LIQUID CONCENTRATED HUMAN MILK FORTIFIER CONTAINING
HYPOALLERGENIC PROTEIN AND LUTEIN
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims priority to and any benefit of U.S. Provisional
Application No. 61/738,463, filed December 18, 2012, the content of which is incorporated
herein by reference in its entirety.
FIELD OF THE DISCLOSURE
[0002] The present disclosure relates to a stable, concentrated liquid human milk
fortifier containing a hypoallergenic protein source and carotenoids. More particularly, the
present disclosure relates to a long term stable, concentrated liquid human milk fortifier
containing extensively hydrolyzed casein as a protein source, a stabilizer system, and lutein.
BACKGROUND OF THE DISCLOSURE
[0003] Human milk is generally recognized as an ideal feeding for most infants due to
its overall nutritional composition. It is well known and generally accepted that human milk
provides infants with unique immunologic and developmental benefits as compared generally to
commercially available infant formulas.
[0004] For some infants, however, especially preterm infants, human milk does not
always meet the complete nutritional needs. Initially, these preterm infants may grow more
rapidly than many of their term counterparts, and accelerated growth often requires additional
nutrition, which is made possible by the use of a human milk fortifier in combination with
human milk. Although these infants still generally benefit from human milk, it is often desirable
to supplement their human milk feedings with additional nutrients.
[0005] Lutein has been identified in human milk. Lutein is an antioxidant that also
happens to concentrate within the retina of the eye. It is generally known that dietary lutein may
provide individuals with eye health benefits, and it is speculated that such benefits may be
extended to infants receiving lutein from either human milk or supplemented infant formula. It
has now been found, however, that lutein concentrations in infant formula must be much higher
than the lutein concentrations found in human milk in order to achieve the same plasma lutein
concentrations found in breast fed infants due to a lower relative bioavailability of lutein from
infant formula. Although infant formulas today typically contain less than about 20 meg/liter of
lutein, most of which comes inherently from added fats and oils, it has now been found that such
lutein concentrations must exceed about 50 meg/liter, preferably from about 100 meg/liter to
about 200 meg/liter, in order to duplicate plasma lutein concentrations found in exclusively
breast fed infants.
[0006] Arachidonic acid and docosahexaenoic acid, for example, have been identified
in human milk and subsequently added to infant formulas. These fatty acids support brain and
vision development in infants, and are now commonly found in commercially available formulas
such as Similac® Advance® Infant Formula, Isomil® Advance® Infant formula, and Similac®
Special Care® Advance® infant formula, all of which are available from Ross Products
Division, Abbott Laboratories, Columbus, Ohio, USA.
[0007] It is now believed that a combination of lutein and docosahexaenoic acid may be
particularly important in promoting retinal health and vision development in infants. Both
materials are present in human milk and both are known to concentrate in the retina in otherwise
healthy subjects. Docosahexaenoic acid (DHA), as a polyunsaturated fatty acid, is highly
susceptible to damage by oxidation and degradation within the eye, while lutein is a known
antioxidant. It is believed that by adding lutein to infant formulas, not only will it concentrate
within the retina, it may also reduce oxidative degradation of the retinal DHA and thus further
promote retinal health and vision development in the infant.
[0008] Consequently, it has also been found that infant formulas containing
combinations of lutein and DHA, as described above, should now be formulated with higher
ratios (lutein to DHA) than are commonly found in human milk. These weight ratios of lutein
(meg) to DHA (mg) should now range from about 1:2 to about 10:1.
[0009] It has also been found that the severity or risk of retinopathy of prematurity
(ROP) is influenced by skin carotenoid levels found in preterm infants fed human milk. This
finding suggests that preterm infants can be monitored for skin carotenoid concentrations, and
then for those infants demonstrating low skin carotenoid levels, supplemental carotenoids may
be administered in amounts sufficient to increase skin carotenoid levels, to thus reduce the risk or
severity of retinopathy of prematurity.
[0010] Most of the human milk fortifiers described in the literature and commercially
available have been formulated as reconstitutable powders rather than liquids in order to
minimize the volume displacement of human milk by the fortifier. Recently, however, liquid
human milk fortifiers, and specifically highly concentrated human milk fortifier liquids, have
received more attention as an alternative to powders. Although these highly concentrated human
milk fortifiers do generally displace slightly more volume that the conventional powders, the
liquids have the significant benefit of being commercially sterile as they can be subjected to
sufficient heat treatment during manufacturing, including aseptic manufacturing.
[001 1] It may also be advantageous to utilize extensively hydrolyzed proteins in human
milk fortifiers. Such proteins are generally hypoallergenic and are desirable for use with infants
and preterm infants. However, as compared to intact proteins, extensively hydrolyzed proteins
(i.e., proteins having a degree of hydrolysis of about 20% or more) tend to have poor ability to
form long term stable emulsions. Additionally, the presence of high levels of insoluble minerals
such as calcium salts may also cause a number of stability issues when used in combination with
extensively hydrolyzed proteins. As such, manufacturing long term stable liquid concentrated
human milk fortifiers including extensively hydrolyzed proteins has proven difficult.
[0012] Many liquid human milk fortifiers have been manufactured with stabilizers,
such as carrageenan. The stabilizers act to hold the nutrients and insolubles in solution over time
and thus improve long term stability of the product. Although stabilizers such as carrageenan
have generally proven to retard precipitation of many ingredients in the liquid nutritional
formulations, these types of stabilizers are not permitted in infant formulas and human milk
fortifiers in many countries around the world. When stabilizers cannot be used in highly
concentrated human milk fortifiers, it can be very difficult to produce a long term stable highly
concentrated human milk fortifier.
[0013] As such, there is a need for highly concentrated liquid human milk fortifiers that
have sufficient long term stability and include hypoallergenic proteins, such as extensively
hydrolyzed casein proteins. Additionally, it would be very beneficial if the highly concentrated
human milk fortifier could be formulated to provide additional nutrients such as lutein to protect
pre-term infants from oxidative stress, without unwanted fallout during storage.
SUMMARY OF THE DISCLOSURE
[0014] The present disclosure is directed to long term stable concentrated liquid human
milk fortifiers including extensively hydrolyzed casein, a stabilizer system comprised of an
octenyl succinic anhydride modified corn starch and a low acyl gellan gum, and carotenoids,
such as lutein. The stabilizer system allows for the use of an extensively hydrolyzed casein
protein without the associated problems of mineral fallout and poor emulsion stability, and
allows for the fortifier, in some embodiments, to be carrageenan-free. In some embodiments, the
long term concentrated liquid human milk fortifiers are hypoallergenic.
[0015] The present disclosure is specifically directed to a liquid human milk fortifier
comprising from about 5% to about 50% by weight extensively hydrolyzed casein protein, on a
dry weight basis. The supplemental carotenoids may be provided by a liquid human milk
fortifier, containing from about 100 to about 2200 meg/liter of total carotenoids, wherein the
total carotenoids include at least about 50 meg/liter of lutein, as fed, for the product nutrient
levels. The human milk fortifier may further comprise docosahexaenoic acid in a weight ratio of
lutein (meg) to docosahexaenoic acid (mg) of from about 1:2 to about 10:1.
[0016] The liquid human milk fortifier also comprises a stabilizer system comprising
from about 0.1% to about 3.5% by weight of the concentrated liquid human milk fortifier, or
from about 0.8% to about 1.5% by weight of the concentrated liquid human milk fortifier, of an
octenyl succinic anhydride modified corn starch, and from about 125 to about 800 ppm low acyl
gellan gum.
[0017] It has been unexpectedly found that liquid human milk fortifiers can be prepared
utilizing a synergistic stabilization system that includes an octenyl succinic anhydride modified
corn starch in combination with a low acyl gellan gum. When used together, the octenyl succinic
anhydride modified corn starch and low acyl gellan gum provide a stable concentrated liquid
human milk fortifier that is emulsion stable and highly resistant to mineral fallout such that a
homogeneous and precise delivery of macronutrients and micronutrients can be delivered to
human milk and consequently will be precisely delivered to preterm infants.
[0018] Additionally, it has further been discovered that liquid human milk fortifiers can
advantageously be prepared to include hypoallergenic extensively hydrolyzed casein proteins
without disrupting the long term stability or emulsion properties of the fortifier. By utilizing the
stabilizer system including the octenyl succinic anhydride modified corn starch and low acyl
gellan gum, the concentrated liquid human milk fortifiers may include up to 100% extensively
hydrolyzed casein (by weight of the protein component) while maintaining the desired emulsion
and stability properties.
[0019] Further, liquid human milk fortifiers can be prepared to administer supplemental
carotenoids to those infants in need thereof, wherein the supplemental carotenoids comprise
lutein, lycopene, beta-carotene, and zeaxanthin. The supplemental carotenoids may be provided
by the liquid human milk fortifiers, in quantities from about 100 to about 2200 meg/liter of total
carotenoids, wherein the total carotenoids include at least about 50 meg/liter of lutein.
[0020] It has been found that infant formulas, including liquid human milk fortifiers,
may be prepared with lutein concentrations of at least 50 meg/liter if they are to produce the
same plasma lutein concentrations found in breast fed infants, even though human milk itself
typically contains no more than about 30 meg/liter of lutein. The liquid human milk fortifier
may further comprise docosahexaenoic acid in a weight ratio of lutein (meg) to docosahexaenoic
acid (mg) of from about 1:2 to about 10:1.
[0021] The supplemental carotenoids may also be administered alone or in combination
with other ingredients as a preterm infant formula comprising fat, protein, carbohydrate,
vitamins, and minerals. The human milk fortifier may further comprise docosahexaenoic acid in
a weight ratio of lutein (meg) to docosahexaenoic acid (mg) of from about 1:2 to about 10:1,
including from about 1.5:1 to about 9:1, also including from about 1.7:1 to about 5:1.
[0022] When supplemental carotenoids are administered in the form of a preterm infant
formula, that formula may be prepared and administered as a sole source, primary source, or
supplemental source of nutrition.
[0023] Eye and vision development occurs at a rapid rate during the first year of life. At
birth, infants can only see high-contrast objects at perhaps 25-30 cm away. During the next 6
months, the infant's retina develops enough to see and discern small details. And as an infant's
vision develops, most of which will occur during the first year, the infant becomes better able to
learn through visual stimulation now made possible with a newly developed sight. For infants,
this visual learning then plays a key role in brain and cognitive development, especially during
the first 2-3 years of life.
[0024] The concentrated liquid human milk fortifier may also contain 20% by weight of
added lutein which may be a combination of free lutein and zeaxanthin from a single source
being a crystalline extract of Tagetes erecta in which the free lutein represents from 85% to 95%
by weight of the combination and the free zeaxanthin represents from about 5% to about 15% by
weight of the combination. The concentrated liquid human milk fortifier may also comprise from
about 10% to about 50%> by weight extensively hydro lyzed casein protein, on a dry weight basis,
and at least 50 meg/liter lutein, as fed, wherein the concentrated liquid human milk fortifier
comprises a stabilizer system comprising from about 0.6% to about 2.0% by weight of an octenyl
succinic anhydride modified corn starch and from about 125 to about 800 ppm low acyl gellan
gum. The concentrated liquid human milk fortifier may also comprise from about 20% to about
4 0% by weight extensively hydrolyzed casein protein and from about 0.8%> to about 1.5% by
weight of an octenyl succinic anhydride modified corn starch with about 150 to about 400 ppm
low acyl gellan gum.
[0025] The concentrated liquid human milk fortifier may also comprise from about 50
to about 1150 meg/liter of lutein, as fed. The concentrated human milk fortifier may further
contain a combination of free lutein and zeaxanthin from a single source being a crystalline
extract of Tagetes erecta in which the free lutein represents from 85% to 95% by weight of the
combination and the free zeaxanthin represents from about 5% to about 15% by weight of the
combination.
[0026] The concentrated liquid human milk fortifier may be aseptically-sterilized and
comprise from about 10% to about 50%> by weight extensively hydrolyzed casein protein, on a
dry weight basis, and at least 50 meg/liter lutein, wherein the concentrated liquid human milk
fortifier comprises a stabilizer system comprising from about 0.6% to about 2.0% by weight of
an octenyl succinic anhydride modified corn starch and from about 125 to about 800 ppm low
acyl gellan gum.
DETAILED DESCRIPTION OF THE DISCLOSURE
[0027] The concentrated liquid human milk fortifier compositions of the present
disclosure generally comprise protein, fat, carbohydrate, OSA-modified starch, low acyl gellan
gum, and carotenoids such as lutein. These and other essential or optional elements or limitations
of the concentrated liquids and methods of the present disclosure are described in detail
hereinafter.
[0028] This and all other 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.
[0029] 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.
[0030] 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.
[003 1] The term "infant" as used herein refers generally to individuals less than about 1
year of age, actual or corrected.
[0032] 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 grams, or both.
[0033] 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 pre
term 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.
[0034] The term "human milk fortifier" as used herein, unless otherwise specified,
refers to nutritional compositions for use in combination and admixture with human milk or an
infant nutritional formula, preferably human milk. Unless otherwise specified, the term "human
milk fortifier" specifically excludes conventional infant formulas that provide the sole or primary
source of infant nutrition and are not typically combined and admixed with human milk to
supplement human milk feedings. The human milk fortifier of the present invention preferably
excludes those compositions derived from concentrated or otherwise modified natural human
milk. (See US 2006/0204632, the content of which is herein incorporated by reference in its
entirety).
[0035] 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 of the concentrated human milk fortifier, unless otherwise specified.
[0036] The terms "fortifier solids" or "total solids", unless otherwise specified, are used
interchangeably herein and refer to all material components of the compositions of the present
disclosure, less water.
[0037] 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.
[0038] 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.
[0039] 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.
[0040] 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.
[0041] 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.
[0042] 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.
[0043] The various embodiments of the concentrated liquid human milk fortifiers of the
present disclosure may also be substantially free of any optional or selected essential ingredient
or feature described herein, provided that the remaining concentrated liquid human milk fortifier
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 concentrated
liquid human milk fortifier contains less than a functional amount of the optional ingredient,
typically less than 0.1% by weight, and also including zero percent by weight of such optional or
selected essential ingredient.
[0044] The concentrated liquid human milk fortifiers and corresponding manufacturing
methods of the present disclosure may comprise, consist of, or consist essentially of the essential
elements and limitations of the disclosure as described herein, as well as any additional or
optional ingredients, components, or limitations described herein or otherwise useful in the
concentrated liquid human milk fortifier.
[0045] Percentages as relating to the liquid human milk fortifier may be those prior to
mixing with breast milk, or other pre-term or full term nutritional formulations.
Product Form
[0046] Concentrated liquid human milk fortifiers have been disclosed, and non-limiting
examples are described in PCT WO 2012/061242 (Vurma et al), and WO 2006/099013
(Baerrett-Reis et al.), the contents of which are incorporated herein by reference in their entirety.
The concentrated liquid human milk fortifiers of the present disclosure have a solids content of at
least about 20%, or even at least about 25%, including from about 25% to about 45%, and further
including from about 29% to about 32%. The concentrated liquid human milk fortifiers are
liquids that are capable of being poured directly from a package containing them into human
milk or formula.
[0047] The concentrated liquid human milk fortifiers are generally formulated to have a
caloric density of at least about 1.25 kcal/ml (37 kcal/fl oz), including from about 1.4 kcal/ml (42
kcal/fl oz) to about 5 kcal/ml (149 kcal/fl oz), and also including from about 1.5 kcal/ml (44
kcal/fl oz) to about 2.5 kcal/ml (74 kcal/fl oz), and also including from about 1.9 kcal/ml (56
kcal/fl oz) to about 2.0 kcal/ml (59 kcal/fl oz).
[0048] The concentrated liquid human milk fortifiers include packaged compositions
further comprising a suitable unit dose package or container. These unit dose packages are single
use containers that alone, or in combination with other unit dose packages, provide sufficient
human milk fortifier to supplement human milk for immediate use, e.g., preferably within 8-24
hours, more preferably within 0-4 hours, of mixing with human milk.
[0049] The amount or volume of concentrated liquid human milk fortifier in each unit
dose package includes those embodiments in which the package contains an amount suitable to
prepare an infant's next feeding. These unit dose packages typically contain sufficient fortifier to
provide from about 0.5 g to about 10 g of fortifier solids, more typically from about 0.8 g to
about 7.5 g of fortifier solids, and even more typically from about 0.85 g to about 6.0 g, of
fortifier solids.
[0050] The concentrated liquid human milk fortifiers of the present disclosure are
preferably formulated so as to provide fortified human milk having an osmolality of less than
about 500 mOsm/kg water, preferably from about 300 mOsm/kg water to about 400 mOsm/kg
water. Based on the disclosure herein, one skilled in the art can readily formulate the
concentrated liquid human milk fortifier with the appropriate carbohydrate sources and
corresponding DE (dextrose equivalence) values to obtain or otherwise provide for the targeted
osmolality of the human milk fortifier when combined with human milk.
[005 1] The term "unit dose" as used herein refers to individual, single-use, packages of
concentrated liquid human milk fortifier containing an amount of human milk fortifier that can
be used in a preparation of an infant feeding. The amount of fortified human milk prepared for a
premature infant, for example, typically ranges from 25 ml to 150 ml a day. Consequently, a
single unit dose is the appropriate amount of fortifier solids to fortify a 25 ml preparation.
Multiple packages can be used to prepare larger feeding volumes, especially for term infants.
Extensively Hydrolyzed Casein Protein
[0052] The concentrated liquid human milk fortifiers of the present disclosure contain
hypoallergenic extensively hydrolyzed casein as a protein source. Generally, the concentrated
liquid human milk fortifiers will include at least about 35%, including at least about 50%,
including at least about 60%, including at least about 75%, including at least about 90%> and
further including about 100% extensively hydrolyzed casein, by total weight of protein in the
concentrated human milk fortifier.
[0053] In one desirable embodiment of the present disclosure, the concentrated liquid
human milk fortifier includes 100% extensively hydrolyzed casein, by total weight of the protein
in the concentrated human milk fortifier. In this desirable embodiment, the concentrated liquid
human milk fortifier is hypoallergenic. In some embodiments, the concentrated liquid human
milk fortifier will include from about 10%-40%, 20%-50%, 35%-100%, 50%-100%, further
including from about 75%- 100% extensively hydrolyzed casein, by total weight of protein in the
concentrated human milk fortifier. As discussed further below, in some embodiments of the
present disclosure, the concentrated liquid human milk fortifiers of the present disclosure may
optionally include other hypoallergenic or non-hypoallergenic proteins in addition to the
extensively hydrolyzed casein protein.
[0054] Extensively hydrolyzed casein proteins suitable for use in the concentrated
liquid human milk fortifiers of the present disclosure include those having a degree of hydrolysis
of from about 10% to about 70%, including from about 30% to about 60%, and further including
from about 40% to about 60%. Generally, the extensively hydrolyzed casein has a ratio of total
amino nitrogen (AN) to total nitrogen (TN) of from about 0.2 AN to 1.0 TN to about 0.4 AN to
about 0.8 TN. Suitable commercially available extensively hydrolyzed caseins will generally
have a protein level in the ingredient of from about 50% to about 95%, including from about
70% to about 90%. One suitable commercially available extensively hydrolyzed casein is Dellac
CE90, which is a spray dried powder casein hydrolysate (Friesland Campina Domo, Amersfoort,
The Netherlands).
Stabilizer System
[0055] The concentrated liquid human milk fortifiers of the present disclosure include a
synergistic two component stabilizer system. The first component is an octenyl succinic
anhydride (OSA) modified starch, such as an octenyl succinic anhydride (OSA) modified corn
starch. The second component is a low acyl gellan gum. These two components act in a
synergistic manner to stabilize the concentrated liquid human milk fortifier emulsion and retard
the precipitation of nutrients therefrom.
[0056] The OSA-modified starch, including the desirable OSA-modified corn starch, is
generally prepared by esterifying a dextrinized, ungelatinized waxy corn starch with 1-octenyl
succinic anhydride. Methods of this type are well known in the art. One suitable commercially
available OSA-modified corn starch is Uni-Pure IMF 2332 (Ingredion Incorporated,
Westchester, IL).
[0057] The OSA-modified starch is present in the concentrated liquid human milk
fortifier in an amount of from about 0.1% to about 3.5%, including from about 0.6% to about
2 .0%, including from about 0.8%> to about 1.5%, and further including about 1.2% by weight of
the concentrated liquid human milk fortifier.
[0058] The low acyl gellan gum (also known as and commonly referred to as
deacylated gellan gum) may be a water-soluble polysaccharide produced by fermentation of a
pure culture of Sphingomonas elodea. As used herein, "low acyl" means that the gellan gum has
been treated such that it forms firm, non-elastic, brittle gels, that are heat stable, as compared to
"high acyl" which forms soft, very elastic, non-brittle gels. One suitable commercially available
low acyl gellan gum is Kelcogel F (CP Kelco U.S. Inc., Atlanta Georgia).
[0059] The low acyl gellan gum is present in the concentrated liquid human milk
fortifier in an amount from greater than 125 ppm to about 800 ppm, including from about 150
ppm to about 400 ppm, including from about 200 ppm to about 300 ppm and further including
about 200 ppm.
Macronutrients
[0060] The concentrated liquid human milk fortifiers of the present disclosure comprise
carbohydrate, fat, and protein macronutrients of sufficient types and amounts, that when used in
combination with human milk or other infant feeding formula, they help meet the nutritional
needs of the infant, especially the premature infant. The concentration of these macronutrients in
the various embodiments of the present disclosure includes the ranges described hereinafter.
Protein
[0061] The concentrated liquid human milk fortifiers of the present disclosure comprise
a protein suitable for use in infants, especially preterm infants, at concentrations ranging from
about 5% to about 50%, including from about 20%> to about 40%>, including from about 5% to
about 30%, including from about 10%> to about 25%, and also including from about 15% to about
25%, on a dry weight basis. In some embodiments, the protein may be at a concentration of less
than 10%, on a dry weight basis. In some desirable embodiments, the protein concentration may
be from about 7 to about 15 grams, including from about 9 to about 12 grams of protein per 100
grams of final liquid product.
[0062] As noted above, the protein component of the concentrated liquid human milk
fortifiers of the present disclosure is comprised of extensively hydrolyzed casein. In a
particularly desirable embodiment of the present disclosure, the protein component of the
concentrated human milk fortifier is entirely comprised of extensively hydrolyzed casein. In
embodiments wherein additional proteins sources (i.e., one or more protein sources in addition to
the extensively hydrolyzed protein source) are to be used in the concentrated liquid human milk
fortifier in addition to the extensively hydrolyzed casein (i.e., the concentrated human milk
fortifier protein component is not 100% extensively hydrolyzed casein), the fortifier may still be
made hypoallergenic by including additional hypoallergenic proteins such as soy protein
hydrolysate, whey protein hydrolysate, rice protein hydrolysate, potato protein hydrolysate, fish
protein hydrolysate, egg albumen hydrolysate, gelatin protein hydrolysate, pea protein
hydrolysate, bean protein hydrolysate, combinations of animal and vegetable protein
hydrolysates, and combinations thereof.
[0063] In this context, the terms "protein hydrolysates" and "hydrolyzed protein" are
used interchangeably herein and include extensively hydrolyzed proteins, wherein the degree of
hydrolysis is most often at least about 10%>, including from about 10%> to about 80%>, and also
including from about 30%> to about 80%>, even more preferably from about 40%> to about 60%>.
The degree of hydrolysis is the extent to which peptide bonds are broken by a hydrolysis method.
The degree of protein hydrolysis for purposes of characterizing the extensively hydrolyzed
protein component of these embodiments may be readily determined by one of ordinary skill in
the formulation arts by quantifying the amino nitrogen to total nitrogen ratio (AN/TN) of the
protein component of the selected formulation. The amino nitrogen component is quantified by
USP titration methods for determining amino nitrogen content, while the total nitrogen
component is determined by the Tecator Kjeldahl method, all of which are well known methods
to one of ordinary skill in the analytical chemistry art.
[0064] In other embodiments of the present disclosure, the concentrated liquid human
milk fortifier, in addition to the extensively hydrolyzed protein, may include an additional nonhypoallergenic
protein source including for example, partially hydrolyzed or non-hydrolyzed
(intact) protein, and can be derived from any known or otherwise suitable source such as milk
(e.g., casein, whey, lactose-free milk protein isolates), animal (e.g., meat, fish), cereal (e.g., rice,
corn), vegetable (e.g., soy, pea, bean), or combinations thereof. The protein can include, or be
entirely or partially replaced by, free amino acids known or otherwise suitable for use in
nutritional products, non-limiting examples of which include L-alanine, L-arginine, Lasparagine,
L-aspartic acid, L- carnitine, L-cystine, L-glutamic acid, L-glutamine, glycine, Lhistidine,
L-isoleucine, L-leucine, L-lysine, L-methionine, L-phenylalanine, L-proline, L-serine,
L-taurine, L- threonine, L-tryptophan, L-tyrosine, L-valine, and combinations thereof.
Carbohydrate
[0065] The concentrated liquid human milk fortifiers of the present disclosure comprise
a carbohydrate suitable for use in infants, especially preterm infants, at concentrations most
typically ranging up to about 75% by weight on a dry weight basis, including from about 5% to
about 50%, and also including from about 20%> to about 40%> by weight on a dry weight basis.
[0066] Carbohydrates suitable for use in the concentrated liquid human milk fortifiers
may include hydrolyzed or intact, naturally and/or chemically modified, starches sourced from
corn, tapioca, rice or potato, in waxy or non-waxy forms.
[0067] Other non-limiting examples of suitable carbohydrate sources include
hydrolyzed cornstarch, maltodextrin (i.e. non-sweet, nutritive polysaccharide having a DE value
less than 20), corn maltodextrin, glucose polymers, sucrose, corn syrup, corn syrup solids (i.e.,
polysaccharide having a DE value greater than 20), glucose, rice syrup, fructose, high fructose
corn syrup, indigestible oligosaccharides such as fructooligosaccharides (FOS), and
combinations thereof. The carbohydrates may comprise lactose or can be substantially free of
lactose.
[0068] One embodiment of the present disclosure includes a non-reducing carbohydrate
component, which may represent from about 10% to 100%, including from about 80%> to 100%,
and also including 100%, by weight of the total carbohydrate in the concentrated liquid human
milk fortifier. The selection of a non-reducing carbohydrate may enhance the product stability
and is generally better tolerated by infants, especially premature infants. Non-limiting examples
of non-reducing carbohydrates include sucrose or other carbohydrates that do not readily oxidize
or react with Tollen's, Benedict's, or Fehling's reagents. The present invention therefore includes
those embodiments comprising a carbohydrate component, wherein the carbohydrate component
comprises a mono- and/or disaccharide such that at least about 50%, including from about 80%
to 100%, and also including 100%, of the mono- and/or disaccharide is a non-reducing
carbohydrate.
Fat
[0069] The concentrated liquid human milk fortifiers of the present disclosure also
comprise a fat component suitable for use in infants, especially preterm infants, at concentrations
most typically ranging up to about 40%> by weight on a dry weight basis, including from about
10% to about 40%, and also including from about 15% to about 37%, and also including from
about 18% to about 30%>, by weight on a dry weight basis.
[0070] Fats suitable for use in the concentrated liquid human milk fortifiers of the
present disclosure may include coconut oil, soy oil, corn oil, olive oil, safflower oil, high oleic
safflower oil, MCT (medium chain triglycerides) oil, sunflower oil, high oleic sunflower oil,
structured triglycerides, palm oil, palm kernel oil, palm olein, canola oil, marine oil, cottonseed
oil, and combinations thereof.
[0071] Suitable fats for use in the concentrated liquid human milk fortifiers include
emulsifiers to help the various fortifier components readily disperse when combined with human
milk. Non-limiting examples of suitable emulsifiers include soya bean lecithin, polyoxythylene
stearate, polyoxyethylene sorbitan mono-oleate, polyoxy ethylene sorbitan monopalmitate,
polyoxyethylene sorbitan monostearate, ammonium phosphatides, polyoxyethylene sorbitan
monolaurate, citric acid esters of mono and diglycerides of fatty acids, tartaric acid esters of
mono and diglycerides of fatty acids, and combinations thereof. Natural soy lecithin is especially
useful in this respect.
[0072] The fat component of the concentrated liquid human milk fortifier may therefore
optionally include any emulsifier suitable for use in infant nutritional products. Emulsifier
concentrations in these products may range up to about 10%, including from about 1% to about
10%, even more typically from about 1.5% to about 5%, by weight of the total fat component.
[0073] Another aspect of the present disclosure includes those embodiments in which
the weight ratio of fat to protein in the concentrated liquid human milk fortifier is at least about
0.3, including from about 0.4 to about 5, and also including from about 2 to about 4. These ratios
may be helpful in further stabilizing the concentrated liquid human milk fortifier.
[0074] The concentrated liquid human milk fortifiers of the present disclosure also
include those embodiments that comprise as part of the fat component one or more of
arachidonic acid, docosahexaenoic acid, or combinations thereof, alone or in further combination
with linoleic acid, linolenic acid, or both.
Supplemental Carotenoids
[0075] Eye and vision development occurs at a rapid rate during the first year of life. At
birth, infants can only see high-contrast objects at perhaps 25-30 cm away. During the next 6
months, the infant's retina develops enough to see and discern small details. And as an infant's
vision develops, most of which will occur during the first year, the infant becomes better able to
learn through visual stimulation now made possible with a newly developed sight. For infants,
this visual learning then plays a key role in brain and cognitive development, especially during
the first 2-3 years of life.
[0076] By promoting retinal health and vision development in infants, the infant
formulas of the present invention may also help children develop their ability to visually learn as
soon as possible, and to potentially accelerate brain and cognitive development associated with
early visual stimulation through the developing retina of the eye. The infant formulas described
herein are therefore useful in promoting vision development in infants, and consequently are
useful in promoting secondary benefits such as associated cognitive and brain development
through early visual stimulation. It is also useful in preterm infants to help accelerate the
development of normal vision, to thus reduce the time needed to catch-up with development
milestones set by their term infant counterparts.
[0077] The methods described herein are particularly useful to reduce the risk or
severity of retinopathy of prematurity. This condition often affects preterm infants and is most
commonly characterized by abnormal development of retinal vessels in the eye possibly as a
result of oxidative stress secondary to high oxygen tension. This affliction can occur to varying
degrees, from slight vessel involvement with minimal or no impact on vision, to partial or
complete retinal detachment leading to blindness. Historically, therapy for appropriate cases
included laser treatment as well as cryotherapy.
[0078] In accordance with the methods herein, the supplemental carotenoids, including
lutein, may be administered to those infants with a measured Raman Count of less than about
20,000, including from about 100 to about 15,000, also including from about 400 to about
10,000, wherein all such ranges are proceeded by administration of supplemental carotenoids in
amounts sufficient to increase the Raman Count in the infant, typically by at least about 5%,
including from about 20% to about 500%. Raman counts correlate with serum and tissue
carotenoid levels.
[0079] The supplemental carotenoids (e.g., lutein, lycopene, beta-carotene, and
zeaxanthin) for use herein may be provided or otherwise administered in any form suitable for
use in preterm infants and infants.
Lutein
[0080] The term "lutein" as used herein, unless otherwise specified, refers to one or
more of free lutein, lutein esters, lutein salts, or other lutein derivatives or related structures as
described or otherwise suggested herein. Lutein or lutein sources suitable for use in the infant
formulas of the present invention include free lutein as well as esters, salts or other derivatives or
related structures thereof, including those that conform to the formula:
[0081] The above formula includes the general structure of lutein and related
derivatives or structures. Free lutein, for example, corresponds to the formula wherein Rl and R2
are both hydrogen, and includes cis and trans isomers thereof as well as salts thereof, e.g.,
sodium, potassium.
[0082] Lutein esters suitable for use herein include any lutein ester of the above
formula wherein Ri and R2 are the same or different, and are nutritionally acceptable monovalent
salts, hydrogen or an acyl residue of a carboxylic acid, provided that at least one of Ri or R is an
acyl residue of a carboxylic acid. Suitable lutein esters include, as well, both cis and trans
isomers. The Ri and R2 moieties are residues of a saturated or unsaturated Ci to C22 fatty
carboxylic acids, non-limiting examples of which include formic, acetic, propionic, butyric,
valeric, caproic, caprylic, capric, lauric, myristic, palmitic, stearic, and oleic acids.
[0083] Lutein for use herein includes any natural or synthetic source that is known for
or is otherwise an acceptable source for use in oral nutritionals, including infant formulas. Lutein
sources can be provided as individual ingredients or in any combination with other materials or
sources, including sources such as multivitamin premixes, mixed carotenoid premixes, pure
lutein sources, and inherent lutein from other fat or oil components in the infant formula. The
lutein concentrations and ratios as described herein are calculated based upon added and inherent
lutein sources. The infant formulas, as constituted from human milk fortifier of the present
invention, preferably comprise at least about 25%, more preferably from about 50% to about
95%, by weight of total lutein as added lutein, the remainder being inherent lutein that
accompanies added fats and oils. Lutein concentrations, on an as-fed basis may be at least about
50 meg/liter, or from about 100 meg/liter to about 250 meg/liter, or from about 50 to about 1150
meg/liter, after reconstitution, in order to duplicate plasma lutein concentrations found in
exclusively breast fed infants. Lutein concentrations in the concentrated human milk fortifier
may contain a minimum lutein concentration of at least about 170 mcg/liter or about 0.85 meg of
lutein per 5 mL pouch. In certain embodiments, the lutein concentration in the concentrated
human milk fortifier may be about 170 mcg/liter to about 1360 mcg/liter.
[0084] Each of the carotenoids for use herein may be obtained from any known or
otherwise suitable material source for use in infant nutritional formulas, and each can be
provided individually, or all together, or in any combination and from any number of sources,
including sources such as multivitamin premixes containing other vitamins or minerals in
combination with one or more of the other carotenoids as described herein. Non-limiting
examples of some suitable carotenoid sources include LycoVit® synthetic lycopene dispersion in
vegetable oil provided by BASF (Mount Olive, New Jersey), Lyc-O-Mato® tomato extract in
oil, powder, or bead form provided by LycoRed Natural Products Industries, Ltd. (Bear Sheba,
Israel), water-dispersible and oil soluble lycopene provided by DSM Nutritional Products (Basel,
Switzerland), FloraGLO® brand free lutein provided by Kemin Foods (Des Moines, Iowa),
Xangold® Lutein Esters provided by Cognis (Cincinnati, Ohio), and beta-carotene provided by
BASF (Mount Olive, New Jersey).
[0085] Non-limiting examples of some suitable lutein sources for use herein include
FloraGLO® Crystalline Lutein, available from Kemin Foods (Des Moines, Iowa); and Xangold
® Lutein Esters provided by Cognis (Cincinnati, Ohio).
[0086] The infant formulas for use herein include those comprising a single source
combination of free lutein and zeaxanthin, in a purified crystalline extract from the marigold
flower (Tagetes erecta), wherein the free lutein represents from 85% to 95% by weight of the
combination and the zeaxanthin represents from about 5% to about 15% by weight of the
combination. A lutein-zeaxanthin combination is available from Kemin Foods (Des Moines,
Iowa) under the FloraGLO® brand.
Docosahexaenoic Acid (DHA)
[0087] The human milk fortifier for use herein may comprise docosahexaenoic acid, in
a concentration range from at least about 30 mg/liter of docosahexaenoic acid, wherein the
weight ratio of lutein (meg) to docosahexaenoic acid (mg) is from about 1:2 to about 10:1.
[0088] Docosahexaenoic acid (DHA) is an organic carboxylic acid having a chain
length of 22 carbons with 6 double bonds beginning with the third carbon from the methyl end
(22:6 n-3). Any source of docosahexaenoic acid is suitable for use herein provided that such a
source is also known for or otherwise suitable for use in infant formulas and is compatible with
the other selected ingredients in the formula.
[0089] Docosahexaenoic acid concentrations in the human milk fortifier may be
selected so that the resulting weight ratio of lutein to docosahexaenoic acid falls within the range
as defined herein. Such concentrations most typically range from at least about 30 mg/liter,
including from about 36 to 360 mg/liter, including from about 72 to about 280 mg/liter, and also
including from about 150 to about 230 mg/liter of DHA, as calculated on an as-fed basis, (as fed
after mixing 1 part human milk fortifier with 5 parts human milk). A minimum DHA
concentration may be about 174.40 mg/liter. The weight ratio of lutein (meg) to docosahexaenoic
acid (mg) is from about 1:2 to about 10:1. The human milk fortifier may contain minimum DHA
levels of about 753 mg/liter.
[0090] The docosahexaenoic acid may be added to the human milk fortifier as free fatty
acids or as compounds or materials that can otherwise provide a source of such free fatty acids
upon or following administration to the infant, including non-egg phospholipids and glyceride
esters (mono-, di-, tri-) of docosahexaenoic acids. Polyunsaturated fatty acids and sources thereof
are described in U.S. Pat. No. 6,080,787 (Carlson, et al.) and U.S. Pat. No. 6,495,599 (Auestad,
et al.), which descriptions are incorporated by reference herein. Some non-limiting examples of
suitable docosahexaenoic acid sources include fish oils, algal oils, other single cell oils, and
combinations thereof.
[0091] The human milk fortifier may further comprise, in addition to the
docosahexaenoic acid as described herein, other long chain polyunsaturated fatty acids such as
arachidonic acid (20:4 n-6), eicosapentaenoic acid or EPA (20:5 n-3), linoleic acid (18:2 n-6), g -
linolenic acid or GLA (18:3 n-6), a-linolenic acid (18:3 n-3), dihomo-y-linolenic or DHGLA
(20:3 n-6), a-linolenic (18:3 n-3), stearidonic acid (18:4 n-3), and combinations thereof. Such
optional long chain polyunsaturated fatty acids may likewise be formulated into the infant
formula as free fatty acids or as compounds or materials that can otherwise provide a source of
such free fatty acids upon or following administration to the infant, including non-egg
phospholipids and glyceride esters (mono-, di-, tri-) of docosahexaenoic acids.
Vitamins and Minerals
[0092] The concentrated liquid human milk fortifiers of the present disclosure may
further comprise any of a variety of vitamins, non-limiting examples of which include vitamin A,
vitamin D , vitamin E, vitamin K, thiamine, riboflavin, pyridoxine, vitamin B12, niacin, folic
acid, pantothenic acid, biotin, vitamin C, choline, inositol, salts and derivatives thereof, and
combinations thereof.
[0093] The concentrated liquid human milk fortifiers may also further comprise any of
a variety of minerals known or otherwise suitable for us in infant or other nutritional formulas,
non-limiting examples of which include phosphorus, magnesium, calcium as described
hereinbefore, zinc, manganese, copper, iodine, sodium, potassium, chloride, selenium, and
combinations thereof.
[0094] The concentrated liquid human milk fortifiers of the present disclosure include
those embodiments comprising per 100 kcal of fortifier solids one or more of the following:
vitamin A (from about 250 to about 6500 IU), vitamin D (from about 40 to about 1200 IU),
vitamin K, vitamin E (at least about 0.3 IU), vitamin C (at least about 8 mg), thiamine, vitamin
B12, niacin, folic acid, pantothenic acid, biotin, choline (at least about 7 mg), and inositol (at
least about 2 mg).
[0095] The concentrated liquid human milk fortifiers also include those embodiments
comprising per 100 kcal of the fortifier solids one or more of the following: calcium (at least
about 50 mg), phosphorus (at least about 25 mg), magnesium (at least about 6 mg), iodine, zinc
(at least about 0.5 mg), copper, manganese, sodium (from about 20 to about 60 mg), potassium
(from about 80 to about 200 mg), chloride (from about 55 to about 150 mg) and selenium (at
least about 0.5 meg).
Other Optional Ingredients
[0096] The concentrated liquid human milk fortifiers of the present disclosure may
further optionally comprise other ingredients that may modify the physical, chemical, aesthetic
or processing characteristics of the formulas or serve as pharmaceutical or additional nutritional
components when used in the targeted population. Many such optional ingredients are known for
use in food and nutritional products, including infant formulas, and may also be used in the
concentrated liquid human milk fortifiers of the present disclosure, provided that such optional
materials are compatible with the essential materials described herein, are safe and effective for
their intended use, and do not otherwise unduly impair product performance.
[0097] Non-limiting examples of such optional ingredients include preservatives, anti
oxidants, various pharmaceuticals, buffers, other carotenoids, colorants, flavors, nucleotides and
nucleosides, thickening agents, prebiotics, probiotics, sialic acid-containing materials, and other
excipients or processing aids.
Aseptic Packaging
[0098] The concentrated liquid human milk fortifiers of the present disclosure may be
sterilized and aseptically packaged. The aseptic packaging can be accomplished using any of a
variety of techniques well known to those of ordinary skill in the formulation art, so long as the
heat treatment is sufficient to achieve long term shelf stability of the concentrated liquid. In one
specific example, an aseptic process is utilized that includes a high temperature short time
(HTST) processing step (i.e., about 74°C for about 16 seconds) or an ultra high temperature
(UHT) processing step (i.e., about 135°C for about 5 seconds).
[0099] A typical aseptic process in accordance with the present disclosure involves the
preparation of a slurry from one or more fluid combinations that may contain water and one or
more of the following: carbohydrates, extensively hydrolyzed casein protein, fats, vitamins and
minerals. This slurry is typically emulsified, deaerated, homogenized and cooled to form a
sterilized formula, and then aseptically packaged to form a sterilized, aseptically packaged
concentrated liquid human milk fortifier. Various other solutions may be added to the slurry at
most any time before, during, or after processing.
[00100] Suitable aseptic packaging techniques include any of the well known aseptic
packaging methods disclosed in the formulation arts for preparing a nutritional formulation, all
of which are generally directed to the sealing or filling of a sterilized liquid into a sterilized, air
tight container. Many variations on the basic method exist and are well known to those of
ordinary skill in the formulation art, non- limiting examples of which are described in U.S. Pat.
No. 6,096,358 (Murdick et al); U.S. Pat. No. 6,227,261 (Das et al); and U.S. Pat. No. 6,371,319
(Yeaton et al), which descriptions are incorporated herein by reference.
[00 101] The aseptically packaged embodiments of the present disclosure may include
any container or package suitable for use with liquid human milk fortifiers and also capable of
withstanding aseptic processing conditions (e.g., high temperature sterilization). Non- limiting
examples of such containers include single or multi use bags, plastic bottles or containers,
pouches, metal cans glass bottles, foil or other flexible pouches, syringes, vials, or any other
container meeting the above-described criteria.
[00102] The aseptically packaged container for these embodiments is typically
sterilized prior to being filled with its sterilized contents. The container is most typically
sterilized by the application of hydrogen peroxide or other suitable disinfectant to the inside
surface of the container. The hydrogen peroxide or other disinfectant is often applied in an
atomized mist. After a disinfectant is applied, the container may be transported along a conveyor
system during which time the container may be subjected to one or more sprayings of hot
sterilized air, preferably hot, sterilized, dry air. The container is then preferably injected with
nitrogen gas. The aseptically prepared container is then aseptically filled with sterilized product
and sealed.
[00103] For aseptic packaging, the concentrated liquid human milk fortifier is typically
heat treated with a high temperature short time (HTST) process or an ultra high temperature
(UHT) process to sufficiently reduce the bioburden to allow the products to remain commercially
sterile over an extended shelf- life of the finished product exceeding about 12 months. The treated
formula is then homogenized at 1000 psi or higher and aseptically packaged.
[00104] In an alternative embodiment, the concentrated human milk fortifiers of the
present disclosure may also be sterilized and retort packaged utilizing conventional means
known in the art.
Method of Use
[00105] The concentrated liquid human milk fortifier of the present disclosure is used
in combination with human milk or other suitable infant formula, wherein the resulting fortified
human milk or fortified infant formula has an osmolality suitable for oral administration to an
infant. As noted, the osmolality will most typically be less than about 500 mOsm/kg water, more
typically from about 300 mOsm/kg water to about 400 mOsm/kg water.
[00106] The concentrated liquid human milk fortifier of the present disclosure may be
added directly to human milk in a volume to volume ratio of from about 1:3 to about 1:9,
including from about 1:3.5 to about 1:7, and also including from about 1:4 to about 1:6. The ratio
is ultimately selected based primarily upon the ingredients and osmolality of the concentrated
liquid human milk fortifier and in view of the particular nutritional needs of the infant. The
concentrated liquid human milk fortifier may be added directly to every feeding or to a sufficient
number of feedings (e.g., once or twice daily) to provide optimal nutrition in view of the
particular nutritional needs of the infant.
[00107] Human milk or other infant formula, after fortification with the concentrated
liquid human milk fortifier will most typically have a caloric density ranging from about 19
kcal/fl oz (0.64 kcal/ml) to about 26.7 kcal/fl oz (0.9 kcal/ml), with the 22-25 kcal/fl oz
formulations (0.74-0.84 kcal/ml) being more useful in preterm infants, and the 19-21 kcal/fl oz
(0.64-0.71 kcal/ml) formulations more useful for term infants.
[00108] The methods of the present disclosure therefore include a method of providing
nutrition to infants, especially preterm infants, said method comprising the addition of the
concentrated liquid human milk fortifier to human milk or other infant feeding composition,
followed by the administration of the fortified human milk or feeding composition to the infant.
[00109] The methods of the present disclosure also include a method of reducing the
risk of microbial contamination, including Cronobacter (Enterobacter) sakazakii contamination,
of term or preterm infant feeding compositions, said method comprising the direct addition of the
concentrated liquid human milk fortifier to human milk or other infant feeding composition
followed by the administration of the fortified composition to the infant.
Manufacture
[001 10] The concentrated liquid human milk fortifiers of the present disclosure may be
prepared in accordance with the methods described hereinafter, which methods are described in
association with the exemplified embodiments (see Examples). In one embodiment, the
concentrated liquid human milk fortifier is prepared by solubilizing and combining/mixing
ingredients into a homogeneous aqueous mixture which is subjected to a sufficient thermal
treatment and aseptic filling to achieve long term physical and microbial shelf stability.
[001 11] To begin the manufacturing process, macronutrients (carbohydrate, protein, fat,
and minerals) are combined in several slurries together and with water. This blend is subjected to
an initial heat treatment and then tested to verify proper nutrient levels. Additional detail on this
process is provided in the following paragraphs.
[001 12] An intermediate aqueous carbohydrate-mineral (CHO-MIN) slurry is prepared
by heating an appropriate amount of water. With agitation, the following soluble ingredients are
added: maltodextrin, potassium citrate, magnesium chloride, potassium chloride, sodium
chloride, and choline chloride. The carbohydrate-mineral slurry is held at elevated temperature
under agitation until added to the blend.
[001 13] An intermediate oil slurry is prepared by heating MCT oil and coconut oil to an
elevated temperature and then adding distilled monoglycerides with agitation for a minimum 10
minutes in order to allow the ingredients to dissolve. Soy oil, vitamin A palmitate, vitamin D3,
dl-alpha-tocopheryl-acetate, phylloquinone, ARA, DHA, and mixed carotenoids are then added
with agitation to the oil blend. Insoluble mineral calcium source, ultra micronized tricalcium
phosphate, is added to the oil. Gellan gum and OSA-modified starch are then added to the oil
blend with proper agitation. The oil blend slurry is maintained at an elevated temperature under
agitation until added to the blend.
[001 14] The blend is prepared by combining the ingredient water, casein hydrolysate,
all of the CHO-MIN slurry and whole oil blend slurry. The blend is maintained at about 49°C for
a period of time not to exceed two hours before further processing. The blend is then
homogenized using one or more in-line homogenizers at pressures from 1000-4000 psig with or
without a second stage homogenization from 100-500 psig followed by heat treatment using a
UHTST (ultrahigh temperature short time, about 144-147°C for 1-30 seconds) process. After the
appropriate heat treatment, the batch is cooled in a plate cooler to about 1-7°C and then
transferred to a refrigerated holding tank, where it is subjected to analytical testing.
[001 15] The next step in the manufacturing process involves adding vitamins, trace
minerals and water in order to reach the final target total solids and vitamin/mineral content. The
final batch is filled into a suitable container under aseptic conditions or treated with a terminal
sterilization process so the product will be stable at room temperature for an extended shelf-life.
Additional detail on this process is provided in the following paragraphs.
[001 16] A trace mineral/vitamin/nutrient solution (STD 1) is prepared by heating water
to about 25-38°C and adding the following ingredients with agitation: potassium citrate, ferrous
sulfate, zinc sulfate, copper sulfate, manganese sulfate, sodium selenate, pyridoxine
hydrochloride, riboflavin, thiamine hydrochloride, cyanocobalamin, folic acid, calcium
pantothenate, niacinamide, biotin, m-inositol, nucleotide/choline premix, L-carnitine, L-Leucine,
and L-tyrosine.
[001 17] A vitamin C solution (STD2) is prepared by adding ascorbic acid to water
solution with agitation.
[001 18] All STD1 and STD2 solutions are then added to the refrigerated batch, with
agitation. The appropriate amount of ingredient dilution water is then added to the batch to
achieve a target total solids level of 28.0-32.0%. The final batch is then subjected to appropriate
thermal treatment and filled into a suitable container under an aseptic conditions and processes.
[001 19] The concentrated liquid human milk fortifiers of the present disclosure may, of
course, be manufactured by other known or otherwise suitable techniques not specifically
described or shown herein without departing from the spirit and scope of the present disclosure.
The present embodiments are, therefore, to be considered in all respects as illustrative and not
restrictive and that all changes and equivalents also come within the description of the present
disclosure. The following non-limiting examples will further illustrate the formulations and
methods of the present disclosure.
EXAMPLE
[00120] The following example illustrates a specific embodiment of the concentrated
liquid human milk fortifiers products of the present disclosure. This example is given solely for
the purpose of illustration and are not to be construed as limitations of the present disclosure, as
many variations thereof are possible without departing from the spirit and scope of the
disclosure. All exemplified amounts are weight percentages based upon the total weight of the
formulation, unless otherwise specified.
[00121] 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, unless otherwise specified.
[00122] In Example 1, the concentrated liquid human milk fortifier is prepared in
accordance with the present disclosure. The ingredients for the concentrated liquid human milk
fortifier are shown in the following table.
Potassium Chloride 1.5 lb
Sodium Chloride 431.4 g
Distilled monoglycerides 390.1 g
M-Inositol 200.0 g
Choline Chloride 160.0 g
Zinc Sulfate 130.3 g
Niacinamide 127.3 g
dl-Alpha-Tocopheryl Acetate 108.7 g
L-Carnitine 100.00 g
Gellan Gum 99.8 g
Calcium Pantothenate 60.0 g
Ferrous Sulfate 52.0 g
Vitamin A Palmitate 25.8 g
Riboflavin 15.0 g
Thiamin Hydrochloride 11.0 g
Pyridoxine Hydrochloride 8.9 g
Vitamin D3 6.7 g
Cupric Sulfate 6.0 g
Lutein, 20% in safflower oil 3.2 g
Folic Acid 1.4 g
Beta Carotene 940 mg
Biotin 860 mg
Manganese Sulfate 840 mg
Phylloquinone 285 mg
Sodium Selenate 44 mg
Cyanocobalamin 40 mg
Potassium Hydroxide q.s.
[00123] The concentrated liquid human milk fortifier is prepared by solubilizing and
combining/mixing ingredients into a homogeneous aqueous mixture which is subjected to a
sufficient thermal treatment and aseptic filling to achieve long term physical and microbial shelf
stability.
[00124] To begin the manufacturing process, macronutrients (carbohydrate, protein, fat,
and minerals) are combined in several slurries together and with water. This blend is subjected to
an initial heat treatment and then tested to verify proper nutrient levels. Additional detail on this
process is provided in the following paragraphs.
[00125] An intermediate aqueous carbohydrate-mineral (CHO-MIN) slurry is prepared
by heating appropriate amount of water to about 60-70°C. With agitation, the following soluble
ingredients are added: maltodextrin, potassium citrate, magnesium chloride, potassium chloride,
sodium chloride, and choline chloride. The carbohydrate-mineral slurry is held at 54-66°C under
agitation until added to the blend.
[00126] An intermediate oil slurry is prepared by heating MCT oil and coconut oil to
about 66-77°C and then adding distilled monoglycerides with agitation for a minimum of 10
minutes in order to the ingredient to dissolve. Soy oil, vitamin A palmitate, vitamin D3, di-alphatocopheryl-
acetate, phylloquinone, ARA-containing oil, DHA-containing oil, beta carotene and
lutein are then added with agitation to the oil blend. Insoluble mineral calcium source, and ultra
micronized tricalcium phosphate is added to the oil. Gellan gum and OSA-modified starch are
then added to the oil blend with proper agitation. The oil blend slurry is maintained at about 54-
66°F under agitation until added to the blend.
[00127] The blend is prepared by combining the ingredient water, casein hydrolysate,
all of the CHO-MIN slurry and whole oil blend slurry. The blend is maintained at about 49°C for
a period of time not to exceed two hours before further processing.
[00128] The blend is then homogenized using one or more in-line homogenizers at
pressures from 1000-4000 psig with or without a second stage homogenization from 100-500
psig followed by heat treatment using a UHTST (ultrahigh temperature short time, 144-147°C
for 5-15 seconds) process. After the appropriate heat treatment, the batch is cooled in a plate
cooler to 1-°C and then transferred to a refrigerated holding tank, where it is subjected to
analytical testing.
[00129] The next step in the manufacturing process involves adding vitamins, trace
minerals, other ingredients, and water in order to reach the final target total solids and
vitamin/mineral contents. The final batch is filled into a suitable container under aseptic
conditions or treated with a terminal sterilization process so the product will be stable at room
temperature for an extended shelf-life. Additional detail on this process is provided in the
following paragraphs.
[00130] A trace mineral/vitamin/nutrient solution (STD 1) is prepared by heating water
to about 25-38°C and adding the following ingredients with agitation: potassium citrate, ferrous
sulfate, zinc sulfate, copper sulfate, manganese sulfate, sodium selenate, pyridoxine
hydrochloride, riboflavin, thiamine hydrochloride, cyanocobalamin, folic acid, calcium
pantothenate, niacinamide, biotin, m-inositol, nucleotide/choline premix, L-carnitine, L-Leucine,
and L-tyrosine.
[0013 1] A vitamin C solution (STD2) is prepared by adding ascorbic acid to a water
solution with agitation.
[00132] All STD1 and STD2 solutions are then added to the refrigerated batch, with
agitation. The appropriate amount of ingredient dilution water is then added to the batch to
achieve a target total solids level of 29.0-32.0%. The final batch is then subjected to appropriate
thermal treatment and filled into a suitable container under an aseptic conditions and processes.

WHAT IS CLAIMED IS:
1. A concentrated liquid human milk fortifier comprising from about 5% to about
50% by weight extensively hydrolyzed casein protein, on a dry weight basis, and
lutein, wherein the concentrated liquid human milk fortifier comprises a stabilizer
system comprising an octenyl succinic anhydride modified corn starch and a low
acyl gellan gum.
2. The concentrated liquid human milk fortifier of claim 1 comprising from about
20% to about 4 0% by weight extensively hydrolyzed casein, on a dry weight
basis.
3. The concentrated liquid human milk fortifier of claim 1, wherein the lutein
concentration is at least about 50 meg/liter, based on an as-fed basis.
4. The concentrated liquid human milk fortifier of claim 3, wherein the concentrated
human milk fortifier further comprises at least about 30 mg/liter docosahexaenoic
acid, based on an as-fed basis, wherein the weight ratio of lutein (meg) to
docosahexaenoic acid (mg) is from about 1:2 to about 10:1.
5. The concentrated liquid human milk fortifier of claim 4, wherein the concentrated
human milk fortifier further comprises from about 54 to about 360 mg/liter
docosahexaenoic acid, based on an as-fed basis, wherein the weight ratio of lutein
(meg) to docosahexaenoic acid (mg) is from about 1:2 to about 10:1.
6. The concentrated liquid human milk fortifier of claim 4 wherein the octenyl
succinic anhydride modified corn starch is present in an amount of from about
0.1% to about 3.5% by weight of the concentrated liquid human milk fortifier.
7. The concentrated liquid human milk fortifier of any one of claims 1-5 wherein the
octenyl succinic anhydride modified corn starch is present in an amount of from
about 0.8% to about 1.5% by weight of the concentrated liquid human milk
fortifier.
8. The concentrated liquid human milk fortifier of claim 4 wherein the low acyl
gellan gum is present in an amount of from greater than 125 to about 800 ppm.
9. The concentrated liquid human milk fortifier of any one of claims 1-6 wherein the
low acyl gellan gum is present in an amount of from about 150 ppm to about 400
ppm.
10. The concentrated liquid human milk fortifier of any one of claims 1-6 and 8
further including carbohydrate, fat, vitamins and minerals.
11. The concentrated liquid human milk fortifier of any one of claims 1-6 and 8
wherein the concentrated liquid human milk fortifier is carrageenan-free.
12. The concentrated liquid human milk fortifier of any one of claims 1-6 and 8,
wherein the concentrated liquid human milk fortifier comprises from about 170 to
about 1360 meg/liter of lutein.
13. The concentrated liquid human milk fortifier of claim 12, wherein the
concentrated liquid human milk fortifier further comprises from about 30 to about
1200 mg/liter of docosahexaenoic acid, wherein the weight ratio of lutein (meg)
to docosahexaenoic acid (mg) is from about 1:2 to about 10:1.
14. The concentrated liquid human milk fortifier of claim 12, wherein the lutein
comprises at least about 20% by weight of added lutein.
15. The concentrated liquid human milk fortifier of claim 12, wherein the human milk
fortifier comprises a combination of free lutein and zeaxanthin from a single
source being a crystalline extract of Tagetes erecta in which the free lutein
represents from 85% to 95% by weight of the combination and the free
zeaxanthin represents from about 5% to about 15% by weight of the combination.
16. A concentrated liquid human milk fortifier comprising from about 10% to about
50% by weight extensively hydrolyzed casein protein, on a dry weight basis, and
at least 50 meg/liter lutein, as fed, wherein the concentrated liquid human milk
fortifier comprises a stabilizer system comprising from about 0.6% to about 2.0 %
by weight of an octenyl succinic anhydride modified corn starch and from about
125 to about 800 ppm low acyl gellan gum.
17. The concentrated liquid human milk fortifier of claim 16 comprising from about
20% to about 40% by weight extensively hydrolyzed casein protein, on a dry
weight basis.
18. The concentrated liquid human milk fortifier of claim 1 comprising from about
0 .8% to about 1.5% by weight of an octenyl succinic anhydride modified corn
starch.
19. The concentrated liquid human milk fortifier of claim 18 comprising from about
150 to about 400 ppm low acyl gellan gum.
20. The concentrated liquid human milk fortifier of any one of claims 16-19, wherein
the concentrated liquid human milk fortifier comprises from about 50 to about
1150 meg/liter of lutein, on an as-fed basis.
2 1. The concentrated liquid human milk fortifier of any one of claims 16-19, wherein
the concentrated liquid human milk fortifier comprises a combination of free
lutein and zeaxanthin from a single source being a crystalline extract of Tagetes
erecta in which the free lutein represents from 85% to 95% by weight of the
combination and the free zeaxanthin represents from about 5% to about 15% by
weight of the combination.
22. An aseptically-sterilized concentrated liquid human milk fortifier comprising
from about 10%> to about 50%> by weight extensively hydrolyzed casein protein,
on a dry weight basis, and at least 170 meg/liter lutein, wherein the concentrated
liquid human milk fortifier comprises a stabilizer system comprising from about
0 .6% to about 2. % by weight of an octenyl succinic anhydride modified corn
starch and from about 125 to about 800 ppm low acyl gellan gum.
The aseptically-sterilized concentrated liquid human milk fortifier of claim 22,
wherein the lutein concentration is at least about 170 mcg/liter, or about 0.85 meg
of lutein per a 5 mL unit.