Oral composition for use as an adjunct to ketogenic diet therapy and its use

Abstract

To provide an oral supplement for ketogenic diet therapy that contains the components of a special milk containing medium-chain fatty acid oil and β-hydroxybutyric acid, which have been conventionally used as supplemental foods for enhancing blood ketone bodies in ketogenic diet therapy, and has an improved taste. [Solution] An oral composition containing 5-40% by mass of protein, 30-80% by mass of lipids, 0-15% by mass of carbohydrates, and 5-20% by mass of β-hydroxybutyric acid or its salt, wherein the ratio of medium-chain fatty acid oil in the lipids is 30% by mass or more.

Description

Technical Field

[0001] The present invention relates to an oral composition for assisting ketogenic diet therapy and its use.

Background Art

[0002] As a type of dietary therapy, the ketogenic diet is known. The ketogenic diet is a low-carbohydrate, high-fat diet, in which 60 to 90% of the ingested energy is derived from fat. The ketogenic diet has been used as a nutritional therapy for epilepsy treatment since ancient times. In recent years, it has been reported that the ketogenic diet has various effects on our health, such as weight loss, improvement of lipid profiles, and enhancement of cognitive function (Non-Patent Documents 1-4). Furthermore, the ketogenic diet and ketone bodies have been shown to have therapeutic effects in several pathological conditions, such as diabetes, polycystic ovary syndrome, acne, neurological diseases, respiratory diseases, cardiovascular diseases, and cancer (Non-Patent Documents 5-9).

[0003] In order to enhance blood ketone bodies in ketogenic diet therapy, supplementary foods containing medium-chain fatty acid oil are used. As such supplementary foods containing medium-chain fatty acid oil, special milk for infants with a high-fat, low-carbohydrate composition that has been used for a long time as a ketogenic diet therapy for infants with congenital metabolic disorders and refractory epilepsy (Meiji's Ketone Formula (registered trademark) or special milk with a similar composition, hereinafter referred to as "special milk containing medium-chain fatty acid oil") is used. Regarding the inductive effect on blood ketone bodies, its effects have been reported (Non-Patent Documents 10-11). The effect of ketogenic diet therapy increases with continuous use. However, since the special milk containing medium-chain fatty acid oil does not taste good, there has been a problem that users have difficulty in continuous intake while understanding its necessity. Therefore, improvement to a delicious special milk containing medium-chain fatty acid oil has been desired. However, there was a problem that adding carbohydrates that give a sweet taste would cause the ketone body induction effect to disappear. It is also known that gastrointestinal discomfort appears after ingestion, and there is room for improvement in this regard.

[0004] Furthermore, in ketogenic diet therapy, attempts have been made to directly ingest ketones (β-hydroxybutyrate), which are normally produced in the liver, in order to enhance blood ketone levels. However, β-hydroxybutyrate has a very strong sour taste, which has made continuous intake difficult. [Prior art documents] [Non-patent literature]

[0005] [Non-Patent Document 1] Drabinska N, Wiczkowski W, Piskula MK. Trends Food Sci Technol. (2021) 110:28-38. doi: 10.1016 / j.tifs.2021.01.080 [Non-Patent Document 2] Dowis K, Banga S. Nutrients. (2021) 13:1654. doi: 10.3390 / nu13051654 [Non-Patent Document 3] Ota M, et al. Psychopharmacology. (2016) 233:3797-3802. doi: 10.1007 / s00213-016-4414-7 [Non-Patent Document 4] Yomogida Y, et al. Nutrients. (2021) 13:2134. doi: 10.3390 / nu13072134 [Non-Patent Document 5] Cavaleri F, Bashar E. J Nutr Metab. (2018) 2018:7195760. doi: 10.1155 / 2018 / 7195760 [Non-Patent Document 6] Paoli A, Rubini A, Volek JS, Grimaldi KA. Eur J Clin Nutr. (2013) 67:789-796. doi: 10.1038 / ejcn.2013.116 [Non-Patent Document 7] Ota M, et al. Neurosci Lett. (2019) 690:232-236. doi: 10.1016 / j.neulet.2018.10.048 [Non-Patent Document 8] Egashira R, et al. Nutrients. (2023) 15(10):2334. doi: 10.3390 / nu15102334. [Non-Patent Document 9] Hagihara K, et al. Nutrients. (2020) 12(5):1473. doi: 10.3390 / nu12051473. [Non-Patent Document 10] Nakamura K, et al. Nutrients. (2022) 14(6):1199. doi: 10.3390 / nu14061199. [Non-Patent Document 11] Nakamura K, et al. Front Nutr. (2023) 10:1224740. doi: 10.3389 / fnut.2023.1224740. eCollection 2023. [Overview of the project] [Problems that the invention aims to solve]

[0006] The present invention aims to provide an oral composition for supplementing ketogenic diet therapy that contains components of a special milk containing medium-chain fatty acid oil and β-hydroxybutyric acid, which have been conventionally used as supplemental foods for enhancing blood ketones in ketogenic diet therapy, and has an improved taste. [Means for solving the problem]

[0007] To solve the above problems, the present invention includes the following inventions. [1] An oral composition containing 5-40% by mass of protein, 30-80% by mass of lipids, 0-15% by mass of carbohydrates, and 5-20% by mass of β-hydroxybutyric acid or its salt, wherein the ratio of medium-chain fatty acid oil to lipids is 30% by mass or more. [2] An oral composition containing 10 to 30% by mass of the oral composition described in [1] above. [3] The oral composition according to [1] or [2] above, which is used in combination with a carbohydrate-restricted diet. [4] A composition for use as an adjunct to ketogenic diet therapy, comprising the oral composition described in [3] above. [5] A composition for the prevention or improvement of frailty, comprising the oral composition described in [1] or [2] above. [6] An energy supplement composition comprising the oral composition described in [1] or [2] above. [7] A dietary composition comprising the oral composition described in [1] or [2] above. [8] A composition for improving athletic performance, comprising the oral composition described in [1] or [2] above. [Effects of the Invention]

[0008] The present invention provides an oral supplement for ketogenic diet therapy that contains components of a special milk containing medium-chain fatty acid oil and β-hydroxybutyric acid, which have been conventionally used as supplemental foods for enhancing blood ketones in ketogenic diet therapy, and has an improved taste. Because the taste of the oral supplement for ketogenic diet therapy of the present invention has been improved, it can be consumed continuously on a daily basis. [Brief explanation of the drawing]

[0009] [Figure 1] This figure shows the results of a statistical analysis of the responses to question 1 of the sensory evaluation questionnaire. [Figure 2] This figure shows the results of a statistical analysis of the responses to question 2 of the sensory evaluation questionnaire. [Figure 3] This figure shows the results of a statistical analysis of the responses to question 3 of the sensory evaluation questionnaire. [Figure 4] This figure shows the results of a statistical analysis of the responses to question 4 of the sensory evaluation questionnaire. [Figure 5] This figure shows the results of a statistical analysis of the responses to question 5 of the sensory evaluation questionnaire. [Figure 6]It is a diagram showing the VAS (Visual Analog Scale) method for Question 5.

Mode for Carrying Out the Invention

[0010] Supplementary foods containing medium-chain fatty acid oil-containing special milk used to enhance blood ketone bodies in the ketogenic diet have a problem that it is difficult to continuously ingest them every day because they taste bad. Similarly, attempts to enhance blood ketone bodies by directly ingesting β-hydroxybutyric acid (hereinafter referred to as "BHB") also have a problem that it is difficult to continuously ingest it every day because BHB tastes bad. The applicant of the present application repeated trials and errors by combining components containing no carbohydrates in order to improve these tastes, but no effective solution was found. Finally, when attempting to mix the above two types, which were finally evaluated as having a bad taste, contrary to the expectation that mixing foods with a bad taste would make the taste even worse, it was found that the taste was improved and became delicious, and the present invention was completed.

[0011] 〔Oral Composition〕 The present invention provides an oral composition (hereinafter referred to as "the first oral composition") containing 5 to 40% by mass of protein, 30 to 80% by mass of lipid, 0 to 15% by mass of carbohydrate, and 5 to 20% by mass of BHB or a salt thereof, and the ratio of medium-chain fatty acid oil in the lipid is 30% by mass or more. The first oral composition of the present invention may contain protein, lipid, carbohydrate, and BHB in the above contents, and may contain other components as long as the intended effects are achieved.

[0012] The protein can be any type of protein and is not particularly limited. Examples of animal proteins include milk protein, egg protein, meat protein, and fish and shellfish protein. Examples of plant proteins include soy protein, rice protein, and wheat protein. The lower limit of the protein content is 5% by mass or more, and may be 10% by mass or more, 15% by mass or more, 20% by mass or more, or 25% by mass or more. The upper limit of the protein content is 40% by mass or less, and may be 35% by mass or less, or 30% by mass or less. These lower and upper limits can be combined arbitrarily.

[0013] The lipids may be short-chain fatty acid oils, medium-chain fatty acid oils, long-chain fatty acid oils, or any combination thereof. It is preferable that the lipids have a high proportion of medium-chain fatty acids. The proportion of medium-chain fatty acids in the lipids may be 10% by mass or more, 20% by mass or more, 30% by mass or more, 40% by mass or more, 50% by mass or more, 60% by mass or more, 70% by mass or more, 80% by mass or more, or 90% by mass or more. Preferably, it is 100% by mass.

[0014] Medium-chain fatty acid oils refer to oils in which the fatty acids that make up the oil have a medium chain length, and are also called MCTs (Medium Chain Triglycerides). Typically, they refer to oils composed of fatty acids with 6 to 12 carbon atoms, preferably those composed of fatty acids with 8 to 12 carbon atoms, those composed of fatty acids with 8 to 11 carbon atoms, or those composed of fatty acids with 8 to 10 carbon atoms. Medium-chain fatty acid oils are more easily digested and absorbed than general oils and are readily converted into energy. Examples of medium-chain fatty acids include hexanoic acid (caproic acid; C6), octanoic acid (caprylic acid; C8), nonanoic acid (pelargonic acid; C9), decanoic acid (capric acid; C10), and dodecanoic acid (lauric acid; C12).

[0015] Medium-chain triglyceride (MCT) oils are present in plant matter such as coconuts and palm fruit, and in fats and oils contained in dairy products such as milk. Therefore, MCT oils extracted (including crude extraction) or refined (including crude refining) from these fats and oils (preferably vegetable oils such as palm kernel oil) can be used as is or as a raw material. Alternatively, products produced by chemical synthesis or commercially available products can be used as MCT oils. Examples of MCT oils that can be used include Nisshin MCT Oil & Powder (manufactured by Nisshin Oillio Co., Ltd.) and Extra Virgin Coconut Oil (manufactured by Nisshin Oillio Co., Ltd.).

[0016] The first oral composition of the present invention may contain 15% by mass or less of carbohydrates, or it may not contain carbohydrates. A low carbohydrate content is preferred, and the absence of carbohydrates is particularly preferred.

[0017] BHB may be an optical isomer (D-isomer or L-isomer) or a racemic mixture, but it is preferable to include the D-isomer, which acts as a physiologically active component. The proportion of D-BHB in BHB is preferably 10% by mass or more, 30% by mass or more, 50% by mass or more, 70% by mass or more, 80% by mass or more, or 90% by mass or more, and most preferably 100% by mass. BHB may also be a salt of BHB. Examples of salts of BHB include sodium salt, magnesium salt, and calcium salt.

[0018] Commercially available BHB can be used. Examples of commercially available BHB include chemically synthesized BHB and BHB produced by fermentation using microorganisms. Fermented BHB is preferred due to its high purity of the D-isomer, and BHB produced by fermentation using microorganisms with biomass raw materials is even more preferred. Examples of commercially available BHB that can be used include "OKETOA(registered trademark) D-BHB Acid" (Osaka Gas) and "OKETOA(registered trademark) D-BHB Neutralized Salt" (Osaka Gas).

[0019] The first oral composition of the present invention may contain carnitine. Furthermore, the first oral composition of the present invention may contain dietary fiber.

[0020] The first oral composition of the present invention may contain a sweetener. The sweetener may be a carbohydrate-based sweetener or a non-carbohydrate sweetener. Examples of carbohydrate-based sweeteners include sugar, isomerized sugar, maltose, corn syrup, glucose, fructose, palatinose, fructooligosaccharides, galactooligosaccharides, emulsified oligosaccharides, raffinose, trehalose, lactose, honey, galactose, arabinose, sorbitol, mannitol, reduced maltose syrup, maltitol, reduced palatinose, erythritol, xylitol, etc. Examples of non-carbohydrate sweeteners include stevia, glycyrrhizin, monk fruit, aspartame, saccharin, acesulfame K, sucralose, neotame, etc. Stevia or erythritol are preferred.

[0021] The first oral composition of the present invention may contain vitamins and minerals. Examples of vitamins include vitamin A, vitamin B1, vitamin B2, vitamin B6, vitamin B12, vitamin C, vitamin D, vitamin E, vitamin K, pantothenic acid, niacin, folic acid, and biotin. Examples of minerals include calcium, magnesium, sodium, potassium, phosphorus, chlorine, iron, copper, zinc, manganese, chromium, molybdenum, selenium, and iodine.

[0022] The present invention provides an oral composition (hereinafter referred to as "second oral composition") containing 10 to 30% by mass of the first oral composition. The content of the first oral composition in the second oral composition may be 10 to 20% by mass, 12 to 16% by mass, or 14 to 15% by mass. The second oral composition can be prepared by adding water or an excipient to the first oral composition and mixing. Examples of excipients include dextrin (liquid dextrin, indigestible dextrin, etc.), gum arabic, inulin, cellulose, etc.

[0023] The first and second oral compositions of the present invention, by mixing a special milk containing medium-chain fatty acid oil, which has an unpleasant taste and is difficult to consume continuously on a daily basis, with BHB, which also has an unpleasant taste and is difficult to consume continuously on a daily basis, to create oral compositions containing both components simultaneously, yielded the unexpected effect of improved taste, and at the same time, it was found that gastrointestinal discomfort caused by the intake of medium-chain fatty acid oil was also improved. Furthermore, because the first and second oral compositions of the present invention involve the simultaneous intake of medium-chain fatty acid oil and BHB (ketone bodies), BHB is absorbed immediately after ingestion, causing an increase in blood ketone bodies, and then ketone bodies produced from the medium-chain fatty acid oil are absorbed, allowing the elevated blood ketone body state to be maintained for a long period of time.

[0024] The first and second oral compositions of the present invention can be implemented as food and beverages. Food and beverages include nutritional supplements, health foods, functional foods, foods for the sick, foods for infants, foods for the elderly, etc. The form of food and beverages is not particularly limited and includes, for example, supplements, beverages, processed foods, confectionery, dairy products, processed oils and fats, etc. Examples of supplements include fine granules, tablets, powders, capsules (including soft capsules and hard capsules), chewable tablets, syrups, drinks, natural liquid foods, semi-digested nutritional foods, elemental nutritional foods, gastric nutritional supplements, enteral nutritional supplements, etc. Examples of beverages include tea beverages, soft drinks, carbonated drinks, nutritional drinks, fruit drinks, lactic acid drinks, etc. Examples of processed foods include bread, noodles, pasta, ham, bacon, sausages, fish cakes, etc. Examples of confectionery include candy, jam, chewing gum, ice cream, snack foods, cookies, biscuits, cakes, wafers, sweet buns, chocolate, Japanese sweets, etc. Dairy products include processed milk, fermented milk, butter, cheese, and yogurt. Processed oils and fats include margarine, mayonnaise, shortening, whipped cream, and dressings.

[0025] The first and second oral compositions of the present invention can be used as pharmaceuticals. When used as pharmaceuticals, they can be formulated for oral administration by appropriately incorporating pharmaceutically acceptable carriers or additives according to known manufacturing methods for pharmaceutical preparations (e.g., methods described in the Japanese Pharmacopoeia). Specifically, examples include tablets, pills, powders, granules, capsules, lozenges, syrups, liquids, emulsions, etc. The proportions of carriers or additives can be appropriately set based on the ranges commonly used in the pharmaceutical field.

[0026] The first oral composition of the present invention is preferably used in a form that is diluted with water or the like by the person taking it or their caregiver at the time of ingestion. Furthermore, the first oral composition of the present invention is preferably used in the form of a raw material for the production of the second oral composition. The second oral composition of the present invention is preferably used in a form that can be directly ingested by the person taking it as is.

[0027] [Uses of oral compositions] • Compositions for use as an adjunct in ketogenic diet therapy The present invention provides a composition for use as an adjunct to ketogenic diet therapy, containing the first and second oral compositions of the present invention (hereinafter referred to as "the oral compositions of the present invention"). The ketogenic diet therapy adjunct of the present invention is preferably used in combination with a carbohydrate-restricted diet for patients who are known to benefit from ketogenic diet therapy. The ketogenic diet therapy adjunct of the present invention can increase blood ketone levels in patients undergoing ketogenic diet therapy immediately after ingestion and maintain elevated blood ketone levels for a long period of time, thereby enhancing the effects of ketogenic diet therapy.

[0028] Diseases for which ketogenic diet therapy has been shown to be effective include epilepsy, cancer, kidney disease, liver disease, neurological disorders, respiratory diseases, cardiovascular diseases, diabetes, polycystic ovary syndrome, acne, genetic diseases, dementia, developmental disorders, and mental illnesses.

[0029] • Compositions for preventing or improving frailty The present invention provides a composition for preventing or improving frailty, which contains the oral composition of the present invention. The composition for preventing or improving frailty of the present invention can be taken in addition to a regular diet for people who are physically and / or mentally weakened due to aging or the like (Brianna J Stubbs, et al. PLoS One. 2024 Sep 18;19(9):e0307951. doi: 10.1371 / journal.pone.0307951. eCollection 2024.).

[0030] • Energy supply composition The oral composition of the present invention can be used as an energy supplement composition. The energy supplement composition of the present invention can be taken in addition to a regular diet for people who need energy supplementation, including healthy individuals (Hagele FA, et al. Clin Nutr ESPEN. 2023 Jun;55:292-299. doi: 10.1016 / j.clnesp.2023.03.025. Epub 2023 Apr 10. PMID: 37202059 Clinical Trial.).

[0031] Dietary composition The oral composition of the present invention can be used for weight loss. The weight loss composition of the present invention can be taken in combination with a carbohydrate-restricted diet for people who wish to lose weight through dietary restrictions (carbohydrate restriction) (Muscogiuri G, et al. Obes Facts. 2021;14(2):222-245. doi: 10.1159 / 000515381. Epub 2021 Apr 21., Paoli A, et al. Nutrients. 2021 Jan 26;13(2):374. doi: 10.3390 / nu13020374.).

[0032] ·Composition for improving athletic performance The oral composition of the present invention can be used to improve athletic performance. It can be taken in combination with a regular diet or a carbohydrate-restricted diet, targeting athletes and individuals who wish to improve their athletic performance (Paoli A, et al. Nutrients. 2021 Jan 26;13(2):374. doi: 10.3390 / nu13020374.). Specific examples of improved athletic performance include prevention of carbohydrate depletion, prevention of fatigue, reduction of carbohydrate supplementation frequency in long-distance sports, reduction of body weight and body fat, and improvement of sprinting ability. [Examples]

[0033] The present invention will be described in detail below with reference to examples, but the present invention is not limited to these examples.

[0034] [Test Example 1: Sensory Test] 1. Test Method (1) Panelists The study included 26 men and women (11 men and 15 women) aged 20 to 60 who did not have allergies to milk or soy protein. The average age was 43.0 ± 10.0 years, the average weight was 59.7 ± 9.7 kg, and the average BMI was 21.9 ± 2.6.

[0035] (2) Test food (2-1) Preparation of test food 1 15 g of special milk powder containing medium-chain fatty acid oil having the composition described in Table 1 was dissolved in water, and the total volume was adjusted to 100 mL and filled into a beverage carton.

[0036] [Table 1]

[0037] (2-2) Test Foods • Test food 1 (comparative example): 100 mL of special milk containing medium-chain fatty acid oil in a paper carton after the above preparation (the composition of major nutritional components is shown in Table 2). • Test food 2 (comparative example): 15 mL of β-hydroxybutyrate beverage in an aluminum pack having the composition described in Table 2. • Test food 3 (Example): 115 mL of beverage prepared by thoroughly mixing control food 1 and control food 2 in a glass immediately before consumption.

[0038] [Table 2]

[0039] [Table 3]

[0040] (3) Sensory evaluation The panelists were given each sample food and informed that it was a nutritional food. The panelists tasted the samples in the order of test food 1, 2, and 3, and after tasting each food, they answered a questionnaire about that food. Before tasting the next sample food, they rinsed their mouths with mineral water.

[0041] (4) Questionnaire content The questionnaire content was the same for each test food product, and respondents were asked to answer the following questions 1-6. Question 1: Do you think you could drink this food every day (1-2 glasses)? I strongly agree (5 points) · I agree (4 points) · Neither agree nor disagree (3 points) · I disagree (2 points) · I strongly disagree (1 point) Question 2: Do you think it would be easy to incorporate this food into your daily routine? Very easy (5 points) · Easy (4 points) · Neither easy nor difficult (3 points) · Not very easy (2 points) · Not easy at all (1 point) Question 3: Do you find this food easy to drink? Very easy to drink (5 points) · Easy to drink (4 points) · Average (3 points) · Difficult to drink (2 points) · Very difficult to drink (1 point) Question 4: Do you feel that continuing to consume this food will have a positive effect on your health? Very much so (5 points) · Feel (4 points) · Neither agree nor disagree (3 points) · Not really (2 points) · Not at all (1 point) Question 5: Do you find this food delicious? (Please mark your answer with a circle.) Question 5 employed the VAS (Visual Analog Scale) method. Specifically, panelists were asked to indicate the degree of deliciousness on a 100mm long line (left end representing "not tasty," right end representing "tasty") (see Figure 6). The distance (mm) from the left end representing "not tasty" was measured to quantify the deliciousness. Question 6: Please write down any changes in your physical condition or taste you noticed after consuming this food. (Free response) Question 6 was optional. For questions 1 to 5, a t-test was used to compare the two groups of test food 3 (example) and test food 1 (comparative example), and also the two groups of test food 3 (example) and test food 2 (comparative example).

[0042] 2 Results The results of the questionnaire for questions 1 to 5 are shown in Figures 1 to 5. Significant differences were observed between the two groups, Test Food 3 (Example) and Test Food 1 (Comparative Example), and between the two groups, Test Food 3 (Example) and Test Food 2 (Comparative Example), for all of questions 1 to 5. In the optional responses to question 6, four panelists reported gastrointestinal discomfort after consuming Test Food 1 (Comparative Example), and thirteen panelists reported that Test Food 2 (Comparative Example) was too sour. Based on these results, it was shown that test food 3 (Example) is superior to test food 1 (Comparative Example) and test food 2 (Comparative Example) in terms of long-term continuous consumption.

[0043] It should be noted that the present invention is not limited to the embodiments and examples described above, and various modifications are possible within the scope of the claims. Embodiments obtained by appropriately combining the technical means disclosed in different embodiments are also included in the technical scope of the present invention.

Claims

1. An oral composition containing 5-40% by mass of protein, 30-80% by mass of lipids, 0-15% by mass of carbohydrates, and 5-20% by mass of β-hydroxybutyric acid or its salt, wherein the proportion of medium-chain fatty acid oil in the lipids is 30% by mass or more.

2. An oral composition containing 10 to 30% by mass of the oral composition described in claim 1.

3. An oral composition according to claim 1 or 2, to be used in combination with a carbohydrate-restricted diet.

4. A composition for use as an adjunct to ketogenic diet therapy, comprising the oral composition described in claim 3.

5. A composition for preventing or improving frailty, comprising the oral composition according to claim 1 or 2.

6. An energy supplementation composition containing the oral composition according to claim 1 or 2.

7. A dietary composition comprising the oral composition according to claim 1 or 2.

8. A composition for improving athletic performance, comprising the oral composition described in claim 1 or 2.

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