KR20080111026A - Antiepileptic action enhancer - Google Patents

Abstract

In the drug therapy for epilepsy, the development of a drug or agent which improves problems of an antiepileptic drug such as a side effect or drug resistance has been demanded. The invention relates to an antiepileptic action enhancer for an antiepileptic drug characterized by containing a leukotriene receptor antagonist, and being administered in combination with an antiepileptic drug, or an antiepileptic agent containing a leukotriene receptor antagonist and an antiepileptic drug in which the antiepileptic action is enhanced. By administering the leukotriene receptor antagonist, particularly a planlukast hydrate which has less side effects and does not cause drug interaction, in combination with the antiepileptic drug, the effect on enhancing the antiepileptic action of the antiepileptic drug, for example an effect on reducing the dose of the antiepileptic drug, an effect on improving the side effects of the antiepileptic drug, an effect on reducing the frequency of epileptic seizure, an effect on improving the degree of epileptic seizure or the like, can be obtained. ® KIPO & WIPO 2009

Description

Antiepileptic action enhancer

The present invention relates to antiepileptic action enhancers and the like.

More specifically, the antiepileptic action enhancer of an antiepileptic drug comprising a leukotriene receptor antagonist and administered in combination with an antiepileptic drug, an antiepileptic agent having an enhanced antiepileptic action, including a leukotriene receptor antagonist and an antiepileptic drug and the drug It is about use.

Epilepsy is a chronic disease of the cerebrum caused by various causes and is characterized by repetitive seizures (epileptic seizure) resulting from the excessive activity of neurons in the cerebrum, and is characterized by abundant clinical And an abnormality of the inspection. Epilepsy is largely divided into localized epilepsy and general epilepsy according to the International Classification by the International Anti-epileptic Association (ILAE) (see Non-Patent Document 1). In addition, epileptic seizures are classified into generalized seizures and partial seizures according to the manner in which interstitial discharge spreads from the focal point of the seizures occurring in the cerebrum (see Non-Patent Document 2). Most epilepsy develops before age 15, and is known to be particularly prevalent in early childhood. The cause of epilepsy is currently unknown, but up to now, excitability of neurons, suppression of inhibitory systems, and channel abnormalities are considered to be part of the cause. Recently, there have been reports that the breakdown of the immune system is involved in its development (see Non-Patent Document 3).

Epilepsy is a neurological disease with a high prevalence of 0.5 to 1%. In the current clinical field, how to suppress epileptic seizures is an important task of treating epilepsy patients, and a treatment strategy is established with the highest priority among them. Among them, drug therapy using antiepileptic drugs has been given priority. It is commercially available. However, conventional antiepileptic drugs in these drug therapies have so-called refractory epilepsy, which is difficult to suppress seizures due to drug resistance, and thus there is a problem that a plurality of antiepileptic drugs must be used in combination for a long time. Moreover, due to this situation, many patients cannot avoid discontinuation due to the side effects of antiepileptic drugs. For example, carbamazepine, which is widely used for partial seizures, has side effects such as liver disorders, drowsiness, and skin rashes. Sodium valproate, which is frequently used for generalized seizures, has side effects such as weight gain, tremor, and hair loss. In particular, in pediatric epilepsy patients, these side effects are a very serious problem. In this regard, for patients already on the administration of one or more antiepileptic drugs, the combination of drugs used in the treatment of new epilepsy that can improve side effects by enhancing antiepileptic action and further reducing the dosage of antiepileptic drugs Development is required.

On the other hand, 4-oxo-8- [4- (4-phenylbutoxy) benzoylamino] -2- (tetrazol-5-yl) -4H-1-benzopyran hemihydrate (general name: franlukast hydrate) ) Is known as a leukotriene receptor antagonist (see Patent Document 1), and is a drug that is actually applied to clinical practice as a therapeutic drug for bronchial asthma and allergic rhinitis, and sufficient safety has been confirmed. Moreover, the use of franlukast hydrate as a therapeutic drug, such as a migraine (refer patent document 2), an exudative otitis media (refer patent document 3), is discovered. However, these documents have no description or suggestion that leukotriene receptor antagonists, among others, are effective for epilepsy, particularly that they can enhance antiepileptic action by using them in combination with existing antiepileptic drugs. none.

Patent Document 1: Japanese Patent Application Laid-Open No. 61-050977

Patent Document 2: Japanese Patent Application Laid-Open No. 2004-168718

Patent Document 3: International Publication No. 2005/58879

Non-Patent Literature 1 Epilepsia, Vol. 30, pages 389-399, 1989

Non-Patent Document 2: Epilepsia, Vol. 22, pages 489-501, 1981

Non-Patent Document 3 Clinical and De-elopement Immunology, Vol. 11, pp. 241 to 252, 2004

[Initiation of invention]

[Problems that the invention tries to solve]

In the treatment of epilepsy drugs, administration of a combination of a plurality of antiepileptic drugs and other drugs used for the treatment of epilepsy is generally performed, and side effects and drug resistance derived from the antiepileptic drugs are problematic. Therefore, there is an urgent need for the development of drugs or drugs that improve these problems.

[Means for solving the problem]

The present inventors have diligently studied to achieve the above object, and surprisingly, the anti-epileptic action of the antiepileptic drug is enhanced by using a combination of a leukotriene receptor antagonist, in particular, franc hydrate, and an antiepileptic drug described below. It was found and completed the present invention.

That is, the present invention

[1] an antiepileptic drug-enhancing agent of an antiepileptic drug, comprising a leukotriene receptor antagonist and administered in combination with an antiepileptic drug,

[2] an antiepileptic agent with enhanced antiepileptic action, including a leukotriene receptor antagonist and an antiepileptic drug,

[3] The antiepileptic agent according to the above [1] or [2], wherein the leukotriene receptor antagonist is franlukast hydrate,

[4] The antiepileptic agent according to the above [1] or [2], which is a dose reducing agent for an antiepileptic drug,

[5] The antiepileptic agent according to the above [4], which is a side effect improver of the antiepileptic drug,

[6] The antiepileptic agent according to the above [1] or [2], which is a recovery agent for epileptic seizures,

[7] The antiepileptic agent according to the above [1] or [2], which is a degree improving agent of epileptic seizures,

[8] The antiepileptic drug is phenobarbital, primidone, phenytoin, etotoin, trimetadione, acetazolamide, sultiam, ethoximide, acetylphenetolide, nitrazepam, diazepam, clonazepam, clovazam , The antiepileptic agent according to the above-mentioned [1] or [2] selected from the group consisting of carbamazepine, sodium valproate, zonisamide and gabapentin,

[9] The antiepileptic drug is at least one selected from the group consisting of phenobarbital, primidone, phenytoin, ethoximide, diazepam, clonazepam, clovazam, carbamazepine, sodium valproate and zonisamide. The antiepileptic agent described in 8],

[10] The antiepileptic agent according to the above [9], wherein the antiepileptic drug is at least one selected from the group consisting of phenobarbital, phenytoin, ethoximide, clonazepam, clovazam, carbamazepine, sodium valproate and zonisamide. ,

[11] The antiepileptic agent according to the above [3], wherein the daily dose of franlukast hydrate is about 112.5 mg to about 450 mg.

[12] The antiepileptic agent according to the above [3], wherein the daily dosage per kg of body weight of the franlukast hydrate patient is about 2 mg to about 10 mg.

[13] The antiepileptic agent according to the above [8], wherein the daily dose of phenytoin is from about 200 mg to about 300 mg,

[14] The antiepileptic agent according to the above [8], wherein the daily dose of phenytoin is from about 20 mg to about 300 mg,

[15] The leukotriene receptor antagonist is franlukast hydrate, wherein the daily dose of the hydrate is about 112.5 mg to about 450 mg, the antiepileptic drug is phenytoin, and the daily dose of the phenytoin is about 200 mg to about 300 mg. The antiepileptic agent according to [1] or [2],

[16] The leukotriene receptor antagonist is franlukast hydrate, and the daily dose of about 1 kg of body weight of the patient of the hydrate is about 2 mg to about 10 mg, the antiepileptic drug is phenytoin, and the daily dose of the phenytoin is about 20 mg to about The antiepileptic agent according to the above [1] or [2], which is 300 mg,

[17] The antiepileptic agent according to the above [8], wherein the daily dose of sodium valproate is about 300 mg to about 2500 mg,

[18] The leukotriene receptor antagonist is franlukast hydrate, the daily dose of the hydrate is about 112.5 mg to about 450 mg, the antiepileptic drug is sodium valproate, and the daily dose of the sodium valproate is about 300 mg. The antiepileptic agent according to the above [1] or [2], which is from about 2500 mg,

[19] The leukotriene receptor antagonist is franlukast hydrate, and the daily dose per kilogram of body weight of the hydrate is about 2 mg to about 10 mg, the antiepileptic drug is sodium valproate, and the daily dose of the sodium valproate The antiepileptic agent according to the above [1] or [2], which is about 300 mg to about 2500 mg,

[20] antiepileptic action enhancers of antiepileptic drugs, including leukotriene receptor antagonists,

[21] The enhancer according to the above [20], wherein the leukotriene receptor antagonist is franlukast hydrate and the daily dose of the hydrate is about 112.5 mg to about 450 mg.

[22] The enhancer according to the above [20], wherein the leukotriene receptor antagonist is franlukast hydrate, wherein the daily dosage per kg of body weight of the hydrate is about 2 mg to about 10 mg.

[23] In addition, anti-anxiety drugs, anticonvulsants, muscle relaxants, anti-clonic muscle spasms, carbonic anhydrase inhibitors, 5-lipoxygenase inhibitors, antibiotics, steroids, ACTH preparations, vitamin B6 preparations and TRH preparations The antiepileptic agent according to the above [1] or [2], which is administered by combining one or more selected species,

[24] A method for enhancing the antiepileptic action of an antiepileptic drug in a mammal, characterized by administering a leukotriene receptor antagonist and an antiepileptic drug to a mammal;

[25] use of a leukotriene receptor antagonist for producing an antiepileptic action enhancer of an antiepileptic drug, characterized in combination with an antiepileptic drug,

[26] An antiepileptic method with enhanced antiepileptic action in a mammal, comprising administering to a mammal a drug formed by combining a leukotriene receptor antagonist and an antiepileptic drug, and

[27] The present invention relates to the use of a drug that combines a leukotriene receptor antagonist and an antiepileptic drug to produce an antiepileptic agent with enhanced antiepileptic action.

[Effects of the Invention]

In the present invention, a leukotriene receptor antagonist, in particular one or two or more thereof, is combined with an antiepileptic drug by using a lanukast hydrate that has little side effects and does not cause drug interaction in combination with an antiepileptic drug. Compared with the effects of administration of antiepileptic drugs alone, the effect of enhancing antiepileptic action, e.g., reducing the dose of antiepileptic drugs, improving the side effects of antiepileptic drugs, reducing the number of epileptic seizures Effects, such as improving the degree of epileptic seizures, can be obtained.

Best Mode for Carrying Out the Invention

In the present invention, as a leukotriene receptor antagonist, for example, Franlukast hydrate, Montelukast sodium, Zafirlukast, Ablukast, Pobililuk ( Pobilukast, Sulukast, Iralukast Sodium, Verlukast, Ritolukast, Cinalukast, Pirodomast, Tomelucast ( Tomelukast), Doqualast, MK-571, LY-203647, WY-46016, WY-48422, WY-49353, WY-49451, RG-12553, MDL-43291, CGP-44044A, RG-14524, LY-287192, LY-290324, L-695499, RPR-105735B, WAY-125007, OT-4003, LM-1376, LY-290154, SR-2566, L-740515, LM-1453, CP-195494, LM- 1484, CR-3465, L-648051, RG-12525, RG-7152, SK & F-106203, SR-2640, WY-50295, MCC-847, BAY-x-7195, CGP-44826, FK-011, YM- 158, MEN-91507, KCA-757, RS-601, RS-635, S-36496, ZD-3523, DS-4574, AS-35, YM-57158, MCI-82 6, NZ-107, 4414-CERM, YM-16638, Wy-48252, Wy-44329, Wy-48090, VUF-4679, SM-11044, SC-39070, OT-3473, N-2401, LY-243364, L-649923, DP-1934, YM-17551, Wy-47120, VUF-K-8707, SK & F-88046, SK & F-101132, SK & F-102922, LY-137617, LY-163443, LY-302905, L-647438, L-708738, KY-234, FPL-55712, CP-288886, S-36527, CS-615, MDL-19301D, SCH-40120, ZD-3705, and the like. Preferably, it is franlukast hydrate, montelukast sodium, and zafirlukast, More preferably, it is franlukast hydrate. Moreover, such a leukotriene receptor antagonist can be manufactured by a well-known method. For example, the production of montelukast sodium can be carried out in accordance with the method described in European Patent Publication No. 0480717 and Zafirlukast in the specification of European Patent Publication No. 0199543.

The above leukotriene receptor antagonists are illustrative and are not limited to these. In addition, the leukotriene receptor antagonist includes not only what was discovered so far but also what is discovered in the future.

Franlukast hydrate used in the present invention is 4-oxo-8- [4- (4-phenylbutoxy) benzoylamino] -2- (tetrazol-5-yl) -4H-1-benzopyran of formula (1). Hemihydrate.

The production of franlukast hydrate can be carried out in accordance with the methods described in the specifications, such as, for example, Japanese Patent Application Laid-Open No. 61-050977, Japanese Patent Application Laid-Open No. 03-095144, and Japanese Patent Application Laid-Open No. 05-279305.

In the present invention, epilepsy means a chronic disease of the cerebrum characterized by seizure brain dysfunction caused by excessive discharge of neurons. Specifically, according to the international classification by the International Association of Antiepileptic Associations (ILAE): (1) Localization-related (focal, local); epilepsies, generalized epilepsies, generalized epilepsies, epilepsies with indefinite focal or general epilepsies, or epilepsies with specific epidermal syndromes, or specific syndromes. (Epilepsia, vol. 30, pages 389-399, 1989).

Localization-related epilepsy can be further divided into (1) idiopathic localization-related epilepsy, (2) symptomatic localization-related epilepsy, and (3) cryptogenic localization-related epilepsy. Idiopathic localized epilepsy includes, for example, Benign 양성 childhood epilepsy with centrotemporal spike in the central temporal region, Childhood epilepsy with occipital paroxysms, and primary reading epilepsy in the larynx. epilepsy). Symptomatic localized epilepsy includes, for example, children with chronic progressive persistent partial epilepsy (Kogenjicov syndrome) (Shronic syndrome), and epilepsy with specific seizure-induced modalities (Kojewnikow® s syndrome). seizures with specific modesofofprecipitation, temporal lobe epilepsy, frontal lobe epilepsy, parietal lobe epilepsy, occipital lobe epilepsy.

General epilepsy can be further divided into (1) idiopathic general epilepsy, (2) latent or symptomatic general epilepsy, and (3) symptomatic general epilepsy. Idiopathic general epilepsy includes, for example, Benign neonatal familial conｖulsions, Benign neonatal cunｖulsions, Benign myoclonic epilepsy in infancy, childhood Child food 노 abilesepilepsy, juvenile absence epilepsy, juvenile myoclonic epilepsy (Juvenile myoclonic epilepsy, impulseｖe petit mal) Epilepsy (Epilepsy with grand mal seizures on awakening), other idiopathic general epilepsy (Other generalized idiopathic epilepsies not defined aboｖe), epilepsy with specific seizure-induced modalities (Epilepsies with seizures precipitated by actimodesationof In latent or symptomatic general epilepsy, for example, West syndrome (infantile epilepsy), Lennox-Gastaut syndrome (Epilepsy) with myoclonic-astatic seizures, epilepsy and myoclonic absences. Symptomatic general epilepsy includes, for example, early myoclonic encephalopathy, early childhood interstitial encephalopathy (Otahara syndrome) with sudden suppression (Early infantile epileptic encephalopathy with suppression burst). Symptomatic general epilepsy (Other symptomatic generalized epilepsies not defined above) and specific syndromes.

Examples of epilepsy, whether focal or general, include neonatal seizures, infantile severe myoclonial epilepsy (Dravet syndrome) (Severe myolonic epilepsy in infancy (Dravet syndrome)), and persistent cryowaves during slow wave sleep. Epilepsy (Epilepsy with continuous spike-wavesduring slow wave sleep), Acquired interstitial aphasia (Landau-Kleffner-syndrome) (Landau-Kleffner-syndrome), other microcrystalline epilepsy (Other undetermined epilepsies) not defined above).

Special syndromes include, for example, only acute metabolic or addictive disorders such as febrile convulsions, isolated seizures or isolated epilepticus (Isolated seizures or isolated status epilepticus), alcohol, drugs, pregnancy addiction, and non-ketone hyperglycemia. Seizures, occurring, only, when, there, isis, acute, metabolic, or toxic, event, due, tofactors, such as asalcohol, drugs, eclampsia, and nonketotic hyperglycemia.

In the present invention, as epilepsy, symptomatic localized epilepsy, symptomatic generalized epilepsy, and the like, and symptomatic localized epilepsy are preferably temporal lobe epilepsy, frontal lobe epilepsy, parietal lobe epilepsy, or occipital lobe epilepsy. As symptomatic general epilepsy, West syndrome, Lennox-Gasto syndrome, etc. are preferable.

In addition, epilepsy in the present invention is classified into pediatric epilepsy, which is epilepsy that occurs in infancy or childhood, and adult epilepsy, which occurs in adults, depending on the onset time of the epilepsy regardless of the kind of epilepsy classified as described above. Preferably pediatric epilepsy.

Furthermore, in the present invention, epilepsy can be divided into those due to genetic predisposition (congenital), due to organic lesions of the brain (acquired), and the like. In the present invention, epilepsy resulting from organic lesions of the brain is preferred. Examples of the disease causing the lesion include cerebral edema (e.g., pregnancy intoxication, hypertensive encephalopathy, etc.), cerebral hypoxia (e.g., Adams-Stokes syndrome, apnea, carbon monoxide poisoning, carotid sinus hypersensitivity, cerebral infarction, etc.). Cerebral trauma (e.g., birth injury, cranial fractures), infections of the central nervous system (e.g. AIDS, brain abscesses, encephalitis, encephalitis (e.g. Rasmussenmusencephalitis, acute disseminated encephalomyelitis) Autoimmune encephalitis)), tropical fever malaria, meningitis, neurosyphilis, rabies, tetanus, toxoplasmosis, etc., dilated brain lesions (e.g. intracranial bleeding, cancer, etc.), abnormal high fever (e.g., acute systemic Infectious diseases, heat stroke, etc., metabolic disorders (e.g., hyperglycemia, hypernatremia, hypocalcemia, hypoglycemia, hypomagnesemia, hyponatremia, parathyroidism, phenylketonuria, etc.), convulsive or toxic drugs (e.g. , Egg Has come, camphor, keulrorokin, cocaine, lead, pentylene tetrazole, diseases which are caused by the use of a peak toxin, strychnine, etc.), and the like. Preferably, epilepsy resulting from brain trauma, infection of the central nervous system, and the like can be given. More preferably, epilepsy due to infection of the central nervous system, and especially encephalitis is mentioned.

In the present invention, the symptoms of epilepsy include epileptic seizures and the like. Epilepsy seizures are roughly classified into partial (focal, local) seizures and generalized seizures as described above (Epilepsia, vol. 22, pages 489-501). , 1981). Partial seizures include, for example, Simple partial seizures, Complex Partial seizures (eg, automatism, etc.), Seizures that develop from partial seizures to secondary generalized seizures. (Parial seizures eｖolｖing to secondarily generalized seizures). General seizures include, for example, absencesseizures, atypical absence seizures, myoclonus seizures, seizure seizures, tonic seizures, and tonic seizures. Seizures (Tonic-clonic seizures), and seizure (Atonic seizures) (Astatic). Such epileptic seizures also include seizure-mediated epileptic seizures in which the epileptic seizure continues and continues, as is apparent to those skilled in the art.

In the present invention, among the antiepileptic drugs, for example, phenobarbital, primidone, hydantoin-based antiepileptic drugs, phenytoin, phosphphenytoin, etotoin (ethotoin), phenytoin phenobarbital compounding agent (phenytoin + phenobarbital, for example, phenytoin phenobarbital (2: 1) compounding agent, phenytoin phenobarbital (2.5: 1) compounding agent, phenytoin phenobarbital (3: 1 compounding agent) , Trimethadione as an oxazolidine antiepileptic drug, acetazolamide, sulthiame, zonisamide, topiramate, succimide as a sulfonamide antiepileptic drug Ethosuximide as an antiepileptic drug, acetylpheneturide as an acetylurea-based antiepileptic drug, nitrazepam and diazepam as a benzodiazepine antiepileptic drug zepam, clonazepam, clobazam, carbamazepine as an iminostilbene antiepileptic drug, oxcarbazepine, valproic acid as a branched fatty acid antiepileptic drug Sodium valproate (sodium 프로 valproate), divalproex sodium (dialproex sodium, a 1: 1 formulation of valproic acid and sodium valproate), an amino acid derivative-based antiepileptic drug, gabapentin, pregabalin ( pregabalin, vigabatrin, tiagabine, lacosamide, and other antiepileptic drugs such as lamotrigine, felbamate, levetiracetam, and lupinamide (levinracetam) rufinamide, losigamone, carisbamate, ganaxolone, lacosamide, and the like.

Among these antiepileptic drugs, preferably, phenobarbital, primidone, phenytoin, etotoin, trimetadione, acetzolamide, sulfatim, ethoximide, acetylphenetolide, nitrazepam, diazepam, clonazepam, Clovazam, carbamazepine, sodium valproate, zonisamide, gabapentin, and the like, and more preferably phenobarbital, primidone, phenytoin, ethoximide, diazepam, clonazepam, clovazam, carbamazepine , Sodium valproate, zonisamide, and particularly preferably phenobarbital, phenytoin, ethoximide, clonazepam, clovazam, carbamazepine, sodium valproate, zonisamide and the like.

Moreover, when paying attention to the action which an antiepileptic drug has, in this invention, as an antiepileptic drug which has a sodium channel inhibitory effect, it is a phenytoin, a phenytoin phenobarbital compounding agent (phenytoin + phenobarbital, For example, a phenytoin phenobarbital (2: 1) compounding agent, a phenytoin phenobarbital (2.5: 1) compounding agent, a phenytoin phenobarbital (3: 1 compounding agent), phosphphenytoin, carbamazepine, Oxcarbazepine, Valproic Acid, Sodium Valproate, Divalproex Sodium, 1: 1 Formulation of Valproic Acid and Sodium Valproate, Lamotrigine (lamotrigine), zonisamide, felbamate, topiramate, rufinamide, antiepileptic drugs with calcium channel inhibitory activity, ethosuximide, lamotrigine Antiepileptic drug with motrigine, zonisamide, calcium channel α2δ inhibitory effect, gabapentin, pregabalin, GABA (GammaAmino Butyric Acid) As an epileptic, valproic acid, sodium valproate, sodium divalproex (sodium, 1: 1 formulation of valproic acid and sodium valproate), phenobarbital, and phenytoin Phenobarbital compounding agent (Phenytoin + phenobarbital, for example, phenytoin phenobarbital (2: 1) compounding agent, phenytoin phenobarbital (2.5: 1) compounding agent, phenytoin phenobarbital (3: 1 compounding agent), clonazepam ( antiepileptic drug with inhibitors of clonazepam, primidone and GABA aminotransferase, vigabatrin, antiepileptic drug with inhibitory effect on GABA reuptake, tiagabine, GABA An antiepileptic drug with receptor-regulating action, nitrazepam, losigamone, and an antiepileptic drug with GABA A receptor action. Ganaxolone, an antiepileptic drug with carbonic anhydrous dehydrogenase inhibitory action. Amidazolamide, an antiepileptic drug with benzodiazepine receptor inhibitory action, diazepam, clobazam, an antiepileptic drug with muscarinic receptor action action, levetiracetam, and other etotoin as antiepileptic drug (ethotoin), trimethadione (trimethadione), sulthiame, acetylpheneturide (acetylpheneturide), lacosamide (carcosbamate), lacosamide (lacosamide) and the like.

The above antiepileptic drugs are examples and are not limited to these. In addition, antiepileptic drugs include not only those found to date but also those found in the future.

In the present invention, by using a combination of a leukotriene receptor antagonist and an antiepileptic drug (hereinafter sometimes abbreviated as drug combination of the present invention), for example, to enhance the antiepileptic action of the antiepileptic drug. It is possible to obtain effects such as things. Here, a leukotriene receptor antagonist and an antiepileptic drug may be used individually by 1 type, or may be used in combination of 2 or more types as appropriate. Also disclosed herein is the prevention and / or treatment of epilepsy and / or symptomatic improvement which are achieved by containing a leukotriene receptor antagonist. The drug does not use an antiepileptic drug in combination but uses only a leukotriene receptor antagonist to prevent and / or treat and / or improve symptoms of epilepsy. In this case, the dosage of the leukotriene receptor antagonist may be based on the description of the dosage of the later-genrucastate hydrate, montecaste or zafirlukast.

The drug combination of the present invention may be administered in the form of a formulation in which a leukotriene receptor antagonist, an antiepileptic drug and a commonly used additive (formulation base) are combined in one formulation, or administered as a separate formulation. That is, you may administer as a combination agent. The drug combination of the present invention is preferably administered as a combination. When administering as a combination agent, you may administer simultaneously, and you may administer with time difference. In addition, when administering at a time difference, the leukotriene receptor antagonist may be administered first and the antiepileptic drug may be administered later, the antiepileptic drug may be administered first, and the leukotriene receptor antagonist may be administered later. The number may be the same or different. In addition, each method of administration may be oral or parenteral, when the leukotriene receptor antagonist is orally administered, the antiepileptic drug may be oral or parenteral, and when the leukotriene receptor antagonist is administered parenterally, The antiepileptic drug may be oral or parenteral, and when the leukotriene receptor antagonist is orally administered, the antiepileptic drug is preferably orally administered. In the drug combination of the present invention, the weight ratio of the leukotriene receptor antagonist and the antiepileptic drug is not particularly limited.

In the present invention, "comprising a leukotriene receptor antagonist and administered in combination with an antiepileptic drug" means that the leukotriene receptor antagonist and an antiepileptic drug are combined and administered as separate agents, that is, administered as a combination agent. do. When administered as a combination, as described above, may be administered at the same time or at a time difference, and when administered at a time difference, the leukotriene receptor antagonist is administered first and then the antiepileptic drug or the antiepileptic drug first. And leukotriene receptor antagonists may be administered later. In addition, each method of administration is oral or parenteral as described above, when the leukotriene receptor antagonist is orally administered, the antiepileptic drug is oral or parenteral, and when the leukotriene receptor antagonist is parenterally administered, The epileptic may be oral or parenteral, and when the leukotriene receptor antagonist is administered orally, the antiepileptic drug is preferably administered orally.

In the present invention, "comprising a leukotriene receptor antagonist and an antiepileptic drug" means the form of the compounding agent which combined the leukotriene receptor antagonist, an antiepileptic drug, and the additive (formulation base) generally used. In addition, the administration method may be oral administration or parenteral administration as described above in this case.

In the present invention, "an antiepileptic action enhancer of an antiepileptic drug including a leukotriene receptor antagonist" means a drug that enhances the antiepileptic action of an antiepileptic drug used in combination with a leukotriene receptor antagonist and an antiepileptic drug. . In this case, the antiepileptic drug used in combination with the leukotriene receptor antagonist may be administered in the form of the combination or combination, preferably administered as a combination. In the case of administration as a combination, administration can be carried out at the same time or at a time difference as described above. In addition, the administration method may be oral administration or parenteral administration as described above in this case.

In the present invention, "combination of a leukotriene receptor antagonist and an antiepileptic drug to a mammal" means a combination of an antiepileptic drug used in combination with a leukotriene receptor antagonist and administration to late mammals. In this case, the antiepileptic drug used in combination with the leukotriene receptor antagonist may be administered in the form of a combination or a combination as described above, and is preferably administered in a combination. In the case of administration as a combination, administration may be performed simultaneously or at a time difference as described above. In addition, the administration method may be oral administration or parenteral administration as described above in this case.

In the present invention, the dosage as a compounding agent or a combination used in combination with a leukotriene receptor antagonist and an antiepileptic drug varies depending on age, weight, symptoms, therapeutic effect, administration method, treatment time, and the like. By oral administration once or several times a day in the range of 1 mg to 5000 mg each per adult. For parenteral administration, one to several parenteral administrations per day range from 0.1 mg to 500 mg each, once per adult. Parenteral administration is administered intravenously in the range of 1 hour to 24 hours per day for intravenous administration.

The dosage of franlukast hydrate used in combination or single administration of the drug of the present invention is, for example, about 25 mg to about 2500 mg, preferably about 112.5 mg to about 450 mg, more preferably, per day per adult. Is about 225 mg to about 450 mg.

As a method of administering franlukast hydrate, oral administration is preferable, and it is administered orally once to several times a day, preferably once to four times a day, more preferably once or twice a day. It may also be administered orally in one to several capsules per time, preferably orally in one or two capsules per time.

In addition, as a dosage for the pediatric pediatric hydrate, about 2 mg to about 10 mg per 1 kg body weight of the pediatric patient is preferred, more preferably about 5 mg to about 8 mg per kg of body weight, even more preferred Preferably about 7 mg / kg body weight. However, the maximum daily dose is preferably about 450 mg. In addition, for pediatric patients weighing 12 kg or more and less than 18 kg, it is preferable to administer Franlukast hydrate at about 50 mg to about 100 mg per day, more preferably about 50 mg or about 100 mg. For pediatric patients with a body weight of at least 18 kg and less than 25 kg, it is preferred to administer Franlukast hydrate at about 70 mg to about 140 mg per day, more preferably about 70 mg or about 140 mg. For pediatric patients weighing 25 kg or more and less than 35 kg, it is preferred to administer from about 100 mg to about 200 mg per day, more preferably about 100 mg or about 200 mg of franlukast hydrate. For pediatric patients weighing 35 kg or more and less than 45 kg, it is preferred to administer from about 140 mg to about 280 mg per day of lanlukast hydrate, more preferably about 140 mg or about 280 mg. In addition, in order to administer a franlukast hydrate to a child, it is preferable to use the dry syrup (for example, brand name: Onon dry syrup) of franlukast hydrate.

Examples of the dose and administration method of zafirlukast used in combination or single administration of the drug of the present invention include, for example, a method of orally administering about 20 mg to about 100 mg twice a day. Of course, depending on the age and symptoms can be increased or decreased appropriately.

Examples of the dosage and administration method of montelukast used in the combination or single administration of the drug of the present invention include, for example, a method of orally administering about 8 mg to about 12 mg once a day in an adult. In children, a method of orally administering about 3 mg to about 7 mg once a day is provided.

The dosage and administration method of the antiepileptic drug used in the drug combination of the present invention are preferably used in the clinic, and the like. The dosage and administration method of each antiepileptic drug are exemplified below.

Examples of the dose and administration method of sodium valproate used in the drug combination of the present invention include a method of orally administering about 300 mg to about 2500 mg twice or twice a day. However, depending on the age and symptoms can be appropriately increased or decreased.

Dosage and administration method of zonamidamide used in combination with the drug of the present invention, in adults, orally administered from about 100 mg to about 200 mg once daily or divided into two or three times a day for the first day, Thereafter, the dose is increased every 1 to 2 weeks, usually about 200 mg to about 400 mg per day, orally administered once or twice or three times a day, and up to about 600 mg per day. How to do it. In children, between about 2 mg / kg for the first day (mg / kg means the same number of units per kg of body weight below) to about 4 mg / kg once a day or twice a day, or Oral administration in three divided doses, followed by an increase every 12 weeks, usually from about 4 mg / kg to about 8 mg / kg per day, orally administered once or twice or three times a day, up to 1 The daily dose is up to about 12 mg / kg.

As the dosage and method of administration of phenytoin used in the combination of the present invention, for adults, a method of orally administering about 200 mg to about 300 mg once a day or divided twice or three times a day may be used. have. In children, it is administered orally in the range of about 20 mg to about 300 mg per day, more specifically about 100 mg to about 300 mg per day for students, about 50 mg to about 200 mg per day for infants, In this case, there is a method of orally administering about 20 mg to about 100 mg per day or divided into two or three times daily.

The dosage and method of administration of clovazam used in combination with the drug of the present invention start at about 10 mg per day and gradually increase according to symptoms, and the maintenance amount is about 10 mg to about 30 mg per day. Once a day or divided into two or three times a day orally administered, depending on the symptoms are appropriately increased and decreased, the maximum amount per day up to about 40 mg, and the like. In children, starting with the administration of about 0.2 mg / kg per day, gradually increasing according to symptoms, and the maintenance amount is about 0.2 mg / kg to about 0.8 mg / kg once a day or 2 or 3 times a day. Divided orally, divided orally, depending on the symptoms are appropriately increased, the maximum daily dose is about 1.0mg / kg and the like.

As a dosage and a method of administering clonazepam used in the drug combination of the present invention, in the case of an adult or a child, about 0.5 mg to about 1 mg per day is administered once or divided into two or three times a day, Thereafter, depending on the symptoms, the dose is gradually increased until the desired effect is obtained, and the maintenance amount is about 2 mg to about 6 mg per day divided by 1 to 3 times per day orally administered. In infants or young children, about 0.025 mg / kg of body weight per day is administered once a day or divided into two or three times a day, and then gradually increased until the desired effect is obtained depending on the symptoms. There is a method of orally administering about 0.1 mg per 1kg of body weight once a day or divided into two or three times a day.

As a dosage and a method of administration of carbamazepine used in combination with the drug of the present invention, in adults, about 200 mg to about 400 mg per day are divided once or twice a day to initiate oral administration, and gradually depending on symptoms. There is usually a method of increasing the amount to about 600 mg per day, up to about 1200 mg per day. In children, depending on age and symptoms, there is usually a method of orally administering about 100 mg to about 700 mg once a day or divided into several times.

Examples of the dose and administration method of phenobarbital used in the drug combination of the present invention include a method of orally administering about 30 mg to about 200 mg once a day to 4 times per day for an adult. In the case of children, depending on the age and symptoms, there is a method of orally administering once or a day divided by a moderate increase or decrease.

Examples of the dose and administration method of ethoximemid used in combination with the drug of the present invention include a method of orally administering about 450 mg to about 1000 mg twice or twice a day for adults. In children, about 150 mg to about 600 mg per day may be administered orally once a day or divided into two or three times a day.

In addition, as is apparent to those skilled in the art, the dosage of the antiepileptic drugs described above is not limited to the examples, and may be appropriately increased or decreased depending on the age, symptoms, combination with the combination drug, and the like.

The method of administering the antiepileptic drug used in combination with the drug of the present invention is not particularly limited, but oral administration, intravenous administration, rectal administration and the like are preferred.

As a combination of a leukotriene receptor antagonist and an antiepileptic drug for use in the drug combination of the present invention, for example, a leukotriene receptor antagonist, franlukast hydrate, phenobarbital, primidone, phenytoin, etotoin, trimetadione 1 selected from the group consisting of acetazolamide, sultiam, ethoximide, acetylphenetolide, nitrazepam, diazepam, clonazepam, clovazam, carbamazepine, sodium valproate, zonisamide and gabapentin Combinations with species or more, more preferably, for example, franlukast hydrate as a leukotriene receptor antagonist, phenobarbital, primidone, phenytoin, ethoximide, diazepam, clonazepam, clovazam, Combination with one or more selected from the group consisting of carbamazepine, sodium valproate and zonisamide, in particular wind Directly, for example, a group consisting of franlukast hydrate as a leukotriene receptor antagonist and phenobarbital, phenytoin, ethoximide, clonazepam, clovazam, carbamazepine, sodium valproate and zonisamide There is a combination with one or more selected from. Here, as a preferable embodiment in the case of using 2 or more types of the said antiepileptic drugs, for example, in combination with the zonamide, sodium valproate, phenytoin and clovazam, sodium valproate, phenytoin and Combinations with clonazepam, combinations with phenytoin and carbamazepine, combinations with sodium valproate and phenobarbital, combinations with phenytoin, carbamazepine and phenobarbital, and the like. As will be apparent to those skilled in the art, the composition of two or more antiepileptic drugs is not limited to those listed here, and the composition usually used for the treatment of epilepsy can also be used in combination with the drug of the present invention.

In addition, the dosage of each drug in the preferable composition used for the combined drug use of the present invention illustrated above is clear to those skilled in the art, the dosage of the above-mentioned franlukast hydrate in adults and the adult of each antiepileptic drug. It can apply combining the dose in or the dose in children of franlukast hydrate, and the dose in children of each antiepileptic drug. Specifically, a combination of (1) a daily dose of franlukast hydrate of about 112.5 mg to about 450 mg, and a daily dose of phenytoin of about 200 mg to about 300 mg, (2) franlukast A combination of from about 2 mg to about 10 mg per day of body weight of the patient of hydrate and from about 20 mg to about 300 mg of phenytoin per day, (3) 1 of franlukast hydrate A combination with a daily dose of about 112.5 mg to about 450 mg and a dose of sodium valproate from about 300 mg to about 2500 mg, (4) daily administration per kg body weight of the patient of franlukast hydrate A dose of from about 2 mg to about 10 mg and a dose of sodium valproate from about 300 mg to about 2500 mg, (5) a daily dose of franlukast hydrate from about 112.5 mg to about 450 mg, the daily dose of phenytoin is from about 200 mg to about 300 mg, Combination with a dosage of about 300 mg to about 2500 mg and (6) a daily dose of about 2 mg to about 10 mg per kg body weight of the patient of franlukast hydrate, with a daily dose of phenytoin The amount is about 20 mg to about 300 mg, and the combination of the sodium valproate dose is about 300 mg to about 2500 mg, and the like, but the present invention is not limited to such a combination.

Of course, the dosage of each drug used in the combination of the above-described drugs of the present invention may vary depending on various conditions, for example, age, sex, weight, symptoms, types of antiepileptic drugs to be combined, and the like. A small amount may be sufficient, and administration may be necessary beyond the range.

The effect brought about by the combined drug of the present invention is a synergistic effect produced by using a combination of a leukotriene receptor antagonist, in particular, a franlukast hydrate and an antiepileptic drug, that is, an antiepileptic effect enhancing effect. As an antiepileptic effect enhancing effect, for example, the dosage of antiepileptic drugs, the improvement of side effects of antiepileptic drugs, the reduction of the number of epileptic seizures, the improvement of the degree of epileptic seizures, the inhibition of drug resistance, the developmental disorders in pediatric patients with epilepsy Improvement, inhibition of brain function decline, inhibition of neuronal cell death, and inhibition of cytokines leading to excitatory toxicity. The effects enumerated here are not limited to one type but may express two or more types simultaneously.

In the present invention, an antiepileptic action-enhancing agent is an agent that enhances and / or promotes the effect thereof in comparison with the effect of administration of only one or two or more combination antiepileptic drugs, and / or drug efficacy. It means an agent that has an effect of shortening the timing of expression, that is, a rapid drug expression effect.

In the present invention, as an antiepileptic action enhancer, a dose reducing agent of an antiepileptic drug, an agent for improving side effects of an antiepileptic drug, an agent for reducing the number of epileptic seizures, an agent for improving the degree of epileptic seizures, an inhibitor of drug resistance, and a pediatric epilepsy patient Also included are amelioration of developmental disorders, inhibitors of brain function decline, inhibitors of neuronal cell death, and inhibitors of cytokines that induce excitatory toxicity.

In the present invention, the dose reducing agent of the antiepileptic drug is compared with the effect of the administration of only one or a combination of two or more antiepileptic drugs, and the drug is sufficiently maintained without degrading the expected effect. By an agent that shows the effect of reducing the dosage of the epileptic drug. By reducing the dose of the antiepileptic drug used in combination with the drug of the present invention, it is possible to expect desirable effects such as side effects reduction and avoidance derived from the antiepileptic drug.

In the present invention, the side effect improving agent of an antiepileptic drug means a drug having an effect of improving various undesirable actions that may occur due to treatment with the antiepileptic drug. Such side effects include, for example, liver disorders, drowsiness, skin rashes, weight gain, tremors, hair loss, impaired dysfunction, gingival hyperplasia, aplastic anemia, headache, thrombocytopenia, diplopia, dizziness, nystagmus, gastrointestinal disorders, bad feelings, Colloquial disorders, leukocyte reduction, granulocyte reduction, dermatitis, systemic lupus erythematosus (SLE), pruritus, perceptual abnormalities, megaloblastic anemia, osteopenia, hairy, adenoma, vomiting, confusion.

In the present invention, the agent for reducing the number of epileptic seizures is to reduce the number of epileptic seizures without increasing the dose of the antiepileptic drug, compared with the effect of administration of only one or two or more antiepileptic drugs. Means an agent having an effect.

In the present invention, the agent for improving the degree of epileptic seizures improves the degree of symptoms of an epileptic seizure without increasing the dosage of the antiepileptic drug in comparison with the effect of administration of only one or two or more antiepileptic drugs. It means a formulation having an effect to make. Symptoms of such epileptic seizures include, for example, body stiffness, convulsions, exhaustion, abnormal feelings, loss of consciousness, conscious turbidity, loss of consciousness, numbness, tinnitus, hallucinations, hallucinations, facial paleness, flushing, Hair, pupillary band, involuntary movement of the eyelids, respiratory depression, saliva secretion, dizziness, sweating, vomiting, memory disorders, cognitive impairment, loud screaming, nodding repeatedly, moving hands and feet violently Etc. In addition, improving the degree of symptoms of an epileptic seizure means a reduction in the intensity of the symptoms of the epileptic seizure, a shortening of time, a decrease in the number of times, and the like.

In the present invention, a developmental disorder means a developmental disorder that causes epilepsy, a developmental disorder that merges with epilepsy, or a developmental disorder that occurs after an epileptic seizure. Examples of such a developmental disorder include a learning disorder (Learning (Disorder: LD). , Cerebral palsy, mental retardation, general developmental disorders (eg, autism, Asperger's syndrome, etc.), attention deficit hyperactivity disorder (Attention Deficit / Hyperactivity Disorder: ADHD).

In the present invention, as a method for evaluating the antiepileptic action by the drug combination of the present invention, a known evaluation method which is generally used clinically can be cited. For example, the number of epileptic seizures and the degree of observation, the brain wave Examination (Electroencephalogram: EEG), ADL (Daily Activities: ofDaily Living) Assessment Methods (e.g., Barthhel Index, Functional Independence Measure (FIM)), Intelligence Index (Intelligence) Quotient: IQ).

In the present invention, "prevention" refers to suppressing the expression of an epileptic seizure by administering when it detects a precursor of an epileptic seizure, and by "treatment" to prevent recurrence of an epileptic seizure. "Improved symptoms" means reducing or decreasing the number, extent, and the like of epileptic seizures, and "drug interaction" refers to the absorption, distribution, protein binding, metabolism, and excretion of drugs when used in combination. It may have a negative effect on the drug, increase or reduce the pharmacological action of the drug, increase the side effects, the appearance of new side effects or worsening of the original disease.

[toxicity]

The toxicity of franlukast hydrate used in the drug combination of this invention was extremely low, and it was confirmed that it is safe enough to be used as a medicine. For example, the minimum lethal dose as an acute toxicity of franlukast hydrate was 2000 mg / kg or more when orally or subcutaneously administered to mice and rats (all males).

[Application to pharmaceutical products]

By using the drug of the present invention in combination with the antiepileptic drug alone in the treatment of epilepsy, a useful effect of enhancing antiepileptic action can be obtained as described above.

The drug combination of the present invention can be applied to mammals (humans and non-human animals (for example, monkeys, sheep, cattle, horses, dogs, cats, rabbits, rats, mice, etc.) and the like. In particular, the effect of enhancing the antiepileptic action by oral or parenteral administration to a mammal, preferably a human, for example, reducing the dose of antiepileptic drugs, reducing the number of epileptic seizures, The effect which improves the grade can be acquired. Even when the leukotriene receptor antagonist is administered alone, the effect of preventing, treating and / or improving symptoms of epilepsy can be expected. In addition, leukotriene receptor antagonists can be used as an adjuvant of antiepileptic drugs.

The adjuvant of the antiepileptic drug herein corresponds to an agent having an effect caused by the combination of the drug of the present invention, that is, an antiepileptic drug enhancing agent of the antiepileptic drug.

The drug combination of the present invention may furthermore be used to: 1) supplement and / or enhance the effects of the drug combination of the present invention, 2) the dynamics, improvement of absorption, reduction of dosage, and / or 3) according to the drug combination of the present invention. In order to reduce the side effects of the drug combination of the present invention, it may be administered as a combination drug in combination with other drugs.

The other drug may be a low molecular compound, a polymer of a polymer, a polypeptide, a polynucleotide (DNA, RNA, gene), an antisense, a decoy, an antibody, a vaccine, or the like. Dosages of other drugs may be appropriately selected based on the dose being used clinically. In addition, the ratio of the dose of a leukotriene receptor antagonist and an antiepileptic drug to the dose of another drug in the combined drug use of the present invention is determined by the age and weight of the subject, the method of administration, the time of administration, the target disease, symptoms, combination You can choose the enemy. For example, the dosage of the other drug may be 0.01 to 100 parts by weight based on 1 part by weight of the total dosage of the leukotriene receptor antagonist and the antiepileptic drug in the drug combination of the present invention. The other drug can be administered from the following homologous and heterologous groups, optionally in combination of one or two or more thereof in an appropriate ratio.

Examples of the other drugs include anti-anxiety drugs, anticonvulsants, muscle relaxants, anti-interstitial muscle spasms, carbonic anhydrous dehydrogenase inhibitors, 5-lipoxygenase inhibitors, antibiotics, steroids, and adrenal cortex stimulating hormones ( Adrenocorticotropic hormone (ACTH) preparations, vitamin B6 preparations, and thyrotropin releasing hormone (TRH) preparations.

-오리자놀(

-oryzanol), 알프라졸람(alprazolam), 에티졸람(etizolam), 옥사제팜(oxazepam), 옥사졸람(oxazolam), 구연산 탄도스피론(tandospirone　citrate), 클록사졸람(cloxazolam), 클로티아제팜(clotiazepam), 클로라제프산 이칼륨(clorazepate　dipotassium), 클로르디아제폭사이드(chlordiazepoxide), 디아제팜(diazepam), 토피소팜(tofisopam), 트리아졸람(triazolam), 파모산 하이드록시진(hydroxyzine　pamoate), 염산 히드록시 진(hydroxyzine　hydrochloride), 프라제팜(prazepam), 플루디아제팜(fludiazepam), 플루타졸람(flutazolam), 플루토프라제팜(flutoprazepam), 플루니트라제팜(flunitrazepam), 브로마제팜(bromazepam), 멕사졸람(mexazolam), 메다제팜(medazepam), 로플라제프산 에틸(ethyl　loflazepate), 로라제팜(lorazepam) 등이 있다.As an anti-anxiety medicine, for example,

-Orizanol (

-oryzanol, alprazolam, etizolam, oxazepam, oxazolam, tandospirone citrate, cloxazolam, clotiazepam ), Clorazepate dipotassium, chlordiazepoxide, diazepam, tofisopam, triazolam, hydroxyzine pamoate, hydrochloric acid Hydroxyzine hydrochloride, prazepam, fludiazepam, flutazolam, flutoprazepam, flunitrazepam, bromazepam, mexazole Mexazolam, medazepam, ethyl loflazepate, lorazepam, and the like.

Examples of anticonvulsants include carbamazepine, phenytoin, ethotoin, phenobarbital, mephobarbital, metabital and primidone. ), Trimethadione, acetylpheneturide, ethosuximide, sodium valproate, acetazolamide, zonisamide, diazepam (diazepam), clonazepam (clonazepam) and the like.

As a muscle relaxant, for example, tolperisone hydrochloride, chlorzoxazone, chlormezanone, metocarbamol, methprobamate, phenprobamate, mesylic acid fridi Phenol (pridinol mesilate), chlorphenesin carbamate, baclofen, eperisone hydrochloride, afloqualone, tizanidine hydrochloride, alkauchlor chloride Aluminum (alcuronium chloride), suxamethonium chloride (chloride), tubocurarine chloride (chloride), dantrolene sodium (sodium), pancuronium bromide (bromide), bromide (meth) bromide Butyl bromide scopolamine (scopolamine butylbromide).

As an anti-myelo muscle spasms, piracetam etc. are mentioned, for example.

Examples of carbonic anhydrous dehydrogenase inhibitors include acetazolamide, diclofenamide, brinzolamide, metazolamide, dozolamide hydrochloride, and the like. have.

As 5-lipoxygenase inhibitor, ABT-761, A-64077, A-78773, etc. are mentioned, for example.

Examples of antibiotics include mynocycline, doxycycline, chlortetracycline, oxytetracycline, tetracycline, and the like.

Examples of steroids include amcinonide, difluprednate, dipropionate betamethasone, dipropionate, dexamethasone, triamcinolone, triamcinolone acetonide, and triamcinolone hydroacetic acid. Hydrocortisone, mometasone furoate, fluorosinide, fluocinonide, prednisolone, clobetasol propionate, propionate dexamethasone propionate depropionate ), Betamethasone, methylprednisolone, sodium dexamethasone (dexamathasone sodium phosphate), sodium betamethasone sodium phosphate, betamethasone valerate, diacetate diacelacone diacetate Dexamethasone (dexameth asone acetate, paramethasoneacetate, and the like.

Examples of the ACTH agent include tetracosactide acetate and the like.

Examples of the vitamin B6 preparation include pyridoxine hydrochloride, pyridoxal phosphate, and the like.

As a TRH agent, there are, for example, taltirelin, protyreline tartarate, and the like.

In addition, the said other drug includes not only what was discovered so far but also what is discovered in the future based on the mechanism of each said drug.

(1) a drug used in the combination of the drug of the present invention (a drug used as a compound or a combination), (2) a drug containing franlukast hydrate, or (3) in addition to the drug combination of the present invention. When orally administering a drug (a compound used as a combination or a combination) of drugs (hereinafter, these may be abbreviated as a drug of the present invention), an oral solid or oral for oral administration, respectively Used as a solvent.

Solid dosage forms for oral administration include tablets, pills, capsules, powdered medicines, granules, dry syrups and the like. Capsules include hard capsules and soft capsules.

In the internal solids, the drug may be left as it is, or mixed or granulated with additives (eg, stirred granulation method, fluidized bed granulation method, dry granulation method, etc.) and formulated according to a conventional method (eg, capsule filling, tableting, etc.). Is used. An additive can be used 1 type or in mixture of 2 or more types as appropriate. As an additive, an excipient (for example, lactose, mannitol, glucose, microcrystalline cellulose, corn starch, etc.), a binder (for example, hydroxypropyl cellulose, polyvinylpyrrolidone, magnesium methacrylate, etc.) ), Dispersants (e.g., corn starch, etc.), disintegrants (e.g., calcium cellulose glycolate, etc.), glidants (e.g., magnesium stearate, etc.), stabilizers, dissolution aids (e.g., glutamic acid, Aspartic acid, etc.), water-soluble polymers (e.g., celluloses (e.g., hydroxypropyl cellulose, hydroxypropylmethyl cellulose, methyl cellulose, etc.), synthetic polymers (e.g., polyethylene glycol, polyvinylpyrrolidone , Polyvinyl alcohol, etc.), sweeteners (e.g., sugar, fructose, sucrose, fructose, glucose, lactose, reduced maltose cane, powdered reduced maltose cane, glucose fructose liquid) Sugar, fructose glucose liquid sugar, honey, sorbitol, maltitol, mannitol, xylitol, erythritol, aspartame, saccharin, sodium saccharin, and the like. In addition, it may be coated with a coating agent (eg, white sugar, gelatin, hydroxypropyl cellulose, hydroxypropylmethyl cellulose phthalate, etc.) as necessary, and two or more layers may be coated. In addition, capsules of absorbable materials such as gelatin can be used.

The oral solution for oral administration includes pharmaceutically acceptable homemade, suspending, emulsion, syrup, ericsil and the like. In such liquids, the drug is dissolved, suspended or emulsified in commonly used diluents (e.g., purified water, ethanol or mixtures thereof). The liquid agent may also contain a humectant, a suspending agent, an emulsifier, a sweetener, a flavoring agent, a fragrance, a preservative, a buffer, and the like.

When the drug of the present invention is administered parenterally, it is used as an injection, external preparation, and inhalation for parenteral administration, respectively.

Injections for parenteral administration include all injections. Examples include injections into muscles, injections into veins, ring gels into veins, and the like.

Injectables for parenteral administration include solutions, suspensions, emulsions and solid injectables used by dissolving or suspending them in a solvent. Injectables are prepared by dissolving, suspending or emulsifying the drug in a solvent. As the solvent, for example, distilled water for injection, physiological saline, vegetable oil, propylene glycol, polyethylene glycol, alcohols such as ethanol, a combination thereof, and the like are used. Injectables may also include stabilizers, dissolution aids (eg, glutamic acid, aspartic acid, Polysorbate 80®, etc.), suspending agents, emulsifying agents, analgesics, buffers, preservatives, and the like. Injections are either sterilized in the final process or prepared by aseptic manipulation. In addition, a sterile solid agent, for example, a lyophilized product, may be prepared and dissolved in sterile injectable distilled water or another solvent during use.

In parenteral administration, the formulation of the external preparation includes, for example, an ointment, a gel, a cream, a poultice, a patch, a linen, a spray, an inhalant, a spray, an eye drop, a nasal drop, and the like. The formulation contains a drug and is prepared and prepared by a known method or a commonly used prescription.

Ointments are prepared by known or commonly used methods. For example, the drug is prepared by softening or dissolving in a base. Ointment bases are selected from those known or commonly used. For example, higher fatty acids or higher fatty acid esters (adipic acid, myristic acid, palmitic acid, stearic acid, oleic acid, adipic acid ester, myristic acid ester, palmitic acid ester, stearic acid ester, oleic acid ester) Rows, whale rowes, ceresin, etc.), surfactants (polyoxyethylene alkyl ether phosphate esters, etc.), higher alcohols (cetanol, stearyl alcohol, set stearyl alcohol, etc.), silicone oils (dimethyl polysiloxane, etc.), hydrocarbons (Hydrophilic petrolatum, white petrolatum, purified lanolin, liquid paraffin, etc.), glycols (ethylene glycol, diethylene glycol, propylene glycol, polyethylene glycol, macrogol, etc.), vegetable oils (castor oil, olive oil, sesame oil, terepine oil, etc.) ), One kind of animal oil (mink oil, yolk oil, squalene, squawalene, etc.), water, absorption accelerator, inhibitor It is used as a mixture of two or more. It may also include moisturizers, preservatives, stabilizers, antioxidants, flavoring agents, and the like.

Gels are prepared by known or commonly used methods. For example, the drug can be prepared by dissolving it in a base. The gel base is selected from those known or commonly used. For example, lower alcohols (ethanol, isopropyl alcohol, etc.), gelling agents (carboxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, ethyl cellulose, etc.), neutralizing agents (triethanolamine, diisopropanolamine, etc.) ), A surfactant (polyethylene glycol monostearate, etc.), gums, water, an absorption accelerator, and a dermatitis inhibitor, may be used alone or in combination. It may also include preservatives, antioxidants, flavoring agents and the like.

Creams are prepared by known or commonly used methods. For example, a drug is prepared and prepared by dissolving or emulsifying in a base. Cream bases are selected from those known or commonly used. For example, higher fatty acid esters, lower alcohols, hydrocarbons, polyhydric alcohols (propylene glycol, 1,3-butylene glycol, etc.), higher alcohols (2-hexyldecanol, cetanol, etc.), emulsifiers ( Polyoxyethylene alkyl ethers, fatty acid esters, and the like), water, absorption accelerators, and dermatitis inhibitors, and one or two or more thereof are selected and used. It may also include preservatives, antioxidants, flavoring agents and the like.

Poultice agents are prepared by methods known or commonly used. For example, it is prepared by applying the leading edge on the support using the drug dissolved in the base. The poultice base is selected from those known or commonly used. For example, thickeners (polyacrylic acid, polyvinylpyrrolidone, gum arabic, starch, gelatin, methylcellulose, etc.), wetting agents (urea, glycerin, propylene glycol, etc.), fillers (kaolin, zinc oxide, talc, calcium, magnesium Etc.), 1 type, or 2 or more types are selected from water, a dissolution adjuvant, a tackifier, and a dermatitis inhibitor, and mixed and used. In addition, preservatives, antioxidants, flavoring agents and the like may be further included.

The patch is produced by a known or commonly used method. For example, it is prepared by dissolving a drug in a base and applying it to the support on the support. The base for patch is selected from those known or commonly used. For example, it selects and mixes 1 type (s) or 2 or more types from a polymer base, fats and oils, a higher fatty acid, a tackifier, and a dermatitis inhibitor. In addition, preservatives, antioxidants, flavoring agents and the like may be further included.

The lining agent is produced by a known or commonly used method. For example, the drug is prepared, prepared by dissolving, suspending or emulsifying one or two or more types of water, alcohols (ethanol, polyethylene glycol, etc.), higher fatty acids, glycerin, soaps, emulsifiers, suspending agents, and the like. In addition, preservatives, antioxidants, flavoring agents and the like may be further included.

Sprays, inhalants and sprays may contain, in addition to the diluents generally used, stabilizers such as sodium hydrogen sulfite and buffers that impart isotonicity, for example, isotonic agents such as sodium chloride, sodium citrate or citric acid. Methods of making sprays are described in detail, for example, in US Pat. Nos. 2,868,691 and 3,095,355. It can also be used as an aerosol.

Inhalants for parenteral administration include aerosols, powders for inhalation or liquids for inhalation, which may be in the form of dissolved or suspended in water or other suitable medium for use. Such inhalants are prepared according to known methods.

For example, in the case of a liquid for inhalation, a preservative (benzalkonium chloride, paraben, etc.), a coloring agent, a buffering agent (sodium phosphate, sodium acetate, etc.), an isotonic agent (sodium chloride, concentrated glycerin, etc.), a thickener (carboxyvinyl polymer, etc.) ), Absorption accelerators and the like are appropriately selected and prepared as necessary.

In the case of inhalable powders, lubricants (stearic acid and salts thereof), binders (starch, dextrin, etc.), excipients (lactose, cellulose, etc.), colorants, preservatives (benzalkonium chloride, parabens, etc.), absorption accelerators, etc. It selects suitably as needed and is prepared.

A nebulizer (atomizer, nebulizer) is usually used when administering a liquid for inhalation, and a powder inhalation dispenser is usually used when administering a powder for inhalation.

Other formulations for parenteral administration include suppositories for rectal administration containing drugs and prepared by conventional methods, pessaries for intravaginal administration, and the like.

Although the clinical pharmacological test example and formulation example are specifically mentioned to the drug combination of this invention below, this invention is not limited to this. It is also apparent that various conditions can be changed without departing from the scope of the present invention.

[Clinical pharmacological test example]

In the following eight cases, the antiepileptic effect, the dose reducing effect of the antiepileptic drug, the side effect of the antiepileptic drug, the effect of reducing the number of epileptic seizures, and epileptic seizure in epilepsy patients The effect of improving the extent of was confirmed by clinical pharmacological studies. Specific drugs, dosages, administration methods, and administration intervals used in the drug combination of the present invention are as indicated in the respective test examples. In each test example, unless specifically rejected, the dose of each antiepileptic drug did not change the dose and the method of administration before and after the start of the combined administration of francaste hydrate. In addition, even if it is described with a brand name, the dose value of all the drugs described below shows the dose as a drug rather than the quantity as a product.

Test Example 1

To child with localized relational epilepsy and asthma who were transformed from West syndrome of 1 year 8 months (weight 11 kg), we took 110 mg (one day amount) of zonamide (brand name: eksegran) of antiepileptic drug a day 2 The dose was divided into two doses. Subsequently, in addition to the above-mentioned administration of zonisamide, 80 mg (daily amount) of franlukast hydrate (trade name: Onon dry syrup) was divided into 2 times a day, and co-administered with zonisamide.

As a result, although the number of epileptic seizures before the use of franlukast hydrate was 10 times per day, seizures were completely suppressed for about 1 to 2 weeks after commencement of the combined administration with franlukast hydrate.

Test Example 2

To 8-year-old epilepsy (locally related epilepsy) child after encephalitis, zonamidamide (90 mg daily, twice a day), sodium valproate (brand name: depaken syrup, daily 500 mg, 1) as antiepileptic drug Minomycin (as twice a day), phenytoin (brand name: phenytophosphate, daily amount 220 mg, twice a day) and clovazam (brand name: Maytan fine grain, daily dose 7 mg, twice a day), and antibiotic Brand name: Minofene granules, daily dose 25 mg, twice daily) were administered in combination. Subsequently, in addition to the combined administration of the antiepileptic drug and the antibiotic, 100 mg (daily amount) of franlukast hydrate (trade name: Onon dry syrup) was divided and administered twice daily. At this time, the dose of zonamidamide was reduced to 80 mg per day.

As a result, although the number of seizures before the use of franlukast hydrate was observed 10 to 20 times per day, the number of epileptic seizures began to decrease two to three days after the start of the co-administration with the franlukast hydrate. The decrease was 7 to 8 times per day. In addition, a decrease was observed once daily. Furthermore, the degree of cramps is lighter. ADL has improved along with improving the symptoms of seizures, making it possible to attend school.

Test Example 3

To symptomatic general epilepsy patient with continuation seizure of stiffness seizure of 30 years old, sodium valproate sustained release (brand name: depaken R, daily dose 2400 mg, twice a day), phenytoin (one day quantity) as antiepileptic drug We use diazepam (brand name: Horizon, 10 mg / time, money use) as 200 mg, twice a day) and clonazepam (brand name: ribitol, 0.5 mg daily, once a day) and anticonvulsant Administered. Later, in addition to the combined administration of the antiepileptic drug and anticonvulsant drug, 450 mg (1 day amount, 4 capsules per day) of franlukast hydrate (trade name: Onon capsule) twice a day (two capsules once) It divided into and administered together.

As a result, continuity seizures seen 4 to 5 times a month decreased before use of franlukast hydrate decreased to about once a month after starting co-administration with franlukast hydrate. .

Test Example 4

To children suffering from localized epilepsy and allergic conjunctivitis and rhinitis of 8 years old, phenytoin (daily dose 175 mg, twice a day), carbamazepine (brand name: tegretol granules, 185 mg per day) Twice a day), and diazepam (10 mg / time, for money) was administered in combination as an anticonvulsant at seizure. Then, in addition to the combined administration of the antiepileptic drug and the anticonvulsant drug, 150 mg (daily dose) of franlukast hydrate (trade name: Onon dry syrup) was divided and administered twice a day.

As a result, seizures were observed 4 to 5 times a week before the use of franlukast hydrate, but seizures decreased once a week 10 days after the start of the combined administration. In addition, seizures decreased twice a month one month after the start of administration.

Test Example 5

For 6-year-old, children with locally related epilepsy and asthma, sodium valproate (325 mg daily, twice daily) and phenobarbital (105 mg daily, twice daily) as antiepileptic drugs, and asthma medications Franlukast hydrate (trade name: Onon dry syrup, daily amount 112.5 mg, twice daily) was administered in combination. Thereafter, the dose of franlukast hydrate was increased to 140 mg per day, and at the same time the dose of phenobarbital was reduced to 100 mg per day.

After changing the dosage of each drug, the frequency of epileptic seizures in one to two weeks was compared to before the change, and the number of seizures of seizure-complex partial seizures, such as complex seizures mainly caused by loss of consciousness during the day and nighttime Halved, leaving severe condition. ADL improved with the symptom improvement of seizures, and it was possible to go to school.

Test Example 6

A 26-year-old West syndrome (symptomatic general epilepsy syndrome) developed and adult women with spasms and partial seizures received phenytoin (275 mg daily, twice daily) as an antiepileptic drug. Subsequently, in addition to the phenytoin administration, 112.5 mg (daily dose, once capsule, once daily) was administered in combination with franlukast hydrate (trade name: Onon capsule).

As a result, the epileptic seizure in both unidirectional directions twice a day on the 10th day after the start of the combined administration of franlukast hydrate decreased at a frequency of about once every two days, and the worsening of seizures accompanying menstruation disappeared.

Test Example 7

To 6-year-old epilepsy after seizure-neutral encephalitis (locally related epilepsy) and children with bronchitis, phenytoin (225 mg daily, twice daily), carbamazepine (700 mg daily, as an antiepileptic drug) Twice a day) and phenobarbital (115 mg daily, twice daily), and minomycin (30 mg daily, twice daily) as antibiotics. Then, in addition to the combined administration of the antiepileptic drug and the antibiotic, the capsules of franlukast hydrate (trade name: Onon capsule) were divided, the contents thereof were taken out, and 135 mg (daily dose, 1.2 capsules per day) thereof were administered in combination. .

As a result, there was a seizure several times a day in seizure-mediated state before concomitant administration start of franlukast hydrate, and it was the situation to use diazepam (brand name: diap suppository) as anticonvulsant once a day, but combination administration start After 10 days, the number of seizures decreased twice per day, leaving the neutral state. It also eliminates the need for diazepam. As a result, symptoms such as drowsiness and saliva secretion, which are side effects of diazepam, were improved.

Test Example 8

A 5-year-old child suffering from frontal lobe epilepsy (locally related epilepsy) was administered phenytoin (200 mg per day, twice daily) as an antiepileptic drug. Then, in addition to the above phenytoin, 150 mg (daily amount) of franlukast hydrate (trade name: Onon dry syrup) was divided twice a day, and co-administered with phenytoin.

As a result, seizures that were several times a day for one week after the start of the combined administration of franlukast hydrate decreased once per two days. In addition, a period of two months without epileptic seizures was observed. In addition, improvements in developmental disabilities have been shown to improve mental development.

As is clear from each of the test examples described above, an antiepileptic effect is enhanced or a dose of an antiepileptic drug is administered to an epileptic patient who has already been administered one or more antiepileptic drugs or the like in combination. It can be seen that the effect of reducing or improving the side effects of antiepileptic drugs, reducing the number of epileptic seizures, or improving the degree of epileptic seizures.

[Production example]

Hereinafter, although the specific formulation example of the franlukast hydrate used for the drug combination of this invention is disclosed, this invention is not limited to these.

Formulation Example 1 Preparation of Capsule

Granulcast hydrate (40 kg), lactose (19 kg) and additives (appropriate amount) were spray dried and granulated according to a conventional method, and granules containing 625 mg of franlukast hydrate in 1 kg of granules. Got. The obtained granulated product was filled in No. 3 capsules according to a conventional method such that the content of franlukast hydrate in 1 capsule was 112.5 mg, thereby preparing a capsule containing franlukast hydrate.

Formulation Example 2 Preparation of Dry Syrup

Franlukast hydrate (10 kg), white sugar (80 kg) and additives (suitable) were prepared in granules according to a conventional method to obtain a dry syrup containing 100 mg of franlukast hydrate in 1 g of granules.

In the present invention, by combining a leukotriene receptor antagonist, in particular, Franchast hydrate and an antiepileptic drug, the antiepileptic effect is enhanced as compared with the effect of administration of only one or two or more antiepileptic drugs. Effects, for example, the effect of reducing the dosage of the antiepileptic drug, the effect of improving the side effects of the antiepileptic drug, the effect of reducing the number of epileptic seizures, the effect of improving the degree of epileptic seizure, and the like can be obtained.

Claims (25)

An antiepileptic drug for enhancing antiepileptic action, comprising an leukotriene receptor antagonist and being administered in combination with an antiepileptic drug. An antiepileptic drug with enhanced antiepileptic action, including a leukotriene receptor antagonist and an antiepileptic drug. The agent according to claim 1 or 2, wherein the leukotriene receptor antagonist is franlukast hydrate. The drug of Claim 1 or 2 which reduces the dose of an antiepileptic drug. The agent according to claim 4, which improves the side effects of the antiepileptic drug. The drug according to claim 1 or 2, which reduces the number of epileptic seizures. The agent according to claim 1 or 2, which improves the degree of epileptic seizures. The antiepileptic drug according to claim 1 or 2, wherein the antiepileptic drug is phenobarbital, primidone, phenytoin, etotoin, trimetadione, acetzolamide, sultiam, ethoximide, acetylphenetolide, nitrazepam, diazepam, A medicament selected from the group consisting of clonazepam, clovazam, carbamazepine, sodium valproate, zonisamide and gabapentin. The antiepileptic agent according to claim 8, wherein the antiepileptic drug is selected from the group consisting of phenobarbital, primidone, phenytoin, ethoximide, diazepam, clonazepam, clovazam, carbamazepine, sodium valproate and zonisamide Become pharmaceutical. The agent according to claim 9, wherein the antiepileptic drug is selected from the group consisting of phenobarbital, phenytoin, ethoximide, clonazepam, clovazam, carbamazepine, sodium valproate and zonisamide. The agent of claim 3, wherein the daily dose of franlukast hydrate is 112.5 mg to 450 mg. The medicament according to claim 3, wherein the daily dose per kg body weight of the patient of franlukast hydrate is 2 mg to 10 mg. The agent according to claim 8, wherein the daily dose of phenytoin is 200 mg to 300 mg. The medicament according to claim 8, wherein the daily dose of phenytoin is from 20 mg to 300 mg. The leukotriene receptor antagonist of claim 1, wherein the leukotriene receptor antagonist is franlukast hydrate, the daily dosage of the drug is 112.5 mg to 450 mg, the antiepileptic drug is phenytoin, and the daily dose of the drug is 200 mg to Pharmaceutical, which is 300 mg. 3. The leukotriene receptor antagonist according to claim 1 or 2, wherein the leukotriene receptor antagonist is franlukast hydrate, the daily dose per kilogram of body weight of the patient of the drug is from 2 mg to 10 mg, the antiepileptic drug is phenytoin and the drug is administered per day The amount is 20 mg to 300 mg. The agent of claim 8, wherein the daily dose of sodium valproate is 300 mg to 2500 mg. The leukotriene receptor antagonist according to claim 1, wherein the leukotriene receptor antagonist is franlukast hydrate, the daily dose of the drug is 112.5 mg to 450 mg, the antiepileptic drug is sodium valproate, and the daily dose of the drug 300 mg to 2500 mg. 3. The leukotriene receptor antagonist according to claim 1 or 2, wherein the leukotriene receptor antagonist is franlukast hydrate, the daily dose per kilogram of body weight of the drug is 2 mg to 10 mg, the antiepileptic drug is sodium valproate, and the drug per day The dosage amount is 300 mg to 2500 mg. An agent for enhancing antiepileptic action of an antiepileptic drug, including a leukotriene receptor antagonist. The medicament according to claim 20, wherein the leukotriene receptor antagonist is franlukast hydrate and the daily dose of the drug is 112.5 mg to 450 mg. The medicament according to claim 20, wherein the leukotriene receptor antagonist is franlukast hydrate, with a daily dosage of 2 mg to 10 mg per kg body weight of the drug. The anti-anxiety drug, anticonvulsant drug, muscle relaxant drug, antimyoclonic muscle spasm drug, carbonic anhydrase inhibitor, 5-lipoxygenase inhibitor, antibiotic, steroid, ACTH preparation, vitamin An agent, which is administered in combination in combination of at least one selected from a B6 agent and a TRH agent. A method for enhancing antiepileptic action of an antiepileptic drug in a mammal, characterized by administering to the mammal a combination of a leukotriene receptor antagonist and an antiepileptic drug. Use of a leukotriene receptor antagonist for the preparation of an antiepileptic agonist of an antiepileptic drug, which is used in combination with an antiepileptic drug.