JP2016047838A - Eslicarbazepine acetate and methods of use - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a pharmaceutical composition and method for treating various conditions or diseases such as, for example, epilepsy, trigeminal neuralgia, and affective brain disorders, that has a high potency and a low occurrence of side effects.SOLUTION: The present invention relates to the method of using eslicarbazepine acetate in an once-daily administration for the treatment of various diseases and conditions like affective disorders, schizoaffective disorders, bipolar disorders, attention disorders, anxiety disorders, neuropathic pain and neuropathic pain-related disorders, sensorimotor disorders, vestibular disorders, or nervous function alternations in degenerative and post-ischemic diseases, etc. The present invention also relates to the method for use of eslicarbazepine acetate in which the administration is conducted in an amount resulting in a maximum observation plasma concentration Cof eslicarbazepine greater than about 7400 ng/mL, preferably, greater than about 12000 ng/mL.SELECTED DRAWING: None

Description

(background)
The present disclosure relates to pharmaceutical compositions and methods of treatment using eslicarbazepine acetate.

Pain conditions such as epilepsy, trigeminal neuralgia, and affective brain disorders such as bipolar disorder are generally treated with carbamazepine. However, treatment with carbamazepine can have serious side effects due to the production of toxic metabolites. Oxcarbazepine has been developed to reduce the severity of these side effects, but oxcarbazepine is very weak. For example,
Almeida, L. & Soares-da-Silva, P., “The safety, tolerability and pharmacokinetic properties of BIA 2-093, a novel putative antiepileptic agent in an elevated multidose study in healthy young humans J. Clin. Pharmacol., 44, 906-918 (2004) (referred to herein as “Almeida I”).
Accordingly, there is a need for pharmaceutical compositions and methods for treating various conditions or diseases, such as epilepsy, trigeminal neuralgia and affective brain disorders, which are potent and have a low incidence of side effects.

  The present invention provides eslicarbazepine acetate and methods of use.

(Summary)
Eslicarbazepine acetate, (S)-(-)-10-acetoxy-10,11-dihydro-5H-dibenz / b, f /
Azepine-5-carboxamide (“BIA 2-093”) is a novel drug that is currently being developed, including various conditions such as epilepsy and affective brain disorders, as well as pain states, debilitating and postischemic diseases It is useful for the treatment of neurological function changes. Eslicarbazepine acetate is chemically related to carbamazepine and oxcarbazepine, but avoids the formation of certain toxic metabolites (e.g., epoxides), without reducing the pharmacological activity and It is believed to avoid unnecessary formation of complex enantiomers or diastereoisomers. Benes et al., “Anticonvulsant and sodium channel blocking properties of novel 10,11-dihydro-5H-diabenz [b, f] azepine-5-carboxamide derivatives”, J. Med. Chem., 42, 2582-2587. (1999).

Like carbamazepine and oxcarbazepine, eslicarbazepine acetate is a voltage-gated sodium channel (VGSC) that interacts competitively with site 2 of the inactivated state of the sodium channel. It is considered to be a blocking agent. The affinity of the channel for this state is similar to that of carbamazepine, but the affinity for the resting state of the channel is about one third of the affinity of carbamazepine. This characteristic suggests that the inhibitory selectivity of eslicarbazepine acetate to rapidly firing neurons is higher than that of neurons exhibiting normal activity. For example, Bonifacio et al., “New anticonvulsant BIA 2-0.
Interaction of 93 with voltage-gated sodium channels: Comparison with carbamazepine ", Epilepsia
42, 600-608 (2001).

Evaluation of the metabolic properties of eslicarbazepine acetate by chiral analysis in rat, dog, monkey and human liver microsomes is the S (+) enantiomer of licarbazepine, (S)-(+)-10,11- Dihydro
-10-hydroxy-5H dibenz / b, f / azepine-5-carboxamide (also known as `` eslicarbazepine '') and recarbazepine, (R)-(-)-10,11- It was found that dihydro-10-hydroxy-5H dibenz / b, f / azepine-5-carboxamide (also known as “R-licarbazepine”) was not given.

After oral administration, eslicarbazepine acetate has been rapidly and extensively metabolized to become the active metabolizing eslicarbazepine and a small amount of R-licarbazepine has been shown in human studies. See Silveira et al., "Pharmacokinetics of BIA 2-093 in healthy elderly subjects", Epilepsia, 45 (suppl. 3), 157 (2004). For example, the plasma concentration of the parent drug (eslicarbazepine acetate) is determined by the limit of quantification (LOQ) (10 ng
/ mL) was found throughout the body. Almeida I; Almeida, L. & Soares-da
-Silva, P., “A new putative antiepileptic drug BI during the first administration to humans.
See Safety, Tolerability and Pharmacokinetic Properties of A 2-093 "Drugs R & D, 4, 269-284 (2003) (referred to herein as" Almedia II "). When non-chiral methods were used, eslicarbazepine and R-enantiomer were not distinguished by the assay, and the mixture was reported as “BIA 2-005” or “racemic carbazepine”.

The inventors conducted human tests on healthy subjects and described the results in the Almeida I and Almeida II literature, both of which are incorporated herein by reference. In these studies, healthy subjects are given a single oral dose of eslicarbazepine acetate, the dosage ranges from 20 mg to 1200 mg (see Almeida II), and eslicarbazepine acetate The daily multiple doses ranged from 200 mg (twice a day) to 1200 mg (twice a day) (see Almeida I). In further studies (not yet published) by the inventors, higher doses of eslicarbazepine acetate were investigated, including, for example, doses ranging up to 2400 mg (once daily). Observed BIA
The maximum plasma concentration of 2-005 (C _max ) is achieved about 1 to about 4 hours (t _max ) after administration, and the magnitude of systemic exposure to BIA 2-005 is approximately proportional to the dose, and BIA 2 These studies have shown that a steady state of -005 plasma concentration is achieved in about 4 to 5 days. The average renal clearance rate of BIA 2-005 from plasma is 20-30 mL / min, and the total amount of BIA 2-005 recovered in the urine is about 20% and 40% within 12 and 24 hours after administration, respectively. %Met.

Those tests also showed that the apparent terminal half-life of BIA 2-005 ranges from about 8 hours to about 17 hours. See, for example, Almeida II.
US Pat. No. 6,296,873 discloses a sustained release delivery system for carbamazepine having a half-life in the range of 25 to 85 hours. To avoid adverse effects, U.S. Pat.No. 6,296,873
The number teaches that carbamazepine is administered in tablet form more than once a day, gradually releasing the compound to maintain the concentration value between 4-12 μg / mL. The delivery system requires a form that is capable of delivering the compound over an extended period of time, such as a tablet form.

In one aspect of the present disclosure, the inventors have increased the efficacy of eslicarbazepine acetate in the treatment of various conditions when using once-daily administration compared to twice-daily administration. I discovered it unexpectedly. Apparent half-life of eslicarbazepine acetate (t _1/2 = about 8 hours to about 17 hours)
This discovery is particularly surprising because it is significantly shorter than the _half -life of carbamazepine, a compound typically administered 3-4 times a day (t _1/2 = 25 to 85 hours) .

In another embodiment of the present disclosure, the inventors have exposed to eslicarbazepine in humans after administration of eslicarbazepine acetate once daily as compared to twice daily administration. It was discovered unexpectedly that it improved. Surprisingly, once-daily administration of eslicarbazepine acetate
Increases exposure to eslicarbazepine compared to splitting the same drug into twice daily doses.

The foregoing and following aspects and embodiments, including the tests described herein, have been described and illustrated for purposes of illustration only and are not to be construed as limiting the scope.
One aspect of the present disclosure relates to a method for treating at least one disease or condition in a patient in need thereof by administering a pharmaceutical composition comprising a pharmacologically effective amount of eslicarbazepine acetate. .

In one exemplary embodiment of the present disclosure, a pharmaceutical composition comprising eslicarbazepine acetate is administered on a once daily dosing regimen.
In another exemplary embodiment of the present disclosure, the pharmaceutical composition maximizes total exposure to eslicarbazepine, measured by exposure rate and exposure scale (C _max and AUC _0-τ ). Is administered at the intended dose.

In exemplary embodiments of the present disclosure, the at least one disease or condition to be treated is, for example, affective disorder, schizoaffective disorder, bipolar disorder, attention disorder, anxiety disorder, neuropathic pain and neuropathic It can be selected from pain-related disorders, sensorimotor disorders, vestibular disorders, and neurological function changes in debilitating and post-ischemic diseases.
Examples of affective disorders include depression, premenstrual dysphoric disorder, postpartum depression, climacteric depression, anorexia,
Examples include bulimia and neurodegeneration-related depression.

Using the methods disclosed in this disclosure, for example, schizophrenia syndrome, schizophrenia, extreme psychotic condition, schizophrenia syndrome, discomfort and aggressive behavior, accidental control difficulties or intermittent explosive disorder, and borderline personality disorder Can treat schizophrenic injury.
Bipolar disorders that can be treated according to the methods of the present disclosure include, for example, hyperbolic and unstable hyperbolic disorders with rapid agitation (rapid cyclers), manic depression disorders, acute enthusiasm, mood seizures, and mania and Hypomania seizures can be mentioned.

Examples of attention disorders include attention deficit hyperactivity disorder and other attention disorders such as autism.
Examples of the anxiety disorder include social anxiety disorder, post-traumatic stress disorder, panic, obsessive compulsive disorder, alcoholism, drug withdrawal syndrome and desire.
Neuropathic pain and neuropathic pain-related disorders that can be treated according to the methods of the present disclosure include, by way of example: neuropathic pain and related pain sensations, including trigeminal neuralgia, herpes neuralgia, postherpetic neuralgia, and spinal cord neuralgia Hypersensitive; diabetic neuropathic pain; migraine; tension headache: burning pain; and afferent block syndrome such as brachial plexus ablation.

Examples of sensorimotor disorders include restless leg syndrome, convulsions, unilateral facial convulsions, nocturnal paroxysmal ataxia, cerebral ischemia-related movements and sensory deficits, Parkinson's and Parkinson's disease-like disorders, antipsychotic-induced deficits Dyskinesia, incidental nighttime migration and myotonia.
Exemplary vestibular disorders include tinnitus or other cochlear excitation related diseases such as neuronal loss, hearing loss, sudden hearing loss, dizziness and Meniere's disease.

In other exemplary embodiments, the at least one disease or condition can be selected from epilepsy, bipolar disorder and trigeminal neuralgia.
Those of ordinary skill in the art will understand that these conditions are exemplary only, and from the disclosure, understand what other diseases and conditions are considered to be within the scope of this disclosure. Let's go.
Another aspect of the present disclosure relates to a pharmaceutical composition comprising eslicarbazepine acetate and at least one pharmaceutical excipient, at least one auxiliary substance, at least one carrier material, or a combination thereof.

A further aspect of the present disclosure relates to a method for preparing a pharmaceutical composition comprising combining eslicarbazepine acetate with at least one excipient, at least one auxiliary substance, at least one carrier material, or a combination thereof. . Suitable excipients, carrier materials and other auxiliary substances useful in the present invention are known to those skilled in the art and are readily determined. Methods for preparing pharmaceutical compositions are also known to those skilled in the art.

In one exemplary embodiment of the present disclosure, the pharmaceutical composition may be in tablet form,
It may contain at least one excipient, auxiliary substance and / or carrier material. At least 1
One excipient, auxiliary substance and / or carrier material is selected from, for example, povidone, croscarmellose sodium, magnesium stearate, sodium saccharin, dicalcium phosphate dihydrate, sodium lauryl sulfate, perfume, and combinations thereof. It's okay. Exemplary tablets may be formed using granulated liquids such as purified water and ethanol.

In another exemplary embodiment of the present disclosure, the pharmaceutical composition may be in the form of an oral suspension and may include at least one excipient, auxiliary substance and / or carrier material. The at least one excipient, auxiliary substance and / or carrier material is, for example, xanthan gum, macrogol stearate (e.g. Myrj 59 P from UNIQEMA), methylparaben, propylparaben,
You may select from sodium saccharin, sorbitol, buffering agents, perfumes, and combinations thereof.

Another aspect of the present disclosure reduces or reduces the number, duration or frequency of seizures in a patient by administering to the patient a pharmaceutical composition comprising a pharmacologically effective amount of eslicarbazepine acetate. It relates to a method for making it. In one exemplary embodiment of the present disclosure,
A method for reducing epileptic seizures in a patient comprises administering a once-daily dose of a pharmaceutical composition comprising a pharmacologically effective amount of eslicarbazepine acetate.

The present disclosure also provides eslicarbase in a patient by administering to the patient a pharmaceutical composition comprising an effective amount of eslicarbazepine acetate to increase the plasma concentration of eslicarbazepine at dosing intervals. It relates to a method for increasing exposure to pins. In one exemplary embodiment, exposure to eslicarbazepine can be increased by delivering the pharmaceutical composition in a manner that minimizes the number of daily doses. In a further exemplary embodiment of the present disclosure, a method for increasing exposure to eslicarbazepine in a patient is effective in increasing plasma concentrations of eslicarbazepine during dosing intervals. Administering a once daily dose of a pharmaceutical composition comprising eslicarbazepine acetate to a patient.

In a further exemplary embodiment of the present disclosure, the active ingredient of the pharmaceutical composition can consist essentially of eslicarbazepine acetate.
In further embodiments of the present disclosure, eslicarbazepine acetate can be administered to a patient in an amount that results in a maximum plasma concentration (C _max ) of eslicarbazepine that is greater than about 7400 ng / mL. In other exemplary embodiments, eslicarbazepine acetate can be administered to a patient in an amount that results in a C _max of eslicarbazepine greater than about 12000 ng / mL, or greater than about 16100 ng / mL. . In further exemplary embodiments, the eslicarbazepine acetate is greater than about 22700 ng / mL, such as greater than about 36500 ng / mL, greater than about 45200 ng / mL, or greater, the C _{max of} eslicarbazepine. Can be administered to a patient in an amount that results in

In further exemplary embodiments, eslicarbazepine acetate is 58800 ng / mL or 6780.
The patient can be administered in an amount that results in a maximum plasma concentration (C _max ) of eslicarbazepine up to 0 ng / mL. In a further exemplary embodiment, eslicarbazepine acetate is 885000 ng
The patient can be administered in an amount that results in a maximum plasma concentration (C _max ) of eslicarbazepine up to 1 / mL or 1000000 ng / mL.

For example, about 4 resulting in a maximum plasma concentration (C _max ) of eslicarbazepine above about 7400 ng / mL.
A once daily dose of 00 mg can be administered to the patient. As a further example, an eslicarbazepine C _max of greater than about 16100 ng / mL, or greater than 22700 ng / mL, respectively.
A once daily dose of 800 mg or about 1200 mg can be administered to the patient. In other examples, a once-daily dose of esriacetate greater than 1200 mg, such as about 1800 mg or about 2400 mg, which results in a C _max of eslicarbazepine greater than about 36500 ng / mL and about 45200 ng / mL, respectively. Carbazepine can be administered.

In a further embodiment of the present disclosure, an amount of acetic acid that provides an area under the concentration curve (corresponding to the magnitude of systemic exposure) (AUC _0-τ ) during dosing intervals of eslicarbazepine greater than about 110000 ng · h / mL Eslicarbazepine can be administered to the patient. In other exemplary embodiments, the AU of eslicarbazepine greater than about 240000 ng · h / mL, or greater than about 375000 ng · h / mL, respectively.
An amount of eslicarbazepine acetate that provides C _0-τ can be administered to the patient. In another exemplary embodiment, an amount of eslicarbase acetate that results in an AUC _0-τ of eslicarbazepine greater than about 595000 ng · h / mL, greater than about 790000 ng · h / mL, or greater. Pins can be administered to the patient.

For example, the area under the concentration curve of the administration interval of eslicarbazepine exceeding about 110000 ngh / mL (
A once daily dose of about 400 mg can be administered which results in (AUC _0-τ ) corresponding to the magnitude of systemic exposure. In other exemplary embodiments, about 800 mg or about 1200 mg resulting in an AUC _0-τ of eslicarbazepine of greater than about 240000 ng · h / mL, or greater than about 375000 ng · h / mL, respectively.
Can be administered once a day. In other embodiments, about 595,000 ng
AU of eslicarbazepine above h / mL, above about 790000 ngh / mL, or greater
1 day above about 1200 mg, such as about 1800 mg, about 2400 mg or more, resulting in C _0-τ
Multiple doses of eslicarbazepine acetate can be administered.

In one exemplary embodiment of the present disclosure, a once daily dose can be administered in a dosage comprising at least about 400 mg of eslicarbazepine acetate. In another exemplary embodiment, a once daily dosage can be administered in a dosage comprising eslicarbazepine acetate in an amount ranging from about 800 mg to about 1200 mg. In a further exemplary embodiment, the once daily dose can be administered in a dosage comprising an amount of eslicarbazepine greater than about 1200 mg, such as an amount of about 1800 mg, about 2400 mg or more. .

A pharmaceutical composition comprising eslicarbazepine acetate may optionally be administered by any route known to those skilled in the art and is in a form selected from, for example, tablets or oral suspensions, or others It may be a form.
According to another aspect of the invention there is provided the use of eslicarbazepine acetate or a salt thereof in combination with at least one other antiepileptic drug in the manufacture of a pharmaceutical composition for treating epilepsy, The pharmaceutical composition is for administration once a day. The concentration of at least one other antiepileptic drug is not significantly reduced by once daily administration of a pharmaceutical composition comprising eslicarbazepine acetate. Preferably, the at least one other antiepileptic drug is selected from valproate, lamotrigine, topiramate, and combinations thereof.

According to another aspect of the invention, the dosage form comprises about 400 to 1200 mg of eslicarbazepine acetate, the dosage form being a maximum dose up to 1200 mg per day for the treatment of the above mentioned diseases excluding epilepsy. Pharmaceutical unit dosage compositions suitable for oral administration are provided.
As used herein, the term “about” means that the number modified by the term may be considered an approximation that may vary depending on the desired property or effect sought for a particular application. Therefore, it should be considered as encompassing a range that would be understood by one of ordinary skill in the art to achieve the desired or described characteristics or effects.

As used herein, a “treatment method” refers to administering to a patient any amount of the described compound effective to reduce, suppress or eliminate the effect of the disease or condition being treated, or symptoms thereof. It means to do.
As described herein, “a method for increasing exposure to eslicarbazepine in a patient” is useful for increasing the plasma concentration of eslicarbazepine during a dosing interval in a patient. It means that any amount of the described compound is administered to the patient. This is, for example,
It may be an increase by administration once a day as compared to administration twice a day.

As used herein, “reduction of epileptic seizures in a patient” refers to the number, duration or duration of epileptic seizures in a patient compared to the number, duration or frequency of epileptic seizures experienced by an untreated patient. Or any decrease in frequency.
A “pharmacologically effective amount” of eslicarbazepine acetate in the pharmaceutical compositions described herein refers to any amount sufficient to have the desired pharmacological activity.
All effective amounts described herein will depend on a variety of well-known and understood factors such as, for example, the condition being treated and the physiological characteristics of the patient being treated. Thus, an effective amount is well within the ability of those skilled in the art to determine.

(Test materials and methods)
As an example of the present disclosure, the determination and administration of an effective amount of a pharmaceutical composition comprising eslicarbazepine acetate for treating epilepsy in a patient in need thereof is demonstrated below. An effective amount of a pharmaceutical composition for treating other diseases and / or conditions is determined by one of ordinary skill in the art based on the techniques and concepts described herein and techniques and concepts known in the art. can do.

The effect of eslicarbazepine acetate in humans was investigated in at least the following clinical trials. In the first study, the placebo-controlled treatment exploration study, once daily and twice daily
A comparison was made in patients with epilepsy that are difficult to treat with standard antiepileptic drugs. In the second study, healthy subjects were given an oral dose of 900 mg eslicarbazepine acetate once daily (od) or 4
A dose of 50 mg eslicarbazepine acetate twice daily (bid) was given. In the third study, healthy subjects were given a single oral dose of eslicarbazepine acetate ranging from 20 mg to 2400 mg, and
Repeated once a day (od) oral doses of eslicarbazepine acetate ranging from 400 to 2400 mg.
The bioequivalence of tablets and oral suspensions was demonstrated by relative bioavailability tests.

(Trial in patients with epilepsy)
This clinical trial was conducted in Croatia, the Czech Republic, Germany, Lithuania and Poland.
Is a double-blind, randomized, placebo-controlled trial conducted in one center. The regular purpose of the study was to evaluate the efficacy and safety of BIA 2-093 as an adjunct therapy in patients with refractory partial epilepsy. One or two antiepileptic drugs (AED) (e.g.
A total of 143 patients aged 18-65 who have at least 4 partial seizures per month regardless of treatment with phenytoin, valproate, primidone, phenobarbital, lamotrigine, gabapentin, topiramate or clonazepan) for 12 weeks (+1 week taper): placebo treatment (n = 47); once daily BIA 2-093 (n = 50); or twice daily BIA 2-093 (n =
46); randomly assigned to one of three groups. For the first 4 weeks, the daily dose was 400 mg. The daily dose was then increased to 800 mg (5-8 weeks) and finally to 1200 mg (9-12 weeks). 200 mg, 400 mg and 600 mg eslicarbazepine acetate tablets and placebo tablets were manufactured by BIAL (S. Mamede do Coronado (Portugal)) according to good manufacturing practice. As described herein, a plasma assay to measure the concentration of BIA 2-005
It was performed by non-chiral method using isocratic liquid chromatography (LC) with single quadrupole mass spectrometric detection (MS). See, for example, Almeida I and Almeida II.

(Examination in healthy human volunteers)
Exam A
This human pharmacology study was conducted once a day and 2 times a day for eslicarbazepine acetate in healthy subjects.
This was a study to examine the steady-state pharmacokinetics of a single dose regimen. The trial consisted of 12 healthy volunteers consisting of a 2 x 8 day treatment period separated by a 10-15 day withdrawal period (
This was a single-center, open-label, randomized two-way crossover study with 6 men and 6 women). During each treatment period, volunteers received 900 mg of eslicarbazepine acetate once a day (od), or 2 times a day.
A daily oral dose of 450 mg eslicarbazepine acetate was administered. A 450 mg strength tablet of eslicarbazepine acetate manufactured by BIAL (S. Mamede do Coronado (Portugal)) according to proper manufacturing standards was used.

Blood samples for drug plasma assays were collected at the following times:
Stage A:
Before administration, and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36, 48, 72 and 96 hours after administration;
Stage B:
From day 5 to day 11: before daily administration (about trough concentration test);
Day 12: Before administration and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36, 48, 72, 96 and 120 hours after administration.

Blood samples were introduced into lithium heparin tubes directly by venipuncture or intravenous catheter and centrifuged at approximately 1500 g for 10 minutes at 4 ° C. The resulting plasma was divided into two equal aliquots of 1 mL and stored at −20 ° C. until required for analysis.
Plasma concentrations of eslicarbazepine acetate, eslicarbazepine acetate and R-licarbazepine were measured using isocratic liquid chromatography (LC) with single quadrupole mass spectrometry detection (MS).

The method consists of about 0.5 μg / mL 10,11-dihydrocarbamazepine (acetonitrile: water 3:97 (v: v)
It was necessary to add 500 μL to the 250 μL plasma (centrifuged at 1800 rpm prior to analysis) in a polypropylene tube. After vortexing for 10 seconds, the mixture was transferred to a Schleicher & Schuell C18 / 100 mg 96 well solid phase extraction plate. Prior to application of the entire sample volume, each well is preconditioned with 800 μL of methanol and then 800 μL.
Of acetonitrile and acetonitrile: water (3:97 (v: v)). Each polypropylene tube was then washed with 500 μL acetonitrile: water (3:97 (v: v)) and the wash was transferred to each well. The compound was eluted into a collection plate using 750 μL of acetonitrile and the extract was evaporated to dryness at 40 ° C. under oxygen free nitrogen. All solid phase extraction operations were performed using a Tomtec QUADRA 96® Model 320 system and a vacuum was applied at each elution step. The final extract was reconstituted with 100 μL water: methanol (90:10 (v: v)) and mixed. The collection plate was then centrifuged at about 3000 rpm (about 10 minutes at about 4 ° C.) prior to analysis. An aliquot (10 μL) of the final extract was injected into the LC-MS system.

The LC-MS system used for the analysis was a Perkin Elmer series 200 micropump, Perkin E
Perkin equipped with lmer series 200 automatic sampler and Turbo IonSpray® source
It consisted of an Elmer / Sciex API 150EX single quadrupole mass spectrometer. LichroCART 250-4 Ch
iraDex column (β-cyclodextrin (5 μm)), LichroCART 4-4 ChiraDex column guard column (β-cyclodextrin (5 μm)), Jones chromatography at 50 ° C. 7971 column heater, mobile phase A (0.2 mM sodium acetate, Separation was achieved using water) and mobile phase B (0.2 mM sodium acetate, MeOH). Operating the MS detector in positive ion mode, the mass transitions for BIA 2-093, eslicarbazepine, R-licarbazepine and the internal standard were 319.16 amu (200 m
s), 277.08 amu (200 ms), 277.08 amu (200 ms) and 261.05 amu (200 ms). The limit of quantification of the assay was 10 ng / mL for eslicarbazepine acetate and 100 ng / mL for eslicarbazepine and R-licarbazepine.

Eslicarbazepine acetate, (S)-(-)-10-acetoxy-10,11-dihydro-5H dibenz / b, f / azepine-5-carboxamide; eslicarbazepine, (S)-(+ ) -10,11-Dihydro-10-hydroxy
-5H dibenz / b, f / azepine-5-carboxamide was synthesized at a BIAL chemistry laboratory with a purity greater than 99.5%. The internal standard, ie 10,11-dihydrocarbamazepine, is Sigma-Aldr
Powered by ich (St. Louis, MO).

WinNonlin (version 4.0, Pharsight (Mountain Vie, California)
w)) was used to derive pharmacological parameters from noncompartmental analysis. Individual plasma concentration - led to the following parameters as appropriate from time characteristic: C _max Maximum observed plasma concentration of the occurrence of (C _max) time (t _max); from time 0, the concentration is, the linear trapezoidal rule a calculated quantified Area under the plasma concentration versus ti up to the final sampling time above the limit (AUC _0-τ )
me curve) (AUC); dosing interval, i.e. 24 hours and 1 in groups of once daily and twice daily, respectively
AUC (AUC _0-∞ ) from time 0 to infinity calculated from 2 hours AUC (AUC _τ ); AUC _0-τ + (C _last / λ _z ) (C _last is the final quantifiable concentration) The apparent terminal rate constant (λ _z ) calculated by logarithmic linear regression of the terminal portion of the plasma concentration versus time curve; the apparent terminal half-life (t _1/2 ) calculated from ln 2 / λ _z .

Actual sampling time was used for pharmacological analysis.
When extrapolating AUC infinitely, the ratio of extrapolated area to total area was evaluated. If it exceeded 20%, the AUC value was considered unreliable. In all calculations, the plasma concentration was set to 0 (below the limit of quantification) (BLQ). All calculations were performed using raw data. The value of t _max was displayed as the nominal time.

Geometric mean, arithmetic mean, standard deviation (SD), coefficient of variation
variation) (CV), median, minimum and maximum values were used as appropriate to report statistical summaries for each group and sampling time schedule. Comparison of the elderly and younger groups for single-dose and multiple-dose data is based on the analysis of variance of the log-transformed C _max , AUC _t, and AUC _0-∞ parameters.
f variance) (one-way ANOVA). The t _max comparison between age groups was performed assuming a non-parameter method using the Wilcoxon signed rank test. Also, the difference in logarithmic transformation parameters (C _max , AUC _t and AUC _0-∞ ) between age groups in the form of ratios on a linear scale and their 95% confidence interval (95% Cl) was estimated. The median and difference in t _max between age groups and 95% Cl were reported. All significant tests were performed at the p = 0.05 level. The statistical package SAS (version 8.2, SAS Institute Inc, (Cary, NC)) was used.

Exam B
This human pharmacological test was a test for measuring the pharmacokinetics of eslicarbazepine acetate after single and repeated administration.
This study integrated the results of three double-blind randomized placebo-controlled trials. To measure the pharmacokinetics of eslicarbazepine acetate after a single dose, healthy young male subjects were administered oral single doses of eslicarbazepine acetate ranging from 20 mg to 2400 mg (1 6 subjects per dose). Over a period of 8 days, repeated oral doses of eslicarbazepine acetate ranging from 400 mg to 2400 mg are administered to healthy young male subjects (6 subjects per dose), thereby allowing estoacetate after repeated administration. Ricarbazepine pharmacokinetics were measured. The analytical test method and experimental procedure were the same as described for test A above.

(Test results)
(Trial in patients with epilepsy)
Baseline characteristics At baseline, treatment groups were similar in terms of age, height, weight and weight index.
All 143 patients were Caucasian. As for gender, women were once a day (56.0%)
The twice-daily group (65.2%) was relatively more common than the placebo group (57.4%). This difference had little effect on the results. There was no significant difference in the number of AEDs used. One AED treated 30.0%, 34.8%, and 29.8% of patients in the once daily, twice daily, and placebo groups, respectively. The remaining patients were treated with 2 AEDs. The most frequently used combination AED is valproic acid (once daily,
Twice daily and 68.0%, 60.9% and 66.0% of patients in the placebo group, topiramate (
36.0%, 34.8% and 21.3% respectively) and lamotrigine (30.0%, 28.3% and 31.9% respectively).

At baseline, the average duration of epilepsy was 16.7, 19.5, and 20.0 years in the once-daily group, twice-daily group, and placebo group, respectively. With regard to seizure type frequency, simple partial seizure IA, complex partial seizure IB, and partial seizure IC that develops systemically secondary, 1
Was present in 34.0%, 72.0%, and 80.0% of the twice daily group, 37.0%, 71.7%, and 80.4% of the twice daily group, and 27.7%, 80.9%, and 72.3% of the placebo group. The average total number of seizures per month prior to the study was 14.1, 13.6, and 11.8 in the once-daily group, twice-daily group, and placebo group, respectively.

Outcome Results In the intention-to-treat (ITT) population (n = 143), the primary effect endpoint was the proportion of patients whose seizure frequency decreased by 50% or more in the treatment period compared to the baseline period. . 120
At a dose of 0 mg / day (9-12 weeks), the proportion of responders (54%) in the once-daily group was the placebo group
Significantly higher than (28%) (p = 0.008). The proportion of responders in the once daily group (54%) was higher than in the twice daily group (41%). At a dose of 800 mg / day, the proportion of responders in the once-daily group (58
%) Was significantly higher (p <0.05) than the twice daily group (33%) and the placebo group (38%). At this dose, no significant difference was found between the twice daily group and the placebo group.

Secondary endpoints are a decrease in overall seizure frequency, the proportion of patients without seizures, the distribution of responders, 1 daily
Includes a comparison of single and double therapies, and an overall assessment of investigators and patients.
The greatest reduction in the number of seizures was achieved at once daily doses of 1200 mg and 800 mg, and the once daily group results were better than those obtained in the twice daily groups (Figure 1). Any dose (
(400 mg, 800 mg and 1200 mg), patients who received a once-daily dose of eslicarbazepine acetate had a reduced number of seizures compared to patients in the twice-daily and placebo groups. It was substantially large.

The number of seizures in patients receiving 1200 mg and 800 mg once daily doses of eslicarbazepine acetate was reduced by 59.5% and 55.8%, respectively. On the other hand, 1200mg and 800mg 1
Seizures in patients given twice daily dose decreased by 45.7% and 38.1%, respectively. 400
Patients who received a once-daily dose of eslicarbazepine acetate had 38.9% seizures
It was almost twice the reduction in seizures (20.2%) observed in patients receiving 400 mg twice daily dose of eslicarbazepine acetate.

At the end of the 12-week treatment phase, 27.9% of patients in the once-daily group no longer had seizures.
In addition, the evaluation of the effect by the investigator (CGI-clinical Global Impression) and the evaluation of the acceptability by the patient were the best in the once-daily group.

Pharmacokinetic results
Plasma / serum samples for “trough” (pre-dose) levels of BIA 2-005 and combined AED were collected at all rounds except V5 (post-test round). The objective was to characterize the effect of eslicarbazepine acetate on the pharmacokinetic behavior of combined AEDs (eg, phenytoin, valproate, primidone, phenobarbital, lamotrigine, gabapentin, topiramate and clonazepan). The average trough plasma concentration of BIA 2-005 is shown in Table 1. As shown in FIG. 2, no significant difference in BIA 2-005 trough (pre-dose) values was found between the once daily and twice daily groups.

結果を、対応する標準偏差（sd）（括弧内）とともに算術平均として記載した。

Results were listed as arithmetic mean with the corresponding standard deviation (sd) (in parentheses).

For a relatively small number of patients who received phenytoin, primidone, phenobarbital, gabapentin and clonazepan, we excluded appropriate characterization of the ultimate effect of eslicarbazepine acetate on the pharmacokinetic behavior of these combined AEDs . For valproate, lamotrigine and topiramate, the number of patients was also small, but an exploratory analysis of the effects of eslicarbazepine acetate on the trough blood values of these combined AEDs was performed. Once a day (7.0%;
95% IC: -7.6, 36.2) or twice daily (6.3%; 95% IC: -7.5, 20.1) co-administration of eslicarbazepine acetate significantly changed the mean trough serum concentration of valproate I didn't. There was a significant increase in valproate serum levels in the placebo group (25.4%; 95% IC: 5.1, 45.8).
For lamotrigine, once daily (-10.0%; 95% IC: -46.2, 26.2) eslicarbazepine acetate or placebo (12.6%; 95% IC: -12.6, 37.8) added to therapy However, the serum level did not change significantly. When eslicarbazepine acetate was used twice a day, the serum level of lamotrigine was significantly reduced (-46.7%; 95% IC: -69.7; -23.8). For topiramate, once daily eslicarbazepine acetate (-15.2%; 95% IC: -34.8, 4.4) was added to the therapy, its serum levels did not change significantly. When eslicarbazepine acetate was used twice a day, the serum level of topiramate was significantly reduced (-32.4%; 95% IC: -49.5; -15.3). One skilled in the art will know if the change in serum level is significant.

(Examination in healthy human volunteers)
Exam A
Pharmacokinetic results It has been shown that eslicarbazepine acetate is metabolized in large amounts to eslicarbazepine and a small amount to R-licarbazepine. Steady state eslicarbazepine plasma concentrations were achieved on days 4-5 of administration in both groups.

Average of eslicarbazepine and R-licarbazepine in the once daily group after the last dose
C _max is 22210 ng / mL and 674 ng / mL, respectively, and 2.45 hours and 9.42 after administration, respectively.
Achieved in time (median t _max ). Mean AUC _{0-t for} eslicarbazepine and R-licarbazepine
Were 381601 ng · h / mL and 19600 ng · h / mL, respectively. In the twice daily group, the mean C _max of eslicarbazepine and R-licarbazepine was 16667 ng / mL and 718 ng / mL, respectively, achieved at 2.09 hours and 6.40 hours after administration (median t _max ), respectively. It was done. The average AUC _0-t of eslicarbazepine and R-licarbazepine was 283014 ng · h / mL and 19661 ng · h / mL, respectively. After 8 days of multiple doses of eslicarbazepine acetate, eslicarbazepine is
It was shown to be the main metabolite accounting for about 95% and 96% of overall systemic drug exposure (assessed with AUC _0-24 ) in subjects once and twice daily, respectively. Tables 2 and 3 show the pharmacokinetic parameters of eslicarbazepine and R-licarbazepine in the once daily and twice daily groups after the last dose of eslicarbazepine acetate. The overall exposure of healthy volunteers to eslicarbazepine in the once daily group was unexpectedly at least 26% higher than in the twice daily group.

Exam B
Pharmacokinetic Results As described in Study A, eslicarbazepine acetate was metabolized in large amounts to eslicarbazepine, and only a small amount was converted to R-licarbazepine. Steady state eslicarbazepine plasma concentrations were achieved on days 4-5 of once daily dosing.
In the once daily group after the last dose, the mean C _max of eslicarbazepine was 8800 ng / ML (coefficient of variation (CV) 16.0%) when 400 mg of eslicarbazepine acetate was administered ) To 56500 ng / ML (CV20.0%) when eslicarbazepine acetate 2400 mg was administered. Maximum plasma concentrations for all doses were achieved in 2 to 3.5 hours (median t _max ).
The area under the average concentration AUC _0-24h for the 24-hour dosing interval is from 126300 ng · h / mL when the daily dose of eslicarbazepine acetate is 400 mg to eslicarbamate acetate once a day. When the dose of Zepin was 2400 mg, the range was up to 905900 ng · h / mL. Tables 4 and 5 show the pharmacokinetic parameters of eslicarbazepine and R-licarbazepine after a single dose of eslicarbazepine acetate,
As well as pharmacokinetic parameters after the last dose of eslicarbazepine acetate repeated administration.

(Examination of examination)
The once-daily administration of eslicarbazepine acetate is more effective than dividing the same total dose into twice-daily doses and is clearly more effective in reducing epileptic seizures than placebo Was recognized. The once-daily doses of 800 mg and 1200 mg of eslicarbazepine acetate have been shown to be significantly more effective in reducing epileptic seizures than twice-daily doses with the same overall daily dose. It was.

It has been shown that eslicarbazepine acetate is metabolized in large amounts to eslicarbazepine and a small amount to R-licarbazepine. Eslicarbazepine accounted for 95% to 98% of total systemic drug exposure (assessed with AUC _0-τ , i.e., AUC at dosing intervals), so pharmacology after administration of eslicarbazepine acetate It is thought to be mainly responsible for activity. Overall, the plasma concentration of the parent drug (eslicarbazepine acetate) was found to be below the limit of quantification. For multiple doses, steady state plasma concentrations are achieved in days 4 to 5 days of administration in both groups, about 20-
Consistent with the effective half-life of the order of 24 hours.

The kinetic characteristics of eslicarbazepine in the once daily group are significantly different from those in the twice daily group, and the pharmacokinetic parameters evaluated after multiple oral doses of eslicarbazepine acetate Statistical differences were observed for some (C _max , AUC _0-τ and AUC _0-∞ ). In fact, the overall exposure of healthy volunteers to eslicarbazepine in the once-daily group is unexpected, 2
It was at least 26% higher than the times group. This unexpected result suggests that once-daily administration of eslicarbazepine acetate is more effective in patients with epilepsy than dividing the same overall daily dose into twice-daily doses. Matches. This result suggests that the improvement in clinical efficacy is due to an increase in the rate (C _max ) and magnitude (AUC) of exposure to eslicarbazepine,
The reason for this increase in the scale of exposure after once daily dosing compared to two dosing is unclear.

In addition to the illustrative aspects and embodiments described above, further aspects and embodiments will become apparent to those skilled in the art upon review of the above description. Those skilled in the art will recognize that the above description is susceptible to minor modifications and that such changes are considered to be within the scope of the present invention. Accordingly, the appended claims (including any amendments thereof) and any claims subsequently introduced are intended to be construed as including all such aspects, embodiments and modifications. To do.

FIG. 2 shows the rate of decrease in seizure frequency for each dosing period relative to the baseline (400 mg twice daily and once daily for placebo; 800 mg twice daily and once daily for placebo; twice daily and 1200mg once a day for placebo). Average (95% Cl) trough plasma concentration of BIA 2-005 after administration of 400 mg, 800 mg and 1200 mg BIA-2-093 daily dose (od) or twice daily (bid) (μg / mL).

The inventors conducted human tests on healthy subjects and described the results in the Almeida I and Almeida II literature, both of which are incorporated herein by reference. In these studies, healthy subjects are given a single oral dose of eslicarbazepine acetate, the dosage ranges from 20 mg to 1200 mg (see Almeida II), and eslicarbazepine acetate The daily multiple doses ranged from 200 mg (twice a day) to 1200 mg (twice a day) (see Almeida I). In further studies (not yet published) by the inventors, higher doses of eslicarbazepine acetate were investigated, including, for example, doses ranging up to 2400 mg (once daily). The observed maximum plasma concentration of BIA 2-005 (C _max ) is achieved about 1 to about 4 hours (t _max ) after administration, and the magnitude of systemic exposure to BIA 2-005 is approximately proportional to dose However, these studies have shown that a steady state of BIA 2-005 plasma concentration is achieved in about 4 to 5 days. The mean renal clearance rate of BIA 2-005 from plasma is about 20-30 mL / min , and the total amount of BIA 2-005 recovered in urine is about 20% and within 12 and 24 hours after administration, respectively. 40%.

In a further exemplary embodiment, eslicarbazepine acetate may be administered to the patient in an amount that results in a maximum plasma concentration (C _max ) of eslicarbazepine up to about 58800 ng / mL or about 67800 ng / mL. it can. In a further exemplary embodiment, eslicarbazepine acetate may be administered to a patient in an amount that results in a maximum plasma concentration (C _max ) of eslicarbazepine of up to about 885000 ng / mL or about 1000000 ng / mL. it can.

For example, a once daily dose of about 400 mg that results in a maximum plasma concentration (C _max ) of eslicarbazepine greater than about 7400 ng / mL can be administered to the patient. As a further example, the patient may be administered a daily dose of about 800 mg or about 1200 mg that results in a C _max of eslicarbazepine of greater than about 16100 ng / mL, or greater than about 22700 ng / mL, respectively. it can. In other examples, a once-daily dose of esriacetate greater than 1200 mg, such as about 1800 mg or about 2400 mg, which results in a C _max of eslicarbazepine greater than about 36500 ng / mL and about 45200 ng / mL, respectively. Carbazepine can be administered.

(Trial in patients with epilepsy)
This clinical trial was conducted in Croatia, the Czech Republic, Germany, Lithuania and Poland.
Is a double-blind, randomized, placebo-controlled trial conducted in one center. The regular purpose of the study was to evaluate the efficacy and safety of BIA 2-093 as an adjunct therapy in patients with refractory partial epilepsy. One or two antiepileptic drugs (AED) (e.g.
A total of 143 patients aged 18-65 who have at least 4 partial seizures per month regardless of treatment with phenytoin, valproate, primidone, phenobarbital, lamotrigine, gabapentin, topiramate or clonazepam ) for 12 weeks (+1 week taper period): treatment with placebo (n = 47); once-daily BIA 2-093 (n = 50); or twice-daily BIA 2-093 (n = 46); Randomly assigned to one of three groups. For the first 4 weeks, the daily dose was 400 mg. The daily dose was then increased to 800 mg (5-8 weeks) and finally to 1200 mg (9-12 weeks). 200 mg, 400 mg and 600 mg eslicarbazepine acetate tablets and placebo tablets were manufactured by BIAL (S. Mamede do Coronado (Portugal)) according to good manufacturing practice. As described herein, a plasma assay for measuring the concentration of BIA 2-005 was performed by isocratic liquid chromatography with single quadrupole mass spectrometric detection (MS). Performed by achiral method using (liquid chromatography) (LC). See, for example, Almeida I and Almeida II.

Eslicarbazepine acetate, (S)-(-)-10-acetoxy-10,11-dihydro-5H dibenz / b, f / azepine-5-carboxamide; eslicarbazepine, (S)-(+ ) -10,11-dihydro-10-hydroxy-5H dibenz / b, f / azepine-5-carboxamide; and R-licarbazepine, (R)-(−)-10,11-dihydro-10-hydroxy-5H dibenz / b, f / azepine-5-carboxamide was synthesized at a BIAL chemistry laboratory with a purity greater than 99.5%. An internal standard, ie 10,11-dihydrocarbamazepine, was supplied by Sigma-Aldrich (St. Louis, MO).

Pharmacological parameters were derived from noncompartmental analysis using WinNonlin (version 4.0, Pharsight (Mountain View, Calif.)). Individual plasma concentration - led to the following parameters as appropriate from time characteristic: C _max Maximum observed plasma concentration of the occurrence of (C _max) time (t _max); from time 0, the concentration is, the linear trapezoidal rule a calculated quantified Area under the plasma concentration versus time curve (AUC) until the last sampling time (t ) above the limit (AUC _0-τ ); dosing interval, ie once each day and From time 0 calculated from 24-hour and 12-hour AUC (AUC _τ ); AUC _0-τ + (C _last / λ _z ) (C _last is the final quantifiable concentration) in the twice daily group AUC to infinity (AUC _0-∞ ); apparent terminal rate constant (λ _z ) calculated by logarithmic linear regression of the terminal part of the plasma concentration versus time curve; apparent terminal half calculated from ln 2 / λ _z Period (t _1/2 ).

Geometric mean, arithmetic mean, standard deviation (SD), coefficient of variation
variation) (CV), median, minimum and maximum values were used as appropriate to report statistical summaries for each group and sampling time schedule. Comparison of elderly and younger groups for single-dose and multiple-dose data was based on analysis of variance (one-way ANOVA) of log-transformed C _max , AUC _τ and AUC _0-∞ parameters . The tmax comparison between age groups was performed assuming a non-parametric method using the Wilcoxon signed rank test. Also, the difference in logarithmic transformation parameters (C _max , AUC _τ and AUC _0-∞ ) between age groups in the form of ratios on a linear scale and their 95% confidence interval (95% Cl) was estimated. The median and difference in t _max between age groups and 95% Cl were reported. All significant tests were performed at the p = 0.05 level. The statistical package SAS (version 8.2, SAS Institute Inc, (Cary, NC)) was used.

Outcome Results In the intention-to-treat (ITT) population (n = 143), the primary effect endpoint was the proportion of patients whose seizure frequency decreased by 50% or more in the treatment period compared to the baseline period. . 120
At the dose of 0 mg / day (9-12 weeks), the proportion of responders in the once daily group (54%) was significantly higher than the placebo group (28%) (p = 0.008). The proportion of responders in the once daily group (54%) was higher than in the twice daily group (41%). At 800 mg / day (5-8 weeks) , the proportion of responders in the once daily group (58%) was more significant than the twice daily group (33%) and the placebo group (38%) (P <0.05). At this dose, no significant difference was found between the twice daily group and the placebo group.

Pharmacokinetic results
Plasma / serum samples for “trough” (pre-dose) levels of BIA 2-005 and combined AED were collected at all rounds except V5 (post-test round). The objective was to characterize the effect of eslicarbazepine acetate on the pharmacokinetic behavior of combined AEDs (eg, phenytoin, valproate, primidone, phenobarbital, lamotrigine, gabapentin, topiramate and clonazepam ). The average trough plasma concentration of BIA 2-005 is shown in Table 1. As shown in FIG. 2, no significant difference in BIA 2-005 trough (pre-dose) values was found between the once daily and twice daily groups.

For a relatively small number of patients receiving phenytoin, primidone, phenobarbital, gabapentin and clonazepam , we excluded the appropriate characterization of the ultimate effect of eslicarbazepine acetate on the pharmacokinetic behavior of these combined AEDs . For valproate, lamotrigine and topiramate, the number of patients was also small, but an exploratory analysis of the effects of eslicarbazepine acetate on the trough blood values of these combined AEDs was performed. In the simultaneous administration of eslicarbazepine acetate once a day (7.0%; 95% IC: -7.6, 36.2) or twice a day (6.3%; 95% IC: -7.5, 20.1), valproate Mean trough serum concentration did not change significantly. There was a significant increase in valproate serum levels in the placebo group (25.4%; 95% IC: 5.1, 45.8). For lamotrigine, once daily (-10.0%; 95% IC: -46.2, 26.2) eslicarbazepine acetate or placebo (12.6%; 95% IC: -12.6, 37.8) added to therapy However, the serum level did not change significantly. When eslicarbazepine acetate was used twice a day, the serum level of lamotrigine was significantly reduced (-46.7%; 95% IC: -69.7; -23.8). For topiramate, once daily eslicarbazepine acetate (-15.2%; 95% IC: -34.8, 4.4) was added to the therapy, its serum levels did not change significantly. When eslicarbazepine acetate was used twice a day, the serum level of topiramate was significantly reduced (-32.4%; 95% IC: -49.5; -15.3). One skilled in the art will know if the change in serum level is significant.

Claims (40)

Neural function changes in affective disorders, schizoaffective disorders, bipolar disorders, attention disorders, anxiety disorders, neuropathic pain and neuropathic pain-related disorders, sensorimotor disorders, vestibular disorders, or debilitating and post-ischemic disorders Use of eslicarbazepine acetate in the manufacture of a pharmaceutical composition for the treatment of said pharmaceutical composition, wherein said pharmaceutical composition is for once daily administration. The once-daily dose is a maximum observed plasma concentration C of eslicarbazepine greater than about 7400 ng / mL.
_2. Use according to claim 1, wherein the administration is in an amount which results in _max . The use according to claim 2, wherein the once-daily dose is administered in an amount that results in a C _max of eslicarbazepine of greater than about 12000 ng / mL. Administering the once-daily dose in an amount that results in an area AUC _0-τ under the concentration curve of eslicarbazepine greater than about 111000 ng · h / mL, where τ is the dose interval; Use according to claim 1. 5. Use according to claim 4, wherein the once-daily dose is administered in an amount that results in an AUC _0-τ of eslicarbazepine greater than about 140000 ng · h / mL. 6. The use according to any one of claims 1 to 5, wherein the once-daily dose is administered in a dosage comprising at least about 400 mg eslicarbazepine acetate. 7. The use of claim 6, wherein the once-daily dose is administered in a dosage comprising eslicarbazepine acetate in an amount ranging from about 800 mg to about 2400 mg. 8. Use according to any one of claims 1 to 7, wherein the active ingredient in the pharmaceutical composition consists essentially of eslicarbazepine acetate. Use according to any one of claims 1 to 8, wherein the affective disorder is depression, premenstrual dysphoric disorder, postpartum depression, menopause depression, anorexia nervosa, bulimia or neurodegeneration-related depression syndrome. The schizoaffective disorder is schizophrenia syndrome, schizophrenia, extreme psychotic condition, schizophrenia syndrome, discomfort and aggressive behavior, accidental control difficulties or intermittent explosive disorder, or borderline personality disorder Use according to any one of 9. Said bipolar disorder is a hyperbolic disorder with rapid agitation and unstable hyperbolic disorder (rapid cycle)
11. Use according to any one of claims 1 to 10, which is: manic depression disorder, acute enthusiasm, mood seizures, and mania and hypomania seizures. The use according to any one of claims 1 to 11, wherein the attention disorder is attention deficit hyperactivity disorder or autism. 13. Use according to any one of claims 1 to 12, wherein the anxiety disorder is social anxiety disorder, post traumatic stress disorder, panic, obsessive compulsive disorder, alcoholism, drug withdrawal syndrome or desire. Said neuropathic pain and neuropathic pain-related disorders are: trigeminal neuralgia, herpes neuralgia, postherpetic neuralgia and spinal cord neuralgia and related hyperalgesia; diabetic neuropathic pain; 14. Use according to any one of claims 1 to 13, which is a headache; tension-type headache; burning pain; or afferent block syndrome such as brachial plexus ablation. Said sensorimotor disorders include restless leg syndrome, convulsions, unilateral facial convulsions, nocturnal paroxysmal ataxia, cerebral ischemia-related movements and sensory deficits, Parkinson's disease and Parkinson's disease-like disorders, antipsychotic-induced motor deficits, delayed dyskinesia, 15. Use according to any one of claims 1 to 14, which is accidental night migration or myotonia. 16. Use according to any of claims 1 to 15, wherein the vestibular disorder is tinnitus or other cochlear excitement related diseases such as neuronal loss, hearing loss, sudden hearing loss, dizziness and Meniere's disease. Use according to any one of claims 1 to 8, wherein the disease is bipolar disorder or trigeminal neuralgia. Use of eslicarbazepine acetate in the manufacture of a pharmaceutical composition for increasing exposure to eslicarbazepine in a patient, wherein the pharmaceutical composition is for once daily administration . 19. Use according to claim 18, wherein the active ingredient in the pharmaceutical composition consists essentially of eslicarbazepine acetate. The once-daily dose is a maximum observed plasma concentration C of eslicarbazepine greater than about 7400 ng / mL.
_{20. Use according} to claim 18 or 19, wherein the dose is administered in an amount that results in _max . Administering the once-daily dose in an amount that results in an area AUC _0-τ under the concentration curve of eslicarbazepine greater than about 111000 ng · h / mL, where τ is the dose interval; 20. Use according to claim 18 or 19. The use according to any one of claims 18 to 21, wherein the once-daily dose is administered in a dosage comprising at least about 400 mg eslicarbazepine acetate. 23. The use of claim 22, wherein the once daily dose is administered in a dosage comprising eslicarbazepine acetate in an amount ranging from about 800 mg to about 2400 mg. 24. Use according to any one of claims 1 to 23, wherein the pharmaceutical composition is formulated for oral administration. A method for treating at least one condition or disease excluding epilepsy in a patient in need thereof, comprising a pharmacologically effective amount of eslicarbazepine acetate per day
Administering said dose to said patient. The once-daily dose is a maximum observed plasma concentration C of eslicarbazepine greater than about 7400 ng / mL.
26. The method of claim 25, wherein the method is administered in an amount that results in _max . 27. The method of claim 26, wherein the once-daily dose is administered in an amount that results in a C _max of eslicarbazepine greater than about 12000 ng / mL. Administering the once-daily dose in an amount that results in an area AUC _0-τ under the concentration curve of eslicarbazepine greater than about 111000 ng · h / mL, where τ is the dose interval; 26. The method of claim 25. 29. The method of claim 28, wherein the once-daily dose is administered in an amount that results in an AUC _0-τ of eslicarbazepine greater than about 140000 ng · h / mL. 26. The method of claim 25, wherein the once-daily dose is administered in a dosage comprising at least about 400 mg eslicarbazepine acetate. 32. The method of claim 30, wherein the once daily dose is administered in a dosage comprising eslicarbazepine acetate in an amount ranging from about 800 mg to about 2400 mg. The active ingredient in the pharmaceutical composition consists essentially of eslicarbazepine acetate.
25. The method according to 25. Said at least one disease or condition is affective disorder, schizophrenic disorder, bipolar disorder, attention disorder, anxiety disorder, neuropathic pain and neuropathic pain related disorder, sensorimotor disorder, vestibular disorder, and debilitating 26. The method according to claim 25, wherein the method is selected from neurological changes in post-ischemic disease. 34. The method according to any one of claims 25 to 33, wherein the disease is bipolar disorder or trigeminal neuralgia. A method for increasing exposure to eslicarbazepine in a patient, comprising administering to said patient a daily dose of a pharmaceutical composition comprising eslicarbazepine acetate. Method. 36. The method of claim 35, wherein the active ingredient in the pharmaceutical composition consists essentially of eslicarbazepine acetate. The once-daily dose is a maximum observed plasma concentration C of eslicarbazepine greater than about 7400 ng / mL.
_37. The method of claim 35 or 36, wherein the method is administered in an amount that results in _max . Administering the once-daily dose in an amount that results in an area AUC _0-τ under the concentration curve of eslicarbazepine greater than about 111000 ng · h / mL, where τ is the dose interval; 37. A method according to claim 35 or 36. 39. The method of any one of claims 35 to 38, wherein the once daily dose is administered in a dose comprising at least about 400 mg eslicarbazepine acetate. 40. The method of claim 39, wherein the once daily dose is administered in a dosage comprising eslicarbazepine acetate in an amount ranging from about 800 mg to about 2400 mg.

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