阅读说明：本技术 用于治疗癫痫的包含癸酸的组合 (Combinations comprising capric acid for the treatment of epilepsy ) 是由 R·S·B·威廉姆斯 M·沃克 于 2018-06-28 设计创作，主要内容包括：本发明公开了用于在治疗癫痫中使用的癸酸,其中所述癸酸与吡仑帕奈或其药学上可接受的盐组合使用,或者其中所述癸酸与结合到与吡仑帕奈相同的AMPA受体位点的AMPA受体抑制剂组合使用。(Disclosed is a decanoic acid for use in the treatment of epilepsy, wherein the decanoic acid is used in combination with Perampanel or a pharmaceutically acceptable salt thereof, or wherein the decanoic acid is used in combination with an AMPA receptor inhibitor that binds to the same AMPA receptor site as Perampanel.)

1. Capric acid for use in the treatment of epilepsy, wherein the capric acid is used in combination with perampanel or a pharmaceutically acceptable salt thereof, or wherein the capric acid is used in combination with an AMPA receptor inhibitor that binds to the same AMPA receptor site as perampanel.

2. Perampanel or a pharmaceutically acceptable salt thereof for use in the treatment of epilepsy, wherein the Perampanel or a pharmaceutically acceptable salt thereof is used in combination with capric acid.

3. An AMPA receptor inhibitor that binds to the same AMPA receptor site as perampanel for use in treating epilepsy, wherein the AMPA receptor inhibitor is used in combination with capric acid.

4. The decanoic acid for the use of claim 1 or the perampanel for the use of claim 2, or a pharmaceutically acceptable salt thereof, or the AMPA receptor inhibitor for the use of claim 3, wherein the decanoic acid and the perampanel, or a pharmaceutically acceptable salt thereof, are administered separately or sequentially, or wherein the decanoic acid and the AMPA receptor inhibitor are administered separately or sequentially.

5. A combination of (i) capric acid and perampanel or a pharmaceutically acceptable salt thereof or (ii) capric acid and an AMPA receptor inhibitor that binds to the same AMPA receptor site as perampanel for use in the treatment of epilepsy.

6. A composition comprising (i) capric acid and perampanel or a pharmaceutically acceptable salt thereof or (ii) capric acid and an AMPA receptor inhibitor that binds to the same AMPA receptor site as perampanel.

7. The composition of claim 6, wherein the composition is a pharmaceutical composition and further comprises one or more of a pharmaceutically acceptable carrier, excipient, and/or diluent.

8. The composition according to claim 6 or 7, for use in the treatment of epilepsy.

9. A kit comprising (i) capric acid and perampanel or a pharmaceutically acceptable salt thereof or (ii) capric acid and an AMPA receptor inhibitor that binds to the same AMPA receptor site as perampanel.

10. Decanoic acid for use according to claim 1 or 4, perampanel or a pharmaceutically acceptable salt thereof for use according to claim 2 or 4, an AMPA receptor inhibitor for use according to claim 3 or 4, a combination for use according to claim 5 or a composition for use according to claim 8, wherein the use is the treatment of an individual identified as one who will respond to AMPA receptor inhibition.

11. The decanoic acid for said use according to claim 1, 4 or 10, perampanel or a pharmaceutically acceptable salt thereof for said use according to claim 2, 4 or 10, an AMPA receptor inhibitor for said use according to claim 3, 4 or 10, a combination for said use according to claim 5 or 10, a composition for said use according to claim 6 or 7, a composition for said use according to claim 8 or 10 or a kit according to claim 9, wherein the decanoic acid is in the form of a triglyceride.

12. The decanoic acid for use according to claim 1, 4, 10 or 11, the perampanel or pharmaceutically acceptable salt thereof for use according to claim 2, 4, 10 or 11, the AMPA receptor inhibitor for use according to claim 3, 4, 10 or 11, the combination for use according to claim 5, 10 or 11, the composition for use according to claim 6, 7 or 11, the composition for use according to claim 8, 10 or 11 or the kit according to claim 9 or 11, wherein the decanoic acid is comprised in an oil-in-water emulsion, powder or foodstuff.

13. The decanoic acid for use according to claim 1, 4, 10 or 11, the perampanel or pharmaceutically acceptable salt thereof for use according to claim 2, 4, 10 or 11, the AMPA receptor inhibitor for use according to claim 3, 4, 10 or 11, the combination for use according to claim 5, 10 or 11, the composition for use according to claim 6, 7 or 11, the composition for use according to claim 8, 10 or 11 or the kit according to claim 9 or 11, wherein the decanoic acid is comprised in a medical food, tube feed, nutritional composition or nutritional supplement.

14. The decanoic acid for said use according to claim 1, 4, 10 or 11, pirampanel or a pharmaceutically acceptable salt thereof for said use according to claim 2, 4, 10 or 11, an AMPA receptor inhibitor for said use according to claim 3, 4, 10 or 11, a combination for said use according to claim 5, 10 or 11, a composition for said use according to claim 6, 7 or 11, a composition for said use according to claim 8, 10 or 11 or a kit according to claim 9 or 11, wherein the decanoic acid is comprised in a pharmaceutical composition, wherein the pharmaceutical composition further comprises one or more pharmaceutically acceptable carriers, diluents and/or excipients.

15. A method for treating epilepsy, comprising the step of administering capric acid to a patient in need thereof, wherein said capric acid is administered to said patient in combination with perampanel or a pharmaceutically acceptable salt thereof, or wherein said capric acid is administered to said patient in combination with an AMPA receptor inhibitor that binds to the same AMPA receptor site as perampanel.

Technical Field

The present invention relates generally to a combination of (i) decanoic acid and perampanel (perampael) or a pharmaceutically acceptable salt thereof or (ii) decanoic acid and an AMPA receptor inhibitor that binds to the same AMPA receptor site as perampanel. In particular, the present invention provides such combinations for the treatment of epilepsy.

Background

Epilepsy encompasses a variety of neurological disorders characterized by seizures. Seizures are caused by abnormal neuronal activity and manifest in a variety of ways, including twitching and loss of consciousness. In many cases, epilepsy can be controlled by the use of anticonvulsant drugs. However, for a proportion of patients with epilepsy, treatment with conventional medications may have little effect on seizure activity. While surgery is an option for treating patients with certain seizures, for many individuals, successful management can be achieved with ketogenic diets less invasively.

The Medium Chain Triglyceride (MCT) ketogenic diet was first identified in 1971 as a treatment for intractable epilepsy. It provides one of the most effective treatments for children with drug-resistant epilepsy (Liu, Epilepsia 2008; 49 suppl 8: 33-36), and has been shown to be effective in childhood epilepsy in randomized controlled trials (Neal et al, Epilepsia2009, 50: 1109-. However, this diet has adverse gastrointestinal related side effects such as diarrhea, vomiting, flatulence and cramping (Liu, Epilepsia2008, 49 suppl 8: 33-36). Furthermore, high loss rates of diet are also exhibited, as many patients find diets difficult to tolerate (Levy et al, Cochrane Database Syst Rev, 2012, 3: CD 001903).

Although it has been postulated that ketone bodies from ketogenic diets exert therapeutic effects, seizure control correlates poorly with ketone body levels (Likhodii et al, Epilepsia2000, 41: 1400-. In addition to ketones, diets also resulted in increased plasma levels of two fatty acids provided in MCT oil, linear decadecanoic acid and octaoctanoic acid (Haidukewych et al, Clin Chem, 1982, 28: 642-645). Capric acid, but not caprylic acid, has recently been shown to have clinically relevant concentrations of anti-seizure effects in vitro and in vivo (Chang et al, Neuropharmacology 2013; 69: 105-.

α -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPA receptor) plays a key role in the generation and transmission of epileptic activity and adaptive cellular plasticity associated with epileptogenesis in the long term (Chapman, J Nutr, 2000, 130: 1043S-1045S; Rogawski and Donevan, Adv Neurol, 1999, 79: 947-.

We have recently shown that capric acid inhibits the AMPA receptor (Chang et al Brain 2016, month 2, 139 (2): 431-443).

Perampanel (Fycompa) is a non-competitive AMPA receptor antagonist that has been approved as an adjunct treatment for partial seizures and primary generalized tonic-clonic seizures (Frampton JE, 2015, Drugs, 75: 1657-68). Adjuvant pyrinepalene has also been found to be effective in children with refractory partial-onset epilepsy and tonic clonic seizures in idiopathic generalized seizures (Heyman e., Developmental Medicine & Child Neurology, 2017, 59: 441-. However, it has dose-dependent behavioral side effects that limit its use in certain patients (Rugg-Gunn f., 2014, Epilepsia, 55 suppl 1: 13-5).

The most common side effects reported for patients who have received treatment with perampanel are dizziness, somnolence, tiredness, irritability, nausea and falls, but patients are particularly concerned with side effects of the drug in terms of cognition and mental aspects. Rugg-Gunn f. describes how patients taking pirampanel, especially at higher doses, report the overall situation of depression and aggressive behavior more frequently than patients taking placebo. Heyman e. reports that perampanel is associated with a higher rate of behavioral adverse reactions that occur mainly in adolescents with refractory epilepsy.

There remains a need for improved medicaments for the treatment of epilepsy.

Disclosure of Invention

The inventors have surprisingly shown that there is a synergistic effect between perampanel and decanoic acid in terms of direct AMPA receptor inhibition and seizure control. These findings are useful for combination therapy with either perampanel or an AMPA receptor inhibitor that binds to the same AMPA receptor site as perampanel and capric acid.

Drawings

FIG. 1: unless otherwise stated, AMPA (GluA2/3, GluA1/2, or GluA3) receptors were expressed in xenopus oocytes and perfused with L-glutamic acid (100 μ M) and the indicated compounds. The current was recorded using TEVC. (A) Representative current traces of inhibitory dose-response curves for Perampanel at GluA1/2 and GluA2/3 receptors. (B) Dose-response curves showing inhibition by Perampanel of GluA1/2 (N-10) and GluA2/3 (N-6), corresponding to IC₅₀Values are shown in the bar graph inset. (C) Perampanel concentration versus glutamate EC for GluA1/2 changes₅₀The effect of (a). The points are normalized to the maximum response and represent the mean and SEM of 6 (glutamic acid only) and 5 (containing 2.5 μ M and 5 μ M of perampanel). (D) Quantitative representation of the average currents recorded in wild-type and mutant GluA3 normalized to the maximum response in the presence of perampanel (wild-type N-5, mutant N-6) and decanoic acid DA (both wild-type and mutant N-4).

FIG. 2: unless otherwise stated, AMPA (GluA2/3, GluA1/2, or GluA3) receptors were expressed in xenopus oocytes and perfused with L-glutamic acid (100 μ M) and the indicated compounds. The current was recorded using TEVC. (A) Representative current traces of inhibitory dose-response curves of capric acid (DA) at 1 μ M or 4 μ M Perampanel for GluA2/3 receptors. Dose-response inhibition curves of decanoic acid at 1 μ M or 4 μ M Perampanel for (B) GluA2/3 receptor and (C) GluA1/2 receptor, respectively. The points are normalized to the maximum response to L-glutamic acid and solvent, 1 μ M perampanel or 4 μ M perampanel and represent the mean and SEM of 8 to 13 readings. Inset shows the corresponding IC in the presence of Perampanel₅₀The value is obtained. (D) Generation of inhibitory dose-response curves for Perampanel at GluA2/3 receptors in 50 μ M to 100 μ M capric acidRepresentative current trace. (E) (F) dose-response inhibition curves of Perampanel at 50. mu.M and 100. mu.MDA for GluA2/3 receptor (E) and GluA1/2 receptor (F). The points are normalized to the maximum response to L-glutamic acid with solvent, 50 μ M and 100 μ M DA, and represent the mean and SEM of 8 to 13 readings. Inset shows the corresponding perampanel IC in the presence of DA₅₀The value is obtained. The scales correspond to 150nA in GluA1/2 and 30nA (A) and 50nA (E) and 200nA (H) in GluA 2/3. The scale bar corresponds to 60nA for +1 μ M of perampanel and to 75nA (k) and 200nA (l) for +4 μ M of perampanel.

FIG. 3: (A) by administering PTZ (2mM) and [ K +](to 6mM) epileptiform (paroxysmal) activity was induced in rat entorhinal cortex-hippocampal slices and recordings were made over time at fixed pyrinepalene and increasing Decanoic Acid (DA) concentrations. (B) Epileptiform activity was normalized to activity in the absence or presence of each concentration (100nM and 500nM) and shown as variable DA concentrations. Inset shows DA IC of epileptiform activity with Perampanel₅₀And (4) data. Data were derived from at least three biological replicates.

Detailed Description

Combination of

According to the invention, capric acid and perampanel or a pharmaceutically acceptable salt thereof are used in combination, or capric acid and an AMPA receptor inhibitor which binds to the same AMPA receptor site as perampanel are used in combination.

As used herein, the term "combination" or phrase "used in combination with", "in combination with", or "combined formulation" refers to (i) the combined administration of capric acid and perampanel, or pharmaceutically acceptable salts thereof, or (ii) the combined administration of capric acid and an AMPA receptor inhibitor that binds to the same AMPA receptor site as perampanel, wherein capric acid and perampanel, or pharmaceutically acceptable salts thereof, may be administered simultaneously, sequentially or separately, or wherein capric acid and AMPA receptor inhibitor may be administered simultaneously, sequentially or separately.

As used herein, the terms "simultaneously" or "simultaneously" are used to indicate that the agents are administered simultaneously (i.e., at the same time).

The term "sequentially" or "sequentially" is used to indicate that two agents are administered one after the other, with capric acid first, or with perampanel, a pharmaceutically acceptable salt thereof, or an AMPA receptor inhibitor first.

The term "separate" or "separately" is used to indicate that the two agents are administered independently of each other but within a time interval such that the agents exhibit a synergistic effect. Thus, "separate" administration may allow for administration of one agent, for example, within 1 minute, 5 minutes, or 10 minutes after administration of the other agent, provided that the two agents exhibit a synergistic effect.

The agents may be administered as separate formulations or as a single combined formulation. When combined in the same formulation, it is understood that the two agents must be stable and compatible with each other as well as with any other components of the formulation.

When the agents are co-formulated, i.e. co-formulated in the same composition or formulation, they can only be administered simultaneously. When the agents are formulated in separate compositions or formulations, they may be administered simultaneously, sequentially or separately. The simultaneous administration of agents in the same formulation or separate formulations may also be described as the co-or combined administration of the two agents.

In one embodiment, the capric acid and perampanel, or pharmaceutically acceptable salts thereof, are mixed in an admixture. In another embodiment, the decanoic acid and the perampanel, or pharmaceutically acceptable salts thereof, are in the form of a kit comprising: a formulation of capric acid and perampanel or a pharmaceutically acceptable salt thereof; and optionally instructions for administering the formulation simultaneously, sequentially or separately to a patient in need thereof.

In an alternative embodiment, the decanoic acid and the AMPA receptor inhibitor that binds to the same AMPA receptor site as perampanel are in a blend. In another embodiment, the capric acid and AMPA receptor inhibitor that binds to the same AMPA receptor site as perampanel are present in the form of a kit comprising: formulations of capric acid and AMPA receptor inhibitors; and optionally instructions for administering the formulation simultaneously, sequentially or separately to a patient in need thereof.

In another embodiment, capric acid and perampanel, or pharmaceutically acceptable salts thereof, are present in the product as a combined preparation for simultaneous, separate or sequential use in the treatment of epilepsy or inhibition of AMPA receptors in a subject in need of such inhibition.

Alternatively, the capric acid and AMPA receptor inhibitor are present in the product as a combined preparation for simultaneous, separate or sequential use in the treatment of epilepsy or inhibition of AMPA receptors in an individual in need of such inhibition.

Capric acid and compositions comprising capric acid

Capric acid (also known as n-capric acid) is of formula CH₃(CH₂)₈Saturated fatty acids of COOH.

It will be appreciated that the decanoic acid can be in free form (or a salt thereof) or in the form of, for example, a triglyceride, diacyl glyceride, monoacyl glyceride, with a triglyceride being generally preferred.

Medium Chain Triglycerides (MCT) are triglycerides wherein all three fatty acid moieties are medium chain fatty acid moieties. Medium Chain Fatty Acids (MCFA) are fatty acids having 6 to 12 carbon atoms, but fatty acids having 8 and 10 carbon atoms (i.e., caprylic and capric) are preferred and may be referred to herein as C8 fatty acids or C8, and C10 fatty acids or C10.

The term "fatty acid moiety" refers to the portion of MCT produced from fatty acids in an esterification reaction with glycerol. For example, esterification reaction between glycerol and decanoic acid alone will produce MCT with decanoic acid moiety.

Homotriglycerides (i.e., all of the fatty acid moieties of the MCT have the same properties, e.g., a C10 homotriglyceride may contain 3 decanoic acid moieties) and/or heterotypic triglycerides (i.e., the fatty acid moieties of the MCT do not always have the same properties) may be used in the present invention. Preferred heterotypic triglycerides are those composed of an octanoic acid moiety and a decanoic acid moiety.

The capric acid (or triglyceride containing capric acid) may be in the form of a composition. Perampanel can be administered in the same composition or separately.

In one embodiment, the composition is free or substantially free of fatty acid moieties that are not capric or caprylic acid. In one embodiment, the composition is free or substantially free of fatty acid moieties other than capric acid. In one embodiment, the composition is free or substantially free of MCT comprising fatty acid moieties other than capric and caprylic acids. In one embodiment, the composition is free or substantially free of MCT comprising a fatty acid moiety other than decanoic acid. However, such MCTs may be present in minor amounts (e.g., less than 3, 2, 1, or 0.5 wt%).

Examples of natural sources of MCTs include vegetable sources such as coconut, coconut oil, palm kernel oil, and animal sources such as milk. Capric acid comprises about 5% to 8% of the fatty acid composition of coconut oil.

MCTs can also be synthesized by esterifying glycerol with one or more Medium Chain Fatty Acids (MCFAs). For example, MCT-C10 can be synthesized by esterification of glycerol with capric acid.

The capric acid-containing composition may also contain Long Chain Triglycerides (LCTs). Preferably, the level of LCT is less than 5%, 2%, 1%, 0.5% or 0.1% by weight of the composition. In one embodiment, LCT is not present in the composition.

The composition may also contain substances such as minerals, vitamins, salts, functional additives including, for example, flavoring agents, colorants, emulsifiers, antimicrobial agents, or other preservatives. Minerals that can be used in such compositions include, for example, calcium, phosphorus, potassium, sodium, iron, chlorine, boron, copper, zinc, magnesium, manganese, iodine, selenium, chromium, molybdenum, fluoride, and the like. Examples of vitamins that can be used in the compositions described herein include water-soluble vitamins (such as thiamine (vitamin B1), riboflavin (vitamin B2), niacin (vitamin B3), pantothenic acid (vitamin B5), pyridoxine (vitamin B6), biotin (vitamin B7), inositol (vitamin B8), folic acid (vitamin B9), cobalamin (vitamin B12), and vitamin C), and fat-soluble vitamins including salts, esters, or derivatives thereof (such as vitamin a, vitamin D, vitamin E, and vitamin K). Included in various embodiments are inulin, taurine, carnitine, amino acids, enzymes, coenzymes, and the like, which may be used.

In one embodiment, the composition is in the form of an oil-in-water emulsion. The emulsion may be substantially free of protein or carbohydrate. In one embodiment, the total fat content of the oil-in-water emulsion is from 5g/100ml to 40g/100ml, such as from 5g/100ml to 30g/100ml, from 5g/100ml to 25g/100ml, from 10g/100ml to 25g/100ml or from 10g/100ml to 20g/100ml or from 15g/100ml to 25g/100 ml. In one embodiment, the energy value of the emulsion is between 50kcal/100ml to 300kcal/100ml, such as 100kcal/100ml to 300kcal/100ml, 50kcal/100ml to 200kcal/100ml, 150kcal/100ml to 250kcal/100ml or 160kcal/100ml to 200kcal/100 ml.

In another embodiment, the composition comprising capric acid is delivered as part of a ketogenic diet. If the invention is delivered as part of a ketogenic diet, the total fat content can be altered during the treatment: protein/carbohydrate content ratio to achieve nutritional goals and optimize clinical benefits. The ratio may be in the range of, for example, 1: 1 to 7: 1, 1: 1 to 5: 1, such as 1: 1, 1.5: 1, 2: 1, 2.5: 1, 3: 1, 3.5: 1, 4: 1, 4.5: 1, or 5: 1.

In one embodiment, the ratio is from 2.25: 1 to 3.9: 1. In another embodiment, the ratio is from 2.26 to 3.8: 1 or from 2.7 to 3.4: 1. In further embodiments, the ratio is 3.21: 1, 3.23: 1, 3.24: 1, 3.25: 1, 3.26: 1, 3.27: 1, 3.28: 1, or 3.29: 1.

Capric acid or compositions comprising capric acid may be used for enteral or parenteral administration. In a preferred embodiment, the composition is for oral administration.

In one embodiment, the decanoic acid or the composition comprising decanoic acid is in the form of a tablet, dragee, capsule, gel-pill, powder, granule, solution, emulsion, suspension, coated granule, spray-dried granule or pill.

In another embodiment, the decanoic acid or the composition comprising decanoic acid can be in the form of a powder. The powder may for example be a spray-dried powder or a freeze-dried powder.

The composition is useful for reconstitution in water.

The decanoic acid or the composition comprising decanoic acid can be inserted or mixed into the food material. The composition may be in the form of a foodstuff or feed. In one embodiment, the foodstuff is a human foodstuff.

The decanoic acid or the composition comprising decanoic acid can be in the form of a medical food. As used herein, the term "medical food" refers to a food product specifically formulated for dietary management of a medical disease or condition; for example, a medical disease or disorder may have unique nutritional needs that cannot be met with a normal diet alone. The medical food may be administered under medical supervision. The medical food may be for oral ingestion or tube feeding.

The composition comprising capric acid may be in the form of a tube feed. The term "tube feeding" refers to products intended to introduce nutrients directly into the gastrointestinal tract of an individual through a feeding tube. Tube feeding may be administered, for example, through feeding tubes placed through the nose of the individual (such as nasogastric, sinus, and nasojejunal tubes) or directly into the abdomen of the individual (such as gastrostomy, gastrojejunostomy, or jejunostomy feeding tubes).

The composition comprising capric acid may be in the form of a nutritional composition or nutritional supplement. The term "nutritional supplement" refers to a product intended to supplement the general diet of an individual.

The composition comprising capric acid may be in the form of a complete nutritional product. The term "complete nutritional product" refers to a product that is capable of being the sole source of nutrition for an individual.

In various embodiments, the composition can be in the form of a beverage, mayonnaise, salad dressing, margarine, low fat spread, dairy product, spread cheese, processed cheese, dairy dessert, flavored milk, cream, fermented dairy product, cheese, butter, condensed milk product, ice cream mix, soy product, pasteurized egg liquid, baked product, confectionary product, candy bar, chocolate bar, high fat bar, liquid emulsion, spray dried powder, freeze dried powder, UHT pudding, pasteurized pudding, gel, jelly, yogurt, or food with a fat-based filling or a water-containing filling.

In still other embodiments, the composition can be used to coat food.

The composition may be in the form of a pharmaceutical composition and may comprise one or more suitable pharmaceutically acceptable carriers, diluents and/or excipients.

Examples of such suitable Excipients for the compositions described herein can be found in "Handbook of Pharmaceutical Excipients, 2 nd edition, (1994)" edited by a Wade and PJ Weller.

Acceptable carriers or diluents for therapeutic use are well known in the Pharmaceutical arts and are described, for example, in Remington's Pharmaceutical Sciences, Mack Publishing Co (a.r. gennaro editors, 1985).

Examples of suitable carriers include lactose, starch, glucose, methyl cellulose, magnesium stearate, mannitol, sorbitol, and the like. Examples of suitable diluents include ethanol, glycerol and water.

The choice of pharmaceutical carrier, excipient or diluent may be selected with reference to the intended route of administration and standard pharmaceutical practice. The pharmaceutical composition may comprise or in addition to a carrier, excipient or diluent as: any suitable binder, lubricant, suspending agent, coating agent and/or solubilizing agent.

Examples of suitable binders include starch, gelatin, natural sugars such as glucose, anhydrous lactose, free-flowing lactose, β -lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethylcellulose, and polyethylene glycol.

Examples of suitable lubricants include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like.

Preservatives, stabilizers, dyes and even flavoring agents may be provided in the composition. Examples of preservatives include sodium benzoate, sorbic acid and esters of p-hydroxybenzoic acid. Antioxidants and suspending agents may also be used.

Nutritionally acceptable carriers, diluents and excipients include those suitable for human or animal consumption and are used as standards in the food industry. Typical nutritionally acceptable carriers, diluents and excipients will be familiar to those skilled in the art.

Perampanel

Perampanel is a non-competitive AMPA glutamate receptor antagonist. It is known by the name Fycompa^TMMarketed, and indicated as an adjunct treatment for partial seizure in adult and juvenile epileptic patients, whether or not accompanied by secondary generalized seizures. It also indicates an adjuvant treatment for primary generalized tonic clonic seizures in adult and juvenile patients with idiopathic generalized seizures, and shows potential efficacy in treating drug-resistant epilepsy.

As used herein, the term "perampanel" refers to a compound having the structure:

perampanel has the chemical name 3- (2-cyanophenyl) -5- (2-pyridyl) -1-phenyl-1, 2-dihydropyridin-2-one. The invention also encompasses pharmaceutically acceptable salts of perampanel.

As used herein, a "pharmaceutically acceptable salt" is any salt formulation suitable for use in pharmaceutical applications. Pharmaceutically acceptable salts include, but are not limited to: amine salts such as N, N '-dibenzylethylenediamine, chloroprocaine, choline, ammonia, diethanolamine and other hydroxyalkylamines, ethylenediamine, N-methylglucamine, procaine, N-benzylphenethylamine, 1-p-chloro-benzyl-2-pyrrolidinyl-1' -ylmethylbenzimidazole, diethylamine and other alkylamines, piperazine, tris (hydroxymethyl) aminomethane, and the like; alkali metal salts such as lithium salts, potassium salts, sodium salts, and the like; alkaline earth metal salts such as barium salt, calcium salt, magnesium salt, and the like; transition metal salts such as zinc salts, aluminum salts, and the like; other metal salts such as sodium hydrogen phosphate, disodium phosphate, and the like; inorganic acids such as hydrochloride, sulfate, and the like; and salts of organic acids such as acetate, lactate, malate, tartrate, citrate, ascorbate, succinate, butyrate, valerate, fumarate, and the like.

Perampanel can be administered according to the individual response of the patient to optimize the balance between efficacy and tolerability.

Preferably, Perampanel is administered orally.

Perampanel at doses of 4 mg/day to 12 mg/day has been shown to be an effective therapy for the treatment of partial seizure. Perampanel at doses up to 8 mg/day has been shown to be effective against primary generalized tonic-clonic seizures. In one embodiment, the dose of perampanel used in the invention is between 4 mg/day and 12 mg/day. However, the dose of perampanel is not limited to these doses, and may be increased or decreased depending on the individual response.

AMPA receptor inhibitors that bind to the same AMPA receptor site as Perampanel

AMPA receptors are non-N-methyl-D-aspartate-type (non-NMDA-type) ionotropic transmembrane receptors of glutamate, which mediate rapid synaptic transmission in the central nervous system, and it is known that Perampanel can selectively inhibit AMPA receptor-mediated synaptic firing without affecting NMDA receptor response (Rogawski MA, Acta Neurol Scand supplement, 2013; (197): 19-24). Yelshanskaya, m.v. (Neuron 2016, 91, 1305-1315) specifically characterized the binding site of perampanel on the AMPA receptor and revealed that binding occurs at allosteric sites outside the ion channel cell.

As used herein, the expression "an AMPA receptor inhibitor that binds to the same AMPA receptor site as perampanel" or "an AMPA receptor inhibitor that binds to the same receptor site as perampanel" means that the AMPA receptor inhibitor binds to the same site on the AMPA receptor as perampanel. It is suggested that perampanel and related compounds bind at the S1-M1 and S2-M4 connectors between the transmembrane and extracellular domain domains of the GluA2 subunit of the AMPA receptor. The AMPA receptor site that binds to Perampanel is characterized in Yelshanskaya, M.V. (Neuron 2016, 91: 1305-1315). The specific disclosure of Yelshanskaya, m.v. regarding the site of AMPA receptors to which perampanel binds is incorporated herein by reference.

Various techniques are known in the art for identifying and characterizing agents that inhibit AMPA receptors, including identifying specific binding sites for inhibitors at AMPA receptors. For example, electrophysiological techniques (such as the whole-cell patch clamp method) are suitable for quantitatively determining AMPA receptor activity and inhibition thereof by candidate agents. Exemplary methods for characterizing AMPA receptor inhibitors, including identifying specific binding sites for the inhibitors at the AMPA receptor, are described in Chang et al (Brain, 2016, 2, 139 (2): 431-443) and Yelshanskaya, M.V. et al (Neuron 2016, 91: 1305-1315).

To determine inhibition, AMPA receptors may be expressed in suitable cells (e.g., xenopus oocytes or HEK293 cells) and the level of inhibition of receptor current (e.g., glutamate-induced receptor current) by candidate agents may be measured using patch clamp current recording. Quantitative determination of inhibition can be achieved by measuring the degree of current inhibition in different concentrations of the candidate agent.

The inhibitory activity of the candidate agent may be, for example, IC₅₀The values are represented. IC (integrated circuit)₅₀Is the concentration of agent required to cause a 50% reduction in protein activity (e.g., a 50% reduction in AMPA receptor activity). In one embodiment, the IC of the agents of the invention for AMPA receptor inhibition₅₀The value is less than 10. mu.M, 5. mu.M, 4. mu.M, 3. mu.M, 2. mu.M, 1. mu.M, 0.9. mu.M, 0.8. mu.M, 0.7. mu.M, 0.6. mu.M, 0.5. mu.M, 0.4. mu.M, 0.3. mu.M, 0.2. mu.M or 0.1. mu.M.

In one embodiment, the AMPA receptor inhibitor that binds to the same AMPA receptor site as perampanel is a small molecule, such as an organic compound. The organic compound can, for example, have a molecular weight of less than about 900 daltons (Da). In another embodiment, the AMPA receptor inhibitor is a polypeptide or protein. Preferably, the AMPA receptor inhibitor that binds to the same AMPA receptor site as perampanel is a small molecule. In one embodiment, the AMPA receptor inhibitor is a perampanel derivative.

Treatment of

As used herein, the term "treating" refers to administering a combination or composition described herein to an individual having a disorder in order to prevent, alleviate, reduce or ameliorate at least one symptom associated with the disorder and/or slow, slow or block the progression of the disorder.

By "preventing" is meant administering a combination or composition as described herein to an individual who does not exhibit any symptoms of the disorder in order to slow or arrest the development of at least one symptom associated with the disorder.

The individual to be treated may be identified as one that will respond to AMPA receptor inhibition. For example, such individuals may be identified as individuals who have previously responded to an AMPA receptor inhibitor using perampanel or a pharmaceutically acceptable salt thereof, or which binds to the same AMPA receptor site as perampanel.

Epilepsy

Epilepsy is a neurological disorder in which nerve cell activity in the brain is disrupted, causing seizures or a period of abnormal behavior, sensation and sometimes loss of consciousness.

AMPA receptors play a key role in the generation and spread of seizures (Rogawski et al, actaneurol. scand. supplement 127 (197): 9-18). Receptors are present in all areas associated with epilepsy, including the cerebral cortex, amygdala, thalamus and hippocampus. In addition, AMPA receptor antagonists have broad spectrum anticonvulsant activity in a variety of in vitro and in vivo models of Epilepsy (rogawski., Epilepsy Curr, 2011, 11: 56-63).

Due to the ability of the combinations mentioned herein to optimally inhibit AMPA receptors, the combinations or compositions described herein may be used for the treatment of epilepsy.

Amyotrophic lateral sclerosis

Amyotrophic Lateral Sclerosis (ALS), also known as Lou Gehrig's disease and Motor Neuron Disease (MND), is the most common adult onset motor neuron disease and is characterized by gradual loss of upper and lower motor neurons, resulting in muscle weakness and systemic atrophy. ALS may be inherited or sporadic. Typically, patients with ALS die within a few years after the onset of the disease due to progressive respiratory muscle paralysis. Excitotoxicity is a pathological process in which neurons are destroyed and killed by the overactivity of AMPA receptors and has been implicated as the basis of the pathogenesis of ALS. Perampanel administered orally prevented the progression of the ALS phenotype in a mouse model of ALS (Akamatsu et al, Sci. Rep (2017) 6: 28649). Due to the ability of the combination or composition mentioned herein to optimally inhibit AMPA receptors, the composition may be used for the treatment of ALS.

Ischemia of local area

Ischemia is a restriction of blood flow to tissues associated with harmful deficiencies in oxygen and glucose supply (e.g., hypoxia and hypoglycemia). Ca of AMPA receptor during ischemia²⁺Permeability can be increased, which can lead to excitotoxicity and associated neuronal cell death. Ca²⁺Permeable AMPA receptors have been shown to be highly expressed in 1 pyramidal neurons of CA (the hippocampal region that is more susceptible to cell death following an ischemic event than other hippocampal regions). AMPA receptor antagonists, such as NBQX, have been shown to be useful in preventing neuronal loss in animal models of ischemia (Chang et al, (2012) European Journal of Neuroscience, 35, 1908-. Due to the ability of the combinations or compositions mentioned herein to optimally inhibit AMPA receptors, the combinations or compositions described herein may be used for the treatment of ischemia.

Cancer treatment

The association between MCT ketogenic diet, AMPA receptors and Cancer therapy has been confirmed by studies showing that human Glioblastoma cells exhibit increased levels of AMPA receptors (Choi, J. et al, Globastomata cell differential Cancer gene expressions in human tumor-associated pathoglia/macroviruses and monoclonal-derived macroviruses, Cancer Biol Ther, 2015, 16 (8): p.1205-13), and that migration and proliferation of Glioblastoma multiforme cells (GBM) is inhibited by inhibition of AMPA receptors (Ishiuchi, S. et al, Ca2+ -peripheral AMPA receptors expression of human fibroblast proliferation of human fibroblast lineage patent virus t, J. activation, Neoshima, 30, P.2007, P.2002-30, P.8000, S.978; human pathogen culture of human fibroblast expression, S.978, S. 978, et al, y, et al, Serum-dependent of AMPA receiver-mediated promotion in Lioma cells, Pathol Int, 2006, 56 (5): p.262-71.) and migration and proliferation of other Cancer cells (von roemering, c.a. et al, neural positive 2support clear cell secondary cell activation the AMPA-selective glutamate receptor-4, Cancer Res, 2014, 74 (17): p.4796-810). Furthermore, Perampanel has been shown to be a potential chemotherapeutic co-agent in single case studies of GBM treatment (Rosche, J. et al, [ Perampanel in the treatment of a patient with a viral multiple with out IDH1 multiple and with out MGMT promoter, Fortscher neural inhibitor 2015, 83 (5): pages 286-9). Thus, these studies indicate that AMPA receptor inhibition by the combination of decanoic acid and perampanel has the potential to provide adjuvant cancer therapy.

Alzheimer's disease

There is clear evidence that amyloid β (A β) increases AMPA receptor current and triggers subunit internalization, which is a theory directly correlating Glutamate receptor overactivity with neurotoxicity and memory loss of Alzheimer's disease A β has been shown to interact with β adrenergic Receptors that are responsible for the increased activity of various Receptors including AMPA-type Glutamate Receptors via cAMP/PKA signaling cascade (Wang, D. et al, Binding of amyloid peptide receptor 2) in response to neuronal Receptors, PKA-dependent Receptors, FASEB J, 2010, 24 (9): p.3511-21; wiy, E.V., Y.K, Xia and S.Oddo, Genetic damage of neuronal Receptors 3-mediated Receptors, which is shown to increase the probability of neuronal toxicity, induction of neuronal toxicity, induction of cell proliferation, induction of neuronal cell proliferation, cell proliferation, cell.

Administration of

The combination, product or composition described herein may be administered enterally or parenterally.

Preferably, the product, combination or composition is administered enterally.

Enteral administration may be oral, gastric and/or rectal.

Generally, administration of the combinations or compositions described herein may be, for example, by the oral route or another route into the gastrointestinal tract, for example, by gavage.

The subject can be a mammal, such as a human, canine, feline, equine, goat, bovine, ovine, porcine, cervid, and primate. Preferably, the subject is a human.