CN105193822A - Eslicarbazepine acetate and application method thereof - Google Patents
Eslicarbazepine acetate and application method thereof Download PDFInfo
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Abstract
The invention relates to a method for using eslicarbazepine acetate for treating various diseases and symptoms such as affective disorder, emotional schizophrenia, bipolar disorder, attention disorder, anxiety disorder, neuropathic pain, disorder related to neuropathic pain, sensorimotor dysfunction, vestibular disorder and neurological function alternation caused by retrogressive and post-ischemic diseases. The invention further relates to application of eslicarbazepine acetate to a method for reducing or relieving epileptic seizure of a patient, and a method for improving the exposing degree of eslicarbazepine acetate to a patient. The invention further relates to a method for preparing a medicine composition containing eslicarbazepine acetate.
Description
No. 200580050978.8 denomination of invention in the application to be the applying date be on May 6th, 2005 is the divisional application of the Chinese patent application of " eslicarbazepine acetate and application process thereof ".
Technical field
The present invention openly relates to the pharmaceutical composition and Therapeutic Method that use eslicarbazepine acetate (Eslicarbazepineacetate).
Background technology
Usually epilepsy, antalgesic is treated if trigeminal neuralgia and affective brain disorders are as bipolar disorder with carbamazepine.But, serious side effect may be caused owing to producing toxic metabolites with carbamazepine treatment.Develop oxcarbazepine to reduce the seriousness of those side effect, but oxcarbazepine has the effect greatly reduced.See such as Almeida, L. & Soares-da-Silva, P., " Safety, Tolerability; andPharmacokineticProfileofBIA2-093; aNovelPutativeAntiepileptic, inaRisingMultiple-DoseStudyinYoungHealthyHumans, " J.Clin.Pharmacol., 44,906-918 (2004) (being called herein " AlmeidaI ").
Therefore, the pharmaceutical composition of efficient and low incidence of side effects and method is needed to have to treat various disease or disease as epilepsy, trigeminal neuralgia and affective brain disorders.
Summary of the invention
Eslicarbazepine acetate, i.e. (S)-(-)-10-acetoxyl group-10,11-dihydro-5H-dibenzo/b, f/ azepine
-5-Methanamide (" BIA2-093 ") is the new drug developed at present, it can be used for treating various disease such as epilepsy and affective brain disorders, and antalgesic in degeneration and post-ischemic diseases and function of nervous system are alternately (nervousfunctionalternations).Although chemically relevant with carbamazepine and oxcarbazepine, but eslicarbazepine acetate is considered to can avoid producing some toxic metabolites (such as epoxide), and the enantiomer or the diastereomer that unnecessarily produce metabolite and conjugate can be avoided, and can not pharmacologically active be lost.See Benes etc., " AnticonvulsantandSodiumChannel-BlockingPropertiesofNovel 10,11-Dihydro-5H-dibenz [b; f] azepine-5-carboxamideDerivatives ", J.Med.Chem., 42,2582-2587 (1999).
The same with oxcarbazepine with carbamazepine, eslicarbazepine acetate is considered to voltage-gated sodium channel (VGSC) blocker, it can with 2 site competitions of the sodium channel of inactivated state interact.Affinity for the passage of this state is similar to the affinity of carbamazepine, and lower than the affinity of carbamazepine about 3 times to the affinity of the quiescent condition of passage.This characteristic may show that the neuron that the neuronic suppression selectivity ratios of eslicarbazepine acetate to electric discharge rapidly has normal activity to those is strong.See Bonifacio etc., " InteractionoftheNovelAnticonvulsant, BIA2-093, withVoltageGatedSodiumChannels:ComparisonwithCarbamazepi ne, " Epilepsia, 42,600-608 (2001).
In the hepatomicrosome from rat, Canis familiaris L., monkey and people, the metabolic chart of eslicarbazepine acetate is evaluated according to chiral analysis, find S (+) enantiomer obtaining licarbazepine, i.e. (S)-(+)-10,11-dihydro-10-hydroxyl-5H-dibenzo/b, f/ azepine
-5-Methanamide (also referred to as " eslicarbazepine "), instead of R (-) form of licarbazepine, i.e. (R)-(-)-10,11-dihydro-10-hydroxyl-5H-dibenzo/b, f/ azepine
-5-Methanamide (also referred to as " R-licarbazepine ").
Human research shows, and after oral administration, eslicarbazepine acetate seems to be metabolized to active metabolite eslicarbazepine in large quantities rapidly, and a small amount of metabolism is R-licarbazepine.See Silveira etc., " BIA2-093PharmacokineticsinHealthyElderlySubjects, " Epilepsia, 45 (suppl.3), 157 (2004).Such as, systematically found that the plasma concentration of parent drug (eslicarbazepine acetate) is lower than the quantitative limit (LOQ, 10ng/mL) measured.See AlmeidaI; Almeida, L. & Soares-da-Silva, P., " Safety, TolerabilityandPharmacokineticProfileofBIA2-093, aNovelPutativeAntiepilepticAgent; duringFirstAdministrationtoHuman; " DrugsR & D, 4,269-284 (2003) (being called herein " AlmeidaII ").When using non-chiral method, mensuration can not distinguish eslicarbazepine and R-enantiomer, is therefore reported as by mixture " BIA2-005 " or " raceme licarbazepine ".
Inventor has carried out entering human research (entry-into-manstudies) in health volunteer, and they will the results are described in AlmeidaI and AlmeidaII article, and both is all incorporated herein by reference.In these researchs, health volunteer accepts the eslicarbazepine acetate of single oral dose, wherein dosage range is 20mg to 1200mg (see AlmeidaII), with the eslicarbazepine acetate of multiple daily dose, its scope is twice 200mg every day 1200mg (see AlmeidaI) extremely once a day.The further research (also not delivering) of inventor have studied the more high dose of eslicarbazepine acetate, comprises the dosage of the high 2400mg extremely once a day of such as scope.Research display, about 1 is little of about 4 hours (t upon administration
max) reach the maximum observation plasma concentration of BIA2-005 (C
max), the systemic exposure degree of BIA2-005 roughly with dose proportional, about 4 to 5 days time, reach the Cpss of BIA2-005.BIA2-005 removes as about 20-30mL/min from the average kidney of blood plasma, and upon administration in 12 hours and 24 hours, the BIA2-005 total amount reclaimed in urine is respectively about 20% and 40%.
Research also shows, and the apparent t1/2 scope of BIA2-005 is about 8 little of about 17 hours.See such as AlmeidaII.
United States Patent (USP) the 6th, 296, No. 873 Atrigels disclosing carbamazepine, its half-life scope is 25 little of 85 hours.In order to avoid side effect, United States Patent (USP) the 6th, 296, No. 873 instructions should be high to twice or more time administration carbamazepine with tablet form every day, with slow releasing compound, thus remained on by concentration level between 4-12 μ g/mL.This drug-supplying system needs the form can sending compound within the period extended, such as tablet form.
In one of the present disclosure, the present inventor has been surprisingly found that, when treating various disease, compared with twice administration every day, uses the effectiveness to eslicarbazepine acetate once a day with enhancing.This discovery is especially beat all, because the apparent half-life (t of eslicarbazepine acetate
1/2=about 8 is little of about 17 hours) be significantly shorter than the half-life (t of carbamazepine
1/2=25 is little of 85 hours), and carbamazepine usual administration every day 3-4 time.
In another aspect of the present disclosure, the present inventor also has been surprisingly found that, in human body, compared with every day twice scheme, is strengthening after giving eslicarbazepine acetate once a day to the exposure of eslicarbazepine.Compared with the same medicine dosage being divided into twice administration every day, unexpectedly provide the exposure to eslicarbazepine of raising to once a day eslicarbazepine acetate.
Accompanying drawing explanation
Fig. 1: (400mg is once a day relative to every day twice and placebo relative to baseline for the outbreak number in each administration phase; 800mg is once a day relative to every day twice and placebo; 1200mg is once a day relative to every day twice and placebo) minimizing percentage ratio.
Fig. 2: once a day (o.d.) or every day twice (b.i.d.) administration 400mg, 800mg and 1200mg daily dose BIA-2-093 after, average (95%Cl) trough plasma concentration (μ g/mL) of BIA2-005.
Detailed description of the invention
Aforementioned and following aspect and embodiment, comprise the research discussed herein, only for describing in an illustrative manner and illustrating, should not be understood to the restriction to scope.
An aspect of the present disclosure relates to the method that the pharmaceutical composition comprising the eslicarbazepine acetate of pharmaceutical effective amount by administration treats at least one disease or disease in the patient of these needs.
In an exemplary of the present disclosure, to comprise the pharmaceutical composition of eslicarbazepine acetate described in Dosage Regimens Dosage once a day.
In another exemplary of the present disclosure, to expose speed and degree of exposure (C
maxand AUC
0-τ) be standard, make to eslicarbazepine described in the maximized dosed administration of total exposure pharmaceutical composition to expect.
In exemplary of the present disclosure, at least one disease for the treatment of or disease can be selected from such as: the function of nervous system in the obstacle of affective disorder, schizoaffective disorders, bipolar disorder, attention deficit disorder (attentiondisorder), anxiety disorder, neuropathic pain relevant with neuropathic pain (neurophraticpain-related), sensorimotor obstacle, vestibular disorder and degeneration and post-ischemic diseases alternately.
The example of affective disorder comprises depression, premenstrual dysphoric disorder, postpartum depression, post-menopausal depression, nervous anorexia, depressive symptom that bulimia nervosa is relevant with neural degeneration.
Method disclosed in the disclosure may be used for treatment schizoaffective disorders as division depressive syndrome (schizodepressivesyndromes), schizophrenia, extreme psychotic state (extremepsychoticstates), division manic syndrome (schizomanicsyndromes), anxiety and aggressive behavior, ictal out of control or intermittent explosive disorder and borderline personality disorder.
The bipolar disorder and unstable bipolar disorder, manic-depressive, acute mania, emotion outbreak and manic and hypomanic episode such as with rapid fluctuations (Rapid Circulation (rapidcyclers)) can be comprised with the bipolar disorder that method of the present disclosure is treated.
The example of attention deficit disorder comprises attention deficit hyperactivity disorder obstacle and other attention deficit disorder, such as infantile autism.
Anxiety disorder can comprise disease as social anxiety disorder, post-traumatic stress disorder, terrified, obsession, alcoholism, withdrawal syndrome with thirst for (cravings).
The obstacle that the neuropathic pain can treated by method of the present disclosure is relevant with neuropathic pain comprises such as neuropathic pain and relevant hyperpathia, comprises trigeminal neuralgia, heretic, postherpetic neuralgia and tabetic neuralgia (tabeticneuralgia), diabetic neuropathic pain, migraine, tension headache, causalgia and goes to import syndrome (deafferentationsyndromes) such as avulsion of brachial plexus (brachialplexusavulsion) into.
The example of sensorimotor obstacle comprises restless legs syndrome (restlesslegssyndrome), spasticity, hemifacial spasm, nocturnal paroxysmal dystonia (nocturnalparoxysmaldystonia), the motion that cerebral ischemia is relevant and sensitive defect (motorandsensitivedeficits), parkinson disease and parkinsonian disorders (Parkinson ' sdiseaseandparkinsoniandisorders), the movement defect of psychosis induction, tardive dyskinesia, paroxysmal sleep-walking (episodicnocturnalwandering), and myotonia.
Exemplary vestibular disorders comprises the relevant disease of tinnitus or other internal ear/cochlear excitability, such as neurone loss (neuronalloss), hearing loss, sudden deafness, dizzy and Meniere (Meniere ' sdisease).
In other example embodiment, described at least one disease or disease can be selected from epilepsy, bipolar disorder and trigeminal neuralgia.
It will be understood by those skilled in the art that these diseases are exemplary, and Other diseases will be understood from the disclosure and disease should considered to be in scope of the present invention.
Another aspect of the present disclosure relates to pharmaceutical composition, and it comprises eslicarbazepine acetate and at least one drug excipient, at least one auxiliary substance, at least one carrier mass or its combination.
Another aspect of the present disclosure relates to the method for the preparation of pharmaceutical composition, described method comprise by eslicarbazepine acetate and at least one excipient, at least one auxiliary substance, at least one carrier mass or its combine and merge.Suitable excipient used in the present invention, carrier mass and other auxiliary substance are known to those skilled in the art, and will easily determine.Method for the preparation of pharmaceutical composition is also known to those skilled in the art.
In an exemplary of the present disclosure, described pharmaceutical composition can be tablet form, can comprise at least one excipient, auxiliary substance and/or carrier mass.Described at least one excipient, auxiliary substance and/or carrier mass can be selected from such as polyvidone, cross-linking sodium carboxymethyl cellulose, magnesium stearate, saccharin sodium, dicalcium phosphate dihydrate, sodium lauryl sulphate, aromatic and combination thereof.Can use granulation liquid as purify waste water and ethanol form exemplary tablet.
In another exemplary of the present disclosure, described pharmaceutical composition can be the form of oral suspensions, can comprise at least one excipient, auxiliary substance and/or carrier mass.Described at least one excipient, auxiliary substance and/or carrier mass can be selected from such as xanthan gum, polyethylene glycol mono stearate (Myrj59P such as manufactured by UNIQEMA), methyl hydroxybenzoate, propylparaben, saccharin sodium, sorbitol, buffer agent, aromatic and combination thereof.
Another aspect of the present disclosure pharmaceutical composition related to by comprising the eslicarbazepine acetate of pharmaceutical effective amount to patient's administration potion reduces or reduces the method for the number of times of the epilepsy of patient, persistent period or frequency.In an exemplary of the present disclosure, the described method for reducing patient's epilepsy comprises the pharmaceutical composition comprising the eslicarbazepine acetate of pharmaceutical effective amount of administration dosage once a day.
The disclosure also relates to by improving the method for patient to the exposure of eslicarbazepine to patient's administration medicine compositions, and described pharmaceutical composition comprises the eslicarbazepine acetate that effectively can improve the amount of eslicarbazepine plasma concentration in dosing interval.In an exemplary embodiment, can pass through to make the minimized mode of number of times daily send described pharmaceutical composition to improve the exposure to eslicarbazepine.In other exemplary of the present disclosure, describedly comprise pharmaceutical composition to patient's administration dosage once a day for improving the method for patient to the exposure of eslicarbazepine, described pharmaceutical composition comprises the eslicarbazepine acetate that effectively can improve the amount of eslicarbazepine plasma concentration in dosing interval.
In other exemplary of the present disclosure, the active component of described pharmaceutical composition can be made up of eslicarbazepine acetate substantially.
In another aspect of the present disclosure, can to cause the maximal plasma concentration (C of eslicarbazepine
max) be greater than about 7,400ng/mL amount to patient to eslicarbazepine acetate.In other exemplary, can to cause the C of eslicarbazepine
maxbe greater than about 12,000ng/mL or be greater than about 16,100ng/mL amount to patient to eslicarbazepine acetate.In other exemplary, can to cause the C of eslicarbazepine
maxbe greater than about 22,700ng/mL, such as, be greater than about 36,500ng/ml, be greater than about 45,200ng/mL or more amount to patient to eslicarbazepine acetate.
In other example embodiment, can to cause the maximal plasma concentration (C of eslicarbazepine
max) high to about 58,800ng/mL or high to about 67,800ng/mL amount to patient to eslicarbazepine acetate.In other example embodiment, can to cause the maximal plasma concentration (C of eslicarbazepine
max) high to about 885,000ng/mL or high to about 1,000,000ng/mL amount to patient to eslicarbazepine acetate.
Such as, the dosage once a day of 400mg can be about to patient's administration, thus cause the maximal plasma concentration (C of eslicarbazepine
max) be greater than about 7,400ng/mL.As other example, the dosage once a day of 800mg or about 1200mg can be about to patient's administration, thus cause the C of eslicarbazepine respectively
maxbe greater than about 16,100ng/mL or be greater than about 22,700ng/mL.In other example, administration can be greater than the eslicarbazepine acetate of about 1200mg dosage once a day, such as about 1800mg or about 2400mg, to cause the C of eslicarbazepine respectively
maxbe greater than about 36,500ng/mL, about 45,200ng/mL.
Of the present disclosure other in, can to cause in eslicarbazepine dosing interval area (AUC under concentration curve
0-τ) (degree of its corresponding systemic exposure) be greater than about 110,000ngh/mL amount to patient to eslicarbazepine acetate.In other exemplary, can to cause the AUC of eslicarbazepine respectively
0-τbe greater than about 240,000ngh/mL or be greater than about 375,000ngh/mL amount to patient to eslicarbazepine acetate.In other example, can to cause the AUC of eslicarbazepine
0-τbe greater than about 595,000ngh/mL, the amount of about 790,000ngh/mL or more that is greater than to patient to eslicarbazepine acetate.
Such as, administration can be about the dosage once a day of 400mg, thus cause eslicarbazepine area (AUC under concentration curve in dosing interval
0-τ) (degree of its corresponding systemic exposure) be greater than about 110,000ngh/mL.In other exemplary, administration can be about the dosage once a day of 800mg or about 1200mg, thus cause the AUC of eslicarbazepine respectively
0-τbe greater than about 240,000ngh/mL or be greater than about 375,000ngh/mL.In other example, administration can be greater than the eslicarbazepine acetate of the dosage once a day of about 1200mg, such as about 1800mg, about 2400mg or more, to cause the AUC of eslicarbazepine
0-τbe greater than about 595,000ngh/mL respectively, be greater than about 790,000ngh/mL or more.
In an exemplary of the present disclosure, can to comprise the dosed administration dosage once a day at least about 400mg eslicarbazepine acetate.In another exemplary embodiment, can to comprise the dosed administration dosage once a day of the eslicarbazepine acetate amount within the scope of about 800mg to about 1200mg.In other exemplary, about 1200mg can be greater than to comprise, the dosed administration dosage once a day of the eslicarbazepine amount of such as about 1800mg, about 2400mg or more.
The pharmaceutical composition comprising eslicarbazepine acetate can optionally by any administration well known by persons skilled in the art, and its form can be selected from such as tablet or oral suspensions, or other form.
According to a further aspect in the invention, provide eslicarbazepine acetate or its salt and other antuepileptic of at least one and be combined in application for the preparation for the treatment of in the pharmaceutical composition of epilepsy, wherein said pharmaceutical composition is used for administration once a day.The concentration of described other antuepileptic of at least one can not obviously reduce the dosage once a day of pharmaceutical composition of involved eslicarbazepine acetate.Preferably, other antuepileptic of described at least one is selected from valproate, lamotrigine, topiramate and combination thereof.
According to a further aspect in the invention, provide the unit dose drug compositions comprising about 400 to 1200mg eslicarbazepine acetate, described unit dosage forms be applicable to height to every day 1200mg maximal dose oral administration to treat above-mentioned disease except epilepsy.
Term " about " used herein means to represent that the numeral of being modified by this term can be considered to approximate number, its can pursue according to embody rule needed for character or effect and change, therefore should be considered to contain it will be appreciated by those skilled in the art that for reaching required or shown character or the scope of effect.
Described herein " method for the treatment of " refers to that any amount of disease or disease or its symptom for the treatment of with the impact that effectively can reduce treated disease or disease or its symptom, antagonism or elimination is to compound described in patient's administration.
Described herein " improving the method that patient exposes eslicarbazepine " refers to any amount that effectively can improve patient's eslicarbazepine plasma concentration in dosing interval to the compound described in patient's administration.This may be such as relative to the raising that every day, twice administration was caused by administration once a day.
Described herein " reducing the epilepsy of patient " refers to the number of times of the epilepsy experienced relative to untreated patient, persistent period or frequency, any minimizing of the number of times of the epilepsy of patient, persistent period or frequency.
In pharmaceutical composition described herein, " pharmaceutical effective amount " of eslicarbazepine acetate refers to any amount being enough to have required pharmacological activity.
Whole effective doses described herein all by according to the various known and factors vary understood, such as, the disease for the treatment of and treat the physiological feature of patient.Therefore, defining effective amount will be in the limit of power of those skilled in the art completely.
Research material and method
As an example of the present disclosure, following content demonstration is used for the treatment of the determination comprising the pharmaceutical composition of eslicarbazepine acetate and administration that there are the effective dose of the epilepsy of the patient of these needs.Those skilled in the art can determine the effective dose of the pharmaceutical composition for the treatment of Other diseases and/or disease based on technology and concept disclosed herein and known in the art.
At least in following clinical research, have studied the effect of eslicarbazepine acetate in human body.In Section 1 research and placebo-controlled therapeutic exploratory study, standard anti-epileptic drug to treat in refractory epileptic more once a day with two doses every day.In Section 2 research, health volunteer accepts twice (b.i.d.) dosage every day of (o.d.) oral dose or the 450mg eslicarbazepine acetate once a day of 900mg eslicarbazepine acetate.In Section 3 research, health volunteer accepts the eslicarbazepine acetate single oral dose in 20mg to 2400mg scope, and (o.d.) once a day oral dose of the repetition of eslicarbazepine acetate in 400mg to 2400mg scope.
The bioequivalence of tablet and oral suspensions is confirmed in Study on relative bioavailability.
Research in epileptic
This clinical experiment is the double blinding carried out by 20 centers of Croatia, Czech Republic, Germany, Lithuania and Poland, random, placebo-controlled study.The define objective of research evaluates BIA2-093 as auxiliary treatment in the effectiveness had in refractory partial epilepsy patient and safety.Although will treat with a kind or 2 kinds of antuepileptics (AED) (such as phenytoin, valproate, primidone, phenobarbital, lamotrigine, gabapentin, topiramate or clonazepam), but monthly still have 143 18-65 altogether of at least 4 second part outbreaks year patient be assigned randomly in following three groups in one group: (added 1 week to stop gradually (taperingoff)) in 12 weeks, with placebo (n=47), twice BIA2-093 of BIA2-093 (n=50), or every day once a day (n=46) treats.For first 4 weeks, daily dose is 400mg.Then, daily dose rises to 800mg (5-8 week), finally arrives 1200mg (9-12 week).Intensity is that the tablet of 200mg, 400mg and 600mg eslicarbazepine acetate and placebo tablet are manufactured according to GMP by BIAL (S.MamededoCoronado, Portugal).Use has liquid chromatograph such as the degree such as grade (LC) that single-stage four-electrode spectrum detects (MS), carries out determination of plasma to measure the concentration of BIA2-005 with non-chiral method, as described herein.See such as AlmeidaI and AlmeidaII.
Research in Healthy People volunteer
Experiment A
This human pharmacology trial for study eslicarbazepine acetate once a day with the Steady Pharmacokinetics of twice scheme every day in health volunteer.This research be carry out in 12 healthy volunteers (6 male and 6 women) single centre, open-label, random, dual crossing research, described research was made up of two treatment phases of 8 days, and two treatment phases were separated by removing phase (washoutperiod) of 10-15 days.Interim in each treatment, volunteer accept once a day (o.d.) 900mg eslicarbazepine acetate or every day twice (b.i.d.) 450mg eslicarbazepine acetate oral dose every day.Use is the tablet of 450mg eslicarbazepine acetate according to the intensity that GMP manufactures by BIAL (S.MamededoCoronado, Portugal).
The blood sample being used for plasma drug and measuring is gathered in the following time:
The A stage:
Before administration, and after administration 0.5,1,1.5,2,3,4,6,8,12,24,36,48,72 and 96 hour;
B-stage:
5th to the 11st day (comprising end value): before administration every day (for " trough " concentration determination);
12nd day: before administration, and after administration 0.5,1,1.5,2,3,4,6,8,12,24,36,48,72,96 and 120 hour.
By direct venipuncture or by venous duct, blood sample is drawn into Lithium acid heparin in vitro, at 4 DEG C, under about 1500g centrifugal 10 minutes.Gained blood plasma is divided into 2 aliquots of 1mL, storage at-20 DEG C is until analyze needs.
Use has single-stage four-electrode spectrum and detects the plasma concentration that liquid chromatograph such as the degree such as grade (LC) of (MS) measures eslicarbazepine acetate, eslicarbazepine and R-licarbazepine.
The method comprises adds to 10, the 11-dihydro carbamazepine of 500 μ L about 0.5 μ g/mL (be the acetonitrile of 3:97 in volume ratio: the interior mark prepared in water) in 250 μ L blood plasma (centrifugal with 1800rpm before analysis) of polypropylene tubes.In vortex mixed after 10 seconds, mixture is transferred on the solid-phase extraction plate of Schleicher and SchuellC18/100mg96 hole.Before application total sample volume, with 800 μ L methanol, then use 800 μ L acetonitriles and 800 μ L acetonitriles: each hole of water (3:97, volume ratio) pretreatment.Then 500 μ L acetonitriles are used: water (3:97, volume ratio) washs each polypropylen tubes, washing liquid is transferred in each hole.With 750 μ L acetonitriles, compound is eluted in collecting board, at 40 DEG C, extract is evaporated to dry under anaerobic nitrogen.Use TomtecQUADRA
model320 system carries out Ali solid phase extraction manipulations, applies vacuum to each elution step.Last extract is redissolved to 100 μ L water: mix in methanol (90:10, volume ratio).Then before analysis, with about 3000rpm collected by centrifugation plate (carrying out about 10 minutes at about 4 DEG C).The aliquot (10 μ L) of final extract is expelled in LC-MS system.
Use in analysis LC-MS system by PerkinElmer series 200 micro pumps, PerkinElmer series 200 automatic samplers and be furnished with Turbo
the PerkinElmer/SciexAPI150EX single-stage quadrupole mass spectrometer composition in source.Use LichroCART250-4ChiraDex post (beta-schardinger dextrin-; 5 μm), LichroCART4-4ChiraDex post guard column (beta-schardinger dextrin-; 5 μm), Jones chromatograph 7971 post heater, mobile phase A (0.2mM sodium acetate at 50 DEG C; aq) and Mobile phase B (0.2mM sodium acetate, MeOH) realize be separated.MS detector runs with positive ion mode, and BIA2-093, eslicarbazepine, R-licarbazepine and interior target mass shift are respectively 319.16amu (200ms), 277.08amu (200ms), 277.08amu (200ms) and 261.05amu (200ms).What measure Dichlorodiphenyl Acetate eslicarbazepine is quantitatively limited to 10ng/mL, is quantitatively limited to 100ng/mL to eslicarbazepine and R-licarbazepine.
Eslicarbazepine acetate i.e. (S)-(-)-10-acetoxyl group-10,11-dihydro-5H-dibenzo/b, f/ azepine
-5-Methanamide; Eslicarbazepine i.e. (S)-(+)-10,11-dihydro-10-hydroxyl-5H-dibenzo/b, f/ azepine
-5-Methanamide; With R-licarbazepine i.e. (R)-(-)-10,11-dihydro-10-hydroxyl-5H-dibenzo/b, f/ azepine
-5-Methanamide synthesizes in BIAL chemical laboratory, purity >99.5%.Interior mark, namely 10,11-dihydro carbamazepine are provided by Sigma-Aldrich (St.Louis, MO).
Pharmacokinetic parameter derives from the non-compartment model analysis (noncompartmentalanalysis) using WinNonlin (4.0 editions, PharsightCorporation, MountainView, California).In due course, following parameters is obtained by independent plasma concentration v. time curve: maximum observation plasma concentration (C
max) C
maxtime of origin (t
max); By linear trapezoidal rule calculate from zero time to be in or higher than the plasma concentration v. time area under curve (AUC) of the last sample time (t) of quantitative limit to concentration, (AUC
0-τ); Dosing interval, namely being respectively AUC (AUC in 24 hours and 12 hours once a day with in every day twice group
τ); From zero time to infinite AUC (AUC
0-∞), by AUC
0-τ+ (C
finally/ λ
z) calculate, wherein C
finallyfor concentration that finally can be quantitative; Apparent end last speed constant (λ
z), the log-linear regression divided by plasma concentration v. time curve terminal portion calculates; Apparent t1/2 (t
1/2), by ln2/ λ
zcalculate.
Pharmacokinetic analysis uses the true samples time.
When AUC is extrapolated to infinite, the percentage ratio of assessment extrapolation area and the gross area; If be greater than 20%, then AUC value be labeled as unreliable.For all calculating, be considered as zero by lower than the plasma concentration analyzing quantitative limit (BLQ).Initial data is used to carry out all calculating.By t
maxvalue show for nominal time.
In due course, geometrical mean, arithmetic mean of instantaneous value, standard deviation (SD), the coefficient of variation (CV), intermediate value, minima and maximum is used to report the tabulate statistics of each group and schedule sampling time.Old group is to the C of the comparison of the single dose and multiple dose data between young group based on Logarithm conversion
max, AUC
τand AUC
0-∞the variance analysis (single factor test ANOVA) of parameter.Use Wilcoxon signed rank test, the t between age group is carried out in employing nonparametric technique
maxrelatively.In addition, between each age group, the parameter (C of Logarithm conversion is evaluated with the rate form in the range of linearity
max, AUC
τand AUC
0-∞) difference and relevant 95% confidence interval (95%Cl).Report the t between each age group
maxintermediate value and difference and 95%Cl.All significance test all carry out with p=0.05 level.Using statistics bag SAS (8.2 editions, SASInstituteInc, Cary, NC).
Experiment B
This human pharmacology trial is for measuring the pharmacokinetics of eslicarbazepine acetate after single and repeat administration.
Research incorporates the result of three double blindings, random, placebo controlled trial.In order to measure the pharmacokinetics of eslicarbazepine acetate after single-dose, to the eslicarbazepine acetate (every dosage 6 experimenters) in 20mg to the 2400mg scope of healthy young male subjects's oral administration single dose.By within 8 day time, repeat the eslicarbazepine acetate (every dosage 6 experimenters) in 400mg to the 2400mg scope of oral dose to healthy young male subjects's administration, measure the pharmacokinetics of eslicarbazepine acetate after repeat administration.Analytical control method and experimental procedure to test described in A above similar.
Result of study
Research in epileptic
Baseline characteristic
At baseline place, each treatment group is uniform in age, height, body weight and Body Mass Index.All 143 patients are Caucasian.For sex, the female patient in every day twice group is relatively more than the female patient (being respectively 65.2%, 56.0% and 57.4%) organized once a day and in placebo group; This species diversity does not obviously affect result.Notable difference is not found: once a day, in every day twice and placebo group, have 30.0%, 34.8% and 29.8% patient to treat with a kind of AED respectively in the number of AED used; All the other patients treat with 2 kinds of AED.The most frequently used adjoint AED is valproic acid (once a day, every day twice and placebo group in be respectively 68.0%, 60.9% and 66.0% patient), topiramate (being respectively 36.0%, 34.8% and 21.3%) and lamotrigine (being respectively 30.0%, 28.3% and 31.9%).
At baseline place, once a day, in every day twice and placebo group, the average duration of epilepsy is respectively 16.7,19.5 and 20.0.For seizure types frequency, IA simple partial seizure, IB complex partial seizure and IC develop into secondary generalized partial seizure and are respectively: be 34.0%, 72.0% and 80.0% in group once a day; Be 37.0%, 71.7% and 80.4% in every day twice group; Be 27.7%, 80.9% and 72.3% in placebo group.Once a day, in every day twice and placebo group, the every monthly average outbreak sum before research is respectively 14.1,13.6 and 11.8.
Validity result
In Intentionality treatment (intention-to-treat, ITT) crowd (n=143), the treatment phase, the interior Proportion of patients relative to the seizure frequency minimizing 50% in baseline period or more was main effectiveness terminal.Under 1200mg/ days dosage (9-12 week), the respondent's ratio (54%) once a day in group is significantly higher than (p=0.008) placebo group (28%).The respondent's ratio (54%) organized once a day is also higher than every day twice group (41%).Under 800mg/ days dosage (5-8 week), the respondent's ratio (58%) organized once a day is significantly higher than (p<0.05) every day twice group (33%) and placebo group (38%).Under this dosage level, between every day twice group and placebo group, do not find notable difference.
Secondary terminal comprise total seizure frequency minimizing, without the outbreak ratio of patient, respondent distribution, once a day with every day twice scheme comparison and the overall assessment of researcher and patient.
With 1200mg and 800mg once a day dosage obtain the maximum minimizing of attack times, and the result organized once a day is better than the result (Fig. 1) that obtains in every day twice group.For all dosage (400mg, 800mg and 1200mg), compare for twice with every day with the patient of placebo group, the attack times accepting the patient of eslicarbazepine acetate dosage once a day reduces more abundant.
In the patient of 1200mg and 800mg accepting eslicarbazepine acetate dosage once a day, attack times reduces by 59.5% and 55.8% respectively.By contrast, in the patient accepting 1200mg and 800mg two doses every day, outbreak reduces 47.5% and 38.1% respectively.The attack times of the 400mg the accepting eslicarbazepine acetate patient of dosage once a day reduces 38.9%, is almost the twice reducing (20.2%) in the outbreak accepting to observe in the patient of 400mg two doses every day of eslicarbazepine acetate.
At the end of 12 weeks treatment stages, in administration group once a day, the patient of 27.9% becomes without outbreak.
In addition, it is best that the researcher efficiency evaluation (CGI-clinical global impression) organized once a day and patient acceptance evaluate rank.
Pharmacokinetics results
The plasma/serum sample being used for BIA2-005 and " trough " (before administration) level with AED is collected in all examinations except V5 (after research examination).Object characterizes the impact of eslicarbazepine acetate on the pharmacokinetics behavior with AED (such as phenytoin, valproate, primidone, phenobarbital, lamotrigine, gabapentin, topiramate and clonazepam).Table 1 shows the mean trough plasma concentration of BIA2-005.As shown in Figure 2, not finding the notable difference of BIA2-005 trough (before administration) value once a day between group and every day twice group.
Table 1: the trough plasma concentration of BIA2-005 after (o.d.) and every day twice (b.i.d) oral administration eslicarbazepine acetate once a day
Result represents with the respective standard difference (sd) in arithmetic mean of instantaneous value and bracket.
The relatively small amount patient of administration phenytoin, primidone, phenobarbital, gabapentin and clonazepam fails suitably to characterize eslicarbazepine acetate to these final impacts with the pharmacokinetics behavior of AED.For valproate, lamotrigine and topiramate, patient's number is also very little, but has carried out eslicarbazepine acetate to these exploratory analysis with the impact of the trough blood values of AED.The mean trough serum concentrations of valproate is not because concomitant dosing once a day (7.0%; 95%IC:-7.6,36.2) or every day twice (6.3%; 95%IC:-7.5,20.1) eslicarbazepine acetate and obviously changing.In placebo group, notice that the serum levels of valproate obviously rises (25.4%; 95%IC:5.1,45.8).For lamotrigine, when inciting somebody to action eslicarbazepine acetate (-10.0% once a day; 95%IC:-46.2,26.2) or placebo (12.6%; 95%IC:-12.6,37.8), when adding treatment, its serum levels does not have significant change.When twice eslicarbazepine acetate every day, the serum levels of lamotrigine obviously declines (-46.7%; 95%IC:-69.7 ,-23.8).For topiramate, when inciting somebody to action eslicarbazepine acetate (-15.2% once a day; 95%IC:-34.8,4.4), when adding treatment, its serum levels does not have significant change.When twice eslicarbazepine acetate every day, the serum levels of topiramate obviously declines (-32.4%; 95%IC:-49.5 ,-15.3).One skilled in the art will know that whether serum levels change is obvious.
Research in Healthy People volunteer
Experiment A
Pharmacokinetics results
The a large amount of metabolism of display eslicarbazepine acetate is eslicarbazepine, and metabolism is R-licarbazepine to lesser extent.In two groups, all reach the Cpss of eslicarbazepine when administration 4 to 5 days.
In the end after administration, in group once a day, the average C of eslicarbazepine and R-licarbazepine
maxbe respectively 22,210ng/mL and 674ng/mL, occur in (intermediate value t respectively
max) after administration 2.45 hours and 9.42 hours.The average A UC of eslicarbazepine and R-licarbazepine
0-tbe respectively 381,601ngh/mL and 19,600ngh/mL.In every day twice group, the average C of eslicarbazepine and R-licarbazepine
maxbe respectively 16,667ng/mL and 718ng/mL, occur in (intermediate value t respectively
max) after administration 2.09 hours and 6.40 hours.The average A UC of eslicarbazepine and R-licarbazepine
0-tbe respectively 283,014ngh/mL and 19,661ngh/mL.At multiple dosing eslicarbazepine acetate after 8 days, display eslicarbazepine is major metabolite, and once a day with in every day twice experimenter, the total systemic drug showing about 95% and 96% respectively exposes (by AUC
0-24evaluate).Table 2 and 3 is depicted as once a day with in every day twice group, the eslicarbazepine after the last administration of eslicarbazepine acetate and the pharmacokinetic parameter of R-licarbazepine.In group once a day, healthy volunteer to the total exposure of eslicarbazepine unexpectedly than twice group of height at least 26% every day.
Table 2: the repeatedly mean pharmacokinetic parameter of eslicarbazepine and R-licarbazepine after oral administration 900mg eslicarbazepine acetate once a day
Eslicarbazepine
R-licarbazepine
N=experimenter's quantity; A
on average=arithmetic mean of instantaneous value; SD=standard deviation.
Table 3: the mean pharmacokinetic parameter of eslicarbazepine and R-licarbazepine after every day more than twice oral administration 900mg eslicarbazepine acetate
Eslicarbazepine
R-licarbazepine
N=experimenter's quantity; A
on average=arithmetic mean of instantaneous value; SD=standard deviation.
Experiment B
Pharmacokinetics results
As tested described in A, a large amount of metabolism of eslicarbazepine acetate is eslicarbazepine, and metabolism is R-licarbazepine to lesser extent.The Cpss of eslicarbazepine is reached 4 to 5 days of administration once a day time.
In the end after administration, in the group once a day repeated, the average C of eslicarbazepine
maxscope is 56,500ng/ML (20.0%CVs) of 8,800ng/ML (16.0% coefficient of variation, CV) to 2400mg eslicarbazepine acetate dosage of 400mg eslicarbazepine acetate dosage.The maximal plasma concentration of all dosage occurs in 2 little of 3.5 hours (intermediate value t
max).For the dosing interval of 24 hours, the average area AUC under concentration curve
0-24hscope be 400mg once a day eslicarbazepine acetate dosage 126,300ng/ML to 2400mg once a day eslicarbazepine acetate dosage 905,900ng/ML.Table 4 and 5 is depicted as the pharmacokinetic parameter of eslicarbazepine and R-licarbazepine after eslicarbazepine acetate single-dose and the pharmacokinetic parameter after last eslicarbazepine acetate repeat administration.
Table 4: the mean pharmacokinetic parameter (every dosage group n=6 name experimenter) of eslicarbazepine and R-licarbazepine after eslicarbazepine acetate single-dose
The CV=coefficient of variation (%); C
max=maximal plasma concentration; AUC
0-24hplasma concentration v. time area under curve in=24h; t
max=arrive C
maxtime; t
1/2=eliminate the half-life
Table 5: the mean pharmacokinetic parameter (every dosage group n=6 name experimenter) of eslicarbazepine and R-licarbazepine after the last administration of 8 days repeat administration schemes of eslicarbazepine acetate
The CV=coefficient of variation (%); C
max=maximal plasma concentration; AUC
0-24hplasma concentration v. time area under curve in=24h; t
max=arrive C
maxtime; t
1/2=eliminate the half-life
Research is discussed
Find to be divided into every day two doses than by identical accumulated dose to eslicarbazepine acetate once a day more effective, reduce in epilepsy more effective than placebo undoubtedly.With obtain the every day of identical total daily dose compared with two doses, dosage is obviously more effective in minimizing epilepsy once a day for 800mg and 1200mg of eslicarbazepine acetate.
The a large amount of metabolism of display eslicarbazepine acetate is eslicarbazepine, and metabolism is R-licarbazepine to lesser extent.Eslicarbazepine represents the total systemic drug exposure of 95% to 98% (by AUC
0-τevaluate, the AUC namely in dosing interval), therefore, believe that it causes to the main cause of the pharmacological activity after eslicarbazepine acetate.Systematically find that the plasma concentration of parent drug (eslicarbazepine acetate) is lower than quantitative limit.When multiple dosing, in two groups, all reach Cpss when administration 4 to 5 days, consistent with the effective half-life of roughly about 20-24 hour.
The dynamics of eslicarbazepine in group once a day is obviously different from every day twice group, after repeatedly oral administration eslicarbazepine acetate, at evaluated some pharmacokinetic parameters (C
max, AUC
0-τand AUC
0-∞) in found significant difference.In fact, healthy volunteer to the total exposure of eslicarbazepine in group once a day unexpectedly than every day twice group in height at least 26%.This beat all result is consistent with the following discovery in epileptic, to be namely divided into every day two doses than by identical total daily dose to eslicarbazepine acetate once a day more effective.Although the clinical effectiveness that this possibility of result hint strengthens may be the ratio (C owing to exposing eslicarbazepine
max) and degree (AUC) increase, but still cannot explain for the reason that degree of exposure this after administration once a day strengthens relative to twice administration every day.
Except above-mentioned illustrative aspects and embodiment, by research description above, other side and embodiment will become obvious to those skilled in the art.One of skill in the art will appreciate that to some amendment above-described be possible, and these amendments also considered to be in scope of the present invention.Therefore expect that following appended claims (comprising its any amendment) and any claim hereafter introduced all should be interpreted as comprising all these aspects, embodiment and amendment.
Claims (17)
1. eslicarbazepine acetate is manufacturing the application be used for the treatment of in the pharmaceutical composition of epilepsy partial seizures, wherein said pharmaceutical composition is unit dosage form once a day, and described unit dosage form once a day comprises the eslicarbazepine acetate of the amount in 400mg to 1200mg scope.
2. eslicarbazepine acetate is manufacturing the application be used for the treatment of in the pharmaceutical composition of refractory partial epilepsy, wherein said pharmaceutical composition is unit dosage form once a day, and described unit dosage form once a day comprises the eslicarbazepine acetate of the amount in 400mg to 1200mg scope.
3. apply as claimed in claim 2, wherein said refractory partial epilepsy is the refractory epilepsy of simple part.
4. apply as claimed in claim 2, wherein said refractory partial epilepsy is the refractory epilepsy of complicated part.
5. apply as claimed in claim 2, wherein said refractory partial epilepsy develops into secondary generalized epilepsy.
6. as application, wherein said eslicarbazepine acetate and other antuepileptic therapeutic alliance of at least one of aforementioned arbitrary claim.
7. apply as claimed in claim 6, other antuepileptic of wherein said at least one is selected from valproate, lamotrigine and topiramate.
8., as the application of aforementioned arbitrary claim, for the seizure trequency experienced relative to untreated patient, reduce the seizure trequency of patient.
9. apply as claimed in claim 8, the reduction of wherein said seizure trequency is 50% or higher.
10., as the application of aforementioned arbitrary claim, for the epilepsy number of times experienced relative to untreated patient, reduce the epilepsy number of times of patient.
11. as the application of aforementioned arbitrary claim, for the seizure duration experienced relative to untreated patient, reduces the seizure duration of patient.
12. as the application of aforementioned arbitrary claim, and wherein by the administration of pharmaceutical composition, patient becomes without outbreak.
The pharmaceutical composition of 13. oral administrations, for treating epilepsy partial seizures by improving the exposure of patient to eslicarbazepine, comprises the eslicarbazepine acetate of the effective dosage once a day of pharmacology of 400mg to 1200mg amount.
The pharmaceutical composition of 14. oral administrations, for treating refractory partial epilepsy by improving the exposure of patient to eslicarbazepine, comprises the eslicarbazepine acetate of the effective dosage once a day of pharmacology of 400mg to 1200mg amount.
15. as the pharmaceutical composition of the oral administration of claim 13 or 14, and the effective dosage once a day of wherein said pharmacology is to cause the maximum observation plasma concentration C of eslicarbazepine
maxbe greater than the dosed administration of 7,400ng/mL.
16. as the pharmaceutical composition of the oral administration of claim 13 or 14, and the effective dosage once a day of wherein said pharmacology is with area AUC under the concentration curve causing eslicarbazepine
0-τbe greater than the dosed administration of 111,000ngh/mL, wherein τ is dosing interval.
17. as the pharmaceutical composition of the oral administration of any one of claim 13 to 16, and it is tablet form or oral suspensions form.
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| J.MAIA等: "BIA 2-093 as add-on therapy for refractory partial epilepsy in adults", 《EPLIEPSIA》 * |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN114958937A (en) * | 2022-05-12 | 2022-08-30 | 黄冈人福药业有限责任公司 | Synthesis process of eslicarbazepine acetate and intermediate thereof |
| CN114958937B (en) * | 2022-05-12 | 2023-12-29 | 黄冈人福药业有限责任公司 | Eslicarbazepine acetate and synthesis process of intermediate thereof |
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