WO2024002816A1

WO2024002816A1 - Fat composition to prevent infantile regurgitation

Info

Publication number: WO2024002816A1
Application number: PCT/EP2023/066790
Authority: WO
Inventors: Christina Josephina Antonia Maria Timmer-Keetels; Teartse Tim Lambers; Urszula KUDLA
Original assignee: Frieslandcampina Nederland B.V.
Priority date: 2022-06-28
Filing date: 2023-06-21
Publication date: 2024-01-04

Abstract

A synthetic nutritional composition comprising a carbohydrate fraction, a protein fraction and a lipid fraction wherein the amount of butyrate in the lipid fraction is at least 0.2 wt% as determined to the total amount of fatty acids in the lipid fraction; and wherein amount of butyrate (i.e. C4:0) linked to sn-1,3 is more than 70% of the total amount of butyrate for use in the treatment and/or prevention of infantile regurgitation.

Description

Fat composition to prevent infantile regurgitation

Introduction

[0001] The present invention generally relates to improved nutritional products. More specifically, in one aspect, the present invention relates to synthetic nutritional compositions and methods and systems regarding same.

[0002] The purpose of these products, in part, is to provide necessary nutrition to the consumer. In addition to providing nutrition to the consumer, it is important that these products are safe for consumption.

[0003] The invention relates to a synthetic nutritional composition comprising a carbohydrate fraction, a protein fraction and a lipid fraction. More specifically wherein the lipid fraction comprises the amount of butyrate in the lipid fraction is at least 0.2 wt% as determined to the total amount of fatty acids in the lipid fraction; and wherein amount of butyrate (i.e. C4:0) linked to sn-1 ,3 is more than 70% of the total amount of butyrate. The invention further relates to the synthetic composition of the invention for use in the treatment and prevention of infantile regurgitation. The invention also relates to the use of the synthetic composition according to the invention to treat and/or prevent infantile regurgitation. In another aspect the invention relates to a method of treatment of infantile regurgitation comprising the step of administering the synthetic composition of the invention.

Background

[0004] After birth, mothers provide the best nutrition for their infants through breast feeding. Human milk contains various precious valuable macro- and micro-nutrients, bioactive components, and microbiota to nourish the new-born but also support the colonization and development of the gut microbiota (GM). Human milk is designed to deliver the nutritious components to the site of action and due to its balanced composition and matrix is easy to digest. As a result, for an infant, human milk is the preferred nutrition (Ell Directive 2006/141 ). However, in case breastfeeding is not an option cow-milk based alternatives are on the market, often supplemented with ingredients that mimic the many functions of breast milk components like e.g. the human milk oligosaccharides (HMOs). [0005] A wide range of infant formulas are available, varying in the sourcing and processing of their ingredients. In addition to being an important energy source, the carbohydrates, fat, and protein are considered to be important in regulating the infants’ gut comfort. The majority of infants fed with infant formula suffers from gastro-intestinal (Gl) complaints, albeit to a different extent. Although these Gl problems are usually considered minor and not harmful for the infant, they may cause distress when present for both the affected infants and their caregivers. The distress may manifest itself in more and/or longer periods of crying, fussiness, and sleeping problems for the infant, which in turn may increase stress for their caregivers. As such, prevention, or management of Gl symptoms through a nutritional approach is considered relevant and desirable. Gut (dis)comfort is affected by a complex combination of several formula parameters: amongst others the ingredient composition and the digestibility of (macro-) nutrients.

[0006] The main functional gastrointestinal disorder in infants is regurgitation (i.e. gastroesophageal reflux: GER). Prevalence rates range from 8 to 87%, but overall global prevalence is estimated at 25 to 30% with a peak of 67 to 87% at 2 to 4 months of age. Regurgitation is the backward movement of stomach content up to the oesophagus into the mouth. It can occur with or without vomiting. When GER leads to troublesome complications it is classified as GER disease (GERD). Underlaying pathophysiological mechanism include anatomical (e.g. underdeveloped oesophageal sphincter & short oesophagus), postural (feeding while child is lying down) and behavioural (overfeeding) mechanisms. Since GER is transient and benign, there is no need to treat it with pharmacological means (in most cases), and the advice is to adapt the way of feeding (lower volumes, more upright position) as well as to use special infant formula designed to mitigate the GER symptoms. There are two main ways to deal with the GER: a) thickening of the formulation with use of thickeners such as starch, carob-bean gum (CBG), or locust bean gum (LBG), which will make it more difficult for the liquid in stomach to come up into the oesophagus. Studies have found that appropriate thickening formulas can reduce the incidence of infant vomiting. Locust bean gum is a good "natural thickener". The addition of less than 1 % locust bean gum to milk powder can make the milk easier to sink to the bottom of the baby's stomach, and it is not easy to reflux back into the esophagus. b) increase the rate of stomach emptying with the use of partially hydrolysed proteins to decrease the amount of liquid that is available for regurgitation.

[0007] Locust bean gum (Locust/Carob bean gum/CBG), also known as locust bean gum and carob bean gum, is derived from the endosperm part of the locust tree seed. It is a natural food thickener, and its main ingredient is galactomannan. Locust bean gum is a water-soluble colloid with low concentration and high viscosity.

[0008] Accordingly, there is a consensus in the prior art that GER and GERD may be treated by using specifically designed formulas. In addition to existing products and solutions, there is a need for alternative infant formulae that reduce GER and I or GERD and I or contribute to better sleeping babies.

[0009] It is an objective to develop an infant formula that address one or more of these needs. In particular, there is a need for alternative infant formulas that treat or reduce GER and/or GERD and I or improves sleep of the children, without further negative effects. Such composition is not only beneficial to the baby as it causes less discomfort, it is also beneficial for parents as less crying of a baby causes less stress for the parent. Regurgitation is a known cause of discomfort of babies after feeding. It is therefore an object of the present invention to develop an infant formula that prevents regurgitation or at least reduces the seventy of regurgitation in an infant fed such a formula.

[0010] The inventors surprisingly found that a lipid fraction, also referred to as fat i.e. a glycerol unit with up to three fatty acids linked to it by an ester bond, with a high level of butyrate at the sn1 ,3 position of glycerol and preferably with a high level of long chain saturated fatty acids at the sn-2 position of glycerol lead to improved digestion of the fat into fatty acids and increase overall lipid absorption.

[0011 ] The presence of fat at the distal end of the small intestine is a potent inhibitor of gastric emptying, which results in relaxation of the proximal stomach and diminished contractions of the distal part. Hence, it is believed that the digestion and absorption of fat removes the inhibitory stimulus leading to resuming of the gastric motility. Therefore, the rate of gastric emptying is, amongst others, dependent on the digestion of fat into fatty acids. It was surprisingly found that milk fat (MF) has such high levels of saturated fatty acids at the sn-2 position of glycerol and high levels of short chain fatty acids (SCFA) at the sn1-3 position of glycerol.

[0012] Using MF in infant formula can therefore aid the gastric emptying and decrease the amount of digesta available for regurgitation. Consequently, MF may be used for treating or preventing symptoms of GER I GERD.

Summary of the invention

[0013] The invention relates to uses and methods as defined in the claims.

[0014] Accordingly, in a first aspect the invention relates to a synthetic nutritional composition comprising a carbohydrate fraction, a protein fraction and a lipid fraction wherein the amount of butyrate in the lipid fraction is at least 0.2 wt% as determined to the total amount of fatty acids in the lipid fraction; and wherein amount of butyrate (i.e. C4:0) linked to sn-1 ,3 is more than 70% of the total amount of butyrate, preferably more than 80%, more preferably more than 90%.

In another aspect the invention relates to the synthetic composition of the invention for use in the treatment and/or prevention of infantile regurgitation; preferably the treatment of infantile regurgitation. In still another aspect, the invention relates to the use of the synthetic composition according to the invention to treat and/or prevent infantile regurgitation; preferably the treatment of infantile regurgitation. In yet another aspect, the invention relates to a method of treatment of infantile regurgitation comprising the step of administering the synthetic composition of the invention.

Definitions

[0015] A prerequisite to an infant formula is that the final product must be microbiologically safe, and for that reason traditional processing mandates that the final product be adequately heat processed e.g. pasteurization. Thus, products in powder form are typically heat treated before spray-drying. Products in liquid form~ however, are subject to a more rigorous treatment such as by exposure to high temperatures for short time (UHT - aseptic process). [0016] As used herein the term “reconstituted beverage” relates to a drinkable product that is prepared by dissolving a powder in a liquid such as dissolving an infant formula in water in accordance with the manufacturer’s instructions. The drinkable product preferably is drinkable by an infant using a bottle with a teat. Such bottles with teat are well-known and readily commercially available. The drinkable product preferably has a viscosity of less than 800 cP (at 25 °C and a pressure of 1 atmosphere) such as between 1 and 500 cP, preferably between 1 and 400 cP, more preferably between 1 and 200 cP. An advantage of the product and uses of the invention is that the drinkable product (e.g. infant formula) does not necessarily have to be made more viscous by adding a thickener such as CBG, which is more convenient for the caregiver who needs to prepare the product. In one other embodiment, it may be necessary to add a thickener to the composition of the invention. In one embodiment the synthetic composition of the invention additionally comprising a thickener selected from the group consisting of locust bean gum (LBG), carob bean gum (CBG) and starch; wherein the amount of thickener as determined to the dry weight of the composition is between 0.001 and 5 wt%, preferably between 0.01 and 2.5 wt%, more preferably between 0.1 and 1 .5 wt%.

[0017] A formula product as used herein refers to a product which upon reconstitution with a liquid, preferably with water, more preferably boiled water (which preferably is cooled to below 37 °C), provides a reconstituted drinkable product.

Once the reconstituted beverage is consumed, its temperature should not be too high in order to avoid burning of the subject’s tongue or mouth. Hence normally the temperature of the liquid should be 37 °C or below.

[0018] The formula product usually is a powder, although in some instances it may be a readily dissolvable tablet or cube. Examples of formula products include products that after reconstitution into a reconstituted beverage provide a complete nutrition for a subject such as IFT products, Follow-on-Formula (FOF), and Young Child Formula (YCF-Jr) products. A formula product has a recommended dosage (i.e. amount) of formula product per subject per day; a recommended number of feeding moments per subject per day and a recommended ratio between the desired amount of the formula product and the desired amount of liquid. These recommendations may depend on the type and brand of formula and are provided by the manufacturer. [0019] The term "infant formula" as used herein refers to a nutritional composition intended for infants and as defined in Codex Alimentarius, (Codex STAN 72-1981 ) and Infant Specialties (incl. Food for Special Medical Purpose) as defined in Codex Alimentarius, (Codex STAN 72-1981 ). It also refers to a foodstuff intended for particular nutritional use by infants during the first months of life and satisfying by itself the nutritional requirements of this category of person (Article 2(c) of the European Commission Directive 2006/141 /EC of 22 December 2006 on infant formulae and follow-on formulae). The infant formulas can encompass the starter infant formulas, the follow-up or follow-on formulas, and young child formulas. Generally, a starter formula is for infants from birth as breast-milk substitute, and a follow-up or follow-on formula from the 6th month onwards. So, an infant formula may be dedicated for infants of 0 to 6 months, 6 to 12 months, or 12 months and older. A young child formula may be dedicated for children aged 1 - 3 years old.

[0020] As used herein, the term "prevention" in relation to a given disease or disorder means preventing the onset of disease development if none had occurred, preventing the disease or disorder from occurring in a subject that may be predisposed to the disorder or disease but has not yet been diagnosed as having the disorder or disease, and/or preventing further disease/disorder development if already present.

[0021] As used herein, the term “treatment” in relation to a given disease or disorder means preventing further disease/disorder development, and I or ameliorating disease symptoms in a subject.

[0022] As used herein, the term “synthetic nutritional composition” is a composition which is artificially prepared and is containing at least one compound that is produced ex vivo chemically and/or biologically and/or physically, e.g. by means of chemical reaction, enzymatic reaction or by a fractionation process. An example of such a fractionation process is a process wherein bovine milk is separated into different fractions like a fat and protein fraction. For the avoidance of doubt, a synthetic composition is not made in vivo by man or animal.

[0023] Compositions used according to the invention should be safe and preferably without adverse effects. [0024] Unless otherwise specified, all amounts are per gram of dry weight of composition. Likewise, wt%, or percentages by weight, are per gram of dry weight of composition.

Brief description of the drawings

[0025] In Figure 1 the results of the in vitro digestion experiment as described in Example 1 is disclosed. IF1 is an infant formula containing a fat fraction with 50 wt% milk fat and 50wt% vegetable oils; IF2 is an infant formula containing a fat fraction of vegetable oils, without milk fat. The decreased pH from neutral at the start to 6 to 3.5 represents the progress in the digestion in the stomach. AFFA is the increase in Free Fatty Acids during gastric digestion. It follows from the data that the amount of FFA is significantly higher in IF1 as compared to IF2 at the end of the gastric digestion i.e. at pH 3.5.

Details of the invention

[0026] Accordingly, in a first aspect the invention relates to a synthetic nutritional composition comprising a carbohydrate fraction, a protein fraction and a lipid fraction wherein the amount of butyrate in the lipid fraction is at least 0.2 wt% as determined to the total amount of fatty acids in the lipid fraction; and wherein amount of butyrate (i.e. C4:0) linked to sn-1 ,3 is more than 70% of the total amount of butyrate, preferably more than 80%, more preferably more than 90%. In one embodiment, the lipid fraction of the composition of the invention further comprises long chain saturated fatty acids (LC SFA) linked to glycerol and at least 20 mole % of the LC SFA is linked to the sn-2 position of glycerol. Preferably in one embodiment, at least 30 mole % of the LC SFA is linked to the sn-2 position of glycerol more preferably at least 35 mole %, most preferably at least 41 mole % of the LC SFA is linked to the sn-2 position.

[0027] In another embodiment, the lipid fraction of the composition of the invention further comprises long chain saturated fatty acids (LC SFA) linked to glycerol and the % of LC SFA on sn2 is at least 30%, preferably at least 40% expressed as a percentage of all fatty acids linked to sn2; and at least 20 mole % of the LC SFA is linked to the sn-2 position of glycerol, preferably at least 30 mole % of the LC SFA is linked to the sn-2 position of glycerol more preferably at least 35 mole %, most preferably at least 41 mole % of the LC SFA is linked to the sn-2 position.

[0028] In another embodiment, the lipid fraction of the composition of the invention further comprises saturated fatty acids (SFA) linked to glycerol and at least 20 mole % of the SFA is linked to the sn-2 position of glycerol. Preferably in one embodiment, at least 30 mole % of the SFA is linked to the sn-2 position of glycerol more preferably at least 35 mole %, most preferably at least 41 mole % of the SFA is linked to the sn-2 position.

[0029] As used herein, the term "synthetic" means obtained by chemical and/or biological means, to the contrary of "natural” (found in the nature), for example a synthetic nutritional composition is not of human or animal origin (e.g. it is not breast milk or cow’s milk). An infant formula is an example of a synthetic nutritional composition; it aims to replicate the nutritional value of human milk which is not a simple task.

[0030] As used herein the term "nutritional" means that it nourishes a subject. The synthetic nutritional compositions according to the invention, are typically to be taken by enteral, oral, orogastric or nasogastric feeding, preferably orally, and include a carbohydrate, fat and a protein source.

[0031] The synthetic nutritional compositions according to the invention may be intended for infants and/or young children, and may be for example be formulated as an infant formula, a growing-up milk, or any other milk-based nutritional composition, a supplement (or a complement), or as a fortifier such as a milk fortifier (e.g. human milk fortifier). The nutritional compositions can be in powder or liquid form.

[0032] The synthetic nutritional compositions tailored for infants of specific ages may be prepared by methods well known in the art for preparing the type of synthetic nutritional composition in question e.g. infant formulae, follow on formulae, a composition for infants that is intended to be added or diluted with human milk e.g. human milk fortifier, or food stuffs intended for consumption by infants either alone or in combination with HM e.g. complementary foods.

[0033] An exemplary method for preparing an age tailored powdered infant formula is as follows. A protein source, carbohydrate source, and fat source may be blended together in appropriate proportions. Emulsifiers maybe included in the blend.

Vitamins and minerals may be added at this point but are usually added later to avoid thermal degradation. Any lipophilic vitamins, emulsifiers and the like may be dissolved into the fat source prior to blending. Water, preferably water which has been subjected to reverse osmosis, may then be mixed in to form a liquid mixture. The liquid mixture may then be thermally treated to reduce bacterial loads. For example, the liquid mixture may be rapidly heated to a temperature in the range of about 80°C to about 110°C for about 5 seconds to about 5 minutes. This may be carried out by steam injection or by heat exchanger; for example a plate heat exchanger. The liquid mixture may then be cooled to about 60°C to about 85°C; for example by flash cooling. The liquid mixture may then be homogenized; for example in two stages at about 7 M Pa to about 40 M Pa in the first stage and about 2 MPa to about 14 M Pa in the second stage. The homogenised mixture may then be further cooled to add any heat sensitive components such as vitamins and minerals. The pH and solids content of the homogenised mixture is conveniently standardised at this point. The homogenised mixture can be transferred to a suitable drying apparatus such as a spray drier or freeze drier and converted to powder. The powder should have a moisture content of less than about 3% by weight.

[0034] If it is desired probiotic(s) can be added, they may be cultured according to any suitable method and prepared for addition to the infant formula by freeze-drying or spray-drying for example. Alternatively, bacterial preparations can be bought from specialist suppliers such as Christian Hansen and Morinaga already prepared in a suitable form for addition to food products such as infant formula. Such bacterial preparations may be added to the age tailored powdered infant formula by dry mixing. Likewise, prebiotics and Human Milk Oligosaccharides (HMO) may be added to the formula by dry mixing. Prebiotics and HMOs can be bought from specialist suppliers like FrieslandCampina or others.

[0035] Examples of prebiotics include but are not limited to galacto oligosaccharides (GOS), inulin and fructo oligosaccharides (FOS) or combinations thereof. Examples of HMOs include but are not limited to 2’FL, 3FL, LNT, LNnT, 3’GL, 6’GL, 3SL, 6SL and combinations thereof. 2’Fucosyl lactose (2’FL) being a preferred HMO.

[0036] Human milk oligosaccharides are also known as human milk glycans, oligomers of monosaccharides that can be found in high concentrations exclusively in human breast milk. Human milk oligosaccharides promote the development of the immune system, can reduce the pathogen infections and improve brain development and cognition. Human milk oligosaccharides (HMOs) form the third most abundant solid component of human milk, after lactose and fat. HMOs are present in a concentration of 9.9-24.9 g/L. Approximately 200 structurally different human milk oligosaccharides are known. The composition of human milk oligosaccharides in breast milk is individual to each mother and varies over the period of lactation. The dominant oligosaccharide in 80% of all women is 2’-fucosyl lactose (2’ FL), which is present in human breast milk at a concentration of approximately 2.5 g/L. Other oligosacchardies include lacto-N-tetraose (LNT), lacto-N-neotetraose (LNnT), and lacto-N-fucopentaose (LNFP). (Bode, L. (2012) "Human milk oligosaccharides: every baby needs a sugar mama". Glycobiology. 22 (9): 1147-1162). doi:10.1093/glycob/cws074). Preferably the HMOs are selected from the group consisting of 2’FL, 3FL, LNT, LNnT, LNFP, 3’GL, 3’SL, and 6’SL.

[0037] In one embodiment the protein fraction comprises goat or bovine milk protein and the amount of goat or bovine milk protein in the protein fraction of the composition of the invention is more than 80 wt% as determined relative to the total amount of protein in the composition, preferably, the amount of protein is more than 90 wt%. In another embodiment, the amount of bovine milk protein in the protein fraction of the composition of the invention is more than 80 wt% as determined relative to the total amount of protein in the composition, preferably, the amount of bovine protein is more than 90 wt%. In yet another embodiment the amount of goat protein in the protein fraction of the composition of the invention is more than 80 wt% as determined relative to the total amount of protein in the composition, preferably, the amount of goat protein is more than 90 wt%.

[0038] The protein fraction may be a milk protein such as casein or whey, alternatively it is a vegetable protein like soy protein, rice protein. Preferably it is a ruminant milk protein, more preferably from cow’s milk, sheep milk, or goat milk, or a combination thereof, most preferably from cow’s milk. WPC and SPC are well-known whey protein-comprising milk fractions. Both WPC and SPC are the result of separating skimmed milk into a casein-rich and a whey protein-rich fraction; either by renneting (i.e. cheese making), acidification, or microfiltration.

[0039] Whey protein concentrate (WPC) is a product obtained by ultrafiltration and optionally reverse osmosis, to further concentrate the product (water removal), and optionally demineralization of acid or cheese whey. By ultrafiltration, a large part of the water, lactose and ash are removed from the product, thereby concentrating the whey proteins. Reverse osmosis can be used to remove water and to further concentrate the WPC. [0040] Serum protein concentrate (SPC) is also a concentrated protein product and differs from WPC in the origin of the whey fraction. Instead of acid or cheese whey, the proteins in SPC result from microfiltration of skimmed milk. Said microfiltration results in a concentrated casein retentate fraction and a serum fraction containing most of the whey proteins as the permeate fraction. Conventionally, this permeate fraction is then subjected to ultrafiltration and/or reverse osmosis in order to remove lactose, ash, and water. The product obtained may be demineralized, if so required.

[0041] As used herein, FA is referring to Fatty Acid; SFA is referring to Saturated Fatty Acid and LC SFA is referring to Long Chain Saturated Fatty Acid. A long chain saturated fatty acid is referring to saturated fatty acids with 12 carbon atoms or more. [0042] The lipid fraction in the synthetic composition of the invention may comprise different fats and oils, such as a vegetable oil, fish oil, ruminant milk fat or combinations thereof. Preferably the composition comprises ruminant milk fat, more preferably a combination of vegetable oils and ruminant milk fat. Even more preferably, this combination of lipids is supplemented with fish oil.

[0043] Fat consists of a glyceride residue linked to a carboxylic acid via an ester bond. As such, a fat molecule comprises a glyceride residue and three fatty acid acyl groups. An acyl group linked to the first carbon of a glyceride is also referred to as an sn1 linked acyl group, like an acyl group linked to the second carbon of a glyceride is referred to as an sn2 linked acyl group and an acyl group linked to the third carbon of a glyceride is referred to as sn3 linked acyl group.

[0044] An acyl group contains a carbonyl group (C double-bonded oxygen) linked to an alkyl group R; (R-C=O). In organic chemistry, the acyl group (IIIPAC name: alkanoyl) is usually derived from a carboxylic acid, it has the formula RCO-, where R represents an alkyl group that is linked to the carbon atom of the C=O group by a single bond. As used herein, the alkanoyl group is referred to by the name of the corresponding anion that is the conjugated base of an acid. For example, a C4 acyl group (CH3-CH2-CH2-C(O)-) is referred to as butyrate or C4:0, wherein the “4” indicates the total number of carbon atoms in the group and the “:0” the number of unsaturated carbon-carbon bonds. Likewise, C16:0 is referring to palmitic acid (CH₃(CH2)I₄COOH) and palmitate to CH₃(CH₂)i4CO.

[0045] The lipid fraction in the composition for use of the current invention may comprise a mixture of different fats and oils, such as a mixture of plant oils and milk fat. Optionally long chain poly unsaturated fatty acids (LC-PUFA) such as in one embodiment selected from the group consisting of DHA, ARA, and EPA may be added to the lipid fraction; preferably the composition comprises DHA, ARA and EPA. Such LC-PUFA are present in fish oil. It is understood that the fish oil may be replaced by any other source of poly unsaturated fatty acid (PUFA) source that provides docosahexaenoic acid (DHA), Eicosapentaenoic acid (EPA), and optionally arachidonic acid (ARA).

[0046] The lipid fraction in the synthetic composition of the invention comprises at least 0.2 wt% of butyrate as determined to the total amount of fatty acids in the lipid fraction, preferably at least 0.5 wt%, more preferably at least 1 .0 wt%, particularly preferably at least 1 .5 wt%, most preferably at least 1 .8 wt%; further the amount of butyrate (C4:0) linked to sn-1 ,3 is more than 70% of the total amount of butyrate, preferably more than 80%, more preferably more than 90%.

[0047] In another embodiment, the lipid fraction in the synthetic composition of the invention comprises at least 0.5 wt% of butyrate, and further the amount butyrate linked to sn-1 ,3 is more than 70% of the total amount of butyrate, preferably more than 80%, more preferably more than 90%. Preferably, in another embodiment, the lipid fraction in the synthetic composition of the invention comprises at least 1 .0 wt% butyrate, and further the amount of butyrate linked to sn-1 ,3 is more than 70% of the total amount of butyrate, preferably more than 80%, more preferably more than 90%. More preferably, in another embodiment, the lipid fraction in the synthetic composition of the invention comprises at least 1 .5 mol%, and further the amount of butyrate linked to sn-1 ,3 is more than 70% of the total amount of butyrate, preferably more than 80%, more preferably more than 90%. Even more preferably, in another embodiment, the lipid fraction in the synthetic composition of the invention comprises at least 1 .8 wt%, and further the amount of butyrate linked to sn-1 ,3 is more than 70% of the total amount of butyrate, preferably more than 80%, more preferably more than 90%.

[0048] In one embodiment, the amount of milk fat as determined with respect to the total amount of fat in the composition of the invention is at least 10 wt%, preferably at least 20 wt%, more preferably at least 30 wt%, even more preferably at least 40 wt%, most preferably at least 50 wt%.

[0049] In still another embodiment, the lipid fraction is further comprising vegetable oils and fat and the amount of vegetable oil and fat as determined with respect to the total amount of fat in the synthetic composition of the invention is at least 10 wt%, preferably at least 20 wt%, more preferably at least 30 wt%, most preferably at least 40 wt%.

[0050] Preferably, in one embodiment, the amount of milk fat as determined with respect to the total amount of fat in the composition of the invention is at least 10 wt%, and the amount of vegetable oil and fat as determined with respect to the total amount of fat in the synthetic composition of the invention is at least 10 wt%, preferably at least 20 wt%, more preferably at least 30 wt%, most preferably at least 40 wt%.

[0051 ] Preferably, in one embodiment, the amount of milk fat as determined with respect to the total amount of fat in the composition of the invention is at least 30 wt%, and the amount of vegetable oil and fat as determined with respect to the total amount of fat in the synthetic composition of the invention is at least 10 wt%, preferably at least 20 wt%, more preferably at least 30 wt%, most preferably at least 40 wt%.

[0052] Preferably, in one embodiment, the amount of milk fat as determined with respect to the total amount of fat in the composition of the invention is at least 40 wt%, and the amount of vegetable oil and fat as determined with respect to the total amount of fat in the synthetic composition of the invention is at least 10 wt%, preferably at least 20 wt%, more preferably at least 30 wt%, most preferably at least 40 wt%.

[0053] Preferably, in yet another embodiment, the amount of milk fat as determined with respect to the total amount of fat in the composition of the invention is at least 50 wt%, and the amount of vegetable oil and fat as determined with respect to the total amount of fat in the synthetic composition of the invention is at least 10 wt%, preferably at least 20 wt%, more preferably at least 30 wt%, most preferably at least 40 wt%.

[0054] Plant oils for human consumption are well known in the art and include sunflower oil, palm oil, rape seed oil.

[0055] Suitable milk fat for the composition of the invention is mammalian milk fat. Preferably milk fat from a ruminant, more preferably wherein the milk fat is selected from the group consisting of cow’s milk fat, sheep milk fat, goat milk fat, camel milk fat, and horse milk fat; even more preferably from bovine milk fat or goat milk fat; most preferably bovine milk fat, particularly preferably cow’s milk fat. The milk fat may be obtained from different milk fractions such as whole milk, cream, butter, anhydrous milk fat and the like. The term "ruminant milk fat" as used in this connection refers to a source of milk fat from milk of ruminants, preferably bovine milk fat. The milk fat source can in principle be any available ruminant milk fat source, such as whole milk, cream, anhydrous milk fat (AMF) or milk fat fractions resulting from dry fractionation, critical CO2 extraction or other fractionation methods known in the art. It was, however, found particularly suitable to use whole milk and/or cream as the milk fat source.

[0056] Preferably the ruminant milk fat is bovine milk fat and the fat is selected from the group consisting of whole milk, cream, and anhydrous milk fat (AMF). More preferably, the bovine is a cow. In one embodiment the milk fat is bovine whole milk or cream. In one embodiment, the ruminant milk fat is bovine whole milk, in another embodiment the ruminant milk fat is bovine cream, in still another embodiment the ruminant milk fat is bovine AMF.

[0057] In still another embodiment, the protein in the protein fraction of the composition of the invention is partially hydrolysed. This improves the digestibility of the composition and hence contributes to the prevention and/or treatment of GER(D). In one embodiment the protein fraction comprises at least 10 wt% of partially hydrolysed protein as determined to the total amount of protein. Hydrolysed protein suitable for the composition of the invention may be obtained using methods known in the art, for example via chemical hydrolysation or enzymatic hydrolysation, for example as disclosed in W02006130204 or EP0922392. As used herein, the hydrolysed protein has a molar mass of 5000 Daltons or lower.

[0058] Alternatively, or additionally, in one embodiment the composition of the invention additionally comprises a thickener, in another embodiment the thickener is selected from the group consisting of locust bean gum (LBG), carob bean gum (CBG) and starch; preferably wherein the amount of thickener as determined to the dry weight of the composition is between 0.001 and 5 wt%, more preferably between 0.01 and 2.5 wt%, even more preferably between 0.1 and 1.5 wt%.

[0059] In still another embodiment the synthetic nutritional product is a complete nutritional product, preferably an infant formula product such as a neonatal food product, IFT product, Follow-on-Formula (FOF), and/or Young Child Formula (YCF- Jr). Preferably, the product is an IFT product, Follow-on-Formula (FOF), and/or Young Child Formula (YCF-Jr). [0060] The composition of the invention may further comprise vitamins and minerals. Addition of levels and types of vitamins and minerals depends on the type of product and is known to the person skilled in the art.

[0061] The composition of the invention may be used in the treatment and/or prevention of infantile regurgitation (GER I GERD). So, in one aspect the invention relates to the synthetic composition of the invention for use in the treatment and/or prevention of infantile regurgitation; preferably the treatment of infantile regurgitation. In another aspect, the invention relates to the use of the synthetic composition according to the invention to treat and/or prevent infantile regurgitation; preferably the treatment of infantile regurgitation. In yet another aspect, the invention relates to a method of treatment of infantile regurgitation comprising the step of administering the synthetic composition of the invention.

[0062] In still another aspect, the invention relates to the use of the composition of the invention for increasing the lipid digestion in the stomach into free fatty acids with at least 15% as determined by the level of free fatty acids and as compared to an infant formula with a similar macronutrient level comprising a fat fraction consisting essentially of vegetable fats and oils. Preferably, the increase in free fatty acids is at least 30%, more preferably at least 45%, most preferably at least 60%. In one embodiment the fat fraction in the composition of the invention comprises at least 50 wt% milk fat and the increase in free fatty acids is at least 30%, preferably at least 45%, more preferably at least 60%. In another embodiment the fat fraction in the composition of the invention comprises at least 30 wt% milk fat and the increase in free fatty acids is at least 20%, preferably at least 25%, more preferably at least 30%. In yet another embodiment the fat fraction in the composition of the invention comprises at least 20 wt% milk fat and the increase in free fatty acids is at least 15%, preferably at least 20%, more preferably at least 30%.

[0063] In yet another aspect, the invention relates to use of the composition according to the invention for the manufacture of a medicament for the treatment and/or prevention of infantile regurgitation. In a further aspect the invention relates to the use of the composition according to the invention for the manufacture of a medicament for increasing the lipid digestion in the stomach into free fatty acids with at least 15% as determined by the level of free fatty acids and as compared to an infant formula with a similar macronutrient level comprising a fat fraction consisting essentially of vegetable fats and oils; preferably, the increase in free fatty acids is at least 30%, more preferably at least 45%, most preferably at least 60%.

[0064] In a preferred aspect, the composition of the invention is free of yak milk.

[0065] It must also be noted that, as used in the specification, the aspects, embodiments and the appended claims, the singular form "a", "an" and "the" comprise plural referents unless the context clearly indicates otherwise. For example, reference to a component in the singular is intended to comprise a plurality of components.

[0066] Unless defined otherwise, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0067] Except in the examples, or where otherwise expressly indicated, all numerical quantities in this description indicating amounts of material or conditions of reaction and/or use are to be understood as modified by the word "about" in describing the broadest scope of the invention. Practice within the numerical limits stated is generally preferred. Also, unless expressly stated to the contrary: percent, "parts of," and ratio values are by weight; the description of a group or class of materials as suitable or preferred for a given purpose in connection with the invention implies that mixtures of any two or more of the members of the group or class are equally suitable or preferred; description of constituents in chemical terms refers to the constituents at the time of addition to any combination specified in the description, and does not necessarily preclude chemical interactions among the constituents of a mixture once mixed; the first definition of an acronym or other abbreviation applies to all subsequent uses herein of the same abbreviation and applies, mutatis mutandis, to normal grammatical variations of the initially defined abbreviation; and, unless expressly stated to the contrary, measurement of a property is determined by the same technique as previously or later referenced for the same property.

[0068] The invention is hereinafter illustrated with reference to the following, nonlimiting, examples.

Examples Fatty acid determination

[0069] The content of the different fatty acids in the lipid of the composition of the invention can be determined by standard method ISO 15884/IDF 182:2002 (Milk fat - Preparation of fatty acid methyl esters) and ISO 15885/IDF 184 (Milk fat — Determination of the fatty acid composition by gas-liquid chromatography). These ISO methods allow for determination of molar concentration of a fatty acid relative to total moles of this fatty acid in TAG ([FA-TAG]). The distribution of fatty acids over the glycerol backbone can be determined according to the method disclosed in JOCS/AOCS Official Method Ch 3a-19 Determination of the composition of fatty acids at the 2-position of oils and fats - Enzymatic Transesterification method using Candida antarctica lipase (Approved 2019). In essence, this method involves hydrolysis of triacylglycerols (TAG) by a sn-1 ,3 specific pancreatic lipase (porcine). The required 2-monoacylglycerols formed are isolated by thin layer chromatography and these are subsequently methylated for gas chromatographic analysis and quantified in molar concentrations relative to the total moles of fatty acids at the sn-2 position ([FA(sn-2)]).

Experimental

[0070] Two different infant formula (IF1 and IF2) were used in this experiment. The fat fraction in IF1 consisted of a blend of vegetable oils and milkfat (fat blend containing 50 wt% milk fat). The fat fraction in IF2 consisted of vegetable oils (IF2). The macronutrient level of IF1 and IF2 is shown in Table 1.

Table 1 Macronutrient levels of IF 1 and IF2.

Nutrient

Energy (kcal/100 mL) 65.8 66

Protein (g/100 kcal) 2.2 2.3

Carbohydrate (g/100 kcal) 10.6 10.6

Fat (g/100 kcal) 5.3 * 5.2

Minerals (g/100 kcal) 0.51 0.60

*Of which 50% is milkfat Table 2 Fatty acid composition of IF 1 and IF2

Fatty acid

C4:0 (wt% on total fatty acid) 1 .8 <0.1

C4:0 on sn1 ,3 (% of total C4:0) 97% not determined

C16:0 on sn2 (% of total C16:0) 37% 10%

% LC SFA on total FA (blauw) 39 42

% LC SFA on sn2 (% of all FA on sn2) (groen) 48 22

% LC SFA on sn2 (% of total LC SFA) (oranje) 41 17

% SFA on total FA 53 46

% SFA (sn2) (% of all FA on sn2) 54 24

% SFA on sn2 (% of total SFA) 34 18

FA = Fatty Acid

SFA = Saturated Fatty Acid

LC SFA = Long Chain Saturated Fatty Acid, i.e. saturated fatty acids with 12 or more carbon atoms.

[0071] IF1 and IF2 were subjected to an in vitro digestion model simulating infant conditions according to INFOGEST conditions (as described in Brodkorb et al Nat Protoc. 2019 Apr; 14(4):991 -1014). Over time the pH of the samples is lowered representing a longer duration time in the stomach. Samples were taken (i.e. sampled) at different fixed pH (from neutral to acidic pH), during simulated gastric acidification and analysed for lipid digestion. As compared to a formula containing only vegetable oils (IF2), the formula containing milk fat (IF1) had a higher gastric lipid digestion during simulated infant digestion as illustrated by the increased levels of free fatty acids (FFA), as a result of triglyceride hydrolysis during gastric digestion. This is illustrated in Figure 1 . As referred to in Figure 1 , AFFA is referring to amount of Free Fatty Acids (FFA) as released during the gastric digestion experiment.

[0072] It follows from the data that at the end of the gastric digestion i.e. at pH 3.5, that the amount of FFA is significantly higher in IF1 as compared to IF2 (230 vs 137.5 pmol, respectively). Substituting 50 wt% of the vegetable oils and fat thus resulted in an increase of fat digestion in the stomach of ~67%. It is believed that this increased lipid digestion in the stomach improves the digestion of the product (e.g. infant formula) and/or reduces the levels of GER / GERD. Interpretation

[0073] Milk fat has a more complex triglyceride structure as compared to vegetable oils including, amongst others, more saturated fatty acids in the sn-2 position and a larger percentage of short-chain fatty acids at the sn1-3 position as compared to vegetable oils. Especially the latter may explain the observed higher gastric lipid digestion of the milkfat-containing formula. This will be beneficial for IF in general because of known differences between human milk and IF with respect to (gastric) lipid digestion. For example, studies in infants have demonstrated that gastric lipid digestion of human milk is higher than formula (Armand et al Pediatr Res. 1996 Sep;40(3):429-37).

[0074] Gastric lipid digestion of human milk is higher than with infant formula predominantly containing vegetable oils and fat (Armand et al Pediatr Res. 1996 Sep;40(3):429-37).

Extrapolation of these results

[0075] Presence of fat at the distal end of the small intestine is a potent inhibitor of gastric emptying, resulting amongst others in relaxation of the proximal stomach and diminished contractions of the distal part thereby inhibiting gastric emptying. A higher gastric digestion of the lipid source may result in a more rapid absorption of fat in the proximal small intestine thereby possibly diminishing the inhibitory stimulus of lipids in the distal small in intestine on overall gastric emptying which may be beneficial for infants suffering from GER(D).

[0076] As compared to a formula containing vegetable oils (IF2), a formula containing milk fat (50% of fat fraction was milk fat, IF1 ) had a higher gastric lipid digestion during simulated infant digestion as illustrated by the increased levels of free fatty acids during gastric digestion, from neutral to acidic pH. Numbered embodiments

1 . A synthetic nutritional composition comprising a carbohydrate fraction, a protein fraction and a lipid fraction wherein the amount of butyrate in the lipid fraction is at least 0.2 wt% as determined to the total amount of fatty acids in the lipid fraction; and wherein amount of butyrate (i.e. C4:0) linked to sn-1 ,3 is more than 70% of the total amount of butyrate, preferably more than 80%, more preferably more than 90%.

2. The synthetic composition of embodiment 1 wherein the lipid fraction is comprising milk fat and preferably further comprising vegetable oils and fat.

3. The synthetic composition of any of the preceding embodiments wherein the lipid fraction comprises long chain saturated fatty acids (LC SFA) linked to glycerol and at least 20 mole % of the LC SFA is linked to the sn-2 position of glycerol, preferably at least 30 mole %.

4 The synthetic composition of any of the preceding embodiments wherein the lipid fraction comprises saturated fatty acids (SFA) linked to glycerol and at least 20 mole % of the SFA is linked to the sn-2 position of glycerol, preferably at least 30 mole %, more preferably at least 35 mole%, most preferably at least 41 mole%.

5. The synthetic composition of anyone of embodiments 2-4 wherein the amount of milk fat as determined with respect to the total amount of fat in the composition is at least 10 wt%, preferably at least 20 wt%, more preferably at least 30 wt%, even more preferably at least 40 wt%, most preferably at least 50 wt%.

6. The synthetic composition of anyone of embodiments 2 - 5 wherein the lipid fraction is further comprising vegetable oils and fat and wherein the amount of vegetable oil and fat as determined with respect to the total amount of fat in the composition is at least 10 wt%, preferably at least 20 wt%, more preferably at least 30 wt%, most preferably at least 40 wt%.

7. The synthetic composition of anyone of claims 2 - 6 wherein the milk fat is mammalian milk fat, preferably from a ruminant.

8. The synthetic composition of any of the preceding embodiments wherein the protein fraction comprises goat or bovine milk protein and wherein the amount of goat or bovine milk protein in the protein fraction is more than 80 wt% as determined to the amount of protein in the protein fraction, preferably more than 90wt%. 9. The synthetic composition of any of the preceding embodiments wherein the protein fraction comprises at least 10wt% of partially hydrolysed protein.

10. The synthetic composition of any of the preceding embodiments additionally comprising a thickener selected from the group consisting of locust bean gum (LBG), carob bean gum (CBG) and starch; preferably wherein the amount of thickener as determined to the dry weight of the composition is between 0.001 and 5 wt%, more preferably between 0.01 and 2.5 wt%, even more preferably between 0.1 and 1.5 wt%.

11 . The synthetic nutritional product of any of the preceding embodiments, wherein the product is a complete nutritional product, preferably a neonatal food product, IFT product, Follow-on-Formula (FOF), and/or Young Child Formula (YCF-Jr).

12. The synthetic nutritional product of any of the preceding embodiments wherein the food product further comprises vitamins and minerals.

13. The synthetic nutritional product of any of the preceding embodiments wherein the lipid fraction comprises one or more from the group consisting of DHA, ARA, and EPA, preferably comprises DHA, ARA and EPA.

14. The synthetic composition of any of the preceding embodiments for use in the treatment and/or prevention of infantile regurgitation.

15. Use of synthetic composition according to anyone of embodiments 1 - 13 to treat and/or prevent infantile regurgitation.

16. Use of the composition according to anyone of embodiments 1 - 13 for increasing the lipid digestion in the stomach into free fatty acids with at least 15% as determined by the level of free fatty acids and as compared to an infant formula with a similar macronutrient level comprising a fat fraction consisting essentially of vegetable fats and oils; preferably, the increase in free fatty acids is at least 30%, more preferably at least 45%, most preferably at least 60%.

17. Use of the composition according to anyone of embodiments 1 - 13 for the manufacture of a medicament for the treatment and/or prevention of infantile regurgitation.

18. Use of the composition according to anyone of embodiments 1 - 13 for the manufacture of a medicament for increasing the lipid digestion in the stomach into free fatty acids with at least 15% as determined by the level of free fatty acids and as compared to an infant formula with a similar macronutrient level comprising a fat fraction consisting essentially of vegetable fats and oils; preferably, the increase in free fatty acids is at least 30%, more preferably at least 45%, most preferably at least 60%.

Claims

1 . A synthetic nutritional composition comprising a carbohydrate fraction, a protein fraction and a lipid fraction wherein the amount of butyrate in the lipid fraction is at least 0.2 wt% as determined to the total amount of fatty acids in the lipid fraction; and wherein amount of butyrate (i.e. C4:0) linked to sn-1 ,3 is more than 70% of the total amount of butyrate, for use in the treatment and/or prevention of infantile regurgitation, preferably wherein amount of butyrate (i.e. C4:0) linked to sn-1 ,3 is more than 80%, more preferably more than 90%.

2. The synthetic composition for use of claim 1 wherein the lipid fraction is comprising milk fat and preferably further comprising vegetable oils and fat.

3. The synthetic composition for use of any of the preceding claims wherein the lipid fraction comprises long chain saturated fatty acids (LC SFA) linked to glycerol and at least 20 mole % of the LC SFA is linked to the sn-2 position of glycerol, preferably at least 30 mole %.

4. The synthetic composition for use of anyone of claims 2 or 3 wherein the amount of milk fat as determined with respect to the total amount of fat in the composition is at least 10 wt%, preferably at least 20 wt%, more preferably at least 30 wt%, even more preferably at least 40 wt%, most preferably at least 50 wt%.

5. The synthetic composition for use of anyone of claims 2 - 4 wherein the lipid fraction is further comprising vegetable oils and fat and wherein the amount of vegetable oil and fat as determined with respect to the total amount of fat in the composition is at least 10 wt%, preferably at least 20 wt%, more preferably at least 30 wt%, most preferably at least 40 wt%.

6. The synthetic composition for use of anyone of claims 2 - 5 wherein the milk fat is mammalian milk fat, preferably from a ruminant.

7. The synthetic composition for use of any of the preceding claims wherein the protein fraction comprises goat or bovine milk protein and wherein the amount of goat or bovine milk protein in the protein fraction is more than 80 wt% as determined to the amount of protein in the protein fraction, preferably more than 90wt%.

8. The synthetic composition for use of any of the preceding claims wherein the protein fraction comprises at least 10wt% of partially hydrolysed protein.

9. The synthetic composition for use of any of the preceding claims additionally comprising a thickener selected from the group consisting of locust bean gum (LBG), carob bean gum (CBG) and starch; preferably wherein the amount of thickener as determined to the dry weight of the composition is between 0.001 and 5 wt%, more preferably between 0.01 and 2.5 wt%, even more preferably between 0.1 and 1.5 wt%.

10. The synthetic nutritional composition for use of any of the preceding claims, wherein the product is a complete nutritional product, preferably a neonatal food product, IFT product, Follow-on-Formula (FOF), and/or Young Child Formula (YCF-Jr).

11 . The synthetic nutritional composition for use of any of the preceding claims wherein the food product further comprises vitamins and minerals.

12. The synthetic nutritional composition for use of any of the preceding claims wherein the lipid fraction comprises one or more from the group consisting of DHA, ARA, and EPA, preferably comprises DHA, ARA and EPA.

13. Use of synthetic composition according to anyone of claims 1 - 12 to treat and/or prevent infantile regurgitation, or alternatively, the synthetic composition of any of the claims 1 - 12 for use in the treatment and/or prevention of infantile regurgitation.

14. Use of the composition according to anyone of claims 1 - 12 for increasing the lipid digestion in the stomach into free fatty acids with at least 15% as determined by the level of free fatty acids and as compared to an infant formula with a similar macronutrient level comprising a fat fraction consisting essentially of vegetable fats and oils; preferably, the increase in free fatty acids is at least 30%, more preferably at least 45%, most preferably at least 60%.

15. Use of the composition according to anyone of claims 1 - 12 for the manufacture of a medicament for the treatment and/or prevention of infantile regurgitation.