Pediatric formulations for phenylketonuria and tyrosinemia and specific free amino acid mixtures

Abstract

The present invention relates to infant formula or follow-on formula suitable for children up to 2 years of age, and their use in the dietary management of phenylketonuria and tyrosinemia. In particular, the present invention relates to infant formula or follow-on formula comprising casein glycomacropeptide and free amino acids, and their use in the dietary management of phenylketonuria and tyrosinemia and their symptoms. The present invention relates to a mixture of free amino acids for use in the manufacture of infant formula or follow-on formula.

Description

Technical Field

[0001] This invention relates to infant formula or follow-up formula for children under 2 years of age, and their use in the dietary management of phenylketonuria and hypertyrosinemia. Specifically, this invention relates to infant formula or follow-up formula comprising casein macropeptides and free amino acids, and their use in the dietary management of phenylketonuria and hypertyrosinemia and their symptoms. This invention also relates to a mixture of free amino acids for the manufacture of infant formula or follow-up formula. Background Technology

[0002] Phenylketonuria and tyrosinemia are diseases caused by congenital metabolic errors of the aromatic amino acids phenylalanine and tyrosine, respectively.

[0003] Phenylketonuria (PKU) is an autosomal recessive genetic disorder of phenylalanine metabolism, in which exceptionally high concentrations of phenylalanine can cause brain dysfunction. If left untreated, this brain dysfunction can lead to severe intellectual disability, epilepsy, and behavioral problems (van Spronsen et al. (2021) Nature Reviews Disease Primers, 7, 36). PKU is characterized by a deficiency of the liver enzyme phenylalanine hydroxylase (PAH), an enzyme essential for the conversion of the essential amino acid phenylalanine (Phe) to tyrosine (Tyr). Low-protein diets are prescribed to reduce phenylalanine intake to very low levels and to prevent irreversible intellectual disability, microcephaly, motor deficits, autism, seizures, developmental problems, abnormal behaviors, and psychiatric symptoms.

[0004] If initiated immediately after birth, dietary intervention with a low-phenylalanine diet can prevent major cognitive and neurological deficits (Rocha and MacDonald (2018) Expert Opinion on Orphan Drugs, 6, 667-681). This typically prevents the gold standard of breastfeeding and requires the administration of at least some infant formula (van Rijn et al. (2003) European Journal of Pediatrics 162, 323-326).

[0005] Tyrosinemia encompasses several conditions characterized by elevated levels of the amino acid tyrosine in the blood (Chinsky et al. (2017) Genetics in Medicine 19, 1380-1395; Beyzaei et al. (2022) Orphanet Journal of Rare Diseases 17, 424). These conditions are rare, including hereditary tyrosinemia and tyrosinemia caused by nitixinon treatment in alkaptonuria (AKU). Hereditary tyrosinemia has three types—Type I, Type II, and Type III—characterized by their symptoms and genetic causes. To lower tyrosine levels, low-phenylalanine, low-tyrosine diets are prescribed to reduce the intake of Tyr and Phe (i.e., because Phe is a precursor to Tyr) to a safe minimum.

[0006] Dietary interventions for patients aged 3 years and older with PKU or tyrosinemia are known in the field, but studies have focused on PKU because of its high prevalence and relatively homogeneous genetic causes (most cases are associated with mutations in the PAH gene (OMIM 612,349), some of which are associated with tetrahydrobiopterin-related genes such as GCH1, “GTPCH”, PTS, PCBD1, QDPR and SPR genes).

[0007] Casein glycomacropeptide (GMP) is often included in dietary interventions for PKU patients aged 3 years and older because it contains only about 2 mg of Phe per gram of GMP protein (about 0.2% by weight). GMP can be used alone (e.g., JPH04126051A) or in combination with essential amino acids (e.g., WO 1998 / 008402).

[0008] WO 2019 / 239439 describes a nutritional preparation suitable for managing a diet for phenylketonuria, which contains GMP as the primary protein source and additional supplemental essential amino acids to complete the required protein profile, provided in a mixture of arginine, cystine, histidine, tryptophan, tyrosine and leucine.

[0009] WO 2016 / 003263 and WO 2016 / 003273 describe amino acid-based nutritional compositions that have improved taste but do not compromise (regulatory) dietary restrictions on essential and conditionally essential amino acids.

[0010] US 9,414,619 B describes a ready-to-drink liquid nutritional preparation for the treatment of PKU, hypertyrosinemia, or other metabolic disorders. The preparation contains GMP as the primary protein source, along with supplemental essential amino acids to complete the required protein profile. The beverage also includes vitamins and minerals to meet daily requirements for these elements, and when used as a complete nutritional diet, the preparation also includes sources of carbohydrates and fats.

[0011] FR 3,002,831 A1 describes a ready-to-eat food for patients with metabolic pathologies of one or more amino acids. It does not disclose that the food is suitable for children under 2 years of age.

[0012] WO 2010 / 144821 describes a GMP-based medical food for nutritional management of PKU and other metabolic disorders, which, in addition to GMP, includes additional amounts of arginine, leucine, and optional other amino acids such as tyrosine.

[0013] WO 2000 / 022937 describes a protein material with low digestibility for use in the preparation of an intestinal composition capable of regulating postprandial amino acid levels in plasma.

[0014] WO 1998 / 008402 describes a nutritional formula for patients with PKU, which contains GMP as a protein source and a mixture of supplemental essential amino acids except phenylalanine.

[0015] PKU sphere ® It features a GMP-predominant protein source and is supplemented with amino acids for dietary management of PKU starting at age 4.

[0016] Ahring et al. (J. Nutr. Metab. (2018) 6352919) compared the absorption of CGMP-20 with that of free synthetic amino acids to evaluate its short-term effects on plasma amino acids and biomarkers related to food intake. Patients were aged 15 to 48 years, and the formulation was not described as suitable for children under 2 years of age.

[0017] US 2018 / 0064784 describes liquid metabolic formula foods for dietary management of hypertyrosinemia, including nutritional formula foods and rehydration drinks (sports drinks). It emphasizes that not all compositions are suitable for children, and no formula foods suitable for children under 2 years of age are disclosed.

[0018] Most of the formula foods described above are not designed for children under 2 years of age with PKU or tyrosinemia. WO1998 / 008402 emphasizes that the amino acids Arg, Cys, Gln, His, Ile, Leu, Lys, Met, Thr, Trp, Tyr, Phe, and Val are considered essential or conditionally essential for children under 2 years of age. It recommends that protein sources should contain approximately 40% to approximately 60% of GMP and specific amounts of supplemental free amino acids, including Tyr, which is abundant compared to human milk.

[0019] During infancy, this low-phenylalanine diet is provided by a combination of low-phenylalanine formula and prescription and controlled amounts of breast milk / standard infant formula.

[0020] For children under 2 years old, a low-phenylalanine diet is usually based on free amino acid formula foods.

[0021] WO 2011 / 119023 discloses free amino acid infant formula for the treatment of PKU, maple syrup diabetes mellitus (MSUD), or tyrosinemia. It is recommended to remove GMP from the protein source to advantageously reduce threonine content.

[0022] PKU Anamix Infant (Nutricia) is a free amino acid formula with prebiotic fiber that maintains phenylalanine control consistent with established infant protein alternatives without prebiotics, maintains bifidobacteria levels, and lowers fecal pH (MacDonald et al. (2011) Molecular Genetics and Metabolism 104, S55-S59).

[0023] PKU Start ® Vitaflo International Ltd is a free amino acid formula that is well tolerated, helps maintain good metabolic control, and supports normal growth in infants with PKU (Yilmaz et al. (2023) Orphanet Journal of Rare Diseases 18, 16).

[0024] These formula foods are recommended for infants with PKU, but they may cause gastrointestinal side effects such as constipation, and there have been reports of compliance problems, possibly due to the known bitterness and / or sourness of free amino acid formula foods.

[0025] WO 1998 / 008402 describes two infant formulas for patients with PKU, containing approximately 50% GMP and approximately 50% free amino acids. However, it does not describe the effects of these formulas on infants with PKU.

[0026] Therefore, there are currently no recommended infant formulas for infants with PKU or tyrosinemia that have proven palatability, tolerability, low gastrointestinal side effects, and the ability to maintain metabolic control of Tyr and Phe levels while supporting normal growth. Summary of the Invention

[0027] The inventors have developed a GMP-based and free amino acid-based infant formula (or follow-up formula) suitable for dietary intervention and management of children under 2 years of age, preferably infants, with PKU or tyrosinemia. This formula exhibits excellent sensory properties and stability, and is an ideal candidate for dietary intervention and management of children under 2 years of age with congenital Tyr or Phe metabolic disorders.

[0028] Therefore, in a first general embodiment, the present invention provides a formula food for children under 2 years of age, preferably an infant formula food, the formula food containing whole casein glycomacropeptide (GMP) and free amino acids, the formula food being used for dietary management of phenylketonuria (PKU) or tyrosinemia.

[0029] In a second general embodiment, the present invention provides the use of whole GMP and free amino acids in the preparation of formula foods for children under 2 years of age, preferably infant formula foods, for dietary management of PKU or tyrosinemia in individuals in need.

[0030] In a third general embodiment, the present invention provides a method for providing dietary management of PKU or tyrosinemia, the method comprising administering to an individual in need a formula food for children under 2 years of age, preferably an infant formula food, containing complete GMP and free amino acids.

[0031] In a fourth general embodiment, the present invention provides a complete infant formula for dietary management of PKU or tyrosinemia, the complete infant formula comprising complete GMP and free amino acids, wherein the GMP and free amino acids are present in a weight ratio of 1:4 to 4:1.

[0032] In a fifth general embodiment, the present invention provides a mixture of free amino acids comprising Arg, Asp+Asn, Cys, Gly, His, Ile, Leu, Lys, Met, Trp, and Val, and optionally Tyr, wherein the mixture of free amino acids contains less than 0.1% by weight of any one of Ala, Gln, Glu, Pro, Phe, Ser, or Thr. Detailed Implementation

[0033] A. Definition

[0034] Unless otherwise limited in a specific instance, the following definitions apply to the terminology used throughout this specification.

[0035] The term "management," particularly in the context of "dietary management," refers to the prevention of one or more symptoms of a disease or condition, or the reduction of the severity or frequency of one or more symptoms of a disease or condition. This includes improving one or more existing symptoms of a disease or condition, preventing one or more existing symptoms of a disease or condition, preventing one or more underlying causes of a disease or condition, improving one or more underlying causes of a disease or condition, reducing the prevalence of one or more symptoms of a disease or condition, and / or reducing the occurrence of one or more symptoms of a disease or condition. It should be understood to include stabilizing a disease or condition and preventing its progression. It should also be understood that the management of a disease or condition, more specifically dietary management, includes meeting the nutritional needs of a subject suffering from a disease or condition that prevents the fulfillment of nutritional needs in a normal or non-specialized dietary context. In the absence of management, more specifically dietary management, subjects may experience adverse effects such as malnutrition due to one or more of the following: limited, impaired, or disordered capacity to ingest, digest, absorb, metabolize, or excrete ordinary food or certain nutrients or metabolites contained therein; and / or symptoms of a disease or condition resulting from limited, impaired, or disordered capacity to ingest, digest, absorb, metabolize, or excrete ordinary food or certain nutrients or metabolites contained therein. Management, more specifically dietary management, may include medically determined nutritional requirements and / or uncontrolled and / or normal dietary changes, and may include supervision by a medical professional. Technicians will be familiar with the diagnosis and management of such diseases or conditions, and more specifically dietary management (see, for example, Commission Directive 1999 / 21 / EC, including its amendments; Commission notification on the classification of foods for special medical purposes (2017 / C 401 / 01); Commission Authorisation Regulation (EU) 2016 / 128 supplemented by Regulation (EU) 609 / 2013 of the European Parliament and of 25 September 2015). In the context of a disease or condition that can be classified as a congenital metabolic disorder, subjects may lack the ability to utilize specific nutrients and / or consume a normal diet. Management of the disease or condition, more specifically dietary management, may be the only effective treatment to prevent further disability or death in the subject (see, for example, Berry et al., Peds 145(3): March 2020:e20192261). For example, in infants for whom dietary management is initiated at or near birth, dietary management is likely to prevent or stabilize PKU or tyrosinemia. In infants for whom dietary management is initiated when there are obvious symptoms, dietary management is likely to reduce the severity and / or frequency of one or more symptoms of PKU or tyrosinemia. Symptoms of PKU or tyrosinemia for which dietary management is possible are described below.

[0036] The term "dietary intervention" is defined as a transition from a diet with a standard amino acid profile (i.e., breast milk or standard infant formula) to a diet including the formula foods described herein, in order to manage (specifically, dietary management), prevent, and / or treat one or more symptoms of PKU or hypertyrosinemia. Where possible, the infant should maintain the maximum possible amount of breast milk. However, dietary interventions based entirely on the infant formula foods described herein may be necessary to stabilize or reduce blood Phe or Tyr levels and ensure improvement in PKU or hypertyrosinemia. Older infant formula may be given in conjunction with a carefully selected low-Phe and / or low-Tyr diet.

[0037] The term "treatment" refers to the complete or partial treatment of one or more symptoms of PKU and / or tyrosinemia described below. Similarly, "treatment" may refer to the prevention of known symptoms that a patient does not yet have but is expected to have based on their age or disease severity. Prevention and treatment can be achieved through dietary interventions and / or dietary management.

[0038] The term "infant" is generally used for very young children under 1 year old, preferably under 6 months old.

[0039] As used herein, the term "infant formula" refers to a nutritional composition intended for use in infants, as defined in Codex Alimentarius, (Codex STAN 72-1981) and / or as defined in Codex Alimentarius, (Codex STAN 72-1981) (Codex Alimentarius, (Codex STAN 72-1981)) and / or as defined in Codex Alimentarius, (Codex STAN 72-1981) (Codex Alimentarius, (Codex STAN 72-1981)) (Infant Specialities (incl. Food for Special Medical Purpose)). It may also refer to a food intended to provide specific nutritional purposes for infants in the first few months of life, which itself meets the nutritional needs of such infants (in accordance with Article 2(c) of European Commission Directive 91 / 321 / EEC 2006 / 141 / EC of 22 December 2006 concerning infant formula and follow-up formula).

[0040] The term "starter formula" refers to formula foods intended as a substitute for breast milk for newborns.

[0041] The term "follow-up formula" refers to formula given to infants starting from the 6th month of age when they begin to be weaned. Infant formula constitutes a major liquid element in the gradually diversifying diet of these individuals.

[0042] The term "liquid" is defined as a nearly incompressible fluid that conforms to the shape of its container but maintains a nearly constant volume regardless of pressure. It is one of the four fundamental states of matter and the only one with a definite volume but no fixed shape. Typically, the liquid described in this article is at 20°C for 100 seconds... -1 The viscosity of a solution or emulsion is less than 200 mPa·s, measured at a shear rate. Viscosity can be determined by methods known to those skilled in the art, for example, by using a rheometer equipped with a plate / plate geometry (60 mm diameter) and a 1 mm gap (e.g., Netzsch Kinexus Pro+).

[0043] The term "reconfigurable powder" is defined as a powder that dissolves into a liquid formula in less than one minute when shaken vigorously by an adult. The reconfigured liquid formula should be able to pass through a standard infant formula bottle nipple and therefore must be free of particles larger than the nipple hole, such as particles with a diameter of 1 mm or greater.

[0044] The term "spoonable food" is defined as food that is scoopable at 20°C for 100 seconds. -1 Viscosities measured at shear rates ranging from less than 400 mPa·s to 4000 mPa·s for liquids, gels, or semi-solids. Viscosities can be determined by methods known to those skilled in the art, for example, by using a rheometer (e.g., Netzsch Kinexus Pro+) equipped with a plate / plate geometry (60 mm diameter) and a 1 mm gap.

[0045] The term "storage stable" means that a formulated food product is chemically stable and maintains the same (low) level of bacterial contamination when stored at 20°C in a sealed, sterile container for at least 3 months, preferably at least 6 months, more preferably at least 9 months, and most preferably at least 1 year. During this period, the state of the formulated food product should not change to the point that it cannot be transformed into a homogeneous form (e.g., liquid, gel, or powder) with minimal shaking or mixing.

[0046] The term "storage-stable liquid" means that a formulated food product is chemically stable and maintains the same (low) level of bacterial contamination when stored at 20°C in a sealed, sterile container for at least 3 months, preferably at least 6 months, more preferably at least 9 months, and most preferably at least 1 year. During this period, the state of the formulated food product should not change to the point that it cannot be transformed into a homogeneous form (e.g., a liquid solution or emulsion) with minimal shaking or mixing.

[0047] The term "phenylketonuria" is defined as an abnormally high level of Phe in the blood, >360 μmol / L, prior to the initiation of dietary intervention. Traditionally, the Guthrie test is used (Guthrie and Susi (1963) Pediatrics 32; 338-43), but more modern systems based on tandem mass spectrometry are frequently used in developed countries. PKU can be confirmed by testing for pathogenic mutations in the PAH or DNAJC12 gene.

[0048] The term "tyrosinemia" is defined as an abnormally high Tyr level in the blood, >200 μmol / L, prior to the initiation of dietary intervention. However, clinical manifestations often do not become apparent until plasma levels >500 μmol / L. Tyrosinemia can be confirmed by testing for pathogenic mutations in the FAH gene (expressing fumaroyl acetoacetate hydrolase; type I tyrosinemia), the TAT gene (expressing tyrosine aminotransferase; type II tyrosinemia), or the HPD gene (expressing 4-hydroxyphenylpyruvate dioxygenase; type III tyrosinemia).

[0049] The term "hyperphenylalanineemia" is defined as an abnormally high level of Phe in the blood, ranging from 120 μmol / L to 360 μmol / L, prior to the initiation of dietary intervention, suggesting possible PKU. In patients with hyperphenylalanineemia, PKU can be confirmed by continuous monitoring of Phe levels in the blood and / or by testing for pathogenic mutations in the PAH or DNAJC12 gene. Dietary intervention may be applicable to children under 2 years of age with hyperphenylalanineemia.

[0050] The term "good metabolic control" is defined as partial or complete control of amino acid concentrations in the blood. For PKU, a Phe level of 120 μmol / L to 360 μmol / L in the blood is considered good metabolic control. A normal Phe level in the blood is 35 μmol / L to 120 μmol / L, and is preferred. For tyrosinemia, a Tyr level of 200 μmol / L to 400 μmol / L in the blood is considered good metabolic control. A moderately elevated Tyr level in the blood is 120 μmol / L to 200 μmol / L, and is preferred. A normal Tyr level in the blood is 20 μmol / L to 120 μmol / L, and is more preferred.

[0051] The term “improved gastrointestinal tolerance” is defined by a caregiver questionnaire that records symptoms of vomiting, regurgitation, abdominal discomfort or colic, flatulence, frequency and characteristics of daily bowel movements [loose, soft, hard], and the occurrence of any feeding difficulties (Yilmaz et al. (2023) Orphanet Journal of Rare Diseases 18, 16). Generally, improvement is an improvement in the obvious symptoms described above. However, because gastrointestinal damage can be insidious, improved tolerance includes a reduced prevalence of one or more symptoms of gastrointestinal intolerance and / or a reduction in the occurrence of one or more symptoms of gastrointestinal intolerance that would occur without dietary intervention and management.

[0052] The terms “casein glycomacropeptide,” “glycomacropeptide,” or “GMP” refer to a casein-derived peptide formed during curdling and retained in a soluble fraction known as “sweet whey.” Specifically, GMP corresponds to the 64 carboxyl-terminal amino acids of κ-casein (methionine-106 to valine-169). Within the meaning of this application, GMP preferably also includes non-glycosylated “casein macropeptide” or “CMP”, which are present in whey in approximately equal proportions (Neelima et al. (2013) Diary Science and Technology 93, 21-43). Commercially available GMP may contain approximately a 1:1 ratio of glycosylated GMP to non-glycosylated GMP.

[0053] The term "intact GMP" refers to GMP that has not been further hydrolyzed, especially not completely hydrolyzed into free amino acids. As discussed above, it includes glycosylated GMP and non-glycosylated GMP.

[0054] The term "free amino acids" refers to the 20 classic amino acids found in human proteins when they are not in the form of peptides or proteins.

[0055] The terms "Asp+Asn" and "Glu+Gln" refer to the total amount of these amino acids in a sample. Extraction procedures often use dilute acids, which partially convert Gln and Asn into Glu and Asp. Therefore, it is common practice to quantify these amino acids in pairs. The standard three-letter codes for amino acids are known to those skilled in the art.

[0056] Those skilled in the art, when implementing the claimed invention, can understand and implement other variations of the disclosed embodiments by studying this disclosure and the appended claims. In the claims, the word "comprising" does not exclude other elements or steps, and the indefinite articles "a" or "an" do not exclude multiple / a plurality of elements / steps. The mere fact that certain measures are stated in mutually different dependent claims does not imply that a combination of these measures cannot be used advantageously.

[0057] B. Dietary management for phenylketonuria (PKU) or hypertyrosinemia containing casein glycomacropeptide (GMP) and Formula foods containing free amino acids

[0058] In a first general embodiment, the present invention provides a formula food for children under 2 years of age, preferably an infant formula food, the formula food containing intact casein glycomacropeptide (GMP) and free amino acids, the formula food being used for dietary management of phenylketonuria (PKU) or hypertyrosinemia.

[0059] In a second general embodiment, the present invention provides the use of whole GMP and free amino acids in the preparation of formula foods for children under 2 years of age, preferably infant formula foods, for dietary management of PKU or tyrosinemia in individuals in need. Infant formula foods may be classified as medicines that can be used to treat patients.

[0060] In a third general embodiment, the present invention provides a method for providing dietary management of PKU or tyrosinemia, the method comprising administering to an individual in need a formula food for children under 2 years of age, preferably an infant formula food, containing complete GMP and free amino acids.

[0061] These general implementation schemes can be readily combined with specific compositions, patient groups, and symptoms described below. These general implementation schemes for dietary management can be used to prevent or treat PKU and tyrosinemia in the patient groups and symptoms described below.

[0062] Dietary intervention / dietary management

[0063] Compared with the period before dietary intervention, dietary intervention and management ensured good metabolic control of PKU and tyrosinemia—that is, target phenylalanine blood concentrations (120 μmol / L to 360 μmol / L) were achieved in children under 2 years of age with PKU and target tyrosine blood concentrations (200 μmol / L to 400 μmol / L) were achieved in children under 2 years of age with tyrosinemia.

[0064] Compared with dietary management using amino acid-based formula foods without GMP, this dietary management ensures normal growth and development in children under 2 years of age with PKU and tyrosinemia—that is, maintaining or increasing age-specific height, age-specific weight, and / or age-specific body mass index (BMI) percentiles (compared to the WHO 50th percentile for that age: WHO. Global Database on Child Growth and Malnutrition; WHO: Geneva, Switzerland, 1997).

[0065] Compared with dietary management using GMP-free amino acid-based formula, this dietary management ensured improved gastrointestinal tolerance—that is, improved gastrointestinal tolerance as defined by a caregiver questionnaire that records symptoms of vomiting, regurgitation, abdominal discomfort or colic, flatulence, frequency and characteristics of daily bowel movements [loose, soft, hard], and the occurrence of any feeding difficulties (Yilmaz et al. (2023) Orphanet Journal of Rare Diseases 18,16).

[0066] Therefore, in one implementation, dietary management results in good metabolic control compared to before dietary intervention, and / or results in normal growth and / or improved gastrointestinal tolerance compared to dietary management using GMP-free amino acid-based formulated foods.

[0067] In a specific implementation, dietary management results in good metabolic control. Preferably, good metabolic control achieves a target phenylalanine blood concentration (120 μmol / L to 360 μmol / L). This is particularly preferred for children under 2 years of age with PKU. Preferably, for children under 2 years of age with tyrosinemia, good metabolic control achieves a target tyrosine blood concentration (200 μmol / L to 400 μmol / L). This is particularly preferred for children under 2 years of age with tyrosinemia.

[0068] In a specific implementation, this dietary management results in normal growth in children with PKU or tyrosinemia compared to dietary management using GMP-free amino acid-based formula. Preferably, normal growth results in maintaining age-specific height, weight, and / or BMI compared to dietary management using GMP-free amino acid-based formula. More preferably, normal growth results in increasing age-specific height, weight, and / or BMI compared to dietary management using GMP-free amino acid-based formula.

[0069] In a specific implementation, compared with dietary management using amino acid-based formula foods without GMP, this dietary management results in improved gastrointestinal tolerance, wherein the improved gastrointestinal tolerance is selected from the group consisting of: reduced vomiting, reduced regurgitation, reduced symptoms of abdominal discomfort or colic, reduced flatulence, reduced proportion of loose or hard stools, and / or reduced feeding difficulties.

[0070] In the preferred implementation, dietary management resulted in good metabolic control compared to children before dietary intervention, and normal growth and improved gastrointestinal tolerance compared to dietary management using GMP-free amino acid-based formula.

[0071] Dietary management typically continues until the infant or child reaches 2 years of age. Preferably, dietary management continues for at least 3 months, more preferably at least 6 months, or even more preferably at least 1 year.

[0072] Given the presence of complete GMP and an improved amino acid profile, it is predicted that the dietary interventions and management of the present invention will result in improved metabolic control, normal growth, and / or improved gastrointestinal tolerance compared to standard free amino acid infant and follow-up formulas currently used for dietary interventions and management of PKU and tyrosinemia.

[0073] Diseases and their symptoms

[0074] phenylketonuria

[0075] Phenylketonuria (PKU; also known as phenylalanine hydroxylase (PAH, EC 1.14.16.1) deficiency (OMIM #261600) and Følling disease) is primarily caused by a pathogenic mutation in the PAH gene that results in a congenital error in Phe metabolism. PAH is responsible for converting Phe to Tyr, a reaction that requires the co-substrate tetrahydrobiopterin (BH4).

[0076] PKU (or the related but less severe condition hyperphenylalaninemia) can also be caused by defects in tetrahydrobiopterin (BH4) metabolism or pathogenic mutations in DNA JC12.

[0077] Mutations that can cause PKU are known to technicians and can be confirmed through genetic testing.

[0078] In infants, PKU is diagnosed by detecting high levels of Phe in the blood (i.e., >360 μmol / L), usually as part of a heel prick test in the first few days or weeks after birth. Hyperphenylalanineemia is an intermediate state between normal Phe levels (35 μmol / L to 120 μmol / L) and PKU, where Phe levels in the blood range from 120 μmol / L to 360 μmol / L.

[0079] Therefore, in one implementation, formula foods for children under 2 years of age, preferably infant formula foods, are used for dietary management of PKU.

[0080] Symptoms of phenylketonuria

[0081] Without treatment, PKU can lead to pervasive intellectual disability, significant delays in developmental milestones, hyperactivity with autistic characteristics, seizures, eczema, mild body odor, and mild pigmentation (eyes, hair, and skin), resulting in severe lifelong disability (Camp et al. (2014) Molecular Genetics and Metabolism, 112, 87-122; Rocha and MacDonald (2018) Expert Opinion on Orphan Drugs, 6, 667-681).

[0082] Therefore, in one implementation, the formula food is used for dietary management of symptoms in children with PKU selected from the following groups: intellectual disability, developmental milestone delay, hyperactivity, seizures, eczema, mild body odor, and mild pigmentation (e.g., mild pigmentation of the eyes, hair, and / or skin).

[0083] If an infant is diagnosed with PKU via newborn screening (NBS) and dietary management begins within 28 days of birth (preferably 21 days, more preferably 14 days, or even more preferably 7 days), symptoms may be mild and preventable. If an infant or child is diagnosed with PKU at a later stage or does not begin dietary management within 28 days of birth (preferably 21 days, more preferably 14 days, or even more preferably 7 days), symptoms may be severe and treatable or improve.

[0084] In a specific implementation plan, the symptom is intellectual disability. For example, the Bayley Scale of Infant Development (3rd edition) can be used from birth to 42 months.

[0085] In a specific implementation, symptoms are delays in one or more developmental milestones. For example, anthropometric milestones such as age-specific length, age-specific weight, and / or BMI can be measured. For example, developmental milestones known to a skilled pediatrician can be assessed individually or collectively at specific ages. For example, developmental milestones at 2 months can be selected from the following groups: turning head towards a sound; paying attention to a face; beginning to show boredom (e.g., crying, fussiness) if activity does not change; and / or being able to lift head. For example, developmental milestones at 4 months can be selected from the following groups: beginning to babble; reaching for toys with one hand; maintaining head stability without support; and / or being able to roll from belly to back. For example, developmental milestones at 6 months can be selected from the following groups: responding to sounds by making sounds; beginning to sit without support; and / or looking around at nearby objects. For example, developmental milestones at 9 months can be selected from the following groups: understanding the word "no"; playing games such as peek-a-boo; pointing to objects; and / or crawling. For example, developmental milestones at 12 months can be selected from the following groups: saying simple words; beginning to use objects correctly; standing up; and / or following simple instructions.

[0086] In a specific implementation plan, the symptom is hyperactivity. For example, the Rutter assessment can be used to predict hyperactivity in infants (Østergaard et al. (2016 PLoS ONE, 11, e0157352)).

[0087] In the specific implementation plan, the symptom is an epileptic seizure.

[0088] In the specific implementation plan, the symptom is eczema.

[0089] In a specific implementation, the symptom is a musty body odor (e.g., in breath, skin, and / or urine). This symptom is associated with high levels of Phe in saliva, sweat, and / or urine and can be detected by parents, healthcare professionals, or caregivers. This symptom can be unpleasant and distressing for parents; it is a clear sign of illness.

[0090] In a specific implementation, the symptom is mild pigmentation (e.g., milder pigmentation of the eyes, hair, and / or skin). This symptom can be detected by parents, medical professionals, or caregivers (referencing the skin color of parents and / or siblings) and can lead to sun sensitivity.

[0091] Clearly, the later dietary management begins, the more obvious the symptoms will be identified.

[0092] Tyrosinemia

[0093] Tyrosinemia is a metabolic disorder, usually congenital, in which the body is unable to efficiently break down the amino acid tyrosine. Due to its low prevalence, tyrosinemia is not typically included in the newborn heel prick test (NBS). Therefore, the condition is usually diagnosed when obvious clinical symptoms appear. There are three recognized types, each associated with different genetic causes and exhibiting distinct symptoms.

[0094] The mutations that confirm tyrosinemia are known to those skilled in the art and are described further below.

[0095] In children, tyrosinemia is usually diagnosed after the onset of symptoms by detecting high Tyr levels in the blood (i.e., >200 μmol / L). Symptoms typically become apparent only when plasma levels are >500 μmol / L. The target blood tyrosine concentration in patients is 200 μmol / L to 400 μmol / L. Moderately elevated Tyr levels in the blood are 120 μmol / L to 200 μmol / L, and normal Tyr levels in the blood are 20 μmol / L to 120 μmol / L.

[0096] Therefore, in one implementation, the formulated food is used for dietary management of tyrosinemia.

[0097] Clearly, if dietary management is delayed, more obvious symptoms will be identified.

[0098] Type I tyrosinemia

[0099] Type I tyrosinemia is associated with a pathogenic mutation in the FAH gene (which expresses fumaroacetoacetate hydrolase). It is linked to the substrate fumaroacetoacetate and is the most common and serious form of tyrosinemia. Accumulation of fumaroacetoacetate can lead to toxicity to the kidneys and liver, as well as the brain, eyes, heart, and endocrine system. Untreated type I tyrosinemia can lead to liver failure (Chinsky et al. (2017) Genetics in Medicine, 19, 1380). While type I tyrosinemia can be treated with nitixinone (NTBC), this increases tyrosine levels, meaning dietary management is still necessary, and patients may exhibit the symptoms of type II tyrosinemia described below.

[0100] Therefore, in one implementation, the formulated food is used for dietary management of type I tyrosinemia.

[0101] In one implementation, the formulated food is used for dietary management of symptoms selected from hepatotoxicity, nephrotoxicity, neurotoxicity, and endocrine dysfunction in children with type I tyrosinemia.

[0102] In a specific implementation plan, the symptoms are hepatotoxic. For example, symptoms could be hemophilia-like symptoms, such as impaired blood clotting, increased bruising, intra-articular hemorrhage, or intracerebral hemorrhage. For example, symptoms could be acute liver failure. For example, symptoms could be hypoalbuminemia. For example, symptoms could be hepatocellular carcinoma.

[0103] In a specific implementation plan, the symptom is nephrotoxicity. For example, the symptom could be hypophosphatemic rickets. For example, the symptom could be impaired kidney function. For example, the symptom could be renal tubular damage. For example, the symptom could be kidney failure.

[0104] In a specific implementation plan, the symptoms are neurotoxic. For example, the symptoms could be porphyria. For example, the symptoms could be peripheral neuropathy.

[0105] In the specific implementation plan, the symptoms are endocrine dysfunctions. For example, symptoms may be dopamine, norepinephrine, and / or thyroid hormone dysfunction.

[0106] Symptoms associated with type I tyrosinemia can be treated with nitixinone (NTBC). Therefore, formulated foods can be used for dietary management of type I tyrosinemia in patients also treated with nitixinone (NTBC).

[0107] When nitixinone (NTBC) treatment is successful, the symptoms associated with type I tyrosinemia may be consistent with the symptoms of type II tyrosinemia described below.

[0108] Type II tyrosinemia

[0109] Type II tyrosinemia is associated with pathogenic mutations in the TAT gene (which expresses tyrosine aminotransferases). Symptoms include ocular toxicity, skin toxicity, and mental disability.

[0110] Therefore, in one implementation, the formulated food is used for dietary management of type II tyrosinemia.

[0111] In one implementation, the formulated food is used for dietary management of symptoms selected from ocular toxicity, skin toxicity, and / or mental disability in children with type II tyrosinemia (and / or children with type I tyrosinemia treated with nitixinone (NTBC)).

[0112] In the specific implementation plan, the symptoms are ocular toxicity. For example, symptoms may include epiphora (excessive tearing). For example, symptoms may include photophobia (abnormal sensitivity to light). For example, symptoms may include eye pain. For example, symptoms may include congestion (red eye).

[0113] In a specific implementation plan, the symptom is skin toxicity. For example, the symptom could be palmoplantar keratosis (painful skin lesions).

[0114] In the specific implementation plan, the symptom is mental disability.

[0115] Type III tyrosinemia

[0116] Type III tyrosinemia is associated with pathogenic mutations in the HPD gene (which expresses 4-hydroxyphenylpyruvate dioxygenase). Symptoms include intellectual disability, seizures, and intermittent ataxia (periodic loss of balance and coordination).

[0117] Therefore, in one implementation, the formulated food is used for dietary management of type III tyrosinemia.

[0118] In one implementation, the formulated food is used for dietary management of symptoms selected from intellectual disability, seizures, and intermittent ataxia in children with type III tyrosinemia.

[0119] In the specific implementation plan, the symptom is intellectual disability.

[0120] In the specific implementation plan, the symptom is an epileptic seizure.

[0121] In the specific implementation plan, the symptom is intermittent ataxia.

[0122] Infants and children under 2 years old

[0123] Of the congenital metabolic errors described in this article, PKU is the most common, followed by type I tyrosinemia, then type II tyrosinemia, and finally type III tyrosinemia.

[0124] The child is a child with congenital Phe and / or Tyr metabolic disorders, preferably with PKU, type I tyrosinemia, type II tyrosinemia, or type III tyrosinemia. Preferably, the child is a child with PKU, type I tyrosinemia, or type II tyrosinemia. More preferably, the child is a child with PKU or type I tyrosinemia. Most preferably, the child is a child with PKU.

[0125] The child is preferably a human child, more preferably a child under 2 years old, even more preferably an infant at most 1 year old, and most preferably an infant at most 6 months old.

[0126] Formula food

[0127] This formula food is suitable for children under 2 years old.

[0128] The formulated foods described herein may be in the form of liquid, reconfigurable powder, or scoopable food. Preferably, the formulated food is in the form of liquid or reconfigurable powder, which can be administered to a child in liquid form via a bottle with a nipple. More preferably, the formulated food is in liquid form. Even more preferably, the formulated food is a storage-stable liquid. Most preferably, the formulated food is a packaged storage-stable liquid.

[0129] When sealed in a container (i.e., packaged), the described formulated food is preferably storage stable. In this context, stability means that once sterilized, the formulated food remains in a stable physical state (liquid, reconfigurable powder, or scoopable food) over a prolonged period. Moderate shaking or mixing may be necessary to ensure homogeneity or uniformity. The formulated food is preferably storage stable for at least 3 months, preferably at least 6 months, more preferably at least 9 months, and most preferably at least 1 year.

[0130] To ensure optimal consistency of milk or single cream, liquid or reconstituted liquid formulations can have a viscosity of 20°C for 100 seconds. -1 Viscosity measured at shear rates below 200 mPa·s, preferably from 5 mPa·s to 180 mPa·s, and more preferably from 20 mPa·s to 150 mPa·s. Viscosity can be determined by methods known to those skilled in the art, for example by using a rheometer (Netzsch Kinexus Pro+) equipped with a plate / plate geometry (60 mm diameter) and a 1 mm gap.

[0131] The density of liquid or reconstituted liquid formulations can be in the range of 1.02 g / L to 1.2 g / L, preferably 1.03 g / L to 1.25 g / L, and more preferably 1.05 g / L to 1.25 g / L.

[0132] The pH of liquid or reconstituted liquid formulations can be in the range of 7 to 8, preferably 7 to 7.5.

[0133] Formula foods preferably have a neutral flavor and may optionally be flavored with flavorings such as vanilla. Flavorings are generally only used in compositions for children over 6 months of age. Therefore, when formula foods are used for infants under 6 months of age, the formula foods are preferably flavor-free.

[0134] When in liquid form, the formulated food may have a calorific density of 0.6 kcal / mL to 3.0 kcal / mL. Preferably, when in liquid form, the formulated food may have a calorific density of 0.6 kcal / mL to 2.0 kcal / mL, more preferably 0.6 kcal / mL to 1.0 kcal / mL.

[0135] The formulated food contains the protein sources described in detail below. The protein may be present in amounts from 1 g / 100 mL to 15 g / 100 mL, preferably from 1 g / 100 mL to 10 g / 100 mL.

[0136] Formulated foods preferably have an amino acid balance that meets the minimum requirements in Table 36 of “Protein and Amino Acid Requirements in Human Nutrition WHO / FAO Consultation 2007”. For infants under 1 year of age, this includes at least: 20 mg / g His, 32 mg / g Ile, 66 mg / g Leu, 57 mg / g Lys, 28 mg / g sulfur-containing amino acids (Cys+Met), 52 mg / g aromatic amino acids (Phe+Trp+Tyr), 31 mg / g Thr, 8.5 mg / g Trp, and 43 mg / g Val. For children under 2 years of age, this includes at least: 18 mg / g His, 31 mg / g Ile, 63 mg / g Leu, 52 mg / g Lys, 26 mg / g sulfur-containing amino acids (Cys+Met), 46 mg / g aromatic amino acids (Phe+Trp+Tyr), 27 mg / g Thr, 7.4 mg / g Trp, and 42 mg / g Val.

[0137] Formulated foods may contain lipid sources. Lipids may be derived from animal, plant, and / or microbial sources. Preferably, the lipids comprise fats selected from the group consisting of: milk fat, sunflower oil, rapeseed oil, low-erucic acid rapeseed oil, safflower oil, canola oil, olive oil, coconut oil, palm kernel oil, soybean oil, fish oil, palmitoleic acid, high-oleic sunflower oil, and high-oleic safflower oil, as well as microbially fermented oils containing long-chain polyunsaturated fatty acids. Preferably, the fats comprise docosahexaenoic acid (DHA) and / or arachidonic acid (RAA).

[0138] Formulated foods may contain a source of digestible carbohydrates. Preferred digestible carbohydrates are selected from the group consisting of: lactose, glucose, sucrose, fructose, galactose, maltose, starch, and maltodextrin.

[0139] Formulated foods may contain vitamin sources. Vitamins may include vitamin A, vitamin D3, vitamin E, vitamin C, vitamin K, thiamine (B1), riboflavin (B2), niacin (B3), vitamin B6, folic acid, vitamin B12, biotin, and / or pantothenic acid. Preferably, the vitamin source includes vitamin A, vitamin D3, vitamin E, vitamin C, vitamin K, thiamine (B1), riboflavin (B2), niacin (B3), vitamin B6, folic acid, vitamin B12, biotin, and pantothenic acid.

[0140] Formulated foods may contain mineral sources. These minerals may include sodium, potassium, chlorine, fluorine, calcium, phosphorus, magnesium, iron, copper, zinc, manganese, iodine, molybdenum, selenium, and / or chromium. Preferably, the mineral sources include sodium, potassium, chlorine, fluorine, calcium, phosphorus, magnesium, iron, copper, zinc, manganese, iodine, molybdenum, selenium, and chromium.

[0141] Formulated foods preferably contain protein, fat, carbohydrates, vitamins, and minerals. More preferably, formulated foods are complete formulated foods.

[0142] Formula foods may contain other nutrients selected from the following groups: choline, taurine, L-carnitine, and inositol.

[0143] Formulated foods may contain other substances selected from the group consisting of prebiotics, probiotics, fiber, and / or nucleotides that have beneficial effects.

[0144] Formulated foods may contain thickeners. Preferably, the thickener is selected from the group consisting of guar gum, locust bean gum, xanthan gum, and pectin. More preferably, the thickener is xanthan gum.

[0145] Formulated foods may contain additives. Preferably, the additives are selected from the group consisting of starch and carrageenan.

[0146] Formulated foods may contain emulsifiers. Preferably, the emulsifier is selected from the group consisting of lecithin, monoglycerides and diglycerides, as well as citrates and fatty acid esters of glycerol. More preferably, the emulsifier is monoglyceride and diglyceride.

[0147] Formulated foods may contain acidity regulators. Preferably, the acidity regulators are selected from the group consisting of: sodium bicarbonate, sodium carbonate, potassium hydroxide, potassium bicarbonate, potassium carbonate, calcium hydroxide, L(+) lactic acid, citric acid, sodium dihydrogen citrate, trisodium citrate, potassium citrate, sodium dihydrogen phosphate, disodium hydrogen phosphate, trisodium phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, and tripotassium phosphate.

[0148] Formulated foods may contain antioxidants. Preferably, the antioxidants are selected from the group consisting of tocopherols and ascorbyl palmitate.

[0149] Formula foods can be follow-up formula or infant formula, or preferred infant formula.

[0150] Infant formula

[0151] This infant formula is intended for use by weaned infants who do not require formula to obtain complete nutrition. Preferably, this infant formula provides 1.0g / 100kcal to 3.5g / 100kcal of protein, 3.0g / 100kcal to 8.0g / 100kcal of fat, and 6.0g / 100kcal to 20.0g / 100kcal of digestible carbohydrates. Since this infant formula may be intended for specific medical purposes, it more preferably provides 1.8g / 100kcal to 3.0g / 100kcal of protein, 4.4g / 100kcal to 6.0g / 100kcal of fat, and 9.0g / 100kcal to 14.0g / 100kcal of digestible carbohydrates.

[0152] Infant formula can be in the form of liquid, reconfigurable powder, or scoopable food. Preferably, infant formula is in the form of liquid or reconfigurable powder (e.g., it can be administered to the infant in liquid form via a bottle with a nipple). More preferably, infant formula is liquid. Even more preferably, infant formula is a storage-stable liquid. Storage-stable liquid infant formula is preferably storage-stable for at least 3 months, preferably at least 6 months, more preferably at least 9 months, and most preferably at least 1 year. Storage-stable liquids are typically stored in sealed containers.

[0153] Liquid infant formula can have an energy density of 60 kcal / 100 mL to 75 kcal / 100 mL.

[0154] Protein sources typically provide 7% to 15% of the total calories in infant formula. Preferably, liquid infant formula contains 9% to 13% of the total calories from protein sources. More preferably, liquid infant formula contains 10% to 12% of the total calories from protein sources.

[0155] The protein concentration in infant formula is determined by the sum of protein, peptides, and free amino acids. Based on dry weight, infant formula preferably contains 10% to 20% by weight of protein, more preferably 12% to 19% by weight, and even more preferably 14% to 18% by weight. Based on liquid or reconstituted infant formula, infant formula preferably contains 1g protein / 100mL to 2.5g protein / 100mL, more preferably 1.2g / 100mL to 2.3g / 100mL, and even more preferably 1.5g / 100mL to 2.1g / 100mL.

[0156] Protein sources

[0157] Formulated foods contain a specific ratio of GMP and a mixture of free amino acids as a protein source. The protein fraction includes all proteins, peptides, and amino acids present in the formulated food.

[0158] The formulated food may contain GMP and free amino acids in a weight ratio of 1:4 to 4:1. Preferably, the formulated food contains GMP and free amino acids in a weight ratio of 1:3 to 3:1. More preferably, the formulated food contains GMP and free amino acids in a weight ratio of 1:2 to 2:1. In one embodiment, the formulated food contains GMP and free amino acids in a weight ratio of about 1:1. In a preferred embodiment, the protein fraction consists of a mixture of GMP and free amino acids.

[0159] For infant formula, a lower ratio of GMP to free amino acids is advantageous; therefore, a GMP to free amino acid ratio of 1:4 to 1:2 by weight is particularly preferred. Despite the high proportion of free amino acids, these infant formulas have a neutral taste when combined with the free amino acid mixtures described below.

[0160] Therefore, in a fourth general embodiment, the present invention provides a complete infant formula for dietary management of PKU or tyrosinemia, the complete infant formula comprising complete GMP and free amino acids, wherein the GMP and free amino acids are present in a ratio of 1:4 to 4:1, preferably 1:4 to 3:1, more preferably 1:4 to 2:1, more preferably 1:4 to 1:2, and most preferably 1:3 to 1:2 by weight.

[0161] Complete infant formula is particularly effective for dietary management of PKU or tyrosinemia when the free amino acids are based on a mixture of free amino acids described below.

[0162] Free amino acid mixture

[0163] It is well known that free amino acids can impart bitter and / or sour tastes to formula foods and other foods. The specific amino acid blends used in the infant formula described above and below unexpectedly exhibit a neutral flavor.

[0164] Therefore, in a fifth general embodiment, the present invention provides a mixture of free amino acids comprising Arg, Asp+Asn, Cys, Gly, His, Ile, Leu, Lys, Met, Trp, and Val, and optionally Tyr, wherein the mixture of free amino acids contains less than 0.1% by weight of any one of Ala, Gln, Glu, Pro, Phe, Ser, or Thr.

[0165] Mixtures of free amino acids can be used in the formulated foods described above and below.

[0166] In a preferred embodiment, the mixture of free amino acids comprises, by weight percentage of the total free amino acids in the mixture: Arg (9 wt% to 13 wt%), Asp+Asn (8 wt% to 12 wt%), Cys (2 wt% to 6 wt%), Gly (12 wt% to 16 wt%), His (4 wt% to 8 wt%), Ile (2 wt% to 6 wt%), Leu (13 wt% to 17 wt%), Lys (5 wt% to 9 wt%), Met (0.5 wt% to 4 wt%), Trp (1 wt% to 5 wt%), Val (5 wt% to 9 wt%), and Tyr (13 wt% to 17 wt%). This mixture of free amino acids is particularly suitable for use with GMP (preferably in a weight ratio of 1:4 to 4:1, more preferably 1:4 to 3:1, more preferably 1:4 to 2:1, more preferably 1:4 to 1:2, and most preferably 1:3 to 1:2) to produce infant formula, preferably for dietary management of PKU.

[0167] In a more preferred embodiment, the mixture of free amino acids comprises, by weight percentage of the total free amino acids in the mixture: Arg (10 wt% to 12 wt%), Asp+Asn (9 wt% to 11 wt%), Cys (3 wt% to 5 wt%), Gly (13 wt% to 15 wt%), His (5 wt% to 7 wt%), Ile (3 wt% to 5 wt%), Leu (14 wt% to 16 wt%), Lys (6 wt% to 8 wt%), Met (1 wt% to 3 wt%), Trp (2 wt% to 4 wt%), Val (6 wt% to 8 wt%), and Tyr (14 wt% to 16 wt%). This mixture of free amino acids is particularly suitable for use with GMP (preferably in a weight ratio of 1:4 to 4:1, more preferably 1:4 to 3:1, more preferably 1:4 to 2:1, more preferably 1:4 to 1:2, and most preferably 1:3 to 1:2) to produce infant formula, preferably for dietary management of PKU.

[0168] In another preferred embodiment, the mixture of free amino acids comprises, by weight percentage of the total free amino acids in the mixture: Arg (11 wt% to 15 wt%), Asp+Asn (10 wt% to 14 wt%), Cys (2 wt% to 6 wt%), Gly (15 wt% to 19 wt%), His (5 wt% to 9 wt%), Ile (3 wt% to 7 wt%), Leu (16 wt% to 20 wt%), Lys (6 wt% to 10 wt%), Met (0.5 wt% to 4 wt%), Trp (2 wt% to 6 wt%), and Val (7 wt% to 11 wt%). This mixture of free amino acids is particularly suitable for use with GMP (preferably in a weight ratio of 1:4 to 4:1, more preferably 1:4 to 3:1, more preferably 1:4 to 2:1, more preferably 1:4 to 1:2, and most preferably 1:3 to 1:2) to produce infant formula, and is preferably used for dietary management of tyrosinemia.

[0169] In another preferred embodiment, the mixture of free amino acids comprises, by weight percentage of the total free amino acids in the mixture: Arg (12 wt% to 14 wt%), Asp+Asn (11 wt% to 13 wt%), Cys (3 wt% to 5 wt%), Gly (16 wt% to 18 wt%), His (6 wt% to 8 wt%), Ile (4 wt% to 6 wt%), Leu (17 wt% to 19 wt%), Lys (7 wt% to 9 wt%), Met (1 wt% to 3 wt%), Trp (3 wt% to 5 wt%), and Val (8 wt% to 10 wt%). This mixture of free amino acids is particularly suitable for use with GMP (preferably in a weight ratio of 1:4 to 4:1, more preferably 1:4 to 3:1, more preferably 1:4 to 2:1, more preferably 1:4 to 1:2, and most preferably 1:3 to 1:2) to produce infant formula, and is preferably used for dietary management of tyrosinemia.

[0170] In the extreme case, the mixture of free amino acids can consist of the amino acids described above, such that less than 0.2% by weight of any other single amino acid may be present.

[0171] Mixtures of free amino acids can be used in formulated foods and dietary interventions / management as described above and below.

[0172] C. Preparations

[0173] Storage-stable liquid and solid infant formula suitable for children under 1 year old

[0174] Table 1: Ingredients for liquid infant formula (or powdered infant formula derived therefrom) according to the present invention The batch production of the dried components is shown below. :

[0175]

[0176] Powdered infant formula can be produced by mixing the ingredients listed above using methods known in the art. If wet mixing is used, it can be dried for use. To produce liquid infant formula, the ingredients or powdered infant formula (10g to 20g, preferably 13g to 15g) are reconstituted in water (100mL) and shaken to form a homogeneous liquid emulsion. Optionally, the emulsion can be pasteurized (e.g., at 86°C for 30 seconds). The emulsion can be sterilized (e.g., UHT sterilized at 142.5°C for 5 seconds) to form a storage-stable liquid emulsion that, once packaged, is stable for at least 9 months, has a neutral flavor, a consistency of milk to single cream, and a density of about 1.05g / L. 13.4g of the mixed ingredients listed in Table 1 are reconstituted (13.4% solids; 86.6% water) to produce the liquid infant formula in Table 2.

[0177] Table 2: Examples of liquid infant formula foods according to the present invention are shown below. :

[0178]

[0179]

[0180] The final sterilized product has a pH of 7.1 to 7.2, a density of 1.03, and a viscosity of 15 mPa·s to 35 mPa·s (10s). -1 (@20℃).

[0181] The ingredients or powdered infant formula are diluted in water at amounts of 10 g / 100 mL to 20 g / 100 mL, preferably 13 g / 100 mL to 15 g / 100 mL, homogenized, and sterilized (e.g., by direct steam injection). Alternatively, the powdered formula can be reconstituted for direct use. Liquid infant formula can be packaged in sterile containers (stable for up to 1 year) or dried (e.g., spray-dried) and packaged in sterile containers (stable for up to 2 years) for reconstitution as needed. Liquid infant formula has a neutral flavor, a consistency from milk to single cream, and a density of approximately 1.05 g / L.

[0182] The infant formula contains 38% by weight GMP protein and 62% by weight free amino acid protein. The final amino acid profile (for the combined GMP and free amino acids) is as follows: Ala (2.3%), Arg (7.2%), Asp+Asn (9.3%), Cys (2.4%), Glu+Gln (7.1%), Gly (9.4%), His (3.8%), Ile (6.7%), Leu (10.4%), Lys (6.5%), Met (1.8%), Pro (4.4%), Ser (2.8%), Thr (6.3%), Trp (2.1%), Tyr (9.8%), Val (7.7%), and Phe (0.1%).

[0183] By modifying amino acids to minimize tyrosine, equivalent formulated foods suitable for individuals or patients with PKU and / or tyrosinemia can be obtained.

[0184] D. Clinical trials

[0185] Research Design

[0186] This is a two-part study conducted on full-term infants diagnosed with PKU and identified through newborn screening. Infants were recruited from specialized phenylketonuria and tyrosinemia centers. Inclusion criteria included: infants diagnosed with PKU through newborn screening and receiving ongoing low-protein diets supplemented with phenylalanine-free and / or tyrosine-free infant amino acid formula. Infants <4 weeks or >1 year old, diagnosed with hyperphenylalaninemia (untreated phenylalanine blood concentration <360 μmol / L) or mild tyrosinemia (untreated phenylalanine blood concentration <600 μmol / L), or with comorbidities such as diabetes were excluded. Infants who had begun eating solid foods were included in the study.

[0187] Part I: A 28-day short-term acceptability and tolerability study in which infants replaced their daily dose of regular infant amino acid formula (e.g., PKU Anamix Infant: Nutricia, or PKU Start: Vitaflo) with the same amount of study formula (based on the storage-stable liquid infant formulas for children under 1 year of age in Table 2). Demographic data of subjects were recorded at baseline, including PKU classification based on pre-treatment phenylalanine blood levels (classical PKU [>1200 μmol / L], moderate PKU [600 μmol / L to 1200 μmol / L], or mild PKU [360 μmol / L to 600 μmol / L]), tyrosinemia classification based on pre-treatment tyrosine blood levels (classical tyrosinemia [>1200 μmol / L], moderate tyrosinemia [600 μmol / L to 1200 μmol / L], or mild tyrosinemia [360 μmol / L to 600 μmol / L]), infant gestational age, sex, race, relevant medical history, and any concomitant medications. Information regarding routine infant amino acid formula (dosage, type, daily volume, and frequency of daily feedings), source and amount of natural protein (breast milk or standard infant formula), and the time of initiation of solid food intake was recorded prior to baseline. During the pre-baseline period and Part I (28-day study), parents / caregivers completed daily questionnaires to record gastrointestinal tolerance / intolerance: vomiting, regurgitation, abdominal discomfort or colic symptoms, flatulence, daily bowel movement frequency and characteristics [loose, soft, hard], any feeding difficulties and concomitant medications, and the occurrence of disease symptoms. At baseline and week 4, the most recent three retrospective blood phenylalanine and / or tyrosine concentrations, body weight, length, dietary energy, and total protein intake were collected. At the end of week 4, parents described the ease of preparation and solubility characteristics of the study formula.

[0188] Part II: An extended follow-up study will be conducted on infants who continue using the investigational formula for 12 months or until the investigational formula is discontinued. At each outpatient visit, a dietitian will record dietary prescriptions (energy, total protein, and protein equivalents from protein substitutes) and anthropometric measurements (weight and length). Routine phenylalanine and / or tyrosine blood concentrations will also be recorded (twice weekly / once weekly). Parents / caregivers will report any relevant medications and gastrointestinal problems.

[0189] The prevalence of the symptoms described above was also monitored throughout the trial.

[0190] Research on formulated foods

[0191] The research formula (based on the storage-stable liquid infant formulas for children under 1 year old in Table 2) is a GMP-compliant, amino acid-based powdered phenylalanine-free infant formula containing essential and non-essential amino acids (but low phenylalanine levels), carbohydrates, fats, vitamins, minerals, trace elements, and other nutrients described in Table 1. It is diluted in water at 13 g / 100 mL to 15 g / 100 mL, homogenized, pasteurized, and sterilized. It is provided as a storage-stable ready-to-drink formula with 2 g / 100 mL of protein.

[0192] Stool characteristics, gastrointestinal symptoms and medications

[0193] Data on gastrointestinal symptoms (constipation, abdominal discomfort, colic, vomiting, regurgitation, flatulence), any feeding difficulties, and concomitant medications were collected at each outpatient visit during the three days prior to baseline, the 28-day short-term evaluation period, and the 12-month follow-up period. Parents / caregivers recorded stool characteristics (three categories: soft, loose, and hard) during the pre-baseline and 28-day short-term evaluation periods.

[0194] Anthropometry

[0195] Height was measured using the Holtain Harpenden Infant Measurement System (Holtain Ltd., Crymych, UK), head circumference was measured using a measuring tape, and weight was measured on a calibrated electronic infant scale (Seca, Medical Measuring Systems and Scales, Model 875, UK). Weight was measured to the nearest 0.1g, and height and circumference were measured to the nearest 0.1cm. Data were converted into z-scores of weight, height, head circumference, and body mass index (BMI) based on age, according to WHO / UK growth definitions (WMGRS Group (2006) Acta Paediatrica 95, 76-85).

[0196] Phenylalanine blood levels

[0197] Blood spots were collected at home by caregivers using Perkin Elmer 226 filter cards (UK Standard NBS) on an empty morning fasting heel for phenylalanine and / or tyrosine detection. Fasting hours depended on the number of nighttime feedings and feeding intervals. All caregivers received blood spot training as a specialist nurse. All blood spot samples were sent to the hospital laboratory via first-class mail for phenylalanine and / or tyrosine analysis. The cards were of standard thickness, and phenylalanine and / or tyrosine blood concentrations were calculated using MS / MS tandem mass spectrometry on a 3.2 mm punch.

[0198] Dietary assessment

[0199] Dietary intake was determined using a 24-hour retrospective method, recorded at baseline, week 4, and at each outpatient visit during the 12-month long-term follow-up period. Prescribed energy, total protein, natural protein, and protein equivalents from protein substitutes were assessed using computer software, such as the nutritional analysis program Nutritics (Nutritics, R.Edition (v5.09) [computer software]).

[0200] Symptoms and effects

[0201] The prevalence of the symptoms described above was also monitored throughout the trial.

[0202] Statistical analysis

[0203] Due to the rarity of the disease and the exploratory nature of the study, no sample size calculation was performed. Only descriptive statistics are used to present the results of this study.

[0204] Ethical Approval

[0205] This study will be approved by a recognized research ethics committee. Written informed consent will be obtained from all participants from at least one caregiver with parental responsibilities.

[0206] result

[0207] It is predicted that formulated foods will be well tolerated, help maintain good metabolic control, and contribute to the normal growth of infants with PKU and hypertyrosinemia. Good metabolic control is predicted to lead to good dietary management of the disease and its symptoms.

[0208] Embodiments of the present invention :

[0209] Implementation Scheme 1. A formula food for children under 2 years of age, the formula food containing complete casein glycomacropeptide and free amino acids, the formula food being used for dietary management of phenylketonuria or tyrosinemia in individuals in need.

[0210] Implementation Scheme 2. A formulated food for the purpose according to Implementation Scheme 1, wherein the dietary management results in good metabolic control, normal growth and / or improved gastrointestinal tolerance.

[0211] Implementation Scheme 3. A formulated food for the purpose according to Implementation Scheme 1, wherein the dietary management results in good metabolic control, normal growth and improved gastrointestinal tolerance.

[0212] Implementation Scheme 4. A formulated food for the purpose according to Implementation Scheme 2 or Implementation Scheme 3, wherein the good metabolic control achieves a phenylalanine blood concentration of 120 μmol / L to 360 μmol / L in individuals with phenylketonuria or a tyrosine blood concentration of 200 μmol / L to 400 μmol / L in individuals with tyrosinemia.

[0213] Implementation Scheme 5. A formulated food for the purpose according to Implementation Scheme 2 or Implementation Scheme 3, wherein the normal growth results in maintaining, preferably increasing, age-specific height, age-specific weight and / or age-specific BMI.

[0214] Implementation Scheme 6. A formulated food for the purpose according to Implementation Scheme 2 or Implementation Scheme 3, wherein the improved gastrointestinal tolerance is selected from the group consisting of: reduced vomiting, reduced regurgitation, reduced abdominal discomfort or colic symptoms, reduced flatulence, reduced proportion of loose or hard stools, and / or reduced feeding difficulties.

[0215] Implementation Scheme 7. A formulated food for the purpose described in any of the foregoing implementation schemes, wherein the purpose is for dietary management of phenylketonuria.

[0216] Implementation Scheme 8. A formulated food for the purpose according to Implementation Scheme 7, wherein the dietary management results in the prevention of one or more symptoms selected from the group consisting of or a reduction in the severity or frequency of one or more symptoms selected from the group consisting of: intellectual disability, developmental milestone delay, hyperactivity, seizures, eczema, mild body odor, and less pigmentation (e.g., less pigmentation of the eyes, hair, and / or skin).

[0217] Implementation Scheme 9. A formulated food for the purpose according to Implementation Scheme 8, wherein the symptom is intellectual disability.

[0218] Implementation Scheme 10. A formulated food for the purpose according to Implementation Scheme 8, wherein the symptom is a delay in one or more developmental milestones, preferably anthropometric milestones, including age-specific length, age-specific weight and / or BMI; and / or developmental milestones at 2 months, 4 months, 6 months, 9 months and / or 12 months.

[0219] Implementation Scheme 11. A formulated food for the purpose described in Implementation Scheme 8, wherein the symptom is hyperactivity.

[0220] Implementation Scheme 12. A formulated food product for the purpose described in Implementation Scheme 8, wherein the symptom is an epileptic seizure.

[0221] Implementation Scheme 13. A formulated food for the purpose described in Implementation Scheme 8, wherein the symptom is eczema.

[0222] Implementation Scheme 14. A formulated food product for the purpose described in Implementation Scheme 8, wherein the symptom is a musty body odor.

[0223] Implementation Scheme 15. A formulated food product for the purpose described in Implementation Scheme 8, wherein the symptom is mild pigmentation.

[0224] Implementation Scheme 16. A formulated food for the purpose described in any one of Implementation Schemes 1 to 6, wherein the purpose is for dietary management of tyrosinemia.

[0225] Implementation Scheme 17. A formulated food for the purpose described in Implementation Scheme 16, wherein the purpose is for dietary management of type I tyrosinemia.

[0226] Implementation Scheme 18. A formulated food for the purpose according to Implementation Scheme 17, wherein the dietary management results in the prevention of one or more symptoms selected from the group consisting of or a reduction in the severity or frequency of one or more symptoms selected from the group consisting of: hepatotoxicity, nephrotoxicity, neurotoxicity, and endocrine dysfunction.

[0227] Implementation Scheme 19. A formulated food for the purpose according to Implementation Scheme 18, wherein the symptoms are hepatotoxicity; preferably selected from the group consisting of: hemophilia-like symptoms, such as impaired coagulation, increased bruising, intra-articular hemorrhage or intracerebral hemorrhage; acute liver failure; hypoalbuminemia and hepatocellular carcinoma.

[0228] Implementation Scheme 20. A formulated food for the purpose according to Implementation Scheme 18, wherein the symptom is nephrotoxicity; preferably selected from the group consisting of: hypophosphatemic rickets; impaired renal function; renal tubular injury; and renal failure.

[0229] Implementation Scheme 21. A formulated food for the purpose according to Implementation Scheme 18, wherein the symptom is neurotoxicity; preferably selected from the group consisting of: porphyria; and peripheral neuropathy.

[0230] Implementation Scheme 22. A formulated food for the purpose according to Implementation Scheme 18, wherein the symptom is an endocrine dysfunction; preferably selected from the group consisting of: dopamine dysfunction; norepinephrine dysfunction; and thyroid hormone dysfunction.

[0231] Implementation Scheme 23. A formulated food for the purpose described in Implementation Scheme 16, wherein the purpose is for dietary management of type II tyrosinemia and / or type I tyrosinemia treated with niticinone (NTBC).

[0232] Implementation Scheme 24. A formulated food for the purpose according to Implementation Scheme 23, wherein the dietary management results in the prevention of one or more symptoms selected from the group consisting of, or a reduction in the severity or frequency of one or more symptoms selected from the group consisting of: ocular toxicity, skin toxicity, and mental disability.

[0233] Implementation Scheme 25. A formulated food product for the purpose according to Implementation Scheme 24, wherein the symptom is ocular toxicity; preferably selected from the group consisting of: epiphora; photophobia; eye pain; and congestion.

[0234] Implementation Scheme 26. A formulated food for the purpose according to Implementation Scheme 24, wherein the symptom is skin toxicity; preferably palmoplantar keratosis.

[0235] Implementation Scheme 27. A formulated food for the purpose described in Implementation Scheme 24, wherein the symptom is mental disability.

[0236] Implementation Scheme 28. A formulated food for the purpose described in Implementation Scheme 16, wherein the purpose is for dietary management of type III tyrosinemia.

[0237] Implementation Scheme 29. A formulated food for the purpose described in Implementation Scheme 28, wherein the dietary management results in the prevention of one or more symptoms selected from the group consisting of, or a reduction in the severity or frequency of one or more symptoms selected from the group consisting of: intellectual disability, seizures, and intermittent ataxia.

[0238] Implementation Scheme 30. A formulated food for the purpose described in Implementation Scheme 29, wherein the symptom is intellectual disability.

[0239] Implementation Scheme 31. A formulated food for the purpose according to Implementation Scheme 29, wherein the symptom is an epileptic seizure.

[0240] Implementation Scheme 32. A formulated food for the purpose described in Implementation Scheme 29, wherein the symptom is intermittent ataxia.

[0241] Implementation Scheme 33. A formulated food for the purpose according to any of the foregoing implementation schemes, wherein the individual is a child under 2 years of age, preferably an infant, more preferably an infant up to 6 months of age.

[0242] Implementation Scheme 34. A formulated food for the purpose according to any of the foregoing implementation schemes, wherein the dietary management lasts for at least 3 months, preferably at least 6 months, and more preferably at least 1 year.

[0243] Implementation Scheme 35. A formulated food for the purpose according to any of the foregoing implementation schemes, wherein the formulated food is in the form of a liquid, a reconfigurable powder, or a scoopable food; preferably in the form of a liquid or a reconfigurable powder.

[0244] Implementation Scheme 36. A formulated food for the purpose according to Implementation Scheme 35, wherein the formulated food is in liquid form; more preferably in the form of a storage-stable liquid; and even more preferably in the form of a packaged storage-stable liquid.

[0245] Implementation Scheme 37. A formulated food for the purpose according to Implementation Scheme 36, wherein the formulated food has a temperature of 20°C for 100 seconds. -1 Viscosity measured at a shear rate of less than 200 mPa·s, preferably from 5 mPa·s to 180 mPa·s, and more preferably from 20 mPa·s to 150 mPa·s.

[0246] Implementation Scheme 38. A formulated food for the purpose according to any one of Implementation Schemes 35 to 37, wherein the formulated food is in the form of a liquid or a scoopable food and has a density in the range of 1.02 g / L to 1.2 g / L, preferably 1.05 g / L to 1.25 g / L.

[0247] Implementation Scheme 39. A formulated food for the purpose according to any one of Implementation Schemes 35 to 38, wherein the formulated food is in the form of a liquid or a scoopable food and has a calorific density of 0.6 kcal / mL to 3.0 kcal / mL, preferably 0.6 kcal / mL to 2.0 kcal / mL, more preferably 0.6 kcal / mL to 1.0 kcal / mL.

[0248] Implementation Scheme 40. A formulated food for the purpose according to any one of Implementation Schemes 35 to 39, wherein the formulated food is in the form of a liquid or scoopable food, and the protein is present in an amount of 1 g / 100 mL to 15 g / 100 mL, preferably 1 g / 100 mL to 10 g / 100 mL.

[0249] Implementation Scheme 41. A formulated food for the purpose according to any of the foregoing implementation schemes, wherein the formulated food comprises GMP and free amino acids in a weight ratio of 1:4 to 4:1, preferably 1:3 to 3:1, more preferably 1:2 to 2:1.

[0250] Implementation Scheme 42. A formulated food for the purpose according to any of the foregoing implementation schemes, wherein the formulated food contains a lipid source, preferably the lipid source comprising fats selected from the group consisting of: milk fat, sunflower oil, rapeseed oil, low erucic acid rapeseed oil, safflower oil, rapeseed oil, olive oil, coconut oil, palm kernel oil, soybean oil, fish oil, palmitoleic acid, high oleic acid sunflower oil and high oleic acid safflower oil, and microbially fermented oils containing long-chain polyunsaturated fatty acids, more preferably the lipid source comprising docosahexaenoic acid and / or arachidonic acid.

[0251] Implementation Scheme 43. A formulated food for the purpose according to any of the foregoing implementation schemes, wherein the formulated food contains a digestible carbohydrate source, the digestible carbohydrate source preferably selected from the group consisting of: lactose, glucose, sucrose, fructose, galactose, maltose, starch and maltodextrin.

[0252] Implementation Scheme 44. A formulated food for the purpose according to any of the foregoing implementation schemes, wherein the formulated food contains a vitamin source, wherein the vitamin source preferably comprises vitamin A, vitamin D3, vitamin E, vitamin C, vitamin K, thiamine (B1), riboflavin (B2), niacin (B3), vitamin B6, folic acid, vitamin B12, biotin, and / or pantothenic acid.

[0253] Implementation Scheme 45. A formulated food for the purpose according to any of the foregoing implementation schemes, wherein the formulated food contains a mineral source, the mineral source preferably comprising sodium, potassium, chlorine, calcium, phosphorus, magnesium, iron, copper, zinc, manganese, iodine, molybdenum, selenium and / or chromium.

[0254] Implementation Scheme 46. A formulated food for the purpose according to any of the foregoing implementation schemes, wherein the formulated food comprises protein, fat, carbohydrate, vitamins and minerals.

[0255] Implementation Scheme 47. A formulated food for the purpose according to any of the foregoing implementation schemes, wherein the formulated food comprises prebiotics, probiotics, fiber and / or nucleotides; and / or choline, taurine, L-carnitine and inositol.

[0256] Implementation Scheme 48. A formulated food for the stated purpose according to any of the foregoing implementation schemes, wherein the formulated food comprises one or more thickeners, additives, emulsifiers, acidity regulators and / or antioxidants.

[0257] Implementation Scheme 49. A formulated food for the purpose according to any of the foregoing implementation schemes, wherein the formulated food is an infant formula, preferably wherein the infant formula provides 1.8g / 100kcal to 3.0g / 100kcal of protein, 4.4g / 100kcal to 6.0g / 100kcal of fat and 9.0g / 100kcal to 14.0g / 100kcal of digestible carbohydrates.

[0258] Implementation Scheme 50. An infant formula for the purpose described in Implementation Scheme 49, wherein the infant formula is a liquid and has an energy density of 60 kcal / 100 mL to 75 kcal / 100 mL.

[0259] Implementation Scheme 51. Use of complete GMP and free amino acids in the preparation of formula foods for children under 2 years of age, preferably infant formula foods, for dietary management of PKU or tyrosinemia in individuals in need.

[0260] Implementation Scheme 52. Providing a method for dietary management of PKU or tyrosinemia, the method comprising administering to individuals in need a formula food for children under 2 years of age, preferably an infant formula food, containing complete GMP and free amino acids.

[0261] Implementation Scheme 53. A complete infant formula for dietary management of PKU or tyrosinemia, the complete infant formula comprising complete GMP and free amino acids, wherein the GMP and the free amino acids are present in a ratio of 1:4 to 4:1, preferably 1:4 to 3:1, more preferably 1:4 to 2:1, more preferably 1:4 to 1:2, and most preferably 1:3 to 1:2 by weight.

[0262] Implementation Scheme 54. A mixture of free amino acids, said mixture comprising Arg, Asp+Asn, Cys, Gly, His, Ile, Leu, Lys, Met, Trp, and Val, and optionally Tyr, wherein said mixture of free amino acids contains less than 0.1% by weight of any one of Ala, Gln, Glu, Pro, Phe, Ser, or Thr.

[0263] Implementation Scheme 55. A mixture of free amino acids according to Implementation Scheme 54, the mixture comprising, by weight percentage of the total free amino acids in the mixture: Arg (9 wt% to 13 wt%), Asp + Asn (8 wt% to 12 wt%), Cys (2 wt% to 6 wt%), Gly (12 wt% to 16 wt%), His (4 wt% to 8 wt%), Ile (2 wt% to 6 wt%), Leu (13 wt% to 17 wt%), Lys (5 wt% to 9 wt%), Met (0.5 wt% to 4 wt%), Trp (1 wt% to 5 wt%), Val (5 wt% to 9 wt%), and Tyr (13 wt% to 17 wt%).

[0264] Preferred ingredients: Arg (10 wt% to 12 wt%), Asp+Asn (9 wt% to 11 wt%), Cys (3 wt% to 5 wt%), Gly (13 wt% to 15 wt%), His (5 wt% to 7 wt%), Ile (3 wt% to 5 wt%), Leu (14 wt% to 16 wt%), Lys (6 wt% to 8 wt%), Met (1 wt% to 3 wt%), Trp (2 wt% to 4 wt%), Tyr (14 wt% to 16 wt%), and Val (6 wt% to 8 wt%).

[0265] Implementation Scheme 56. A mixture of free amino acids according to Implementation Scheme 54, the mixture comprising, by weight percentage of the total free amino acids in the mixture: Arg (12 wt% to 16 wt%), Asp+Asn (10 wt% to 14 wt%), Cys (2 wt% to 6 wt%), Gly (15 wt% to 19 wt%), His (5 wt% to 9 wt%), Ile (3 wt% to 7 wt%), Leu (16 wt% to 20 wt%), Lys (6 wt% to 10 wt%), Met (0.5 wt% to 4 wt%), Trp (2 wt% to 6 wt%), and Val (7 wt% to 11 wt%).

[0266] Preferred ingredients: Arg (12 wt% to 14 wt%), Asp+Asn (11 wt% to 13 wt%), Cys (3 wt% to 5 wt%), Gly (16 wt% to 18 wt%), His (6 wt% to 8 wt%), Ile (4 wt% to 6 wt%), Leu (17 wt% to 19 wt%), Lys (7 wt% to 9 wt%), Met (1 wt% to 3 wt%), Trp (3 wt% to 5 wt%), and Val (8 wt% to 10 wt%).

[0267] Implementation Scheme 57. A complete infant formula for dietary management of PKU or tyrosinemia, said complete infant formula comprising complete GMP and free amino acids as described in Implementation Scheme 53, wherein said free amino acids consist of a mixture of free amino acids as described in any one of Implementation Schemes 54 to 56.

[0268] Implementation Scheme 58. A complete infant formula comprising complete GMP and free amino acids as described in Implementation Scheme 53, wherein the free amino acids consist of a mixture of free amino acids as described in Implementation Scheme 55, the complete infant formula being used for dietary management of phenylketonuria in individuals in need.

[0269] Implementation Scheme 59. A complete infant formula comprising complete GMP and free amino acids as described in Implementation Scheme 53, wherein the free amino acids consist of a mixture of free amino acids as described in Implementation Scheme 56, the complete infant formula being used for dietary management of tyrosinemia in individuals in need.

[0270] Implementation Scheme 60. Use of complete GMP and free amino acids in the preparation of formula foods for children under 2 years of age, preferably infant formula foods, said formula foods for dietary management of PKU or tyrosinemia in individuals in need, said formula foods being described in any one of Implementation Schemes 35 to 50, 53, 58 or 59.

[0271] Implementation Scheme 61. A method for dietary management of PKU or tyrosinemia, the method comprising administering to an individual in need a formula food for children under 2 years of age, preferably an infant formula food, containing complete GMP and free amino acids, wherein the formula food is as described in any one of Implementation Schemes 35 to 50, 53, 58 or 59.

[0272] Implementation Scheme 62. A formula food for children under 2 years of age, the formula food comprising complete casein glycomacropeptide and free amino acids, the formula food being used to treat or prevent phenylketonuria or tyrosinemia in patients in need.

[0273] Implementation Scheme 63. A formulated food for the purpose according to Implementation Scheme 62, wherein the treatment or prevention results in good metabolic control, normal growth and / or improved gastrointestinal tolerance.

[0274] Implementation Scheme 64. A formulated food for the purpose according to Implementation Scheme 62, wherein the treatment or prevention results in good metabolic control, normal growth and improved gastrointestinal tolerance.

[0275] Implementation Scheme 65. A formulated food for the purpose according to Implementation Scheme 63 or Implementation Scheme 64, wherein the good metabolic control achieves a phenylalanine blood concentration of 120 μmol / L to 360 μmol / L in patients with phenylketonuria or a tyrosine blood concentration of 200 μmol / L to 400 μmol / L in patients with tyrosinemia.

[0276] Implementation Scheme 66. A formulated food for the purpose according to Implementation Scheme 63 or Implementation Scheme 64, wherein the normal growth results in maintaining, preferably increasing, age-specific height, age-specific weight and / or age-specific BMI.

[0277] Implementation Scheme 67. A formulated food for the purpose according to Implementation Scheme 63 or Implementation Scheme 64, wherein the improved gastrointestinal tolerance is selected from the group consisting of: reduced vomiting, reduced regurgitation, reduced symptoms of abdominal discomfort or colic, reduced flatulence, reduced proportion of loose or hard stools, and / or reduced feeding difficulties.

[0278] Implementation Scheme 68. A formulated food for the purpose described in any one of the preceding Implementation Schemes 62 to 67, wherein the purpose is for the treatment or prevention of phenylketonuria.

[0279] Implementation Scheme 69. A formulated food for the purpose according to Implementation Scheme 68, wherein the treatment or prevention results in the prevention of one or more symptoms selected from the group consisting of, or a reduction in the severity or frequency of one or more symptoms selected from the group consisting of: intellectual disability, developmental milestone delay, hyperactivity, seizures, eczema, mild body odor, and less pigmentation (e.g., less pigmentation of the eyes, hair, and / or skin).

[0280] Implementation Scheme 70. A formulated food for the purpose according to Implementation Scheme 69, wherein the symptom is intellectual disability.

[0281] Implementation Scheme 71. A formulated food for the purpose according to Implementation Scheme 69, wherein the symptom is a delay in one or more developmental milestones, preferably anthropometric milestones, including age-specific length, age-specific weight and / or BMI; and / or developmental milestones at 2 months, 4 months, 6 months, 9 months and / or 12 months.

[0282] Implementation Scheme 72. A formulated food for the purpose according to Implementation Scheme 69, wherein the symptom is hyperactivity.

[0283] Implementation Scheme 73. A formulated food for the purpose according to Implementation Scheme 69, wherein the symptom is an epileptic seizure.

[0284] Implementation Scheme 74. A formulated food product for the purpose described in Implementation Scheme 69, wherein the symptom is eczema.

[0285] Implementation Scheme 75. A formulated food for the purpose according to Implementation Scheme 69, wherein the symptom is a musty body odor.

[0286] Implementation Scheme 76. A formulated food product for the purpose according to Implementation Scheme 69, wherein the symptom is mild pigmentation.

[0287] Implementation Scheme 77. A formulated food product for the purpose described in any one of Implementation Schemes 62 to 67, wherein the purpose is for the treatment or prevention of tyrosinemia.

[0288] Implementation Scheme 78. A formulated food product for the purpose described in Implementation Scheme 77, wherein the purpose is for the treatment or prevention of type I tyrosinemia.

[0289] Implementation Scheme 79. A formulated food for the purpose according to Implementation Scheme 78, wherein the treatment or prevention results in the prevention of one or more symptoms selected from the group consisting of, or a reduction in the severity or frequency of one or more symptoms selected from the group consisting of: hepatotoxicity, nephrotoxicity, neurotoxicity, and endocrine dysfunction.

[0290] Implementation Scheme 80. A formulated food for the purpose according to Implementation Scheme 79, wherein the symptoms are hepatotoxicity; preferably selected from the group consisting of: hemophilia-like symptoms, such as impaired coagulation, increased bruising, intra-articular hemorrhage or intracerebral hemorrhage; acute liver failure; hypoalbuminemia and hepatocellular carcinoma.

[0291] Implementation Scheme 81. A formulated food for the purpose according to Implementation Scheme 79, wherein the symptom is nephrotoxicity; preferably selected from the group consisting of: hypophosphatemic rickets; impaired renal function; renal tubular injury; and renal failure.

[0292] Implementation Scheme 82. A formulated food for the purpose according to Implementation Scheme 79, wherein the symptom is neurotoxicity; preferably selected from the group consisting of: porphyria; and peripheral neuropathy.

[0293] Implementation Scheme 83. A formulated food for the purpose according to Implementation Scheme 79, wherein the symptom is an endocrine dysfunction; preferably selected from the group consisting of: dopamine dysfunction; norepinephrine dysfunction; and thyroid hormone dysfunction.

[0294] Implementation Scheme 84. A formulated food product for the purpose described in Implementation Scheme 77, wherein the purpose is for the treatment or prevention of type II tyrosinemia and / or type I tyrosinemia treated with niticinone (NTBC).

[0295] Implementation Scheme 85. A formulated food for the purpose according to Implementation Scheme 84, wherein the treatment or prevention results in the prevention or reduction of the severity or frequency of one or more symptoms selected from the group consisting of: ocular toxicity, skin toxicity, and mental disability.

[0296] Implementation Scheme 86. A formulated food for the purpose according to Implementation Scheme 85, wherein the symptom is ocular toxicity; preferably selected from the group consisting of: epiphora; photophobia; eye pain; and congestion.

[0297] Implementation Scheme 87. A formulated food for the purpose according to Implementation Scheme 85, wherein the symptom is skin toxicity; preferably palmoplantar keratosis.

[0298] Implementation Scheme 88. A formulated food for the purpose described in Implementation Scheme 85, wherein the symptom is mental disability.

[0299] Implementation Scheme 89. A formulated food product for the purpose described in Implementation Scheme 77, wherein the purpose is for the treatment or prevention of type III tyrosinemia.

[0300] Implementation Scheme 90. A formulated food for the purpose according to Implementation Scheme 89, wherein the treatment or prevention results in the prevention or reduction of the severity or frequency of one or more symptoms selected from the group consisting of: intellectual disability, seizures, and intermittent ataxia.

[0301] Implementation Scheme 91. A formulated food for the purpose according to Implementation Scheme 90, wherein the symptom is intellectual disability.

[0302] Implementation Scheme 92. A formulated food product for the purpose described in Implementation Scheme 90, wherein the symptom is an epileptic seizure.

[0303] Implementation Scheme 93. A formulated food for the purpose according to Implementation Scheme 90, wherein the symptom is intermittent ataxia.

[0304] Implementation Scheme 94. A formulated food for the purpose according to any of the foregoing implementation schemes, wherein the patient is a child under 2 years of age, preferably an infant, more preferably an infant up to 6 months of age.

[0305] Implementation Scheme 95. A formulated food for the purpose according to any of the foregoing implementation schemes, wherein the treatment or prevention lasts for at least 3 months, preferably at least 6 months, more preferably at least 1 year.

[0306] Implementation Scheme 96. A formulated food for the purpose according to any of the foregoing implementation schemes, wherein the formulated food is in the form of a liquid, a reconfigurable powder, or a scoopable food; preferably in the form of a liquid or a reconfigurable powder.

[0307] Implementation Scheme 97. A formulated food for the purpose according to Implementation Scheme 96, wherein the formulated food is in liquid form; more preferably in the form of a storage-stable liquid; and even more preferably in the form of a packaged storage-stable liquid.

[0308] Implementation Scheme 98. A formulated food for the purpose according to Implementation Scheme 97, wherein the formulated food has a temperature of 20°C for 100 seconds. -1 Viscosity measured at a shear rate of less than 200 mPa·s, preferably from 5 mPa·s to 180 mPa·s, and more preferably from 20 mPa·s to 150 mPa·s.

[0309] Implementation Scheme 99. A formulated food for the purpose according to any one of Implementation Schemes 96 to 98, wherein the formulated food is in the form of a liquid or a scoopable food and has a density in the range of 1.02 g / L to 1.2 g / L, preferably 1.05 g / L to 1.25 g / L.

[0310] Implementation Scheme 100. A formulated food for the purpose according to any one of Implementation Schemes 96 to 99, wherein the formulated food is in the form of a liquid or a scoopable food and has a calorific density of 0.6 kcal / mL to 3.0 kcal / mL, preferably 0.6 kcal / mL to 2.0 kcal / mL, more preferably 0.6 kcal / mL to 1.0 kcal / mL.

[0311] Implementation Scheme 101. A formulated food for the purpose according to any one of Implementation Schemes 96 to 100, wherein the formulated food is in the form of a liquid or scoopable food, and wherein the protein is present in an amount of 1 g / 100 mL to 15 g / 100 mL, preferably 1 g / 100 mL to 10 g / 100 mL.

[0312] Implementation Scheme 102. A formulated food for the purpose according to any of the foregoing implementation schemes, wherein the formulated food comprises GMP and free amino acids in a weight ratio of 1:4 to 4:1, preferably 1:3 to 3:1, and more preferably 1:2 to 2:1.

[0313] Implementation Scheme 103. A formulated food for the purpose according to any of the foregoing implementation schemes, wherein the formulated food contains a lipid source, preferably the lipid source comprising fats selected from the group consisting of: milk fat, sunflower oil, rapeseed oil, low erucic acid rapeseed oil, safflower oil, rapeseed oil, olive oil, coconut oil, palm kernel oil, soybean oil, fish oil, palmitoleic acid, high oleic acid sunflower oil and high oleic acid safflower oil, and microbially fermented oils containing long-chain polyunsaturated fatty acids, more preferably the lipid source comprising docosahexaenoic acid and / or arachidonic acid.

[0314] Implementation Scheme 104. A formulated food for the purpose according to any of the foregoing implementation schemes, wherein the formulated food contains a digestible carbohydrate source, the digestible carbohydrate source preferably selected from the group consisting of: lactose, glucose, sucrose, fructose, galactose, maltose, starch and maltodextrin.

[0315] Implementation Scheme 105. A formulated food for the purpose according to any of the foregoing implementation schemes, wherein the formulated food contains a vitamin source, wherein the vitamin source preferably comprises vitamin A, vitamin D3, vitamin E, vitamin C, vitamin K, thiamine (B1), riboflavin (B2), niacin (B3), vitamin B6, folic acid, vitamin B12, biotin, and / or pantothenic acid.

[0316] Implementation Scheme 106. A formulated food for the purpose according to any of the foregoing implementation schemes, wherein the formulated food contains a mineral source, the mineral source preferably comprising sodium, potassium, chlorine, calcium, phosphorus, magnesium, iron, copper, zinc, manganese, iodine, molybdenum, selenium and / or chromium.

[0317] Implementation Scheme 107. A formulated food for the purpose according to any of the foregoing implementation schemes, wherein the formulated food comprises protein, fat, carbohydrate, vitamins and minerals.

[0318] Implementation Scheme 108. A formulated food for the purpose according to any of the foregoing implementation schemes, wherein the formulated food comprises prebiotics, probiotics, fiber and / or nucleotides; and / or choline, taurine, L-carnitine and inositol.

[0319] Implementation Scheme 109. A formulated food for the stated purpose according to any of the foregoing implementation schemes, wherein the formulated food comprises one or more thickeners, additives, emulsifiers, acidity regulators and / or antioxidants.

[0320] Implementation Scheme 110. A formulated food for the purpose according to any of the foregoing implementation schemes, wherein the formulated food is an infant formula, preferably wherein the infant formula provides 1.8g / 100kcal to 3.0g / 100kcal of protein, 4.4g / 100kcal to 6.0g / 100kcal of fat and 9.0g / 100kcal to 14.0g / 100kcal of digestible carbohydrates.

[0321] Implementation Scheme 111. An infant formula for the purpose described in Implementation Scheme 110, wherein the infant formula is a liquid and has an energy density of 60 kcal / 100 mL to 75 kcal / 100 mL.

[0322] Implementation Scheme 112. Use of complete GMP and free amino acids in the preparation of a medicament, preferably an infant formula, for use in the treatment or prevention of PKU or tyrosinemia in patients in need.

[0323] Implementation Scheme 113. A method for treating or preventing PKU or tyrosinemia, the method comprising administering to patients in need a formula food for children under 2 years of age, preferably an infant formula food, containing complete GMP and free amino acids.

[0324] Implementation Scheme 114. A complete infant formula for the treatment or prevention of PKU or tyrosinemia, said complete infant formula comprising complete GMP and free amino acids, wherein said GMP and said free amino acids are present in a ratio of 1:4 to 4:1, preferably 1:4 to 3:1, more preferably 1:4 to 2:1, more preferably 1:4 to 1:2, and most preferably 1:3 to 1:2 by weight.

[0325] Implementation Scheme 115. A mixture of free amino acids, said mixture comprising Arg, Asp+Asn, Cys, Gly, His, Ile, Leu, Lys, Met, Trp and Val and optionally Tyr, wherein said mixture of free amino acids contains less than 0.1% by weight of any one of Ala, Gln, Glu, Pro, Phe, Ser or Thr.

[0326] Implementation Scheme 116. A mixture of free amino acids according to Implementation Scheme 115, the mixture comprising, by weight percentage of the total free amino acids in the mixture: Arg (9 wt% to 13 wt%), Asp + Asn (8 wt% to 12 wt%), Cys (2 wt% to 6 wt%), Gly (12 wt% to 16 wt%), His (4 wt% to 8 wt%), Ile (2 wt% to 6 wt%), Leu (13 wt% to 17 wt%), Lys (5 wt% to 9 wt%), Met (0.5 wt% to 4 wt%), Trp (1 wt% to 5 wt%), Val (5 wt% to 9 wt%), and Tyr (13 wt% to 17 wt%).

[0327] Preferred ingredients: Arg (10 wt% to 12 wt%), Asp+Asn (9 wt% to 11 wt%), Cys (3 wt% to 5 wt%), Gly (13 wt% to 15 wt%), His (5 wt% to 7 wt%), Ile (3 wt% to 5 wt%), Leu (14 wt% to 16 wt%), Lys (6 wt% to 8 wt%), Met (1 wt% to 3 wt%), Trp (2 wt% to 4 wt%), Tyr (14 wt% to 16 wt%), and Val (6 wt% to 8 wt%).

[0328] Implementation Scheme 117. A mixture of free amino acids according to Implementation Scheme 115, the mixture comprising, by weight percentage of the total free amino acids in the mixture: Arg (12 wt% to 16 wt%), Asp+Asn (10 wt% to 14 wt%), Cys (2 wt% to 6 wt%), Gly (15 wt% to 19 wt%), His (5 wt% to 9 wt%), Ile (3 wt% to 7 wt%), Leu (16 wt% to 20 wt%), Lys (6 wt% to 10 wt%), Met (0.5 wt% to 4 wt%), Trp (2 wt% to 6 wt%), and Val (7 wt% to 11 wt%).

[0329] Preferred ingredients: Arg (12 wt% to 14 wt%), Asp+Asn (11 wt% to 13 wt%), Cys (3 wt% to 5 wt%), Gly (16 wt% to 18 wt%), His (6 wt% to 8 wt%), Ile (4 wt% to 6 wt%), Leu (17 wt% to 19 wt%), Lys (7 wt% to 9 wt%), Met (1 wt% to 3 wt%), Trp (3 wt% to 5 wt%), and Val (8 wt% to 10 wt%).

[0330] Implementation Scheme 118. A complete infant formula for the treatment or prevention of PKU or tyrosinemia, said complete infant formula comprising complete GMP and free amino acids as described in Implementation Scheme 114, wherein said free amino acids consist of a mixture of free amino acids as described in any one of Implementation Schemes 115 to 117.

[0331] Implementation Scheme 119. A complete infant formula comprising complete GMP and free amino acids as described in Implementation Scheme 114, wherein the free amino acids consist of a mixture of free amino acids as described in Implementation Scheme 116, the complete infant formula being used to treat or prevent phenylketonuria in patients in need.

[0332] Implementation Scheme 120. A complete infant formula comprising complete GMP and free amino acids as described in Implementation Scheme 114, wherein the free amino acids consist of a mixture of free amino acids as described in Implementation Scheme 117, the complete infant formula being used to treat or prevent tyrosinemia in patients in need.

[0333] Implementation Scheme 121. Use of complete GMP and free amino acids in the preparation of a medicament, preferably an infant formula, for children under 2 years of age, said medicament or said formula for the treatment or prevention of PKU or tyrosinemia in patients in need, said formula being according to any one of Implementation Schemes 96 to 111, 114, 119 or 120.

[0334] Implementation Scheme 122. A method for treating or preventing PKU or tyrosinemia, the method comprising administering to a patient in need a formula food for children under 2 years of age, preferably an infant formula food, containing complete GMP and free amino acids, wherein the formula food is as described in any one of Implementation Schemes 96 to 111, 114, 119 or 120.

Claims

1. A formula food for children under 2 years of age, the formula food containing complete casein glycomacropeptide and free amino acids, the formula food being used for dietary management of phenylketonuria or tyrosinemia in individuals in need.

2. The formulated food for the stated purpose according to claim 1, wherein the dietary management results in: (a) Good metabolic control, normal growth, and / or improved gastrointestinal tolerance; or (b) Good metabolic control, normal growth and improved gastrointestinal tolerance.

3. The formulated food for the said purpose according to claim 2, wherein... (a) The good metabolic control described herein achieves a phenylalanine blood concentration of 120 μmol / L to 360 μmol / L in individuals with phenylketonuria or a tyrosine blood concentration of 200 μmol / L to 400 μmol / L in individuals with tyrosinemia. (b) The normal growth results in maintaining, preferably increasing, age-specific height, age-specific weight, and / or age-specific BMI; or (c) The improved gastrointestinal tolerance is selected from the group consisting of: reduced vomiting, reduced regurgitation, reduced symptoms of abdominal discomfort or colic, reduced flatulence, reduced proportion of loose or hard stools, and / or reduced feeding difficulties.

4. A formulated food product for the stated purpose according to any one of the preceding claims, wherein... (a) The stated use is for dietary management of phenylketonuria; or (b) The use is for dietary management of phenylketonuria, and the dietary management results in the prevention of one or more symptoms selected from the group consisting of or a reduction in the severity or frequency of one or more symptoms selected from the group consisting of: intellectual disability, developmental milestone delay, hyperactivity, seizures, eczema, mild body odor, and less pigmentation (e.g., less pigmentation of the eyes, hair, and / or skin).

5. A formulated food product for the stated purpose according to any one of claims 1 to 3, wherein the stated purpose is for dietary management of the following diseases: (a) Tyrosinemia; (b) Tyrosinemia, wherein the tyrosinemia is type I tyrosinemia.

6. The formulated food for the purpose according to claim 5, wherein the dietary management results in the prevention of one or more symptoms selected from the group consisting of, or a reduction in the severity or frequency of one or more symptoms selected from the group consisting of: hepatotoxicity, nephrotoxicity, neurotoxicity, and endocrine dysfunction.

7. The formulated food product for the said purpose according to claim 6, wherein the symptoms are (a) Hepatotoxicity; preferably selected from the group consisting of: hemophilia-like symptoms, such as impaired coagulation, increased bruising, intra-articular hemorrhage or intracerebral hemorrhage; acute liver failure; hypoalbuminemia and hepatocellular carcinoma; (b) Nephrotoxicity; preferably selected from the group consisting of: hypophosphatemic rickets; impaired renal function; renal tubular injury; and renal failure; (c) Neurotoxicity; preferably selected from the group consisting of: porphyria; and peripheral neuropathy; or (d) Endocrine dysfunction; preferably selected from the group consisting of: dopamine dysfunction; norepinephrine dysfunction; and thyroid hormone dysfunction.

8. The formulated food for the purpose of claim 5(a), wherein the purpose is for dietary management of type II tyrosinemia and / or type I tyrosinemia treated with niticinon (NTBC).

9. The formulated food for the purpose according to claim 8, wherein the dietary management results in the prevention of one or more symptoms selected from the group consisting of or a reduction in the severity or frequency of one or more symptoms selected from the group consisting of: ocular toxicity, skin toxicity, and mental disability.

10. The formulated food for the said purpose according to claim 9, wherein the symptoms are (a) Ocular toxicity; preferably selected from the group consisting of: epiphora; photophobia; eye pain; and congestion; (b) Dermatological toxicity; palmoplantar keratoderma is preferred; or (c) Mental disability.

11. The formulated food for the purpose of claim 5(a), wherein the purpose is for dietary management of type III tyrosinemia.

12. The formulated food for the purpose according to claim 11, wherein the dietary management results in the prevention of one or more symptoms selected from the group consisting of, or a reduction in the severity or frequency of one or more symptoms selected from the group consisting of: intellectual disability, seizures, and intermittent ataxia.

13. A formulated food for the purpose according to any one of the preceding claims, wherein the dietary management lasts for at least 3 months, preferably at least 6 months, more preferably at least 1 year.

14. A formulated food product for the said purpose according to any of the preceding claims, wherein one or more of the following are applicable: (a) The formulated food is in the form of a liquid, a reconfigurable powder, or a scoopable food; preferably in the form of a liquid or a reconfigurable powder; (b) The formulated food is in liquid form; more preferably in the form of a storage-stable liquid; even more preferably in the form of a packaged storage-stable liquid; (c) The formulated food has a temperature of 20°C for 100 seconds. -1 Viscosity measured at shear rates below 200 mPa·s, preferably from 5 mPa·s to 180 mPa·s, and more preferably from 20 mPa·s to 150 mPa·s; (d) The formulated food is in the form of a liquid or a spoonable food, and has a density in the range of 1.02 g / L to 1.2 g / L, preferably 1.05 g / L to 1.25 g / L; (e) The formulated food is in liquid or spoonable form and has a calorific density of 0.6 kcal / mL to 3.0 kcal / mL, preferably 0.6 kcal / mL to 2.0 kcal / mL, more preferably 0.6 kcal / mL to 1.0 kcal / mL; and (f) The formulated food is in the form of a liquid or spoonable food, and the protein is present in an amount of 1g / 100mL to 15g / 100mL, preferably 1g / 100mL to 10g / 100mL.

15. A formulated food for the purpose according to any one of the preceding claims, wherein the formulated food comprises GMP and free amino acids in a weight ratio of 1:4 to 4:1, preferably 1:3 to 3:1, more preferably 1:2 to 2:

1.

16. A formulated food product for the said purpose according to any of the preceding claims, wherein one or more of the following are applicable: (a) The formulated food contains a lipid source, preferably the lipid source comprises fats selected from the group consisting of: milk fat, sunflower oil, rapeseed oil, low erucic acid rapeseed oil, safflower oil, rapeseed oil, olive oil, coconut oil, palm kernel oil, soybean oil, fish oil, palmitoleic acid, high oleic acid sunflower oil and high oleic acid safflower oil, and microbially fermented oil containing long-chain polyunsaturated fatty acids, more preferably the lipid source comprises docosahexaenoic acid and / or arachidonic acid; (b) The formulated food contains a digestible carbohydrate source, which is preferably selected from the group consisting of: lactose, glucose, sucrose, fructose, galactose, maltose, starch and maltodextrin; (c) The formulated food contains a vitamin source, which preferably includes vitamin A, vitamin D3, vitamin E, vitamin C, vitamin K, thiamine (B1), riboflavin (B2), niacin (B3), vitamin B6, folic acid, vitamin B12, biotin and / or pantothenic acid; (d) The formulated food contains a mineral source, which preferably includes sodium, potassium, chlorine, calcium, phosphorus, magnesium, iron, copper, zinc, manganese, iodine, molybdenum, selenium and / or chromium; (e) The formulated food contains protein, fat, carbohydrates, vitamins and minerals; (f) The formulated food contains prebiotics, probiotics, fiber and / or nucleotides; and / or choline, taurine, L-carnitine and inositol; and (g) The formulated food contains one or more thickeners, additives, emulsifiers, acidity regulators and / or antioxidants.

17. A formulated food product for the said purpose according to any one of the preceding claims, wherein... (a) The formulated food is an infant formula, preferably wherein the infant formula provides 1.8 g / 100 kcal to 3.0 g / 100 kcal of protein, 4.4 g / 100 kcal to 6.0 g / 100 kcal of fat, and 9.0 g / 100 kcal to 14.0 g / 100 kcal of digestible carbohydrates; or (b) The formulated food is an infant formula, preferably wherein the infant formula provides 1.8 g / 100 kcal to 3.0 g / 100 kcal of protein, 4.4 g / 100 kcal to 6.0 g / 100 kcal of fat and 9.0 g / 100 kcal to 14.0 g / 100 kcal of digestible carbohydrates, and wherein the infant formula is a liquid and has an energy density of 60 kcal / 100 mL to 75 kcal / 100 mL.

18. A complete infant formula for dietary management of PKU or tyrosinemia, the complete infant formula comprising complete GMP and free amino acids, wherein the GMP and the free amino acids are present in a ratio of 1:4 to 4:1, preferably 1:4 to 3:1, more preferably 1:4 to 2:1, more preferably 1:4 to 1:2, and most preferably 1:3 to 1:2 by weight.

19. A mixture of free amino acids, said mixture comprising Arg, Asp+Asn, Cys, Gly, His, Ile, Leu, Lys, Met, Trp, and Val, and optionally Tyr, wherein said mixture of free amino acids contains less than 0.1% by weight of any one of Ala, Gln, Glu, Pro, Phe, Ser, or Thr.

20. The mixture of free amino acids according to claim 19, wherein the mixture comprises, by weight percentage of the total free amino acids in the mixture: (a) Arg (9 wt% to 13 wt%), Asp+Asn (8 wt% to 12 wt%), Cys (2 wt% to 6 wt%), Gly (12 wt% to 16 wt%), His (4 wt% to 8 wt%), Ile (2 wt% to 6 wt%), Leu (13 wt% to 17 wt%), Lys (5 wt% to 9 wt%), Met (0.5 wt% to 4 wt%), Trp (1 wt% to 5 wt%), Val (5 wt% to 9 wt%), and Tyr (13 wt% to 17 wt%). Preferred: Arg (10 wt% to 12 wt%), Asp + Asn (9 wt% to 11 wt%), Cys (3 wt% to 5 wt%), Gly (13 wt% to 15 wt%), His (5 wt% to 7 wt%), Ile (3 wt% to 5 wt%), Leu (14 wt% to 16 wt%), Lys (6 wt% to 8 wt%), Met (1 wt% to 3 wt%), Trp (2 wt% to 4 wt%), Tyr (14 wt% to 16 wt%), and Val (6 wt% to 8 wt%); or (b) Arg (12 wt% to 16 wt%), Asp+Asn (total 10 wt% to 14 wt%), Cys (2 wt% to 6 wt%), Gly (15 wt% to 19 wt%), His (5 wt% to 9 wt%), Ile (3 wt% to 7 wt%), Leu (16 wt% to 20 wt%), Lys (6 wt% to 10 wt%), Met (0.5 wt% to 4 wt%), Trp (2 wt% to 6 wt%), and Val (7 wt% to 11 wt%). Preferred ingredients: Arg (12 wt% to 14 wt%), Asp+Asn (11 wt% to 13 wt%), Cys (3 wt% to 5 wt%), Gly (16 wt% to 18 wt%), His (6 wt% to 8 wt%), Ile (4 wt% to 6 wt%), Leu (17 wt% to 19 wt%), Lys (7 wt% to 9 wt%), Met (1 wt% to 3 wt%), Trp (3 wt% to 5 wt%), and Val (8 wt% to 10 wt%).

21. A complete infant formula for dietary management of PKU or tyrosinemia, said complete infant formula comprising the complete GMP and free amino acids as described in claim 18, wherein said free amino acids consist of a mixture of free amino acids as described in claim 19 or claim 20.

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