Combination for the treatment of epilepsy comprising decanoic acid

Abstract

1. Decanoic acid for use in the treatment of epilepsy, in combination with perampanel or a pharmaceutically acceptable salt thereof, or in combination with an AMPA receptor inhibitor that binds to the same AMPA receptor site as perampanel. [Selection diagram] None

Description

Technical Field

[0001] The present invention generally relates to (i) a combination of decanoic acid and perampanel or a pharmaceutically acceptable salt thereof, or (ii) a combination of decanoic acid and an AMPA receptor inhibitor that binds to the same AMPA receptor site as perampanel. Specifically, the present invention provides such a combination for treating epilepsy.

Background Art

[0002] Epilepsy encompasses a broad range of neurological disorders characterized by seizures. Seizures result from abnormal neural activity and manifest in a number of ways, including convulsions and loss of consciousness. In many cases, epilepsy can be managed by the use of anti-convulsant drugs. However, for a certain percentage of epilepsy patients, treatment with conventional drugs may have minimal effect on seizure activity. Surgery is an option for treating patients suffering from specific seizures, but in many individuals, a ketogenic diet can be managed less invasively and successfully.

[0003] The medium-chain triglyceride (MCT) ketogenic diet was first identified in 1971 as a treatment for refractory epilepsy. It provides one of the most effective treatment approaches for children with drug-resistant epilepsy (Liu, Epilepsia 2008; 49 Suppl. 8: 33-36) and has been demonstrated to be effective in pediatric epilepsy in randomized controlled trials (Neal et al., Epilepsia 2009; 50: 1109-1117). However, this diet has adverse gastrointestinal-related side effects such as diarrhea, vomiting, flatulence, and severe abdominal pain (Liu, Epilepsia 2008; 49 Suppl 8: 33-36). Furthermore, it has been shown that the dropout rate from this diet is high because many patients find it intolerable (Levy et al., Cochrane Database Syst Rev 2012; 3: CD001903).

[0004] Ketone bodies produced from a ketogenic diet are assumed to play a therapeutic role, but seizure control does not correlate well with ketone body levels (Likhodii et al., Epilepsia 2000;41:1400-1410; Thavendiranathan et al., Exp Neurol 2000;161:696-703). In addition to ketones, this diet also causes an increase in plasma concentrations of two fatty acids provided by MCT oil, the straight-chain decanoic acid with 10 carbons, and the straight-chain octanoic acid with 8 carbons (Haidukewych et al., Clin Chem 1982;28:642-645). In recent years, it has been established that decanoic acid, rather than octanoic acid, has an anti-seizure effect at clinically appropriate concentrations in vitro and in vivo (Chang et al., Neuropharmacology 2013;69:105-114; Wlaz et al., Progress in Neuropsychopharmacology&Biological Psychiatry 2014).

[0005] The α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPA receptor) plays an important role in the generation and propagation of seizure activity and also in the long-term adaptive cellular plasticity associated with seizure generation (Chapman, J Nutr 2000;130:1043S-1045S; Rogawski and Donevan, Adv Neurol 1999;79:947-963). This receptor is present in all regions involved in epilepsy, including the cerebral cortex, amygdala, thalamus, and hippocampus. Furthermore, AMPA receptor antagonists have a broad anti-convulsant effect in various in vitro and in vivo epilepsy models (Rogawski., Epilepsy Curr 2011;11:56-63).

[0006] In recent years, the inventors have demonstrated that decanoic acid inhibits the AMPA receptor (Chang et al., Brain.2016 Feb;139(2):431-443).

[0007] Perampanel (Fycompa) is a non-competitive AMPA receptor antagonist and is approved as an adjunctive treatment for partial-onset seizures and primary generalized tonic-clonic seizures (Frampton JE. 2015. Drugs 75:1657-68). Additionally, adjunctive perampanel has been found to be effective in children with refractory partial seizures and in the tonic-clonic seizures of idiopathic generalized epilepsy (Heyman E. Developmental Medicine & Child Neurology 2017, 59:441-444). However, it has dose-dependent behavioral side effects, and its use is restricted in some patients (Rugg-Gunn F. 2014. Epilepsia 55 Suppl 1:13-5).

[0008] The most common side effects reported in patients receiving perampanel were dizziness, somnolence, fatigue, irritability, nausea, and falls, but of particular concern to patients were the drug's cognitive and psychiatric side effects. Rugg-Gunn F. described the overall extent to which depression and aggression were reported more frequently in patients taking perampanel, especially those at higher doses, than in patients taking placebo. Heyman E. reported that a relatively high proportion of behavioral side effects were associated with perampanel, mainly in adolescents with refractory epilepsy.

SUMMARY OF THE INVENTION

PROBLEMS TO BE SOLVED BY THE INVENTION

[0009] There remains a need for improved agents for treating epilepsy.

MEANS FOR SOLVING THE PROBLEMS

[0010] The inventors have surprisingly revealed a synergistic interaction between perampanel and decanoic acid in direct AMPA receptor inhibition and seizure control. These findings are useful for combination therapy using perampanel or an AMPA receptor inhibitor that binds to the same AMPA receptor site as perampanel and decanoic acid.

[0011] (Description of the Invention) According to a first aspect of the present invention, decanoic acid for use in the treatment of epilepsy is provided, wherein the decanoic acid is used in combination with perampanel or a pharmaceutically acceptable salt thereof, or the decanoic acid is used in combination with an AMPA receptor inhibitor that binds to the same AMPA receptor site as perampanel.

[0012] According to another aspect of the present invention, perampanel or a pharmaceutically acceptable salt thereof for use in the treatment of epilepsy is provided, wherein the perampanel (or a pharmaceutically acceptable salt thereof) is used in combination with decanoic acid.

[0013] According to another aspect of the present invention, an AMPA receptor inhibitor that binds to the same AMPA receptor site as perampanel for use in the treatment of epilepsy is provided, wherein the AMPA receptor inhibitor is used in combination with decanoic acid.

[0014] Decanoic acid and perampanel or a pharmaceutically acceptable salt thereof may be administered simultaneously, separately, or sequentially, or decanoic acid and the AMPA receptor inhibitor may be administered simultaneously, separately, or sequentially. If the drugs are not administered simultaneously, the drugs are administered within a time interval capable of showing a synergistic effect of the drugs.

[0015] According to another aspect of the present invention, there is provided a combination of (i) decanoic acid and perampanel 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 for use in the treatment of epilepsy.

[0016] According to another aspect of the present invention, there is provided a product comprising (i) decanoic acid and perampanel 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 as a combined preparation for simultaneous use, separate use, or sequential use in the treatment of epilepsy.

[0017] According to another aspect of the present invention, there is provided a composition comprising (i) decanoic acid and perampanel 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 one embodiment, the composition is for use in the treatment of epilepsy.

[0018] According to another aspect of the present invention, there is provided a kit comprising (i) decanoic acid and perampanel 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. The kit may optionally include instructions for co-administering, sequentially administering, or separately administering (i) decanoic acid and perampanel or a pharmaceutically acceptable salt thereof, or (ii) decanoic acid and the AMPA receptor inhibitor to a patient in need thereof.

[0019] According to another aspect of the present invention, there is provided a method for treating epilepsy comprising the step of administering decanoic acid to a patient in need thereof, wherein the decanoic acid is administered to the patient in combination with perampanel or a pharmaceutically acceptable salt thereof, or the decanoic acid is administered to the patient in combination with an AMPA receptor inhibitor that binds to the same AMPA receptor site as perampanel.

[0020] According to another aspect of the present invention, there is provided a method for treating epilepsy comprising the step of administering perampanel or a pharmaceutically acceptable salt thereof to a patient in need thereof, wherein the perampanel or a pharmaceutically acceptable salt thereof is administered to the patient in combination with decanoic acid.

[0021] According to another aspect of the present invention, there is provided a method for treating epilepsy comprising the step of administering an AMPA receptor inhibitor that binds to the same AMPA receptor site as perampanel to a patient in need thereof, wherein the AMPA receptor inhibitor is administered to the patient in combination with decanoic acid.

[0022] According to another aspect of the present invention, there is provided a method for treating epilepsy, comprising the step of administering to a patient in need thereof a composition comprising (i) perampanel or a pharmaceutically acceptable salt thereof, and decanoic acid, or (ii) an AMPA receptor inhibitor that binds to the same AMPA receptor site as perampanel, and decanoic acid.

[0023] According to another aspect of the present invention, there is provided a combination for use in inhibiting the AMPA receptor in a subject in need thereof, the combination comprising (i) a combination of decanoic acid and perampanel or a pharmaceutically acceptable salt thereof, or (ii) a combination of decanoic acid and an AMPA receptor inhibitor that binds to the same AMPA receptor site as perampanel. The subject may be suffering from epilepsy. According to another aspect of the present invention, the subject may be suffering from ischemia, amyotrophic lateral sclerosis (ALS), cancer, or Alzheimer's disease.

[0024] In one embodiment, the subject to be treated by the present invention is identified as a subject responsive to AMPA receptor inhibition.

[0025] According to another aspect of the present invention, there is provided decanoic acid for use in the treatment of ischemia, amyotrophic lateral sclerosis (ALS), cancer or Alzheimer's disease, wherein the decanoic acid is used in combination with perampanel or a pharmaceutically acceptable salt thereof, or the decanoic acid is used in combination with an AMPA receptor inhibitor that binds to the same AMPA receptor site as perampanel.

[0026] According to another aspect of the present invention, there is provided perampanel or a pharmaceutically acceptable salt thereof for use in the treatment of ischemia, amyotrophic lateral sclerosis (ALS), cancer or Alzheimer's disease, wherein perampanel or a pharmaceutically acceptable salt thereof is used in combination with decanoic acid.

[0027] According to another aspect of the present invention, there is provided an AMPA receptor inhibitor that binds to the same AMPA receptor site as perampanel for use in the treatment of ischemia, amyotrophic lateral sclerosis (ALS), cancer or Alzheimer's disease, wherein the AMPA receptor inhibitor is used in combination with decanoic acid.

[0028] According to another aspect of the present invention, there is provided a method for treating ischemia, amyotrophic lateral sclerosis (ALS), cancer or Alzheimer's disease, comprising the step of administering decanoic acid to a patient in need thereof, wherein the decanoic acid is administered to the patient in combination with perampanel or a pharmaceutically acceptable salt thereof, or the decanoic acid is administered in combination with an AMPA receptor inhibitor that binds to the same AMPA receptor site as perampanel.

[0029] According to another aspect of the present invention, there is provided a method for treating ischemia, amyotrophic lateral sclerosis (ALS), cancer or Alzheimer's disease, comprising the step of administering perampanel or a pharmaceutically acceptable salt thereof to a patient in need thereof, wherein perampanel or a pharmaceutically acceptable salt thereof is administered to the patient in combination with decanoic acid.

[0030] According to another aspect of the present invention, there is provided a method for treating ischemia, amyotrophic lateral sclerosis (ALS), cancer or Alzheimer's disease, comprising the step of administering an AMPA receptor inhibitor that binds to the same AMPA receptor site as perampanel to a patient in need thereof, wherein the AMPA receptor inhibitor is administered to the patient in combination with decanoic acid.

[0031] According to another aspect of the present invention, there is provided a method for treating ischemia, amyotrophic lateral sclerosis (ALS), cancer or Alzheimer's disease, comprising the step of administering to a patient in need thereof a composition comprising (i) perampanel or a pharmaceutically acceptable salt thereof, and decanoic acid, or (ii) an AMPA receptor inhibitor that binds to the same AMPA receptor site as perampanel, and decanoic acid.

[0032] The treatment of epilepsy referred to in this specification may include controlling epileptic seizures.

[0033] The decanoic acid referred to in this specification may be in the form of triglycerides.

[0034] Alternatively, the decanoic acid referred to in this specification may be in the form of a pharmaceutically acceptable salt or ester. The salts and esters of decanoic acid are also known in the art as decanoates or caprates.

[0035] Decanoic acid may be included in a composition, such as a pharmaceutical composition. As described in more detail below, perampanel or a pharmaceutically acceptable salt thereof may be present in the same composition as decanoic acid or in a different composition. Alternatively, an AMPA receptor inhibitor that binds to the same AMPA receptor site as perampanel may be present in the same composition as decanoic acid or in a different composition.

[0036] In one embodiment, decanoic acid comprises at least 50, 60, 70, 80, 85, 90, 95 or 99% by weight, or 100% by weight, of the total fatty acid content of the composition. In one embodiment, decanoic acid is in the form of medium-chain triglycerides, and the triglycerides comprise at least 50, 60, 70, 80, 85, 90, 95 or 99%, or 100%, of the total fat content of the composition. In one embodiment, substantially all of the fatty acid moieties of the MCT are octanoic acid moieties and decanoic acid moieties. In one embodiment, substantially all of the fatty acid moieties of the MCT are decanoic acid moieties.

[0037] In one embodiment, the composition is substantially free of mono- or poly-unsaturated fatty acids. In one embodiment, the composition is in the form of an oil-in-water emulsion, a powder, or a food product. In one embodiment, decanoic acid is present in the composition at 5 g / L to 500 g / L, 5 g / L to 200 g / L, 5 g / L to 100 g / L, 5 g / L to 50 g / L, 5 g / L to 30 g / L, 5 g / L to 20 g / L, 10 g / L to 500 g / L, 10 g / L to 200 g / L, 10 g / L to 100 g / L, 10 g / L to 50 g / L, 10 g / L to 30 g / L, or 10 g / L to 20 g / L.

[0038] For example, decanoic acid may be present in the composition at about 5 g / L, about 10 g / L, about 15 g / L, about 20 g / L, about 30 g / L, about 40 g / L, about 50 g / L, about 60 g / L, about 70 g / L, about 80 g / L, about 90 g / L, about 100 g / L, about 110 g / L, about 120 g / L, about 130 g / L, about 140 g / L, about 150 g / L, about 175 g / L, about 200 g / L, about 225 g / L, about 250 g / L, or about 500 g / L.

[0039] In other embodiments, decanoic acid is present in a composition that is free of, or substantially free of, carbohydrates and proteins, for example, the composition has less than 2 wt%, 0.5 wt%, or 0.1 wt% carbohydrates and proteins. In one embodiment, the weight amount of lipid, relative to the total of protein and carbohydrate in the composition, is from 1 to 5 to 1. For example, the weight amount of lipid, relative to the total of protein and carbohydrate, may be 1 to 1, 2 to 1, 3 to 1, 4 to 1, 5 to 1, 2.4 to 4.0 to 1, or 2.6 to 3.8 to 1.

[0040] Decanoic acid may be included in the oil-in-water emulsion. In one embodiment, the emulsion contains decanoic acid in the form of medium-chain triglycerides, and the medium-chain triglycerides account for at least 50, 60, 70, 80, 85, 90, 95 or 99%, or 100% of the total fat content of the composition. In one embodiment, all or substantially all of the fatty acid moieties of the MCTs are decanoic acid moieties and octanoic acid moieties. In one embodiment, all or substantially all of the fatty acid moieties of the MCTs are decanoic acid moieties. The emulsion may be substantially free of protein or carbohydrate. In one embodiment, the total fat content of the oil-in-water emulsion is 5 to 40 g / 100 mL, such as 5 to 30 g / 100 mL, 5 to 25 g / 100 mL, 10 to 25 g / 100 mL or 10 to 20 g / 100 mL, or 15 to 25 g / 100 mL. In one embodiment, the energy value of the emulsion is 50 to 300 kcal per 100 mL, such as 100 to 300 kcal per 100 mL, 50 to 200 kcal per 100 mL, 150 to 250 kcal per 100 mL, or 170 to 200 kcal per 100 mL.

[0041] In one embodiment, decanoic acid is present in the powdered composition.

[0042] In other embodiments, decanoic acid is present in the composition in spray-dried form.

[0043] In other embodiments, decanoic acid is included in a fortified food or beverage.

[0044] In other embodiments, decanoic acid is present in a food product.

[0045] In other embodiments, decanoic acid is present in a medical food.

[0046] In other embodiments, decanoic acid is present in tube feed.

[0047] In other embodiments, decanoic acid is included in beverages, mayonnaise, salad dressings, margarine, low-fat spreads, dairy products, cheese spreads, processed cheese, dairy desserts, flavored milk, cream, fermented dairy products, cheese, butter, condensed milk products, ice cream mixes, soy products, pasteurized liquid eggs, bakery products, confectionery products, confectionery bars, chocolate bars, high-fat bars, UHT desserts, pasteurized desserts, gels, jellies, yogurt, or foods having a fat-based filling or a water-containing filling.

[0048] In other embodiments, decanoic acid is included in a pharmaceutical composition. The pharmaceutical composition may include one or more suitable pharmaceutically acceptable carriers, diluents, and / or excipients.

Brief Description of the Drawings

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DETAILED DESCRIPTION OF THE INVENTION

[0050] Combination According to the present invention, decanoic acid is used in combination with perampanel or a pharmaceutically acceptable salt thereof, or decanoic acid is used in combination with an AMPA receptor inhibitor that binds to the same AMPA receptor site as perampanel.

[0051] As used herein, the term "combination" or the phrases "administered in combination", "used in combination", or "combination formulation" refers to (i) the combined administration of decanoic acid with perampanel or a pharmaceutically acceptable salt thereof, or (ii) the combined administration of decanoic acid with an AMPA receptor inhibitor that binds to the same AMPA receptor site as perampanel, where the decanoic acid and perampanel or a pharmaceutically acceptable salt thereof may be administered simultaneously, separately, or sequentially, or where the decanoic acid and the AMPA receptor inhibitor may be administered simultaneously, separately, or sequentially.

[0052] As used herein, the terms "simultaneous" or "simultaneously" are used to mean that the agents are administered at the same time, i.e., concurrently.

[0053] The terms "sequentially" or "in sequence" are used to mean that two agents are administered one after the other, meaning either that decanoic acid is administered first, or that perampanel, a pharmaceutically acceptable salt thereof, or an AMPA receptor inhibitor is administered first.

[0054] The terms "separately" or "individually" are used to mean that two agents are administered independently of each other, but within a time interval such that a synergistic effect of the agents is possible. Thus, "separate" administration means that, subject to the agents showing a synergistic effect, another agent can be administered, for example, within 1 minute, 5 minutes, or 10 minutes of the administration of one agent.

[0055] The agents may be administered either as separate formulations or as a single combination formulation. It will be understood that when combined in the same formulation, the two agents must be stable and compatible with each other and with the other components of the formulation.

[0056] When the agents are co-formulated, i.e., in the same composition or formulation, they are only capable of being co-administered. When the agents are formulated in separate compositions or formulations, they can be co-administered, sequentially administered, or administered individually. Co-administration of the agents in the same formulation or separate formulations can also be described as co-administration or joint administration of the two agents.

[0057] In one embodiment, decanoic acid and perampanel or a pharmaceutically acceptable salt thereof are mixed. In other embodiments, decanoic acid and perampanel or a pharmaceutically acceptable salt thereof are present in the form of a kit comprising a formulation of decanoic acid and perampanel or a pharmaceutically acceptable salt thereof and, optionally, instructions for co-administering, sequentially administering, or individually administering the formulation to a patient in need thereof.

[0058] In alternative embodiments, an AMPA receptor inhibitor that binds to the same AMPA receptor site as decanoic acid and perampanel is mixed. In other embodiments, an AMPA receptor inhibitor that binds to the same AMPA receptor site as decanoic acid and perampanel is present in the form of a kit comprising a formulation of decanoic acid and the AMPA receptor inhibitor and, optionally, instructions for co-administering, sequentially administering, or individually administering the formulation to a patient in need thereof.

[0059] In other embodiments, decanoic acid and perampanel or a pharmaceutically acceptable salt thereof are present in a product as a combination formulation for concurrent, individual, or sequential use in the treatment of epilepsy or in the inhibition of an AMPA receptor in a subject in need of such inhibition.

[0060] Alternatively, decanoic acid and an AMPA receptor inhibitor are present in a product as a combination formulation for concurrent, individual, or sequential use in the treatment of epilepsy or in the inhibition of an AMPA receptor in a subject in need of such inhibition.

[0061] Decanoic acid and compositions containing the same Decanoic acid (also known as capric acid) has the formula CH 3 (CH 2 ) 8 COOH and is a saturated fatty acid.

[0062] Decanoic acid may be in free form (or its salts), or, for example, in the form of triglycerides, diacylglycerols, monoacylglycerols. It will be understood that triglycerides are generally preferred.

[0063] Medium-chain triglycerides (MCTs) are triglycerides in which all three fatty acid moieties are medium-chain fatty acid moieties. Medium-chain fatty acids (MCFAs) are fatty acids having 6 to 12 carbon atoms, but fatty acids having 8 and 10 carbon atoms (i.e., octanoic acid and decanoic acid) are preferred and may be referred to herein as C8 fatty acids or C8, and C10 fatty acids or C10.

[0064] The term "fatty acid moiety" refers to a part of an MCT derived from a fatty acid in an esterification reaction with glycerol. For example, an esterification reaction of glycerol with only decanoic acid results in an MCT having a decanoic acid moiety.

[0065] Homotriglycerides (i.e., all of the fatty acid moieties of the MCT are the same, for example, a C10 homotriglyceride may contain three decanoic acid moieties) and / or heterotriglycerides (i.e., not all of the fatty acid moieties of the MCT are the same) can be used in the present invention. Preferred heterotriglycerides are heterotriglycerides consisting of an octanoic acid moiety and a decanoic acid moiety.

[0066] Decanoic acid (or triglycerides containing decanoic acid) can be in the form of a composition. Pellampanel may be in the same composition or administered individually.

[0067] In one embodiment, the composition does not contain or substantially does not contain fatty acid moieties other than decanoic acid or octanoic acid. In one embodiment, the composition does not contain or substantially does not contain fatty acid moieties other than decanoic acid. In one embodiment, the composition does not contain or substantially does not contain medium-chain triglycerides (MCTs) containing fatty acid moieties other than decanoic acid and octanoic acid. In one embodiment, the composition does not contain or substantially does not contain MCTs containing fatty acid moieties other than decanoic acid. However, trace amounts (e.g., less than 3 wt%, less than 2 wt%, less than 1 wt%, or less than 0.5 wt%) of such MCTs may be present.

[0068] Examples of natural sources of MCTs include plant sources such as coconuts, coconut oil, palm kernels, palm kernel oil, and animal sources such as milk. Decanoic acid forms about 5-8% of the fatty acid composition of coconut oil.

[0069] 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 esterifying glycerol with decanoic acid.

[0070] Compositions containing decanoic acid may also contain long-chain triglycerides (LCTs). Preferably, the LCTs are at a concentration of less than 5 wt%, less than 2 wt%, less than 1 wt%, less than 0.5 wt% or less than 0.1 wt% of the composition. In one embodiment, no LCTs are present in the composition.

[0071] The composition can further contain a plurality of substances, such as minerals, vitamins, salts, for example, a plurality of palatants, a plurality of colorants, a plurality of emulsifiers, a plurality of antibacterial agents, or a plurality of other preservatives, and a plurality of functional additives. Examples of minerals that may be useful in such compositions include, for example, calcium, phosphorus, potassium, sodium, iron, chloride, boron, copper, zinc, magnesium, manganese, iodine, selenium, chromium, molybdenum, fluoride, etc. Examples of vitamins that may be useful in the compositions described herein include water-soluble vitamins (e.g., thiamine (vitamin B1), riboflavin (vitamin B2), niacin (vitamin B3), pantothenic acid (vitamin B5), pyridoxine (vitamin B6), biotin (vitamin B7), myo-inositol (vitamin B8), folic acid (vitamin B9), cobalamin (vitamin B12), and vitamin C), as well as fat-soluble vitamins (vitamin A, vitamin D, vitamin E, and vitamin K, etc.), and their salts, esters, or derivatives. Inulin, taurine, carnitine, amino acids, enzymes, coenzymes, etc. may be useful when included in various embodiments.

[0072] In one embodiment, the composition is in the form of an oil-in-water emulsion. The emulsion may substantially contain no protein or carbohydrate. In one embodiment, the total fat content of the oil-in-water emulsion is 5 - 40 g / 100 mL, for example 5 - 30 g / 100 mL, 5 - 25 g / 100 mL, 10 - 25 g / 100 mL or 10 - 20 g / 100 mL, or 15 - 25 g / 100 mL. In one embodiment, the energy value of the emulsion is 50 - 300 kcal per 100 mL, for example 100 - 300 kcal per 100 mL, 50 - 200 kcal per 100 mL, 150 - 250 kcal per 100 mL, or 160 - 200 kcal per 100 mL.

[0073] In other embodiments, the composition containing decanoic acid is delivered as part of a ketogenic diet. When the product of the present invention is delivered as part of a ketogenic diet, the ratio of total fat content: protein / carbohydrate content can be changed during treatment to achieve nutritional goals and optimize clinical benefits. The ratio can be, for example, in the range of 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.

[0074] In one embodiment, the ratio is from 2.25:1 to 3.9:1. In other embodiments, 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.

[0075] Decanoic acid or a composition containing it may be for enteral administration or parenteral administration. In a preferred embodiment, the composition is for oral administration.

[0076] In one embodiment, decanoic acid or a composition containing it is in the form of tablets, dragees, capsules, gel caps, powders, granules, solutions, emulsions, suspensions, coated particles, spray-dried particles, or pills.

[0077] In other embodiments, decanoic acid or a composition containing it may be in the form of a powder. The powder may be, for example, a spray-dried powder or a freeze-dried powder.

[0078] The composition may be one that can be used after being reconstituted with water.

[0079] Decanoic acid or a composition containing it may be inserted or mixed into food substances. The composition may be in the form of food products or feeds. In one embodiment, the food product is a human food product.

[0080] Decanoic acid or a composition containing the same may be in the form of a medical food. As used herein, the term "medical food" refers to a food product specially formulated for the dietary management of a medical disease or condition, for example, a medical disease or condition may have specific nutritional requirements that cannot be met by a normal diet alone. A medical food may be administered under medical supervision. A medical food may be for oral ingestion or tube feeding.

[0081] A composition containing decanoic acid may be in the form of a tube feed. The term "tube feed" refers to a product intended to be introduced directly into the gastrointestinal tract of a subject through a feeding tube. A tube feed may be administered, for example, through a feeding tube placed through the subject's nose (such as a nasogastric tube, a nasoduodenal tube, and a nasojejunal tube), or through a feeding tube placed directly on the subject's abdomen (such as a gastrostomy tube, a gastrojejunostomy tube, or a jejunostomy feeding tube).

[0082] A composition containing decanoic acid may be in the form of a nutritional composition or a nutritional supplement. The term "nutritional supplement" refers to a product intended to supplement the subject's normal diet.

[0083] A composition containing decanoic acid may be in the form of a complete nutritional product. The term "complete nutritional product" refers to a product that can be the sole source of nutrition for a subject.

[0084] In various embodiments, the composition may be in the form of a beverage, mayonnaise, salad dressing, margarine, low-fat spread, dairy product, cheese spread, processed cheese, dairy dessert, flavored milk, cream, fermented dairy product, cheese, butter, condensed milk product, ice cream mix, soy product, pasteurized liquid egg, bakery product, confectionery product, confectionery bar, chocolate bar, high-fat bar, liquid emulsion, spray-dried powder, freeze-dried powder, UHT dessert, pasteurized dessert, gel, jelly, yogurt, or a food having a fat-based filling or a water-containing filling.

[0085] In still other embodiments, the composition may be used to coat a food product.

[0086] The composition may be in the form of a pharmaceutical composition and may include one or more pharmaceutically acceptable carriers, diluents, and / or excipients.

[0087] Examples of such excipients suitable for the compositions described herein can be found in "Handbook of Pharmaceutical Excipients, 2nd Edition, (1994), (edited by A Wade and PJ Weller).

[0088] Carriers or diluents acceptable for therapeutic use are known in the pharmaceutical art and are described, for example, in Remington’s Pharmaceutical Sciences, Mack Publishing Co. (edited by A.R. Gennaro, 1985).

[0089] Examples of suitable carriers include lactose, starch, glucose, methylcellulose, magnesium stearate, mannitol, sorbitol, etc. Examples of suitable diluents include ethanol, glycerol, and water.

[0090] In selecting a pharmaceutical carrier, excipient, or diluent, it can be selected in relation to the intended route of administration and standard pharmacy practice. The pharmaceutical composition may contain, as a carrier, excipient, or diluent, or in addition thereto, any suitable binder(s), lubricant(s), suspending agent(s), coating agent(s), and / or solubilizing agent(s).

[0091] Examples of suitable binders include starches, gelatin, glucose, anhydrous lactose, flowable lactose, natural sugars such as β-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth, or sodium alginate, carboxymethylcellulose, and polyethylene glycol.

[0092] Examples of suitable lubricants include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like.

[0093] Multiple preservatives, multiple stabilizers, multiple dyes, and even multiple flavoring agents may be provided in the composition. Examples of multiple preservatives include sodium benzoate, sorbic acid, and esters of p-hydroxybenzoic acid. Multiple antioxidants and multiple suspending agents may also be used.

[0094] Nutritionally acceptable carriers, diluents, and excipients include those used as standards in the food industry that are suitable for ingestion by humans or animals. Typical nutritionally acceptable carriers, diluents, and excipients are well known to those skilled in the art.

[0095] Perampanel Perampanel is a non-competitive AMPA glutamate receptor antagonist. Perampanel is marketed under the name Fycompa (trademark) and is indicated for the adjunctive treatment of partial-onset seizures, with or without secondary generalization, in adults and adolescents with epilepsy. It is also indicated for the adjunctive treatment of primary generalized tonic-clonic seizures in adults and adolescents with idiopathic generalized epilepsy and has shown potential in the treatment of drug-resistant epilepsy. As used herein, the term "perampanel" refers to a compound having the following structure:

Chemical formula

[0096] As used herein, the term "pharmaceutically acceptable salts" refers to any salt preparation 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-pyrrolidin-1'-ylmethylbenzimidazole, diethylamine and other alkylamines, piperazine, tris(hydroxymethyl)aminomethane; alkali metal salts such as lithium, potassium, sodium; alkaline earth metal salts such as barium, calcium, magnesium; transition metal salts such as zinc, aluminum; other metal salts such as sodium hydrogen phosphate, disodium phosphate; mineral acids such as hydrochloride, sulfate; and salts of organic acids such as acetate, lactate, malate, tartrate, citrate, ascorbate, succinate, butyrate, valerate, fumarate.

[0097] Perampanel can be administered according to an individual patient response in order to optimize the balance between efficacy and tolerability.

[0098] Preferably, perampanel is administered orally.

[0099] Perampanel at a dose of 4 mg / day to 12 mg / day has been shown to be an effective treatment for partial seizures. Perampanel at a dose of up to 8 mg / day has been shown to be effective for primary generalized tonic-clonic seizures. In one embodiment, the dose of perampanel used in the present invention is 4 mg / day to 12 mg / day. However, the dose of perampanel is not limited to these doses and may be increased or decreased according to the response of the subject.

[0100] An AMPA receptor inhibitor that binds to the same AMPA receptor site as perampanel The AMPA receptor is a non-N-methyl-D-aspartic acid type (non-NMDA type) ion channel type glutamate membrane-penetrating receptor that mediates fast synaptic transmission in the central nervous system, and perampanel is known to selectively inhibit synaptic excitation via the AMPA receptor without affecting the NMDA receptor response (Rogawski M.A., Acta Neurol Scand Suppl. 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 an allosteric site outside the ion channel extracellular side.

[0101] As used herein, the expression "AMPA receptor inhibitor that binds to the same AMPA receptor site as perampanel" or "AMPA receptor inhibitor that binds to the same receptor site as perampanel" means that the AMPA receptor inhibitor binds to a site on the same AMPA receptor as perampanel. Perampanel and related compounds have been suggested to bind to the S1-M1 and S2-M4 linkers between the transmembrane domain and the extracellular domain of the GluA2 subunit of the AMPA receptor. The AMPA receptor site to which perampanel binds has been characterized in Yelshanskaya, M.V., Neuron 2016, 91:1305-1315. The specific disclosure of Yelshanskaya, M.V. regarding the AMPA receptor site to which perampanel binds is incorporated herein by reference.

[0102] Numerous techniques suitable for identifying and characterizing agents that inhibit the AMPA receptor, including determining the specific binding site of the inhibitor to the AMPA receptor, are known in the art. For example, electrophysiological techniques such as the whole-cell patch clamp method are suitable for quantitatively assaying AMPA receptor activity and its inhibition by candidate agents. Exemplary methods for characterizing AMPA receptor inhibitors, including determining the specific binding site of the inhibitor to the AMPA receptor, are described in Chang et al., Brain. 2016 Feb;139(2):431-443, and Yelshanskaya, M.V. et al., Neuron 2016, 91:1305-1315.

[0103] For determination of inhibition, the AMPA receptor can be expressed in a suitable cell (e.g., Xenopus oocytes or HEK293 cells), and patch clamp current recordings can be used to measure the level of inhibition of receptor current (e.g., receptor current induced by glutamate) by the candidate agent. A quantitative determination of inhibition can be achieved by varying the concentration of the candidate agent and measuring the degree of current inhibition.

[0104] The inhibitory activity of the candidate agent can be, for example, IC 50It can be represented by a value. IC 50 is the concentration of the agent required to cause a 50% decrease in the activity of the protein (e.g., a 50% decrease in AMPA receptor activity). In one embodiment, the agent of the present invention has an IC 50 value for AMPA receptor inhibition of less than 10 μM, 5 μM, 4 μM, 3 μM, 2 μM, 1 μM, 0.9 μM, 0.8 μM, 0.7 μM, 0.6 μM, 0.5 μM, 0.4 μM, 0.3 μM, 0.2 μM, or 0.1 μM.

[0105] In one embodiment, an 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 may have a molecular weight of less than about 900 daltons (Da), for example. In other embodiments, the AMPA receptor inhibitor is a polypeptide or a 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.

[0106] Treatment As used herein, the term "treatment" refers to administering to a subject having a condition, for the purpose of preventing, attenuating, reducing, or ameliorating at least one symptom associated with that condition and / or for the purpose of retarding, reducing, or preventing the progression of that condition, the combinations or compositions described herein.

[0107] "Preventing" means administering the combinations or compositions described herein to a subject that does not exhibit any symptoms of the condition for the purpose of reducing or preventing the onset of at least one symptom associated with that condition.

[0108] The subject to be treated can be identified as a subject responsive to AMPA receptor inhibition. Such a subject can be identified, for example, as a subject that has previously responded to treatment with perampanel or a pharmaceutically acceptable salt thereof, or an AMPA receptor inhibitor that binds to the same AMPA receptor site as perampanel.

[0109] Epilepsy Epilepsy is a neurological disorder in which nerve cell activity in the brain is disrupted, causing seizures, or periods of abnormal behavior, sensation, and sometimes loss of consciousness.

[0110] AMPA receptors play an important role in the generation and spread of epileptic seizures (Rogawski et al., Acta Neurol. Scand. Suppl. 127(197):9 - 18). The receptors are present in all regions involved in epilepsy, including the cerebral cortex, amygdala, thalamus, and hippocampus. Furthermore, AMPA receptor antagonists have a broad antiepileptic effect in various in vitro and in vivo epilepsy models ((Rogawski, Epilepsy Curr 2011;11:56 - 63).

[0111] Since the combinations referred to herein can optimally inhibit AMPA receptors, epilepsy can be treated using the combinations or compositions described herein.

[0112] 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, characterized by the progressive loss of both upper and lower motor neurons, resulting in muscle weakness and atrophy throughout the body. ALS can be either genetic or sporadic. Typically, patients with ALS die within a few years of disease onset due to progressive respiratory muscle paralysis. Excitotoxicity, that is, the pathological process by which neurons are damaged and killed by the over - activity of AMPA receptors, has been proposed to underlie the cause of ALS. In a mouse model of ALS, oral administration of perampanel inhibited the progression of the ALS phenotype (Akamatsu et al., Sci. Rep(2017)6:28649). Since the combinations or compositions referred to herein can optimally inhibit AMPA receptors, ALS can be treated using the composition.

[0113] Ischemia Ischemia is a restriction of blood flow to tissues that is associated with a deleterious lack of oxygen and glucose supply, such as hypoxia and hypoglycemia. During ischemia, the Ca 2+ permeability of AMPA receptors may increase, leading to excitotoxicity and associated neuronal death. Ca 2+ permeable AMPA receptors have been shown to be highly expressed in CA1 pyramidal neurons, and this region of the hippocampus is more vulnerable to cell death following an ischemic event than other hippocampal regions. AMPA receptor antagonists such as NBQX have been demonstrated to be beneficial in preventing neuronal loss in animal models of ischemia (Chang et al., (2012) European Journal of Neuroscience, 35, 1908-1916). Since the combinations or compositions referred to herein can optimally inhibit AMPA receptors, ischemia can be treated using the combinations or compositions described herein.

[0114] Cancer The association between the MCT ketone diet, AMPA receptors, and cancer treatment has been established by studies demonstrating that human glioblastoma cells express high levels of AMPA receptors (Choi, J., et al., Glioblastoma cells induce differential glutamatergic gene expressions in human tumor-associated microglia / macrophages and monocyte-derived macrophages. Cancer Biol Ther, 2015. 16(8): p. 1205-13), and inhibition of AMPA receptors suppresses the migration and proliferation of glioblastoma multiforme cells (GBM) (Ishiuchi, S., et al., Ca2+-permeable AMPA receptors regulate growth of human glioblastoma via Akt activation. J Neurosci, 2007. 27(30): p. 7987-8000, Ishiuchi, S., et al., Blockage of Ca(2+)-permeable AMPA receptors suppresses migration and induces apoptosis in human glioblastoma cells. Nat Med, 2002. 8(9): p. 971-8, Yoshida, Y., et al., Serum-dependence of AMPA receptor-mediated proliferation in glioma cells. Pathol Int, 2006. 56(5): p. 262-71.) and other cancer cells (von Roemeling, C. A., et al., Neuronal pentraxin 2 supports clear cell renal cell carcinoma by activating the AMPA-selective glutamate receptor-4. Cancer Res, 2014. 74(17): p. 4796-810).Furthermore, perampanel has been shown to be a potentially chemotherapeutically active adjuvant in a single case study of GBM treatment (Rosche, J., et al., [Perampanel in the treatment of a patient with glioblastoma multiforme without IDH1 mutation and without MGMT promotor methylation]. Fortschr Neurol Psychiatr, 2015. 83(5): p. 286-9). Thus, these studies suggest that AMPA receptor inhibition by the combination of decanoic acid and perampanel may offer adjuvant cancer therapy.

[0115] Alzheimer's disease There is strong evidence that amyloid-beta (Aβ) increases AMPA receptor current and induces internalization of subunits, and there is a theory that relates the hyperactivity of glutamate receptors to neurotoxicity and memory loss directly in Alzheimer's disease. Aβ has been shown to interact with beta-adrenergic receptors that control the gene expression and activity of various receptors, including AMPA-type glutamate receptors, via the cAMP / PKA signaling cascade (Wang, D., et al., Binding of amyloid beta peptide to beta2 adrenergic receptor induces PKA-dependent AMPA receptor hyperactivity. FASEB J, 2010. 24(9): p. 3511-21, Wisely, E.V., Y.K. Xiang, and S. Oddo, Genetic suppression of beta2-adrenergic receptors ameliorates tau pathology in a mouse model of tauopathies. Hum Mol Genet, 2014. 23(15): p. 4024-34). Phosphorylation of the GluA1 subunit of the AMPA receptor by PKA has been shown to increase channel opening probability, thereby increasing calcium influx into the cell (Banke, T.G., et al., Control of GluR1 AMPA receptor function by cAMP-dependent protein kinase. J Neurosci, 2000. 20(1): p. 89-102). Indeed, numerous studies have shown that adding Aβ to neuronal cultures increases the generated current by calcium-dependent AMPA receptors and causes neurotoxicity (Whitcomb, D.J., et al., Intracellular oligomeric amyloid-beta rapidly regulates GluA1 subunit of AMPA receptor in the hippocampus. Sci Rep, 2015. 5: p. 10934).This suggests that Aβ-induced excitotoxicity may contribute to widespread neuronal death in Alzheimer's disease. Thus, in addition to ketones that provide energy to glucose-tolerant neurons, an MCT ketogenic diet can improve neuronal survival through inhibition of AMPA receptors by decanoic acid. Additionally, there is evidence that Aβ treatment induces internalization of the GluA2 subunit, the only AMPA receptor subunit type that confers calcium impermeability. Thus, internalization of GluA2 may further increase total calcium influx at the postsynaptic site and further increase inflammation and neurotoxicity (Beppu, K., et al., Expression, subunit composition, and function of AMPA-type glutamate receptors are changed in activated microglia; possible contribution of GluA2(GluR-B)-deficiency under pathological conditions. Glia, 2013. 61(6): p. 881-91, Noda, M., Dysfunction of Glutamate Receptors in Microglia May Cause Neurodegeneration. Curr Alzheimer Res, 2016. 13(4): p. 381-6), which suggests the role of AMPA receptor antagonists in the treatment of Alzheimer's disease. Since the combinations or compositions referred to herein can optimally inhibit AMPA receptors, Alzheimer's disease can be treated using the combinations or compositions referred to herein.

[0116] Administration The combinations, products, or compositions described herein can be administered enterally or parenterally.

[0117] Preferably, the product, combination, or composition is administered enterally.

[0118] Enteral administration may be oral, intragastric, and / or rectal administration.

[0119] Generally speaking, the administration of the combinations or compositions described herein may be, for example, by the oral route or another route to the gastrointestinal tract, for example, the administration may be by tube feeding.

[0120] The subject may be a mammal such as a human, dog, cat, horse, goat, cow, sheep, pig, deer, and primate. Preferably, the subject is a human.

Examples

[0121] Unless otherwise indicated, the practice of the present invention employs conventional techniques of chemistry, molecular biology, microbiology, recombinant DNA, and immunology, which are within the capabilities of those skilled in the art. Such techniques are explained in the literature. See, for example, J. Sambrook, E. F. Fritsch, and T. Maniatis, 1989, Molecular Cloning: A Laboratory Manual, Second Edition, Books 1-3, Cold Spring Harbor Laboratory Press; Ausubel, F. M. et al. (1995 and periodic supplements; Current Protocols in Molecular Biology, ch. 9, 13, and 16, John Wiley & Sons, New York, N.Y.); B. Roe, J. Crabtree, and A. Kahn, 1996, DNA Isolation and Sequencing: Essential Techniques, John Wiley & Sons; J. M. Polak and James O’D. McGee, 1990, In Situ Hybridization: Principles and Practice; Oxford University Press; M. J. Gait (Editor), 1984, Oligonucleotide Synthesis: A Practical Approach, Irl Press; D. M. J. Lilley and J. E. Dahlberg, 1992, Methods of Enzymology: DNA Structure Part A: Synthesis and Physical Analysis of DNA Methods in Enzymology, Academic Press; and E. M. Shevach and W. Strober, 1992 and periodic supplements, Current Protocols in Immunology, John Wiley & Sons, New York, NY. Each of these general texts is incorporated herein by reference.

[0122] Example 1 - Method Direct AMPA Receptor Current Recording As described above (Chang et al. 2016. Brain 139:431 - 43), AMPA receptor subunits (GluA2 / 3, GluA1 / 2, and GluA3) were expressed in Xenopus oocytes, and inhibition by decanoic acid (Sigma Ltd) and perampanel (Apexmol Technology Co., Ltd) was measured using agonist - induced inward currents.

[0123] Analysis of PTZ - like Seizure Activity in Rat Hippocampus As described above (Chang et al. 2016. Brain 139:431 - 43), PTZ (2 mM) was applied to the perfusion fluid, [K+] was increased (up to 6 mM), and seizure - like activity was induced in rat olfactory cortex - hippocampal slices. Perampanel (100 or 500 nM) or DMSO was applied to the perfusion fluid, and then decanoic acid (Sigma Ltd) was applied at increasing concentrations at 10 - minute intervals. The change in the discharge frequency was measured at 1 - minute intervals, averaged every 5 minutes, and normalized to the baseline. Data were analyzed using Origin (OriginLab Corporation, MA, USA) and SPSS (IBM, UK), and IC 50 values were calculated from the data values fitted using a Hill plot. Statistical analysis was performed using one - way ANOVA and two - sided Dunnett's post - hoc test.

[0124] Example 2 - Direct Inhibition of AMPA Receptors by Perampanel and Decanoic Acid First, the effect of perampanel on the current induced by applying glutamate (100 μM) to Xenopus oocytes expressing GluA1 / 2 or 2 / 3, which are the two most commonly observed combinations of AMPA receptor subunits in the hippocampus, was determined (Jacob and Weinberg, 2015. Hippocampus 25:798 - 812). Perampanel had an IC50 Inhibited AMPA receptor current at the value (Figure 1A, B). In addition, perampanel inhibited AMPA receptor current in a non-competitive manner, and the inhibition by perampanel did not reverse even when the glutamate concentration increased (Figure 1C). Perampanel also reduced the glutamate-induced maximum response to 75.2% (2.5 μM) and 16.9% (5 μM). These data directly demonstrate for the first time the inhibition of AMPA receptors by perampanel via non-competitive inhibition without subunit specificity.

[0125] ​Recent studies have suggested that the binding sites of perampanel and decanoic acid on the AMPA receptor are different (Chang P, Augustin K, Boddum K, Williams S, Sun M, et al. 2016. Brain 139:431-43; Yelshanskaya MV, Singh AK, Sampson JM, Narangoda C, Kurnikova M, Sobolevsky AI. 2016. Neuron 91:1305-15). Perampanel and related compounds have been suggested to bind to the S1-M1 and S2-M4 linkers between the transmembrane and extracellular domains (Yelshanskaya MV, Singh AK, Sampson JM, Narangoda C, Kurnikova M, Sobolevsky AI. 2016. Neuron 91:1305-15). In contrast, decanoic acid modeling has suggested binding to the M3 region (Chang P, Augustin K, Boddum K, Williams S, Sun M, et al. 2016. Brain 139:431-43). To confirm this, the GluA3 variant (11) of the GYKI-resistant subunit was expressed and evaluated for sensitivity to perampanel and decanoic acid (Figure 1C). Perampanel (20 μM) decreased the glutamate-induced current of the wild-type AMPA receptor (GluA3) by 94.7%, but only by 54.3% in the mutant receptor (p<0.0001). In contrast, decanoic acid (1 mM) decreased the wild-type and mutant glutamate-induced currents by 74.5% (SEM 6.4) and 72.8% (SEM 0.3), respectively, strongly supporting that decanoic acid interacts with the AMPA receptor at a different site.

[0126] To investigate the possibility of synergy between decanoic acid and perampanel, the sensitivity of the AMPA receptor (GluA2 / 3) to decanoic acid within the concentration range observed in patients on the MCT ketogenic diet (12) was tested with two concentrations of perampanel (1 μM and 4 μM) (Figure 1E, F). In these experiments, the potency of decanoic acid was increased by perampanel, and the IC 50decreased from 0.52 mM (in the absence of perampanel) to 0.10 mM or 0.04 mM in the presence of 1 μM or 4 μM perampanel, respectively (p < 0.0001). This effect was also observed in the GluA1 / 2 AMPA receptor (Figure 1G), and the IC 50 decreased from 0.92 mM (in the absence of perampanel) to 0.21 mM and 0.09 mM in the presence of 1 μM and 4 μM, respectively (p < 0.0001). Repeating this approach using perampanel and two concentrations of decanoic acid (50 mM and 100 mM) (Figure 1H, I, J) also showed a significant increase in the potency of perampanel, and the IC 50 values decreased from 5.1 μM (in the absence of DA) to 1.7 μM and 1.6 μM in the presence of 50 mM and 100 mM DA, respectively, for GluA2 / 3, and from 6.2 μM to 2.1 μM and 2.2 μM, respectively, for GluA1 / 2 (both p < 0.0001). These results suggest a synergistic inhibition of the AMPA receptor by decanoic acid and perampanel.

[0127] Example 3 - Effects of Perampanel and Decanoic Acid on Seizure Models Next, the synergistic effects of perampanel and decanoic acid on seizures were examined in rat hippocampal slices with seizure-like activity induced by pentylenetetrazole (PTZ) treatment. In these experiments, as the concentration of decanoic acid was increased, seizure-like activity decreased at 300 μM and was blocked at 1000 μM (Figure 3A), which is consistent with previous data (Chang P, Augustin K, Boddum K, Williams S, Sun M, et al. 2016. Brain 139:431-43). Repeating this assay with the addition of perampanel (100 and 500 nM) and normalizing the data to perampanel alone showed an increase in seizure-like control with decanoic acid at 10-1000 μM. Modeling these data showed that decanoic acid (10 μM) combined with perampanel (100 nM) significantly decreased seizure activity from 95.6% (CI 80.8-110.4) in the absence of decanoic acid to 76.8% (CI 63.1-90.4, p = 0.048) in the presence of decanoic acid and blocked activity at 600 μM. Similar activity was shown with high concentrations of perampanel (500 nM), with a decrease in baseline (10 μM) inhibition to 69.6% (CI 53.1-86, p = 0.015). These data also show that the IC 50 of decanoic acid decreased from 352 μM (CI: 200.1-621.5) to 196 μM (145.2-264.8) and 122 μM (49.13-302.9, p = 0.0252) with 100 nM and 500 nM, respectively.

[0128] Summary The data presented herein examine the use of combinations containing decanoic acid and perampanel for the treatment of epilepsy. The data provided herein show the IC of perampanel against combinations of the two most common AMPA receptor subunits (GluA2 / 3 and GluA1 / 2). 50This indicates a significant decrease of about 3-fold in value, demonstrating direct synergistic inhibition of these receptors at the molecular level. The synergistic effect of combination therapy has also been shown to be evident in an ex vivo seizure model that induced seizure-like activity by application of PTZ.

[0129] The potential synergistic effect between perampanel and decanoic acid depends on the appropriate concentration of each compound. In an initial study on the peripheral blood concentration of medium-chain fatty acids in patients on a MCT ketogenic diet, the blood concentration of decanoic acid was approximately 87 - 552 μM, with an average of 157 μM (Haidukewych D, Forsythe WI, Sills M. 1982. Clin Chem 28:642 - 5; Sills MA, Forsythe WI, Haidukewych D. 1986. Arch Dis Child 61:1173 - 7).

[0130] In a rodent model, the ratio of plasma decanoic acid to brain decanoic acid in the animal model is approximately 0.7 (Wlaz P, Socala K, Nieoczym D, Zarnowski T, Zarnowska I, et al. 2015. Prog Neuropsychopharmacol Biol Psychiatry 57:110 - 6). Extrapolating this ratio to the human brain suggests that decanoic acid is likely to be present in the brain at an average concentration of about 110 μM. The data in this specification suggest that 100 μM of decanoic acid triples the inhibition of AMPA receptors by perampanel and has an even greater impact on seizure activity.

[0131] These data support the potential clinical relevance of this synergistic effect in patients. This can provide a means to reduce the side effect profile of perampanel, or can result in significant improvements in the treatment of diseases such as seizure control where AMPA receptor inhibition is beneficial. Thus, the synergistic inhibition of AMPA receptors by the combination of perampanel and decanoic acid can lead to both improved treatment and reduced side effects in the patient population. Considering the side effects of perampanel, particularly the cognitive and psychiatric side effects observed at high doses as reported by Rugg-Gunn, F. 2014 Jan;55 Suppl 1:13-5, this is a significant advantage of the present invention. The inventors believe that the combination of decanoic acid and perampanel (or a pharmaceutically acceptable salt thereof) enables the use of perampanel at lower doses in the treatment of epilepsy, thereby reducing the severity and / or morbidity of side effects.

Claims

Claim 1 A composition for treating epilepsy, comprising decanoic acid, wherein the decanoic acid is used in combination with perampanel or a pharmaceutically acceptable salt thereof, and the decanoic acid and the perampanel are administered simultaneously, separately, or sequentially. Claim 2 A composition for treating epilepsy, comprising perampanel or a pharmaceutically acceptable salt thereof, wherein the perampanel or the pharmaceutically acceptable salt thereof is used in combination with decanoic acid, and the perampanel and the decanoic acid are administered simultaneously, separately, or sequentially. Claim 3 A combination for treating epilepsy, comprising decanoic acid and perampanel or a pharmaceutically acceptable salt thereof, and the decanoic acid and the perampanel are administered simultaneously, separately, or sequentially. Claim 4 A composition for treating epilepsy, comprising decanoic acid and perampanel or a pharmaceutically acceptable salt thereof. Claim 5 The composition according to claim 4, wherein the composition is a pharmaceutical composition and further comprises one or more of a pharmaceutically acceptable carrier, excipient, and / or diluent. Claim 6 The composition according to any one of claims 1, 2, 4, and 5, wherein the composition is for treating a subject identified as a subject responsive to AMPA receptor inhibition. Claim 7 The composition according to any one of claims 1, 2, and 4 to 6, wherein the decanoic acid is in the form of a triglyceride. Claim 8 The composition according to any one of claims 1, 2, and 4 to 7, wherein the decanoic acid is contained in an oil-in-water emulsion, powder, or food product. Claim 9 The composition according to any one of claims 1, 2, and 4 to 8, wherein the decanoic acid is contained in a medical food, tube feed, nutritional composition, or nutritional supplement. Claim 10 The composition according to any one of claims 1, 2, and 4 to 9, wherein the decanoic acid is contained in a pharmaceutical composition, and the pharmaceutical composition further comprises one or more pharmaceutically acceptable carriers, diluents, and / or excipients. Claim 11 The combination according to claim 3, wherein the combination is for treating a subject identified as a subject responsive to AMPA receptor inhibition. Claim 12 The combination according to claim 3 or 11, wherein the decanoic acid is in the form of a triglyceride. Claim 13 The combination according to any one of claims 3, 11, and 12, wherein the decanoic acid is contained in an oil-in-water emulsion, powder, or food product.

14. The combination according to any one of claims 3 and 11 to 13, wherein the decanoic acid is contained in a medical food, tube feed, nutritional composition, or nutritional supplement.

15. The combination according to any one of claims 3 and 11 to 14, wherein the decanoic acid is contained in a pharmaceutical composition, and the pharmaceutical composition further comprises one or more pharmaceutically acceptable carriers, diluents, and / or excipients.

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