WO2014034756A1 - Composition pharmaceutique utilisée pour traiter l'état de mal épileptique - Google Patents

Composition pharmaceutique utilisée pour traiter l'état de mal épileptique Download PDF

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Publication number
WO2014034756A1
WO2014034756A1 PCT/JP2013/073092 JP2013073092W WO2014034756A1 WO 2014034756 A1 WO2014034756 A1 WO 2014034756A1 JP 2013073092 W JP2013073092 W JP 2013073092W WO 2014034756 A1 WO2014034756 A1 WO 2014034756A1
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Prior art keywords
seizures
pharmaceutical composition
convulsive
present
minutes
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PCT/JP2013/073092
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English (en)
Japanese (ja)
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花田　敬久
克俊 井戸
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エーザイ・アール・アンド・ディー・マネジメント株式会社
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Publication of WO2014034756A1 publication Critical patent/WO2014034756A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/4025—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil not condensed and containing further heterocyclic rings, e.g. cromakalim
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A61P21/02—Muscle relaxants, e.g. for tetanus or cramps
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to a pharmaceutical composition for the treatment of convulsive seizures containing perampanel, a pharmacologically acceptable salt thereof or a hydrate thereof, peranpanel, a pharmacologically acceptable salt thereof or water thereof.
  • a method for treating convulsive seizures using a hydrate a pharmaceutical composition for the treatment of convulsive seizures comprising a GABAergic drug and peranpanel, a pharmacologically acceptable salt thereof or a hydrate thereof
  • the present invention relates to a method for treating convulsive seizures using GABAergic drugs and peranpanels, pharmacologically acceptable salts thereof or hydrates thereof.
  • Convulsive seizures are defined as convulsive seizures that last for a certain length of time or repeat even with short seizures and no recovery of consciousness during that time. In general, the condition persists for more than 30 minutes and does not recover, but in recent years, if it does not converge even after 5 minutes from the onset of convulsions, it has been proposed that treatment should be considered as a seizure intussusception and treatment should begin. (Status epilepticus: pathophysiology and management in adults. Lancet Neurol 2006, 5, 246-56).
  • Incidence of convulsive seizures is not limited to people with a history of epilepsy, but can be caused by a variety of causes, including drug addiction, medical illness, acute brain damage (encephalitis, cerebral hemorrhage, cerebral infarction, post-choking encephalopathy, etc.) Can occur.
  • antiepileptic drugs are not necessarily expected to be effective in treating convulsive seizures.
  • Convulsive seizures are considered to be a neurological emergency. In the treatment of convulsive seizures, it is necessary to achieve rapid seizure cessation in order to prevent death, the persistence of serious sequelae, and the onset of epilepsy. Drug treatment for convulsive seizures is performed by intravenous administration. Currently, according to the European Neurological Society Guidelines (EFNS guideline on the management of status epilepticus in adults.
  • benzodiazepines such as lorazepam or diazepam (including combinations with phenytoin) If treatment is started with drugs and seizures are not stopped, rapid seizure control using general anesthetics such as midazolam, propofol, and barbiturate is recommended for brain protection. For partial seizures, if benzodiazepine drugs are ineffective, there is no clear basis for considering the use of injections such as phenobarbital, valproic acid, and levetiracetam to alleviate physical stress due to general anesthesia. Is shown as
  • antiepileptic drugs as therapeutic agents for convulsive seizures has been reported at the animal experiment level, but there are actually injectable preparations that can be used for convulsive seizures.
  • Available antiepileptic drugs are limited to benzodiazepines such as diazepam and lorazepam, phenytoin, phosphenytoin, phenobarbital, and valproic acid.
  • Intravenous preparations of levetiracetam and lacosamide can be used, although indications for convulsive seizures are not approved.
  • AMPA-type glutamate receptor antagonists are known to have convulsive seizure seizure action in various seizure status models (Effect of novel AMPA antagonist, NS1209, on status epilepticus An experimental study in rat) .
  • AMPA antagonist ZK 200775 in patients with acute ischaemic stroke a double-blind, multicentre, placebo -controlled safety and tolerability study. Cerebrovasc Dis 2005, 20, 304-9).
  • AMPA-type glutamate receptor antagonists to treat convulsive seizures, new methodologies are needed that allow for dose reduction.
  • Perampanel (Fycompa (registered trademark)), one of AMPA-type glutamate receptor antagonists, has been approved in Europe as a combination therapy for epileptic partial seizures (including secondary generalized seizures). Treatment of epilepsy using peranpanels is described in US Pat. No. 6,949,571, WO 09/082038, WO 09/082039. However, none of these patents describe the use of perampanels for the treatment of convulsive seizures.
  • an object of the present invention is to provide a pharmaceutical composition or a therapeutic method for the treatment of an epileptic seizure.
  • perampanel has a seizure-stopping effect on convulsive seizures
  • the combination of perranpanel and diazepam has a seizure-stopping effect on seizures seizures.
  • this combination of perampanel and diazepam can reduce the perampanel dose by at least a factor of 10 when used alone, with diazepam when the therapeutic dose is used alone. It has been found that it can be reduced to at least 1/8 or less.
  • the inventor has also found that the combination of perampanel and lorazepam also has a seizure-stopping effect on convulsive seizures.
  • this combination of perampanel and lorazepam can reduce the perampanel dose by at least one-eighth when used alone, with lorazepam when using a medicinal dose alone. It has been found that it can be reduced to at least a quarter or less.
  • the present inventor completed the present invention based on these findings.
  • the present invention relates to convulsions in a patient in need of treating a convulsive seizure by administering perranpanel, a pharmacologically acceptable salt thereof or a hydrate thereof.
  • a method of treating a seizure is provided.
  • Peranpanels may be used in combination with GABAergic drugs.
  • the present invention entails treating seizure status attacks by administering perampanel, a pharmaceutically acceptable salt or hydrate thereof and a GABA agonist.
  • a method of treating a patient's convulsive seizure is provided.
  • the present invention relates to administering perampanel, a pharmacologically acceptable salt thereof or a hydrate thereof and at least one of a benzodiazepine drug and a barbituric acid drug.
  • a method for treating a convulsive seizure in a patient in need of treating the convulsive seizure in another embodiment of the present invention, the present invention relates to perampanel, a pharmacologically acceptable salt thereof or a hydrate thereof and at least lorazepam, diazepam, midazolam and a pharmacologically acceptable salt thereof.
  • a method of treating a convulsive status epilepticus in a patient in need of treatment of the convulsive status epilepticus is provided by administering either.
  • a method of treating a convulsive status epilepticus includes treatment of one or more symptoms of the convulsive status seizure.
  • the invention provides non-convulsive seizure status, partial seizures, or generalized seizures by administering perranpanel, a pharmacologically acceptable salt thereof, or a hydrate thereof.
  • Methods are provided for treating non-convulsive convulsive seizures, partial seizures or generalized seizures in patients with convulsive seizures in need of treatment.
  • the present invention relates to non-convulsive convulsive status epilepticus, partial seizure by administering perranpanel, a pharmacologically acceptable salt or hydrate thereof, and a GABA agonist.
  • the present invention relates to administering perampanel, a pharmacologically acceptable salt thereof or a hydrate thereof and at least one of a benzodiazepine drug and a barbituric acid drug.
  • a method of treating a non-convulsive convulsive intussusception, partial seizure, or generalized seizure in a patient with a convulsive intussusception requiring treatment of a non-convulsive seizure intussusception, partial seizure, or generalized seizure is provided.
  • the present invention relates to perampanel, a pharmacologically acceptable salt thereof or a hydrate thereof and at least lorazepam, diazepam, midazolam and a pharmacologically acceptable salt thereof.
  • Treating non-convulsive convulsive seizures, partial seizures or generalized seizures in patients with convulsive seizures who need to treat non-convulsive seizures, partial seizures, or generalized seizures Provide a way to do it.
  • a method of treating a non-convulsive convulsive status epilepticus, partial seizure, or generalized seizure includes treatment of one or more symptoms of a non-convulsive seizure status seizure, partial seizure, or generalized seizure.
  • kits and / or pharmaceutical compositions comprising a first active ingredient (eg, perampanel).
  • the present invention provides kits and / or pharmaceutical compositions comprising a first active ingredient (eg, peranpanel) and a second active ingredient (eg, GABA agonist).
  • the invention provides a kit comprising a first active ingredient (eg peranpanel) and a second active ingredient (eg benzodiazepine drug and / or barbituric acid drug) and / or Alternatively, a pharmaceutical composition is provided.
  • the present invention provides a first active ingredient (eg peranpanel) and a second active ingredient (eg lorazepam, diazepam, midazolam and / or their pharmacologically acceptable). Salt) and kits and / or pharmaceutical compositions.
  • the kit and the pharmaceutical composition may further contain a pharmacologically acceptable carrier.
  • the present invention relates to the following.
  • a pharmaceutical composition for treating seizure intussusception comprising perampanel, a pharmacologically acceptable salt thereof or a hydrate thereof for combination therapy with a GABA agonist.
  • a pharmaceutical composition for treating seizure intussusception comprising a GABA agonist and peranpanel, a pharmacologically acceptable salt thereof or a hydrate thereof.
  • GABAergic agent and peranpanel, pharmacologically acceptable salt or hydrate thereof are administered separately to the patient or administered to the patient in the form of a single pharmaceutical composition
  • Benzodiazepines are lorazepam (Lorazepam), diazepam (Diazepam), midazolam (Clonazepam), chlorazepate (Clorazepate), flunitrazepam (Nitrazepam), henazepam (Clobazam) and the pharmaceutical composition according to [4] above, which is at least one selected from the group consisting of pharmacologically acceptable salts thereof.
  • the present invention provides a pharmaceutical composition or method for treating seizures.
  • the present invention also provides a pharmaceutical composition or method for treating non-convulsive seizure status epilepticus, partial seizures or generalized seizures.
  • the treatment mode of the convulsive status seizure according to the present invention in which a perampanel and a GABA agonist are used in combination has a marked therapeutic effect as compared with the administration of each drug alone.
  • a perampanel and a GABA agonist are used in combination.
  • the treatment method and the pharmaceutical composition of the present invention can reduce or stop the convulsive seizure more effectively than the administration of each drug alone, and are useful for the treatment of the convulsive seizure.
  • the treatment mode of the convulsive status epilepticus according to the present invention using a combination of a perampanel and a GABA agonist can provide a sufficient effect with a small amount of use compared to the case of individual administration of each drug, For example, it is useful for reducing or preventing respiratory depression.
  • Patient refers to animals, preferably mammals, more preferably humans.
  • patient includes men and women and includes adults, children and infants.
  • an “active ingredient” is an ingredient involved in the treatment and / or prevention of a disease or disorder, such as peranpanels described herein, pharmaceutically acceptable salts or hydrates thereof, As well as GABAergic drugs, benzodiazepine drugs, and barbituric acid drugs. Active ingredients also include lorazepam, diazepam, midazolam, clonazepam, chlorazepic acid, flunitrazepam, nitrazepam, phenazepam, clobazam and / or their pharmacologically acceptable salts.
  • the active ingredient may have a known action mechanism or an unknown action mechanism, and the active ingredient may have one or more action mechanisms.
  • the active ingredient may have an asymmetric carbon depending on the type of substituent, and may have a stereoisomer (eg, geometric isomer, enantiomer, diastereomer, etc.).
  • the active ingredient or its stereoisomer can form a pharmacologically acceptable salt.
  • the active ingredient, its pharmacologically acceptable salt, its stereoisomer, or its pharmacologically acceptable salt may be anhydrous and forms a solvate There is also.
  • the active ingredient, its pharmacologically acceptable salt, its stereoisomer, its pharmacologically acceptable salt or its solvate may be crystalline or amorphous. May be.
  • Crystalline polymorphism may exist in the active ingredient, its pharmacologically acceptable salt, its stereoisomer, its pharmacologically acceptable salt or its solvate, Without being limited thereto, any type of crystal may be present alone or in combination and these are within the scope of the present invention.
  • active ingredient drug
  • drug drug and “compound” can be used interchangeably.
  • Treatment and “treating” refer to obtaining a desired pharmacological and / or physiological effect. These effects are prophylactic in terms of completely or partially hindering the disease and / or one or more symptoms of the disease and partially ameliorating the disease and / or one or more symptoms caused by the disease. Or it is therapeutic in terms of complete healing.
  • Treatment and “treating” include all treatments of a patient's disease (eg, convulsive seizures), such as (a) suspected of being susceptible to a disease Preventing a disease or one or more symptoms of the disease in a patient who has not been diagnosed as afflicted, or who has been previously diagnosed as afflicted with a disease but is not currently diagnosed with the disease (B) suppressing one or more symptoms of the disease, ie, suppressing or delaying the progression of one or more symptoms of the disease, (c) reducing one or more symptoms of the disease, Ie, reverse or eliminate one or more symptoms of the disease, (d) reverse progression of one or more symptoms of the disease, or (e) stabilize one or more symptoms of the disease.
  • a patient's disease eg, convulsive seizures
  • Specific treatment regimens for patients include specific compound activity, age, weight, general health, sex, diet, administration time, secretion time, drug combination, physician judgment, and severity of symptoms being treated It can depend on various factors including degrees.
  • “separately administered” refers to two or more active ingredients individually in two or more different formulations. It means to administer.
  • Simultaneous administration of the formulations means that the compounds are administered to the patient substantially simultaneously or strictly simultaneously, depending on the mode of administration.
  • Continuous administration of the formulations may be performed in any order, and the time between administration of the compounds may be arbitrary. Sequential dosing is based on factors that affect which compound should be administered first, which compound should be given second, and how much time should be interrupted between administrations of the compound. It can be carried out.
  • factors that affect when a compound is administered to a patient include, for example, (a) the best efficacy for the administered compound. (B) the time at which side effects are minimized for the compound being administered, (c) the dosage of the compound, (d) the route of administration of the compound, (e) the disease or disorder being treated, (f) being treated Patient, (g) in vivo relationship between the compound to be administered and other factors known in the art.
  • the time interval for continuous administration is an additive level of effect on the disease or disorder being treated when used in combination with the active ingredient compared to the effect obtained using only one of the active ingredients. Is preferably selected so as to exceed.
  • “Combination” or “combination” means that a first active ingredient and a second active ingredient different from the first active ingredient are administered separately as different pharmaceutical compositions (eg, peranpanel A second pharmaceutical composition comprising a GABAergic agent) or a single pharmaceutical composition. Further, in combination or combination, three or more active ingredients may be used.
  • the pharmaceutical compositions may have the same or different modes of administration.
  • the perampanel, GABA agonist may be any of those described herein.
  • “Monotherapy” is a treatment that uses only one active ingredient (eg, peranpanel) for the treatment of a disease or disorder.
  • a “combination therapy” is a therapy in which two or more active ingredients are administered separately or in the form of a single pharmaceutical composition for the treatment of a disease.
  • the perampanel, GABA agonist may be any of those described herein.
  • a first pharmaceutical composition comprising a perampanel and a second pharmaceutical composition comprising a GABA agonist may be administered separately, or A pharmaceutical composition containing the peranpanel and GABAergic agent separately may be administered.
  • a pharmaceutical composition comprising a perampanel and a GABAergic agent together may be administered.
  • the composition may be prepared just prior to administration or stored as an integrated formulation.
  • two or more active ingredients used in the combination may be administered at the same site or at different sites. Two or more active ingredients may also be administered via the same route or different routes.
  • a “kit”, also known as a “commercial package”, can include a combination of: (i) a first pharmaceutical composition comprising a first active ingredient (eg, perampanel). (Ii) a second pharmaceutical composition comprising a second active ingredient (eg, a GABA agonist), (iii) instructions for using the pharmaceutical composition to treat a disease, and (iv )
  • a first pharmaceutical composition comprising a first active ingredient (eg, perampanel).
  • a second pharmaceutical composition comprising a second active ingredient (eg, a GABA agonist)
  • instructions for using the pharmaceutical composition to treat a disease eg, a GABA agonist
  • instructions for using the pharmaceutical composition to treat a disease eg, a GABA agonist
  • instructions for using the pharmaceutical composition to treat a disease eg, a GABA agonist
  • a second active ingredient eg, a GABA agonist
  • instructions for using the pharmaceutical composition to treat a disease eg, a GABA agonist
  • the “kit” can include: (i) both a first active ingredient (eg, peranpanel) and a second active ingredient (eg, GABA agonist).
  • a pharmaceutical composition comprising, (ii) instructions for using the pharmaceutical composition to treat a disease, and (iii) optionally, for administering the pharmaceutical composition (eg, syringe, diluent, medical glove) , Hand sanitizers, etc.), other materials for monitoring drug levels in the body, to support patient compliance with respect to taking drugs, or to monitor disease status.
  • the kit can supply enough drugs and materials for days, weeks or months.
  • the kit can provide sufficient pharmaceutical compositions and materials to implement all or part of a treatment regimen.
  • the perampanel, GABA agonist may be any of those described herein.
  • Solvates are well known in the art.
  • the solvate is preferably a pharmacologically acceptable solvate.
  • the pharmacologically acceptable solvate may be either a hydrate or a non-hydrate, but is preferably a hydrate.
  • a solvent such as water, alcohol (eg, methanol, ethanol, n-propanol), dimethylformamide, dimethyl sulfoxide (DMSO), or the like can be used.
  • “Hydrate” refers to a compound containing crystalline water molecules.
  • the water molecule of the crystal may take an integer value of 1 or more (for example, 1 to 10), an arbitrary fraction larger than 0, or an integer fraction of 1 to 10.
  • hydrates are compound ⁇ 1/4 H 2 O, compound ⁇ 1/2 H 2 O, compound ⁇ 3/4 H 2 O, compound ⁇ 2 H 2 O, compound ⁇ 5 1/2 H 2 O , Compound 6 H 2 O and the like.
  • “compound” includes any of the compounds described herein, such as peranpanel (3- (2-cyanophenyl) -5- (2-pyridyl) -1-phenyl-1,2-dihydropyridin-2-one). It may be.
  • “Pharmaceutically acceptable salts” are well known in the art and include salts of inorganic acids (eg, hydrochloride, sulfate, hydrobromide and phosphate), and organic acids. Salts such as formate, tartrate, acetate, trifluoroacetate, methanesulfonate, benzenesulfonate and toluenesulfonate.
  • the compound that is the active ingredient of the present invention can be, for example, an alkali metal salt (eg, sodium salt or potassium salt), an alkaline earth metal salt (eg, calcium salt or magnesium salt), Organic amine salts (eg, salts with trimethylamine, triethylamine, pyridine, picoline, dicyclohexylamine or N, N′-dibenzylethylenediamine) can be formed.
  • an alkali metal salt eg, sodium salt or potassium salt
  • an alkaline earth metal salt eg, calcium salt or magnesium salt
  • Organic amine salts eg, salts with trimethylamine, triethylamine, pyridine, picoline, dicyclohexylamine or N, N′-dibenzylethylenediamine
  • the active ingredients of the present invention can be made in the form of any other pharmaceutically acceptable salt.
  • a patient in need of treating a seizure intussusception by administering a perampanel, a pharmacologically acceptable salt thereof or a hydrate thereof and / or a GABA agonist provides a method for treating convulsive status epilepticus.
  • the invention provides non-convulsive convulsive seizures by administering perranpanel, a pharmaceutically acceptable salt or hydrate thereof and / or a GABA agonist.
  • a method of treating a non-convulsive convulsive seizure in a patient in need of treatment is provided.
  • the invention treats partial or systemic seizures by administering perranpanel, a pharmaceutically acceptable salt or hydrate thereof and / or a GABA agonist.
  • Methods of treating partial or generalized seizures in patients in need thereof are provided.
  • the present invention provides kits and / or pharmaceutical compositions comprising a first active ingredient (eg, peranpanel) and a second active ingredient (eg, GABA agonist).
  • the present invention relates to perampanel, a pharmacologically acceptable salt thereof or a hydrate thereof, in a single agent therapy, a combination therapy, a primary treatment of seizures, and It can also be used as a secondary treatment for intractable seizures that are already evident in previous treatments.
  • a convulsive seizure (Status epilepticus) is a convulsive seizure that lasts for a certain length of time or repeats even a short seizure and there is no recovery of consciousness during that time. These include generalized convulsive seizures (Generalized (convulsive status epilepticus), non-convulsive status epilepticus, and complex seizures (Complex partial status epilepticus). Incidence of convulsive seizures is not limited to people with a history of epilepsy, but can be caused by a variety of causes, including drug addiction, medical illness, acute brain damage (encephalitis, cerebral hemorrhage, cerebral infarction, post-choking encephalopathy, etc.), trauma, etc. Can occur.
  • convulsions are not limited to the above-mentioned examples, they are seizure pathological conditions caused by abnormal abnormal excitement of the brain that can occur due to various causes, but epilepsy is a chronic disease that is caused by repeated convulsions. Therefore, the treatment of epilepsy is aimed at preventing seizures.
  • convulsive seizures are conditions in which abnormal excitement persists for a long time due to abnormalities in the brain mechanism that converges convulsions, and treatment aims to prevent brain damage due to cessation of seizures and improve life prognosis.
  • Convulsive seizures include long-lasting seizures that are refractory or partially refractory or become refractory in their duration. These refractory convulsive seizures include disease states that are at least partially refractory or substantially refractory to one or more drugs used to treat convulsive seizures.
  • the refractory convulsive status epilepticus is at least partially refractory or substantially to at least one or more drugs selected from GABAergic drugs, pharmacologically acceptable salts thereof, and solvates. Including diseases or conditions that are intractable.
  • the convulsive seizures treated by the methods of the invention are at least 5 minutes, at least about 10 minutes, at least about 15 minutes, at least about 20 minutes, at least 25 minutes, at least about 30 minutes, at least About 35 minutes, at least about 40 minutes, at least about 45 minutes, at least about 50 minutes, at least about 55 minutes, at least about 60 minutes, at least about 90 minutes, at least about 120 minutes, or more, preferably at least about 30 minutes, It is at least partially refractory because of its duration of at least about 45 minutes, or at least about 60 minutes.
  • the convulsive seizure treated by the method of the invention initially responds to treatment with one or more drugs, but the convulsive seizure is at least 5 minutes, at least 10 minutes, at least 15 minutes, at least 20 minutes, at least 25 minutes, at least 30 minutes, at least about 35 minutes, at least 40 minutes, at least 45 minutes, at least 50 minutes, at least 55 minutes, at least 60 minutes, or more, preferably It is at least partially refractory because of its duration of at least 30 minutes, at least 45 minutes, or at least 60 minutes.
  • Convulsive seizures include partial seizures and generalized seizures.
  • Generalized seizures are classified as convulsive seizures and non-convulsive seizures. These are further classified as absence seizures, myoclonic seizures, clonic seizures, tonic seizures, tonic clonic seizures, and weakness seizures.
  • a generalized seizure refers to a seizure that occurs simultaneously in both hemispheres of the brain.
  • Partial seizures refers to focal seizures that occur only in part of the brain.
  • Deficient seizure refers to a seizure that temporarily loses consciousness.
  • Myoclonic seizures refers to seizures that cause sudden jerk or twitch in the muscles such as the face, limbs, and trunk.
  • Clonic seizures refers to seizures that cause the limbs to flex and extend suddenly and shake.
  • a tonic seizure refers to a seizure that suddenly causes muscle tension or stiffness in the extremities, neck, trunk, etc., resulting in loss of consciousness at the same time that the body is twisted.
  • “Ankylosing clonic seizures” refers to seizures that cause generalized tonic convulsions with loss of consciousness, followed by clonic seizures.
  • “Lacking attacks” (“drop attacks”) means that the muscle weakness necessary to maintain the posture of the head, trunk, limbs, etc. occurs in a short period of time, so , Refers to seizures that crawl head forward and at the same time momentary loss of consciousness.
  • Perampanel is the IUPAC name, 2- (2-oxo-1-phenyl-5-pyridin-2-yl-1,2-dihydropyridin-3-yl) benzonitrile.
  • the “peran panel” is also sometimes called 3- (2-cyanophenyl) -5- (2-pyridyl) -1-phenyl-1,2-dihydropyridin-2-one.
  • the GABA agonist is a drug that activates or increases the activity of the GABA receptor, and is not particularly limited as long as it is a drug that activates or increases the activity of the GABA receptor.
  • GABAergic agents used in the treatment of convulsive seizures in combination with peranpanel, a pharmacologically acceptable salt thereof or a hydrate thereof include, for example, benzodiazepines and barbiturates Either or both.
  • GABAergic drugs for example, benzodiazepine drugs, barbituric acid drugs
  • Benzodiazepine drugs are commercially available and can be prepared by methods well known in the literature.
  • Benzodiazepines include, for example, Lorazepam: WYPAX (registered trademark) (Pfizer, Takeda Pharmaceutical), Diazepam: CERCINE (registered trademark) (Takeda Pharmaceutical), Horizon (Horizon) ) (Registered trademark) (Astellas Pharma), Midazolam: Dormicum (registered trademark) (Astellas Pharma), Clonazepam: RIVOTRIL (registered trademark) (Chugai Pharmaceutical), Landsen (Registered trademark) (Dainippon Sumitomo Pharma Co., Ltd.), chlorazepate (Clorazepate): Tranxene (registered trademark) (Abbott), flunitrazepam (Flunitrazepam): Silece (registered trademark) (Eisai), Nitrazepam (Nitrazepam) :
  • a benzodiazepine drug used for the treatment of convulsive seizures in combination with peranpanel a pharmacologically acceptable salt thereof or a hydrate thereof, lorazepam, diazepam, midazolam, clonazepam, It is at least one selected from the group consisting of chlorazepic acid, flunitrazepam, nitrazepam, phenazepam, and clobazam, and more preferably at least one selected from the group consisting of lorazepam, diazepam, and midazolam.
  • Barbituric acid drugs are commercially available and can be prepared by methods well known in the literature.
  • Barbituric acid drugs include, for example, Pentobarbital: RAVONA (registered trademark) (Mitsubishi Tanabe Seiyaku), Phenobarbital: PHENOBAL (registered trademark) (Daiichi Sankyo), And Thiopental: Ravonal (R) (Mitsubishi Tanabe Pharma).
  • the barbituric acid drug used for the treatment of convulsive seizures in combination with peranpanel a pharmacologically acceptable salt thereof or a hydrate thereof is preferably pentobarbital, phenobarbital and It is at least one selected from thiopental.
  • GABAergic drugs for example, benzodiazepine drugs and barbituric acid drugs
  • GABAergic drugs can be similarly used in the form of pharmacologically acceptable salts and solvates thereof.
  • the present invention provides a pharmaceutical composition comprising a first active ingredient (eg, peranpanel).
  • the pharmaceutical composition is used in combination therapy with a second active ingredient (eg, a GABA agonist).
  • a pharmaceutical composition comprising a first active ingredient (eg peranpanel) and a second active ingredient (eg GABA agonist).
  • the present invention provides a pharmaceutical composition comprising a first active ingredient (eg peranpanel) and a second active ingredient (eg benzodiazepine and / or barbituric acid) Offer things.
  • the present invention provides a first active ingredient (eg, peranpanel) and a second active ingredient (eg, lorazepam, diazepam, midazolam and / or their pharmacologically acceptable).
  • a pharmaceutical composition comprising a salt).
  • the perampanel, GABA agonist may be any of those described herein.
  • the pharmaceutical composition may further contain a pharmacologically acceptable carrier.
  • the invention provides a pharmaceutical composition comprising perranpanel, a pharmacologically acceptable salt thereof or a hydrate thereof, and lorazepam or a pharmaceutically acceptable salt thereof. . In one embodiment of the invention, the invention provides a pharmaceutical composition comprising perranpanel, a pharmaceutically acceptable salt or hydrate thereof, and diazepam or a pharmaceutically acceptable salt thereof. . In one embodiment of the invention, the invention provides a pharmaceutical composition comprising perampanel, a pharmacologically acceptable salt or hydrate thereof, and midazolam or a pharmaceutically acceptable salt thereof. . The pharmaceutical composition may further contain a pharmacologically acceptable carrier.
  • the present invention provides a combination comprising a first active ingredient (eg, peranpanel) and a second active ingredient (eg, GABA agonist), wherein the compound is the active ingredient Also provides a combination that can be administered separately (eg, simultaneously, sequentially) to a patient to treat the diseases described herein, or a combination that can be administered as a single formulation .
  • a first active ingredient eg, peranpanel
  • a second active ingredient eg, GABA agonist
  • the invention provides a combination comprising a first active ingredient (eg peranpanel) and a second active ingredient (eg benzodiazepine and / or barbituric acid)
  • a first active ingredient eg peranpanel
  • a second active ingredient eg benzodiazepine and / or barbituric acid
  • the compound that is the active ingredient can be administered separately (eg, simultaneously, sequentially) to a patient to treat the diseases described herein, a combination or a single formulation Combinations that can be administered as are also provided.
  • the perampanel, GABA agonist may be any of those described herein.
  • the present invention provides a first active ingredient (eg, peranpanel) and a second active ingredient (eg, lorazepam, diazepam, midazolam and / or their pharmacologically acceptable).
  • the active ingredient compound can be administered separately (eg, simultaneously, sequentially) to the patient to treat the diseases described herein. Combinations or combinations that can be administered as a single formulation are also provided.
  • the perampanel, GABA agonist may be any of those described herein.
  • the invention provides a combination comprising perranpanel, a pharmaceutically acceptable salt or hydrate thereof, and lorazepam or a pharmaceutically acceptable salt thereof,
  • the compounds can also be administered separately (eg, simultaneously, sequentially) to a patient to treat the diseases described herein, or combinations that can be administered as a single formulation.
  • the invention is a combination comprising perranpanel, a pharmaceutically acceptable salt or hydrate thereof, and diazepam or a pharmaceutically acceptable salt thereof,
  • the compounds can also be administered separately (eg, simultaneously, sequentially) to a patient to treat the diseases described herein, or combinations that can be administered as a single formulation. provide.
  • the invention is a combination comprising perranpanel, a pharmaceutically acceptable salt or hydrate thereof, and midazolam or a pharmaceutically acceptable salt thereof,
  • the compounds can also be administered separately (eg, simultaneously, sequentially) to a patient to treat the diseases described herein, or combinations that can be administered as a single formulation. provide.
  • the present invention provides a first active ingredient (e.g. peranpanel), a second active ingredient (e.g. GABA agonist), as well as in the treatment of the diseases described herein,
  • a kit eg, a commercial package
  • the perampanel, GABA agonist may be any of those described herein.
  • the invention provides a first active ingredient (eg, peranpanel), a second active ingredient (eg, benzodiazepine drug and / or barbituric acid drug), and
  • a kit eg, a commercial package
  • a kit eg, a commercial package
  • the perampanel, GABA agonist may be any of those described herein.
  • the present invention provides a first active ingredient (eg peranpanel), a second active ingredient (eg lorazepam, diazepam, midazolam and / or their pharmacologically acceptable). Salt), as well as instructions for simultaneous, separate or sequential use in the treatment of the diseases described herein.
  • the perampanel, GABA agonist may be any of those described herein.
  • the invention provides perampanel, a pharmacologically acceptable salt or hydrate thereof, lorazepam or a pharmacologically acceptable salt thereof, and the diseases described herein.
  • a kit (eg, a commercial package) is provided that includes instructions for simultaneous, separate, or sequential use in the treatment of.
  • the present invention provides perampanel, a pharmaceutically acceptable salt or hydrate thereof, diazepam or a pharmaceutically acceptable salt thereof, and a disease described herein.
  • a kit (eg, a commercial package) is provided that includes instructions for simultaneous, separate, or sequential use in the treatment of.
  • the present invention provides perampanel, a pharmaceutically acceptable salt or hydrate thereof, midazolam or a pharmaceutically acceptable salt thereof, and a disease described herein.
  • a kit (eg, a commercial package) is provided that includes instructions for simultaneous, separate, or sequential use in the treatment of.
  • the invention provides for one of the convulsive seizures by administering a first active ingredient (eg, peranpanel) and / or a second active ingredient (eg, GABA agonist).
  • a first active ingredient eg, peranpanel
  • a second active ingredient eg, GABA agonist
  • Methods of treating one or more symptoms of a convulsive seizure include (i) a method of reducing the frequency of one or more symptoms of the convulsive seizure, and (ii) the severity of one or more symptoms of the convulsive seizure.
  • (Iii) reduce the duration of one or more symptoms of a convulsive seizure, (iv) reduce the frequency of one or more symptoms of a convulsive seizure, and reduce the severity Methods, (v) reducing the frequency of one or more symptoms of convulsive seizures and shortening the duration, (vi) reducing the severity of one or more symptoms of convulsive seizures and reducing the duration Methods of shortening as well as (vii) methods of reducing the frequency, reducing the severity and shortening the duration of one or more symptoms of convulsive seizures.
  • the perampanel, GABA agonist may be any of those described herein.
  • the dosage form of the combination, kit and / or pharmaceutical composition of the present invention is not particularly limited.
  • the combinations, kits and / or pharmaceutical compositions of the present invention are useful as combinations, kits and / or pharmaceutical compositions for treating convulsive seizures.
  • the combination, kit and / or pharmaceutical composition of the present invention can be used as a drug for treating convulsive seizures in one embodiment of the present invention.
  • the combination, kit and / or pharmaceutical composition of the present invention can be used for administration to a mammal, preferably a human, in one embodiment of the present invention.
  • the combination, kit and / or pharmaceutical composition of the present invention can be used by oral administration or parenteral administration.
  • the combination, kit and / or pharmaceutical composition comprises the dose of the drug contained therein, the combination ratio in the case of two or more drugs, and the administration sequence thereof, the degree of the disease state or symptom of the patient, It depends on age, sex, weight and sensitivity differences, mode of administration, duration of administration, interval of administration, nature of the pharmaceutical composition, formulation and type, and type of active ingredient.
  • Convulsive seizures require emergency treatment, so drugs are generally administered as soon as possible after onset.
  • the combinations, kits and / or pharmaceutical compositions of the present invention are used immediately after the onset of a convulsive seizure or as soon as possible after the onset of a convulsive seizure.
  • the combination, kit and / or pharmaceutical composition of the present invention can be used for the primary treatment of convulsive seizures.
  • a pharmaceutical composition comprising the perampanel of the present invention, a pharmacologically acceptable salt thereof or a hydrate thereof can be used for the primary treatment of seizures.
  • the combination, kit and / or pharmaceutical composition is at least about 5 minutes, at least about 10 minutes, at least about 15 minutes, at least about 20 minutes, at least about 25 minutes after the onset of convulsive seizures. At least about 30 minutes, at least about 35 minutes, at least about 40 minutes, at least about 45 minutes, at least about 50 minutes, at least about 55 minutes, at least about 60 minutes, at least about 90 minutes, at least about 120 minutes or more Preferably at least about 30 minutes, at least about 45 minutes, or at least about 60 minutes.
  • the pharmaceutical composition comprising perampanel, a pharmacologically acceptable salt or hydrate thereof is at least about 5 minutes after the onset of seizures. At least about 10 minutes, at least about 15 minutes, at least about 20 minutes, at least about 25 minutes, at least about 30 minutes, at least about 35 minutes, at least about 40 minutes, at least about 45 minutes, at least about 50 minutes, at least about 55 minutes At least about 60 minutes, at least about 90 minutes, at least about 120 minutes, or more, preferably at least about 30 minutes, at least about 45 minutes, or at least about 60 minutes.
  • the combination, kit and / or pharmaceutical composition of the invention has already become resistant after a prior primary treatment with a drug used to treat one or more status epilepticus.
  • the combination, kit and / or pharmaceutical composition of the invention comprises a drug used for the treatment of status epileptic seizures, such as lorazepam, diazepam, midazolam, clonazepam, chlorazepate, flunitrazepam, nitrazepam, fenazepam , Clobazam, pentobarbital, phenobarbital, thiopental, propofol, valproic acid, barbiturate, levetiracetam, carbamazepine, phenytoin, phosphenytoin, oxcarbazepine, lamotrigine, gabapentin, pregabalin and their pharmacologically acceptable salts Given to patients with convulsive seizures (refractory convulsive seizures) that are at least partially or substantially resistant to at least one drug It can be used for.
  • a drug used for the treatment of status epileptic seizures such as lorazepam, diazepam
  • a pharmaceutical composition comprising perranpanel, a pharmaceutically acceptable salt thereof or a hydrate thereof is a drug used for the treatment of seizures, such as Convulsive seizures (refractory) that are at least partially or substantially resistant to at least one drug selected from: diazepam, lorazepam, midazolam and pharmacologically acceptable salts thereof Can be used to administer to patients suffering from seizures.
  • seizures such as Convulsive seizures (refractory) that are at least partially or substantially resistant to at least one drug selected from: diazepam, lorazepam, midazolam and pharmacologically acceptable salts thereof.
  • Continuous administration usually involves a pharmaceutical composition comprising a first active ingredient of the invention (eg, peranpanel) and a pharmaceutical composition comprising a second active ingredient (eg, a GABA agonist) in about 120 minutes or less.
  • a pharmaceutical composition comprising a first active ingredient of the invention (eg, peranpanel) and a pharmaceutical composition comprising a second active ingredient (eg, a GABA agonist) in about 120 minutes or less.
  • Administration at intervals of about 15 minutes or less, about 10 minutes or less, or about 5 minutes or less.
  • the interval between administrations is the dosage form and / or administration of a pharmaceutical composition comprising the first active ingredient (eg, peranpanel) of the present invention and a second active ingredient (eg, GABA agonist).
  • the order of administration is not particularly limited, and the second active ingredient (eg, GABA agonist) is included even if the pharmaceutical composition containing the first active ingredient (eg, peranpanel) is administered first.
  • the pharmaceutical composition may be administered first.
  • the combination ratio when two or more drugs are administered is, for example, that for humans, peranpanel, a pharmacologically acceptable salt thereof or a hydrate thereof and diazepam or a combination thereof.
  • the combination ratio is as follows: Peranpanel, its pharmacologically acceptable salt or its hydrate is 1, diazepam or its pharmacological
  • Peranpanel, its pharmacologically acceptable salt or its hydrate is 1, diazepam or its pharmacological
  • peranpanel its pharmacologically acceptable salt or its hydrate is 1
  • lorazepam or its pharmacologically acceptable salt is, for example, about 1 to 20 times, about 1 to 15 Times, about 2.5 to 10 times, and about 5 to 10 times, preferably about 5 to 10 times, more preferably about 5 times and about 10 times.
  • the pharmaceutical composition of the present invention can be in various forms (for example, oral solid preparations, injection solutions, etc.).
  • the first active ingredient (eg, peranpanel) and / or the second active ingredient (eg, GABA agonist) of the present invention may be a conventional pharmaceutically acceptable non-toxic carrier (eg, adjuvant, Can be administered orally, topically, parenterally, aspirated (nasally or orally), or rectally as a dosage unit formulation optionally containing (including forms, diluents, and vehicles) .
  • a conventional pharmaceutically acceptable non-toxic carrier eg, adjuvant, Can be administered orally, topically, parenterally, aspirated (nasally or orally), or rectally as a dosage unit formulation optionally containing (including forms, diluents, and vehicles) .
  • parenteral includes subcutaneous, intravenous, intramuscular, intrathecal, intrasternal injection or infusion techniques.
  • the perampanel, GABA agonist may be any of those described herein.
  • the daily dose of the perampanel of the present invention is usually 0.1 mg to 100 mg / day, 1 mg to 50 mg / day, 2 mg to 20 mg / day or 2 mg to 12 mg per adult (60 kg) when orally administered.
  • / Day Preferred are 2 mg / day, 4 mg / day, 6 mg / day, 8 mg / day, 10 mg / day, 12 mg / day, 14 mg / day, 16 mg / day, 18 mg / day and 20 mg / day.
  • the daily dose is usually 0.1 mg to 30 mg / day, 1 mg to 20 mg / day or 2 mg to 12 mg / day.
  • the perampanel of the present invention is administered once a day or divided into several times a day.
  • the weight values refer to the weight of the peran panel, excluding salts, counterions, hydrates and the like.
  • the daily dose of the GABAergic drug of the present invention is usually 0.04 mg / day to 500 mg / day, 0.1 mg / day to 500 mg / day, 0.1 mg / day to 10 mg per adult (60 kg). / Day, 50 mg / day to 200 mg / day, or 0.4 mg / day to 4 mg / day.
  • the GABAergic drug of the present invention is administered once a day or divided into several times a day.
  • weight values refer to the weight of GABAergic drugs excluding salt and the like.
  • the daily dose of lorazepam of the present invention is usually 0.04 mg / day to 10 mg / day, preferably 0.1 mg / day to 5 mg / day, 0.4 mg / day, per adult (60 kg). ⁇ 4 mg / day, or 1 mg / day to 4 mg / day.
  • Lorazepam of the present invention is administered once a day or divided into several times a day.
  • the weight value refers to the weight of lorazepam excluding salt and the like.
  • the daily dose of the diazepam of the present invention is usually 0.1 mg / day to 30 mg / day, preferably 0.5 mg / day to 20 mg / day, or 1 mg / day, per adult (60 kg). ⁇ 10 mg / day.
  • the diazepam of the present invention is administered once a day or divided into several times a day.
  • the weight value refers to the weight of diazepam, excluding salt and the like.
  • the daily dose of the midazolam of the present invention is usually 0.04 mg / day to 10 mg / day, preferably 0.1 mg / day to 6 mg / day, 0.4 mg / day, per adult (60 kg). Daily to 6 mg / day, 1 mg / day to 6 mg / day or 4 mg / day to 6 mg / day.
  • the midazolam of the present invention is administered once a day or divided into several times a day.
  • the weight value refers to the weight of midazolam excluding salt and the like.
  • the daily dose of the phenobarbital of the present invention is usually, for example, 1 mg / day to 500 mg / day, preferably 5 mg / day to 300 mg / day, 10 mg / day to 200 mg / day, per adult (60 kg). Or 100 mg / day to 200 mg / day.
  • the phenobarbital of the present invention is administered once a day or divided into several times a day.
  • the weight values refer to the weight of phenobarbital excluding salt and the like.
  • the dose When administered to children, the dose may be lower than that for adults in some cases.
  • the actual method of administration will vary widely and may deviate from the preferred methods described herein.
  • the daily dose can be increased until a predetermined daily dose is reached, which can be maintained during further treatment.
  • the mode of administration is preferably by injection such as subcutaneous injection, intramuscular injection, intravenous injection or intraarterial injection.
  • Suitable dispersing or wetting agents eg methylcellulose, Polysorbate® 80, hydroxyethylcellulose, acacia, powdered tragacanth, sodium carboxymethylcellulose, polyoxyethylene sorbitan monolaurate, etc. pH adjusters, buffers , Solubilizers (eg polyoxyethylene hydrogenated castor oil, Polysorbate® 80, nicotinamide, polyoxyethylene sorbitan monolaurate, macrogol, castor oil fatty acid ethyl ester), stabilizers (eg sodium sulfite and pyrosulfite) Sodium (metasulfite), tonicity agents and preservatives (eg, methyl paraoxybenzoate, ethyl paraoxybenzoate, sorbic acid, phenol, cresol, chlorocresol, etc.
  • suspending agents eg methyl
  • the sterile injectable preparation may be, for example, a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent (eg, 1,3-butanediol solution).
  • a non-toxic parenterally acceptable diluent or solvent eg, 1,3-butanediol solution.
  • acceptable vehicles and solvents eg, water, Ringer's solution and isotonic sodium chloride solution.
  • sterile fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil can be employed including synthetic mono- or diglycerides, and fatty acids such as oleic acid can be used in injectable preparations.
  • Such preparations can be lyophilized by methods known in the art.
  • excipients and, if necessary, binders, disintegrants, lubricants, coloring agents, flavoring agents, etc. are added to the main drug, and then tablets, coatings according to conventional methods Molded into tablets, granules, fine granules, dispersants, capsules, etc.
  • the excipient for example, lactose, corn starch, sucrose, glucose, sorbitol, crystalline cellulose, silicon dioxide and the like
  • the binder for example, polyvinyl alcohol, ethyl cellulose, methyl cellulose, gum arabic , Hydroxypropylcellulose, hydroxypropylmethylcellulose and the like
  • the lubricant for example, magnesium stearate, talc, silica, etc.
  • the colorant it can be added to the drug
  • the flavoring agent for example, cocoa powder, menthol, aromatic acid, peppermint oil, camphor oil, cinnamon powder and the like can be used.
  • these tablets and granules may be appropriately coated with sugar coating, gelatin coating or the like.
  • solid dosage forms for oral administration include chewing gum, capsules, tablets, sublingual agents, powders, granules and gels.
  • the active compound can be admixed with one or more inert diluents such as lactose or starch.
  • inert diluents such as lactose or starch.
  • dosage forms can also contain other materials, including lubricants such as magnesium stearate.
  • the dosage forms can also contain buffering agents. Tablets can also be prepared with enteric coating or film coating (preferably film coating).
  • vehicles eg lactose, white sugar, mannitol, glucose, starch, calcium carbonate, crystalline cellulose, silicic acid etc.
  • binders eg water, ethanol, myranol, glucose
  • starch solutions gelatin solutions, polyvinylpyrrolidone, etc.
  • degrading agents eg dry starch, sodium alginate, sodium bicarbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid ester, sodium lauryl sulfate, monoglyceride stearate, starch, lactose, etc.
  • Absorption enhancers eg, quaternary ammonium base, sodium lauryl sulfate, etc.
  • wetting agents eg, glycerin, starch, etc.
  • lubricants eg, stearic acid, polyethylene glycol, etc.
  • flavoring agents e.g., sweeteners
  • sweeteners may be mixed known drug and pharmacologicallyce
  • Sublingual administration refers to administration in the mouth (for example, under the tongue, between the cheek and gingiva, between the tongue and the palate).
  • the highly vascular mucosal lining in the mouth is a convenient location for administering the compound to the body.
  • the solid dosage form may be packaged as a granule or powder in a pharmacologically acceptable carrier, and the granule or powder is removed from the package and sprinkled on food. Or mixed with a liquid such as water or juice, or the granules are encapsulated.
  • the compounds described herein can be mixed with flavoring or sweetening agents.
  • the packaging material may be plastic or coated paper, or any material that prevents water or moisture from reaching the granules and / or powder.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, sublingual solutions, suspensions containing inert diluents commonly used in the art (eg, water). Mention may be made of suspensions and syrups. Such compositions can also contain adjuvants such as wetting agents, emulsifying and suspending agents, and sweetening, flavoring and perfuming agents. In order to make sublingual solutions, the compounds can be prepared from various carriers, excipients, pH adjusters, etc.
  • the embodiment of the present invention has a significant effect as compared to the administration of each drug alone. For example, in pilocarpine-induced convulsion status model rats, a significant improvement effect of convulsion status seizures was observed when these two drugs were administered in combination, compared to when each of the two drugs was administered alone. Embodiments of the present invention are more effective in reducing or stopping convulsive seizures compared to single administration of each drug, and are useful in treating convulsive seizures.
  • the embodiment of the present invention reduces the side effects (for example, respiratory depression) of the drug, because a sufficient effect can be obtained by using a small amount when compared with the case where each drug is administered alone. Useful for prevention.
  • Example 1 Preparation of pilocarpine-induced convulsion intussusception model Electrodes for electroencephalography are implanted and recovered on the cerebrum and cerebellar dura mater of Sprague Dawley male rats (obtained from Charles River, Japan). Lithium chloride (LiCl) 3 mEq / kg is intraperitoneally administered 1 day before pilocarpine administration. The next day, scopolamine methyl bromide 5 mg / kg and pilocarpine 30 mg / kg are administered intraperitoneally to induce convulsions. The convulsion expression was defined as the convulsion expression based on the continuous manifestation of spike waves on the electroencephalogram.
  • Lithium chloride (LiCl) 3 mEq / kg is intraperitoneally administered 1 day before pilocarpine administration. The next day, scopolamine methyl bromide 5 mg / kg and pilocarpine 30 mg / kg are administered intraperitoneally to induce convulsions.
  • Example 2 Evaluation of drug efficacy in the pilocarpine-induced convulsion status model
  • the drug was administered once from the tail vein 30 minutes after the onset of convulsions.
  • the drugs were mixed and administered (simultaneous administration).
  • the effect was judged to be effective when complete disappearance of the convulsion wave was achieved 30 minutes after drug administration, and other effects were judged to be ineffective.
  • the results of drug effectiveness are shown in Table 1 with the number of effective cases as the numerator and the number of cases as the denominator.

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Abstract

L'invention concerne la fourniture d'une composition pharmaceutique utilisée pour traiter l'état de mal épileptique ou une méthode de traitement de l'état de mal épileptique. L'invention concerne une composition pharmaceutique utilisée pour traiter l'état de mal épileptique, qui comprend un agoniste de GABA et du perampanel ou un sel pharmaceutiquement acceptable ou un hydrate de celui-ci.
PCT/JP2013/073092 2012-08-31 2013-08-29 Composition pharmaceutique utilisée pour traiter l'état de mal épileptique WO2014034756A1 (fr)

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