of the immediate e formulation, (iii) a fractional AUC from 12 noon to 2 PM that is between 80 to 125% of the immediate e formulation, and preferably greater than 100% of the immediate release formulation; (iv) a fractional AUC from 2 PM to 4 PM that is between 80 to 125% of the immediate release formulation, and preferably greater than 100% of the ate release formulation; (v) a fractional AUC from 4 PM to 8 PM that is between 80 to 125% of the immediate release ation, and preferably greater than 100% of the immediate release ation; (vi) a fractional AUC from 8 PM to 12 AM that is between 50 to 100% of the immediate release formulation, and preferably less than 80% of the immediate release formulation; (vii) a fractional AUC from 12 AM to 8 AM that is between 80 to 125% of the immediate release formulation, and preferably less than 100% of the ate release ation. In some embodiments, 3 or more of these fractional AUC conditions are met. In some embodiments, 5 or more of these fractional AUC conditions are met. In some ments, 6 or more of these fractional AUC conditions are met. In other embodiments, at least one of conditions (iv) and (V) are met and at least one of conditions (vi) and (vii) are met.

Swing is deﬁned as a percentage equal to (100%)"‘(Cmax,SS - Cmin,ss)/Cmin,ss. It is a measure of the peak to trough difference in the course of one dosing interval. Thus, it is a measure of the diurnal ion provided from dose to dose. In some embodiments, the swing for a once daily administered composition, as determined from a fasted human cokinetic study, is 45%, 50%, 55%, 60%, 65% 70% to 58%, 63%, 68%, 73%, 78%, 83%, 88%, 93%, 98%, 103%, 108%, 113%, 128%, 140%, 150%, 160%, 180%, 200%, preferably 60% to 160%, 60% to 128%, 65% to 128%, 65 to 98%; more preferably 65 to 78%. In some embodiments, a composition administered once daily has a single dose Tmax of 14 to 20 hours and a swing of 63% to 77%; in another embodiment, a composition administered once daily has a single dose Tmax of 14 to 20 hours, a Tmax,SS of 13 to 17 hours, and a swing of 63% to 77%. In another embodiment, once daily administration of the composition provides a steady state plasma concentration proﬁle characterized by a Tmax,ss of 10 to 18 hours, preferably 12 to 18 hours, and a swing of 80% to 180%, preferably 85% to 160%. In some embodiments, the composition is stered orally, once daily at a predetermined administration time and the steady state plasma concentration proﬁle is characterized by a swing of 80% to 160% and a peak plasma concentration is during the period from 9 am to 3 pm. In such embodiments, the l variation also results in a reduced plasma concentration at night such that the C-ave-day to C- ave nght ratio is 1.2 to 2.0, ably 1.4 to 2.0.

The dC/dt is the rate at which the drug in the composition is absorbed in a human over a deﬁned period of time. It is conveniently determined over a deﬁned time period from the plasma concentration proﬁle of a human pharmacokinetic study. Except as speciﬁed otherwise, dC/dt values are determined from a single dose, fasted, human pharmacokinetic study. It is convenient to express the rate in absolute terms (e.g, ng/ml/hr per mg drug substance over a speciﬁed time) or as a fraction of the dC/dt for an immediate release composition of the same drug substance. In some embodiments, the dC/dt over the period from 0 to 1.4 hours is less than % of the dC/dt of an IR form of the same drug at the same dose in an immediate release form over the same time period, preferably, the dC/dt is less than 10%, is less than 5%, is less than 3%, 2%, 1.5% of the dC/dt for the IR form of the drug. In some embodiments, the dC/dt over the period from O to 2, 3, 4 hours is less than 15% of the dC/dt of an [R form of the same drug at the same dose in an ate release form over the same time period; preferably, the dC/dt is less than 12%, is less than 10%, is less than 8%, 6%, 4%, 2%, 1.5% of the dC/dt for the IR form of the drug.

In some ments, the dC/dt over the ﬁrst 2, 3, 4 hours after stration is less than 0.8, 0.6, 0.5, 0.4, 0.3, 0.2, 0.1 ug/ml/ hr. In some embodiments, the composition comprises lacosamide and the dC/dt for mide over the ﬁrst 4 hours after stration of the composition is less than 0.5 ug/ml/hr.

The maximum slope (“max slope”) over a deﬁned period of time after administration of a single dose of the composition in a fasted human pharmacokinetic study is therefore a useful pharmacokinetic parameter. In some embodiments, the max slope is determined over the period from administration, To, to Tmax. In another ment, the max slope is determined over the period from To to a speciﬁed time, t. In some embodiments, the max slope is determined as the maximum slope over a time interval of not less than 2, 3, 4 hours within the period from administration to a speciﬁed time, t, using standard methods for determining slopes from models of the concentration proﬁle over the time period from T0 to t (eg. simple linear or non-linear least squares regression, or symmetric difference quotient, Simpson method, or Trapezium rule).

In some embodiments, the max slope for a lacosamide composition is determined as the m slope over 3 hour intervals from administration to 12 hours after administration using non-linear regression model of the plasma concentration proﬁle from a single dose, fasted, 2016/069581 human pharrnacokinetic study. In some embodiments, the max slope is less than 4 ng/ml/hr per mg drug; preferably less than 3 ng/ml/hr per mg drug, more preferably less than 2.5 ng/ml/hr per mg drug. In some embodiments, the max slope for a mide composition over a 3 hour interval in the period from administration to 24 hours after administration, the max slope is less than 2.4 ng/ml/hr per mg lacosamide; preferably less than 2.1 ng/ml/hr per mg lacosamide; more preferably less than 18 ng/ml/hr per mg lacosamide. In some embodiments, the max slope over a 3 hour interval in the period from T0 to 24 hours after administration, the max slope is about 1.0 to 2.0 ng/ml/hr per mg lacosamide, preferably 1.4 to 1.9 ng/ml/hr per mg lacosamide.

Importantly, the maximum slope of a composition may be reduced for compositions with reduced bioavailability, in preferred embodiments, the max slope is ed for bioavailability to provide an “adjusted max slope” (i,e., max slope / bioavailability = max slope achieved for a composition with bioavailability equivalent to 100% of an IR form of the same drug).

In some embodiments described herein a lacosamide composition is administered to a patient 0 to 4 hours prior to bedtime. In some embodiments, the lacosamide composition is administered to a patient from O to 3, 0 to 2, or 0 to 1 hours prior to bedtime. In some ments, the lacosamide composition is administered to a patient from 0 to 240 minutes, from 0 to 180 s, e. g, from 0 to 120 minutes, from 0 to 60 minutes, from 0 to 45 minutes, from 0 to 30 minutes, from 0 to 15 minutes or from 0 to 10 minutes prior to bedtime. In some embodiments, the lacosamide composition is administered to a patient from 60 to 240 minutes, from 60 to 180 s, from 60 to 120 minutes or from 60 to 90 minutes prior to e.

Unless otherwise specified herein, the term “bedtime” has the normal meaning of a time when a person retires for the primary sleep period during a twenty-four hour period of time.

While for the general populace, bedtime occurs at night, there are patients, such as those who work nights, for whom bedtime occurs during the day. Thus, in some embodiments, bedtime may be anytime during the day or night.

In some embodiments, herein a mide composition is administered to a patient in the morning, i.e., 0 to 3 hours after waking for the day, ably, 0 to l, 0 to 2 hours after waking for the day. By the term “waking for the day” we mean the time at which the subject rises to begin the day’s activities. While for many people, waking for the day is typically between the hours of 5 am and 9 am, for some it may be r or later in the day or even in the night ing upon an individual’s normal sleep e.

It is to be understood that administration to a patient includes administration by a healthcare professional and/or self-administration by the patient.

In some embodiments, the invention provides a method of reducing e effects associated with administration of lacosamide to a human subject in need thereof. The method comprises administering a eutically effective dose of lacosamide in an oral, extended release form to a subject once per day, zero to 1, 2, 3, or 4 hours before bedtime. A therapeutically effective dose of lacosamide may be 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg 200 mg, 225 mg 250 mg, 275 mg, 300 mg to about 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg per day, 600 mg per day, 650 mg per day, 700 mg per day, 750 mg per day, 800 mg per day, 850 mg per day, or 900 mg per day. Some embodiments, the amount of mide administered once daily is 100 mg to 400 mg, 200 to 400 mg, 225 mg to 375 mg, 250 mg to 375 mg per day, 400 to 600 mg per day, 500 to 700 mg per day, or 600 to 800 mg per day.

Some embodiments e a method of treating a subject with a e disorder comprising administering a therapeutically effective dose of lacosamide in an oral, extended release form to a subject once per day, zero to 1, 2, 3 hours before bedtime. In some embodiments, the composition for administration 0 to 4 hours before bedtime provides a single dose Tmax of 10 to 20 hours as determined from a single dose, fasted, human pharmacokinetic study and/or a Tum,SS of 10, l 1, or 12 hours to 16, 18, or 20 hours as ined from a fasted human pharmacokinetic study.

Some embodiments provide a method of treating a subject with a seizure disorder comprising administering a therapeutically effective dose of lacosamide in an oral, extended release form to a subject once per day to 1, 2, 3, 4 hours after waking for the day. In some embodiments, the composition for administration to l, 2, 3, 4 hours after waking for the day provides a Tmax less than 8, 7, 6, 5 hours, preferably 3 to 6, 3 to 5 hours after administration as determined from a single dose, fasted, human pharmacokinetic study.

The method comprises administration of a controlled e lacosamide composition in l, 2, 3, or 4 unit dosage forms once daily; ably 1 or 2 unit dosage forms.

In some ments, administration of mide according to a method described herein provides a peak plasma concentration, Cmax, that is less than the Cmax for an immediate release form of lacosamide as determined from a single dose, fasted, human pharmacokinetic study, and the time from administration to Cmax, Tmax, that is 8, 9, 10, 11, 12, 13, 14 hours to 13, 14, 16, 18, 20, 22, 24 hours; preferably 10 hours to 20 hours, more preferably 11 hours to 18 hours such that administration zero to 1, 2, 3, 4 hours before bedtime es a peak concentration at steady state that is in the middle of the following day. Administration according to methods described herein provides a reduction in adverse effects and/or may increase tolerability, compliance, or adherence to the treatment n.

Lacosamide compositions described herein may be used in treatment regimens with other known anti —epileptic drugs.

Making Controlled Release Formulations In some embodiments, pharmaceutical compositions are prepared by combining an AED, such as lacosamide, with one or more onal ingredients which, when administered to a subject, cause the AED, such as lacosamide to be released at a ed concentration range over a speciﬁed period of time. The AED, such as lacosamide is released at more slowly from the compositions than the AED, such as mide is released from an ate release (IR) dosage form. The slower e results in a reduced rate of absorption, providing a dC/dt that is signiﬁcantly reduced relative to the 1R dosage form of the same strength.

The precise slope for a given individual will vary according to the AED, such as lacosamide composition being used or other s, such as whether the patient has eaten or not.

For other doses, e.g., those ned above, the slopes vary directly in relationship to dose, The determination of initial slopes of plasma concentration is described, for example, by U. S.

Pat. No. 6,913,768, or US. Pat. No, 8,389,578 hereby incorporated by reference.

Using the formulations described , eutic levels may be achieved while minimizing debilitating side-effects that are usually associated with immediate release formulations. rmore, as a result of the increase in the time to reach peak plasma level and the extended period of time at the therapeutically effective plasma level, the dosage frequency may be reduced to, for example, once daily dosing, y ing patient compliance and adherence.

It has been found surprisingly that the frequency of adverse effects is associated with the rapid rate of increase in plasma concentration of an AED such as lacosamide after administration of an immediate release form of the drug may be decreased or lessened in severity using the methods and compositions described herein. For e, side s including, but not limited to, psychosis, dizziness, and cognitive deﬁcits associated with the administration of an AED, such as lacosamide may be ed in severity and frequency through the use of these controlled—release methods that reduce the max slope, pAUC0.4, pAUC4- g, or dC/dT of the drug.

Formulations for each active pharmaceutical ingredient may then be evaluated in human studies to determine the pharmacokinetic characteristics, including dC/dt, Cmax, Tmax, AUC, Tm, max slope, etc. of such formulations using methods known to the skilled artisan. Techniques for determining pharmacokinetic characteristics for a given formulation are routine in the art.

Combination compositions may be conveniently prepared either by combining the desired quantities of formulations for each drug composition, blending and ﬁlling into hard gelatin capsules the desired quantity for each dosage form. Alternatively, combination compositions may be conveniently ed ﬁlling desired quantities of each of the drug compositions directly into hard gelatin es using automated ﬁlling es.

For a speciﬁed range a physician or other riate health professional will typically determine the best dosage for a given patient, according to his sex, age, weight, pathological state, and other parameters. In some cases, it may be necessary to use dosage outside of the range stated in ceutical packaging insert to treat a subject. Those cases will be apparent to the prescribing physician.

In some embodiments, the compositions e therapeutic levels while minimizing tating side—effects that are usually associated with immediate release formulations. In some embodiments, the extended release compositions enable once daily administration of the AED, thereby improving patient compliance and adherence.

Modes of Administration The composition may be administered in an oral formulation. In some embodiments, the lacosamide may be formulated to provide controlled, extended release (as described herein). For example, a pharmaceutical composition that provides controlled release of the lacosamide causes the agent to be released at a targeted rate for a speciﬁed period of time.

The preparation of pharmaceutical or pharmacological compositions are known to those of skill in the art in light of the present disclosure, General techniques for formulation and administration are found in “Remington: The Science and Practice of Pharmacy, Twentieth Edition,” Lippincott Williams & Wilkins, Philadelphia, Pa. Tablets, capsules, pills, powders, granules, dragees, and slurries, are examples of such formulations.

“Pharmaceutically or Pharmacologically Acceptable” es molecular entities and itions that do not produce adverse, ic or other untoward reaction when administered to an animal, or a human, as appropriate. “Pharmaceutically Acceptable Carrier” includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, ic and absorption delaying agents and the like. The use of such media and agents for pharmaceutical active sub stances is well known in the art. Except insofar as any conventional media or agent is atible with the active ingredient, its use in the eutic compositions is contemplated. Supplementary active ients can also be incorporated into the compositions. “Pharmaceutically Acceptable Salts” include acid addition salts and which are formed with inorganic acids such as, for example, hydrochloric or oric acids, or such organic acids as acetic, oxalic, tartaric, ic, and the like. Salts formed with the free carboxyl groups can also be derived from inorganic bases such as, for example, sodium, potassium, ammonium, calcium, or ferric hydroxides, and such organic bases as isopropylamine, hylamine, histidine, procaine and the like.

Formulations for Oral Administration The brivaracetam, divalproex sodium, lacosamide, levetiracetam, oxcarbazepine, valproic acid, vigabatrin or other agent may be provided in a controlled, extended release form.

In one example, at least 50%, 90%, 95%, 96%, 97%, 98%, 99%, or even in excess of 99% of the lacosamide is provided in an extended release dosage form. In another example, at least 50%, 90%, 95%, 96%, 97%, 98%, 99%, or even in excess of 99% of the acetam is provided in an extended release dosage form. In another example, at least 50%, 90%, 95%, 96%, 97%, 98%, 99%, or even in excess of 99% of the levetiracetam is provided in an extended release dosage form In another example, at least 50%, 90%, 95%, 96%, 97%, 98%, 99%, or even in excess of 99% of the oxcarbazepine is provided in an extended release dosage form. In another e, at least 50%, 90%, 95%, 96%, 97%, 98%, 99%, or even in excess of 99% of the divalproex sodium is provided in an extended release dosage form. In another example, at least 50%, 90%, 95%, 96%, 97%, 98%, 99%, or even in excess of 99% of the valproic acid is ed in an extended release dosage form. In another e, at least 50%, 90%, 95%, 96%, 97%, 98%, 99%, or even in excess of 99% of the vigabatrin is ed in an extended release dosage form. If desired, the release of the lacosamide, brivaracetam, levetiracetam, oxcarbazepine, divalproex sodium, valproic acid, or the vigabatrin may be asic or hasic (e. g., biphasic).

The pharmacokinetic half-lives of lacosamide is about 13 hours. Thus, suitable formulations may be conveniently selected to achieve the desired proﬁles over an extended period (preferably from 12 to 24 hours) thereby maintaining an optimal tration range to maximize therapeutic beneﬁt while minimizing adverse effects.

The pharmacokinetic half-life of brivaracetam is about 7-8 hours. Thus, suitable formulations may be conveniently selected to achieve the desired proﬁles over an extended period (preferably over 24 hours) thereby maintaining an optimal concentration range to maximize therapeutic beneﬁt while minimizing adverse effects.

The cokinetic half-life of levetiracetam is about 7 hours. Thus, suitable formulations may be iently selected to achieve the desired s over an extended period (preferably over 24 hours) thereby maintaining an optimal concentration range to maximize therapeutic beneﬁt while minimizing adverse effects.

The cokinetic ife of oxcarbazepine is about 20 hours. Thus, suitable formulations may be conveniently selected to achieve the desired proﬁles over an extended period (preferably from 24-36) thereby ining an optimal concentration range to maximize eutic beneﬁt while minimizing adverse effects.

The pharmacokinetic half—life of divalproex sodium is about 15 hours. Thus, suitable ations may be conveniently selected to achieve the desired proﬁles over an extended period (preferably from 15 to 24 hours) thereby maintaining an optimal concentration range to maximize therapeutic beneﬁt while minimizing adverse effects.

The pharmacokinetic half-life of valproic acid is about 9-16 hours. Thus, suitable formulations may be conveniently selected to achieve the d proﬁles over an extended period (preferably from 15 to 24 hours) thereby maintaining an optimal concentration range to maximize therapeutic beneﬁt while minimizing adverse effects.

The pharmacokinetic half—life of vigabatrin is about 10 hours. Thus, suitable fonnulations may be conveniently ed to achieve the desired s over an extended period (preferably from 12 to 24 hours) thereby maintaining an optimal concentration range to maximize therapeutic beneﬁt while minimizing adverse effects.

Extended Release Formulations Extended release compositions suitable for use in the method can be made using a y of extended release technologies, such as those described in the patent publications referenced herein, which publications are incorporated herein by reference in their entireties. In some embodiments, the ed release form is a pellet in capsule dosage form. In some embodiments, the pellets comprise a pellet core, which is coated with at least one drug layer and at least one extended release coating layer. In some embodiments, the pellets are coated with at least one drug layer, an intermediate layer such as a seal coat and an extended release coating layer. In some embodiments, the pellet, the drug layer or both comprise one or more binders.

In some embodiments, the dosage unit comprises a plurality of coated pellets. In some embodiments, the pellets have a diameter of for example, 300 to 1700 microns, in some cases 500 to 1200 s. The pellets will comprise, for example, inert substrates, such as sugar spheres, microcrystalline cellulose (MCC) spheres, starch pellets. In some embodiments, pellets can be prepared by other processes such as pelletization, extrusion, spheronization, etc. or combinations thereof. The core pellets may comprise the AED (e.g. brivaracetam, divalproex , lacosamide, levetiracetam, oxcarbazepine, valproic acid, or vigabatrin and pharmaceutically acceptable ents thereof).

Delayed Release Formulations In some embodiments, at least a n of the anti-epileptic composition is formulated in a delayed release formulation. Per the United States Pharrnacopeia (USP), delayed-release tablets are c-coated to delay release of the medication until the tablet has passed through the h to prevent the drug from being destroyed or inactivated by c juices or where it may irritate the gastric mucosa. In contrast, extended-release tablets are “formulated in such a manner to make the contained ment ble over an extended period of time following mgmmM’&mewwwdmkwﬁmmmmmwmwbanmeﬁmuwaM%ﬁwmmor In some embodiments, the delayed release formulation provides a 1 hour, 2 hour, 4 hour, 6 hour, or 8 hour release of the active ingredient. In some embodiments, the delay in release is between 1 and 3 hours, between 1 and 4 hours, n 1 and 5 hours, between 1 and 6 hours, between 1 and 7 hours, between 1 and 8 hours, between 2 and 3 hours, between 2 and 4 hours, between 2 and 5 hours, between 2 and 6 hours, n 2 and 7 hours, between 2 and 8 hours, between 2 and 9 hours, between 2 and 10 hours, between 3 and 4 hours, between 3 and 5 hours, between 3 and 6 hours, between 3 and 7 hours, between 3 and 8 hours, between 3 and 9 hours, between 3 and 10 hours, between 4 and 5 hours, between 4 and 6 hours, between 4 and 7 hours, between 4 and 8 hours, between 4 and 9 hours, between 4 and 10 hours, between 5 and 6 hours, between 5 and 7 hours, between 5 and 8 hours, between 5 and 9 hours, between 5 and 10 hours, between 6 and 7 hours, between 6 and 8 hours, between 6 and 9 hours, between 6 and 10 hours, 7 and 8 hours, between 7 and 9 hours, between 7 and 10 hours, between 8 and 9 hours, between 8 and 10 hours, or between 9 and 10 hours. Preferably, the delay in release is between 2 and 6 hours In some embodiments, only a n of the active ingredient is a delayed e fonnulaﬁon, hisonuzenﬂoodnnents 9096,8596,8096,7596,7096,6596,6096,5596,5096,4598 4ma3ﬂﬁ3m@2ﬂ@2mﬁ1&61m6m5%oﬂmaaWemgwmmmaDRﬁmmmmm.m other embodiments, n l—25%, between 10—25%, n 10—30%, between , between 10-5 0%, between 25-50%, between 25-75%, between 20-40%, between , between 20 -75%, n 30-60%, between 40-75%, between 50-75%, between 60-85%, between , or between 80-95% of the active ingredient is a DR formulation.

In other embodiments, 100% of the anti-epileptic agent is formulated for delayed release.

In some embodiments a portion of the anti-epileptic agent is formulated for delayed release, and the balance of the anti—epileptic agent is ated for extended release.

Release Profile The compositions prepared as described herein release the drug substance over a mdmgdmmﬂﬁmmmhmwmmmmmmammmmMmt$MW®ﬁwwmmmmm may be tested for release of the drug substance in vitro using standard methods. For example, hummnweammommmsdwaﬂmdhmﬂnnmybemgowahmmgaUSPgme1oereZ ammﬂmmme®ambﬁmmﬁbmmhmehmmmmmmmmmpHmmm®Mammg, ution of the compositions are done in the type 1 apparatus with the protocol described herein. When using a type 1 (basket) apparatus, the dissolution may be med in 900 ml 0.1 N HCl for 2 hours followed by dissolution in the same volume of USP phosphate buffer, pH 6.8; the ution is performed at 37.0::0.5°C and 100 rpm. atively, the dissolution may be performed at .5°C and 100 rpm using the following dissolution media: 900 ml ted gastric ﬂuid (pH 1.2) for 2 hours, followed by 900 ml simulated intestinal ﬂuid (pH 6.8) for 4 hours, ed by 900 ml USP phosphate buffer at pH 7.5 for 18 hours. In embodiments without pH dependent coatings (i.e., without delayed release, enteric coating) dissolutions of the itions may be done in the type 1 apparatus or the type 2 apparatus with the protocol described herein, preferably, dissolutions for embodiments without pH dependent coatings are performed with the type 2 apparatus. When using a type 2 (paddle) apparatus, the dissolution may be performed in 900 ml 0.1N HCl; the dissolution is performed at O.5°C and 50 rpm.

The samples for is may be taken over 16 to 24 hours at time points such as 1 hour, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 10 hours, 12 hours, 16 hours, 20 hours, 24 hours.

Some embodiments, compositions described herein have dissolution es (using the apparatus and protocol appropriate to the presence or absence of delayed release coating as be above) characterized by at least two of the following: (i) less than 10% of the drug substance in 1 hour, preferably less than 5% in 1 hour, or more preferably not more than 3.6% of the drug substance in 1 hour; (ii) less than 15% of the drug nce in 2 hours, preferably less than 12% in 2 hours, more preferably less than 9% in 2 hours, and even more preferably not more than 6% in 2 hours; (iii) less than 26% of the drug substance in 4 hours, preferably less than 22% in 4 hours, more preferably, less than 18% in four hours, and even more preferably not more than 15% in four hours; (iv) less than 42% of the drug substance in 6 hours, preferably less than 36% in 6 hours, more preferably less than 32% in 6 hours, and even more preferably not more than 28% in 6 hours; or (v) at least 50% of the drug substance in 12 hours, ably more than 63% in 12 hours, more preferably more than 77% in 12 hours. In some embodiments, at least 3 of the aforementioned criteria are met. In some embodiments, all of the aforementioned criteria are met. In some embodiments, compositions have dissolutions proﬁles characterized by release of 0% to 9% of the drug nce at 2 hours, 3% to 24% of the drug substance at 4 hours, and 85% to 100% of the drug substance at 16 hours. In some embodiments, compositions have dissolutions proﬁles characterized by release of 0% to 9% of the drug substance at 2 hours, 3% to 19% of the drug substance at 4 hours, 12% to 41% at 6 hours, and 85% to 100% of the drug substance at 16 hours.

Coated Pellets The pellet cores are coated with the active ingredient, e. g., brivaracetam, divalproex sodium, lacosamide, levetiracetam, oxcarbazepine, valproic acid, or vigabatrin or pharmaceutically acceptable salts and/or polymorphs thereof. In some embodiments, in addition to the active ingredient, the pellets also comprise one or more binders, such as for example WO 17569 hydroxypropyl methyl cellulose, copovidone, povidone, hydroxypropyl ose, hydroxyethyl cellulose, methyl cellulose, carboxymethyl cellulose etc. In some embodiments, the pellets also contain one or more additional excipients, such as anti-tack agents (e. g. talc, ium te etc.) In some embodiments, the pellets cores are coated with a drug layer comprising active ient, and optionally one or more binders, anti-tack agents and/or solvents by conventional coating techniques such as ﬂuidized bed coating, pan coating.

Intermediate Layer Coating In some embodiments, the pellets are coated with an intermediate layer, such as a seal coat. In some embodiments, the seal coat is adapted to prevent ingredients in the extended release g from interacting with ingredients in the pellet core, to prevent migration of the ients in the pellet core from diffusing out of the pellet core into the extended release layer, etc. As bed herein, the seal coat can comprise one or more ﬁlm forming polymers including but not limited to hydroxypropylmethyl cellulose (HPMC), copovidone, povidone, polyvinylpyrrolidone, hydroxypropyl cellulose, hydroxyethyl cellulose, methyl cellulose, carboxymethyl cellulose or any combination thereof and the like.

The seal coat can further comprise other additives like plasticizers, such as, propylene glycol, triacetin, polyethylene glycol, tributyl citrate and optionally anti-tacking agents, such as, magnesium stearate, calcium silicate, magnesium silicate, and colloidal silicon dioxide or talc.

Apart from cizers and anti—tacking agents as mentioned above, the seal coat can optionally n buffers, colorants, opaciﬁers, tants or bases, which are known to those skilled in the art.

Sea] coating can be applied to the core using conventional g techniques such as ﬂuidized bed g, pan coating etc. In some embodiments, the drug coated pellets cores are coated with a seal coat layer that optionally comprises one or more s, anti-tack agents and/or solvents by ﬂuidized bed g or pan coating.

In some embodiments, the pellet cores, the intermediate g layer, or both may comprise one or more binders (e.g., ﬁlm forming polymers). Suitable binders for use herein include, e.g.: alginic acid and salts thereof; cellulose derivatives such as carboxymethylcellulose, methylcellulose (e.g, Methocel®), hydroxypropylmethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose (e. g., Klucel®), ethylcellulose (e. g., Ethocel®), and microcrystalline cellulose (e. g, Avicel®); microcrystalline dextrose; amylose; magnesium aluminum silicate, polysaccharide acids, bentonites, gelatin, polyvinylpyrrolidone/vinyl acetate copolymer; crospovidone; povidone, starch; pregelatinized starch; tragacanth, dextiin, a sugar, such as sucrose (e.g., Dipac®), e, dextrose, molasses, mannitol, sorbitol, xylitol (e.g., Xylitab®), and lactose; a natural or synthetic gum such as acacia, tragacanth, ghatti gum, mucilage of isapol husks, polyvinylpyrrolidone (e.g, Polyvidone®® CL, Kollidon® CL, asdone® XL-lO), larch alactan, Veegum®, polyethylene glycol, waxes, sodium alginate, and the like.

Extended Release Coating The pellets may be coated with an extended release coating. The extended release coating is adapted to delay release of the drug from the coated drug cores for a period of time after introduction of the dosage form into the use environment. In some embodiments, the extended release coating includes excipients. Examples of non-pH ent extended release polymers include ethyl cellulose, hydroxypropylmethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, ymethyl cellulose, copolymer of ethyl acrylate, methyl methacrylate (e. g., Eudragit® RS), etc. es of pH dependent extended release excipients e methacrylic acid mers, hydroxypropylmethyl cellulose e succinate, hydroxypropylmethyl cellulose phthalate, and cellulose acetate phthalate etc. The extended e coating may also include a pore , such as povidone, polyethylene glycol, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, etc, sugars such as sucrose, mannitol, lactose, and salts, such as sodium de, sodium citrate, etc, a plasticizer, such as acetylated citrated esters, acetylated glycerides, castor oil, citrate esters, lsebacate, glyceryl monostearate, diethyl phthalate, ol, medium chain triglycerides, propylene , hylene glycol. The extended release coating may also include one or more additional excipients, such as lubricants (e.g., magnesium stearate, talc etc).

Extended e coating can be applied using conventional coating techniques such as ﬂuidized bed coating, pan coating etc. The drug coated pellets cores, which optionally comprise a seal coat, are coated with the extended release coating by ﬂuidized bed coating.

Extended e Excipients (Coating Polymers) As described herein, exemplary extended release excipients include, but are not limited to, insoluble plastics, hydrophilic polymers, and fatty compounds. Plastic matrices include, but are not limited to, methyl acrylate—methyl methacrylate, polyvinyl chloride, and polyethylene.

Hydrophilic polymers include, but are not limited to, cellulosic polymers such as methyl and ethyl cellulose, hydroxyalkyl celluloses such as hydroxypropyl cellulose, hydroxypropylmethyl cellulose, sodium carboxymethyl ose, and cross-linked acrylic acid polymers like ol® 934, polyethylene oxides and mixtures thereof. Fatty compounds include, but are not limited to, s waxes such as carnauba wax and glyceryl tristearate and wax-type substances including hydrogenated castor oil or hydrogenated vegetable oil, or mixtures thereof.

In certain embodiments, the c material can be a pharmaceutically acceptable acrylic polymer, including but not limited to, acrylic acid and methacrylic acid copolymers, methyl methacrylate, methyl methacrylate copolymers, ethoxyethyl rylates, thyl methacrylate, aminoalkyl methacrylate copolymer, poly(acrylic acid), poly(methacrylic acid), methacrylic acid alkylamine copolymer poly(methyl methacrylate), poly(methacrylic acid)(anhyd1ide), polymethacrylate, polyacrylamide, ethacrylic acid anhydride), and yl methacrylate copolymers.

In certain other embodiments, the acrylic polymer is comprised of one or more ammonio methacrylate copolymers. Ammonio methacrylate mers are well known in the art, and are described in NF XVII as fully Iized copolymers of acrylic and methacrylic acid esters with a low content of quaternary ammonium groups.

In still other embodiments, the acrylic polymer is an acrylic resin lacquer such as that which is commercially available from Rohm Pharma under the trade name Eudragit®. In further embodiments, the acrylic polymer comprises a mixture of two acrylic resin lacquers commercially available from Rohm Pharma under the trade names Eudragit® RL30D and Eudragit® RS3OD, tively. Eudragit® RL30D and Eudragit® RS30D are copolymers of acrylic and methacrylic esters with a low content of quaternary ammonium groups, the molar ratio of ammonium groups to the remaining neutral (meth)acrylic esters being 1:20 in Eudragit RL30D and 1:40 in Eudragit® RS3OD. The mean molecular weight is about 150,000. Eudragit® 8—100 and Eudragit® L—lOO are also suitable for use . The code ations RL (high permeability) and RS (low permeability) refer to the permeability properties of these agents. it® RL/RS mixtures are insoluble in water and in digestive ﬂuids. However, multiparticulate systems formed to include the same are swellable and permeable in aqueous solutions and ive ﬂuids.

The polymers described above such as Eudragit® RL/RS may be mixed together in any desired ratio in order to ultimately obtain an extended release formulation having a desirable dissolution proﬁle. One skilled in the art will recognize that other acrylic polymers may also be used, such as, for example, Eudragit® L.

Pore Formers In some embodiments, the extended release coating includes a pore . Pore formers le for use in the extended release coating can be organic or inorganic agents, and include materials that can be dissolved, extracted or leached from the coating in the environment of use.

Examples of pore formers include but are not limited to organic compounds such as mono-, oligo-, and polysaccharides including sucrose, glucose, fructose, mannitol, mannose, galactose, e, ol, pullulan, dextran, polymers soluble in the environment of use such as water— soluble hydrophilic polymers, such as povidone, crospovidone, polyethylene glycol, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, hydroxyalkyl celluloses, carboxyalkyl celluloses, cellulose ethers, acrylic , polyvinylpyrrolidone, linked nylpyrrolidone, polyethylene oxide, carbowaxes, Carbopol®, and the like, diols, polyols, polyhydric alcohols, polyalkylene glycols, polyethylene glycols, polypropylene glycols, or block polymers f, polyglycols, poly(a-Q) alkylenediols; inorganic compounds such as alkali metal salts, lithium ate, sodium chloride, sodium bromide, potassium chloride, potassium sulfate, ium phosphate, sodium acetate, sodium citrate, suitable calcium salts, and the like.

In certain embodiments, plasticizers can also be used as a pore former.

Delayed Release Coating The pellets can be coated with a delayed release coating. The delayed release coating as deﬁned in United States Pharmacopeia (USP) refers to an enteric coating to delay the release of drug until it has passed through the stomach and to e the drug in the desired segments of small or large intestine. The release mechanism is controlled by the dissolution of the ﬁlm at different pHs located in ent regions of the intestine. It provides an initial delay for releasing the drug with minimum alteration on the release rate iate release or extended release) once the pellets reach target release zone in the intestine. The period for the initial delay as well as the following drug release rate can be varied by changing the film thickness and/or the ratio of polymer combinations. Examples of delayed release polymers include, but not limited to, polymethacrylates and derivatives (methacrylic acid and ethylacrylate derivatives: Eudragit® 5, L100 or 8100, or any combination), cellulose esters and derivatives (hydroxypropylmethyl ose acetate succinate, hydroxypropylmethyl cellulose phthalate, cellulose e trimellitate, and cellulose acetate phthalate etc.), and polyvinyl derivatives (polyvinyl acetate phthalate).

The pH-dependent DR ﬁlm can contain pH—independent, time-release polymers to create blocks for controlling the rate of drug release. e excipients include, but not limited to, copolymer of ethyl acrylate, methyl methacrylate (e.g., Eudragit® RS or RL, or combination of the two polymers) and cellulose derivatives (ethyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, etc.) The c polymer comprises a mixture of two acrylic resin lacquers commercially available from Rohm Pharma under the trade names Eudragit® RL3OD and Eudragit® RS3 0D, respectively. Eudragit® RL3OD and Eudragit® RS3OD are copolymers of acrylic and methacrylic esters with a low content of quaternary ammonium groups, the molar ratio of ammonium groups to the remaining neutral (meth)acrylic esters being 1:20 in Eudragit® RL30D and 1:40 in it® RS30D.

A plasticizer in the ﬁlm includes, but not limited to, acetylated citrated esters, acetylated glycerides, castor oil, citrate esters, l te, glyceryl monostearate, diethyl ate, glycerol, medium chain triglycerides, propylene glycol, polyethylene glycol, etc. A lubricant in the ﬁlm includes, but not limited to, magnesium stearate, talc etc.

Compositions characterized by a delayed release greater than 2 hours may be prepared using a higher coat weight comprising it L100. In other embodiments, a delayed release r than 2 hours may be achieved using a mixture of polymers, e. g., Eudragit L100 and S 100.

Capsules The extended release (ER) or extended e/delayed release pellets may be uced into a suitable capsule by using an ulator equipped with pellet dosing chamber. The capsule sizes may be 00, OOEL, 0, OEL, 1, lEL, 2, 2EL, 3, 4 or 5. A particularly suitable composition that provides ideal pharmacokinetic properties and plasma concentration proﬁles is a pellet-in-capsule composition that comprises a ity of pellets, typically having a diameter of about 500 pm to 1.2 mm, and preferably about 700 pm to 1000 um, where each pellet comprises a core comprising brivaracetam, divalproex sodium, lacosamide, levetiracetam, oxcarbazepine, valproic acid, or vigabatrin and a binder, and an extended release coating surrounding the core that extends release of the pharrnaceutically active compound so as to provide the desired pharmacokinetic properties and plasma concentration proﬁles described above.

In some embodiments, the pellets in the pellet—in—capsule are in a size 0 or smaller, preferably a size 1 or smaller capsule. Mean pellet diameters in some embodiments may be in a range of 500 um to 1200 um, e.g., from 500 pm to 1100 um, from 500 pm to 1000 pm, from 500 um to 900 pm, from 500 um to 800 pm, from 500 pm to 700 pm, from 600 pm to 1100 pm, from 600 pm to 1000 pm, from 600 pm to 900 pm, from 600 pm to 800 pm, from 600 pm to 700 pm, from 700 pm to 1100 pm, from 700 pm to 1000 pm, from 700 pm to 900 pm, or from 700 pm to 800 pm. In some embodiments the mean particle ers are, ::10%, 6g: 500 pm, 550 mm, 600 um, 650 um, 700 pm, 750 pm, 800 pm, 850 pm, 900 pm, 950 pm, 1000 pm, 1050 0 pm, 1150 pm or 1200 pm.

One suitable composition is a pellet—in—capsule composition n each pellet comprises a core that comprises a core seed with a mixture of brivaracetam, divalproex sodium, lacosamide, levetiracetam, oxcarbazepine, valproic acid, or vigabatrin and a binder coated onto the core seed, and an extended release coating surrounding the core comprising ethyl cellulose, a pore forming agent such as hydroxypropyl methyl cellulose or povidone, and a plasticizer. In some embodiments, the pellets may further se a seal coating between the pellet core and the extended release coating. The pellets are formulated using methods known in the art, such as those described in Example 1 below. In a speciﬁc embodiment, based on the combined weight of the pellet core and extended release coating, the brivaracetam, divalproex , lacosamide, levetiracetam, oxcarbazepine, ic acid, or Vigabatrin is present in amounts from 20-80 wt %, 45-70 wt %, 40-50 wt %, 45—55 wt %, 50-60 wt %, 55—65 wt %, 60-70 wt %, 65-75 wt %, 70-80 wt %, or 40 to 60 wt %, the binder, which is preferably hydroxypropyl methyl cellulose, copovidone, or mixtures thereof, is t in amounts from 1 to 25 wt %, the core seed, preferably a sugar sphere (nonpareil) or microcrystalline cellulose seed (e. g, Celphere®), is present in amounts from 8 to 25 wt %, the ethyl cellulose is present in s from 10 to 20 wt %, the pore forming agent, preferably povidone, is present in amounts from 1 to 4 wt %, and the plasticizer is present in amounts from 1 to 4 wt %. In another speciﬁc embodiment, based on the ed weight of the pellet core and extended e coating, the acetam, divalproex sodium, lacosamide, levetiracetam, oxcarbazepine, valproic acid, or Vigabatrin is present in amounts from 50 to 70 wt %, the binder, which is preferably hydroxypropyl methyl cellulose, copovidone, or mixtures thereof, is present in amounts from 1 to 25 wt %, the core seed, preferably a sugar sphere (nonpareil) or microcrystalline cellulose seed (e.g., Celphere®), is present in amounts from 5 to 15 wt %, the ethyl cellulose is present in amounts from 1 to 15 wt %, the pore forming agent, preferably povidone, is present in amounts from 0.25 to 4 wt %, and the plasticizer is t in amounts from 0.25 to 4 wt %. In a red ment, the AED is 45-70 wt % of the composition.

Additional embodiments are illustrated in the Table 1, below, ed “Various lacosamide ER e Size 1 Formulations.” By means of methods and itions described herein, formulations can be made that e the desired dissolution characteristics and target pharmacokinetic proﬁles described herein. More speciﬁcally, therapeutically effective doses of lacosamide can be administered once nightly in no more than two size 1 (or smaller, e. g, size 2 or 3) capsules using the manufacturing methods and compositions that have been described herein to achieve these results. In particular, higher drug loading can be achieved using compositions and manufacturing methods described herein. In some embodiments, higher drug g may be achieved, with the required dissolution proﬁle, using smaller core pellet sizes and concomitantly increased drug layering on smaller cores, but with no change in the extended release coat. In some embodiments, using alternative manufacturing approaches described herein, e. g., extrusion and spheronization, even higher drug loads can be achieved to realize the desired dissolution proﬁle, enabling high lacosamide drug loads with suitable pharmacokinetic proﬁles, resulting in compositions that are therapeutically more effective, and at least as well tolerated, and can be ﬁlled in relatively small sized capsules (e. g., size 1, 2 or 3), enabling ease of administration to patients.

WO 17569 Table 1: Various Lacosamide ER Ca sule Size 1 Formulations Extended Lacosamide Release Strength Manufacture ' Coating% % Fill in Size (m Method /w 1 Capsule -fi‘:t?n:ed 03-05 40-50% 10-3 0% 0.6-1.0 60-70% -12:;::;d 03-05 40-50% 10-30% 0 60-70% -1;1):1§n:ed 03-05 45-50% 10-3 0% 06-10 80-90% 100mg Elﬁntg’ed 03-05 50-55% 10-30% 0.6-1.0 80-90% 55-75% 10-30% 65-75% . . N/A 55-75% 10-30% 75-85% pan or ﬂuidized ed coating Extrusion Sphemmzaul’n’ N/A 55-75% 10-30% 80-90% pan or ﬂuldizeu Extrusion Sphemmzanl’n’ N/A 55-75% 10-30% 85-95% pan or ﬂuidizec ed coating For larger capsules, such as size 00 or 00el, strengths of 250 mg, 275 mg, 300 mg, or 325 mg may be ﬁlled.

Additional embodiments are illustrated in Table 2, below, entitled us Brivaracetam ER Capsule Size 1 Formulations.” By means of methods and itions described herein, formulations can be made that achieve the desired dissolution characteristics and target pharmacokinetic proﬁles described herein. More speciﬁcally, therapeutically ive doses of brivaracetam can be stered once y in no more than two size 1 (or smaller, e.g., size 2 or 3) capsules using the manufacturing methods and compositions that have been described herein to achieve these results. In particular, higher drug loading can be achieved using compositions and manufactuiing methods described herein. In some embodiments, higher drug loading may be achieved, with the required ution proﬁle, using r core pellet sizes and concomitantly increased drug layering on smaller cores, but with no change in the extended release coat. In some embodiments, using alternative manufacturing approaches described herein, e. g., extrusion and spheronization, even higher drug loads can be achieved to realize the desired dissolution proﬁle, enabling high brivaracetam drug loads with le pharmacokinetic proﬁles, resulting in compositions that are therapeutically more effective, and at least as well tolerated, and can be ﬁlled in relatively small sized capsules (e. g., size 1, 2 or 3), enabling ease of administration to patients.

Table 2: Brivaracetam ER Ca sule Size 1 Formulations acetam % Fill in Size Strength (mg) I ethod 1 Capsule 0.3—0.5 40-50% 6-30% 60—70% 0.3-0.5 40-50% 6-30% 60-70% 0.3-0.5 45-50% 6-30% 80-90% 03-05 50-55% 6-30% 80-90% 0.2-0.3 50—55% 6-30% 80-90% | xtrusion pheronization, N/A 55—75% 65-75% pan or ﬂuidized | xtrusion pheronization, 75-85% pan or ﬂuidized | on pheronization, 55-75% 80-90% pan or ﬂuidized ed coating | xtrusion spheronization, 85—95% The formulation techniques described for lacosamide and brivaracetam could be applied to other AEDs.

One or both agents of the combination may additionally be prepared as described in US WO 17569 Pat. No. 268, involving a biocompatible, radable microcapsule delivery system.

Thus, the lacosamide may be formulated as a composition containing a blend of free-ﬂowing spherical particles obtained by individually microencapsulating quantities of lacosamide, for e, in different copolymer ents which biodegrade at different rates, therefore releasing lacosamide into the circulation at a predetermined rates. A quantity of these particles may be of such a copolymer excipient that the core active ingredient is released quickly after administration, and thereby rs the active ient for an initial period. A second quantity of the particles is of such type excipient that delivery of the encapsulated ingredient begins as the ﬁrst quantity‘s delivery begins to decline. A third quantity of ingredient may be encapsulated with a still different excipient which s in delivery beginning as the delivery of the second quantity beings to decline. The rate of delivery may be altered, for example, by varying the lactide/glycolide ratio in a poly(D,L-lactide— co-glycolide) encapsulation. Other polymers that may be used include polyacetal polymers, polyonhoesters, polyesteramides, polycaprolactone and mers thereof, polycarbonates, polyhydroxybuterate and copolymers thereof, polymaleamides, copolyaxalates and polysaccharides.

In some embodiments, the lacosamide, brivaracetam, may be provided in a controlled or extended e form with or without an immediate release component in order to maximize the eutic beneﬁt of each, while reducing unwanted side effects associated with each. When these drugs are provided in an oral form t the beneﬁt of controlled or extended e components, they are released and transported into the body ﬂuids over a period of minutes to several hours. Thus, compositions may contain a lacosamide and a sustained release component, such as a coated sustained release matrix, a sustained release matrix, or a ned release bead matrix, In one example, lacosamide (e. g., 5-80 mg) is formulated Without an ate release component using a polymer matrix (e.g, Eudragit), Hydroxypropyl methyl cellulose (HPMC) and a polymer coating (e. g., Eudragit). Such formulations are compressed into solid tablets or granules or formed into pellets for capsules or tablets. ally, a coating such as Opadry® or Surelease® is used.

Optionally, the brivaracetam, divalproex sodium, lacosamide, levetiracetam, oxcarbazepine, valproic acid, or trin is prepared using the OROS® technology, described for example, in US. Pat. Nos. 6,919,373, 6,923,800, 6,929,803, 6,939,556, and 6,930,128, all of which are hereby incorporated by reference. This technology employs osmosis to provide e, controlled drug delivery for up to 24 hours and can be used with a range of compounds, including poorly soluble or highly soluble drugs. OROS® technology can be used to deliver high drug doses meeting high drug loading requirements. By targeting speciﬁc areas of the intestinal tract, OROS® technology may provide more efﬁcient drug absorption and enhanced bioavailability. The osmotic driving force of OROS® and protection of the drug until the time of release eliminate the variability of drug absorption and metabolism often caused by gastric pH and motility.

Alternatively, the combination may be prepared as described in US. Pat. No. 5,395,626 features a multilayered controlled release pharmaceutical dosage form. The dosage form contains a ity of coated particles wherein each has multiple layers about a core containing an lacosamide and/or the brivaracetam whereby the drug containing core and at least one other layer of drug active is overcoated with a controlled release barrier layer ore providing at least two lled releasing layers of a water soluble drug from the multilayered coated particle.

By way of example, ed release oral formulation can be prepared using additional methods known in the art. For example, a suitable extended release form of the either active pharmaceutical ingredient or both may be a matrix tablet composition. Suitable matrix forming als include, for example, waxes (e. g., carnauba, bees wax, paraffin wax, ceresine, shellac wax, fatty acids, and fatty alcohols), oils, hardened oils or fats (e.g., ed rapeseed oil, castor oil, beef tallow, palm oil, and soya bean oil), and polymers (e. g., hydroxypropyl cellulose, polyvinylpyrrolidone, hydroxypropyl methyl ose, and hylene glycol). Other suitable matrix tabletting materials are rystalline ose, powdered ose, ypropyl cellulose, ethyl cellulose, with other carriers, and ﬁllers. Tablets may also contain granulates, coated powders, or pellets. Tablets may also be multi—layered. Multi—layered tablets are especially suitable when the active ingredients have markedly different pharrnacokinetic proﬁles. Optionally, the ed tablet may be coated or uncoated.

The coating composition typically contains an insoluble matrix r (approximately -85% by weight of the coating ition) and a water soluble material (e.g., approximately -85% by weight of the coating composition). ally an enteric polymer (approximately 1 to 99% by weight of the coating composition) may be used or included. Suitable insoluble matrix polymers include ethyl cellulose, cellulose acetate butyrate, cellulose acetates, polymethacrylates containing quaternary ammonium groups or other ceutically acceptable polymers. Suitable water soluble materials include polymers such as polyethylene glycol, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinylpyrrolidone, polyvinyl alcohol, and monomeric als such as sugars (e. g., lactose, sucrose, fructose, mannitol and the like), salts(e.g., sodium chloride, potassium chloride and the like), organic acids (e. g, fumaric acid, succinic acid, lactic acid, and tartaric acid), and mixtures thereof.

Suitable enteric polymers include hydroxypropyl methyl ose, acetate succinate, hydroxypropyl methyl cellulose, phthalate, polyvinyl acetate phthalate, cellulose acetate phthalate, cellulose acetate trimellitate, shellac, zein, and polymethacrylates containing carboxyl groups.

The coating composition may be cized according to the properties of the coating blend such as the glass transition temperature of the main agent or mixture of agents or the solvent used for applying the g compositions. Suitable plasticizers may be added from 0 to 50% by weight of the coating composition and include, for example, diethyl phthalate, citrate esters, hylene glycol, glycerol, acetylated glycerides, acetylated citrate esters, dibutylsebacate, and castor oil. If desired, the coating composition may include a filler. The amount of the filler may be 1% to approximately 99% by weight based on the total weight of the coating composition and may be an ble material such as silicon dioxide, titanium dioxide, talc, kaolin, alumina, starch, powdered cellulose, MCC, or polacrilin potassium.

The coating composition may be d as a solution or latex in organic solvents or aqueous solvents or mixtures thereof. If solutions are applied, the solvent may be present in amounts from approximate by 25—99% by weight based on the total weight of dissolved .

Suitable solvents are water, lower alcohol, lower chlorinated hydrocarbons, ketones, or mixtures thereof. If latexes are applied, the solvent is present in amounts from approximately 25-97% by weight based on the quantity of polymeric material in the latex. The solvent may be predominantly water.

The pharmaceutical composition bed herein may also include a carrier such as a solvent, dispersion media, coatings, antibacterial and antifungal agents, isotonic and tion delaying . The use of such media and agents for ceutically active substances is well known in the art. Pharmaceutically acceptable salts can also be used in the composition, for example, l salts such as hydrochlorides, hydrobromides, phosphates, or sulfates, as well as the salts of organic acids such as acetates, proprionates, malonates, or benzoates. The composition may also contain s, such as water, saline, glycerol, and ethanol, as well as substances such as g agents, emulsifying agents, or pH buffering agents. Liposomes, such as those described in US. Pat. No. 5,422,120, WO 95/13796, WO 91/14445, or EP 524,968 B1, may also be used as a carrier. In some embodiments, lactose and/or casein are not preferred components of the composition. In some embodiments of any of the aspects described herein, the composition does not contain lactose, casein, or both. onal methods for making controlled e formulations are described in, e.g., US. Pat. Nos. 5,422,123, 5,601,845, 5,912,013, and 000, all of which are hereby incorporated by reference.

If d, the agents may be provided in a kit. The kits include a therapeutically ive dose of an agent for treating epilepsy or other seizure—related conditions. The dosage forms may be packaged on blister cards for daily administration convenience and to improve adherence.

Indications Suitable for Treatment Any subject experiencing or at risk of experiencing a seizure-related disorder, including nic seizures in myoclonic epilepsy, primary generalized tonic-clonic seizures in patients with idiopathic generalized epilepsy, partial onset seizures, status epilepticus, acute mania management, paroxysmal kinesigenic athetosis, phasic spasticity in multiple sclerosis, Landau-Kleffner me, migraine treatment or prophylaxis, ric migraine, Meige syndrome, late-onset seizures in patients with Alzheimer's disease, anxiety disorders, severe myoclonic sy of infancy, tardive dyskinesia, lumbar radiculopathy, late onset myoclonic epilepsy in Down syndrome, neuropathic pain, atypical pain syndromes, and Alzheimer's disease may be treated with compounds and methods described herein. Preferably, the methods of the invention treat ts experiencing or at risk of partial-onset seizures.

A subject of the invention may be experiencing or at risk of experiencing the seizure— related disorder. The subject may be diagnosed with a seizure-related er.

References to methods of treatment herein can e methods of prevention.

Administration of the Compositions Immediate release formulations of an AED such as lacosamide (e.g., ) are typically administered at low doses (e.g., 100 mg/day) and progressively administered at increasing dose over time to reach a steady state serum concentration that is therapeutically ive. According to the manufacturer's recommendation, Vimpat, an immediate release formulation of lacosamide, is ﬁrst administered to subjects at a dose of 50 mg twice daily. Doses are increased weekly by 100 mg/day to a daily dose of 200-400 mg/day. Using a sustained release formulation (at a constant daily dose of 200 mg, for example), a therapeutically effective steady state concentration may be achieved substantially sooner, without using a dose ting regimen or reducing the escalation to one step (e. g. 200 mg/day for 1 week followed by 400 mg/day fter). Furthermore, the slope during each absorption period for the sustained release formulation is less (i.e. not as steep) than the slope for the ate release form of an AED such as lacosamide. Accordingly, the dC/dt of the sustained release formulation is reduced ve to the ate e formulation. Based on this model, a sustained release formulation of an AED such as lacosamide may be administered to a subject in an amount that is approximately the full strength dose (or that ively reaches a therapeutically effective dose) from the onset of therapy and throughout the duration of treatment. Accordingly, a dose escalation may not be required. Alternatively, the sustained release formulation of an AED such as lacosamide may be titrated at an rated schedule compared to immediate release 2016/069581 lacosamide (e. g. 200 or 300 mg/day for 1 week followed by 400 or 600 mg/day thereafter; or 150 mg/day for 1 week, followed by 300 mg/day for 1 week, followed by 600 mg/day thereafter).

The recommended dose of immediate release lacosamide (e. g. VIMPAT®) for the treatment of partial onset seizures is 100 mg to 200 mg twice daily (200 mg to 400 mg a day, VIMPAT package ). There is no prescribing information on the time of day VIMPAT should be taken. Data from published literature suggests that, in partial onset seizures, a greater number of seizures may occur between 9 AM and 6 PM. Based on the known PK proﬁle of immediate release lacosamide, it is expected that a BID regimen of immediate release AED such as lacosamide lacosamide would provide a ile plasma proﬁle that is out of sync with this seizure pattern (i.e., a g dose may e some coverage for part of the period where there is a high seizure burden, but the evening dose would occur outside of this window) resulting in long periods of time throughout the day where there is high seizure tibility and low plasma concentration. Additionally, an evening dose of TR AED such as lacosamide would provide higher levels of the AED lacosamide on board during the nighttime hours when the need for seizure control is reduced. Thus, a sustained release formulation of an AED such as lacosamide that provides sustained and high plasma levels between 9 AM and 6 PM will provide better seizure control.

Drug ranges for the drug The inventors have found surprisingly that a eutically ive dose of an AED such as lacosamide administered less than 4 hours before bedtime in an extended release form with the pharmacokinetic characteristics described herein provides a reduction in adverse effects associated with therapy with the AED.

As described herein, the unit doses of an AED such as lacosamide administered as described herein are generally higher than the ranges ly prescribed for ate release compositions of the AED. For example, the ended dose of lacosamide for the treatment of epilepsy is 100 mg to 200 mg immediate release lacosamide administered twice daily. In clinical trials, higher doses appeared to provide greater beneﬁt in subjects who were able to tolerate the high doses, although the higher doses were associated with increased adverse reactions and a higher rate of dropouts. As bed herein, doses of 50 to 600 mg (or up to 800 mg) of lacosamide may be stered for ent of patients, and methods and compositions described herein may comprise once-nightly administration of a dose as deﬁned of up to 400, 500, 600 mg, 700 mg, or 800 mg once nightly, i.e., after 4 pm. and/or within 4 hours of bedtime. In additional embodiments the administration of such higher doses may be in the form of l, 2, 3 or 4 capsules of size 00, O, l or 2 in the normal or EL format administered once nightly.

In some embodiment of any of the aspects described herein, a total daily mide dose of 50 mg to 600 mg is administered as a once nightly formulation after 4 pm. and/or within 4 hours of bedtime. In some embodiments, the once nightly dose of lacosamide administered exceeds 300 mg per day. In various speciﬁc embodiments, the once nightly dose of lacosamide or pharmaceutically acceptable salt thereof may be 50 mg to 75 mg, 70 mg to 95 mg, 90 mg to 115 mg, 110 mg to 135 mg, 130 mg to 155 mg, 150 mg to 175 mg, 170 to 195 mg, 190 mg to 215 mg, 210 mg to 235 mg, 230 mg to 255 mg, 250 mg to 275 mg, 270 mg to 295 mg, 290 mg to 315 mg, 310 mg to 335 mg, 330 mg to 355 mg, 350 mg to 375 mg, 370 mg to 395 mg, 390 mg to 415 mg, 410 mg to 435 mg, 430 mg to 455 mg, 450 mg to 475 mg, 470 mg to 495 mg, 490 mg to 515 mg, 510 mg to 535 mg, 530 mg to 555 mg, 550 mg to 575 mg, 570 mg to 595 mg, 590 mg to 600 mg, 590 to 620 mg, 600 to 625 mg, 620 to 645 mg, 640 to 665 mg, 650 to 675 mg, 670 to 695 mg, 690 to 725 mg, 700 to 750 mg, 725 to 775 mg, or 750 to 800 mg.

In c embodiments described herein, a subject‘s entire daily dose of an AED such as lacosamide is administered once, during a period of less than about four, three, two or one hours before bedtime (i.e., after 4 pm. and/or the time at which the subject wishes to go to sleep for the night). In some embodiments of any of the above aspects, administration of the composition to a patient results in a signiﬁcant reduction in symptoms.

In some embodiments, herein a an AED such as lacosamide composition is administered to a patient in the morning, i.e., 0 to 3 hours after waking for the day, preferably, 0 to l, O to 2 hours after waking for the day. By the term “waking for the day” we mean the time at which the subject rises to begin the day’s activities. While for many people, waking for the day is typically between the hours of 5 am and 9 am, for some it may be earlier or later in the day or even in the night ing upon an individual’s normal sleep routine.

Suitable plasticizers include medium chain triglycerides, diethyl ate, citrate esters, polyethylene glycol, glycerol, acetylated glycerides, castor oil, and the like. The pellets are ﬁlled into capsules to provide the desired strength of an AED such as lacosamide. An advantage of this composition is it provides the desired release properties that make the composition le for administration during said period before bedtime. A further advantage is that the extended release coating is sufﬁciently durable so that the capsule can be opened and the pellets sprinkled onto food for administration to patients who have difﬁculty swallowing pills, without adversely ing the release ties of the ition. When the composition is administered by sprinkling onto food, it may be sprinkled on a soft food such as applesauce or chocolate pudding, which is consumed within 30 minutes, and preferably within 15 s. A yet further advantage of the above described composition is that it has very good batch—to—batch reproducibility and shelf-life stability.

A suitable pellet-in-capsule composition may have the above in vitro dissolution properties and/or any of the described pharmacokinetic properties (e.g, in vivo release proﬁle, Tmax, pAUC0.4, pAUC4.8, Cum/Cmn ratio, max slope, dC/dt, swing, C-ave-day/C-ave- night ratio, PTF, etc.) to make the composition suitable for administration in said period before bedtime. The composition may be further characterized by providing a Cmax of 8-21 ng/ml per mg of lacosamide and an AUCO-inf of 200-5 50 ng*h/mL per mg of lacosamide after oral administration of a single dose of the capsule to a human subject in a fasted state. A suitable pellet-in-capsule composition is further characterized by a steady state plasma concentration in which once nightly oral administration of the capsule to a human subject provides a Cmax of 12 to 36 ng/ml per mg of lacosamide, a Cmin of 6 to 15 ng/ml per mg of lacosamide, and an 4 of 200-550 ng*h/mL per mg oflacosamide.

Other Extended Release Dosage Forms The person of skill in the art will recognize that other embodiments of ed e compositions may be envisioned, in addition to the capsule formulation described above. Such other embodiments e extended release solid dosage forms, such as tablets, capsules, gel caps, powders, pellets, beadlets, etc. Included in such ed release compositions are those that have the e teristics and in vivo pharmacokinetic proﬁles suitable for employment in methods described herein. In some embodiments, the person skilled in the art may , with riate adjustment of design characteristics to achieve the ary pharmacokinetic proﬁle described herein, the extended release technology described in US.

Patent No. 5,358,721, to Guittard et al., or US. Patent No. 6,217,905, to Edgren et al., each of which disclose an oral osmotic dosage form of lacosamide, and each of which is incorporated herein by nce in its entirety. In other embodiments, the person of skill in the art may employ, again with appropriate adjustment of design characteristics, the technology described in US. Patent No. 6,194,000, to Smith et al. or US. Patent Appl. Publication Nos. US 2006/0252788, US 2006/0189694, US 2006/0142398, US 2008/0227743 and USZOI 1/0189273, all to Went et al., each of which disclose the administration of an NMDA receptor antagonist, optionally in controlled release form, and each of which is incorporated herein by reference in its entirety.

Manufacturing Considerations Compositions may be prepared as extended e coated pellets. These compositions may be prepared, for example, in a ed bed processor. In such examples, the AED, such as lacosamide, is combined with water and, optionally, other excipients such as s and/or anti- tacking agents.

The drug layering suspension or solution used in the ﬂuidized bed processor should have a solids content ranging from 15 to 45% w/w, preferably 20% to 35%, more preferably 25% to %. Some AEDs, such as lacosamide, have modest solubility in aqueous s (about 20 mg/ml), and the drug loading is expected to be signiﬁcant, i.e., 10% to 60% of an extended release pellet composition. To avoid very long processing times, the mide content in the aqueous sion will be beyond the solubility limit.

Thus for drug layering suspensions for the ﬂuidized bed drug coating, the AED, such as lacosamide, should have deﬁned particle characteristics to i) provide a suspension with high solids content to reduce the coating time, ii) provide a suspension that does not clog the spray nozzles within the ﬂuidized bed coater, iii) provide a uniform suspension to maximize the homogeneity of the t.

The le size for the AED, such as lacosamide, should be small enough to avoid clogging the spray nozzles and to be atomized in the ﬂuidized bed apparatus. This may be achieved with lacosamide which is either amorphous or crystalline with a length that is less than 3 times the width, The particle size should be small enough to pass h the ﬂuidized bed spray system t clogging and preferably less than 150 urn, more preferably less than 100 um, even more preferably less than 75 um and most preferably less than 50 um in size Passing the material through a sieve of an appropriate size is the typical method to ensure the material size, e.g., a 100 mesh sieve will permit material that is less than 149 um to pass through. The lacosamide particle size may be d by g or other s and equipment known to the skilled artisan. The suspension to be used in a ﬂuidized bed processor may require agitation or mixing and temperature control of the suspension to maintain homogeneity during the coating process.

In such examples, an extended release coating is then added to the drug coated particles to provide a composition with a release proﬁle as described herein. The ER coated particles may then be encapsulated to provide dosage forms suitable for administration to a subject in need thereof Alternatively, coated particles may be prepared by adding an extended release coating to granules of lacosamide prepared by mixing lacosamide with excipients, extruding the ition and spheronizing the extruded composition. The ed release coating may be added in a ﬂuidized bed sor or by other methods known in the art.

EXAMPLES Example 1: Lacosamide Extended Release Formulations mide extended release coated pellet compositions designed for nighttime administration are prepared using the ents and relative s shown in the table below. For each composition, the drug coating solution is prepared by adding HPMC 5 cps and Copovidone to isopropyl alcohol with continuous stirring. Puriﬁed water is added to this dispersion and ng continued until a clear solution is formed. Drug (lacosamide) is then added to this binder solution and stirring continued until the drug is completely ved.

Finally, talc is added and dispersed uniformly by stirring.

Celphere beads (screen sizes #35 to #50 i.e., 300 to 500 micron) are loaded in a Wurster coating unit. The drug coating dispersion is sprayed onto the beads followed by a period of drying. The resulting drug coated pellets are sieved to retain the on between screens #18 and #24 (approximately 700 pm to 1000 um diameter).

The seal coating solution is prepared by adding HPMC 5 cps to isopropyl alcohol with continuous stirring. Puriﬁed water is added to this dispersion and stirring continued until a clear solution is formed. Talc is added and dispersed uniformly by stirring. The sieved drug coated pellets are loaded in a Wurster coating unit. The seal g dispersion is sprayed over the drug coated pellets followed by a period of drying to remove the residual solvent and water in the s. The resulting seal coated pellets are sieved to retain the fraction between screens #18 and #24.

The ER coating solution is prepared by dissolving ethyl cellulose (viscosity 7 cps) in isopropyl alcohol and d water and stirring until a clear solution is . ne K-90 is then dissolved in this clear solution followed by addition of plasticizer Miglyol 812N with continuous stirring to form a clear on. The sieved seal coated pellets are loaded in a Wurster coating unit. The ER coating solution is sprayed over the seal coated pellets followed by a period of drying to affect the ER coat and remove the residual solvent and water in the pellets. After drying, magnesium stearate is spread on the top bed of the coated s in the annulus region followed by recirculation of the pellets in the Wurster unit to blend the magnesium stearate with the coated pellets. The resulting ER coated pellets are sieved to retain the on between screens #18 and #24.

The desired weight of the ER coated pellets containing the unit dose are ﬁlled into empty #1 hard n capsule shell (size #1 for 100 mg strength) using an encapsulator equipped with pellet dosing chamber. For the composition shown in the table below, 237 mg pellets contain 100 mg lacosamide, 2016/069581 TableEx1: Lacosamide ER Com osition Component Function Combined W/wof capsule Pellet Core 42.17% (Celphere®) USP r Extended Release Coating 1 Removed upon drying Example 2: Extended Release Lacosamide formulations Lacosamide extended e coated pellet compositions designed for once daily administration are prepared using the components and relative amounts shown below. For each composition, the drug coating sion is prepared by adding HPMC 5 cps to puriﬁed water with continuous stirring until a clear solution is formed. Drug (lacosamide) is then added to this binder solution with continuous stirring until a well-dispersed drug sion is formed.

Celphere beads (300 to 500 micron) are loaded in a Wurster coating unit. The drug coating dispersion is sprayed onto the beads followed by a period of drying.

The ER coating solution is prepared by dissolving ethyl cellulose (viscosity 7 cps) in isopropyl alcohol and d water. Hydroxypropyl methyl cellulose is dissolved in the solution followed by addition of plasticizer, diethyl phthalate. The sieved drug coated pellets are loaded in a Wurster coating unit. The ER coating solution is sprayed over the drug coated s followed by a period of drying to affect the ER coat and remove the residual solvent and water in the pellets. The resulting ER coated pellets are sieved.

The d weight of the ER coated s containing the unit dose are ﬁlled into empty #0 hard gelatin capsule shell (200 mg strength) using an encapsulator equipped with pellet dosing chamber.

Table Ex 2A: ER Lacosamide Form 1 comprises the following: Component on Combined w/w of capsule Active-loaded pellets mide Active 53.58% Microcrystalline cellulose spheres Core seeds 13.02% (Celphere®) Hydroxypropyl methyl cellulose Binder/Coating polymer 13.40% Puriﬁed water Solvent >—‘ ER-coated pellets Ethyl cellulose Coating polymer 13.3 3% Hydroxypropyl methyl cellulose Pore former 3.33% Diethyl phthalate Plasticizer 3.34% Isopropyl alcohol Solvent Puriﬁed water Solvent >—- I: removed during process Table EX 2B: ER mide Form 2 Component Function Combined W/w of capsule Active—loaded pellets Lacosamide Active 54.49% Microcrystalline ose spheres Core seeds 13.24% (Celphere®) Hydroxypropyl methyl cellulose Binder/Coating polymer 13.63% Puriﬁed water Solvent >—- ER-coated pellets Ethyl cellulose Coating polymer 13.56% Hydroxypropyl methyl ose Pore former 3 .3 9% Diethyl phthalate Plasticizer 1 70%- pyl alcohol Solvent >—‘ Puriﬁed water Solvent >—‘ I: removed during process Form 3 is ated as Form 1 + 3-hr DR.

Table Ex 2C: ER Lacosamide Form 3 Component Function Combined w/w of capsule Active-loaded pellets Lacosamide Active 47.42% Microcrystalline cellulose spheres Core seeds 11.52% (Celphere®) ypropyl methyl cellulose Binder/Coating polymer 11.86% Puriﬁed water Solvent ER-coated pellets Ethyl cellulose g polymer 1 1.80% Hydroxypropyl methyl cellulose Pore former 2.95% Diethyl phthalate Plasticizer 295% Isopropyl alcohol Solvent Puriﬁed water Solvent DR—coated pellets Methacrylic Acid and Ethyl g polymer Acrylate mer Triethyl citrate Anti-tack 0.88% I: removed during process e 3: ER Lacosamide Formulations with Partial Delayed Release Components Lacosamide extended release coated pellet compositions designed for nighttime administration are prepared using the ents and relative amounts shown below. For each composition, the drug coating suspension is prepared by adding HPMC 5 cps to puriﬁed water With continuous stirring until a clear solution is formed. Drug (lacosamide) is then added to this binder on with continuous stirring until a well—dispersed drug suspension is formed.

Celphere beads (300 to 500 micron) are loaded in a Wurster coating unit. The drug coating dispersion is sprayed onto the beads ed by a period of drying.

The ER coating solution is prepared by ving ethyl cellulose (viscosity 7 cps) in isopropyl alcohol and puriﬁed water, Hydroxypropyl methyl cellulose is dissolved in the solution followed by addition of plasticizer, diethyl phthalate. The sieved drug coated pellets are loaded in a Wurster coating unit. The ER coating solution is sprayed over the drug coated s followed by a peiiod of drying to affect the ER coat and remove the residual solvent and water in the pellets. The ing ER coated pellets are then sieved.

The delayed-release (DR) coating dispersion is ed by mixing water, triethyl citrate, and talc with methacrylic acid and ethyl acrylate mer aqueous dispersion. The sieved ER coated pellets are loaded in a Wurster coating unit. The DR coating solution is sprayed over the ER coated pellets followed by a period of drying. The resulting DR/ER coated pellets are then sieved.

The desired weight of the DR/ER coated pellets containing the unit dose are ﬁlled into empty #0 hard gelatin capsule shell (200 mg strength) using an encapsulator equipped with pellet dosing chamber.

Table Ex 3A: ER Lacosamide Formulation 2 + 2 Hour Delayed Release Component Function Combined w/w of Microcrystalline cellulose s Core seeds 11.72% (Celphere®) Hydroxypropyl methyl cellulose USP Binder/Coating 15.06% polymer/pore former Ethyl cellulose Coating r 12.00% Methacrylic Acid and Ethyl Acrylate Coating polymer Copolymer 1: removed during processing An ER lacosamide formulation characterized by a longer delayed release, i.e., 4 hours comprises a higher DR coating level, resulting in an approximate 20% weight se in the ER pellets.

Table Ex 3B: ER Lacosamide Formulation 4 hour Delayed e Component on Combined w/w of capsule Active-loaded s Microcrystalline cellulose spheres Core seeds 10.20% (Celphere®) Hydroxypropyl methyl cellulose Binder/Coating polymer 10.50% ——I_ ted pellets Ethyl cellulose Coating r DR-coated pellets Methacrylic Acid and Ethyl Acrylate Coating polymer 17.69% Copolymer Talc Plasticizer Triethyl citrate Anti-tack Puriﬁed water Solvent I: removed during processing Example 4: Brivaracetam Coated Pellet Formulations Brivaracetam extended release coated pellet compositions designed for nighttime administration are prepared using the components and relative amounts shown in the table below. For each composition, the drug g solution is prepared by adding HPMC 5 cps and Copovidone to pyl alcohol with continuous stirring. Puriﬁed water is added to this dispersion and stirring continued until a clear solution is formed. Drug (brivaracetam) is then added to this binder solution and stirring continued until the drug is completely dissolved.

Finally, talc is added and dispersed uniformly by stirring.

Celphere beads (screen sizes #35 to #50 i.e., 300 to 500 micron) are loaded in a Wurster coating unit. The drug coating dispersion is sprayed onto the beads followed by a period of drying. The resulting drug coated s are sieved to retain the fraction between s #18 and #24 (approximately 700 pm to 1000 um diameter).

The seal coating solution is prepared by adding HPMC 5 cps to isopropyl alcohol with continuous stirring. Puriﬁed water is added to this dispersion and stirring continued until a clear solution is fonned. Talc is added and dispersed uniformly by stirring. The sieved drug coated pellets are loaded in a Wurster coating unit. The seal coating dispersion is sprayed over the drug coated pellets ed by a period of drying to remove the residual t and water in the s The resulting seal coated pellets are sieved to retain the fraction n screens #18 and #24. Portions of these seal coated pellets are used to make extended release formulations as described below. Also, a first portion of these seal coated pellets is also retained as an immediate release form of brivaracetam. For the retained portion, magnesium stearate is spread on the top bed of the coated pellets in the annulus region followed by recirculation of the pellets in the Wurster unit to blend the magnesium stearate with the coated pellets to provide immediate release acetam pellets (“Form A”). The desired weight of the Form A s containing the unit dose are ﬁlled into empty #1 hard gelatin capsule shells (size #1 for 100 mg strength) using an encapsulator equipped with a pellet dosing r. For the Form A composition described in the table below, 197 mg pellets contain 100 mg brivaracetam.

The ER coating solution is prepared by dissolving ethyl cellulose (viscosity 7 cps) in isopropyl alcohol and puriﬁed water and ng until a clear solution is formed. Povidone K—90 is then dissolved in this clear solution followed by addition of plasticizer Miglyol 812N with continuous stirring to form a clear on. The sieved seal coated pellets are loaded in a Wurster coating unit. The ER coating solution is sprayed over one portion of the seal coated pellets to provide a faster release composition (about 8% coat weight, “Form B”) and over another portion of the s to provide a slower release composition (about 17% coat weight, “Form C”), in each case followed by a period of drying to affect the ER coat and remove the residual solvent and water in the pellets. After drying, magnesium te is spread on the top bed of the coated pellets in the annulus region followed by recirculation of the pellets in the Wurster unit to blend the magnesium stearate with the coated pellets. The resulting ER coated pellets from each of the sub—batches are sieved to retain the on between screens # 18 and #24.

The desired weight of the ER coated pellets containing the unit dose are ﬁlled into empty #1 hard gelatin capsule shell (size #1 for 100 mg strength) using an encapsulator equipped with pellet dosing chamber. For the Form Band Form C pellets shown in the table below, 100 mg acetam is contained in 216 mg pellets and 250 mg pellets, respectively.

Table Ex 4: Brivaracetam compositions Component ed w/W of Capsule Form A Form B Form C Brivaracetam 50.65% 46.40% 39.97% Microcrystalline cellulose Core seeds 16.86% 15.45% 14.57% spheres (Celphere®) - Hydroxypropyl methyl cellulose Binder/ Coating 22.76% 20.85% 19.67% USP polymer Copovidone Binder 3.58% 3.28% 3.09% Ethyl ose Coating r 6.60% 13.46% Povidone Pore former 1.00% 2.03% Medium chain triglycerides Plasticizer 0.79% 1.61% Talc USP Anti-tack 6.01% 5 50% 5.24% Magnesium Stearate NF Lubricant 0.13% 0 13% 0.13% Isopropyl Alcohol Solvent Solvent ,_‘ ,_i ,_i Water Removed upon drying Example 5: Dissolution of lacosamide formulations USP method <711> and Ph. Eur. 2.9.3, respectively, refer to an in vitro dissolution test for pharmaceutical ition. A rotating basket apparatus 1 as described in method <711> of the Us Pharmacopeoeia (edition 33) and chapter 2.9.3 of the Pharmacopoeia European on 6.8), respectively, with 900 mL dissolution media at 37i0.5°C at a stirring speed of 100 rpm is used to determine the in vitro release of lacosamide from solid lacosamide formulations. lly, the dissolution media is 0.1 N HCl; after 2 hours, the media is changed to 0.1 molar sodium phosphate buffer at pH 6.8 (same volume and temperature). Samples are taken for analysis at predetermined time points (as shown in the table below). The amount of lacosamide released at any time is determined via UV ometric detection. The values of replicate samples from separate dissolution baths (N=6) are averaged for each time point.

The dissolution rates for Formulations l, 2, Form 2.2 (a 50:50 mixture of Form 2 and Form 2 with an additional 2 hour DR coat), Form 2.4, (a 50:50 mixture of Form 2 and Form 2 with an increased DR coat), Form 2.6 (a 50:50 mixture of Form 2 and Form 2 with an even r DR coat), Form 3, Form 4, Form 4.2 (a 50:50 mixture of Form 4 and Form 4 with an additional 2 hour DR coat), Form 4.4, (a 50:50 mixture of Form 4 and Form 4 with an increased DR coat), and Form 4.6 (a 50:50 mixture of Form 4 and Form 4 with an even greater DR coat) —104— are shown in the following Tables and in Figures lA-lC: Table Ex 5A: Dissolution Table 1 Percent Released m——6 84 8 70 -—95 94 91 87 Percent Released Form 4.2 Form 4.4 Form 4.6 m-78 Example 6: Dissolution of brivaracetam ations The in vitro dissolution s for compositions described herein containing brivaracetam are performed according to USP <71 l> using a rotating basket apparatus 1 with 900 mL 0.1 molar phosphate buffer pH 6.8 at a ng speed of 100 rpm at 37::0.5°C. The analytical assay of the samples is performed using GC or another method known in the art.

Example 7 : ed Release Formulation made by Extrusion Spheronization Extended release compositions designed for nighttime administration are prepared using the components and relative amounts shown in the table below and the manufacturing process described below.

A blend of drug substance, microcrystalline ose and lactose monohydrate is prepared and a wet mass is prepared in a high shear granulator using an aqueous solution of povidone. The wet mass is extruded using 1 mm sieve and extruded mass is spheronized using a spheronizerr The s are dried in a tray drier to yield core pellets. The core pellets are coated with extended release coating solution in a pan coater. The desired weight of the ER coated pellets containing the unit dose is ﬁlled into empty 1 hard gelatin capsule shell (150 mg strength) using an ulator equipped with pellet dosing chamber. In vitro dissolution proﬁles for the itions are performed using the methods described herein.

Table Ex 7: AED Capsule Compositions _Function Combined w/w% of Ca n sule varacetam Pellet Core I-ru: substance _2.87% ||iluent 17.31% 0.78% II-inder 0.59% 71% Extended Release Coatin_ ICoatin 01 mer 14.83% 5.58% 456% lllasticizer 1.69% .76% 1 Removed upon drying Example 8: Pharmacokinetic measurement of the Formulation of Lacosamide ER compared to IR mide Objective: The primary objective of the study is to evaluate the pharmacokinetic proﬁle, safety and tolerability of a prototype formulation of ER Lacosamide (as ed in es 1- 3), relative to a 100 mg IR Lacosamide tablet (VlMPAT® ) given as single doses to healthy adult subjects under fasting ions.

Study : This is a Phase 1, randomized, single dose, open-label, two-period, two- treatment crossover, fasting pharmacokinetic study in which single 200 mg doses of lacosamide ER prepared according to Example 1 are compared to single 200 mg doses of marketed lacosamide IR s (VIMPAT®).

Methods: Subjects are admitted to the unit for the ﬁrst period of dosing within 21 days of study screening. There is a 7 day washout between dosing in period 1 and 2. In each dosing period subjects are dosed on the day after checking into the unit and discharged 72 hours post dose. A ﬁnal follow up end of study is conducted within 14 days of dosing in the second period.

After an ght fast, the formulation is administered to the subjects with 240 mL of water while they are in a sitting position. Blood samples are collected at 0 (pre-dose), 1, 2, 3, 4, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 18, 24, 30, 36, 48, 60, 72 hours following each dose.

Plasma samples are assayed for lacosamide by a validated liquid chromatography/tandem mass spectroscopy (LC/MS/MS) method. Pharrnacokinetic parameters are calculated using a non- compartmental analysis with WinNonlin software on 5.3 or higher, Pharsight Corporation).

An analysis of variance (ANOVA) is performed on the natural logarithms of Cmax and AUCOnO determined from the data following a single dose of study drug using linear mixed s model. The model includes ce, period, and regimen as ﬁxed effects and subject with sequence as random effect. Ratio of ER to IR for both AUC (relative bioavailability for ER ation) and Cmax is calculated. (Adverse events are monitored throughout the study. Vital signs (pulse rate, blood pressure and body temperature), clinical laboratory measures (biochemistry, hematology, and urinalysis) and ECGs are collected at various times during the study.

The PK results from this study demonstrate the ER form provides an increased Tmax (in the range of 11 to 19 hours vs about 1.5 hours for VIlVIPAT), a reduced Cmax on a dose tionate basis (about 2.5 to 3.5 ug/ml for the ER form versus more than 5 [1ng for the IR form), and an AUCO.00 that is bioequivalent to the IR form (i.e. 80-125% of the IR form on an equivalent dose basis). e 9: Simulation of ER and IR lacosamide PK proﬁles Dissolution proﬁles for immediate release and extended release compositions of lacosamide were used to model plasma concentration proﬁles with the re e GastroPlus, version 9.0. Physicochemical and Biopharmaceutical properties for lacosamide were ﬁrst determined using ADMET Predictor v. 7.2. The GastroPlus model with those parameters was then tested against published mide data to verify suitability for estimating plasma proﬁles for itions described herein. The release proﬁle for Form 4 and an immediate release form were input into the GastroPlus model and the single dose and multiple dose plasma concentrations were determined. Linear interpolation was used to determine intervening data points to generate plasma proﬁles with uniform time intervals of 0.1 hours. The plasma concentration curves were then used to determine PK parameters for the compositions, including Cmax, Tmax, AUC0-OO, dC/dt from O to 1.4 hours (Tmax for the 1R composition). Multi— dose models were also ted to ine the steady state PK parameters for these compositions.

The study results from the simulation of 400 mg Form 4 administered once daily and 200 mg IR stered twice daily (at 12 hour intervals)are provided in the table below and in Figure 2A. The IR results are based on the ﬁrst dose (ie. 200 mg). The Form 4 s were also based on the ﬁrst dose, however, the dose was 400 mg. Comparison of the dose normalized values for Cmax, AUC and dC/dt show the Form 4 AUCOm is 91% of the IR AUC0_00 the ER Cmax is 65% of the 1R Cmax, and the dC/dt is 0.6% of the 1R dC/dt. The Tmax ofForm 4 is 14.5 hours, while the Tmax for the IR form is 1.4 hours.

Table Ex 9: PK Properties of Lacosamide Compositions —m- W cm (pg/m1) “— WWI/ma AUC0_m/mg(ug*hr/ml/mg) 91% dC/dt/mg (ug/ml/hr/mg) 0.6% Example 10: Steady State Plasma Concentrations for Lacosamide The steady state plasma lacosamide concentrations for the compositions shown in Figures 1A—1C were simulated according to the method of Example 9 using GastroPlus, version 9.0. The plasma tration proﬁles were indexed to a speciﬁc dosing schedules as shown here. The dosing for ER forms was 400 mg once daily. For Form 1, the dosing was simulated at 8 am, for Forms 2, 2.2, 2.4, 2.6, and Form 3, the dosing was ted once nightly at 12 am; for Forms 4, 4.2, 4.4, and 4.6, the dosing was simulated once nightly at 10 pm. The dosing for the IR form was 200 mg BID at 8 am and 8 pm.

The plasma proﬁles at steady state are shown in Figures 3A, 3B, 3C, and 3D. As illustrated in the Figures, the minimum concentrations for all but Form 1 and the IR form occur during the night between about 12 am and about 4 am; for Form 1, the minimum occurs about 8 am, the time of dosing; and for the IR formulation, the two minimums also occur near the time of dosing, i.e., 8 am and 8 pm. Conversely all of the ER compositions e a Cmax,SS n about 10 am and 4 pm (10 to 18 hours after last administration), while the IR ation provides Cmax,ss at around 9:30 am and 9:30 pm.

Example 11: Steady State Plasma Profiles with Modified Dosing Regimens The plasma concentration proﬁle for single dose administration of the IR form was dose adjusted for administration according to the label for VIMPAT, then by superposition, the dosing of 100 mg BID for 1 week (starting at 8 am on day 1), followed by closing of 150 mg BID for 1 week, followed by the maintenance dose of 200 mg BID. The multi dose plasma concentration proﬁles for Form 4.2 administration and Form 3 as 400 mg QD was plotted as a function of time starting with the ﬁrst dose at 10 pm and 12 am, respectively, following the day l dosing for the IR form.

The results of the simulation are shown in Figure 4. As can be seen in the ﬁgure, the IR stration begins before the controlled release form administration on day l and, using the administration ol from the VIMPAT label, achieves a steady state proﬁle at 200 mg BID about 18 days after initiation of y. Conversely, the controlled release forms administered once nightly with no titration, achieved steady state about 4 days after initiation of therapy.

Therapeutically effective levels are achieved about 14 days earlier for these controlled release formulation regimens than for the [R regimen.

Example 12: Rotarod Study to Determine the Effects of Lacosamide (LCM) on Motor Coordination in Mice A pharrnacokinetic (PK)—pharmacodynamic (PD) study is performed in mice to evaluate the effects of lacosamide on motor coordination using the rotarod test following single intravenous (IV) or oral (PO) doses. The ive of this study is to trate that decreasing the rate of rise of plasma concentration of lacosamide s in a reduction in CNS side effects.

PK Phase For the PK phase, male CD—1 mice were ed to treatment groups according to the study design in Table Ex 12 below. Lacosamide was prepared as a solution in 0.9% saline, at concentrations indicated in Table Ex 12. IV dosing was done via tail vein injection and oral delivery was done with oral gavage tube. Dosing levels by each route are as shown in Table Ex Table Ex 12: Stud Desi nfor Pharmacokinetic Sam lin Group Route Dose Plasma collection N per collection concentration times (min) time (mg/mL) , 15, 30, 60, 120, 4 mice/ plasma 240, 480, 720 collection time , 15, 30, 60, 120, 4 mice/plasma 240, 480, 720 tion time , 15, 30, 60, 120, 4 mice/plasma 240, 480, 720 collection time , 15, 30, 60, 120, 4 mice/plasma 240, 480, 720 collection time WO 17569 Results The Cmax of lacosamide after a single 10 mg/kg IV dose was comparable to the Cmax after a single 30 mg/kg oral dose (~15 ug/mL), while Cmax values following a single 30 mg/kg IV dose was comparable to those following a 90 mg/kg oral dose (~40 ug/mL). The Tmax values varied based on the route of stration (<5 to ~15 min by the IV and oral routes, respectively), g that the Cmax was reached more slowly in the animals in the PO groups than the IV groups, PD Phase The rotarod (Ugo Basile, Germany) is a device that allows for quantitative measurement of motor coordination in rodents. Animals are pre-trained prior to testing on the d. 24 hours prior to the test day, mice are trained to run on the accelerating rotarod for at least 120 sin two consecutive trials. The mice are given up to 12 trials to achieve this performance criterion. Any mice not meeting this criterion are excluded from the test study.

Mice are randomized to treatment groups (vehicle; IV: 3, 10 30 mg/kg; P0: 10, 30, 90 . On the day of the test, the animals are dosed with test article and placed on the rotarod 5 minutes post-dosing. The rotarod is accelerated from 0-40 rpm over a 5 minute session, using the built—in function of the ent. The rotarod test is repeated for each mouse at 15, 30 and 60 minutes post-drug administration. Animals that stay on the rotarod are assigned a run-time of 300 s. The time that each animal stays on the rotarod prior to falling is tically recorded as the animal’s fall latency.

The latency to fall time on the rotarod ed for each animal is reported at each time point ose. Latency to fall is averaged (:: SEM) across the 10 animals in each treatment group at each time point. Lacosamide groups are compared against vehicle-treated means to determine if there is a signiﬁcant effect of lacosamide treatment on rotarod performance.

RESULTS By the same route of administration (IV or PO), an increase in dose results in a corresponding decrease in the latency to fall time on the rotarod, indicative that an increase in dose results in greater CNS impairment. However, at doses that produce equivalent Cmax by different routes of administration but different Tmax (e. g. 30 mg/kg IV and 90 mg/kg PO), administration by P0 which results in a reduced rate of rise results in greater latency to fall on the rotarod (less ment) compared to administration by IV. 2016/069581 Example 13: Pharmacokinetic Study of Lacosamide stered By Continuous Subcutaneous Infusion to Rats for 7 Days The objective of this study is to demonstrate that the PK proﬁle from a standard regimen of 200 mg IR lacosamide BID in humans, along with a novel PK proﬁle of 400 mg ER lacosamide QD, can be replicated in rats using programmable subcutaneous on pumps.

Jugular vein cannulated male and female Sprague Dawley rats weighing between 240- 260 grams are used for this study. Rats are implanted with programmable infusion pumps (iPRECIO SMP—200).

Simulated IR BID dosing Rats are assigned to 2 groups consisting of 4 rats each. Both groups are dosed identically using the same infusion protocol but the blood collection times for each group differ. Animals are allocated into the treatment groups to ensure similar distribution of body weights across all groups (+/-10% difference in mean body weight between groups). Two different on rates are employed over a 12 hour period to achieve a simulated 131D proﬁle and the infusion ol is repeated every 12 hours for 7 days. The solution in the programmable pump is reﬁlled every 3 days. Approximately 0.10 mL blood is collected from each rat via a r cannula at the time- points speciﬁed in Table EX 13. The actual plasma collection time are recorded for each animal.

The last collection time is the terminal time point for each animal.

Table Ex 13A: Stud Desi n and on Protocol for Simulated BID dosin Number Dose Dose Concentrati Plasma of Period2 rate/ratl on in pump Flow rate Collection animals (mg/h/rat) (mg/mL) Times (hours) 0-2 h 1, 4, 8, 14, 20, 84,144,158 2_12 h 0-2 h r 2, 6, 12, 18, 24, 98, 156, 168 2-12h 1. Lacosamide dose tes are based on average animal body weight of 250 g 2. Pump infusion protocol is repeated every 12 hours for a total of 7 days Simulated ER QD dosing Rats are assigned to three groups consisting of 4 rats each. All three groups are dosed cally using the same infusion protocol but blood collection times for each group will be different. The iPRECIO pump is programmed to provide two different infusion rates over a 24 hour period to achieve a simulated QD proﬁle and the infusion protocol will be repeated every 24 hours for 7 days. The pump is reﬁlled every 3 days. Animals are allocated into the treatment groups to ensure similar distribution of body weights across both groups (+/-10% ence in mean body weight between ). Approximately 0.10 mL blood is collected from each rat via a jugular cannula at the time-points speciﬁed in Table Ex 13B. The actual plasma tion time is recorded for each . The last collection time point is the terminal point for each animal.

Table Ex 13B: Stud Desi n and Infusion Protocol for Simulated D dosin Number Dose Dose Concentrati Plasma of Period2 rate/rat1 on in pump Flow rate Collection animals (mg/h/rat) ) Times (hours) 0-12h 0.30 3,9,15,21,30, 42’ 96’ 156 12—24 h 0.15 0-12 h 0.30 6, 12, 18, 24, 36, 48, 144, 168 12-24 h 0.15 l. Lacosamide dose estimates are based on average animal body weight of 250 g 2. Pump infusion protocol is repeated every 12 hours for a total of 7 days The following parameters are calculated: 0 Individual and mean plasma concentrations over time (ng/mL) o The plasma lacosamide concentration at each time point tabulated for each animal by group, and the mean (and SD) concentration for each group 0 The mean (and SD) concentrations for each group plotted as a function of time.

Descriptive PK parameters, such as but not limited to, AUC0.24h (11g >< h/mL), 4 (i.e. AUC,ss, ng x h /mL), Cm,SS (ng/mL), Cmin’ss (ug/mL) and Cum,ss (ug/mL) are calculated for individual animals and the mean (and SD) is tabulated by group.

RESULTS The PK parameters (Cmax, Tmax, T1/2, AUC) of 200 mg IR lacosamide BID and 400 mg ER lacosamide QD in humans can be replicated in rats using mmable subcutaneous infusion pumps, Example 14. Comparison of the effect of Lacosamide administered as an IR or an ER infusion profile on motor coordination and CNS oral effects in ratsThe primary objective of this study is compare the CNS side effects of lacosamide when delivered as a subcutaneous on in rats to simulate a once-a day extended release (ER) dosing profile or a twice a day (BID) immediate release (1R) dosing proﬁle in humans. The example investigates reducing the rate of rise of plasma trations with the ER proﬁle compared to the IR profile s in d CNS impairment. CNS side effects are measured as an impairment of motor coordination in rodents using the rotarod. Performance of rodents in a battery of ehavioral tests conducted during the infusion peﬁod are used as secondary endpoints as measures of CNS impairment.

Groups of rats are ted subcutaneously with programmable pumps that administer lacosamide as an on for 7 days. The infusion protocols are designed to produce pharmacokinetic proﬁles of lacosamide similar to that of IR lacosamide stered twice-a- day (BID) to humans (IR proﬁle) or an extended release proﬁle stered once-a—day (QD) to humans (ER proﬁle) at varying doses administered as IR BID or ER QD.

The 400 mg/day ER and [R (BID) doses in humans are predicted to yield -state plasma Cmax and Cmin of 102-1 1 .Zug/mL and 5.1-7.1pg/mL. In this study, dosing for rats designed to achieve these plasma levels is referred to as 400 mg/day human equivalent dose (“HE ”). For the 600 mg/day HED (300 mg BID dose) and 800 mg/day HED (400 mg BID dose) the targeted Cmax values to be achieved arel4.5 ug/mL and 18.4 pg/mL, respectively.

Rats are pre—trained on the rotarod prior to testing and assigned to groups based on their body weights. Groups of rats are implanted with pumps and tested on the rotarod prior to initiation of lacosamide infusion, and at time points that correspond to the Cmax, Cmm during the initial infusion phase and at steady state.

Following the period of acclimation, rats are surgically implanted with subcutaneous programmable pumps (iPRECIO), per the manufacturer’s ctions. Prior to tation, pumps are pre—programmed and ﬁlled with sterile 0.9% saline ing to the manufacturer’s instructions. Implantation is done under anesthesia by using c techniques.

Three days following pump implantation surgery, rats are pre-trained on the rotarod and assigned to treatment groups based on their body weights.

Infusion of lacosamide commences on day four post-pump implantation surgery.

Baseline measurements are made on the rotarod on Day 4. Immediately thereafter, saline in the iPRECIO pumps is Withdrawn and the pump is reﬁlled with lacosamide solution (25 mg/mL in 0.9% saline). Pumps are reﬁlled during the 7 day period as ary, through the access port of the iPRECIO pump.

Twenty four hours prior to the ﬁrst test day (on day 3 post—pump implantation), rats are trained to run on the accelerating rotarod for at least 120 s in two consecutive trials, The rats are given up to 12 trials to achieve this performance criterion. Any rats not meeting this criterion are excluded from the test study. Once rats achieve this criterion, they are considered fully trained and returned to their home cage. The acceleration on the rotarod is the same as that used during test day (0-40 rpm over a 5 mins).

On the test day at the speciﬁed time point, rats are placed on the rotarod and the rotarod is accelerated from 0-40 rpm over a 5 minute session, using the built-in function of the equipment. Each rat is run only once at each time point. A rat that has been incorrectly placed on the d and falls off in less than 5 seconds may be re—run at the discretion of the -ll3- 2016/069581 experimenter, who is blinded to the identity of the treatment groups. Animals that stay on the rotarod for the entire session are assigned a run-time of 300 seconds. The time that each animal stays on the rotarod prior to falling is automatically recorded as the animal’s fall latency.

A series of additional tests are conducted to characterize the CNS adverse events for the IR and ER proﬁles. These include ehavioral tests to assess an assortment of cognitive and motor on.

RESULTS By a given infusion protocol, time spent on the rotarod can decrease in a dose—dependent manner, such that the impairment produced by the 800 mg/day HED is greater than that produced at the 400 mg/day HED when comparing data at Cmax.

Surprisingly, for a given dose level, comparison of time spent on the rotarod for rats treated with the IR versus ER infusion protocol at Cmax show that rats in the IR proﬁle have a signiﬁcantly d time spent on the rotarod (i.e. greater impairment) ed to those in the ER group. These results show that at similar plasma Cmax concentrations, slowing the rate of rise of the plasma lacosamide concentration via an ER proﬁle results in a signiﬁcantly reduced impairment on the rotarod.

Similar results are observed with other secondary endpoints tested. Overall, when assessed by multiple measures, the results demonstrate a consistent beneﬁt in reducing CNS impairment by reducing the rate of rise of plasma concentrations with the ER proﬁle compared to the 1R proﬁle.

Example 15. Comparison of the Effect of Lacosamide Administered as an IR or an ER Profile on Motor nation in Rats The primary objective of this study was to compare the CNS side effects of lacosamide when delivered as a continuous infusion to rats to simulate an extended e (ER) plasma proﬁle or as a bolus to te an immediate release (IR) plasma proﬁle. It is hypothesized that ng the rate of rise of plasma concentrations with the ER proﬁle compared to the IR proﬁle results in d CNS impairment. CNS side effects were measured as an impairment of motor coordination in rodents using the d. The d (Ugo Basile, Italy) is a device that allows for tative measurement of motor coordination in rodents. Animals experiencing CNS side effects such as dizziness would fall off the rotarod faster than normal animals.

Rats were pre-trained on the rotarod prior to g and animals that did not meet the training criterion (at least 120 seconds time on rotarod in two consecutive trials) were excluded from the study. An acceleration protocol was used for training and test sessions, wherein the rotarod was rated from 0-40 rpm over a 5 minute session. All rats were then surgically implanted subcutaneously with programmable pumps (iPRECIO, Durect Corporation, —114— Cupertino, CA), per the manufacturer’s instructions, under anesthesia and using c techniques.

Three days following pump tation surgery, all rats were tested on the rotarod to obtain ne performance values. Rats were assigned to treatment groups such that the mean time spent on the rotarod was similar for each group. Four groups of rats were ed in this study, with 8-10 rats per group: e IP via programmable pump Lacosamide 1P viaprogrammable pump To reproduce the plasma proﬁle of ER lacosamide (ER e, group 2), rats were administered lacosamide as a continuous on into the intraperitoneal (IP) space. The infusion protocol was designed to produce a linear rise of lacosamide plasma tration with a Tmax of 18 hours. The total pump infusion duration was 18 hours. Control animals (group 1) were infused with vehicle (20% N—methy1pyrrolidone, NMP) using the same infusion protocol. To reproduce the ate release (IR) profile (group 4), rats were implanted with programmable pumps containing vehicle (20% NMP) and were given an IP bolus of lacosamide with an expected Tmax of 0.5 hours. Control animals (group 3) were implanted with pumps containing vehicle and were given an 1P bolus of vehicle. The slope of the rate of rise of plasma concentration of the ER profile was designed to be 310% of the slope of the IR proﬁle, while keeping the target Cmax for both the ER and IR proﬁles similar (~20 ug/mL).

Immediately following the 18 hour pump infusion for the ER groups, or 1 hour after IP injection for the IR groups, rats were placed on the rotarod and the rotarod was accelerated from 0-40 rpm over a 5 minute session, using the built-in function of the equipment. Animals that stayed on the rotarod for the entire session were ed a run—time of 300 seconds. The time that each animal stayed on the rotarod prior to falling was tically recorded. Immediately after the rotarod test, the rats were euthanized and blood was collected to determine the lacosamide plasma concentration.

In order to fully elucidate the plasma concentration-time profile of lacosamide administered by the ER and IR protocols, two groups ofPK satellite rats (n=4 each) were administered lacosamide using identical protocols to groups 2 and 4 above to reproduce the ER and IR proﬁles, respectively. Blood was collected at varying time points and the plasma lacosamide trations were determined. No rotarod g was performed on the PK satellite rats.

RESULTS Pharmacokinetic analysis of the PK ite groups demonstrated that the ER infusion protocol resulted in a slow and linear rate of rise of plasma lacosamide concentration with a median Tmax of 15 hours, whereas the [P bolus resulted in a rapid rise in plasma lacosamide concentration with a median Tmax of 0.75 hours. The Cmax for the ER and IR proﬁles in the PK satellite rats were similar (19 and 22 ug/mL, respectively). The ER proﬁle resulted in a 98% reduction in the rate of the rise (slope) of mide plasma concentration compared to IR (1.4 ug/mL/h for the ER proﬁle ed to 62 ug/mL/h for the IR proﬁle, Table X). While the ER and IR proﬁles produced similar Cmax values, due to the 18 hour infusion time required to produce the ER proﬁle, rats administered lacosamide by the ER proﬁle received ~6-fold higher dose and had 12-fold higher exposure (AUC0.13h) compared to rats administered mide by the [R proﬁle (Table 15).

Table 15. Lacosamide pharmacokinetic ters from PK satellite rats Parameter Group 2 (ER) Group 4 (IR)"< ER/IR Ratio *Slope ated from initiation of drug administration ** AUC calculated based on 18 hour infusion for ER proﬁle To conﬁrm that plasma concentrations were similar between the rats treated with lacosamide by the ER and IR proﬁle and tested on the rotarod (groups 2 and 4, respectively), plasma lacosamide concentrations were ined for these groups subsequent to rotarod testing. Analysis of the plasma taken immediately after rotarod testing demonstrated that lacosamide levels were similar for group 2 (ER proﬁle) and group 4 (IR proﬁle), approximately 19 ug/mL for both groups, and also similar to lacosamide levels in the PK satellite rats (Table Surprisingly, when dosed to achieve the same Cmax, comparison of time spent on the rotarod showed that rats dosed with the 1R proﬁle had greater impairment when compared to vehicle controls than those dosed with the ER proﬁle. Speciﬁcally, when ed to the baseline rotarod values, rats treated with lacosamide using the ER proﬁle (group 2) showed an increase in time on the rotarod of 45% after drug treatment, ed to a 27% increase in rotarod values for vehicle treated rats (group 1), see Figure 9. The percent change from ne in time on the rotarod was not statistically different (p>0.05) between the lacosamide ER group (group 2) and the vehicle ER group (group 1). In contrast, rats administered an IP bolus of lacosamide to produce the IR proﬁle (group 4) showed a 55% reduction in time on the rotarod from baseline values, whereas the matched vehicle controls (group 3) showed a 54% se.

For the IR groups, the difference in percent change from baseline between the mide treated (group 4) and vehicle (group 3) groups was statistically signiﬁcant (p=0.026).

These results shows that at similar plasma Cmax concentrations, slowing the rate of rise of the plasma lacosamide concentration via an ER proﬁle results in a signiﬁcantly reduced impairment on the rotarod. Furthermore, these results demonstrate that, by reducing the rate of rise, it is le to administer a higher dose of lacosamide and provide greater exposure without inducing signiﬁcant impairment.

Example 16. ison of the Effect of Brivaracetam Administered as an IR or an ER e on Motor Coordination in Rats The primary objective of this study is to compare the CNS side effects of brivaracetam when delivered as a continuous infusion to rats to simulate an extended release (ER) plasma proﬁle or as a bolus to simulate an immediate release (IR) plasma proﬁle. It is hypothesized that reducing the rate of rise of plasma concentrations with the ER proﬁle compared to the IR proﬁle results in reduced CNS impairment. CNS side effects are measured as an impairment of motor coordination in s using the rotarod. The rotarod (Ugo Basile, Italy) is a device that allows for quantitative measurement of motor coordination in rodents. Animals experiencing CNS side effects such as dizziness would fall off the rotarod faster than normal animals.

Rats are pre-trained on the d prior to testing and animals that did not meet the ng criterion (at least 120 seconds time on rotarod in two consecutive trials) are excluded from the study. An acceleration protocol is used for training and test sessions, n the rotarod is rated from 0—40 rpm over a 5 minute session. All rats are then surgically implanted subcutaneously with programmable pumps (iPRECIO, Durect Corporation, Cupertino, CA), per the manufacturer’s instructions, under esia and using aseptic ques.

Three days following pump implantation surgery, all rats are tested on the rotarod to obtain ne performance values. Rats are assigned to treatment groups such that the mean time spent on the rotarod was similar for each group. Four groups of rats are utilized in this study, with 8-10 rats per group: -ll7- 2016/069581 Vehicle IP via programmable pump Brivaracetam IP viaprogrammable pump To reproduce the plasma proﬁle of ER brivaracetam (ER , group 2), rats are stered acetam as a continuous infusion into the intraperitoneal (IP) space. The infusion protocol is designed to produce a linear rise of acetam plasma concentration with a Tmax of >10 hours. Control animals (group 1) are inﬁised with vehicle using the same infusion protocol. To uce the immediate release (IR) proﬁle (group 4), rats are implanted with programmable pumps containing e and are given an IP bolus of brivaracetam that results in a Tmax of <1 hour. l animals (group 3) were implanted with pumps containing vehicle and were given an IP bolus of vehicle. The slope of the rate of rise of plasma concentration of the ER proﬁle is designed to be 310% of the slope of the IR proﬁle, while keeping the target Cmax for both the ER and [R proﬁles similar.

Approximately 30 minutes following the Tmax for the ER or IR proﬁle, rats are placed on the rotarod and the rotarod is accelerated from 0—40 rpm over a 5 minute session, using the built— in function of the equipment. Animals that stay on the rotarod for the entire session are assigned a run-time of 300 seconds. The time that each animal stays on the d prior to falling is automatically recorded Immediately after the rotarod test, the rats are euthanized and blood is ted to determine the brivaracetam plasma concentration.

In order to fully elucidate the plasma concentration-time proﬁle of acetam administered by the ER and [R protocols, two groups ofPK satellite rats are administered brivaracetam using identical protocols to groups 2 and 4 above to reproduce the ER and IR s, respectively. Blood is collected at varying time points and the plasma brivaracetam concentrations are determined. No rotarod testing is performed on the PK satellite rats.

RESULTS Pharmacokinetic analysis of the PK satellite groups demonstrate that the ER infusion protocol results in a slow and linear rate of rise of plasma brivaracetam concentration which is <10% of the rate of rise of the 1R proﬁle. The Cmax for the ER and IR proﬁles in the PK satellite rats are similar.

When dosed to achieve the same Cmax, comparison of time spent on the rotarod shows greater impairment for rats dosed with the 1R proﬁle than those dosed with the ER proﬁle (when each are compared to vehicle controls). Speciﬁcally, in rats treated using the ER proﬁle, the change from baseline in time on the rotarod is not different between brivaracetam treated and vehicle animals. In contrast, rats administered an IF bolus of brivaracetam to produce the IR proﬁle have greater reduction in time on the rotarod than matched vehicle controls.

These results show that at similar plasma Cmax concentrations, slowing the rate of rise of the plasma acetam concentration via an ER proﬁle results in a signiﬁcantly reduced impairment on the rotarod. Furthennore, these s demonstrate that, by reducing the rate of rise, it is possible to administer a higher dose of brivaracetam and provide greater exposure without inducing signiﬁcant impairment.

Example 17: Lacosamide Coated Pellet Formulations Lacosamide extended release coated pellet compositions, Formulations A, B, C, D, were prepared using the components and relative amounts shown in the table below. For each composition, the drug g suspension was prepared by combining the active pharmaceutical ient with Hypromellose USP in puriﬁed water. This suspension was applied onto microcrystalline cellulose spheres in a Wurster ﬂuidized bed processor to provide immediate release cores shown in the table below. An extended e g solution was prepared by dissolving ethyl cellulose, Hypromellose USP, and diethyl phthalate in isopropyl alcohol and puriﬁed water. The extended release coating was then applied to the immediate release cores in a Wurster ed bed processor to ing extended release pellets described in the table below. For Formulations B, C, and D, an additional delayed release coating was added; the delayed release coating suspensions were prepared by combining the methyacrylic acid and methyl methacrylate copolymer(s) with triethyl citrate, talc, isopropyl alcohol and puriﬁed water. These coating suspensions were then applied to the extended release coated pellets in a Wurster ﬂuidized bed sor to the levels indicated in the table below. The coated pellets were subsequently machine encapsulated into size 00 hard gelatin capsules at a strength of 200 mg lacosamide Table 17: Compositions of Lacosamide MR Capsules, 200 mg, Formulation A-D F—ormulation A—mountper Amount per Amount per Amount per unit unit unit unit CI—omonen’tFunctionalit m1 e m1 e m1 caIsule m1 caIsule Immediate-release core Lacosamide Active 200.00 200.00 200.00 200.00 Pharmaceutical Ingredient Hypromellose, USP 50.01 50.01 50.01 50.01 Microcrystalline ose Ineit spherical 48.58 48.58 48.58 48.58 Spheres, NF core ed Water, USP1 Coating solvent - - - - Extended-release membrane Amount per Amount per Amount per Amount per C—omuonent Functionalit Ethylcellulose, NF Rate-controlling 2597 25. 95 20.76 31.14 polymer —————— —————— Delayed-release membrane Methacrylic Acid and Rate-controlling Methyl rylate polymer mer (1:1), NF rylic Acid and Rate-controlling 25. 84 22.45 26.41 Methyl Methacrylate polymer Copolymer (1 :2), NF Triemylcmatem ————— mom ————— _-----[sopropyl Alcohol, USP1 Coating solvent —————— —————— 1:Removed during process Example 18: Dissolution profiles of Lacosamide Compositions The dissolution proﬁles for the lacosamide formulations prepared according to Example 17 above were determined as described in USP method <71 l> of the US Pharmacopeoeia (edition 33 and chapter 2.9.3 of the Pharmacopoeia European (edition 6.8). Brieﬂy, a rotating basket apparatus as described in the aforementioned references was used with 900 mL of dissolution media at 37 .0::O.5°C at a stirring speed of 100 rpm to ine the in Vitro e of the lacosamide. Initially, the dissolution media was simulated gastric ﬂuid (pH 1.2); after two hours at pH 1.2, the media was changed to simulated intestinal ﬂuid (pH 6.8); after four hours at pH 6.8, the media was changed to phosphate buffer (pH 7 .5) for the ﬁnal 18 hours. Samples were taken at the time points shown in the table below and the amount of lacosamide ed was determined by UV spectrometric detection. The mean dissolution percentages for each formulation at the speciﬁed times are provided in the table below and in Figure 5.

Table 18: ution profiles for mide Compositions 2 O 4 O 6 4 9 42 WO 17569 2016/069581 24 105 101 105 89 Example 19: Simulation of Lacosamide Plasma Concentration s Dissolution proﬁles for the lacosamide compositions shown in Example 18 above were used to model plasma concentration s with the software package GastroPlus, version 9.0 as described in Example 9 above for single doses at 400 mg. The plasma concentration curves were then used to determine PK ters for the compositions, including Cmax, Tmax, AUC0_OQ, AUC0.4, AUC4.g, and dC/dt from O to 1.4, 2, 3, 4 hours. These parameters were also determined from the plasma concentration curve for the immediate release mide formulation of Example 9, adjusted to a single dose of 400 mg. The plasma concentration curves based on the models from GastroPlus are shown in Figure 6. As shown in the table below, when compared to the immediate release formulations, the modified release formulations all provide delayed Tmax values and provides AUC equivalence to IR. The pAUC0-4 values are substantially lower than the [R pAUC0-4 value; the pAUC4-g and pAUC0-3 values for Formulation B, Formulation C, and Formulation D are also much lower than the corresponding values for IR and Formulation A.

The dC/dT values over each of the time periods shown in the table are 50% or less than the corresponding [R value, and over the ﬁrst 1.2, 2, or 3 hours after administration of a single dose of the compositions or an equivalent dose of the IR formulation, the dC/dT for the formulations of the compositions are less than 33% of the corresponding values. The dC/dT values for Formulation B, Formulation C, and ation D are all less than 5% of the corresponding IR value.

Table 19A: Single Dose PK Parameters IR Form. A Form. B Form. C Form. D Tmax (h) 14-4 cm (Hg/ml) -——-ﬁ 5-5 Aucm (ug*hr/m|) 156-0 mm-——— 82% -——— pAUC0_4 (pg*hr/m|) 35.01 699 0.00 0.19 0.00 onal AUC (%) 0% pAUC4_g (pg*hr/m|) 31.73 25.42 12. 89 1.57 FractionaIAUC(%) 7% 1% pAUC0_8 (ug*hr/m|) 66.74 32.42 2.93 13.08 1.57 FractionalAUC (%) 35% 17% 2% 7% 1% dc/dT 0 to 1.4 hr (ug/mI/hr)“mm-m dC/eIT 0 to 2 hr /hr) “mm-m chr o to 3 hr (ug/mI/hr)“mm dC/dr o to 4 hr /hr) -——-m-m Multi-dose plasma concentration proﬁles for the IR and modiﬁed release formulations each dosed once daily at 400 mg per day were also generated from GastroPlus. Additionally, a multi-dose plasma concentration proﬁle for the 1R formulation dosed at 200 mg BID was generated from GastroPlus. These multi-dose plasma tration proﬁles were extended to 6 days to provide a steady state proﬁle for the ﬁnal day; the steady state proﬁles were used to determine the steady state PK parameters for the compositions, including Tmams, Cmaxss, Cumss, AUC0.24, swing and PTF. As shown in the table below, each of the formulations of Example 17 provide a Tmax,SS that is substantially greater than the 1R Tmams. The Tum,SS for Formulation B and Formulation D are both r than 12 hours, consistent with suitability for night time administration once daily. The swing values and PTF values for the formulations of the Example 17 are greater than the swing provided by the BID and QD dosing regimens for IR.

Table 19B: Steady State PK Parameters -—_lmm max,“ (h) Cmax.ss (Hg/ml) 13-7 10-6 ”El-m cm (pg/ml) AUCo-24 (ug*hr/m|) %oflR-QD 100% 98% 90% 95% 77% cmamS/D (ng/mI/mg) 34.1 26.4 24.4 27.1 20.0 cmms/D (ng/mI/mg) 9.5 11.9 11.5 11.1 10.2 AUC0_24/D (ng*hr/m|/mg) 475.6 465.1 426.5 453.0 365.3 SWing (Cmax,ss'cmin,ss)/Cmin,ss (%) 83% 260% 122% 112% 143% 95% ((Cmax‘SS—CminISS)/(AUC0.24/tau) 59% 124% 75% 73% 84% 64% e 20: Steady State Lacosamide Plasma Profiles with Modified Dosing Regimens The steady state plasma concentration proﬁles prepared in the previous example were based on once daily, oral dosing of the modiﬁed e lacosamide itions at 8:00 am. By adjusting the dosing time the Cmax)SS and Cmin,ss were also d as shown in Figures 7A to 7D.

The C-ave-day and C-ave night averages were determined over the periods of 9 am to 6 pm and 11 pm to 8 am, respectively, for various administration times to determine the optimum administration times for each of the compositions, i.e., the time at which C-ave-day is 50% to 100% greater than C-ave-night. As shown in the table below, Formulation A provides a substantially higher C-ave-day than C-ave-night when administered in the morning hours (e.g., 6 am to 9 am); similarly Formulation B and Formulation D provide a substantially higher C-ave- day than night when administered in the evening hours (eg, 8 pm to 11 pm). None of the formulations from e 17 provided a C-ave-day that met the 50% to 100% ia when administration times were between 9 am and 8 pm. Formulation C met the criteria when stered late at night (i.e., at or after midnight). Importantly, each of the Fonnulations of Example 17 could be dosed at a predetermined administration time to provide a C-ave-day that is greater than C—ave—night by 50% to 100%, Furthermore, once daily dosing at these predetermined administration times typically led to steady state peak trations from about am to about 2 pm as shown in Figure 8. These periods of increased exposure are thus designed to be synchronous with an increased partial onset seizure frequency during the late morning to mid-day hours.

Table 20: Does Daily Dosing Within the Time Period Provide day increase of 50- 100% over C—ave-night? Example 21: Single dose Pharmacokinetic Study of Lacosamide Compositions Objective: The primary objective of the study was to evaluate the pharmacokinetic proﬁle, safety and tolerability of prototype modified release formulations of mide (as prepared in Example 17 above), relative to IR Lacosamide tablets (VIMPAT® ) given as single doses to healthy adult subjects under fasting ions, Study design: This was a Phase 1, randomized, single dose, open-label, three-period, two—parallel group, balanced crossover, g pharmacokinetic study in which single 400 mg doses of lacosamide ER ed according to Example 17 were compared to single 400 mg doses of marketed lacosamide IR tablets T®). Within each group, as illustrated in Table 21A below, individuals were randomly assigned to a “sequence” and received two of the modiﬁed release formulations and the immediate release formulation over the three treatment periods.

Methods: Subjects were screened within 14 days of the ﬁrst dose of the ﬁrst treatment . Qualiﬁed subjects entered the clinic one day prior to the ﬁrst dose (ﬁrst treatment period) and were conﬁned within the clinic until completion of the 7 day safety follow-up after the third dose (third ent period). Each treatment period of 7 days consisted of dosing on the ﬁrst day, followed by sampling, starting from the time of dose. In each treatment period, the subjects were administered a single, oral dose at approximately 8:00 (after an overnight fast of at least 10 hours). Safety monitoring and study drug tolerability assessments se events, vital signs, clinical laboratory parameters) were ted throughout the study for all subj ects. cokinetic blood samples were collected to measure plasma lacosamide concentrations.

While conﬁned to the clinic (once day before ﬁrst dose through the study completion) subjects followed a standard meal le. At each dosing time, the study drug (either one of the 4 formulations prepared according to Example 17 or IR lacosamide) was administered as a single dose containing 400 mg lacosamide with 240 mL of noncarbonated, room-temperature water. Subjects were required to refrain from drinking water for the hour prior to receiving the dose and for one hour after receiving the dose. Subjects were allowed to eat 4 hours after dosing. Subjects were required to remain in a sitting or semi-supine position for at least 2 hours after each study drug administration in each treatment period (other than any protocol—required assessments conducted by the site staff); thereafter subjects were allowed to engage in non- strenuous activities. Following each treatment period dose, subjects were required to te study ments and scheduled blood draws from day 1 h day 7.

Plasma lacosamide trations were measured for the following time points in each treatment period: se (0), 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 18, 20, 24, 30, 36, 48, and 72 hours post dose. Adverse events were reported for each subject throughout each treatment period. Clinical laboratory tests (hematology, clinical chemistry, and urinalysis) were completed for each subject at check-in, day 2 (36 hour time point), during and on the last day of each treatment period. Vital signs were collected at screening, check—in, prior to study drug dosing and 6, 8, 24, 36, and 72 hours post dose and at the end of each treatment . Electrocardiograms were recorded and assessed at screening and baseline and at 2 hours, 12 hours, at day 1 prior to dose for each treatment period and at the end of study.

Table 21A: Treatment Sequences GROUP 1 —Treatment Period A Treatment Period B Treatment Period C —124— GROUP 1 Sequence 4 Sequence 5 Sequence 6 GROUP 2 Sequence 7 Sequence 8 Sequence 9 Sequence 10 Sequence 1 l Sequence 12 *1, 2, 3, 4, and IR refer to Formulation A, ation B, Formulation C, Formulation D, and the [R lacosamide tablets, respectively Twenty-four subjects meeting the study criteria were randomly assigned to the 12 sequences of the two el study . Of these, 22 completed the three treatment periods.

The two ts not completing the study were exited from the study before Treatment Period C for reasons unrelated to study drugs.

Samples for mide concentration measurement were quantiﬁed using a validated liquid chromatography/tandem mass spectroscopy (LC/MS/MS) method.

Results: Plasma concentrations for the four test formulations, when compared to the 1R lacosamide tablets, conﬁrmed delayed Tmax and reduced Cmax, generally tent with the Plus s of Example 19. A graph of the mean lacosamide plasma concentrations vs time for the four test formulations and IR is shown in Figure 10.

The safety results from this study are shown in Table 218 below. The lacosamide compositions ed ing to Example 17 had fewer adverse events than an equivalent dose of the IR lacosamide composition. Of the adverse events observed, hypoaesthesia oral was observed in 11 of 24 (45.8%) of the subjects receiving the IR lacosamide and only 1 of 12 (8.3%) of the subjects receiving Formulation B; similarly, dizziness was observed in 8 of 24 ) of subjects receiving the 1R lacosamide and only 1 of 12 (8.3%) subjects receiving Formulation A, 1 of 12 (8.3%) subjects receiving Formulation B, 1 of 12 (8.3%) subjects receiving Formulation C, and 1 of 10 (10.0%) subjects receiving Formulation D. For a given adverse event, no more than one subject in any of the experimental formulations reported the event.

Table 21B. Incidence of Subjects with Adverse Events within 24 hours after dosing System Organ Class Preferred Term Subjects with At Least One 4 (33.3%) 2 (16.7%) 1 (10.0%) 15 (62.5%) Adverse Event within 24 Hours Not Coded 0 (0.0%) 0 (0.0%) o (0.0%) 0 (0.0%) 2 (8.3%) Hypoaesthesia Nose 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 1 (4.2%) Paresthesia bital 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 1 (4.2%) Ear and labyrinth disorders 0 (0.0%) 0 (0.0%) 0 (0.0%) o (0.0%) 2 (8.3%) Ear discomfort 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 1 (4.2%) Tinnitus 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 1 (4.2%) Eye disorders 0 (0.0%) 0 (0.0%) 1 (8.3%) 1 (10.0%) 1 (4.2%) Diplopia 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 1 (4.2%) Vision blurred 0 (0.0%) O (0.0%) 1 (8.3%) 1 (10.0%) 0 (0.0%) Gastrointestinal disorders 1 (8.3%) 2 (16.7%) 0 (0.0%) 0 (0.0%) 13 (54.2%) Dry mouth 0 (0.0%) 1 (8.3%) 0 (0.0%) 0 (0.0%) 0 (0.0%) gia 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 1 (4.2%) Hypoaesthesia oral 0 (0.0%) 1 (8.3%) 0 (0.0%) 0 (0.0%) 11 ) Nausea 1 (8.3%) O (0.0%) 0 (0.0%) O (0.0%) 1 (4.2%) Paraesthesia oral 0 (0.0%) O (0.0%) 0 (0.0%) 0 (0.0%) 2 (8.3%) General disorders and O (0.0%) 1 (8.3%) 0 (0.0%) 0 (0.0%) 1 (4.2%) administration site conditions Fatigue 0 (0.0%) 1 (8.3%) 0 (0.0%) 0 (0.0%) 0 (0.0%) System Organ Class Form. B Form. C Form. D IR Form Preferred Term (N=12) (N=12) (N=10) (N=24) Feeling hot 0 (0.0%) o (0.0%) o (0.0%) 1 (4.2%) Musculoskeletal and tive 0 (0.0%) o (0.0%) o (0.0%) o (0.0%) 1 (4.2%) tissue disorders Myalgia o (0.0%) o (0.0%) o (0.0%) o (0.0%) 1 (4.2%) s system disorders 1 (8.3%) 1 (8.3%) 2 (16.7%) 1 (10.0%) 10 (41.7%) Altered state of ousness o (0.0%) o (0.0%) 0 (0.0%) o (0.0%) 1 (4.2%) Disturbance in attention 0 (0.0%) o (0.0%) o (0.0%) o (0.0%) 1 (4.2%) Dizziness 1 (8.3%) 1 (8.3%) 1 (8.3%) 1 (10.0%) 8 (33.3%) Headache o (0.0%) o (0.0%) o (0.0%) 1 (10.0%) 0 (0.0%) Hypoaesthesia 0 (0.0%) 0 (0.0%) 1 (8.3%) o (0.0%) 1 (4.2%) Somnolence o (0.0%) o (0.0%) o (0.0%) o (0.0%) 2 (8.3%) Respiratory, thoracic and 1 (8.3%) O (0.0%) 0 (0.0%) 0 (0.0%) 1 (4.2%) mediastinal disorders Pharyngeal paraesthesia 0 (0.0%) o (0.0%) o (0.0%) o (0.0%) 1 (4.2%) Rhinorrhoea 1 (8.3%) o (0.0%) 0 (0.0%) o (0.0%) 0 (0.0%) Sneezing 1 (8.3%) o (0.0%) 0 (0.0%) o (0.0%) 0 (0.0%) 1: For each formulation, adverse events are tabulated once based on their first occurrence post dose administration.

WO 17569

Claims

CLAIMS 1. What is d is:

1. A method of administering a pharmaceutical composition to a human patient, comprising administering to said human patient orally, once daily, a therapeutically effective dose of said pharmaceutical composition, wherein said pharmaceutical composition comprises (i) a drug selected from the group consisting of brivaracetam, divalproex, lacosamide, levetiracetam, oxcarbazepine, vigabatrin, and pharmaceutically acceptable salts of any of the foregoing, and (ii) at least one excipient, wherein at least one of said at least one ents modiﬁes the release of said drug to provide an extended release form, wherein said pharmaceutical composition has a plasma concentration proﬁle for said drug characterized by a 4 that is less than 4% of AUC0-mf for said drug as ined by dosing said pharmaceutical composition to a t of a fasted, single dose, human pharmacokinetic study.

2. The method of claim 1, wherein said pharmaceutical composition has a plasma concentration proﬁle for said drug characterized by a pAUC4.g that is less than 14% of AUCO.inf for said drug as determined by dosing said pharmaceutical composition to a subject of a fasted, single dose, human pharmacokinetic study.

3, The method of claim 1 or claim 2, wherein said drug is selected from the group consisting of brivaracetam, lacosamide, racetam, and ceutically acceptable salts of any of the foregoing.

4. The method of claim 1 or claim 2, wherein said drug is mide,

5. The method of one of claims l-4, wherein said therapeutically effective dose is 300 to 900 mg of said drug.

6, The method of one of claims 1-4, wherein said therapeutically effective dose is 400 to 800 mg of said drug.

7. The method of one of claims l-4, wherein said eutically effective dose is 450 to 800 mg of said drug.

8. The method of one of claims l-7, wherein at least one of said at least one excipients modiﬁes the release of said drug to provide a delayed release form.

9. The method of one of claims l-8, wherein said pharmaceutical composition has a steady state plasma concentration proﬁle for said drug upon once daily dosing of said pharmaceutical composition characterized by a Tmax,SS of 10 to 20 hours, as determined by dosing said pharmaceutical composition to a subject of a fasted pharmacokinetic study.

10. The method of one of claims 1-9, n said plasma concentration proﬁle for said drug is further characterized by an AUCO_inf that provides AUC equivalence to IR.

11. The method of one of claims 1-10, wherein said pharmaceutical composition has a plasma concentration proﬁle for said drug characterized by a pAUC4-g that is less than 8% of AUCo.-mf for said drug as ined by dosing said pharmaceutical composition to a subject of a fasted, single dose, human pharmacokinetic study.

12. The method of one of claims 1-11, wherein said pharmaceutical composition has a plasma concentration proﬁle for said drug characterized by a Tmax of 8 to 20 hours as determined by dosing said pharmaceutical composition to a subject of a , single dose, human pharmacokinetic study, and wherein said pharmaceutical composition has a steady state plasma concentration proﬁle for said drug upon once daily dosing of said pharmaceutical composition characterized by a swing of 40% to 200%, as determined by dosing said pharmaceutical composition to a subject of a fasted human pharmacokinetic study.

13. The method of one of claims 1-12, wherein said pharmaceutical ition has a plasma concentration proﬁle for said drug characterized by a TmaX of 8 to 20 hours and a dC/dT of less than 2.2 ng/ml/hr per mg of said drug over the ﬁrst 2 hours after dosing, both as determined by dosing said pharmaceutical composition to a subject of a fasted, single dose, human pharmacokinetic study.

14. The method of one of claims 1-13, wherein said pharmaceutical composition has a plasma concentration proﬁle for said drug characterized by a Tmax of 8 to 20 hours and a dC/dT of less than 1 ug/ml/hr over the ﬁrst 2 hours after , both as determined by dosing said pharmaceutical composition to a subject of a fasted, single dose, human pharmacokinetic study.

15. The method of one of claims 1-14, wherein said composition is administered at a predetermined administration time, which ermined administration time is a time ined from a fasted, human pharmacokinetic study of said pharmaceutical composition and said predetermined time is a time at which once daily dosing of the pharmaceutical composition to a human subject of said pharmacokinetic study provides a C—ave—day that is 20% to 100% r than C-ave-night, wherein C-ave-day is the average plasma concentration of said drug determined over the period from 9:00 am to 6:00 pm and C-ave—night is the average plasma concentration of said drug determined over the period from 11:00 pm to 8:00 am,

16. The method of one of claims 1-15, wherein said pharmaceutical composition has a dissolution proﬁle terized by three or more of the ing: (a) less than 10% release at 1 hour, (b) less than 15% release at 2 hours, (c) less than 25% release at 4 hours, (d) at least 35% release at 9 hours, (e) at least 65% at 12 hours, wherein said dissolution is carried out in 900 mL simulated gastric ﬂuid (pH 1.2) at 37:0.50C for the ﬁrst two hours, followed by 900 mL simulated intestinal ﬂuid (pH 6.8) at 37::0.5°C for the subsequent four hours, followed by 900 mL phosphate buffer (pH 7.5) at 37i0.5°C for the subsequent 18 hours, n all dissolution is med in a USP Apparatus 1 (Basket), with a rotational speed of 100 rpm, and wherein said pharmaceutical composition has a plasma concentration proﬁle for said drug characterized by a Tmax of 8 to 20 hours as detennined by closing said pharmaceutical composition to a subject of a fasted, single dose, human cokinetic study.

17. A method of administering a pharmaceutical composition to a human t, comprising administering to said human patient orally, once daily, a therapeutically effective dose of said pharmaceutical composition, wherein said pharmaceutical composition comprises (i) a drug selected from the group consisting of brivaracetam, divalproex, lacosamide, levetiracetam, oxcarbazepine, vigabatrin, and pharmaceutically acceptable salts of any of the foregoing, and (ii) at least one excipient, wherein at least one of said at least one excipients modiﬁes the release of said drug to e an extended release form, wherein said pharmaceutical composition has a plasma concentration proﬁle for said drug characterized by a pAUC4.g that is less than 8% of nf for said drug as determined by dosing said pharmaceutical ition to a subject of a fasted, single dose, human pharmacokinetic study.

18. The method of claim 17, wherein said drug is selected from the group ting of brivaracetam, lacosamide, levetiracetam, and pharmaceutically acceptable salts of any of the foregoing.

19. The method of claim 17 wherein said drug is mide.

20. The method of one of claims 17-19, wherein said therapeutically effective dose is 300 to 900 mg of said drug.

21. The method of one of claims 17-19, wherein said therapeutically effective dose is 400 to 800 mg of said drug.

22. The method of one of claims 17-19, wherein said therapeutically effective dose is 450 to 800 mg of said drug.

23. The method of one of claims 17-22, wherein at least one of said at least one excipients -l30- WO 17569