WO2023234166A1 - Antiepileptic composition - Google Patents

Antiepileptic composition Download PDF

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Publication number
WO2023234166A1
WO2023234166A1 PCT/JP2023/019470 JP2023019470W WO2023234166A1 WO 2023234166 A1 WO2023234166 A1 WO 2023234166A1 JP 2023019470 W JP2023019470 W JP 2023019470W WO 2023234166 A1 WO2023234166 A1 WO 2023234166A1
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bifidobacterium
epileptic
culture
composition
seizures
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PCT/JP2023/019470
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French (fr)
Japanese (ja)
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利明 石井
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森永乳業株式会社
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    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/135—Bacteria or derivatives thereof, e.g. probiotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/66—Microorganisms or materials therefrom
    • A61K35/74—Bacteria
    • A61K35/741—Probiotics
    • A61K35/744—Lactic acid bacteria, e.g. enterococci, pediococci, lactococci, streptococci or leuconostocs
    • A61K35/745—Bifidobacteria
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants

Definitions

  • Epilepsy is a condition that causes repeated epileptic seizures.
  • "Epileptic seizures” are seizures caused by abnormal electrical activity of nerve cells in the brain, and the nervous system such as motor nerves, sensory nerves, autonomic nerves, consciousness, or higher brain functions suddenly becomes abnormally activated. It is caused by doing this. Therefore, “epileptic seizures” correspond to each nervous system, and some parts of the body become stiff (caused by abnormalities in motor nerves), numbness in the hands and feet, and ringing in the ears (caused by abnormalities in sensory nerves). It causes a variety of symptoms, including palpitations and nausea (caused by abnormalities in the autonomic nervous system), loss of consciousness, and difficulty speaking (caused by abnormalities in higher brain function).
  • the prevalence of epilepsy is said to be 0.5 to 1%, and according to Non-Patent Document 1, it is a disease with a relatively high prevalence. Furthermore, epilepsy can occur in any age group, from infants to the elderly.
  • Diagnosis of epilepsy can include neurological examination and blood tests. Brain abnormalities can be detected using electroencephalogram (EEG), high-density EEG, computed tomography (CT) scans, magnetic resonance imaging (MRI), and positron emission tomography (PET). :positron emission tomography) It is detected by scans, single photon emission computed tomography (SPECT), and neuropsychological tests to assess thinking, memory, and speech abilities. Analysis techniques include statistical parametric mapping (SPM), curry analysis, and magnetoencephalography (MEG).
  • EEG electroencephalogram
  • CEG computed tomography
  • MRI magnetic resonance imaging
  • PET positron emission tomography
  • SPM statistical parametric mapping
  • MEG magnetoencephalography
  • antiepileptic drugs do not eliminate the cause of epilepsy, but rather make epileptic seizures less likely to occur. However, for some cases of epilepsy, even if two antiepileptic drugs are tried alone or in combination at sufficient blood concentrations to have no side effects, antiepileptic drugs that are appropriate for the epilepsy may not be used for a certain period of time (specifically It is known that seizures may not be controlled for a period of one year or more or for a period of three times the longest pre-treatment seizure interval, whichever is longer), and this is considered drug-resistant epilepsy. being called. According to Non-Patent Document 2, 20 to 30% of epilepsy patients fall under this drug-induced epilepsy.
  • drugs used for drug therapy are pharmaceuticals, they are not easy to use and are generally prone to side effects.
  • Side effects of antiepileptic drugs include an idiosyncratic acute initial reaction to the drug that involves an allergic mechanism, and a dose-dependent suppressive effect on the nervous system (specifically, dizziness, nystagmus, double vision, drowsiness, nausea, or (loss of appetite, etc.) and chronic side effects (specifically, weight gain, hirsutism or hair loss, urinary stones, cerebellar atrophy, etc.) that occur during long-term use are known.
  • a dose-dependent suppressive effect on the nervous system specifically, dizziness, nystagmus, double vision, drowsiness, nausea, or (loss of appetite, etc.
  • chronic side effects specifically, weight gain, hirsutism or hair loss, urinary stones, cerebellar atrophy, etc.
  • Non-Patent Document 3 shows that children who followed a ketogenic diet for one year showed a reduction in epilepsy symptoms. This is reported.
  • the ketogenic diet is a diet characterized by high fat and low carbohydrate content, it may lead to hypoglycemia, dyslipidemia, or growth disorders.
  • One of the objects of the present invention is to provide an antiepileptic composition effective for preventing, treating, or alleviating epileptic seizures.
  • the antiepileptic composition according to any one of [1] to [7] which contains one or both of the Bifidobacterium bacterium and its culture as an active ingredient.
  • [9] Use of one or both of a Bifidobacterium bacterium and a culture thereof in the manufacture of a composition for administration to a subject in need of prevention, treatment, or alleviation of epileptic seizures.
  • a Bifidobacterium bacterium and a culture thereof in the manufacture of a composition for administration to a subject in need of prevention, treatment, or alleviation of epileptic seizures.
  • an antiepileptic composition that is effective in preventing, treating, or alleviating epileptic seizures.
  • the effects described here are not necessarily limited, and may be any effects described in this specification.
  • the administration schedule of Pentylenetetrazole (PTZ) and Bifidobacterium breve MCC1274 strain (FERM BP-11175) in a test example is shown.
  • a graph showing the relationship between the number of administrations of PTZ and the average convulsion score in the administration group and non-administration group of Bifidobacterium breve MCC1274 strain (FERM BP-11175) is shown.
  • the anti-epileptic composition of the present invention is an anti-epileptic composition containing one or both of a Bifidobacterium bacterium and a culture thereof as an active ingredient.
  • the active ingredient of the antiepileptic composition of the present invention is one or both of a Bifidobacterium bacterium and a culture thereof.
  • Bifidobacterium bacteria targeted by the present invention include Bifidobacterium breve, Bifidobacterium lactis, Bifidobacterium longum, and Bifidobacterium longum.
  • Bifidobacterium infantis Bifidobacterium adolescentis, Bifidobacterium bifidum, and Bifidobacterium animalis. These Bifidobacterium species may be used alone or in any combination of two or more species.
  • Preferred examples include, but are not limited to, Bifidobacterium breve, Bifidobacterium longum, and Bifidobacterium infantis. More preferred are Bifidobacterium longum and Bifidobacterium breve. More preferably, one or both of Bifidobacterium breve MCC1274 strain (FERM BP-11175) and a culture thereof. One or both of Bifidobacterium and its culture are used for producing the antiepileptic composition of the present invention. It is preferable that the bacteria of the genus Bifidobacterium and the culture thereof are live bacteria.
  • Bifidobacterium breve is a type of bacteria belonging to the genus Bifidobacterium. Bifidobacterium breve lives mainly in the large intestines of infants and young children, and among the bacterial species belonging to the genus Bifidobacterium, Bifidobacterium longum subsp. infantis ), it is known as an infant-type Bifidobacterium bacterium.
  • the anti-epileptic composition of the present invention contains either or both of a Bifidobacterium bacterium and a culture containing a Bifidobacterium bacterium, which mainly resides in large numbers in the large intestine of infants. Therefore, it is extremely safe, and there is little need to worry about side effects even when administered continuously for a long period of time, making it very useful. Furthermore, it is highly safe when used in combination with other drugs.
  • examples of Bifidobacterium breve include Bifidobacterium breve MCC1274 strain (FERM BP-11175), Bifidobacterium breve M-16V (NITE BP-02622), and the like.
  • MCC means Morinaga Culture Collection (Morinaga Milk Industry Co., Ltd.).
  • strains identified by the strain names listed above are not limited to the strains themselves that have been deposited and registered with designated institutions under the strain names (hereinafter also referred to as "deposited strains” for convenience of explanation).
  • Substantially equivalent bacterial strains are also included. That is, for example, the present invention is not limited to the strain deposited with the above-mentioned depository institution under the deposit number Bifidobacterium breve strain MCC1274 (FERM BP-11175), but also includes strains substantially equivalent thereto.
  • a strain that is substantially equivalent to the deposited strain may be, for example, a derivative strain that uses the deposited strain as a parent strain.
  • Derivative strains include strains bred from the deposited strain or naturally occurring strains from the deposited strain.
  • Examples of the derived strains include the following strains.
  • Bacterial strains determined to be the same by the Randomly Amplified Polymorphic DNA (RAPD) method or the Pulsed-field gel electrophoresis (PFGE) method 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.
  • RAPD Randomly Amplified Polymorphic DNA
  • PFGE Pulsed-field gel electrophoresis
  • MCC1274 is located at the Patent Organism Depositary Center, National Institute of Advanced Industrial Science and Technology (Chuo 6, 1-1-1 Higashi, Tsukuba City, Ibaraki Prefecture, 305-8566, Japan (currently IPOD), Patent Organism Depositary Center, National Institute of Advanced Industrial Science and Technology, Japan).
  • NITE-IPOD Room 120, 2-5-8 Kazusa Kamatari, Kisarazu, Chiba 292-0818, Japan, has been deposited with the accession number IPOD FERM BP-11175 since August 25, 2009. .
  • M-16V was transferred to the National Institute of Technology and Evaluation, Patent Microorganism Depositary (Room 122, 2-5-8 Kazusa Kamatari, Kisarazu City, Chiba Prefecture, 292-0818, Japan) from January 26, 2018, to NITE. It has been deposited under accession number BP-02622. These bacteria are generally available from the above-mentioned repositories.
  • Bifidobacterium breve strain MCC1274 can be easily obtained by culturing a distributed strain of Bifidobacterium breve FERM BP-11175.
  • the culturing method is not particularly limited, and the culturing can be carried out under appropriate conditions depending on the properties of the bacterium.
  • the culture temperature is usually 25 to 50°C, preferably 35 to 42°C.
  • the culture is preferably performed under anaerobic conditions, and for example, the culture can be performed while aerating an anaerobic gas such as carbon dioxide gas. Alternatively, it may be cultured under microaerobic conditions such as liquid static culture.
  • the 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.
  • a carbon source for example, sugars such as glucose, galactose, lactose, arabinose, mannose, sucrose, starch, starch hydrolyzate, and blackstrap molasses can be used depending on their assimilation properties.
  • a nitrogen source for example, ammonia, ammonium salts such as ammonium sulfate, ammonium chloride and ammonium nitrate, and nitrates can be used.
  • the inorganic salts for example, sodium chloride, potassium chloride, potassium phosphate, magnesium sulfate, calcium chloride, calcium nitrate, manganese chloride, ferrous sulfate, etc. can be used.
  • organic ingredients such as peptone, soybean flour, defatted soybean meal, meat extract, and yeast extract may be used.
  • the obtained culture may be used as is, it may be diluted or concentrated, and the bacterial cells recovered from the culture may be used.
  • the antiepileptic composition of the present invention not only Bifidobacterium breve MCC1274 strain but also a culture or culture supernatant containing Bifidobacterium breve MCC1274 strain can be used as an active ingredient.
  • the culture is preferably one in which Bifidobacterium breve MCC1274 strain is cultured and propagated, and then as much as possible other than bacterial bodies is removed, and one consisting essentially only of bacterial bodies is more preferable.
  • substantially consisting only of bacterial bodies means that 95% by mass or more of the total mass of the culture is composed of bacterial bodies in terms of wet mass.
  • the culture supernatant is the culture solution obtained when culturing Bifidobacterium breve MCC1274 strain, or its supernatant solution, and the culture supernatant is preferably sterilized by filtering. .
  • the culture of Bifidobacterium bacteria may contain other components in addition to Bifidobacterium cells, as long as they do not interfere with the effects of the present invention. Good too.
  • examples of such components include components such as the medium used for culture, and components such as buffers used for recovery, separation, or washing of the culture.
  • the antiepileptic composition of the present invention may consist only of the above-mentioned active ingredient, or may be a composition containing the above-mentioned active ingredient and any other ingredient other than the above-mentioned active ingredient.
  • the optional components are not particularly limited, and additives conventionally included in pharmaceuticals can be included.
  • additives include antioxidants, excipients, binders, disintegrants, lubricants, stabilizers, flavoring agents, and diluents, as well as formulation carriers described below.
  • the product form of the anti-epileptic composition of the present invention is not particularly limited, but forms such as foods and medicines described below are preferred.
  • the subject to whom the anti-epileptic composition of the present invention is administered is a subject in need of prevention, treatment or alleviation of epileptic seizures.
  • the subject is usually a human, but it is also possible to administer to mammals other than humans, for example, pet animals such as dogs and cats, and livestock such as cows, sheep, and pigs. Below, a case where the subject is a human will be explained.
  • the subject in need of prevention, treatment or alleviation of epileptic seizures is preferably one of the following (1) to (4).
  • Subjects with a history of head trauma, stroke, brain tumor, Alzheimer's disease, etc., or brain diseases Subjects whose family members have epilepsy (3) Subjects who have been diagnosed with epilepsy (4) Subjects who have had an epileptic seizure subject of something
  • treatment refers to completely or partially inhibiting a disease, disorder, or condition, eg, halting its onset over a period of time.
  • therapy refers to therapeutic treatment.
  • prevention refers to preventing a disease, disorder, or condition from occurring in a patient who may be predisposed to, but has not yet been diagnosed with, the disease, disorder, or condition.
  • Prevention refers to preventive measures.
  • the term "alleviation” refers to the complete or partial alleviation of a disease, disorder or condition in a patient who has been diagnosed as having a predisposition to the disease, disorder and/or condition, e.g. , refers to causing regression of a disease, disorder, and/or condition. It also means reducing the frequency of seizures associated with a disease, disorder, or condition.
  • ⁇ Epileptic seizure> The seizure types seen in epilepsy are broadly classified by the International Federation of Epilepsy into focal seizures, generalized seizures, and seizures of unknown origin, and are subcategorized into focal seizures with preserved consciousness, focal impaired consciousness seizures, and focal motor onset seizures. It is classified into onset seizures, focal nonmotor onset seizures, focal onset bilateral tonic-clonic seizures, generalized motor seizures, generalized nonmotor seizures, motor seizures of unknown origin, nonmotor onset seizures of unknown origin, and unclassifiable seizures.
  • the composition according to the present invention is provided for the prevention, treatment, or alleviation of epileptic seizures, but the targeted seizure types are not particularly limited.
  • prevention, treatment, and alleviation of epileptic seizures mean prevention of onset of seizures, disappearance of seizures, and reduction in the frequency of onset of seizures before and after administration of the antiepileptic composition of the present invention, respectively. .
  • Administration routes for the antiepileptic composition of the present invention include, for example, oral administration, tube administration (nasally, gastrostomy, intestinal fistula, etc.), intraperitoneal administration, intramuscular administration, transmucosal administration, intranasal administration, and rectal administration. Examples include internal administration, but oral administration is particularly preferred.
  • the content of Bifidobacterium bacteria in the anti-epileptic composition of the present invention is not particularly limited, but the content of Bifidobacterium bacteria is such that the amount of Bifidobacterium bacteria can be easily ingested per day to exhibit effective anti-epileptic effects.
  • it contains bacteria of the genus P. genus.
  • the content of Bifidobacterium bacteria in the antiepileptic composition is preferably 1 ⁇ 10 6 to 1 ⁇ 10 12 CFU/g, more preferably 1 ⁇ 10 8 to 1 ⁇ 10 per gram of the composition. 11 CFU/g, more preferably 1 ⁇ 10 9 to 5 ⁇ 10 10 CFU/g, but more preferably.
  • the antiepileptic composition of the present invention containing Bifidobacterium bacteria may be administered once per day, or may be administered in two or more divided doses per day.
  • the anti-epileptic composition of the present invention may be administered at any time during the day, but is preferably administered, for example, before meals, after meals, or before going to bed.
  • the anti-epileptic composition of the present invention containing Bifidobacterium bacteria may be administered once, but preferably once a week or more, and preferably once every 3 days or more. is more preferable, it is even more preferable that the drug is administered once or more every two days, and it is most preferable that the drug is administered continuously every day. For example, it is preferable to administer it daily for three weeks or more.
  • ⁇ Evaluation method> The effectiveness of the antiepileptic compositions described herein in preventing, treating, or alleviating epileptic seizures can be evaluated based on animal models such as mouse or rabbit or monkey models.
  • animal models such as mouse or rabbit or monkey models.
  • animal models that can be used to evaluate the anti-epileptic compositions described herein include the Kindling mouse model by administration of pentylenetetrazole, which can also be used to evaluate the effects of drugs, etc. It is being In addition, as an evaluation item for antiepileptic effects in animal models, for example, convulsion scores are used (Giovambattista De Sarro, Neuropharmacology 39 (2000) 2147-2161).
  • treating epileptic seizures may mean reducing the convulsion score to 0, and alleviating epileptic seizures may mean reducing the convulsion score.
  • Prevention of epileptic seizures may also mean suppressing an increase in convulsion scores in subjects who are predisposed to having epileptic seizures compared to a group that does not take the anti-epileptic composition.
  • treating epileptic seizures may mean preventing epileptic seizures from occurring for two years or more, and alleviating epileptic seizures means shortening the duration of seizures and reducing seizure frequency.
  • epileptic seizures which may mean reduction in severity, reduction in the severity of symptoms, and elimination of some seizure types, is the use of anti-epileptic drugs in subjects who have not been diagnosed with epilepsy but are predisposed to having epileptic seizures. It may also mean reducing the incidence of epilepsy compared to a group not receiving the composition.
  • the anti-epileptic composition of the present invention may be a pharmaceutical and contains either or both of a Bifidobacterium bacterium and a Bifidobacterium bacterium culture.
  • the subject to be administered, the active ingredient Bifidobacterium bacteria, and the culture of Bifidobacterium bacteria are the same as in the antiepileptic composition of the present invention described above.
  • the medicine according to the present invention can be prepared by adding the anti-epileptic composition of the present invention to a known medicine, or a new medicine can be prepared by mixing the anti-epileptic composition into the raw material of the medicine. You can also.
  • the medicines of the present technology include those in which the anti-epileptic composition of the present invention is used as a medicine, and those in which the anti-epileptic composition of the present invention is added to existing medicines.
  • the antiepileptic composition of the present invention When using the antiepileptic composition of the present invention as a medicine, it may be used as it is, after being concentrated, or after being processed into a solid, granule, or powder form.
  • the antiepileptic composition of the present invention can be formulated into a desired dosage form as appropriate depending on the administration method, such as oral administration or parenteral administration.
  • the dosage form is not particularly limited, but for oral administration, for example, solid preparations such as powders, granules, tablets, troches, and capsules; liquid preparations such as solutions, syrups, suspensions, and emulsions; can be converted into
  • parenteral administration it can be formulated into suppositories, sprays, inhalants, ointments, patches, injections, and the like.
  • formulation can be carried out by a known method as appropriate depending on the dosage form.
  • a pharmaceutical carrier When formulating, a pharmaceutical carrier may be added as appropriate.
  • components such as excipients, pH adjusters, coloring agents, and flavoring agents that are commonly used in formulation can be used.
  • components having the effect of preventing, treating, or alleviating diseases and symptoms that are known or will be discovered in the future may be used in combination depending on the purpose.
  • various organic or inorganic carriers can be used depending on the dosage form.
  • carriers for solid preparations include excipients, binders, disintegrants, lubricants, stabilizers, and flavoring agents.
  • excipient examples include sugar derivatives such as lactose, sucrose, glucose, mannitol and sorbitol; starch derivatives such as corn starch, potato starch, ⁇ -starch, dextrin and carboxymethyl starch; crystalline cellulose and hydroxypropyl cellulose. , cellulose derivatives such as hydroxypropyl methylcellulose, carboxymethylcellulose and carboxymethylcellulose calcium; gum arabic; dextran; pullulan; silicate derivatives such as light anhydrous silicic acid, synthetic aluminum silicate and magnesium aluminate metasilicate; phosphate derivatives such as calcium phosphate; Examples include carbonate derivatives such as calcium carbonate; and sulfate derivatives such as calcium sulfate.
  • sugar derivatives such as lactose, sucrose, glucose, mannitol and sorbitol
  • starch derivatives such as corn starch, potato starch, ⁇ -starch, dextrin and carboxymethyl starch
  • binder examples include, in addition to the excipients described above, gelatin; polyvinylpyrrolidone; macrogol, and the like.
  • disintegrant examples include, in addition to the excipients described above, chemically modified starch or cellulose derivatives such as croscarmellose sodium, sodium carboxymethyl starch, and crosslinked polyvinylpyrrolidone.
  • lubricant examples include talc; stearic acid; stearic acid metal salts such as calcium stearate and magnesium stearate; colloidal silica; waxes such as beegum and gay wax; boric acid; glycol; carboxylic acid such as fumaric acid and adipic acid. Acids; carboxylic acid sodium 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 silicic anhydride and silicic acid hydrate; starch derivatives, etc. Can be mentioned.
  • the stabilizer examples include paraoxybenzoic acid esters such as methylparaben and propylparaben; alcohols such as chlorobutanol, benzyl alcohol and phenylethyl alcohol; benzalkonium chloride; acetic anhydride; sorbic acid and the like.
  • the flavoring agent examples include sweeteners, acidulants, fragrances, and the like.
  • carriers used in the case of liquid preparations for oral administration include solvents such as water, flavoring agents, and the like.
  • anti-epileptic composition of the present invention can be used in combination with drugs that are known or will be discovered in the future and have an anti-epileptic effect.
  • the content of Bifidobacterium bacteria in the medicine of this technology is not particularly limited, but it contains Bifidobacterium bacteria in an amount that can be easily ingested in a daily dose to exhibit an effective antiepileptic effect. It is preferable to do so.
  • the content of Bifidobacterium bacteria in the medicine is preferably 1 ⁇ 10 6 to 1 ⁇ 10 12 CFU/g, more preferably 1 ⁇ 10 8 to 1 ⁇ 10 11 CFU/g, per 1 g of medicine. More preferably, it is 1 ⁇ 10 9 to 5 ⁇ 10 10 CFU/g.
  • the daily dosage of Bifidobacterium bacteria in the pharmaceutical of the present technology is preferably at least 1 ⁇ 10 6 CFU/kg body weight/day or more.
  • the daily dose may be administered once a day, or may be divided into two or more doses per day.
  • Administration routes include, for example, oral administration, tube administration (nasally, gastrostomy, intestinal fistula, etc.), intraperitoneal administration, intramuscular administration, transmucosal administration, intranasal administration, and intrarectal administration.
  • oral administration is preferred.
  • the subject of administration is usually a human, but the present invention also includes mammals other than humans, such as pet animals such as dogs and cats, and livestock such as cows, sheep, and pigs.
  • the anti-epileptic composition of the present invention may be a food and contains either or both of a Bifidobacterium bacterium and a Bifidobacterium bacterium culture.
  • the subjects to be ingested, the active ingredients of Bifidobacterium bacteria, and the culture of Bifidobacterium bacteria are the same as in the antiepileptic composition of the present invention described above.
  • Foods in the present invention include foods and drinks.
  • Food and beverages include tablets, liquid foods, and feed (including for pets), regardless of their form such as liquid, paste, solid, or powder, as well as flour products, instant foods, processed agricultural products, and marine products.
  • dairy products include fermented milk, milk drinks, lactic acid bacteria drinks, sweetened condensed milk, skim milk powder, sweetened milk powder, modified milk powder, cream, cheese, butter, and ice creams.
  • dairy products include fermented milk, milk drinks, lactic acid bacteria drinks, sweetened condensed milk, skim milk powder, sweetened milk powder, modified milk powder, cream, cheese, butter, and ice creams.
  • flour products include bread, macaroni, spaghetti, noodles, cake mixes, fried flour, and bread crumbs.
  • instant foods include instant noodles, cup noodles, retort/cooked foods, cooked canned foods, microwave foods, instant soups/stews, instant miso soup/suimono, canned soups, freeze/dried foods, and other instant foods. Can be mentioned.
  • processed agricultural products include canned agricultural products, canned fruits, jams and marmalades, pickles, boiled beans, dried agricultural products, and cereals (processed grain products).
  • processed marine products include canned marine products, fish meat hams and sausages, seafood paste products, marine delicacies, and boiled fish meat.
  • processed livestock products include canned livestock products, pastes, and livestock hams and sausages.
  • fats and oils examples include butter, margarines, and vegetable oils.
  • Examples of basic seasonings include soy sauce, miso, sauces, processed tomato seasonings, mirin, and vinegar.
  • Examples of complex seasonings and foods include cooking mixes, curry ingredients, sauces, dressings, noodle soups, spices, and other complex seasonings.
  • frozen foods examples include raw frozen foods, semi-cooked frozen foods, and cooked frozen foods.
  • sweets examples include caramel, candy, chewing gum, chocolate, cookies, biscuits, cakes, pies, snacks, crackers, Japanese sweets, rice sweets, bean sweets, dessert sweets, and other sweets.
  • beverages include carbonated drinks, natural fruit juices, fruit juice drinks, soft drinks with fruit juice, pulp drinks, fruit drinks with fruit particles, vegetable drinks, soy milk, soy milk drinks, coffee drinks, tea drinks, powder drinks, and concentrated drinks. , sports drinks, nutritional drinks, alcoholic drinks, and other beverages.
  • dairy products are particularly preferred as the anti-epileptic food of the present invention, and fermented milk is particularly preferred.
  • fermented milk is particularly preferred.
  • the content of Bifidobacterium bacteria in the food of the present invention is not particularly limited, but the content of Bifidobacterium bacteria is such that the amount of Bifidobacterium bacteria can be easily ingested per day to exhibit effective antiepileptic effects. It is preferable to contain.
  • the food provided by the present invention can be used in the same manner as described for the above-mentioned pharmaceuticals, and can also be used for purposes other than anti-epileptic effects.
  • the content of Bifidobacterium bacteria in the food is the same as the Bifidobacterium bacteria contained in the medicine. As such, it can be applied to the target of the above-mentioned medicine.
  • the content of Bifidobacterium bacteria in food is preferably 1 x 10 6 to 1 x 10 12 CFU/g, more preferably 1 x 10 8 to 1 x 10 11 CFU/g, per 1 g of food. More preferably, it contains 1 ⁇ 10 9 to 5 ⁇ 10 10 CFU/g.
  • the daily intake of Bifidobacterium bacteria in the food of the present invention is preferably at least 1 ⁇ 10 6 CFU/kg body weight/day or more.
  • the consumer may consume the daily amount of Bifidobacterium bacteria once a day, or may divide the intake into two or more times per day.
  • routes of intake include oral intake and tube intake (nasally, gastrostomy, intestinal fistula, etc.), and oral intake is particularly preferred.
  • Ingestants are usually humans, but the present invention also includes mammals other than humans, such as pet animals such as dogs and cats, and livestock such as cows, sheep, and pigs.
  • the food according to the invention is also suitable for subjects (e.g., humans or other mammals) that do not have "morbid” or "abnormal” symptoms, conditions, or diseases, i.e., "healthy”. or to a subject (e.g., a human or other mammal) in a "normal” state, to maintain a "healthy” or “normal” state. Furthermore, it can be applied to "healthy people concerned about epilepsy symptoms" in order to maintain a "healthy" or "normal” state.
  • the Bifidobacterium bacterium and its culture are a component of a pharmaceutical composition or a food ingredient, the Bifidobacterium bacterium and its culture Their pharmacological effects are basically the same. Therefore, the amount and method of application of the food can be adjusted as appropriate, based on the Bifidobacterium bacterium and its culture itself, depending on the expected effect.
  • the food related to the present invention is a health food, a functional food, an enteral nutritional food, a food for special use, a food with health claims, a food for specified health uses, a food with nutritional function claims, a food with functional claims, or Examples include foods such as quasi-drugs. Specifically, it may be a food that is ingested 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 adjusted as appropriate based on the Bifidobacterium bacterium and its culture itself, depending on the expected effect. .
  • the present invention also provides a method for preventing, treating, or alleviating epileptic seizures using the above-mentioned antiepileptic composition, or its active ingredients, Bifidobacterium bacteria and its culture. provide.
  • the present invention also provides a non-therapeutic administration method of administering the above-mentioned antiepileptic composition, or one or both of its active ingredients, a Bifidobacterium bacterium and a culture thereof.
  • the anti-epileptic composition, one or both of the Bifidobacterium bacterium and its culture, and the dosage, frequency and timing of administration are as described above.
  • an effective amount of a Bifidobacterium bacterium or a culture thereof is used in the method of preventing, treating or alleviating epileptic seizures.
  • the present application includes the following embodiments.
  • Composition for use [2] The anti-epileptic composition is orally administered to the subject at a concentration of 1 ⁇ 10 6 to 1 ⁇ 10 12 CFU/g of Bifidobacterium breve MCC1274 strain (FERM BP-11175) per day.
  • the anti-epileptic composition according to [1] which contains the active ingredient in an amount of .
  • Bifidobacterium breve strain MCC1274 (FERM BP-11175) or a culture thereof for use in the prevention, treatment or alleviation of epileptic seizures.
  • Non-containing method comprising administering an effective amount of one or both of Bifidobacterium breve strain MCC1274 (FERM BP-11175) and its culture to a subject in need of prevention, treatment or alleviation of epileptic seizures. Therapeutic Administration Methods.
  • mice were divided into two groups (14 mice in the non-administration group and 12 mice in the administration group), and one group (administration group) was suspended in physiological saline to a concentration of 1.3 x 10 10 cfu/mL.
  • Bifidobacterium breve MCC1274 strain [FERM BP-11175] (hereinafter referred to as B.
  • breve MCC1274 strain) was orally administered (3.25 x 10 9 cfu/0.25 mL/mouse) every other day on days when PTZ was not administered ( Figure 1 ).
  • the other group (non-administration group) included B.
  • mice was orally administered.
  • Mouse behavior was observed for 30 minutes after PTZ administration, and the degree of convulsion was scored according to the following evaluation method.
  • a new anti-epileptic composition can be provided.
  • the anti-epileptic composition of the present invention has excellent safety and can be continuously administered over a long period of time because its active ingredient is a culture containing one or both of a Bifidobacterium bacterium and a culture thereof. It is very useful because there is little need to worry about side effects.

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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

抗てんかん用組成物Antiepileptic composition
　本発明は、抗てんかん用組成物に関する。
　本願は、２０２２年６月１日に日本に出願された特願２０２２－０８９５４６号について優先権を主張し、その内容をここに援用する。 TECHNICAL FIELD The present invention relates to antiepileptic compositions.
This application claims priority to Japanese Patent Application No. 2022-089546 filed in Japan on June 1, 2022, the contents of which are incorporated herein.
　てんかんは、「てんかん発作」を繰り返し起こす状態のことである。「てんかん発作」は、脳にある神経細胞の異常な電気活動により引き起こされる発作のことで、突発的に運動神経、感覚神経、自律神経、意識又は高次脳機能などの神経系が異常に活動することで発症する。そのため、「てんかん発作」ではそれぞれの神経系に対応し、体の一部が固くなる（運動神経の異常により引き起こされる）、手足がしびれたり耳鳴りがしたりする（感覚神経の異常により引き起こされ+る）、動悸や吐き気を生じる（自律神経の異常により引き起こされる）、意識を失う、言葉が出にくくなる（高次脳機能の異常により引き起こされる）などのさまざまな症状を生じる。
　てんかんの有病率は、０．５～１％と言われており、非特許文献１によれば、比較的有病率の高い疾患である。また、てんかんは、乳幼児から高齢者のいずれの年齢層でも発症する。 Epilepsy is a condition that causes repeated epileptic seizures. "Epileptic seizures" are seizures caused by abnormal electrical activity of nerve cells in the brain, and the nervous system such as motor nerves, sensory nerves, autonomic nerves, consciousness, or higher brain functions suddenly becomes abnormally activated. It is caused by doing this. Therefore, "epileptic seizures" correspond to each nervous system, and some parts of the body become stiff (caused by abnormalities in motor nerves), numbness in the hands and feet, and ringing in the ears (caused by abnormalities in sensory nerves). It causes a variety of symptoms, including palpitations and nausea (caused by abnormalities in the autonomic nervous system), loss of consciousness, and difficulty speaking (caused by abnormalities in higher brain function).
The prevalence of epilepsy is said to be 0.5 to 1%, and according to Non-Patent Document 1, it is a disease with a relatively high prevalence. Furthermore, epilepsy can occur in any age group, from infants to the elderly.
　てんかんの診断は、神経学的検査及び血液検査を含むことができる。脳異常は、脳波（ＥＥＧ：Ｅｌｅｃｔｒｏｅｎｃｅｐｈａｌｏｇｒａｍ）、高密度ＥＥＧ、コンピュータ断層撮影法（ＣＴ：ｃｏｍｐｕｔｅｄ　ｔｏｍｏｇｒａｐｈｙ）スキャン、磁気共鳴イメージング（ＭＲＩ：ｍａｇｎｅｔｉｃ　ｒｅｓｏｎａｎｃｅ　ｉｍａｇｉｎｇ）、陽電子放出断層撮影法（ＰＥＴ：ｐｏｓｉｔｒｏｎ　ｅｍｉｓｓｉｏｎ　ｔｏｍｏｇｒａｐｈｙ）スキャン、単一光子放出コンピュータ断層撮影法（ＳＰＥＣＴ：ｓｉｎｇｌｅ　ｐｈｏｔｏｎ　ｅｍｉｓｓｉｏｎ　ｃｏｍｐｕｔｅｄ　ｔｏｍｏｇｒａｐｈｙ）、並びに思考、記憶及び発話能力を評価するための神経心理学的試験により検出される。解析技術としては、統計的パラメトリックマッピング（ＳＰＭ：Ｓｔａｔｉｓｔｉｃａｌ　ｐａｒａｍｅｔｒｉｃ　ｍａｐｐｉｎｇ）、カリー（ｃｕｒｒｙ）解析、及び脳磁図検査（ＭＥＧ：Ｍａｇｎｅｔｏ－Ｅｎｃｅｐｈａｌｏ－Ｇｒａｐｈｙ）が挙げられる。 Diagnosis of epilepsy can include neurological examination and blood tests. Brain abnormalities can be detected using electroencephalogram (EEG), high-density EEG, computed tomography (CT) scans, magnetic resonance imaging (MRI), and positron emission tomography (PET). :positron emission tomography) It is detected by scans, single photon emission computed tomography (SPECT), and neuropsychological tests to assess thinking, memory, and speech abilities. Analysis techniques include statistical parametric mapping (SPM), curry analysis, and magnetoencephalography (MEG).
　てんかんに対する治療では、主に抗てんかん薬による治療が行われる。抗てんかん薬は、てんかんの原因を取り除くものではなく、てんかん発作を起こりにくくするものである。しかし、てんかんの中には、そのてんかんに対して適切とされる抗てんかん薬を単剤或いは多剤併用で副作用がない範囲の十分な血中濃度で２剤試みても一定期間（具体的には、１年以上の期間若しくは治療前の最長発作間隔の３倍以上の期間のうちいずれか長い方の期間）発作を抑制できない場合があることが知られており、これは薬剤抵抗性てんかんと呼ばれている。非特許文献２によれば、てんかん患者のうち、２０～３０％がこの薬剤性てんかんに該当するとされる。
　また薬物療法に用いられる薬剤は、医薬品であるため容易に使用できるものではなく、一般的に副作用が生じやすい。抗てんかん薬の副作用として、アレルギー機序が関与する薬剤に対する特異体質による急性初期反応、用量依存性の神経系への抑制作用（具体的には、めまい、眼振、複視、眠気、吐気又は食欲低下等）及び長期服用時に見られる慢性期副作用（具体的には、体重増加、多毛或いは脱毛、尿路結石、又は小脳萎縮等）が知られている。 The main treatment for epilepsy is antiepileptic drugs. Antiepileptic drugs do not eliminate the cause of epilepsy, but rather make epileptic seizures less likely to occur. However, for some cases of epilepsy, even if two antiepileptic drugs are tried alone or in combination at sufficient blood concentrations to have no side effects, antiepileptic drugs that are appropriate for the epilepsy may not be used for a certain period of time (specifically It is known that seizures may not be controlled for a period of one year or more or for a period of three times the longest pre-treatment seizure interval, whichever is longer), and this is considered drug-resistant epilepsy. being called. According to Non-Patent Document 2, 20 to 30% of epilepsy patients fall under this drug-induced epilepsy.
Furthermore, since drugs used for drug therapy are pharmaceuticals, they are not easy to use and are generally prone to side effects. Side effects of antiepileptic drugs include an idiosyncratic acute initial reaction to the drug that involves an allergic mechanism, and a dose-dependent suppressive effect on the nervous system (specifically, dizziness, nystagmus, double vision, drowsiness, nausea, or (loss of appetite, etc.) and chronic side effects (specifically, weight gain, hirsutism or hair loss, urinary stones, cerebellar atrophy, etc.) that occur during long-term use are known.
　薬剤抵抗性てんかんに該当するような場合には、食事療法としてケトン食が用いられることがあり、非特許文献３は、一年間ケトン食を行った子供において、てんかん症状の軽減効果がみられたことを報告している。一方で、ケトン食療法は、高脂質及び低糖質を特徴とする食事であることから、低血糖、脂質異常症、又は発育障害などに繋がる可能性がある。 In cases of drug-resistant epilepsy, a ketogenic diet may be used as dietary therapy, and Non-Patent Document 3 shows that children who followed a ketogenic diet for one year showed a reduction in epilepsy symptoms. This is reported. On the other hand, since the ketogenic diet is a diet characterized by high fat and low carbohydrate content, it may lead to hypoglycemia, dyslipidemia, or growth disorders.
　本発明は、てんかん発作の予防、治療又は軽減に有効な抗てんかん用組成物を提供することを目的のひとつとする。 One of the objects of the present invention is to provide an antiepileptic composition effective for preventing, treating, or alleviating epileptic seizures.
［１］　ビフィドバクテリウム属細菌及びその培養物の一方又は両方を含む、抗てんかん用組成物。
［２］　前記ビフィドバクテリウム属細菌がビフィドバクテリウム・ブレーベである、［１］に記載の抗てんかん用組成物。
［３］　前記ビフィドバクテリウム属細菌がビフィドバクテリウム・ブレーベ　ＭＣＣ１２７４株（ＦＥＲＭ　ＢＰ－１１１７５）である、［１］又は［２］に記載の抗てんかん用組成物。
［４］　前記ビフィドバクテリウム属細菌及びその培養物の一方又は両方を１×１０６～１×１０１２ＣＦＵ／ｇ含む、［１］～［３］のいずれかに記載の抗てんかん用組成物。
［５］　てんかん発作の予防、治療又は軽減のために用いられる、［１］～［４］のいずれかに記載の抗てんかん用組成物。
［６］　前記抗てんかん用組成物が医薬品又は食品である、［１］～［５］のいずれかに記載の抗てんかん用組成物。
［７］　前記抗てんかん用組成物がてんかん発作の予防、治療又は軽減が必要な対象に投与される、［１］～［６］のいずれかに記載の抗てんかん用組成物。
［８］　前記ビフィドバクテリウム属細菌及びその培養物の一方又は両方を有効成分とする、［１］～［７］のいずれかに記載の抗てんかん用組成物。
［９］　てんかん発作の予防、治療又は軽減が必要な対象に投与するための組成物の製造における、ビフィドバクテリウム属細菌及びその培養物の一方又は両方の使用。
［１０］　前記ビフィドバクテリウム属細菌がビフィドバクテリウム・ブレーベである、［９］に記載の使用。
［１１］　前記ビフィドバクテリウム属細菌がビフィドバクテリウム・ブレーベ　ＭＣＣ１２７４株（ＦＥＲＭ　ＢＰ－１１１７５）である、［９］または［１０］記載の使用。
［１２］　てんかん発作の予防、治療又は軽減における使用のための、ビフィドバクテリウム属細菌又はその培養物。
［１３］　前記ビフィドバクテリウム属細菌がビフィドバクテリウム・ブレーベである［１２］に記載のビフィドバクテリウム属細菌又はその培養物。
［１４］　前記ビフィドバクテリウム属細菌がビフィドバクテリウム・ブレーベ　ＭＣＣ１２７４株（ＦＥＲＭ　ＢＰ－１１１７５）である、［１２］または［１３］に記載のビフィドバクテリウム属細菌又はその培養物。
［１５］　ビフィドバクテリウム属細菌及びその培養物の一方又は両方の有効量をてんかん発作の予防、治療又は軽減を必要とする対象に投与することを含む、てんかん発作の予防、治療又は軽減をする方法。
［１６］　前記ビフィドバクテリウム属細菌がビフィドバクテリウム・ブレーベである、［１５］に記載の方法。
［１７］　前記ビフィドバクテリウム属細菌がビフィドバクテリウム・ブレーベ　ＭＣＣ１２７４株（ＦＥＲＭ　ＢＰ－１１１７５）である、［１５］又は［１６］に記載の方法。 [1] An antiepileptic composition containing one or both of a Bifidobacterium bacterium and 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] The antiepileptic composition according to any one of [1] to [3], which contains 1×10 6 to 1×10 12 CFU/g of one or both of the Bifidobacterium bacterium and its culture. thing.
[5] The anti-epileptic composition according to any one of [1] to [4], which is used for the prevention, treatment, or alleviation of epileptic seizures.
[6] The anti-epileptic composition according to any one of [1] to [5], wherein the anti-epileptic composition is a medicine or a food.
[7] The anti-epileptic composition according to any one of [1] to [6], wherein the anti-epileptic composition is administered to a subject in need of prevention, treatment, or alleviation of epileptic seizures.
[8] The antiepileptic composition according to any one of [1] to [7], which contains one or both of the Bifidobacterium bacterium and its culture as an active ingredient.
[9] Use of one or both of a Bifidobacterium bacterium and a culture thereof in the manufacture of a composition for administration to a subject in need of prevention, treatment, or alleviation of epileptic seizures.
[10] The use according to [9], wherein the Bifidobacterium bacterium is Bifidobacterium breve.
[11] The use according to [9] or [10], wherein the Bifidobacterium bacterium is Bifidobacterium breve MCC1274 strain (FERM BP-11175).
[12] A Bifidobacterium bacterium or a culture thereof for use in preventing, treating or alleviating epileptic seizures.
[13] The Bifidobacterium bacterium or the culture thereof according to [12], wherein the Bifidobacterium bacterium is Bifidobacterium breve.
[14] The Bifidobacterium bacterium or the culture thereof according to [12] or [13], wherein the Bifidobacterium bacterium is Bifidobacterium breve MCC1274 strain (FERM BP-11175).
[15] Prevention, treatment or alleviation of epileptic seizures, comprising administering an effective amount of one or both of a Bifidobacterium bacterium and a culture thereof to a subject in need of the prevention, treatment or alleviation of epileptic seizures. how to.
[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).
　本発明によれば、てんかん発作の予防、治療又は軽減に有効な抗てんかん用組成物を提供できる。
　なお、ここに記載された効果は、必ずしも限定されるものではなく、本明細書中に記載されたいずれの効果であってもよい。 According to the present invention, it is possible to provide an antiepileptic composition that is effective in preventing, treating, or alleviating epileptic seizures.
Note that the effects described here are not necessarily limited, and may be any effects described in this specification.
試験例におけるＰｅｎｔｙｌｅｎｅｔｅｔｒａｚｏｌｅ（ＰＴＺ）及びビフィドバクテリウム・ブレーベ　ＭＣＣ１２７４株（ＦＥＲＭ　ＢＰ－１１１７５）の投与スケジュールを示す。The administration schedule of Pentylenetetrazole (PTZ) and Bifidobacterium breve MCC1274 strain (FERM BP-11175) in a test example is shown. ビフィドバクテリウム・ブレーベ　ＭＣＣ１２７４株（ＦＥＲＭ　ＢＰ－１１１７５）の投与群及び非投与群における、ＰＴＺの投与回数と平均痙攣スコアの関係を表すグラフを示す。A graph showing the relationship between the number of administrations of PTZ and the average convulsion score in the administration group and non-administration group of Bifidobacterium breve MCC1274 strain (FERM BP-11175) is shown.
　以下、本発明を実施するための好適な実施形態について説明する。なお、以下に説明する実施形態は、本発明の代表的な実施形態の一例を示したものであり、これにより本発明の範囲が狭く解釈されることはない。 Hereinafter, preferred embodiments for carrying out the present invention will be described. Note that the embodiment described below is an example of a typical embodiment of the present invention, and the scope of the present invention should not be interpreted narrowly thereby.
［１．抗てんかん用組成物］
　本発明の抗てんかん用組成物は、ビフィドバクテリウム属細菌及びその培養物の一方又は両方を有効成分とする抗てんかん用組成物である。 [1. Antiepileptic composition]
The anti-epileptic composition of the present invention is an anti-epileptic composition containing one or both of a Bifidobacterium bacterium and a culture thereof as an active ingredient.
〈有効成分〉
　本発明の抗てんかん用組成物の有効成分は、ビフィドバクテリウム属細菌及びその培養物の一方又は両方である。本発明が対象とするビフィドバクテリウム属細菌としては、例えばビフィドバクテリウム・ブレーベ（Bifidobacterium breve）、ビフィドバクテリウム・ラクティス（Bifidobacterium lactis）、ビフィドバクテリウム・ロンガム（Bifidobacterium longum）、ビフィドバクテリウム・インファンティス(Bifidobacterium infantis)、ビフィドバクテリウム・アドレセンティス（Bifidobacterium adolescentis）、ビフィドバクテリウム・ビフィダム（Bifidobacterium bifidum）、ビフィドバクテリウム・アニマリス（Bifidobacterium animalis）などが挙げられる。これらのビフィズス菌は一種単独を対象にしてもよいし、また二種以上を任意に組み合わせて対象とすることもできる。制限はされないものの、好ましくは、ビフィドバクテリウム・ブレーベ、ビフィドバクテリウム・ロンガム、及びビフィドバクテリウム・インファンティスを挙げることができる。より好ましくはビフィドバクテリウム・ロンガム、及びビフィドバクテリウム・ブレーベである。更に好ましくはビフィドバクテリウム・ブレーベ　ＭＣＣ１２７４株（ＦＥＲＭ　ＢＰ－１１１７５）及びその培養物の一方又は両方である。
　ビフィドバクテリウム属細菌及びその培養物の一方又は両方は、本発明の抗てんかん用組成物の製造のために使用される。
　ビフィドバクテリウム属細菌及びその培養物は、いずれも、生菌であることが好ましい。 <Active ingredient>
The active ingredient of the antiepileptic composition of the present invention is one or both of a Bifidobacterium bacterium and a culture thereof. Examples of Bifidobacterium bacteria targeted by the present invention include Bifidobacterium breve, Bifidobacterium lactis, Bifidobacterium longum, and Bifidobacterium longum. Examples include Bifidobacterium infantis, Bifidobacterium adolescentis, Bifidobacterium bifidum, and Bifidobacterium animalis. These Bifidobacterium species may be used alone or in any combination of two or more species. Preferred examples include, but are not limited to, Bifidobacterium breve, Bifidobacterium longum, and Bifidobacterium infantis. More preferred are Bifidobacterium longum and Bifidobacterium breve. More preferably, one or both of Bifidobacterium breve MCC1274 strain (FERM BP-11175) and a culture thereof.
One or both of Bifidobacterium and its culture are used for producing the antiepileptic composition of the present invention.
It is preferable that the bacteria of the genus Bifidobacterium and the culture thereof are live bacteria.
　以下では、ビフィドバクテリウム属細菌がビフィドバクテリウム・ブレーベである場合について説明するが、これにより本発明の範囲が狭く解釈されることはない。
　ビフィドバクテリウム・ブレーベとは、ビフィドバクテリウム属に属する細菌の１種である。ビフィドバクテリウム・ブレーベは、主に乳幼児の大腸内に多く住みついており、ビフィドバクテリウム属に属する菌種の中でもビフィドバクテリウム・ロンガム・サブスピーシーズ・インファンティス（Ｂｉｆｉｄｏｂａｃｔｅｒｉｕｍ　ｌｏｎｇｕｍ　ｓｕｂｓｐ．　ｉｎｆａｎｔｉｓ）等とともに、乳幼児型のビフィドバクテリウム属細菌として知られている。 In the following, a case where the Bifidobacterium bacterium is Bifidobacterium breve will be described, but the scope of the present invention is not interpreted narrowly by this.
Bifidobacterium breve is a type of bacteria belonging to the genus Bifidobacterium. Bifidobacterium breve lives mainly in the large intestines of infants and young children, and among the bacterial species belonging to the genus Bifidobacterium, Bifidobacterium longum subsp. infantis ), it is known as an infant-type Bifidobacterium bacterium.
　本発明の抗てんかん用組成物は、その有効成分が、主に乳幼児の大腸内に多く住みついている、ビフィドバクテリウム属細菌及びビフィドバクテリウム属細菌を含む培養物のいずれか一方又は両方であることから、安全性に優れ、長期間、連続的に投与しても副作用を心配する必要性も低く、非常に有用である。さらに、他の薬剤との併用においても安全性が高い。 The anti-epileptic composition of the present invention contains either or both of a Bifidobacterium bacterium and a culture containing a Bifidobacterium bacterium, which mainly resides in large numbers in the large intestine of infants. Therefore, it is extremely safe, and there is little need to worry about side effects even when administered continuously for a long period of time, making it very useful. Furthermore, it is highly safe when used in combination with other drugs.
　本発明においては、ビフィドバクテリウム・ブレーベの中でもビフィドバクテリウム・ブレーベ　ＭＣＣ１２７４株（ＦＥＲＭ　ＢＰ－１１１７５）、ビフィドバクテリウム・ブレーベ　Ｍ―１６Ｖ（ＮＩＴＥ　ＢＰ－０２６２２）等が挙げられる。ここで、ＭＣＣは、Ｍｏｒｉｎａｇａ　Ｃｕｌｔｕｒｅ　Ｃｏｌｌｅｃｔｉｏｎ（Ｍｏｒｉｎａｇａ　Ｍｉｌｋ　Ｉｎｄｕｓｔｒｙ　Ｃｏ．，Ｌｔｄ．）を意味する。 In the present invention, examples of Bifidobacterium breve include Bifidobacterium breve MCC1274 strain (FERM BP-11175), Bifidobacterium breve M-16V (NITE BP-02622), and the like. Here, MCC means Morinaga Culture Collection (Morinaga Milk Industry Co., Ltd.).
　上記例示した菌株名で特定される菌株には、当該菌株名で所定の機関に寄託及び登録がなされている菌株そのもの（以下、説明の便宜上、「寄託株」ともいう。）に限られず、それと実質的に同等な菌株（以下、「派生株」又は「誘導株」ともいう。）も包含される。すなわち、例えば、ビフィドバクテリウム・ブレーベ　ＭＣＣ１２７４株（ＦＥＲＭ　ＢＰ－１１１７５）の寄託番号で上記寄託機関に寄託されている菌株そのものに限られず、それと実質的に同等な菌株も包含される。
　上記寄託株と実質的に同等の菌株は、例えば、当該寄託株を親株とする派生株であってよい。派生株としては、寄託株から育種された菌株又は寄託株から自然に生じた菌株が挙げられる。 The strains identified by the strain names listed above are not limited to the strains themselves that have been deposited and registered with designated institutions under the strain names (hereinafter also referred to as "deposited strains" for convenience of explanation). Substantially equivalent bacterial strains (hereinafter also referred to as "derivative strains" or "derived strains") are also included. That is, for example, the present invention is not limited to the strain deposited with the above-mentioned depository institution under the deposit number Bifidobacterium breve strain MCC1274 (FERM BP-11175), but also includes strains substantially equivalent thereto.
A strain that is substantially equivalent to the deposited strain may be, for example, a derivative strain that uses the deposited strain as a parent strain. Derivative strains include strains bred from the deposited strain or naturally occurring strains from the deposited strain.
　前記派生株としては、以下のような菌株が挙げられる。
（１）Ｒａｎｄｏｍｌｙ　Ａｍｐｌｉｆｉｅｄ　Ｐｏｌｙｍｏｒｐｈｉｃ　ＤＮＡ（ＲＡＰＤ）法又はＰｕｌｓｅｄ－ｆｉｅｌｄ　ｇｅｌ　ｅｌｅｃｔｒｏｐｈｏｒｅｓｉｓ（ＰＦＧＥ）法により同一の菌株と判定される菌株（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.　Ｐａｇｅ４３に記載）
（２）当該寄託菌株由来の遺伝子のみ保有し、外来由来の遺伝子を持たず、ＤＮＡの同一性が９５％以上である菌株
（３）当該菌株から育種された菌株、又は遺伝子工学的改変、突然変異若しくは自然突然変異を含む同一の形質を有する菌株 Examples of the derived strains include the following strains.
(1) Bacterial strains determined to be the same by the Randomly Amplified Polymorphic DNA (RAPD) method or the Pulsed-field gel electrophoresis (PFGE) method (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 derived from the deposited strain, has no foreign-derived genes, and has a DNA identity of 95% or more. (3) A strain bred from the strain, or a strain that has been genetically modified or suddenly Strains with identical traits, including mutations or natural mutations
　ＭＣＣ１２７４は、独立行政法人産業技術総合研究所　特許生物寄託センター（日本国〒３０５－８５６６　茨城県つくば市東１－１－１　中央第６（現ＩＰＯＤ　独立行政法人製品評価技術基盤機構　特許生物寄託センター（ＮＩＴＥ－ＩＰＯＤ）：日本国　〒２９２-０８１８　千葉県木更津市かずさ鎌足２－５－８　１２０号室））に、２００９年８月２５日より、ＩＰＯＤ　ＦＥＲＭ　ＢＰ－１１１７５の受託番号で寄託されている。
　Ｍ－１６Ｖは、独立行政法人製品評価技術基盤機構　特許微生物寄託センター（日本国　〒２９２－０８１８　千葉県木更津市かずさ鎌足２－５－８　１２２号室）に、２０１８年１月２６日より、ＮＩＴＥ　ＢＰ－０２６２２の受託番号で寄託されている。
　これらの細菌は、上記保存機関より一般に入手可能である。 MCC1274 is located at the Patent Organism Depositary Center, National Institute of Advanced Industrial Science and Technology (Chuo 6, 1-1-1 Higashi, Tsukuba City, Ibaraki Prefecture, 305-8566, Japan (currently IPOD), Patent Organism Depositary Center, National Institute of Advanced Industrial Science and Technology, Japan). NITE-IPOD): Room 120, 2-5-8 Kazusa Kamatari, Kisarazu, Chiba 292-0818, Japan, has been deposited with the accession number IPOD FERM BP-11175 since August 25, 2009. .
M-16V was transferred to the National Institute of Technology and Evaluation, Patent Microorganism Depositary (Room 122, 2-5-8 Kazusa Kamatari, Kisarazu City, Chiba Prefecture, 292-0818, Japan) from January 26, 2018, to NITE. It has been deposited under accession number BP-02622.
These bacteria are generally available from the above-mentioned repositories.
　ビフィドバクテリウム・ブレーベ　ＭＣＣ１２７４株は、ビフィドバクテリウム・ブレーベ　ＦＥＲＭ　ＢＰ－１１１７５の分譲株を培養することにより容易に取得できる。培養する方法は、特に限定されず、本細菌の性質に応じた適当な条件下で培養を行うことができる。
　具体的には、例えば、培養温度は、通常、２５～５０℃であり、３５～４２℃が好ましい。また、培養は嫌気条件下で行うことが好ましく、例えば、炭酸ガス等の嫌気ガスを通気しながら培養できる。また、液体静置培養等の微好気条件下で培養してもよい。 Bifidobacterium breve strain MCC1274 can be easily obtained by culturing a distributed strain of Bifidobacterium breve FERM BP-11175. The culturing method is not particularly limited, and the culturing can be carried out under appropriate conditions depending on the properties of the bacterium.
Specifically, for example, the culture temperature is usually 25 to 50°C, preferably 35 to 42°C. Further, the culture is preferably performed under anaerobic conditions, and for example, the culture can be performed while aerating an anaerobic gas such as carbon dioxide gas. Alternatively, it may be cultured under microaerobic conditions such as liquid static culture.
　ビフィドバクテリウム・ブレーベ　ＭＣＣ１２７４株を培養する培地としては、特に限定されず、ビフィドバクテリウム属に属する細菌の培養に、通常用いられる培地を用いることができる。 The 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.
　すなわち、炭素源としては、例えば、グルコース、ガラクトース、ラクトース、アラビノース、マンノース、スクロース、デンプン、デンプン加水分解物及び廃糖蜜等の糖類を資化性に応じて使用できる。窒素源としては、例えば、アンモニア、硫酸アンモニウム、塩化アンモニウム及び硝酸アンモニウムなどのアンモニウム塩類並びに硝酸塩類を使用できる。また、無機塩類としては、例えば、塩化ナトリウム、塩化カリウム、リン酸カリウム、硫酸マグネシウム、塩化カルシウム、硝酸カルシウム、塩化マンガン及び硫酸第一鉄等を用いることができる。また、ペプトン、大豆粉、脱脂大豆粕、肉エキス及び酵母エキス等の有機成分を用いてもよい。 That is, as a carbon source, for example, sugars such as glucose, galactose, lactose, arabinose, mannose, sucrose, starch, starch hydrolyzate, and blackstrap molasses can be used depending on their assimilation properties. As a nitrogen source, for example, ammonia, ammonium salts such as ammonium sulfate, ammonium chloride and ammonium nitrate, and nitrates can be used. Further, as the inorganic salts, for example, sodium chloride, potassium chloride, potassium phosphate, magnesium sulfate, calcium chloride, calcium nitrate, manganese chloride, ferrous sulfate, etc. can be used. Additionally, organic ingredients such as peptone, soybean flour, defatted soybean meal, meat extract, and yeast extract may be used.
　ビフィドバクテリウム・ブレーベ　ＭＣＣ１２７４株は、培養後、得られた培養物をそのまま用いてもよく、希釈又は濃縮して用いてもよく、培養物から回収した菌体を用いてもよい。 After culturing Bifidobacterium breve MCC1274 strain, the obtained culture may be used as is, it may be diluted or concentrated, and the bacterial cells recovered from the culture may be used.
　また、本発明の抗てんかん用組成物では、ビフィドバクテリウム・ブレーベ　ＭＣＣ１２７４株のみならず、ビフィドバクテリウム・ブレーベ　ＭＣＣ１２７４株を含む培養物や培養上清も有効成分として用いることができる。
　なお、前記培養物としては、ビフィドバクテリウム・ブレーベ　ＭＣＣ１２７４株を培養して増殖した後、細菌体以外を極力除去したものが好ましく、実質的に細菌体のみからなるものがより好ましい。ここで、「実質的に細菌体のみからなる」とは、湿質量で、培養物の全質量の９５質量％以上が細菌体であることを意味する。
　培養上清とは、ビフィドバクテリウム・ブレーベ　ＭＣＣ１２７４株を培養した際に得られる培養液部分、又はその上澄み溶液であり、培養上清は、フィルタリングにより除菌処理されたものであることが好ましい。 Furthermore, in the antiepileptic composition of the present invention, not only Bifidobacterium breve MCC1274 strain but also a culture or culture supernatant containing Bifidobacterium breve MCC1274 strain can be used as an active ingredient.
The culture is preferably one in which Bifidobacterium breve MCC1274 strain is cultured and propagated, and then as much as possible other than bacterial bodies is removed, and one consisting essentially only of bacterial bodies is more preferable. Here, "substantially consisting only of bacterial bodies" means that 95% by mass or more of the total mass of the culture is composed of bacterial bodies in terms of wet mass.
The culture supernatant is the culture solution obtained when culturing Bifidobacterium breve MCC1274 strain, or its supernatant solution, and the culture supernatant is preferably sterilized by filtering. .
　本発明の抗てんかん用組成物において、ビフィドバクテリウム属細菌の培養物は、ビフィドバクテリウム属細菌の菌体の他に、本発明の効果を妨げない限り、他の成分を含んでいてもよい。このような成分として、例えば、培養に用いた培地等の成分、培養物の回収、分離又は洗浄等に用いた緩衝液等の成分が挙げられる。 In the anti-epileptic composition of the present invention, the culture of Bifidobacterium bacteria may contain other components in addition to Bifidobacterium cells, as long as they do not interfere with the effects of the present invention. Good too. Examples of such components include components such as the medium used for culture, and components such as buffers used for recovery, separation, or washing of the culture.
　本発明の抗てんかん用組成物は、前記有効成分のみからなるものであってもよく、前記有効成分と前記有効成分以外の任意成分とを配合した組成物であってもよい。
　前記任意成分は、特に限定されず、従来、医薬品に配合されている添加剤を配合できる。 The antiepileptic composition of the present invention may consist only of the above-mentioned active ingredient, or may be a composition containing the above-mentioned active ingredient and any other ingredient other than the above-mentioned active ingredient.
The optional components are not particularly limited, and additives conventionally included in pharmaceuticals can be included.
　添加剤としては、酸化防止剤、賦形剤、結合剤、崩壊剤、滑沢剤、安定剤、矯味矯臭剤及び希釈剤等、さらに、後述する製剤担体等が挙げられる。 Examples of additives include antioxidants, excipients, binders, disintegrants, lubricants, stabilizers, flavoring agents, and diluents, as well as formulation carriers described below.
〈製品形態〉
　本発明の抗てんかん用組成物の製品形態は特に限定されないが、後述する食品、医薬品等の形態が好ましい。 <Product form>
The product form of the anti-epileptic composition of the present invention is not particularly limited, but forms such as foods and medicines described below are preferred.
〈投与対象〉
　本発明の抗てんかん用組成物の投与の対象は、てんかん発作の予防、治療又は軽減が必要な対象である。
　前記対象は、通常ヒトであるが、ヒト以外の哺乳動物、例えば、イヌ及びネコ等のペット動物、ウシ、ヒツジ及びブタ等の家畜に投与することも可能である。以下では、対象がヒトである場合について説明する。
　前記てんかん発作の予防、治療又は軽減が必要な対象は、以下の（１）～（４）のいずれかが好ましい。
（１）頭部外傷、脳卒中、脳腫瘍、アルツハイマー病等又は脳疾患の既往歴がある対象
（２）家族がてんかん患者である対象
（３）てんかんと診断された対象
（４）てんかん発作を起こしたことがある対象 <Administration target>
The subject to whom the anti-epileptic composition of the present invention is administered is a subject in need of prevention, treatment or alleviation of epileptic seizures.
The subject is usually a human, but it is also possible to administer to mammals other than humans, for example, pet animals such as dogs and cats, and livestock such as cows, sheep, and pigs. Below, a case where the subject is a human will be explained.
The subject in need of prevention, treatment or alleviation of epileptic seizures is preferably one of the following (1) to (4).
(1) Subjects with a history of head trauma, stroke, brain tumor, Alzheimer's disease, etc., or brain diseases (2) Subjects whose family members have epilepsy (3) Subjects who have been diagnosed with epilepsy (4) Subjects who have had an epileptic seizure subject of something
　本明細書において使用される場合、「治療」という用語は、疾患、障害若しくは状態を完全若しくは部分的に阻害し、例えば、その発症を一定期間以上停止させることを指す。同様に、「治療」は、治療的処置を指す。 As used herein, the term "treatment" refers to completely or partially inhibiting a disease, disorder, or condition, eg, halting its onset over a period of time. Similarly, "therapy" refers to therapeutic treatment.
　本明細書において使用される場合、「予防」という用語は、疾患、障害及び／若しくは状態の素因を持ち得るが、それを有すると未だ診断されていない患者において疾患、障害若しくは状態が起こることを完全若しくは部分的に予防し、疾患、障害若しくは状態にかかわる発作の発症頻度を低減させることを指す。予防は、予防的手段を指す。 As used herein, the term "prevention" refers to preventing a disease, disorder, or condition from occurring in a patient who may be predisposed to, but has not yet been diagnosed with, the disease, disorder, or condition. Refers to the complete or partial prevention and reduction of the frequency of attacks associated with a disease, disorder, or condition. Prevention refers to preventive measures.
　本明細書において使用される場合、「軽減」という用語は、疾患、障害及び／若しくは状態の素因を有すると診断されている患者において、疾患、障害若しくは状態を完全若しくは部分的に緩和し、例えば、疾患、障害及び／若しくは状態の退縮を引き起こすことを指す。また疾患、障害もしくは状態にかかわる発作の発症頻度を低減させることを意味する。 As used herein, the term "alleviation" refers to the complete or partial alleviation of a disease, disorder or condition in a patient who has been diagnosed as having a predisposition to the disease, disorder and/or condition, e.g. , refers to causing regression of a disease, disorder, and/or condition. It also means reducing the frequency of seizures associated with a disease, disorder, or condition.
〈てんかん発作〉
　てんかんに見られる発作型については、国際てんかん連盟により、大分類として、焦点発作、全般発作及び起始不明発作と分類され、さらに小分類として、焦点意識保持発作、焦点意識減損発作、焦点運動起始発作、焦点非運動起始発作、焦点起始両側強直間代発作、全般運動発作、全般非運動発作、起始不明運動発作、起始不明非運動発作及び分類不能発作に分類されている。
　本発明に係る組成物は、てんかん発作の予防、治療又は軽減のために提供されるが、対象となる発作型は特に限定されない。 <Epileptic seizure>
The seizure types seen in epilepsy are broadly classified by the International Federation of Epilepsy into focal seizures, generalized seizures, and seizures of unknown origin, and are subcategorized into focal seizures with preserved consciousness, focal impaired consciousness seizures, and focal motor onset seizures. It is classified into onset seizures, focal nonmotor onset seizures, focal onset bilateral tonic-clonic seizures, generalized motor seizures, generalized nonmotor seizures, motor seizures of unknown origin, nonmotor onset seizures of unknown origin, and unclassifiable seizures.
The composition according to the present invention is provided for the prevention, treatment, or alleviation of epileptic seizures, but the targeted seizure types are not particularly limited.
〈てんかん発作の予防、治療、軽減〉
　本発明において、てんかん発作の予防、治療及び軽減は、それぞれ本発明の抗てんかん用組成物の投与の前後で、発作の発症予防、発作の消失及び発作の発症頻度の低減をさせることを意味する。 <Prevention, treatment, and alleviation of epileptic seizures>
In the present invention, prevention, treatment, and alleviation of epileptic seizures mean prevention of onset of seizures, disappearance of seizures, and reduction in the frequency of onset of seizures before and after administration of the antiepileptic composition of the present invention, respectively. .
〈投与経路〉
　本発明の抗てんかん用組成物の投与経路は、例えば、経口投与、経管投与（経鼻、胃瘻及び腸瘻等）、腹腔内投与、筋肉内投与、経粘膜投与、鼻腔内投与及び直腸内投与等が挙げられるが、特に、経口投与が好ましい。 <Route of administration>
Administration routes for the antiepileptic composition of the present invention include, for example, oral administration, tube administration (nasally, gastrostomy, intestinal fistula, etc.), intraperitoneal administration, intramuscular administration, transmucosal administration, intranasal administration, and rectal administration. Examples include internal administration, but oral administration is particularly preferred.
〈投与量、投与頻度及び投与タイミング〉
　本発明の抗てんかん用組成物におけるビフィドバクテリウム属細菌の含有量は、特に制限されないが、効果的な抗てんかん作用を示すための１日当たりの投与量を無理なく摂取できる程度のビフィドバクテリウム属細菌を含むことが好ましい。例えば、抗てんかん用組成物におけるビフィドバクテリウム属細菌の含有量は、組成物１ｇあたり、好ましくは１×１０６～１×１０１２ＣＦＵ／ｇ、より好ましくは１×１０８～１×１０１１ＣＦＵ／ｇ、さらに好ましくは１×１０９～５×１０１０ＣＦＵ／ｇであるがより好ましい。
　また、ビフィドバクテリウム属細菌を含む本発明の抗てんかん用組成物を、１日当たり１～３ｇ投与することが好ましい。なお、ＣＦＵは、コロニー形成単位（Ｃｏｌｏｎｙ　Ｆｏｒｍｉｎｇ　Ｕｎｉｔ）を表す。
　ビフィドバクテリウム属細菌を含む本発明の抗てんかん用組成物は、１日あたり１回の投与でも良いが、１日あたり２回以上に分けて投与されることもできる。
　本発明の抗てんかん用組成物は、１日のうちでいつ投与されてもよいが、例えば、食前、食後、又は就寝前に投与されることが好ましい。
　また、ビフィドバクテリウム属細菌を含む本発明の抗てんかん用組成物は、単回投与でもよいが、１週間に１回以上投与されることが好ましく、３日に１回以上投与されることがより好ましく、２日に１回以上投与されることがさらに好ましく、毎日継続して投与されることが最も好ましい。例えば３週間以上毎日投与されることが好ましい。 <Dose, frequency and timing of administration>
The content of Bifidobacterium bacteria in the anti-epileptic composition of the present invention is not particularly limited, but the content of Bifidobacterium bacteria is such that the amount of Bifidobacterium bacteria can be easily ingested per day to exhibit effective anti-epileptic effects. Preferably, it contains bacteria of the genus P. genus. For example, the content of Bifidobacterium bacteria in the antiepileptic composition is preferably 1×10 6 to 1×10 12 CFU/g, more preferably 1×10 8 to 1×10 per gram of the composition. 11 CFU/g, more preferably 1×10 9 to 5×10 10 CFU/g, but more preferably.
Furthermore, it is preferable to administer 1 to 3 g of the antiepileptic composition of the present invention containing Bifidobacterium bacteria per day. Note that CFU represents colony forming unit.
The antiepileptic composition of the present invention containing Bifidobacterium bacteria may be administered once per day, or may be administered in two or more divided doses per day.
The anti-epileptic composition of the present invention may be administered at any time during the day, but is preferably administered, for example, before meals, after meals, or before going to bed.
Further, the anti-epileptic composition of the present invention containing Bifidobacterium bacteria may be administered once, but preferably once a week or more, and preferably once every 3 days or more. is more preferable, it is even more preferable that the drug is administered once or more every two days, and it is most preferable that the drug is administered continuously every day. For example, it is preferable to administer it daily for three weeks or more.
〈評価方法〉
　本明細書に記載されている抗てんかん用組成物による、てんかん発作の予防、治療又は軽減の効果は、マウス又はウサギ若しくはサルモデルのような動物モデルに基づいて評価することができる。例えば、本明細書に記載される抗てんかん用組成物の評価に使用することができる動物モデルの例には、Pentylenetetrazole投与によるKindlingマウスモデルが含まれ、当該モデルは医薬品等の効果評価にも用いられている。また、動物モデルにおける抗てんかん効果の評価項目として、例えば痙攣スコア等が用いられる（Giovambattista De Sarro, Neuropharmacology 39 (2000) 2147-2161）。 <Evaluation method>
The effectiveness of the antiepileptic compositions described herein in preventing, treating, or alleviating epileptic seizures can be evaluated based on animal models such as mouse or rabbit or monkey models. For example, examples of animal models that can be used to evaluate the anti-epileptic compositions described herein include the Kindling mouse model by administration of pentylenetetrazole, which can also be used to evaluate the effects of drugs, etc. It is being In addition, as an evaluation item for antiepileptic effects in animal models, for example, convulsion scores are used (Giovambattista De Sarro, Neuropharmacology 39 (2000) 2147-2161).
　本明細書において、抗てんかん用組成物の評価の一態様として、てんかん発作の治療は痙攣スコアを０にすることを意味してもよく、てんかん発作の軽減は痙攣スコアを減少させることを意味してもよく、てんかん発作の予防はてんかん発作を起こす素因を有する対象において抗てんかん用組成物の非摂取群と比べて痙攣スコアの上昇を抑制することを意味してもよい。
　また、抗てんかん用組成物の評価の一態様として、てんかん発作の治療はてんかん発作を２年以上発症させないことを意味してもよく、てんかん発作の軽減は発作の持続時間の短縮、発作頻度の低減、症状の程度軽減、及び一部の発作型の消失などを意味してもよく、てんかん発作の予防はてんかんであると診断されていないがてんかん発作を起こす素因を有する対象において、抗てんかん用組成物の非摂取群と比べててんかんの発症率を低減することを意味してもよい。 As used herein, as one aspect of evaluating the anti-epileptic composition, treating epileptic seizures may mean reducing the convulsion score to 0, and alleviating epileptic seizures may mean reducing the convulsion score. Prevention of epileptic seizures may also mean suppressing an increase in convulsion scores in subjects who are predisposed to having epileptic seizures compared to a group that does not take the anti-epileptic composition.
Furthermore, as one aspect of evaluation of anti-epileptic compositions, treating epileptic seizures may mean preventing epileptic seizures from occurring for two years or more, and alleviating epileptic seizures means shortening the duration of seizures and reducing seizure frequency. Prevention of epileptic seizures, which may mean reduction in severity, reduction in the severity of symptoms, and elimination of some seizure types, is the use of anti-epileptic drugs in subjects who have not been diagnosed with epilepsy but are predisposed to having epileptic seizures. It may also mean reducing the incidence of epilepsy compared to a group not receiving the composition.
［２．医薬品］
　本発明の抗てんかん用組成物は、医薬品であってよく、ビフィドバクテリウム属細菌及びビフィドバクテリウム属細菌の培養物のいずれか一方又は両方を含む。
　投与対象、有効成分であるビフィドバクテリウム属細菌及びビフィドバクテリウム属細菌の培養物については、上述した本発明の抗てんかん用組成物と同様である。 [2. Pharmaceutical products]
The anti-epileptic composition of the present invention may be a pharmaceutical and contains either or both of a Bifidobacterium bacterium and a Bifidobacterium bacterium culture.
The subject to be administered, the active ingredient Bifidobacterium bacteria, and the culture of Bifidobacterium bacteria are the same as in the antiepileptic composition of the present invention described above.
　本発明に係る医薬は、公知の医薬に本発明の抗てんかん用組成物を添加して調製することもできるし、医薬の原料中に該抗てんかん用組成物を混合して新たな医薬を製造することもできる。 The medicine according to the present invention can be prepared by adding the anti-epileptic composition of the present invention to a known medicine, or a new medicine can be prepared by mixing the anti-epileptic composition into the raw material of the medicine. You can also.
　また、本発明の抗てんかん用組成物を医薬品として用いたものや、本発明の抗てんかん用組成物を既存の医薬品に添加したものも本技術の医薬に含まれる。 Furthermore, the medicines of the present technology include those in which the anti-epileptic composition of the present invention is used as a medicine, and those in which the anti-epileptic composition of the present invention is added to existing medicines.
　本発明の抗てんかん用組成物を医薬として用いる際には、そのまま、又は濃縮してから、或いは固体状、顆粒状又は粉末状に加工してから用いてもよい。 When using the antiepileptic composition of the present invention as a medicine, it may be used as it is, after being concentrated, or after being processed into a solid, granule, or powder form.
〈製剤化〉
　本発明の抗てんかん用組成物は、経口投与や非経口投与等の投与方法に応じて適宜所望の剤形に製剤化することができる。その剤形は特に限定されないが、経口投与の場合、例えば、散剤、顆粒剤、錠剤、トローチ剤及びカプセル剤等の固形製剤；溶液剤、シロップ剤、懸濁剤及び乳剤等の液剤等に製剤化することができる。非経口投与の場合、例えば、座剤、噴霧剤、吸入剤、軟膏剤、貼付剤及び注射剤等に製剤化することができる。本発明では、経口投与の剤形に製剤化することが好ましい。
　なお、製剤化は剤形に応じて、適宜、公知の方法により実施できる。 <Formulation>
The antiepileptic composition of the present invention can be formulated into a desired dosage form as appropriate depending on the administration method, such as oral administration or parenteral administration. The dosage form is not particularly limited, but for oral administration, for example, solid preparations such as powders, granules, tablets, troches, and capsules; liquid preparations such as solutions, syrups, suspensions, and emulsions; can be converted into For parenteral administration, it can be formulated into suppositories, sprays, inhalants, ointments, patches, injections, and the like. In the present invention, it is preferable to formulate the drug into a dosage form for oral administration.
In addition, formulation can be carried out by a known method as appropriate depending on the dosage form.
　製剤化に際しては、適宜製剤担体を配合する等して製剤化してもよい。また、本発明の抗てんかん用組成物のほか、通常製剤化に用いられている賦形剤、ｐＨ調整剤、着色剤及び矯味剤等の成分を用いることができる。さらに、公知の又は将来的に見出される疾患や症状の予防、治療又は軽減の効果を有する成分を、適宜目的に応じて併用することも可能である。 When formulating, a pharmaceutical carrier may be added as appropriate. In addition to the antiepileptic composition of the present invention, components such as excipients, pH adjusters, coloring agents, and flavoring agents that are commonly used in formulation can be used. Furthermore, components having the effect of preventing, treating, or alleviating diseases and symptoms that are known or will be discovered in the future may be used in combination depending on the purpose.
　前記製剤担体としては、剤形に応じて、各種有機又は無機の担体を用いることができる。
　固形製剤の場合の担体としては、例えば、賦形剤、結合剤、崩壊剤、滑沢剤、安定剤及び矯味矯臭剤等が挙げられる。 As the pharmaceutical carrier, various organic or inorganic carriers can be used depending on the dosage form.
Examples of carriers for solid preparations include excipients, binders, disintegrants, lubricants, stabilizers, and flavoring agents.
　前記賦形剤としては、例えば、乳糖、白糖、ブドウ糖、マンニット及びソルビット等の糖誘導体；トウモロコシデンプン、馬鈴薯デンプン、α－デンプン、デキストリン及びカルボキシメチルデンプン等のデンプン誘導体；結晶セルロース、ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロース、カルボキシメチルセルロース及びカルボキシメチルセルロースカルシウム等のセルロース誘導体；アラビアゴム；デキストラン；プルラン；軽質無水珪酸、合成珪酸アルミニウム及びメタ珪酸アルミン酸マグネシウム等の珪酸塩誘導体；リン酸カルシウム等のリン酸塩誘導体；炭酸カルシウム等の炭酸塩誘導体；及び硫酸カルシウム等の硫酸塩誘導体等が挙げられる。 Examples of the excipient 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; crystalline cellulose and hydroxypropyl cellulose. , cellulose derivatives such as hydroxypropyl methylcellulose, carboxymethylcellulose and carboxymethylcellulose calcium; gum arabic; dextran; pullulan; silicate derivatives such as light anhydrous silicic acid, synthetic aluminum silicate and magnesium aluminate metasilicate; phosphate derivatives such as calcium phosphate; Examples include carbonate derivatives such as calcium carbonate; and sulfate derivatives such as calcium sulfate.
　前記結合剤としては、例えば、上記賦形剤の他、ゼラチン；ポリビニルピロリドン；マクロゴール等が挙げられる。 Examples of the binder include, in addition to the excipients described above, gelatin; polyvinylpyrrolidone; macrogol, and the like.
　前記崩壊剤としては、例えば、上記賦形剤の他、クロスカルメロースナトリウム、カルボキシメチルスターチナトリウム及び架橋ポリビニルピロリドン等の化学修飾されたデンプン又はセルロース誘導体等が挙げられる。 Examples of the disintegrant include, in addition to the excipients described above, chemically modified starch or cellulose derivatives such as croscarmellose sodium, sodium carboxymethyl starch, and crosslinked polyvinylpyrrolidone.
　前記滑沢剤としては、例えば、タルク；ステアリン酸；ステアリン酸カルシウム及びステアリン酸マグネシウム等のステアリン酸金属塩；コロイドシリカ；ビーガム及びゲイロウ等のワックス類；硼酸；グリコール；フマル酸及びアジピン酸等のカルボン酸類；安息香酸ナトリウム等のカルボン酸ナトリウム塩；硫酸ナトリウム等の硫酸塩類；ロイシン；ラウリル硫酸ナトリウム及びラウリル硫酸マグネシウム等のラウリル硫酸塩；無水珪酸及び珪酸水和物等の珪酸類；デンプン誘導体等が挙げられる。 Examples of the lubricant include talc; stearic acid; stearic acid metal salts such as calcium stearate and magnesium stearate; colloidal silica; waxes such as beegum and gay wax; boric acid; glycol; carboxylic acid such as fumaric acid and adipic acid. Acids; carboxylic acid sodium 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 silicic anhydride and silicic acid hydrate; starch derivatives, etc. Can be mentioned.
　前記安定剤としては、例えば、メチルパラベン及びプロピルパラベン等のパラオキシ安息香酸エステル類；クロロブタノール、ベンジルアルコール及びフェニルエチルアルコール等のアルコール類；塩化ベンザルコニウム；無水酢酸；ソルビン酸等が挙げられる。
　前記矯味矯臭剤としては、例えば、甘味料、酸味料及び香料等が挙げられる。
　なお、経口投与用の液剤の場合に使用する担体としては、水等の溶剤及び矯味矯臭剤等が挙げられる。 Examples of the stabilizer include paraoxybenzoic acid esters such as methylparaben and propylparaben; alcohols such as chlorobutanol, benzyl alcohol and phenylethyl alcohol; benzalkonium chloride; acetic anhydride; sorbic acid and the like.
Examples of the flavoring agent include sweeteners, acidulants, fragrances, and the like.
Note that carriers used in the case of liquid preparations for oral administration include solvents such as water, flavoring agents, and the like.
　また、本発明の抗てんかん用組成物は、公知の又は将来的に見出される抗てんかん作用を有する薬等と併用することも可能である。 Furthermore, the anti-epileptic composition of the present invention can be used in combination with drugs that are known or will be discovered in the future and have an anti-epileptic effect.
　本技術の医薬におけるビフィドバクテリウム属細菌の含有量は特に制限されないが、効果的な抗てんかん作用を示すための１日当たりの投与量を無理なく摂取できる程度のビフィドバクテリウム属細菌を含有することが好ましい。例えば、医薬におけるビフィドバクテリウム属細菌の含有量は、医薬１ｇあたり、好ましくは１×１０６～１×１０１２ＣＦＵ／ｇ、より好ましくは１×１０８～１×１０１１ＣＦＵ／ｇ、さらに好ましくは１×１０９～５×１０１０ＣＦＵ／ｇであることがより好ましい。
　また、本技術の医薬におけるビフィドバクテリウム属細菌の１日当たりの投与量は、少なくとも１×１０6ＣＦＵ／ｋｇ体重／日、又はそれ以上であることが好ましい。 The content of Bifidobacterium bacteria in the medicine of this technology is not particularly limited, but it contains Bifidobacterium bacteria in an amount that can be easily ingested in a daily dose to exhibit an effective antiepileptic effect. It is preferable to do so. For example, the content of Bifidobacterium bacteria in the medicine is preferably 1 × 10 6 to 1 × 10 12 CFU/g, more preferably 1 × 10 8 to 1 × 10 11 CFU/g, per 1 g of medicine. More preferably, it is 1×10 9 to 5×10 10 CFU/g.
Further, the daily dosage of Bifidobacterium bacteria in the pharmaceutical of the present technology is preferably at least 1×10 6 CFU/kg body weight/day or more.
　本技術の医薬において、１日の投与量を１日１回で投与してもよく、１日あたり２回以上に分けて投与してもよい。投与経路は、例えば、経口投与、経管投与（経鼻、胃瘻、腸瘻等）、腹腔内投与、筋肉内投与、経粘膜投与、鼻腔内投与及び直腸内投与等が挙げられるが、特に、経口投与が好ましい。投与対象は、通常ヒトであるが、本発明では、ヒト以外の哺乳動物、例えばイヌ及びネコ等のペット動物、ウシ、ヒツジ及びブタ等の家畜も含む。 In the pharmaceutical of the present technology, the daily dose may be administered once a day, or may be divided into two or more doses per day. Administration routes include, for example, oral administration, tube administration (nasally, gastrostomy, intestinal fistula, etc.), intraperitoneal administration, intramuscular administration, transmucosal administration, intranasal administration, and intrarectal administration. , oral administration is preferred. The subject of administration is usually a human, but the present invention also includes mammals other than humans, such as pet animals such as dogs and cats, and livestock such as cows, sheep, and pigs.
［３．食品］
本発明の抗てんかん用組成物は、食品であってよく、ビフィドバクテリウム属細菌及びビフィドバクテリウム属細菌の培養物のいずれか一方又は両方を含む。
摂取対象、有効成分であるビフィドバクテリウム属細菌及びビフィドバクテリウム属細菌の培養物については、上述した本発明の抗てんかん用組成物と同様である。 [3. Food】
The anti-epileptic composition of the present invention may be a food and contains either or both of a Bifidobacterium bacterium and a Bifidobacterium bacterium culture.
The subjects to be ingested, the active ingredients of Bifidobacterium bacteria, and the culture of Bifidobacterium bacteria are the same as in the antiepileptic composition of the present invention described above.
　本発明における食品は、飲食品を含む。飲食品としては、液状、ペースト状、固体及び粉末等の形態を問わず、錠菓、流動食及び飼料（ペット用を含む）等のほか、例えば、小麦粉製品、即席食品、農産加工品、水産加工品、畜産加工品、乳・乳製品、油脂類、基礎調味料、複合調味料・食品類、冷凍食品、菓子類、飲料及びこれら以外の市販食品等が挙げられる。 Foods in the present invention include foods and drinks. Food and beverages include tablets, liquid foods, and feed (including for pets), regardless of their form such as liquid, paste, solid, or powder, as well as flour products, instant foods, processed agricultural products, and marine products. Processed products, processed livestock products, milk/dairy products, oils and fats, basic seasonings, composite seasonings/foods, frozen foods, confectionery, beverages, and other commercially available foods.
　乳製品としては、例えば、発酵乳、乳飲料、乳酸菌飲料、加糖れん乳、脱脂粉乳、加糖粉乳、調整粉乳、クリーム、チーズ、バター及びアイスクリーム類等が挙げられる。
小麦粉製品としては、例えば、パン、マカロニ、スパゲッティ、めん類、ケーキミックス、から揚げ粉及びパン粉等が挙げられる。 Examples of dairy products include fermented milk, milk drinks, lactic acid bacteria drinks, sweetened condensed milk, skim milk powder, sweetened milk powder, modified milk powder, cream, cheese, butter, and ice creams.
Examples of flour products include bread, macaroni, spaghetti, noodles, cake mixes, fried flour, and bread crumbs.
　即席食品類としては、例えば、即席麺、カップ麺、レトルト・調理食品、調理缶詰め、電子レンジ食品、即席スープ・シチュー、即席みそ汁・吸い物、スープ缶詰め、フリーズ・ドライ食品及びその他の即席食品等が挙げられる。 Examples of instant foods include instant noodles, cup noodles, retort/cooked foods, cooked canned foods, microwave foods, instant soups/stews, instant miso soup/suimono, canned soups, freeze/dried foods, and other instant foods. Can be mentioned.
　農産加工品としては、例えば、農産缶詰め、果実缶詰め、ジャム・マーマレード類、漬物、煮豆類、農産乾物類及びシリアル（穀物加工品）等が挙げられる。
水産加工品としては、例えば、水産缶詰め、魚肉ハム・ソーセージ、水産練り製品、水産珍味類及びつくだ煮類等が挙げられる。 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 marine products include canned marine products, fish meat hams and sausages, seafood paste products, marine delicacies, and boiled fish meat.
　畜産加工品としては、例えば、畜産缶詰め・ペースト類及び畜肉ハム・ソーセージ等が挙げられる。 Examples of processed livestock products include canned livestock products, pastes, and livestock hams and sausages.
　油脂類としては、例えば、バター、マーガリン類及び植物油等が挙げられる。 Examples of fats and oils include butter, margarines, and vegetable oils.
　基礎調味料としては、例えば、しょうゆ、みそ、ソース類、トマト加工調味料、みりん類及び食酢類等が挙げられる。複合調味料・食品類としては、調理ミックス、カレーの素類、たれ類、ドレッシング類、めんつゆ類、スパイス類及びその他の複合調味料等が挙げられる。 Examples of basic seasonings include soy sauce, miso, sauces, processed tomato seasonings, mirin, and vinegar. Examples of complex seasonings and foods include cooking mixes, curry ingredients, sauces, dressings, noodle soups, spices, and other complex seasonings.
　冷凍食品としては、例えば、素材冷凍食品、半調理冷凍食品及び調理済冷凍食品等が挙げられる。 Examples of frozen foods include raw frozen foods, semi-cooked frozen foods, and cooked frozen foods.
　菓子類としては、例えば、キャラメル、キャンディー、チューインガム、チョコレート、クッキー、ビスケット、ケーキ、パイ、スナック、クラッカー、和菓子、米菓子、豆菓子、デザート菓子及びその他の菓子等が挙げられる。 Examples of sweets include caramel, candy, chewing gum, chocolate, cookies, biscuits, cakes, pies, snacks, crackers, Japanese sweets, rice sweets, bean sweets, dessert sweets, and other sweets.
　飲料類としては、例えば、炭酸飲料、天然果汁、果汁飲料、果汁入り清涼飲料、果肉飲料、果粒入り果実飲料、野菜系飲料、豆乳、豆乳飲料、コーヒー飲料、お茶飲料、粉末飲料、濃縮飲料、スポーツ飲料、栄養飲料、アルコール飲料及びその他の嗜好飲料等が挙げられる。 Examples of beverages include carbonated drinks, natural fruit juices, fruit juice drinks, soft drinks with fruit juice, pulp drinks, fruit drinks with fruit particles, vegetable drinks, soy milk, soy milk drinks, coffee drinks, tea drinks, powder drinks, and concentrated drinks. , sports drinks, nutritional drinks, alcoholic drinks, and other beverages.
　前記以外の市販食品としては、例えば、ベビーフード、ふりかけ及びお茶漬けのり等が挙げられる。 Commercially available foods other than those mentioned above include, for example, baby food, furikake, and ochazuke nori.
　また、本発明の抗てんかん用食品としては、これらの中でも特に、乳製品とすることが好ましく、発酵乳とすることが特に好ましい。これにより、抗てんかん作用に加え、乳製品の有する高い栄養価をも享受できる。 Furthermore, among these, dairy products are particularly preferred as the anti-epileptic food of the present invention, and fermented milk is particularly preferred. As a result, in addition to antiepileptic effects, the high nutritional value of dairy products can also be enjoyed.
　本発明の食品におけるビフィドバクテリウム属細菌の含有量は、特に制限されないが、効果的な抗てんかん作用を示すための１日当たりの摂取量を無理なく摂取できる程度のビフィドバクテリウム属細菌を含有することが好ましい。
　本発明が提供する食品は、上記医薬品で記載した、医薬品の使用方法と同様に使用できることに加えて、抗てんかん作用を目的としない範囲においても使用することができる。本発明に係る食品に含まれるビフィドバクテリウム属細菌を基準としたとき、食品中のビフィドバクテリウム属細菌の含有量が、前記医薬に含まれるビフィドバクテリウム属細菌と同量になるように、前記医薬の適用対象に適用することができる。
　例えば、食品におけるビフィドバクテリウム属細菌の含有量は、食品１ｇあたり、好ましくは１×１０６～１×１０１２ＣＦＵ／ｇ、より好ましくは１×１０８～１×１０１１ＣＦＵ／ｇ、さらに好ましくは１×１０９～５×１０１０ＣＦＵ／ｇ含むことがより好ましい。
　また、本発明の食品におけるビフィドバクテリウム属細菌の１日当たりの摂取量は、少なくとも１×１０6ＣＦＵ／ｋｇ体重／日、又はそれ以上であることが好ましい。 The content of Bifidobacterium bacteria in the food of the present invention is not particularly limited, but the content of Bifidobacterium bacteria is such that the amount of Bifidobacterium bacteria can be easily ingested per day to exhibit effective antiepileptic effects. It is preferable to contain.
The food provided by the present invention can be used in the same manner as described for the above-mentioned pharmaceuticals, and can also be used for purposes other than anti-epileptic effects. Based on the Bifidobacterium bacteria contained in the food according to the present invention, the content of Bifidobacterium bacteria in the food is the same as the Bifidobacterium bacteria contained in the medicine. As such, it can be applied to the target of the above-mentioned medicine.
For example, the content of Bifidobacterium bacteria in food is preferably 1 x 10 6 to 1 x 10 12 CFU/g, more preferably 1 x 10 8 to 1 x 10 11 CFU/g, per 1 g of food. More preferably, it contains 1×10 9 to 5×10 10 CFU/g.
Furthermore, the daily intake of Bifidobacterium bacteria in the food of the present invention is preferably at least 1×10 6 CFU/kg body weight/day or more.
　本発明の食品において、摂取者は、１日当たりのビフィドバクテリウム属細菌の摂取量を１日１回で摂取してもよく、１日あたり２回以上に分けて摂取してもよい。摂取経路は、例えば、経口摂取、及び経管摂取（経鼻、胃瘻及び腸瘻等）が挙げられるが、特に、経口摂取が好ましい。摂取対象は、通常ヒトであるが、本発明では、ヒト以外の哺乳動物、例えばイヌ及びネコ等のペット動物、ウシ、ヒツジ及びブタ等の家畜も含む。 In the food of the present invention, the consumer may consume the daily amount of Bifidobacterium bacteria once a day, or may divide the intake into two or more times per day. Examples of routes of intake include oral intake and tube intake (nasally, gastrostomy, intestinal fistula, etc.), and oral intake is particularly preferred. Ingestants are usually humans, but the present invention also includes mammals other than humans, such as pet animals such as dogs and cats, and livestock such as cows, sheep, and pigs.
　また、一つの実施態様において、本発明に係る食品は、「病的な」又は「異常な」症状、状態又は疾患を有しない対象（例えば、ヒト又はその他の哺乳動物）、すなわち、「健常な」又は「正常な」状態にある対象（例えば、ヒト又はその他の哺乳動物）に対して、「健常な」又は「正常な」状態を維持するために適用することができる。更には、「てんかん症状が気になる健常者」に対して、「健常な」又は「正常な」状態を維持するために適用することができる。この場合、前記ビフィドバクテリウム属細菌及びその培養物の一方又は両方が医薬組成物の成分であっても、又は食品の成分であっても、前記ビフィドバクテリウム属細菌及びその培養物それ自体の薬理効果は、基本的に同じである。そのため、前記食品の適用量及び適用方法は、期待する効果に応じて、前記ビフィドバクテリウム属細菌及びその培養物それ自体を基準として、適宜、調整することができる。 In one embodiment, the food according to the invention is also suitable for subjects (e.g., humans or other mammals) that do not have "morbid" or "abnormal" symptoms, conditions, or diseases, i.e., "healthy". or to a subject (e.g., a human or other mammal) in a "normal" state, to maintain a "healthy" or "normal" state. Furthermore, it can be applied to "healthy people concerned about epilepsy symptoms" in order to maintain a "healthy" or "normal" state. In this case, even if one or both of the Bifidobacterium bacterium and its culture is a component of a pharmaceutical composition or a food ingredient, the Bifidobacterium bacterium and its culture Their pharmacological effects are basically the same. Therefore, the amount and method of application of the food can be adjusted as appropriate, based on the Bifidobacterium bacterium and its culture itself, depending on the expected effect.
　また、1つの実施態様において、本発明に関わる食品は、健康食品、機能性食品、経腸栄養食品、特別用途食品、保健機能食品、特定保健用食品、栄養機能食品、機能性表示食品、又は医薬用部外品等としての食品が挙げられる。具体的には、「てんかんを発症するリスクを低減するかもしれません。」といった用途で摂取される食品であってもよい。この場合においても上記と同様に、前記食品の適用量及び適用方法は、期待する効果に応じて、前記ビフィドバクテリウム属細菌及びその培養物それ自体を基準として、適宜、調整することができる。 In one embodiment, the food related to the present invention is a health food, a functional food, an enteral nutritional food, a food for special use, a food with health claims, a food for specified health uses, a food with nutritional function claims, a food with functional claims, or Examples include foods such as quasi-drugs. Specifically, it may be a food that is ingested 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 adjusted as appropriate based on the Bifidobacterium bacterium and its culture itself, depending on the expected effect. .
［４．てんかん発作の予防、治療又は軽減をする方法］
　本発明は、また、上述した抗てんかん用組成物、又はその有効成分であるビフィドバクテリウム属細菌及びその培養物の一方又は両方を使用した、てんかん発作の予防、治療又は軽減をする方法を提供する。
　本発明は、また、上述した抗てんかん用組成物、又はその有効成分であるビフィドバクテリウム属細菌及びその培養物の一方又は両方を投与する非治療的投与方法を提供する。
　抗てんかん用組成物、ビフィドバクテリウム属細菌及びその培養物の一方又は両方、並びに投与量、投与頻度及び投与タイミングは、上述したとおりである。
　てんかん発作の予防、治療又は軽減をする方法には、ビフィドバクテリウム属細菌又はその培養物の有効量を使用することが好ましい。 [4. Methods for preventing, treating or alleviating epileptic seizures]
The present invention also provides a method for preventing, treating, or alleviating epileptic seizures using the above-mentioned antiepileptic composition, or its active ingredients, Bifidobacterium bacteria and its culture. provide.
The present invention also provides a non-therapeutic administration method of administering the above-mentioned antiepileptic composition, or one or both of its active ingredients, a Bifidobacterium bacterium and a culture thereof.
The anti-epileptic composition, one or both of the Bifidobacterium bacterium and its culture, and the dosage, frequency and timing of administration are as described above.
Preferably, an effective amount of a Bifidobacterium bacterium or a culture thereof is used in the method of preventing, treating or alleviating epileptic seizures.
　もう一つの側面として、本願は以下の態様を包含する。
［１］　てんかん発作の予防、治療又は軽減が必要な対象に投与される、ビフィドバクテリウム・ブレーベ　ＭＣＣ１２７４株（ＦＥＲＭ　ＢＰ－１１１７５）及びその培養物の一方又は両方を有効成分とする、抗てんかん用組成物。
［２］　前記抗てんかん用組成物が、前記対象に一日あたり前記ビフィドバクテリウム・ブレーベ　ＭＣＣ１２７４株（ＦＥＲＭ　ＢＰ－１１１７５）が１×１０６～１×１０１２ＣＦＵ／ｇとなるよう経口投与される量の前記有効成分含む、［１］に記載の抗てんかん用組成物。
［３］前記対象がてんかん発作の治療が必要な対象である、［１］又は［２］に記載の抗てんかん用組成物。
［４］　てんかん発作の予防、治療又は軽減のために用いられる、［１］～［３］のいずれかに記載の抗てんかん用組物。
［５］　前記抗てんかん用組成物が医薬品又は食品である、［１］～［４］のいずれかに記載の抗てんかん用組成物。
［６］　てんかん発作の予防、治療又は軽減が必要な対象に投与される組成物の製造における、ビフィドバクテリウム・ブレーベ　ＭＣＣ１２７４株（ＦＥＲＭ　ＢＰ－１１１７５）及びその培養物の一方又は両方の使用。
［７］　てんかん発作の予防、治療又は軽減における使用のための、ビフィドバクテリウム・ブレーベ　ＭＣＣ１２７４株（ＦＥＲＭ　ＢＰ－１１１７５）又はその培養物。
［８］　ビフィドバクテリウム・ブレーベ　ＭＣＣ１２７４株（ＦＥＲＭ　ＢＰ－１１１７５）及びその培養物の一方又は両方の有効量をてんかん発作の予防、治療又は軽減を必要とする対象に投与することを含む、非治療的投与方法。
［９］　前記対象に一日あたり前記ビフィドバクテリウム・ブレーベ　ＭＣＣ１２７４株（ＦＥＲＭ　ＢＰ－１１１７５）が１×１０６～１×１０１２ＣＦＵ／ｇとなるように、ビフィドバクテリウム・ブレーベ　ＭＣＣ１２７４株（ＦＥＲＭ　ＢＰ－１１１７５）及びその培養物の一方又は両方を投与することを含む［８］に記載の方法。 In another aspect, the present application includes the following embodiments.
[1] An antiepileptic drug containing one or both of Bifidobacterium breve MCC1274 strain (FERM BP-11175) and its culture as active ingredients, which is administered to a subject in need of prevention, treatment, or alleviation of epileptic seizures. Composition for use.
[2] The anti-epileptic composition is orally administered to the subject at a concentration of 1×10 6 to 1×10 12 CFU/g of Bifidobacterium breve MCC1274 strain (FERM BP-11175) per day. The anti-epileptic composition according to [1], which contains the active ingredient in an amount of .
[3] The anti-epileptic composition according to [1] or [2], wherein the subject is a subject who requires treatment for epileptic seizures.
[4] The antiepileptic composition according to any one of [1] to [3], which is used for the prevention, treatment, or alleviation of epileptic seizures.
[5] The anti-epileptic composition according to any one of [1] to [4], wherein the anti-epileptic composition is a medicine or a food.
[6] Use of one or both of Bifidobacterium breve strain MCC1274 (FERM BP-11175) and its culture in the manufacture of a composition to be administered to a subject in need of prevention, treatment, or alleviation of epileptic seizures.
[7] Bifidobacterium breve strain MCC1274 (FERM BP-11175) or a culture thereof for use in the prevention, treatment or alleviation of epileptic seizures.
[8] Non-containing method comprising administering an effective amount of one or both of Bifidobacterium breve strain MCC1274 (FERM BP-11175) and its culture to a subject in need of prevention, treatment or alleviation of epileptic seizures. Therapeutic Administration Methods.
[9] Apply Bifidobacterium breve MCC1274 strain (FERM BP-11175) to the subject so that the amount of Bifidobacterium breve MCC1274 strain (FERM BP-11175) is 1×10 6 to 1×10 12 CFU/g per day. (FERM BP-11175) and a culture thereof, or the method according to [8].
　以下に、実施例を用いて本発明をさらに詳細に説明する。なお、以下に説明する実施例は、本発明の代表的な一例を示したものにすぎず、本発明はこれにより限定されるものではない。 The present invention will be explained in more detail below using Examples. Note that the embodiment described below is merely a representative example of the present invention, and the present invention is not limited thereto.
（１）実験方法
　８週齢雄のＣ５７ＢＬ／６ＪＪｃｌマウス（日本クレア（株）石部育成場）に生理食塩水で溶解した低容量ｐｅｎｔｙｌｅｎｅｔｅｔｒａｚｏｌｅ（以下ＰＴＺ、ＳＩＧＭＡ－Ａｌｄｒｉｃｈ）（３７ｍｇ／ｋｇ、３．１ｍｇ／ｍＬ）を２日に１回の割合で８回腹腔内投与（ｉ．ｐ．）することでｋｉｎｄｌｉｎｇマウスを作出した（図１）。 (1) Experimental method Low-volume pentylenetetrazole (PTZ, SIGMA-Aldrich) (37 mg/kg, 3.1 mg) dissolved in physiological saline was administered to 8-week-old male C57BL/6JJcl mice (Ishibe Nursery, CLEA Japan Co., Ltd.). Kindling mice were generated by intraperitoneally administering (i.p./mL) 8 times once every 2 days (Fig. 1).
　上記のｋｉｎｄｌｉｎｇマウスを２群（非投与群１４匹、投与群１２匹）に分け、片方の群（投与群）には、生理食塩水で１．３×１０１０ｃｆｕ／ｍＬになるよう懸濁したＢｉｆｉｄｏｂａｃｔｅｒｉｕｍ　ｂｒｅｖｅ　ＭＣＣ１２７４株［ＦＥＲＭ　ＢＰ－１１１７５］（以下Ｂ．　ｂｒｅｖｅ　ＭＣＣ１２７４株）を、ＰＴＺを投与しない日に隔日で経口投与（３．２５×１０９ｃｆｕ／０．２５ｍＬ／マウス）した（図１）。もう一方の群（非投与群）には、Ｂ．　ｂｒｅｖｅ　ＭＣＣ１２７４株を含まない、懸濁に使用した生理食塩水のみを同様に経口投与した。マウスの行動観察は、ＰＴＺ投与後３０分間観察し痙攣の程度を以下の評価方法に従いスコア化した。 The above kindling mice were divided into two groups (14 mice in the non-administration group and 12 mice in the administration group), and one group (administration group) was suspended in physiological saline to a concentration of 1.3 x 10 10 cfu/mL. Bifidobacterium breve MCC1274 strain [FERM BP-11175] (hereinafter referred to as B. breve MCC1274 strain) was orally administered (3.25 x 10 9 cfu/0.25 mL/mouse) every other day on days when PTZ was not administered (Figure 1 ). The other group (non-administration group) included B. Similarly, only the physiological saline used for suspension, which does not contain the breve MCC1274 strain, was orally administered. Mouse behavior was observed for 30 minutes after PTZ administration, and the degree of convulsion was scored according to the following evaluation method.
（２）痙攣スコア
　痙攣のスコアは、Ｓｈｉｍａｄａ　＆　Ｙａｍａｇａｔａ　（２０１８）の方法に従い以下の評価方法で行った［Ｓｈｉｍａｄａ　＆　Ｙａｍａｇａｔａ　（２０１８）　Ｊ．　Ｖｉｓｕａｌｉｚｅｄ　Ｅｘｐｅｒｉｍｅｎｔｓ，　１３６：１－１０．］。
０：正常
１：不動化
２：うなずき行動・部分的ミオクローヌス（不随意運動）
３：全身性のミオクローヌス（不随意運動）
４：立ち上がり行動・間代性痙攣
５：間代強直痙攣
６：死 (2) Convulsion score The convulsion score was determined using the following evaluation method according to 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 convulsion 5: Clonic tonic convulsion 6: Death
（３）結果
　ＰＴＺの投与回数を増すごとに平均痙攣スコアが増加した（図２）。Ｂ．　ｂｒｅｖｅ　ＭＣＣ１２７４株の投与群では、非投与群と比べてＰＴＺによる痙攣スコアがいずれも抑制された（図２）。この際、Ｂ．　ｂｒｅｖｅ　ＭＣＣ１２７４株によるＰＴＺ誘発性痙攣の有意な抑制は、ＰＴＺ４回目投与後（Ｂ．　ｂｒｅｖｅ　ＭＣＣ１２７４株の４回目投与２４時間後）から認められ、最終ＰＴＺ投与日であるＰＴＺ８回目投与後（Ｂ．　ｂｒｅｖｅ　ＭＣＣ１２７４株の８回目投与２４時間後）まで持続した（図２）。
　本結果より、Ｂ．　ｂｒｅｖｅ　ＭＣＣ１２７４株入りの組成物は抗てんかん作用を有していることが示された。 (3) Results The average convulsion score increased as the number of PTZ administrations increased (Figure 2). B. In the breve MCC1274 strain administration group, all PTZ-induced convulsion scores were suppressed compared to the non-administration group (FIG. 2). At this time, B. Significant suppression of PTZ-induced convulsions by B. breve MCC1274 strain was observed after the fourth administration of PTZ (24 hours after the fourth administration of B. breve MCC1274 strain), and after the eighth administration of PTZ (B. breve MCC1274 strain), which was the final PTZ administration day. It persisted until 24 hours after the 8th administration of MCC1274 strain (Fig. 2).
From this result, B. The composition containing the breve MCC1274 strain was shown to have antiepileptic effects.
　本発明によれば、新たな抗てんかん用組成物を提供することができる。本発明の抗てんかん用組成物は、その有効成分がビフィドバクテリウム属細菌及びその培養物の一方又は両方を含む培養物であることから、安全性に優れ、長期間、連続的に投与しても副作用を心配する必要性も少ないため、非常に有用である。 According to the present invention, a new anti-epileptic composition can be provided. The anti-epileptic composition of the present invention has excellent safety and can be continuously administered over a long period of time because its active ingredient is a culture containing one or both of a Bifidobacterium bacterium and a culture thereof. It is very useful because there is little need to worry about side effects.
ＦＥＲＭ　ＢＰ－１１１７５
ＮＩＴＥ　ＢＰ－０２６２２ FERM BP-11175
NITE BP-02622

Claims (11)

  1. 　ビフィドバクテリウム属細菌及びその培養物の一方又は両方を含む、抗てんかん用組成物。 An anti-epileptic composition containing one or both of a Bifidobacterium bacterium and a culture thereof.
  2. 　前記ビフィドバクテリウム属細菌がビフィドバクテリウム・ブレーベである、請求項１に記載の抗てんかん用組成物。 The antiepileptic composition according to claim 1, wherein the Bifidobacterium bacterium is Bifidobacterium breve.
  3. 　前記ビフィドバクテリウム属細菌がビフィドバクテリウム・ブレーベ　ＭＣＣ１２７４株（ＦＥＲＭ　ＢＰ－１１１７５）である、請求項１に記載の抗てんかん用組成物。 The anti-epileptic composition according to claim 1, wherein the Bifidobacterium bacterium is Bifidobacterium breve MCC1274 strain (FERM BP-11175).
  4. 　前記ビフィドバクテリウム属細菌及びその培養物の一方又は両方を１×１０６～１×１０１２ＣＦＵ／ｇ含む、請求項１に記載の抗てんかん用組成物。 The anti-epileptic composition according to claim 1, comprising 1×10 6 to 1×10 12 CFU/g of one or both of the Bifidobacterium bacterium and its culture.
  5. 　てんかん発作の予防、治療又は軽減のために用いられる、請求項１に記載の抗てんかん用組成物。 The anti-epileptic composition according to claim 1, which is used for the prevention, treatment, or alleviation of epileptic seizures.
  6. 　前記抗てんかん用組成物が医薬品又は食品である、請求項１に記載の抗てんかん用組成物。 The anti-epileptic composition according to claim 1, wherein the anti-epileptic composition is a pharmaceutical or a food.
  7. 　前記抗てんかん用組成物がてんかん発作の予防、治療又は軽減が必要な対象に投与される、請求項１に記載の抗てんかん用組成物。 The anti-epileptic composition according to claim 1, wherein the anti-epileptic composition is administered to a subject in need of prevention, treatment, or alleviation of epileptic seizures.
  8. 　前記ビフィドバクテリウム属細菌及びその培養物の一方又は両方を有効成分とする、請求項１に記載の抗てんかん用組成物。 The anti-epileptic composition according to claim 1, which contains one or both of the Bifidobacterium bacterium and its culture as an active ingredient.
  9. 　てんかん発作の予防、治療又は軽減が必要な対象に投与するための組成物の製造における、ビフィドバクテリウム属細菌及びその培養物の一方又は両方の使用。 Use of one or both of a Bifidobacterium bacterium and a culture thereof in the manufacture of a composition for administration to a subject in need of prevention, treatment, or alleviation of epileptic seizures.
  10. 　てんかん発作の予防、治療又は軽減における使用のための、ビフィドバクテリウム属細菌又はその培養物。 A Bifidobacterium bacterium or a culture thereof for use in the prevention, treatment or alleviation of epileptic seizures.
  11. 　ビフィドバクテリウム属細菌及びその培養物の一方又は両方の有効量をてんかん発作の予防、治療又は軽減を必要とする対象に投与することを含む、てんかん発作の予防、治療又は軽減をする方法。 A method for preventing, treating, or alleviating epileptic seizures, the method comprising administering an effective amount of one or both of a Bifidobacterium bacterium and a culture thereof to a subject in need of the prevention, treatment, or alleviation of epileptic seizures.
PCT/JP2023/019470 2022-06-01 2023-05-25 Antiepileptic composition WO2023234166A1 (en)

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