LIQUID HUMAN MILK SUPPLEMENT

Abstract

A liquid human milk supplement comprising at least the amino acids leucine, isoleucine, valine, lysine, methionine, threonine, phenylalanine, histidine, and tryptophan, and at least one free semi-essential amino acid selected from tyrosine, cysteine, glycine, glutamic acid and arginine, wherein the weight ratio of the amount of the essential amino acids and the semi-essential amino acids to the total amount of free amino acids is at least 80%. The supplement is particularly suitable for feeding infants and low-birth-weight infants. A single-dose and a multi-dose dispenser comprise the supplement in suitable and adjustable volumes. The dispensers can be used for administration of the liquid human milk supplement to an infant during feeding.

Claims

1. A liquid human milk supplement comprising at least the free essential amino acids leucine, isoleucine, valine, lysine, methionine, threonine, phenylalanine, histidine, and tryptophan, and at least one free semi-essential amino acid selected from tyrosine, cysteine, glycine, glutamic acid and arginine, wherein the weight ratio of the amount of the essential amino acids and the semi-essential amino acids to the total amount of free amino acids is at least 80%.

2. The liquid human milk supplement of claim 1, wherein the total amount of free amino acids comprises at least 25% of the caloric content of the liquid human milk supplement.

3. The liquid human milk supplement of claim 2, comprising at least two, three or four of said semi-essential free amino acids.

4. The liquid human milk supplement of claim 3, further comprising at least one non-essential free amino acid.

5. The liquid human milk supplement of claim 4, wherein the weight ratio of the amount of the essential amino acids and the semi-essential amino acids to the total amount of free amino acids is in the range of from 80% to 99%.

6. The liquid human milk supplement of claim 5, wherein the free amino acids are present in the following amounts per 30 ml liquid human milk supplement: leucine in a range of 50 to 503 mg, isoleucine in a range of 25 to 270 mg, valine in a range of 35 to 380 mg, lysine in a range of 50 to 515 mg, threonine in a range of 25 to 265 mg, phenylalanine in a range of 29 to 295 mg, methionine in a range of 19 to 200 mg, histidine in a range of 18 to 190 mg, and tryptophan in a range of 13 to 130 mg.

7. The liquid human milk supplement of claim 6, wherein the free amino acids, if present, are present in the following amounts per 30 ml liquid human milk supplement: tyrosine in a range of 11 to 115 mg, cysteine in a range of 8 to 88 mg, glycine in a range of 50 to 520 mg, glutamic acid in a range of 50 to 528 mg, arginine in a range of 35 to 365 mg, alanine in a range of 25 to 255 mg, aspartic acid in a range of 15 to 163 mg, proline in a range of 29 to 293 mg, and serine in a range of 7 to 78 mg.

8. The liquid human milk supplement of claim 7, further comprising at least one selected from of a lipid component, a carbohydrate component, vitamins, minerals, and trace elements.

9. The liquid human milk supplement of claim 8, further comprising at least one selected from B vitamins, choline, cysteine, and methionine.

10. The liquid human milk supplement of claim 9, further comprising vegetable oil, medium chain triglycerides, docosahexaenoic acid, arachidonic acid, linoleic acid and/or alpha-linolenic acid.

11. A ready-to-use supplement comprising the liquid human milk supplement according to claim 1.

12. An enteral supplement comprising the liquid human milk supplement according to claim 1.

13. A single-dose dispenser comprising the liquid human milk supplement according to claim 1, wherein the single-dose dispenser protects the liquid human milk supplement in an air-sealed and sterile environment, wherein the single-dose dispenser comprises a compressible balloon that is connected to a tip, wherein the tip comprises a closure system, wherein the compressible balloon comprises a volume in a range of 0.5 to 5 ml.

14. A multi-dose dispenser comprising the liquid human milk supplement according to claim 1, wherein the multi-dose dispenser protects the liquid human milk supplement in an air-sealed and sterile environment, wherein the multi-dose dispenser comprises a volume in a range 7.5 to 50 ml, and wherein the multi-dose dispenser is adapted to dispense adjustable volumes of 0.5 to 50 ml of the liquid human milk supplement.

15. A method of feeding an infant, comprising administering the infant the liquid human milk supplement of claim 1, wherein the liquid human milk supplement is added to breast milk or breast milk substitute in a volume-to-volume ratio of 1 ml-5 ml supplement to 15 ml milk.

16-18. (canceled)

19. A method of preventing suboptimal growth and development in extremely low-birth-weight infants, very-low-birth-weight infants, and or low-birth-weight infants who are appropriate or small for their gestational age, comprising administering the infants the liquid human milk supplement of claim 1.

20-23. (canceled)

24. The liquid human milk supplement of claim 1, wherein the total amount of free amino acids comprises at least 50% of the caloric content of the liquid human milk supplement.

25. The liquid human milk supplement of claim 3, further comprising at least one non-essential free amino acid selected from alanine, aspartic acid, proline and serine.

26. The liquid human milk supplement of claim 5, wherein the free amino acids are present in the following amounts per 30 ml liquid human milk supplement: leucine in a range of 100 to 400 mg, isoleucine in a range of 55 to 210 mg, valine in a range of 75 to 305 mg, lysine in a range of 100 to 410 mg, threonine in a range of 52 to 210 mg, phenylalanine in a range of 58 to 235 mg, methionine in a range of 40 to 156 mg, histidine in a range of 37 to 150 mg, and tryptophan in a range of 26 to 104 mg.

27. The liquid human milk supplement of claim 6, wherein the free amino acids, if present, are present in the following amounts per 30 ml liquid human milk supplement: tyrosine in a range of 23 to 92 mg cysteine in a range of 17 to 70 mg, glycine in a range of 100 to 410 mg, glutamic acid in a range of 105 to 420 mg, arginine in a range of 72 to 290 mg, alanine in a range of 50 to 204 mg, aspartic acid in a range of 30 to 130 mg, proline in a range of 58 to 235 mg, and serine in a range of 15 to 62 mg.

Description

4. BRIEF DESCRIPTION OF THE DRAWINGS

[0074] Preferred embodiments of the present invention are further described in the following detailed description, with reference to the following figures:

[0075] FIG. 1 shows a 3D printer mockup of an example single-dose dispenser;

[0076] FIG. 2 shows a technical drawing of an example single-dose dispenser;

[0077] FIG. 3 shows a technical drawing of the pipette-like tip and of the compressible balloon of an example single-dose dispenser;

[0078] FIG. 4 shows an example and a technical drawing of a multiple-dose dispenser;

[0079] FIG. 5 shows application examples of multiple-dose dispensers.

5. DETAILED DESCRIPTION OF THE INVENTION

[0080] Further preferred embodiments and examples of the invention are described hereinafter in detail with reference to the figures.

[0081] The present invention relates to liquid human milk supplements (fortifiers or human milk fortifiers; hereinafter also referred to as the present invention), preferably having about 0.5 grams to 5.15 grams of free amino acids per 30 ml liquid human milk supplement. The supplements have relatively high concentrations of free amino acids and are therefore concentrated.

[0082] The liquid human milk supplement comprises the amino acids in free acid form.

[0083] Free amino acids are readily absorbed in the gut and have no allergenic potential. The amino acids of the human milk supplement of the invention may be preferably all in free acid form. In various embodiments at least 50% (w/w), at least 70% (w/w) or at least 90% (w/w) of the amino acid are in a free acid form.

[0084] In addition to the essential-, semi-essential-, and non-essential amino acids, the supplements may include lipids, carbohydrates, vitamins, minerals, and trace elements, by selecting any one of the following variations: a) blends of essential, semi-essential, and non-essential amino acids, b) concentrates which are aseptically- or retort filled or packaged and c) in multi-dose dispensers which can deliver variable amounts of the supplement to feeding syringes/devices (hospital supply-enteral feeding period) or in single-dose dispensers which are used during the breastfeeding procedure (in home supply). The human milk supplements are especially suited for low-birth-weight (LBW) infants who are appropriate—(AGA) or small for their gestational age [SGA; 1], but may also be used in malnourished young infants. They are specifically useful in regional/local neonatal intensive care nurseries (NICUs), and other special care nurseries and they minimize the risk of microbiological contamination during preparation in institutional settings and when used at home. The liquid human milk supplement can be used as a ready-to-use supplement for human milk. The amino acids of the liquid human milk supplement, and preferably specific lipids, electrolytes, trace elements and vitamins, complement the human milk that usually contains only insufficient amounts thereof. Such complementation is in particular important for providing an optimal nutrition to LBW infants.

[0085] The supplements of the present invention can comprise all essential-, semi-essential-, and non-essential amino acids in free form for LBW infants who receive human milk.

[0086] Preferred examples of concentrations of free amino acids (preferred; minimum and maximum) in the present invention for LBW infants with weights between 0.5-1.5 kg are presented in Table 1 of Example 1. Human milk fortified with the supplement provides at least twofold the amounts of all essential amino acids to infants between 0.5-1.5 kg that are necessary for growth and development. All amino acids used in the present invention are L-amino acids, preferably synthetically produced. Alternatively, the L-amino acids may be produced via fermentation. LBW infants receiving amino acids based supplements together with human milk are not at risk of sensitization to cow's milk, other proteins, and exposure to peptide chains with sizes >1000 Dalton (from hydrolyzed protein). The supplement is hypoallergenic.

[0087] The supplement of the invention is prepared by mixing the free amino acids and optionally other components with water. The water is preferably doubly distilled water. In another embodiment, a specific pH value of the liquid human milk supplement may be adjusted. In a preferred embodiment, the pH is adjusted to a pH value within the range of pH 4 to pH 7, preferably 4.6.

[0088] Human milk fortifiers are commercially available as powders to be reconstituted in pumped- or donor human milk or in concentrated liquid form that can be added to human milk prior to feeding. The use of those fortifiers requires that the mother has to pump her milk from the breast prior to mixing it with the fortifier, which interferes with the natural way of breastfeeding. Examples of such fortifiers are mentioned: EP1871182B1/US20060204632, EP2152089B1/US2008286414A and WO2010/134810A1. Once LBW infants have reached a weight of approximately 1500-1800 grams and a certain developmental maturity, they start nutritive suckling and subsequently can be breastfed like term infants. The present invention is thus directed to a human milk supplement (fortifier) in the form of a concentrated liquid, which preferably can be applied by a) employing single-dose dispensers during each breastfeeding procedure (in-home supply), and b) employing a multi-dose dispenser according to the needs of the LBW infant during the enteral nutrition period (hospital supply).

[0089] The preferred device mentioned under a) for delivery of the supplement during the breastfeeding procedure (body weight >1500 (1800) g) is a soft plastic single-serving dispenser with a compressible balloon which is connected to a pipette like tip.

[0090] FIG. 1 illustrates a 3D printer mockup of a single-dose dispenser. The single-dose dispenser may be made, for example, from a PP/EVOH/PP multilayer or a single layer of polypropylene material. It comprises a pipette-like tip with a twist-off closure connected to a balloon reservoir. FIG. 2 illustrates a technical drawing of the single-dose dispenser with a top-view (indicated with the reference numeral 201a), a side-view (201b), a further side-view after 90° C. rotation (201c), and an inside view (201d) of the dispenser. Exemplary, not-limiting dimensions are indicated. FIG. 3 contains further details on the pipette-like tip (301a, 301b, 301c) and the compressible balloon (302a, 302b, 302c, 302d). 301a illustrates the side view of the pipette like tip with a twist-off closure, 301b illustrates the inside view of the pipette like tip. 301c illustrates a 3D model of the pipette like tip. 302a illustrates the top-view of the compressible balloon that is connected to the pipette like tip. The compressible balloon with dimensions as indicated in 302b comprises a volume of 2.2 ml. In general, the dimensions of the compressible balloon may be chosen such that other volumes, e.g. in a range of 0.5 ml to 5 ml, of the liquid human milk supplement may be squeezed out. 302c illustrates the side view of the balloon, indicating the asymmetry of the curvatures of the balloon. 302d presents a 3D view of the compressible balloon.

[0091] By using the single-dose dispenser, as illustrated in FIGS. 1, 2, and 3, a certain amount of the supplement may be given directly into the mouth of the suckling infant via compressing the balloon and directing the pipette-like tip to the mouth of the infant (in-home supply).

[0092] By squeezing out the balloon the supplement is directly applied into the mouth of the LBW infant during breastfeeding. The preferred device mentioned under a) is a further development of the “finger feeder” dispenser system known in the art. The device of the present invention which is mentioned under a) is a new and safe in-home method of providing supplements to infants, especially LBW infants, during, before, and after breastfeeding. Therefore, the way how the supplement is provided by employing the preferred device mentioned under a) does not interfere with the natural, recommended, and preferred way to feed infants.

[0093] The preferred device mentioned under b) for delivery of the supplement, e.g. during the enteral (tube) feeding period (weight range of LBW infants 500 g-1500/1800 g) preferably is a multi-dosage dispenser (7.5-50 ml) similar to a patented device (EP1674399B1) where specified volumes or exact numbers of drops can be added to human milk which is generally provided by enteral feeding syringes or other open/closed systems. The supplement can be added to human milk according to feeding tolerance and individual needs of the LBW infant.

[0094] FIG. 4 illustrates an exemplary multi-dose dispenser (401). The multi-dose dispenser comprises a cover (402), a push-button (403), a snap on with anti-activation feature (404), a plunger (405), a LDPE snapping part (406), an upper cap with thread (407), a delaminating bag-in-bottle (408), and a base cap (409).

[0095] By employing a multi-dose dispenser, variable amounts of the supplement can be added to human milk which is provided by enteral feeding syringes or other open/closed feeding systems (hospital supply).

[0096] FIG. 5 illustrates possible connections of the multi-dose dispenser for hospital supply. Multi-dose dispensers may be connected to syringes or feeding tubes that allow enteral feeding of LBW infants with weights below e.g. 1500/1800 grams.

[0097] The present invention also includes aseptically packaged, which are preferred, or retort-packaged embodiments having improved stability. The aseptically packaged embodiments of the present invention can be prepared or manufactured using any of a variety of techniques well known to those of ordinary skill in the formulation art (e.g. using filling lines). Suitable aseptic packaging techniques include any of the well-known aseptic filling/packaging methods disclosed in the formulation arts for preparing liquid nutritional formulas, all of which are generally directed to the sealing or filling of a sterilized liquid into a sterile container. The aseptically packaged embodiments of the present invention may include any container or package suitable for use with liquid nutritional products and also capable of withstanding aseptic processing conditions (e.g., sterilization). Preferred examples of containers are multi- and single-dose dispensers and other non-limiting examples of such containers include single or multi- or single-use bags, plastic bottles or containers, pouches, metal cans glass bottles, foil or other flexible pouches, syringes, vials, or any other container meeting the above-described criteria. The aseptically packaged container for these embodiments is typically sterilized prior to being filled with its sterilized contents. The present invention is also directed to a method of reducing the risk of microbial contamination of infant feeding compositions. Microbiological quality of the supplements (fluid or gel) needs to be maintained during the whole shelf-life.

[0098] The supplements of the present invention can further comprise or consist of the essential elements and limitations of the invention described herein, as well as any additional or optional ingredients, components, or limitations useful in infant nutrition applications.

[0099] The supplement, in addition to the amino acids, can comprise carbohydrates, and lipids as macronutrients of sufficient types and amounts that when used in combination with human milk or other infant feeding formula, help to meet the nutritional needs of the infant, especially the LBW infant. The macronutrients in the various embodiments of the present invention are described in Table 2 of Example 2. The energy density of breast-milk requires that LBW infants be fed with volumes of milk that are too high to be tolerated by those infants. LBW infants require 100-130 kcal/kg/day [3, 4]. In order to provide a caloric intake, which meets the needs of LBW infants in a volume they can tolerate, the caloric content of breast-milk can be supplemented with amino acids, fat and carbohydrates.

[0100] The supplement can comprise a carbohydrate suitable for use in infants, especially LBW infants, in particular hydrolyzed or intact, naturally and/or modified, starches. Other non-limiting examples of suitable carbohydrate sources include hydrolyzed cornstarch, maltodextrin (i.e. non-sweet, nutritive polysaccharide having a DE value less than 20), glucose polymers, sucrose, corn syrup, corn syrup solids (i.e., polysaccharide having a DE value greater than 20), glucose, rice syrup, fructose, high fructose corn syrup, and indigestible human milk oligosaccharides (HMOs). The carbohydrates may comprise lactose or can be substantially free of lactose.

[0101] The supplement also can comprise a lipid component suitable for use in infants, especially LBW. Lipids suitable for use in the present invention may include coconut oil, soy oil, corn oil, olive oil, safflower oil, high oleic safflower oil, MCT oil (medium chain triglycerides), sunflower oil, high oleic sunflower oil, structured triglycerides, palm and palm kernel oils, palm olein, canola oil, marine oils, cottonseed oils, and combinations thereof. Suitable fats for use in the liquid supplement include emulsifiers to help the various fortifier components readily disperse when combined with human milk. Non-limiting examples of suitable emulsifiers include soya bean lecithin, polyoxythylene stearate, polyoxyethylene sorbitan mono-oleate, polyoxyethylene sorbitan monopalmitate, polyoxyethylene sorbitan monostearate, ammonium phosphatides, polyoxyethylene sorbitan monolaurate, citric acid esters of mono and diglycerides of fatty acids, tartaric acid esters of mono and diglycerides of fatty acids, and combinations thereof. Natural soy lecithin is especially useful in this respect. The lipid component may include emulsifiers suitable for use in infant nutritional products.

[0102] The present invention also includes those embodiments that comprise as part of the fat component one or more of arachidonic acid, docosahexaenoic acid, or combinations thereof, alone or in further combination with linoleic acid, linolenic acid, or both. The weight ratio of arachidonic acid:docosahexaenoic acid preferably should be between 1.0-2.0 [3]. The supplement will be with oils that can be made using standard techniques known in the art.

[0103] The supplement can comprise vitamins, minerals, and trace minerals as recommended by regulatory bodies and international nutrition committees [3, 4]. It may comprise any of a variety of vitamins, non-limiting examples of which include vitamin A, vitamin D, vitamin E, vitamin K, thiamine (vitamin B1), riboflavin (vitamin B2), pyridoxine (vitamin B2), vitamin B12, niacin, folic acid, pantothenic acid, biotin, vitamin C, choline, inositol, salts and derivatives thereof, and combinations thereof. An example how much minerals, vitamins, and trace elements can be added with the liquid human milk supplement to 150 ml of human milk is provided in Table 2.

[0104] The supplement can be supplemented with levels of vitamins B2, B6, B12, folate, as well as methionine, cysteine, and choline, which are crucial co-factors and substrates for many basic biological pathways including one-carbon metabolism, and in LBW infants they are particularly important for brain function and development and epigenetic mechanisms. These are essential nutrients that cannot be synthesized endogenously and thus need to be taken by LBW infants via the diet [8]. In particular, this can be important for LBW infants in developing countries, where mothers more often suffer from folate- and vitamin B12 deficiencies [9].

[0105] In LBW infants of vitamin D-deficient mothers, a vitamin D intake of 800 to 1500 IU/day is necessary to reach a circulating 25(OH) vitamin D concentration above 75 nmol/L, which rules out osteopenia and rickets. During metabolic balance studies, calcium net absorption increased from 50% to 71% by feeding appropriate-for-gestational age preterm infants weighing <1500 g banked human milk alone or supplemented with 30 mg/day (1200 IU) without calcium fortification [3]. Nutrition committees therefore recommend vitamin D intakes between 800-1000 IU/day [3, 4]. Because vitamin D concentration in breast milk is low, the present invention provides 100-800; preferable 300 IU vitamin D3 to be added to 150 ml of human milk to satisfy the requirements of LBW infants.

[0106] The supplement may also further comprise any of a variety of minerals known or otherwise suitable for us in infant or other nutritional formulas, non-limiting examples of which include phosphorus, magnesium, calcium, zinc, manganese, copper, iodine, sodium, potassium, chloride, selenium, iron and combinations thereof. The calcium:phosphorus ratio (mg:mg) in the supplement may be between 1.5 and 2.0, preferably 1.75. An example how much minerals, trace elements, choline, inositol, and taurine can be added to 150 ml of human milk is provided in Table 2.

[0107] In one embodiment (weight range 500-1500 (1800) g), the amount of iron which is added to 150 ml of breast milk can be as low as between as 0.1-2 mg. This is because VLBW are extremely prone to infections and iron should not be given in such situations. Moreover, VLBW frequently receive blood transfusions and can be overloaded with iron. Iron supplements for the rapidly growing LBW at the latest are necessary if their birthweight has doubled. Therefore, in another embodiment (weight >1500 (1800) g) the amount of iron which is added to 150 ml of human milk can be 2.0-4.5 mg.

[0108] The supplement may further comprise other optional ingredients that may modify the physical, chemical, aesthetic or processing characteristics of the formulas or serve as pharmaceutical or additional nutritional components when used in the targeted population. Many such optional ingredients are known for use in food and nutritional products, including infant formulas, and may also be used in the present invention, provided that such optional materials are compatible with the essential materials described herein, are safe and effective for their intended use, do not otherwise unduly impair product performance, and are accepted by the regulatory bodies. Non-limiting examples of such optional ingredients include preservatives, antioxidants, various pharmaceuticals, buffers, carotenoids, colorants, flavors, nucleotides and nucleosides, thickening agents, stabilizers, human milk oligosaccharides, probiotics, sialic acid-containing materials, and other excipients or processing aids.

[0109] EP 0 148 680 A1 refers to a nutrient solution of amino acids, which solution is an alternative for breast milk when administered together with carbohydrates, lipids and micronutrients. In contrast, the supplement or fortifier of the present invention is preferably used with breast milk, preferably for LBW infants. In particular, the supplement of the present invention is a human milk fortifier. That means, the use of proteins (amino acids) meets the increased protein/amino acid requirements of the infants fed. By using calories from other sources (e.g. carbohydrates, lipids) and micronutrients, the specific (increased) requirements of LBW infants can be met when they are fed with breast milk.

[0110] EP 0 148 680 A1 (page 4) discloses solutions with 2 to 10 g of amino acids per 100 ml solution. For parenteral administration the solution is mixed with e.g. glucose, soy bean oil and micronutrients. For enteral administration the amino acid solution is mixed with other macro- and micronutrients and then administered (mixing provides the complete nutrient solution). EP 0 148 680 A1 does not mention a supplement for breast milk. The pattern of the essential amino acids of the supplement of the present invention and that of the amino acid solution of EP 0 148 680 A1 are different. EP 0 148 680 A1 reflects the essential amino acid composition of breast milk. Since the requirements of LBW infants are not met quantitatively and qualitatively in an optimal way by breast milk, the pattern of the essential amino acids of the supplement of the present invention and that of the amino acid solution of EP 0 148 680 A1 are different. The supplement of the present invention supplements the amino acid composition of breast milk and thus better meets the specific requirements of the infants fed, in particular of LBW infants. Due to fast growth of the LBW infants, their need concerning some essential amino acids is particularly high and not met in an optimal way by the amino acid pattern of breast milk. The use of breast milk together with the supplement of the invention provides a superior supply of the essential amino acids for fast growth of LBW infants.

[0111] In alternative embodiments, the invention relates to a liquid human milk supplement comprising at least the amino acids leucine, isoleucine, valine, lysine, methionine, threonine, phenylalanine, histidine, and tryptophan, wherein the total amount of amino acids comprises at least 25% of the caloric content of the liquid human milk supplement, in particular wherein the liquid human milk supplement is defined as described above.

[0112] The invention is further explained by the following examples without limiting it.

Example 1

[0113] A liquid human milk supplement according to the invention is prepared by adding free amino acids in amounts as described in Table 1 to double-distilled water. The amino acids are given in the three-letter code. The supplements are suitable for LBW infants (ca. 0.5-1.5 (1.8) kg) and may be added to 150 ml of breast milk or breast milk substitute. The volume of the supplement is 30 ml.

TABLE-US-00001 TABLE 1 Liquid human supplement comprising amino acids Amount of amino acid in supplement Minimum Optimum Maximum Amino acid (ca.25%) (100%) (ca.250%) Nutrient in (mg) total amino acids 513 2053 5132 essential (mg) LEU 50 201 503 ILE 25 108 270 VAL 35 152 380 LYS 50 205 515 MET 19 78 200 THR 25 105 265 PHE 29 117 295 HIS 18 75 190 TRP 13 52 130 Σ (essential) 264 1093 2748 semi-essential TYR 11 46 115 CYS 8 35 88 GLY 50 208 520 GLU/AMATE 50 211 528 ARG 35 145 365 Σ (semi-essential) 154 645 1616 non-essential ALA 25 102 255 ASP 15 65 163 PRO 29 117 293 SER 7 31 78 Σ (non-essential) 76 315 789

Example 2

[0114] The liquid human milk supplement of Example 1 is prepared, wherein the additional lipid, carbohydrate, vitamin and other supplements according to Table 2 are added. The supplements with macro/micronutrients are suitable for LBW infants (ca. 0.5-2.5 kg) and may be added to 150 ml of breast milk or breast milk substitute. The volume of the supplement is 30 ml.

TABLE-US-00002 TABLE 2 Supplements with additional components to the amino acid composition of table 1 Total calories (kcal) 25.6 Amino acids of Table 1 (g) 2.053 Lipids (g) 1.08 Medium-chain triglycerides (g) 0.7 Percentage of medium-chain 65 triglycerides in total lipid amount (%) Arachidonic acid (mg) 16.8 Docosahexaenoic acid (mg) 9.4 Ratio of arachidonic acid: 1.8 docosahexaenoic acid Linoleic acid (mg) 57.5 alpha-Linolenic acid (mg) 25 Ratio of linoleic acid: 2.3 alpha-linolenic acid Carbohydrates (g) 1.95 Lactose (g) 0 Maltodextrin (g) 1.95 Minerals Na (mg) 55.08 K (mg) 60 Cl (mg) 48.18 Ca (mg) 113.4 P (mg) 64.95 Ca/P ratio 1.74 Mg (mg) 6 Mn (ug) 12.12 Fe (mg) 2.7 I (ug) 25.38 Cu (ug) 75 Zn (mg) 1.41 Se (ug) 5.58 Cr (mg) 1.38 Mo (ug) 1.2 F (ug) 3.6 Vitamins A (IU) 1774.5 D (IU) 300 E (IU) 8.955 K1 (ug) 12 C (mg) 30 B1 (ug) 225 B2 (ug) 300 Niacin (ug) 2250 B6 (ug) 195 Folate (ug) 60 Pantothenic acid (mg) 1.05 B12 (ug) 0.4 Biotin (ug) 5.25 Further ingredients Choline (mg) 25 Inositol (mg) 6.66 Taurine (mg) 3 Carnitine (mg) 3.96

REFERENCES

[0115] 1) MS Kramer—Bulletin of the World Health Organization, 1987-ncbi.nlm.nih.gov [0116] 2) https://intergrowth21.tghn.org/ . . . /intergrowth-21st-fetal-growth-s [0117] 3) Agostoni C et al for the ESPGHAN COMMITTEE on Nutrition. Enteral Nutrient Supply for Preterm Infants: Commentary From the European Society of Paediatric Gastroenterology, Hepatology and Nutrition Committee on Nutrition. Journal of Pediatric Gastroenterology & Nutrition: January 2010; 50: 85-91 doi: 10.1097/MPG.0b013e3181adaee0 [0118] 4) Sourabh Dutta,* Balpreet Singh, Lorraine Chessell, et al Guidelines for Feeding Very Low Birth Weight Infants Nutrients. 2015 January; 7(1): 423-442. doi: 10.3390/nu7010423 [0119] 5) Ziegler E E. Preterm and low-birth-weight infants. World Rev Nutr Diet. 2015; 113:214-7. doi: 10.1159/000360342. Epub 2015 Apr. 13. Review. [0120] 6) Haschke F, Grathwohl D, Haiden N. Metabolic Programming: Effects of Early Nutrition on Growth, Metabolism and Body Composition. iIn: Bhatia J, Shamir R, Vandenplas Y (eds): Protein in Neonatal and Infant Nutrition: Recent Updates. Nestlé Nutr Inst Workshop Ser, vol 86, pp 87-95, (DOI: 10.1159/000442728) [0121] 7) Underwood M A.sup.1, Gilbert W M, Sherman M P. Amniotic fluid: not just fetal urine anymore. Journal of Perinatology (2005) 25, 341-348. doi:10.1038/sj.jp.7211290 [0122] 8) Widdowson E M, Southgate, Hey E N. Body composition of the fetus. Academic Press 1982 [0123] 9) Zhang Z, Adelman A S, Rai D, Boettcher J, Lönnerdal B. Amino acid profiles in term and preterm human milk through lactation: a systematic review. Nutrients. 2013 Nov. 26; 5(12):4800-21. doi: 10.3390/nu5124800. [0124] 10) Hogewind-Schoonenboom J E, Zhu L, Ackermans E C, et al. Phenylalanine requirements of enterally fed term and preterm neonates. Am J Clin Nutr. 2015 June; 101(6):1155-62. doi: 10.3945/ajcn.114.089664. [0125] 11) de Groof F, Huang L, Twisk J W, et al. New insights into the methodological issues of the indicator amino acid oxidation method in preterm neonates. Pediatr Res. 2013 May; 73(5):679-84. doi: 10.1038/pr.2013. [0126] 12) van den Akker C H, Schierbeek H, Minderman G et al. Amino acid metabolism in the human fetus at term: leucine, valine, and methionine kinetics. Pediatr Res. 2011 December; 70(6):566-71. doi: 10.1203/PDR.0b013e31823214d1. [0127] 13) Van den Akker C H, Van Goudoever J B. Recent advances in our understanding of protein and amino acid metabolism in the human fetus. Curr Opin Clin Nutr Metab Care. 2010 January; 13(1):75-80. doi: 10.1097/MCO.0b013e328333aa4f Gut. 2004 January; 53(1):38-43. [0128] 14) van der Schoor S R, Schierbeek H, Bet P M, et al Majority of dietary glutamine is utilized in first pass in preterm infants. Pediatr Res. 2010 February; 67(2):194-9. doi: 10.1203/PDR.0b013e3181c34609 17) Te Braake F W, Schierbeek H, de Groof K et al. Glutathione synthesis rates after amino acid administration directly after birth in preterm infants. Am J Clin Nutr. 2008 August; 88(2):333-918) van der Schoor S R1, Reeds P J, Stellaard F, et al Lysine kinetics in preterm infants: the importance of enteral feeding. Gut. 2004 January; 53(1):38-43 [0129] 15) Riedijk M A, Voortman G, van Beek R H et al Cyst(e)ine requirements in enterally fed very low birth weight preterm infants. Pediatrics. 2008 March; 121(3):e561-7. doi: 10.1542/peds.2007-0494. [0130] 16) Huang L, Hogewind-Schoonenboom J E, Zhu L et al. Tryptophan requirement of the enterally fed term infant in the first month of life. J Pediatr Gastroenterol Nutr. 2014 September; 59(3):374-9. doi: 10.1097/MPG.0000000000000434. [0131] 17) de Groof F, Huang L, van Vliet I, et al. Branched-chain amino acid requirements for enterally fed term neonates in the first month of life. Am J Clin Nutr. 2014 January; 99(1):62-70. doi: 10.3945/ajcn.112.038927. [0132] 18) de Groof F, Huang L, Twisk J W et al New insights into the methodological issues of the indicator amino acid oxidation method in preterm neonates. Pediatr Res. 2013 May; 73(5):679-84. doi: 10.1038/pr.2013.31. Epub 2013 February 13. [0133] 19) Huang L, Hogewind-Schoonenboom J E, de Groof F L e al Lysine requirement of the enterally fed term infant in the first month of life. Am J Clin Nutr. 2011 December; 94(6):1496-503. doi: 10.3945/ajcn.111.024166. Epub 2011 November 2. [0134] 20) van den Akker C H, Schierbeek H, Minderman G et al. Amino acid metabolism in the human fetus at term: leucine, valine, and methionine kinetics. Pediatr Res. 2011 December; 70(6):566-71. doi: 10.1203/PDR.0b013e31823214d1. [0135] 21) van der Schoor S R, Schierbeek H, Bet P M, et al Majority of dietary glutamine is utilized in first pass in preterm infants. Pediatr Res. 2010 February; 67(2):194-9. doi: 10.1203/PDR.0b013e3181c34609. [0136] 22) Oosterink J E, Naninck E F, Korosi A et al. Accurate measurement of the essential micronutrients methionine, homocysteine, vitamins B6, B12, B9 and their metabolites in plasma, brain and maternal milk of mice using LC/MS ion trap analysis. J Chromatogr B Analyt Technol Biomed Life Sci. 2015 Aug. 15; 998-999: 106-13. doi: 10.1016/j.jchromb.2015.07.008. [0137] 23) Yajnik C S, Deshmukh U S Fetal programming: maternal nutrition and role of one-carbon metabolism. Rev Endocr Metab Disord. 2012 June; 13(2):121-7. doi: 10.1007/s11154-012-9214-8