Use of milk fat globule membrane in synthesis of infant nutrition

Abstract

The present application provides a synthetic nutritional composition comprising a milk fat globule membrane (MFGM) in the range of from about 10 [mu] g / 100 kcal to about 1500 mg / 100 kcal for use in improving neurological development in a pediatric subject. During a first year of life, a synthetic nutritional composition is administered to the pediatric subject for at least three months, and the administration of the synthetic nutritional composition improves neural development of the pediatric subject starting from at least two years old.

Description

Technical Field

[0001] The present application relates to a synthetic nutritional composition comprising milk fat globule membrane (MFGM) for improving neurodevelopment in a pediatric subject, comprising the step of administering to the subject a synthetic nutritional composition comprising milk fat globule membrane (MFGM). More specifically, the present application relates to a synthetic nutritional composition comprising MFGM in the range of about 10 μg / 100 kcal to about 1500 mg / 100 kcal for improving neurodevelopment in a pediatric subject, wherein the synthetic nutritional composition is administered to the pediatric subject for at least three months during the first year of life, and wherein administration of the synthetic nutritional composition improves neurodevelopment in the pediatric subject starting at least two years of age. Background Art

[0002] Human milk contains many components that contribute to infant brain growth and development. Observational studies of infant cognitive function have shown that breastfed infants have an advantage over formula-fed infants, even after controlling for socioeconomic factors. Changing infant formula to more closely match the dynamics of breast milk has resulted in closer approximations in composition, function, and health-based outcomes for infants receiving either human milk or infant formula.

[0003] Synthetic nutritional compositions for human consumption based on bovine dairy products are usually made using skimmed milk powder as the main dairy component. Skimmed milk powder contains small amounts of bioactive components, such as phospholipids, sphingolipids and gangliosides. Some of these bioactive components have been shown to have a profound and lasting effect on human brain function, particularly when infants are developing. Although skimmed milk powder contains these beneficial bioactive components, they are only present in small amounts, which are insufficient to provide the desired benefits for human brain function.

[0004] Many of these bioactive components are present in the milk fat globule membrane (MFGM). MFGM is a bioactive membrane structure that surrounds fat droplets and is naturally present in human milk and other mammalian milk (e.g., bovine milk). MFGM contains a three-layer lipid structure that includes a complex mixture of phospholipids (such as phosphatidylethanolamine, phosphatidylcholine, phosphatidylserine, and phosphatidylinositol), glycolipids, glycosphingolipids (such as sphingomyelin and gangliosides), other polar lipids, proteins, glycoproteins (such as xanthine dehydrogenase, xanthine oxidase, lactadherin, fatty acid binding protein (FABP), mucin-1, butyrophilin, adipose differentiation-associated protein, and cluster of differentiation 36 (CD36)), triglycerides, cholesterol, 7-dehydrocholesterol, enzymes, and other components.

[0005] Benefits on neurodevelopment in pediatric subjects aged 12 to 18 months have been reported by supplementing infant formula with MFGM during the first year of life.

[0006] Timby et al., Am J Clin Nutr 2014;99:860–8 reported a study in which infants were fed either an experimental formula (EF) or a standard formula (SF) supplemented with MFGM until six months of age. At 12 months of age, cognitive scores as tested by the Bayley Scales of Infant and Toddler Development, third edition (“Bayley-III”) were higher in the EF group than in the SF group and did not differ significantly from the cognitive scores of the reference breast-fed infant group.

[0007] Li et al., J Pediatr 2019, 215, 24-31 reported a study in which infants were fed infant formula supplemented with MFGM and lactoferrin (MFGM+Lf) or standard cow's milk-based infant formula (control) until six months of age. The primary outcome was the Bayley-III cognitive score at day 365 (i.e., 12 months of age). At 12 months of age, the MFGM+Lf group had higher Bayley-III test cognitive scores than the control group. However, at day 545 of life (i.e., 18 months of age), no group differences were detected in any Bayley-III domain (cognition, language, and movement), although the MFGM+Lf group had higher scores in some subcategories of the MacArthur-Bates Communicative Development Inventories (p<0.05). At 18 months of age, the MFGM+Lf group achieved higher scores compared with controls on sentence complexity (using words in longer and more grammatically correct combinations) and two classification items: absent owners (absentowners) (naming the absent owner to whom a visible object belonged) and Chinese classifiers (grammatical markers specific to Chinese).

[0008] It would be desirable to provide a synthetic nutritional composition for administration to pediatric subjects up to 12 months of age that provides neurological benefits that persist beyond 12 months of age or even 18 months of age. Summary of the invention

[0009] According to a first aspect of the present invention, there is provided a synthetic nutritional composition comprising milk fat globule membrane (MFGM) in the range of about 10 μg / 100 kcal to about 1500 mg / 100 kcal for use in improving neurodevelopment in a pediatric subject,

[0010] wherein the synthetic nutritional composition is administered to the pediatric subject for at least three months during the first year of life,

[0011] And wherein administration of the synthetic nutritional composition improves neurodevelopment in a pediatric subject beginning at least two years of age.

[0012] Preferably, the improvement in neurodevelopment is an improvement in cognitive development.

[0013] Preferably, the improvement in cognitive development is selected from at least one of improvements in memory, verbal comprehension, visuospatial ability, fluid reasoning, mental processing speed, rule learning, executive function and language acquisition development.

[0014] Preferably, administration of the synthetic nutritional composition occurs for at least six months during the first year of life.

[0015] Preferably, administration of the synthetic nutritional composition occurs between three and six months of age.

[0016] Preferably, the improvement in neurodevelopment in the pediatric subject begins at least two years of age and continues until at least five years of age.

[0017] Preferably, the synthetic nutritional composition comprises MFGM in the range of about 15 μg / 100 kcal to about 1000 mg / 100 kcal, preferably about 100 μg / 100 kcal to about 500 mg / 100 kcal.

[0018] Preferably, the synthetic nutritional composition comprises phospholipids in the range of about 6 mg / 100 kcal to about 300 mg / 100 kcal, preferably about 12 mg / 100 kcal to about 150 mg / 100 kcal, more preferably about 18 mg / 100 kcal to about 85 mg / 100 kcal.

[0019] Preferably, the synthetic nutritional composition comprises sphingomyelin in the range of about 1 mg / 100 kcal to about 30 mg / 100 kcal, preferably about 3.5 mg / 100 kcal to about 24 mg / 100 kcal, more preferably about 6 mg / 100 kcal to about 21 mg / 100 kcal.

[0020] Preferably, the synthetic nutritional composition comprises gangliosides in the range of about 0.25 mg / 100 kcal to about 6 mg / 100 kcal, preferably about 0.7 mg / 100 kcal to about 5.2 mg / 100 kcal, more preferably about 1.1 mg / 100 kcal to about 4.5 mg / 100 kcal.

[0021] Preferably, the MFGM is provided by whey protein concentrate.Preferably, the synthetic nutritional composition comprises whey protein concentrate in the range of about 6.5 to about 12.0 wt%, preferably about 7.9 wt% to about 10.3 wt%, on a dry weight basis.

[0022] Preferably, MFGM is provided by an enriched dairy product.Preferably, the synthetic nutritional composition comprises an enriched dairy product in the range of about 0.06 g / 100 kcal to about 1.5 g / 100 kcal, preferably about 0.3 g / 100 kcal to about 1.4 g / 100 kcal, more preferably about 0.4 g / 100 kcal to about 1 g / 100 kcal.

[0023] Preferably, the MFGM is provided by buttermilk.Preferably, the synthetic nutritional composition comprises buttermilk in the range of about 0.06 g / 100 kcal to about 10.5 g / 100 kcal, preferably about 0.3 g / 100 kcal to about 8.5 g / 100 kcal, more preferably about 0.4 g / 100 kcal to about 7 g / 100 kcal.

[0024] Preferably, the synthetic nutritional composition further comprises lactoferrin.Preferably, the synthetic nutritional composition comprises lactoferrin in the range of about 5 mg / 100 kcal to about 300 mg / 100 kcal, preferably about 60 mg / 100 kcal to about 150 mg / 100 kcal, more preferably about 60 mg / 100 kcal to about 100 mg / 100 kcal.

[0025] Preferably, the synthetic nutritional composition further comprises polydextrose (PDX) and / or galacto-oligosaccharides (GOS). Preferably, the synthetic nutritional composition comprises PDX in the range of about 0.015 g / 100 kcal to about 1.5 g / 100 kcal, preferably about 0.05 g / 100 kcal to about 1.5 g / 100 kcal, more preferably about 0.2 g / 100 kcal to about 0.6 g / 100 kcal. Preferably, the synthetic nutritional composition comprises GOS in the range of about 0.015 g / 100 kcal to about 1.0 g / 100 kcal, preferably about 0.2 g / 100 kcal to about 0.5 g / 100 kcal.

[0026] Preferably, the synthetic nutritional composition further comprises at least one human milk oligosaccharide (HMO) selected from the group consisting of 2'-fucosyllactose (2FL), 3'-fucosyllactose (3FL), lacto-N-tetraose (LNT), lacto-N-neotetraose (LNnT), lacto-N-fucopentaose I (LNFP-I), 3'-sialyllactose (3SL), 6'-sialyllactose (6SL), or any combination thereof. Preferably, the synthetic nutritional composition comprises HMO in the range of about 0.01 g / 100 kcal to about 2.0 g / 100 kcal, preferably about 0.01 g / 100 kcal to about 1.5 g / 100 kcal.

[0027] Preferably, the synthetic nutritional composition further comprises a source of long chain polyunsaturated fatty acids (LCPUFAs) comprising docosahexaenoic acid (DHA), arachidonic acid (ARA), or a combination thereof. Preferably, the synthetic nutritional composition comprises LCPUFAs in the range of about 5 mg / 100 kcal to about 100 mg / 100 kcal, preferably about 10 mg / 100 kcal to about 50 mg / 100 kcal.

[0028] According to an aspect related to the first aspect of the invention, there is provided a method of improving neurodevelopment in a pediatric subject, the method comprising the steps of administering a synthetic nutritional composition comprising milk fat globule membrane (MFGM) in the range of about 10 μg / 100 kcal to about 1500 mg / 100 kcal,

[0029] wherein the synthetic nutritional composition is administered to the pediatric subject for at least three months during the first year of life,

[0030] And wherein administration of the synthetic nutritional composition improves neurodevelopment in a pediatric subject beginning at least two years of age.

[0031] According to an aspect related to the first aspect of the invention, there is provided use of a synthetic nutritional composition comprising milk fat globule membrane (MFGM) in the range of about 10 μg / 100 kcal to about 1500 mg / 100 kcal in the manufacture of a medicament for improving neurodevelopment in a pediatric subject,

[0032] wherein the synthetic nutritional composition is administered to the pediatric subject for at least three months during the first year of life,

[0033] And wherein administration of the synthetic nutritional composition improves neurodevelopment in a pediatric subject beginning at least two years of age.

[0034] definition

[0035] "Milk" refers to a substance extracted or extracted from the mammary glands of mammals.

[0036] A "milk-based composition" refers to a composition comprising any mammalian milk-derived product or mammalian milk-based product known in the art. For example, a "milk-based composition" may comprise bovine casein, bovine whey, bovine lactose, bovine milk fat globule membrane (MFGM), bovine milk fat, or any combination thereof.

[0037] "Enriched milk product" generally refers to a milk ingredient enriched with MFGM and / or certain MFGM components (such as proteins and lipids found in MFGM) and having a fat content between 14 and 20 wt%. For example, Lacprodan MFGM-10 available from Arla Foods Ingredients is a form of enriched milk product.

[0038] "Lactoferrin" refers to lactoferrin produced or obtained from a source other than human breast milk.

[0039] "Pediatric subject" refers to a person less than 18 years old. The term "pediatric subject" may refer to a premature infant, a full-term infant, and / or a child, as described below. A pediatric subject may be a human subject between birth and 8 years old. In another aspect, a "pediatric subject" refers to a human subject between 1 and 6 years old. Alternatively, a "pediatric subject" refers to a human subject between 6 and 13 years old or between 6 and 12 years old.

[0040] "Infant" refers to a human subject whose age ranges from birth to no more than one year old, and includes infants whose corrected age is 0 to 12 months. The phrase "corrected age" refers to the actual age of the infant minus the amount of time when the infant was born prematurely. Therefore, the corrected age is the age of the infant under full-term conditions. The term infant includes full-term infants, premature infants, low-birth-weight infants, very-low-birth-weight infants, and extremely-low-birth-weight infants. "Premature" refers to an infant born before the end of the 37th week of pregnancy. "Full-term" refers to an infant born after the end of the 37th week of pregnancy. "Low-birth-weight infant" refers to an infant weighing less than 2500 grams (about 5 pounds 8 ounces) at birth. "Extremely low-birth-weight infant" refers to an infant weighing less than 1500 grams (about 3 pounds 4 ounces) at birth. "Extremely low-birth-weight infant" refers to an infant weighing less than 1000 grams (about 2 pounds 3 ounces) at birth.

[0041] "Child" refers to a human subject ranging from 12 months to 13 years old. A child can be a subject between 1 and 12 years old. In another aspect, the term "child" can refer to a subject between 1 and about 6 years old. Alternatively, the term "child" can refer to a subject between about 7 and about 12 years old. The term "toddler" refers to a human subject ranging from 1 to 3 years old.

[0042] The term "synthetic" when applied to a composition, nutritional composition or mixture refers to a composition, nutritional composition or mixture obtained by biological and / or chemical means, which may be chemically identical to the mixture naturally occurring in mammalian milk. A composition, nutritional composition or mixture is called "synthetic" if at least one of its components is obtained by biological (e.g., enzymatic) and / or chemical means.

[0043] "Nutritional composition" refers to a substance or composition that meets at least a portion of the nutritional requirements of a subject. "Nutritional composition" may refer to a liquid, powder, solution, gel, paste, solid, concentrate, suspension, ready-to-use enteral formula, oral formula, infant formula, follow-on formula, formula for pediatric subjects, children's formula, and / or toddler milk.

[0044] "Infant formula" refers to a composition that meets at least a portion of the nutritional requirements of an infant, and ideally can provide the sole source of nutrition for an infant.

[0045] "Follow-on formula", also known as "second stage formula", refers to a composition that meets at least part of the nutritional requirements of infants over 6 months old and toddlers from 1 to 3 years old.

[0046] "Liquid concentrate" refers to a liquid that requires dilution before it is ready for administration to or consumption by a patient.

[0047] The term "enteral" means deliverable through or within the gastrointestinal tract or digestive tract. "Enteral administration" includes oral feeding, intragastric feeding, transpyloric administration, or any other administration into the digestive tract. "Administration" is broader than "enteral administration" and includes parenteral administration or any other administration route of a substance into a subject.

[0048] The "gut" of a subject may also refer to the subject's gastrointestinal system, gastrointestinal tract, digestive system, and / or digestive tract.

[0049] The term "substantially free" means containing less than a functional amount of a particular component, typically less than 0.1 wt %, and including 0 wt % of a particular component.

[0050] The term "essential" when applied to nutrients refers to any nutrient that cannot be synthesized by the body in amounts sufficient for normal growth and that must therefore be supplied through the diet. The term "conditionally essential" when applied to nutrients refers to a nutrient that must be supplied through the diet when the body is unable to obtain sufficient amounts of a precursor compound for endogenous synthesis.

[0051] "Prebiotic" refers to a non-digestible food ingredient that beneficially affects the host by selectively stimulating the growth and / or activity of one or a limited number of bacteria in the digestive tract, which can improve the health of the host. Prebiotics exert health benefits that may include, but are not limited to: selectively stimulating the growth and / or activity of one or a limited number of beneficial intestinal bacteria; stimulating the growth and / or activity of ingested probiotic microorganisms; selectively reducing intestinal pathogens; and favorably affecting the intestinal short-chain fatty acid profile. The prebiotics of the composition may be naturally occurring, synthetic, or developed by genetic manipulation of organisms and / or plants, whether such new sources are now known or later developed.

[0052] The term "human milk oligosaccharides" or "HMOs" generally refers to a group of complex carbohydrates found in human breast milk.

[0053] "N-acetylated oligosaccharides" refer to both "N-acetyllactosamine" and "oligosaccharides containing N-acetyllactosamine". They are neutral oligosaccharides with N-acetyllactosamine residues. Suitable examples are LNT (lactose-N-tetraose) and LNnT (lactose-N-neotetraose).

[0054] The term "sialic acid" refers to a family of neuraminic acid derivatives. N-acetylneuraminic acid (Neu5Ac) and N-glycolylneuraminic acid (Neu5Gc) are the most abundant naturally occurring forms of sialic acid, especially Neu5Ac in human and bovine milk.

[0055] "Probiotics" refers to microorganisms, such as bacteria or yeast, that have been shown to exert a beneficial effect on the health of a host subject. Probiotics can generally be classified as "live" or "non-live". The term "live probiotic" refers to live microorganisms, and the amount of live probiotics is specified in colony forming units (CFU). Probiotics that have been killed by heat or otherwise inactivated are referred to as "non-live probiotics", i.e., non-live microorganisms. Non-live probiotics may retain the ability to favorably affect the health of the host even though they may have been killed by heat or otherwise inactivated.

[0056] The term "degree of hydrolysis" refers to the extent to which peptide bonds in a protein are broken by a hydrolysis process. One of ordinary skill in the art of formulation readily determines the degree of protein hydrolysis of a hydrolyzed protein component used to characterize a composition by quantifying the amino nitrogen to total nitrogen ratio (AN / TN) of the protein component of a selected composition. The amino nitrogen component is quantified by USP titration to determine the amino nitrogen content, and the total nitrogen component is determined by Kjeldahl nitrogen determination. These methods are well known to one of ordinary skill in the art of analytical chemistry.

[0057] For purposes of this disclosure, the term "partially hydrolyzed" means a degree of hydrolysis greater than 0% but less than about 40%.

[0058] For purposes of this disclosure, the term "extensively hydrolyzed" refers to a degree of hydrolysis greater than or equal to about 40%.

[0059] For purposes of this disclosure, a "reconstituted solution" refers to a solution prepared when a diluent (eg, water, saline, etc.) is added to an ingredient (eg, powder, solution, gel, suspension, paste, solid, liquid, liquid concentrate, etc.).

[0060] “Executive function” refers to the ability to identify, evaluate, and choose among alternatives and strategies. The term encompasses goal-directed behavior, planning, and / or cognitive flexibility.

[0061] Unless otherwise indicated, all percentages, parts and ratios as used herein are specified by weight of the total composition.All amounts specified as "daily" administration may be delivered in a single unit dose, in a single portion or in two or more doses or portions administered over the course of 24 hours.

[0062] All references to singular features or limitations in this disclosure shall include the corresponding plural features or limitations, and vice versa, unless the context of the reference dictates otherwise or clearly implies the contrary.

[0063] All combinations of method or process steps disclosed herein can be performed in any order unless the context of the referenced combination dictates otherwise or clearly implies to the contrary.

[0064] The compositions of the present disclosure can comprise, consist of, or consist essentially of any of the components described herein, as well as including any additional useful components.

[0065] All features disclosed in this specification (including any accompanying claims, abstract and drawings) and / or all steps of any method or process so disclosed may be combined in any combination, except combinations where at least some of such features and / or steps are mutually exclusive.

[0066] Each feature disclosed in this specification (including any accompanying claims, abstract and drawings) may be replaced by an alternative feature having the same, equivalent or similar purpose, unless expressly stated otherwise. Therefore, unless expressly stated otherwise, each feature disclosed is only an example of a generic series of equivalent or similar features. DETAILED DESCRIPTION

[0067] The inventors have unexpectedly discovered that administering a synthetic nutritional composition comprising MFGM to a pediatric subject for at least three months during the first year of life improves the pediatric subject's subsequent neurodevelopment during childhood (ie, when the pediatric subject is at least two years old).

[0068] As discussed above, supplementation with MFGM in the first year of life was previously shown in Timby et al. 2014 to have an effect at 12 months of age, while Li et al. 2019 showed that adding MFGM and lactoferrin to a synthetic nutritional composition administered in the first year of life had an effect at 12 months of age and limited effect at 18 months of age.

[0069] As detailed in Example 1, the inventors followed up the study detailed in Li et al. 2019 with participants aged between 5.5 and 6 years who completed study feedings during the first year of life (i.e., throughout 365 days of age). The inventors unexpectedly found that feeding infants formula supplemented with MFGM and lactoferrin throughout 12 months of age resulted in improved neurodevelopment (relative to a control group) later in life between 5.5 and 6 years of age. The results suggest that the addition of MFGM and lactoferrin to infant formula has a lasting effect on supporting neurodevelopment during childhood.

[0070] Although the test formula in Example 1 contained both MFGM and lactoferrin, there is clinical evidence that MFGM and its components support the development of language and cognitive areas (Li et al. (2019)).

[0071] A large amount of preclinical data indicates that MFGM or its components (including sphingomyelin, gangliosides, phosphatidylserine and phosphatidylcholine) play a role in neural development and function, gastrointestinal immune defense and intestinal health. Glycosylated proteins (mucin-1, mucin-15, butyrophilin and lactadherin) and glycosylated sphingolipids from MFGM can promote the development of healthy infant intestinal microbiota by favoring beneficial bifidobacterium species (Bourlieu et al., Current Opinion in Clinical Nutrition and Metabolic Care: March 2015, 18(2), 118-127).

[0072] Clinical reports also suggest that MFGM and its components can directly affect brain function. For example, nutritional intervention via administration of sphingomyelin-fortified milk was positively correlated with neurodevelopment in low birth weight infants (Tanaka et al. (2013), Brain & Development, 35(1), 45–52).

[0073] Therefore, it was hypothesized that similar neurological benefits to those observed in Example 1 would be observed in the absence of lactoferrin.

[0074] This is supported by the results of clinical studies detailed in Example 2. As discussed in Example 2, the inventors found that infants who received infant formula supplemented with MFGM during the first year of life showed lower event-related potential (ERP) amplitudes at two years of age compared to infants who received standard formula and a control group of breast-fed infants. The lower ERP potential amplitudes observed in the MFGM group may reflect a higher degree of neural circuit maturation. The inventors also found that the MFGM group showed lower ERP latency to a subset of stimuli (native unfamiliar stimuli) at two years of age, which may indicate improved myelination.

[0075] Therefore, administration of synthetic nutritional compositions supplemented with MFGM during the first year of life may be more likely to achieve improved neurodevelopmental outcomes at an older age based on improved neural maturation and myelination, as shown by the results presented in Example 2.

[0076] The finding that the effects of MFGM (optionally in the presence of lactoferrin) persisted in subsequent childhood was unexpected based on the studies of Timby et al. 2014 and Li et al. 2019. The study of Timby et al. 2014 did not measure neurodevelopment beyond 12 months of age. As noted by the authors of Li et al. (2019), the observation that few group differences in neurological outcomes were detected at 18 months may indicate that the control group caught up developmentally, while the early advantages observed in the MFGM+Lf group did not persist. Although differences were observed in some language subcategories at day 545, it is noteworthy that no differences were detected at day 365. The authors speculate that differences in Bayley-III domains at day 365 and differences in some language subcategories at day 545 may indicate developmental cascades (Masten AS, Cicchetti D. Developmental cascades. Dev Psychopathol. 2010; 22: 491-5).

[0077] To the best of the inventors' knowledge, the finding that supplementation of MFGM to a synthetic nutritional composition administered in the first year of life enhances neurodevelopment in pediatric subjects beginning at two years of age has not been shown previously and certainly would not have been predicted by the results of Timby et al. 2014 or Li et al. 2019.

[0078] Accordingly, the present invention provides a synthetic nutritional composition comprising milk fat globule membrane (MFGM) in the range of about 10 μg / 100 kcal to about 1500 mg / 100 kcal for use in improving neurodevelopment in a pediatric subject, wherein the synthetic nutritional composition is administered to the pediatric subject for at least three months during the first year of life, and wherein administration of the synthetic nutritional composition improves neurodevelopment in the pediatric subject starting from at least two years of age.

[0079] The pediatric subject may be a neurologically healthy pediatric subject. For example, administration of a synthetic nutritional composition comprising MFGM as defined above during the first year of life may promote the healthy establishment of cognitive function in a pediatric subject starting from at least two years of age.

[0080] Alternatively, the pediatric subject may have impaired neurological health. For example, the improvement in neurodevelopment according to the present invention may be restoration of cognitive dysfunction or reduction in severity in a pediatric subject. Administration of a synthetic nutritional composition comprising MFGM during the first year of life may result in treatment of conditions associated with delayed establishment of cognitive function or deficits in cognitive function in pediatric subjects beginning at least two years of age. Non-limiting examples of conditions include delayed and / or defective learning ability, loss or stunted development of executive function, memory deficits, and delays in language development.

[0081] The neurodevelopmental improvements in pediatric subjects are relative to the neurodevelopment observed at the same age when administered a standard infant formula (ie, an infant formula not supplemented with MFGM).

[0082] The improvement in neurodevelopment may be an improvement measured in a clinical setting following consumption of a composition according to the invention.

[0083] As explained above, the use of MFGM may lead to greater neural circuit maturity and / or improved myelination. This would translate into fundamental benefits for brain development and normal brain function.

[0084] Improvements in neurodevelopment may be improvements in cognitive development.

[0085] The improvement in cognitive development can be an improvement measured by at least one standardized clinical neuropsychological test.Non-limiting examples include the Bayley Scales of Infant Development, 3rd or 4th edition ("Bayley-III" and "Bayley-IV").

[0086] The improvement in cognitive development can be selected from at least one of the development of memory, verbal comprehension, visuospatial ability, fluid reasoning, mental processing speed, rule learning, executive function, language acquisition, and an improvement in overall or global IQ score. Preferably, the improvement in cognitive development is selected from at least one of the improvement in memory, verbal comprehension, visuospatial ability, fluid reasoning, mental processing speed, rule learning, executive function, and language acquisition.

[0087] The improvement in memory, verbal comprehension, visual-spatial ability, fluid reasoning and / or mental processing speed development can be an improvement measured by at least one standardized clinical neuropsychological test. A non-limiting example of a suitable neuropsychological test is the Wechsler Preschool & Primary Scale of Intelligence, Fourth Edition (WPPSI-IV).

[0088] Executive function is the ability to coordinate and integrate cognitive perceptual processes related to time and space, which determines how well the subject can identify, evaluate, and choose among various alternatives and strategies. Skills that comprise executive function include attention, working memory, inhibitory control (e.g., rule learning), and cognitive flexibility.

[0089] The improvement in executive function can be an improvement measured by at least one standardized clinical neuropsychological test. Non-limiting examples of suitable neuropsychological tests are:

[0090] Stroop task test - demonstrating rule learning and inhibitory control

[0091] Dimensional Change Card Sorting (DCCS) Task – Demonstrating Rule Learning and Cognitive Flexibility.

[0092] The improvement of language acquisition can be an improvement measured by at least one standardized clinical neuropsychological test. Non-limiting examples include Bayley-III, Bayley-IV or auditory event-related potential measurement (Choudhury N, Benasich AA. Clin Neurophysiol: Official J Int Fed Clin Neurophysiol. 2011; 122 (2): 320–38; Riva V et al. Cereb Cortex. 2017; 28 (6): 2100–8.). In Example 2, auditory event-related potential measurement is performed with stimulation presented in a mismatch negative wave (MMN) paradigm.

[0093] During the first year of life, synthetic nutritional composition of the present invention is applied to infants for at least three months. Application can start from birth or after a few days / weeks / months. Application can be continuous (e.g., daily application) or not continuous. It can be applied throughout the time period, or only applied during a portion thereof, such as after the first month of infant life, such as from 0 to 6 months, 1 to 6 months, 2 to 6 months, 3 to 6 months or from 1 to 12 months, 2 to 12 months, 3 to 12 months, 4 to 12 months, 5 to 12 months, 6 to 12 months, 7 to 12 months, 8 to 12 months or 9 to 12 months.

[0094] The synthetic nutritional composition may be administered from 3 months to 6 months of age. For the avoidance of doubt, administration may commence before this specific age range and / or continue beyond this specific age range.

[0095] The synthetic nutritional composition may be a single composition according to the invention. Alternatively, different compositions according to the invention intended for different age stages may be administered. For example, a stage 1 composition may be administered until six months of age (or 180 days of age), and then a stage 2 composition may be administered starting at 6 months of age and until 1 year of age.

[0096] Administration of the synthetic nutritional composition occurs for at least three months during the first year of life, or a longer total period, such as at least four months, at least five months, at least six months, at least seven months, at least eight months, at least nine months, at least ten months, or at least eleven months. Preferably, administration of the synthetic nutritional composition occurs for at least six months during the first year of life.

[0097] In addition to administration during the first year of life, administration of the synthetic nutritional composition according to the invention may continue beyond the first year of life. For example, in addition to administration during the first year of life, the synthetic nutritional composition may be administered as a toddler milk with a composition according to the invention from 12 months of age (i.e. one year old) to 18 months of age, or from 12 months of age to 24 months of age (i.e. two years old), or from 12 months of age to three years of age. Likewise, the toddler milk composition may be the same as the composition administered until one year of age, or may be different from the composition administered until one year of age.

[0098] As mentioned, administration of the synthetic nutritional composition during the first year of life improves neurodevelopment in pediatric subjects from at least two years of age. Preferably, the improvement in neurodevelopment in pediatric subjects from at least two years of age continues until at least five years of age. The improvement may continue from 2 years of age until subsequent childhood, such as until 5, 6, 7, 8, 9, 10, 11, 12, or 13 years of age. Alternatively, the improvement may occur from 3 years of age and until 13 years of age, until 12 years of age, until 11 years of age, until 10 years of age, until 9 years of age, until 8 years of age, until 7 years of age, or until 6 years of age. Alternatively, the improvement may occur from 4 years of age and until 13 years of age, until 12 years of age, until 11 years of age, until 10 years of age, until 9 years of age, until 8 years of age, until 7 years of age, or until 6 years of age. Alternatively, the improvement may occur from 5 years of age and until 13 years of age, until 12 years of age, until 11 years of age, until 10 years of age, until 9 years of age, until 8 years of age, until 7 years of age, or until 6 years of age.

[0099] As mentioned, the synthetic nutritional composition comprises milk fat globule membrane (MFGM). MFGM is a biologically active membrane structure that surrounds fat droplets and is naturally present in human milk and other mammalian milk (e.g., bovine milk). MFGM comprises a three-layer lipid structure that comprises a complex mixture of phospholipids (such as phosphatidylethanolamine, phosphatidylcholine, phosphatidylserine, and phosphatidylinositol), glycolipids, glycosphingolipids (such as sphingomyelin and gangliosides), other polar lipids, proteins, glycoproteins (such as xanthine dehydrogenase, xanthine oxidase, lactadherin, fatty acid binding protein (FABP), mucin-1, butyrophilin, adipose differentiation-associated protein, and cluster of differentiation 36 (CD36)), triglycerides, cholesterol, 7-dehydrocholesterol, enzymes, and other components.

[0100] The MFGM of any aspect described in detail below may be provided by whey protein concentrate, enriched dairy product, buttermilk or any combination thereof.

[0101] The whey protein concentrate, enriched milk product and / or buttermilk may be derived from non-human milk sources such as whole cow's milk, cow's milk, pig's milk, horse's milk, buffalo's milk, goat's milk, rat's milk, camel's milk or any combination thereof.

[0102] The composition comprises MFGM in the range of about 10 μg / 100 kcal to about 1500 mg / 100 kcal. Preferably, the composition comprises MFGM in the range of about 15 μg / 100 kcal to about 1000 mg / 100 kcal. More preferably, the composition comprises MFGM in the range of about 100 μg / 100 kcal to about 500 mg / 100 kcal.

[0103] When the composition comprises a reconstitution solution, the reconstitution solution may contain MFGM in the range of about 0.5 mg / mL to about 1.5 mg / mL. Preferably, the reconstitution solution contains MFGM in the range of about 0.6 mg / mL to about 1.3 mg / mL. Alternatively, the reconstitution solution may contain MFGM in the range of about 0.1 grams / liter (g / L) to about 6 g / L. Preferably, the reconstitution solution contains MFGM in the range of about 0.6 g / L to about 5 g / L.

[0104] MFGM may be provided by whey protein concentrate (WPC). The whey protein concentrate may be provided in any form suitable for preparing the composite nutritional composition, preferably the whey protein concentrate is provided in powder form or in liquid form. The whey protein content may have a milk fat content between 6.5 and 10.0 wt%.

[0105] The synthetic nutritional composition used according to the invention preferably has a whey protein to casein ratio of between 60:40 and 100:0 on a dry weight basis; more preferably a whey protein to casein ratio of 60:40 to 80:20; more preferably a whey protein to casein ratio of 60:40 to 70:30, and most preferably a whey protein to casein ratio of 60:40.

[0106] The composition can include WPC at a level of about 0.5 grams per liter (g / L) to about 10g / L. Preferably, WPC is present at a level of about 1g / L to about 9g / L. More preferably, WPC is present at a level of about 3g / L to about 8g / L in the composition. Alternatively, the composition can include WPC at a level of about 0.06 grams per 100 kilocalories (g / 100kcal) to about 1.5g / 100kcal. Preferably, WPC is present at a level of about 0.3g / 100kcal to about 1.4g / 100kcal. More preferably, WPC is present at a level of about 0.4g / 100kcal to about 1g / 100kcal in the composition. Alternatively, WPC is present at a level of about 6.5 wt % to about 12.0 wt %, preferably about 7.9 wt % to about 10.3 wt % by dry weight in the composition.

[0107] MFGM may be provided by an enriched dairy product. The milk fat content of the enriched dairy product is in the range of between 14 and 20% by weight. The enriched dairy product may be formed by fractionation of non-human milk, such as bovine milk. Alternatively, enriched dairy products are commercially available, including under the trade name Lacprodan MFGM-10, available from Arla Food Ingredients.

[0108] The total protein level of the enriched dairy product may range between 20% and 90%; preferably, the total protein level of the enriched dairy product ranges between 65% and 80%.

[0109] The enriched lipid fraction can be produced by a variety of fractionation techniques. These techniques include, but are not limited to, melting point fractionation, organic solvent fractionation, supercritical fluid fractionation, and any variants and / or any combination thereof.

[0110] The composition may include an enriched dairy product at a level of about 0.5 grams per liter (g / L) to about 10g / L. Preferably, the enriched dairy product is present at a level of about 1g / L to about 9g / L. More preferably, the enriched dairy product is present at a level of about 3g / L to about 8g / L in the composition. Alternatively, the composition may include an enriched dairy product at a level of about 0.06 grams per 100 kilocalories (g / 100kcal) to about 1.5g / 100kcal. Preferably, the enriched dairy product is present at a level of about 0.3g / 100kcal to about 1.4g / 100kcal. More preferably, the enriched dairy product is present at a level of about 0.4g / 100kcal to about 1g / 100kcal in the composition. Alternatively, the enriched dairy product is present at a level of about 6.5% by weight to about 12.0% by weight, preferably about 7.9% by weight to about 10.3% by weight, on a dry weight basis.

[0111] MFGM can be provided by buttermilk. In the context of the present disclosure, buttermilk refers to the aqueous byproduct of different milk fat manufacturing processes, especially the butter making process. Buttermilk is a concentrated source of MFGM components compared to other milk sources. Buttermilk includes cheese milk (defined as having a protein content of not less than 30%) and cheese milk products (defined as having a protein content of less than 30%). The minimum fat content of both types of cheese milk is 4.5%, and the maximum moisture content is 5%. Fermented buttermilk is also within the contemplation of the present disclosure. Buttermilk contains components such as lactose, minerals, oligosaccharides, immunoglobulins, milk lipids and milk proteins, each of which is present in the aqueous phase during certain dairy cream processing steps.

[0112] Buttermilk can be obtained by different processes such as: churning cream during the production of butter or cheese; producing butter variants (such as sweet cream, clarified butter, butterfat); producing anhydrous milk fat (butter oil) from cream or butter; removing fat-free dry matter and water (which are required for the production of anhydrous milk fat) from milk, cream or butter to obtain buttermilk as a by-product; the removal can be done by mechanical and / or chemically induced separation; or, producing anhydrous milk fat (butter oil) by mixing together secondary skim and beta-whey (and / or butter whey) streams separately.

[0113] When the MFGM is provided by buttermilk, the composition may include buttermilk at a level of about 0.5 grams per liter (g / L) to about 70 g / L. Preferably, buttermilk is present at a level of about 1 g / L to about 60 g / L. More preferably, buttermilk is present in the composition at a level of about 3 g / L to about 50 g / L. Alternatively, the composition may include buttermilk at a level of about 0.06 grams per 100 kilocalories (g / 100 kcal) to about 10.5 g / 100 kcal. Preferably, buttermilk is present at a level of about 0.3 g / 100 kcal to about 8.5 g / 100 kcal. More preferably, buttermilk is present in the composition at a level of about 0.4 g / 100 kcal to about 7 g / 100 kcal.

[0114] It is hypothesized that administration of a synthetic nutritional composition comprising MFGM (and wherein the MFGM is present in the specific amounts detailed in the above description and defined in the claims) over a certain period of time will be useful for improving neurodevelopment in pediatric subjects starting from at least two years of age.

[0115] MFGM may contain phospholipids (such as phosphatidylethanolamine (PE), phosphatidylcholine (PC), phosphatidylserine (PS) and phosphatidylinositol (PI)), glycolipids, glycosphingolipids (such as sphingomyelin and gangliosides), other polar lipids, proteins, glycoproteins, triglycerides, cholesterol, 7-dehydrocholesterol, enzymes or any combination thereof. Preferably, MFGM provides at least one of phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidylserine (PS), phosphatidylinositol (PI) and / or derivatives thereof and / or glycosphingolipids and / or glycoproteins and / or cholesterol.

[0116] More preferably, MFGM provides at least one phospholipid selected from phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidylserine (PS), phosphatidylinositol (PI) and / or derivatives thereof; and / or sphingomyelin; and / or one or more gangliosides.

[0117] The amount of MFGM may be sufficient to provide at least 50 mg of phospholipids to the synthetic nutritional composition. The amount of MFGM may be sufficient to provide 50 mg to 30 g of phospholipids; preferably, 250 mg to 10 g of phospholipids. Alternatively, the synthetic nutritional composition contains phospholipids in the range of about 50 mg / L to about 2000 mg / L, preferably about 100 mg / L to about 1000 mg / L, more preferably about 150 mg / L to about 550 mg / L of phospholipids. Alternatively, the synthetic nutritional composition contains phospholipids in the range of about 6 mg / 100 kcal to about 300 mg / 100 kcal, preferably about 12 mg / 100 kcal to about 150 mg / 100 kcal, more preferably about 18 mg / 100 kcal to about 85 mg / 100 kcal.

[0118] The amount of MFGM may be sufficient to provide at least 10 mg of sphingomyelin to the synthetic nutritional composition. The amount of MFGM may be sufficient to provide 10 mg to 5 g of sphingomyelin; preferably, 50 mg to 1 g of sphingomyelin. Alternatively, the synthetic nutritional composition comprises sphingomyelin in the range of about 10 mg / L to about 200 mg / L, preferably about 30 mg / L to about 150 mg / L, more preferably about 50 mg / L to about 140 mg / L. Alternatively, the synthetic nutritional composition comprises sphingomyelin in the range of about 1 mg / 100 kcal to about 30 mg / 100 kcal, preferably about 3.5 mg / 100 kcal to about 24 mg / 100 kcal, more preferably about 6 mg / 100 kcal to about 21 mg / 100 kcal.

[0119] The amount of MFGM may be sufficient to provide at least 0.5 mg of gangliosides to the synthetic nutritional composition. The amount of MFGM may be sufficient to provide 0.5 mg to 3 g of gangliosides; preferably, 6 mg to 600 mg of gangliosides. Alternatively, the synthetic nutritional composition comprises gangliosides in the range of about 2 mg / L to about 40 mg / L, preferably about 6 mg / L to about 35 mg / L, more preferably about 9 mg / L to about 30 mg / L. Alternatively, the synthetic nutritional composition comprises gangliosides in the range of about 0.25 mg / 100 kcal to about 6 mg / 100 kcal, preferably about 0.7 mg / 100 kcal to about 5.2 mg / 100 kcal, more preferably about 1.1 mg / 100 kcal to about 4.5 mg / 100 kcal.

[0120] It is hypothesized that administration of a synthetic nutritional composition comprising a phospholipid content, a sphingomyelin content and / or a ganglioside content as detailed above (and wherein MFGM is present in the specific amounts detailed in the above description and defined in the claims) over a certain period of time will be useful for improving neurodevelopment in pediatric subjects starting from at least two years of age.

[0121] The synthetic nutritional composition may further comprise lactoferrin.

[0122] Lactoferrin is a multifunctional iron-binding glycoprotein naturally present in milk. Lactoferrin may include human lactoferrin, humanized lactoferrin, non-human lactoferrin or a combination thereof produced by a genetically modified organism. Non-human lactoferrin may include bovine lactoferrin, porcine lactoferrin, horse lactoferrin, buffalo lactoferrin, goat lactoferrin, mouse lactoferrin or camel lactoferrin.

[0123] Lactoferrin is known to have antimicrobial properties. Preclinical data reported in Mastromarino et al., Biometals 27, 1077–1086 (2014) suggest that lactoferrin has a potential regulatory effect on the intestinal microbiota. There is also emerging preclinical evidence that lactoferrin has a potential role in brain development and cognitive function. Preclinical studies in animal models have reported that lactoferrin can play a role in learning and memory (Chen Y et al., Mol Neurobiol 2015, 52(1): 256-269).

[0124] The composition may comprise lactoferrin in the range of about 15 mg / 100 kcal to about 300 mg / 100 kcal. Preferably, the composition comprises lactoferrin in the range of about 60 mg to about 150 mg / 100 kcal. More preferably, the composition comprises lactoferrin in the range of about 60 mg / 100 kcal to about 100 mg / 100 kcal.

[0125] When the composition comprises a reconstitution solution, the reconstitution solution may comprise lactoferrin in the range of about 0.5 mg / mL to about 1.5 mg / mL. Preferably, the reconstitution solution comprises lactoferrin in the range of about 0.6 mg / mL to about 1.3 mg / mL. Alternatively, the reconstitution solution may comprise lactoferrin in the range of about 0.1 grams / liter (g / L) to about 2 g / L. Preferably, the reconstitution solution comprises lactoferrin in the range of about 0.6 g / L to about 1.5 g / L.

[0126] Compositions may include one or more prebiotics. Prebiotics may include oligosaccharides, polysaccharides or any other prebiotics, including fructose, xylose, soybeans, galactose, glucose, mannose, or any combination thereof. More specifically, prebiotics may include polydextrose (PDX), polydextrose powder, lactulose, lactosucrose (lactosucrose), raffinose, oligoglucose (glucoligosaccharide), inulin, oligofructose, isomaltooligosaccharide, soybean oligosaccharides, oligolactose, oligoxylose, chitooligosaccharides, oligomannosaccharides, oligoarabinose, sialic acid oligosaccharides, oligofucose, galacto-oligosaccharide (GOS) and oligogentiosaccharide.

[0127] The composition may include a prebiotic in a composition range of about 1.0 g / L to about 10.0 g / L. Preferably, the composition includes a prebiotic in a composition range of about 2.0 g / L to about 8.0 g / L. Alternatively, the composition may include a prebiotic in a composition range of about 0.01 g / 100 kcal to about 1.5 g / 100 kcal. Preferably, the composition includes a prebiotic in a composition range of about 0.15 g / 100 kcal to about 1.5 g / 100 kcal.

[0128] Preferably, the prebiotic comprises polydextrose (PDX) and / or galacto-oligosaccharides (GOS).The prebiotic may comprise at least 20% weight / weight (w / w) of PDX, GOS or a combination thereof.

[0129] The composition may include PDX in the range of about 1.0 g / L to 10.0 g / L. Preferably, the composition includes PDX in the range of about 2.0 g / L to 8.0 g / L. Alternatively, the composition includes PDX in the range of about 0.015 g / 100 kcal to about 1.5 g / 100 kcal. Preferably, the composition includes PDX in the range of about 0.05 g / 100 kcal to about 1.5 g / 100 kcal. More preferably, the composition includes PDX in the range of about 0.2 g / 100 kcal to about 0.6 g / 100 kcal.

[0130] The composition may comprise GOS in the range of about 0.015 g / 100 kcal to about 1.0 g / 100 kcal. Preferably, the composition comprises GOS in the range of about 0.2 g / 100 kcal to about 0.5 g / 100 kcal.

[0131] The composition may comprise PDX in combination with GOS. Advantageously, the combination of PDX and GOS can stimulate and / or enhance the production of endogenous butyrate by the microbiota. The composition may comprise a total amount of at least about 0.015 g / 100 kcal of GOS and PDX. The composition may comprise a total amount of GOS and PDX in the range of about 0.015 g / 100 kcal to about 1.5 g / 100 kcal. Preferably, the composition comprises a total amount of GOS and PDX in the range of about 0.1 g / 100 kcal to about 1.0 g / 100 kcal.

[0132] The composition may include one or more human milk oligosaccharides (HMOs). The HMOs may include 2'-fucosyllactose (2FL), 3'-fucosyllactose (3FL), lacto-N-tetraose (LNT), lacto-N-neotetraose (LNnT), lacto-N-fucopentaose I (LNFP-I), 3'-sialyllactose (3SL), 6'-sialyllactose (6SL), or any combination thereof.

[0133] The composition may include HMO in the range of about 0.01 g / L to about 5.0 g / L. Preferably, the composition includes HMO in the range of about 0.05 g / L to about 4.0 g / L. More preferably, the composition includes HMO in the range of about 0.05 g / L to about 2.0 g / L. Alternatively, the composition may include HMO in the range of about 0.01 g / 100 kcal to about 2.0 g / 100 kcal. Preferably, the composition includes HMO in the range of about 0.01 g / 100 kcal to about 1.5 g / 100 kcal.

[0134] The composition may include a source of long-chain polyunsaturated fatty acids (LCPUFA). The LCPUFA source may include docosahexaenoic acid (DHA), α-linoleic acid, γ-linoleic acid, linoleic acid, linolenic acid, eicosapentaenoic acid (EPA), arachidonic acid (ARA), or any combination thereof. Preferably, the composition includes a source of LCPUFA containing DHA, ARA, or a combination thereof.

[0135] The composition may comprise LCPUFAs in an amount of at least about 5 mg / 100 kcal. The composition may comprise LCPUFAs in the range of about 5 mg / 100 kcal to about 100 mg / 100 kcal. Preferably, the composition comprises LCPUFAs in the range of about 10 mg / 100 kcal to about 50 mg / 100 kcal.

[0136] The composition may include DHA in the range of about 5 mg / 100 kcal to about 80 mg / 100 kcal. Preferably, the composition includes DHA in the range of about 10 mg / 100 kcal to about 20 mg / 100 kcal. More preferably, the composition includes DHA in the range of about 15 mg / 100 kcal to about 20 mg / 100 kcal.

[0137] The composition may include ARA in the range of about 10 mg / 100 kcal to about 100 mg / 100 kcal. Preferably, the composition includes ARA in the range of about 15 mg / 100 kcal to about 70 mg / 100 kcal. More preferably, the composition includes ARA in the range of about 20 mg / 100 kcal to about 40 mg / 100 kcal.

[0138] The composition may include both DHA and ARA. The weight ratio of ARA:DHA may be in the range of about 1:3 to about 9:1. Preferably, the weight ratio of ARA:DHA is in the range of about 1:2 to about 4:1. The composition may include an oil containing DHA and / or ARA. If used, the source of DHA and / or ARA may be any source known in the art, such as marine oil, fish oil, single cell oil, egg yolk lipids, or brain lipids. DHA and ARA may be derived from single cell oils, and Or its variant. DHA and ARA can be in natural form, provided that the rest of the LCPUFA source does not cause any substantial harmful effects to the subject. Alternatively, DHA and ARA can be used in refined form.

[0139] The synthetic nutritional composition comprises a protein source comprising MFGM which is also a fat or lipid source. The synthetic nutritional composition may comprise a protein source and / or a fat or lipid source in addition to MFGM, a carbohydrate source, or any combination thereof. The synthetic nutritional composition may comprise one or more of: probiotics; beta-glucan; sialic acid; a suitable composition ingredient; or any combination thereof.

[0140] In addition to MFGM or lactoferrin (if present), the composition may also include at least one protein source. The protein source provides protein for the composition. The protein source may include intact protein, partially hydrolyzed protein, highly hydrolyzed protein, small amino acid peptides or any combination thereof. The protein source may be derived from any mammalian milk protein or vegetable protein and their fractions, or any combination thereof. The protein source may include cow's milk, goat's milk, whey protein, casein, soy protein, rice protein, pea protein, peanut protein, egg protein, sesame protein, fish protein, wheat protein, hydrolyzed protein or any combination thereof. The cow's milk protein source may include, but is not limited to, milk protein powder, milk protein concentrate, milk protein isolate, buttermilk solids, buttermilk, skim milk powder, whey protein, whey protein isolate, sweet whey, acid whey, casein, acid casein, caseinate (e.g., sodium caseinate, sodium calcium caseinate, calcium caseinate) or any combination thereof.

[0141] The composition may include a protein source in the range of about 1 g / 100 kcal to about 7 g / 100 kcal. Preferably, the composition includes a protein source in the range of about 3.5 g / 100 kcal to about 4.5 g / 100 kcal. The protein source may include whey protein in the range of about 40% to about 85% and casein in the range of about 15% to about 60%.

[0142] As mentioned above, the protein source may include a complete protein source. The composition may include complete proteins in the range of about 1g / 100kcal to about 3g / 100kcal. Preferably, the composition includes complete proteins in the range of about 1g / 100kcal to about 2.5g / 100kcal. More preferably, the composition includes complete proteins in the range of about 1.3g / 100kcal to about 2.1g / 100kcal. The protein source may include a combination of complete proteins and partially hydrolyzed proteins, wherein the degree of hydrolysis of the partially hydrolyzed proteins may be between about 4% and 10%.

[0143] As mentioned above, the protein source of the composition can include partially hydrolyzed protein, deeply hydrolyzed protein or its combination. The protein that can be hydrolyzed with enzyme treatment is to decompose some or most of the protein that causes adverse symptoms, and the purpose is to reduce allergic reactions, intolerance and sensitization. Protein can be hydrolyzed with any method known in the art. The terms "protein hydrolysate" or "hydrolyzed protein" are used interchangeably in this article and refer to hydrolyzed protein, wherein the degree of hydrolysis can be about 20% to about 80%, or about 30% to about 80%, or even about 40% to about 60%.

[0144] The composition may also include at least one fat or lipid source in addition to MFGM, wherein the fat or lipid source provides fat and / or lipid to the composition. Suitable fat or lipid sources of the composition may be any fat or lipid source known or used in the art. The fat or lipid source may be present in the composition together with another fat or lipid source (such as LCPUFA). The fat or lipid source may include animal sources, such as milk fat, butter, butter fat or egg yolk lipids; marine sources, such as fish oil, marine oil or single cell oil; vegetable and plant oils, such as corn oil, canola oil, sunflower oil, soybean oil, palm oil, coconut oil, high oleic sunflower oil, evening primrose oil, rapeseed oil, olive oil, flaxseed (linseed) oil, cottonseed oil, high oleic safflower oil, palm stearin, palm kernel oil or wheat germ oil; medium chain triglyceride oil; emulsions and esters of fatty acids; or any combination thereof.

[0145] The composition may include a fat or lipid source in the range of about 1g / 100kcal to about 10g / 100kcal. Preferably, the composition includes a fat or lipid source in the range of about 2g / 100kcal to about 7g / 100kcal. More preferably, the composition includes a fat or lipid source in the range of about 2.5g / 100kcal to about 6g / 100kcal. Most preferably, the composition includes a fat or lipid source in the range of about 3g / 100kcal to about 4g / 100kcal.

[0146] The composition may include at least one carbohydrate source, wherein the carbohydrate source provides carbohydrates for the composition. The carbohydrate source may be present in the composition together with another carbohydrate source (such as one or more prebiotics). The carbohydrate source may include lactose, glucose, fructose, sucrose, starch, maltodextrin, maltose, oligofructose, corn syrup, high fructose corn syrup, dextrose, corn syrup solids, rice syrup solids or any combination thereof. In addition, due to the digestibility of hydrolyzed, partially hydrolyzed and / or deeply hydrolyzed carbohydrates, it may be desirable to include them in the composition. More specifically, hydrolyzed carbohydrates are unlikely to contain allergen epitopes. Therefore, the composition may include a carbohydrate source, the carbohydrate source comprising hydrolyzed or complete, natural or chemically modified starch derived from corn, cassava, rice or potato, which is in waxy or non-waxy form, such as hydrolyzed corn starch.

[0147] The composition may include a carbohydrate source in the range of about 5 g / 100 kcal to about 25 g / 100 kcal. Preferably, the composition includes a carbohydrate source in the range of about 6 g / 100 kcal to about 22 g / 100 kcal. More preferably, the composition includes a carbohydrate source in the range of about 12 g / 100 kcal to about 14 g / 100 kcal.

[0148] The composition may comprise one or more probiotics. The probiotics may comprise any Bifidobacterium species, any Lactobacillus species, or a combination thereof. Preferably, the probiotic is Bifidobacterium adolescentis (ATCC No. 15703), Bifidobacterium animalis subsp. lactis, Bifidobacterium breve, Bifidobacterium longum subsp. infantis (B. infantis), Lactobacillus acidophilus, Lactobacillus gasseri (ATCC No. 33323), Lactobacillus reuteri (DSM No. 17938), Lactobacillus rhamnosus GG (LGG; ATCC No. 53103), or any combination thereof. More preferably, the probiotic is LGG, Bifidobacterium infantis, or a combination thereof.

[0149] Probiotics may be live or non-live. Probiotics incorporated into the composition may include both live colony forming units and non-live probiotic cell equivalents. Probiotics may be naturally occurring, synthetic, or developed by genetic manipulation of an organism, whether such sources are now known or later developed.

[0150] The composition may contain about 1×10 4 colony forming units / 100 kcal (CFU / 100 kcal) to about 1.5×10 12 CFU / 100kcal range of live probiotics. Preferably, the composition comprises about 1×10 6 CFU / 100kcal to about 1×10 9 More preferably, the composition comprises about 1×10 7 CFU / 100kcal to about 1×10 8 Live probiotics in the CFU / 100kcal range.

[0151] The composition may comprise β-glucan. Preferably, the β-glucan comprises β-1,3-glucan. Preferably, the β-1,3-glucan comprises β-1,3;1,6-glucan. The composition may comprise β-glucan present in the range of about 0.010 grams to about 0.080 grams per 100 grams of the composition. Alternatively, the composition may comprise β-glucan in the range of about 3 mg / 100 kcal to about 17 mg / 100 kcal. Preferably, the composition comprises β-glucan in the range of about 4 mg / 100 kcal to about 17 mg / 100 kcal.

[0152] The composition may include sialic acid. Mammalian brain tissue contains the highest levels of sialic acid because sialic acid is incorporated into brain-specific proteins such as neural cell adhesion molecules (NCAM) and lipids such as gangliosides. Therefore, sialic acid is believed to play an important role in neural development and function, learning, cognition and memory.

[0153] The composition may include sialic acid provided by an intrinsic source (such as an enriched dairy product), exogenous sialic acid, sialic acid from a source (such as cGMP), or any combination thereof. The composition may include sialic acid in the range of about 100mg / L to about 800mg / L. Preferably, the composition includes sialic acid in the range of about 120mg / L to about 600mg / L. More preferably, the composition includes sialic acid in the range of about 140mg / L to about 500mg / L. Alternatively, the composition may include sialic acid in the range of about 1mg / 100kcal to about 120mg / 100kcal. Preferably, the composition includes sialic acid in the range of about 14mg / 100kcal to about 90mg / 100kcal. More preferably, the composition includes sialic acid in the range of about 15mg / 100kcal to about 75mg / 100kcal.

[0154] The synthetic nutritional composition may comprise one or more suitable composition ingredients, wherein suitable composition ingredients include vitamins, minerals, choline, inositol, emulsifiers, preservatives, stabilizers, or any combination thereof.

[0155] Composition can comprise all vitamins and minerals that are considered to be necessary in daily diet and comprise with significant amount in nutrition.The minimum requirement of some vitamins and minerals has been established.The example of minerals, vitamins and other nutrients that are optionally present in the nutritional composition can comprise vitamin A, vitamin B1, vitamin B2, vitamin B6, vitamin B12, vitamin E, vitamin K, vitamin C, vitamin D, folic acid, inositol, niacin, biotin, pantothenic acid, choline, calcium, phosphorus, iodine, iron, magnesium, copper, zinc, manganese, chloride, potassium, sodium, selenium, chromium, molybdenum, taurine and L-carnitine.Mineral is usually added in the form of salt.The existence and amount of specific minerals and other vitamins will change according to expected consumer (whether it is children or infants).

[0156] As mentioned above, the composition may include choline. Choline is a nutrient necessary for the normal function of cells. Choline is a precursor of membrane phospholipids, and it accelerates the synthesis and release of acetylcholine, a neurotransmitter involved in memory storage. Without being bound by theory, it is believed that dietary choline and docosahexaenoic acid (DHA) work synergistically to promote the biosynthesis of phosphatidylcholine, and thus help promote synapse formation in human subjects. In addition, choline and DHA work synergistically to promote the formation of dendritic spines, which is important for maintaining established synaptic connections. The composition may include about 20 mg to about 100 mg of choline per 8 fluid ounces (236.6 milliliters) of servings.

[0157] As mentioned above, the composition may include inositol. Inositol may exist as exogenous inositol, intrinsic inositol or a combination thereof. The composition may include inositol in the range of about 10mg / 100kcal to 40mg / 100kcal. Preferably, the composition includes inositol in the range of about 20mg / 100kcal to 40mg / 100kcal. Alternatively, the composition includes inositol in the range of about 130mg / L to about 300mg / L.

[0158] The composition may include one or more emulsifiers, as the emulsifiers can increase the stability of the composition. The emulsifiers may include, but are not limited to, egg yolk lecithin, soy lecithin, α-lactalbumin, monoglycerides, diglycerides, or any combination thereof.

[0159] The composition may include one or more preservatives, as preservatives can extend the shelf life of the composition. Preservatives may include, but are not limited to, potassium sorbate, sodium sorbate, potassium benzoate, sodium benzoate, calcium disodium EDTA, or any combination thereof.

[0160] The composition may include one or more stabilizers, as the stabilizer can help maintain the structure of the composition. The stabilizer may include, but is not limited to, gum arabic, gum ghatti, gum karaya, gum tragacanth, agar, furcellaran, guar gum, gellan gum, locust bean gum, pectin, low methoxyl pectin, gelatin, microcrystalline cellulose, CMC (sodium carboxymethylcellulose), methylcellulose hydroxypropyl methylcellulose, hydroxypropyl cellulose, DATEM (diacetyl tartaric acid mono- and diglycerides), dextran, carrageenan, or any combination thereof.

[0161] The synthetic nutritional composition may be intended for use in a pediatric subject. The pediatric subject may be an infant or a child. The infant may be a vaginally delivered infant. Alternatively, the infant may be a Caesarian section infant.

[0162] The synthetic nutritional composition may include nutritional supplements, children's nutritional products, infant formula, human milk fortifier, older infant formula, toddler milk or any other composition designed for infants or pediatric subjects. The nutritional composition may be provided in any form known in the art. The nutritional composition may be provided in the form of a powder, gel, suspension, paste, solid, liquid, liquid concentrate, reconstituted powder, reconstituted solution or ready-to-use product. The composition may be provided in an orally absorbable form, wherein the orally absorbable form includes food, beverage, tablet, capsule or powder.

[0163] Preferably, the synthetic nutritional composition is in the form of a reconstitutable powder, a reconstituted solution or a ready-to-use product. Most preferably, the synthetic nutritional composition is provided in the form of a reconstitutable powder.

[0164] The synthetic nutritional composition may be discharged directly into the digestive tract of the subject. The synthetic nutritional composition may be discharged directly into the intestinal tract. The synthetic nutritional composition may be formulated for consumption or enteral administration under the supervision of a physician.

[0165] The synthetic nutritional composition may be suitable for a variety of dietary needs. The composition may be kosher. The composition may be a non-genetically modified product. The composition may be free of sucrose. The composition may also be free of lactose. The composition may be free of any medium chain triglyceride oils. Carrageenan may not be present in the composition. The composition may be free of any gums.

[0166] The scope of the present invention is defined by the appended claims. It should be understood that those skilled in the art may modify the scope of the claims without departing from the scope of the present disclosure.

[0167] The foregoing detailed description is provided as explanation and illustration and is not intended to limit the scope of the appended claims. Many variations in the presently preferred embodiments described herein will be apparent to those of ordinary skill in the art and remain within the scope of the appended claims and their equivalents. BRIEF DESCRIPTION OF THE DRAWINGS

[0168] By way of example only, embodiments of the present invention will now be described with reference to the following drawings, in which:

[0169] Figure 1 A graph is shown comparing the neurophysiological syllable sound perception of pediatric subjects aged 2 years as described in Example 2. Results are shown for infants receiving infant formula until 12 months of age (SF and EF) and a reference group of infants receiving only human milk (HM). Figure 1 A shows the overall P1 amplitude by group (combined native familiar stimulus, native unfamiliar stimulus, and foreign stimulus). Figure 1 B shows overall P1 latency by group. Figure 1 C shows the P1 latency in response to native unfamiliar stimuli (NUS) by group.

[0170] The invention will now be described with respect to the following non-limiting examples.

[0171] Experimental Section

[0172] Example 1 - Follow-up studies

[0173] The inventors conducted a follow-up study of the study detailed in Li et al., J Pediatr 2019, 215, 24-31 on participants who completed the full 365 days of study feeding.

[0174] 292 participants were eligible for the follow-up study (control: 148, MFGM+Lf: 144). 116 participants between 5.5 and 6 years of age were enrolled and completed the follow-up assessment (control: 59, MFGM+Lf: 57). Follow-up assessments were conducted as outlined below.

[0175] Wechsler Intelligence Scale for Preschoolers and Primary School Children

[0176] Each participant was tested with the Wechsler Preschool and Primary Scale of Intelligence (4th edition; WPPSI-IV, adapted for the Chinese population). The primary outcome was a standardized IQ test from 4 years 0 months to 6 years 11 months, and secondary outcomes were verbal comprehension (VC), visuospatial (VS), fluid reasoning (FR), working memory (WM), and processing speed (PS). The composite score of each variable was analyzed separately by analysis of variance (ANOVA) (to adjust for variables including study group, location, and sex) and post hoc analysis of covariance (ANCOVA) (to adjust for additional participant and family demographic variables (number of family members in the household, average monthly household income, highest level of education of the mother and father, years of early education completed before primary school, and smoking exposure at home)). The results are detailed in Table 1.

[0177] Table 1. WPPSI-IV results

[0178]

[0179] The WPPSI-IV full-scale IQ, visual-spatial, and processing speed composite scores were significantly higher in MFGM+Lf compared to the control group. The other composite scores were also higher in MFGM+Lf compared to the control group, but not significantly so.

[0180] Stroop task

[0181] The Stroop task measures inhibitory control and rule learning. The task involves inhibiting a congruent response to a simple stimulus and providing an incongruent response. There are two formats for completing the task: (i) banana = red, apple = yellow and (ii) sun = night, moon = day. Each participant performed 16 trials, and the outcome variable was the number of correct enumerations. Scores were analyzed by a repeated measures mixed model including study group, location, sex, and task.

[0182] The Stroop task scores (mean ± SE) were significantly higher in the MFGM+Lf group compared with the control group (15.6 ± 0.4 vs. 13.2 ± 0.4; p < 0.001).

[0183] Dimensional Change Card Sorting (DCCS) Task

[0184] The DCCS task measures rule learning and flexibility in cognitive reasoning in three sequential phases:

[0185] Preconversion phase (6 trials): Children categorized multidimensional stimuli (colored shapes) according to color;

[0186] Post-conversion phase (6 trials): categorization of the same stimuli based on shape;

[0187] and

[0188] • Boundary phase (12 trials): Classification criteria were based on boundary presence (ie, boundary presence = color, boundary absence = shape).

[0189] The outcome variable was the number of correct responses. Scores were analyzed by ANOVA including study group, site, and sex. Highest stage passed was analyzed by Cochran-Mantel-Haenszel stratified by site and sex.

[0190] In the DCCS task, there were no differences in scores during the pre- or post-switch phases, but scores in the MFGM+Lf group (7.4±0.27) were higher than those in the control group (6.5±0.28) during the boundary phase (p=0.013).

[0191] Significant between-group differences were also detected in the highest stage passed (p=0.039); the border stage was the highest stage passed by more children in the MFGM+Lf group (18, 32%) compared with the control group (7, 12%), while passing before and after conversion was the highest stage reached by more children in the control group (49, 83%) compared with the MFGM+Lf group (36, 63%).

[0192] Child Behavior Checklist

[0193] The Child Behavior Checklist, a parent-report measure used to detect behavioral and emotional problems in children and adolescents, was administered. No differences were observed between the groups.

[0194] in conclusion

[0195] The inventors found that feeding infants a formula with MFGM and Lf throughout 12 months of age resulted in improved neurological outcomes later in life between 5.5 and 6 years (relative to a control group). The results suggest that the addition of MFGM and Lf to infant formula has a lasting effect on supporting neurodevelopment during childhood. In the absence of lactoferrin, similar results to those observed in the follow-up study of Example 1 are expected.

[0196] Example 2 - Clinical Study

[0197] Methods: A double-blind, randomized, controlled trial was conducted by the Institute of Nutrition and Food Technology (INTA) of the University of Chile. The protocol and informed consent were approved by the Institutional Review Board of INTA. Participants were randomly assigned to an experimental formula (EF) or a control formula (SF). A reference group of infants receiving human milk (HM) was also recruited.

[0198] Infants eligible for randomization to the study formula consumed infant formula as the sole source of nutrition for at least 48 hours before randomization.

[0199] Infants in the human milk reference group condition consumed the mother's own breast milk as the sole source of nutrition and were planned to be fed the mother's own breast milk throughout approximately 180 days of age.

[0200] Additional inclusion criteria for all infants were:

[0201] Single birth;

[0202] Up to 120 days of age at study enrollment or randomization;

[0203] Birth weight between 2500 and 4500 g;

[0204] Gestational age between 37 and 42 weeks;

[0205] Normal growth history (weight between the 10th and 90th percentiles, inclusive, of the WHO growth charts

[28] ); and

[0206] · Parents agreed not to have their infant participate in another intervention study and signed an informed consent form.

[0207] Exclusion criteria include:

[0208] Use of complementary feeding;

[0209] · Underlying endocrine, metabolic or chronic disease, history of congenital malformation, or any other condition that may interfere with the infant's ability to ingest food or grow and develop normally;

[0210] Evidence of feeding difficulties or formula intolerance;

[0211] Immunodeficiency; and

[0212] ·The mother is illiterate.

[0213] The experimental formulas and standard formula are shown in Table 2 below.

[0214] Table 2. Study formulas

[0215]

[0216]

[0217] The protein sources of SF were buttermilk and whey protein concentrate (WPC), and the protein sources of EF were buttermilk, WPC, and whey protein-lipid concentrate (5 g / L, bovine MFGM source; Lacprodan MFGM-10, Arla Foods Ingredients).

[0218] The fat source for both formulas was a base mix of palm oil, soybean oil, coconut oil, high oleic sunflower oil, fungal derived single cell oil (ARA source) and algae derived single cell oil (DHA source). ARA is arachidonic acid and DHA is docosahexaenoic acid.

[0219] The carbohydrate sources for both formulas were available carbohydrates (source: lactose, galactose, glucose, fructose, epilactose): 10.8 g; and prebiotic oligosaccharides: 0.6 g (4 g / L; source: a prebiotic mixture of polydextrose [PDX] and galacto-oligosaccharides [GOS; 1:1 ratio])

[0220] All infants were enrolled before 120 days of age, and those receiving infant formula were randomized to receive either a standard bovine milk-based infant formula (SF) or a similar formula supplemented with whey protein-lipid concentrate (5 g / L MFGM-10; bovine MFGM source) (EF) throughout 12 months of age to assess growth and tolerance.

[0221] A total of 347 infants were randomized (SF, n=174; EF, n=173), and a reference group of infants receiving only human milk was also recruited (HM, n=235).

[0222] Sound Perception

[0223] In a subset of participants (SF, n = 42; EF, n = 35; HM, n = 45), neurophysiological syllable sound perception was assessed at day 730 of life (2 years).

[0224] Auditory event-related potential (ERP) data were collected by electroencephalographic recordings of children using a network of geodesic sensors (128 scalp sites; Electric Geodesic, Inc., Eugene, Oregon, USA).

[0225] The stimuli used were consonant-vowel syllables. Native familiar stimuli (NFS; also called standard stimuli) were consonant-vowel (CV) syllables (ta) associated with Spanish speech. Two CV syllables were used as deviant syllables: native unfamiliar stimuli (NUS; also called native deviant syllables) (da) and foreign stimuli (FS; also called non-native deviant syllables) (sha). Stimuli were presented in a mismatched negative wave (MMN) paradigm, which included NFS (80%), NUS (10%) and FS (10%), for a total of 1000 stimuli.

[0226] The amplitude and latency of the P1 wave response (the first wave that appeared after stimulus onset) in the time period between 100 and 250 ms were analyzed.

[0227] Overall, the P1 amplitude of the NFS wave response was significantly smaller than that of the NUS wave response (1.88±0.05μV vs. 2.09±0.06μV, p<0.004). The P1 latency of the NFS was also shorter than that of the NUS (115.53±1.16ms vs. 124.25±0.89ms, p<0.001). Overall, the inventors found that children showed perceptual differences between familiar and unfamiliar auditory stimuli at 24 months, with the former being associated with lower ERP amplitudes and shorter latencies. This is desirable for young children. As language acquisition improves, the perceptual differences between familiar and unfamiliar auditory stimuli are expected to decrease.

[0228] Figure 1 A and 1B show the amplitude and latency of the P1 wave response of the feeding group. The overall P1 amplitude (combined native familiar stimulus, native unfamiliar stimulus, and foreign stimulus) was significantly lower in the EF group compared with HM (1.81 ± 0.09 μV vs. 2.1 ± 0.08 μV, p < 0.04) ( Figure 1 A). No significant differences in overall P1 latency were detected between feeding groups ( Figure 1 B).

[0229] Figure 1 C shows the P1 latency of the original unfamiliar stimulus (NUS). Figure 1 The responses to NUS were significantly different between the study feeding groups as shown in C. The P1 latency was significantly shorter in EF (120.29 ± 10.4 ms) compared to HM and SF groups (125.1 ± 9.5 ms, p < 0.03 and 127.36 ± 9.59 ms, p < 0.003, respectively).

[0230] Overall, the inventors found that infants who received MFGM-enriched infant formula during the first year of life showed lower ERP amplitudes at two years of age, compared to standard formula-fed infants and breast-fed infants, which may reflect greater neural circuit maturation. The inventors also found that infants who received MFGM-enriched infant formula during the first year of life showed lower ERP latencies to native unfamiliar stimuli at two years of age, which may indicate improved myelination.

[0231] Summarize

[0232] The results of Examples 1 and 2 demonstrate that supplementation of infant formula with MFGM supports neurodevelopment in healthy infants and toddlers.

Claims

1. A synthetic nutritional composition comprising milk fat globule membrane (MFGM) in the range of about 10 μg / 100 kcal to about 1500 mg / 100 kcal for use in improving neurodevelopment in a pediatric subject, wherein the synthetic nutritional composition is administered to the pediatric subject for at least three months during the first year of life, And wherein administration of the synthetic nutritional composition improves neurodevelopment of the pediatric subject beginning at least two years of age.

2. Synthetic nutritional composition for use according to claim 1, wherein the improvement in neurodevelopment is an improvement in cognitive development.

3. The synthetic nutritional composition for use according to claim 2, wherein the improvement in cognitive development is selected from at least one of improvements in memory, verbal comprehension, visuospatial ability, fluid reasoning, mental processing speed, rule learning, executive function and language acquisition development.

4. Synthetic nutritional composition for use according to any one of claims 1 to 3, wherein said administration of the synthetic nutritional composition occurs for at least six months during the first year of life.

5. A synthetic nutritional composition for use according to any one of claims 1 to 4, wherein administration of the synthetic nutritional composition occurs between three and six months of age.

6. Synthetic nutritional composition for use according to any one of claims 1 to 5, wherein the improvement in neurodevelopment of the pediatric subject continues from at least two years of age until at least five years of age.

7. A synthetic nutritional composition for use according to any one of claims 1 to 6, wherein the synthetic nutritional composition comprises MFGM in the range of about 15 μg / 100 kcal to about 1000 mg / 100 kcal, preferably about 100 μg / 100 kcal to about 500 mg / 100 kcal.

8. A synthetic nutritional composition for use according to any one of claims 1 to 7, wherein the synthetic nutritional composition comprises phospholipids in the range of about 6 mg / 100 kcal to about 300 mg / 100 kcal, preferably about 12 mg / 100 kcal to about 150 mg / 100 kcal, more preferably about 18 mg / 100 kcal to about 85 mg / 100 kcal.

9. A synthetic nutritional composition for use according to any one of claims 1 to 8, wherein the synthetic nutritional composition comprises sphingomyelin in the range of about 1 mg / 100 kcal to about 30 mg / 100 kcal, preferably about 3.5 mg / 100 kcal to about 24 mg / 100 kcal, more preferably about 6 mg / 100 kcal to about 21 mg / 100 kcal.

10. A synthetic nutritional composition for use according to any one of claims 1 to 9, wherein the synthetic nutritional composition comprises gangliosides in the range of about 0.25 mg / 100 kcal to about 6 mg / 100 kcal, preferably about 0.7 mg / 100 kcal to about 5.2 mg / 100 kcal, more preferably about 1.1 mg / 100 kcal to about 4.5 mg / 100 kcal.

11. Synthetic nutritional composition for use according to any one of claims 1 to 10, wherein the MFGM is provided by whey protein concentrate.

12. The synthetic nutritional composition for use according to claim 11, wherein the synthetic nutritional composition comprises whey protein concentrate in the range of about 6.5 to about 12.0 wt. %, preferably about 7.9 wt. % to about 10.3 wt. % on a dry weight basis.

13. A synthetic nutritional composition for use according to any one of claims 1 to 10, wherein the MFGM is provided by an enriched dairy product.

14. The synthetic nutritional composition for use according to claim 13, wherein the synthetic nutritional composition comprises enriched dairy product in the range of about 0.06 g / 100 kcal to about 1.5 g / 100 kcal, preferably about 0.3 g / 100 kcal to about 1.4 g / 100 kcal, more preferably about 0.4 g / 100 kcal to about 1 g / 100 kcal.

15. A synthetic nutritional composition for use according to any one of claims 1 to 10, wherein the MFGM is provided by buttermilk.

16. The synthetic nutritional composition for use according to claim 15, wherein the synthetic nutritional composition comprises buttermilk in the range of about 0.06 g / 100 kcal to about 10.5 g / 100 kcal, preferably about 0.3 g / 100 kcal to about 8.5 g / 100 kcal, more preferably about 0.4 g / 100 kcal to about 7 g / 100 kcal.

17. Synthetic nutritional composition for use according to any one of claims 1 to 16, wherein the synthetic nutritional composition further comprises lactoferrin.

18. The synthetic nutritional composition for use according to claim 17, wherein the synthetic nutritional composition comprises lactoferrin in the range of about 5 mg / 100 kcal to about 300 mg / 100 kcal, preferably about 60 mg to about 150 mg / 100 kcal, more preferably about 60 mg / 100 kcal to about 100 mg / 100 kcal.

19. A synthetic nutritional composition for use according to any one of claims 1 to 18, wherein the synthetic nutritional composition further comprises polydextrose (PDX) and / or galacto-oligosaccharides (GOS).

20. The synthetic nutritional composition for use according to claim 19, wherein the synthetic nutritional composition comprises PDX in the range of about 0.015 g / 100 kcal to about 1.5 g / 100 kcal, preferably about 0.05 g / 100 kcal to about 1.5 g / 100 kcal, more preferably about 0.2 g / 100 kcal to about 0.6 g / 100 kcal.

21. A synthetic nutritional composition for use according to claim 19 or claim 20, wherein the synthetic nutritional composition comprises GOS in the range of about 0.015 g / 100 kcal to about 1.0 g / 100 kcal, preferably about 0.2 g / 100 kcal to about 0.5 g / 100 kcal.

22. A synthetic nutritional composition for use according to any one of claims 1 to 21, wherein the synthetic nutritional composition further comprises at least one human milk oligosaccharide (HMO) selected from the group consisting of 2'-fucosyllactose (2FL), 3'-fucosyllactose (3FL), lacto-N-tetraose (LNT), lacto-N-neotetraose (LNnT), lacto-N-fucopentaose I (LNFP-I), 3'-sialyllactose (3SL), 6'-sialyllactose (6SL) or any combination thereof.

23. The synthetic nutritional composition for use according to claim 21, wherein the synthetic nutritional composition comprises HMO in the range of about 0.01 g / 100 kcal to about 2.0 g / 100 kcal, preferably about 0.01 g / 100 kcal to about 1.5 g / 100 kcal.

24. A synthetic nutritional composition for use according to any one of claims 1 to 23, wherein the synthetic nutritional composition further comprises a source of long chain polyunsaturated fatty acids (LCPUFA) comprising docosahexaenoic acid (DHA), arachidonic acid (ARA) or a combination thereof.

25. The synthetic nutritional composition for use according to claim 24, wherein the synthetic nutritional composition comprises LCPUFAs in the range of about 5 mg / 100 kcal to about 100 mg / 100 kcal, preferably about 10 mg / 100 kcal to about 50 mg / 100 kcal.

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