INFANT NUTRITIONAL PRODUCT WITH RRR ALPHA-TOCOPHEROL
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application claims priority to and any benefit of U.S. Provisional
Application No. 61/778,653, filed March 13, 2013, the entire content of which is
incorporated herein by reference.
FIELD
[0002] The present disclosure relates to compositions and methods of
enhancing brain development and central nervous system (CNS) maturation of an
individual. The compositions comprise a mixture of natural tocopherols, wherein the
compositions contain an optimum tocopherol profile similar to that found in human
breast milk, and can encompass a tocopherol profile from early stage to transitional to
mature human breast milk. The present disclosure also relates to nutritional
compositions having a tocopherol profile wherein a weight ratio range for RRR alphatocopherol
to RRR gamma-tocopherol is from about 2 :1 to about 20: 1. The tocopherol
mixture is typically added to a delivery vehicle such as powders, liquids, and
nutritional formulas.
BACKGROUND
[0003] Maturation of the central nervous system ("CNS"), including the brain
and eyes, is a key developmental area for the fetus and newborn. Accordingly, it is
imperative that sufficient nutrition is provided in utero and after birth such that
maturation may occur.
[0004] Infant formulas are commonly used today to provide a supplemental
or sole source of nutrition early in life to both preterm and term infants. These
formulas typically contain protein, carbohydrate, fat, vitamins, minerals, and other
nutrients, and are commercially available as powders, ready-to-feed liquids, and liquid
concentrates. Many infant formulas provide a quality alternative to human milk, as not
all infants can receive human milk.
SUMMARY
[0005] This present disclosure relates generally to a method of enhancing
brain development and CNS maturation in individuals, namely infants and preterm
infants as defined herein, and protection from oxidative stress, by administering a
mixture of optimized natural alpha- and gamma-tocopherols, optionally in combination
with various vitamins, minerals and macronutrients, in a nutritional composition.
[0006] The nutritional composition may comprise fat, protein, carbohydrates,
minerals and from about 5 mg/L to about 100 mg/L of an optimized tocopherol blend
having a weight ratio of RRR alpha-tocopherol to RRR gamma-tocopherol of from
about 2 :1 to about 20: 1, and less than about 8 mg/L of non-RRR alpha-tocopherol
isomer. The weight ratio of RRR alpha-tocopherol to RRR gamma-tocopherol may
also be from about 3:1 to about 15:1. The weight ratio of RRR alpha-tocopherol to
RRR gamma-tocopherol may also be from about 4 :1 to about 10: 1. The weight ratio of
RRR alpha-tocopherol to RRR gamma-tocopherol may also be about 5:1.
[0007] The nutritional composition may be an infant formula which may be a
liquid or a powdered nutritional product. The composition may have from about 20
g/L to about 50 g/L fat, from about 10 g/L to about 15 g/L protein, and at least about 4
mg/L of RRR alpha-tocopherol. The composition may also comprise one or more
materials including, but not limited to, a polyunsaturated fatty acid selected from
arachidonic acid, docosahexaenoic acid, and a combination thereof, vitamin C,
carotenoids, and trans-lutein.
[0008] The nutritional composition may be used to enhance brain
development in individuals, namely infants and/or preterm infants, by administering a
nutritional composition, in the form of an infant formula or a preterm infant formula,
comprising: i) from about 20 g/L to about 50 g/L of fat; ii) from about 10 g/L to about
15 g/L of protein; wherein said fat includes oils comprising RRR alpha-tocopherol and
RRR gamma-tocopherol, with a weight ratio of RRR alpha-tocopherol to RRR gammatocopherol
ranging from about 3.5:1 to about 10: 1; and iii) no more than about 8 mg/L
of a non-RRR alpha-tocopherol isomer. The weight ratio of RRR alpha-tocopherol to
RRR gamma-tocopherol may also be about 5:1. The nutritional composition may also
comprise one or more materials selected from a carbohydrate, a polyunsaturated fatty
acid, a carotenoid, vitamin C, trans-lutein, and a combination thereof.
[0009] The present disclosure also relates to a method of improving CNS
maturation in individuals, namely infants and preterm infants. The present disclosure
also relates to a method of improving CNS maturation and protection in individuals,
namely infants and preterm infants, from oxidative stress by administering an
optimized mixture of natural tocopherols comprising RRR alpha-tocopherol and RRR
gamma-tocopherol, optionally in combination with various vitamins, minerals and
macronutrients. For ease of administration and maximized efficacy, the optimized
mixture of natural tocopherols are typically delivered in an oral dosage form with a
limited level of non-RRR alpha-tocopherols to maximize the efficacy efficiency of the
RRR alpha-tocopherol on stimulating postnatal CNS development.
DETAILED DESCRIPTION
[0010] The instant disclosure provides compositions and methods believed to
have enhanced effects on cognitive, CNS, and/or brain development, due to an
optimized mixture of natural tocopherols and limited levels of non-RRR alphatocopherol
isomers. The gamma-tocopherol and non-RRR alpha-tocopherols may
compete with RRR alpha-tocopherol for absorption and for lipoprotein at the intestine
and liver level. In addition, these compounds may compete with RRR alphatocopherol
for absorption into brain. Not wishing to be bound by the hypothesis, the
applicants believe that RRR alpha-tocopherol binds TAP and the resultant complex upregulate
genes that regulate cholesterol, myelin protein and synaptic protein synthesis.
[001 1] The term "retort packaging" and "retort sterilizing" are used
interchangeably herein, and unless otherwise specified, refer to the common practice of
filling a container, most typically a metal can or other similar package, with a
nutritional liquid and then subjecting the liquid-filled package to the necessary heat
sterilization step, to form a sterilized, retort packaged, nutritional liquid product.
[0012] The term "aseptic packaging" as used herein, unless otherwise
specified, refers to the manufacture of a packaged product without reliance upon the
above-described retort packaging step, wherein the nutritional liquid and package are
sterilized separately prior to filling, and then are combined under sterilized or aseptic
processing conditions to form a sterilized, aseptically packaged, nutritional liquid
product.
[0013] The term "infant" as used herein, refers generally to individuals up to
age 36 months of age, actual or corrected.
[0014] The term "preterm infant" as used herein refers to those infants born at
less than 37 weeks gestation, have a birth weight of less than 2500 gm, or both.
[0015] The term "as-fed basis" as used herein, unless otherwise specified,
refers to feeding the infant a suitable nutritional formula in liquid form, which has been
properly reconstituted from substances such as liquids, gels, powders and the like;
these substances may be reconstituted with human milk or formula, in addition to
water, diluted concentrates, and manufactured liquids. In one example, an "as-fed"
basis may refer to feeding an infant or preterm infant the human milk fortifier after
mixing the human milk fortifier with human milk in the ratio of 1 part human milk
fortifier to 5 parts human milk.
[0016] The terms "ready-to-feed" and "RTF" refer to a formula that may be
consumed without requiring additional compositional changes prior to consumption.
For example, an RTF infant formula may be fed directly to the infant without having to
mix with water or another fluid, as would be the case with powdered formulas or
concentrated forms of liquid products.
[0017] As used herein, all concentrations expressed as either "meg/liter" or
"mg/liter" refer to ingredient concentrations within the described infant formulas as
calculated on an as-fed basis or the concentrated human milk fortifier, unless otherwise
specified.
[0018] The terms "fortifier solids" and "total solids," unless otherwise
specified, are used interchangeably herein and refer to all material components of the
compositions of the present disclosure, less water.
[0019] The term "hypoallergenic" as used herein means that the concentrated
liquid human milk fortifier has a decreased tendency to provoke an allergic reaction in
a preterm or term infant as compared to non-hypoallergenic fortifiers.
[0020] The term "stable" as used herein means that the concentrated liquid
human milk fortifier is resistant to separation and precipitation for time period after
manufacture of at least three months, and preferably at least six months.
[0021] The terms "fat," "lipid," and "oil" as used herein, unless otherwise
specified, are used to refer to lipid materials derived or processed from plants. These
terms may also include synthetic lipid materials so long as such synthetic materials are
suitable for oral administration to humans.
[0022] The terms "natural tocopherol ratio," "alpha- to gamma-tocopherol
ratio," "vitamin E," "natural vitamin E," and "mixture of natural tocopherols" as used
herein refers to the RRR alpha-tocopherol, RRR alpha-tocopherol acetate, RRR alphatocopherol
succinate and RRR gamma-tocopherol, RRR gamma-tocopherol acetate,
RRR gamma-tocopherol succinate forms and derivatives thereof.
[0023] The terms "nutritional composition," "nutritional product," and
"nutritional formula" as used herein, unless otherwise specified, are used
interchangeably to refer to nutritional liquids and nutritional powders that comprise at
least one of protein, fat, and carbohydrate and are suitable for oral administration to a
human. The nutritional composition may further comprise vitamins, minerals, and
other ingredients and represent a sole, primary, or supplemental source of nutrition.
Nutritional compositions include infant formulas.
[0024] The term "nutritional liquid," as used herein, unless otherwise
specified, refers to nutritional products in ready-to-drink liquid form, concentrated
form, and nutritional liquids made by reconstituting the nutritional powders described
herein prior to use.
[0025] The term "nutritional powder," as used herein, unless otherwise
specified, refers to nutritional products in flowable or scoopable form that can be
reconstituted with water or another aqueous liquid prior to consumption and includes
both spray dried and dry mixed/dry blended powders.
[0026] All percentages, parts and ratios as used herein, are by weight of the
total composition, unless otherwise specified. All such weights as they pertain to listed
ingredients are based on the active level and, therefore, do not include solvents or by
products that may be included in commercially available materials, unless otherwise
specified.
[0027] Numerical ranges as used herein are intended to include every number
and subset of numbers within that range, whether specifically disclosed or not. Further,
these numerical ranges should be construed as providing support for a claim directed to
any number or subset of numbers in that range. For example, a disclosure of from 1 to
10 should be construed as supporting a range of from 2 to 8, from 3 to 7, from 5 to 6,
from 1 to 9, from 3.6 to 4.6, from 3.5 to 9.9, and so forth. All references to singular
characteristics or limitations of the present disclosure shall include the corresponding
plural characteristic or limitation, and vice versa, unless otherwise specified or clearly
implied to the contrary by the context in which the reference is made.
[0028] All combinations of method or process steps as used herein can be
performed in any order, unless otherwise specified or clearly implied to the contrary by
the context in which the referenced combination is made.
[0029] The various embodiments of the nutritional compositions of the
present disclosure may also be substantially free of any ingredient or feature described
herein, provided that the remaining formula still contains all of the required ingredients
or features as described herein. In this context, and unless otherwise specified, the
term "substantially free" means that the selected composition contains less than a
functional amount of the optional ingredient, typically less than 1%, including less than
0.5%, including less than 0.1%, and also including zero percent, by weight of such
optional or selected essential ingredient.
[0030] The nutritional compositions may comprise, consist of, or consist
essentially of the elements of the products as described herein, as well as any
additional or optional element described herein or otherwise useful in nutritional
product applications.
[003 1] All referenced patents and applications are incorporated herein by
reference in their entirety. Where a definition or use of a term in an incorporated
reference is inconsistent or contrary to the definition of that term provided herein, the
definition of that term provided herein applies and the definition of that term in the
reference does not apply.
[0032] The Food and Nutrition Board (FNB) previously issued an edition of
"DRI: Dietary Reference Intakes for Vitamin C, Vitamin E, Selenium, and
Carotenoids" (Washington, D.C.: National Academy of Sciences. 2000), in which the
occurrence, adequate intake, and biological activity of vitamin E are summarized in
detail. It is emphasized that there are two groups of compounds found in plant
materials that have vitamin E biological activity, that is, tocopherols and tocotrienols.
The tocopherols are characterized by a substituted, hydroxylated ring system
(chromanol ring) with a long, saturated (phytyl) side chain. Tocotrienols differ from
tocopherols only in that they have an unsaturated side chain. The naturally occurring
tocopherols include alpha-, beta-, gamma-, and delta-tocopherols. These various forms
are not interconvertible in the human and thus do not behave the same metabolically.
The FNB limits the vitamin E activity of alpha-tocopherol to that available from the
naturally occurring form (RRR-) and the other three synthetic 2R-stereoisomer forms
(RSR-, RRS-, and RSS-) of alpha-tocopherol for purposes of establishing the human
requirement for vitamin E. Other natural occurring forms of vitamin E (beta-, gamma-,
delta-tocopherols and the tocotrienols) do not contribute toward meeting the vitamin E
requirement because, although absorbed, there are not converted to alpha-tocopherol
by humans and are recognized poorly by the alpha-tocopherol transfer protein in the
liver.
[0033] Based on a review of the data by the FNB, the 2R-stereoisomeric
forms of alpha-tocopherol (RSR-, RRS-, and RSS-) were used to estimate the vitamin
E requirement. Thus, the Estimated Average Requirements (EARs), Recommended
Dietary Allowances (RDAs), and Adequate Intakes (AIs) that are listed below apply
only to intake of the 2R-stereoisomeric forms of alpha-tocopherol from food, fortified
food and multivitamins. The Upper Limits (ULs) apply to any forms of supplemental
alpha-tocopherol. The FNB found no functional criteria of vitamin E status that
reflected the response to dietary intake in infants. Thus, the recommended intakes of
vitamin E are based on AIs, which reflects a calculated mean vitamin E intake of
infants fed principally with human milk. The UL was judged not determinable by the
FNB because of insufficient data on adverse effects in this age group. Table 1 lists the
Adequate Intake (AI) for infants ages 0 through 1 months.
TABLE 1
Infant Adequate Intake for Vitamin E
Infants AI
(ages) (alpha-tocopherol)
0-6 months 4.0 mg/day (-0.6 mg/kg)
7-12 months 5.0 mg/day (-0.6 mg/kg)
RRR Alpha-Tocopherol
[0034] It is imperative that early in life infants receive sufficient nutrition to
provide for adequate maturation both physically and mentally, and specifically in the
brain and central nervous system. Insufficient nutrition can result in numerous health
problems that can be life-long in many individuals. In particular, brain and central
nervous system maturation are key developmental areas for infants.
[0035] Our brain analysis showed a correlation between cholesterol,
glutamate, and RRR alpha-tocopherol. Cholesterol is a major component of myelin,
and thus, is a marker for extent of CNS myelination. Glutamate is a neurotransmitter,
which is reported to stimulate neuron outgrowth and branching. Our discoveries
suggest that RRR alpha-tocopherol stimulate new born infant CNS development.
Accordingly, an excessively high level of dietary gamma-tocopherol may hinder the
brain uptake of RRR alpha-tocopherol, and thus, may hinder CNS development.
[0036] Brain accretion of RRR alpha-tocopherol enhances CNS maturation
and cognition. That is, the presence of RRR alpha-tocopherol in the brain of a human
infant enhances the maturation of the infant's central nervous system and cognitive
development. The brains of breast fed infants have a higher level of myelination as
indicated by the higher lipid and cholesterol content. It has been observed that
although formula and breast milk fed infants have about the same level of alphatocopherol,
formula fed infants have more non-RRR alpha-tocopherol. It has been
reported that supernatant protein factor binds alpha-tocopherol, forming a complex that
stimulates cholesterol synthesis, and thus, myelination. It is the belief of the Applicant
that non-RRR alpha-tocopherol isomers compete with RRR alpha-tocopherol for the
binding sites on supernatant protein factor activity, resulting in a decrease in the
beneficial effect of RRR alpha-tocopherol on CNS maturation by such competition. In
other words, efficacy of RRR alpha-tocopherol in obtaining these effects is believed to
be dependent, in part, on the ability of RRR alpha-tocopherol to form a complex that
exerts the desired effect, and that non-RRR alpha-tocopherol isomers reduce RRR
alpha-tocopherol efficacy by interfering with this binding.
[0037] Thus, the Applicants have surprisingly found that by limiting the
amount of non-RRR alpha-tocopherol isomers, the efficacy of RRR alpha-tocopherol
in enhancing cognitive, brain and/or CNS development is increased. It is believed that
by enhancing the effect of RRR alpha-tocopherol isomers using the nutritional
compositions described herein, the CNS maturation of an infant may be enhanced and
improved through improved neuron myelination via cholesterol synthesis.
[003 8] It is further believed that the presence of elevated levels of RRR
alpha-tocopherol in the brain correlates with the production of glutamate in the brain.
Glutamate is shown to stimulate neurite outgrowth and branching. Neurite outgrowth
and branching allow neuron cells to establish new gap junctions. Increased neuronal
communication via newly formed gap junctions may allow the brain to process more
data in a given period of time. Accordingly, maximizing RRR alpha-tocopherol
efficacy can improve overall brain health. Thus, it is believed that by these
mechanisms at a minimum, the presence of RRR alpha-tocopherol plays an important
role in the brain development of the fetus or newborn.
[0039] As used herein, the term "RRR alpha-tocopherol" refers to both
exogenous sources and inherent sources of RRR alpha-tocopherol and RRR
alpha-tocopherol acetate that are present in a nutritional composition, including an
infant formula. Inherent sources include RRR alpha-tocopherol that is inherently
present in components that are present in a nutritional composition and may include for
example, various oils and fats. Exogenous sources of RRR alpha-tocopherol include
RRR alpha-tocopherol that is added to the nutritional composition not as part of
another component.
[0040] Tocopherols, generically referred to as vitamin E, are available in four
forms: alpha-, beta-, gamma-, and delta-, which differ in the number and position of
the methyl groups on the chroman ring, as shown by the structure below and Table 2.
TABLE 2
Structure of Natural Tocopherols
Compound Ri R2
alpha-tocopherol Me Me Me
beta-tocopherol Me H Me
gamma-tocopherol H Me Me
delta-tocopherol H H Me
[004 1] Further, tocopherols can exist in a number of stereoisomer^ forms
depending on the chirality of the phytyl tail. Of the alpha-tocopherols, RRR alphatocopherol
(also referred to as "natural vitamin E") has the greatest biological activity
and is reported to be the dominant form of the alpha-tocopherol in the brain. RRR
alpha-tocopherol is a single stereoisomer whereas synthetic vitamin E (all-rac-alphatocopherol
or tocopherol acetate) is an equimolar mixture of eight isomers, only one of
which is RRR alpha-tocopherol. The fact that the dominant form of alpha-tocopherol
is RRR alpha-tocopherol (based on animal studies) strongly suggests that the other
seven chiral isomers must be absorbed at a lower rate by the brain or oxidized at a
faster rate.
[0042] Both free tocopherol and its acetate ester are water-insoluble,
nonswelling amphiphiles, as are triglycerides and cholesterol. Thus, many of the
factors and processes necessary for the absorption of dietary lipids are also required for
absorption of tocopherols. These factors include: efficient emulsification,
solubilization within mixed bile salt micelles, uptake by the small intestinal cell
(enterocyte), packaging within lipoprotein particles (chylomicrons) and secretion into
the circulation via the lymphatic system.
[0043] Tocopherols must be emulsified and solubilized before their
absorption across the brush-border membrane of the enterocyte. Emulsification begins
in the stomach by predominantly mechanical forces that break up large emulsion
particles into smaller particles. Within the small intestine chyme mixes with pancreatic
and biliary secretions, pancreatic lipase hydrolyzes triglyceride into monoglycerides
and fatty acids. These lipolytic products ferry the lipid soluble vitamins in the oil phase
into the aqueous digesta. Together with bile salts and free fatty acids and
monoglycerides from triglyceride (TG) digestion, they form molecular aggregates
known as mixed micelles. These mixed micelles diffuse across the unstirred water
layer to reach the brush-border membrane of the enterocyte and the lipotic products
and the lipid soluble vitamins are absorbed.
[0044] The uptake of fatty acids and lipid soluble nutrients such as
carotenoids and tocopherol by the enterocyte are thought to be via passive diffusion.
However, recent research has indicated that the absorption of fatty acids and lipid
soluble nutrients are via a facilitated process. In another word, these compounds are
bound to a lipid transfer protein, then, transport across the microvilli membrane
(Reboul et al, J. Bio. Chem. (2006), Vol. 281:4739). Reboul et al. (2006) suggest that
tocopherol absorption is, in part, facilitated by Scavenger Receptor Class B Type 1
(SRBl). Thus, there will be competition for intestinal absorption between gamma- and
alpha-tocopherol. Within the enterocyte, the tocopherols are incorporated into
chylomicrons and secreted into the intracellular spaces and lymphatics and thus into
the bloodstream.
[0045] Supplements of vitamin E are generally given in the form of alphatocopherol
acetate in which the relative hydroxyl group of alpha-tocopherol is
esterified, rendering the molecule more stable than the free form. Tocopherol acetate is
digested by pancreatic esterase. The resultant free tocopherols are then ferried into the
aqueous phase of digesta by the free fatty acids from triglycerides digestion. It is
known that both alpha- and gamma-tocopherols are absorbed by the enterocyte and
packaged into chylomicron.
[0046] Portions of the tocopherols in the chylomicron are transported to the
adipose tissue by the free fatty acids from chylomicron triglyceride (TG) digestion.
Chylomicrons are quickly digested by serum lipoprotein lipase. The tocopherols in the
remnant chylomicron is absorbed into liver and digested. The released tocopherols are
bound by tocopherol transfer protein and deliver to Golgi body to be packaged into
very low density lipoprotein (VLDL), low density lipoprotein (LDL), and high density
lipoprotein (HDL) to re-enter circulation. The half life of LDL and HDL are much
longer than chylomicron and LDL, thus, most of the tocopherols and carotenoids in
circulations are associated with lipoproteins. A high level of gamma tocopherol in the
liver may compete with alpha-tocopherol for LDL and HDL. Thus, a high level of
gamma tocopherol may reduce the bio-availability of alpha-tocopherol.
[0047] It is well established that alpha and gamma tocopherols function as an
in vivo antioxidant, protecting lipids against peroxidative damage and it is known that
red blood cells (RBCs) from newborns are more sensitive to in vitro oxidative stress
than adult RBCs. Most of the intracellular hemoglobin (HB) in neonatal RBCs is fetal
hemoglobin (HBF), which has a stronger tendency to denature and oxidize than adult
hemoglobin (HBA). Denatured and oxidized HB is a potent catalyst for lipid
peroxidation. Further, exposure to free radicals places the preterm infant at risk for
diseases of prematurity including intraventricular hemorrhage, retinopathy of
prematurity, bronchopulmonary dysplasia and necrotizing enterocolitis.
[0048] It has been reported that the RRR alpha-tocopherol content and alphato
gamma-tocopherol ratio of human milk decrease with stage of lactation. The alphato
gamma-tocopherol ratio of colostrum is about 10 and it decreases to about 4-6 in
mature milk. It is possible that these alpha- to gamma-tocopherol ratios are optimized
for maximum protection of infant from oxidative stress without adversely affecting
infant CNS development.
[0049] The RRR alpha-tocopherol may be present in the nutritional
compositions in an amount sufficient to improve brain or CNS development. In some
aspects, the nutritional compositions may comprise RRR alpha-tocopherol in
concentrations of at least about 5 mg/L, including at least about 7 mg/L, including at
least about 8 mg/L, including at least about 9 mg/L, including at least about 10 mg/L,
including at least about 15 mg/L, including at least about 18 mg/L, including at least
about 20 mg/L, including from at least about 5 mg/L to about 100 mg/L, including
from at least about 7 mg/L to about 50 mg/L, and including from about 20 mg/L to
about 40 mg/L. The total amounts of RRR alpha-tocopherol include both exogenous
and inherent sources of RRR alpha-tocopherol, as noted above.
[0050] Our brain analysis work showed over 60% of the alpha-tocopherol in
formula fed infant brain is RRR alpha-tocopherol. Most commercial infant formulas
are fortified with synthetic alpha-tocopherols. It has been reported that the plasma
contraction of the 2R isomers are about equal for animals fed a diet containing
synthetic alpha-tocopherols. These findings indicate that RRR alpha-tocopherol is
preferably absorbed into the brain or it is metabolized at a much slower rate than RSR,
RRS and RSS tocopherols.
[005 1] It is reported that tocopherol association protein (TAP) binds
tocopherol and the resultant complex translocates into cell nucleus to regulate gene
expression. These findings lead the applicant to believe that TAP preferably binds
RRR alpha-tocopherol and this complex formation prevent the RRR alpha-tocopherol
from being metabolized or oxidized. Thus, RRR alpha-tocopherol is metabolized at a
slower rate than other 2R isomers. In other words, applicants believe that RRR alphatocopherol
is more potent than the other 2R isomers in stimulating CNS maturation.
Accordingly, applicants believe that the presence of a high level of non-RRR alphatocopherol
isomers will compete with RRR alpha-tocopherol for the tocopherol
association protein, thus compromising the efficacy of RRR alpha-tocopherol. Based
upon these findings, the applicants believe that an optimized blend of tocopherols
should provide an infant: 1) no less than 0.25 mg/Kg body weight/day of RRR alphatocopherol;
2) appropriate levels of RRR gamma-tocopherol so that the alpha- to
gamma-tocopherol ratio ranges from 2:1 to 20:1; and 3) less than 0.4 mg of non-RRR
alpha-tocopherol isomers.
[0052] It has been discovered that non-RRR alpha-tocopherol isomers may
compete with RRR alpha-tocopherol for absorption into brain. In other words, non-
RRR alpha-tocopherol acts as an agonist of RRR alpha-tocopherol, because the
presence of high levels of non-RRR alpha-tocopherol can compromise its beneficial
effects. Thus, by limiting the non-RRR alpha-tocopherol chiral isomers and
combining RRR alpha-tocopherol with other enhancers of CNS development in
specific combinations and amounts, a synergistic impact on the development of the
brain and CNS of the fetus, and breast-feeding newborn may occur.
[0053] In some embodiments, the nutritional compositions include another
additional tocopherol, particularly RRR gamma-tocopherol, in addition to the RRR
alpha-tocopherol. RRR gamma-tocopherol has been used in food applications as an
antioxidant, thereby preventing deterioration of foods and beverages resulting from
oxidation of susceptible components such as some fats.
[0054] RRR gamma-tocopherol, however, has now been found to negatively
correlate with phospholipids. Accordingly, when present, the RRR gamma-tocopherol
may be present in the infant formulas in concentrations of less than 7 mg/L, including
less than 5 mg/L, including from 0 mg/L to 3 mg/L including from about 1 mg/L to 3
mg/L of the nutritional composition.
[0055] The nutritional compositions of the present disclosure may include
vitamin C in addition to the RRR alpha-tocopherol to provide oxidative protection.
Vitamin C, also referred to as L-ascorbic acid or L-ascorbate, is available from many
fruit and vegetable sources. Any source of vitamin C that is suitable for use in an oral
nutritional product and is compatible with the essential elements and features of such
products may be used with the nutritional compositions of the present disclosure.
[0056] Vitamin C may chelate free ferrous iron, which has been found to
lower serum vitamin E levels in formula fed preterm infants, thereby preventing iron
from acting as a pro-oxidant. Further, high levels of arachidonic acid (ARA) and
docosahexaenoic acid (DHA) may generate high levels of lipid peroxides due to
oxidation induced by intestine xanthin oxidase (XO), which can also degrade RRR
alpha-tocopherol before RRR alpha-tocopherol can be absorbed in the gut.
Accordingly, vitamin C may be included in the infant formulas of the present
disclosure to reduce the oxidative degradation of RRR alpha-tocopherol. In this
aspect, the nutritional compositions of the present disclosure may include vitamin C in
a concentration of at least 130 mg/L, including at least 150 mg/L, including at least
175 mg/L, including at least 200 mg/L, including at least 225 mg/L, including at least
250 mg/L, including at least 300 mg/L and including from 130 mg/L to about 1000
mg/L, and including from about 200 mg/L to about 500 mg/L.
Non-RRR Alpha-Tocopherol Isomer
[0057] As used herein, the term "non-RRR alpha-tocopherol isomer" is
intended to mean any stereoisomer of alpha-tocopherol that is not in the RRR
configuration as will be readily understood by one of ordinary skill in the art.
[0058] The nutritional compositions disclosed herein may, in some aspects,
be substantially free of non-RRR alpha-tocopherol isomers. In other aspects, the
composition may comprise less than about 9 mg/L, or less than about 8 mg/L, or less
than about 7 mg/L, or less than about 6 mg/L, or less than about 5 mg/L, or less than
about 4 mg/L, or less than about 3 mg/L, or less than about 2 mg/L, or less than about
1 mg/L, or less than about 0.5 mg/L of non-RRR alpha-tocopherol isomers. In other
aspects, the amount of non-RRR alpha-tocopherol isomers are limited to an amount
that allows RRR alpha-tocopherol to effectively enhance brain, CNS, and/or cognitive
development in an individual, particularly an infant. In one aspect, the compositions
may be substantially free of non-RRR alpha-tocopherol isomers.
Vitamin E Activity
[0059] The eight known tocopherols have different biological activities. The
naturally occurring RRR alpha-tocopherol has been assigned an activity of 1mg alphatocopherol
equivalent (TE) per milligram. The relative activities of other tocopherols
are listed in Table 3. The vitamin E activity of a food may be calculated by taking the
sum of the values obtained by multiplying the number of milligrams of each
component tocopherol by the appropriate factor given in Table 3.
TABLE 3
Vitamin E Activity of the Tocopherols and Tocotrienols
Activity as alpha-TE
Tocopherol (mg/mg compound)
RRR alpha-tocopherol 1.0
RRR beta-tocopherol 0.5
RRR gamma-tocopherol 0.1
RRR delta-tocopherol 0.03
RRR alpha-tocotrienol 0.3
RRR beta-tocotrienol 0.05
RRR gamma-tocotrienol
RRR delta-tocotrienol
Synthetic alpha-tocopherol acetate 0.74
alpha-tocopherol equivalents(TE)
**Table from Vitamin E in Health and Disease, edited by Lester Packer and
Jurgen Fuchs; Marcel Dekker, Inc, New York, New York, 1993, p. 2 1
Dashes denote unknown activities
Alpha- to Gamma-Tocopherol Ratio
[0060] The instant invention relates to a method of improving CNS
maturation in an infant by administering the required amount of vitamin E to said
infant in an alpha- to gamma-tocopherol ratio from about 2 :1 to about 20: 1, or from
about 3.5:1 to about 15:1; or from about 5:1 to about 10:1. Vitamin E or a source
thereof having an alpha- to gamma-tocopherol ratio from about 2 :1 to about 20: 1 is
also referred to herein as "an optimized tocopherol blend."
[0061] Alternatively, isolated alpha- and/or gamma-tocopherol components
may be admixed with oil rich in alpha- and/or gamma-tocopherol. Based on the known
tocopherol content of different oils, one skilled in the art would be able to select a fat
source or blend of fats which when supplemented with alpha- and/or gammatocopherol
will achieve the desired alpha- to gamma-tocopherol ratio of the instant
invention. For example, alpha-tocopherol is blended with a fat system rich in gammatocopherol.
Commercial sources for isolated alpha- and gamma-tocopherol are readily
available and known to one practicing the art. For example, RRR alpha-tocopherol and
RRR alpha-tocopherol acetate are available from Eastman Chemical Corp. of
Kingsport, Tenn.
[0062] The tocopherol ratio described above may be delivered in any
acceptable oral dosage form. One knowledgeable in the art would be able to select an
appropriate carrier to aid in the ease of administration and to improve the organoleptic
properties depending on the target population, e.g., infants. The alpha- to gammatocopherol
ratio of the present invention may be administered in a partial, i.e.,
fractional dose, one or more times during a 24 hour period, a single dose during a 24
hour period of time, a double dose during a 24 hour period of time, or more than a
double dose during a 24 hour period of time. Fractional, double or other multiple doses
may be taken simultaneously or at different times during the 24-hour period. An infant
may receive an alpha- to gamma-tocopherol ratio from about 2 :1 to about 20: 1, or from
about 3.5:1 to about 15:1; or from about 5:1 to about 10:1, for example, as a
concentrated liquid or infant nutritional supplement.
[0063] In one embodiment, a nutritional composition of the present disclosure
comprises fat, protein, carbohydrates, minerals, and from about 5 mg/L to about 100
mg/L of an optimized tocopherol blend having a weight ratio of RRR alpha-tocopherol
to RRR gamma-tocopherol of from about 2:1 to about 20:1, and less than about 8 mg/L
of non-RRR alpha-tocopherol isomer. In certain embodiments, the nutritional
composition comprises from about 7 mg/L to about 75 mg/L of the optimized
tocopherol blend, including from about 10 mg/L to about 50 mg/L, and also including
from about 20 mg/L to about 40 mg/L of the optimized tocopherol blend.
[0064] The nutritional compositions of the present disclosure generally
contain less than about 8 mg/L of non-RRR alpha-tocopherol isomer. In certain
embodiments, the nutritional compositions of the present disclosure comprise less than
about 5 mg/L of non-RRR alpha-tocopherol isomer, including less than about 1 mg/L
of non-RRR alpha-tocopherol isomer, and also including less than about 0.5 mg/L of
non-RRR alpha-tocopherol isomer. In other embodiments, the nutritional
compositions of the present disclosure are substantially free of non-RRR alphatocopherol
isomer.
[0065] The optimized tocopherol blend of the present disclosure comprises a
weight ratio of RRR alpha-tocopherol to RRR gamma-tocopherol of from about 2:1 to
about 20: 1. In certain embodiments, the nutritional composition comprises an
optimized tocopherol blend having a weight ratio of RRR alpha-tocopherol to RRR
gamma-tocopherol ranging from about 3:1 to about 15:1. In certain embodiments, the
nutritional composition comprises an optimized tocopherol blend having a weight ratio
of RRR alpha-tocopherol to RRR gamma-tocopherol ranging from about 4:1 to about
10:1. In certain embodiments, the nutritional composition comprises an optimized
tocopherol blend having a weight ratio of RRR alpha-tocopherol to RRR gammatocopherol
of about 5:1.
[0066] In certain embodiments, the nutritional compositions of the present
disclosure include (i) from about 20 g/L to about 50 g/L f; (ii) from about 10 g/L to
about 15 g/L protein; and at least about 4 mg/L of RRR alpha-tocopherol.
[0067] The nutritional compositions of the present disclosure may also
comprise one or more materials including, but not limited to, a polyunsaturated fatty
acid selected from arachidonic acid, docosahexaenoic acid, and a combination thereof,
vitamin C, and a carotenoid, such as trans-lutein.
[0068] The nutritional compositions of the present disclosure may be
formulated in a wide variety of product forms. In one embodiment, the nutritional
composition is a liquid nutritional product. In another embodiment, the nutritional
composition is a powdered nutritional product. In one embodiment, the nutritional
composition is an infant formula. In another embodiment, the nutritional composition
is a preterm infant formula.
Infant Dietary Supplement
[0069] The alpha- to gamma-tocopherol ratio of the instant invention may be
delivered to an infant in the form of a concentrated liquid, reconstitutable particles, and
microparticles, for example. Syrups, honeys and elixirs may be admixed with the
natural tocopherol ratio to improve the flavor. Oil in water emulsions may be better
suitable for oral use in infants because these are water-miscible and thus their oiliness
is masked. Emulsions are well known in the pharmaceutical sciences. The supplement
of this invention can be manufactured using techniques well known to those skilled in
the art. Generally speaking, an emulsifying agent is dissolved in the oil. The
emulsifier/oil mixture may be added directly to the water to form an oil-in-water
emulsion. Alternatively, the emulsifying agent is dissolved in the water and the oil is
added, with agitation, to the emulsifier/aqueous solution. Examples, of typical natural
emulsifying agents include gelatin, egg yolk, casein, wool fat, cholesterol, acacia,
tragacanth, chondrus and pectin. The mixtures require physical manipulation to
achieve the emulsified physical state. Emulsification equipment includes a wide
variety of agitators, homogenizers, colloid mills and ultrasonic devices.
[0070] The alpha- and gamma-tocopherol emulsion of the instant invention
may be stored in conventional containers and are dispensed in small but precise
quantities or unit dosages. Such dosages are characteristically dispensed using a pipette
and compressible, resilient bulb dropper assembly.
[0071] As discussed above, the FNB recommends a dose of 0.6 mg/kg of
infant body weight per day for vitamin E. Typically the amount of liquid required to
provide a unit dose of the alpha- and gamma-tocopherol emulsion will typically range
from about 0.1ml to about 8 ml, more preferably from about 0.5 ml to about 5.0 ml,
most preferably from about 0.5 ml to about 2.0 ml.
[0072] The infant dietary supplement of the present inventive subject matter
may be administered in a partial, i.e., fractional dose, one or more times during a 24
hour period, a single dose during a 24 hour period of time, a double dose during a 24
hour period of time, or more than a double dose during a 24 hour period of time.
Fractional, double or other multiple doses may be taken simultaneously or at different
times during the 24 hour period.
[0073] Typically, a unit dose of the infant dietary supplement of the invention
comprises at least 50% of the AI for vitamin E for infants in the alpha- to gammatocopherol
ratio of the invention in about 1 ml. Typically, a unit dose is administered
to the infant at least once a day.
[0074] Additional nutrients may be added to the alpha- and gammatocopherol
dietary supplement. Optional nutrients may include a blend of antioxidants
such as trans beta-carotene, cis beta-carotenes, cis alpha-carotenes, trans lycopene, cis
lycopene, trans gamma-carotene, cis gamma-carotene, zeta-carotene, phytofluene,
phytoene, vitamin C, cis lutein, trans lutein, cis lutein esters, trans lutein esters, cis
zeaxanthin, trans zeaxanthin, cis zeaxanthin ester, trans zeaxanthin ester, beta
crytoxantyhin and glutamine and other nutrients such as vitamin A, vitamin Bi,
vitamin B2, vitamin B6, vitamin B12, vitamin C, vitamin D, vitamin K, biotin, folic
acid, pantothenic acid, niacin, m-inositol, calcium, phosphorus, magnesium, zinc,
manganese, copper, sodium, potassium, chloride, iron, chromium, molybdenum, and
selenium.
[0075] An optional infant dietary supplement of the instant invention
typically supplies about 80% of the AI for vitamin E for infants in the alpha- to
gamma-tocopherol ratio of the invention per day, from about 65 to 145 meg/day betacryptoxanthin,
from about 100 to about 145 meg/day lycopene, from about 40 to about
80 meg/day alpha-carotene, from about 175 to about 355 meg/day beta-carotene and
from about 175 to about 355 meg/day lutein/zeaxanthin. Typically, 1ml is a unit dose
which is administered to the infant at least once a day. Alternatively, the optimized
tocopherol blend of the instant invention may be added to a nutritional composition,
such as an infant nutritional formula.
Infant Nutritional Formula
[0076] Infant formulas are known in the art and one knowledgeable in the art
would be able to adjust the formula to include the alpha- to gamma-tocopherol ratio of
the instant invention. For example, an infant formula typically contains a protein
component comprising from about 6 to about 25% of the total caloric content of said
infant formula; a carbohydrate component comprising from about 35 to about 50% of
the total caloric content of said infant formula; and a lipid component comprising from
about 30 to about 50% of the total caloric content of said infant formula. These ranges
are provided as examples only, and are not intended to be limiting. The fat component
of an infant formula is an ideal source of energy for infants, not only because of its
high caloric density but also because of its low osmotic activity in solution. The fat
component also solubilizes fat-soluble vitamins and emulsifiers in the aqueous
solution.
[0077] Based on the known tocopherol content of different oils, one skilled in
the art would be able to select a fat source or blend of fats to achieve the desired alphato
gamma-tocopherol ratio of the instant invention as well as meet the desired fatty
acid profile for the specific application. Suitable fats will be readily apparent to those
skilled in the art.
[0078] Alternatively, isolated alpha- and gamma-tocopherol may be
individually added to a fat system to achieve the desired alpha- to gamma-tocopherol
ratio.
[0079] One knowledgeable in the art would understand that appropriate
additional amounts of vitamin E may need to be provided to nutritional compositions
to compensate for some loss during processing and storage of such compositions.
Practitioners would also understand that the degree of unsaturation of the component
oils must be considered when calculating the required amount of vitamin E. A
predictable amount of the Vitamin E would be required to prevent oxidation of the
component oils in the nutritional product.
[0080] Additional components of the infant formula typically include, for
example, protein, carbohydrates, vitamins and minerals. Protein is needed for growth,
synthesis of enzymes and hormones, and replacement of protein lost from the skin and
in urine and feces. These metabolic processes determine the need for both the total
amount of protein in a feeding and the relative amounts of specific amino acids. The
adequacy of the amount and type of protein in a feeding for infants is determined by
measuring growth, nitrogen absorption and retention, plasma amino acids, certain
blood analytes and metabolic responses.
[008 1] The proteins that may be utilized in the infant nutritional products of
the invention include any proteins or nitrogen source suitable for human consumption.
Such proteins are well known by those skilled in the art and can be readily selected
when preparing such products. Examples of suitable protein sources for an infant
typically include casein, whey, condensed skim milk, nonfat milk, soy, pea, rice, corn,
hydrolyzed protein, free amino acids, protein sources which contain calcium in a
colloidal suspension with the protein. Any single protein listed above, or any
combination thereof, as appropriate may be utilized. Other suitable proteins will be
readily apparent to those skilled in the art.
[0082] A preferred protein system typically comprises 7% whey protein
concentrate and 93% nonfat milk.
[0083] Commercial protein sources are readily available and known to one
practicing the art. For example, caseinates, whey, hydrolyzed caseinates, hydrolyzed
whey, and milk proteins are available from New Zealand Milk Products of Santa Rosa,
California. Soy and hydrolyzed soy proteins are available from Protein Technologies
International of Saint Louis, Missouri. Pea protein is available from Feinkost
Ingredients Company of Lodi, Ohio. Rice protein is available from California Natural
Products of Lathrop, California. Corn protein is available from EnerGenetics Inc. of
Keokuk, Iowa. Additionally, mineral enriched proteins are available from New
Zealand Milk Products of Santa Rosa, California and Protein Technologies
International of Saint Louis, Missouri.
[0084] An additional component of the infant formula of this invention is a
source of carbohydrates. Carbohydrates are a major source of readily available energy
that the infant needs for growth and that protects the infant from tissue catabolism. In
human milk and most standard milk-based infant formulas, the carbohydrate is lactose.
[0085] The carbohydrates that may be used in the infant formula can vary
widely. Examples of carbohydrates suitable for infants typically include hydrolyzed
cornstarch, maltodextrin, glucose polymers, sucrose, lactose, corn syrup, corn syrup
solids, rice syrup, glucose, fructose, high fructose corn syrup and indigestible
oligosaccharides such as fructooligosaccharides (FOS). Any single carbohydrate listed
above, or any combination thereof, as appropriate may be utilized. Other suitable
carbohydrates will be readily apparent to those skilled in the art.
[0086] Typically, lactose is the preferred carbohydrate source that comprises
100% of the carbohydrate component.
[0087] Commercial sources for the carbohydrates listed above are readily
available and known to one practicing the art. For example, corn syrup solids are
available from Cerestar USA, Inc. in Hammond, Indiana. Glucose and rice based
syrups are available from California Natural Products in Lathrop, California. Various
corn syrups and high fructose corn syrups are available from Cargill in Minneapolis,
Minnesota. Fructose is available from A. E. Staley in Decatur, Illinois. Maltodextrin,
glucose polymers, and hydrolyzed corn starch are available from American Maize
Products in Hammond, Indiana. Sucrose is available from Domino Sugar Corp. in
New York, New York. Lactose is available from Foremost in Baraboo, Wisconsin,
and indigestible oligosaccharides, such as FOS, are available from Golden
Technologies Company of Golden, Colorado.
[0088] The infant formula of the present invention typically includes
supplemented vitamins and minerals.
[0089] Infants require the electrolytes sodium, potassium and chloride for
growth and for acid-base balance. Sufficient intakes of these electrolytes are also
needed for replacement of losses in the urine and stool and from the skin. Calcium,
phosphorus and magnesium are needed for proper bone mineralization. For bones to
grow, adequate amounts of these minerals must be present in a feeding. Infants may
develop rickets or osteopenia if they do not receive adequate amount of calcium and
phosphorus in their diet. Phosphorus and magnesium are also found in intracellular
fluid. These minerals are needed for the growth and function of soft tissue.
[0090] Trace minerals are associated with cell division, immune function and
growth. Consequently, provision of sufficient amounts of trace minerals is needed for
rapid growth in infants. Another trace mineral, iron, is important for the synthesis of
hemoglobin, myoglobin, and iron-containing enzymes. However, it is not certain that
infants need the recommended amounts of iron during the first 2 months of life. Also,
it is estimated that infants have sufficient iron stores without receiving iron
supplementation, if blood loss is small, until 2 months of age. Consequently, the infant
formula of the instant invention may be optionally fortified with iron. Zinc is needed
for growth, for the activity of numerous enzymes, and for DNA, RNA and protein
synthesis. Copper is necessary for the activity of several important enzymes.
Manganese is needed for the development of bone and cartilage and is important in the
synthesis of polysaccharides and glycoproteins.
[0091] Vitamin A is a fat-soluble vitamin essential for normal bone formation
and for maintenance of specialized epithelial surfaces, which include mucous
membranes of the eyes; the mucosa of the respiratory, gastrointestinal and
genitourinary tracts; the ducts of various glands; and the skin, hair, gums and teeth.
Vitamin D is important for absorption of calcium and to a lesser extent, phosphorus,
and for the development of bone. Vitamin K is important in the biosynthesis of
prothrombin and other blood-clotting factors. Newborn infants have little reserve of
vitamin K and do not have a source for vitamin K until after intestinal bacteria are
established, thereby becoming an important source of vitamin K for the infant. Vitamin
E (tocopherol) prevents peroxidation of polyunsaturated fatty acids in the cell, thus
preventing tissue damage. Infants may develop hemolytic anemia and vitamin E
deficiency when fed feedings low in vitamin E and high in iron and polyunsaturated
fatty acids.
[0092] Vitamin C is necessary in the formulation of collagen and dentine and
is required for the metabolic reactions of amino acids and for the synthesis of anti
inflammatory steroids by the adrenal glands. Folic acid is important in amino acid and
nucleotide metabolism. Serum folate concentrations have been shown to fall below
normal after 2 weeks of age in infants with low folic acid intakes. Thiamine (vitamin
Bl) functions as a coenzyme in oxidative metabolism. Riboflavin (vitamin B2) assists
in the transfer of oxygen from plasma to substrate of tissue cells and also functions in
hydrogen transport mechanisms. Niacin plays an essential role in the electron transport
involved in cellular respiration and appears to be involved in pigment and fat
metabolism. Pyridoxine (vitamin B6) functions as a coenzyme in amino acid
decarboxylation, in transamination, and in tryptophan metabolism. Vitamin B12 is
essential in the formulation of DNA, nuclear maturation, and cell division. Pantothenic
acid functions as an important cofactor for all acylation reaction in the body. It is
involved in gluconeogenesis, synthesis of fatty acids, and sterols, and cellular
metabolism of fats, carbohydrates, and proteins.
[0093] Based on the requirements described above, the infant formula
requires fortification to insure that a developing infant receives adequate amounts of
vitamins and minerals while not over fortifying and possibly causing, for example,
hypercalcemia. Using the recommendations of the FNB, one skilled in the art can
readily calculate how much of a vitamin or mineral source should be added to the
nutritional product in order to deliver the desired amount of a vitamin or mineral.
Practitioners also understand that appropriate additional amounts of vitamin and
mineral ingredients need to be provided to nutritional compositions to compensate for
some loss during processing and storage of such compositions.
[0094] Examples of vitamins and minerals that may be added to the infant
formula of the instant invention typically include vitamin A, vitamin Bi, vitamin B2,
vitamin B6, vitamin B12, vitamin C, vitamin D, vitamin K, vitamin E, biotin, folic acid,
pantothenic acid, niacin, m-inositol, calcium, phosphorus, magnesium, zinc,
manganese, copper, sodium, potassium, chloride, iron and selenium. The additional
nutrients chromium, molybdenum, iodine, taurine, carnitine and choline may also
require supplementation. As discussed above, the infant formula will include the
natural form of vitamin E in the alpha- to gamma-tocopherol ratio of the instant
invention.
[0095] Typically, 100% of the AI for vitamin E in the alpha- to gammatocopherol
ratio of the instant invention is added to a liter of infant formula, which is a
typical volume of formula consumed by an infant in a day.
[0096] The infant formula of this invention can be manufactured using
techniques well known to those skilled in the art. While manufacturing variations are
certainly well known to those skilled in the nutritional formulation arts, a few of the
manufacturing techniques are described in detail in the Examples. Generally speaking
a protein-in-oil blend is prepared containing all oils, any emulsifier, the fat-soluble
vitamins and a portion of the protein. A second slurry is prepared by mixing the
carbohydrate and minerals together. The protein-in-oil and any remaining protein are
added to the carbohydrate/mineral slurry. The resulting mixture is homogenized, heat
processed, standardized with water-soluble vitamins. The concentrated formula may be
filled into appropriate packaging and sterilized; aseptically filled into sterile packaging;
or dried and filled into appropriate packaging. The resulting powder may be milled to a
specific particle size and/or agglomerated to modify particle size and mixability
characteristics. Those skilled in the nutritional formulation arts would also be able to
dry blend the individual starting materials and add the liquid ingredients through
agglomeration or during the dry blending step. The concentrated blend may also be
diluted and filled into appropriate packaging and sterilized or aseptically filled into
sterile packaging.
[0097] Numerous types of packaging are readily available and known to one
practicing the art. Desirable packaging characteristics include: effective protection
against impact, light, and heat; ease of opening; and efficient sealing for storage
stability.
Human Milk Fortifier
[0098] Premature infants require additional nutrients to support their growth
and are at risk for the diseases related to prematurity related to oxidation. Therefore, a
human milk fortifier would be a preferred vehicle to deliver the alpha- to gammatocopherol
ratio of the instant invention. A human milk fortifier of this invention is a
powder which when added to human milk delivers the preferred alpha- to gammatocopherol
ratio and supplements the levels of protein, fat, vitamins and minerals.
[0099] Although not intended to limit the invention in any manner, but to
merely serve as a general guideline, the human milk fortifier powder of this invention
will typically provide the following macronutrient distribution. The protein component
will typically be present in an amount of from about 24 wt/wt % to about 55 wt/wt %
of the fortifier powder. The fat component will typically be present in an amount of
from about 1 wt/wt % to about 30 wt/wt % of the fortifier powder. The carbohydrate
component will typically be present in an amount of from about 15 wt/wt % to about
75 wt/wt % of the fortifier powder. Additionally, the amount of powder required to
provide a unit dose of the fortifier will typically range from about 0.5 grams to about
10 grams of powder in a unit dose. The caloric density is typically from about 1.0
kcal/gram of powder to about 8.5 kcal/gram of powder.
[00100] The first component of the fortifier powder of this invention is a
source of protein. As in the term infant, the preterm infant requires protein for growth,
synthesis of enzymes and hormones, and replacement of protein lost from the skin and
in urine and feces. These metabolic processes determine the need for both the total
amount of protein in a feeding and the relative amounts of specific amino acids. The
adequacy of the amount and type of protein in a feeding for infants is determined by
measuring growth, nitrogen absorption and retention, plasma amino acids, certain
blood analytes and metabolic responses.
[00 10 1] As stated above, the protein component will typically be present in
an amount of from about 24 wt/wt % to about 55 wt/wt % of the fortifier powder. The
proteins that may be utilized in the nutritional products of the invention include any
proteins or nitrogen source suitable for human consumption. Such proteins are well
known by those skilled in the art and can be readily selected when preparing such
products. Examples of suitable protein sources for a premature infant typically include
casein, whey, condensed skim milk, nonfat milk, soy, pea, rice, corn, hydrolyzed
protein, free amino acids, protein sources which contain calcium in a colloidal
suspension with the protein. Any single protein listed above, or any combination
thereof, as appropriate may be utilized. Other suitable proteins will be readily apparent
to those skilled in the art.
[00102] The preferred protein system will typically be comprised of about 51
wt/wt % of the protein component as whey protein concentrate and about 49 wt/wt %
of the protein component as nonfat dry milk, which corresponds to about 60 wt/wt %
of the protein component as whey and about 40 wt/wt % of the protein component as
casein.
[00103] Commercial protein sources are readily available and known to one
practicing the art. For example, caseinates, whey, hydrolyzed caseinates, hydrolyzed
whey and milk proteins are available from New Zealand Milk Products of Santa Rosa,
California. Soy and hydrolyzed soy proteins are available from Protein Technologies
International of Saint Louis, Missouri. Pea protein is available from Feinkost
Ingredients Company of Lodi, Ohio. Rice protein is available from California Natural
Products of Lathrop, California. Corn protein is available from EnerGenetics Inc. of
Keokuk, Iowa. Additionally, mineral enriched proteins are available from New
Zealand Milk Products of Santa Rosa, California and Protein Technologies
International of Saint Louis, Missouri.
[00104] The second component of the fortifier powder of this invention is a
source of fat. Fat is an ideal source of energy for low birth weight (LBW) infants, not
only because of its high caloric density but also because of its low osmotic activity in
solution.
[00105] As stated above, the fat component will typically be present in an
amount of from about 1 wt/wt % to about 30 wt/wt % of the fortifier powder. Suitable
fats will be readily apparent to those skilled in the art
[00106] Docosahexaenoic acid (DHA) is an omega-3 fatty acid and is thought
to be essential for the proper brain and vision development of infants because it is the
most abundant long chain polyunsaturated fatty acid (PUFA) in the brain and retina.
Although a metabolic pathway exists in mammals for the biosynthesis of DHA from
dietary linoleic acid, this pathway is bioenergetically unfavorable and mammals are
thought to obtain most of their DHA from dietary sources. In the case of infants, the
most likely source would be human milk. Indeed, DHA is the most abundant 20 carbon
omega-3 PUFA in human milk. However, human milk DHA content will vary greatly
depending on the diet of the mother. If the mother eats fish high in DHA often, her
milk will contain higher DHA levels, while a mom with less access to fish will have
lower DHA levels in her milk. Consequently, human milk may require DHA
supplementation to insure that the preterm infant is receiving sufficient amounts of
DHA. Preferably, DHA supplementation is accompanied by arachidonic acid (ARA)
supplementation. U.S. Pat. No. 5,492,938 to Kyle et al. describes a method of
obtaining DHA from dinoflagellates and its use in pharmaceutical composition and
dietary supplements.
[00107] Typically, medium chain triglycerides (MCT) oil is the preferred fat
source, which comprises 100% of the fat component. This fat source, at this level
provides well-tolerated fat calories to the premature infant in addition to providing a
vehicle for the desired alpha- to gamma-tocopherol ratio of the invention, other fatsoluble
vitamins and emulsifiers. Since MCT oil (e.g., fractionated coconut oil)
contains negligible levels of alpha- and gamma-tocopherol, the human milk fortifier is
fortified with isolated alpha- and gamma-tocopherol to achieve the alpha- to gammatocopherol
ratio of the instant invention.
[00108] An emulsifier is typically incorporated into the fortifier powder.
Emulsifiers help the water soluble and insoluble components of the fortifier powder
incorporate into the human milk. Examples of suitable emulsifiers typically include
soya bean lecithin, polyoxythylene stearate, polyoxyethylene sorbitan mono-oleate,
polyoxyethylene sorbitan monopalmitate, polyoxyethylene sorbitan monostearate,
ammonium phosphatides, polyoxyethylene sorbitan monolaurate, citric acid esters of
mono and diglycerides of fatty acids, tartaric acid esters of mono and diglycerides of
fatty acids.
[00109] The preferred emulsifier source is natural soy lecithin. The amount
of emulsifier will typically be present in an amount of from about 1 wt/wt % to about
10 wt/wt % of the fat component, which corresponds to about 0.1 wt/wt % to about 1
wt/wt % of the fortifier powder.
[001 10] Numerous commercial sources for the emulsifiers listed above are
readily available and known to one practicing the art. For example, soya bean lecithin
is available from Archer Daniels Midland Company in Decatur, Illinois.
Polyoxythylene stearate, polyoxyethylene sorbitan mono-oleate, polyoxyethylene
sorbitan monopalmitate, polyoxyethylene sorbitan monostearate, polyoxyethylene
sorbitan monolaurate, citric acid esters of mono and diglycerides of fatty acids, and
tartaric acid esters of mono and diglycerides of fatty acids are available from Quest in
Owings Mills, Maryland.
[001 11] The third component of the fortifier powder of this invention is a
source of carbohydrates. Carbohydrate is a major source of readily available energy
that the LBW infant needs for growth and that protects the infant from tissue
catabolism. In human milk and most standard milk-based infant formulas, the
carbohydrate is lactose. LBW infants may be unable to fully digest lactose because
lactase activity in the fetal intestine is not fully developed until late in gestation (36 to
40 weeks). On the other hand, sucrose activity is maximal by 32 weeks' gestation, and
glucosoamylase activity, which digests corn syrup solids (glucose polymers), increase
twice as rapidly as lactase activity during the third trimester.
[001 12] As noted above, the carbohydrates will typically be present in an
amount of from about 15 wt/wt % to about 75 wt/wt % of the fortifier powder. The
preferred carbohydrate level and source is selected to decrease osmolality and viscosity
of the reconstituted product. The preferred carbohydrate source is 100% of the
carbohydrate component as corn syrup.
[001 13] The carbohydrates that may be used in the fortifier powder can vary
widely. Examples of carbohydrates suitable for preterm infants typically include
hydrolyzed cornstarch, maltodextrin, glucose polymers, sucrose, corn syrup, corn
syrup solids, rice syrup, glucose, fructose, lactose, high fructose corn syrup and
indigestible oligosaccharides such as fructooligosaccharides (FOS). Any single
carbohydrate listed above, or any combination thereof, as appropriate may be utilized.
[001 14] Commercial sources for the carbohydrates listed above are readily
available and known to one practicing the art. For example, corn syrup solids are
available from Cerestar USA, Inc in Hammond, Indiana. Glucose and rice based
syrups are available from California Natural Products in Lathrop, California. Various
corn syrups and high fructose corn syrups are available from Cargil in Minneapolis,
Minnesota. Fructose is available from A. E. Staley in Decatur, Illinois. Maltodextrin,
glucose polymers, hydrolyzed corn starch are available from American Maize Products
in Hammond, Indiana. Sucrose is available from Domino Sugar Corp. in New York,
New York. Lactose is available from Foremost in Baraboo, Wisconsin, and
indigestible oligosaccharides such as FOS are available from Golden Technologies
Company of Golden, Colorado.
[001 15] The osmolality of the fortified human milk plays an important role in
the infant's tolerance of their feedings such as abdominal distention and vomiting/spitup.
Osmolality of the fortified human milk is tied to the level and source of
carbohydrate utilized in the fortifier powder. The osmolality of the fortifier powder of
the instant invention reconstituted in human milk is typically less than about 400
mOsm/kg water. The substitution of fat for some of the carbohydrate in the fortifier
powder of the instant invention serves to reduce the osmolality of fortified human milk
by replacing the carbohydrate, which has a high osmotic activity with fat, which has a
low osmotic activity. The type of carbohydrate incorporated into the fortifier powder
also impacts the osmolality of the fortified human milk. The more hydrolyzed the
carbohydrate source (higher DE) the higher the osmotic activity. Additionally, partially
hydrolyzed carbohydrate sources may further increase the osmolality when
reconstituted with human milk due to further hydrolysis by human milk amylase.
Based on the DE values for carbohydrates, one skilled in the art can readily select the
carbohydrate source or combination of carbohydrates that will result in the preferred
osmolality of the reconstituted fortifier powder/human milk solution.
[001 16] As stated above, viscosity is also a characteristic of carbohydrates.
Viscosity of the reconstituted fortifier powder/human milk solution plays a role in
suspending the insoluble minerals during feeding. While higher viscosities tend to
reduce insoluble mineral fallout, the higher viscosity can cause tube/nipple clogging. A
clogged feeding tube in a continuous feeding apparatus requires additional attention by
the nursing staff, who will have to unclog the tube, reset the pump system, which may
require a new preparation of fortified human milk. More importantly, a clogged tube
prevents the timely delivery of much needed nutrients to a premature infant. The
viscosity of the reconstituted fortifier powder/human milk solution of the instant
invention is typically less than about 30 cps. Viscosity is inversely related to
osmolality. The more hydrolyzed a starch is (higher DE), the lower the viscosity and
the higher the osmolality. Based on the DE values for carbohydrates, one skilled in the
art can readily select the carbohydrate source or combination of carbohydrates that will
drive the viscosity and osmolality characteristics of the reconstituted fortifier
powder/human milk solution to the preferred levels.
[00 117] The fourth component of the fortifier powder of the present invention
typically includes supplemented vitamins and minerals.
[001 18] The preterm infant requires the electrolytes sodium, potassium and
chloride for growth and for acid-base balance. Sufficient intakes of these electrolytes
are also needed for replacement of losses in the urine and stool and from the skin.
Calcium, phosphorus and magnesium are needed for proper bone mineralization. For
bones to grow, adequate amounts of these minerals must be present in a feeding. LBW
infants may develop rickets or osteopenia if they do not receive adequate amount of
calcium and phosphorus in their diet. Phosphorus and magnesium are also found in
intracellular fluid. These minerals are needed for the growth and function of soft tissue.
Human milk does not provide enough calcium or phosphorus, even if these minerals
were to be totally absorbed and retained, which they are not.
[001 19] Trace minerals are associated with cell division, immune function
and growth. Consequently, provision of sufficient amounts of trace minerals is needed
for rapid growth in LBW infants. Human milk does not provide sufficient amounts of
the trace minerals, especially zinc and copper, to meet the needs of a growing LBW
infant. Another trace mineral, iron, is important for the synthesis of hemoglobin,
myoglobin and iron-containing enzymes. However, it is not certain that LBW infants
need the recommended amounts of iron during the first 2 months of life. The anemia of
prematurity occurring shortly after birth cannot be avoided by giving supplemental
iron. Also, the preterm infant is estimated to have sufficient iron stores without
receiving iron supplementation, if blood loss is small, until 2 months of age.
Consequently, the powdered human milk fortifier of the instant invention is low in
iron. Zinc is needed for growth, for the activity of numerous enzymes, and for DNA,
R A and protein synthesis. Copper is necessary for the activity of several important
enzymes. It is estimated that about 75% of the copper in a term neonate is accumulated
during the last 10 to 12 weeks in utero. Consequently, LBW infants, especially those
born weighing less than 1500 gm, are likely to have low copper stores. Manganese is
needed for the development of bone and cartilage and is important in the synthesis of
polysaccharides and glycoproteins.
[00120] LBW infants are likely to need more of most vitamins than provided
by human milk alone because of low vitamin stores at birth, low intake of feedings,
poor absorption of vitamins and clinical conditions requiring increased vitamin intakes.
[00121] Vitamin A is a fat-soluble vitamin essential for growth, cell
differentiation, vision and the immune system. The vitamin A stores in LBW infants
are adequate shortly after birth but decrease soon thereafter. Therefore, preterm infants
may require higher intakes of vitamin A than term infants. Vitamin D is important for
absorption of calcium and to a lesser extent, phosphorus, and for the development of
bone. For many years it was thought that poor bone development observed in LBW
infants was due to insufficient vitamin D intake and metabolism and the LBW infants
required significantly greater vitamin D intake than term infants. It is now recognized
that calcium and phosphorus intakes are more important than vitamin D for bone
growth in preterm infants. Vitamin E (tocopherol) prevents peroxidation of
polyunsaturated fatty acids in the cell, thus preventing tissue damage. LBW infants
may develop hemolytic anemia and vitamin E deficiency when fed feedings low in
vitamin E and high in iron and polyunsaturated fatty acids. Additionally, preterm milk
contains very low levels of vitamin K.
[00122] As are several other water-soluble vitamins, vitamin C is low in
mature preterm milk. Folic acid is important in amino acid and nucleotide metabolism.
Serum folate concentrations have been shown to fall below normal after 2 weeks of
age in LBW infants with low folic acid intakes. Additionally, several B vitamins are
present at low concentrations in preterm milk.
[00123] The variability of human milk vitamin and mineral concentrations
and the increased needs of the preterm infant require a minimal fortification to insure
that a developing premature infant is receiving adequate amounts of vitamins and
minerals while not over fortifying and possibly causing, for example, hypocalcaemia.
Using the recommendations of the FNB, one skilled in the art can readily calculate
how much of a vitamin or mineral source should be added to the nutritional product in
order to deliver the desired amount of a vitamin or mineral. Practitioners also
understand that appropriate additional amounts of vitamin and mineral ingredients
need to be provided to nutritional compositions to compensate for some loss during
processing and storage of such compositions.
[00124] Examples of supplemental vitamins and minerals in the fortifier
powder of the instant invention typically include vitamin A, vitamin Bi, vitamin B2,
vitamin B6, vitamin B12, vitamin C, vitamin D, vitamin E, vitamin K, biotin, folic acid,
pantothenic acid, niacin, m-inositol, calcium, phosphorus, magnesium, zinc,
manganese, copper, sodium, potassium, chloride, iron and selenium. The additional
nutrients chromium, molybdenum, iodine, taurine, carnitine and choline may also
require supplementation. As discussed above, the fortifier powder will include the
natural form of vitamin E in the alpha- to gamma-tocopherol ratio of the instant
invention. Preferably, a unit dose typically comprises at least about 25% of the AI for
infants for vitamin E.
[00125] The nutritional powder of this invention can be manufactured using
techniques well known to those skilled in the art. While manufacturing variations are
certainly well known to those skilled in the nutritional formulation arts, a few of the
manufacturing techniques are described in detail in the Examples. Generally speaking
an oil blend is prepared containing all oils, any emulsifier, and the fat soluble vitamins.
Two more slurries (carbohydrate and protein) are prepared separately by mixing the
carbohydrate and minerals together and the protein in water. The two slurries are then
mixed together with the oil blend. The resulting mixture is homogenized, heat
processed, standardized with water soluble vitamins, and dried. The resulting powder
may be milled to a specific particle size and /or agglomerated to modify particle size
and mixability characteristics. Those skilled in the nutritional formulation arts would
also be able to dry blend the individual starting materials and add the liquid ingredients
through agglomeration or during the dry blending step.
[00126] Individual unit dose size packages are preferred over bulk packaging.
Because of the small volumes of milk administered to premature infants over the
course of a day's feeding, small volumes of fortified human milk are prepared. Powder
sterility in a bulk container that has been repeatedly opened, powder scooped out,
recovered and stored is always a concern in a hospital environment. Individual unit
doses allow for addition of small amounts of powder to human milk without the
possibility of contamination of the remaining powder since all of the powder is used in
a single preparation. As noted above, the unit dose of the invention typically is the
amount of from about 0.5 grams to about 10 grams of fortifier powder in a unit dose.
Depending on the volume of a day's feeding, from about 1 to about 4 unit doses will be
added to about 25 ml to about 100 ml, respectively.
[00127] Numerous types of containers are readily available and known to one
practicing the art. Examples of container types typically include packets or sachets,
which may be manufactured of paper, foil and plastic film, and foil and plastic film
coated paper; and ampoules which may be manufactured of plastic, reinforced paper
and glass.
Methods of Use
[00128] The methods of the present disclosure include the oral administration
of the nutritional compositions, and, in some aspects, infant formulas, disclosed herein
to enhance brain development in an individual. The methods include administering to
the individual a nutritional composition comprising: i) from about 20 g/L to about 50
g/L of fat; ii) from about 10 g/L to about 15 g/L of protein; wherein said fat comprises
RRR alpha-tocopherol and RRR gamma-tocopherol, with a weight ratio of RRR alphatocopherol
to RRR gamma-tocopherol ranging from about 3.5:1 to about 10:1; and iii)
no more than about 8 mg/L of a non-RRR alpha-tocopherol isomer.
[00129] In some aspects, the methods include the administration of
nutritional compositions having one or more of additional properties (e.g., ingredients
and/or concentrations of ingredients) of nutritional compositions disclosed above.
Thus, in one aspect, the method involves administering a nutritional composition that
has a weight ratio of RRR alpha-tocopherol to RRR gamma-tocopherol of about 5:1.
In another aspect, the method involves administering a nutritional composition that is
substantially free of non-RRR alpha-tocopherol isomers. In another aspect, the
administered nutritional composition includes one or more of a carbohydrate, a
polyunsaturated fatty acid, a carotenoid, vitamin C, trans-lutein, and combinations
thereof. In a particular aspect, the administered nutritional composition includes a
carotenoid. In another aspect, the administered nutritional composition includes a
trans-lutein, and, more particularly, all trans-lutein. In another particular aspect, the
administered nutritional composition includes vitamin C (e.g. , ascorbic acid). In a
specific aspect, the administered nutritional composition contains a combination of
properties of the above-disclosed nutritional compositions.
[00130] In addition to enhancing brain development, the nutritional
compositions can be administered to improve cognitive performance, including
cognitive development, in an individual, including in an infant or a preterm infant.
Particularly, the disclosed combination of RRR-alpha tocopherol, fat, and protein,
wherein the presence of non-RRR alpha-tocopherol isomers are limited, including
where the administered nutritional composition is substantially free of a non-RRR
alpha-tocopherol isomer, may improve general cognition by enhancing memory
acquisition, memory retention and memory recall that contributes to the cognitive
functions of learning, thinking, and memory.
[0013 1] The nutritional compositions as described herein can be administered
to individuals including infants generally, or may, in some embodiments, be
administered to a specific subclass of infants that are "in need thereof;" that is, to
specific infants that would specifically benefit by administration of the infant formula.
For example, a specific infant may be "in need of the infant formulas as described
herein if they are susceptible to (i.e., genetically predisposed, have a family history of,
and/or having symptoms of the disease or condition) neurodegenerative diseases or
other diseases and conditions that can impair/reduce cognition generally or specific
aspects of cognition. In certain embodiments of the methods, the individual is a preterm
infant.
[00132] The individual desirably consumes at least one serving of the
nutritional composition daily, and in some embodiments, may consume two, three, or
even more servings per day. In certain embodiments of the methods, the nutritional
composition is an infant formula. In certain embodiments of the methods, the
nutritional composition is a preterm infant formula. Each serving is desirably
administered as a single, undivided dose, although the serving may also be divided into
two or more partial or divided servings to be taken at two or more times during the day.
The methods of the present disclosure include continuous day after day administration,
as well as periodic or limited administration, although continuous day after day
administration is generally desirable. The methods of the present disclosure are
preferably applied on a daily basis, wherein the daily administration is maintained
continuously for at least 3 days, including at least 5 days, including at least 1 month,
including at least 6 weeks, including at least 8 weeks, including at least 2 months,
including at least 6 months, desirably for at least about 18-24 months, desirably as a
long term, continuous, daily, dietary source or supplement.
EXAMPLE 1
[00133] As discussed above, the alpha- to gamma-tocopherol ratio of this
invention may be incorporated into infant nutritional formulas.
[00134] A batch of powder infant formula is manufactured as described in
Example II except that the processed mix is sent to a spray dryer as described below.
[00135] The processed mix is preheated through a plate heater to 71° C-82° C
before going to a surge tank. The mix leaves the surge tank and passes through the
steam injector where it is heated to 88° C-93° C. The mix enters the vapor-flash
chamber where it is cooled to 71° C-82° C, then pumped through an in-line 200 micro
filter prior to the high-pressure pump and into the dryer. The dryer settings are as
follows: the nozzle pressure 3000-5000 psig, the liquid flow rate 11 gpm max, the
ingoing air temperature 160° C-207° C, and outgoing air temperature 82° C-108° C.
[00136] To control bulk density, dispensability, particle size, moisture and
physical stability, the specific spray nozzle, nozzle pressure, drying temperatures and
fine reinjection parameters may vary depending upon the drying conditions of the day.
The powder passes from the dryer into the powder cooler where the powder is cooled
to below 43° C. The cooled powder is stored in appropriate containers until being filled
into the desired packaging.
EXAMPLE II
[00137] As discussed above, the alpha- to gamma-tocopherol ratio of this
invention may be incorporated into a human milk fortifier powder, which is added to
human milk.
[00 138] A batch of fortifier powder is manufactured by combining the
appropriate ingredients to generate one carbohydrate/mineral (CHO/MGN) slurry, one
oil blend and one protein in water (PIW) slurry. The CHO/MIN, oil blend and PIW
slurries are mixed together to form the final blend. The final blend is then processed
with an HTST treatment. After standardization, the final blend is spray dried.
[00139] Table 5 presents a bill of materials for manufacturing 8,172 kg of
powdered human milk fortifier. A detailed description of its manufacture follows.
TABLE 5
Bill of Materials
Ingredient Amount
Ingredient water 16,205 L
Corn syrup solids 1603 kg
Magnesium chloride 96.2 kg
Potassium citrate 223.8 kg
Sodium citrate 6.6 kg
Sodium chloride 15.4 kg
MCT oil 801 kg
Lecithin 16.6 kg
Vitamin A 2.36 kg
Vitamin D 359.3 g
Vitamin K 27.5 g
RRR alpha-tocopherol acetate 13.2 kg
RRR gamma-tocopherol acetate 2.6 kg
Calcium carbonate 33.1 kg
Tricalcium phosphate 646 kg
Whey protein concentrate 1506 kg
Non fat dry milk 3307 kg
Potassium citrate 257.2 g
Ferrous sulfate 3.7 kg
Zinc sulfate 11.1 kg
Copper sulfate 1.84 kg
Manganese sulfate 0.320 kg
Sodium selenate 0.001 kg
Niacinamide 0.98 k
Riboflavin 1.14 k g
Calcium pantothenate 4.08 k g
Pyridoxine hydrochloride 0.655 kg
m-inositol 9.55 k g
Biotin 0.0727 k g
Folic acid 0.0775 k g
Cyanocobalamin 0.0016 k g
Ascorbic acid 153.5 kg
[00140] A carbohydrate/mineral slurry is prepared by heating 2,763 liters of
ingredient water to 54° C-62° C. With agitation, the specified amounts of corn syrup
solids (Maltrin M200 distributed by Grain Processing Corporation, Muscatine, Iowa),
magnesium chloride, sodium chloride, sodium citrate, potassium citrate, ultra
micronized tricalcium phosphate and calcium carbonate are added to the heated water.
The slurry is held under agitation at 54° C-62° C for not longer than six hours until it
is blended with the other slurries.
[00 141] An oil blend is prepared by heating the specified amount of oil
(distributed by Stepan, Maywood, N.J.) to 32° C-37° C. with agitation. An emulsifier
(standard fluid lecithin distributed by Central Soya, Ft. Wayne, Ind.) is then added
under agitation and allowed to dissolve. Vitamin A, D , K and Vitamin E (distributed
by Vitamins, Inc., Chicago, 111.) are then added to the slurry with agitation. The
completed oil slurry is held under moderate agitation at a temperature from 26° C to
48° C. for a period of no longer than six hours until it is blended with the other slurries.
[00142] A protein-in- water slurry is prepared by heating 9,053 liters of
ingredient water to 48° C-60° C. With agitation, the specified amount of whey protein
concentrate (AMP 800 distributed by AMPC, Inc. Ames, Iowa) and nonfat dry milk is
added to the heated water. The completed protein-in-water slurry is not held but
blended directly with the other slurries.
[00143] The protein-in-water, oil blend and carbohydrate/mineral slurries are
blended together with agitation and the resultant blend is maintained at a temperature
from 5 1° C to 60° C. After waiting for at least five minutes with agitation the final
blend H is adjusted with IN KOH to a pH from 6.45 to 6.80. The total solids of the
final blend is 30%. The final blend is held for no longer than two hours after the pH
check.
[00144] After waiting for a period of not less than five minutes nor greater
than two hours, the blend is subjected to deaeration, high-temperature-short-time heat
treatment, and homogenization, as follows: deaerate the blend at 10-15 inches Hg;
emulsify the blend at 900-1 100 psig in a single stage homogenizer; pass the blend
through a plate/coil heater and heat the mix to 71° C to 82° C; homogenize the blend at
3900 to 4100/400 to 600 psig in a double stage homogenizer; pass the blend through a
16 second hold tube at a temperature from 73° C to 85° C; cool the blend to a
temperature from 1° C to 7° C; and store the blend at a temperature from 1° C to 7° C.
[00145] After the above steps have been completed, appropriate analytical
testing for quality control is conducted. Based on the analytical results of the quality
control tests, batch corrections are made if need be. Final blend total solids are from
29% to 31%.
[00146] A water soluble vitamin solution, ascorbic acid solution and trace
mineral solution are prepared separately and added to the processed blend.
[00147] The ascorbic acid solution is prepared by adding the required amount
of ascorbic acid to 2,453 liters of 10° C to 37° C water with agitation.
[00148] The mineral solution is prepared by heating 321 liters of ingredient
water to 37° C to 65° C. Under agitation, add the required amount of potassium citrate
and ferrous sulfate. Allow to agitate until the solution is a clear green color. Add the
required amounts of zinc sulfate, copper sulfate, manganese sulfate and sodium
selenate to the green mineral solution. Agitate five minutes minimum.
[00149] The water soluble vitamin solution is prepared by heating 530 liters
of ingredient water to 37° C to 65° C. The required quantities of niacinamide,
riboflavin, calcium pantothenate, pyridoxine hydrochloride, thiamine hydrochloride,
m-inositol, biotin, folic acid and cyanocobalamin are added to the heated water.
[00150] All of the ascorbic acid solution, the mineral solution and water
soluble vitamin solution is then added to the blended slurry under agitation.
[00 151] The final mix is preheated through a plate heater to 71° C-82° C
before going to a surge tank. The mix leaves the surge tank and passes through the
steam injector where it is heated to 88° C-93° C. The mix enters the vapor-flash
chamber where it is cooled to 71° C-82° C, then pumped through an in-line 200 micro
filter prior to the high pressure pump and into the dryer. The dryer settings are as
follows: the nozzle pressure of 3000-5000 psig, the liquid flow rate at 11 gpm max,
the in-going air temperature at 160° C-207° C, and the out-going air temperature at
82° C-108° C.
[00152] To control bulk density, dispensability, particle size, moisture and
physical stability, the specific spray nozzle, nozzle pressure, drying temperatures and
fine reinjection parameters may vary depending upon the drying conditions of the day.
The powder passes from the dryer into the powder cooler where the powder is cooled
to below 43° C. The cooled powder is stored in appropriate containers until being filled
in individual packets.

WHAT IS CLAIMED IS:
1. A nutritional composition comprising fat, protein, carbohydrates, minerals and
from about 5 mg/L to about 100 mg/L of an optimized tocopherol blend
having a weight ratio of RRR alpha-tocopherol to RRR gamma-tocopherol of
from about 2 :1 to about 20: 1 and less than about 8 mg/L of non-RRR alphatocopherol
isomer.
2. The nutritional composition of claim 1, wherein the nutritional composition
comprises less than about 5 mg/L of non-RRR alpha-tocopherol isomer.
3. The nutritional composition of claim 1, wherein the nutritional composition
comprises less than about 0.5 mg/L of non-RRR alpha-tocopherol isomer.
4. The nutritional composition of claim 1, wherein the nutritional composition is
substantially free of non-RRR alpha-tocopherol isomer.
5. The nutritional composition of claim 1, wherein the weight ratio of RRR
alpha-tocopherol to RRR gamma-tocopherol ranges from about 3:1 to about
15:1.
6. The nutritional composition of claim 1, wherein the weight ratio of RRR
alpha-tocopherol to RRR gamma-tocopherol ranges from about 4:1 to about
10:1.
7. The nutritional composition of claim 1, wherein the weight ratio of RRR
alpha-tocopherol to RRR gamma-tocopherol is about 5:1.
8. The nutritional composition of any one of claims 1-7, having: (i) from about
20 to about 50 g/L fat; ii) from about 10 to about 15 g/L protein; and iii) at
least about 4 mg/L of RRR alpha-tocopherol.
9. The nutritional composition of any one of claims 1-8 wherein the nutritional
composition comprises a polyunsaturated fatty acid selected from arachidonic
acid, docosahexaenoic acid, and a combination thereof.
The nutritional composition of any one of claims 1-9 wherein the nutritional
composition comprises vitamin C.
The nutritional composition of any one of claims 1-10 wherein the nutritional
composition comprises a carotenoid.
The nutritional composition of any one of claims 1-11 wherein the nutritional
composition comprises trans-lutein.
The nutritional composition of any one of claims 1-12 wherein the nutritional
composition is a liquid nutritional product.
The nutritional composition of any one of claims 1-13 wherein the nutritional
composition is a powdered nutritional product.
The nutritional composition of any one of claims 1-14 wherein the nutritional
composition is an infant formula.
The nutritional composition of any one of claims 1-15 wherein the nutritional
composition is a preterm infant formula.
A method for enhancing brain development in an individual, the method
comprising administering to said individual a nutritional composition
comprising: i) from about 20 g/L to about 50 g/L of fat; ii) from about 10 g/L
to about 15 g/L of protein; wherein said fat comprises RRR alpha-tocopherol
and RRR gamma-tocopherol, with a weight ratio of RRR alpha-tocopherol to
RRR gamma-tocopherol ranging from about 3.5:1 to about 10:1; and iii) no
more than about 8 mg/L of a non-RRR alpha-tocopherol isomer.
The method of claim 17, wherein the weight ratio of RRR alpha-tocopherol to
RRR gamma-tocopherol is about 5:1.
The method of claim 17, wherein the nutritional composition comprises one or
more materials selected from a carbohydrate, a polyunsaturated fatty acid, a
carotenoid, vitamin C, trans-lutein, and a combination thereof.
20. The method of claim 17, wherein the nutritional composition is substantially
free of non-RRR alpha-tocopherol isomer.
21. The method of any one of claims 17-20, wherein said individual is an infant.
22. The method of any one of claims 17-20, wherein said individual is a preterm
infant.
23. The method of any one of claims 17-21, wherein said nutritional composition
comprises an infant formula.
24. The method of any one of claims 17-20 and 22, wherein said nutritional
composition comprises a preterm infant formula.