Nutritional composition for use in glycogen storage disease

Abstract

The present invention relates to nutritional compositions comprising lipids, OSA starch, protein, encapsulating agent and carbohydrate, wherein the composition comprises lipid-containing particles having a lipid core, and wherein the lipid core is coated with OSA starch, and wherein the lipid core and OSA starch coating together comprise less than 4 wt% of protein, and to methods of preparing these nutritional compositions, and further to nutritional compositions for use in glycogen storage diseases.

Description

Technical Field

[0001] This invention belongs to the field of medical food, and relates to nutritional compositions for use in glycogen storage diseases, and to methods for preparing these nutritional compositions. Background Technology

[0002] Glycogen storage disease (GSD) is a rare, inherited metabolic disorder in which the body is unable to properly break down glycogen to provide energy. Glycogen is one of the body's primary energy sources and is mainly stored in the liver. When the body needs energy, enzymes in the liver break down glycogen to provide glucose. Individuals with GSD lack one of the enzymes associated with breaking down stored glycogen or have a mutation in that enzyme. Based on enzyme deficiency / mutation and the affected tissues, GSD can be classified into more than 12 types. Symptoms of GSD include hypoglycemia, enlarged liver, growth retardation, abdominal swelling, muscle weakness, muscle cramps and pain, and easy bruising.

[0003] Patients with gastroscopy-induced hypoglycemia (GSD) and idiopathic ketoacidosis (IKH) must frequently consume carbohydrate-rich meals and raw cornstarch to maintain normal blood glucose levels throughout the 24-hour period. GSD is neither preventable nor curable; therefore, treatment focuses on disease management. In clinical practice, patients must consume carbohydrate-rich meals and raw cornstarch (e.g., maizena) every 2-4 hours to prolong the fasting period (24 / 7). At night, some GSD patients either require continuous nighttime gastric drip feeding or must consume 1-3 carbohydrate-rich meals. This impacts the quality of life for both patients and their families, as it often leads to sleep deprivation.

[0004] Current nutritional solutions in this field are less than ideal, with patients still experiencing limited fasting periods, impacting their quality of life. Furthermore, these nutritional compositions are incomplete, low in nutritional value, and can lead to nutritional imbalances. Relatively high carbohydrate intake can result in excessive glycogen storage in the liver and muscles. Excessively high glucose spikes after consuming food (such as rapidly digestible carbohydrates) are detrimental and can ultimately lead to insulin resistance.

[0005] WO 2006 / 028122 describes the use of octenyl succinic anhydride modified starch (OSA starch) for the prevention and improvement of obesity; and further describes its use as an inhibitor of elevated blood glucose levels; or as a medicament for the prevention and improvement of diabetes. Here, OSA starch is used as dietary fiber to slow digestion. OSA starch is present in relatively high amounts to achieve the desired inhibition of postprandial blood glucose elevation, making its application in complete and balanced nutritional formulations for patients with GSD challenging and less than ideal.

[0006] Wolf BW et al., “Effects of chemical modification on in vitro rate and extent of food starch digestion: an attempt to discover a slowly digested starch,” Journal of Agricultural and Food Chemistry, 1999, Vol. 47, pp. 4178-4183, describe the application of slowly digested starch (SDS) in type 2 diabetes and mention the use of SDS, particularly uncooked / raw corn starch, in GSD.

[0007] Gremse DA et al., “Efficacy of cornstarch therapy in type III glycogen-storage disease,” *American Journal of Clinical Nutrition*, 1990, Vol. 52, No. 4, pp. 671-674, describe the use of cornstarch in type III GSD for the prevention of hypoglycemia / maintaining normoglycemia, and further mention the use of protein supplementation in GSD patients. However, challenges remain: GSD patients must consume such carbohydrate-rich meals every 2-4 hours to prolong the fasting period.

[0008] Food emulsions (such as emulsions in dietary supplements) are typically stabilized by proteins or low-molecular-weight emulsifiers (such as CITREM, lecithin, etc.). Such emulsions offer good processing performance and shelf-life stability; however, during gastric digestion, proteins become significantly unstable due to the acidic environment and mechanical action in the stomach. Therefore, these emulsions are not ideal for GSD patients who would otherwise benefit from delayed gastric emptying through stabilized food emulsions.

[0009] EP 0504055 describes such a liquid nutrition composition for use in GSD, comprising a carbohydrate component containing glucose polymers and slowly absorbed carbohydrates, and further describes a method for preparing the composition by preparing an emulsion from a lipid phase, wherein two other components (including proteins and soluble fiber, and slowly absorbed carbohydrates) are added to the lipid phase, which is representative of the prior art in the field of GSD management. However, proteins are less stable in the gastric environment, so the lipids emulsified with proteins break down prematurely in the stomach, resulting in uneven dispersion of lipids, proteins, and carbohydrates in the bolus and causing a delayed cholecystokinin response, which is detrimental to patients with GSD.

[0010] CN 114847359 describes a method for obtaining the composition, wherein a core material solution comprising lipids and OSA starch in a ratio of 1:2.2 is obtained, and a wall material solution comprising cassava dextrin dissolved in water is obtained. It further describes the use of this composition in the dietary treatment of diabetes, and the benefit that cassava dextrin does not cause an increase in blood sugar levels. However, the high dosage of OSA starch taught in this document may cause digestive discomfort.

[0011] WO 2023 / 006894 describes the use of OSA starch to obtain an emulsified liquid composition, wherein OSA starch, water, and glucose syrup are mixed to obtain an aqueous phase, and then lipids are added to this aqueous phase. The emulsion is then homogenized and spray-dried. Furthermore, the teachings further mention the addition of protein to the pre-emulsion. Disadvantageously, this may result in uneven dispersion of lipids, proteins, and carbohydrates in the bolus.

[0012] Although research has focused on the inherent properties of raw corn starch in glucose metabolism, information is lacking regarding the effect of the food matrix in the composition on glucose release. There remains a need in this field to develop a nutritional composition comprising a slowly digestible starch source with slow glucose release properties, which is particularly tolerant of the acidic environments of the mouth and stomach. Summary of the Invention

[0013] For patients at risk of hypoglycemia (such as those with GSD), controlled gastric emptying is required to allow for sustained nutrient release over time, along with slow carbohydrate digestion, to reduce and / or treat the disease, i.e., through disease management. Appropriate disease management through a diet rich in slowly digestible carbohydrates ensures that GSD patients maintain normal blood glucose levels for a longer period. Furthermore, it is important that lipids ingested in the diet of GSD patients remain adequately emulsified under gastric conditions to enter the duodenum at a stable rate. In this invention, the inventors have developed a composition characterized by comprising a matrix of a gastric-stabilizing emulsion using OSA starch as an emulsifier, an encapsulating agent encapsulating the gastric-stabilizing emulsion, and optionally containing citric acid as an additional component. The composition of this invention reduces the rate of glucose release from carbohydrates by slowing gastric emptying and decreasing the rate of enzymatic starch hydrolysis, thereby providing a prolonged glucose response that is beneficial for GSD patients to maintain normal blood glucose levels for a longer period. To further optimize treatment, the pH of the nutritional composition is optionally lowered using a food-grade pH adjuster, which can further reduce the role of α-amylase in oral digestion.

[0014] More specifically, the inventors have developed a nutritional composition and a method for preparing such a composition, which can remain dispersed in a liquid under in vitro gastric conditions by using OSA starch as an emulsifier. Such a gastric-stabilizing composition is essential for influencing gastric emptying rate and controlling the overall digestion of nutrients in food or supplements. Furthermore, the inventors have found that such a gastric-stabilizing composition with a specific matrix design (containing resistant maltodextrin as a spray-dried encapsulating agent and optionally containing citric acid) further benefits patients with GSD by further controlling the rate of carbohydrate release, as these components modulate carbohydrate digestion and help prolong the maintenance of normal blood glucose levels.

[0015] The inventors' discoveries aim to provide patients with a prolonged and substantially constant glucose response, and to maintain normal blood glucose levels for an extended period. Therefore, this invention provides a method for manufacturing a nutritional composition comprising lipids, octenyl succinic anhydride-substituted starch (OSA starch), proteins, an encapsulating agent, and digestible carbohydrates, the method comprising: (a) The lipid is emulsified with a first aqueous phase and OSA starch to obtain an emulsified O / W composition, wherein preferably the dry weight ratio of OSA starch to lipid is in the range of 1:3 to 1:5; (b) Homogenize the protein, water, and optionally other water-soluble components to obtain a second aqueous phase; (c) The emulsified O / W composition from step (a) is combined with the second aqueous phase from step (b) to obtain a mixture, and optionally additional ingredients are added to the mixture; (d) Optionally, the mixture provided in step (c) is pasteurized; (e) The mixture obtained in step (c) or step (d) is spray-dried to provide a spray-dried composition; (f) Digestible carbohydrates are dry-blended into the spray-dried composition to obtain the nutritional composition; In this nutritional composition, based on the total protein weight, less than 4 wt% of the protein is present in the first aqueous phase and the emulsified O / W composition in step (a), and an encapsulating agent is added prior to spray drying in step (e), i.e., in any of steps (a) to (d). Preferably, the encapsulating agent is added to... The emulsified O / W in step (a) The composition is neutralized and / or added to the second aqueous phase of step (b) and / or added to the mixture of step (c).

[0016] According to the inventors, in this method, limiting the presence of proteins during the emulsification of lipids with OSA starch is crucial to prevent interference with the migration of OSA starch to the O / W emulsion interface and / or the attachment of proteins at the O / W emulsion interface. The inventors have surprisingly discovered that the presence of proteins or other surfactants at the emulsion interface reduces its tolerance to the gastric environment and destabilizes the emulsion during gastric digestion. Therefore, in the absence of proteins at the O / W interface, emulsification of lipids with OSA starch yields a more stable emulsion and an improved OSA starch coating around the lipid globules. In this way, the nutrient composition containing the O / W emulsion remains stable during gastric digestion after reconstitution. Therefore, limiting the presence of proteins at the O / W interface is crucial in the emulsified O / W composition; hence, lipids are emulsified with OSA starch, while proteins are added after emulsion formation, for example, before pasteurization and spray drying, or after spray drying via dry blending.

[0017] Particularly preferred is that, during emulsification, the amount of digestible carbohydrates is maintained at a reduced or limited level, preferably less than 10 wt%, more preferably less than 4 wt%, based on the total dry weight of the composition; in other words, the emulsified O / W composition preferably contains less than 10 wt% digestible carbohydrates, more preferably less than 4 wt%, based on the total dry weight of the emulsified O / W composition. The advantage of using a limited amount of digestible carbohydrates during emulsification is that it prevents digestible carbohydrates from interfering with the coating of OSA starch on lipid globules. This interference could lead to gastric instability after administration, as digestible carbohydrates are more readily digested, potentially resulting in uneven dispersion of the composition in the stomach. The nutritional composition comprises carbohydrate-containing particles and lipid-containing particles.

[0018] In view of the above, the present invention also provides a nutritional composition comprising lipids, OSA starch, protein, an encapsulating agent, and digestible carbohydrates, wherein the composition comprises lipid-containing particles having a lipid core, wherein the lipid core is coated with OSA starch, and wherein the lipid core and the OSA starch coating together comprise less than 4 wt% protein based on the total protein weight in the nutritional composition, wherein the OSA starch coating is coated with an adjacent second layer containing protein, and wherein the encapsulating agent may be present in the second layer and / or the encapsulating agent may coat the second layer, and wherein the composition comprises 1-14 wt%, preferably 2-10 wt%, more preferably 2-6 wt% OSA starch based on the total dry weight of the composition. Preferably, the digestible carbohydrates comprise digestible starch, preferably at least 55 wt% slow-digesting starch based on the total dry weight of these digestible carbohydrates, wherein the slow-digesting starch is digested within 20 to 120 minutes based on in vitro enteric digestion. In other words, the present invention provides a nutritional composition comprising lipids, OSA starch, protein, an encapsulating agent, and digestible carbohydrates, wherein the nutritional composition comprises 1-14 wt% OSA starch based on the total dry weight of the composition, and wherein the digestible carbohydrates comprise digestible starch, preferably at least 55 wt% slow-digesting starch based on the total dry weight of these digestible carbohydrates. Preferably, the composition comprises lipid-containing particles having a lipid-containing core (i.e., a lipid-containing core or "lipid core"), wherein the lipid core is coated with OSA starch, and wherein the lipid core and the OSA starch coating together comprise less than 4 wt% protein based on the total protein weight in the nutritional composition. The coating prevents the lipid core from contacting the protein-containing outer layer and also prevents the lipid core from contacting proteins that can adsorb onto or form a separate layer on the OSA starch coating. Preferably, the encapsulating agent is located on the surface of the lipid-containing particles and on an outer layer comprising protein and optionally other additional components, the outer layer surrounding the lipid-containing particles, and wherein the composition comprises 1-14 wt% OSA starch. This composition is preferably obtained through the invention described herein.

[0019] Alternatively, the compositions of the present invention may also be characterized as nutritional compositions obtainable by the method according to the invention, comprising lipids, OSA starch, protein, an encapsulating agent, and digestible carbohydrates, wherein the nutritional composition comprises 1-14 wt%, preferably 2-10 wt%, more preferably 2-6 wt% OSA starch based on the total dry weight of the composition, and wherein these digestible carbohydrates comprise digestible starch, preferably at least 55 wt% slow-digesting starch based on the total dry weight of these digestible carbohydrates, preferably wherein the slow-digesting starch is digested within 20 to 120 minutes based on in vitro enteric digestion. The composition preferably comprises lipid-containing particles having a lipid core, wherein the lipid core is coated with OSA starch, and wherein the lipid core and OSA starch coating together comprise less than 4 wt% protein based on the total protein weight in the nutritional composition.

[0020] The above-described compositions of the present invention are further described in detail below: Preferably, the nutritional composition comprises, based on the total dry weight of the composition: - At least 10 wt% lipids; preferably, the lipids comprise sunflower seed oil; -1 - 14 wt% OSA starch, preferably 2 - 10 wt%, more preferably 2 - 6 wt% OSA starch; -25-75 wt% digestible carbohydrates, preferably 30-70 wt%; -2 - 15 wt% encapsulating agent, preferably The encapsulating agent has a glycemic index in the range of 0 to 50, preferably... The ground is in the range of 0 to 25, more preferably the ground. The encapsulating agent contains resistant maltodextrin; and -10 - 35 wt% protein.

[0021] In connection with prolonged or sustained glucose response, the present invention further provides the nutritional compositions described above for use in reducing and / or treating carbohydrate-related metabolic disorders associated with impaired glucose response. In other words, the present invention also relates to the use of the nutritional compositions described herein in the manufacture of products for reducing and / or treating carbohydrate-related metabolic disorders. Relatedly, the present invention also relates to a method for reducing and / or treating carbohydrate-related metabolic disorders in a subject of need, the method comprising administering the nutritional compositions described herein. In the foregoing, the method or use is preferably for use in reducing and / or treating diabetes, glycogen storage disease (GSD), fatty acid oxidation disorder (FAOD), and / or idiopathic ketotic hypoglycemia (IKH), more preferably for use in liver-related GSD subtypes 0, III, VI, and IX.

[0022] Therefore, regulating the slow release of glucose through components in the matrix design helps prolong the maintenance time of normal blood glucose levels: 1. The OSA starch-stabilized emulsion is encapsulated by a resistant maltodextrin shell. The OSA starch oil-in-water (O / W) emulsion remains dispersed under gastric conditions, ensuring uniform distribution of lipids throughout the gastric digestate. Consequently, lipids and other nutrients are emptied from the stomach together. Upon reaching the small intestine, the lipid digestion products trigger a hormonal feedback response (CCK) that controls gastric emptying. Resistant maltodextrin avoids the rapid carbohydrate digestion associated with conventional food encapsulating agents (e.g., conventional maltodextrin used in spray drying), thus limiting the overall glucose release from the composition.

[0023] 2. The nutritional composition uses a digestible carbohydrate source containing a high proportion of slowly digestible starch (SDS), preferably corn starch, as the primary source of glucose in the composition. The preservation of the starch structure enables slower carbohydrate digestion, which, together with the gastric stabilizing emulsion, ensures a slow and more sustained release of glucose during digestion.

[0024] 3. Optionally, a food-grade pH adjuster is used to generate an acidic product (i.e., pH < 6, preferably pH < 5), which reduces the starch-degrading activity of salivary amylase, whose optimal pH is about 7. Salivary amylase may cause instability of the emulsion droplets in the composition due to the enzymatic hydrolysis of starch. By lowering the pH, an acidified nutrient composition is obtained, which mitigates the action of salivary amylase.

[0025] Gastric-duodenal transport is particularly regulated by biochemical events triggered by total calorie intake and free fatty acids. The unstable gastric composition rapidly aggregates within the gastric environment, forming a lipid layer above the aqueous phase containing carbohydrates. Consequently, lipid digestion occurs later, and lipids enter the duodenum later than the aqueous phase. The aqueous phase containing carbohydrates has lower caloric content (± 4 kcal / g) than the lipid layer (9 kcal / g lipid), thus resulting in faster gastric emptying. Furthermore, the aggregation of oil droplets reduces the surface area for fat breakdown, leading to a decrease in the release of free fatty acids.

[0026] In vivo gastrointestinal digestion of the gastric stabilizing composition may lead to a decreased gastric emptying rate, possibly due to stronger stimulation of CCK release into the plasma. The inventors have found that OSA starch is a suitable emulsifier in the formulation of the gastric stabilizing composition, thereby reducing oil separation (demulsification) and maintaining a stable droplet size distribution throughout all in vitro gastric digestion experiments, while also reducing aggregation. Furthermore, the inventors have found that resistant maltodextrin, as an encapsulating agent, does not affect blood glucose levels after digestion; therefore, its combination with OSA starch in nutritional compositions is beneficial for slowing glucose release and maintaining normal blood glucose levels.

[0027] Unbound by any theoretical framework, it is hypothesized that the free fatty acids contained in the lipid core of the emulsified nutritional composition bind to G-coupled receptors (GPRs) in the midgut endocrine cells (EEC) of the small intestine after digestion. This binding influences satiety and gastrointestinal motility by releasing peptides such as cholecystokinin (CCK), glucagon-like peptide-1 (GLP-1), and peptide tyrosine (peptide YY). Increased exposure to these peptides may reduce the gastric emptying rate, thus controlling the rate of gastric emptying, and the retention of nutrients in the stomach ensures their gradual digestion in the gastrointestinal tract.

[0028] Importantly, the lipid-containing emulsions remain dispersed under gastric conditions to influence gastric emptying rate and control overall nutrient digestion in patients with gastrointestinal disorders (GSD). This stability is thought to be attributed to the steric hindrance created by the branched structure of OSA starch. Furthermore, the presence of OSA starch in the nutritional product is presumed to significantly hinder gastric enzymes, suggesting that OSA starch-coated lipid droplets can resist degradation by ionic strength and α-amylase, mimicking those found in saliva. Their stability under gastric conditions is presumed to stem from the presence of carboxyl groups in OSA starch, which provide a high total net negative charge in the emulsion and contribute to the formation of a more rigid and dense surface, thus resisting droplet aggregation.

[0029] The improved gastric stability achieved by using OSA starch as an emulsifier ensures that lipids are evenly distributed throughout the gastric digestate. This allows lipids and other nutrients to empty from the stomach together. Upon reaching the small intestine, lipid digestion products trigger a hormonal feedback response (CCK), slowing gastric emptying and thus controlling overall glucose release. In unstable emulsions, such as those using protein as an emulsifier, the protein covering the lipid globules has already been partially digested or broken down in the stomach due to the acidic environment, releasing lipid droplets. Therefore, after the aqueous phase containing other nutrients empties, a lipid layer remains on top of the chyme, delaying the feedback response controlling gastric emptying. Furthermore, the reduced surface area of ​​unstable emulsions limits fat breakdown and the release of lipid digestion products that trigger the hormonal feedback response. According to the invention, the use of OSA starch avoids all of this. Since fasting gastric motility recovers 3-5 hours after the intake of a normal-sized meal, expelling particles of any size remaining in the stomach, the gastric stabilizing composition ideally remains stable for at least 3 hours after ingestion.

[0030] Furthermore, and importantly, the encapsulating agent does not affect blood glucose levels or increase glucose digestion in the stomach. Therefore, unlike regular maltodextrin, which is rapidly broken down into glucose and absorbed in the small intestine, resistant maltodextrin passes through the small intestine without complete digestion. Instead, it is fermented by the gut microbiota in the large intestine, resulting in the production of short-chain fatty acids (SCFAs) and other beneficial metabolites. Additionally, the addition of food-grade pH adjusters to the nutritional composition improves rheological properties, increases viscosity, and makes its texture thicker than nutritional compositions with a neutral pH. Therefore, all nutrients in the nutritional composition can be absorbed simultaneously, preventing the formation of a thick carbohydrate slurry. By producing sustained-release formulations and controlling the rate of carbohydrate digestion, the fasting time after ingestion of the nutritional composition can be prolonged, thereby improving the quality of life for patients in need, such as those with GSD. Attached Figure Description

[0031] The invention will now be discussed in more detail with reference to the accompanying drawings.

[0032] Figure 1 Particle size distribution of pH 7 reconstituted base powder (1A) and pH 4 acidic reconstituted base powder (1B) at t = 0 (just reconstituted) and t = 4h (4 hours after reconstitution).

[0033] Figure 2 Particle size distribution of spray-dried compositions containing OSA starch-stabilized emulsions or WPI-stabilized emulsions after reconstitution.

[0034] Figure 3. Particle size distribution of spray-dried compositions containing either OSA starch-stabilized emulsion (3A) or WPI-stabilized emulsion (3B) after reconstitution during 2 hours of simulated oral and gastric digestion in vitro.

[0035] Figure 4 Particle size distribution of acidic reconstituted base powder (pH 4) containing OSA starch-stabilized emulsion, prior to and during in vitro simulated oral and gastric digestion (GE-0 min to GE-120 min) (“base powder, pH 4.0”), where GE-0 represents the oral digestion stage prior to gastric digestion.

[0036] Figure 5. Glucose (5A) and acetaminophen (5B) curves for three different treatment groups (UCCS, neutral prototype, and acidic prototype), where blood samples were collected and glucose and acetaminophen levels were measured every 30 minutes over 6 hours postprandial.

[0037] Figure 6 Particle size distribution of reconstituted OSA starch-stabilized emulsion-base powder A and WPI-stabilized emulsion-base powder B.

[0038] Figure 7 Particle size distribution of base powder A during 120 min of gastric digestion. Samples were collected at 24, 48, 72, and 120 min.

[0039] Figure 8 Particle size distribution of basic powder B during gastric digestion, with samples collected after 24, 48, 72, and 120 min.

[0040] The particle size distribution depicted in the figure is a volume-weighted distribution determined by laser diffraction using a laser diffractometer (Mastersizer 2000, Malvern Instruments Ltd, Worcestershire, UK), for example, by the method described in Michalski et al., 2001, Lait [Milk], 81, 787-789. The particle size distribution was obtained using polydispersity analysis, and particle size measurements were recorded as mean diameter D50 and volume mean diameter (D4,3) to observe the effect of gastric digestion on changes in oil droplet particle size distribution, as further explained in the examples.

[0041] List of preferred embodiments 1. A method for manufacturing a nutritional composition comprising lipids, octenyl succinic anhydride-substituted starch (OSA starch), proteins, an encapsulating agent, and carbohydrates, the method comprising: (a) The lipid is emulsified with a first aqueous phase and OSA starch to obtain an emulsified O / W composition, wherein preferably the dry weight ratio of OSA starch to lipid is in the range of 1:3 to 1:5; (b) Homogenize the protein, water, and optionally other water-soluble components to obtain a second aqueous phase; (c) The emulsified O / W composition from step (a) is combined with the second aqueous phase from step (b) to obtain a mixture, and optionally additional ingredients are added to the mixture; (d) Optionally, the mixture provided in step (c) is pasteurized; (e) The mixture obtained in step (c) or step (d) is spray-dried to provide a spray-dried composition; (f) These carbohydrates are dry-blended into the spray-dried composition. To obtain this nutritional composition; In this embodiment, less than 4 wt% of the protein is co-present in the emulsified O / W composition of step (a) based on the total protein weight in the nutritional composition, and the encapsulating agent comprises resistant maltodextrin, which is preferably added in any of steps (a) to (d) prior to spray drying in step (e).

[0042] 2. The method according to Example 1, wherein in step (a) the lipids are emulsified with a first aqueous phase and OSA starch at a pH of 3-5.5, preferably 3.5 to 5.

[0043] 3. The method according to Example 1 or 2, wherein a food-grade pH adjuster is added to the first aqueous phase in step (a) and / or to the second aqueous phase in step (b), and / or added as an additional component to the mixture in step (c), and / or dry-blended into the spray-dried composition in step (f).

[0044] 4. The method according to any one of Examples 1-3, wherein the dry weight ratio of OSA starch to lipid is in the range of 1:3.5 to 1:4.5.

[0045] 5. A nutritional composition comprising lipids, OSA starch, protein, an encapsulating agent, and carbohydrates, wherein the composition comprises lipid-containing particles having a lipid core, wherein the lipid core is coated with OSA starch, and wherein the lipid core and the OSA starch coating together comprise less than 4 wt% of protein based on the total protein weight in the nutritional composition.

[0046] 6. The nutritional composition according to Example 5, wherein the OSA starch coating is further coated by an encapsulating agent comprising resistant maltodextrin.

[0047] 7. The nutritional composition according to Example 5 or 6, wherein the composition comprises, based on the total dry weight of the composition: - At least 10 wt% lipids; preferably, the lipids comprise sunflower seed oil; -2 - 6 wt% OSA starch; -25 - 75 wt% total carbohydrates, wherein these carbohydrates contain at least 90 wt% natural corn starch based on the total dry weight of these carbohydrates; -2 - 15 wt% of encapsulating agent, wherein the encapsulating agent contains resistant maltodextrin; -10 - 35 wt% protein, preferably intact whey protein.

[0048] 8. The nutritional composition according to any one of Examples 5-7, wherein the composition comprises 2-14 wt% of a food-grade pH adjuster based on the total dry weight of the composition, preferably the food-grade pH adjuster is an organic acid selected from citric acid, lactic acid, malic acid, acetic acid and / or ascorbic acid, more preferably the food-grade pH adjuster is citric acid.

[0049] 9. The nutrient composition according to Example 8, wherein when the nutrient composition is dissolved at room temperature to form a 50% w / v solution of the nutrient composition in water, its pH is in the range of 3.5 to 4.5.

[0050] 10. The nutritional composition according to any one of Examples 5-9, wherein the natural corn starch comprises at least 55 wt% slow-digestible starch (SDS) and less than 20 wt% resistant starch (RS) based on the total dry weight of the natural corn starch.

[0051] 11. The nutritional composition according to any one of Examples 5-10, wherein the dry weight ratio of SDS to rapidly digestible starch (RDS) in the natural corn starch is in the range of 1:1 to 2:1, preferably in the range of 1.3:1 to 2:1, and more preferably in the range of 1.5:1 to 2:1.

[0052] 12. The nutritional composition according to any one of Examples 5-11, wherein the nutritional composition is a powder.

[0053] 13. The nutritional composition according to any one of Examples 5-12 is used for reducing and / or treating carbohydrate-related metabolic disorders, preferably for reducing and / or treating diabetes, glycogen storage disease (GSD), fatty acid oxidation disorder (FAOD) and / or idiopathic ketotic hypoglycemia (IKH), more preferably for use in liver-related GSD subtypes 0, III, VI and IX.

[0054] 14. The nutritional composition for use according to Example 13, wherein reducing and / or treating diabetes, GSD, FAOD and / or IKH includes preventing and / or reducing one or more of insomnia or sleep deprivation, impaired normoglycemia, fasting hypoglycemia, hyperinsulinemia, insulin resistance, and gastrointestinal side effects, including one or more of bloating, flatulence, and diarrhea, and wherein reducing and / or treating diabetes, GSD, FAOD and / or IKH further includes maintaining normal blood glucose, slowing gastric emptying rate, prolonging carbohydrate digestion, and prolonging glycolysis during digestion. Detailed Implementation

[0055] List of abbreviations

[0056] Definition List Throughout this application, the following terms and abbreviations may be used. "Nutritional composition" means a substance or preparation that meets at least a portion of the nutritional needs of a subject. Throughout this disclosure, the terms "one or more nutrients," "one or more nutritional formulations," "one or more enteral nutrients," and "one or more nutritional supplements" are used as non-limiting examples of one or more nutritional compositions. Furthermore, "one or more nutritional compositions" may refer to enteral formulations, oral formulations, pediatric subject formulations, children's formulations, growing-up milk, and / or adult formulations in liquid, powder, gel, paste, solid, concentrate, suspension, or ready-to-use form.

[0057] The term “nutritional complete” or “nutritional complete composition” refers to a composition that contains essential nutrients (including essential amino acids, essential fatty acids, vitamins and minerals), or has sufficient calories to meet an individual’s energy needs (based on their age, sex, activity level and other factors), or has a balance of macronutrients in carbohydrates, proteins and lipids to support a variety of bodily functions.

[0058] The terms “treatment,” “relief,” and “reduction” include therapeutic or disease-modifying treatments, including therapeutic measures to slow or alleviate symptoms of a diagnosed pathological condition or disorder as defined herein and / or to halt its progression, preferably by improving daily life to alleviate symptoms and / or improve quality of life, and / or improve sleep patterns in subjects with one or more diseases as defined herein; the term “treatment” includes treating patients at risk of or suspected of having the disease, and patients who have or have been diagnosed with a disease or medical condition as defined herein. This term does not imply treating a subject until complete recovery. The terms “treatment” and “relief” are also intended to include intensifying or otherwise enhancing one or more primary therapeutic measures.

[0059] The terms “lipid”, “lipid fraction”, “lipid component”, and “lipid composition” are synonyms and can be used interchangeably.

[0060] The terms “stabilized emulsion”, “stabilized emulsion”, and “OSA starch-stabilized emulsion” are used interchangeably and refer to the emulsion stabilized with OSA starch according to the present invention.

[0061] The term "gastric stable" refers to the stability of the OSA starch-stabilized emulsion according to the present invention under human gastric conditions. Here, gastric conditions refer to the increase in acidity pH over 120 minutes in simulated human gastric conditions in the presence of gastric enzymes, as described in Mulet-Cabero et al., A standardized semi-dynamic... in vitro The standardized in vitro digestion method described in the international consensus [A standardized semi-dynamic in vitro digestion method suitable for food], Food Funct., 2020, 11, 1702-1720.

[0062] The terms "oil-in-water composition", "O / W composition", and "emulsified O / W composition" refer to emulsified compositions of lipids in water and / or in aqueous solutions.

[0063] As used herein, the term "spray-dried composition" refers to a nutrient powder composition that has been spray-dried and can be dry-blended or mixed with other components to obtain a final nutrient composition. As used herein, a spray-dried composition refers to a composition that has been spray-dried to obtain a powder, i.e., a powder composition.

[0064] As used herein, the term "powder" refers to fine, individual particles, preferably less than 1 mm in diameter, which have higher flowability and solubility compared to particles with a coarser structure and a particle size typically in the range of 1 to 10 mm (based on volume).

[0065] In the context of this invention, the term "substantially free" means the absence of the mentioned ingredient, or if present, the composition contains less than 4 wt%, more preferably less than 3 wt%, even more preferably less than 1 wt% of the mentioned ingredient based on the total dry weight of the composition, and most preferably below detectable levels. Specifically, the term "substantially protein-free" means the absence of protein or the presence of less than 4 wt% of protein based on the total dry weight of the emulsified O / W composition, preferably less than 3 wt%, more preferably less than 1 wt%. Or, in other words, less than 4 wt%, preferably less than 3 wt%, more preferably less than 1 wt% of protein based on the total protein weight in the nutritional composition, present together in the first aqueous phase and the emulsified O / W composition of step (a). Regarding the spray-dried composition and the final nutritional composition, "substantially protein-free" means the presence of less than 4 wt% of protein based on the total protein weight of the nutritional composition, preferably less than 3 wt%, more preferably less than 1 wt%, in the lipid core and the OSA starch coating surrounding the lipid core.

[0066] Furthermore, in the context of this invention, the terms "coated with OSA starch," "OSA starch coating," and "coating with OSA starch," etc., refer to OSA starch located on the surface of the lipid core. Preferably, these terms refer to a lipid core coated with OSA starch, which prevents the lipid core from contacting the protein-containing outer layer and / or prevents the lipid core from contacting proteins adsorbed onto or forming a separate layer on the OSA starch coating. In a further preferred embodiment, the OSA starch coating is a layer of OSA starch surrounding the lipid core.

[0067] The terms "encapsulating agent," "spray drying aid," "spray drying assisted carbohydrate," or simply "spray drying agent" refer to a component in a composition used to coat a liquid composition in the spray drying step (e), particularly the mixture obtained in step (c) or (d) that has undergone spray drying, to obtain the spray-dried composition as defined herein. More specifically, it refers to an encapsulating agent for an OSA starch-stabilized emulsion present in a coating nutrient composition.

[0068] Furthermore, the terms "encapsulating agent coating," "encapsulating agent coating," and "coating with an encapsulating agent" refer to the encapsulating agent being located on the surface of the lipid-containing particles and optionally on an outer layer containing proteins and optionally other additional components, which surrounds the lipid-containing particles. In this regard, encapsulating agent coating forms an additional coating on the lipid-containing particles, which contain OSA starch coating. Preferably, these terms refer to lipid-containing particles coated with an encapsulating agent and / or the outer layer surrounding these lipid-containing particles, which prevents the lipid-containing particles and / or the outer layer from contacting additional components adsorbed on the encapsulating agent or forming a separate layer on the encapsulating agent. In a further preferred embodiment, the encapsulating agent coating is a layer of encapsulating agent surrounding the lipid-containing particles. More preferably, the encapsulating agent covers at least 75% of the surface of the lipid-containing particles and / or the outer surface of the optional outer layer containing proteins and optionally other additional components, more preferably at least 85%, and most preferably at least 90%.

[0069] As used in this article, the term "food grade" means that a product, material, or additive is safe for consumption, meaning it is edible and poses no health risk. Substances added to food during processing or production are subject to strict regulation and approval by regulatory agencies such as the U.S. Food and Drug Administration (FDA) or the European Food Safety Authority (EFSA) of the European Union.

[0070] Unless otherwise stated, all percentages are by weight.

[0071] As used in this article, the term "dry weight" refers to weight excluding water, or in other words, weight without water.

[0072] In this document and its claims, the verb “comprising” and its inflections are used in their non-limiting sense to mean including the item following the word, but not excluding items not specifically mentioned. Furthermore, when used herein, the term weight percentage (wt%) is based on the weight percentage of total dry weight. Moreover, reference to an element by the indefinite article “a / an” does not preclude the possibility of more than one such element, unless the context explicitly requires the presence of one and only one such element. Therefore, the indefinite article “a / an” generally means “at least one / a type”.

[0073] Any reference to prior art documents in this specification should not be construed as an admission that such prior art is well-known or forms part of common general knowledge in the art.

[0074] The invention will now be described in more detail.

[0075] This invention relates firstly and most importantly to a nutritional composition comprising lipids, OSA starch, protein, an encapsulating agent, and digestible carbohydrates. In another aspect, the invention relates to a method for manufacturing said nutritional composition, and further to the medical use of said nutritional composition. Before defining each aspect of the invention in more detail, various features of the invention are defined in more detail. It should be noted that the various aspects, features, examples, and embodiments described in this application can be compatible and / or combined together.

[0076] In a preferred aspect, the present invention relates to a method for manufacturing a nutritional composition comprising lipids, octenyl succinic anhydride-substituted starch (OSA starch), proteins, an encapsulating agent, and digestible carbohydrates, the method comprising: (a) The lipid is emulsified with a first aqueous phase and OSA starch to obtain an emulsified O / W composition, wherein preferably the dry weight ratio of OSA starch to lipid is in the range of 1:3 to 1:5; (b) Homogenize the protein, water, and optionally other water-soluble components to obtain a second aqueous phase; (c) The emulsified O / W composition from step (a) is combined with the second aqueous phase from step (b) to obtain a mixture, and optionally additional ingredients are added to the mixture; (d) Optionally, the mixture provided in step (c) is pasteurized; (e) The mixture obtained in step (c) or step (d) is spray-dried to provide a spray-dried composition; (f) Digestible carbohydrates are dry-blended into the spray-dried composition to obtain the nutritional composition; Based on the total protein weight in the nutritional composition, less than 4 wt% of the protein is present together in the first aqueous phase and the emulsified O / W composition in step (a), and the encapsulating agent is added prior to spray drying in step (e), i.e., in any of steps (a) to (d). Preferably, the encapsulating agent comprises resistant maltodextrin. Preferably, the encapsulating agent is added to the first aqueous phase in step (a), and / or to the second aqueous phase in step (b), and / or as an additional component to the mixture in step (c), more preferably to the emulsified O / W composition and / or the second aqueous phase and / or the mixture.

[0077] In another preferred aspect, the present invention relates to a nutritional composition comprising lipids, OSA starch, protein, an encapsulating agent, and digestible carbohydrates, wherein the composition comprises lipid-containing particles having a lipid core, wherein the lipid core is coated with OSA starch, and wherein the lipid core and the OSA starch coating together comprise less than 4 wt% protein based on the total protein weight in the nutritional composition, and wherein the OSA starch coating is coated with an adjacent second layer comprising protein, and wherein the encapsulating agent may be present in the second layer and / or the encapsulating agent may coat the second layer, and wherein the composition comprises 1-14 wt% OSA starch based on the total dry weight of the composition. Preferably, the digestible carbohydrates comprise digestible starch, preferably at least 55 wt% slow-digesting starch based on the total dry weight of these digestible carbohydrates, wherein the slow-digesting starch is digested within 20 to 120 minutes based on in vitro enteric digestion.

[0078] In other words, the present invention relates to a nutritional composition comprising lipids, OSA starch, protein, an encapsulating agent, and digestible carbohydrates. Preferably, the composition comprises lipid-containing particles having a lipid-containing core, wherein the lipid core is coated with OSA starch, and wherein the lipid core and the OSA starch coating contain less than 4 wt% protein based on the total protein weight of the nutritional composition. Preferably, the composition contains 1-14 wt% OSA starch based on the total dry weight of the composition, and wherein the digestible carbohydrates comprise digestible starch, preferably at least 55 wt% slow-digesting starch based on the total dry weight of these digestible carbohydrates, wherein the slow-digesting starch is digested within 20 to 120 minutes based on in vitro enteric digestion. Preferably, the OSA starch coating prevents the lipid core from contacting the protein-containing outer layer, and / or prevents the lipid core from contacting proteins adsorbed onto the OSA starch coating or forming a separate layer on the OSA starch coating. In another preferred aspect, the lipid-containing particles are coated with an encapsulating agent, more preferably, wherein the encapsulating agent prevents the lipid-containing particles from contacting any other components adsorbed onto the encapsulating agent or forming a separate layer on the encapsulating agent. In other words, preferably, the encapsulating agent is located on the surface of the lipid-containing particles and on an outer layer comprising proteins and optionally other additional components, which surrounds the lipid-containing particles.

[0079] As described above, the dry weight ratio of OSA starch to lipid in the lipid core and the OSA starch coating directly on the lipid core is in the range of 1:3 to 1:5, more preferably 1:3.5 to 1:4.5; unless otherwise specified in the formulation, these figures do not include any OSA starch that may be present as an encapsulating agent in the second outer layer.

[0080] The embodiments of the present invention defined below relate to the above-described characterization of the composition in terms of structure, and the above-described characterization of the product form defined by the method.

[0081] Preferably, based on the total dry weight of the composition, the nutritional composition comprises: - At least 10 wt% lipids; preferably, the lipids comprise sunflower seed oil; -1 - 14 wt% OSA starch, preferably 2 - 10 wt%, more preferably 2 - 6 wt% OSA starch; -25 - 75 wt% of digestible carbohydrates, preferably 30 - 70 wt%, preferably wherein these digestible carbohydrates contain at least 55 wt% slow-digesting starch (SDS) based on the total dry weight of these digestible carbohydrates. -2 - 15 wt% of encapsulating agent, preferably wherein the glycemic index of the encapsulating agent is in the range of 0 to 50, preferably in the range of 0 to 25, more preferably wherein the encapsulating agent contains resistant maltodextrin; -10 - 35 wt% protein, preferably intact whey protein.

[0082] In another preferred aspect, the present invention relates to a nutritional composition comprising lipids, OSA starch, protein, an encapsulating agent, and digestible carbohydrates, wherein the composition comprises 1-14 wt% OSA starch based on the total dry weight of the composition, and wherein the digestible carbohydrates comprise digestible starch, preferably at least 55 wt% slow-digesting starch based on the total dry weight of these digestible carbohydrates. Additionally, preferably, the composition comprises lipid-containing particles having a lipid-containing core, wherein the lipid core is coated with OSA starch, and wherein the lipid core and OSA starch coating comprise less than 4 wt% protein based on the total protein weight in the nutritional composition, for use in reducing and / or treating carbohydrate metabolism disorders, preferably for use in reducing and / or treating diabetes, glycogen storage disease (GSD), fatty acid oxidation disorder (FAOD), and / or idiopathic ketotic hypoglycemia (IKH), more preferably for use in liver-associated GSD subtypes 0, III, VI, and IX.

[0083] The present invention can also be described as a method for reducing and / or treating carbohydrate metabolism disorders, preferably for reducing and / or treating diabetes, glycogen storage disease (GSD), fatty acid oxidation disorder (FAOD), and / or idiopathic ketotic hypoglycemia (IKH), more preferably liver-related GSD subtypes 0, III, VI, and IX; said method comprising administering a nutritional composition to a patient in need, the nutritional composition comprising lipids, OSA starch, protein, an encapsulating agent, and digestible carbohydrates, wherein the composition comprises 1-14 wt% OSA starch based on the total dry weight of the composition, and wherein the digestible carbohydrates comprise digestible starch, preferably at least 55 wt% slow-digesting starch based on the total dry weight of these digestible carbohydrates. Furthermore, preferably, the composition comprises lipid-containing particles having a lipid-containing core, wherein said lipid core is coated with OSA starch, and wherein the lipid core and OSA starch coating comprise less than 4 wt% protein based on the total protein weight in the nutritional composition.

[0084] The present invention can also be described as the use of OSA starch in the manufacture of nutritional compositions for reducing and / or treating carbohydrate metabolism disorders, preferably in reducing and / or treating diabetes, glycogen storage disease (GSD), fatty acid oxidation disorder (FAOD), and / or idiopathic ketotic hypoglycemia (IKH), more preferably liver-associated GSD subtypes 0, III, VI, and IX, wherein the nutritional composition comprises lipids, OSA starch, protein, encapsulating agent, and carbohydrates, wherein the composition comprises 1-14 wt% OSA starch based on the total dry weight of the composition, and wherein the digestible carbohydrates comprise digestible starch, preferably at least 55 wt% slow-digesting starch based on the total dry weight of these digestible carbohydrates. Furthermore, preferably, the composition comprises lipid-containing particles having a lipid-containing core, wherein the lipid core is coated with OSA starch, and wherein the lipid core and OSA starch coating comprise less than 4 wt% protein based on the total protein weight in the nutritional composition.

[0085] Method for manufacturing the nutritional composition according to the invention Embodiments of the present invention include a method for manufacturing a nutritional composition comprising lipids, OSA starch, proteins, an encapsulating agent, and digestible carbohydrates, wherein the lipids are emulsified with a first aqueous phase and OSA starch in a substantially protein-free manner, and wherein the encapsulating agent is resistant maltodextrin, which is added to the first or second aqueous phase, or as an additional component to a mixture comprising the first and second aqueous phases.

[0086] In another embodiment, the method for producing a nutritional composition comprising lipids, OSA starch, protein, encapsulating agent, and digestible carbohydrates, as detailed above, includes the following steps: a) The lipids were emulsified with a first aqueous phase and octenyl succinic anhydride-substituted starch (OSA starch) to obtain an emulsified O / W composition; (b) Homogenize the protein, water and other water-soluble components to obtain a second aqueous phase; (c) The emulsified O / W composition from step (a) is combined with the second aqueous phase from step (b) to obtain a mixture, and optionally additional ingredients are added to the mixture; (d) Optionally, the mixture provided in step (c) is pasteurized; (e) The mixture obtained in step (c) or step (d) is spray-dried to provide a spray-dried composition; (f) Digestible carbohydrates are dry-blended into the spray-dried powder to obtain the nutritional composition; Based on the total protein weight in the nutritional composition, less than 4 wt% of the protein is present together in the first aqueous phase and the emulsified O / W composition in step (a), and the encapsulating agent is added prior to spray drying in step (e), i.e., in any of steps (a) to (d). Preferably, the encapsulating agent is added to the emulsified O / W composition and / or to the second aqueous phase and / or to the mixture.

[0087] In typical production of spray-dried nutrient compositions, water-soluble / hydrophilic components (proteins, emulsifiers, and optionally digestible carbohydrates) are dispersed and homogenized with lipids to form an emulsified aqueous phase, followed by pasteurization and spray drying. However, in the method according to the invention, emulsification is carried out substantially without protein, with preferably less than 4 wt%, more preferably less than 3 wt%, and most preferably less than 1 wt% protein present based on the total dry weight of the emulsified composition. Or in other words, less than 4 wt%, more preferably less than 3 wt%, and most preferably less than 1 wt% protein is present in the first aqueous phase and the emulsified O / W composition of step (a) based on the total protein weight in the nutrient composition. The protein is added to the emulsified O / W composition after emulsification, more preferably before pasteurization and spray drying. In a further preferred embodiment, digestible carbohydrates, preferably less than 4 wt%, are present during emulsification based on the dry weight of the emulsified O / W composition. In other words, the emulsified O / W composition preferably contains less than 10 wt% of digestible carbohydrates based on the total dry weight of the emulsified O / W composition, more preferably less than 4 wt%.

[0088] Therefore, the method according to the invention preferably employs a splitting process, in which lipids and proteins are treated separately, thereby obtaining an emulsified O / W composition stable only by a selected emulsifier, avoiding the formation of a mixed interface containing proteins and emulsifiers. The inventors have surprisingly discovered that such emulsification yields a more stable composition upon reconstitution, and an improved interface design for lipids containing negatively charged OSA starch, and that such emulsification is optimized to achieve target performance during digestion (e.g., the composition remains stable during gastric digestion in the acidic environment of the stomach).

[0089] Preferably, during the emulsification process in step (a), the dry weight ratio of OSA starch to lipids is in the range of 1:3 to 1:5, more preferably in the range of 1:3.5 to 1:4.5. In a preferred embodiment, based on the total dry weight of the emulsified O / W composition in step (a), there is less than 4 wt% protein, more preferably less than 3 wt%, and most preferably less than 1 wt%. Or, in other words, based on the total protein weight in the nutritional composition, less than 4 wt% protein is present in the first aqueous phase and the emulsified O / W composition in step (a), more preferably less than 3 wt%, and most preferably less than 1 wt%. In a further preferred embodiment, the first aqueous phase contains less than 10 wt% carbohydrates, preferably less than 5 wt% carbohydrates. It is also preferred that the emulsified O / W composition in step (a) and the mixture obtained in step (c) contain less than 10 wt% carbohydrates, preferably less than 5 wt% carbohydrates.

[0090] Depending on the type of OSA starch used, lipid emulsification is carried out at a neutral or acidic pH. Steric repulsion or steric hindrance is crucial for the emulsifying properties of OSA starch. The emulsification of proteins and the provision of stable emulsions depend primarily on electrostatic repulsion, and are therefore pH-dependent. Therefore, emulsification at pH values ​​closer to the isoelectric point of proteins may be insufficient, leading to emulsion instability. OSA starch has the advantage of being able to emulsify at lower pH values ​​and remain stable at acidic pH values, thus being more tolerant to the acidic environment of the stomach. Preferably, lipid emulsification with a first aqueous phase and OSA starch is carried out at a pH range of 3-6.5, more preferably 3-5.5, and even more preferably 3.5-5. In this document, the pH range refers to the pH of the first aqueous phase; therefore, preferably, the first aqueous phase has a pH range of 3-6.5, more preferably 3-5.5, and even more preferably 3.5-5.

[0091] Preferably, OSA starch is dissolved in water and added to both the lipids and the first aqueous phase, or it can be added to the first aqueous phase prior to emulsification. Preferably, OSA starch is dissolved in the first aqueous phase. In a further preferred embodiment, the first aqueous phase comprises at least water and optionally further comprises one or more of the following: OSA starch, encapsulating agent, water-soluble vitamins, water-soluble minerals, flavoring agent, coloring agent, and / or sweetener. In a further preferred embodiment, the first aqueous phase comprises less than 10 wt%, preferably less than 4 wt%, of digestible carbohydrates based on the total dry weight of digestible carbohydrates in the nutritional composition obtained by the method according to the invention. In a preferred embodiment, emulsification of the lipids with OSA starch and the first aqueous phase is performed by homogenization, preferably at a temperature of 50°C to 75°C.

[0092] In a preferred embodiment, in the method according to the invention, the protein is mixed with the emulsified O / W composition by: adding the protein to a second aqueous phase and combining the emulsified O / W composition with the second aqueous phase to obtain a mixture, followed by spray drying, and / or adding the protein as a (dry) blend to the spray-dried composition. Adding the protein as a (dry) blend to the spray-dried composition depends on the microbiological quality of the protein powder; therefore, it is preferable to add the protein to the spray-dried composition when the protein has been treated separately and is microbiologically safe. This protects the protein from undesirable heating conditions. In a particularly preferred embodiment, the protein is mixed with the emulsified O / W composition by adding it to the second aqueous phase before the spray-drying step and optionally also before the pasteurization step. In a further preferred embodiment, the protein is added to the second aqueous phase by homogenization.

[0093] Preferably, the second aqueous phase comprises at least water and optionally further comprises one or more of proteins, encapsulating agents, and other water-soluble components selected from water-soluble vitamins, water-soluble minerals, flavoring agents, coloring agents, and / or sweeteners. More preferably, the second aqueous phase comprises water and protein. In a further preferred embodiment, the second aqueous phase comprises less than 4 wt% digestible carbohydrates based on the total dry weight of digestible carbohydrates in the nutritional composition. In a preferred embodiment of the method, the second aqueous phase is combined with an emulsified O / W composition by homogenization to obtain a mixture.

[0094] In a preferred embodiment, the mixture comprises an emulsified O / W composition and a second aqueous phase comprising at least water, and preferably, additional components are added to the mixture, for example by blending and / or homogenization, such as one or more selected from encapsulating agents, other vitamins, minerals, flavoring agents, coloring agents, and / or sweeteners. The additional components added to the mixture may comprise fat-soluble and / or water-soluble components, preferably water-soluble, to prevent an increase in the free lipid content of the composition. If fat-soluble components are added to the emulsified O / W composition after lipid emulsification in step (a), it is preferred that the total amount of fat-soluble components is less than 10 wt%, more preferably less than 8 wt%, and most preferably less than 4 wt%, based on the total dry weight of the mixture subjected to spray drying. Therefore, in a preferred embodiment, the mixture remains an O / W composition. In a further preferred embodiment, the mixture comprises less than 4 wt% digestible carbohydrates based on the total dry weight of digestible carbohydrates in the nutritional composition. This is to prevent the digestible carbohydrates from gelatinizing during the spray drying process.

[0095] In a preferred embodiment, the encapsulating agent is added to the mixture prior to spray drying. Preferably, in the method according to the invention, the encapsulating agent is added to the emulsified O / W composition prior to spray drying, more preferably prior to spray drying in step (e), i.e., in any of steps (a) to (d), and most preferably, the encapsulating agent is added to the first aqueous phase and / or to the second aqueous phase, and / or added as an additional component to the spray-dried mixture. In a preferred embodiment, during the spray drying process in step (e) of the method according to the invention, the mixture is coated with the encapsulating agent; more preferably, during the spray drying process, the encapsulating agent coats the lipid particles in the mixture of step (c) or (d). In a further preferred embodiment, the encapsulating agent coats OSA starch-stabilized lipid particles. Preferably, the encapsulating agent... of The glycemic index is in the range of 0 to 50, preferably in the range of 0 to 25, and more preferably the encapsulating agent. It contains resistant maltodextrin.

[0096] Preferably, the method according to the invention includes a pasteurization step, preferably prior to a spray drying step. Preferably, the pasteurization of the mixture is carried out via direct heating (e.g., direct steam injection or steam perfusion) or via indirect heating (e.g., tubular pasteurization, plate heat exchanger, or distillation).

[0097] In a further preferred embodiment, a mixture comprising at least an emulsified O / W composition and a second aqueous phase is subjected to a spray drying step to obtain a spray-dried composition. In this regard, any spray drying equipment suitable for drying food compositions can be used. In one embodiment, the spray-dried composition as used herein is not a nutritionally complete composition because additional ingredients are added to the spray-dried composition by dry blending or mixing them into the spray-dried composition. In an alternative embodiment, the spray-dried composition is a nutritionally complete composition, and any additional ingredients (such as micronutrients) are added to the first or second aqueous phase or to the lipids in step (a).

[0098] The spray-dried composition is preferably considered to be gastrostomically stable. In other words, the spray-dried composition comprises an OSA starch-stabilized emulsion according to the invention.

[0099] Furthermore, preferably, digestible carbohydrates are excluded from wet-phase processing in the method according to the invention. Preferably, digestible carbohydrates are added to the spray-dried composition in a (dry) blending step to obtain the nutritional composition according to the invention. This is preferably done to avoid gelatinization and to preserve the original (natural) structure of the digestible carbohydrates. Preservation of the digestible carbohydrate structure enables slower carbohydrate digestion, which, together with the gastric stabilizing emulsion, ensures a slow and more sustained release of glucose during digestion. Therefore, it is preferred that digestible carbohydrates be added to the spray-dried composition in the form of a (dry) blend, optionally together with one or more additional dry components such as acidity regulators, flavoring agents, coloring agents, and / or sweeteners. In a preferred embodiment, at least 80 wt%, more preferably at least 85 wt%, and most preferably at least 96 wt% of the total dry weight of digestible carbohydrates in the nutritional composition are added in the form of a (dry) blend to the spray-dried composition, optionally together with one or more other dry ingredients such as acidity regulators, flavoring agents, coloring agents and / or sweeteners, preferably food-grade pH regulators.

[0100] In a further preferred embodiment, a food-grade pH adjuster is added to the first aqueous phase and / or to the second aqueous phase, and / or added to the mixture as an additional component before spray drying, and / or dry-blended into the spray-dried composition. More preferably, the food-grade pH adjuster is added to the spray-dried composition during the dry-blending step.

[0101] OSA starch The emulsifier used in this invention is an octenyl succinic anhydride-substituted starch compound (also referred to herein as "OSA starch"), and is considered stable under gastric conditions. OSA starch is typically obtained in the form of a sodium salt. OSA starch is preferably food-grade OSA starch (International Numbering System code E1450). In the examples, OSA starch is derived from waxy corn starch, cassava starch, rice starch, potato starch, wheat starch, and starches from other plant sources substituted with octenyl succinic anhydride groups, such as starches from other corn or other crops. Refer to "Structure and physicochemical properties of octenyl succinic anhydride modified starches: Areview" in Carbohydrate Polymers 92 (2013) 905-920, which discloses several OSA starches that can be used in this invention. Preferably, the OSA starch used herein is non-gelatinized; more preferably, the OSA starch comprises a granular structure and has not undergone a gelatinization process. This invention does not preclude the use of additional emulsifiers in the preparation of gastric-stable O / W emulsions and emulsified O / W compositions, but preferably uses only one or more OSA starch compounds. In this regard, additional emulsifiers should be gastric-stable in the acidic environment of the stomach as defined above, or in other words, additional emulsifiers should be stable under gastric conditions in the stomach as further defined below.

[0102] Based on the total dry weight of the nutritional composition, the amount of OSA starch is preferably in the range of 1-14 wt%, more preferably 2-10 wt%, and even more preferably 2-6 wt%. In a further preferred embodiment, based on the dry weight of the nutritional composition, the amount of OSA starch is in the range of 2.5 to 5 wt%, most preferably in the range of 3-4 wt%. The dry weight ratio of OSA starch to lipids in the nutritional composition is preferably in the range of 1:3 to 1:5, more preferably 1:3.5 to 1:4.5. Under these conditions, the lipid core is optimally encapsulated. In this regard, if the amount of OSA starch is low or if the weight ratio of OSA starch to lipids is low, the O / W emulsion may become less stable and more prone to rapid aggregation in the gastric environment. Therefore, a lipid layer may be formed on top of the aqueous phase, replacing or superimposing the desired lipid homogeneous dispersion system. On the other hand, if the amount of OSA starch is higher than the above range, or if the weight ratio of OSA starch to lipids is higher than the above range, there may be more uncovered free OSA starch in the O / W composition (and nutritional composition), which may cause side effects such as bloating and abdominal distension in subjects with carbohydrate-related metabolic disorders.

[0103] Due to its amphiphilic nature, OSA starch can be used as an emulsifier. OSA starch preferably has low viscosity properties to achieve high lipid concentrations in the emulsion, resulting in a low-viscosity emulsion and ensuring effective emulsification. Therefore, OSA starch preferably has a viscosity of 100-400 mPas at 1000 1 / s at 70°C and 100-600 mPas at 100 1 / s at 70°C. Viscosity can be determined using any suitable method for measuring viscosity, preferably according to ISO 3219-1 and 2:2021. The advantage of this particular OSA starch is that it increases the viscosity of the aqueous phase relative to the lipid phase in an O / W emulsion, thereby reducing the fluidity of lipid droplets and decreasing lipid aggregation, providing a homogeneous emulsion of lipids and water. The reduction in lipid aggregation in OSA starch-stabilized emulsions leads to the formation of a gastric-stabilized nutritional composition with a low free lipid content.

[0104] lipids In a preferred embodiment, the nutritional composition comprises at least 10 wt% lipids based on the dry weight of the nutritional composition, more preferably 10 to 30 wt% lipids based on the dry weight of the composition, and even more preferably 11 to 20 wt% lipids.

[0105] Based on the total energy content of the nutritional composition, the lipids in the nutritional composition provide 15 to 40 en, preferably 20 to 35 en, and most preferably 25 to 30 en.

[0106] Of course, lipids are edible fats or oils. Edible oils used in the context of this invention can be obtained from natural sources, such as plant, microbial, and marine sources, and algae oils. Suitable plant sources include, but are not limited to, flaxseed, walnut, sunflower seed, rapeseed oil, safflower oil, soybean, wheat germ, leafy greens such as kale, spinach, and parsley, and corn oil. Edible oils can be present in purified form and / or as extracts from suitable sources. The lipid component can be an edible oil, but it can also be a mixture of edible fats or oils, such as a mixture of edible oils from two or more sources.

[0107] The lipids of the present invention preferably comprise (tri) glycerides. Triglycerides comprise a glycerol molecule to which three fatty acid residues are attached via ester bonds. These three fatty acid residues may be the same or different, and are generally selected from saturated and unsaturated fatty acids containing 6 to 26 carbon atoms, including but not limited to linoleic acid (18:2 n6) (LA), α-linolenic acid (18:3 n3) (ALA), oleic acid (C18:1), palmitic acid (16:0), and / or stearic acid (C18:0). The fatty acid residues of such fatty acid triglycerides may be different, and these fatty acid residues may be present and / or located at one or more corresponding positions of the fatty acid residues, for example, at sn-1, -2, and / or -3 positions.

[0108] The lipids in the nutritional composition preferably comprise plant lipids. The presence of plant lipids provides a fatty acid profile rich in (poly)unsaturated fatty acids (PUFAs), which is nutritionally advantageous when the nutritional composition is a medical nutritional powder. Preferably, the lipids comprise sunflower seed oil (SFO), and more preferably, it comprises long-chain triglycerides or fatty acids. In the context of this invention, long chain refers to a fatty acid chain of 13 to 22 carbon atoms.

[0109] Using plant lipids as part of a lipid composition is advantageous because they are digested into free fatty acids and glycerol in the small intestine, but to a lesser extent in the stomach. Before being absorbed into the bloodstream, free fatty acids exert physiological effects, influencing gastrointestinal motility and secretion through sensory mechanisms mediated by them in the small intestinal mucosa. Without being bound by any particular theory, it is hypothesized that free fatty acids bind to G-coupled receptors (GPRs) located in the midgut endocrine cells (EECs) of the small intestinal epithelium, thereby affecting satiety and gastrointestinal motility by releasing peptides such as CCK, GLP-1, and peptide YY. Increased expression of these peptides may lead to slower gastric emptying. In particular, the presence of long-chain free fatty acids (fatty acid chains containing 13 or more carbon atoms) in the intestinal phase can increase plasma CCK levels, while unsaturated long-chain free fatty acids can promote GLP-1 secretion. The reduced gastric emptying rate and the retention of nutrients in the stomach ensure gradual digestion in the gastrointestinal tract.

[0110] Therefore, in preferred embodiments, the lipids comprise at least 50 wt% plant lipids based on the total dry weight of the lipids in the nutritional composition, more preferably at least 75 wt%, even more preferably at least 85 wt%, and most preferably at least 95 wt%. In further preferred embodiments, the plant lipids comprise sunflower seed oil, more preferably sunflower seed oil is the only plant lipid in the nutritional composition. In preferred embodiments, the lipids comprise 4-8 wt% palmitic acid, 3-6 wt% stearic acid, 16-22 wt% oleic acid, 60-70 wt% LA, and 0.3-0.8 wt% ALA based on the total dry weight of the lipids in the nutritional composition.

[0111] Preferably, the lipids in the emulsified O / W composition and the nutritional composition are present in lipid-containing particles comprising lipids and OSA starch, wherein these lipid-containing particles have a lipid-containing core, and wherein the core is coated with OSA starch. Preferably, the lipid core and OSA starch coating are substantially protein-free.

[0112] In this respect, coating with OSA starch does not mean that it must completely cover the surface of the lipid core, but rather that the resulting nutritional composition is a gastric-stabilizing composition containing a gastric-stabilizing emulsion and can be reconstituted into a gastric-stabilizing emulsion, because, as defined herein, the lipid emulsification with OSA starch is carried out in a substantially protein-free state, preferably wherein the emulsification process contains less than 4% protein based on the total protein weight in the nutritional composition, more preferably less than 3 wt%, and most preferably less than 1 wt%, and / or wherein the lipid-containing particles have a lipid-containing core, and the core is coated with OSA starch, wherein the lipid core and the OSA starch coating contain less than 4 wt% protein based on the total protein weight in the nutritional composition, more preferably less than 3 wt%, and most preferably less than 1 wt%, of protein.

[0113] The stability is attributed to the steric hindrance created by the branched structure of OSA starch, which prevents other components from covering the lipid core. Furthermore, lipid emulsification occurs in the presence of OSA starch but in the absence of substantially no protein, with preferably less than 4 wt%, more preferably less than 3 wt%, and most preferably less than 1 wt% protein present based on the total dry weight of the emulsified O / W composition. These advantageous effects can be achieved when OSA starch is added to the lipids before or during emulsification, wherein the dry weight ratio of OSA starch to lipids is in the range of 1:3 to 1:5, preferably 1:3.5 to 1:4.5.

[0114] Advantageously, the nutritional composition has a low free lipid content. In the context of this invention, "free lipid content" is understood to refer to all lipid particles that are not coated with OSA starch and are therefore easily oxidized. Therefore, based on the total lipid weight in the nutritional composition, preferably at least 90 wt% of the lipids are emulsified with OSA starch, more preferably at least 95 wt%, and most preferably at least 98 wt%. Free lipids oxidize in both the O / W composition and the nutritional composition, thereby reducing the palatability of the final product. Furthermore, when not coated with OSA starch, free lipids can affect digestion and gastric emptying rates. Therefore, it is preferred that the free lipid content (i.e., all lipids not coated with OSA starch) is less than 10 wt% of the total lipid weight in the nutritional composition, preferably less than 8 wt%, and most preferably less than 4 wt%.

[0115] In the context of this invention, the free lipid content is determined by the method described in "Determination of Free Fat on the Surface of Milk Powder Particles," Analytical Method for Dry Milk Products, NS NIRO ATOMIZER (1978). The sample is prepared by finely grinding the powder using a cutting machine to avoid complete grinding. The powder is then passed through a 32-mesh sieve, and the free lipid content in the sample is measured using NS NIRO ATOMIZER. The free lipid content determined by this method is expressed as wt% of lipids extracted with carbon tetrachloride under constant-rate oscillation over a specified time.

[0116] The lipid portion of the nutritional composition of the present invention may further comprise non-plant lipids. Non-plant lipids may include milk fat, milk-derived lipids as a preferred source of phospholipids, and fish oil, marine bio-oils, and / or microbial oils as a source of long-chain polyunsaturated fatty acids. Preferably, the lipids comprise fish oil. Preferably, the lipids comprise EPA, DPA, and / or DHA, more preferably DHA and EPA. The content of ω-3 LC-PUFA (more preferably DHA and EPA) in the nutritional composition preferably does not exceed 10 wt% of the total fatty acid weight, preferably does not exceed 7 wt%, and even more preferably does not exceed 3 wt% of the total fatty acid content. Preferably, the nutritional composition of the present invention comprises at least 0.15 wt% of the total fatty acid content, preferably at least 0.35 wt%, more preferably at least 0.65 wt% of ω-3 LC-PUFA (more preferably DHA and EPA). In one embodiment, the lipid portion comprises at least 0.15 wt% of ω-3 LC-PUFA based on the total fatty acid content, selected from the group consisting of DHA, EPA, and DPA, more preferably DHA and EPA.

[0117] Furthermore, the lipid portion of the nutritional composition preferably includes one or more additional lipid-compatible (hydrophobic) components, such as lipid-compatible vitamins, such as vitamins A, D, and E. The amounts of these vitamins comply with regulations for foods for special medical purposes, such as Directive 1999 / 21 / EC of March 25, 1999, for Foods for Special Medical Purposes (FSMP). In this regard, the amounts of vitamins and minerals depend on the age of the consumer and are therefore preferably in the range of 20% to 100% of the recommended daily intake, more preferably in the range of 50% to 75%.

[0118] Digestible carbohydrates The nutritional composition preferably contains 25-75 wt% of digestible carbohydrates based on the total dry weight of the nutritional composition, more preferably 30-70 wt%, and most preferably 35-65 wt%.

[0119] Preferably, the nutritional composition comprises digestible carbohydrates, such as modified starch and / or natural starch. In the context of this invention, based on Englyst et al., Classification and measurement of nutritionally important starch fractions, Eur J Clin Nutr The method described in [European Journal of Clinical Nutrition], 1992, 46, Supplement 2, pp. 33-50, classifies starch digestion into rapidly digestible starch (RDS), slowly digestible starch (SDS), and resistant starch (RS) fractions. The relative amounts of each fraction are based on the amount of glucose released during in vitro digestion. In the context of this invention, RDS is defined herein as starch digested within 20 minutes of in vitro enteral digestion, SDS is defined herein as starch digested within 20 to 120 minutes of in vitro enteral digestion, and RS is defined herein as starch that remains undigested after 120 minutes of in vitro enteral digestion.

[0120] In the context of this invention, digestible carbohydrates preferably comprise digestible starch, more preferably digestible starch, or also referred to as digestible carbohydrates, and are usable for digestion and glycolysis. In this regard, it should be noted that a source of digestible carbohydrates may simultaneously contain portions of SDS, RDS, and RS. For example, raw corn starch, which can be used as a source of digestible carbohydrates to be administered to patients suffering from carbohydrate-related metabolic disorders, contains portions of RDS, SDS, and RS.

[0121] In a preferred embodiment, the digestible carbohydrate source, more preferably the SDS source, is selected from one or more starch-rich foods such as grains, legumes, roots, and tubers. In a further preferred embodiment, the digestible carbohydrate is selected from corn, maize, wheat, potato, rice, cassava, and / or tapioca starch, more preferably, these digestible carbohydrates include corn starch. Preferably, corn starch is the primary digestible carbohydrate source, more preferably the sole digestible carbohydrate source. Corn starch breaks down into glucose during digestion and contains the majority of SDS. Different starches and corn starch components have varying degrees of tolerance to gastrointestinal digestion. A high proportion of RDS in digestible carbohydrate sources may lead to a rapid rise in postprandial blood glucose, resulting in peak blood glucose levels and stimulating insulin secretion. The increased insulin demand due to elevated plasma glucose levels may be associated with an increased risk of type 2 diabetes mellitus (T2DM). Besides the risk of developing type 2 diabetes mellitus (T2DM), elevated plasma glucose levels may also be associated with the development of other chronic diseases, cardiovascular disease caused by oxidative stress, and obesity. SDS starch may lead to a slow rise in postprandial plasma glucose levels and a sustained release of glucose, thus preventing a sharp initial increase in plasma glucose levels. The starch portion of SDS can support prolonged normal blood glucose in subjects who need it, such as those with gastrointestinal dysplasia (GSD). An excessively high proportion of RS starch can cause gastrointestinal discomfort, including bloating and nausea.

[0122] Preferably, the digestible carbohydrates comprise natural starch or processed starch, wherein the processed starch is increased in SDS content through retrogradation, annealing, or other processes used for modifying starch. In the context of this invention, “natural” starch refers to starch that is untreated or minimally treated, but in all cases, the starch is at least raw starch and therefore contains a higher proportion of SDS. The original particle and crystalline structure of natural starch remains as it is in grains, thus limiting the accessibility of starch to amylases, resulting in slower digestion of natural starch. The “naturalness” of starch refers to its inherent properties, including its structure and behavior in its natural, unmodified state. A common method for assessing the naturalness of starch is through X-ray diffraction analysis.

[0123] In a preferred embodiment, the digestible carbohydrate comprises natural starch, more preferably natural corn starch. If the starch is not natural, the original granular and crystalline structure is likely not present unless such a structure has been intentionally modified in this manner through recrystallization (i.e., retrogradation) during the cooling process after heating. Therefore, in alternative embodiments, the digestible carbohydrate may comprise modified starch, preferably modified corn starch, obtained through recrystallization and / or retrogradation.

[0124] Preferably, the digestible carbohydrates present in the nutritional composition comprise at least 55 wt% SDS based on the total dry weight of the digestible carbohydrates, more preferably at least 60 wt% SDS, and most preferably at least 65 wt% SDS. Preferably, the digestible carbohydrates comprise less than 20 wt% RS based on the total dry weight of these digestible carbohydrates, more preferably less than 15 wt% RS based on the total dry weight of the digestible carbohydrates, and most preferably less than 13 wt% RS. The amount of RDS as part of the digestible carbohydrates is preferably kept low. Preferably, the digestible carbohydrates comprise less than 45 wt% RDS based on the total dry weight of the digestible carbohydrates, more preferably less than 40 wt%, and most preferably less than 35 wt%. In a further preferred embodiment, the dry weight ratio of SDS to RDS is in the range of 1:1 to 2:1, preferably in the range of 1.3:1 to 2:1, and more preferably in the range of 1.5:1 to 2:1.

[0125] Furthermore, in the context of this invention, OSA starch is considered an emulsifier and is not included in the weight of digestible carbohydrates.

[0126] In a preferred embodiment, digestible carbohydrates are added to the spray-dried composition comprising OSA starch and lipids after emulsification and spray drying. Preferably, the digestible carbohydrates comprising slow-digesting starch are added to the spray-dried composition via a dry blend to prevent the carbohydrates from gelatinizing during wet-phase processing.

[0127] Based on the total energy content of the nutritional composition, the digestible carbohydrates in the nutritional composition provide 40 to 65% energy, preferably 45 to 60% energy, and most preferably 50 to 55% energy.

[0128] protein In the emulsification of lipids with OSA starch, only a very limited amount of protein must be present to prevent interference with the migration of OSA starch to the emulsion interface and / or the adhesion of protein, rather than OSA starch, to the emulsion interface. The inventors have surprisingly discovered that the presence of protein or other surfactants at the emulsion interface results in poor tolerance to the gastric environment and destabilizes the emulsion during gastric digestion. Therefore, in the absence or with a limited amount of protein, emulsification of lipids with OSA starch yields a more stable emulsion and an improved OSA starch coating around the lipid globules / lipid core after reconstitution. In this way, the nutrient composition remains stable during gastric digestion after reconstitution. Therefore, it is preferable to add protein to the emulsified O / W composition prior to pasteurization and spray drying and / or as a dry blend after spray drying.

[0129] The nutritional composition according to the invention comprises protein to obtain a more nutritionally complete product. Protein digestion stimulates the secretion of insulin and incretin and helps slow gastric emptying, thereby facilitating the slow release of digestible carbohydrates in the small intestine. Preferably, the nutritional composition comprises 10-35 wt% protein based on the total dry weight of the nutritional composition, more preferably 12-30 wt% based on the dry weight of the nutritional composition, and most preferably 15-27 wt%.

[0130] In a preferred embodiment, the protein is added to an emulsified O / W composition, followed by pasteurization and spray drying. Preferably, the protein is present in a second aqueous phase, which is added to an emulsified O / W composition containing lipids and OSA starch to obtain a mixture.

[0131] If protein is present during emulsification, it is preferably present in an amount of less than 4 wt%, more preferably less than 3 wt%, and most preferably less than 1 wt%, based on the total dry weight of the emulsified O / W composition. In other words, less than 4 wt%, preferably less than 3 wt%, and more preferably less than 1 wt%, of protein is present in the first aqueous phase and the emulsified O / W composition of step (a), based on the total protein weight in the nutrient composition. Regarding the nutrient composition, less than 4 wt%, preferably less than 3 wt%, and more preferably less than 1 wt%, of protein is present together in the lipid core and its OSA starch coating, based on the total protein weight in the nutrient composition. Preferably, no protein is added before and during the emulsification of the lipid with the aqueous phase and OSA starch. Therefore, with no protein or low protein in the lipid core, a gastric-stabilized emulsion is obtained that degrades less in the acidic environment of the stomach and releases nutrients more slowly.

[0132] Based on the total energy content, the protein in the nutritional composition preferably provides 5 to 35 en%, more preferably 10 to 30 en%, and most preferably 15 to 25 en%, based on the total energy content of the nutritional composition. In the current diets of GSD patients, the main energy source is digestible carbohydrates. However, the risk of high carbohydrate intake involves a higher probability of developing hyperinsulinemia. Therefore, it is preferable that the nutritional composition also provides sufficient protein to serve as a metabolic compound and energy supplier in the gluconeogenesis pathway, as well as as a building block for muscle growth.

[0133] Suitable examples of proteins that can be advantageously added to emulsified O / W compositions and / or powdered O / W compositions are proteins derived from dairy, plant, or microbial sources, preferably selected from whey proteins and / or proteins selected from legume proteins, oilseed proteins, cereal proteins, and / or fungal proteins, more preferably selected from one or more of potatoes, cereals such as wheat and / or rice, peas, soybeans, or beets, and mixtures thereof. Optionally, the protein may be completely or partially hydrolyzed or contain free amino acids. Preferably, the protein source involves whole proteins or proteins that are at least 90% whole based on the protein fraction. Mixtures of several protein sources and mixtures of whole proteins and hydrolyzed proteins may also be used. Most preferably, the protein comprises whole whey proteins.

[0134] The degree of hydrolysis of whey protein is measured as the "degree of hydrolysis" (DH). DH is defined as the percentage of the total number of peptide bonds in the protein cleaved during hydrolysis, and is therefore used as a measure of the integrity of the whey protein. The DH of a protein can be determined, for example, by a trinitrobenzenesulfonic acid (TNBS) procedure as known in the art (Adler-Nissen, J. Agr. Food Chem. 1979, 27(6), 1256). When whey protein is hydrolyzed, the whey protein source may already contain a certain (small) amount of peptide moiety prior to the hydrolysis process. The value of the degree of hydrolysis, as described herein, is corrected according to the presence of this peptide moiety in the whey protein source; in other words, the value of the DH is corrected according to the natural DH of the whey protein. Therefore, in this document, DH refers to additional hydrolysis obtained via a targeted hydrolysis process. When a nutritional composition contains hydrolyzed whey protein, it preferably has a degree of hydrolysis of 1% to 75%, preferably in the range of 5% to 60%, and more preferably in the range of 10% to 50%. As described above, the degree of hydrolysis used herein is corrected for the natural degree of hydrolysis of the whey protein source (i.e., the whey protein used to prepare the hydrolyzed whey protein). In a preferred embodiment, the protein comprises intact whey protein that has not undergone a hydrolysis process, i.e., has not been subjected to additional hydrolysis obtained through an intentional hydrolysis process.

[0135] In alternative embodiments, the protein may be produced or obtained through precise fermentation. In cases where the protein source has poor aggregation properties and is therefore less suitable for spray drying, such as protein hydrolysates and free amino acids, it is preferable to add these hydrolysates and / or amino acids to the stomach-stabilized spray-dried composition during a dry blending step.

[0136] Encapsulating agent - resistant maltodextrin In a preferred embodiment, the nutritional composition comprises an encapsulating agent. The role of the encapsulating agent is to stabilize the composition during the (spray) drying process and to protect the composition, particularly the lipids therein, from degradation or undesirable interactions with the surrounding environment. In a preferred embodiment, prior to spray drying, the encapsulating agent coats lipids and any additional ingredients added to the composition; more preferably, the encapsulating agent coats lipid particles, thereby forming an additional coating on lipids coated with OSA starch. In a further preferred embodiment, when other additional ingredients (preferably proteins) are added to the composition prior to spray drying, the encapsulating agent also coats these additional ingredients, preferably proteins. The encapsulating agent helps to form a protective barrier around the particles in the spray-dried composition, thereby retaining its properties and functions in the powdered product. Encapsulating agents or spray dryers used for microencapsulation of the composition are essential for achieving high encapsulation efficiency, high drying efficiency, and high stability of microcapsules. Maltodextrin or other rapidly digestible carbohydrates are commonly used as spray dryers to produce nutritional powder products by reducing thermoplasticity and hygroscopicity, as well as viscousness and product deposition.

[0137] In a preferred embodiment, the encapsulating agent The glycemic index is in the range of 0 to 50, preferably in the range of 0 to 25. More preferably, the encapsulating agent comprises resistant maltodextrin. In this article, the glycemic index (GI) is a commonly used term to characterize foods, particularly sugars and carbohydrates, ranging from 0 to 100. In this article, a GI of 0 means that the food, sugar, carbohydrate, etc., will not raise blood sugar levels at all. A GI of 100 raises blood sugar levels almost immediately, and this value is typically used to characterize pure glucose.

[0138] In addition, the encapsulating agent is a food-grade encapsulating agent, which means that the encapsulating agent is safe for consumption. More preferably, the encapsulating agent is selected from maltodextrin, glucose syrup, trehalose, maltose, amylose and / or amylopectin, and even more preferably, the encapsulating agent is maltodextrin, and most preferably resistant maltodextrin.

[0139] In one embodiment, OSA starch may also be used or used as the encapsulating agent described herein; when OSA starch is also used or used as the encapsulating agent, the amount of OSA starch described herein is the sum of the amounts of OSA starch in the encapsulating agent and the OSA starch in the coated lipid core. Furthermore, OSA starch may also be used as an encapsulating agent to form an additional coating on lipid particles and other components (e.g., proteins on the first OSA starch layer with the coated lipid core).

[0140] However, it is preferred that the encapsulating agent according to the invention is not OSA starch and does not contain OSA starch.

[0141] The nutritional compositions according to the invention preferably comprise resistant maltodextrin to facilitate the drying and coating of OSA starch-stabilized emulsions. Resistant maltodextrin avoids the rapid carbohydrate digestion seen when using conventional maltodextrin as a processing aid for encapsulating emulsions, as it avoids the glucose release or “peak” observed after consuming the diet or product, an undesirable effect in the patient group considered herein. Resistant maltodextrin is a soluble fiber with high digestive tolerance and therefore can enter the large intestine relatively intact. Examples of commercially available resistant maltodextrins are Promitor® soluble fiber (from Tate & Lyle) and Fibersol®-2 (from Fibersol®).

[0142] In a preferred embodiment, the nutrient composition comprises 2 to 15 wt%, preferably 1.5 to 12 wt%, and most preferably 3 to 9 wt% of an encapsulating agent based on the total dry weight of the nutrient composition.

[0143] Food-grade pH adjusting ingredients The nutritional compositions according to the invention preferably contain a food-grade pH adjuster to lower the pH of the nutritional composition to an acidic value when reconstituted for consumption and when the nutritional composition is in liquid form. Enzymatic digestion of digestible carbohydrates begins in the oral cavity, where α-amylase initiates the digestion of starch into shorter chains. Carbohydrate digestion continues further in the acidic environment of the stomach, where α-amylase continues to hydrolyze starch until it is inactivated at a pH below 4.0 due to gastric acid secretion in the gastric lumen. During in vitro starch digestion simulations, salivary α-amylase can retain most of its initial enzymatic activity even after incubation with simulated gastric juice at pH 4.0. This is likely related to the buffering effect of food ingestion, most likely allowing for prolonged enzymatic activity of salivary α-amylase after ingestion. The optimal pH for salivary α-amylase activity is between 6.5 and 7.0, and it is considered inactive or at least significantly less active at pH below 5.0. Therefore, it is preferable that the pH of the nutritional composition is lower than the optimal pH for salivary α-amylase activity to reduce carbohydrate digestion, maintain a more gastric-stable composition, and further slow down glycolysis in the stomach. In a preferred embodiment, a food-grade pH adjuster is added to obtain a liquid or reconstituted nutritional composition with a pH below 5.0, preferably between 3.5 and 4.5, and more preferably between 3.8 and 4.2.

[0144] Furthermore, when the nutritional composition is used for reconstitution and contains a food-grade pH adjuster, the pH of the nutritional composition is preferably in the range of 3.0-5.0 when dissolved as a 50% w / v aqueous solution at room temperature, more preferably in the range of 3.5-4.5, and most preferably in the range of 3.8-4.2. Powdered nutritional compositions do not have a pH value, therefore the pH of the composition after reconstitution in water is relevant. In alternative embodiments, when the nutritional composition is in packaged, ready-to-use liquid form and contains a food-grade pH adjuster, the pH of the nutritional composition is preferably in the range of 3.0-5.0 at room temperature, more preferably in the range of 3.5-4.5, and most preferably in the range of 3.8-4.2. It is not desirable to be bound by theory, but it is assumed that the low pH of the nutritional composition after reconstitution minimizes salivary α-amylase activity, thereby slowing carbohydrate digestion in the mouth and stomach while maintaining acceptable sensory properties.

[0145] Food-grade pH adjusters, also known as food-grade acidity regulators, are food additives that control the acidity or alkalinity of food and are generally considered safe for consumption (GRAS). Food-grade pH adjusters are preferably acidifiers that can be added to nutritional compositions to obtain a nutritional composition with an acidic pH value, at which the enzymatic activity of salivary α-amylase is reduced upon consumption. The nutritional composition preferably contains 2-14 wt% of the food-grade pH adjuster based on the total dry weight of the nutritional composition, more preferably 4-12 wt%, and most preferably 6-10 wt%.

[0146] Food-grade pH adjusters preferably comprise organic or inorganic acids. In preferred embodiments, the pH adjuster comprises an organic acid selected from the group consisting of citric acid, lactic acid, acetic acid, ascorbic acid, malic acid, tartaric acid, or mixtures thereof; more preferably, the food-grade pH adjuster comprises at least citric acid. In alternative embodiments, the food-grade pH adjuster is an inorganic acid selected from the group consisting of hydrochloric acid and / or phosphoric acid. In the most preferred embodiment, the food-grade pH adjuster is citric acid, particularly anhydrous citric acid.

[0147] In a preferred embodiment of the method according to the invention, a food-grade pH adjuster is added to a first aqueous phase and / or to a second aqueous phase, and / or added as an additional component to a mixture subjected to spray drying, and / or dry-blended into a spray-dried composition; more preferably, the food-grade pH adjuster is dry-blended into a spray-dried composition.

[0148] Other components The nutritional compositions according to the invention preferably contain additional components to obtain a nutritionally complete composition. For subjects who rely primarily on, for example, a single nutritional source, their nutritional needs must be met to ensure the development and maintenance of essential biological processes. For example, patients with GSD consume relatively large amounts of digestible carbohydrates as part of their dietary therapy while restricting the intake of other foods (such as lactose and fructose), thus placing them at higher risk of deficiencies in certain nutrients. Therefore, the bioavailability and bioavailability of minerals and trace elements in nutritional products should be high.

[0149] Therefore, the nutritional compositions of the present invention are preferably supplemented with additional ingredients, such as additional proteins (protein hydrolysates and / or amino acids), additional lipids, additional carbohydrates (digestible and indigestible), minerals, vitamins, biotin (one or more of probiotics, prebiotics, and / or post-biotics), additional trace elements, or other micronutrients such as nucleotides. Preferably, at least vitamins and minerals are added to the nutritional composition to provide a nutritionally complete composition. Optionally, the nutritional compositions of the present invention may be further supplemented with biotin, flavoring agents, coloring agents, and / or sweeteners.

[0150] Preferably, prior to spray drying, additional components are added to the emulsified O / W composition, as well as to the composition present in the spray-dried composition, and / or dry-blended into the spray-dried composition according to the method of the invention.

[0151] In the embodiments, dietary fiber is also included in the nutritional composition. In a preferred embodiment, the dietary fiber comprises fructooligosaccharides, galactooligosaccharides, galacturonic acid oligosaccharides, and more preferably fructooligosaccharides and galactooligosaccharides. In a preferred embodiment of the method according to the invention, the dietary fiber is added to the spray-dried composition in the dry blending step because the fiber is prone to gelatinization, and gelatinization can be avoided as much as possible when these fibers do not undergo spray drying conditions. Preferably, the nutritional composition of the invention includes prebiotics and / or postbiotics. In a preferred embodiment of the method according to the invention, the prebiotics and / or postbiotics are added to the spray-dried composition in the dry blending step because subjecting these to spray drying conditions may reduce their activity.

[0152] In a preferred embodiment, the nutritional composition is supplemented with calcium and / or vitamin D, as patients with ketoacidosis-related GSD have reportedly experienced decreased bone mineral density. In a further preferred embodiment, the nutritional composition is further supplemented with vitamin C, vitamins B1, B2, B3, B5, B6, B9, B11, and B12, copper, iodine, iron, magnesium, manganese, molybdenum, selenium, zinc, vitamin B2, and vitamin B5. In the embodiments, the vitamins and minerals are preferably present in therapeutically effective amounts and refer to at least 1, preferably 1.1, and more preferably 1.3 times the recommended daily intake. The RDI is a commonly used reference in the art, such as the population reference intake (PRI) referred to herein, as determined by the Summary of Dietary Reference Values ​​for the EU population obtained by the European Safety Authority in September 2017. Recommended daily intakes are defined by agencies such as EFSA or the FDA.

[0153] Suitable examples of vitamins include vitamins A, B1, B2, B3, B5, B6, B9, B11, B12, C, D, E, and K. The products and methods of the present invention are compatible with fat-soluble and water-soluble vitamins, as well as water-soluble and water-insoluble minerals. In a preferred embodiment, in the method of preparing the spray-dried composition, a more lipid-compatible vitamin (such as vitamins A, D, E, and K) is added to the lipids and thus to the spray dryer. In another preferred embodiment, a more water-compatible vitamin, such as vitamins B and C, and water-soluble minerals such as calcium and magnesium are added to a first or second aqueous phase, or alternatively, to the spray-dried composition in a dry blending step. In a further preferred embodiment, water-insoluble minerals such as iron, zinc, and copper are added to the emulsified O / W composition in an encapsulated form, or to the spray-dried composition via a dry blending step, prior to the composition undergoing spray drying.

[0154] In the most preferred embodiment, the nutritional composition comprises one or more ingredients selected from the group consisting of: calcium, copper, iron, magnesium, zinc, vitamin B2, vitamin B5, and vitamin D.

[0155] Nutritional composition In a preferred embodiment, the nutritional composition according to the invention is a powder. In an alternative embodiment, the nutritional composition according to the invention is a liquid ready-to-eat composition. Preferably, the nutritional composition is administered orally or via tube feeding.

[0156] In a preferred aspect, the nutritional composition according to the invention can be used as a nutritional product, for example as a nutritional supplement, as an additive to a normal diet, as a fortifier added to a normal diet, or as a complete nutrient, preferably, the nutritional composition is nutritionally complete. In a preferred embodiment, the nutritional composition (nutritional complete) is not the only food consumed, but preferably, the nutritional composition is consumed daily in one or more doses by the subject in need. For example, patients with GSD may consume the nutritional composition before or with meals during the day, and the nutritional composition may also be used as the sole intake at night or before bedtime.

[0157] Preferably, each 100 g dry weight of the nutritional composition contains 325 to 500 total calories, more preferably 350 to 450 total calories. The nutritional composition may contain a daily dose as defined below in one or more dosage units. In a further preferred embodiment, each dosage unit of the nutritional composition provides 10 en% to 50 en% of the required daily energy expenditure, more preferably 15 en% to 40 en% of the required daily energy expenditure.

[0158] Preferably, the nutritional composition is a shelf-stable product. A shelf-stable product refers to a packaged food or beverage that can be stored at room temperature for an extended period without refrigeration or freezing to maintain its quality, safety, and stability. These products are designed to have a long shelf life and be safe for consumption, preferably at least 30 days, during the extended period. The nutritional composition of the present invention is preferably a packaged product ready for transport and sale. Therefore, the composition is preferably a solid (typically a powder or tablet, preferably a powder) that can be reconstituted in a liquid to provide a ready-to-eat liquid nutritional product. In a preferred embodiment, when the nutritional composition is a powder or tablet, the nutritional composition comprises particles containing (digestible) carbohydrates and lipid-containing particles, wherein the lipid-containing particles are coated with an encapsulating agent, and wherein the lipid-containing particles have a lipid-containing core coated with OSA starch.

[0159] Preferably, the nutrient composition is reconstituted in water. Typically, 50-75 grams of the nutrient composition is dissolved in 100 to 300 ml of liquid (preferably water).

[0160] The nutritional composition preferably comprises digestible carbohydrates, proteins, lipids, OSA starch, encapsulating agents, and optionally food-grade pH adjusters. The nutritional composition preferably comprises vitamins, minerals, and trace elements in amounts sufficient to meet the needs of the subjects in need. The amounts of vitamins, minerals, and trace elements comply with regulations for foods for special medical purposes, such as Directive 1999 / 21 / EC of March 25, 1999, for Foods for Special Medical Purposes (FSMP). In this regard, the amounts of vitamins and minerals depend on the age of the consumer and are preferably in the range of 20% to 100% of the recommended daily intake, more preferably in the range of 50% to 75%.

[0161] Preferably, the dry weight ratio of OSA starch to lipids in the nutritional composition is in the range of 1:3 to 1:5, more preferably in the range of 1:3.5 to 1:4.5. These ratios are also preferably applicable to intermediate compositions prior to the final nutritional composition, i.e., the emulsified O / W composition and the (nutritional) spray-dried composition as described above.

[0162] In embodiments of the invention, the nutritional composition comprises lipids, OSA starch, protein, an encapsulating agent, and digestible carbohydrates, wherein the composition comprises lipid-containing particles having a lipid-containing core, wherein the lipid core is coated with OSA starch, and wherein the lipid core and the OSA starch coating contain less than 4 wt% protein based on the total protein weight in the nutritional composition. Preferably, the OSA starch coating prevents the lipid core from contacting the protein-containing outer layer, and / or prevents the lipid core from contacting proteins adsorbed onto the OSA starch coating or forming a separate layer on the OSA starch coating.

[0163] Preferably, based on the total dry weight of the composition, the nutritional composition comprises: - At least 10 wt% lipids; preferably, the lipids comprise sunflower seed oil; -1-14 wt% OSA starch, preferably 2-10 wt%, more preferably 2-6 wt%; -25 - 75 wt% of digestible carbohydrates, wherein these digestible carbohydrates contain digestible starch, preferably at least 55 wt% of slow-digestible starch based on the total dry weight of these digestible carbohydrates; -2 - 15 wt% of encapsulating agent, wherein the encapsulating agent contains resistant maltodextrin; -10 - 35 wt% protein, preferably intact whey protein.

[0164] Preferably, based on the total number of lipid particles in the nutritional composition, the number of lipid globules (also known as lipid particles) not coated with OSA starch in the nutritional composition is less than 10%, more preferably less than 8%, and most preferably less than 4%.

[0165] More preferably, the nutritional composition comprises lipid-containing particles coated with an encapsulating agent, wherein the lipid-containing particles have a lipid-containing core, and the core is coated with OSA starch. Optionally, the lipid-containing particles further comprise an outer layer comprising proteins and optionally additional components. In a preferred embodiment, the lipid-containing particles are coated with an encapsulating agent and / or the outer layer of these lipid-containing particles is surrounded by an encapsulating agent, which prevents the lipid-containing particles and / or the outer layer from contacting additional components adsorbed on or forming a separate layer on the encapsulating agent. In a further preferred embodiment, the encapsulating agent coating is a layer of encapsulating agent surrounding the lipid-containing particles. Furthermore, in a further preferred embodiment, the nutritional composition comprises aggregates of lipid-containing particles, and these aggregates optionally comprise an outer layer comprising proteins and additional components, wherein these aggregates are coated with an encapsulating agent.

[0166] The use of OSA starch as an emulsifier is particularly compatible with nutritional compositions containing slow-digesting starch (SDS) to prolong gastric emptying and promote the slow release of SDS contained in the nutritional composition. In a preferred embodiment, the nutritional composition contains 25-75 wt% digestible carbohydrates, wherein the digestible carbohydrates comprise digestible starch, preferably at least 55 wt% SDS. Preferably, the nutritional composition contains natural corn starch as a source of SDS.

[0167] In a further preferred embodiment, the amount of resistant starch (RS) in the nutritional composition is preferably kept low. In this regard, in addition to digestible carbohydrates, OSA starch as an emulsifier and resistant maltodextrin as an encapsulating agent also contain a portion of RS, as described by Englyst et al. (1992). Therefore, in a preferred embodiment, based on the total dry weight of the nutritional composition, the total proportion of RS in the nutritional composition is preferably less than 30 wt%, more preferably less than 15 wt%, and most preferably less than 10 wt%.

[0168] In addition to digestible carbohydrates, the OSA starch as an emulsifier and the resistant maltodextrin as an encapsulating agent also contain a portion of rapidly digestible starch (RDS), as described by Englyst et al. (1992). Therefore, in a preferred embodiment, the total proportion of RDS in the nutritional composition is preferably less than 18 wt%, more preferably less than 14 wt%, and most preferably less than 12 wt%, based on the total dry weight of the nutritional composition.

[0169] The nutritional composition preferably conforms to the definition of food for special medical purposes, as defined in accordance with Directive 1999 / 21 / EC of 25 March 1999 on Foods for Special Medical Purposes (FSMP) and Article 2.2(g) of Commission Regulation (EU) 609 / 2013.

[0170] In a preferred embodiment, the nutritional composition according to the present invention comprises per 100 kcal: -1 - 5 g of lipid, more preferably 1.5 - 4.5 g, most preferably 2 - 4 g, preferably the lipid comprises sunflower seed oil; -2-9 g of protein, more preferably 3-8 g, most preferably 4-7 g, preferably the protein contains complete whey protein; -6 - 18 g of digestible carbohydrates, more preferably 8 - 16 g, most preferably 10 - 14 g, preferably wherein the digestible carbohydrate portion comprises 3.3 - 9.9 g of slowly digestible starch (SDS), more preferably 4.4 - 8.8 g of SDS, most preferably 5.5 - 7.7 g of SDS; -0.3 - 1.1 g OSA starch, more preferably 0.4 - 1 g, most preferably 0.5 - 0.9 g; -1 - 2.5 g of encapsulating agent, more preferably 1.4 - 2 g, most preferably 1.5 - 1.9 g, wherein the encapsulating agent preferably comprises resistant maltodextrin; - Optionally 0.3 - 1.1 g of food-grade pH adjuster, more preferably 0.4 - 1 g, most preferably 0.5 - 0.9 g, wherein the pH adjuster preferably contains citric acid.

[0171] In a preferred embodiment, the daily dose for subjects aged 1-8 years is preferably 2-4 grams of the nutritional composition per kg of body weight (before reconstitution). In a further preferred embodiment, the daily dose for subjects aged 8 years to the end of puberty is preferably based on 80-200 g of the nutritional composition by dry weight, more preferably 100-150 g, and most preferably 135-150 g of the nutritional composition. In another preferred embodiment, the daily dose for adult subjects comprises based on 50-250 g of the nutritional composition by dry weight, more preferably 75-200 g, and most preferably 90-150 g of the nutritional composition. In a further preferred embodiment, based on total daily energy intake, the daily dose of the composition according to the invention contains 15-85% en%, more preferably 25-75% en%, preferably wherein the total daily energy intake is 1500-3500 calories, more preferably 1800-3000 calories.

[0172] In a preferred embodiment, the daily dose of the composition according to the invention comprises, -13 - 21 g of lipid, more preferably 14 - 19 g, most preferably 15 - 18 g, preferably the lipid comprises sunflower seed oil; -21 - 35 g of protein, more preferably 23 - 31 g, most preferably 25 - 29 g, preferably the protein contains intact whey protein; -48 - 81 g of digestible carbohydrates, more preferably 54 - 73 g, most preferably 59 - 68 g, preferably wherein the digestible carbohydrate portion comprises 26 - 45 g of slow-digesting starch (SDS), more preferably 29 - 41 g of SDS, most preferably 32 - 38 g of SDS; -2.7 - 4.5 g OSA starch, more preferably 3.0 - 4.1 g, most preferably 3.3 - 3.8 g; - 6.3 - 10.5 g of encapsulating agent, more preferably 7.0 - 9.5 g, most preferably 7.7 - 8.8 g, wherein the encapsulating agent preferably comprises resistant maltodextrin; - Optionally 2.7 - 4.5 g of food-grade pH adjuster, more preferably 3.0 - 4.1 g, most preferably 3.3 - 3.8 g, wherein the pH adjuster preferably contains citric acid.

[0173] Application of nutritional compositions The nutritional compositions according to the invention are particularly suitable for use in reducing and / or treating carbohydrate-related metabolic disorders. The invention relates to a method for reducing and / or treating carbohydrate-related metabolic disorders, the method comprising administering the nutritional composition according to the invention to a subject. In other words, the invention relates to the use of OSA starch in the manufacture of nutritional compositions for reducing and / or treating carbohydrate-related metabolic disorders. The method or use is preferably for reducing and / or treating diabetes, glycogen storage disease (GSD), fatty acid oxidation disorder (FAOD), and / or idiopathic ketotic hypoglycemia (IKH), and most preferably for use in GSD subtypes 0, III, VI, and IX. These GSD subtypes are so-called ketotic subtypes associated with glycogen storage in the liver and require relatively high protein intake in addition to slowly digestible carbohydrates. In this respect, the nutritional compositions are suitable for all age groups, preferably for children aged 1 year and older, adolescents, young adults, adults, and the elderly.

[0174] In a further preferred embodiment, the administration regimen of the nutritional composition is: - For subjects aged 1–8 years, 2–3 dose units of the nutritional composition, wherein the dose units are based on body weight and each dose unit contains 1–1.5 g of the nutritional composition per kg of body weight; and / or; - For subjects aged 8-18 years, 2-3 dose units of nutritional composition, wherein the daytime dose unit contains 45-50 g of nutritional composition based on dry weight, and the nighttime dose unit is based on body weight and contains 1-1.5 g of nutritional composition per kg of body weight; - For subjects aged 18 years or older, a nutritional composition of 2-3 dose units, where each dose unit contains 45-50 g of nutritional composition based on dry weight; and / or In a preferred embodiment, diabetes, GSD, FAOD, and / or IKH are reduced and / or treated through disease management, more preferably by reducing the occurrence of symptoms associated with the disease. In a preferred embodiment, the term "reduction and / or treatment" herein means prevention and / or reduction of the occurrence and intensity of symptoms of the disorder / disease. In a further preferred embodiment, reduction and / or treatment of diabetes, GSD, FAOD, and / or IKH is achieved by preventing and / or reducing one or more of insomnia or sleep deprivation, impaired normoglycemia, fasting hypoglycemia, hyperinsulinemia, insulin resistance, and gastrointestinal side effects (including one or more of bloating, flatulence, and diarrhea). In a further preferred embodiment, reduction and / or treatment of diabetes, GSD, FAOD, and / or IKH is achieved by maintaining normal blood glucose levels, slowing gastric emptying rate, prolonging carbohydrate digestion, and prolonging glycolysis during digestion.

[0175] The composition according to the invention ensures that lipids are evenly distributed throughout the gastric digestate. Thus, lipids and other nutrients are emptied from the stomach together. Upon reaching the small intestine, the lipid digestion products trigger a hormonal feedback response (CCK), slowing gastric emptying and thereby controlling bolus digestion and overall glucose release.

[0176] In another embodiment, the method is a non-therapeutic method, preferably selected from one or more of the following non-therapeutic methods: slowing the gastric emptying rate, maintaining normal blood glucose, prolonging carbohydrate digestion, and / or prolonging glycolysis during digestion in healthy subjects (such as athletes) who need to prolong gastric emptying or carbohydrate digestion.

[0177] In another alternative embodiment, the present invention relates to the use of the nutritional compositions according to the invention in the manufacture of products for reducing and / or treating carbohydrate-related metabolic disorders, more preferably for use in reducing and / or treating diabetes, glycogen storage disease (GSD), fatty acid oxidation disorder (FAOD) and / or idiopathic ketotic hypoglycemia (IKH), and most preferably for use in products used in liver-related GSD subtypes 0, III, VI and IX.

[0178] Patients with gastrointestinal dysplasia (GSD) are a particularly preferred target group for nutritional supplements because they cannot (completely) break down glycogen to provide energy and therefore must frequently consume carbohydrate-rich meals and consume slowly digestible carbohydrates to maintain normal blood glucose levels throughout the 24-hour period and avoid excessive glycogen storage in the liver. This impacts the quality of life for patients and their families, as it often leads to sleep deprivation at night. Current treatment options involve supplementing with raw cornstarch (such as cornmeal). This approach is not ideal because patients still face limited fasting periods, directly affecting their sleep and quality of life, and may also lead to additional mealtimes or overeating. Current treatments are nutritionally inadequate, with high carbohydrate intake causing macronutrient imbalances and gastrointestinal side effects (such as bloating), as well as other metabolic abnormalities (such as lactic acidosis and lipid distribution imbalances). This differs from maintaining normal blood glucose levels in diabetic patients, who are still able to store and break down glycogen for energy, and involves hormonal imbalances that are typically treated with hormone supplementation, whereas GSD cannot be treated by supplementing with one or more deficient enzymes. In addition, it is recommended that people with diabetes follow a ketogenic diet, but this is not feasible for people with GSD, as these patients must include digestible carbohydrates as part of their dietary intake.

[0179] The relatively high protein level in a nutritional composition can be beneficial for patients with GSD: when the gluconeogenesis pathway is intact, protein-derived alanine can serve as an alternative source of glucose during fasting. Higher dietary protein intake can also improve muscle function by enhancing muscle protein synthesis and providing a balanced ratio between carbohydrates and protein, reducing unnecessary glycogen storage. Furthermore, the protein in the nutritional composition can support the prevention of hyperinsulinemia, which is commonly observed in patients with GSD due to high carbohydrate intake. Another benefit of the relatively high protein level in the nutritional composition is that it improves the palatability of the food.

[0180] Example The present invention is illustrated in the following examples.

[0181] Example 1. Emulsion stability using OSA starch as an emulsifier In this example, the emulsification of OSA starch and protein by one-step dispersion and homogenization will be compared with the emulsification of OSA starch by splitting alone.

[0182] In the production of the first wet phase emulsion, a water-soluble component containing 56 g of protein (whey protein hydrolysate, Lacprodan DI-3091, Arla), 6.5 g of OSA starch as an emulsifier (HICAP-IMF, Ingredion), and 10 g of resistant maltodextrin as an encapsulating agent (hydrolyzed corn starch, Nutriose FM06, Roquette) is simultaneously processed and homogenized with 28 g of lipids (sunflower oil HOA; high oleic acid) to form a wet phase emulsion in which OSA starch and protein are present at the emulsion interface.

[0183] In the split-flow method for preparing the second wet-phase emulsion, a liquid composition comprising 28 g of lipids (sunflower seed oil HOA; high oleic acid), 6.5 g of OSA starch (HICAP-IMF, Irvine), and 10 g of resistant maltodextrin (hydrolyzed corn starch, Nutriose FM06; Roquette) is homogenized / emulsified in the absence of protein. 56 g of protein (whey protein hydrolysate, Lacprodan DI-3091, Arla) is hydrated in a separate wet phase and subsequently homogenized together with the emulsified liquid composition comprising lipids, OSA starch, and resistant maltodextrin via a split-flow method to obtain a second wet-phase emulsion in which OSA starch is present only at the emulsion interface.

[0184] The stability of two wet-phase emulsions was compared by allowing the emulsified liquid compositions to stand untouched in glass beakers at room temperature for 4 hours. The dispersions of the emulsion compositions were then visually compared. After treatment of the lipids in the presence of protein and OSA starch, the first wet-phase emulsion showed instability within 4 hours, manifested as a sediment layer at the bottom of the glass beaker, indicating decomposition or “oil precipitation” of the emulsion composition. The second wet-phase emulsion (which underwent a splitting process where no protein was present during the emulsification of lipids with OSA starch) remained stable for over a day and, unlike the first wet-phase emulsion, showed no sedimentation or any “oil precipitation” at the bottom of the glass beaker.

[0185] In this regard, the instability of the wet phase emulsion after 4 hours of homogeneous processing of lipids and proteins at room temperature indicates that the emulsion composition may not remain stable after (1) being retained at 70°C before spray drying and (2) being reconstituted by the consumer, (3) being consumed and (4) being digested in the stomach in an acidic environment for 3-5 hours, and is therefore unsuitable for patients with GSD who have prolonged gastric emptying.

[0186] Example 2. Reconstituted base powder containing OSA starch and citric acid, reconstituted UCCS powder, and reconstituted nutrient composition. Features The matrix characteristics and product stability of the reconstituted base powder (also known as “neutral base powder”, with pH 7) and the base powder acidified to pH 4 with citric acid (hereinafter referred to as “acidic base powder”, anhydrous citric acid (Jungbunzlauer)) were examined visually over time, by particle size distribution, and by microscopy. The base powders described herein do not contain a carbohydrate portion. Comparisons were also made with the acidified and neutral forms of the final nutritional product further containing raw corn starch (corn starch, Irvine).

[0187] 40 g of neutral base powder was reconstituted in 200 g of water. The base powder was obtained by a split-flow method, in which lipids were emulsified with OSA starch, and then proteins from a separate wet phase were added to the emulsion composition, followed by spray drying. The base powder consisted of 6.5 g OSA starch / 100 g base powder, 28 g sunflower seed oil / 100 g, 56 g whey protein hydrolysate / 100 g, and 10 g resistant maltodextrin / 100 g. An acidic base powder was prepared by reconstituted 40 g of neutral base powder with 6.2 g anhydrous citric acid in 200 g of water.

[0188] The neutral nutrient composition powder consisted of 2.8 g OSA starch / 100 g nutrient composition powder, 12 g sunflower seed oil / 100 g, 24 g whey protein isolate / 100 g, 4.4 g resistant maltodextrin / 100 g, and 56 g UCCS. 93 g of the nutrient composition powder was reconstituted in 200 g of water. The reconstituted acidic nutrient composition powder consisted of 2.5 g OSA starch / 100 g nutrient composition powder, 11.5 g sunflower seed oil / 100 g, 23 g whey protein isolate / 100 g, 4 g resistant maltodextrin / 100 g, and 53 g UCCS (corn starch, Yiruian Company). Additionally, a sample containing 56 g of UCCS was prepared and reconstituted in 215 g of water.

[0189] Visual observation After reconstitution in water and 4 hours later, the reconstituted acidic and neutral base powders, acidic and neutral composite powders, and reconstituted UCCS powder were directly visually observed. The UCCS samples showed that insoluble starch granules precipitated almost immediately after reconstitution, forming a viscous sediment. No foaming was observed.

[0190] During the reconstitution of all other powders, foams that do not easily disintegrate are formed. The foaming is more pronounced in the reconstituted acidic base powders and acidic nutrient composition powders. In this respect, acidic powders appear more viscous after reconstitution. This foaming is not unexpected, as higher viscosity increases foam stability due to greater drainage resistance, thus explaining why acidic powders show more pronounced foaming after reconstitution.

[0191] Four hours after reconstitution, the neutral base powder showed only minimal sedimentation, and no lipid oil precipitation was observed in the base powder. The reconstituted neutral nutrient composition powder also showed starch sedimentation at the bottom of the glass beaker, although this sedimentation layer was less pronounced compared to the UCCS sample. For both the reconstituted acidic base powder and the reconstituted acidic nutrient composition powder, aqueous layers formed at the top and bottom of the solution, respectively, within two hours of reconstitution. When the reconstituted acidic powder was stirred with a spoon, the product returned to its original state, exhibiting a uniform dispersion without any aqueous layer.

[0192] Microscope imaging Furthermore, the reconstituted powder was observed under a microscope 4 hours after reconstitution. Eight samples were prepared and observed: (1) Undiluted neutral base powder at 10x magnification, (2) Neutral base powder diluted 10x at magnifications of 10x and 40x. (3) Undiluted acidic base powder at 10x magnification, (4) Acidic base powder diluted 10x at magnifications of 10x and 40x. (5) Undiluted neutral nutrient composition powder at 10x magnification, (6) Neutral nutrient composition powder diluted 10x at magnifications of 10x and 40x. (7) Undiluted acidic nutrient composition powder at 10x magnification, and (8) Reconstituted acidic final nutrient powder diluted 10x at magnifications of 10x and 40x.

[0193] Due to the non-uniform distribution of the sample and the phase separation of the UCCS sample, no microscopic images were obtained from the UCCS sample.

[0194] As expected, micrographs of the neutral base powder showed the presence of uniformly sized emulsion droplets without any signs of instability, i.e., agglomeration or aggregation. The proteins added to the emulsified liquid composition were hydrated using a split-flow method and then added to the base powder after emulsification, and therefore could not be observed in the micrographs. Furthermore, micrographs of the reconstituted neutral nutrient composition powder showed larger starch granules trapped between the uniformly sized emulsion droplets, revealing a uniform dispersion of lipid droplets coated with OSA starch and UCCS particles as the primary carbohydrate source. Micrographs of the neutral nutrient composition powder showed a low number of starch granules in the well-dispersed emulsion matrix.

[0195] Micrographs of the undiluted acidic base powder show the formation of a gel network, which appears to break down into granular clusters upon 10x dilution. A similar network is also observed in the acidic nutrient composition powder. In the micrographs of the acidic nutrient composition powder, numerous starch granules are visible, seemingly trapped within the gel network.

[0196] The formation of a water layer in an acidic matrix is ​​explained by the assumption that the gel network can only hold a certain amount of water, and that residual water is expelled through dehydration and shrinkage. The retention of a large number of starch granules, which tend to settle, in the acidic nutrient composition powder may lead to the formation of a gel network in the bottom phase. The retention of starch granules in the gel network also explains the absence of starch sedimentation in the acidic nutrient composition powder. Therefore, starch retention in the gel network ensures a more uniform distribution of starch granules throughout the product. Consequently, all nutrients in the nutrient composition powder can be consumed simultaneously, preventing the formation of a viscous carbohydrate slurry.

[0197] Particle size distribution Finally, the particle size distribution of the neutral and acidic base powders was directly quantified after reconstitution in water and 4 hours later. The droplet size distribution of the base powder samples was determined using a laser diffractometer (Mastersizer 2000, Malvern Instruments Ltd., Worcestershire, UK), for example by the method described in Michalski et al., 2001, Lait [Milk], 81, 787-789. Particle size distribution was obtained using polydispersity analysis.

[0198] Particle sizes ranging from 0.2 to 5 µm were observed in the neutral base powder, validating visual and microscopic observations that the neutral base powder remained stable and uniformly dispersed after 4 hours, without agglomeration or sedimentation. The acidic base powder at pH 4.0 showed increased particle size, matching the size categories of aggregates observed through microscopic analysis of the acidic base powder at a 10x dilution. For the reconstituted base powders at both neutral and acidic pH levels, the particle size distribution remained stable over time (4 hours) (see [link to relevant documentation]). Figure 1 A and Figure 1 B).

[0199] Example 3. OSA starch-emulsified oil-in-water emulsions are more resistant to the acidic gastric environment than protein-emulsified oil-in-water emulsions. In vitro gastric digestion simulations were performed, and the stability of liquid compositions emulsified with OSA starch was compared with that emulsified with whey protein isolate before and during in vitro gastric digestion. The primary objective was to predict the stability of the emulsions in the gastric environment.

[0200] Preparation of oil-in-water emulsion based on OSA starch OSA starch (225 g; emulsifier) ​​was dry-blended with soluble corn fiber (Promitor 70; also known as resistant maltodextrin) (468 g; encapsulating agent) and dissolved in water (1200 g) at a low shear rate using a ViscoJet® agitator at 80°C to avoid foam formation, thus obtaining an aqueous phase. Sunflower oil (1,080 g) was separately heated to 55°C and slowly added to the aqueous phase at 10,000 rpm for 5 minutes using a rotor-stator system (Ultra-Turrax®, IKA T50, Germany) to obtain an oil-in-water preemulsion. Finally, the preemulsion was homogenized in two steps using a high-pressure homogenizer GEA®-Pony at a single pass of 150 / 50 bar and a feed flow rate of 80 liters / hour. To obtain the final O / W emulsion dry powder, the emulsion was spray-dried using a GEA® Mobile Minor spray dryer with a water evaporation capacity of 1-7 kg / h, equipped with a dual-fluid nozzle type (Module System Range 970, Schlick®) for atomization, wherein the inlet air temperature was set to 190°C and the outlet air temperature was set to 90-94°C.

[0201] Based on the total dry matter content, the lipid content was fixed at 60 wt%, the OSA starch content at 14 wt%, and the resistant maltodextrin content at 26 wt%, with the OSA starch to lipid ratio in the dry matter maintained at 1:4.3. The OSA starch base powder was reconstituted in deionized water at a ratio of 1:15 and prepared for use in a semi-dynamic gastric digestion model.

[0202] Preparation of oil-in-water emulsions based on whey protein isolate (WPI) In this study, an oil-in-water emulsion stabilized by WPI was used as a control. Following the guidelines of Mantovani et al., Stability and... in In vitro digestibility of emulsions containing lecithin and whey proteins. Food Funct. The method described in [Food Function], 2013, 4(9), 1322-1331, yielded a WPI-O / W emulsion. In summary, WPI (Lacprodan DI-9212; 105 g) was dissolved in deionized water (3395 g) for 2 hours at room temperature using an overhead agitator (IKA EUROSTAR 20 DIGITAL, Germany) to obtain an aqueous phase. Sunflower oil (1500 g) was slowly added to the aqueous phase at 10,000 rpm for 5 minutes using a rotor-stator system (Ultra-Turrax®, IKAT50, Germany) to produce a pre-emulsion. Finally, the pre-emulsion was homogenized in two steps using a high-pressure homogenizer GEA®-Pony at a single pass of 400 / 50 bar and a feed flow rate of 80 liters / hour. The oil phase content was fixed at 30 wt% and the WPI content at 2.1 wt%.

[0203] Semi-dynamic gastric digestion model According to Mulet-Cabero people, A standardized semi-dynamic in vitro A standardized semi-dynamic in vitro digestion method suitable for food - an international consensus. Food Funct.The standardized in vitro digestion method described in [Food Functions], 2020, 11, 1702-1720, uses a semi-dynamic digestion model to simulate the gastric digestion phase. Gastric conditions include increasing the acidic pH for 120 minutes in the presence of gastric enzymes. Simulated saliva (SSF) and simulated gastric juice (SGF) are based on Brodkorb et al., INFOGESTstatic. in vitro Simulation of gastrointestinal food digestion [INFOGEST static in vitro gastrointestinal food digestion simulation] Nat Protoc. [Natural Protocol] 2019, 14(4), 991-101; prepared according to the protocol described in Mulet-Cabero et al. (2020). The SSF contained 150 U / ml salivary α-amylase, and the SGF contained 4000 U / ml porcine pepsin and 120 U / ml bacterial lipase. A 20 g sample of OSA starch O / W emulsion was placed in a plastic cup placed in a water bath (Fisherbrand™ Isotemp™) at 37°C, and the OSA starch sample was mixed with the oral mixture of SSF at 30 rpm for 10 seconds using a top-mounted stirrer (IKA EUROSTAR 20 DIGITAL, Germany). The volume of SSF added corresponded to the total solids content of the emulsion sample, as described in Mulet-Cabero et al. (2020).

[0204] The mixture was then subjected to simulated gastric digestion. Both solutions were added at a constant rate using separate feed pumps (Flocare® Infinity™ pumps): (1) Add 18 ml of electrolyte simulated gastric juice (eSGF) solution at a rate of 9 ml / h. The gastric mixture at pH 7 contained 17.55% deionized water, 2.40% 1 M HCl and 0.06% 0.3 M CaCl2(H2O)2. The amount of HCl added was based on the amount of acid required to reach pH 2 at the end of gastric digestion.

[0205] (2) Add 2 ml of SGF enzyme solution containing pepsin and lipase at a rate of 1 ml / h.

[0206] Gastric emptying (GE) simulations are based on caloric density. Typically, for volume-reducing systems, a linear GE rate of 2 kcal / min / 500 ml is used and scaled down, which is considered to be the average caloric content emptied in vivo in a regulated manner for an average food volume of 500 mL (Mulet-Cabero et al. (2020)). For simplicity and to be able to compare the results of different emulsion samples subjected to this semi-dynamic digestion model, the in vitro gastric digestion process was always kept constant at 120 minutes. Therefore, for the digestion of OSA starch O / W emulsion samples, the gastric emptying rate was changed from 2 kcal / min to 1.79 kcal / min. This modification made it possible to have similar characteristics in terms of the amount of SGF and enzyme solution delivered, as well as the amount of sample emptied during simulated gastric digestion.

[0207] Gastric emptying (GE) was simulated by sampling every 24 minutes, further designated GE1–24 min, GE2–48 min, etc., up to 120 minutes of digestion. Samples were collected from the bottom of a plastic cup using a manual single-channel pipette with a tip inner diameter of 2 mm, close to the upper limit of particle size found to enter the duodenum through the pyloric opening (Mulet-Cabero et al., 2019). Aliquots of these GE samples were used for microscopy and particle size analysis. The same setup as described above was used for simulated digestion of the control WPI O / W emulsion. The initial volume of the emulsion sample to be digested in vitro was uniquely modified to ensure that the flow rate profiles of eSGF and enzyme solution were identical to those of the OSA starch emulsion sample.

[0208] Particle size distribution The droplet size distribution and mean lipid droplet size of the initial and digested samples were determined using a laser diffractometer (Mastersizer 2000, Malvern Instruments Ltd., Worcestershire, UK). Particle size distribution was obtained using polydispersity analysis, and droplet size measurements were recorded as mean diameter D50 and volume-mean diameter (D4,3) to observe the effect of gastric digestion on changes in oil droplet size distribution. Each sample was quantified in duplicate.

[0209] optical microscope Structural changes in the emulsion samples before and during digestion were observed using an optical microscope (Zeiss Axioskop 2), and the results obtained from particle size distribution analysis were validated. Aliquots (3 μL) of each sample were placed on a microscope slide and covered with a coverslip. For reconstituted powders (1:10 ratio), dilution with deionized water was performed at a ratio of 1:25. Images were captured at 100x magnification using Axovision LE64 software.

[0210] result Figure 2 The particle size distributions of the two emulsions are shown after reconstitution and before gastric digestion. As indicated, the particle size distributions of the two emulsions are similar, but the OSA starch O / W emulsion shows greater diffusion in the particle size range of 0.15–9.2 µm, while the WPI-O / W emulsion has a particle size range of 0.2–7 µm. Therefore, the reconstitution of both emulsions does not lead to any aggregation and they remain dispersed in the sample.

[0211] Figure 3A and 3B This shows a comparison between OSA starch-stabilized emulsions and WPI-stabilized emulsions during simulated gastric digestion. The particle size distribution of the OSA starch emulsion can be clearly observed (…). Figure 3A The diffusion was much smaller, with most particles having a diameter between ±0.4 µm and ±9 µm, and the particle size distribution showed significant overlap compared to the emulsion before gastric digestion simulation (see [link]). Figure 2 In comparison, Figure 3B The data showed a highly variable particle size distribution in the WPI-O / W emulsion, ranging from 0.5 µm to as high as 100 µm, while the initial particle size before simulated gastric digestion ranged from 0.2 to 7 µm. Therefore, the data indicate that lipid droplet aggregation occurs in the WPI-O / W emulsion under gastric digestion conditions.

[0212] refer to Figure 3A It should be noted that the GE1 sample of OSA starch O / W emulsion exhibited a second peak at approximately 20–30 μm, which may represent the presence of flocculated droplets during the initial stage of simulated gastric digestion. However, microscopic analysis of the GE1 sample did not confirm this, as no flocculated or aggregated droplets of approximately 20 μm in size were observed.

[0213] More specifically, during simulated gastric digestion, based on measurements obtained from samples GE1-GE5, the average D50 of the OSA starch O / W emulsion was 2.5 µm, and the D50 of each sample from GE1 to GE5 differed from the average D50 by a maximum of 8%. Regarding the WPI-O / W emulsion, during simulated gastric digestion, based on samples GE1-GE5, the average D50 was 10.4 µm, and the D50 of each sample from GE1 to GE5 differed from the average D50 by at least 41%.

[0214] Furthermore, during simulated gastric digestion, based on measurements from five samples (GE1-GE5), the average volumetric diameter D[4,3] of the OSA starch O / W emulsion was 3.24 µm. The volumetric diameter D[4,3] of each sample GE1 to GE5 differed from the average volumetric diameter by up to 14%. For the WPI-O / W emulsion, based on samples GE1-GE5, the average volumetric diameter D[4,3] was 18.2 µm, and the difference between D[4,3] and the average volumetric diameter for each sample GE1 to GE5 was as high as 66%, indicating a large dispersion in particle size distribution.

[0215] In addition to quantifying particle size, microscopic images of the emulsion samples were taken at 24, 72, and 120 minutes during the simulated gastric digestion. The primary observation confirmed particle aggregation in the WPI-O / W emulsion, which was already visible at 24 minutes during the simulated gastric digestion. A significant amount of free oil phase was observed within the first hour of the simulated gastric digestion, indicating the instability of the WPI-O / W emulsion when subjected to gastric enzymes and salts. The flocculation of oil droplets and the release of free oil can be reasonably attributed to the hydrolysis of the protein-coated interfacial layer by pepsin and salt proteins present in the simulated gastric juice. However, the OSA starch O / W emulsion remained stable throughout the simulated gastric digestion, without any apparent instability or oil precipitation. The particles in the OSA starch O / W emulsion were mostly of uniform size, and only minor changes in particle size were observed after 120 minutes, compared to the numerous large aggregates present in the WPI-O / W emulsion after 120 minutes of digestion.

[0216] In summary, these results indicate that OSA starch O / W emulsions are less prone to fat breakdown under gastric conditions and are therefore more tolerant of the gastric environment than WPI-stabilized O / W emulsions. These results also suggest that OSA starch-stabilized emulsions remain stable in acidic environments and maintain a more uniform distribution within the nutritional composition, thereby enabling earlier initiation of the CCK mechanism and delayed gastric emptying after ingestion of the nutritional composition and oral administration.

[0217] Example 4. OSA starch-based powder is more resistant to the acidic gastric environment than WPI-based powder. Similar to Example 3, an in vitro gastric digestion simulation was performed, and the stability of the reconstituted OSA starch base powder was compared with that of the reconstituted whey protein isolate base powder before and during in vitro gastric digestion.

[0218] OSA starch-based oil-in-water emulsion = base powder A First, 1740 g of OSA starch (HICAP-IMF, Irvine) was dry-blended with 2772 g of resistant maltodextrin (Nutriose FM06, Roquette), and then dissolved in 8030 g of water at 40°C using a top-mounted stirrer to prevent foaming and eddying. The pH of the aqueous phase was then adjusted to 4.2 using a 10% citric acid solution. 7458 g of sunflower oil was heated to 55°C and added to the aqueous phase using a top-mounted stirrer, followed by two-stage homogenization at 150:50 bar and 70°C. The emulsion was then heat-treated using direct steam injection, with a preheating temperature of 70°C, a main heating temperature of 126°C (held for 2–2.6 seconds), and cooled to 65°C. The treated liquid was then spray-dried using a GEA® Mobile Minor spray dryer to obtain a base powder, which in this example is further referred to as base powder A.

[0219] WPI-based oil-in-water emulsion = base powder B First, 1175 g of whey protein isolate (WPI; Lacprodan) was dissolved in 9868 g of water at 40°C using a top-mounted stirrer by slowly adding WPI to prevent foaming and eddying. Subsequently, 2427 g of resistant maltodextrin (Nutriose FM06, Roquette) was dissolved in the protein solution. The pH of the aqueous phase was then adjusted to 4.2 using a 10% citric acid solution. 6529 g of sunflower oil was heated to 55°C and added to the aqueous phase using a top-mounted stirrer, followed by two-stage homogenization at 150:50 bar and 70°C. The emulsion was then heat-treated using direct steam injection, with a preheating temperature of 70°C, a main heating temperature of 115°C (held for 5.6 seconds), and cooled to 65°C. The treated liquid was then spray-dried using a GEA® Mobile Minor spray dryer to obtain a base powder, which in this example is further referred to as base powder B.

[0220] Sample preparation for digestion experiments Following the final product's instructions, add 92 g to the measuring beaker, then add water until a total of 260 ml is reached, which equals 35% dry weight content. During the experiment, redissolve 35 g of each base powder in 65 g of water and stir with a magnetic stirrer until a homogeneous solution is obtained. Perform the same procedure for base powders A and B.

[0221] Semi-dynamic digestion 50 g of each reconstituted base powder solution was placed in a glass beaker in a water bath, maintaining an internal temperature of 37°C (water bath set to 39°C). To initiate salivary digestion, the base powder solution was mixed with preheated electrolyte simulated saliva (eSSF) to 37°C as described by Mulet-Cabrero et al., 2020. The volume of eSSF added corresponded to 35% (w / w) of the total solids content of the base powder solution. The mixture was stirred at 30–50 rpm for 5 minutes using a top-mounted stirrer, and samples were taken for particle size distribution analysis.

[0222] Then, the remaining basic powder solution was subjected to simulated gastric digestion. Two solutions were added at a constant rate using separate feed pumps: (1) 57 ml of electrolyte simulated gastric juice (eSGF) solution was added at a rate of 36 ml / h. Electrolyte simulated gastric juice (eSGF) consisted of KCl, KH2PO4, NaCl, NaHCO3, MgCl2(H2O)6, and (NH4)CO3, and was prepared by mixing different electrolyte stock solutions at the concentrations described in Mulet-Cabrero et al., 2020. The amount of HCl added corresponded to the amount of acid required for the product to reach pH 2 at the end of gastric digestion. (2) 6.2 ml of pepsin solution containing pepsin and lipase was added at a rate of 4 ml / h.

[0223] Gastric emptying (GE) was simulated by sampling every 24 minutes, further designated as GE1-24 min, GE2-48 min, etc., up to 120 minutes of digestion. 12 ml samples were collected from the bottom of a glass beaker using a manual single-channel pipette. Aliquots of these samples at each time point were used to determine the particle size distribution.

[0224] result Basic powder A remained stable in solution (at room temperature 25°C), and no phase separation was observed between the dissolution time and the start of the digestion experiment. Prior to the digestion experiment, the reconstituted sample of basic powder B remained stable in solution, and no phase separation was observed; see [link to relevant documentation]. Figure 6 During digestion, the particle size distribution of the base powder A solution remains unchanged, and this stability can also be maintained within... Figure 7 This was observed in [the study]. In contrast, during gastric digestion, the average particle size of the basic powder B solution changed to a narrower distribution of larger particles ([the study observed]). Figure 8 During gastric digestion, the instability of the base powder B solution led to extensive phase separation. In summary, OSA starch is an effective stabilizer for emulsions during digestion. Throughout the entire digestion experiment (120 min), the emulsion stabilized by OSA starch remained uniformly distributed throughout the gastric system.

[0225] Example 5. Characteristics of acidified base products (pH 4.0) during in vitro gastric digestion. In vitro gastric digestion simulations were conducted, and the stability of an acidic base powder (hereinafter referred to as "acidic base powder") further containing citric acid and emulsified with OSA starch was investigated. The acidic base powder was prepared by reconstituted 40 g of neutral base powder with 6.2 g of anhydrous citric acid in 200 g of water.

[0226] For this example, the semi-dynamic digestion model described by Mulet-Cabero et al., (2020) was used for in vitro oral and gastric digestion of the reconstituted acidic base powder. Aliquots were collected after gastric emptying and subjected to particle size analysis and microscopic imaging according to a procedure similar to that described in Example 3. In this procedure, GE after 0 min represents the reconstituted base powder digested only by in vitro oral administration. It should also be noted that, according to the method of Mulet-Cabero et al., (2020), the pH should reach 2.0 after 2 hours of in vitro gastric digestion, while in the current model the pH reaches 1.0.

[0227] result Figure 4 The changes in oil droplet size during simulated gastric digestion were shown. The GE-0 sample exhibited a similar particle size distribution compared to the reconstituted base powder at pH 4.0, indicating that the OSA starch-stabilized emulsion is resistant to salivary α-amylase and oral conditions.

[0228] During the first 48 minutes of in vitro gastric digestion, a slight shift in particle size distribution towards smaller size categories was observed. Simultaneously, a slight increase in the volume density of the first peak was detected, attributed to emulsion droplets. This can be explained by… Figure 4 Two peaks in the particle size distribution were particularly visible at GE-72 min. Between 72 and 120 min of in vitro gastric digestion, the second peak (2–80 µm) disappeared, while the bulk density of the first peak (0.2–5 µm) increased. It is hypothesized that OSA starch at the emulsion interface deprotonates at lower pH, thus losing its negative charge. Therefore, aggregates formed by reversible electrostatic bonds between hydrolysates and OSA starch at the emulsion interface break down. Furthermore, the proteolytic activity of pepsin on whey hydrolysates may contribute to the breakdown of aggregates, although this is not expected to lead to a sudden increase in the particle size distribution. Additionally, micrographs show the breakdown of larger aggregates during in vitro gastric digestion, and an increase in the presence of emulsion droplets after GE-72 min.

[0229] Particle size distribution and micrographs indicate the stability of the emulsion droplets throughout simulated gastric digestion, presenting as aggregates (GE 0–GE 72 min) or freely floating (GE 72–GE 120 min). Furthermore, the combination of particle size distribution and micrographs taken during the digestion of the acidic formulation did not show unstable emulsion droplets, but showed reduced aggregation due to the acidity of the formulation and the presence of digestive enzymes. Finally, the oral digestion phase at GE-0 min showed minimal influence from salivary α-amylase, with the reconstituted acidic formulation remaining stable.

[0230] Example 6. Method for preparing nutritional compositions First, 3779 g of OSA starch (HICAP-IMF, Irvine) was dry-blended with 6020 g of resistant maltodextrin (Nutriose FM06, Roquette). The mixture was then dissolved in 18000 g of water at 40°C using a top-mounted stirrer to prevent foaming and eddying. The pH of the aqueous phase was then adjusted to 4.2 using a 10% citric acid solution.

[0231] 16,199 g of sunflower seed oil was heated to 55°C and added to the aqueous phase using a top-mounted agitator. The emulsion was then homogenized using a two-stage homogenization process at 150:50 bar and 70°C. 32,455 g of whey protein hydrolysate (Arla DI-3091) was dissolved in 64,911 g of water using a top-mounted agitator at 40°C by slowly adding the protein to prevent foaming and eddying. The emulsion and protein solution were then mixed in a tank with stirring. The mixture was then heat-treated using direct steam injection, with a preheating temperature of 70°C, a main heating temperature of 126°C (held for 2–2.6 seconds), and cooled to 70°C. The treated liquid was then spray-dried using a high-pressure nozzle to obtain a base powder.

[0232] Finally, 3366 g of natural corn starch (Erlian Company) was added to 2600 g of base powder by first adding half of the corn starch and half of the base powder, then adding 30 g of orange flavoring and 3 g of sucralose, followed by adding the other half of the corn starch and base powder. The mixture was dry-mixed for 25 minutes to ensure homogeneity and sieved through a 2 mm sieve. The final product was then prepared for packaging.

[0233] The same manufacturing method as described above was used to obtain the base powder of the acidic nutrient composition with pH 4. Then, 3152 g of natural corn starch (Eruian Company) was added to 2440 g of base powder by first adding half of the corn starch and half of the base powder, followed by 376 g of citric acid, 28.20 g of orange flavoring, and 2.82 g of sucralose, and then adding the other half of the corn starch and base powder. The mixture was dry-mixed for 25 minutes to ensure homogeneity and sieved through a 2 mm sieve. The final product was then prepared for packaging.

[0234] Example 7. Proof-of-concept study of a nutritional composition containing OSA starch in healthy subjects. Research Plan A randomized, controlled, blinded, crossover, single-center proof-of-concept study was conducted in 15 healthy adult participants to compare glucose response and indirect gastric emptying rate between the study products (neutral and acidic prototypes) and raw corn starch alone. Participants were screened after signing informed consent forms, and screening was based on a list containing inclusion and exclusion criteria. Several examples of exclusion criteria included: abnormal blood glucose levels at screening, a known history of gastrointestinal disease and food allergies, and extreme dietary habits (such as the ketogenic diet or the Atkins diet). Eligible participants were randomized to receive one study product at each visit. Overall, according to the randomization protocol, each participant received three study products over three different study visits, with a rest (washout) of at least 48 hours between visits.

[0235] At each study visit, fasting baseline blood samples were collected before the study product was consumed. The available carbohydrate content and total volume of the study product were matched and mixed with acetaminophen before consumption by the study subjects. Blood samples were collected every 30 minutes for 6 hours post-consumption. Following a standardized schedule, subjects drank a 150 mL glass of water at intervals of t = 180 minutes, t = 240 minutes, and t = 300 minutes (mandatory). Glucose and acetaminophen levels in the blood samples were analyzed. Acetaminophen levels were analyzed as an indirect measure of gastric emptying, since acetaminophen is absorbed directly from the stomach into the bloodstream. A total of 15 subjects completed the proof-of-concept study according to the protocol.

[0236] Research Products 1. Raw corn starch (UCCS), per 100 g: 89 g carbohydrates, 0.45 g protein, 0.13 g lipids. A sample was prepared by blending 56 g of UCCS powder with 0.5 g of dried orange spice, and subsequently reconstituted in 215 g of water.

[0237] 2. Neutral prototype (pH 7), per 100 g: 56.1 g carbohydrates (UCCS), 24.1 g protein (whey protein hydrolysate (from milk)), 12.1 g lipids (sunflower oil), 4.5 g resistant maltodextrin, 2.8 g OSA starch, 0.5 g orange flavoring, and 0.05 g sweetener (sucralose). Prepare the sample according to the method explained in Example 5. Redissolve 93 g of the neutral prototype in 200 g of water.

[0238] 3. Acidic prototype (pH 4), per 100 g: 52.5 g carbohydrates (UCCS), 6.3 g organic acid (citric acid), 22.5 g protein (whey protein hydrolysate (from milk)), 11.3 g lipids (sunflower oil), 4.2 g resistant maltodextrin, 2.6 g OSA starch, 0.5 g orange flavoring, and 0.05 g sweetener (sucralose). Prepare the acidic prototype as explained in Example 5. Redissolve 99 g of the acidic prototype in 200 g of water.

[0239] The study matched the available carbohydrate content (50 g) of the product with the total volume (260 mL) after preparation.

[0240] Statistical analysis Using longitudinal analysis, a linear mixed-effects model was employed, taking into account subject variability at time points, treatment groups, and visits, to compare glucose curves across the three treatment groups (UCCS, pH 7, and pH 4).

[0241] result Figure 5A and 5B The blood glucose levels of glucose and acetaminophen over time are shown separately. The acidic and neutral glucose precursors showed stable blood glucose levels after consumption, while UCCS showed an increase in blood glucose levels after consumption. Figure 5A The glucose curves of the two prototypes were significantly lower than those of the UCCS, see Table 1.

[0242] Table 1. Statistical analysis of blood glucose levels over time for GSD prototype and UCCS.

[0243]

[0244] Furthermore, compared to the acetaminophen levels in the UCCS group, blood acetaminophen levels, an indirect measure of gastric emptying, were significantly lower, indicating that the release of nutrients from the stomach was controlled and slower. See [link to relevant documentation]. Figure 5B And Table 2.

[0245] Table 2. Statistical analysis of blood acetaminophen levels over time for GSD prototype and UCCS.

[0246] in conclusion The overall glucose profiles of both prototypes were significantly lower than those of UCCS. Furthermore, the prototypes exhibited lower acetaminophen peaks and a longer duration of action after ingestion of the study product, indicating that both prototypes provided better control of gastric emptying compared to UCCS alone.

[0247] Example 8. Formulations of neutral (pH 7) and acidified (pH 4) nutrient compositions. Formulate an exemplary neutral nutritional composition containing 414 kcal and: -53 g raw corn starch (UCCS) -20 g whey protein hydrolysate (from milk) -12 g sunflower seed oil -2.5 g OSA starch -4 g resistant maltodextrin Formulate an exemplary acidic nutritional composition containing 406 kcal per 100 grams and: -53 g raw corn starch (UCCS) -23 g whey protein hydrolysate (from milk) -11 g sunflower seed oil (high oleic acid) -2.5 g OSA starch -4 g resistant maltodextrin -6.3 g citric acid.

Claims

1. A method for manufacturing a nutritional composition comprising lipids, octenyl succinic anhydride-substituted starch (OSA starch), proteins, an encapsulating agent, and digestible carbohydrates, the method comprising: (a) The lipid is emulsified with a first aqueous phase and OSA starch to obtain an emulsified O / W composition, wherein preferably the dry weight ratio of OSA starch to lipid is in the range of 1:3 to 1:5; (b) Homogenize the protein, water, and optionally other water-soluble components to obtain a second aqueous phase; (c) The emulsified O / W composition from step (a) is combined with the second aqueous phase from step (b) to obtain a mixture, and optionally additional ingredients are added to the mixture; (d) Optionally, the mixture provided in step (c) is pasteurized; (e) The mixture obtained in step (c) or step (d) is spray-dried to provide a spray-dried composition; (f) The digestible carbohydrates are dry-blended into the spray-dried composition; In this embodiment, based on the total protein weight in the nutritional composition, less than 4 wt% of the protein is present in the emulsified O / W composition of step (a), and the encapsulating agent is added prior to spray drying in step (e).

2. The method according to claim 1, wherein in step (a) the lipids are emulsified with a first aqueous phase and OSA starch at a pH range of 3-6.5, preferably 3-5.5, more preferably 3.5 to 5.

3. The method according to claim 1 or 2, wherein the food-grade pH adjuster is added to the first aqueous phase in step (a) and / or to the second aqueous phase in step (b), and / or added as an additional component to the mixture in step (c), and / or dry-blended into the spray-dried composition in step (f).

4. The method according to any one of claims 1-3, wherein the dry weight ratio of OSA starch to lipid is in the range of 1:3.5 to 1:4.

5.

5. The method according to any one of claims 1-4, wherein the encapsulating agent is added to the emulsified O / W composition and / or to the second aqueous phase and / or to the mixture.

6. A nutritional composition obtainable by the method according to any one of claims 1-5, the nutritional composition comprising lipids, OSA starch, protein, encapsulating agent and digestible carbohydrates, wherein the nutritional composition comprises 1-14 wt% OSA starch based on the total dry weight of the composition, and wherein the digestible carbohydrates comprise digestible starch, preferably at least 55 wt% slow-digesting starch based on the total dry weight of the digestible carbohydrates, preferably wherein the slow-digesting starch is digested within 20 to 120 minutes based on in vitro enteric digestion.

7. The nutritional composition of claim 6, wherein the composition comprises lipid-containing particles having a lipid core, wherein the lipid core is coated with OSA starch, and wherein the lipid core and the OSA starch coating together comprise less than 4 wt% of protein based on the total protein weight in the nutritional composition.

8. A nutritional composition comprising lipids, OSA starch, protein, an encapsulating agent, and digestible carbohydrates, wherein the composition comprises lipid-containing particles having a lipid core, wherein the lipid core is coated with OSA starch, and wherein the lipid core and the OSA starch coating together comprise less than 4 wt% protein based on the total protein weight in the nutritional composition, wherein the OSA starch coating is coated with an adjacent second layer containing protein, and wherein the encapsulating agent may be present in the second layer and / or the encapsulating agent may coat the second layer, and wherein the composition comprises 1-14 wt% OSA starch based on the total dry weight of the composition.

9. The nutritional composition according to any one of claims 6-8, wherein the composition comprises, based on the total dry weight of the composition: - At least 10 wt% lipids; preferably, the lipids comprise sunflower seed oil; -1 - 14 wt% OSA starch, preferably 2 - 10 wt%, more preferably 2 - 6 wt% OSA starch; -25-75 wt% digestible carbohydrates, preferably 30-70 wt%; -2 - 15 wt% encapsulating agent; -10 - 35 wt% protein.

10. The nutritional composition according to any one of claims 6-9, wherein the composition comprises 2-14 wt% of a food-grade pH adjuster based on the total dry weight of the composition, preferably the food-grade pH adjuster is an organic acid selected from citric acid, lactic acid, malic acid, acetic acid and / or ascorbic acid, more preferably the food-grade pH adjuster is citric acid.

11. The method according to any one of claims 1-5 or the nutritional composition according to any one of claims 6-10, wherein the glycemic index of the encapsulating agent is in the range of 0 to 50, preferably in the range of 0 to 25, and more preferably the encapsulating agent comprises resistant maltodextrin.

12. The nutritional composition according to any one of claims 6-11, wherein the digestible carbohydrates comprise less than 45 wt% of rapidly digestible starch based on the total dry weight of the digestible carbohydrates.

13. The nutritional composition according to any one of claims 6-12, for use in reducing and / or treating diabetes, glycogen storage disease (GSD), fatty acid oxidation disorder (FAOD) and / or idiopathic ketotic hypoglycemia (IKH), more preferably for use in liver-related GSD subtypes 0, III, VI and IX.

14. The nutritional composition for use according to claim 13, wherein reducing and / or treating diabetes, GSD, FAOD and / or IKH comprises preventing and / or reducing one or more of insomnia or sleep deprivation, impaired normoglycemia, fasting hypoglycemia, hyperinsulinemia, insulin resistance, and gastrointestinal side effects, including one or more of bloating, flatulence, and diarrhea, and wherein reducing and / or treating diabetes, GSD, FAOD and / or IKH further comprises maintaining normal blood glucose, slowing gastric emptying rate, prolonging carbohydrate digestion, and prolonging glycolysis during digestion.

15. A non-therapeutic method for slowing gastric emptying rate, maintaining normal blood glucose, prolonging carbohydrate digestion, and / or prolonging glycolysis during digestion in a healthy subject, the method comprising administering to the healthy subject a nutritional composition according to any one of claims 6-12.

Images