MX2007013882A - Methods of preparing pharmaceutical compositions comprising eslicarbazepine acetate and methods of use. - Google Patents

Abstract

The present disclosure relates to the treatment of various diseases and conditions with eslicarbazepine acetate. The present disclosure also relates to the use of eslicarbazepine acetate in a method for reducing or decreasing epileptic seizures in a patient. The present disclosure also relates to a method for increasing the exposure to eslicarbazepine in a patient. The present disclosure also relates to a method of preparing a pharmaceutical composition comprising eslicarbazepine acetate.

Description

METHODS FOR PREPARING PHARMACEUTICAL COMPOSITIONS COMPRISING ESLARARBAZEPINE ACETATE AND METHODS OF USE FIELD OF THE INVENTION | The present disclosure relates to a pharmaceutical composition and method of treatment using eslicarbazepine acetate. BACKGROUND OF THE INVENTION Epilepsy, painful conditions such as trigeminal neuralgia, and auditory brain disorders such as bipolar disorder are commonly treated with carbamazepine. Treatment with carbamazepine, however, can lead to serious side effects due to production of toxic metabolites. Oxcarbazepine was developed to reduce the severity of these side effects, but oxcarbazepine has a greatly reduced potency. See for example, i Almeida, L & Soares-da-Silva, P., "Safety, Tolerability, and Pharmapokinetic Profile of BIA 2-093, at Novel Putative Antiepilieptic, in a Rising Multiple-Dose Study in Young Health'y Humans'J J. Clin. Pharma col. , 44, 906-918 (2004) (hereinafter referred to as "Almeida I"). Thus, there is a need for a pharmaceutical composition and method for treating various conditions or diseases such as, for example, REF. : 18762? epilepsy, trigeminal neuralgia !, and affective brain disorders, which has a high potency and a low occurrence of side effects. BRIEF DESCRIPTION OF THE INVENTION I 'The eslicarbazep acetate to (S) - (-) -10-acetox? -i 10, 11-dihydro-5H-d? Benz [b, f] azep? N-5 -carboxamide ("BIA 2- 093"), is a new drug that is currently being used for the treatment of various, such as, for example, epilepsy and affective disorders, as well as painful conditions and functional theories. nervous in diseases I degenerative and post-ischemic. Although it is chemically related to carbamazepine and oxcarbazepine, it is believed that | Eslicarbazepine acetate prevents the production of certain toxic metabolites (such as, for example, I epoxides) and to avoid the unnecessary production of enantiomers or diastereoisomers of metabolites and conjugates, without losing pharmacological activity. See Benes et al., I "Anticonvulsant and Sodium Channel-Blockmg Properties of Novel 10, 11-D? Hydro-5H-d? Benz [b, f] azep? Ne-5-carboxam? Of Derivaitives", J. Med. Chem. 42, 2582-2587 (1999). Like carbamazepine and oxcarbazepine, it is believed that eslicarbazepine acetate is a voltage-entry sodium channel blocker (VGSC), which competitively interacts with site 2 of state 1 The evaluation of the metabolic profile of eslicarbazepine acetate, after chiral analysis, hepatic microsomes from rats, dogs, monkeys and humans were found to give the S (+) j enantiomer of licarbazepine, (S) - (+) - 10, 11-dihydro-10-hydroxy-5H -dibenz [b, f] azepine-5-carboxamide (also known as "eslicarbazepine") and not the R (-) - form of licarbazepine, (R) - (-) -10, 11, -dihydro-10- hydroxy-5H-dibenz [b, f] azapen-5-carboxamide (also known as "R-licarbazepine'J. 1 Studies in humans have shown that after I oral administration, eslicarbazepine acetate appears to be rapidly and extensively metabolized to the active metabolite eslicarbazepine and, to a lesser extent, to R-licarbazepine. See Silveira et al., "BIA 2-093 Pharmacokinetics in Healthy Elderly Subjects", Epilepsy, 45 (supplement 3), 157 (2004) For example, plasma concentrations of the progenitor drug (eslicarbazepine acetate) have been systematically found below the quantification limit: (LOQ) of the assay (10 ng / ml). See Almeida I; Almeida! L & Soares-da-Silva, P., "Safety, Tolerability and Pharmacetic Profile of BIA 2-093, to the Novel Putative Antiepileptic Agent, during First Administration to Humans," Drugs R & D, 4, 269-284 (2003) (from hereinafter referred to as "Almeida II"). When a non-chiral method is used, i the assay does not distinguish between eslicarbazepine and the R-I enantiomer, and the mixture was reported as "BIA 2-005" or "Racemic licarbazepine." ii The inventors conducted entry studies into the healthy man, the results of which they (described in the articles by Almeida I and Almeida i II, which are incorporated by reference in the present.) In these studies, healthy subjects received a simple oral dose of eslicarbazepine acetate where the dose was in the range of 20 mg to 1200 mg (see Almeida II), and multiple daily doses of ethylcarbazepine acetate in the range of 200 mg twice daily up to 1200 mg once a day (see Almeida I).

Additional studies I (still unpublished) by the inventors have investigated higher doses acetate I I eslicarpazepina, including, for example, doses ranging up to 2400 mg once a day. The studies showed that the maximum observed plasma concentration of BIA 2-005 (Cmax) was reached approximately from 1 hour to approximately 4 hours after the dose (tmax), the degree of systemic exposure of BIA 2-005 was approximately proportional to the dose, and the resting state of the Plasma concentrations of BIA 2-005 was reached approximately 4 to 5 days. The mean renal clearance of BIA 2-005 from the plasma was approximately 20-30 ml / minute, and the total amount of BIA 2-005 recovered in the urine was approximately 20% and 40% within 12 hours and 24 hours after of the dose, respectively. The studies also showed that the apparent terminal half-life of BIA 2-005 was in the range of about 8 hours to about 17 hours. See for example, Almeida II. U.S. Patent No. 6,296,873 discloses a sustained release distribution system for carbamazepine, which has a half-life in the range of 25 hours to 85 hours. To avoid adverse effects, Patent No. 6,296,893 US carbamazepine teaches that must be administered as tablets Ide to two or more times a day to relieve ! slowly the compound, to maintain concentration levels between 4-12 μg / ml. Such a distribution system requires a form that is capable of distributing the compound over a prolonged period of time, such as a tablet form. In one aspect of the present disclosure, the inventors have unexpectedly discovered a improved efficacy of eslicarbazepine acetate in the treatment of various concentrations such as, for example, the treatment of epilepsy, using administration once a day compared to the administration twice a day.

This finding is particularly surprising because the apparent half-life of eslicarbazepine acetate i (t? / 2 = (approximately 8 hours to approximately 17 hours) is significantly shorter than the half-life of carbamazepine (t? / 2 = 25 hours to 85 hours) a compound typically administered 3-4 times a day. In yet another aspect of the present disclosure, the inventors have also unexpectedly discovered a BRIEF DESCRIPTION OF THE FIGURES Figure 1: Percent reduction in the number of attacks in each dose period versus the baseline (400 mg once a day versus twice a day and placebo, 800 mg once a day versus twice a day) and placebo, 1200 mg once a day versus twice daily and placebo). i 1 Figure 2: Mean (95% Cl) through plasma concentrations (μg / ml) of BIA 2-005 after a daily dose of 400 mg, 800 mg and 1200 mg of BIA-2-093 administered a once a day (od) or twice a day (bid) • DETAILED DESCRIPTION OF THE INVENTION i The foregoing and following aspects and modalities, including the studies discussed herein, are described and illustrated in a manner that purports to be exemplary only, and they should not be considered as Limiting in scope. i 1 One aspect of the present invention relates to a I method to treat at least one disease or condition in a patient in need thereof, by administering a pharmaceutical composition comprising eslicarbazepine acetate in a pharmacologically effective amount. In an exemplary embodiment of the present disclosure, the pharmaceutical composition comprising eslicarbazepine acetate is administered in a once-a-day dosing regimen. In another exemplary embodiment of the present disclosure, the pharmaceutical composition is administered in a dose intended to elevate the maximum total exposure to eslicarbazepine, as measured by the exposure ratio and degree of exposure (Cmax and AUC0-t) • In an exemplary embodiment of the present disclosure, at least one disease or condition treated may be chosen of, for example, epilepsy, central and peripheral nervous system disorders, affective disorders, schizoaffective disorders, bipolar disorders, attention disorders, anxiety disorders, neuropathic pain, and disorders related to neuropathic pain, disorders I sensory-motor, vestibular disorders, and alterations of nervous function in degenerative and post-ischemic diseases. Examples of affective disorders include depression, pre-menstrual dysphoric disorder, postpartum depression, post-menopausal depression, anorexia nervosa, bulimia nervosa, and depressive symptoms related to neurodegeneration. The methods described in the present description can be used to treat schizoaffective disorders such as, for example, schizodepressive syndromes, schizophrenia, extreme psychotic states, schizomaniac syndromes, dysphoric and aggressive behavior, episode decontrol or intermittent explosive disorder, and personality disorder. of boundary line. Bipolar disorders that can be treated according to the methods of the present disclosure include, for example, bipolar disorder and unstable bipolar disorder with rapid fluctuations (rapid cyclers), manic disorders, depressives, acute mania, mood episodes and manic episodes. and hypomaniacs. Examples of attention disorders include attention deficit hyperactivity disorders and other attention disorders such as, for example, autism. Anxiety disorders can include conditions such as, for example, social anxiety disorders! post-traumatic stress disorder, panic, obsessive-compulsive disorder, alcoholism, drug withdrawal, and cravings. I i Neuropathic pain and pain-related disorder | Neuropathic that can be treated according to the methods of the present invention include, by way of example, neuropathic pain and associated hyperalgesia, including trigeminal, herpetic, post-herpetic and tabetic neuralgia, diabetic neuropathic pain, migraines, tension-type headaches , causalgia, and defiance syndromes such as, for example, avulsion of the brachial plexus} . Examples of sensorimotor disorders include: restless legs syndrome, spasticity, hemifacial spasm, nocturnal paroxyton dystonia, cerebral ischemia associated with motor and sensory impairments, Parkinson's disease and parkinsonian disorders, motor deficits induced by antipsychotics, tardive dyskinesia, delirium I minus u:? Auxiliary substance, at least one carrier material, or combinations thereof. A further aspect of the present invention relates to a method for the preparation of a pharmaceutical composition comprising the combination of eslicarbazepine acetate with at least one excipient, at least one auxiliary substance, at least one carrier material, or combinations thereof . Suitable excipients, carrier materials and I other auxiliary substances that could be useful in the present description are known to those skilled in the art.

I maieria and could be easily determined. The methods for preparing pharmaceutical compositions are also known to those skilled in the art. I | In an exemplary embodiment of the present disclosure, the pharmaceutical composition may be in the form of tablets and may comprise at least one excipient, auxiliary substance and / or carrier material. At least one excipient, auxiliary substance and / or carrier material can be chosen from, for example, povidone, croscarmellose sodium / magnesium stearate, sodium saccharin, calcium phosphate: dibasic dihydrate, sodium lauryl sulfate, flavorings and combinations thereof . Exemplary tablets can be formulated using granulation liquids, such as, for example, 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 comprise at least one excipient, auxiliary substance, and / or carrier material. At least one excipient, auxiliary substance, and / or carrier material may To be chosen from, for example, xanthan gum, macrogol stearate (such as, for example, Myrj 59 P, produced by UNIQEMAi), methylparaben, propylparaben, sodium saccharin, sorbitol 1, buffers, flavorings and combinations thereof. Another aspect of the present disclosure is a method for reducing or decreasing the number, or frequency of epileptic seizures in a patient, by administering to the patient a dose of a composition.

I pharmaceutical comprising eslicarbazepine acetate in a I pharmacologically effective amount. In a modality I exemplary of the present disclosure, the method for reducing epileptic seizures in patients comprises administering a once-a-day dose of the pharmaceutical composition comprising a pharmacologically effective amount of eslicarbazepine acetate. ! The present disclosure also relates to a method for increasing exposure to eslicarbazepine in I a papient, upon administering to the patient a pharmaceutical composition comprising eslicarbazepine acetate in an amount effective to increase the plasma concentration of eslicarbazepine over a dosing interval. In an exemplary embodiment, exposure to eslicarbazepine can be increased by decreasing the pharmaceutical composition in a manner that minimizes the number of daily doses. In an exemplary embodiment, of the present disclosure, the method for increasing the exposure to eslicarbazepine in the patient comprises administering to a patient a dose once a day of a pharmaceutical composition comprising an amount of eslicarbazepine acetate, effective to increase the plasma concentration of eslicarbazepine over the dosing interval. In a further exemplary embodiment of the present disclosure, the active ingredient of the composition ! The pharmaceutical composition may consist essentially of eslicarbazepine acetate. In a further aspect 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 greater than about 7.400 mg / ml. In other exemplary embodiments, eslicarbazepine acetate can be administered to a patient in an amount that results in a Cmax of eslicarbazepine greater than about 12,000 ng / ml or greater than about 16,100 ng / ml. In further exemplary embodiments, eslicarbazepine acetate can be administered to a patient in an amount that results in a Cmax of eslicarbazepine greater than about 22,700 ng / ml, such as greater than about 36,500 ng / ml, greater than about 45,200 as a result a maximum plasma concentration (Cmax of eslicarbazepine up to about 885,000 ng / ml or I up to approximately 1,000,000 ng / ml. For example, once-a-day doses of approximately 400 mg can be administered to a patient, resulting in a maximum plasma concentration! (Cmax) of eslicarbazepine, greater than about 7,400 ng / ml. As a further example, a once daily dose of about 800 mg or about 1200 mg can be administered to a patient, resulting in a Cmax of eslicarbazepine greater than about 16,100 ng / ml or greater than about 22,700 ng / ml, respectively . In other examples, eslicarbazepine acetate can be administered at a dose once a day greater than about 1200 mg, such as about 1800 mg or about 2400 mg, to result in a Cmax of eslicarbazepine greater than about 36,500 ng / ml, approximately 45,200 ng / ml, respectively. In a further aspect of the present disclosure, eslicarbazepine acetate can be administered to a patient in an amount that results in an area under the concentration curve (corresponding to the degree of systemic exposure) over the dosage range (AUCo-t) of eslicarbazepine greater than about 110,000 ng-h / ml In other exemplary embodiments, eslicarbazepine acetate can be administered to a patient in an amount that results in an AUCo-t of eslicarbazepine greater than about 240, 00 ng-hr / ml, or greater than i approximately 375,000 ng-hr / ml, respectively. In others For example, eslicarbazepine acetate may be ! administered to a patient in an amount that results in an AUC0-t of eslicarbazepine greater than about 595,000 ng-hr / ml, greater than about 790,000 ng-hr / ml, or greater. For example, a dose per day of approximately 400 mg can be administered, resulting in an area under the concentration curve (which corresponds to the degree of systemic expiration) over the dosage range (AUCo-J of eslicarbazepine greater than approximately 110,000 ng-h / ml In other exemplary embodiments, a once-a-day dose of approximately 800 mg or approximately 1200 mg can be administered resulting in an AUC0_t of eslicarbazepine greater than about 240,000 ng-hr / ml or greater than about 375,000 ng-hr / ml, respectively In other examples, eslicarbazepine acetate can be administered in a once daily dose of approximately 1200 mg, such as approximately 1800 mg, approximately 2400 mg or more, to result in a respective AUC0-t of eslicarbazepine greater than about 595,000 ng-hr / ml, greater than about 790,000 ng-hr / ml or more. In an exemplary embodiment of the present disclosure, a once-a-day dose may be administered in a dose comprising at least about 400 mg of eslicarbazepine acetate. In another exemplary embodiment, a dose once a day can be administered in a dose comprising an amount of eslicarbazepine acetate in the range of about 800 pgg to about 1200 mg. In additional exemplary embodiments, a once-a-day dose may be administered in a dose comprising an amount of eslicarbazepine greater than about 1200 mg, such as about 1800 mg, about 2400 mg, or more. The pharmaceutical composition comprising eslicarbazepine acetate can optionally be administered by any route known to those skilled in the art, and can be in a form chosen from, for example, oral tablets or suspensions or other I forms .i I I The term "approximately" as used herein is understood to mean that the number modified by the term may be considered as an approximation.

I can vary depending on the desired properties or the effect sought by the particular application, and thus, i should be considered to cover the interval that a person skilled in the art understand it to achieve the properties or effect desired or indicated . i j A "treatment method" as described in | present, it refers to the administration to a patient, of the described compueist, in any amount effective to reduce the effects of, counteract or eliminate the disease or condition being treated, or the symptoms thereof. A "method to increase exposure to eslicarbazepine in a patient" as described in I present, refers to administering to a patient the compound described in any effective amount to increase the plasma concentration of eslicarbazepine in the patient over the dosage range. For example; this may be an increase due to the dosage once a day in relation to dosing twice a day. j "Reduction of epileptic seizures in a patient" as described herein, refers to any decrease in the number, duration or frequency of epileptic seizures in a patient in relation to the number, duration or frequency of epileptic seizures Experienced by the patient without treatment. A "pharmacologically effective amount" of eslicarbazepine acetate in a pharmaceutical composition as described herein, refers to any amount sufficient to have the desired pharmacological activity. All effective amounts as described herein will vary according to the invention. to the various well-known and understood factors, such as, for example, the condition being treated and the physiological characteristics of the patient being treated. Consequently, the effective amount will be very within the ability of a person skilled in the art, to determine it.

MATERIALS AND METHODS OF STUDY I The following demonstrates, as an example of the present disclosure, the determination and administration of an effective amount of a pharmaceutical composition comprising eslicarbazepine acetate to treat epilepsy in patients in need of it. The effective amount of a pharmaceutical composition for treating other diseases and / or conditions could be determined by a person skilled in the art based on the techniques and concepts described herein, and known in the art. The effects of eslicarbazepine acetate in humans were studied in at least the following clinical studies. In the first study, an exploratory placebo-controlled therapeutic study, dosing once a day1 and twice daily were compared in epileptic patients refractory to standard therapy with the anti-epileptic drug. In the second study, healthy subjects received either an oral dose of once daily (or.d.) 900 mg of eslicarbazepine acetate or a twice daily dose (b.i.d.) of 450 mg of eslicarbazepine acetate. In the third study, healthy subjects received single oral doses of eslicarbazepine acetate in the range of 20 mg to 2400 mg, and repeated oral doses once a day (od) in the range of 400 mg to 2,400 mg of eslicarbazepine acetate . I The bioequivalence of tablets and oral suspensions was tested in a study of relative bioavailability.

Study in epileptic patients This clinical trial was a randomized, double-blind, placebo-controlled study conducted by 20 centers in Croatia, the Czech Republic, Germany, Lithuania and Poland. The established objectives of the study were to evaluate efficacy and safety of BIA 2-093 as adjunctive therapy and in patients with partial refractory epilepsy. In total, 1143 patients aged 18 to 65 years with at least 4 partial onset attacks per month despite treatment with 1 or 2 anti-epileptic drugs (AEDs) (eg phenytoin, valproate, primidone, phenobarbital) , lamotrigine, gabapentin, topiramate or clonazepam) were randomly assigned to one of three groups: placebo treatment (n = 47), BJIA 2-093 once a day (n = 50), or BIA 2-093 twice i a day (n = 46), for 12 weeks (plus 1 week of gradual dismimination). For the first 4 weeks, the daily dose was 400 mg. Then daily doses were increased up to 800 mg (weeks 5-8), and finally to 1200 mg (weeks 9-12). Tablets with strengths of 200 mg, 400 mg, and | 600 mg of eslicarbazepine acetate and placebo tablets were manufactured by BIAL (S. Mamede do Coronado, Portugal) in accordance with good manufacturing practices. The test plasma to determine the concentration of BIA 2-005 was performed with a non-chiral method using isocratic liquid chromatography (LC) with single quadrupole mass spectrometry (MS) detection, as described herein. See for example, Almeida I and Almeida II. I Study on healthy human volunteers Test \ A This human pharmacology test was a study to investigate the steady-state pharmacokinetics of once a day and twice a day acetate in healthy subjects. The study was a single-center, open label, randomized, two-way crossover study in 12 healthy volunteers (6 males and 6 females) that consisted of two 8-day treatment periods separated by a washout period of 10-15 days. In each of the treatment periods, the volunteers received either a daily oral dose of 900 mg of eslicarbazepine acetate once a day (or d.o.) or 450 mg of eslicarbazepine acetate twice a day (b.i.d.).

I The tablets were used with a strength of 450 mg of eslicarbazepine acetate, manufactured by BIAL (S. Mamede do Coronado, Portugal) in accordance with good manufacturing practice. Blood samples for plasma drug trials were taken at the following times: i Phase A: \ il Pre-dose, and * á, 1, l * s, 2, 3, 4, 6, 8, 12, 24 , 36, 48, 72 and 96 hours post-dose; I Phase ß;? i Day 5 to day 11 (included): before the daily dose i (for the trial of "basal" concentrations); ! Day 12: pre-dose, and **, 1, 1 * 4, 2, 3, 4, 6, 8, 12, 24, 36¡ 48, 72, 96 and 120 post-dose hours. I Blood samples were drawn either I by direct venipuncture or via an intravenous catheter I inside lithium heparin tubes, and centrifuged at approximately 1500 g for 10 minutes at 4 ° C. The plasma The resulting product was separated into 2 equal aliquots of 1 ml and stored at -20 ° C until required for analysis. Plasma concentrations of eslicarbazepine acetate, eslicarbazepine and R-licarbazepine were determined using isocratic liquid chromatography (LC) with simple quadrupole mass spectrometric (MS) detection. | The method involved the addition of 500 μl of approximately 0.5 μg / ml of 10, 11-dihydrocarbamazepine.

Internal standard prepared in acetonitrile: water, 3:97, v: v) to 250 μl of plasma (centrifuged at 1800 rpm, before analysis) in a polypropylene tube. After mixing in a vortex for 10 seconds, the mixture was transferred to a 96-well solid phase extraction plate Scheleicher and Schuellj C18 / 100 mg. Each well was pre-conditioned with 800 μl of methanol, followed by 800 μl of acetonitrile, and 800 μl of acetonitrile-water (3:97, v: v), before the application of the total sample volume. Each polypropylene tube was then washed with 500 μl of acetonitrile: water (3:97, v: v) and the washes were transferred to the respective well. The compounds were eluted on a collection plate with 750 μl of! acetonitrile and the extract evaporated to dryness under oxygen-free nitrogen at 40 ° C. All I manipulations and extractions in solid phase were undertaken using the Tomtec QUADRA 96® Model 320 system and a vacuum was applied in each elution step. The final extract was reconstituted in 100 μl of water: methanol (90:10, v: v) and mixed. The collection plate was then centrifuged at approximately 3000 rpm (approximately 4 ° C, approximately 10 minutes) before analysis. An aliquot of the final extract (10 μl) was injected onto the I system | LC-MS. The LC-MS system used in the analysis consisted of a Perkin Elmer 200 series micropump, a Perkin Elmer 200 series auto-sampler, and a Perkin Elmer / Sciex API 150EX single quadrupole mass spectrometer equipped with a Turbo IonSpray source ®. The separation was achieved using a LichroCART 250-4 ChiraDex column (ß-cyclodextrin, 5 μm) a column protection column LichroCART 4-4 ChiraDex (β-cyclodextrin, 5 μm), a Jones Chromatography 7971 column heater at 50 ° C, a mobile phase A (0.2 mM sodium acetate, aqueous) and a mobile phase B (0.2 mM sodium acetate, methanol). The detector MS was operated in the positive ion mode with mass transitions for BIA 2-093, eslicarbazepine, R-licarbazepine, and the internal standard of 319.16 amu (200 ms), 277.08 amu (200 ms), 277.08) amu (200 ms ) and 261.05 amu (200 ms), respectively. 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-dibenzo [b, f] azepine-5-carboxamide; eslica rbazepine, S) - (+) - 10, 11-dihydro-10-hydroxy-5H-dibenzo [b, f] azepine-5-carboxamide; and R-licarbazepine, (R) - (-) - 10,11-dihydro-10-hydroxy-5H-dibenzo [b, f] azepine-5-carboxamide, were synthesized in the Chemistry Laboratory, BIAL, with purities > 99.5%. The internal standard, 10,11-dihydroparbamazepine was supplied by Sigma-Aldrich (St. Louis, MO). i I Pharmacokinetic parameters were derived from non-compartmental analysis using WinNonlin (Version i 4.0, Pharsight Corporation, Mountain View, California).

The following parameters were derived, where appropriate, from the individual plasma concentration-time profiles: the maximum observed plasma concentration (Cmax); the time of occurrence of Cmax (tmax); the area under the plasma concentration versus time curve, (AUC) from time zero to the last sample time (t) at which the concentrations were at or above! of the quantification limit (AUCo-t), calculated by the linear trapezoidal rule j; AUC over the range of I dosage (AUCt), for example, 24 hours and 12 hours in group I once a day and twice daily, respectively; AUC from time zero to infinity (AUCo-J), calculated from AUC0-t + (C? As /? Z), where C? Ast is the last! quantifiable concentration; the apparent terminal velocity constant (? z) calculated by the logarithmic-linear regression of the terminal segment of the plasma concentration versus time curve; apparent terminal half-life (t? / 2), calculated from ln 2 /? z. i Effective sampling times were used for the pharmacokinetic analysis. Where an AUC was extrapolated to infinity, the percentage of the area extrapolated to the total area was evaluated; if it is greater than 20%, the AUC value was marked as not reliable. Plasma concentrations below the assay quantitation limit (BLQ) were taken as zero for all calculations. All calculations were made using raw data. The values for tmax were shown as I nominal times. The summary statistics for each group and programmed sampling time were reported, as appropriate, using the geometric mean, the arithmetic mean, the standard deviation (SD), the variance coefficient (CV), the median, the minimum and the maximum . The comparisons between the elderly versus the younger groups for the single dose and multiple dose data were based on the analysis of variance (one-way ANOVA) of the logarithmic transformed Cmax parameters, AUCt and AUCo- ",). A tmax comparison between age groups was performed assuming a nonparametric procedure using the Wilcoxon signed rank test. In addition, the differences in the logarithmic transformed parameters (Cmax,! AUCt and AUC0-) and their associated 95% confidence intervals (95% Cl) were estimated between the age groups to take the form of proportions on a linear scale.

The values of the median and the differences of tmax between the i age groups and 95% Cl were reported. All significance tests were performed at the level of p = 0.05. The SAS statistical package (Version 8.2, SAS Institute Inc., Cary, NC) was used.

Test B This human pharmacology test was a study to determine the pharmacokinetics of eslicarbazepine acetate after single and repeated doses. The study integrated the results of three controlled tests I by placebo, randomized, double blind. To measure the pharmacokinetics of eslicarbazepine acetate after i dose | simple, oral single doses of J eslicarbazepine acetate in the range of 20 mg to 2400 mg were I administered to healthy young male subjects (6 Subject by dose). The pharmacokinetics of acetate RESULTS OF THE STUDY Study in Epileptic Patients Baseline Characteristics In the baseline, the treatment groups were homogeneous with respect to age, height, weight and body mass index. The 143 patients were Caucasian. With regard to gender, these were relatively more female patients in the twice-daily group than in the once-a-day and placebo groups (65.2%, 56.0% and 57.4%, respectively); this difference did not significantly affect the results. No significant differences were found in the number of AEDs used: respectively 30.0%, 34.8% and 29.8% of the patients in the groups | once a day, twice a day, and placebo were treated with 1 AED; the remaining patients were treated with 2 AEDs. The most frequently used concomitant AEDs were valproic acid (68.0%, 60.9% and 66.0% of patients in the groups once a day, twice a day and placebp, respectively), topiramate (36.0%, 34.8% and 21.3%, Respectively) and lamotrigine (30.0%, 28.3% and 31.9%, respectively) I At baseline, the mean duration of epilepsy was 16.7, 19.5 and 20.0 years in the groups once a day, twice a day and placebo, respectively With respect to the frequency of the type of attack, partial simple IA, partial complex IB, and partial IC that evolves to the secondarily generalized were present in, respectively, 34.0%, 72.0% and 80.0%, in the group once a day; 37.0%, 71.7% and 80.4%, in the group twice a day; and 27.7%, 80.9% and 72.3% in the placebo group. The mean of the total number of attacks per month before the study was 14.1, 13.6 and 11.8, in the groups once a day, twice a day j and placebo, respectively.

RESULTS OF EFFECTIVENESS I The proportion of patients with a 50% greater reduction in the attack frequency in the treatment period compared to the baseline period in the intention to treat (ITT) population (n = 143) was the final point of primary efficacy. At a dose of 1200 mg / day I (weeks 9-12), the proportion of responders in the group once a day (54%) was significantly higher (p = 0.008) than in the placebo group (28%). The proportion of sponsors in the group once a day (54%) was also higher than in the group twice daily (41%). At the 800 mg / day dose (weeks 5-8), the proportion of responders in the once-a-day group (58%) was significantly higher (p <0.05) than in the two-time groups. day (33%) and placebo (38%). At this dose level, no significant difference was found between the twice-daily and placebo groups. Secondary endpoints include the reduction in the total frequency of attacks, the proportion of patients free of attacks, the distribution of responders, the comparison of regimens once a day and twice a day, and the overall evaluation of the researcher and of the patient. The greatest decrease in the number of attacks was achieved with the once-daily doses of 1200 mg and 800 mg, and the results with the once-a-day group were better than those obtained in the twice-daily group ( Figure 1). For all doses (400 mg, 800 mg and 1200 mg), patients who received once-daily doses of eslicarbazepine acetate had a substantially greater reduction in the number of attacks compared to patients in the two-fold groups daily and placebo.

! The number of attacks in patients who received 1200 mg and 800 mg once a day of acetate I eslica | rbazepina was reduced by 59.5% and 55.8%, respectively. In comparison, the attachments in patients I who received the twice-daily doses of 1200 mg and 800 mg were reduced by 47.5% and 38.1%, respectively. Patients who received a dose of 400 mg once daily of eslicarbazepine acetate experienced a 38.9% reduction in the number of attacks, almost twice the reduction in seizures observed in patients receiving doses of 400 mg twice daily of eslicarbazepine acetate (20.2%) At the end of the 12-week treatment phase, 27.9% of the patients in the dosing group once a day became attack-free. In addition, the evaluation of the efficacy of the researcher (CGI-Global Clinical Impression) and the patient's acceptability was rated better in the group once a day.

Pharmacokinetic results i Plasma / serum samples for the "basal" (pre-dose) levels of BIA 2-005 and concomitant AEDs gabapehtina, topiramate and clonazepam). The mean baseline plasma concentrations of BIA 2-005 are shown in the Table 'l. As shown in Figure 2, they were not found I I significant differences in the baseline values of BIA 2- 005 (re-dose) between the groups once a day and twice a day.

Table: Baseline plasma concentrations of BIA 2-005 after oral administration of eslicarbazepine acetate once a day (or d) and twice daily (b.i.d. 400 mg / day 800 mg / day 1200 mg / day group group group group group o.d. b.i.d. o.d. b.i.d. o.d. b.i.d.

Average (μg / ml) 4.0 4.9 10.7 13.5 14.6 15.5 (3.2! (2.3) (7.0) (9.6) (8.8) (8.8) Results expressed as arithmetic means with the corresponding standard deviations (sd) in parentheses.

The relatively small number of patients who are administered phenytoin, pyrimidone, phenobarbital, gabapentin and clonazepam excluded the appropriate characterization of the eventual effect of eslicarbazepine acetate on the pharmacokinetic behavior of these concomitant AEDs. For valproate, lamotrigine and topiramate, the number of patients was also small, but an exploratory analysis of the effect of eslicarbazepine acetate on baseline blood values of these iconcomitant AEDs was also performed. The mean baseline serum concentrations of valproate were not significantly changed by the concomitant administration of eslicarbazepine acetate once a day (7.0%; 95% CI: -7.6, 36.2) or twice a day (6.3%; 95% CI: -7.5, 20.1). In the placebo group, there was a significant increase in serum levels of valproate (25.4%, 95% CI: 5.1, 45.8). With respect to lamotrigine, their serum levels were not significantly changed when eslicaibazepine acetate once a day (-10.0%, 95% CI: -46.2, 26.2) significantly changed when i eslicarbazepine acetate once a day (-15.2%; 95% CI: -34.8, 4.4) was added to the therapy. With eslicarbazepine acetate twice daily, serum levels of topiramate decreased significantly (-32.4%, 95% CI: -49.5; 15. 3) . A person skilled in the art will know if a change in serum levels is significant or not, Healthy Voluntary Human Study A Test I Pharmacokinetic Resolutions i It was shown that eslicarbazepine acetate is extensively metabolized to eslicarbazepine and, to a lesser extent, to R-licarbazepine. The steady state of the plasma concentrations of eslicarbazepine was reached 4 to 5 days after administration in both groups. After the last dose, in the once-a-day group, the mean Cmax of eslicarbazepine and R-licarba.zepin was, respectively, 22,210 ng / ml and 674 ng / ml and occurred at (median tmax ) 2.45 hours and 9.42 hours after the dose, respectively. The mean AUC0-t of eslicarbazepine and R-licarbazepine was 381,601 ng-hor / ml and 19,600 ng-hour / ml, respectively. In the twice-daily group, the mean Cmax of eslicarbazepine and R-licarbazepine was 16.667 ng / ml and 718 ng / ml, respectively, and occurred (median tmax) at 2.09 hours and 6.40 hours post-dose , respectively. The mean AUC0-t of eslicarbazepine and R-licarbazepine was 283.014 ng-hour / ml and 19.661 ng-hour / ml, respectively. After multiple administration of eslicarbazepine acetate for 8 days, it was shown that eslicarbazepine is the major metabolite representing approximately 95% and 96% of the total exposure of the systemic drug (as evaluated by AUCo-2 |) in subjects once a day and twice a day, ! respectively. Tables 2 and 3 describe the pharmacokinetic parameters j of eslicarbazepine and R-licarbazepine in the 1 groups once a day and twice a day after the last dose of eslicarbazepine acetate. The total exposure of the healthy volunteers to the eslicaijbazepina in the group once a day was unexpectedly at least 26% higher than in the group of two I times a day.

Table Mean pharmacokinetic parameters of the eslica? Bazepine and R-licarbazepine after an oral dose and multiple doses of 900 ma of eslicarbazepine acetate once a day. Cmax tmax (h) AUCo-, AUC (vt AUCo- tia (h) (ng / ml) (ng-h / ml) (ng-h / ml) (ng / ml) eslicarba;: epina n 11 11 11 11 11 11 Amedia 22210 2.45 381601 294019 389344 9.12 SD 7257 0.879 95368 58364 97383 1.19 R-licarba? Epina n 12 12 12 12 12 12 Amedia, 674 9.42 19600 13397 23989 15.0 I SD 184 6.48 6763 3187 7144 3.41 I N = number of subjects; Amelia = arithmetic code; SD = standard deviation.

Amedia 16667 2.09 283014 142080 289792 9.17 SD 3981 0.664 74203 25933 74346 1.49 R-licarbazepine n 10 10 10 10 10 10 Amedia 718 6.40 19661 7783 23807 14.8 SD i 184 3.06 6049 2083 7150 4.09 n = number of subjects; Amedia = arithmetic mean; SD = standard deviation.

Test B Pharmaceutical-derived results j As in Test A, eslicarbazepine acetate was extensively metabolized to eslicarbazepine and, to a lesser extent, R-licarbazepine. The stable state of the plasma concentrations of eslicarbazepine was aleanjzado at 4-5 days of dosing once a day.

After the last dose, in the repeated group once a day, the mean Cmax of the eslica) f ba zepina was in the range of 8,800 ng / ml- (16.0% variation coefficient, CV) for the doses of 400 mg of eslicarbazepine acetate up to 56, 500 ng / ml- (20.0% CV) for the 2400 mg doses of eslicarbazepine acetate. The maximum plasma concentration for all doses occurred (median tmax) at 2 hours to 3.5 hours. The mean area under I concentration for the 24-hour dosing interval, AUCo-2 h, was in the intervjalo of 126,300 ng / ml for the doses of 400 mg once a day of eslicarbazepine acetate up to 905,900 ng / ml for once-a-day doses of 2400 mg of eslicarbazepine acetate. Tables 4 I and 5 describe the parameters of eslicarbazepine and R-licarba zepine after the single dose of ciscarbazepine acetate and the pharmacokinetic parameters after the last of the repeated doses of eslicarbazepine acetate. CV = coefficient of variation (%); Cmax = maximum plasma concentration; AUC0-24h = area under the curve of plasma concentration tica-time in 24 hours; tmax = time for Cmax; t? / 2 = half-life Ide elimination.

Table 5: Mean pharmacokinetic parameters of eslicarbazepine and R-licarbazepine after the last dose of an 8-day repeated-dose regimen of eslicarbazepine acetate (n = 6 subjects per dose group). Dosage Average Cma medium t? ^ Average UC0-24h mean t1 / 2 apparent ng / ml (% CV) h ng-h / ml (% CV) mean h (% CV) (range) 400 pjg 8,800 (16.0) [0.5 -7! 126,300 (11.7) 9.50 (18.8) I o.d. j 800 ilg 18,700 3.5 (1-7) 268,400 (10.3) 12.3 (22.9) I o.d. | (14.0) 1200 mg 25,500 3 (0.5-6) 423,000 (10.9) 13.1 (20.1¡ od '(10.8) 1800 mg 47,700 2 (0.5-4) 740,300 (19.6) 11.3 (2Í od (23.3) 2400 mg 56,500: i .5-í 905,900 (12.8) 10.4 (24.1) od [20.0) CV = coefficient of variation (%); Cmax = maximum plasma concentration; AUC0-2 h = area under the curve of the tica-time plasma concentration in 24 hours; tmax = time for Cmax; t? / 2 = elimination half-life.

STUDY It was found that the once-daily administration of eslicarbazepine acetate is more effective than the same total dose divided into doses twice a day, and is clearly more effective in reducing epileptic seizures than placebo. The doses of 800 mg and 1200 mg once a day of eslicarbazepine acetate were shown to be significantly more effective in reducing epileptic seizures than the twice-daily doses that achieve the The same total daily dose was shown to be intensely metabolized to eslicarbazepine and, to a lesser extent, to r-licarbazepine. Eslicarbazepine represented between 95% and 98% of the total systemic exposure to the drug (as assessed by AUC0-t, eg, AUC over the dosing interval) and, therefore, is believed to be primarily responsible for the activity pharmacological after the administration of eslicarbazepine acetate.

I Plasma doncentraciones of the parent drug (eslicarbazepine acetate) were systemically found below the limit of quantification. With multiple dosing, plasma concentrations at steady state were reached 4 to 5 days after administration in both groups, consistent with a jeffing half-life of the order of approximately 20 to 24 hours. The kinetic profile of eslicarbazepine in the once-a-day group was markedly different from the twice-daily group with different statistics found for some of the pharmacokinetic parameters evaluated.

(Cmax, AUCo-t and ACUo-8) after multiple oral dosing of eslicarbazepine acetate. In fact, the total exposure of healthy volunteers to eslicarbazepine in the group once a day was unexpectedly at least 26% this result may imply that the improved clinical efficacy would result from an increase in the speed (Cmax) and grade! (AUC) of exposure to eslicarbazepine, the reasons for such increased exposure after administration once a day versus twice per day, they remain unexplained. In addition to the exemplary aspects and modalities described above, additional aspects and modalities will become apparent to those skilled in the art by the! study of the previous description. Those skilled in the art will recognize that certain modifications of the above description are possible, and such modifications are considered within the scope of the invention. It is intended therefore that the following appended claims (including any amendments thereto) any claims subsequently filed must be construed to include all such aspects, modalities and modifications. It is noted that in relation to this date the best method known by the applicant to carry out the aforementioned invention is that which is clear from the present description of the invention.

Claims (36)

1. CLAIMS 1 Having described the invention as above it is
2. I claim as property what is contained in the following claims. A method for treating at least one condition or disease in a patient in need thereof, characterized in that it comprises: administering to the patient a once a day dose of a pharmaceutical composition comprising eslicarbazepine acetate in a pharmacologically effective amount.
3. I 2. The method of compliance with the claim
4. I 1, characterized in that the dose once a day is administered in an amount that results in a maximum observed plasma concentration, Cmax, of eslicarbazepine greater than about 7,400 ng / ml. 3. The method according to claim 2, characterized in that the once-a-day dose is administered in an amount which results in a C max of j-ilabazepine greater than about 12,000 ng / ml. | 4. The method according to claim 1, characterized in that the dose once a day is administered in an amount that results in an area under the concentration curve, AUCo-t, of eslicarbazepine greater than about 111,000 ng- h / ml, where t is the dosing interval.
5. 5. The method according to claim 4, characterized in that the once-a-day dose is administered in an amount that results in an AUC0-t of eslicarbazepine greater than 140,000 ng-hr / ml.
6. 6. The method of compliance with the claim 1, characterized in that the dose once a day is administered in a dose comprising at least 400 mg of eslicarbazepine acetate.
7. 7. The method according to claim 6, characterized in that the dose once a day is administered in a dose comprising an amount of eslicarbazepine acetate in the range of about 800 mg | to approximately 2400 mg.
8. 8. The method according to claim 1, characterized in that the active ingredient in the pharmaceutical composition consists essentially of eslicarbazepine acetate. i
9. 9. The method according to the claim 1, characterized in that at least one disease or condition is chosen from epilepsy, disorders of the central and peripheral nervous system, affective disorders, disorders I schizoaffective, attention disorders, anxiety disorders, neuropathic pain and disorders related to neuropathic pain, sensory-motor disorders, vestibular disorders, and alterations in nerve function in post-ischemic degenerative diseases.
10. 10. The method of compliance with the claim 9, carailcterizado because the disease is epilepsy,
11. 11. The method in accordance with the claim 10, characterized in that the once-a-day dose of the pharmaceutical composition comprising eslicarbazepine acetate is administered concomitantly with at least one other anti-epileptic drug.
12. 12. The method according to claim 11, characterized in that the concentration of at least one other anti-epileptic drug is not significantly decreased by the once-daily dose of the pharmaceutical composition comprising eslicarbazepine acetate.
13. 13. The method according to claim 11, characterized in that at least one other anti-epileptic drug is chosen from valproate, lamotrigine, topiramate and combinations thereof. I I
14. 14. The method of compliance with the claim 9, characterized in that the affective disorders are chosen from bipolar disorders.
15. 15. The method according to claim 1, characterized in that the disease is bipolar disorder, I partial refractory epilepsy, or trigeminal neuralgia.
16. 16. A method for reducing epileptic seizures in a patient, characterized in that it comprises: administering to the patient a dose once a day of a pharmaceutical composition comprising eslicarbazepine acetate in a pharmacologically effective amount.
17. 17. The method according to claim 16, characterized in that the active ingredient in the pharmaceutical composition consists essentially of eslicarbazepine acetate.
18. 18. The method according to claim 16, characterized in that the dose once a day is administered in a dose comprising at least about 400 mg of eslicarbazepine acetate.
19. 19. The method according to claim 18, characterized in that the dose once a day is administered in a dose comprising an amount of acetacto of eslicarbazepine in the range of approximately 800 mg! to approximately 2400 mg.
20. 20. A method for increasing exposure to eslicajrbazepine in a patient, characterized in that it comprises: I administering to the patient a dose once a day of a pharmaceutical composition comprising eslicarbazepine acetate.
21. 21. The method according to claim 20, characterized in that the active ingredient in the pharmaceutical composition consists essentially of eslicarbazepine acetate.
22. 22. The method according to claim 20, characterized in that the dose once a day is administered in an amount that results in a maximum observed plasma concentration, Cmax, of eslicarjbazepine greater than about 7.400 ng / ml.
23. 23. The method according to claim 22, characterized in that the dose once a day is administered in an amount that results in an area under the concentration curve, AUCo-t, of eslicarbazepine greater than about 111,000 ng-h / ml, where t is the dosing interval.
24. 24. The method according to claim I 20, characterized in that the dose once a day is administered in a dose comprising at least about 400 mg of eslicarbazepine acetate.
25. 25. The method according to claim 24, characterized in that the dose once a day is administered in a dose comprising an amount of eslicarbazepine acetate in the range of about 800 mg1 to approximately 2400 mg. !
26. 26. A method for preparing a pharmaceutical composition suitable for administration once a day, characterized in that it comprises: I combining an amount of eslicarbazepine acetate, effective to treat at least one disease or condition in a patient in need thereof, with at least one pharmaceutically acceptable excipient, an auxiliary substance, carrier material or combination thereof, | wherein at least one disease or condition is chosen from epilepsy, central and peripheral nervous system disorders, affective disorders, schizoaffective disorders, attention disorders, anxiety disorders, neuropathic pain and pain-related disorders (neuropathic, sensory-motor disorders, vestibular disorders and alterations of nervous function in post-ischemic degenerative diseases.
27. 27. The method according to claim 26, characterized in that the active ingredient in the pharmaceutical composition consists essentially of sodium acetate. I eslicairbazepina. !
28. 28. The method of compliance with the claim 26, characterized in that the pharmaceutical composition is administered in a form chosen as a tablet and oral suspension form.
29. 29. The method of compliance with the claim 26, characterized in that the affective disorders are chosen from bipolar disorders.
30. 30. A method for treating at least one condition or disease in a patient in need thereof, characterized in that it comprises: administering to the patient a dose once a day of a pharmaceutical composition comprising eslicarbazepine acetate in a pharmacologically effective amount, wherein at least one disease or condition is chosen from epilepsy, central and peripheral nervous system disorders, affective disorders, schizoaffective disorders, attention disorders, anxiety disorders, neuropathic pain and disorders related to neuropathic pain, sensory-motor disorders, vestibular disorders, and alterations in nerve function in post-ischemic degenerative diseases.
31. 31. The method according to claim 30, characterized in that the affective disorders are selected from bipolar disorders.
32. 32. A method for treating at least one condition or disease in a patient in need thereof, characterized in that it comprises: administering to the patient a dose once a day of a pharmaceutical composition comprising eslicarbazepine acetate in a pharmacologically effective amount, sufficient for resulting in a maximum observed plasma concentration Cmax of eslicarbazepine greater than about 7,400 ng / ml, wherein at least one disease or condition is chosen from epilepsy, central nervous system disorders I and peripheral, affective disorders, schizoaffective disorders, attention disorders, anxiety disorders, neuropathic pain and disorders related to neuropathic pain, sensorimotor disorders, vestibular disorders, and alterations of nervous function in post-ischemic degenerative diseases.
33. 33. The method according to claim 32, characterized in that the affective disorders are chosen from bipolar disorders. I
34. 34. The use of an effective amount of eslicarbazepine acetate in the manufacture of a pharmaceutical composition for treating at least one disease and / or condition, wherein the pharmaceutical composition is for administration once a day.
35. 35. The use of an effective amount of esical acetate rbazepine in the manufacture of a pharmaceutical composition to treat at least one disease or condition is caused by epilepsy, central and peripheral nervous system disorders, affective disorders, schizloaffective disorders, of attention, disorders of I anxiety, neuropathic pain and disorders related to neuropathic pain, sensory-motor disorders, vestibular disorders, and alterations of nervous function in post-ischemic degenerative diseases, where the pharmaceutical composition is for administration once a day.
36. 36. The use according to claim 35, wherein the affective disorders are chosen from bipolar disorders.