U.S. patent application number 11/646671 was filed with the patent office on 2007-07-19 for method of reducing the risk of retinopathy of prematurity in preterm infants.
Invention is credited to Bridget Barrett-Reis.
Application Number | 20070166354 11/646671 |
Document ID | / |
Family ID | 39273540 |
Filed Date | 2007-07-19 |
United States Patent
Application |
20070166354 |
Kind Code |
A1 |
Barrett-Reis; Bridget |
July 19, 2007 |
Method of reducing the risk of retinopathy of prematurity in
preterm infants
Abstract
Disclosed is a method of reducing the risk or severity of
retinopathy of prematurity in preterm infants. The method comprises
(a) measuring skin carotenoid levels in preterm infants, preferably
by Raman Spectroscopy, and then (b) administering 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 an
infant formula comprising, on a ready-to-feed basis, from about 100
to about 2000 mcg/liter of total carotenoids, wherein the total
carotenoids include at least about 50 mcg/liter of lutein. The
formulas may further comprise docosahexaenoic acid.
Inventors: |
Barrett-Reis; Bridget;
(Dublin, OH) |
Correspondence
Address: |
ROSS PRODUCTS DIVISION OF ABBOTT LABORATORIES;DEPARTMENT 108140-DS/1
625 CLEVELAND AVENUE
COLUMBUS
OH
43215-1724
US
|
Family ID: |
39273540 |
Appl. No.: |
11/646671 |
Filed: |
December 28, 2006 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11584704 |
Oct 20, 2006 |
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11646671 |
Dec 28, 2006 |
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60730283 |
Oct 26, 2005 |
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Current U.S.
Class: |
424/439 ;
514/690; 514/763; 600/315 |
Current CPC
Class: |
G01N 33/82 20130101;
G01N 2800/38 20130101; A23L 2/66 20130101; A23L 33/115 20160801;
A23L 33/17 20160801; A23L 33/10 20160801; A61P 27/02 20180101; A23L
33/40 20160801; A23V 2002/00 20130101 |
Class at
Publication: |
424/439 ;
514/763; 514/690; 600/315 |
International
Class: |
A61K 47/00 20060101
A61K047/00; A61K 31/12 20060101 A61K031/12; A61K 31/015 20060101
A61K031/015; A61B 5/00 20060101 A61B005/00 |
Claims
1. A method of reducing the risk or severity of retinopathy of
prematurity in preterm infants, said method comprising: (a)
measuring skin carotenoid levels in preterm infants, and then (b)
administering supplemental carotenoids to those infants in need
thereof, wherein the supplemental carotenoids comprise lutein,
lycopene, beta carotene, and zeaxanthin.
2. The method of claim 1 wherein skin carotenoids levels are
measured by Raman Spectroscopy.
3. The method of claim 2 wherein the preterm infants in need of
supplemental carotenoids are those having a Raman Count of less
than about 20,000.
4. The method of claim 2 wherein the supplemental carotenoids are
administered in an amount effective to increase skin carotenoids
levels as measured by Raman Spectroscopy by at least about 5%.
5. The method of claim 1 wherein the preterm infant is born at
between about 26 and about 34 weeks gestation.
6. The method of claim 1 wherein the preterm infant is administered
supplemental carotenoids in an amount effective to provide a total
lutein intake, from all dietary sources, of from about 7 to about
300 mcg/kg/day.
7. The method of claim 1 wherein the preterm infant is administered
supplemental carotenoids in an amount effective to provide a total
lutein intake, from all dietary sources, of from about 14 to about
220 mcg/kg/day.
8. The method of claim 1 wherein the supplemental carotenoid is
provided by an infant formula comprising, on a ready-to-feed basis,
from about 100 to about 2000 mcg/liter of total carotenoids,
wherein the total carotenoids include at least about 50 mcg/liter
of lutein.
9. The method of claim 8 wherein the total carotenoids include from
about 100 to about 1150 mcg/liter of added lutein.
10. The method of claim 8 wherein the infant formula further
comprises fat, protein, carbohydrate, vitamins, and minerals,
including docosahexaenoic acid in a weight ratio of lutein (mcg) to
docosahexaenoic acid (mg) of from about 1:2 to about 10:1.
11. The method of claim 9 wherein the total carotenoids include
from about 100 to about 200 mcg/liter of lutein.
12. The method of claim 11 wherein the weight ratio of lutein (mcg)
to docosahexaenoic acid (mg) is from about 2:1 to about 5:1.
Description
CROSS-REFERENCE TO RELATED APPLICATION
[0001] This application is a continuation-in-part of U.S. Patent
Application No. 11/584,704, filed Oct. 20, 2006, which makes
reference to and claims the benefit of U.S. Provisional Patent
Application 60/730,283 filed Oct. 26, 2005.
TECHNICAL FIELD
[0002] The present invention relates to infant formulas and methods
for using those formulas to promote retinal health and vision
development in infants, including reducing the severity or risk of
retinopathy of prematurity.
BACKGROUND OF THE INVENTION
[0003] Infant formulas are commonly used today to provide
supplemental or sole source nutrition early in life. These formulas
contain protein, carbohydrate, fat, vitamins, minerals, and other
nutrients. They are commercially available as powders,
ready-to-feed liquids, and liquid concentrates.
[0004] Although many infant formulas provide a quality alternative
to human milk, they still do not provide the same high level of
nutrition as found in human milk As such, much of the research
effort into infant formulas over the past several years has been
directed to better understanding the natural constituents of human
milk, and then modifying infant formulas accordingly, or at least
to the extent possible with currently available technology.
[0005] Arachidonic acid and docosahexaenoic acid, for example, have
been identified in human milk and subsequently added to synthetic
infant formulas. These fatty acids support brain and vision
development in infants, and are now commonly found in commercially
available formulas such as Similac.RTM. Advance.RTM. Infant
Formula, Isomil.RTM. Advance.RTM. Infant formula, and Similac.RTM.
Special Care.RTM. Advance.RTM. infant formula, all of which are
available from Ross Products Division, Abbott Laboratories,
Columbus, Ohio, USA.
[0006] Lutein has also been identified in human milk Although it is
not currently added to infant formulas as an isolated ingredient,
lutein can be found at low concentrations in infant formulas as an
inherent ingredient in some of the natural oils commonly used make
such formulas. 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
[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] 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
mcg/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 mcg/liter, preferably from about 100 mcg/liter
to about 200 mcg/liter, in order to duplicate plasma lutein
concentrations found in exclusively in breast fed infants.
[0009] 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
(mcg) to DHA (mg) should now range from about 1:2 to about
10:1.
[0010] 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.
SUMMARY OF THE INVENTION
[0011] A first embodiment is a method of reducing the risk or
severity of retinopathy of prematurity in preterm infants. The
method comprises (a) measuring skin carotenoid levels in preterm
infants, preferably by Raman Spectroscopy, and then (b)
administering supplemental carotenoids to those infants in need
thereof, wherein the supplemental carotenoids comprise lutein,
lycopene, beta arotene, and zeaxanthin. The supplemental
carotenoids may be provided by an infant formula comprising, on a
ready-to-feed basis, from about 100 to about 2000 mcg/liter of
total carotenoids, wherein the total carotenoids include at least
about 50 mcg/liter of lutein.
[0012] The supplemental carotenoids may also be administered as a
preterm infant formula comprising fat, protein, carbohydrate,
vitamins, and minerals. The infant formula may further comprise
docosahexaenoic acid in a weight ratio of lutein (mcg) to
docosahexaenoic acid (mg) of from about 1:2 to about 10:1.
[0013] It has 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 skin
carotenoid levels may be monitored in preterm infants, and then
administered to those infants in need thereof to reduce the risk or
severity of retinopathy of prematurity.
[0014] It has been found that infant formulas may be prepared with
lutein concentrations of at least 50 mcg/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 mcg/liter of lutein. It has also been found,
consequently, that the weight ratio of lutein (mcg) to DHA (mg) in
an infant formula may range from about 1:2 to about 10:1. It is
believed that the combination of lutein and docosahexaenoic acid
are particularly useful in promoting retinal health and vision
development in infants, provided that sufficient quantities of each
are designed into the infant formula as described herein.
BRIEF DESCRIPTION OF THE DRAWINGS
[0015] FIG. 1 is a graph of lutein intake (mcg/day) and
corresponding plasma lutein concentrations (mcg/dl) in infant
groups fed human milk (HM) or infant formulas containing varied
concentrations of lutein [CTRL with 14.6 mcg lutein/liter (no added
lutein, all lutein inherent in ingredients)]; L1 with 32.6 mcg
lutein/liter (approximately 18 mcg/liter added lutein, remainder
inherent), L2 with 52.6 mcg lutein/liter (approximately 38
mcg/liter added lutein, remainder inherent).
[0016] FIG. 2 is a graph showing visual acuity as measured by sweep
visual evoked potential (logMAR) in monkeys at 4, 8, and 12 weeks
of age. The monkeys are fed infant formula with either DHA and
added lutein (n=8) or DHA without added lutein (n-8) during a 12
week feeding period.
DETAILED DESCRIPTION OF THE INVENTION
[0017] The present invention, including essential and some optional
features or limitations, is described hereinafter in detail.
[0018] The terms "infant" and "preterm infant" as used herein,
unless otherwise specified, are used interchangeably to mean
preterm infants born at less than about 37 weeks gestation,
typically from about 26 to about 34 weeks gestation, and or low
birth weight infants (term or preterm) at less than 2.5 kg at
birth, including those less than 1.8 kg at birth.
[0019] The term "infant formula" as used herein, unless otherwise
specified, refers to a nutritional composition, typically free of
egg phospholipids, that is designed for infants and contains
sufficient protein, carbohydrate, fat, vitamins, and minerals to
potentially serve as the sole source of nutrition when provided in
sufficient quantity.
[0020] The term "ready-to-feed" as used herein, unless otherwise
specified, refers to infant formulas in liquid form suitable for
administration to an infant, including reconstituted powders,
diluted concentrates, and manufactured liquids.
[0021] As used herein, all concentrations expressed as either
"mcg/liter" or "mg/liter" refer to ingredient concentrations within
the described infant formulas as calculated on a ready-to-feed or
as fed basis, unless otherwise specified.
[0022] 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.
[0023] All references to singular characteristics or limitations of
the present invention 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.
[0024] 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.
[0025] The infant formulas and methods described herein may also be
substantially free of any optional or selected essential 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, the term "substantially free"
means that the selected composition 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.
[0026] The methods of the present invention may comprise, consist
of, or consist essentially of the essential elements and
limitations of the invention described herein, as well as any
additional or optional ingredients, components, or limitations
described herein or otherwise useful in nutritional formula
applications.
Methods of Use
[0027] A first embodiment of the present invention is a method of
reducing the risk or severity of retinopathy of prematurity in
preterm infants. The method comprises (a) measuring skin carotenoid
levels in preterm infants, preferably by Raman Spectroscopy, and
then (b) administering supplemental carotenoids to those infants in
need thereof, wherein the supplemental carotenoids comprise lutein,
lycopene, beta-otene, and zeaxanthin. The supplemental carotenoids
may be provided by an infant formula comprising, on an as-fed
basis, up to about 2000 mcg/liter of total carotenoids, wherein the
total carotenoids include at least about 50 mcg/liter of
lutein.
[0028] The term "supplemental carotenoids" as used herein, unless
otherwise specified, means a carotenoid blend comprising up to
about 2000 mcg/liter, including from about 50 to about 1500
mcg/liter, and also including from about 100 to about 1200
mcg/liter, of total carotenoids, wherein the total carotenoids
comprise beta-carotene, lycopene, zeaxanthin, and lutein, which
includes at least about 50 mcg/liter of lutein, including from
about 50 to about 1150 mcg/liter, also including from about 75 to
about 230 mcg/liter, and also including from about 100 to about 200
mcg/liter.
[0029] This particular method may therefore provide the infant with
an effective amount of lutein to provide the stated benefits,
including from about 7 to about 300 mcg/kg/day, including from
about 14 to about 220 mcg/kg/day, and also including from about 22
to about 150 mcg/kg/day (of lutein per kg of body weight of the
infant).
[0030] All lutein and carotenoid concentrations and ratios
referenced herein are calculated on a free lutein or carotenoid
basis, unless otherwise specified.
[0031] 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 infant formula may further comprise docosahexaenoic
acid in a weight ratio of lutein (mcg) 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.
[0032] 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.
[0033] 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.
[0034] 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.
[0035] 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.
[0036] In accordance with the methods hereof, the supplemental
carotenoids 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.
Carotenoids
[0037] The supplement carotenoids for us herein--lutein, lycopene,
beta-carotene, and zeaxanthin--may be provided or otherwise
administered in any form suitable for use in preterm infants.
[0038] 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: ##STR1## The above formula includes the general structure
of lutein and related derivatives or structures. Free lutein, for
example, corresponds to the formula wherein R.sub.1 and R.sub.2 are
both hydrogen, and includes cis and trans isomers thereof as well
as salts thereof, e.g., sodium, potassium.
[0039] Lutein esters suitable for use herein include any lutein
ester of the above formula wherein R.sub.1 and R.sub.2 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 R.sub.1 or R.sub.2 is an acyl residue of a carboxylic
acid. Suitable lutein esters include, as well, both cis and trans
isomers. The R.sub.1 and R.sub.2 moieties are residues of a
saturated or unsaturated C.sub.1 to C.sub.22 fatty carboxylic
acids, non-limiting examples of which include formic, acetic,
propionic, butyric, valeric, caproic, caprylic, capric, lauric,
myristic, palmitic, stearic, and oleic acids.
[0040] 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 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.
[0041] 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 sources include LycoVit.RTM. synthetic lycopene dispersion
in vegetable oil provided by BASF, Mount Olive, N.J., USA,
Lyc-O-Mato.RTM. 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.RTM. brand free
lutein provided by Kemin Foods, Des Moines, Iowa, Xangold.RTM.
Lutein Esters provided by Cognis, Cincinnati, Ohio, U.S.A., and
beta-carotene provided by BASF, Mount Olive, N.J.
[0042] Non-limiting examples of some suitable lutein sources for
use herein include FloraGLO.RTM. Crystalline Lutein, available from
Kemin Foods, Des Moines, Iowa, USA; and Xangold.RTM. Lutein Esters
provided by Cognis, Cincinnati, Ohio, USA.
[0043] 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 zeaxantiin represents from about
5% to about 15% by weight of the combination. A lutein-zeaxanthin
combination is available from Kemin Foods, Des Moines, Iowa, USA,
under the FloraGLO.RTM. brand.
Docosahexaenoic Acid (DHA)
[0044] The infant formulas for use herein may comprise
docosahexaenoic acid, 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.
[0045] Docosahexaenoic acid concentrations in the infant formulas
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 about 36 to 360 mg/liter,
including from about 50 to about 144 mg/liter, and also including
from about 72 to about 130 mg/liter, as calculated on a
ready-to-feed basis.
[0046] The docosahexaenoic acid may be added to 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.
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.
[0047] The infant formulas 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),
.gamma.-linolenic acid or GLA (18:3 n-6), .alpha.-linolenic acid
(18:3 n-3), dihomo-.gamma.-linolenic or DHGLA (20:3 n-6),
.alpha.-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.
Other Nutrients
[0048] The infant formulas for use herein may comprise fat,
protein, carbohydrate, minerals, and vitamins, all of which are
selected in kind and amount to meet the dietary needs of the
intended infant population.
[0049] Many different sources and types of carbohydrates, fats,
proteins, minerals and vitamins are known and can be used in the
infant formulas, provided that such nutrients are compatible with
the added ingredients in the selected formulation and are otherwise
suitable for use in an infant formula
[0050] Carbohydrates suitable for use herein may be simple or
complex, lactose-containing or lactose-free, or combinations
thereof, non-limiting examples of which include hydrolyzed, intact,
naturally and/or chemically modified cornstarch, maltodextnin,
glucose polymers, sucrose, corn syrup, corn syrup solids, rice or
potato derived carbohydrate, glucose, fructose, lactose, high
fructose corn syrup and indigestible oligosaccharides such as
fructooligosaccharides (FOS), galactooligosaccharides (GOS), and
combinations thereof.
[0051] Proteins suitable for use herein include hydrolyzed,
partially hydrolyzed, and non-hydrolyzed or intact proteins or
protein sources, and can be derived from any known or otherwise
suitable source such as milk (e.g., casein, whey), animal (e.g.,
meat, fish), cereal (e.g., rice, corn), vegetable (e.g., soy), or
combinations thereof.
[0052] Proteins for use herein may also include, or be entirely or
partially replaced by, free amino acids known for or otherwise
suitable for use in infant formulas, non-limiting examples of which
include alanine, arginine, asparagine, carnitine, aspartic acid,
cystine, glutamic acid, glutamine, glycine, histidine, isoleucine,
leucine, lysine, methionine, phenylalanine, proline, serine,
taurine, threonine, tryptophan, taurine, tyrosine, valine, and
combinations thereof These amino acids are most typically used in
their L-forms, although the corresponding D-isomers may also be
used when nutritionally equivalent Racemic or isomeric mixtures may
also be used.
[0053] Fats suitable for use in the infant formulas include coconut
oil, soy oil, corn oil, olive oil, safflower oil, high oleic
safflower oil, algal oil, MCT oil (medium chain triglycerides),
sunflower oil, high oleic sunflower oil, palm and palm kernel oils,
palm olein, canola oil, marine oils, cottonseed oils, and
combinations thereof.
[0054] Vitamins and similar other ingredients suitable for use in
the infant formulas include vitamin A, vitamin D, vitamin E,
vitamin K, thiamine, nioflavin, pyridoxine, vitamin B12, niacin,
folic acid, pantothenic acid, biotin, vitamin C, choline, inositol,
salts and derivatives thereof, and combinations thereof.
[0055] Minerals suitable for use in the infant formulas include
calcium, phosphorus, magnesium, iron, zinc, manganese, copper,
chromium, iodine, sodium, potassium, chloride, and combinations
thereof.
[0056] The infant formulas preferably comprise nutrients in
accordance with the relevant infant formula guidelines for the
targeted consumer or user population, an example of which would be
the Infant Formula Act, 21 U.S.C. Section 350(a).
[0057] Instant formulas for use herein may comprise the
carbohydrate, fat, and protein concentrations described in the
following table. TABLE-US-00001 TABLE 1 Infant Formula
Nutrients.sup.1 Nutrient Range gm/100 kcal gm/liter.sup.2
Carbohydrate 1.sup.st embodiment 8-16 54-108 2.sup.nd embodiment
9-13 61-88 Fat 1.sup.st embodiment 3-8 20-54 2.sup.nd embodiment
4-6.6 27-45 Protein 1.sup.st embodiment 1-3.5 7-24 2.sup.nd
embodiment 1.5-3.4 10-23 .sup.1All numerical values may be modified
by the term "about" .sup.2From ready-to-feed liquid, reconstituted
powder, or diluted concentrate
[0058] The infant formulas for use herein may include those
formulas that comprise per 100 kcal of formula one or more of the
following: vitamin A (from about 250 to about 750 IU), vitamin D
(from about 40 to about 100 IU), vitamin K (greater than about 4
mcg), vitamin E (at least about 0.3 IU), vitamin C (at least about
8 mg), thiamine (at least about 8 g), vitamin B 12 (at least about
0.15 g), niacin (at least about 250 g), folic acid (at least about
4 g), pantothenic acid (at least about 300 g), biotin (at least
about 1.5 g), choline (at least about 7 mg), and inositol (at least
about 4 mg).
[0059] These infant formulas may also comprise per 100 kcal of
formula one or more of the following: calcium (at least about 50
mg), phosphorus (at least about 25 mg), magnesium (at least about 6
mg), iron (at least about 0.15 mg), iodine (at least about 5 g),
zinc (at least about 0.5 mg), copper (at least about 60 g),
manganese (at least about 5 g), sodium (from about 20 to about 60
mg), potassium (from about 80 to about 200 mg), and chloride (from
about 55 to about 150 mg).
Optional Ingredients
[0060] The infant formulas for use herein may further comprise
other optional ingredients that may modify the physical, chemical,
aesthetic or processing characteristics of the compositions or
serve as pharmaceutical or additional nutritional components when
used in the targeted infant population Many such optional
ingredients are known or are otherwise suitable for use in
nutritional products and may also be used in the infant formulas
for use herein, provided that such optional materials are
compatible with the essential materials described herein and are
otherwise suitable for use in an infant formula.
[0061] Non-limiting examples of such optional ingredients include
preservatives, additional anti-oxidants, emulsifying agents,
buffers, colorants, flavors, nucleotides and nucleosides,
probiotics, prebiotics, lactoferin and related derivatives,
thickening agents and stabilizers, and so forth.
Product Form
[0062] The infant formulas for use herein may be prepared as any
product form suitable for use in infants, including reconstitutable
powders, ready-to-feed liquids, and dilutable liquid concentrates,
which product forms are all well known in the nutrition and infant
formula arts.
[0063] The infant formulas for use herein may have any caloric
density suitable for the intended infant population, or provide
such a density upon reconstitution of a powder embodiment or upon
dilution of a liquid concentrate embodiment Most caloric densities
are at least about 18 kcal/fl oz (609 kcal/liter), more typically
from about 20 kcal/fl oz (675-680 kcal/liter) to about 25 kcal/fl
oz (820 kcal/liter), even more typically from about 20 kcal/fl oz
(675-680 kcal/liter) to about 24 kcal/fl oz (800-810 kcal/liter).
Generally, the 22-30 kcal/fl oz, most typically from about 22-24
kcal/fl oz, formulas are more commonly used in pre-term of low
birth weight infants, and the 20-21 kcal/fl oz (675-680 to 700
kcal/liter) formulas are more often used in term infants. Higher
caloric feedings may be used with pre-term infants of low birth
weight; such feedings are typically from about 27 kcal/fl oz (90-95
kcal/liter) to about 30 kcal/fl oz (1000-1015 kcal/liter).
[0064] For powder infant formulas for use herein, such powders are
typically in the form of flowable or substantially flowable
particulate compositions, or at least particulate compositions that
can be easily scooped and measured with a spoon or similar other
device, wherein the compositions can easily be reconstituted by the
intended user with a suitable aqueous fluid, typically water, to
form a liquid nutritional formula for immediate oral or enternal
use. In this context, "immediate" use generally means within about
48 hours, most typically within about 24 hours, preferably right
after reconstitution. These powder embodiments include spray dried,
agglomerated, dry mixed or other known or otherwise effective
particulate form. The quantity of a nutritional powder required to
produce a volume suitable for one serving can vary.
[0065] The infant formulas for use herein may be packaged and
sealed in single or multi-use containers, and then stored under
ambient conditions for up to about 36 months or longer, more
typically from about 12 to about 24 months. For multi-use
containers, these packages can be opened and then covered for
repeated use by the ultimate user, provided that the covered
package is then stored under ambient conditions (e.g., avoid
extreme temperatures) and the contents used within about one month
or so.
Method of Manufacture
[0066] The infant formulas for use herein may be prepared by any
known or otherwise effective technique suitable for making and
formulating an infant formula or similar other formula, variations
of which may depend upon variables such as the selected product
form, ingredient combination, packaging and container selection,
and so forth, for the desired infant formula Such techniques and
variations for any given formula are easily determined and applied
by one of ordinary skill in the infant nutrition formulation or
manufacturing arts.
[0067] The infant formulas for use herein, including the
exemplified formulas described hereinafter, can therefore be
prepared by any of a variety of known or otherwise effective
formulation or manufacturing methods. These methods most typically
involve the initial formation of an aqueous slurry containing
carbohydrates, proteins, lipids, stabilizers or other formulation
aids, vitamins, minerals, or combinations thereof The slurry is
emulsified, pasteurized, homogenized, and cooled. Various other
solutions, mixtures, or other materials may be added to the
resulting emulsion before, during, or after further processing.
This emulsion can then be further diluted, heat-treated, and
packaged to form a ready-to-feed or concentrated liquid, or it can
be heat-treated and subsequently processed and packaged as a
reconstitutable powder, e.g., spray dried, dry mixed,
agglomerated.
[0068] Other suitable methods for making nutritional formulas are
described, for example, in U.S. Pat. No. 6,365,218 (Borschel, et
al.), U.S. Pat. No. 6,589,576 (Borschel, et al.), U.S. Pat. No.
6,306,908 (Carlson, et al.), U.S. Patent Application 20030118703 A1
(Nguyen, et al.), which descriptions are incorporated herein by
reference.
Experiment
[0069] The purpose of this experiment is to evaluate changes in
visual acuity in animals fed infant formulas comprising either DHA
or DHA with added lutein. Sixteen monkeys are fed one of two
defined infant formulas during their first 12 weeks of life. One is
a control formula--Similac.RTM. Advance.RTM. Infant formula,
available from Abbott Laboratories, Columbus Ohio, and the other is
an experimental formula including Similac.RTM. Advance.RTM. Infant
Formula as a base, but with added carotenoids comprising lutein.
The formulas include the following: TABLE-US-00002 Experimental
Nutrient Control formula formula DHA 50 mg/L 60 mg/L Lutein 0 mcg/L
added (18 mcg/L inherent) 117 mcg/L Zeaxanthin 0 mcg/L added (4
mcg/L inherent) 36 mcg/L Zeaxanthin/ 22% 31% lutein
[0070] The base formula (Similac.RTM. Advance.RTM. Infant formula)
contains water, nonfat milk, lactose, high oleic safflower oil, soy
oil coconut oil, whey protein concentrate; C. cohnii oil, K. alpina
oil, potassium citrate, calcium carbonate, ascorbic acid, mono- and
diglycerides, soy lecithin, carrageenan, potassium chloride,
magnesium chloride, sodium chloride, ferrous sulfate, choline
chloride, choline bitartrate, taurine, m-inositol,
d-alpha-tocopheryl acetate, L arnitine, zinc sulfate, niacinamide,
calcium pantothenate, riboflavin, vitamin A palmitate, cupric
sulfate, thiamine chloride hydrochloride, pyridoxine hydrochloride,
beta-carotene, folic acid, manganese sulfate, phylloquinone,
biotin, sodium selenate, vitamin D3, cyanocobalamin and nucleotides
(adenosine 5'-monophosphate, cytidine 5'-monophosphate, disodium
guanosine 5'-monophosphate, disodium uridine 5'-monophosphate).
[0071] The monkeys are randomized to receive either the
experimental (n=8) or control (n=8) formulas from birth to 12 weeks
of life. The animals do not receive any milk from their mothers.
Infants and mothers are separated at birth. During the study, the
monkeys are exposed to light having the intensity and spectral
characteristics of sunlight for 12 hours per day to simulate the
light-induced oxidative stress potentially experienced by infants.
During the study, the monkeys are evaluated for several parameters,
including plasma lutein concentrations and sweep visual evoked
potential (VEP).
Plasma Lutein
[0072] Plasma concentrations of lutein, lycopene, and beta carotene
are not significantly different between the monkeys fed the control
and experimental formulas at birth (0 weeks of age). Plasma lutein
concentrations are significantly higher in monkeys fed the
experimental formula than monkeys fed the control formula at 4
(p<0.001), 8 (p<0.001), and 12 (p<0.001) weeks of age.
Similarly, plasma lycopene concentrations are significantly higher
in the experimental group compared to the control group at 4
(p<0.001), 8 (p<0.001), and 12 (p<0.001) weeks. Plasma
beta-carotene concentrations are significantly greater in the
experimental formula group than the control formula group at 4
(p=0.005) and 8 (p=0.010), but not 12 (p=0.052) weeks of age.
Visual Acuity
[0073] The monkeys are assessed for changes in visual acuity at 4,
8, and 12 weeks of life. Visual acuity is measured by sweep visual
evoked potential (VEP), a method well known in the art for
measuring visual evoked potential in infants. Visual acuity is
measured by determining the smallest spatial frequency high
contrast grating that evokes a measurable response from the visual
cortex. The VEP from the primary cortical visual area is recorded
using small silver disk EEG electrodes placed on the scalp with
water-soluble electrode paste. The infant is held in an
experimenter's lap while it gazes at a video monitor displaying
phase-reversing black and white gratings. When necessary, the
infant's attention will be drawn to the center of the screen with
small dangling toys. During each "sweep", the spatial frequency of
the grating will be decreased stepwise from above to below the
subject's acuity threshold during a recording period of several
seconds. The amplitude of the second harmonic of the VEP response,
which reflects the response linked to the stimulus reversal rate,
will be plotted as a function of spatial frequency to define the
subject's acuity threshold (Neuringer M, Jeffrey B G: Visual
development: neural basis and new assessment methods. J Pediatr
2003;143:S87-S95).
[0074] VEP scores from the study are summarized in the FIG. 1
graph. Lower VEP (logMAR) scores are indicative of better visual
acuity. Although VEP scores decreased (i.e., visual acuity
improved) for all monkeys during the 12 week testing period, as
expected, the VEP scores at 8 weeks were surprisingly lower in the
experimental group (added lutein+DHA formula) than in the control
group (DHA without added lutein formula) (4 weeks, p=0.412,
etc.)
[0075] The data suggest accelerated development in infant monkeys
fed the experimental formula at 8 weeks of life--specifically in
visual acuity as measured by VEP values. To extrapolate the data to
human infants, the eye development in monkeys at ages of 4, 8, and
12 weeks corresponds to the eye development in human infants at 4,
8, and 12 months, respectively. The data therefore suggests that
even in a human infant, the experimental formula would improve
visual acuity at between about 4 and about 12 months of life.
EXAMPLES
[0076] The following examples represent specific formulas for use
in the methods defined herein, each of which is given solely for
the purpose of illustration and is not to be construed as
limitations of the present invention, as many variations thereof
are possible without departing from the spirit and scope of the
invention. All exemplified amounts are weight percentages based
upon the total weight of the composition, unless otherwise
specified.
Examples 1.1-1.3
[0077] The following are examples of milk based, ready-to-feed,
infant formulas suitable for use in the skin carotenoid methods.
TABLE-US-00003 Example 1.1 Example 1.2 Example 1.3 Amount per
Quantity per Quantity per Ingredient 454 kg 454 kg 454 kg Water QS
QS QS Lactose 27 kg 27 kg 27 kg ARA-containing oil 0.167 kg 0.167
kg 0.167 kg (40% ARA) DHA-containing oil 0.063 kg 0.095 kg 0.145 kg
(40% DHA) Non-fat dry milk 11.33 kg 11.33 kg 11.33 kg High oleic
safflower oil 6.5 kg 6.5 kg 6.5 kg Mono- and di-glycerides 0.162 kg
0.162 kg 0.162 kg Soybean oil 5 kg 5 kg 5 kg Whey protein 2.8 kg
2.8 kg 2.8 kg Calcium carbonate 0.211 kg 0.211 kg 0.211 kg Coconut
oil 4.6 kg 4.6 kg 4.6 kg Citric acid 0.014 kg 0.014 kg 0.014 kg
Potassium citrate 0.245 kg 0.245 kg 0.245 kg Ascorbic acid 178 g
178 g 178 g Lecithin 162 g 162 g 162 g Magnesium chloride 25 g 25 g
25 g Potassium chloride 88 g 88 g 88 g Ferrous sulfate 26 g 26 g 26
g Carrageenan 136 g 136 g 136 g Choline chloride 25 g 25 g 25 g
Nucleotide and 133 g 133 g 133 g choline premix .sup.3 Riboflavin 1
g 1 g 1 g L-Carnitine 1.5 g 1.5 g 1.5 g Potassium hydroxide 998 g
998 g 998 g Water soluble 65 g 65 g 65 g vitamin premix .sup.1
Vitamin ADEK premix .sup.2 21 g 21 g 21 g Vitamin A 0.4 g 0.4 g 0.4
g Added carotenoids .sup.4 -- .sup.4 -- .sup.4 -- .sup.4 Total
carotenoids .sup.4 186 400 555 Total Lutein 90 150 200 w/zeaxanthin
(mcg/L) .sup.5 Total lycopene 30 90 135 Total beta carotene 66 160
220 Total DHA (mg/liter) 50 75 115 .sup.1 premix contains (per 65
g) 19.8 g taurine, 14.4 g inositol, 6.7 g zinc sulfate, 4.2 g
niacinamide, 2.6 g calcium pantothenate, 2.3 g ferrous sulfate, 0.8
g cupric sulfate, 0.6 g thiamine, 0.3 g riboflavin, 0.26 g
pyridoxine, 0.1 g folic acid, 0.07 g manganese sulfate, 0.03 g
biotin, 0.025 g sodium selenate, 0.002 g cyanocobalamin .sup.2
premix contains (per 21 g) 4.0 g alpha-tocopherol acetate, 0.8 g
vitamin A palmitate, 0.05 g phylloquinone, 0.006 g vitamin D3
.sup.3 premix contains (per 133 g): 23 g choline bitartrate, 15 g
5'-CMP, 11 g 5'-GMP, 10 g 5'-UMP, 6 g 5'-AMP .sup.4 Carotenoids
added individually as lycopene, beta carotene, and lutein (with
zeaxanthin) to achieve lutein/zeaxanthin, lycopene, and beta
carotene totals. .sup.5 Lutein/zeaxanthin mixture contains 1.25%
zeaxanthin by weight of lutein.
[0078] The exemplified formulas may be prepared by making at least
three separate slurries that are later blended together, heat
treated, standardized, packaged and sterilized. Initially, a
carbohydrate-mineral slurry is prepared by dissolving lactose in
water at 65-71.degree. C., followed by the addition of magnesium
chloride, potassium citrate, potassium chloride, choline chloride,
and citric acid. The resulting slurry is held with agitation at
55-65.degree. C. for not longer than eight hours until it is later
blended with the other prepared slurries.
[0079] A protein-fat slurry is prepared by combining high oleic
safflower oil, soybean oil, and coconut oil at 55-60.degree. C.,
followed by the addition of vitamin ADEK premix, mono- and
diglycerides, lecithin, carrageenan, vitamin A, carotenoids, ARA
oil, and DHA oil. Whey protein and calcium carbonate are then added
The resulting protein-oil slurry is held under moderate agitation
at 40-43.degree. C. for no longer than two hours until it is later
blended with the other formed slurries.
[0080] The carbohydrate-mineral slurry is then combined with water
and non-fat dry milk and agitated for 10 minutes. The protein-oil
slurry is then added and the resulting mixture agitated for at
least 10 minutes. Lutein and beta-carotene are then added to the
blend and agitated for at least 15 minutes. The pH of the resulting
blend is adjusted to 6.68-6.75 with IN potassium hydroxide.
[0081] After waiting for a period of not less than one minute nor
greater than two hours, the resulting blend is heated to
71-82.degree. C. and dearated under vacuum, emulsified through a
single stage homogenizer at 900-1100 psig, and then heated to
99-110.degree. C., and then heated again to 146.degree. C. for
about 5 seconds. The heated blend is passed through a flash cooler
to reduce the temperature to 99-110.degree. C. and then through a
plate cooler to further reduce the temperature to 71-76.degree. C.
The cooled blend is then homogenized at 3900-4100/400-600 psig, and
then held at 74-80.degree. C. for 16 seconds, and then cooled to
1-7.degree. C. are taken for microbiological and analytical
testing. The mixture is held under agitation. 10081] A
water-soluble vitamin (WSV) solution and an ascorbic acid solution
are prepared separately and added to the processed blended slurry.
The vitamin solution is prepared by adding the following
ingredients to 9.4 kg of water with agitation: potassium citrate,
ferrous sulfate, WSV premix, L-carnitine, riboflavin, and the
nucleotide-choline premix. The ascorbic acid solution is prepared
by adding potassium citrate and ascorbic acid to a sufficient
amount of water to dissolve the ingredients. The vitamin and
ascorbic acid solutions are then added to the blend, and the pH of
the blend adjusted to 7-10 with 45% potassium hydroxide
solution.
[0082] Based on the analytical results of the quality control
tests, an appropriate amount of water is added to the batch with
agitation to achieve the desired total solids. The product pH may
be adjusted to achieve optimal product stability. The completed
product is then placed in suitable containers and subjected to
terminal sterilization.
[0083] The resulting formulas are fed to infants as a sole source
of nutrition during the first 6 to 12 months of life to provide
each infant with 7-300 .mu.g/kg/day of lutein. The formulas provide
improved retinal health and vision development as described
herein.
Examples 2.1-2.3
[0084] The following are examples of soy-based, powder, infant
formulas suitable for use in the methods of the present invention.
TABLE-US-00004 Example 2.1 Example 2.2 Example 2.3 Amount per
Amount per Amount per INGREDIENT 454 kg 454 kg 454 kg Water QS QS
QS High oleic 52.1 kg 52.1 kg 52.1 kg safflower oil Coconut oil
35.2 kg 35.2 kg 35.2 kg Soy oil 38.1 kg 38.1 kg 38.1 kg
ARA-containing oil 1.3 kg 1.3 kg 1.3 kg (40% ARA) DHA-containing
oil 0.381 kg 0.762 kg 0.876 kg (40% DHA) Oil soluble 0.173 kg 0.173
kg 0.173 kg vitamin premix Ascorbyl palmitate 0.162 kg 0.162 kg
0.162 kg Soy protein isolate 66.1 kg 66.1 kg 66.1 kg Corn syrup
236.0 kg 236.0 kg 236.0 kg Calcium phosphate 8.0 kg 8.0 kg 8.0 kg
(di and tribasic) Ferrous sulfate 0.138 kg 0.138 kg 0.138 kg Water
soluble 0.65 kg 0.65 kg 0.65 kg vitamin premix trace
minerals/taurine Choline chloride 0.23 kg 0.23 kg 0.23 kg Potassium
iodide 0.0005 kg 0.0005 kg 0.0005 kg Methionine 0.722 kg 0.722 kg
0.722 kg Ascorbic acid 0.72 kg 0.72 kg 0.72 kg Potassium hydroxide
1.2 kg 1.2 kg 1.2 kg (45% solution) Potassium chloride 0.87 kg 0.87
kg 0.87 kg Magnesium Chloride 0.4 kg 0.4 kg 0.4 kg Carnitine 0.05
kg 0.05 kg 0.05 kg Added carotenoids .sup.1 -- .sup.1 -- .sup.1 --
.sup.1 Total carotenoids 186 400 555 (mcg/liter) Total Lutein with
90 150 200 zeaxanthin (mcg/liter) Total lycopene 30 90 135
(mcg/liter) Total beta carotene 66 160 220 (mcg/liter) .sup.1
Individual carotenoids added as lycopene, beta-carotene, and lutein
(with zeaxanthin) to achieve lutein/zeaxanthin, lycopene, and
bet-carotene totals. .sup.2 Lutein/zeaxanthin mixture contains
1.25% zeaxanthin by weight of lutein.
[0085] The first step in the preparation of the exemplified powder
is the preparation of the oil blend. Soy oil, coconut oil and high
oleic safflower oil are combined in a suitable container or tank at
60-65.degree. C. with agitation. Ascorbyl palmitate and mixed
tocopherols are added to the tank, followed by the oil soluble
vitamin premix, all with agitation. Beta-carotene (BASF, Mount
Olive, N.J.), and lutein (Kemin, Des Moines, Iowa) and other
carotenoids are added to the oil blend and agitated until well
dispersed. Soy protein isolate and methionine are then added to the
oil blend, and the resulting mixture agitated and held at
54.0-60.degree. C. until used later during the manufacturing
process.
[0086] The carbohydrate-mineral slurry is then prepared. Potassium
chloride, sodium chloride, magnesium chloride, and potassium iodide
are added to water 60-65.degree. C., followed by di- and
tri-calcium phosphates, all with agitation. Corn syrup is then
added with agitation, and the slurry held at 54-60.degree. C. until
used later during the manufacturing process.
[0087] The carbohydrate-mineral slurry is added to the oil blend.
Additional water is added as necessary. The ARA and DHA oils are
added to the blend. The pH of the resulting mixture is adjusted to
6.75-6.85 using KOH solution. The adjusted mixture is then held at
54-60C under agitation for at least 15 minutes.
[0088] The resulting mixture is then heated to 74-79C and dearated
under vacuum, emulsified through a single stage homogenizer at
0-2.76 Mpa, passed through a two-stage homogenizer at 6.2-7.6 MPa
and 2.1-3.4 MPa The homogenized mixture is held at 73-79C for 16
seconds and then cooled to 1-7C. Samples are taken for
microbiological and analytical testing The mixture is held under
agitation.
[0089] A calcium carbonate solution may be prepared for use in
adjusting the calcium level of the mixture if outside of
specification.
[0090] A vitamin stock solution containing a water soluble vitamin
premix with trace minerals and taurine is prepared. Potassium
citrate and ferrous sulfate are added to water at 37-66.degree. C.
The vitamin premix is then added and the mixture agitated. The
choline chloride and carnitine are added and then the required
amount of this vitamin mixture is added to the batch.
[0091] An ascorbic acid solution is prepared and added slowly to
the batch with agitation for at least 10 minutes. The batch is then
preheated to 74-79.degree. C. The batch is then held for 5 seconds
at 107-111.degree. C. using direct steam injection. The batch is
then cooled to 71-82.degree. C. before being pumped to a spray
dryer and dried to a flowable powder. The batch is then packaged in
suitable containers and sealed under a headspace of less than 2.0%
oxygen.
[0092] The exemplified powders are reconstituted with water to a
caloric density of 676 kcal/liter. The resulting liquid formulas
are fed to preterm infants as a sole source of nutrition at 7-300
.mu.g/kg/day of lutein. The formula provides improved retinal
health and vision development as described herein, and reduces the
risk or severity of retinopathy of prematurity in the infants.
Examples 3.1-3.3
[0093] The following are examples of milk-based, powder, infant
formulas suitable for use in the methods described herein.
TABLE-US-00005 Example 3.1 Example 3.2 Example 33 Amount per Amount
per Amount per Ingredient Name 454 kg 454 kg 454 kg Water QS QS QS
Soy oil 35.8 kg 35.8 kg 35.8 kg Coconut oil 23.8 kg 23.8 kg 23.8 kg
MCT oil (medium 32.1 kg 32.1 kg 32.1 kg chain triglyceride) High
Oleic 34.6 kg 34.6 kg 34.6 kg Safflower oil Ascorbyl palmitate
0.157 kg 0.157 kg 0.157 kg Vitamin A palmitate 0.002 kg 0.002 kg
0.002 kg Vitamin ADEK 0.192 kg 0.192 kg 0.192 kg premix .sup.1
Mixed tocopherols 0.075 kg 0.075 kg 0.075 kg Whey protein 32.7 kg
32.7 kg 32.7 kg concentrate Calcium carbonate 1.2 kg 1.2 kg 1.2 kg
Lactose 54.5 kg 54.5 kg 54.5 kg Corn syrup solids 117.1 kg 117.1 kg
117.1 kg Magnesium chloride 0.724 kg 0.724 kg 0.724 kg Potassium
citrate 2.8 kg 2.8 kg 2.8 kg Sodium chloride 0.39 kg 0.39 kg 0.39
kg Sodium citrate 0.001 kg 0.001 kg 0.001 kg Non-fat dried milk
116.9 kg 116.9 kg 116.9 kg Calcium phosphate 1.8 kg 1.8 kg 1.8 kg
tribasic ARA-containing oil 1.3 kg 1.3 kg 1.3 kg (40% ARA)
DHA-containing oil 0.43 kg 0.65 kg 1.00 kg (40% DHA) Ascorbic acid
1.29 kg 1.29 kg 1.29 kg Potassium hydroxide 9.8 kg 9.8 kg 9.8 kg 1N
solution Ferrous sulfate 0.168 kg 0.168 kg 0.168 kg Carnitine 0.136
kg 0.136 kg 0.136 kg Choline chloride 0.182 kg 0.182 kg 0.182 kg
Vit. and trace 0.825 kg 0.825 kg 0.825 kg mineral premix .sup.2
Inositol 0.734 kg 0.734 kg 0.734 kg Nucleotide, choline 1.1 kg 1.1
kg 1.1 kg bitartrate premix .sup.3 Added carotenoids .sup.4 --
.sup.4 -- .sup.4 -- .sup.4 Total carotenoids 186 400 555
(mcg/liter) Total Lutein with 90 150 200 zeaxanthin (mcg/liter)
Total lycopene 30 90 135 (mcg/liter) Total beta carotene 66 160 220
(mcg/liter) .sup.1 premix provides 71 gm d-alpha-tocopheryl
acetate, 7.29 gm Vitamin A palmitate, 0.422 gm phylloquinone, and
0.051 gm Vitamin D3 to the product. .sup.2 premix provides 252 gm
taurine, 183 gm inositol, 84.5 gm zinc sulfate, 53.8 gm
niacinamide, 32.6 gm calcium pantothenate, 29 gm ferrous sulfate,
10.1 gm cupric sulfate, 8.4 gm thiamine, 3.7 gm riboflavin, 3.4 gm
pyridoxine (HCl), 1.1 gm folic acid, 1.0 gm manganese sulfate, 0.3
gm biotin, 0.2 gm sodium selenate, and 0.03 gm cyanocobalamin to
the product. .sup.3 premix provides 188 gm choline bitartrate, 118
gm cytidine 5'-monophosphate, 92 gm disodium guanosine
5'-monophosphate, 80 gm disodium uridine 5'-monophosphate, and 51
gm adenosine 5'-monophosphate to the product. .sup.4 Individual
carotenoids added as lycopene, beta-carotene, and lutein (with
zeaxanthin) to achieve lutein/zeaxanthin, lycopene, and
bet-carotene totals. .sup.5 Lutein/zeaxanthin mixture contains
1.25% zeaxanthin by weight of lutein.
[0094] This powder formula is manufactured by preparing at least
two slurries that are later blended together, heat treated,
standardized, spray dried and packaged. Initially, a
carbohydrate-mineral slurry is prepared (45-50% solids) by
dissolving lactose in water at 66-76.degree. C. Corn syrup solids
are then added and allowed to dissolve, followed by the addition of
magnesium chloride, potassium citrate, sodium chloride, choline
chloride, and sodium citrate, all with agitation. The resulting
carbohydrate-mineral slurry is held at 54-60.degree. C. under
agitation until used later during the manufacturing process.
[0095] A protein-fat slurry is prepared by combining high oleic
safflower oil, coconut oil, soy oil, and MCT oil at 40.5-49.degree.
C., followed by ascorbyl palmitate, mixed tocopherols, vitamin A
palpitate, and the vitamin ADEK premix, all with agitation. Lutein
(Kemin, Des Moines, Iowa) and other carotenoids, are then added
with agitation. Whey protein concentrate is then added to the
slurry, followed by calcium carbonate and calcium phosphate
tribasic, all with agitation. The completed protein-fat slurry is
held under moderate agitation at 54-60.degree. C. for no longer
than twelve hours until it is blended with the other prepared
slurries.
[0096] The carbohydrate-mineral slurry is transferred to a tank in
which a sufficient amount of water is added to create a final blend
slurry of approximately 50% solids. Non-fat dry milk is then added
to the blend and allowed to solubilize. The protein-fat slurry is
then added and the entire blend slurry is allowed to agitate for at
least 15 minutes. The resulting blend is maintained at
60-65.degree. C. The blend pH is adjusted to 6.7-6.9 with IN
KOH.
[0097] After waiting for a period of not less than one minute nor
greater than two hours, the resulting blend is heated to
71-79.degree. C, emulsified at 2.754.1 Mpa, and then heated to
115-127.degree. C. for about 5 using direct steam injection. The
heated emulsion is then flash cooled to 87-99.degree. C., and
homogenized at 9.7-11.0/2.75-4.1 MPa. The homogenized slurry is
then cooled to 1.6-7.2.degree. C. Samples are taken for
microbiological and analytical testing. The mixture is held under
agitation.
[0098] A vitamin-trace mineral solution is prepared by adding the
following ingredients to the required amount of water, under
agitation: potassium citrate, ferrous sulfate, carnitine, vitamin
and the trace mineral premix, inositol, and nucleotide and choline
bitartrate premix. The vitamin-trace mineral solution is then added
to the homogenized slurry under agitation.
[0099] An ascorbic acid solution is prepared by adding potassium
citrate and ascorbic acid to water with agitation, and then adding
the aqueous mixture to the homogenized slurry under agitation.
[0100] The product is preheated to 65.5-77.degree. C. The product
is then held at 82-90.5.degree. C. for 5 seconds before being flash
cooled to 71-82.degree. C. and pumped to the spray dryer. The
product is spray dried to produce a desired free-flowing powder.
The resulting powder is packaged under nitrogen to maximize product
stability and flavor.
[0101] The exemplified powders are reconstituted with water to a
caloric density of 676 kcal/liter. The resulting liquid formulas
are fed to preterm infants as a sole source of nutrition during the
first 6 to 12 months of life to provide 7-300 .mu.g/kg/day of
lutein. The formula provides improved retinal health and vision
development as described herein, and reduces the risk or severity
of retinopathy of prematurity in the infants.
Examples 4.1-4.3
[0102] The following are examples of concentrated human milk
fortifier liquids for use in the methods described herein.
TABLE-US-00006 Example 4.1 Example 4.2 Example 4.3 Ingredient Name
Gm per kg Gm per kg Gm per kg Sucrose 125.5 125.5 125.5 Milk
protein isolate 64.6 64.6 64.6 Coconut oil 30.2 30.2 30.2 Whey
protein 24.4 24.4 24.4 concentrate MCT Oil 21.9 21.9 21.9 Soy Oil
21.9 21.9 21.9 Tricalcium phosphate 14.4 14.4 14.4 Potassium
chloride 5.18 5.18 5.18 Calcium carbonate 3.44 3.44 3.44 Magnesium
phosphate 3.05 3.05 3.05 Potassium citrate 1.32 1.32 1.32 DHA
(docosahexaenoic 0.2 0.2 0.2 acid) oil Soy lecithin 0.756 0.756
0.756 ARA (arachidonic 0.729 0.729 0.729 acid) oil Dipotassium
phosphate 0.596 0.596 0.596 Monopotassium 0.466 0.466 0.466
phosphate Vitamin E 0.357 0.357 0.357 Sodium chloride 0.170 0.170
0.170 KOH 5% solution Q.S. Q.S. Q.S. m-Inositol 0.0698 0.0698
0.0698 Ascorbic acid 0.913 0.913 0.913 Taurine 0.0663 0.0663 0.0663
Niacinamide 0.0582 0.0582 0.0582 Vitamin A 0.0494 0.0494 0.0494
Zinc sulfate 0.0461 0.0461 0.0461 Calcium pantothenate 0.0286
0.0286 0.0286 Ferrous sulfate 0.0136 0.0136 0.0136 Cupric sulfate
0.00836 0.00836 0.00836 Riboflavin 0.00763 0.00763 0.00763 Thiamine
chloride HCL 0.00507 0.00507 0.00507 Pyridoxine HCL 0.00459 0.00459
0.00459 Folk acid 0.000778 0.000778 0.000778 Manganese Sulfate
0.000573 0.000573 0.000573 Biotin 0.000507 0.000507 0.000507
Vitamin K 0.000835 0.000835 0.000835 Vitamin D3 0.000235 0.000235
0.000235 Sodium selenate 0.0000491 0.0000491 0.0000491 Potassium
iodide 0.0000105 0.0000105 0.0000105 Cyanocobalamin 0.0000103
0.0000103 0.0000103 Added carotenoids .sup.1 -- .sup.1 -- .sup.1 --
.sup.1 Total carotenoids 186 400 555 (mcg/liter) Total Lutein with
90 150 200 zeaxanthin .sup.2 (mcg/liter) Total lycopene 30 90 135
(mcg/liter) Total beta carotene 66 160 220 (mcg/liter) .sup.1
Individual carotenoids added as lycopene, beta-carotene, and lutein
(with zeaxanthin) to achieve the lutein/zeaxanthin, lycopene, and
beta-carotene totals. .sup.2 Lutein/zeaxanthin mixture contains
1.25% zeaxanthin by weight of lutein.
[0103] The ingredients listed in the preceding table are combined
and processed to form a concentrated human milk fortifier
embodiment of the present invention. One method of preparing such
an embodiment is described below.
[0104] An initial intermediate blend is prepared by heating to
32-37.degree. C. the specified amounts of coconut oil, MCT oil, soy
oil, DHA oil and AA oil, all with agitation. A soy lecithin
emulsifier is added with agitation to the heated blend and allowed
to dissolve. Vitamins A, D, and K, Natural Vitamin E, and lutein
are then added with agitation to the developing blend. Milk protein
isolate (25.8 kg) and the specified amounts of ultra micronized
tricalcium phosphate and calcium carbonate are added to the blend.
The resulting intermediate blend is maintained at 26-48.degree. C.
under moderate agitation for a period of time not to exceed six
hours before being added to the aqueous protein blend described
below.
[0105] An aqueous protein blend is then prepared by heating 573 kg
of ingredient water at 48-60.degree. C., and then adding to it with
agitation milk protein isolate (38.8 kg) and the specified amount
of whey protein concentrate. Thereafter, and with agitation, the
entire intermediate blend described above is added to the aqueous
protein blend. The following ingredients are then added to the
resulting blend in the following order: potassium citrate,
dipotassium phosphate, monopotassium phosphate, magnesium
phosphate, sodium chloride, potassium chloride, potassium iodide
and sucrose. After no less than five minutes, the blend pH is
adjusted to 6.60-6.80 using a 1N KOH solution, and thereafter
maintained at 51-60.degree. C., for a period of time not to exceed
two hours before further processing.
[0106] The pH adjusted 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 HTST (high temperature short time,
74.degree. C. for 16 seconds) or UHTST (ultra-high temperature
short time, 132-154.degree. C. for 5-15 seconds) process. The
choice of UHTST or HTST is normally made based upon a review of the
bioburden of each of the ingredients in the formulation. After the
appropriate heat treatment, the batch is cooled in a plate cooler
to 1.0-5.0.degree. C. and then transferred to a refrigerated
holding tank, where it is subjected to analytical testing and then
standardized to finished product specifications, which includes the
addition of an ascorbic acid solution and a water-soluble vitamin
and trace mineral solution, all of which is prepared separately
before adding to the previously described refrigerated batch
[0107] The ascorbic acid solution is prepared by adding the
specified amount of ascorbic acid to 11.1 kg of 1N KOH solution
with agitation. The water-soluble vitamin and trace mineral
solution is prepared by heating 25.2 kg of ingredient water to
37.degree. C. to 48.degree. C. The water soluble vitamins and trace
minerals are added to the water as a premix which contains
m-inositol, taurine, niacinamide, zinc sulfate, calcium
pantothenate, ferrous sulfate, cupric sulfate, riboflavin, thiamine
hydrochloride, pyridoxine hydrochloride, folic acid, manganese
sulfate, biotin, sodium selenate, and cyanocobalamin. As noted
above, both solutions are then added to the refrigerated batch, all
with agitation. As part of batch standardization, the appropriate
amount of ingredient dilution water is then added to the batch for
a target total solids level of 31% and the pH adjusted to 7.1 with
a 1N KOH solution. The batch is filled into suitably sized
containers containing 5 ml of product.
[0108] The exemplified human milk fortifier concentrates are
combined with human milk (5 ml concentrate with 20-25 ml human
milk). The fortified human milk is then fed to pre-term infants to
provide 7-300 .mu.g/kg/day of lutein. The formula provides improved
retinal health and vision development as described herein,
including reduced risk of retinopathy of prematurity.
Examples 5.1-5.3
[0109] This example illustrates a ready-to-feed, preterm infant
formula embodiment of the present invention. This formula is
similar to Similac.RTM. Special Care.RTM. Advance.RTM. with Iron
Premature Infant formula, a preterm infant formula available from
Abbott Laboratories, Columbus, Ohio, except for the increased
lutein concentrations and subsequent lutein to docosahexaenoic acid
ratios.
[0110] The preterm infant formula includes nonfat milk, corn syrup
solids, lactose, medium chain triglycerides, whey protein
concentrate, soy oil, coconut oil, C. cohnii oil (source of
docosahexaenoic acid), M. alpina oil (source of arachidonic acid),
calcium phosphate, calcium carbonate, potassium citrate, ascorbic
acid, magnesium chloride, soy lecithin, mono- and diglycerides,
m-inositol, sodium citrate, carrageenan, ferrous sulfate, choline
bitartrate, taurine, choline chloride, niacinamide,
d-alpha-tocopheryl acetate, L-carnitine, zinc sulfate, potassium
chloride, potassium phosphate dibasic, calcium pantothenate, cupric
sulfate, vitamin A palmitate, riboflavin, thiamine chloride
hydrochloride, pyridoxine hydrochloride, folic acid, beta-carotene,
manganese sulfate, biotin, phylloquinone, sodium selenate, vitamin
D3, cyanocobalamin and nucleotides (cytidine 5'-monophosphate,
disodium guanosine 5'-sphate, monophosphate, disodium uridine
5'-monophosphate, adenosine 5'-monophosphate). A carotenoid
supplement is added to the formula.
[0111] The above-referenced ingredients are formulated together by
conventional methods to provide the following nutrition profile:
TABLE-US-00007 Example 5.1 Example 5.2 Example 5.3 Amount per
Amount per Amount per 100 kcal 100 kcal 100 kcal Nutrients (or 123
ml) (or 123 ml) (or 123 ml) Protein (from nonfat 3.00 g 3.00 g 3.00
g milk, whey protein concentrate) Fat (form 50:30:18.3 5.43 g 5.43
g 5.43 g mix of MCT oil, soy oil, and coconut oils; --mg DHA, --mg
ARA; 700 mg linoleic acid) Carbohydrate 10.3 g 10.3 g 10.3 g
(source - 50:50 mix of corn syrup solids, lactose) Lutein 18.4 mcg
37 mcg 9141 mcg Vitamin A 1250 IU 1250 IU 1250 IU Vitamin D 150 IU
150 IU 150 IU Vitamin E 4.0 IU 4.0 IU 4.0 IU Vitamin K 12 mcg 12
mcg 12 mcg Thiamine 250 mcg 250 mcg 250 mcg Riboflavin 620 mcg 620
mcg 620 mcg Vitamin B6 250 mcg 250 mcg 250 mcg Vitamin B12 0.55 mcg
0.55 mcg 0.55 mcg Niacin 5000 mcg 5000 mcg 5000 mcg Folic acid 37
mcg 37 mcg 37 mcg Pantothenic acid 1900 mcg 1900 mcg 1900 mcg
Biotin 37.0 mcg 37.0 mcg 37.0 mcg Ascorbic acid 37 mg 37 mg 37 mg
Choline 10 mg 10 mg 10 mg Inositol 40.0 mg 40.0 mg 40.0 mg Calcium
180 mg (9.0 180 mg (9.0 180 mg (9.0 mEq) mEq) mEq) Phosphorus 100
mg 100 mg 100 mg Magnesium 12.0 mg 12.0 mg 12.0 mg Iron 1.8 mg 1.8
mg 1.8 mg Zinc 1.50 mcg 1.50 mcg 1.50 mcg Manganese 12 mcg 12 mcg
12 mcg Copper 250 mcg 250 mcg 250 mcg Iodine 6 mcg 6 mcg 6 mcg
Selenium 1.8 mcg 1.8 mcg 1.8 mcg Sodium 43 mg (1.9 43 mg (1.9 43 mg
(1.9 mEq) mEq) mEq) Potassium 129 mg (3.3 129 mg (3.3 129 mg (3.3
mEq) mEq) mEq) Chloride 81 mg (2.3 81 mg (2.3 81 mg (2.3 mEq) mEq)
mEq) Added -- .sup.1 -- .sup.1 -- .sup.1 carotenoids .sup.1 Total
carotenoids 186 400 555 (mcg/liter) Total Lutein 90 150 200
w/zeaxanthin .sup.2 (mcg/liter) Total lycopene 30 90 135
(mcg/liter) Total beta carotene 66 160 220 (mcg/liter) .sup.1
Individual carotenoids added as lycopene, beta-carotene, and lutein
(with zeaxanthin) to achieve the lutein/zeaxanthin, lycopene, and
beta-carotene totals. .sup.2 Lutein/zeaxanthin mixture contains
1.25% zeaxanthin by weight of lutein.
Example 5.4
[0112] Skin carotenoid levels are measured in a preterm infant born
at 26 weeks gestation, weighing 1.7 kg, age 1 day. Skin carotenoid
levels are measured (800 Raman Counts) using non invasive Raman
Spectroscopy on the infant's palm. The infant is administered the
preterm infant formula of Example 5.2 as a primary form of daily
nutrition until discharge. The formula contains lutein, lycopene,
beta carotene, and zeaxanthin. Skin carotenoids are measured
periodically until discharge to assure adequate carotenoid
supplementation as noted by increasing skin carotenoid levels
(increased Raman Counts). The infant subsequently experiences
minimal or no signs of retinopathy of prematurity.
[0113] The exemplified ready-to-feed formulas (caloric density of
812 kcal/liter) are administered to preterm infants to provide from
7-300 mcg/kg of lutein per day. The administered formula improves
eye health as described herein, and are especially useful as
applied to preterm infants to reduce the risk of retinopathy of
prematurity and helps protect the eyes from natural or artificial
light, especially biliary lights.
Experiment
[0114] A study is conducted to compare plasma lutein concentrations
in breastfed infants with plasma lutein concentrations in formula
fed infants. The latter received one of three formulas defined by
lutein concentrations of 32.6 mcg/liter (L1), 52.6 mcg/liter (L2),
or 14.6 mcg/liter (CTRL). The study groups and resulting plasma
lutein concentrations are summarized in the following table.
TABLE-US-00008 Plasma Lutein (mcg/dL).sup..dagger-dbl. Feeding
Group Study Day 1 Study Day 56 Control (CTRL) - no added 1.37 .+-.
0.29 .sup.a 2.17 .+-. 0.12 .sup.a lutein Total inherent (0.40-5.10)
(1.16-3.25) lutein 14.6 mcg/liter lutein) 20 18 Formula L1 0.78
.+-. 0.09 .sup.a 2.21 .+-. 0.16 .sup.a Added lutein approximately
(0.27-2.09) (0.20-3.61) 18 mcg/liter 24 22 Inherent lutein
approximately 14.6 mcg/liter Total lutein 32.6 mcg/L Formula L2
0.97 .+-. 0.13 .sup.a 3.25 .+-. 0.26 .sup.b Added lutein
approximately (0.20-2.31) (0.60-4.70) 38 mcg/liter 21 19 Inherent
lutein approximately 14.6 mcg/liter Total lutein 52.6 mcg/L Human
Milk (HM) 6.53 .+-. 0.54 .sup.b 5.88 .+-. 0.77 .sup.c 6.5-107.8
mcg/liter (1.69-14.12) (0.49-20.09) lutein 24 26
.sup..dagger-dbl.Values are presented as mean .+-. SEM, (range) n
Values in a column with superscripts without a common letter
differ(p < 0.05). See text for actual p values. Statistical
comparisons among the formula groups are done using the
Kruskal-Wallis test. Comparisons between the formula groups and the
human milk group are done using the Wilcoxon rank-sum test.
[0115] Plasma lutein concentrations (at day 56 of the study) are
used as the primary variable in the study. The primary comparison
is the difference in plasma lutein concentrations between the L2
and CTRL formula groups. Secondary comparisons included differences
in plasma lutein concentrations among the formula groups (CTRL, L1,
L2) and differences between the formula groups and the human milk
group. Plasma lutein concentrations on day 56 from a total of 85
infants (CURL, n-18; L1, n=22; L2, n=19; HM, n=26) is used in these
analyses and results reported as mean.+-.SEM in the following
table.
[0116] Infants in the L2 formula group have significantly higher
(p<0.05) plasma concentrations of lutein than infants in the L1
and CTRL formula groups. Plasma lutein are not different between
the L1 and CTRL formula groups. The human milk group has higher
plasma lutein concentrations than the CTRL (p<0.0001), L1
(p<0.0001), and L2 (0.0052) formula groups. Plasma lutein
concentration is significantly correlated with lutein intake
(r=0.436, p=0.0014). Lutein intake and plasma response from the
study are also summarized in FIG. 1.
[0117] The data from the study show that lutein is surprisingly
less bioavailable from infant formula than from human milk (see
FIG. 1). As such, in order for an infant formula to produce plasma
lutein concentrations in infants similar to that produced by
feeding human milk, an infant formula must be formulated to contain
at least about 50 mcg/liter of lutein, preferably from 100
mcg/liter to about 200 mcg/liter.
Study: Skin Carotenoids
[0118] A purpose of this study is to evaluate the relation of skin
carotenoids in the development or severity of Retinopathy of
Prematurity (ROP) in human milk fed preterm infants. Skin
carotenoid levels are measured using non-invasive Raman
spectroscopy. It is known that skin carotenoid levels as measured
by Raman spectroscopy correlate with serum and tissue carotenoid
levels (Data et al., J Invest Dermatology, 115:441, 200; Hata et
al., J Invest Dermatology 115;441, 2000; Ermakov et al., Optics
Letters, 26:1179, 2001)
[0119] Skin carotenoids are assessed non-invasively using a
BioPhotonic Scanner (available from Phalmanex, Provo, Utah USA).
For each infant tested, a small area of the palm is exposed to a
low-energy monochromatic laser light of 473 nm (blue light)
penetrating into the stratum comeum layer of the skin for
approximately 3 minutes to obtain an adequate measurement
Carotenoids present in the exposed area will shift the wavelength
to 511 nm (green light), which is detected into a relative signal
and converted to Raman Counts (RC).
[0120] Carotenoid molecules are strong Raman scatterers when
excited with wavelengths of light between 450 and 500 nanometers
(nm). This range of visible light can be accomplished with
commercially available laser light sources. The carotenoid
molecules are especially suited for this analysis since their
characteristic double diene bonds emit strong and measurable Raman
spectroscopic signals (511 nm) when excited with laser light of 473
nm.
[0121] In the present study, twenty-two infants whose individual
birth weights (BW) are less than 1800 g, gestation at less than 33
weeks, and fed their own mother's milk are enrolled at the start of
feedings. Skin carotenoids are measured initially and then
biweekly. Days on oxygen are recorded Initial eye exams for ROP are
initiated between 4 and 7 weeks of age. The mean gestation (.+-.SD)
is 28.+-.2.6 weeks with mean BW of 1102.+-.356 g. Forty-one percent
of the infants (9/22) develop ROP, with 3 requiring laser surgery
for stage 3 ROP. Infants with ROP have lower mean gestation (26 v
30 wks), BW (871 v 1262 g) and longer on oxygen (112 v 40 days)
than infants with no ROP.
[0122] After controlling for prematurity, it is also discovered
that infants who develop ROP have lower initial skin carotenoid
levels than infants who had no ROP, 7.8.+-.7.8 v 11.1.+-.4.2 (Mann
Whitney, P<0.02 ROP is negatively associated with initial skin
carotenoids(R=-0.75, P<0.001). Skin carotenoids are positively
associated with birth weight (R=0.66, P<0.001), gestation
(=0.69, P<0.001), day of life (R=0.64, P<0.001), but
negatively associated with days on oxygen (R=-0.57, P<0.01).
[0123] This study shows that ROP is influenced by skin carotenoid
(lutein, beta-carotene, zeaxantin, lycopene) levels found in
preterm infants fed human milk. The study suggests that preterm
infants at risk of developing ROP can be monitored for skin
carotenoid concentrations and may benefit from carotenoid
supplementation. This may result in reducing the risk or severity
of ROP.
* * * * *