TW201919604A - Promoter for ketone body synthesis - Google Patents

Abstract

The promoter for ketone body synthesis provided by the present invention is characterized by comprising a combination of a medium chain fatty acid fat/oil with at least one kind of casein compound which is selected from the group consisting of casein and salts thereof. By taking into the body the casein compound together with the medium chain fatty acid fat/oil, ketone body synthesis from the medium chain fatty acid fat/oil in the body can be promoted, compared with the case of taking the medium chain fatty acid fat/oil alone, and thus the ketone body concentration in the body can be efficiently increased.

Description

Ketone body formation promoter

The present invention relates to a ketone body production promoting agent. The present invention also relates to a product capable of promoting the production of ketone bodies derived from medium-chain fatty acid fats and oils by using the medium-chain fatty acid fats and oils in combination.

Keto system Acetylacetic acid, β-hydroxybutyric acid, and acetone collectively, are synthesized in the liver by β oxidation of fatty acids in the body. The generated ketone bodies are used as energy in many tissues other than the liver such as the brain, heart, or skeletal muscle, as well as glucose. In particular, since the brain can only use glucose and ketone bodies, ketone bodies become an important energy source (Non-Patent Document 1).

As a diet conceived to produce a large amount of ketone bodies in the body, a high-lipid, low-carbohydrate diet (ketogenic diet) has existed since ancient times, and the concentration of ketone bodies in blood has been increased by ingesting a ketogenic diet. In addition, the ketogenic diet is known to be effective in the treatment of GLUT1 (glucose transporter 1) deficiency or the suppression of the onset of refractory epilepsy (Non-Patent Document 2). Furthermore, recently, it has been reported that the prevention or treatment of neurodegenerative diseases such as Alzheimer's disease is effective (Non-Patent Document 3).

Fatty acids that are the main raw material for ketone body production in the body can be classified into long-chain fatty acids, medium-chain fatty acids, and short-chain fatty acids according to the length of the carbon chain. It is generally believed that medium-chain fatty acids can produce ketone bodies more efficiently than long-chain fatty acids due to differences in absorption and metabolic pathways. In fact, it is known that the concentration of ketone bodies in blood of animals containing humans is significantly increased by ingesting medium chain fatty acid triglyceride (MCT) (Non-Patent Document 4). However, it is also known that the ingestion of MCT causes side effects such as diarrhea and vomiting, and it is difficult to ingest MCT in large amounts.
[Prior technical literature]
[Non-patent literature]

Non-Patent Document 1: Cahill GF Jr .: "Fuel metabolism in starvation.", Annu Rev Nutr., Vol. 26, page 1-22, 2006
Non-Patent Document 2: Edited by Tatsuki Fujii, From Basics to Practice of a Ketogenic Diet, Diagnostic and Therapeutic Corporation, 2011 Maciej Gasior, et al: "Neuroprotective and disease-modifying effects of the ketogenic diet", Behav Pharmacol. Vol. 17, page 431-439, 2006
Non-Patent Document 3: Pi-Sunyer FX, et al: "Insulin and ketone responses to ingestion of medium and long-chain triglycerides in man.", Diabetes. Vol. 18, page 96-100, 1969

[Questions to be Solved by the Invention]

In view of the usefulness of such ketone bodies in the body, an object of the present invention is to provide a product (ketone body production promoting agent) which can promote the production of ketone bodies from medium-chain fatty acids in the body. In more detail, the object is to provide a product capable of significantly increasing the concentration of ketone bodies in the body by promoting the production of ketone bodies from medium-chain fatty acids and fats in the body, especially products for oral use.

[Means to solve the problem]

As described above, since MCT has side effects such as diarrhea and vomiting, it is difficult to take a large amount. On the other hand, if there is a composition that can promote the production of ketone bodies from MCT, it is possible to efficiently and rapidly increase the concentration of ketone bodies in the blood without the need to ingest large amounts of MCT. With these considerations in mind, the inventors made intensive studies and found that by ingesting a casein compound containing medium-chain fatty acids as constituents (medium-chain fatty acid oils) and casein sodium and the like, and ingesting medium-chain alone In the case of fatty acids, ketone bodies from medium-chain fatty acids are promoted, and more ketone bodies are produced more rapidly in the body, that is, the blood concentration of ketone bodies rises significantly.

This invention is completed based on the said knowledge, and has the following embodiment.

(I) Ketone body formation promoter and use thereof
(I-1) A ketone body production promoting agent which is a combination of a medium-chain fatty acid oil and fat and a casein compound selected from the group consisting of casein and a salt thereof.

(I-2) The ketone body formation promoter according to (I-1), wherein the ratio of the casein compound to 100 parts by mass of the medium-chain fatty acid oil and fat is 25 parts by mass or more, preferably 25 to 50 parts by mass.

(I-3) The ketone body formation promoter according to (I-1) or (I-2), wherein the composition containing the medium-chain fatty acid oil and fat and the composition containing the casein compound are each treated as an individual composition The packaging, the composition containing the medium-chain fatty acid oil and fat, and the casein-containing compound are administered to the test subject simultaneously or concurrently.

(I-4) A ketone body production promoting agent such as (I-1) or (I-2), which is a preparation containing a medium-chain fatty acid oil and fat and a casein compound.

(I-5) The ketone body production-promoting agent according to any one of (I-1) to (I-4), which is used to prevent or ameliorate the occurrence of a disease caused by an increase in the concentration of ketone bodies in the body or Onset of symptoms.

(I-6) The ketone body production promoting agent according to (I-5), wherein the symptom or disease that produces an effect due to an increase in the body concentration of ketone body is selected from the group consisting of childhood epilepsy, refractory epilepsy, and glucose transporter 1 (GLUT I) Deficiency, neurodegeneration such as pyruvate dehydrogenase complex, Alzheimer's disease, muscular dystrophy, mild cognitive impairment, Parkinson's disease, traumatic brain injury, cancer, depression , Autism, migraine, amyotrophic lateral sclerosis, sudden sleep, diabetes, heart failure, myocardial infarction, autism, and obesity.

(I-7) The ketone body production promoting agent according to any one of (I-1) to (I-6), which is a food (including a beverage), an oral quasi-drug, or an oral drug.

(I-8) A composition which is used to promote ketone body production in the body, and is a medium-chain fatty acid oil and fat, and casein selected from the group consisting of casein and salts thereof. Composition of compounds.

(I-9) A composition which is used for preventing or improving the onset or onset of symptoms or diseases caused by an increase in the concentration of ketone bodies in vivo, and which is a medium-chain fatty acid oil and a compound selected from casein A composition of at least one casein compound in the group formed by the salt and its salt.

(I-10) Use of a composition of a medium-chain fatty acid oil and a casein compound selected from at least one selected from the group consisting of casein and a salt thereof, which is used for producing a ketone body-promoting agent.

(I-11) Use of a composition of a medium-chain fatty acid oil and a casein compound selected from at least one selected from the group consisting of casein and its salt, which is used for the production of ketone bodies due to an increase in the body's concentration Preventive or ameliorative agent for symptoms or diseases that produce efficacy.

(I-12) Use according to (I-10) or (I-11), wherein the aforementioned composition is based on 100 parts by mass of medium-chain fatty acid oil and fat, and the casein compound is used in an amount of 25 parts by mass or more, preferably A combination of 25 to 50 parts by mass.

(I-13) A method for promoting the production of ketone bodies in a test subject, which comprises the steps of administering a medium-chain fatty acid oil and fat, and a group selected from the group consisting of casein and its salt, simultaneously, in time, or in parallel. Steps of at least one casein compound in a group to a subject.

(I-14) The method according to (I-13), wherein the test subject is a human having a disease or symptom that is effective due to an increase in the concentration of the ketone body in vivo.

(I-15) The method according to (I-13) or (I-14), which is a method for improving or preventing a disease or a symptom that produces an effect due to an increase in the body concentration of a ketone body.

(I-16) The method according to (I-14) or (I-15), wherein the disease or symptom that produces an effect due to an increase in the body concentration of the ketone body is selected from the group consisting of childhood epilepsy, refractory epilepsy, and glucose transporter 1 (GLUT I) deficiency, pyruvate dehydrogenase complex abnormalities, neurodegenerative diseases such as Alzheimer's disease, muscular dystrophy, mild cognitive impairment, Parkinson's disease, traumatic brain injury, cancer, Depression, autism, migraine, amyotrophic lateral sclerosis, sudden sleep, diabetes, heart failure, myocardial infarction, autism, and obesity.

(I-17) The method according to any one of (I-13) to (I-16), wherein the medium-chain fatty acid oil and fat, and at least one casein selected from the group consisting of casein and its salt The protein compound is a ketone body production promoting agent derived from any one of (I-1) to (I-6).

(II) Composition containing casein compound and use thereof
(II-1) A composition for promoting a ketone body-forming reaction from a medium-chain fatty acid oil and fat in the body, which is effective by using at least one casein compound selected from the group consisting of casein and salts thereof Ingredient composition (composition containing casein compound), which is characterized by being used in combination with medium-chain fatty acids.

(II-2) The composition according to (II-1), wherein the amount of the aforementioned composition based on 100 parts by mass of the medium-chain fatty acid oil and fat converted into a casein compound is 25 parts by mass or more, preferably A ratio of 25 to 50 parts by mass is used in combination with a medium-chain fatty acid fat.

(II-3) a composition for producing an oral composition for promoting the ketone body-forming reaction from medium-chain fatty acids and fats in the body,
The composition is for users who combine with medium-chain fatty acids,
It is a composition containing at least one casein compound selected from the group consisting of casein and its salt as an active ingredient.

(II-4) A method for enhancing the ketone body-forming ability of a medium-chain fatty acid oil and fat, comprising a casein compound or a composition containing the casein compound selected from at least one selected from the group consisting of casein and salts thereof. Step of using with medium-chain fatty acid fats and oils. In addition, the combined step includes a step of mixing a casein compound or a casein compound-containing composition with a medium-chain fatty acid fat.

(II-5) A method for promoting an increase in the ketone body concentration in the subject, comprising the step of: selecting a casein compound containing at least one selected from the group consisting of casein and a salt thereof or containing the casein compound; The composition is a step of administering the test subject before or after the administration of the medium-chain fatty acid oil and fat.

(II-6) The method according to (II-5), wherein the test subject is a human having a disease or symptom that is effective due to an increase in the in vivo concentration of the ketone body.

(II-7) The method according to (II-5) or (II-6), which is a method for improving or preventing a disease or a symptom that is effective due to an increase in the body concentration of the ketone body.

(II-8) The method according to (II-6) or (II-7), wherein the disease or symptom that produces an effect due to an increase in the body concentration of the ketone body is selected from the group consisting of childhood epilepsy, refractory epilepsy, and glucose transporter 1 (GLUTI) deficiency, pyruvate dehydrogenase complex abnormalities, neurodegenerative diseases such as Alzheimer's disease, muscular dystrophy, mild cognitive impairment, Parkinson's disease, traumatic brain injury, cancer, depression Disease, autism, migraine, amyotrophic lateral sclerosis, sudden sleep, diabetes, heart failure, myocardial infarction, angina, and obesity.

[Effect of the invention]

Based on the ketone body formation promoter of the present invention, a casein compound and a medium-chain fatty acid oil can be simply used in combination. By ingesting the casein compound with the medium-chain fatty acid fat into the body through the ketone body production-promoting agent of the present invention, the ketone derived from the medium-chain fatty acid fat in the body is in comparison with the case of ingesting the medium-chain fatty acid fat alone. Somatogenesis is promoted, and the ketone body concentration in the body can be increased efficiently (in terms of quantity, and / or in terms of time). That is, the ketone body production-promoting agent of the present invention is expected to be used for these purposes, and is applicable to test subjects who want to increase the concentration of ketone bodies in the body, and is particularly suitable for those who want to effectively improve ketone bodies. Test subject.

In addition, the casein compound-containing composition of the present invention exerts a role of promoting ketone production of a medium-chain fatty acid oil by ingesting it with a medium-chain fatty acid oil into a subject. In other words, the casein compound-containing composition of the present invention can be used for the purpose of promoting or enhancing the ketone body-forming ability possessed by medium-chain fatty acids. Therefore, the casein compound-containing composition of the present invention is expected to be used for these purposes, and can be combined with medium-chain fatty acid oils and fats, and is particularly suitable for test subjects who wish to increase the concentration of ketone bodies in the body. For test subjects who want to effectively increase the in vivo concentration of ketone bodies.

(I) Ketone body production promoter The ketone body production promoter of the present invention is characterized in that it is a combination of the following two components:
(1) Medium-chain fatty acids,
(2) A casein compound selected from at least one of the group consisting of casein and its salt.
These components and their combinations are described below.

(1) Medium-chain fatty acid fat and oil The medium-chain fatty acid fat and oil of the present invention means a triglyceride containing a medium-chain fatty acid as a constituent fatty acid. Here, examples of the medium-chain fatty acid include fatty acids having 5 to 12 carbon atoms. Specific examples include valeric acid (C5), caproic acid (C6), heptanoic acid (C7), octanoic acid (C8), nonanoic acid (C9), capric acid (C10), and dodecanoic acid (C12). Fatty acids having 6 to 12 carbon atoms are preferred, fatty acids having 8 to 12 carbon atoms are more preferred, and fatty acids having 8 to 10 carbon atoms are more preferred. The medium-chain fatty acid fat may be a triglyceride composed of one of these medium-chain fatty acids, or may be a triglyceride composed of two or more medium-chain fatty acids. Among the medium-chain fatty acids constituting the medium-chain fatty acid oil and fat, caprylic acid (C8) and capric acid (C10) are particularly preferred. Specifically, although not limited, when the amount of all fatty acids constituting the medium-chain fatty acid oil and fat is 100% by mass, the caprylic acid (C8) is 10% by mass or more, and more preferably 10 to 90% by mass It is contained in a proportion, and the capric acid (C10) is 10% by mass or more, and specifically, it is preferably contained in a proportion of 10 to 90% by mass.

As the target medium-chain fatty acid oil and fat of the present invention, any triglyceride containing the aforementioned medium-chain fatty acid as one of the constituent fatty acids may be used. In this limitation, it may be a short-chain fatty acid containing 5 or less carbon atoms or / And long-chain fatty acids having a carbon number of 14 or more as triglycerides constituting other fatty acids. All of the constituent fatty acids are preferably the aforementioned medium-chain fatty acid and medium-chain fatty acid triglyceride (MCT).

Medium-chain fatty acid oils and fats, especially those containing MCTs, are contained in the seeds of plants such as coconut and palm fruit, milk, etc., and they can be extracted (including crude extraction) or purified (including crude purification) from these and used.于 发明。 In the present invention. In addition, medium-chain fatty acids, especially those containing a large amount of MCT, can be easily obtained commercially. Although there is no limitation, as an oil containing 85 to 100% by mass of medium-chain fatty acid fats and oils (MCT), for example, MCT "Sukore" (Nissin Oleo Group Co., Ltd.) made of caprylic acid and capric acid can be exemplified. , "Nissin MCT oil" (Nissin Olivier Group Co., Ltd.), and "Makuton Oil" (Jusheng Pharmaceutical Industry Co., Ltd.).

(2) Casein compound Examples of the casein compound in the present invention include casein and a salt thereof. Casein is a kind of milk protein containing milk in a proportion of about 80% by mass, and it exists in the form of a calcium salt bound to calcium in cow's milk.

Examples of the casein salt include alkali metal salts of casein, such as sodium and potassium salts of casein, in addition to the calcium salt of casein. Although these salts are not limited, for example, acids such as acetic acid, lactic acid, or hydrochloric acid can be added to cow's milk for isoelectric point precipitation to solidify and separate them from the milk. After dispersing them in water again, they can be added with sodium hydroxide or hydrogen. Potassium oxide is prepared by a neutralization reaction. In this way, the salt of casein is water-soluble and has both hydrophilic and lipophilic properties, and thus can exhibit an emulsifying effect.

In addition, as the casein compound in the present invention, at least one compound selected from the group consisting of casein and a salt thereof may be used alone, or two or more compounds may be used in any combination. A water-soluble salt of casein is preferred, and sodium caseinate is more preferred.

(3) Combined state The ketone body production promoting agent of the sample invention is a combination of the aforementioned medium-chain fatty acid oil and fat and a casein compound. Here, the term "combined" means that the ketone body production promoter that is the subject of the present invention includes the following cases:
(i) a state (mixing agent) including a state in which a medium-chain fatty acid oil and fat and a casein compound are mixed in the same composition;
(ii) the medium-chain fatty acid fats and oils or the composition containing the same, and the casein compound or the composition containing the same are each a composition having a separate form (a product manufactured in a manner having a respective individual form: a product), Both are packaged and sold as a composition (a complete set, a set) administered simultaneously or concurrently;
(iii) The medium-chain fatty acid oil or its composition and the casein compound or its composition are packaged as components (products) each having an individual form, and the two exist in separate circulation channels. The market, when used in combination.

That is, the "combined" ketone body production promoting agent of the present invention includes a medium-chain fatty acid oil and a casein compound to be administered to a test subject at the same time, in parallel, or at a time difference. Those with medium chain fatty acids and fats and casein compounds are sufficient. That is, the form or existence state of medium-chain fatty acid oils and fats and casein compounds may not exist in the market circulation stage including display (store display) or sales, and the two may exist together or separately. Furthermore, in the above aspect, if the medium-chain fatty acid oil and the casein compound are made to coexist in the body, it includes a state in which the medium-chain fatty acid oil is administered to the test subject in comparison with the casein compound. And any of the aspects of the administration of a medium-chain fatty acid fat to a test subject in comparison with a casein compound. In addition, in the present invention (this specification), the term "administration" includes the meanings of the terms "intake" and "take".

Aspect of (i) (dispensing agent)
A compounding agent (compound composition) containing both a medium-chain fatty acid oil and fat and a casein compound in the same composition is sufficient as long as it contains both a medium-chain fatty acid oil and fat and a casein compound, so long as the effects of the present invention are not hindered. It may also contain other edible ingredients. The formulation may be, for example, a mixture of an edible composition containing a medium-chain fatty acid oil and fat and an edible composition containing a casein compound. Here, as an edible composition containing a medium-chain fatty acid oil and fat, for example, the oil and fat containing the medium-chain fatty acid fat mentioned above, or a commercially available oil-and-fat product containing the medium-chain fatty acid fat can be exemplified. In addition, as an edible composition containing a casein compound, for example, dairy products containing the casein compound may be exemplified, and specifically, cow milk, yogurt, cheese, formula milk powder, whole milk powder, Skimmed milk powder, ice cream, etc.

The form of the edible composition containing both the medium-chain fatty acid oil and fat and the casein compound in the same composition is not particularly limited, and may be, for example, solid, semi-solid, or liquid. Therefore, as specific examples of the edible composition containing both the medium-chain fatty acid fat and the casein compound in the same composition of the present invention, beverages, liquid diets, tablets, capsules, jelly, Bar, powder, paste, chocolate, etc.

The formulation of the present invention may contain, in addition to the medium-chain fatty acid fats and oils and casein compounds, carriers or additives for oral preparations. As a carrier or an additive used in the preparation of the oral preparation, various substances widely used in general pharmaceuticals depending on the dosage form of the preparation can be exemplified, such as an excipient, a binder, a disintegrant, a lubricant, a colorant, and a flavoring agent. (flavoring agent), flavoring agent, surfactant, and the like.

The dosage form of the oral preparation is not particularly limited, and examples thereof include lozenges, powders, granules, capsules (including hard capsules and soft capsules), liquids, pills, suspensions, and emulsions.

When the above preparations are solid preparations for oral use such as lozenges, powders, granules, pills, capsules, etc., at the time of preparation, for example, lactose, white sugar, sodium chloride, glucose, urea, starch, carbonic acid can be used as a carrier. Excipients for calcium, kaolin, crystalline cellulose, silicic acid, methyl cellulose, glycerol, sodium alginate, gum arabic, etc .; monosyrup, glucose solution, starch solution, gelatin solution, polyvinyl alcohol, polyvinyl ether, Adhesives of polyvinylpyrrolidone, carboxymethyl cellulose, shellac, methyl cellulose, ethyl cellulose, water, ethanol, potassium phosphate, etc .; dried starch, sodium alginate, agar powder, kumose powder, carbonic acid Disintegrating agent for sodium hydrogen, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, monoglyceryl stearate, starch, lactose, etc .; white sugar, stearic acid, cocoa butter, hydrogenation Oil disintegration inhibitors; absorption enhancers such as sodium lauryl sulfate; humectants such as glycerol and starch; adsorbents for starch, lactose, kaolin, bentonite, colloidal silicic acid; refined talc, hard Salt, boric acid powder, polyethylene glycols and lubricants and the like. Furthermore, the lozenge is a lozenge to which a usual coating is applied if necessary, and examples thereof include a sugar-coated lozenge, a gelatin-coated lozenge, an enteric coated lozenge, a film-coated lozenge, a double lozenge, and a multi-layer lozenge.

When the above preparation is a solid preparation for oral use of pills, excipients such as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, kaolin, talc, etc. can be used as carriers during preparation; acacia powder, scutellaria Adhesives for gum powder, gelatin, etc .; disintegrating agents for konbu sugar, agar, etc.

When the above-mentioned preparation is a capsule solid preparation for oral administration, at the time of preparation, the active ingredient is mixed with the various carriers exemplified above and filled in a hard capsule or a soft capsule to prepare a capsule.

When the above-mentioned preparation is a liquid preparation, it can be an aqueous or oily suspension, solution, syrup, or tincture, and it can be prepared according to a conventional method using ordinary additives.

Although the ratio of the medium-chain fatty acid fat and casein compound contained in the formulation is not particularly limited, for example, the lower limit of the range of the casein compound ratio is preferably 25 parts by mass relative to 100 parts by mass of the medium-chain fatty acid fat and more preferably It is 27 parts by mass, and more preferably 30 parts by mass. The upper limit of the range is, for example, preferably 80 parts by mass, more preferably 50 parts by mass, and even more preferably 40 parts by mass. The lower limit value and the upper limit value may be arbitrarily combined.

Although the range of the amount of medium-chain fatty acid fats to be administered per day is not limited, the lower limit is, for example, preferably 1 g, more preferably 5 g, and even more preferably 10 g. The upper limit of the range is, for example, preferably 100 g, more preferably 50 g, and even more preferably 20 g. The lower limit value and the upper limit value may be arbitrarily combined. The daily dose of the casein compound used in combination with the medium-chain fatty acid oil and fat can be adjusted based on the above-mentioned blending ratio with the medium-chain fatty acid oil and fat based on the daily dose of the medium-chain fatty acid fat.

Formulations containing medium-chain fatty acids, fats, and casein compounds, with reference to the above-mentioned dosage, can be administered once a day or divided into two or three times a day. The lot is packaged for each dose.

(ii) appearance (combination set)
In this aspect, the ketone body production promoting agent of the present invention is characterized by (A) a medium-chain fatty acid oil or fat or a composition containing the same (hereinafter also simply referred to as "(A)"), and (B) a casein compound or The composition containing it (hereinafter also referred to simply as "(B)") each has an individual form, and the two are packaged as a composition to be administered to a test subject simultaneously, concurrently, or with a time difference. Here, although (A) and (B) are individually manufactured as separate forms, in the packaging stage, in order to make it easy for the user (subject) to use together, a complete set is used. (Also known as a kit). In addition, each of (A) and (B) may have the same or different shapes (liquid, solid, or semi-solid).

The "packaging" referred to herein is a storage device that respectively stores (A) or (B), and includes a container, a wrapper, an inner seal, and the like. These storage devices are not particularly limited, and include, for example, cans, bottles, boxes, ampoules, vials, tubes, single-dose containers, paper, cloth, vinyl bags, plastic bags, SP tablets, PTP film, plastic container, etc. The packaged composition is generally combined with an outer container or an outer wrapper in a state in which at least one of a product label, an instruction manual (a product instruction manual, an instruction manual), an instruction manual, or an attachment is combined. ) Packaging and circulating in the market. Although the items described in the aforementioned documents are not limited, for example, they include information on effects, indications, usage, dosage, administration methods, warnings, and / or contraindications. Here, the product label means the concept of printing on a package or a printed matter accompanying the product in addition to those directly marked on the container.

Examples of the composition containing the medium-chain fatty acid oil and fat included in (A) include, for example, the above-mentioned medium-chain fatty acid oil and fat, or a commercially available oil-and-fat product containing the medium-chain fatty acid oil and fat. Further, in addition to the medium-chain fatty acid fats and oils, a carrier or an additive for the aforementioned oral preparation may be contained.

The composition containing the casein compound contained in (B) is, for example, a dairy product containing the casein compound, and a carrier or an additive for the oral preparation may be contained in addition to the casein compound.

The ratio (combination ratio) of (A) to (B) used as a combination is not particularly limited to the content of the casein compound contained in (B) with respect to 100 parts by mass of the content of the medium chain fatty acid oil and fat contained in (A) The lower limit is, for example, preferably 25 parts by mass, more preferably 27 parts by mass, and even more preferably 30 parts by mass. The upper limit of the range is, for example, preferably 80 parts by mass, more preferably 50 parts by mass, and even more preferably 40 parts by mass. The lower limit value and the upper limit value may be arbitrarily combined.

Although the range of the amount of medium-chain fatty acid fats per day is not particularly limited, the lower limit is, for example, preferably 1 g, more preferably 5 g, and even more preferably 10 g. The upper limit of the range is, for example, preferably 100 g, more preferably 50 g, and even more preferably 20 g. These lower limit values and upper limit values may be arbitrarily combined. The daily dosage of the casein compound used in combination with the medium-chain fatty acid oil and fat can be adjusted based on the daily dosage of the medium-chain fatty acid oil and fat according to the blending ratio with the medium-chain fatty acid fat.

The combination set of the present invention uses the recommended daily dosage of medium-chain fatty acid fats and oils as a reference, and individually packs (A) containing the medium-chain fatty acid fats and oils for one day, and adjusts it to contain the amount adjusted according to the aforementioned combination ratio. A combination set of (B) of the casein compound administered in one day, that is, a combination set including (A) and (B) administered in one day ). In addition, it may be a method of administering multiple times by dividing once per day or two or three times per day. In accordance with the above-mentioned number of administrations, (A) and (B) are divided into small portions each time. A combination set made by pre-dosing (a single-administration set). Furthermore, in order to enable continuous administration for one week, ten days, or one month, a combination set of (A) and (B) each having a large capacity may be used. In this case, in order to enable (A) It can be divided into (B) and (B) small doses for each day or each time, and it can also have a small measuring cup, scale, scale, etc.

(iii) appearance (a combination used in use)
In this aspect, the ketone body production-promoting agent of the present invention is (A) a medium-chain fatty acid oil or a composition containing the same, and (B) a casein compound or a composition containing the same as separate forms. Individually manufacture packaging, circulate to the market, and the user (test subject) combines the two at the same time, in parallel or with a time difference. This item includes the case where (A) and (B) are displayed side by side on the storefront (in the case of online sales, it is on the Internet), and it is also included in the product manual or instruction manual. By using (A) and ( B) When ketone body production is promoted (or the ketone body concentration in the body is increased), and it is recommended to use it together. Furthermore, (A) and (B) may each have the same or different shapes (liquid, solid, or semi-solid).

The composition containing the medium chain fatty acid oil and fat contained in (A), and the casein compound containing the casein compound contained in (B) are as described in (ii) above, and this description can be incorporated herein.

As a user, the ratio (combination ratio) of (A) and (B) used in combination is relative to 100 parts by mass of the content of the medium chain fatty acid oil and fat contained in (A), although the ratio of the casein compound contained in (B) is not It is particularly limited, and the lower limit thereof is, for example, preferably 25 parts by mass, more preferably 27 parts by mass, and even more preferably 30 parts by mass. The upper limit of the range is, for example, preferably 80 parts by mass, more preferably 50 parts by mass, and even more preferably 40 parts by mass. The lower limit value and the upper limit value may be arbitrarily combined.

Although the range of the amount of medium-chain fatty acid fats per day is not particularly limited, the lower limit is, for example, preferably 1 g, more preferably 5 g, and even more preferably 10 g. The upper limit of the range is, for example, preferably 100 g, more preferably 50 g, and even more preferably 20 g. The lower limit value and the upper limit value may be arbitrarily combined. The daily dosage of the casein compound used in combination with the medium-chain fatty acid oil and fat can be adjusted based on the daily dosage of the medium-chain fatty acid oil and fat according to the blending ratio with the medium-chain fatty acid fat.

(4) The use and usage of the ketone body production promoter are shown in the experimental examples described below. By ingesting a casein compound into the body together with a medium-chain fatty acid fat, it is compared with the case where the medium-chain fatty acid fat is ingested into the body alone. The production of ketone bodies from medium-chain fatty acids and fats in the body is promoted, and the ketone body concentration in the body can be effectively (in terms of amount and / or time) increased. The ketone body formation promoter of the present invention, which combines a medium-chain fatty acid oil and a casein compound, is expected to be used for these purposes, and is suitable for test subjects who want to increase the body concentration of ketone bodies, especially It is suitable for test subjects who want to effectively increase the in vivo concentration of ketone bodies.

Here, the test subject may be a ketone body capable of producing a medium-chain fatty acid oil and fat in vivo, and is preferably a human. Here, the ketone body is an incomplete metabolite of a fatty acid, and includes acetoacetic acid, β-hydroxybutyric acid, and acetone. The term "ketone body" in the present invention is used as a general term for acetoacetic acid, β-hydroxybutyric acid, and acetone. Furthermore, among the ketone bodies generated in the body, acetoacetic acid and β-hydroxybutyric acid can be mainly detected in blood and urine, and acetone can be detected in exhalation. Therefore, the aforementioned ketone body concentration in blood means the total concentration of acetoacetic acid and β-hydroxybutyric acid. However, whether or not the ketone body concentration in the body is increased can be evaluated by using blood or urine as a sample, using either the acetic acid or β-hydroxybutyric acid as an index. When exhalation is used as a specimen, acetone concentration can be used as an index for evaluation. The blood concentration of β-hydroxybutyric acid is preferred. Specifically, as shown in Experimental Example 1 described later, the β-hydroxybutyric acid concentration in the blood when the casein compound is taken into the body together with the medium-chain fatty acid oil and the blood In contrast, when the β-hydroxybutyric acid concentration becomes higher in terms of quantity and / or time (the rate of increase in concentration), it can be judged that the production of ketone bodies from medium-chain fatty acids and fats in the body is promoted, and ketones in the body are promoted. Body concentration is effectively increased.

The administration period of the ketone body formation promoter of the present invention is not particularly limited. For example, the administration can be performed within a period necessary to prevent, treat, or ameliorate a disease or symptom that is considered to have an effect due to an increase in ketone body concentration in the body. Although it is not limited, the administration period is, for example, 1, 4, 10, 20, 30, or 50 weeks or more, and a more preferable administration period can be appropriately set therein. Although it is not limited, it can be administered daily, for example, at intervals of 1 day and at intervals of 2 days, and is preferably daily.

The ketone body formation promoting agent of the present invention can be used as a monomer of each of the medium-chain fatty acid oil and fat and casein compound, or as a composition combining other components (a composition containing a medium-chain fatty acid fat and oil, and a composition containing a casein compound). Separate administration is performed simultaneously or concurrently by oral administration, administrative administration (gastrostomy, colostomy, transnasal). Preferably, both are administered orally.

As described above, the ketone body production-promoting agent of the present invention may be prepared in the form of oral administration or administration according to the above-mentioned administration form, and can be prepared into food (including beverages. The same applies hereinafter), liquid diet, and Medicine or pharmaceuticals. Food is preferred. Here, the food includes a food (ketogenic diet) used for ketogenic diet therapy. In addition, foods include specific health foods, nutritionally functional foods, functionally labeled foods, and general foods (including health foods). These forms may be those having ordinary foods (including processed foods), or may be in the form of preparations. Nutritional supplements (supplement).

In addition, when the ketone body production-promoting agent of the present invention has the form (ii) or (iii), the so-called (A) medium-chain fatty acid fat or oil or a composition containing the same, and (B) a casein compound or a product containing the same The compositions may have the same or different forms, respectively, and both of them may be food, or one of them may be a food and the other a quasi-drug or a medicinal product. Moreover, both of them may be specific health foods, nutritionally functional foods, functionally labeled foods, or general foods (including health foods), or one of them may be general foods, and the other may be specific health foods, nutritional foods. Or functionally labeled food.

When the ketone body production-promoting agent of the present invention has the form (ii) or (iii), the subject is administered (A) a medium-chain fatty acid oil or a composition containing the same, and (B) a casein compound, or The timing of the composition is limited to a state in which the medium-chain fatty acid oil and the casein compound can coexist in the body, and it may be at the same time or different. Examples of the different situations include a case where the administration of (A) and a case of (B) are performed with a time difference, and a case where the administration of (A) and the case of (B) are performed in parallel. For example, the aspect in which (A) is administered to the test subject earlier than (B), and the manner in which (A) is administered to the test subject later than (B) Included.

The ketone body production-promoting agent of the present invention can be suitably administered to a test subject having the disease or symptom in order to treat or improve a disease or symptom which is said to have an effect due to an increase in ketone body concentration in the body. In addition, in order to prevent (inhibit the onset of) the disease or symptom, it can be administered to a healthy person or a test subject having a possibility of the onset of the disease or symptom. Here, examples of diseases or symptoms that are said to have effects due to an increase in ketone body concentration in the body include childhood epilepsy, refractory epilepsy, glucose transport protein 1 (GLUTI) deficiency, pyruvate dehydrogenase complex abnormalities, and Neurodegenerative diseases such as Zheimer's disease, muscular dystrophy, mild cognitive impairment, Parkinson's disease, traumatic brain injury, cancer, depression, autism, migraine, amyotrophic lateral sclerosis , Sleepiness, diabetes, heart failure, myocardial infarction, autism, obesity, etc. Preferred are children with epilepsy, intractable epilepsy, glucose transporter 1 (GLUTI) deficiency, pyruvate dehydrogenase complex abnormality, neurodegenerative diseases such as Alzheimer's disease, muscular dystrophy, and mild cognitive impairment , Parkinson's disease, cancer, obesity, more preferably children with epilepsy, refractory epilepsy, glucose transport protein 1 (GLUTI) deficiency, Alzheimer's disease, mild cognitive impairment.

(II) A casein compound-containing composition used in combination with a medium-chain fatty acid fat and oil As one aspect of the present invention, a casein-containing compound-containing composition is characterized in that the casein compound-containing composition and the medium-chain fatty acid fat and oil Use in combination. This composition is used in combination with a medium-chain fatty acid to promote the production of ketone bodies from medium-chain fatty acids in the body. In other words, the composition can increase the body concentration of ketone bodies (in terms of quantity and / or time) by promoting the production of ketone bodies from medium-chain fatty acids and fats in the body. It is used to treat or ameliorate a disease or symptom which is said to be effective due to an increase in the concentration of ketone bodies in the body.

Here, as the target "casein compound", "casein compound-containing composition (casein compound-containing composition)", and "medium chain fatty acid oil and fat", as described in the above item (I), Records are also used in this section. The combination of casein compound and medium-chain fatty acid oil and fat, the combination ratio, the amount of casein compound administered per day, the method of administration, and the subject (subject) are also the same as the item (I) above. The description can be similarly applied to this item.

The casein-containing compound composition of the present invention may include the following aspects:
(a) A package of a composition containing a casein compound.
(b) It is described that the composition is used in combination with the medium-chain fatty acid oil and fat in order to promote ketone body production or increase ketone body concentration in the body. And at least one of the instruments in the group formed by the product label.

The "package" in (a) is a storage device for storing a casein compound or a composition containing a casein compound, and includes a container, a wrapper, inner seals, and the like. These storage devices are not particularly limited, and include, for example, cans, bottles, boxes, ampoules, vials, tubes, single-dose containers, paper, cloth, vinyl bags, plastic bags, SP sheets, PTP sheets, plastic containers, and the like. The packaged composition is generally combined with an outer container or an outer wrapper in a state in which at least one of a product label, an instruction manual (a product instruction manual, an instruction manual), an instruction manual, or an attachment is combined. ) Packaging and circulating in the market.

Although the items described in these documents are not limited, for example, they contain information about the effectiveness, indications, usage, dosage, administration methods, warnings, and / or contraindications. Here, the product label means the concept of printing on a package or a printed matter accompanying the product in addition to those directly marked on the container.

As described above, the casein compound or the casein compound-containing composition functions to promote the production of a ketone body derived from the medium chain fatty acid fat in the body by using the medium chain fatty acid fat in combination. Therefore, a casein compound or a composition containing a casein compound can be used to administer a test subject before or after the administration of the medium-chain fatty acid oil and fat, thereby promoting the increase of the ketone body concentration in the body of the test subject. . Although not limited, the test subject is preferably a human having a disease or symptom that produces an effect due to an increase in the in vivo concentration of the ketone body. In this case, by promoting an increase in the ketone body concentration in the body of the subject, the above-mentioned diseases or symptoms can be improved or prevented. In addition, as for the disease or symptom that produces an effect due to an increase in the body concentration of the ketone body, as described in (I) above, the description thereof can be similarly applied here.

In addition, in this specification, the terms "including" and "including" include the meanings of "substantially made of" and "made of".

[Example]

Hereinafter, in order to make the structure and effects of the present invention clearer, the present invention will be described based on experimental examples. However, this invention is not limited at all by this experimental example.

Experimental Example 1: Effect on promoting ketone body production of casein compounds of medium-chain fatty acid oils and fats:

(1) Experimental method
(1-1) Test animal As a test animal, a male Wistar rat (Japanese SLC) was used. After the rats were purchased, they were domesticated for one week and used for experiments. After the rats were fasted for 4 hours on the test day, the rats were classified into 4 groups in such a way that the average body weight and the β-hydroxybutyric acid (bHB) concentration as an index of ketone bodies in the blood were as equal as possible (test group: CZ1 ～ CZ3 group, and control group) (n = 8 for each group).

(1-2) After the experimental method was divided into groups, an aqueous solution of a casein compound (sodium casein) (manufactured by Fonterra) as a test substance was orally administered to the test group at a ratio of 20 mL / kg body weight ( CZ1 to CZ3) rats. The rats in the control group were orally administered with water instead of the test substance. The test substance or water was orally administered to each group of rats, and then triglyceryl caprylate (manufactured by Riken Vitamin) was orally administered to medium-chain fatty acid-containing fats and oils (medium-chain fatty acid fats and oils). (Hereinafter referred to as "MCT"). In addition, as shown in Table 1, the casein compound administration amount to the rats in the test group was 1.13 to 2.27 g / kg body weight, and the MCT administration amount was 4.5 g / kg body weight.

Before administration of the test substance (in the control group, before water administration), and after 1, 2, 3, 4, 5, and 6 hours from MCT administration, rats in each group were removed from the tail vein Blood was drawn, and the bHB concentration in blood was measured using a β-hydroxybutyric acid tester (Precision Xceed, manufactured by Abbott) for self-test. Calculate the maximum values of the bHB concentration after administration of MCT from the change over time (ΔbHB (mmol / L)) relative to the bHB concentration (initial value) of the test substance before administration (or before water administration). (ΔCmax) and the area under the curve (ΔAUC), based on the following formula, the relative values (% ΔCmax,% ΔAUC) when each value obtained from the control group was set to 100% were obtained.

[Number 1]
% ΔCmax = [ΔCmax of test group / ΔCmax of control group] × 100
% ΔAUC = [ΔAUC of the test group / ΔAUC of the control group] × 100

(2) Experimental results Regarding rats of each group (test group: CZ1 to CZ3 and control group), the bHB concentration after MCT administration is relative to the bHB concentration before the test substance administration (or water administration) (initial) The change in the difference (ΔbHB (mmol / L)) over time is shown in FIG. 1.

In addition, the relative values calculated from the maximum value (ΔCmax) and the area under the curve (ΔAUC) obtained from FIG. 1 and the control group set to 100 according to the above formula are shown in FIGS. 2 (A) and (B). . As shown in Figs. 1 and 2, it is thought that the concentration of bHB in blood is significantly increased by ingesting a casein compound together when MCT is ingested compared to when MCT is ingested alone. Thus, it has been shown that by ingesting a casein compound (sodium salt) and MCT together, it is possible to promote (hyper) ketone body production from MCT in the body. Specifically, the casein compound is administered simultaneously at an amount of 1.13 to 2.27 g / kg body weight (approximately 25% to 50% of the MCT administration amount) with respect to the MCT administration amount of 4.5 g / kg body weight, and Increased ketone body production due to MCT intake.
Moreover, no side effects such as inferiority caused by the administration of the casein compound were not confirmed.

Prescription example 1
The components (total 16.3 g) described in Table 2 below can be mixed with water to prepare a ketone body production promoter of the present invention having a liquid diet shape with a capacity of 125 mL.

Prescription example 2
The ketone body formation promoter composition of the present invention can be prepared by mixing the components described in Table 3 below to form a powder.

FIG. 1 shows the blood bHB concentration after the administration of medium chain fatty acid fats in rats of each group (test group: CZ1 to CZ3, and control group) in Experimental Example 1 with respect to the test substance (casein compound). The difference (ΔbHB (mmol / L): vertical axis) in the β-hydroxybutyric acid (bHB) concentration (initial value) in the blood before administration (the control group was before administration of water). The horizontal axis represents the elapsed time (hours) after the administration of the medium-chain fatty acid fat to each group of rats.

(A) of FIG. 2 shows the relative value (ΔCmax) of the ΔbHB of the rats in each test group obtained from FIG. 1, and the value corresponding to the control group is set to 100%, and the relative value ( % ΔCmax (%)). (B) of FIG. 2 shows the area under the curve (ΔAUC) of the time elapsed after the administration of ΔbHB and medium-chain fatty acid fats of rats in each test group obtained from FIG. The relative value (% ΔAUC (%)) calculated by setting the value to 100%.

Claims (12)

A ketone body production promoter, which is a medium-chain fatty acid oil and fat, and A combination of at least one casein compound selected from the group consisting of casein and a salt thereof. For example, the ketone body formation promoter of claim 1, wherein the ratio of the casein compound to 100 parts by mass of the medium-chain fatty acid oil and fat is 25 parts by mass or more. For example, if the ketone body formation promoter of claim 1 or 2 contains a composition containing a medium-chain fatty acid oil and fat, and a composition containing a casein compound, each is packaged as an individual composition, The administration of the composition containing the medium-chain fatty acid oil and fat and the composition containing the casein compound to the test subject is performed simultaneously, in time, or in parallel. The ketone body production promoter according to claim 1 or 2, which is a preparation containing a medium-chain fatty acid oil and fat and a casein compound. If the ketone body-promoting agent of claim 1 or 2 is a food, an oral quasi-drug or an oral medicine. Use of a composition of a medium-chain fatty acid fat and a casein compound selected from the group consisting of casein and its salt, which is used for the production of ketone body-promoting agents, or due to the in vivo concentration of ketone bodies A preventive or ameliorative agent for symptoms or diseases that have risen to produce efficacy. As used in claim 6, wherein the aforementioned composition is a combination of a casein compound in a proportion of 25 parts by mass or more relative to 100 parts by mass of a medium-chain fatty acid oil and fat. As used in claim 6 or 7, wherein the aforementioned composition is a composition containing a medium-chain fatty acid oil and fat, and a casein-containing compound each as a separate composition, and The administration of the composition containing the medium-chain fatty acid oil and fat and the composition containing the casein compound to the test subject is performed simultaneously, in time, or in parallel. As used in claim 6 or 7, wherein the aforementioned composition is a formulation containing a medium-chain fatty acid oil and fat and a casein compound. If the use of claim 6 or 7 is mentioned, the above-mentioned symptom or disease that produces efficacy due to an increase in the body concentration of ketone bodies is selected from the group consisting of childhood epilepsy, refractory epilepsy, glucose transport protein 1 (GLUT I) deficiency, pyruvate dehydrogenase Neurodegenerative diseases such as complex abnormalities, Alzheimer's disease, muscular dystrophy, mild cognitive impairment, Parkinson's disease, traumatic brain injury, cancer, depression, autism, migraine, muscular atrophy Lateral sclerosis, sudden sleep, diabetes, heart failure, myocardial infarction, asthma, and obesity. A method for enhancing the ketone body-generating ability of medium-chain fatty acid fats and oils, which comprises at least one casein compound selected from the group consisting of casein and its salt or a composition containing the same, and a medium-chain fatty acid Steps of using grease together. According to the method of claim 11, the aforementioned combined step is a step of mixing a casein compound or a composition containing the casein compound and a medium chain fatty acid fat.