Antiepileptic composition

Abstract

This antiepileptic composition contains one of or both of a bacterium of the genus Bifidobacterium and a culture thereof. The bacterium of the genus Bifidobacterium may be Bifidobacterium breve. The bacterium of the genus Bifidobacterium may be an MCC1274 strain (FERM BP-11175) of Bifidobacterium breve. The antiepileptic composition may contain one of or both of the bacterium of the genus Bifidobacterium and a culture thereof in an amount of 1×106 to 1×1012 CFU / g.

Description

[Technical Field]

[0001] This invention relates to an anti-epileptic composition. This application claims priority with respect to Japanese Patent Application No. 2022-089546, filed in Japan on June 1, 2022, and the contents of that application are incorporated herein by reference. [Background technology]

[0002] Epilepsy is a condition characterized by repeated epileptic seizures. Epileptic seizures are caused by abnormal electrical activity in nerve cells in the brain, and they occur when the nervous system, including motor nerves, sensory nerves, autonomic nerves, consciousness, or higher brain functions, suddenly becomes abnormally active. Therefore, epileptic seizures produce a variety of symptoms corresponding to each part of the nervous system, such as stiffness in a part of the body (caused by abnormal motor nerves), numbness in the limbs or tinnitus (caused by abnormal sensory nerves), palpitations or nausea (caused by abnormal autonomic nerves), loss of consciousness, or difficulty speaking (caused by abnormal higher brain functions). The prevalence of epilepsy is said to be 0.5-1%, and according to Non-Patent Document 1, it is a relatively common disease. Furthermore, epilepsy can occur at any age, from infants to the elderly.

[0003] The diagnosis of epilepsy may include neurological and blood tests. Brain abnormalities are detected by electroencephalogram (EEG), high-density EEG, computed tomography (CT) scans, magnetic resonance imaging (MRI), positron emission tomography (PET) scans, single-photon emission computed tomography (SPECT), and neuropsychological tests to assess thinking, memory, and speech abilities. Analytical techniques include statistical parametric mapping (SPM), Curry analysis, and magnetoencephalography (MEG).

[0004] Treatment for epilepsy primarily involves the use of antiepileptic drugs. Antiepileptic drugs do not eliminate the cause of epilepsy, but rather reduce the likelihood of seizures. However, it is known that in some cases of epilepsy, seizures cannot be controlled for a certain period (specifically, for more than one year or more than three times the longest seizure interval before treatment, whichever is longer) even when two antiepileptic drugs, either alone or in combination, are administered at sufficient blood concentrations within a range that does not cause side effects. This is called drug-resistant epilepsy. According to Non-Patent Literature 2, 20-30% of epilepsy patients are estimated to have drug-induced epilepsy. Furthermore, the drugs used in drug therapy are pharmaceuticals and therefore not easily administered, and generally tend to cause side effects. Known side effects of antiepileptic drugs include acute initial reactions due to drug idiosyncrasies involving allergic mechanisms, dose-dependent depressant effects on the nervous system (specifically, dizziness, nystagmus, double vision, drowsiness, nausea, or loss of appetite), and chronic side effects seen with long-term use (specifically, weight gain, hirsutism or hair loss, urinary tract stones, or cerebellar atrophy).

[0005] In cases of drug-resistant epilepsy, a ketogenic diet may be used as a dietary therapy, and Non-Patent Document 3 reports that a child who followed a ketogenic diet for one year showed a reduction in epileptic symptoms. On the other hand, because the ketogenic diet is characterized by a high fat and low carbohydrate diet, it may lead to hypoglycemia, dyslipidemia, or developmental disorders. [Prior art documents] [Non-patent literature]

[0006] [Non-Patent Document 1] Yuji Inoue, Epilepsy Research, 2005, Vol. 23, pp. 249-253. [Non-Patent Document 2] Hiroto Iwasa, et al., Brain Science, 2001, Vol. 23, pp. 951-959. [Non-Patent Document 3] Freitas, Alessandra, et al., “Ketogenic diet for the treatment of refractory epilepsy: a 10-year experience in children,” Arquivos de Neuro-Psiquiatria, 2007, Vol. 65, No. 2B, pp. 381-384. [Overview of the Initiative] [Problems that the invention aims to solve]

[0007] One of the objectives of the present invention is to provide an antiepileptic composition that is effective in preventing, treating, or alleviating epileptic seizures. [Means for solving the problem]

[0008] [1] An antiepileptic composition comprising either or both a bacterium of the genus Bifidobacterium and / or a culture thereof. [2] The antiepileptic composition according to [1], wherein the Bifidobacterium bacterium is Bifidobacterium breve. [3] The antiepileptic composition according to [1] or [2], wherein the Bifidobacterium bacterium is Bifidobacterium breve MCC1274 strain (FERM BP-11175). [4] Bifidobacterium bacteria and / or their cultures, one or both, 1 × 10 6 ~1 × 10 12 An antiepileptic composition according to any one of [1] to [3], comprising CFU / g. [5] An antiepileptic composition according to any one of [1] to [4], used for the prevention, treatment, or reduction of epileptic seizures. [6] The antiepileptic composition according to any one of [1] to [5], wherein the antiepileptic composition is a pharmaceutical or food product. [7] The antiepileptic composition according to any one of [1] to [6], wherein the antiepileptic composition is administered to subjects who require prevention, treatment, or reduction of epileptic seizures. [8] An antiepileptic composition according to any one of [1] to [7], comprising either or both of the Bifidobacterium bacteria and their culture as active ingredients. [9] Use of one or both of Bifidobacterium bacteria and their cultures in the manufacture of compositions for administration to subjects in need of prevention, treatment or reduction of epileptic seizures.

[10] The use described in [9], wherein the bacterium of the genus Bifidobacterium is Bifidobacterium breve.

[11] Use according to [9] or

[10] , wherein the Bifidobacterium bacterium is Bifidobacterium breve MCC1274 strain (FERM BP-11175).

[12] Bifidobacterium bacteria or cultures thereof for use in the prevention, treatment or reduction of epileptic seizures.

[13] The Bifidobacterium bacterium described in

[12] or a culture thereof, wherein the Bifidobacterium bacterium is Bifidobacterium breve.

[14] The Bifidobacterium bacterium or its culture as described in

[12] or

[13] , wherein the Bifidobacterium bacterium is Bifidobacterium breve MCC1274 strain (FERM BP-11175).

[15] A method for preventing, treating or alleviating epileptic seizures, comprising administering an effective amount of one or both of a Bifidobacterium bacterium and its culture to a subject who needs prevention, treatment or alleviation of epileptic seizures.

[16] The method according to

[15] , wherein the Bifidobacterium bacterium is Bifidobacterium breve.

[17] The method according to

[15] or

[16] , wherein the Bifidobacterium bacterium is Bifidobacterium breve MCC1274 strain (FERM BP-11175).

Effects of the Invention

[0009] According to the present invention, an anti-epileptic composition effective for preventing, treating or alleviating epileptic seizures can be provided. Note that the effects described here are not necessarily limited and may be any of the effects described in this specification.

Brief Description of the Drawings

[0010] [Figure 1] Shows the administration schedule of Pentylenetetrazole (PTZ) and Bifidobacterium breve MCC1274 strain (FERM BP-11175) in the test example. [Figure 2] Shows a graph representing the relationship between the number of administrations of PTZ and the average seizure score in the administration group and non-administration group of Bifidobacterium breve MCC1274 strain (FERM BP-11175).

Modes for Carrying Out the Invention

[0011] The following describes preferred embodiments for carrying out the present invention. Note that the embodiments described below are merely examples of typical embodiments of the present invention, and this should not be interpreted as narrowing the scope of the present invention.

[0012] [1. Composition for anti-epileptic use] The present invention provides an antiepileptic composition comprising either or both Bifidobacterium bacteria and / or their cultures as active ingredients.

[0013] <Active ingredients> The active ingredient of the antiepileptic composition of the present invention is either or both Bifidobacterium bacteria and / or their cultures. Examples of Bifidobacterium bacteria targeted by the present invention include Bifidobacterium breve, Bifidobacterium lactis, Bifidobacterium longum, Bifidobacterium infantis, Bifidobacterium adolescentis, Bifidobacterium bifidum, and Bifidobacterium animalis. These Bifidobacterium species may be targeted individually, or two or more species may be arbitrarily combined. While not limited, preferred examples include Bifidobacterium breve, Bifidobacterium longum, and Bifidobacterium infantis. More preferably, Bifidobacterium longum and Bifidobacterium breve. Even more preferably, Bifidobacterium breve strain MCC1274 (FERM BP-11175) and / or its culture. Bifidobacterium bacteria and / or their cultures are used for the production of the anti-epileptic composition of the present invention. It is preferable that both the Bifidobacterium bacteria and their cultures be live.

[0014] The following description will focus on the case where the bacterium in the genus Bifidobacterium is Bifidobacterium breve, but this will not narrow the scope of the present invention. Bifidobacterium breve is a species of bacterium belonging to the genus Bifidobacterium. Bifidobacterium breve is mainly found in the large intestine of infants and is known as an infant-type Bifidobacterium bacterium, along with Bifidobacterium longum subsp. infantis and other species belonging to the genus Bifidobacterium.

[0015] The antiepileptic composition of the present invention is highly safe and extremely useful because its active ingredients are either or both Bifidobacterium bacteria and / or cultures containing Bifidobacterium bacteria, which are mainly found in large quantities in the large intestine of infants. Therefore, there is little need to worry about side effects even with long-term, continuous administration. Furthermore, it is highly safe even when used in combination with other drugs.

[0016] In this invention, examples of Bifidobacterium breve include Bifidobacterium breve strain MCC1274 (FERM BP-11175) and Bifidobacterium breve M-16V (NITE BP-02622). Here, MCC stands for Morinaga Culture Collection (Morinaga Milk Industry Co., Ltd.).

[0017] The strains identified by the strain names exemplified above are not limited to the strains themselves that have been deposited and registered with the designated institution under those strain names (hereinafter, for convenience of explanation, also referred to as "deposited strains"), but also include strains that are substantially equivalent to them (hereinafter, also referred to as "derived strains" or "inducible strains"). That is, for example, the strains identified by the strain names exemplified above are not limited to the strains themselves that have been deposited with the depositary institution under the deposit number Bifidobacterium breve MCC1274 strain (FERM BP-11175), but also include strains that are substantially equivalent to them. A strain substantially equivalent to the deposited strain mentioned above may, for example, be a derivative strain with the deposited strain as the parent strain. Examples of derivative strains include strains bred from the deposited strain or strains that arose naturally from the deposited strain.

[0018] Examples of the aforementioned derivative strains include the following strains. (1) Strains determined to be the same strain by the Randomly Amplified Polymorphic DNA (RAPD) method or the Pulsed-field gel electrophoresis (PFGE) method (as described in FAO / WHO (2006) Probiotics in Food: Health and Nutritional Properties and Guidelines for Evaluation. Report of a Joint FAO / WHO Expert Consultation on Evaluation of Health and Nutritional Properties of Probiotics in Food Including Powder Milk with Live Lactic Acid Bacteria, Cordoba, Argentina, 1-4 October 2001 [and] Report of a Joint FAO / WHO Working Group on Drafting Guidelines for the Evaluation of Probiotics in Food, London, Ontario, Canada, 30 April-1 May 2002. FAO Food and Nutrition Paper 85, Food and Agriculture Organization of the United Nations, World Health Organization, Rome. Page 43) (2) A strain that possesses only genes originating from the deposited strain, does not have any foreign genes, and has a DNA identity of 95% or more. (3) Strains bred from the strain in question, or strains having the same traits, including genetically modified, spontaneously mutated, or naturally mutated strains.

[0019] MCC1274 has been deposited with the Patent Organism Depository Center of the National Institute of Advanced Industrial Science and Technology (AIST) (1-1-1 Higashi, Tsukuba, Ibaraki 305-8566, Japan, Central Building 6 (currently IPOD, National Institute of Technology and Evaluation Patent Organism Depository Center (NITE-IPOD): Room 120, 2-5-8 Kazusa Kamatari, Kisarazu, Chiba 292-0818, Japan)) since August 25, 2009, under the accession number IPOD FERM BP-11175. M-16V has been deposited with the Patent Microorganism Depositary Center of the National Institute of Technology and Evaluation (NITE, Room 122, 2-5-8 Kazusa-Kamatari, Kisarazu City, Chiba Prefecture 292-0818, Japan) since January 26, 2018, under accession number NITE BP-02622. These bacteria are generally available from the aforementioned storage institutions.

[0020] The Bifidobacterium breve MCC1274 strain can be easily obtained by culturing a distributed strain of Bifidobacterium breve FERM BP-11175. The culturing method is not particularly limited, and cultivation can be carried out under appropriate conditions according to the properties of this bacterium. Specifically, for example, the culture temperature is usually 25-50°C, with 35-42°C being preferred. Furthermore, it is preferable to carry out the culture under anaerobic conditions, for example, by aerating with an anaerobic gas such as carbon dioxide. Alternatively, the culture may be carried out under microaerophilic conditions such as liquid static culture.

[0021] The culture medium for culturing Bifidobacterium breve strain MCC1274 is not particularly limited, and any medium commonly used for culturing bacteria belonging to the genus Bifidobacterium can be used.

[0022] Specifically, as a carbon source, sugars such as glucose, galactose, lactose, arabinose, mannose, sucrose, starch, starch hydrolysates, and molasses can be used depending on their assimilation properties. As a nitrogen source, ammonium salts such as ammonia, ammonium sulfate, ammonium chloride, and ammonium nitrate, as well as nitrates, can be used. In addition, inorganic salts such as sodium chloride, potassium chloride, potassium phosphate, magnesium sulfate, calcium chloride, calcium nitrate, manganese chloride, and ferrous sulfate can be used. Organic components such as peptone, soybean flour, defatted soybean meal, meat extract, and yeast extract may also be used.

[0023] The Bifidobacterium breve strain MCC1274 may be used as is after culturing, diluted or concentrated, or the bacterial cells recovered from the culture may be used.

[0024] Furthermore, in the antiepileptic composition of the present invention, not only Bifidobacterium breve MCC1274 strain, but also cultures and culture supernatants containing Bifidobacterium breve MCC1274 strain can be used as active ingredients. Furthermore, the culture is preferably prepared by culturing and growing Bifidobacterium breve MCC1274 strain, and then removing as much non-bacterial material as possible; more preferably, it consists substantially only of bacterial material. Here, "consisting substantially only of bacterial material" means that, by wet mass, 95% or more of the total mass of the culture is bacterial material. The culture supernatant is the culture medium portion obtained when culturing Bifidobacterium breve strain MCC1274, or the supernatant solution thereof, and it is preferable that the culture supernatant has been sterilized by filtering.

[0025] In the antiepileptic composition of the present invention, the culture of Bifidobacterium bacteria may contain other components in addition to the Bifidobacterium bacteria, as long as they do not interfere with the effects of the present invention. Examples of such components include components of the culture medium used for cultivation, and components of the buffer used for recovery, separation, or washing of the culture.

[0026] The antiepileptic composition of the present invention may consist only of the active ingredient, or it may be a composition comprising the active ingredient and any other optional ingredients. The aforementioned optional components are not particularly limited, and can include additives that have been conventionally used in pharmaceuticals.

[0027] Examples of additives include antioxidants, excipients, binders, disintegrants, lubricants, stabilizers, flavoring and odor-correcting agents, and diluents, as well as formulation carriers, which will be described later.

[0028] <Product form> The product form of the antiepileptic composition of the present invention is not particularly limited, but the form of food, pharmaceuticals, etc., as described later, is preferred.

[0029] <Target recipients> The antiepileptic composition of the present invention is intended for use in individuals who require prevention, treatment, or reduction of epileptic seizures. The aforementioned target is usually humans, but it can also be administered to other mammals, such as pet animals like dogs and cats, and livestock like cattle, sheep, and pigs. The following section will describe the case where the target is humans. The subjects who require prevention, treatment, or reduction of the aforementioned epileptic seizures are preferably any of the following (1) to (4). (1) Subjects with a history of head injury, stroke, brain tumor, Alzheimer's disease, or other brain diseases. (2) Individuals whose family members have epilepsy. (3) Subjects diagnosed with epilepsy (4) Individuals who have a history of epileptic seizures

[0030] As used herein, the term “treatment” means to completely or partially inhibit a disease, disorder, or condition, for example, to suspend its onset for a certain period of time or longer. Similarly, “treatment” means a therapeutic procedure.

[0031] As used herein, the term “prevention” means completely or partially preventing the occurrence of a disease, disorder, or condition, or reducing the frequency of seizures associated with a disease, disorder, or condition, in a patient who may be predisposed to such a disease, disorder, or condition but has not yet been diagnosed with it. Prevention refers to preventive measures.

[0032] As used herein, the term "reduction" means, in patients diagnosed with a predisposition to a disease, disorder, and / or condition, completely or partially alleviating the disease, disorder, or condition, for example, causing regression of the disease, disorder, and / or condition. It also means reducing the frequency of seizures related to the disease, disorder, or condition.

[0033] <Epileptic seizures> The International Epilepsy Federation classifies seizure types into three main categories: focal seizures, generalized seizures, and seizures of unknown origin. These are further subdivided into focal seizures with preserved consciousness, focal seizures with impaired consciousness, focal motor-initiated seizures, focal non-motor-initiated seizures, focal bilateral tonic-clonic seizures, generalized motor seizures, generalized non-motor seizures, motor seizures of unknown origin, non-motor seizures of unknown origin, and unclassifiable seizures. The compositions according to the present invention are provided for the prevention, treatment, or reduction of epileptic seizures, but the type of seizure to be treated is not particularly limited.

[0034] <Prevention, treatment, and reduction of epileptic seizures> In the present invention, prevention, treatment, and reduction of epileptic seizures mean preventing the onset of seizures, eliminating seizures, and reducing the frequency of seizures, respectively, before and after administration of the antiepileptic composition of the present invention.

[0035] <Route of administration> The routes of administration of the antiepileptic composition of the present invention include, for example, oral administration, enteral administration (nasogastric, gastrostomy, and jejunostomy, etc.), intraperitoneal administration, intramuscular administration, transmucosal administration, intranasal administration, and rectal administration, but oral administration is particularly preferred.

[0036] <Dosage, frequency of administration, and timing of administration> The content of Bifidobacterium bacteria in the antiepileptic composition of the present invention is not particularly limited, but it is preferable to include an amount of Bifidobacterium bacteria that allows for the easy intake of a daily dose necessary to exhibit an effective antiepileptic effect. For example, the content of Bifidobacterium bacteria in the antiepileptic composition is preferably 1 × 10⁶ per gram of composition. 6 ~1 × 10 12 CFU / g, more comfortable 1×10 8 ~1 × 10 11 CFU / g, more preferably 1 × 10 9 ~5×10 10 CFU / g is more preferable. Furthermore, it is preferable to administer 1 to 3 g of the antiepileptic composition of the present invention, which contains Bifidobacterium bacteria, per day. CFU stands for Colony Forming Unit. The antiepileptic composition of the present invention, which contains Bifidobacterium bacteria, may be administered once a day, or it may be administered in two or more divided doses per day. The antiepileptic composition of the present invention may be administered at any time of day, but it is preferably administered, for example, before meals, after meals, or before bedtime. Furthermore, the antiepileptic composition of the present invention, which contains Bifidobacterium bacteria, may be administered as a single dose, but it is preferably administered once a week or more, more preferably once every three days or more, even more preferably once every two days or more, and most preferably continuously every day. For example, it is preferable to administer it daily for three weeks or more.

[0037] <Evaluation Method> The effects of the antiepileptic compositions described herein on preventing, treating, or reducing epileptic seizures can be evaluated based on animal models such as mouse, rabbit, or monkey models. For example, an example of an animal model that can be used to evaluate the antiepileptic compositions described herein is the Kindling mouse model administered with pentylenetetrazole, which is also used to evaluate the efficacy of pharmaceuticals. In addition, seizure scores, for example, can be used as evaluation items for antiepileptic effects in animal models (Giovambattista De Sarro, Neuropharmacology 39 (2000) 2147-2161).

[0038] In this specification, as one aspect of evaluating an antiepileptic composition, treatment of epileptic seizures may mean reducing the seizure score to 0, reduction of epileptic seizures may mean decreasing the seizure score, and prevention of epileptic seizures may mean suppressing the increase in the seizure score in subjects with a predisposition to epileptic seizures compared to a group that does not receive the antiepileptic composition. Furthermore, as one aspect of evaluating the antiepileptic composition, treatment of epileptic seizures may mean preventing the occurrence of epileptic seizures for two years or more, reduction of epileptic seizures may mean shortening the duration of seizures, reducing the frequency of seizures, reducing the severity of symptoms, and eliminating certain types of seizures, and prevention of epileptic seizures may mean reducing the incidence of epilepsy in subjects who have a predisposition to epileptic seizures but have not been diagnosed with epilepsy, compared to a group that does not take the antiepileptic composition.

[0039] [2. Pharmaceuticals] The antiepileptic composition of the present invention may be a pharmaceutical product and may contain either or both Bifidobacterium bacteria and / or a culture of Bifidobacterium bacteria. The target of administration, the active ingredient, Bifidobacterium bacteria, and the culture of Bifidobacterium bacteria are the same as those of the antiepileptic composition of the present invention described above.

[0040] The pharmaceutical product according to the present invention can be prepared by adding the antiepileptic composition of the present invention to a known pharmaceutical product, or a new pharmaceutical product can be manufactured by mixing the antiepileptic composition into the raw materials of a pharmaceutical product.

[0041] Furthermore, pharmaceuticals using the antiepileptic composition of the present invention as a pharmaceutical product, or those in which the antiepileptic composition of the present invention is added to existing pharmaceutical products, are also included in the pharmaceutical products of this technology.

[0042] When using the antiepileptic composition of the present invention as a pharmaceutical, it may be used as is, after being concentrated, or after being processed into a solid, granular, or powder form.

[0043] <Formulation> The antiepileptic composition of the present invention can be formulated into any desired dosage form depending on the method of administration, such as oral or parenteral administration. The dosage form is not particularly limited, but in the case of oral administration, it can be formulated into solid preparations such as powders, granules, tablets, lozenges, and capsules; or liquid preparations such as solutions, syrups, suspensions, and emulsions. In the case of parenteral administration, it can be formulated into suppositories, sprays, inhalants, ointments, patches, and injections. In the present invention, formulation into an oral dosage form is preferred. The formulation can be carried out using known methods as appropriate, depending on the dosage form.

[0044] During formulation, a formulation carrier may be added as appropriate. In addition to the antiepileptic composition of the present invention, components such as excipients, pH adjusters, colorants, and flavoring agents commonly used in formulation can be used. Furthermore, components that have the effect of preventing, treating, or alleviating known or future diseases or symptoms may be used in combination as appropriate for the purpose.

[0045] As the aforementioned pharmaceutical carrier, various organic or inorganic carriers can be used depending on the dosage form. Examples of carriers in the case of solid dosage forms include excipients, binders, disintegrants, lubricants, stabilizers, and flavoring / odorizing agents.

[0046] Examples of the excipients include sugar derivatives such as lactose, sucrose, glucose, mannitol, and sorbitol; starch derivatives such as corn starch, potato starch, α-starch, dextrin, and carboxymethyl starch; cellulose derivatives such as crystalline cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, carboxymethylcellulose, and carboxymethylcellulose calcium; gum arabic; dextran; pullulan; silicate derivatives such as light anhydrous silicic acid, synthetic aluminum silicate, and magnesium aluminometasilicate; phosphate derivatives such as calcium phosphate; carbonate derivatives such as calcium carbonate; and sulfate derivatives such as calcium sulfate.

[0047] Examples of the binders include, in addition to the above-mentioned excipients, gelatin; polyvinylpyrrolidone; macrogol, and the like.

[0048] Examples of the disintegrant include, in addition to the above-mentioned excipients, chemically modified starch or cellulose derivatives such as croscarmellose sodium, carboxymethyl starch sodium, and cross-linked polyvinylpyrrolidone.

[0049] Examples of the aforementioned lubricants include talc; stearic acid; metal stearate salts such as calcium stearate and magnesium stearate; colloidal silica; waxes such as beegum and gayl wax; boric acid; glycol; carboxylic acids such as fumaric acid and adipic acid; sodium carboxylate salts such as sodium benzoate; sulfates such as sodium sulfate; leucine; lauryl sulfates such as sodium lauryl sulfate and magnesium lauryl sulfate; silicic acids such as anhydrous silicic acid and silicic acid hydrate; and starch derivatives.

[0050] Examples of the aforementioned stabilizers include para-hydroxybenzoic acid esters such as methylparaben and propylparaben; alcohols such as chlorobutanol, benzyl alcohol and phenylethyl alcohol; benzalkonium chloride; acetic anhydride; sorbic acid, etc. Examples of the flavoring and odor-masking agent include sweeteners, acidulants, fragrances, and the like. In the case of a liquid preparation for oral administration, examples of the carrier used include solvents such as water and flavoring and odor-masking agents.

[0051] The anti-epileptic composition of the present invention can also be used in combination with a drug having an anti-epileptic action that is known or will be found in the future.

[0052] The content of Bifidobacterium bacteria in the medicine of the present technology is not particularly limited, but it preferably contains Bifidobacterium bacteria such that the daily dose for showing an effective anti-epileptic action can be ingested without difficulty. For example, the content of Bifidobacterium bacteria in the medicine is preferably 1 × 10 6 ~1 × 10 12 CFU / g, more preferably 1 × 10 8 ~1 × 10 11 CFU / g, even more preferably 1 × 10 9 ~5 × 10 10 [[ID=Twenty-two]]CFU / g. Also, the daily dose of Bifidobacterium bacteria in the medicine of the present technology is preferably at least 1 × 10 6 CFU / kg body weight / day, or more.

[0053] In the medicine of the present technology, the daily dose may be administered once a day or divided into two or more administrations per day. Examples of the administration route include oral administration, transcatheter administration (nasal, gastrostomy, enterostomy, etc.), intraperitoneal administration, intramuscular administration, transmucosal administration, intranasal administration, and rectal administration, etc. Among them, oral administration is particularly preferred. The administration target is usually a human, but in the present invention, it also includes mammals other than humans, such as pet animals like dogs and cats, and livestock like cows, sheep, and pigs.

[0054] [3. Food] The anti-epileptic composition of the present invention may be a food and contains either or both of Bifidobacterium bacteria and a culture of Bifidobacterium bacteria. The target of ingestion, the active ingredient, Bifidobacterium bacteria, and the culture of Bifidobacterium bacteria are the same as those of the anti-epileptic composition of the present invention described above.

[0055] The term "food" in this invention includes food and beverages. Food and beverages can be in any form, such as liquid, paste, solid, or powder, and include tablets, liquid foods, and animal feed (including pet feed), as well as, for example, wheat flour products, instant foods, processed agricultural products, processed marine products, processed livestock products, milk and dairy products, oils and fats, basic seasonings, compound seasonings and foods, frozen foods, confectionery, beverages, and other commercially available foods.

[0056] Examples of dairy products include fermented milk, milk beverages, lactic acid bacteria beverages, sweetened condensed milk, skim milk powder, sweetened milk powder, modified milk powder, cream, cheese, butter, and ice cream. Examples of wheat flour products include bread, macaroni, spaghetti, noodles, cake mix, fried chicken batter, and breadcrumbs.

[0057] Examples of instant foods include instant noodles, cup noodles, retort / prepared foods, canned prepared foods, microwaveable foods, instant soups / stews, instant miso soup / clear soup, canned soups, freeze-dried foods, and other instant foods.

[0058] Examples of processed agricultural products include canned agricultural products, canned fruits, jams and marmalades, pickles, boiled beans, dried agricultural products, and cereals (processed grain products). Examples of processed seafood products include canned seafood, fish ham and sausage, processed seafood products, seafood delicacies, and tsukudani (simmered seafood).

[0059] Examples of processed livestock products include canned and pasteurized livestock products, as well as meat products such as ham and sausages.

[0060] Examples of fats and oils include butter, margarine, and vegetable oils.

[0061] Basic seasonings include, for example, soy sauce, miso, sauces, tomato-based seasonings, mirin, and vinegars. Compound seasonings and foods include cooking mixes, curry bases, sauces, dressings, noodle soup bases, spices, and other compound seasonings.

[0062] Examples of frozen foods include frozen raw ingredients, partially cooked frozen foods, and pre-cooked frozen foods.

[0063] Examples of confectionery include caramel, candy, chewing gum, chocolate, cookies, biscuits, cakes, pies, snacks, crackers, Japanese sweets, rice crackers, bean snacks, dessert sweets, and other confectionery.

[0064] Examples of beverages include carbonated drinks, natural fruit juices, fruit juice drinks, fruit juice-containing soft drinks, fruit pulp drinks, fruit drinks with fruit pulp, vegetable drinks, soy milk, soy milk drinks, coffee drinks, tea drinks, powdered drinks, concentrated drinks, sports drinks, nutritional drinks, alcoholic beverages, and other beverages for enjoyment.

[0065] Other commercially available foods include, for example, baby food, furikake (rice seasoning), and ochazuke nori (rice seasoning).

[0066] Furthermore, among these, dairy products are particularly preferred as the anti-epileptic food of the present invention, and fermented milk is particularly preferred. This allows consumers to enjoy not only the anti-epileptic effect but also the high nutritional value of dairy products.

[0067] The content of Bifidobacterium bacteria in the food of the present invention is not particularly limited, but it is preferable that it contains Bifidobacterium bacteria in an amount that allows for a reasonable daily intake necessary to exhibit effective antiepileptic effects. The food provided by the present invention can be used in the same manner as the pharmaceuticals described above, and can also be used in applications other than those intended for anticonvulsant effects. The food according to the present invention can be applied to the target area of ​​the pharmaceutical so that the amount of Bifidobacterium bacteria in the food is the same as the amount of Bifidobacterium bacteria in the pharmaceutical, based on the Bifidobacterium bacteria contained in the food according to the present invention. For example, the content of Bifidobacterium bacteria in food is preferably 1 × 10⁶ per gram of food. 6 ~1 × 10 12 CFU / g, more comfortable 1×10 8 ~1 × 10 11 CFU / g, more preferably 1 × 10 9 ~5×10 10 It is more preferable to include CFU / g. Furthermore, the daily intake of Bifidobacterium bacteria in the food of the present invention is at least 1 × 10⁻⁶. 6 It is preferable that the CFU / kg body weight / day or higher.

[0068] In the food of the present invention, the person ingesting the daily intake of Bifidobacterium bacteria may ingest it once a day, or may ingest it in two or more divided doses per day. Ingestion routes include, for example, oral ingestion and enteral ingestion (nasogastric, gastrostomy, and jejunostomy, etc.), but oral ingestion is particularly preferred. While the target of ingestion is usually humans, the present invention also includes mammals other than humans, such as pet animals like dogs and cats, and livestock like cattle, sheep, and pigs.

[0069] Furthermore, in one embodiment, the food according to the present invention can be applied to subjects (e.g., humans or other mammals) that do not have "pathological" or "abnormal" symptoms, conditions, or diseases, that is, subjects (e.g., humans or other mammals) that are in a "healthy" or "normal" state, in order to maintain that "healthy" or "normal" state. Moreover, it can be applied to "healthy individuals who are concerned about epileptic symptoms" in order to maintain that "healthy" or "normal" state. In this case, whether one or both of the Bifidobacterium bacteria and their culture are components of a pharmaceutical composition or components of a food, the pharmacological effects of the Bifidobacterium bacteria and their culture themselves are basically the same. Therefore, the amount and method of application of the food can be appropriately adjusted based on the Bifidobacterium bacteria and their culture themselves, according to the desired effect.

[0070] Furthermore, in one embodiment, the food related to the present invention may be a health food, functional food, enteral nutrition food, special dietary food, health functional food, food for specified health uses, nutrient functional food, functional food, or quasi-drug. Specifically, it may be a food consumed for purposes such as "may reduce the risk of developing epilepsy." In this case as well, the amount and method of application of the food can be appropriately adjusted according to the expected effect, based on the Bifidobacterium bacteria and their culture itself.

[0071] [4. Methods for preventing, treating, or reducing epileptic seizures] The present invention also provides a method for preventing, treating, or reducing epileptic seizures using the above-described antiepileptic composition, or one or both of the active ingredients thereof, Bifidobacterium bacteria and their cultures. The present invention also provides a non-therapeutic administration method for administering the above-mentioned antiepileptic composition, or one or both of the active ingredients thereof, namely Bifidobacterium bacteria and their cultures. The antiepileptic composition, Bifidobacterium bacteria and their cultures (either one or both), and the dosage, frequency and timing of administration are as described above. For methods of preventing, treating, or alleviating epileptic seizures, it is preferable to use an effective amount of Bifidobacterium bacteria or their cultures.

[0072] Another aspect of this application is that it encompasses the following aspects. [1] An antiepileptic composition comprising either or both of Bifidobacterium breve MCC1274 strain (FERM BP-11175) and its culture as active ingredients, for administration to subjects in need of prevention, treatment, or reduction of epileptic seizures. [2] The antiepileptic composition contains 1 × 10⁶ Bifidobacterium breve MCC1274 strain (FERM BP-11175) per day in the subject. 6 ~1 × 10 12 The antiepileptic composition according to [1], comprising the above-mentioned active ingredient in an amount administered orally to a CFU / g ratio. [3] The antiepileptic composition according to [1] or [2], wherein the subject is a subject requiring treatment for epileptic seizures. [4] An antiepileptic compound as described in any of [1] to [3], used for the prevention, treatment, or reduction of epileptic seizures. [5] The antiepileptic composition according to any one of [1] to [4], wherein the antiepileptic composition is a pharmaceutical or food product. [6] Use of either or both of Bifidobacterium breve strain MCC1274 (FERM BP-11175) and its culture in the manufacture of a composition administered to subjects in need of prevention, treatment or reduction of epileptic seizures. [7] Bifidobacterium breve strain MCC1274 (FERM BP-11175) or its culture for use in the prevention, treatment, or reduction of epileptic seizures. [8] A non-therapeutic method of administration comprising administering an effective amount of either or both of Bifidobacterium breve strain MCC1274 (FERM BP-11175) and its culture to a subject in need of prevention, treatment or reduction of epileptic seizures. [9] The subject receives 1 × 10⁶ doses of Bifidobacterium breve MCC1274 strain (FERM BP-11175) per day. 6 ~1 × 10 12 The method according to [8], comprising administering either or both of Bifidobacterium breve MCC1274 strain (FERM BP-11175) and its culture in a CFU / g ratio. [Examples]

[0073] The present invention will be described in more detail below using examples. However, the examples described below are merely representative examples of the present invention and are not limited thereto.

[0074] (1) Experimental method Kindling mice were created by intraperitoneal administration (ip) of low-volume pentylenetetrazole (PTZ, SIGMA-Aldrich) (37 mg / kg, 3.1 mg / mL) dissolved in physiological saline to 8 male C57BL / 6JJcl mice (Ishibe Rearing Center, CREA Japan Co., Ltd.) every other day for 8 doses (Figure 1).

[0075] The above kindling mice were divided into two groups (14 mice in the untreated group and 12 mice in the treated group). One of the groups (the treated group) was given 1.3 × 10⁶ of physiological saline solution. 10 Bifidobacterium breve MCC1274 strain [FERM BP-11175] (hereinafter referred to as B. breve MCC1274 strain), suspended to a cfu / mL concentration, was orally administered every other day on days when PTZ was not administered (3.25 × 10⁻¹⁴). 9The mice were given cfu / 0.25 mL / mouse (Figure 1). The other group (non-administered group) was orally administered only the physiological saline used for the suspension, which did not contain the B. breve MCC1274 strain. The mice's behavior was observed for 30 minutes after PTZ administration, and the degree of convulsions was scored according to the following evaluation method.

[0076] (2) Seizure score Seizure scores were calculated using the following evaluation method, following the method of Shimada & Yamagata (2018) [Shimada & Yamagata (2018) J. Visualized Experiments, 136:1-10.]. 0: Normal 1: Immobilization 2: Nodding behavior / Partial myoclonus (involuntary movement) 3: Generalized myoclonus (involuntary movements) 4: Standing up behavior / clonic seizures 5: Clonic tonic spasms 6: Death

[0077] (3) Results The mean seizure score increased with each additional PTZ administration (Figure 2). In the group treated with B. breve MCC1274 strain, seizure scores induced by PTZ were suppressed in all cases compared to the non-treatment group (Figure 2). In this case, the significant suppression of PTZ-induced seizures by B. breve MCC1274 strain was observed from after the fourth PTZ administration (24 hours after the fourth administration of B. breve MCC1274 strain) and persisted until the final PTZ administration day, after the eighth PTZ administration (24 hours after the eighth administration of B. breve MCC1274 strain) (Figure 2). These results demonstrate that the composition containing the B. breve MCC1274 strain possesses antiepileptic activity. [Industrial applicability]

[0078] The present invention provides a novel antiepileptic composition. Because the active ingredient of the antiepileptic composition of the present invention is a culture containing either or both Bifidobacterium bacteria and / or their culture, it is highly safe and has little risk of side effects even when administered continuously for a long period of time, making it extremely useful. [Accession Number]

[0079] FERM BP-11175 NITE BP-02622

Claims

1. An antiepileptic composition comprising either or both of the Bifidobacterium breve MCC1274 strain (FERM BP-11175) and its culture.

2. The Bifidobacterium breve MCC1274 strain (FERM BP-11175) and / or its culture, one or both, are used in 1 × 10 ６ ~1 x 10 １２ The antiepileptic composition according to claim 1, comprising CFU / g.

3. An antiepileptic composition according to claim 1, used for the prevention, treatment, or reduction of epileptic seizures.

4. The antiepileptic composition according to claim 1, wherein the antiepileptic composition is a pharmaceutical or a food product.

5. The antiepileptic composition according to claim 1, wherein the antiepileptic composition is administered to a subject who needs to prevent, treat, or alleviate epileptic seizures.

6. The antiepileptic composition according to claim 1, comprising either or both of the Bifidobacterium breve MCC1274 strain (FERM BP-11175) and its culture as active ingredients.

7. The use of either or both Bifidobacterium breve MCC1274 strain (FERM BP-11175) and its culture in the manufacture of a composition for administration to subjects in need of prevention, treatment, or reduction of epileptic seizures.

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