Ketogenic diet

Abstract

Provided herein is an endophytic ketone composition comprising (i) a lipid portion comprising 45 to 65 g of a lipid, (ii) a carbohydrate portion comprising 5 to 12 g of a digestible carbohydrate, and (iii) a protein portion comprising 15 to 25 g of a protein per 100 g of a ketogenic composition, and its therapeutic use, the endophytic ketone composition comprising (i) a lipid portion comprising 45 to 65 g of a lipid, (ii) a carbohydrate portion comprising 5 to 12 g of a digestible carbohydrate, and (iii) a protein portion comprising 15 to 25 g of a protein per 100 g of the ketogenic composition, the ketogenic weight ratio of the endophytic ketogenic composition is between 1.5: 1 and 3.0: 1.

Description

Technical Field

[0001] This invention relates to the field of ketogenic compositions and their uses. Background Technology

[0002] Epilepsy is one of the most common neurological disorders after stroke, affecting at least 50 million people worldwide. It is diagnosed in individuals with recurrent, unexplained seizures. This occurs when cortical neurons overfire, become hypersynchronous, or both, causing a temporary disruption of normal brain function. This can affect, for example, muscles, senses, consciousness, or a combination thereof. Seizures can be focal (limited to a part of the brain) or generalized (spreading widely throughout the brain and causing loss of consciousness). Epilepsy can have a variety of causes; some forms are classified as epilepsy syndromes, most of which begin in childhood. Epilepsy is considered difficult to treat when two or three anticonvulsant medications fail to control the seizures. Approximately 60% of patients will achieve seizure control with their first medication, while about 30% will not achieve control with medication. When medication fails, other options include epilepsy surgery, vagus nerve stimulation, and the ketogenic diet (KD).

[0003] KD simulates various aspects of starvation by forcing the body to use fat instead of carbohydrates as fuel for cellular energy production. Normally, carbohydrates from food are converted into glucose and then transported throughout the body, playing a crucial role in promoting brain function. However, if the diet contains very few carbohydrates, the liver converts fat into fatty acids and ketone bodies. The term ketone bodies typically refers to three acidic compounds present in small amounts in the blood: acetone (propanone), acetoacetic acid (3-oxobutyric acid), and β-hydroxybutyric acid (3-hydroxybutyric acid). These compounds originate from the metabolism of fats introduced from food and are fundamentally important for the normal function of brain cells because, besides glucose, ketone bodies are the only compounds that these cells can use as an energy source.

[0004] The ketogenic diet (KD) was initially recommended to mimic the metabolic state and biochemical changes associated with fasting because fasting was shown to have anticonvulsant properties. The classic ketogenic diet was first introduced in the 1920s for human children with epilepsy. The classic KD typically has a ketogenic ratio of 4:1 to 3:1, meaning that such a diet contains approximately 3 to 4 times the weight of the total weight of protein and digestible carbohydrates. Various variations of the classic ketogenic diet exist (with reduced fat content), such as the medium-chain triglyceride ketogenic diet (MCTKD), in which a larger percentage (30%–70%) of total daily calories comes from medium-chain triglycerides. Other known variations of the classic KD include the modified Atkins diet with a ketogenic ratio of approximately 1:1 and the low glycemic index diet, both of which are difficult to induce and maintain a ketotic state in practice. Generally, reducing fat content in cKD may come at the cost of reduced ketosis, and some studies have reported that it is not optimal for seizure suppression in patients with epilepsy compared to classic KD (Sondhi et al., JAMA Pediatrics, 2020). Another known variant of classic KD is the mild ketogenic diet according to WO 2019013616 A1, which contains less than 10 kcal% of MCT.

[0005] In subjects receiving ketogenic diets (KD), fat is broken down into fatty acids and ketone bodies in the liver, and these compounds are used in further metabolic pathways to generate adenosine triphosphate (ATP) as a source of chemical energy. KD is thought to cause adaptive changes in energy metabolism, particularly in the brain, thereby increasing energy production. In neurological disorders, this is thought to help neurons maintain function and vitality in the face of increased energy demands and may confer neuroprotective effects. Studies have shown significant benefits of KD and ketosis in treating refractory epilepsy in children and adults. Short-term trials have shown that approximately half of those studies reduced seizures by at least 50% after 6 months, and approximately one-third achieved a reduction of at least 90%. Often, a ketogenic diet is sufficient to effectively reduce or discontinue prescription antiepileptic drugs and improve quality of life.

[0006] Strict control of the ketogenic diet is essential to ensure effective seizure prevention while maintaining adequate nutritional value. Although the ketogenic diet is clearly effective, it is difficult to manage in both children and adults, leading to poor patient adherence. Current ketogenic diet methods can be restrictive, which can result in poor adherence (especially in adults). Furthermore, such diets can cause a variety of side effects, including digestive problems, elevated blood lipid levels, drowsiness, stunted growth, and an increased risk of fractures, particularly attributable to excessive fat intake. Therefore, there remains a need for a combination that avoids these drawbacks while still providing the desired therapeutic effect. Summary of the Invention

[0007] This article provides a ketogenic composition comprising (i) a lipid moiety comprising 45 to 65 g of lipids, (ii) a carbohydrate moiety comprising 5 to 12 g of digestible carbohydrates, and (iii) a protein moiety comprising 15-25 g of protein (including added free amino acids) per 100 g of the ketogenic composition (based on weight). The lipid portion of the ketogenic composition includes -5-50% by weight of medium-chain fatty acids [MCFA] based on the total weight of fatty acids in the lipid fraction, wherein more than 60% by weight of the MCFA are C8:0, C10:0 and C12:0 fatty acids, and wherein at least 70% by weight of the MCFA is provided in the form of medium-chain triglycerides [MCT]. -Based on 50-95% by weight of the total fatty acids in this lipid fraction, even-chain long-chain fatty acids [LCFA] and very long-chain fatty acids [VLCFA] with carbon lengths of 14 to 24, wherein the even-chain LCFA and VLCFA contain at least one ω-3 polyunsaturated fatty acid [LC-PUFA] selected from the group consisting of: docosahexaenoic acid (22:6, ω-3; DHA), eicosapentaenoic acid (20:5, ω-3; EPA) and docosapentaenoic acid (22:5, ω-3; DPA). The carbohydrate portion comprises 30 to 80% by weight of low glycemic index carbohydrates based on the total weight of digestible carbohydrates, and This protein portion contains 5-15% by weight of free amino acids, and The ketogenic composition has a ketogenic weight ratio between 1.5:1 and 3.0:1.

[0008] The ketogenic compositions according to the invention have a specific combination of lipids, carbohydrates, proteins and micronutrients, thereby allowing the provision of the health benefits of a ketogenic diet without causing compliance problems associated with excessive fat intake.

[0009] The inventors have observed that the enteric ketogenic composition according to the invention is beneficial for therapeutic use in treating epilepsy and / or preventing the progression of epilepsy. The inventors have found that the ketogenic composition according to the invention is beneficial for therapeutic use in treating and / or preventing and / or reducing the severity of epilepsy and in preventing and / or delaying the formation of epileptiform circuits in the brain. In addition to its beneficial therapeutic use in epilepsy, the inventors have also observed that the enteric ketogenic composition is beneficial for preventing abnormally high blood triglyceride levels, fatty liver development, and / or the development of metabolic syndrome in subjects following the enteric ketogenic composition. In addition to its beneficial therapeutic use in epilepsy, the inventors have also observed that therapeutic benefits include prevention and / or treatment of the behavioral consequences of epilepsy. Attention deficit hyperactivity disorder (ADHD) is often associated with epilepsy. The inventors have observed that the use of the enteric ketogenic composition according to the invention reduces and / or prevents ADHD-related behavioral patterns. ADHD-related behavioral patterns include hyperactivity, impulsivity, and / or fearlessness.

[0010] In other words, the present invention also relates to the use of the enteric ketogenic composition according to the invention for treating epilepsy and / or preventing the progression of epilepsy in subjects with epilepsy or at risk of seizures. The present invention further relates to the use of the enteric ketogenic composition for preventing abnormally high blood triglyceride levels, fatty liver, and / or the development of metabolic syndrome in subjects with epilepsy or at risk of seizures. The present invention further relates to the use of the enteric ketogenic composition in subjects with epilepsy or at risk of seizures, wherein ADHD-related behavioral patterns are reduced and / or prevented.

[0011] The present invention also relates to a method for treating and / or preventing epilepsy and / or epilepsy progression in a subject suffering from epilepsy or at risk of seizures, the method comprising administering an enteric ketogenic composition to the subject. Furthermore, the method for treatment and / or prevention relates to preventing abnormally elevated blood triglyceride levels, fatty liver, and / or the development of metabolic syndrome in a subject suffering from epilepsy or at risk of seizures. The method for treating and / or preventing epilepsy and / or epilepsy progression further includes reducing and / or preventing ADHD-related behavioral patterns.

[0012] In particular, the present invention provides an enteric ketogenic composition, and methods and uses of the enteric ketogenic composition for treating and / or preventing epilepsy, epilepsy progression, and preventing abnormally high blood triglyceride levels, fatty liver, and / or the development of metabolic syndrome in subjects suffering from epilepsy or at risk of epileptic seizures (preferably epileptiform seizures). Attached Figure Description

[0013] The invention will now be discussed in more detail with reference to the accompanying drawings.

[0014] Figure 1This shows the distribution of seizure scores in animals exposed to a control diet, a classic ketogenic diet, and an alternative ketogenic diet during each stimulation period.

[0015] Figure 2 This shows the distribution of seizure scores in each experimental group after a certain number of stimuli, as well as the latency of seizure grades 4, 5, or complete ignition.

[0016] Figure 3 The average seizure score of the experimental group is shown as the number of stimulations increases. Y-axis: seizure score; x-axis: stimulation period.

[0017] Figure 4A A shows the post-discharge pattern after the initial 10 seconds of electrical stimulation, B shows the duration of the first part of the post-discharge (AD1) for each experimental group, and C shows the latency of the second part of the post-discharge (AD2) for each experimental group.

[0018] Figure 5 This displays the time each experimental group spends entering and remaining in the central region.

[0019] Figure 6 This shows the activities and explorations of animals in different experimental groups.

[0020] Figure 7 This shows the movement of animals in different experimental groups.

[0021] Figure 8 This shows the blood ketone levels of animals in different experimental groups 5 days after receiving the diet.

[0022] Figure 9 This shows the blood ketone levels of animals in different experimental groups after 21 days of receiving the diet.

[0023] Figure 10 This shows the serum triglyceride levels in non-fasting rats in different experimental groups after 5 and 21 days of dieting.

[0024] Figure 11 This shows the serum glucose levels of non-fasting rats in different experimental groups after 5 and 21 days of being fed.

[0025] Figure 12 This shows the serum levels of ω-3 and ω-6 PUFAs in non-fasting rats in different experimental groups after 5 days of dietary exposure.

[0026] Figure 13 This shows the serum levels of ω-3 and ω-6 PUFAs in non-fasting rats in different experimental groups after 21 days of dietary exposure.

[0027] Figure 14This shows the specific LCFA serum levels in non-fasted rats in different experimental groups 5 days after feeding.

[0028] Figure 15 This shows the specific LCFA serum levels in non-fasted rats in different experimental groups after 21 days of dieting.

[0029] Figure 16 This shows the liver triglyceride content (in mg / g liver) in different experimental groups.

[0030] Figure 17 This shows the weight development over time in different experimental groups.

[0031] Figure 18 This shows the serum essential amino acid levels in different experimental groups after 5 days of dietary exposure. On day 5 of dietary exposure, the alternative ketogenic diet provided higher levels of essential amino acids than the classic ketogenic rodent diet.

[0032] Figure 19 This shows the serum essential amino acid levels in different experimental groups after 21 days of dietary exposure. On day 21 of dietary exposure, the alternative ketogenic diet provided higher levels of essential amino acids than the classic ketogenic rodent diet.

[0033] Figure 20 This shows the serum amino acid levels associated with seizure blocking in different experimental groups after 5 days of dietary exposure. On day 5 of dietary exposure, the alternative ketogenic diet provided higher levels of seizure-blocking amino acids than the standard rodent (control) diet.

[0034] Figure 21 This shows the serum amino acid levels associated with seizure blocking in different experimental groups after 21 days of dietary exposure. On day 21 of dietary exposure, the alternative ketogenic diet provided higher levels of seizure-blocking amino acids than the standard rodent (control) diet.

[0035] Figure 22 This shows the serum amino acid levels associated with seizure blocking in different experimental groups after 5 days of dietary exposure. On day 5 of dietary exposure, the alternative ketogenic diet provided higher levels of seizure-blocking amino acids than the standard rodent (control) diet.

[0036] Figure 23 This shows the serum amino acid levels associated with seizure blocking in different experimental groups after 21 days of dietary exposure. On day 21 of dietary exposure, the alternative ketogenic diet provided higher levels of seizure-blocking amino acids than the standard rodent (control) diet.

[0037] Figure 24 The results showed that at 0.8 mM Mg 2+Compared to unstimulated glial cell cultures maintained at 0.1 mg / mL, the results showed improvement with 0.1 mg / mL culture. 2+ The effects of stimulating glial cell cultures on oscillation frequency, amplitude, and area under the curve, as well as on glycolysis and mitochondrial respiration.

[0038] Figure 25 The effects of the lipid blends according to the invention (INV-KD lipid blend) and a comparative lipid blend with a moderate amount of MCT (COMP-KD lipid blend) on mitochondrial respiration in hyperexcited (seizure-like) glial cell cultures are shown. Effects on glycolysis, ATP production, and proton leakage values ​​measured after exposure to each lipid blend are also reported.

[0039] Example List 1. An enteric ketogenic composition comprising (i) a lipid moiety comprising 45 to 65 g of lipids, (ii) a carbohydrate moiety comprising 5 to 12 g of digestible carbohydrates, and (iii) a protein moiety comprising 15-25 g of protein per 100 g of the ketogenic composition. The lipid portion includes -5-50% by weight of medium-chain triglyceride fatty acids [MCFA] based on the total weight of fatty acids in the lipid fraction, wherein more than 60% by weight of the MCFA are C8:0, C10:0 and C12:0 fatty acids, and wherein at least 70% by weight of the MCFA are provided in the form of medium-chain triglycerides [MCT]. -Based on 50-95% by weight of the total fatty acids in the lipid fraction, even-chain long-chain fatty acids [LCFA] and very long-chain fatty acids [VLCFA] with carbon lengths of 14 to 24, and wherein these LCFAs and VLCFAs contain at least one ω-3 polyunsaturated fatty acid [LC-PUFA] selected from the group consisting of: docosahexaenoic acid (22:6, ω-3; DHA), eicosapentaenoic acid (20:5, ω-3; EPA), and docosapentaenoic acid (22:5, ω-3; DPA). The carbohydrate portion comprises 30 to 80% by weight of low glycemic index carbohydrates based on the total weight of digestible carbohydrates, and The protein moiety contains 5-15% by weight of free amino acids based on the total weight of the protein moiety. Furthermore, the ketogenic weight ratio of the ketogenic composition is between 1.5:1 and 3.0:1.

[0040] 2. The enteric ketogenic composition according to Example 1, wherein the composition further comprises 7-15% by weight of dietary fiber, and wherein such fiber is selected from fructooligosaccharides, inulin, resistant starch, cellulose, wheat bran, gum arabic, soybean polysaccharides such as Fuji soybean, oat fiber, galactooligosaccharides, locust bean gum, guar gum, pectin and hydrolyzed pectin.

[0041] 3. The enteric ketogenic composition according to Example 2, wherein the fibers are a fiber mixture comprising cellulose, inulin, galactooligosaccharides, Fuji soybean and resistant starch.

[0042] 4. The enteric ketogenic composition according to the foregoing embodiments, wherein the low glycemic index carbohydrates are selected from trehalose, lactose, galactose and isomaltulose.

[0043] 5. The enteric ketogenic composition according to the foregoing embodiments, wherein the protein portion comprises whole and / or (partially) hydrolyzed proteins selected from: pea, soybean, casein and / or whey, preferably casein.

[0044] 6. The enteric ketogenic composition according to the foregoing embodiments, wherein the protein portion comprises 75-95% by weight of casein based on the total weight of the protein portion.

[0045] 7. The enteric ketogenic composition according to the foregoing embodiments, wherein the protein portion comprises free amino acids selected from the group consisting of: serine, lysine, glycine, valine, cysteine, leucine, and isoleucine, preferably leucine, isoleucine, and / or cysteine.

[0046] 8. The enteric ketogenic composition according to the foregoing embodiments, wherein the protein portion comprises 5-15% by weight of free leucine and 0.5-2.5% by weight of free cysteine ​​based on the total weight of the protein portion.

[0047] 9. The enteric ketogenic composition according to the foregoing embodiments, wherein the ω-3 / ω-6 weight ratio of these lipids is between 0.2:1 and 5:1.

[0048] 10. The enteric ketogenic composition according to the foregoing embodiments, wherein the composition comprises monounsaturated fatty acids [MUFA], and wherein at least 85% by weight of these MUFAs based on the total weight of the MUFAs in the lipid portion are oleic acid.

[0049] 11. The enteric ketogenic composition according to the foregoing embodiments, further comprising citrate and / or nicotinamide nucleoside and / or nicotinamide and / or pyruvate.

[0050] 12. The enteric ketogenic composition according to the foregoing embodiments, wherein the composition comprises less than 20% by weight of palmitic acid based on the total weight of the ketogenic composition.

[0051] 13. The enteric ketogenic composition according to the foregoing embodiments, for use in the treatment and / or prevention of epilepsy in subjects suffering from epilepsy or at risk of epileptic seizures, preferably epileptiform seizures.

[0052] 14. The enteric ketogenic composition according to Example 13 for use in the treatment and / or prevention of epilepsy, wherein the treatment and / or prevention of epilepsy includes treating and / or preventing and / or reducing the severity of epilepsy and preventing and / or delaying the formation of epileptiform circuits in the brain.

[0053] 15. The enteric ketogenic composition for use in the treatment and / or prevention of epilepsy according to any one of Examples 13 and 14, which further prevents the development of dyslipidemia, fatty liver and / or metabolic syndrome in subjects suffering from epilepsy or at risk of seizures, preferably epileptiform seizures.

[0054] 16. The enteric ketogenic composition according to any one of Examples 13 to 15, wherein the treatment and / or prevention of epilepsy and / or epilepsy progression in subjects with epilepsy or at risk of seizures further comprises reducing and / or preventing ADHD-related behavioral patterns. Detailed Implementation

[0055] In a first aspect, the present invention relates to an enteric ketogenic composition comprising (i) a lipid portion comprising 45 to 65 g of lipids, (ii) a carbohydrate portion comprising 5 to 12 g of digestible carbohydrates, and (iii) a protein portion comprising 15-25 g of protein per 100 g of the ketogenic composition (based on weight). The lipid portion of the ketogenic composition includes -5-50% by weight of medium-chain fatty acids [MCFA] based on the total weight of fatty acids in the lipid fraction, wherein more than 60% by weight of the MCFA are C8:0, C10:0 and C12:0 fatty acids, and wherein at least 70% by weight of the MCFA is provided in the form of medium-chain triglycerides [MCT]. -Based on 50-95% by weight of the total fatty acids in this lipid fraction, even-chain long-chain fatty acids [LCFA] and very long-chain fatty acids [VLCFA] with carbon lengths of 14 to 24, wherein the even-chain LCFA and VLCFA contain at least one ω-3 polyunsaturated fatty acid [LC-PUFA] selected from the group consisting of: docosahexaenoic acid (22:6, ω-3; DHA), eicosapentaenoic acid (20:5, ω-3; EPA) and docosapentaenoic acid (22:5, ω-3; DPA). The carbohydrate portion comprises 30 to 80% by weight of low glycemic index carbohydrates based on the total weight of digestible carbohydrates, and The protein moiety contains 5-15% by weight of free amino acids based on the total weight of the protein moiety, and The ketogenic composition has a ketogenic weight ratio between 1.5:1 and 3.0:1, preferably between 1.8:1 and 2.7:1.

[0056] The inventors unexpectedly discovered that enteric (preferably oral) administration of the ketogenic composition according to the invention effectively treats epilepsy. The inventors also unexpectedly discovered that, compared to results obtained with a classic ketogenic diet at a 6:1 ketogenic weight ratio, the new ketogenic diet exhibits stronger therapeutic efficacy despite having a smaller ketogenic weight ratio. In particular, the ketogenic diet according to the invention has been found to be effective in treating epilepsy, showing a delayed progression of seizure severity, reduced seizure severity, and increased latency to elicit a first behavioral response (increased number of electrical stimulations) in an in vivo rapid rat ignition model (acute epilepsy model). In addition to the beneficial effects on epilepsy, a metabolic plasma profile was found to be more similar to that observed when consuming a control diet rather than a classic ketogenic diet. Specifically, plasma triglyceride and glucose levels, as well as liver lipids, were reduced in animals fed the ketogenic composition according to the invention compared to animals fed a classic ketogenic diet.

[0057] The inventors have observed that the enteric ketogenic compositions according to the invention are beneficial for therapeutic use in treating epilepsy and / or preventing the progression of epilepsy. The inventors have found that the ketogenic compositions according to the invention are beneficial for therapeutic use in treating and / or preventing and / or reducing the severity of epilepsy and in preventing and / or delaying the formation of epileptiform circuits in the brain. In addition to their beneficial therapeutic use in epilepsy, the inventors have also observed that the enteric ketogenic compositions are beneficial for preventing abnormally high blood triglyceride levels and / or dyslipidemia, fatty liver development, and / or metabolic syndrome development in subjects following the enteric ketogenic composition.

[0058] In other words, the present invention also relates to the use of the enteric ketogenic composition according to the invention for treating epilepsy and / or preventing the progression of epilepsy in subjects with epilepsy or at risk of seizures. The present invention further relates to the use of the enteric ketogenic composition for preventing the development of dyslipidemia, fatty liver, and / or metabolic syndrome in subjects with epilepsy or at risk of seizures.

[0059] In other words, the present invention relates to an enteric ketogenic composition comprising (i) a lipid portion comprising 45 to 65 g of lipids, (ii) a carbohydrate portion comprising 5 to 12 g of digestible carbohydrates, and (iii) a protein portion comprising 15-25 g of protein per 100 g of ketogenic composition (by weight). The lipid portion of the ketogenic composition includes -5-50% by weight of medium-chain fatty acids [MCFA] based on the total weight of fatty acids in the lipid fraction, wherein more than 60% by weight of the MCFA are C8:0, C10:0 and C12:0 fatty acids, and wherein at least 70% by weight of the MCFA is provided in the form of medium-chain triglycerides [MCT]. -Based on 50-95% by weight of the total fatty acids in this lipid fraction, even-chain long-chain fatty acids [LCFA] and very long-chain fatty acids [VLCFA] with carbon lengths of 14 to 24, wherein the even-chain LCFA and VLCFA contain at least one ω-3 polyunsaturated fatty acid [LC-PUFA] selected from the group consisting of: docosahexaenoic acid (22:6, ω-3; DHA), eicosapentaenoic acid (20:5, ω-3; EPA) and docosapentaenoic acid (22:5, ω-3; DPA). The carbohydrate portion comprises 30 to 80% by weight of low glycemic index carbohydrates based on the total weight of digestible carbohydrates, and This protein portion contains 5-15% by weight of free amino acids, and The ketogenic composition has a ketogenic weight ratio between 1.5:1 and 3.0:1, preferably between 1.8:1 and 2.7:1. This enteric ketogenic composition is used to treat and / or prevent epilepsy, treat and / or prevent the progression of epilepsy, and / or prevent the development of dyslipidemia, fatty liver and / or metabolic syndrome in subjects with epilepsy or at risk of epileptic seizures (preferably epileptiform seizures).

[0060] The present invention also relates to a method for treating and / or preventing epilepsy and / or epilepsy progression in a subject suffering from epilepsy or at risk of seizures, the method comprising administering an enteric ketogenic composition to the subject. Furthermore, the method for treatment and / or prevention relates to preventing the development of dyslipidemia, fatty liver, and / or metabolic syndrome in a subject suffering from epilepsy or at risk of seizures.

[0061] In particular, the present invention provides methods of use and applications of an enteric ketogenic composition for treating and / or preventing epilepsy, treating and / or preventing the progression of epilepsy, and / or preventing the development of dyslipidemia, fatty liver and / or metabolic syndrome in subjects suffering from epilepsy or at risk of seizures (preferably epileptiform seizures).

[0062] According to one embodiment, the present invention also relates to a method for treating epilepsy in a subject, the method comprising administering to the subject an enteroketogenic composition according to the present invention.

[0063] The present invention can also be described as the use of an enteric ketogenic composition for the manufacture of a product for the treatment and / or prevention of epilepsy, the treatment and / or prevention of the progression of epilepsy, and / or prevention of the development of dyslipidemia, fatty liver and / or metabolic syndrome in subjects with epilepsy or at risk of seizures, the enteric ketogenic composition comprising (i) a lipid portion comprising 45 to 65 g of lipids, (ii) a carbohydrate portion comprising 5 to 12 g of digestible carbohydrates, and (iii) a protein portion comprising 15-25 g of protein per 100 g of the ketogenic composition (based on weight). The lipid portion of the ketogenic composition includes -5-50% by weight of medium-chain fatty acids [MCFA] based on the total weight of fatty acids in the lipid fraction, wherein more than 60% by weight of the MCFA are C8:0, C10:0 and C12:0 fatty acids, and wherein at least 70% by weight of the MCFA is provided in the form of medium-chain triglycerides [MCT]. -Based on 50-95% by weight of the total fatty acids in this lipid fraction, even-chain long-chain fatty acids [LCFA] and very long-chain fatty acids [VLCFA] with carbon lengths of 14 to 24, wherein the even-chain LCFA and VLCFA contain at least one ω-3 polyunsaturated fatty acid [LC-PUFA] selected from the group consisting of: docosahexaenoic acid (22:6, ω-3; DHA), eicosapentaenoic acid (20:5, ω-3; EPA) and docosapentaenoic acid (22:5, ω-3; DPA). The carbohydrate portion comprises 30 to 80% by weight of low glycemic index carbohydrates based on the total weight of digestible carbohydrates, and This protein portion contains 5-15% by weight of free amino acids, and The ketogenic composition has a ketogenic weight ratio between 1.5:1 and 3.0:1, preferably between 1.8:1 and 2.7:1. In a particular aspect, the epileptic seizure is an epileptiform seizure.

[0064] In another embodiment of the invention, the methods, products, uses, or compositions of the invention provide for the generation of ketone bodies (particularly acetoacetate, β-hydroxybutyrate, and acetone) wherein plasma levels of the ketone bodies are sufficient to provide a therapeutic effect on subjects suffering from epilepsy or at risk of seizures (preferably epileptiform seizures).

[0065] definition Throughout this application, the following terms and abbreviations are used: Fiber is an indigestible carbohydrate. Indigestible carbohydrates are those that cannot be digested and absorbed in the human stomach and small intestine and pass intact into the colon. Therefore, compounds like lactose, maltose, glucose, (conventionally unmodified) maltodextrin, and (conventionally unmodified) starch are considered digestible. Fiber may or may not ferment in the colon. The term "fermentable" refers to the ability to be broken down into smaller molecules, particularly short-chain fatty acids and lactic acid, by microorganisms (anaerobic processes) in the lower gastrointestinal tract (e.g., the colon). Fermentability can be determined by the method described in Am. J. Clin. Nutr. [American Journal of Clinical Nutrition] 53, 1418-1424 (1991).

[0066] A classic ketogenic diet contains a certain amount of lipids (by weight), which typically weighs four times the total weight of protein and digestible carbohydrates. In the context of this invention, the so-called ketogenic (by weight) ratio is the weight ratio of lipids to the combined (total) weight of protein and digestible carbohydrates in the composition.

[0067] In the context of this invention, the term "ketogenic (weight) ratio" refers to the weight ratio of the total amount of lipids in the composition to the combined weight of protein (including added free amino acids) and digestible carbohydrates. A ketogenic diet as described in the context of this invention is characterized by a ketogenic weight ratio (i.e., the ratio of the amount of fat to the combined amount of protein (including added free amino acids) and digestible carbohydrates) between 1.5:1 and 3:1, preferably between 1.8:1 and 2.4:1. Within the aforementioned range of ketogenic ratios of this invention, a ketogenic diet used in the context of this invention preferably contains at least 1.5 times, and preferably at least twice, the weight of carbohydrates, of lipids.

[0068] As used in this article, the term "ketosis" refers to a serum ketone level above 0.5 mmol / L. Ketone levels maintained above 0.5 mmol / L, ideally within the range of 1 to 3 mmol / L, have a therapeutic effect in humans [Anderson JC et al., Obes Sci Pract. [Obesity Science and Practice] 2021; 7(5):646-656]. Serum ketone levels above 10 mmol / L are associated with signs of ketoacidosis. While ketosis refers to a state of elevated ketones, ketoacidosis is a pathological and potentially life-threatening condition, particularly one that causes a decrease in blood pH and can induce coma.

[0069] As used herein, the term "seizure" refers to a period of time characterized by symptoms caused by abnormally excessive or synchronized neuronal activity in the brain. Seizures typically occur when the brain's electrical activity becomes more "synchronized," as is the case when a person is drowsy. The most common and typical type of seizure is a convulsion (60%). A convulsion is a medical condition in which the body's muscles rapidly and repeatedly contract and relax, resulting in uncontrollable shaking. Epileptic seizures can include convulsions. Epilepsy is a clinical diagnosis characterized by recurrent epileptic seizures, which are the outward manifestation of excessive and / or hypersynchronous abnormal electrical activity of neurons in the brain.

[0070] As used in this article, the term dyslipidemia refers to an imbalance of lipids in the blood (including cholesterol, low-density lipoprotein, triglycerides, and high-density lipoprotein), which constitutes a risk factor for atherosclerotic cardiovascular disease.

[0071] As used in this article, abnormally elevated triglyceride levels can occur in dyslipidemia and are clinically defined as a fasting blood triglyceride level >1.7 mmol / L.

[0072] The glycemic index (GI) of a food is a scale from 0 to 100, which measures the postprandial effect of a particular food on blood glucose levels. High-GI foods give higher postprandial blood glucose levels than low-GI foods. The GI of carbohydrates also predicts insulin response to that food. A score of 100 is based on pure glucose. The glycemic index can be determined by periodically analyzing blood glucose levels over a period of 2–3 hours after ingestion of a test carbohydrate or food and a reference food (which is typically a similar amount of digestible carbohydrate in the form of glucose). The area under the blood glucose curves for the test and reference foods is determined. The GI is expressed as the ratio of the area under the curve for the test food to that for the reference food multiplied by a factor of 100, or in other words, as a percentage of the GI of the reference food (FAO (1998), Carbohydrates in Nutrition, FAO Food and Nutrition Paper, 66, pp. 25–30). On a scale of 1–100, those skilled in the art generally consider food compositions scoring below 55 to be low, while scores between 59 and 56 are considered moderate.

[0073] In the context of this invention, the subjects following or adopting a ketogenic diet are mammals, preferably humans.

[0074] Glycerides are esters of glycerol and carboxylic acids. As an example, triglycerides (also called triacylglycerols) are triesters derived from glycerol and three fatty acids. Under hydrolytic conditions (such as those during digestion), triglycerides can serve as a source of fatty acids. For example, tributyrate esters may be a source of three moles of butyric acid per mole of tributyrate esters. Some glycerides are esters of glycerol and fatty acids in which not all hydroxyl groups are esterified; monobutyrate esters and dibutyrate esters are also sources of butyric acid according to the invention, providing one mole and two moles of butyric acid per mole, respectively.

[0075] Fatty acids can be unsaturated or saturated. Fatty acids that are not attached to other molecules are called free fatty acids (FFA).

[0076] Medium-chain triglycerides (MCTs) are triglycerides in which all three fatty acid moieties are medium-chain fatty acids. MCTs are found in a few foods, such as coconut oil and palm kernel oil.

[0077] As defined herein, medium-chain fatty acids are defined as straight-chain or branched (preferably straight-chain) saturated carboxylic acids having six (C6:0) to twelve (C12:0) carbon atoms. Medium-chain fatty acids having 10 carbon atoms may be referred to herein as "C10 fatty acids" or "C10".

[0078] The term “long-chain polyunsaturated fatty acid” or “LCPUFA” refers to a monocarboxylic acid having at least 20 carbon atoms and at least two double bonds. Examples of LCPUFA include (n-6) fatty acids (such as arachidonic acid (AA)) and (n-3) fatty acids (such as eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA), and docosahexaenoic acid (DHA)).

[0079] The term "fish oil" refers to a relatively rich, fatty or oily extract (whether crude or purified) of PUFAs obtained from marine animals, such as, but not limited to, salmon, tuna, mackerel, herring, sea bass, striped bass, halibut, catfish, and sardines, as well as sharks, shrimp, and clams, or any combination thereof. Fish oil is often a technical term used by raw material suppliers and encompasses a range of products with varying PUFA contents and purities.

[0080] In the context of this invention, when referring to the amount of fatty acids, if different sources or derivatives are used, these weights are calculated based on the (molar weight) of the respective fatty acids.

[0081] In the context of this invention, when referring to "total weight of the ketogenic composition," this means the sum of the weights of the components that form the ketogenic composition without the addition of water, i.e., the anhydrous weight.

[0082] "Nutritional composition" means a substance or preparation that meets at least a portion of a subject's nutritional needs. Throughout this disclosure, the terms "nutrient," "nutritional formulation," "enteral nutrition," and "nutritional supplement" are used as non-limiting examples of nutritional compositions. Furthermore, "nutritional composition" can refer to enteral formulations, oral formulations, infant formulas, pediatric subject formulations, children's formulas, growing milks, and / or adult formulations in liquid, powder, gel, paste, solid, concentrate, suspension, or ready-to-use form.

[0083] The energy provided by nutrients is calculated using the following Atwater coefficients: 9 kcal / g lipids, 4 kcal / g protein or g digestible carbohydrates, 2 kcal / g dietary fiber, and 0 kcal for other components in the product.

[0084] Unless otherwise specified, all percentage ranges reported here are defined as totaling 100%.

[0085] In this document and its claims, the verb “comprising” and its variations are used in their non-limiting sense to mean including the item following the word, but not excluding items not specifically mentioned. “Constitutes substantially of” means that the composition contains the active ingredient and possible additional compounds, provided that these do not materially affect the essential characteristics of the composition. Furthermore, unless the context clearly requires the presence of one / an and only one / a component, reference to an element by the indefinite article “a / an (a or an)” does not exclude the possibility of more than one / an element. Therefore, the indefinite article “a / an” (“a” or “an”) generally means “at least one / an”. When % is mentioned herein, it means % by weight, unless otherwise stated.

[0086] Components of an enteric ketogenic composition The present invention relates to an enteric ketogenic composition comprising (i) a lipid moiety, (ii) a carbohydrate moiety, and (iii) a protein moiety.

[0087] The enteric ketogenic composition comprises (i) a lipid portion containing 45 to 65 g of lipids, (ii) a carbohydrate portion containing 5 to 12 g of digestible carbohydrates, and (iii) a protein portion containing 15-25 g of protein per 100 g of the ketogenic composition (by weight), wherein the ketogenic weight ratio of the ketogenic composition is between 1.5:1 and 3.0:1, preferably between 1.8:1 and 2.7:1. In aspects of the invention, the ketogenic weight ratio of the ketogenic composition is less than 2:1. The ketogenic composition is preferably an enteric nutrition composition. Preferably, the composition is administered orally or as a tube feed. The ketogenic composition can be formulated as a complete nutrition and can potentially be used as the sole source of nutrition. The ketogenic composition is applied in liquid form and can also be provided in solid form to dissolve in water before ingestion. Preferably, the ketogenic composition is in liquid form. In one embodiment, the enteric ketogenic composition of the present invention is a liquid. In one embodiment, preferably, the ketogenic composition of the present invention is a liquid-on-feed composition. In a preferred embodiment, the composition is used as the sole nutrient. In another embodiment, the ketogenic composition provides 20% to 60% of the daily energy intake, more preferably 30% to 50%. As used herein, weights are based on the total anhydrous weight of the intestinal ketogenic composition, or alternatively referred to as dry weight.

[0088] The preferred daily dose range for the ketogenic composition is 500 to 4500 kcal per day, more preferably 500 to 4000 kcal. The daily dose may be provided as a single dose, but is preferably provided as multiple daily doses. In one embodiment, the ketogenic composition is a liquid composition containing 0.8 to 4 kcal per ml.

[0089] In the embodiments, the ketogenic composition is administered at least daily; for example, a subject may receive one or more doses daily, preferably 1 to 6 times daily, more preferably 3 to 4 times daily. In some embodiments, this administration continues for the remainder of the individual's life. Those skilled in the art can determine the ideal duration of administration of the ketogenic composition.

[0090] lipid portion The ketogenic composition according to the invention comprises (i) a lipid moiety.

[0091] The total amount of lipids present in a ketogenic composition (i.e., the combination of all lipids and phospholipids present) is referred to as the "lipid fraction" of the ketogenic composition. Suitable lipid sources for providing the lipid fraction of the ketogenic composition according to the invention are food-grade ingredients, such as lipids derived from eggs, milk, vegetables or plant materials, marine organisms (such as fish or algae), natural or mutant organisms, or lipids prepared by modifying natural lipids, processed lipids from these sources (such as extracts, isolates, cross-esterified lipids, etc.), synthetic compounds, or combinations thereof. Throughout this application, unless otherwise specified, as e.g., when referring to MCT, the amount of lipids is described as the molar weight of fatty acids (FAs) present in the composition and corrected for the weight of glycerol in the oil blend.

[0092] The lipid moiety of the ketogenic composition contains medium-chain, long-chain, and very long-chain saturated fatty acids, as well as a mixture of long-chain and very long-chain monounsaturated and polyunsaturated fatty acids. The fatty acids may exist in the ketogenic composition in free form, or may be combined with or uncombined with glycerol as monoacylglycerol, diacylglycerol, or triacylglycerol, and may be bound to any of the sn-1, sn-2, or sn-3 positions of glycerol.

[0093] Suitable sources of lipids for use in ketogenic compositions include, but are not limited to, fish oil, krill oil, algae oil, soybean oil, rapeseed oil (such as canola oil, low-erucic acid rapeseed oil, and canola oil), high-oleic sunflower oil, coconut oil, palm oil, MCT oil, high-oleic safflower oil, olive oil, poultry-derived oils, and egg-derived oils. Alternative options include lipids derived from the milk of non-human mammals, preferably cow's milk, goat's milk, sheep's milk, horse's milk, buffalo milk, yak milk, reindeer milk, donkey milk, and camel milk, particularly cow's milk and / or goat's milk. Milk lipids are sometimes also referred to as milk fat or cream fat. In preferred embodiments, the lipid portion of the ketogenic composition comprises coconut oil, fish oil, palm oil, rapeseed oil, and / or MCT oil.

[0094] In one embodiment, the lipid portion preferably provides up to 70% of the total calories of the ketogenic composition, more preferably up to 72.5%, and even more preferably up to 75%. In one embodiment, the lipid portion preferably provides 65% to 85% of the calories, more preferably 70% to 82.5%, and even more preferably 75% to 80%. The remaining calories of the ketogenic composition are provided by carbohydrates and protein.

[0095] The ketogenic composition according to the invention comprises a lipid portion, preferably a lipid portion suitable for nutritional use as known in the art. The ketogenic composition preferably comprises 45 to 65 g lipids / 100 g, more preferably 50-60 g lipids / 100 g, and even more preferably 54-56 g / 100 g weight. In other words, the ketogenic composition preferably comprises 45 to 65% by weight of lipids, more preferably 50-60% by weight, and even more preferably 54-56% by weight of lipids.

[0096] Based on calories, preferably, the ketogenic composition may contain 7 to 10 g lipids / 100 kcal, more preferably 7.5 to 9.5 g / 100 kcal, and even more preferably 8 to 9 g lipids / 100 kcal, based on the total energy content of the ketogenic composition.

[0097] The amount of lipid fractions can be determined by applying methods known in the art for measuring fat content in food matrices (where applicable). For example, the fat content of general foods is determined by applying AOACI Official Method 983.23, while the Roese-Gottlieb method (AOACI 932.06) is more suitable for products based on dried milk (Lehner, R., Estoppey, A., (1954) Mitt. Lebensmitteluntersuchung Hyg. [Food Inspection and Sanitation Bulletin] 54:183-185). The amount of individual lipid fractions can be determined by applying methods specifically designed for measuring particular fractions or by fractionation of the fat fraction separated from the chloroform-methanol fraction as given in Method 983.23. In addition, the structural composition of lipids (such as binding at the sn-1, sn-2 or sn-3 positions to form monoacylglycerols, diacylglycerols or triacylglycerols) can be determined and quantified using liquid chromatography, mass spectrometry (also known as lipidomics) and other methods known in the art (Beermann C et al., Lipids, 2005; 40(2): 211-8).

[0098] MCT The ketogenic compositions according to the invention comprise saturated medium-chain fatty acids [MCFA]. Preferably, at least 70% by weight, more preferably at least 80% by weight, and even more preferably at least 90% by weight of the MCFA are provided in the form of medium-chain triglycerides [MCT]. In some embodiments, it is preferred that substantially all of the MCFA are provided in the form of MCT. MCT is a type of fat found in a few foods, such as coconut oil and palm kernel oil. MCT can also be supplied from commercially available MCT oil. MCFA is defined as a straight-chain or branched (preferably straight-chain) saturated carboxylic acid having six to twelve carbon atoms. MCFA exists in the form of MCT when it is bound to the glycerol backbone at the sn-1 to sn-3 positions of glycerol. Within the scope of this application, MCT also includes glycerides, wherein at least one FA is an MCFA, preferably at least two, and most preferably three FAs are MCFAs. The presence of MCT in the ketogenic compositions is highly advantageous because they effectively promote the rapid induction of ketosis, i.e., the condition of rapidly producing ketones by the liver and secreting them into the bloodstream to induce ketosis. In addition, MCT is particularly beneficial to neurons to suppress epileptic seizures, and it also induces glial cells (astrocytes) to locally produce ketones and supply them to neurons in the brain.

[0099] Upon hydrolysis, these oils provide concentrated sources of MCFA with chain lengths of 6 (hexanoic acid), 8 (caprylic acid or caprylic acid), 10 (capric acid or decanoic acid), and 12 (lauric acid or dodecanoic acid) carbon atoms. Therefore, the MCFA according to the invention is preferably provided by or selected from MCTs derived from coconut oil and / or palm kernel oil. The MCFA according to the invention has a chain length of 6, 7, 8, 9, 10, 11, or 12 carbon atoms, preferably 6, 8, 10, and / or 12 carbon atoms. The amounts of MCFA provided herein are based on the molar weight of the MCFA present in the composition and corrected for the weight of glycerol.

[0100] In the embodiments, the ketogenic composition preferably comprises 10-20 g MCFA / 100 g composition based on the total weight of the ketogenic composition, more preferably 12-18 g, and even more preferably 13-16 g / 100 g composition. In other words, the ketogenic composition preferably comprises 10-20% by weight, more preferably 12-18% by weight, and even more preferably 13-16% by weight of MCFA based on the total weight of the ketogenic composition.

[0101] In the embodiments, the MCFA preferably provides 10%-30% of the total energy content of the ketogenic composition, preferably 15%-25%, and more preferably 17%-20%.

[0102] In the embodiments, the amount of MCFA in the lipid fraction is about 5-50 g / 100 g fatty acids, preferably 10-45 g / 100 g fatty acids, more preferably 15-40 g / 100 g fatty acids, more preferably 20-35 g / 100 g fatty acids, and even more preferably 25-30 g / 100 g fatty acids. Alternatively, in the embodiments, the lipid fraction preferably contains 5-50% by weight, preferably 10-45% by weight, preferably 15-40% by weight, more preferably 20-35% by weight, and even more preferably 25-30% by weight of MCFA based on the total weight of fatty acids in the ketogenic composition. In a preferred embodiment, the ketogenic composition contains 4-12 mol% MCFA based on the total amount of fatty acids in the ketogenic composition, preferably 5-10 mol% MCFA, and more preferably 6-9 mol%.

[0103] When calculated as MCT, in the embodiments, the MCT preferably provides 10%-35% of the total energy content of the ketogenic composition, preferably 15%-30%, more preferably 20%-25%. In another embodiment, the lipid portion of the ketogenic composition preferably contains 15-45% by weight of MCT based on the total weight of the lipid portion, more preferably 20-40% by weight, and even more preferably 25-35% by weight of MCT. The ketogenic composition preferably contains 10-20% by weight of MCT based on the total weight of the ketogenic composition, more preferably 12-18% by weight of MCT, and even more preferably 13-17% by weight of MCT.

[0104] The MCT portion of the ketogenic composition is advantageously rich in C8, C10, and C12 fatty acids. It is believed that providing an MCT blend rich in C8:0, C10:0, and C12:0 fatty acids contributes to dietary ketogenicity. In examples, the MCT portion is rich in C8:0, C10:0, and C12:0 fatty acids, wherein “rich” is defined as more than 60% by weight of the FAs together forming the MCT portion, preferably more than 70% by weight of the MCT portion, and even more preferably more than 80% by weight of the MCT portion. In some aspects, up to 100% by weight of the FAs in the MCT portion are C8:0, C10:0, and C12:0 fatty acids.

[0105] In one embodiment, the weight ratio of the total weight of medium-chain fatty acids C6:0 + C8:0 to the total weight ratio of C10:0 and C12:0 in the ketogenic composition is less than 1:1, preferably less than 0.8:1, more preferably less than 0.6:1, and even more preferably less than 0.3:1. In another embodiment, the weight ratio of C12:0 to the total weight ratio of medium-chain fatty acids C6:0 + C8:0 + C10:0 is greater than 1.5:1, preferably greater than 2:1, more preferably greater than 2.3:1, and even more preferably greater than 2.5:1.

[0106] In the embodiments, the ketogenic composition preferably contains 8-12 g of lauric acid or dodecanoic acid (C12:0), more preferably 8.5-11 g of lauric acid, and even more preferably 9-10 g of lauric acid per 100 g of the ketogenic composition. In another embodiment, the ketogenic composition preferably contains 0.5-2.5 g of caprylic acid (C10:0), more preferably 1-2 g of caprylic acid, and even more preferably 1.2-1.8 g of caprylic acid per 100 g of the ketogenic composition. The ketogenic composition further preferably contains 0.5-3 g of caprylic acid (C8:0), more preferably 1-2.5 g of caprylic acid, and even more preferably 1.5-2 g of caprylic acid per 100 g of the ketogenic composition.

[0107] Long-chain and very long-chain fatty acids The ketogenic composition comprises long-chain fatty acids (LCFAs) and very long-chain fatty acids (VLCFAs), wherein the long-chain fatty acids are even-chain fatty acids with a carbon length of 14 to 18, and wherein the very long-chain fatty acids are even-chain fatty acids with a carbon length of 20 or longer. LCFAs with a carbon chain length of 14 to 18 and VLCFAs with a carbon length of 20 or longer comprise both saturated and unsaturated fatty acids. LCFAs and VLCFAs can be provided in any form, such as, but not limited to, triglycerides, diglycerides, monoglycerides, free fatty acids or their salts or esters, phospholipids, lysophospholipids, glyceryl ethers, lipoproteins, ceramides, glycolipids, or combinations thereof. Preferably, the ketogenic composition comprises fatty acids in the form of triglycerides. Suitable sources of LCFAs and VLCFAs are, but not limited to, palm oil and rapeseed oil. The amounts of LCFAs and VLCFAs provided are based on the molar weight of the LCFAs present in the ketogenic composition and corrected for the weight of glycerol.

[0108] In embodiments of the invention, the amount of even-chain LCFAs with a carbon length of 14 to 18 and VLCFAs with a carbon length of 20 or longer is preferably less than 95 g / 100 g of fatty acids, more preferably less than 85 g / 100 g of fatty acids, preferably 50-95 g / 100 g of fatty acids, more preferably 50-85 g / 100 g of fatty acids, more preferably 55 to 80 g / 100 g of fatty acids, and most preferably 60-75 g / 100 g of fatty acids. Alternatively, in embodiments, the lipid portion preferably comprises 50-95% by weight of LCFAs and VLCFAs, 50-85% by weight of LCFAs and VLCFAs, more preferably 55-80% by weight, and even more preferably 60-75% by weight, based on the total weight of fatty acids in the ketogenic composition.

[0109] In the embodiments, the ketogenic composition preferably comprises 25-55 g of LCFA and VLCFA per 100 g of composition based on the total weight of the ketogenic composition, more preferably 25-50 g of LCFA and VLCFA per 100 g of composition, more preferably 30-45 g, and even more preferably 35-40 g per 100 g of composition. In other words, in the embodiments, the ketogenic composition preferably comprises 25-50% by weight, more preferably 30-45% by weight, and even more preferably 35-40% by weight of LCFA and VLCFA based on the total weight of the ketogenic composition. In the embodiments, the LCFA and VLCFA preferably provide 40%-70% of the total energy content of the ketogenic composition, more preferably 45%-65%, and more preferably 50%-60%. In yet another embodiment, the LCFA preferably provides 50%-80% of the total energy content of lipids in the ketogenic composition, more preferably 55%-75%, and more preferably 60%-70%.

[0110] In embodiments of the present invention, the amount of palmitic acid (C16:0) is less than 40 g / 100 g of fatty acids, preferably 10-40 g / 100 g of fatty acids, more preferably 15-35 g / 100 g of fatty acids, and most preferably 20-30 g / 100 g of fatty acids. In other words, in embodiments, the lipid portion preferably contains 10-40% by weight, more preferably 15-35% by weight, and even more preferably 20-30% by weight of palmitic acid.

[0111] In the embodiments, the ketogenic composition preferably contains less than 20 g of palmitic acid, more preferably less than 16 g, and even more preferably less than 14 g / 100 g of the ketogenic composition. In other words, in the embodiments, the ketogenic composition preferably contains less than 20% by weight, more preferably less than 16% by weight, and even more preferably less than 14% by weight of palmitic acid based on the total weight of the ketogenic composition.

[0112] In a preferred embodiment, the LCFA and VLCFA portions preferably contain less than 45% by weight, more preferably less than 40% by weight, and even more preferably less than 35% by weight of palmitic acid (C16:0) based on the total weight of LCFA and VLCFA.

[0113] Unbound by theory, it is believed that myristic acid (C14:0) and palmitic acid (C16:0) can reduce hepatic LDL receptor expression, thereby promoting the formation of atherogenic oxLDL, while stearic acid (C18:0) is associated with lower plasma LDL levels. The ketogenic compositions of the present invention have a beneficially higher ratio of stearic acid to the sum of [palmitic acid and myristic acid], so that despite their high fat content, the ketogenic compositions provide a more beneficial cardiovascular risk profile.

[0114] In one embodiment, the ketogenic composition preferably has a stearic acid to (palmitic acid and myristic acid) weight ratio greater than 1:12, more preferably greater than 1:10, and even more preferably greater than 1:9. In the embodiment, the ketogenic composition preferably comprises MCT, LCT, and VLCT, wherein the weight ratio of MCT to the sum of LCT and VLCT is between 1:2 and 1:5, preferably between 1:2.5 and 1:3, more preferably between 1:2.6 and 1:2.9, and even more preferably between 1:2.7 and 1:2.8.

[0115] Unsaturated fatty acids: MUFA In embodiments of the invention, the ketogenic composition comprises a monounsaturated fatty acid [MUFA]. In preferred embodiments, the MUFA is at least one of palmitic acid (C16:1 ω7), isoleic acid (C18:1 ω7), oleic acid (C18:1 ω9), eicosenoic acid (C20:1 ω9), erucic acid (C22:1 ω9), and nervonic acid (C24:1 ω9), preferably at least oleic acid. Suitable sources of MUFA include, but are not limited to, tea seed oil, olive oil, canola oil, palm oil, and rapeseed oil. It is believed that MUFAs used in ketogenic compositions not only serve as substrates for ketone body production but also provide beneficial effects on glycemic control.

[0116] In the embodiments, the total amount of monounsaturated fatty acids (MUFA) is 15 to 40 g / 100 g, more preferably 20 to 35 g / 100 g, and even more preferably 25 to 30 g / 100 g of fatty acids. In other words, in the embodiments, the lipid portion preferably contains 15-40% by weight, more preferably 20-35% by weight, and even more preferably 25-30% by weight of MUFA based on the total weight of fatty acids in the lipid portion.

[0117] In yet another preferred embodiment, the total amount of MUFA is 5 to 25 g / 100 g, more preferably 10 to 20 g / 100 g, and even more preferably 12 to 16 g / 100 g of the ketogenic composition. In other words, in the embodiments, the ketogenic composition preferably contains 5-25% by weight, more preferably 10-20% by weight, and even more preferably 12-16% by weight of MUFA based on the total weight of the ketogenic composition.

[0118] In the embodiments, MUFA preferably provides 10%-30% of the total energy content of the ketogenic composition, preferably 15%-25%, and more preferably 18%-22%.

[0119] In a preferred embodiment, the ketogenic composition contains at least 8 g of oleic acid per 100 g of composition, more preferably at least 10 g, and even more preferably at least 13 g per 100 g of composition. In other words, in the embodiments, the ketogenic composition preferably contains at least 8% by weight, more preferably at least 10% by weight, and even more preferably at least 13% by weight of oleic acid.

[0120] In the embodiments, based on the total weight of MUFA in the lipid fraction, at least 85% by weight, more preferably at least 90% by weight, and even more preferably at least 95% by weight of MUFA is provided by oleic acid.

[0121] Unsaturated fatty acids: n-3 and n-6 ​​PUFA The ketogenic composition further comprises ω-3 and / or ω-6 polyunsaturated fatty acids (PUFAs), preferably n-3 LC-PUFAs (chain length of 18 carbon atoms) and n-3 VLC-PUFAs (chain length of 20 or more carbon atoms). Providing n-3 VLC-PUFAs beneficially supports neuronal recovery after a seizure and helps reduce neuroinflammation and seizure progression.

[0122] In one embodiment, the ω-3 / ω-6 weight ratio in the ketogenic composition of the present invention preferably ranges from 0.2:1 to 5:1, more preferably from 0.3:1 to 4:1, and even more preferably from 0.5:1 to 3:1. The amount of ω-6 LCPUFA in the ketogenic composition is preferably less than 20% by weight, more preferably less than 15% by weight, and even more preferably less than 10% by weight of the total fatty acids in the ketogenic composition. In other words, the amount of ω-6 LCPUFA in the ketogenic composition is preferably 0-20% by weight, more preferably 0-15% by weight, and even more preferably 0-10% by weight of the total fatty acids in the ketogenic composition.

[0123] In the examples, the ketogenic composition may contain gamma-linolenic acid (C18:3 ω6). Although GLA is an n-6 fatty acid, it provides anti-inflammatory properties.

[0124] It is believed that the supply of omega-3 fatty acids and the reduction of omega-6 fatty acids help limit neuroinflammation after a seizure, thereby contributing to a reduction in epilepsy progression observed in in vivo experiments.

[0125] The ketogenic composition comprises at least one selected from the group consisting of, preferably two ω-3 VLC-PUFAs: docosahexaenoic acid (22:6, ω-3; DHA), eicosapentaenoic acid (20:5, ω-3; EPA), and docosapentaenoic acid (22:5 ω-3; DPA), more preferably DHA and EPA. The weight ratio of EPA to DHA is preferably less than 1, more preferably from 1:1.1 to 1:4, and even more preferably from 1:1.3 to 1:4. In some embodiments, the weight ratio of DHA to EPA is greater than 2:1.

[0126] In the examples, the ketogenic composition may contain alpha-linolenic acid [C18:3ω3, ALA].

[0127] DHA, EPA, and / or DPA may be provided in any form, such as, but not limited to, triglycerides, diglycerides, monoglycerides, free fatty acids or their salts or esters, phospholipids, lysophospholipids, glyceryl ethers, lipoproteins, ceramides, glycolipids, or combinations thereof. Preferably, the ketogenic composition contains at least DHA in the form of triglycerides.

[0128] Suitable sources of ω-3 VLCPUFA and / or DHA and EPA include tuna oil, (other) fish oil, DHA-rich alkyl esters, algae oil, egg yolk, krill oil, or phospholipids rich in ω-3 VLCPUFA, such as phosphatidylserine-DHA. Preferably, the ketogenic composition comprises fish oil providing ω-3 VLCPUFA. Another particularly suitable source of ω-3 VLCPUFA is algae oil.

[0129] In the examples, the ketogenic composition preferably comprises 0.5-3 g VLC-PUFA (selected from DHA, EPA and DPA, most preferably DHA+EPA) / 100 g of the ketogenic composition, more preferably 1-2.5 g, and even more preferably 1.2-2 g / 100 g of the composition.

[0130] In the embodiments, VLC-PUFA (selected from DHA, EPA and DPA, most preferably DHA and EPA) preferably provides 1%-5% of the total energy content of the ketogenic composition, more preferably 1.5%-3.5%, and even more preferably 2%-3%. In another aspect, the total amount of DHA, EPA and DPA (most preferably DHA and EPA) is preferably 1.5 to 7 g / 100 g fatty acids, more preferably 2 to 6 g / 100 g fatty acids, and most preferably 3 to 5 g / 100 g fatty acids.

[0131] In embodiments of the present invention, the total amount of ω-3 LCPUFA with a carbon length of 18 and ω-3 VLCPUFA with a carbon length of 20 to 24 in the ketogenic composition is less than 15 g / 100 g of fatty acids, preferably 2-15 g / 100 g of fatty acids, more preferably 3 to 10 g / 100 g of fatty acids, and even more preferably 4 to 7 g / 100 g of fatty acids.

[0132] The LA:ALA weight ratio of the ketogenic composition preferably ranges from 2:1 to 12:1, more preferably from 4:1 to 10:1, and even more preferably from 6:1 to 8:1.

[0133] choline The ketogenic composition of the present invention preferably optionally further comprises choline. Choline may be present as is or as a choline equivalent in the form of choline salts and / or choline esters. Choline salts are preferably selected from choline chloride, choline tartrate, or choline stearate, preferably choline chloride. Choline esters are preferably selected from phosphatidylcholine and lysophosphatidylcholine, preferably phosphatidylcholine.

[0134] The ketogenic composition preferably contains less than 2000 mg, more preferably less than 1750 mg of choline equivalent (selected from choline, choline salts, and / or choline esters, calculated as choline) per 100 g of the ketogenic composition. In examples, the ketogenic composition contains 500 to 5000 mg of choline, preferably 1000 to 4500 mg, more preferably 1500 to 4000 mg of choline per 100 g of the ketogenic composition, calculated as choline.

[0135] Carbohydrate portion—digestible carbohydrates The ketogenic composition comprises a carbohydrate portion. The ketogenic composition of the present invention comprises digestible carbohydrates, preferably digestible carbohydrates with a low glycemic index. Typically, any digestible carbohydrate known in the art suitable for use in a nutritional composition can be used. Preferably, the ketogenic composition comprises a digestible carbohydrate rich in one or more of non-glucose and non-fructose monosaccharides such as mannose, galactose, xylulose, xylose, glucosamine, and sialic acid. In a preferred embodiment, the composition, combination, or product according to the present invention comprises one or more low glycemic index carbohydrates selected from trehalose, lactose, galactose, and isomaltulose. In a preferred embodiment, the composition, combination, or product according to the present invention comprises galactose and isomaltulose. Typically, such low-GI carbohydrates are carbohydrates with a GI of 55 or less. Low glycemic index carbohydrates advantageously allow carbohydrates to be included in the ketogenic composition without significantly affecting ketosis. The ketogenic composition also comprises indigestible carbohydrates or dietary fiber.

[0136] In a preferred embodiment, the carbohydrate portion of the ketogenic composition comprises about 30 to 80% by weight, more preferably 40 to 70% by weight, and even more preferably 45 to 60% by weight of low glycemic index carbohydrates.

[0137] The amount of galactose is preferably from about 8% to 30% by weight of the carbohydrate portion, more preferably from about 10% to 25% by weight of the carbohydrate portion, and in even more preferred embodiments from about 15% to 20% by weight of the carbohydrate portion. In one embodiment, the amount of isomaltulose is preferably from about 20% to 50% by weight of the carbohydrate portion, more preferably from about 25% to 45% by weight, and in even more preferred embodiments from about 30% to 40% by weight of the carbohydrate portion.

[0138] In the embodiments, the amount of high glycemic index carbohydrates (such as glucose, or rapidly digestible glucose polymers, such as, but not limited to, sucrose) is preferably less than 70% by weight of the carbohydrate portion, more preferably less than 60% by weight of the carbohydrate portion, and even more preferably less than 50% by weight of the carbohydrate portion. In a preferred aspect, the ketogenic composition is substantially free of glucose and / or rapidly digestible glucose polymers.

[0139] In one embodiment, the digestible carbohydrate portion preferably provides less than 8% of the total calories of the ketogenic composition, more preferably less than 6%, and even more preferably less than 4%. The digestible carbohydrate portion of the composition provides at least 1% of the total calories of the ketogenic composition, more preferably at least 2%.

[0140] In the embodiments, the ketogenic composition preferably comprises 5 to 12 g of digestible carbohydrates, more preferably 6 to 10 g of digestible carbohydrates, and even more preferably 7 to 9 g of digestible carbohydrates per 100 g of the ketogenic composition, wherein the digestible carbohydrates preferably comprise low-GI carbohydrates, preferably galactose and isomaltulose. In other words, the ketogenic composition therefore preferably comprises 5 to 12% by weight of digestible carbohydrates based on the total weight of the ketogenic composition, more preferably 6 to 10% by weight, and even more preferably 7 to 9% by weight of digestible carbohydrates.

[0141] In a preferred embodiment, the glycemic index (GI) of the ketogenic composition is below 70, preferably below 65, more preferably below 60, and even more preferably below 55. In a preferred aspect, the glycemic index is between 25 and 65, wherein the glycemic index is based on glucose as a reference value (set to 100).

[0142] fiber Preferably, the ketogenic composition comprises fiber, preferably food-grade dietary fiber. Dietary fiber is largely fermented by the gut microbiota in the colon. The fermentation process of dietary fiber leads to the formation of short-chain fatty acids (SCFAs), which can be used as fuel by intestinal cells, providing beneficial effects on the gut microbiome and also contributing to the ketogenic ratio of the ketogenic composition. Therefore, according to a preferred embodiment of the invention, dietary fiber is included in the ketogenic composition.

[0143] The ketogenic composition preferably contains 7-15 g of dietary fiber, more preferably 8-14 g, and more preferably 10-12 g of fiber per 100 g of the ketogenic composition. In other words, the ketogenic composition preferably contains 7-15% by weight of fiber, more preferably 8-14% by weight, and more preferably 10-12% by weight of dietary fiber based on the total weight of the ketogenic composition.

[0144] In a preferred embodiment, one or more dietary fibers are selected from the group consisting of: fructooligosaccharides, inulin, resistant starch, cellulose, methylcellulose (preferably hydroxypropyl methylcellulose), wheat bran, gum arabic, soybean polysaccharides (such as Fuji soybeans), oat fiber, galactooligosaccharides, locust bean gum, guar gum, pectin, hydrolyzed pectin, and mixtures thereof. The terms "gum arabic" and "arabic gum" are used interchangeably. In a preferred embodiment, a mixture of different dietary fibers is used, such as a mixture of at least two, at least three, at least four, at least five, at least six, or even at least seven different dietary fibers, preferably selected from the above list of preferred dietary fibers.

[0145] In embodiments, the fiber mixture comprises at least galactooligosaccharides, inulin, and / or Fuji soybeans. In preferred embodiments, the fiber mixture further comprises insoluble fibers, such as resistant starch and cellulose. Preferably, the insoluble fiber accounts for less than 50% by weight of the total fiber in the ketogenic composition. The fiber mixture in the ketogenic composition according to the invention provides about 2 kcal / g of fiber, and preferably provides 2.5%-5.5% of the total calories of the ketogenic composition, more preferably 3%-5% of the total calories, and even more preferably 3.5%-4.5% of the total calories.

[0146] In one aspect, the ketogenic composition comprises a fiber mixture containing cellulose, inulin, galactooligosaccharides, Fuji soybean, and resistant starch. Preferably, the fiber mixture comprises cellulose, inulin, galactooligosaccharides, Fuji soybean, and resistant starch in a weight ratio of 4-6 : 1-3 : 1-3 : 0.5-2 : 0.1-0.4, more preferably 4.5-5.5 : 1.5-2.5 : 1.5-2.5 : 1-1.5 : 0.2-0.3.

[0147] Protein portion The ketogenic composition according to the invention comprises a protein source. Proteins include all protein materials, including whole and (partially) hydrolyzed proteins, peptides, and free (added) amino acids. The total protein present in the ketogenic composition (i.e., the combination of all proteins and amino acids present) may be referred to as the "protein portion" of the ketogenic composition. Any protein source suitable for use in a nutritional composition may be included in the ketogenic composition according to the invention. Preferred protein sources include milk proteins such as whey, casein, vegetables (legumes, peas, soybeans, lupins, amaranth, potatoes, seeds, grains, tubers, etc.), fish, krill, algae, animal protein materials, eggs, and mushrooms.

[0148] In the embodiments, the ketogenic composition preferably comprises 15-25 g protein / 100 g composition, more preferably 16-24 g protein / 100 g composition, and more preferably 18-21 g protein / 100 g composition, based on the total protein material of the protein portion. In the embodiments, the ketogenic composition therefore preferably comprises 15-25% by weight of protein, more preferably 16-24% by weight, and even more preferably 18-21% by weight of protein, based on the total weight of the ketogenic composition. The protein therefore includes all protein material, including whole and (partially) hydrolyzed proteins, peptides, and free (added) amino acids.

[0149] In the embodiments, the protein provides 10%-16% of the total energy content of the ketogenic composition, preferably 11%-15%, more preferably 12%-14%.

[0150] In one embodiment, the protein portion comprises at least 75% by weight, preferably at least 80% by weight, and more preferably at least 85% by weight of whole and / or (partially) hydrolyzed protein based on the total weight of the protein portion.

[0151] In a preferred embodiment, the protein portion comprises a complete and / or (partially) hydrolyzed protein selected from casein and / or whey, preferably casein. In one embodiment, the protein portion comprises at least 75% by weight, preferably at least 80% by weight, more preferably at least 85% by weight of casein. The protein portion preferably comprises 75-95 g casein / 100 g, more preferably 80-92 g / 100 g, and even more preferably 85-90 g / 100 g of protein portion. In other words, the protein portion of the ketogenic composition preferably comprises 75-95% by weight, more preferably 80-92% by weight, and even more preferably 85-90% by weight of casein based on the total weight of the protein portion. In a preferred aspect, the casein is essentially complete casein derived from mammalian milk, preferably from bovine milk (…). Bos ), Bison ( Bison ), buffalo ( Bubalus ) or Capricornus ( Capra ) species, preferably from the genus Bos, and most preferably from dairy cows (domestic cattle ( Bos taurus )) milk.

[0152] In one embodiment, the protein portion comprises free amino acids selected from serine, lysine, glycine, valine, cysteine, leucine, and isoleucine, preferably leucine, isoleucine, and / or cysteine. In a more preferred embodiment of the invention, the protein portion comprises the amino acids cysteine ​​and / or leucine in free form. The protein portion comprises at least 5% by weight, more preferably 5 to 15% by weight, even more preferably 7 to 13% by weight, and particularly 8 to 12% by weight of the said amino acids based on the total protein content.

[0153] Unbound by theoretical constraints, it is believed that the provision of leucine beneficially stimulates the remodeling of functional connections between neurons in the brain after epileptic seizures by activating the mTOR pathway, which stimulates cell growth. Furthermore, leucine provides antiepileptic effects by modulating neural excitation.

[0154] Preferably, the protein portion of the ketogenic composition comprises at least 5 g amino acids per 100 g protein portion, preferably at least 7.5 g amino acids per 100 g protein portion, preferably 5-15 g amino acids per 100 g protein portion, more preferably 7-13 g amino acids per 100 g protein portion, and even more preferably 8-12 g amino acids per 100 g protein portion. In other words, the protein portion therefore preferably comprises at least 7.5% by weight, preferably 5-15% by weight, more preferably 7-13% by weight, and even more preferably 8-12% by weight of amino acids based on the total weight of the protein portion. In embodiments, the protein portion comprises up to 15 g amino acids per 100 g protein portion, or up to 15% by weight of amino acids based on the total weight of the protein portion.

[0155] The amino acids are provided in free form (i.e., not as part of a protein or peptide sequence). Preferably, the amino acids comprise at least leucine in free form. The amount of free leucine per 100 g of protein fraction is preferably 5-15 g, more preferably 7.5-12.5 g, and even more preferably 8-10 g in free form. Preferably, the protein fraction comprises 5-15% by weight, more preferably 7.5-12.5% ​​by weight, and even more preferably 8-10% by weight of free leucine based on the total weight of the protein fraction. In one embodiment, the total amount of leucine provided by both free leucine and protein-bound leucine in the protein fraction preferably totals at least 7% by weight, preferably at least 8% by weight, and more preferably at least 9% by weight based on the total protein fraction. In the context of this invention, the terms "leucine" and "L-leucine (i.e., the L-enantiomer of leucine)" are used interchangeably.

[0156] Preferably, the amino acid further comprises cysteine ​​in its free form. The amount of free cysteine ​​in each 100 g of protein fraction is preferably 0.5-2.5 g, more preferably 1-2 g, and even more preferably 1.2-1.6 g of cysteine. Preferably, the protein fraction contains 0.5-2.5% by weight, more preferably 1-2% by weight, and even more preferably 1.2-1.6% by weight of free cysteine ​​based on the total weight of the protein fraction.

[0157] Vitamins, minerals and antioxidants In one embodiment, the ketogenic composition additionally contains minerals, vitamins, antioxidants, and trace elements. The micronutrients are provided in the amounts recommended for nutritionally complete foods and comply with EFSA recommendations regarding adjusted daily requirements for minerals and vitamins based on age and sex.

[0158] In a preferred embodiment, the ketogenic composition comprises a therapeutically effective dose of vitamin B3, preferably nicotinamide nucleoside [NR] or nicotinamide [NAM]. The ketogenic composition preferably comprises 75-225 mg NR / 100 g or 36-108 mg NAM / 100 g, more preferably 100-200 mg NR / 100 g or 50-100 mg NAM / 100 g, and even more preferably 125-175 mg NR / 100 g or 60-85 mg NAM / 100 g of the ketogenic composition. The above ranges apply to the EFSA recommendation that the total daily dose of nicotinamide nucleoside in adult subjects should be limited to 300 mg / day, equivalent to 126 mg NAM / day. Meanwhile, in 2002, the Scientific Committee on Food (SCF) of the European Union set the tolerable upper intake level of NAM for the adult population (excluding pregnant and lactating women) at 900 mg / day (12.5 mg / kg body weight). As used herein, “nicotinamide nucleoside” includes its derivatives, such as L-valine and L-phenylalanine esters of nicotinamide nucleoside. NR and NAM, preferably included in the ketogenic compositions according to the invention, are NAD+ precursors that provide beneficial effects on both oxidative stress and DNA repair, thereby contributing to delaying the progression of epilepsy.

[0159] In a preferred embodiment, the ketogenic composition comprises a therapeutically effective dose of pyruvate. Pyruvate may be incorporated, for example, as a free acid or as its Ca, Na, or K salt, or as a precursor of pyruvate. Pyruvate is preferably provided in the range of 1.5 mg to 25 mg pyruvate / kcal ketogenic composition, more preferably 2.5 mg to 15 mg pyruvate / kcal ketogenic composition, and even more preferably 5.8 mg to 12 mg pyruvate / kcal ketogenic composition. Pyruvate is preferably present in the ketogenic composition at a dose corresponding to 1% to 13% by weight of the total weight of the ketogenic composition, more preferably 1.5% to 9% by weight of the total weight of the ketogenic composition. Any amount of pyruvate equivalents or derivatives is recalculated to an equivalent weight of pyruvate, excluding counterions.

[0160] The weight range and percentage of pyruvate in neuroprotective compositions associated with the ketogenic diet are based on a daily intake of 500 to 4000 kcal / day and a body weight of 5 to 100 kg.

[0161] Another antioxidant preferably included in the ketogenic composition according to the invention is tert-butylhydroquinone. Tert-butylhydroquinone beneficially acts as an antioxidant, thereby helping to prevent neuronal damage in epilepsy, prolonging the latency period of epileptic seizures, and reducing the severity of epileptiform seizures. In a preferred embodiment, the ketogenic composition contains 0.8-2 mg tert-butylhydroquinone / 100 g, more preferably 1-1.5 mg tert-butylhydroquinone, and even more preferably 1.2-1.4 mg tert-butylhydroquinone / 100 g of the ketogenic composition. In other words, the ketogenic composition preferably contains 0.0008-0.002% by weight, more preferably 0.001-0.0015% by weight, and even more preferably 0.0012-0.0014% by weight of tert-butylhydroquinone based on the total weight of the ketogenic composition.

[0162] In a preferred embodiment, the ketogenic composition further comprises a citrate. The citrate used in the neuroprotective composition may be citric acid or a potassium salt (K). + ), sodium salt (Na) + ), magnesium salt (Mg 2+ ) or calcium salts (Ca 2+ (in the form of ).

[0163] Citrate, or citric acid, is converted to isocitrate in the first step of the Krebs cycle (also known as the citrate or TCA cycle). Citrate has been found to increase the rate of glycolysis in in vitro glial cell models and to provide protection against neuronal damage by increasing energy production, preferably through a combined increase in glycolysis in glial cells and mitochondrial oxygen consumption in brain neurons. Citrate is believed to reduce and / or prevent excitotoxicity associated with or following seizures, and thus prevent and / or treat neuroinflammation associated with epileptiform seizures, and thus prevent and / or delay the formation of epileptiform circuits in the brain.

[0164] In a preferred embodiment, the ketogenic composition comprises 100-1000 mg citrate / 100 g, more preferably 250-750 mg citrate, and even more preferably 500-600 mg citrate / 100 g of the ketogenic composition. In other words, the ketogenic composition preferably comprises 0.1-1% by weight, more preferably 0.25-0.75% by weight, and even more preferably 0.5-0.6% by weight of citrate based on the total weight of the ketogenic composition. Any amount of citrate equivalents or derivatives is calculated as an equivalent weight of citrate, excluding counterions.

[0165] In some embodiments, it is preferred that the ketogenic composition comprises both citrate and pyruvate.

[0166] Example To gain a more comprehensive understanding of this disclosure, please refer to the following examples in conjunction with the accompanying drawings.

[0167] Example 1 An exemplary enteric ketogenic composition is formulated as follows: each 100 g of the composition contains 644 kcal and includes 20% by weight protein (including free amino acids), 8% by weight digestible carbohydrates, 56% by weight lipids, 11% by weight dietary fiber, and 5% by weight additional micronutrients. This ketogenic composition contains the ingredients according to Table 1.

[0168] Table 1

[0169]

[0170] Example 2 The ketogenic diets (hereinafter: alternative ketogenic diets) according to Table 1 were evaluated in a so-called rapid rat ignition temporal lobe epilepsy model. Adult male rats were switched from a normal diet to a standard rodent diet one week prior to surgical implantation of the stimulating electrodes into the angular bundle. Animals were allowed one week to recover from surgery. They were then switched to a standard rodent diet, a rodent-adapted classic ketogenic diet (fat to carbohydrate plus protein ratio of 6:1), or an alternative ketogenic diet. Animals were allowed approximately one week to acclimatize to their diets, during which time body weight and food intake were measured. On day 5 of the diet, blood glucose and ketone levels were measured to confirm ketosis induction. Subsequently, the animals were subjected to 36 electrical stimulations over one week via the implanted electrodes. Seizure behavior was scored according to the Racine scale (from 1 (lowest severity) to 5 (highest severity)). EEG activity was recorded during stimulations during seizures. Animals were allowed one week to recover after the last stimulation. Then, they underwent a week-long behavioral analysis (open field test, Barnes maze test, new object recognition test). One week after the behavioral study concluded, the animals were fasted overnight, blood samples were collected for glucose and ketone level measurements, and they were then euthanized by decapitation. Brain and liver samples were subsequently collected for molecular, biochemical, and histological analysis. The number of animals analyzed in each treatment group was n = 14 for the alternative ketogenic diet, n = 16 for the classic ketogenic diet, and n = 15 for the control diet.

[0171] Compared to the classic ketogenic diet and the standard rodent diet, alternative ketogenic diets significantly delayed the progression from mild (Racine score 1) to severe seizure score (Racine score 5) and complete ignition (Racine score 5, subthreshold electrical stimulation of seizures). Figure 1Compared to the classic ketogenic diet group and the control diet group at stimulations 3-5 and 3 respectively, progressive deterioration was observed starting from stimulation 12 in the alternative KD group. Figure 1 Furthermore, rats in the alternative KD group maintained grade 1 for significantly longer and required significantly more stimulation to reach grades 4 and 5. Figure 2 Furthermore, when the seizure scores for each stimulus were averaged, a decrease in the average seizure severity was observed when the ketogenic diet was used as an alternative. Figure 3 Alternative to KD: Dark gray; Classic KD: Dashed line; Control diet: Light gray).

[0172] In addition, electroencephalography (EEG) determined the duration and latency of after-discharge (AD, an additional measure of neural excitability 10 seconds after the initial electrical stimulation). Figure 4A AD consists of a first part (AD1) and a second part (AD2) separated by a latency period. Compared with the control, AD1 in both KD groups was significantly shorter ( Figure 4B Furthermore, compared to the control, the latency between AD1 and AD2 was significantly longer in both KD groups ( Figure 4C ).

[0173] Behavioral analysis was conducted using an open field test. The following parameters were determined using the open field test: (i) time spent entering and remaining in the central area, as measures of anxiety; (ii) frequency and duration of hindlimb standing, as measures of activity and exploration; and (iii) distance and speed of movement, as measures of kinetic activity. Healthy, unlit control animals preferentially remained near the boundaries / boundaries of the open field test, rarely entering and spending little time in the central area. Meanwhile, lit animals receiving a control diet entered and spent significantly more time in the central area of ​​the open field. Figure 5 They also exhibited significantly more hindlimb standing behavior. Figure 6 They also showed alternating increases in speed, distance, and area of ​​movement. Figure 7 Ignition (or seizures) resulted in hyperactivity, excessive exploration, possible impulsivity, and fearlessness in control animals. This behavioral pattern is reminiscent of attention deficit hyperactivity disorder (ADHD). In humans, ADHD is indeed frequently associated with epilepsy, and vice versa. Compared to ignition-treated animals receiving a control diet, both alternative and classic ketogenic diets showed significantly reduced central region entry and residence time. Figure 5 Furthermore, they showed a significant reduction in hindlimb standing (). Figure 6 And there was no excessive exercise. Figure 7 Therefore, both alternative and classic ketogenic diets reversed the abnormal ADHD-like behavior induced by recurrent seizures.

[0174] Blood ketone levels in animals were measured 5 days after exposure to the ketogenic diet (before the ignition) and 21 days after exposure (i.e., approximately one week after the final ignition). Ketone measurements were performed in serum from non-fasting animals obtained during the same morning time period. These measurements showed a significant increase in blood ketone levels in both ketogenic diet groups after 5 and 21 days of ketogenic diet exposure; however, ketone levels with alternative ketogenic diets increased only to approximately 50% of the levels achieved with the classic ketogenic diet. Figure 8 and 9 Therefore, the novel (alternative) KD exhibits lower ketogenicity. This suggests an additional mode of action for alternative KD: not ketone-mediated, and making alternative ketogenic diets more effective. Furthermore, the induction of blood ketosis was identical in both ignited and non-ignited animals exposed to alternative ketogenic diets. Figure 8 and 9 ).

[0175] Fatty acid and glucose concentrations were measured in non-fasting rat serum obtained on the morning of day 5 and day 21 of dietary exposure. In both ignited and non-ignited animals, and after 5 and 21 days of dietary exposure (…),… Figure 10 Compared to a control diet, the classic ketogenic diet significantly increased triglyceride levels, while alternative ketogenic diets did not increase triglyceride levels. Figure 10 There were no significant differences in glucose levels among all groups, indicating that neither ketogenic diet resulted in a significant change in blood glucose compared to the control diet. Figure 11 ).

[0176] Specific assessments of serum ω-3 and ω-6 polyunsaturated fatty acid levels in both ignited and unignited rats showed that, compared to the classic ketogenic diet and the standard rodent diet (control diet), the alternative ketogenic diet increased total ω-3 PUFA levels and decreased total ω-6 PUFA levels, resulting in a significantly increased ω-3 to ω-6 PUFA ratio. Figure 12 and 13 Furthermore, on days 5 and 21 of dietary exposure in both flammable and non-flammable animals, the alternative ketogenic diet significantly increased serum levels of ω-3 PUFA DHA and EPA compared to the classic ketogenic diet and the standard rodent diet (control diet), while significantly decreasing levels of ω-3 PUFA α-linolenic acid (ALA) and ω-6 PUFA linoleic acid (LA). Figure 12 and 13 ).

[0177] Specific assessments of serum levels of other fatty acids showed that, unlike the classic ketogenic diet, after 5 and 21 days of dietary exposure in both flammable and non-flammable animals, the alternative ketogenic diet did not increase serum concentrations of long-chain fatty acids palmitic acid (C16), stearic acid (C18), and oleic acid (C18:1) compared to the standard (control) rodent diet. Figure 14 and 15 Furthermore, in non-flammable animals, after 5 and 21 days of dietary exposure, the alternative ketogenic diet reduced serum concentrations of long-chain fatty acids myristic acid (C14), palmitic acid (C16), stearic acid (C18), and oleic acid (C18:1) compared to the standard (control) rodent diet. Figure 14 and 15 These LCFAs are the most abundant LCFAs found in the alternative ketogenic diet, the classic ketogenic diet, and the standard rodent (control) diet. Notably, although they are more abundant in the alternative ketogenic diet than in the standard rodent (control) diet, their serum levels in the alternative ketogenic diet group were lower than in the control diet group. These LCFAs are known to mediate the development of insulin resistance, metabolic syndrome, and fatty liver. Therefore, the alternative ketogenic diet protects burnt rats (especially non-burnt rats) from the increase of circulating long-chain fatty acids known to lead to the development of fatty liver, insulin resistance, metabolic syndrome, and cardiovascular complications arising therefrom.

[0178] The protective effect against the development of fatty liver was confirmed by visually examining the liver at harvest time and measuring its fatty acid content. Figure 16 Liver samples collected from animals on a classic ketogenic diet showed a pale yellow color, consistent with hepatic steatosis. Liver samples collected from animals on a standard (control) or alternative ketogenic diet for rodents showed a normal dark red color, consistent with normal liver fat content. Measurements of triglyceride content in these livers from non-burning animals showed that triglyceride levels were equal in the alternative ketogenic diet group and the control diet group. Furthermore, they showed that burning rats on both the alternative and classic ketogenic diets accumulated more triglycerides than rats on the control diet, but triglyceride accumulation in burning rats on the alternative ketogenic diet was significantly lower than in burning rats on the classic ketogenic diet. Figure 16 ).

[0179] In both ignition and non-ignition animals, body weight measurements showed a trend toward reduced weight gain when the ketogenic diet was substituted for a standard (control) rodent diet. Figure 17 This is consistent with the obesity or fat loss that can be induced by alternatives to the ketogenic diet compared to the control diet.

[0180] Serum measurements of amino acid concentrations after 5 and 21 days of dietary exposure showed that the alternative ketogenic diet provided higher levels of the essential amino acids leucine (Leu), threonine (Thr), tryptophan (Trp), valine (Val), and phenylalanine (Phe) (amino acids that cannot be produced endogenously and must be obtained through dietary intake) than the classic ketogenic diet. Figure 18 and 19 The alternative ketogenic diet has a higher protein content and provides free Leu, totaling approximately 20% by weight, compared to approximately 9% by weight for the classic ketogenic diet adapted for rodents (fat to protein plus carbohydrate ratio of 6:1) and approximately 14% by weight for the classic human ketogenic diet (fat to protein plus carbohydrate ratio of 4:1). Meanwhile, the protein source (casein) in these diets is the same, so it is unlikely to lead to differences in the supply of essential amino acids.

[0181] Furthermore, after 5 and 21 days of dietary exposure, both the alternative and classic ketogenic diets, compared to the standard rodent (control) diet, increased serum concentrations of several amino acids previously known to reduce neuronal excitability and thus contribute to reducing seizure activity (i.e., leucine, serine, glycine, and lysine). Figure 20 and 21 ).

[0182] Finally, it was found that on both days 5 and 21 of dietary exposure, the alternative ketogenic diet provided fewer gluconeogenic amino acids (i.e., amino acids that can be used by the liver to produce glucose) compared to the standard (control) rodent diet. Figure 22 and 23 This beneficially increases the effectiveness of the diet because less glucose will be produced in the liver, thus forcing more ketones to be produced and utilized.

[0183] Example 3 Fatty acid blends representing fatty acid blends in a ketogenic diet (comparative diet) containing moderate levels of medium-chain triglycerides were prepared, as well as fatty acid blends representative of the diet according to Example 1 (the diet of the present invention). The fatty acid blend corresponding to the comparative diet is referred to as the COMP-KD fatty acid blend, and the fatty acid blend corresponding to the experimental diet of the present invention is referred to as the INV-KD fatty acid blend. The fatty acid composition of COMP-KD and INV-KD is comparable to that of fatty acid blends present in the corresponding nutritionally complete ketogenic diets. COMP-KD contains moderate amounts of MCFA, wherein less than 10% of the total kcal is provided by MCFA, while for INV-KD, approximately 20% of the kcal is provided by MCFA. The weight ratio of MCT to the sum of [LCT and VLCT] in the INV-KD fatty acid blend is approximately 1:2.8, while the weight ratio of MCT to the sum of [LCT and VLCT] in the COMP-KD fatty acid blend is approximately 1:19.

[0184] The fatty acid compositions of the two fatty acid blends are shown in Table 2 (based on a total molar percentage of 100%). These fatty acid blends are similar to those used in comparative diets and diets according to the invention for preparing comprehensive nutritional compositions further comprising protein, carbohydrates, and micronutrients. The ketogenic response and direct effects of the fatty acid blends on neuronal cell cultures can be extrapolated to the effects of the corresponding ketogenic diets.

[0185] Table 2. Mole % of medium-chain, long-chain and very long-chain fatty acids contained in the blends (based on a total of 100%).

[0186]

[0187] Fatty acid-albumin conjugate For COMP-KD and INV-KD, the conjugation of medium-chain, long-chain, and very long-chain fatty acids with bovine serum albumin (BSA) was performed using a modified BSA-palmitate conjugate scheme. In this scheme, each fatty acid was dissolved in a 150 mM sodium chloride solution by heating the solution to 5-8°C above its melting point. Furthermore, the pH of this solution was raised to 7.4 to deprotonate the carboxyl groups of the fatty acids, making them more hydrophilic. The fatty acid solution was then briefly added to a stirred Ultra fatty acid-free BSA solution (Merck LifeScience NV, Zwijndrecht, the Netherlands), at a temperature not exceeding 40°C to avoid protein denaturation. After stirring for one hour, the BSA-conjugated stock solution was filtered through a 0.22 μm polyvinylidene fluoride (PVDF) membrane. Due to their inherent poor solubility in aqueous environments, the final concentrations of all long-chain fatty acids were subsequently measured using gas chromatography. C19:0 was used as an internal standard. Fatty acids were converted to methyl esters using methanol and sulfuric acid. After extraction with hexane, fatty acid methyl esters were separated and quantified using a gas chromatograph GC-2025 (Shimadzu Benelux BV, SW-Helto, Netherlands). The concentrations of the individual fatty acid stock solutions used were calculated using the ratio between the internal standard and the fatty acid methyl ester peaks.

[0188] Under these conditions, by titrating the increased amount of fatty acids, the fatty acid-BSA binding ratio can be determined, well controlled, and reproduced with minimal inter-experimental variability, and good comparisons can be made between different fatty acid-BSA conjugates. For all conjugates, the target molar binding ratio of fatty acids to BSA is 4:1. Very short-chain fatty acids acetic acid, propionic acid, and butyric acid were not conjugated to BSA due to their inherently high water solubility. Aliquots of the saturated fatty acid-BSA conjugate stock solutions were stored at -20°C, and the unsaturated stock solutions were stored at -80°C. They were diluted to the desired concentration in Krebs-Henseleit buffer (KHB) prior to the ketogenic phase. The following fatty acids were used in the assay: sodium acetate, sodium propionate, sodium butyrate, hexanoic acid, caprylic acid, decanoic acid, lauryl acid, myristic acid, palmitic acid, oleic acid, oleic acid-bovine serum albumin, linoleic acid, α-linolenic acid, docosahexaenoic acid, and eicosapentaenoic acid (Merck Life Sciences Public Ltd., Zvehnderrecht, Netherlands).

[0189] Metabolic effects Hippocampal assays were performed on primary rat neuron-glial cell cultures to determine the effects of INV-KD and COMP-KD lipid blends on glycolysis rates, mitochondrial respiration, and total (glycolytic and mitochondrial) ATP production. In the hippocampal assays described below, the INV-KD lipid blend was found to increase glycolysis and respiration, as well as ATP production, in glial cells under seizure-like conditions. Therefore, providing an increased proportion of MCT in the INV-KD blend helps neurons and glial cells meet their energy demands during seizure-like events and provides neuroprotective effects. As explained below, these effects are not attributable to proton leakage.

[0190] Primary glial cell culture Rat cortical cells were isolated from day 18 embryos using a combination of enzymatic digestion and mechanical dissociation of rat cortical tissue. Immediately after dissociation, cells were seeded at a density of 500,000 cells / mL in 96-well plates and incubated at 37°C from day 0 (DIV) to DIV17 supplemented with 2% (v / v) B27 and 0.8 mM magnesium (Mg). 2+ Neuronal cells were grown for two weeks in a basal medium of 25 mM glucose and 1% (v / v) penicillin / streptomycin, with partial medium replacements at DIV3, DIV7, and DIV10. During this period, neuronal axons grew and formed synaptic contacts. Additionally, glial cells (primarily astrocytes) grew and formed contacts with neurons. Incubation in 25 mM glucose accelerated neuronal differentiation and network growth. At DIV16, the medium was replaced with one supplemented with 0.1 mM Mg. 2+ Unbuffered Hanks' Balanced Salt Solution (HBSS) (nutrient-deficient medium) was used to prepare 5 mM glucose and different concentrations of test nutrients. The concentration was changed from higher (0.8 mM) to lower (0.1 mM) Mg. 2+ It will increase the electrical firing frequency of neurons because Mg 2+ It is a known inhibitor of excitatory NMDA-type ionotropic glutamate receptors, which are responsible for most neuronal firing in this cell culture model. (The text abruptly ends here, likely due to an incomplete translation or missing information.) 2+ The increase in neuronal firing induced by incubation is reflected in calcium (Ca) 2+ The increase in the amplitude and / or frequency of the oscillation (this is due to Ca) 2+ The influx of these substances into neurons triggers the release of neurotransmitters, followed by Ca2+. 2+ (Outflow from neurons) and therefore these Ca 2+An increase in the area under the oscillation curve. Furthermore, increased neuronal firing leads to increased energy consumption and production in both neurons and glial cells. Energy production manifests as an increase in basal respiration (as oxygen is used for energy production in neurons) and an increase in glycolysis, which produces energy by converting glucose into lactate in astrocytes (also known as glycolysis). Subsequently, lactate is transferred from astrocytes to neurons, where it acts as fuel to sustain neuronal energy production through respiration. This transfer of lactate from astrocytes to neurons is known as the astrocyte-neuronal lactate shuttle (as described by Magistretti et al., Nature Reviews Neuroscience, 2018).

[0191] Hippocampus measurement Oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) of cells seeded in 96-well plates were monitored in real time at 37°C in unbuffered Hankes balanced salt solution (HBSS). OCR primarily represents mitochondrial respiration and to a lesser extent, non-mitochondrial respiration. ECAR mainly involves the acidification of the culture medium by lactate produced through glycolysis and secreted by the cells (Table 3).

[0192] During hippocampal runs, both OCR and ECAR were measured simultaneously at baseline and after compound injection using a hippocampal instrument (Table 3). HBSS was supplemented with glucose from the start and no glucose was injected via the hippocampal instrument. Measurements were repeated three times at baseline and three times after each compound injection.

[0193] Table 3. Compounds used during hippocampal assays and their effects on oxygen consumption rate (OCR) and extracellular acidification rate (ECAR).

[0194]

[0195] Glycolysis and mitochondrial energy production were assessed at DIV16 by exposing the primary glial cell cultures to a 50 μM lipid blend. The glial cell cultures were pre-incubated for 2 hours in hippocampal medium containing the lipid blend. Immediately after this pre-incubation, the oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) of the glial cell cultures were measured in a hippocampal assay. Each lipid blend was repeated 9 times.

[0196] Ca 2+ Oscillation Measurement Ca 2+Oscillation assays were performed using glial cell cultures grown in the same manner as those used for hippocampal assays. The neurons in these cultures formed dense networks exhibiting spontaneous synchronous activity, or oscillations. These oscillations were measured by incubating the cells with a calcium-sensitive dye, which produced a fluorescent signal when the neurons became active. The frequency, amplitude, and area under the curve of the oscillation pattern are measures of the excitability of the neuronal network, which can be measured under pro-epileptic conditions such as low magnesium (0.1 mM Mg). 2+ Stimulation with ) . Compared with normal magnesium concentration (i.e., 0.8 mM Mg 2+ Compared to the effect of (below), 0.1 mM Mg 2+ Stimulation of neural networks primarily increases the frequency and area under the curve of oscillation patterns, and this can be partially reversed by nutritional interventions such as ketogenic diet fat blends.

[0197] By evaluating Ca at DIV16 2+ To measure neural excitability, the above-mentioned glial cell culture was pre-incubated with a 25 μM lipid blend for 2 hours using oscillation. Immediately afterwards, the Ca2+ levels in the cell culture were recorded in real-time using a fluorescence plate reader (FlexStation, Molecular Devices). 2+ The amplitude and frequency of the oscillations were measured, and the area under the curve was quantified from these measurements using a statistical software package (Prism-GraphPad). Each fatty acid blend was repeated 6 times.

[0198] result Cells were exposed to 0.8 mM Mg 2+ Compared to the control group, the 0.1 mM Mg 2+ Stimulation of glial cells increased the frequency and area under the curve (AUC) of oscillation patterns. Figure 24 AC). Glial cells within it are maintained at 0.8 mM Mg. 2+ Compared to the baseline situation, using 0.1 mM Mg 2+ Stimulation of glial cells also increases energy production, as evidenced by increases in baseline glycolysis rate (ECAR), baseline mitochondrial oxygen consumption rate (OCR), baseline glycolytic ATP production, and baseline mitochondrial ATP production. Figure 24 DG).

[0199] Compared to the COMP-KD fatty acid blend, 0.1 mM Mg was observed in the INV-KD fatty acid blend. 2+ Stimulated Ca of glial cells 2+The frequency, amplitude, and area under the curve (AUC) of the oscillations were moderately reduced. This suggests that the INV-KD fatty acid blend has a moderately stronger potential than the COMP-KD fatty acid blend in inhibiting neural excitability. Figure 25 EG). Furthermore, INV-KD fatty acid blends increased baseline respiratory and oxidative capacity (FCCP response) more than COMP-KD fatty acid blends. Figure 25 AB). INV-KD fatty acid blends also moderately increased the rate of glycolysis more than COMP-KD fatty acid blends. Figure 25 CD). Finally, the INV-KD lipid blend moderately increased mitochondrial and glycolytic ATP production more than the COMP-KD lipid blend. Figure 25 HI). Proton leakage (or uncoupling effect) is the same between the two blends, therefore mitochondrial proton leakage cannot explain the observed differences in mitochondrial or glycolytic energy production between KD lipid blends. Figure 25 (J). In summary, compared with COMP-KD lipid blends, INV-KD lipid blends are more effective at inhibiting neural excitability and increasing mitochondrial and glycolytic energy production in neurons and glial cells.

[0200] Therefore, overall, these data show that the INV-KD fatty acid blend composition unexpectedly has a more direct and better effect on neural excitability and glial cell energy production than the COMP-KD fatty acid blend. These effects are subsequently associated with better seizure control, but not with ketosis or ketosis induction.

Claims

1. An enteric ketogenic composition comprising (i) a lipid moiety comprising 45 to 65 g of lipids, (ii) a carbohydrate moiety comprising 5 to 12 g of digestible carbohydrates, and (iii) a protein moiety comprising 15-25 g of protein per 100 g of the ketogenic composition. The lipid portion includes -5-50% by weight of medium-chain fatty acids [MCFA] based on the total weight of fatty acids in the lipid fraction, wherein more than 60% by weight of the MCFA are C8:0, C10:0 and C12:0 fatty acids, and wherein at least 70% by weight of the MCFA are provided in the form of medium-chain triglycerides [MCT]. -Based on 50-95% by weight of the total fatty acids in the lipid fraction, even-chain long-chain fatty acids [LCFA] and very long-chain fatty acids [VLCFA] with carbon lengths of 14 to 24, and wherein these LCFAs and VLCFAs contain at least one ω-3 polyunsaturated fatty acid [PUFA] selected from the group consisting of: docosahexaenoic acid (22:6, ω-3; DHA), eicosapentaenoic acid (20:5, ω-3; EPA), and docosapentaenoic acid (22:5, ω-3; DPA). The ketogenic composition contains MCT, long-chain triglycerides (LCT), and very long-chain triglycerides (VLCT), with the weight ratio of MCT to the sum of [LCT and VLCT] between 1:2 and 1:

5. The carbohydrate portion comprises 30 to 80% by weight of low glycemic index carbohydrates based on the total weight of digestible carbohydrates, and The protein moiety contains 5-15% by weight of free amino acids based on the total weight of the protein moiety. Furthermore, the ketogenic weight ratio of the ketogenic composition is between 1.5:1 and 3.0:

1.

2. The enteric ketogenic composition according to claim 1, wherein the composition further comprises 7-15% by weight of dietary fiber, and wherein such fiber is selected from fructooligosaccharides, inulin, resistant starch, cellulose, wheat bran, gum arabic, soybean polysaccharides such as Fuji soybean, oat fiber, galactooligosaccharides, locust bean gum, guar gum, pectin and hydrolyzed pectin.

3. The enteric ketogenic composition according to claim 2, wherein the fibers are a fiber mixture comprising cellulose, inulin, galactooligosaccharides, Fuji soybean and resistant starch.

4. The enteric ketogenic composition according to the preceding claims, wherein the low glycemic index carbohydrates are selected from trehalose, lactose, galactose and isomaltulose.

5. The enteric ketogenic composition according to the preceding claims, wherein the protein portion comprises whole and / or (partially) hydrolyzed proteins selected from: pea, soy, casein and / or whey, preferably casein.

6. The enteric ketogenic composition according to the preceding claims, wherein the protein portion comprises 75-95% by weight of casein based on the total weight of the protein portion.

7. The enteric ketogenic composition according to the preceding claims, wherein the free amino acids in the protein moiety are selected from the group consisting of: serine, lysine, glycine, valine, cysteine, leucine, and isoleucine, preferably leucine, isoleucine, and / or cysteine.

8. The enteric ketogenic composition according to the preceding claims, wherein the protein portion comprises 5-15% by weight of free leucine and 0.5-2.5% by weight of free cysteine ​​based on the total weight of the protein portion.

9. The enteric ketogenic composition according to the preceding claims, wherein the ω-3 / ω-6 weight ratio of these lipids is between 0.2:1 and 5:

1.

10. The enteric ketogenic composition according to the preceding claims, wherein the composition comprises monounsaturated fatty acids [MUFA], and wherein at least 85% by weight of these MUFAs based on the total weight of the MUFAs in the lipid moiety is oleic acid.

11. The enteric ketogenic composition according to the preceding claims, further comprising citrate and / or nicotinamide nucleoside and / or nicotinamide and / or pyruvate.

12. The enteric ketogenic composition according to the preceding claims, wherein the composition comprises less than 20% by weight of palmitic acid based on the total weight of the ketogenic composition.

13. The enteric ketogenic composition according to the preceding claims, for use in the treatment and / or prevention of epilepsy in subjects suffering from epilepsy or at risk of epileptic seizures, preferably epileptiform seizures.

14. The enteric ketogenic composition of claim 13 for use in the treatment and / or prevention of epilepsy, wherein the treatment and / or prevention of epilepsy includes treating and / or preventing and / or reducing the severity of epilepsy and preventing and / or delaying the formation of epileptiform circuits in the brain.

15. The enteric ketogenic composition according to any one of claims 13 and 14 for use in the treatment and / or prevention of epilepsy, further preventing the development of dyslipidemia, fatty liver and / or metabolic syndrome in subjects suffering from epilepsy or at risk of seizures, preferably epileptiform seizures.

16. The enteric ketogenic composition according to any one of claims 13 to 15, wherein the treatment and / or prevention of epilepsy and / or epilepsy progression in subjects with epilepsy or at risk of seizures further comprises reducing and / or preventing ADHD-related behavioral patterns.

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