JP2015227288A - Therapeutic pharmaceutical composition for status epilepticus - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a pharmaceutical composition or a therapeutic method for treating status epilepticus.SOLUTION: A therapeutic pharmaceutical composition for status epilepticus comprises a combination of a GABA agonist that is at least one of a benzodiazepine medicine and a barbiturate medicine, and perampanel, pharmacologically acceptable salt thereof or hydrate thereof.

Description

  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.

  Status epilepticus is defined as a convulsive seizure that lasts for a certain length of time, or a short seizure that repeats with 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.), trauma, etc. Can occur. Thus, antiepileptic drugs are not necessarily expected to be effective in treating convulsive seizures.

  Status epilepticus is considered 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 EFNS guideline on the management of status epilepticus in adults. European Journal of Neurology 2012, 17, 348-355, benzodiazepines such as lorazepam or diazepam (including combinations with phenytoin) in the initial treatment 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

  The first-choice benzodiazepine drugs are known to diminish the effect over time from the onset of seizures. It has been reported that GABA receptor, which is the site of action of benzodiazepine, is decreasing with the passage of time (Status epilepticus, pathophysiology and management in adults. Lancet Neurol 2006, 5, 246-56). . In treatment, the dose of the drug is gradually increased until the seizure stops, but high doses of drugs associated with diminished effects can cause serious side effects, and respiratory depression can be a problem when used as a side effect . Reflecting such circumstances, the potential of various 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 a seizure-inhibiting action in various seizure status models (Effect of novel AMPA antagonist, NS1209, on status epilepticus An experimental study in rat Epilepsy Research 2007, 74, 45-54. Treatment of early and late kainic acid-induced status epilepticus with the noncompetitive AMPA receptor antagonist GYKI 52466. Epilepsia 2010, 51, 108-117). However, when a large amount of AMPA antagonist is administered intravenously, serious side effects such as strong muscle relaxation and reduced consciousness level occur (The 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). To more safely use AMPA-type glutamate receptor antagonists to treat convulsive seizures, new methodologies are needed that allow for dose reduction.

  Perampanel (Fycompa®), one of AMPA-type glutamate receptor antagonists, is 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.

U.S. Patent No. 6,949,571 International Publication No. 09/082038 International Publication No. 09/082039

Status epilepticus, pathophysiology and management in adults. Lancet Neurol 2006, 5, 246-56 EFNS guideline on the management of status epilepticus in adults.European Journal of Neurology 2012, 17, 348-355 Status epilepticus, pathophysiology and management in adults. Lancet Neurol 2006, 5, 246-56 Effect of novel AMPA antagonist, NS1209, on status epilepticus An experimental study in rat.Epilepsy Research 2007, 74, 45-54. Treatment of early and late kainic acid-induced status epilepticus with the noncompetitive AMPA receptor antagonist GYKI 52466. Epilepsia 2010, 51, 108-117 The 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

  Under such circumstances, it has been desired to develop a new therapeutic agent and method for convulsive seizures. That is, an object of the present invention is to provide a pharmaceutical composition or a therapeutic method for the treatment of an epileptic seizure.

  The present inventor has found that perampanel has a seizure-stopping effect on seizure status and that the combination of perampanel and diazepam has a seizure-stopping effect on seizure status. Surprisingly, 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 1/10 or less, and the present invention has been completed.

In an embodiment of the present invention, 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.
In an embodiment of the present invention, 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.
In another embodiment of the present invention, 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. Provide 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. Provided is a method of treating a convulsive status seizure in a patient in need of treatment of the seizure status by administering either.
In the present invention, a method of treating a convulsive status epilepticus includes treatment of one or more symptoms of the convulsive status seizure.

In another embodiment of the invention, 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.
In another embodiment of the present invention, 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. Alternatively, a method of treating a non-convulsive convulsive seizure, partial seizure, or generalized seizure in a patient with a convulsive status epilepticus in need of treating a generalized seizure is provided.
In another embodiment of the present invention, 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.
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. 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.
In the present invention, 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.

In other embodiments of the invention, the invention provides kits and / or pharmaceutical compositions comprising a first active ingredient (eg, perampanel).
In other embodiments of the present invention, the present invention provides kits and / or pharmaceutical compositions comprising a first active ingredient (eg, peranpanel) and a second active ingredient (eg, GABA agonist).
In another embodiment of the invention, 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.
In another embodiment of the present invention, 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.
In the present invention, the kit and the pharmaceutical composition may further contain a pharmacologically acceptable carrier.

The present invention relates to the following.
[1] 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.
[2] A pharmaceutical composition for treating seizure intussusception comprising a GABA agonist and peranpanel, a pharmacologically acceptable salt thereof or a hydrate thereof.
[3] 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 The pharmaceutical composition according to [2] above.
[4] The pharmaceutical composition according to any one of [1] to [3] above, wherein the GABAergic drug is at least one of a benzodiazepine drug and a barbituric acid drug.
[5] 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.
[6] The pharmaceutical composition according to the above [4], wherein the benzodiazepine drug is at least one selected from the group consisting of lorazepam, diazepam, midazolam and pharmacologically acceptable salts thereof.
[7] The medicament according to [4] above, wherein the barbituric acid drug is at least one selected from the group consisting of pentobarbital, phenobarbital, thiopental, and pharmacologically acceptable salts thereof. Composition.

  The present invention provides a pharmaceutical composition or method for treating convulsive status epilepticus. The present invention also provides a pharmaceutical composition or method for treating non-convulsive seizure status epilepticus, partial seizures or generalized seizures.

  The therapeutic aspect of the convulsive status epilepticus according to the present invention in which a perampanel and a GABA agonist are used in combination has a marked therapeutic 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. Therefore, 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. .

  In addition, the treatment aspect of the convulsive status epilepticus according to the present invention in which a perampanel and a GABA agonist are used in combination can provide a sufficient effect with a small amount of use compared to the case of single administration of each drug. Useful for reducing or preventing (eg, respiratory depression).

  Hereinafter, the present invention will be described in detail. The following description is an example for explaining the present invention and is not intended to limit the present invention only to the described embodiments. All technical, scientific and technical terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs and are merely specific It is used for the purpose of describing the embodiments of the present invention and is not intended to be limiting. The present invention can be implemented in various modes without departing from the gist thereof. All prior art documents and publications, patent publications and other patent documents cited herein are hereby incorporated by reference and can be used to practice the present invention.

  “Patient” refers to animals, preferably mammals, more preferably humans. The term “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. The active ingredient also includes lorazepam, diazepam, midazolam 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.
The terms “active ingredient”, “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. 1 of the disease Include the above symptoms is prevented also improved deteriorated. 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.

  With respect to administering two or more active ingredients to treat a disease described herein, “separately administered” refers to two or more active ingredients individually in two or more different formulations. It means to administer. For example, continuous administration of the formulations or simultaneous administration of the formulations in any order. 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. For example, when two or more compounds are administered separately and sequentially, 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, perampanel) 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. To administer two or more active ingredients separately, for example, 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. To administer two or more active ingredients in the form of a single pharmaceutical composition, for example, a pharmaceutical composition comprising a perampanel and a GABAergic agent together may be administered. When two or more active ingredients are administered in the form of a single pharmaceutical composition, the composition may be prepared just prior to administration or stored as an integrated formulation.
In the combination therapy of the present invention, 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 the following combinations: (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 ) Optionally, support patient compliance with respect to taking medications to administer pharmaceutical compositions (eg, syringes, diluents, medical gloves, hand sanitizers, etc.), monitor drug levels in the body Or other materials for monitoring disease status. The kit can supply enough drugs and materials for days, weeks or months. In other embodiments of the present invention, 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. Moreover, 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. For example, 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. For example, “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. When a particular substituent is selected, 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. One skilled in the art will recognize that the active ingredients of the present invention can be made in the form of any other pharmaceutically acceptable salt.

In an embodiment of the present invention, 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. Provide a method for treating convulsive status epilepticus.
In another embodiment of the invention, the invention provides non-convulsive convulsive seizures by administering perranpanel, a pharmaceutically acceptable salt or hydrate thereof and / or a GABA agonist. Provided is a method of treating a non-convulsive convulsive seizure in a patient in need of treatment.
In another embodiment of the invention, 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.
In other embodiments of the present invention, the present invention provides kits and / or pharmaceutical compositions comprising a first active ingredient (eg, peranpanel) and a second active ingredient (eg, GABA agonist).
In another embodiment of the present invention, 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 seizure intussusception, previously It can also be used as a secondary treatment for intractable seizures that are already evident in the treatment of convulsions.

  A “status epilepticus” is a convulsive seizure that lasts for a certain length of time or repeats even with a short seizure and there is no recovery of consciousness during that time. These include generalized convulsive status epilepticus, non-convulsive status epilepticus, and 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. Although 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. On the other hand, 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.

  Seizure status epilepticus includes long-lasting seizure status 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. Refractory convulsive status epilepticus is at least partially refractory or substantially to at least one drug selected from GABAergic drugs, pharmacologically acceptable salts, solvates thereof. Includes diseases or conditions that are refractory.

  In embodiments of the invention, 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.

  In an embodiment of the invention, 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.

  Seizures include seizures and partial 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 “systemic seizure” refers to a seizure that occurs simultaneously in both hemispheres of the brain.

  “Partial seizure” refers to a focal seizure that occurs only in a portion of the brain.

  “Deficient seizure” refers to a seizure that temporarily loses consciousness.

  “Myoclonic seizure” refers to a seizure that causes a sudden jerk or twitch in a muscle such as the face, limbs, or trunk.

  A “clonic seizure” refers to a convulsive seizure in which the limb suddenly flexes and stretches and shakes.

  “Tightness seizure” refers to a seizure that suddenly causes muscle tension or stiffness in the extremities, neck, trunk, etc., resulting in loss of consciousness as soon as the body twists.

  “Ankylosing clonic seizures” refers to seizures that cause generalized tonic convulsions with loss of consciousness, followed by clonic seizures.

  “Weak attacks” (“drop attacks”) means that the muscle weakness necessary to maintain postures such as the head, trunk, and limbs occurs in a short period of time, resulting in sticky hips. , 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. In embodiments of the invention, for example, “peranpanel”, “2- (2-oxo-1-phenyl-5-pyridin-2-yl-1,2-dihydropyridin-3-yl) benzonitrile” and “3 -(2-Cyanophenyl) -5- (2-pyridyl) -1-phenyl-1,2-dihydropyridin-2-one "may be a pharmacologically acceptable salt thereof or a hydrate thereof. it can. “Peranpanel”, “2- (2-oxo-1-phenyl-5-pyridin-2-yl-1,2-dihydropyridin-3-yl) benzonitrile” and “3- (2-cyanophenyl) -5” The hydrate of “-(2-pyridyl) -1-phenyl-1,2-dihydropyridin-2-one” can be, for example, 3/4 H ₂ O.

  Peranpanel, pharmacologically acceptable salts thereof or hydrates thereof, and methods for producing them are disclosed in US Pat. No. 6,949,571, US Publication No. 2004/0023973, and PCT International Publication Nos. WO 03/047577, WO 04. / 009553, WO 06/004100, WO 06/004107, WO 07/072868, WO 07/072869, WO 07/126060, and WO 08/093392, the disclosures of which are incorporated herein in their entirety Incorporated by reference.

  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. In the present invention, 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) are commercially available, and can be prepared by methods well known in the literature.

  Benzodiazepines 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) : Benzalin (registered trademark) (Shionogi Pharmaceutical), phenazepam (Phena) zepam): Phenazepam and Clobazam: MYSTAN (registered trademark) (Dainippon Sumitomo Pharma).

  In the present invention, as 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).

  In the present invention, 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) can be similarly used in the form of pharmacologically acceptable salts and solvates thereof.

In an embodiment of the present invention, the present invention provides a pharmaceutical composition comprising a first active ingredient (eg peranpanel) and a second active ingredient (eg GABA agonist).
In another embodiment of the present invention, 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.
In other embodiments of the present invention, 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.

In one embodiment of the invention, 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.

In an embodiment of the present invention, 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 .
In another embodiment of the invention, the invention provides a combination comprising a first active ingredient (eg peranpanel) and a second active ingredient (eg benzodiazepine and / or barbituric acid) Wherein 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.

In other embodiments of the present invention, 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.

In one embodiment of the invention, 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. provide.
In one embodiment of the invention, 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.
In one embodiment of the invention, 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.

In an embodiment of the present invention, 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) is provided that includes instructions for separate or sequential use. The perampanel, GABA agonist may be any of those described herein.
In other embodiments of the invention, 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) is provided that includes instructions for simultaneous, separate, or sequential use in the treatment of the diseases described in. The perampanel, GABA agonist may be any of those described herein.
In other embodiments of the present invention, 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.
In one embodiment of the invention, 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.
In one embodiment of the present invention, 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.
In one embodiment of the present invention, 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.

  In an embodiment of the invention, 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). Provided is a method of treating one or more symptoms of convulsive seizures in a patient in need of treatment for such symptoms. 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.

  In the embodiment of the present invention, 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 medicament for treating a convulsive seizure in one embodiment of the present invention.

  The combinations, kits and / or pharmaceutical compositions of the invention can be used in one embodiment of the invention for administration to a mammal, preferably a human.

  The combination, kit and / or pharmaceutical composition of the present invention can be used by oral or parenteral administration.

  In an embodiment of the present invention, 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.

  Because convulsive seizures require emergency treatment, 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 combinations, kits and / or pharmaceutical compositions of the invention can be used for primary treatment of seizures. In one embodiment of the present invention, 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.

  In embodiments of the invention, 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.

  In one embodiment of the invention, for example, for a human, 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.

  In an embodiment of the invention, 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. As a second-line treatment for administration to patients with at least partially or substantially resistant convulsive seizures (refractory convulsive seizures) it can.

  In an embodiment of the invention, 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 To be administered to patients suffering from convulsive seizures (refractory convulsive seizures) that are at least partially or substantially resistant to at least one drug It can be used.

  In one embodiment of the invention, for example, for humans, 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.

  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. About 90 minutes or less, about 60 minutes or less, about 55 minutes or less, about 50 minutes or less, about 45 minutes or less, about 40 minutes or less, about 35 minutes or less, about 30 minutes or less, about 25 minutes or less, about 20 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). It depends on the route and is not particularly limited. 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.

  In one embodiment of the present invention, 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. When used in combination with a pharmacologically acceptable salt, the combination ratio is as follows: Peranpanel, its pharmacologically acceptable salt or its hydrate is 1, diazepam or its pharmacological For example, about 1 to 20 times, about 1 to 10 times, about 2.5 to 10 times, about 2.5 to 5 times, preferably about 2.5 to 5 times, More preferably, it is about 2.5 times and about 5 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) . The term 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. For administration by injection, 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. Preferred are 1 mg / day, 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, 20 mg / day. It is. The perampanel of the present invention is administered once a day or divided into several times a day. When used in connection with dosages, 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. When used in connection with dosages, 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. When used in connection with dosages, the weight value refers to the weight of lorazepam excluding salt and the like.

  The daily dose of 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. When used in connection with dosages, the weight value refers to the weight of diazepam, excluding salt and the like.

  The daily dose of 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). Day-6 mg / day, 1 mg / day-6 mg / day or 4 mg / day-6 mg / day. The midazolam of the present invention is administered once a day or divided into several times a day. When used in connection with dosage, the weight value refers to the weight of midazolam excluding salt and the like.

  The daily dose of phenobarbital of the present invention is usually 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. When used in connection with dosages, the weight values refer to the weight of phenobarbital excluding salt and the like.

  When administered to children, the dose may optionally be less than that of an adult. The actual method of administration will vary widely and may deviate from the preferred methods described herein.

  Any other compounds described herein are well known in the art with reference to, for example, The Physician's Desk Reference, patents describing compound doses, and articles describing compound doses. The dose can be administered to the patient.

  The daily dose can be increased until a predetermined daily dose is reached, which can be maintained during further treatment.

  In an embodiment of the invention, the mode of administration is preferably by injection, such as subcutaneous injection, intramuscular injection, intravenous injection or intraarterial injection. Suitable dispersing or wetting agents, suspending agents (eg methyl cellulose, Polysorbate 80, hydroxyethyl cellulose, acacia, powdered tragacanth, sodium carboxymethyl cellulose, polyoxytehylene sorbitan monolaurate, etc.) pH adjusting agents, buffering agents , 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) Examples of sodium (metasulfite), preservatives such as methyl paraoxybenzoate, ethyl paraoxybenzoate, sorbic acid, phenol, cresol, chlorocresol, etc.) Therefore it is possible to formulate injectable preparation (e.g., sterile aqueous or oily suspensions for injection). 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). Among the acceptable vehicles and solvents that can be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, 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.

  In order to prepare solid oral preparations, 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.

  As the excipient, for example, lactose, corn starch, sucrose, glucose, sorbitol, crystalline cellulose, silicon dioxide and the like can be used, and as the binder, for example, polyvinyl alcohol, ethyl cellulose, methyl cellulose, gum arabic , Hydroxypropylcellulose, hydroxypropylmethylcellulose and the like can be used, and as the lubricant, for example, magnesium stearate, talc, silica, etc. can be used, and as the colorant, it can be added to the drug As the flavoring agent, for example, cocoa powder, menthol, aromatic acid, peppermint oil, camphor oil, cinnamon powder and the like can be used. Of course, if necessary, these tablets and granules may be appropriately coated with sugar coating, gelatin coating or the like.

  Solid dosage forms for oral administration can include chewing gum, capsules, tablets, sublinguals, powders, granules and gels. In such solid dosage forms, the active compound can be admixed with one or more inert diluents such as lactose or starch. Conventionally, such dosage forms can also contain other materials, including lubricants such as magnesium stearate. In the case of capsules, tablets and pills, the dosage forms can also contain buffering agents. Tablets can also be prepared with enteric coating or film coating (preferably film coating).

  For making tablets, for example, vehicles (eg lactose, white sugar, mannitol, glucose, starch, calcium carbonate, crystalline cellulose, silicic acid etc.), binders (eg water, ethanol, myranol, glucose) Solutions, 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.), Fine flavoring agents (e.g., sweeteners) may be mixed known drug and pharmacologically acceptable carrier and a compound in the art, such as. The tablets can be in the form of conventional tablets, moldings, cachets and the like.

  Sublingual administration refers to administration in the mouth (eg, 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.

  In an embodiment of the invention, 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. In this embodiment, 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. (eg, water, sugar, lactic acid, acetic acid, fructose, glucose, saccharin, polyethylene glycol, propylene glycol, alcohol, Bentonite, tragacanth, gelatin, alginate, aspartame, sorbitol, methylparaben, propylparaben, sodium benzoate, artificial flavoring and coloring agents).

  Embodiments of the present invention have significant effects compared to single administration of each drug. 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.

  In addition, 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.

  Each of the patents, patent applications, and patent publications cited herein are hereby incorporated by reference in their entirety.

  Those skilled in the art will recognize that various modifications can be made to the present invention without departing from the spirit or scope of the appended claims.

  EXAMPLES The present invention will be described in detail below with reference to examples, but these do not limit the scope of the present invention.

Example 1. Preparation of pilocarpine-induced convulsion stack model
Electrodes for electroencephalogram recording are implanted and recovered on the cerebrum and cerebellar dura mater of Sprague Dawley male rats (available 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.

Example 2 Evaluation of drug efficacy in pilocarpine-induced convulsion status model Evaluation of drug efficacy by combination of diazepam, phenytoin or sodium valproate, a benzodiazepine-based drug used for seizure status, and peranpanel 3/4 hydrate The pilocarpine-induced convulsion status model of Example 1 was used. The drug was administered once from the tail vein 30 minutes after the onset of convulsions. When drugs were used in combination, each drug was administered individually. 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.

  30 minutes after the start of convulsions, diazepam 40 mg / kg, phenytoin 50 mg / kg, or sodium valproate 600 mg / kg alone showed no effect, confirming the transition to intractable seizures. On the other hand, in the case of peranpanel-administered animals, the seizure cessation effect was confirmed in 2 cases out of 6 cases at 8 mg / kg, and in 2 cases out of 6 cases at 5 mg / kg. Peranpanel 8 mg / kg was confirmed to have a seizure stopping effect even when administered alone 120 minutes after the onset of convulsions. This result indicates that perampanel is highly time-tolerant showing medicinal effects.

  Furthermore, when diazepam and peranpanel were combined, it was confirmed that all cases of convulsive seizure were achieved with a combination of diazepam 5 mg / kg and peranpanel 1 mg / kg. In addition, even if the dose of perampanel was reduced to 0.5 mg / kg, the convulsive stopping effect was confirmed in 2/6 cases. This surprising finding allowed the combined use of GABAergic drugs and peranpanel to reduce the peranpanel dose by a factor of 10 compared to when used alone, with diazepam reducing the effective dose by 10 It became possible to reduce it to less than 1 / minute.

On the other hand, sodium valproate was confirmed to have a partial action-enhancing action, but phenytoin did not show any combination effect. The combination of diazepam and perampanel provides a new treatment option that avoids the side-effect problems associated with treating seizures. The combination of diazepam and perampanel provides a new treatment option that improves the therapeutic effect.

Claims (7)

  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 the treatment of convulsive seizures comprising a GABAergic drug and peranpanel, a pharmacologically acceptable salt thereof or a hydrate thereof.   The GABAergic agent and peranpanel, a pharmacologically acceptable salt thereof or a hydrate thereof are administered separately to the patient or administered to the patient in the form of a single pharmaceutical composition; The pharmaceutical composition according to claim 2.   The pharmaceutical composition according to any one of claims 1 to 3, wherein the GABAergic drug is at least one of a benzodiazepine drug and a barbituric acid drug.   Benzodiazepines include Lorazepam, Diazepam, Midazolam, Clonazepam, Clorazepate, Flunitrazepam, Nitrazepam, Phenazepam, Phenazepam, Phenazepam, Phenazepam And at least one selected from the group consisting of pharmacologically acceptable salts thereof.   The pharmaceutical composition according to claim 4, wherein the benzodiazepine drug is at least one selected from the group consisting of lorazepam, diazepam, midazolam and pharmacologically acceptable salts thereof. The pharmaceutical composition according to claim 4, wherein the barbituric acid drug is at least one selected from the group consisting of pentobarbital, phenobarbital, thiopental, and pharmacologically acceptable salts thereof.