U.S. patent application number 17/034650 was filed with the patent office on 2021-01-28 for compositions for use in improving stool consistency or frequency in infants or young children.
The applicant listed for this patent is Societe des Produits Nestle S.A.. Invention is credited to Dominique Brassart, Delphine Egli, Norbert Sprenger.
Application Number | 20210023102 17/034650 |
Document ID | / |
Family ID | 1000005137248 |
Filed Date | 2021-01-28 |
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United States Patent
Application |
20210023102 |
Kind Code |
A1 |
Sprenger; Norbert ; et
al. |
January 28, 2021 |
COMPOSITIONS FOR USE IN IMPROVING STOOL CONSISTENCY OR FREQUENCY IN
INFANTS OR YOUNG CHILDREN
Abstract
The present invention relates to a nutritional composition
comprising at least one fucosylated oligosaccharide for use in
preventing and/or treating constipation and/or in improving stool
consistency/frequency in an infant or a young child.
Inventors: |
Sprenger; Norbert; (Savigny,
CH) ; Brassart; Dominique; (Chavannes-pres-Renens,
CH) ; Egli; Delphine; (La Tour-de-Peilz, CH) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Societe des Produits Nestle S.A. |
Vevey |
|
CH |
|
|
Family ID: |
1000005137248 |
Appl. No.: |
17/034650 |
Filed: |
September 28, 2020 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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15554738 |
Aug 31, 2017 |
10821124 |
|
|
PCT/EP2016/054614 |
Mar 4, 2016 |
|
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17034650 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A23L 33/125 20160801;
A23L 33/40 20160801; A61K 31/702 20130101; A61K 2035/115 20130101;
A23L 33/135 20160801; A23V 2002/00 20130101; A23L 33/21 20160801;
A61K 35/741 20130101; A61P 1/00 20180101; A61K 9/0056 20130101 |
International
Class: |
A61K 31/702 20060101
A61K031/702; A23L 33/00 20060101 A23L033/00; A23L 33/135 20060101
A23L033/135; A23L 33/21 20060101 A23L033/21; A61P 1/00 20060101
A61P001/00; A23L 33/125 20060101 A23L033/125; A61K 9/00 20060101
A61K009/00; A61K 35/741 20060101 A61K035/741 |
Foreign Application Data
Date |
Code |
Application Number |
Mar 5, 2015 |
EP |
15157724.4 |
Claims
1. (canceled)
2. A method of treating colics in an infant or a young child in
need thereof, the method comprising administering a nutritional
composition to the infant or young child, the nutritional
composition comprising at least one fucosylated oligosaccharide,
and wherein the fucosylated oligosaccharide(s) is/are in a total
amount of 0.8-1.5 g/L of the composition and/or in a total amount
of 0.55-1.05 g/100 g of composition on a dry weight basis.
3. The method according to claim 2 wherein the fucosylated
oligosaccharide is selected from the group consisting of
2'-fucosyllactose, 3' fucosyllactose, difucosyllactose,
lacto-N-fucopentaose I, lacto-N-fucopentaose II,
lacto-N-fucopentaose III, lacto-N-fucopentaose V,
lacto-N-fucohexaose, lacto-N-difucohexaose I,
fucosyllacto-N-hexaose, fucosyllacto-N-neohexaose I,
fucosyllacto-N-neohexaose II, difucosyllacto-N-hexaose I,
difucosyllacto-N-neohexaose I, difucosyllacto-N-neohexaose II,
fucosyl-para-Lacto-N-hexaose, and any combination thereof.
4. The method according to claim 2, wherein the fucosylated
oligosaccharide comprises a 2' fucosyl-epitope.
5. The method according to claim 2, wherein the fucosylated
oligosaccharide is 2'-fucosyllactose (2'FL).
6. The method according to claim 2, wherein the fucosylated
oligosaccharide(s) is/are in a total amount of 0.2-3 g/L of the
composition and/or in a total amount of 0.13-2.1 g/100 g of
composition on a dry weight basis.
7. The method according to claim 2, wherein the fucosylated
oligosaccharide(s) is/are in a total amount of 0.8-1.5 g/L of the
composition and/or in a total amount of 0.55-1.05 g/100 g of
composition on a dry weight basis.
8. The method according to claim 2, wherein the fucosylated
oligosaccharide(s) is/are in a total amount of 1-1.25 g/L of the
composition and/or in a total amount of 0.69-0.87 g/100 g of
composition on a dry weight basis.
9. (canceled)
10. The method according to claim 2, wherein the composition
further comprising at least one probiotic microorganism.
11-13. (canceled)
14. The method according to claim 2, wherein the nutritional
composition is in a form selected from the group consisting of an
infant formula, a starter infant formula, a follow-on or follow-up
infant formula, a baby food, an infant cereal composition, a
fortifier and a supplement.
15. (canceled)
16. The method according to claim 2, wherein the composition does
not comprise any N-acetylated oligosaccharides.
17. (canceled)
Description
FIELD OF THE INVENTION
[0001] This invention relates to compositions for use in preventing
and/or treating constipation, in improving stool
consistency/frequency, and/or in preventing or treating flatulence,
bloating, colics or gut discomfort in infants or young
children.
BACKGROUND OF THE INVENTION
[0002] Mother's milk is recommended for all infants. However, in
some cases breast feeding is inadequate or unsuccessful for medical
reasons or the mother chooses not to breast feed. Infant formula
have been developed for these situations. Fortifiers have also been
developed to enrich mother's milk or infant formula with specific
ingredients. Infants and young children may suffer from
constipation or hard stool due, especially, to the immaturity of
their gut, the lack of activity at this young age and the
undiversified content of their feeding. Because of their beneficial
effects, prebiotics are therefore often incorporated into infant
formula, fortifiers or any other synthetic nutritional compositions
and nutritional supplements.
[0003] Prebiotics are non-digestible carbohydrates that contribute
to the well-being of their host. They are typically compounds that
pass undigested through the upper part of the gastrointestinal
tract and stimulate the growth and/or activity of advantageous
bacteria such as bifidobacteria that colonize the large bowel by
acting as substrate for them. They will form the basis for
stool.
[0004] However, some fibers including the beneficial prebiotics
inulin and oligofructose, produce gases that fertilize the healthy
bacteria that live in the lower gut. This may lead to flatulence,
bloating, colics and/or gut discomfort in the individual. These
associated effects may be particularly problematic in infants and
young children and can lead to crying periods, feeding
difficulties, irritability, pain, especially abdominal pain,
abdominal cramping, poor sleep.
[0005] Human milk oligosaccharides (HMOs) are, collectively, the
third largest solid constituents in human milk, after lactose and
fat. HMOs usually consist of lactose at the reducing end with a
carbohydrate core that often contains a fucose or a sialic acid at
the non-reducing end. There are over one hundred milk
oligosaccharides that have been isolated and characterized in human
milk.
[0006] Some compositions using HMO ingredients, such as fucosylated
oligosaccharides, lacto-N-tetraose, lacto-N-neotetraose and/or
sialylated oligosaccharides, have been developed and for different
purposes.
[0007] For example WO2005055944 from Children's hospital medical
center describes a pharmaceutical composition comprising a molecule
comprising a fucose group in an alpha-2 linkage, an alpha-3 linkage
or an alpha-4 linkage to a galactose group and a pharmaceutically
acceptable carrier. Various molecules are described such as
2'-fucosyllactose. This application is quite general since several
infections can be prevented or treated, including respiratory or
enteric infections, and there is a large target of patients
(infants, children or adults). In addition, this document suggests
that providing 2FL in medium or high amounts decreases the
incidence of Campylobacter diarrhea.
[0008] WO9956754 from Abbott relates to compositions containing at
least one fucose residue in an alpha 1-2 linkage such as 2FL and
uses thereof. In particular, such compositions can be used in the
treatment and prevention of gastrointestinal infections like
diarrhoea and enterocolitis.
[0009] WO2004002495 describes an oligosaccharide-containing
substance or receptor binding to diarrheagenic Escherichia coli
and/or zoonotic Helicobacter species, and use thereof in, e.g.,
pharmaceutical, nutritional and other compositions for prophylaxis
and treatment of diarrhea, hemorrhagic colitis or haemolytic uremic
syndrome.
[0010] WO2012092156 refer to nutritional composition comprising
HMOs but for a wide list of health benefits including feeding
tolerance and especially reduction of diarrhea and loose stools (so
the opposite of constipation), as well as reduction of the
associated gas and colics.
[0011] Indeed, as indicated in Simone Albrecht et al
"Oligosaccharides in feces of breast- and formula-fed babies",
2005, prebiotic cabohydrates (e.g. HMOs, GOS) have an impact on the
neonatal gut development. However, the effects are specific to the
types of fibers (HMOs and GOS are structurally different). For
example, HMOs have been shown to facilitate a protective gut
colonization in newborn infants (Riccardo Locascio et al, 2007,
reference 2 of this publication) and also to confer a protection
against diarrhea (Newburg et al, 2004, reference 5 of this
publication).
[0012] None of the previous work is therefore focused on the
prevention and/or treatment of constipation and/or the improvement
of stool consistency/frequency without the above-mentioned
associated problems of flatulence, bloating, colics and/or gut
discomfort that can be particularly painful in infants and young
children.
[0013] There is clearly a need for developing suitable methods to
decrease the incidence of these health conditions/problems in
infants and young children and especially there is a need for
nutritional compositions such as infant formula that can provide
softer stool without increasing flatulence, bloating, colics and/or
gut discomfort.
[0014] There is also a need to deliver such health benefits in a
manner that is particularly suitable for the young subjects
(infants and young children), in a manner that does not involve a
classical pharmaceutical intervention as these infants or young
children are particularly fragile.
[0015] There is a need to deliver such health benefits in these
infants or young children in a manner that does not induce side
effects and/or in a manner that is easy to deliver, and well
accepted by the parents or health care practitioners.
[0016] There is also a need to deliver such benefits in a manner
that does keep the cost of such delivery reasonable and affordable
by most.
SUMMARY OF THE INVENTION
[0017] The present inventors have found that a composition
comprising at least one fucosylated oligosaccharide can
advantageously be used to improve stool consistency in an infant or
a young child, especially by reducing stool hardness.
[0018] Accordingly, the present invention therefore provides a
nutritional composition comprising at least one fucosylated
oligosaccharide for use in preventing and/or treating constipation,
in improving stool consistency/frequency, in preventing and/or
treating flatulence, bloating, colics and/or gut discomfort in an
infant or a young child.
[0019] In some embodiments, the nutritional composition comprises
at least a probiotic microorganism, especially a probiotic bacteria
that may be of the following genera: Lactobacillus spp.,
Streptococcus spp., Enterococcus spp. or Bifidobacterium spp. In
some preferred embodiments, the probiotic bacteria is a
Lactobacillus strain. In a particularly advantageous embodiment,
the nutritional composition comprises 2'-fucosyllactose (2-FL) in
an amount of 0.2-3 g/L of the nutritional composition.
FIGURES
[0020] FIG. 1 represent the stool consistency at 1 month of age
(FIG. 1A) and 2 months of age (FIG. 1B) in infants fed a classical
starter infant formula or a classical starter infant formula with
HMO i.e. 2'Fucosyllactose in an amount of 1.24 g/L and
lacto-N-neotetraose in an amount of 0.63 g/L. Numbers indicate
stool consistency according to the Bristol scale: 1: Separate Hard
lumps, like nuts (hard to pass). Result in slow transit, 2:
Sausage-shaped but lumpy, 3: Like a sausage but with cracks on its
surface, 4: Like a sausage or snake-smooth and soft, 5: Soft blobs
with clear cue edges (easy to pass), 6: Fluffy pieces with ragged
edges, a mushy stool, 7: Watery, no solid pieces.
[0021] FIG. 2 represents the number of infants born by C-section
whose parents reported them to experience `never` or `sometimes`
Colics at 4 months of age. A linear association analysis for
treatment and Colics by visit and delivery mode using
Cochran-Mantel-Haenszel test for association showed a significant
difference in the C-section group at 4 months of age.
DETAILED DESCRIPTION OF THE INVENTION
[0022] As used herein, the following terms have the following
meanings.
[0023] The term "infant" means a child under the age of 12
months.
[0024] The expression "young child" means a child aged between one
and three years, also called toddler.
[0025] An "infant or young child born by C-section" means an infant
or young child who was delivered by caesarean. It means that the
infant or young child was not vaginally delivered.
[0026] An "infant or young child vaginally born" means an infant or
young child who was vaginally delivered and not delivered by
caesarean.
[0027] A "preterm" or "premature" means an infant or young child
who was not born at term. Generally it refers to an infant or young
child born prior 36 weeks of gestation.
[0028] The expression "nutritional composition" means a composition
which nourishes a subject. This nutritional composition is usually
to be taken orally or intravenously, and it usually includes a
lipid or fat source and a protein source.
[0029] In a particular embodiment the composition of the present
invention is a hypoallergenic nutritional composition. The
expression "hypoallergenic nutritional composition" means a
nutritional composition which is unlikely to cause allergic
reactions.
[0030] In a particular embodiment the composition of the present
invention is a "synthetic nutritional composition". The expression
"synthetic nutritional composition" means a mixture obtained by
chemical and/or biological means, which can be chemically identical
to the mixture naturally occurring in mammalian milks (i.e. the
synthetic composition is not breast milk).
[0031] The expression "infant formula" as used herein refers to a
foodstuff intended for particular nutritional use by infants during
the first months of life and satisfying by itself the nutritional
requirements of this category of person (Article 2(c) of the
European Commission Directive 91/321/EEC 2006/141/EC of 22 Dec.
2006 on infant formulae and follow-on formulae). It also refers to
a nutritional composition intended for infants and as defined in
Codex Alimentarius (Codex STAN 72-1981) and Infant Specialities
(incl. Food for Special Medical Purpose). The expression "infant
formula" encompasses both "starter infant formula" and "follow-up
formula" or "follow-on formula".
[0032] A "follow-up formula" or "follow-on formula" is given from
the 6th month onwards. It constitutes the principal liquid element
in the progressively diversified diet of this category of
person.
[0033] The expression "baby food" means a foodstuff intended for
particular nutritional use by infants or young children during the
first years of life.
[0034] The expression "infant cereal composition" means a foodstuff
intended for particular nutritional use by infants or young
children during the first years of life.
[0035] The term "fortifier" refers to liquid or solid nutritional
compositions suitable for mixing with breast milk or infant
formula.
[0036] The expression "weaning period" means the period during
which the mother's milk is substituted by other food in the diet of
an infant or young child.
[0037] The expressions "days/weeks/months/years of life" and
"days/weeks/months/years of birth" can be used interchangeably.
[0038] The expression "preventing and/or treating constipation
and/or improving stool consistency/frequency" encompasses one or
several of the following: [0039] preventing constipation [0040]
treating constipation [0041] improving stool consistency [0042]
improving stool frequency.
[0043] The expression "preventing and/or treating flatulence,
bloating, colics and/or gut discomfort" encompasses one or several
of the following: [0044] preventing flatulence [0045] treating
flatulence [0046] preventing bloating [0047] treating bloating
[0048] preventing colics [0049] treating colics [0050] preventing
gut discomfort [0051] treating gut discomfort.
[0052] The expressions "in preventing
constipation/flatulence/bloating/colics/gut discomfort", "to
prevent constipation/flatulence/bloating/ colics/gut discomfort",
"in the prevention of constipation/flatulence/bloating/ colics/gut
discomfort" and "for the prevention of
constipation/flatulence/bloating/ colics/gut discomfort" can be
used interchangeably.
[0053] These expressions mean avoiding that these health
conditions/issues (constipation/flatulence/bloating/colics/gut
discomfort) occur and/or decreasing the incidence of said health
conditions/issues (reduction of the frequency, i.e. the number of
these health conditions/issues). In some embodiments the prevention
of these health conditions/issues occurs during the treatment (i.e.
during the administration of the composition of the present
invention, either immediately after the start of the administration
or some time after, e.g. some days or weeks after the start). It
can also encompass the prevention of these health conditions/issues
later in life. The term "later in life" encompasses the effect
after the termination of the intervention or treatment. The effect
"later in life" can be from 1 week to several months, for example
from 2 to 4 weeks, from 2 to 6 weeks, from 2 to 8 weeks, from 1 to
6 months or from 2 to 12 months.
[0054] The expressions "in treating
constipation/flatulence/bloating/colics/gut discomfort", "to treat
constipation/flatulence/bloating/ colics/gut discomfort", "in the
treatment of constipation/flatulence/bloating/ colics/gut
discomfort" and "for the treatment of
constipation/flatulence/bloating/ colics/gut discomfort" can be
used interchangeably.
[0055] They should be understood as comprising the decrease of the
duration of these health conditions/issues
(constipation/flatulence/bloating/colics/gut discomfort) (e.g.
number of days/weeks/years the infants or young children will
suffer from these health conditions/issues), the decrease of the
severity (or level) of these health conditions/issues (e.g. the
consequences and/or the seriousness of these health
conditions/issues). These expressions also encompass the relieve of
the symptoms or consequences such as blocking stool, crying
periods, feeding difficulties, irritability, pain, especially
abdominal pain, abdominal cramping, poor sleep and any combinations
thereof, and/or the decrease of complications caused by these
health conditions/issues on the infant or young child health, such
as anal fissure, rectal bleeding, the need of a surgical
intervention, the use of medication, the use of stool softeners,
and/or the decrease of pain, and/or the decrease of tiredness,
and/or the ease of the sleep and/or the stabilization of the
activity of the infants or young children suffering from these
health conditions/issues.
[0056] The expressions "no or a limited level" and "no particular
issue" of flatulence, bloating, colics and/or gut discomfort can be
used interchangeably. They have to be understood in the context of
the present invention that infants or young children fed the
composition of the present invention will have no flatulence,
bloating, colics and/or gut discomfort episodes or they will have a
low level of flatulence, bloating, colics and/or gut discomfort or
they will have less (e.g. at least 1% less, or at least 2% less, or
at least 5% less, or at least 10% less, or at least 20% less or at
least 50% less . . . ) flatulence, bloating, colics and/or gut
discomfort episodes in comparison with infants or young children
fed with a standard composition (e.g. the same composition but
without any fucosylated oligosaccharide without any fucosylated
oligosaccharide). The expressions "a limited level" and "a lower
level" can be used interchangeably. They may refer to the frequency
and/or the occurrence and/or the severity.
[0057] The terms "gut", "GUT" and "gastrointestinal" can be used
interchangeably.
[0058] The expression "gut discomfort" includes abdominal pain
and/or cramping.
[0059] The expressions "in improving stool consistency/frequency",
"in improving stool consistency and/or frequency" and "in improving
stool consistency and/or stool frequency" can be used
interchangeably. They encompass the improvement of stool
consistency, the improvement of stool frequency and/or both. The
expression "improving stool consistency" means that the stool of an
infant or young child feeding a nutritional composition according
to the invention has a softer consistency than the stool of an
infant or young child not feeding a nutritional composition
according to the invention. The expression "improving stool
consistency" may especially encompass or mean "reducing stool
hardness", "softening stool" and/or "providing softer stool", e.g.
there will be less hard lumps, like nuts, that are hard to pass.
The expression "improving stool frequency" means that the stool of
an infant or young child will become more frequent, i.e. the
transit will be regulated and/or faster. It may therefore also
encompass or mean "improving/increasing the transit speed" or
"avoiding a slow transit" or "regulating the transit". The
improvement of stool consistency/frequency may especially allow
avoiding pain, especially abdominal pain, abdominal cramping and
also further complications like anal fissure, rectal bleeding, the
need of a surgical intervention, the use of medication, the use of
stool softeners.
[0060] The "mother's milk" should be understood as the breast milk
or the colostrum of the mother.
[0061] An "oligosaccharide" is a saccharide polymer containing a
small number (typically three to ten) of simple sugars
(monosaccharides).
[0062] The term "HMO" or "HMOs" refers to human milk
oligosaccharide(s). These carbohydrates are highly resistant to
enzymatic hydrolysis, indicating that they may display essential
functions not directly related to their caloric value. It has
especially been illustrated that they play a vital role in the
early development of infants and young children, such as the
maturation of the immune system. Many different kinds of HMOs are
found in the human milk. Each individual oligosaccharide is based
on a combination of glucose, galactose, sialic acid
(N-acetylneuraminic acid), fucose and/or N-acetylglucosamine with
many and varied linkages between them, thus accounting for the
enormous number of different oligosaccharides in human milk--over
130 such structures have been identified so far. Almost all of them
have a lactose moiety at their reducing end while sialic acid
and/or fucose (when present) occupy terminal positions at the
non-reducing ends. The HMOs can be acidic (e.g. charged sialic acid
containing oligosaccharide) or neutral (e.g. fucosylated
oligosaccharide).
[0063] A "fucosylated oligosaccharide" is an oligosaccharide having
a fucose residue. It has a neutral nature. Some examples are 2-FL
(2'-fucosyllactose), 3-FL (3-fucosyllactose), difucosyllactose,
lacto-N-fucopentaose (e.g. lacto-N-fucopentaose I,
lacto-N-fucopentaose II, lacto-N-fucopentaose III,
lacto-N-fucopentaose V), lacto-N-fucohexaose, lacto-N-difucohexaose
I, fucosyllacto-N-hexaose, fucosyllacto-N-neohexaose,
difucosyllacto-N-hexaose I, difucosyllacto-N-neohexaose II and any
combination thereof.
[0064] The expressions "fucosylated oligosaccharides comprising a
2'-fucosyl-epitope" and "2-fucosylated oligosaccharides" encompass
fucosylated oligosaccharides with a certain homology of form since
they contain a 2'-fucosyl-epitope, therefore a certain homology of
function can be expected.
[0065] The expression "N-acetylated oligosaccharide(s)" encompasses
both "N-acetyl-lactosamine" and "oligosaccharide(s) containing
N-acetyl-lactosamine". They are neutral oligosaccharides having an
N-acetyl-lactosamine residue. Suitable examples are LNT
(lacto-N-tetraose), para-lacto-N-neohexaose (para-LNnH), LNnT
(lacto-N-neotetraose) or any combination thereof. Other examples
are lacto-N-hexaose, lacto-N-neohexaose, para-lacto-N-hexaose,
para-lacto-N-neohexaose, lacto-N-octaose, lacto-N-neooctaose,
iso-lacto-N-octaose, para-lacto-N-octaose and lacto-N-decaose.
[0066] A "precursor of HMO" is a key compound that intervenes in
the manufacture of HMO, such as sialic acid and/or fucose.
[0067] A "sialylated oligosaccharide" is a charged sialic acid
containing oligosaccharide, i.e. an oligosaccharide having a sialic
acid residue. It has an acidic nature. Some examples are 3-SL (3'
sialyllactose) and 6-SL (6' sialyllactose).
[0068] The nutritional composition of the present invention can be
in solid form (e.g. powder) or in liquid form. The amount of the
various ingredients (e.g. the oligosaccharides) can be expressed in
g/100g of composition on a dry weight basis when it is in a solid
form, e.g. a powder, or as a concentration in g/L of the
composition when it refers to a liquid form (this latter also
encompasses liquid composition that may be obtained from a powder
after reconstitution in a liquid such as milk, water . . . , e.g. a
reconstituted infant formula or follow-on/follow-up formula or
infant cereal product or any other formulation designed for infant
nutrition).
[0069] The term "prebiotic" means non-digestible carbohydrates that
beneficially affect the host by selectively stimulating the growth
and/or the activity of healthy bacteria such as bifidobacteria in
the colon of humans (Gibson G R, Roberfroid M B. Dietary modulation
of the human colonic microbiota: introducing the concept of
prebiotics. J Nutr. 1995; 125:1401-12).
[0070] The term "probiotic" means microbial cell preparations or
components of microbial cells with a beneficial effect on the
health or well-being of the host. (Salminen S, Ouwehand A. Benno Y.
et al. "Probiotics: how should they be defined" Trends Food Sci.
Technol. 1999:10 107-10). The microbial cells are generally
bacteria or yeasts.
[0071] The term "cfu" should be understood as colony-forming
unit.
[0072] All percentages are by weight unless otherwise stated.
[0073] In addition, in the context of the invention, the terms
"comprising" or "comprises" do not exclude other possible elements.
The composition of the present invention, including the many
embodiments described herein, can 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 depending on the needs.
[0074] Any reference to prior art documents in this specification
is not to be considered an admission that such prior art is widely
known or forms part of the common general knowledge in the
field.
[0075] The invention will now be described in further details. It
is noted that the various aspects, features, examples and
embodiments described in the present application may be compatible
and/or combined together.
[0076] A first object of the present invention is therefore a
nutritional composition comprising at least one fucosylated
oligosaccharide, for use in preventing and/or treating constipation
and/or in improving stool consistency/frequency in an infant or a
young child.
[0077] In the same time, the nutritional composition can provide no
or limited flatulence, bloating, colics and/or gut discomfort in
said infant or young child.
[0078] Another object of the present invention is a nutritional
composition comprising at least one fucosylated oligosaccharide for
use in preventing and/or treating flatulence, bloating, colics
and/or gut discomfort in an infant or a young child, and wherein
the fucosylated oligosaccharide(s) is/are in a total amount of
0.8-1.5 g/L of the composition and/or in a total amount of
0.55-1.05 g/100 g of composition on a dry weight basis.
[0079] Without being bound by theory, the inventors of the present
invention believe that the fucosylated oligosaccharide(s) is the
key ingredient that surprisingly provides the above-mentioned
health benefits.
[0080] Without being bound by theory, the inventors also believe
that the observed effect is mediated via an alteration of the
intestinal ecosystem, thus indirectly affecting stool
consistency/frequency, bowel movements and eventually gut
discomfort.
[0081] In some preferred embodiments, the nutritional composition
comprises at least a probiotic microorganism, preferably at least
one probiotic strain. Without being bound by theory, the inventors
believe that the fucosylated oligosaccharide(s) and the probiotic
microorganism(s) may act synergically to further provide the
above-mentioned health benefits.
[0082] The composition of the present invention comprises at least
one fucosylated oligosaccharide. There can be one or several types
of fucosylated oligosaccharide(s). The fucosylated
oligosaccharide(s) can indeed be selected from the list comprising
2'-fucosyllactose, 3'fucosyllactose, difucosyllactose,
lacto-N-fucopentaose (such as lacto-N-fucopentaose I,
lacto-N-fucopentaose II, lacto-N-fucopentaose III,
lacto-N-fucopentaose V), lacto-N-fucohexaose, lacto-N-difucohexaose
I, fucosyllacto-N-hexaose, fucosyllacto-N-neohexaose (such as
fucosyllacto-N-neohexaose I, fucosyllacto-N-neohexaose II),
difucosyllacto-N-hexaose I, difuco-lacto-N-neohexaose,
difucosyllacto-N-neohexaose I, difucosyllacto-N-neohexaose II,
fucosyl-para-Lacto-N-hexaose, tri-fuco-para-Lacto-N-hexaose I and
any combination thereof.
[0083] In some particular embodiments the fucosylated
oligosaccharide comprises a 2'-fucosyl-epitope. It can be for
example selected from the list comprising 2'-fucosyllactose,
difucosyllactose, lacto-N-fucopentaose, lacto-N-fucohexaose,
lacto-N-difucohexaose, fucosyllacto-N-hexaose,
fucosyllacto-N-neohexaose, difucosyllacto-N-hexaose
difuco-lacto-N-neohexaose, difucosyllacto-N-neohexaose,
fucosyl-para-Lacto-N-hexaose and any combination thereof.
[0084] In a preferred embodiment, the nutritional composition
according to the invention comprises 2'-fucosyllactose (or 2FL, or
2'FL, or 2-FL or 2'-FL). In a particular embodiment, there is no
other type of fucosylated oligosaccharide than 2'-fucosyllactose,
i.e. the nutritional composition of the invention comprises only
2'-fucosyllactose as fucosylated oligosaccharide.
[0085] The fucosylated oligosaccharide(s) may be isolated by
chromatography or filtration technology from a natural source such
as animal milks. Alternatively, it may be produced by
biotechnological means using specific fucosyltransferases and/or
fucosidases either through the use of enzyme-based fermentation
technology (recombinant or natural enzymes) or microbial
fermentation technology. In the latter case, microbes may either
express their natural enzymes and substrates or may be engineered
to produce respective substrates and enzymes. Single microbial
cultures and/or mixed cultures may be used. Fucosylated
oligosaccharide formation can be initiated by acceptor substrates
starting from any degree of polymerization (DP), from DP=1 onwards.
Alternatively, fucosylated oligosaccharides may be produced by
chemical synthesis from lactose and free fucose. Fucosylated
oligosaccharides are also available for example from Kyowa, Hakko,
Kogyo of Japan.
[0086] The fucosylated oligosaccharide(s) can be present in the
nutritional composition according to the present invention in a
total amount of 0.2-3 g/L, for example 0.5-2 g/L or 0.75-1.65 g/L
of the composition. In some embodiments, the fucosylated
oligosaccharide(s) may be in a total amount of 0.8-1.5 g/L of the
composition, such as 0.85-1.3 g/L or 0.9-1.25 g/L or 0.9-1.1 g/L or
1-1.25 g/L or 1.05-1.25 g/L of the composition. In a particular
embodiment, the fucosylated oligosaccharide(s) is/are in a total
amount of 1 g/L of the composition. In another particular
embodiment, the fucosylated oligosaccharide(s) is/are in a total
amount of 1.24 g/L of the composition. The fucosylated
oligosaccharide(s) can be present in the nutritional composition in
a total amount of 0.13-2.1 g/100 g, for example 0.34-1.4 g/100 g or
0.52-1.15 g/100 g of composition on a dry weight basis. The
fucosylated oligosaccharide(s) may be in a total amount of
0.55-1.05 g/100 g of the composition, such as 0.59-0.9 g/100 g, or
0.62-0.87 g/100 g or 0.62-0.77 g/100 g or 0.69-0.87 g/100 g or
0.73-0.87 g/100 g of the composition. In a particular embodiment,
the fucosylated oligosaccharide(s) is/are in a total amount of 0.69
g/100 g of the composition. In another particular embodiment, the
fucosylated oligosaccharide(s) is/are in a total amount of 0.86
g/100 g of the composition.
[0087] The nutritional composition according to the present
invention may also comprise at least another oligosaccharide(s)
(i.e. other than the fucosylated oligosaccharide(s) necessarily
present in the composition) and/or at least a fiber(s) and/or at
least a precursor(s) thereof. The other oligosaccharide and/or
fiber and/or precursor thereof may be selected from the list
comprising galacto-oligosaccharides (GOS), fructo-oligosaccharides
(FOS), inulin, xylooligosaccharides (XOS), polydextrose,
N-acetylated oligosaccharides, sialylated oligosaccharides, sialic
acid, fucose and any combination thereof. They may be in an amount
between 0 and 10% by weight of composition.
[0088] Suitable commercial products that can be used in addition to
the oligosaccharides comprised in the oligosaccharide mixture to
prepare the nutritional compositions according to the invention
include combinations of FOS with inulin such as the product sold by
BENEO under the trademark Orafti, or polydextrose sold by Tate
& Lyle under the trademark STA-LITE.RTM..
[0089] In some specific embodiments, the nutritional composition of
the present invention may also comprise at least one the
N-acetylated oligosaccharide. There can be one or several types of
N-acetylated oligosaccharide. The N-acetylated oligosaccharide(s)
can be for example lacto-N-tetraose (LNT), lacto-N-neotetraose
(LNnT) or any combination thereof. In some particular embodiments
the N-acetylated oligosaccharide is lacto-N-neotetraose (LNnT),
para-lacto-N-neohexaose (para-LNnH) or any combination thereof. In
some particular embodiments the N-acetylated oligosaccharide is
LNnT. In some particular embodiments the N-acetylated
oligosaccharide is LNT. In some other particular embodiments the
N-acetylated oligosaccharide is a mixture of LNT and LNnT. In some
particular embodiments the composition comprises both LNT and LNnT
in a ratio LNT:LNnT between 5:1 and 1:2, or from 2:1 to 1:1, or
from 2:1.2 to 2:1.6.
[0090] The N-acetylated oligosaccharide(s) may be synthesised
chemically by enzymatic transfer of saccharide units from donor
moieties to acceptor moieties using glycosyltransferases as
described for example in U.S. Pat. No. 5,288,637 and WO 96/10086.
Alternatively, LNT and LNnT may be prepared by chemical conversion
of Keto-hexoses (e.g. fructose) either free or bound to an
oligosaccharide (e.g. lactulose) into N-acetylhexosamine or an
N-acetylhexosamine-containing oligosaccharide as described in
Wrodnigg, T. M.; Stutz, A. E. (1999) Angew. Chem. Int. Ed.
38:827-828. N-acetyl-lactosamine produced in this way may then be
transferred to lactose as the acceptor moiety.
[0091] The N-acetylated oligosaccharide(s) can be present in the
nutritional composition according to the present invention in a
total amount of 0.1-2 g/L, for example 0.3-1 g/L or 0.45-0.85 g/L
of the composition.
[0092] In some embodiments, the N-acetylated oligosaccharide(s) may
be in a total amount of 0.5-0.8 g/L of the composition, such as
0.5-0.75 g/L or 0.5-0.7 g/L of the composition. In a particular
embodiment, the N-acetylated oligosaccharide(s) is/are in a total
amount of 0.5 g/L of the composition. In another particular
embodiment, the N-acetylated oligosaccharide(s) is/are in a total
amount of 0.63 g/L of the composition.
[0093] The N-acetylated oligosaccharide(s) can be present in the
nutritional composition in a total amount of 0.06-1.4 g/100 g, for
example 0.2-0.7 g/100 g or 0.31-0.59 g/100 g of composition on a
dry weight basis, The N-acetylated oligosaccharide(s) may be in a
total amount of 0.35-0.56 g/100 g of composition, such as 0.35-0.52
g/100 g or 0.35-0.49 g/100 g. In a particular embodiment, the
N-acetylated oligosaccharide(s) is/are in a total amount of 0.35
g/100 g of the composition. In another particular embodiment, the
N-acetylated oligosaccharide(s) is/are in a total amount of 0.44
g/100 g of the composition.
[0094] In some embodiments, the nutritional composition comprises
both 2'-fucosyllactose (2-FL) and lacto-N-neotetraose (LNnT). In
another specific embodiment, the nutritional composition of the
present invention comprises an oligosaccharide mixture that
consists of 2'-fucosyllactose (2-FL) and lacto-N-neotetraose
(LNnT). In other words, the nutritional composition of the
invention comprises only 2'-fucosyllactose (2-FL) as fucosylated
oligosaccharide and only lacto-N-neotetraose (LNnT) as N-acetylated
oligosaccharide.
[0095] The nutritional composition can comprise fucosylated
oligosaccharide(s) and N-acetylated oligosaccharide(s) in a ratio
fucosylated oligosaccharide(s):the N-acetylated oligosaccharide(s)
of from 2:0.065 to 2:20 such as from 2:0.3 to 2:4, for example
2:0.54 to 2:2.26, or 2:0.76-2:1.8 or 2:0.8-2:1.4. In a particularly
advantageous embodiment, this ratio is 2:1 or around 2:1.
[0096] In some other particular embodiments, the nutritional
composition according to the invention does not comprise any
N-acetylated oligosaccharides.
[0097] In a particular embodiment, the composition according to the
invention can comprise sialylated oligosaccharide(s). There can be
one or several sialylated oligosaccharide(s).
[0098] The sialylated oligosaccharide(s) can be selected from the
group comprising 3' sialyllactose (3-SL), 6' sialyllactose (6-SL),
and any combination thereof. In some embodiments of the invention
the composition comprises 3-SL and 6-SL. In some particular
embodiments the ratio between 3'-sialyllactose (3-SL) and
6'-sialyllactose (6-SL) can be in the range between 5:1 and 1:10,
or from 3:1 and 1:1, or from 1:1 to 1:10. In some specific
embodiments the sialylated oligosaccharide of the composition is 6'
sialyllactose (6-SL).
[0099] The sialylated oligosaccharide(s) may be isolated by
chromatographic or filtration technology from a natural source such
as animal milks. Alternatively, they may be produced by
biotechnological means using specific sialyltransferases or
sialidases, neuraminidases, either by an enzyme based fermentation
technology (recombinant or natural enzymes), by chemical synthesis
or by a microbial fermentation technology. In the latter case
microbes may either express their natural enzymes and substrates or
may be engineered to produce respective substrates and enzymes.
Single microbial cultures or mixed cultures may be used.
Sialyl-oligosaccharide formation can be initiated by acceptor
substrates starting from any degree of polymerisation (DP), from
DP=1 onwards. Alternatively, sialyllactoses may be produced by
chemical synthesis from lactose and free N'-acetylneuraminic acid
(sialic acid). Sialyllactoses are also commercially available for
example from Kyowa Hakko Kogyo of Japan.
[0100] In particular examples the composition may comprise from
0.05 to 5 g/L of sialylated oligosaccharide(s), or from 0.1 to 4
g/L, or from 0.3 to 2 g/L, or from 0.4 to 1.5 g/L, or from 0.4 to 1
g/L, for example 0.5 or 0.9 g/L of sialylated oligosaccharide(s).
In some particular embodiments the composition can comprise from
0.8 to 1.7 g/I of sialylated oligosaccharide(s).
[0101] The composition according to the invention can contain from
0.03 to 3.5 g of sialylated oligosaccharide(s) per 100 g of
composition on a dry weight basis, e.g. from 0.1 to 2 g or from 0.2
to 1 g or form 0.3 to 0.6 g of sialylated oligosaccharide(s) per
100 g of composition on a dry weight basis.
[0102] In some particular embodiments of the present invention, the
nutritional composition comprises sialylated oligosaccharide(s) in
an amount of below 0.1g/100 g of composition on a dry weight
basis.
[0103] In some particular embodiments of the present invention, the
nutritional composition does not contain any sialylated
oligosaccharide(s).
[0104] In some other particular embodiments of the present
invention, the nutritional composition does not contain any
galacto-oligosaccharides (GOS).
[0105] In a particular embodiment, the nutritional composition can
also contain at least one BMO (bovine milk oligosaccharide). In
another particular embodiment, the nutritional composition does not
comprise any bovine milk oligosaccharide.
[0106] The composition according to the present invention may
optionally also comprise at least one precursor of oligosaccharide.
There can be one or several precursor(s) of oligosaccharide. For
example the precursor of human milk oligosaccharide is sialic acid,
fucose or a mixture thereof. In some particular embodiments the
composition comprises sialic acid.
[0107] In particular examples the composition comprises from 0 to 3
g/L of precursor(s) of oligosaccharide, or from 0 to 2 g/L, or from
0 to 1 g/L, or from 0 to 0.7 g/L, or from 0 to 0.5 g/L or from 0 to
0.3 g/L, or from 0 to 0.2 g/L of precursor(s) of
oligosaccharide.
[0108] The composition according to the invention can contain from
0 to 2.1 g of precursor(s) of oligosaccharide per 100 g of
composition on a dry weight basis, e.g. from 0 to 1.5 g or from 0
to 0.8 g or from 0 to 0.15 g of precursor(s) of oligosaccharide per
100 g of composition on a dry weight basis.
[0109] In preferred embodiments, the nutritional composition of the
present invention can further comprise at least one probiotic
microorganism, such as a probiotic bacterial strain.
[0110] The probiotic microorganisms most commonly used are
principally bacteria and yeasts of the following genera:
Lactobacillus spp., Streptococcus spp., Enterococcus spp.,
Bifidobacterium spp. and Saccharomyces spp.
[0111] In some particular embodiments, the probiotic is a probiotic
bacterial strain. In some specific embodiments, it is particularly
Lactobacilli. In a preferred embodiment, the nutritional
composition comprises at least one Lactobacillus strain.
[0112] Suitable probiotic bacterial strains include Lactobacillus
rhamnosus ATCC 53103 available from Valio Oy of Finland under the
trademark LGG, Lactobacillus rhamnosus CGMCC 1.3724, Lactobacillus
paracasei CNCM 1-2116, Lactobacillus johnsonii CNCM 1-1225,
Streptococcus salivarius DSM 13084 sold by BLIS Technologies
Limited of New Zealand under the designation KI2, Bifidobacterium
lactis CNCM 1-3446 sold inter alia by the Christian Hansen company
of Denmark under the trademark Bb 12, Bifidobacterium longum ATCC
BAA-999 sold by Morinaga Milk Industry Co. Ltd. of Japan under the
trademark BB536, Bifidobacterium breve sold by Danisco under the
trademark Bb-03, Bifidobacterium breve sold by Morinaga under the
trade mark M-16V, Bifidobacterium infantis sold by Procter &
Gamble Co. under the trademark Bifantis and Bifidobacterium breve
sold by Institut RoseII (Lallemand) under the trademark R0070.
[0113] The nutritional composition according to the invention may
contain from 10e3 to 10e12 cfu of probiotic strain, more preferably
between 10e7 and 10e12 cfu such as between 10e8 and 10e10 cfu of
probiotic strain per g of composition on a dry weight basis.
[0114] In one embodiment the probiotics are viable. In another
embodiment the probiotics are non-replicating or inactivated. There
may be both viable probiotics and inactivated probiotics in some
other embodiments.
[0115] The nutritional composition of the invention can further
comprise at least one phage (bacteriophage) or a mixture of phages,
preferably directed against pathogenic Streptococci, Haemophilus,
Moraxella and Staphylococci.
[0116] The nutritional composition according to the invention can
be for example an infant formula, a starter infant formula, a
follow-on or follow-up formula, a baby food, an infant cereal
composition, a fortifier such as a human milk fortifier, or a
supplement. In some particular embodiments, the composition of the
invention is an infant formula, a fortifier or a supplement that
may be intended for the first 4 or 6 months of age. In a preferred
embodiment the nutritional composition of the invention is an
infant formula.
[0117] In some other embodiments the nutritional composition of the
present invention is a fortifier. The fortifier can be a breast
milk fortifier (e.g. a human milk fortifier) or a formula fortifier
such as an infant formula fortifier or a follow-on/follow-up
formula fortifier.
[0118] When the nutritional composition is a supplement, it can be
provided in the form of unit doses.
[0119] The nutritional composition of the present invention can be
in solid (e.g. powder), liquid or gelatinous form.
[0120] The nutritional composition according to the invention
generally contains a protein source. The protein can be in an
amount of from 1.6 to 3 g per 100 kcal. In some embodiments,
especially when the composition is intended for premature infants,
the protein amount can be between 2.4 and 4 g/100kcal or more than
3.6 g/100kcal. In some other embodiments the protein amount can be
below 2.0 g per 100 kcal, e.g. between 1.8 to 2 g/100 kcal, or in
an amount below 1.8 g per 100 kcal.
[0121] The type of protein is not believed to be critical to the
present invention provided that the minimum requirements for
essential amino acid content are met and satisfactory growth is
ensured. Thus, protein sources based on whey, casein and mixtures
thereof may be used as well as protein sources based on soy. As far
as whey proteins are concerned, the protein source may be based on
acid whey or sweet whey or mixtures thereof and may include
alpha-lactalbumin and beta-lactoglobulin in any desired
proportions.
[0122] In some advantageous embodiments the protein source is whey
predominant (i.e. more than 50% of proteins are coming from whey
proteins, such as 60% or 70%).
[0123] The proteins may be intact or hydrolysed or a mixture of
intact and hydrolysed proteins. By the term "intact" is meant that
the main part of the proteins are intact, i.e. the molecular
structure is not altered, for example at least 80% of the proteins
are not altered, such as at least 85% of the proteins are not
altered, preferably at least 90% of the proteins are not altered,
even more preferably at least 95% of the proteins are not altered,
such as at least 98% of the proteins are not altered. In a
particular embodiment, 100% of the proteins are not altered.
[0124] The term "hydrolysed" means in the context of the present
invention a protein which has been hydrolysed or broken down into
its component amino acids.
[0125] The proteins may be either fully or partially hydrolysed. It
may be desirable to supply partially hydrolysed proteins (degree of
hydrolysis between 2 and 20%), for example for infants or young
children believed to be at risk of developing cow's milk allergy.
If hydrolysed proteins are required, the hydrolysis process may be
carried out as desired and as is known in the art. For example,
whey protein hydrolysates may be prepared by enzymatically
hydrolysing the whey fraction in one or more steps. If the whey
fraction used as the starting material is substantially lactose
free, it is found that the protein suffers much less lysine
blockage during the hydrolysis process. This enables the extent of
lysine blockage to be reduced from about 15% by weight of total
lysine to less than about 10% by weight of lysine; for example
about 7% by weight of lysine which greatly improves the nutritional
quality of the protein source.
[0126] In an embodiment of the invention at least 70% of the
proteins are hydrolysed, preferably at least 80% of the proteins
are hydrolysed, such as at least 85% of the proteins are
hydrolysed, even more preferably at least 90% of the proteins are
hydrolysed, such as at least 95% of the proteins are hydrolysed,
particularly at least 98% of the proteins are hydrolysed. In a
particular embodiment, 100% of the proteins are hydrolysed.
[0127] In one particular embodiment the proteins of the nutritional
composition are hydrolyzed, fully hydrolyzed or partially
hydrolyzed. The degree of hydrolysis (DH) of the protein can be
between 8 and 40, or between 20 and 60 or between 20 and 80 or more
than 10, 20, 40, 60, 80 or 90.
[0128] In a particular embodiment the nutritional composition
according to the invention is a hypoallergenic composition. In
another particular embodiment the composition according to the
invention is a hypoallergenic nutritional composition.
[0129] The nutritional composition according to the present
invention generally contains a carbohydrate source. This is
particularly preferable in the case where the nutritional
composition of the invention is an infant formula. In this case,
any carbohydrate source conventionally found in infant formulae
such as lactose, sucrose, saccharose, maltodextrin, starch and
mixtures thereof may be used although one of the preferred sources
of carbohydrates is lactose.
[0130] The nutritional composition according to the present
invention generally contains a source of lipids. This is
particularly relevant if the nutritional composition of the
invention is an infant formula. In this case, the lipid source may
be any lipid or fat which is suitable for use in infant formulae.
Some suitable fat sources include palm oil, high oleic sunflower
oil and high oleic safflower oil. The essential fatty acids
linoleic and a-linolenic acid may also be added, as well small
amounts of oils containing high quantities of preformed arachidonic
acid and docosahexaenoic acid such as fish oils or microbial oils.
The fat source may have a ratio of n-6 to n-3 fatty acids of about
5:1 to about 15:1; for example about 8:1 to about 10:1.
[0131] The nutritional composition of the invention may also
contain all vitamins and minerals understood to be essential in the
daily diet and in nutritionally significant amounts. Minimum
requirements have been established for certain vitamins and
minerals. Examples of minerals, vitamins and other nutrients
optionally present in the composition of the invention include
vitamin A, vitamin B1, vitamin B2, vitamin B6, vitamin B12, vitamin
E, vitamin K, vitamin C, vitamin D, folic acid, inositol, niacin,
biotin, pantothenic acid, choline, calcium, phosphorous, iodine,
iron, magnesium, copper, zinc, manganese, chlorine, potassium,
sodium, selenium, chromium, molybdenum, taurine, and L-carnitine.
Minerals are usually added in salt form. The presence and amounts
of specific minerals and other vitamins will vary depending on the
intended population.
[0132] If necessary, the nutritional composition of the invention
may contain emulsifiers and stabilisers such as soy, lecithin,
citric acid esters of mono- and diglycerides, and the like.
[0133] The nutritional composition of the invention may also
contain other substances which may have a beneficial effect such as
lactoferrin, nucleotides, nucleosides, and the like.
[0134] The nutritional composition of the invention may also
contain carotenoid(s). In some particular embodiments of the
invention, the nutritional composition of the invention does not
comprise any carotenoid.
[0135] The nutritional composition according to the invention may
be prepared in any suitable manner. A composition will now be
described by way of example.
[0136] For example, a formula such as an infant formula may be
prepared by blending together the protein source, the carbohydrate
source and the fat source in appropriate proportions. If used, the
emulsifiers may be included at this point. The vitamins and
minerals may be added at this point but they are usually added
later to avoid thermal degradation. Any lipophilic vitamins,
emulsifiers and the like may be dissolved into the fat source prior
to blending. Water, preferably water which has been subjected to
reverse osmosis, may then be mixed in to form a liquid mixture. The
temperature of the water is conveniently in the range between about
50.degree. C. and about 80.degree. C. to aid dispersal of the
ingredients. Commercially available liquefiers may be used to form
the liquid mixture.
[0137] The fucosylated oligosaccharide(s) may be added at this
stage, especially if the final product is to have a liquid form. If
the final product is to be a powder, they may likewise be added at
this stage if desired.
[0138] The liquid mixture is then homogenised, for example in two
stages.
[0139] The liquid mixture may then be thermally treated to reduce
bacterial loads, by rapidly heating the liquid mixture to a
temperature in the range between about 80.degree. C. and about
150.degree. C. for a duration between about 5 seconds and about 5
minutes, for example. This may be carried out by means of steam
injection, an autoclave or a heat exchanger, for example a plate
heat exchanger.
[0140] Then, the liquid mixture may be cooled to between about
60.degree. C. and about 85.degree. C. for example by flash cooling.
The liquid mixture may then be again homogenised, for example in
two stages between about 10 MPa and about 30 MPa in the first stage
and between about 2 MPa and about 10 MPa in the second stage. The
homogenised mixture may then be further cooled to add any heat
sensitive components, such as vitamins and minerals. The pH and
solids content of the homogenised mixture are conveniently adjusted
at this point.
[0141] If the final product is to be a powder, the homogenised
mixture is transferred to a suitable drying apparatus such as a
spray dryer or freeze dryer and converted to powder. The powder
should have a moisture content of less than about 5% by weight. The
fucosylated oligosaccharide(s) may also or alternatively be added
at this stage by dry-mixing or by blending them in a syrup form of
crystals, along with the probiotic strain(s) (if used), and the
mixture is spray-dried or freeze-dried.
[0142] If a liquid composition is preferred, the homogenised
mixture may be sterilised then aseptically filled into suitable
containers or may be first filled into the containers and then
retorted.
[0143] In another embodiment, the composition of the invention may
be a supplement. The supplement may be in the form of tablets,
capsules, pastilles or a liquid for example. The supplement may
further contain protective hydrocolloids (such as gums, proteins,
modified starches), binders, film forming agents, encapsulating
agents/materials, wall/shell materials, matrix compounds, coatings,
emulsifiers, surface active agents, solubilizing agents (oils,
fats, waxes, lecithins etc.), adsorbents, carriers, fillers,
co-compounds, dispersing agents, wetting agents, processing aids
(solvents), flowing agents, taste masking agents, weighting agents,
jellifying agents and gel forming agents. The supplement may also
contain conventional pharmaceutical additives and adjuvants,
excipients and diluents, including, but not limited to, water,
gelatine of any origin, vegetable gums, lignin-sulfonate, talc,
sugars, starch, gum arabic, vegetable oils, polyalkylene glycols,
flavouring agents, preservatives, stabilizers, emulsifying agents,
buffers, lubricants, colorants, wetting agents, fillers, and the
like.
[0144] Further, the supplement may contain an organic or inorganic
carrier material suitable for oral or parenteral administration as
well as vitamins, minerals trace elements and other micronutrients
in accordance with the recommendations of Government bodies such as
the USRDA.
[0145] The nutritional composition according to the invention is
for use in infants or young children. The infants or young children
may be born term or preterm. In a particular embodiment the
nutritional composition of the invention is for use in infants or
young children that were born preterm. In a particular embodiment
the nutritional composition of the invention is for use in preterm
infants.
[0146] The nutritional composition of the present invention may
also be used in an infant or a young child that was born by
C-section or that was vaginally delivered.
[0147] In some embodiments the composition according to the
invention can be for use before and/or during the weaning
period.
[0148] The nutritional composition can be administered (or given or
fed) at an age and for a period that depends on the needs. The
nutritional composition of the present invention may be used for
prevention or treatment purposes: [0149] in preventing and/or
treating constipation in an infant or a young child; [0150] in
improving stool consistency in an infant or a young child, e.g. in
reducing stool hardness in said infant or young child; [0151] in
improving stool frequency in an infant or a young child, e.g. in
regulating/fastening the transit in said infant or young child;
[0152] in preventing and/or treating flatulence, bloating, colics
and/or gut discomfort in an infant or young child.
[0153] In some embodiments the nutritional composition is used for
prevention purposes. The nutritional composition can be for example
given immediately after birth of the infants. The composition of
the invention can also be given during the first week of life of
the infant, or during the first 2 weeks of life, or during the
first 3 weeks of life, or during the first month of life, or during
the first 2 months of life, or during the first 3 months of life,
or during the first 4 months of life, or during the first 6 months
of life, or during the first 8 months of life, or during the first
10 months of life, or during the first year of life, or during the
first two years of life or even more. In some particularly
advantageous embodiments of the invention, the nutritional
composition is given (or administered) to an infant within the
first 4 or 6 months of birth of said infant.
[0154] In some other embodiments, the nutritional composition of
the invention is given few days (e.g. 1, 2, 3, 5, 10, 15, 20 . . .
), or few weeks (e.g. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 . . . ), or few
months (e.g. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 . . . ) after birth.
This may be especially the case when the infant is premature, but
not necessarily.
[0155] In one embodiment the composition of the invention is given
to the infant or young child as a supplementary composition to the
mother's milk. In some embodiments the infant or young child
receives the mother's milk during at least the first 2 weeks, first
1, 2, 4, or 6 months. In one embodiment the nutritional composition
of the invention is given to the infant or young child after such
period of mother's nutrition, or is given together with such period
of mother's milk nutrition. In another embodiment the composition
is given to the infant or young child as the sole or primary
nutritional composition during at least one period of time, e.g.
after the 1.sup.st, 2.sup.nd or 4.sup.th month of life, during at
least 1, 2, 4 or 6 months.
[0156] In one embodiment the nutritional composition of the
invention is a complete nutritional composition (fulfilling all or
most of the nutritional needs of the subject). In another
embodiment the nutrition composition is a supplement or a fortifier
intended for example to supplement human milk or to supplement an
infant formula or a follow-on formula.
[0157] In some other embodiments the nutritional composition of the
invention is given for treatment purposes, e.g. when the
composition is used for the treatment of constipation In these
cases, the nutritional composition of the invention can be given
for some days (1, 2, 3, 4, 5, 6 . . . ), or for some weeks (1, 2,
3, 4, 5, 6, 7, 8 or even more), or for some months (1, 2, 3, 4, 5,
6, 7, 8, 9, 10, 11 or even more), depending on the needs. It may be
given once the symptoms appear or once these health
diseases/conditions have been diagnosed. It may be given up to the
symptoms of the treated diseases/conditions disappear, or several
days/weeks/months after said disappearance.
[0158] In some embodiments, the health benefits/effects are
observed during the first few weeks or months of life and/or during
the first few weeks or months after administration of the
nutritional composition, e.g. during the first week, the first 2
weeks, the first month, the first 2 months, the first 4 months or
the first 6 months. Effects at longer term may be less important.
In some embodiments, the nutritional composition according to the
present invention is for use in improving stool
consistency/frequency in an infant during the first month or first
2 months of life and/or after administration of the nutritional
composition. In some other embodiments, the nutritional composition
according to the present invention is for use in preventing and/or
treating colics in infants during the first month, the first 2
months or the first 4 months of life and/or after administration of
the nutritional composition, especially in C-section infants.
[0159] The present inventors have found that the particular
nutritional composition according to the invention is particularly
efficient in reducing stool hardness in infants or young children.
The nutritional composition was also particularly efficient in
terms of flatulence, bloating, colics and gut discomfort since no
or a limited level was observed in said infant or young child.
[0160] In a particular aspect, the present invention also refers to
a nutritional composition comprising at least one fucosylated
oligosaccharide for use in reducing stool hardness in an infant or
a young child, especially without (i.e. no or in a limited level)
any associated flatulence, bloating, colics or gut discomfort.
[0161] Other objects:
[0162] Another object of the present invention is the use of at
least one fucosylated oligosaccharide in the preparation of a
nutritional composition for preventing and/or treating constipation
and/or for improving stool consistency/frequency in an infant or
young child.
[0163] Another object of the present invention is the use of at
least one fucosylated oligosaccharide in the preparation of a
nutritional composition for preventing and/or treating flatulence,
bloating, colics and/or gut discomfort in an infant or a young
child, and wherein the fucosylated oligosaccharide(s) is/are in a
total amount of 0.8-1.5 g/L of the composition and/or in a total
amount of 0.55-1.05 g/100 g of composition on a dry weight
basis.
[0164] Another object of the present invention is the use of at
least one fucosylated oligosaccharide for improving stool
consistency/frequency in an infant or young child.
[0165] Another object of the present invention is the use of at
least one fucosylated oligosaccharide for reducing flatulence, for
reducing bloating, for reducing colics and/or for relieving gut
discomfort in an infant or young child, and wherein the fucosylated
oligosaccharide(s) is/are in a total amount of 0.8-1.5 g/L of the
composition and/or in a total amount of 0.55-1.05 g/100 g of
composition on a dry weight basis.
[0166] The previously-mentioned embodiments and examples (e.g.
related to the types and amounts of oligosaccharide, the
nutritional composition, the administration, the targeted
population . . . ) also apply for these objects (i.e. for these
uses).
[0167] Another object of the present invention is a pharmaceutical
composition comprising at least one fucosylated oligosaccharide for
preventing and/or treating constipation and/or for improving stool
consistency/frequency, and/or for preventing and/or treating
flatulence, bloating, colics and/or gut discomfort in an infant or
a young child.
[0168] The previously-mentioned embodiments and examples (e.g.
related to the types and amounts of oligosaccharide, the
administration, the targeted population . . . ) also apply to this
object (i.e. pharmaceutical composition).
[0169] Another object of the present invention refers to a method
for preventing and/or treating constipation and/or for improving
stool consistency/frequency in an infant or a young child, said
method comprising administering to said infant or young child a
nutritional composition comprising at least one fucosylated
oligosaccharide.
[0170] Another object of the present invention is a method for
preventing and/or treating flatulence, bloating, colics and/or gut
discomfort in an infant or a young child, said method comprising
administering to said infant or young child a nutritional
composition comprising at least one fucosylated oligosaccharide,
and wherein the fucosylated oligosaccharide(s) is/are in a total
amount of 0.8-1.5 g/L of the composition and/or in a total amount
of 0.55-1.05 g/100 g of composition on a dry weight basis.
[0171] The different embodiments, details and examples previously
described in the specification (e.g. related to the types and
amounts of oligosaccharide, the nutritional composition, the
administration, the targeted population . . . ) also apply to these
objects (i.e. methods).
EXAMPLES
[0172] The following examples illustrate some specific embodiments
of the composition for use according to the present invention. The
examples are given solely for the purpose of illustration and are
not to be construed as limitations of the present invention.
Example 1
[0173] An example of the composition of a nutritional composition
(e.g. an infant formula) according to the present invention is
given in the below table 1. This composition is given by way of
illustration only.
TABLE-US-00001 TABLE 1 an example of the composition of a
nutritional composition (e.g. an infant formula) according to the
present invention Nutrients per 100 kcal per litre Energy (kcal)
100 670 Protein (g) 1.83 12.3 Fat (g) 5.3 35.7 Linoleic acid (g)
0.79 5.3 .alpha.-Linolenic acid (mg) 101 675 Lactose (g) 11.2 74.7
Minerals (g) 0.37 2.5 Na (mg) 23 150 K (mg) 89 590 Cl (mg) 64 430
Ca (mg) 62 410 P (mg) 31 210 Mg (mg) 7 50 Mn (.mu.g) 8 50 Se
(.mu.g) 2 13 Vitamin A (.mu.g RE) 105 700 Vitamin D (.mu.g) 1.5 10
Vitamin E (mg TE) 0.8 5.4 Vitamin K1 (.mu.g) 8 54 Vitamin C (mg) 10
67 Vitamin B1 (mg) 0.07 0.47 Vitamin B2 (mg) 0.15 1.0 Niacin (mg) 1
6.7 Vitamin B6 (mg) 0.075 0.50 Folic acid (.mu.g) 9 60 Pantothenic
acid (mg) 0.45 3 Vitamin B12 (.mu.g) 0.3 2 Biotin (.mu.g) 2.2 15
Choline (mg) 10 67 Fe (mg) 1.2 8 I (.mu.g) 15 100 Cu (mg) 0.06 0.4
Zn (mg) 0.75 5 Oligosaccharides 2FL (g) 0.15 1 (HMOs)
Example 2
[0174] Description of the Study
[0175] A controlled, single-blind, randomized, multi-center,
interventional clinical trial of 2 groups in parallel was made.
Infants were recruited and randomized to one of the 2 study arms
within 14 days after birth. The study arms consisted of a classical
infant starter formula without HMO [Control] or this classical
infant starter formula supplemented with 2 HMOs [HMO]. The
composition of the tested infant formula with or without the
addition of HMOs was equivalent to the composition shown in table
1, except that: [0176] the control infant formula contained no
oligosaccharides/HMOs (i.e. no 2'Fucosyllactose and no
lacto-N-neotetraose); [0177] the tested infant formula with HMOs
contained 2'Fucosyllactose but in an amount of 1.24 g/L
(corresponding to an amount of 0.86 g/100 g powder before
reconstitution; reconstitution was 129.18 g powder/900 mL) and
lacto-N-neotetraose but in an amount of 0.63 g/L (corresponding to
0.44 g/100 g powder before reconstitution; reconstitution was
129.18 g powder/900 mL).
[0178] Introduction of weaning food was from 4 months onwards.
[0179] The study consists of a 6 months .+-.7 days treatment period
with one of the two treatments and a 6 months follow-up period
without treatment.
[0180] Findings
[0181] The inventors surprisingly observed that infants of the HMO
group (i.e. those fed a classical formula supplemented with 1.24
g/L of 2'-fucosyllactose and 0.63 g/L lacto-N-neotetraose had less
hard stools, both at 1 month (FIG. 1A) and 2 months (FIG. 1B) of
age. In the same time, no particular issue of flatulence, bloating,
colics and gut discomfort was reported in said infant or young
child.
[0182] In particular, there was also a significant lower level of
colics in infants fed the HMOs born form C-section at 4 months of
age, see FIG. 2.
[0183] A composition comprising at least one fucosylated
oligosaccharide and at least one N-acetylated oligosaccharide is
therefore very efficient in infants for use in improving stool
consistency, and therefore in improving stool frequency, in
preventing and/or treating constipation but also in preventing
and/or treating flatulence, bloating, colics and/or gut discomfort
in said infants.
[0184] In view of the findings of example 3, but without being
bound by theory, it is believed that the fucosylated
oligosaccharide is the key ingredient of said oligosaccharide
mixture that allows getting such effects. So a composition
comprising at least one fucosylated oligosaccharide would therefore
be efficient in infants for use in improving stool consistency, in
improving stool frequency, in preventing and/or treating
constipation but also in preventing and/or treating flatulence,
bloating, colics and/or gut discomfort in said infants.
Example 3
[0185] Description of the Study
[0186] The trial population consists of healthy term infants (both
male and female) who are post-natal age between 0 and 14 days at
enrolment (date of birth=day 0). The following parameters are
assessed: stool patterns (stool frequency and consistency), fecal
microbiota composition and diversity (including potentially
beneficial and potentially pathogenic bacteria and viruses), fecal
markers of gut health, GI tolerance including GI symptoms and GI
related behaviors. [0187] Stool patterns: including stool frequency
and stool consistency [0188] Data collected at Study Day 1, 30, 60,
90, 120, and 180. [0189] Stool consistency is reported as mean
stool consistency from the 3-day GI Symptom and Behavior Record
using a published, validated 5-point stool scale developed for
infants year (1=watery, 2=runny, 3=mushy soft, 4=formed, 5=hard),
and is also reported as the percentage of stools in each of the 5
stool consistency categories. [0190] GI tolerance: including GI
symptoms and GI-related behaviors [0191] Data collected at Study
Day 1, 30, 60, 90, 120, and 180. [0192] GI symptoms are reported as
frequency of spitting-up/vomiting, and flatulence from the 3-day GI
Symptom and Behavior Record [0193] GI-related behaviors are
reported as mean duration of crying and fussiness (min) as well as
sleeping (min), and the frequency of excessive crying (defined as
crying greater than 2.25 hours or 140 minutes per day [52, 53]) as
reported from the 3-day GI Symptom and Behavior Record. [0194]
Fecal microbiota composition and diversity [0195] Stool sample
collected at Study Day 1, 120 and 180. [0196] Fecal microbiota
composition and diversity (including levels of potentially
beneficial and potentially pathogenic bacteria and viruses) are
assessed using shotgun metagenomics sequencing to sample all genes
in all organisms and high throughput sequencing of the 16S
ribosomal genes to provide taxonomic composition and diversity
metrics, while quantitative changes in specific bacterial and viral
targets including pathogenic bacterial species and viruses are
assessed using quantitative polymerase chain reaction (qPCR). qPCR
targets may include Lactobacillus reuteri, Campylobacter jejuni,
Enteropathogenic Escherichia coli (EPEC), Clostridium difficile,
Clostridium perfringens, Klebsiella pneumoniae. Dry stool weight
are also be calculated to normalize the data. [0197] Fecal markers
of gut health [0198] Stool sample collected at Study Day 1, 120 and
180. [0199] Fecal markers of gut health include secretory IgA
[total], human B defensin-2, myeloperoxidase, and lactoferrin.
[0200] Incidence of reported Adverse Events AEs (including common
illnesses of interest identified using a standardized AE Criteria)
and reported use of Concomitant Medications or Non-Pharamacologic
Treatments of Interest. [0201] Data collected on Study Day 1
through the 2 weeks post-study telephone contact on Study Day 194.
Note: the Infant Health Record is a worksheet completed by the
parent anytime the child is ill or takes a medication or visits a
health care provider for any reason during the study. The worksheet
is used a tool to aid in the completion of the Adverse Event
Guidance Forms (used to improve the accuracy of coding for specific
Adverse Events of interest) and ultimately the Adverse Event
reporting as well as the Medication, and Non-pharmacologic
treatment records. [0202] Reported AEs and Serious Adverse Events
(SAEs) including type, incidence, severity, seriousness and
relation to feeding. [0203] Counts of incident cases as well as
cumulative incidence (calculated as described below) and duration
will be summarized from Study Day 1 to 120, from Study Day 1 to
180, and from Study Day 1 to 194.
[0204] Dose Regimen
[0205] The randomized, double-blinded, controlled interventional
clinical trial design is the most appropriate to evaluate the
growth, safety, and efficacy of the experimental formula (EF)
supplemented with 2'FL as compared to control formula (CF).
[0206] There were 3 groups: [0207] CF group: healthy term
exclusively formula-fed infants. The formula was the CF=Lactogen
formula, provided by Nestle SA. [0208] EF group: healthy term
exclusively formula-fed infants. The formula was the EF=Lactogen
formula (provided by Nestle SA) supplemented by a 2'FL dose of 1
g/L. [0209] BF group: healthy term exclusively breast-fed
infants.
[0210] Lactogen formula includes Lactobacillus probiotic strain in
a quantity of 10.sup.6 cfu/g of said formula (dry weight).
[0211] Results
[0212] Tested parameters for the EF group are better than for the
CF group and results tend to get closer to the ones obtained for
the BF group.
* * * * *