U.S. patent application number 14/193918 was filed with the patent office on 2014-07-31 for nutritional composition comprising probiotics and improving sleep patterns.
This patent application is currently assigned to NESTEC S.A.. The applicant listed for this patent is NESTEC S.A.. Invention is credited to Gabriela Bergonzelli Degonda, Isabelle Bureau-Franz, Clara Lucia Garcia-Rodenas.
Application Number | 20140212389 14/193918 |
Document ID | / |
Family ID | 40785276 |
Filed Date | 2014-07-31 |
United States Patent
Application |
20140212389 |
Kind Code |
A1 |
Bergonzelli Degonda; Gabriela ;
et al. |
July 31, 2014 |
NUTRITIONAL COMPOSITION COMPRISING PROBIOTICS AND IMPROVING SLEEP
PATTERNS
Abstract
This invention relates to the use of a probiotic bacterial
strain in the manufacture of a medicament or therapeutic
nutritional composition for improving the maturation of sleep
patterns in infants, young children or young animals and/or for
reducing sleep disturbances and/or improving sleep patterns in
humans or animals at any age.
Inventors: |
Bergonzelli Degonda; Gabriela;
(Bussigny, CH) ; Bureau-Franz; Isabelle;
(Epalinges, CH) ; Garcia-Rodenas; Clara Lucia;
(Forel, CH) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
NESTEC S.A. |
Vevey |
|
CH |
|
|
Assignee: |
NESTEC S.A.
Vevey
CH
|
Family ID: |
40785276 |
Appl. No.: |
14/193918 |
Filed: |
February 28, 2014 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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13127164 |
May 2, 2011 |
|
|
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PCT/EP2009/064276 |
Oct 29, 2009 |
|
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14193918 |
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Current U.S.
Class: |
424/93.4 |
Current CPC
Class: |
A61K 35/742 20130101;
A61P 25/00 20180101; A61K 35/744 20130101; A23L 33/135 20160801;
A61K 31/00 20130101; A61P 25/20 20180101; A61K 35/745 20130101;
A61K 35/747 20130101; A23V 2002/00 20130101; A23V 2002/00 20130101;
A23V 2200/3204 20130101; A23V 2200/322 20130101; A23V 2200/31
20130101; A23V 2250/1882 20130101; A23V 2200/3202 20130101; A23V
2250/156 20130101; A23V 2250/70 20130101 |
Class at
Publication: |
424/93.4 |
International
Class: |
A61K 35/74 20060101
A61K035/74; A23L 1/30 20060101 A23L001/30 |
Foreign Application Data
Date |
Code |
Application Number |
Nov 3, 2008 |
EP |
08168161.1 |
Claims
1: A method for reducing stress-induced sleep disturbances in
humans or animals in need of same comprising administering a
therapeutically-effective amount of a composition including a
probiotic bacterial strain that is Bifidobacterium longum
NCC3001.
2: The method of claim 1 wherein the humans or animals are selected
from the group consisting of infants, young animals and young
children.
3: The method of claim 1, wherein the humans or animals suffer from
poor quality sleep and/or insomnia.
4: The method of claim 1, wherein the composition induces a mature
sleep pattern or reduces the number of episodes of wakefulness in
the humans or animals.
5: The method of claim 1, wherein the daily dose of probiotic
bacteria is from 10.sup.3 to 10.sup.12 colony forming units
(cfu).
6: The method of claim 1, wherein the composition comprises from
10.sup.3 to 10.sup.12 colony forming units (cfu) of probiotic
bacteria per g of composition.
7: The method of claim 1, wherein the composition is a supplement
and the probiotic bacterial strain is present in an amount of from
10.sup.3 to 10.sup.12 cfu per unit dose.
8: The method of claim 1, wherein the composition is in a form
selected from the group consisting of a human milk fortifier, an
infant formula, a follow on formula, a growing up milk, an infant
cereal, a baby food, a yogurt, a cereal bar, a breakfast cereal, a
dessert, a frozen food, a soup, a pet food, a liquid suspension, a
powder, a tablet, a gum, a candy, a nutritional composition, and a
nutritional supplement.
9: The method of claim 1, wherein the composition induces a more
mature sleep pattern.
10: The method of claim 1, wherein the composition comprises
carbohydrates, and the carbohydrates comprise rice
carbohydrates.
11: The method of claim 1, wherein the composition is a starter
infant formula or a follow-up infant formula.
12: A method for improving sleep quality or sleep patterns in
humans or animals in need of same comprising administering a
therapeutically-effective amount of a composition comprising a
probiotic bacterial strain that is Bifidobacterium longum
NCC3001.
13: The method of claim 12, wherein the humans or animals are
selected from the group consisting of infants, young animals and
young children.
14: The method of claim 12, wherein the humans or animals suffer
from poor quality sleep and/or insomnia.
15: The method of claim 12, wherein the composition induces a
mature sleep pattern or reduces the number of episodes of
wakefulness in the humans or animals.
16: The method of claim 12, wherein the daily dose of probiotic
bacteria is from 10.sup.3 to 10.sup.12 colony forming units
(cfu).
17: The method of claim 12, wherein the composition comprises from
10.sup.3 to 10.sup.12 colony forming units (cfu) of probiotic
bacteria per g of composition.
18: The method of claim 14, wherein the poor quality sleep and/or
insomnia is stress-induced.
19: The method of claim 12, wherein the composition is a supplement
and the probiotic bacterial strain is present in an amount of from
10.sup.3 to 10.sup.12 cfu per unit dose.
20: The method of claim 12, wherein the composition is in a form
selected from the group consisting of a human milk fortifier, an
infant formula, a follow on formula, a growing up milk, an infant
cereal, a baby food, a yogurt, a cereal bar, a breakfast cereal, a
dessert, a frozen food, a soup, a pet food, a liquid suspension, a
powder, a tablet, a gum, a candy, a nutritional composition, and a
nutritional supplement.
21: The method of claim 12, wherein the composition induces a more
mature sleep pattern.
22: The method of claim 12, wherein the composition comprises
carbohydrates, and the carbohydrates comprise rice
carbohydrates.
23: The method of claim 12, wherein the composition is a starter
infant formula or a follow-up infant formula.
Description
PRIORITY CLAIM
[0001] This application is a divisional application of U.S. patent
application Ser. No. 13/127,164, filed on May 2, 2011, which is a
National Stage of International Application No. PCT/EP2009/064276,
filed Oct. 29, 2009, which claims priority to European Application
No. 08168161.1, filed Nov. 3, 2008, the entire contents of which
are being incorporated herein by reference.
FIELD OF THE INVENTION
[0002] This invention relates to the use of probiotic bacterial
strains to improve the maturation of sleep patterns and reduce
night wakefulness in infants and young children and/or to reduce
sleep disturbances and improve sleep quality in humans or animals
suffering from sleep alterations at any age.
BACKGROUND
[0003] Sleep disturbances are observed at any stage of the life.
These disturbances are typically characterized by a decrease in the
ability to initiate and maintain sleep, and by a reduced proportion
of the deeper, more restorative sleep. Quality of life is
substantially impaired in individuals suffering from those
alterations.
[0004] Infant sleep normally changes over the first months of life
to follow a diurnal rhythm with sleep lasting for a long unbroken
period at night and, similarly, sleep states change from being
equally distributed between REM (active) and NREM (quiet) sleep at
birth to one third REM and two thirds NREM by 8 months of age. Any
failure to successfully negotiate these changes in infancy can also
have lasting effects on the sleep patterns of the child.
[0005] The most common sleep disturbances in infants and children
are those related to wakefulness (i.e. either difficulties in
settling at bedtime or failure to sleep through the night without
interruptions). It has been estimated that these disturbances
affect 15 to 35% of infants aged less than 24 months (France et al,
"Infant Sleep Disturbance: Description of a problem behaviour
process", Sleep Medicine Reviews, Vol 3, No 4, pp 265-280, 1999).
Infant and child sleep disturbances inevitably lead to parental
sleep disturbance and stress which may result in inadequate
child-parent interaction which in turn aggravates infant and child
symptoms leading to a vicious circle.
[0006] Much of the literature which deals with infant sleep
disturbance focuses on psychological factors such as pre- and
post-natal stress and high levels of anxiety in the mother. For
example, Field and co-workers studied the relationship between
sleep disturbance, depression, anxiety and anger in pregnant women
in the second and third trimesters of pregnancy and sleep patterns
of their new-born infants. They observed that infants born to
depressed mothers also suffered from sleep disturbances including
less time in deep sleep and more time in indeterminate
(disorganised) sleep (Field et al, "sleep disturbances in depressed
pregnant women and their newborns", Infant Behavior and Development
30 (2007) 127-133).
[0007] These and similar observations have led paediatricians when
consulted by parents of infants and children about infant sleep
disturbance to focus on recommending behavioural management
techniques, such as establishing a consistent bedtime ritual,
moving gradually bedtime to an earlier time or gradually reducing
attention given on waking. These measures can be effective but are
often difficult for the parents to apply.
[0008] Normal aging is accompanied by changes in the sleep quality,
quantity, and architecture. Specifically, there appears to be a
measurable decrease in the ability of the healthy elderly to
initiate and maintain sleep, accompanied by a decrease in the
proportion of the deeper, more restorative NREM sleep (Espiritu J
R. Aging-related sleep changes, Clin Geriatr Med. 2008
24(1):1-14)
[0009] Acute and chronic stress, anxiety and depression typically
lead to alterations in sleep patterns and insomnia at any age
(Chorney D B, Detweiler M F, Morris T L, Kuhn B R, The interplay of
sleep disturbance, anxiety, and depression in children, J Pediatr
Psychol. 2008 33(4):339-48; LeBlanc M, Merette C, Savard J, Ivers
H, Baillargeon L, Morin C M, Incidence and risk factors of insomnia
in a population-based sample. Sleep. 2009 32(8):1027-37).
[0010] Occasionally and in extreme cases, anxiolytic drugs (e.g.
benzodiazepin) may be prescribed. However, the efficiency of these
drugs is variable, establishment of the correct dose difficult to
reach and the risk of adverse side-effects is high. In any event,
there is a general reluctance to prescribe powerful medicaments of
this type, specially for infants and young children.
[0011] From the foregoing, it may be seen that there remains a need
for alternative methods to reduce sleep disturbances and improve
sleep patterns in different phases of the life.
SUMMARY
[0012] The present inventors have surprisingly found that
administration of a probiotic bacterial strain may improve sleep
quality and reduce the number of episodes of wakefulness in
individuals suffering from sleep alterations and/or insomnia and,
specifically, induce a more mature sleep pattern in infants and
young children. Thus, in an animal model mimicking the sleep
alterations experienced by infants and children with poor or
immature sleep quality and by adults suffering sleep alterations,
the administration of probiotics completely normalized sleep
patterns by decreasing the time of active sleep (REM), increasing
the time of quiet sleep (NREM) and reducing the number of wake up
episodes.
[0013] Accordingly, the present invention provides the use of a
probiotic bacterial strain in the manufacture of a medicament or
therapeutic nutritional composition for inducing a more mature
sleep pattern in infants and young children and for reducing sleep
disturbance and/or improving sleep patterns at any age. "More
mature" is herewith referring to sleep pattern similar to or close
to the sleep patterns of subjects not suffering of delayed
maturation of the sleep cycle and, in consequence, not suffering
from sleep disturbances. "More mature sleep pattern" is
characterized by sleep lasting for long unbroken period(s) at
night, which is associated to a reduction in the duration of active
(REM) sleep and an increase in the duration of quiet (NREM) sleep.
Such REM and NREM are good indicators of sleep pattern
maturation.
[0014] The invention extends to a method of inducing a more mature
sleep pattern in infants and young children and for reducing sleep
disturbance and/or improving sleep patterns at any age comprising
administering to an individual in need thereof a therapeutic amount
of a probiotic bacterial strain.
[0015] BDNF (Brain-derived neurotrophic factor) is a protein that
promotes the survival of neuronal populations located either in the
central nervous system or directly connected to the central nervous
system. It is a member of a unique family of 15 polypeptide growth
factors that influence proliferation, differentiation, survival and
death of neuronal and non-neuronal cells. BDNF and the other
neurotrophic growth factors, e.g., NGF (nerve growth factor), NT-3
(neurotrophin-3), and NT-4 (neurotrophin-4) are essential for the
health and well-being of the nervous system, and mediate
higher-order activities such as learning, memory, behaviour in
addition to their role in cell survival. It has already been
demonstrated that high BDNF levels in the brain enhance spontaneous
sleep and NREM duration in animal models (Kushikata, Am J Physiol,
1999) whereas blockage of the TrkB receptors of BDNF lead to
perturbations in the sleep patterns (Faraguna et al, J Neurosci,
2008). From unpublished data, the present inventors were aware that
a probiotic bacterial strain, namely Bifidobacterium longum NCC3001
(ATCC BAA-999, initially provided by Morinaga Milk Industry Co.
Ltd. as BB536), increases hippocampal BDNF expression.
[0016] Stress, anxiety and depression have been shown to be
associated to low BDNF levels in the hippocampus (Duman R S,
Malberg J, Nakagawa S, D'Sa C. Neuronal plasticity and survival in
mood disorders. Biol Psychiatry. 2000; 48:732-739). Decreased BDNF
and/or the expression of its receptors (TrkB.FL, TrkB.T1 and
TrkB.T2) have been also described during normal aging
(Tapia-Arancibia L, Aliaga E, Silhol M, Arancibia S. Brain Res Rev.
2008, 59(1):201-20). In infants, many physiological processes are
not fully mature at birth and only become mature in the first
months or years following birth. It is possible that some infants
and children may experience low levels of BDNF. Low levels of BDNF
in these situations may be responsible for disturbed sleep and/or,
in the specific case of infants and children, a failure to develop
mature diurnal sleeping patterns. Without wishing to be bound by
theory, the present inventors believe that the beneficial effect of
administration of a probiotic bacterial strain upon sleep
disturbance and sleep patterns may be explained in this way. In
other words, administration of an agent which is capable of
increasing hippocampal BDNF expression such as a probiotic
bacterial strain may thus result in the observed normalization of
sleep quality and/or improvement in development of mature sleeping
patterns.
BRIEF DESCRIPTION OF THE DRAWINGS
[0017] FIG. 1A shows the total duration (minutes) of wake (A)
states during the 24 hours polygraphic recording period in control
or prenatal stress (PRS) animals.
[0018] FIG. 1B shows the total duration (minutes) of NREM (B)
states during the 24 hours polygraphic recording period in control
or prenatal stress (PRS) animals.
[0019] FIG. 1C shows the total duration (minutes) of REM (C) states
during the 24 hours polygraphic recording period in control or
prenatal stress (PRS) animals.
[0020] FIG. 2A shows the number of episodes of wake (A) states
during the 24 hour polographic recording period in control or
prenatal stress (PRS) animals.
[0021] FIG. 2B shows the number of episodes of NREM (B) states
during the 24 hour polographic recording period in control or
prenatal stress (PRS) animals.
[0022] FIG. 2A shows the number of episodes of REM (C) states
during the 24 hour polographic recording period in control or
prenatal stress (PRS) animals.
DETAILED DESCRIPTION
[0023] In this specification, the following terms have the
following meanings:--
[0024] "infant" means a child under the age of 12 months;
[0025] "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);
[0026] "sleep disturbed infant/young child" means an infant or
young child who awakens in the night and cannot settle back to
sleep without the parents being aware of the awakening and/or an
infant or young child who cannot self-initiate sleep;
[0027] "young child" means a child between the age of one and three
years.
[0028] All percentages are by weight unless otherwise stated.
[0029] The probiotic bacterial strain may be administered as a
medicament, for example as a daily dose equivalent to 10e10 cfu
dissolved in water and administered on a spoon. Alternatively, the
composition of the present invention may be a food product, a
nutritional composition, a nutraceutical, a drink, a food additive
or an animal food product containing an amount equivalent to
between 10e3 and 10e12 cfu/g (dry weight basis), more preferably
between 10e6 and 10e9 cfu/g.
[0030] For example, the composition may be a human milk fortifier,
an infant formula, a follow on formula, a growing up milk, an
infant cereal, a baby food, a yogurt, a cereal bar, a breakfast
cereal, a dessert, a frozen food, a soup, an animal food. a liquid
suspension, a powder, a tablet, a gum. a candy, a nutritional
composition and/supplements that are targeted at supporting
particular pathological (or undesired physiological conditions or
physio-pathological conditions) conditions such as allergies or
intolerances, malnutrition, inflammation, critical illness, colics,
trauma, infection, surgery, attention deficit/hyperactivity
disorders, depression, anxiety, fatigue, or stress and the like,
especially when the particular pathological conditions induce
disturbances in sleep pattern.
[0031] The expression "amount equivalent to" includes the
possibilities that the bacteria are live, inactivated or dead or
even present as fragments such as DNA or cell wall materials or
probiotic metabolites. In other words, the quantity of bacteria is
expressed in terms of the colony forming ability of that quantity
of bacteria as if all the bacteria were live irrespective of
whether only the bacteria metabolites are provided or the bacteria
are, in fact, live, inactivated or dead, fragmented or a mixture of
any or all of these states.
[0032] The probiotic bacterial strain may be a lactobacillus or a
bifidobacterium. Examples of preferred lactobacillus species are
Lactobacillus rhamnosus, Lactobacillus paracasei and Lactobacillus
reuteri. Particularly preferred strains are Lactobacillus rhamnosus
ATCC 53103, Lactobacillus rhamnosus CGMCC 1.3724, Lactobacillus
reuteri ATCC 55730 and Lactobacillus reuteri DSM 17938. Examples of
preferred bifidobacterium species are Bifidobacterium lactis,
Bifidobacterium longum, Bifidobacterium breve and Bifidobacterium
infantis. Particularly preferred strains include Bifidobacterium
lactis CNCM 1-3446 sold inter alia by the Christian Hansen company
of Denmark under the trade mark Bb12, Bifidobacterium longum
NCC3001, ATCC BAA-999 sold by Morinaga Milk Industry Co. Ltd. of
Japan under the trade mark BB536, the strain of Bifidobacterium
breve sold by Danisco under the trade mark Bb-03, the strain of
Bifidobacterium breve sold by Morinaga under the trade mark M-16V,
the strain of Bifidobacterium breve sold by Institut Rosell
(Lallemand) under the trade mark R0070 and the strain of
Bifidobacterium infantis sold by Procter & Gamble Co. under the
trade mark B. infantis. The probiotics can be selected from the
list comprising: the genera Bifidobacteria, Lactobacilli,
Lactococci, Enterococci, Streptococci, Propionibacteria,
Pediococci, Escherichia coli, Debaryomyces, Kluyveromyces,
Saccharoymces, Schizosaccharomyces, Zygosaccharomyces, Yarrowia,
Candida, the species Bifidobacterium longum, Bifidobacterium
lactis, Bifidobacterium animalis, Bifidobacterium breve,
Bifidobacterium infantis, Bifidobacterium bifidum, Bifidobacterium
adolescentis, Lactobacillus acidophilus, Lactobacillus helveticus,
Lactobacillus casei, Lactobacillus paracasei, Lactobacillus
salivarius, Lactobacillus plantarum, Lactobacillus fermentum,
Lactobacillus johnsonii, Lactobacillus reuteri, Lactobacillus
gasseri, Lactobacillus rhamnosus, Lactococcus ssp. such as
Lactococcus lactis, Lactococcus cremoris, Lactococcus
diacetylactis, Enterococcus faecium, Enterococcus faecalis,
Saccharomyces cerevisiae, Saccharomyces boulardii,
Schizosaccharomyces pombe, Kluyveromyces lactis, Yarrowia
lypolitica or mixtures thereof, preferably selected from the group
consisting of Lactobacillus johnsonii (NCC533; CNCM 1-1225),
Bifidobacterium longum (NCC490; CNCM 1-2170), Bifidobacterium
longum (NCC2705; CNCM 1-2618), Bifidobacterium longum (NCC3001;
ATCC BAA-999), Bifidobacterium lactis (NCC2818; CNCM 1-3446),
Bifidobacterium breve (strain A), Lactobacillus paracasei (NCC2461;
CNCM 1-2116), Lactobacillus rhamnosus GG (ATCC53103), Lactobacillus
rhamnosus LPR (NCC4007; CGMCC 1.3724), Lactobacillus reuteri (ATCC
55730), Lactobacillus reuteri (DSM 17938), Enterococcus faecium SF
68 (NCIMB10415), Saccharomices boulardii, and mixtures
thereof.)
[0033] The selected probiotic bacterial strain may be cultured
according to any suitable method known in the art and prepared for
addition to the medicament or nutritional composition of the
invention by freeze-drying or spray-drying for example.
Alternatively, bacterial strains can be bought from specialist
suppliers such as Christian Hansen and Morinaga already prepared in
a suitable form for addition to nutritional compositions such as
infant formula.
[0034] A suitable daily dose of the probiotic bacteria is from 10e3
to 10e12 colony forming units (cfu), more preferably from 10e7 to
10e11 cfu.
[0035] The invention is particularly suitable for induce a more
mature sleep pattern in infants and thus improve their sleep
quality and reduce the episodes of wakefulness. In one embodiment
the invention relates for educing sleep disturbance and/or
improving sleep patterns in infants or young animals.
[0036] If this age group is to be addressed, the therapeutic
nutritional composition is preferably an infant formula or a
follow-up formula or the corresponding product for pets or
animals.
[0037] In one embodiment the improvement of sleep quality or
pattern is characterized, comprised or is limited to the reduction
of the number of episodes of wake states and/or the reduction of
sleep fragmentation and/or the increase of the duration of wake
states (indicator of better, less fragmented sleep/awake
pattern).
[0038] In one embodiment the improvement of sleep quality is
characterized by longer nights without being unwillingly awake and
by a more peaceful sleep.
[0039] In one embodiment the improvement of sleep quality is
characterized by better ability to fall asleep.
[0040] In one embodiment the sleep quality is improved in subject
suffering from disturbed sleep pattern, such as fragmented sleep,
nightmares or insomnia.
[0041] The general composition of an infant formula for use
according to the present invention will now be described by way of
example. The infant formula may contain a protein source in an
amount of not more than 4.0, 3.0 or 2.0 g/100 kcal, preferably 1.8
to 2.0 g/100 kcal. 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 although it is preferred that over
50% by weight of the protein source is whey. In one embodiment the
protein content is between 30% and 80% whey proteins. 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 whatever proportions are desired.
[0042] The proteins may be intact or hydrolysed or a mixture of
intact and hydrolysed proteins. It may be desirable to supply
partially hydrolysed proteins (degree of hydrolysis between 2 and
20%), for example for infants believed to be at risk of developing
cows' 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, a whey protein hydrolysate 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.
[0043] The infant formula may contain a carbohydrate source. Any
carbohydrate source conventionally found in infant formulae such as
lactose, saccharose, maltodextrin, starch and mixtures thereof may
be used although the preferred source of carbohydrates is lactose.
Preferably the carbohydrate sources contribute between 35% and 65%
of the total energy of the formula. In one preferred embodiment of
the invention the carbohydrates comprise rice carbohydrates. In one
embodiment at least 5% at least 10%, at least 25% or at least 50%,
at least 70%, at least 90%, or about 100% of the carbohydrates
(w/w) are rice carbohydrates. It has been shown, in the context of
the present invention, that a minimal proportion of rice
carbohydrates (at least 10% w/w of the total carbohydrates) can
bring a substantial benefit in the sleep pattern. The higher the
content in rice carbohydrates, the higher the improvement may be.
The effect can be hypothesized to being both related to the
presence of starch (in the rice carbohydrates), to the particular
nature of the rice carbohydrates, and/or to the additional
compounds (in addition to starch) comprised in the rice
carbohydrates. Such nutritional composition of the invention
comprising rice carbohydrates can be of particular use in the
context of infant formula, follow-up formula or food intended for
children, young children or infants and especially for those having
disturbances of sleep pattern (for example due to colics) and more
particularly for infants between 0 and 12 months.
[0044] The infant formula may contain a source of lipids. The lipid
source may be any lipid or fat which is suitable for use in infant
formulas. Preferred fat sources include palm olein, high oleic
sunflower oil and high oleic safflower oil. The essential fatty
acids linoleic and .alpha.-linolenic acid may also be added as may
small amounts of oils containing high quantities of preformed
arachidonic acid and docosahexaenoic acid such as fish oils or
microbial oils. In total, the fat content is preferably such as to
contribute between 30 to 55% of the total energy of the formula.
The fat source preferably has 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.
[0045] An infant formula according to the invention preferably
further contains at least one prebiotic in an amount of 0.3 to 10%.
A prebiotic is a non-digestible food ingredient that beneficially
affects the host by selectively stimulating the growth and/or
activity of one or a limited number of bacteria in the colon, and
thus improves host health. Such ingredients are non-digestible in
the sense that they are not broken down and absorbed in the stomach
or small intestine and thus pass intact to the colon where they are
selectively fermented by the beneficial bacteria. Examples of
prebiotics include certain oligosaccharides, such as
fructooligosaccharides (FOS), cow milk oligosaccharides (CMOS) and
galactooligosaccharides (GOS). A combination of prebiotics may be
used such as 90% GOS with 10% short chain fructo-oligosaccharides
such as the product sold under the trade mark Raftilose.RTM. or 10%
inulin such as the product sold under the trade mark
Raftiline.RTM.. Other examples of prebiotics that can be used in
the context of the present invention include the group of
oligosaccharides obtained from milk or other sources, optionally
containing sialic acid, fructose, fucose, galactose or mannose;
Preferred prebiotics are sialo-oligosaccharides (SOS),
fructo-oligosaccharides (FOS), galacto-oligosaccharides (GOS),
isomalto-oligosaccharides (IMO), xylo-oligosaccharides (XOS),
arabino-xylo oligosaccharides (AXOS), mannan oligosaccharides
(MOS), oligosaccharides of soy, glycosylsucrose (GS), lactosucrose
(LS), sialyl-lactose (SL) Fucosyl-lactose (FL), Lacto-N-Neotetraose
(LNNT), lactulose (LA), palatinose-oligosaccharides (PAO),
malto-oligosaccharides, gums and/or hydrolysates thereof, pectins,
starches, and/or hydrolysates thereof.
[0046] The infant formula 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
infant formula include vitamin A, vitamin B 1, 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,
chloride, 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 infant population.
[0047] If necessary, the infant formula may contain emulsifiers and
stabilisers such as soy lecithin, citric acid esters of mono- and
di-glycerides, and the like.
[0048] The infant formula may optionally contain other substances
which may have a beneficial effect such as fibres, lactoferrin,
nucleotides, nucleosides, and the like.
[0049] Finally, the formula will contain a probiotic bacterial
strain 10e3 to 10e12 cfu/g infant formula, more preferably 10e6 to
10e9 cfu/g formula.
[0050] The infant formula described above may be prepared in any
suitable manner. For example, they may be prepared by blending
together the protein, 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 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 about 50.degree. C. to about 80.degree. C. to
aid dispersal of the ingredients. Commercially available liquefiers
may be used to form the liquid mixture. The liquid mixture is then
homogenised; for example in two stages.
[0051] The liquid mixture may then be thermally treated to reduce
bacterial loads, by rapidly heating the liquid mixture to a
temperature in the range of about 80.degree. C. to about
150.degree. C. for about 5 seconds to about 5 minutes, for example.
This may be carried out by steam injection, autoclave or by heat
exchanger; for example a plate heat exchanger.
[0052] Then, the liquid mixture may be cooled to about 60.degree.
C. to about 85.degree. C.; for example by flash cooling. The liquid
mixture may then be again homogenised; for example in two stages at
about 10 MPa to about 30 MPa in the first stage and about 2 MPa to
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.
[0053] The homogenised mixture is transferred to a suitable drying
apparatus such as a spray drier or freeze drier and converted to
powder. The powder should have a moisture content of less than
about 5% by weight. The probiotic bacterial strain may be added at
this stage by dry-mixing.
[0054] In another embodiment, the composition may be a supplement
including the probiotic bacterial strain in an amount sufficient to
achieve the desired effect in an individual. This form of
administration is more suited to children although the probiotic
may be administered to infants in the form of drops of oil in which
the probiotic bacteria are suspended. An example of such a product
is BioGaia Probiotic drops containing L. reuteri DSM 17938 sold by
BioGaia AB, Sweden.
[0055] Preferably the daily dose of the probiotic is from 10e3 to
10e12 cfu. The amount of probiotic to be included in the supplement
will be selected accordingly depending upon how the supplement is
to be administered. For example, if the supplement is to be
administered twice a day, each supplement may contain 5.times.10e2
to 5.times.10e11 cfu of probiotic. The supplement may be in the
form of tablets, capsules, pastilles, suppositories, gums 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,
ligninsulfonate, talc, sugars, starch, gum arabic, vegetable oils,
polyalkylene glycols, flavouring agents, preservatives,
stabilizers, emulsifying agents, buffers, lubricants, colorants,
wetting agents, fillers, and the like.
[0056] Further, the supplement may contain an organic or inorganic
carrier material suitable for oral or enteral administration as
well as vitamins, minerals trace elements and other micronutrients
in accordance with the recommendations of Government bodies such as
the USRDA.
[0057] In one embodiment the invention relates to the reduction of
sleep disturbances and/or improving sleep patterns in humans in
adults, older children (in particular children between 3 and 12),
adolescents or at any age.
[0058] In another embodiment the invention relates to deliver the
described benefits by the use of probiotics to pets and other
animals, such as cats, dogs or horses
[0059] The invention will now be further illustrated by reference
to the following examples:--
Example 1
[0060] An example of the composition of an infant formula for use
according to the present invention is given below. This composition
is given by way of illustration only. The proteins of the below
composition are from whey and casein (for example 70% whey and 30%
casein). In an alternative, the proteins are from whey only.
TABLE-US-00001 Nutrient 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
Prebiotic (100% GOS) (g) 0.64 4.3 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 Lactobacillus
reuteri DSM 2.10.sup.7 cfu/g of powder 17938
Example 2
[0061] An example of the composition of a follow up infant formula
for use according to the present invention is given below. This
composition is given by way of illustration only. The proteins of
the below composition are from whey and casein. In an alternative,
the proteins are from whey only.
TABLE-US-00002 Follow up infant formula For infants 6 to 12 months
Nutrient per 100 kcal per litre Energy (kcal) 100 630 Protein (g)
1.8 11.3 Fat (g) 5.0 31.5 Linoleic acid (g) 0.75 4.7
.alpha.-Linolenic acid (mg) 95 600 Lactose (g) 11.9 75 Prebiotic
(100% GOS) (g) 0.63 4.0 Minerals (g) 0.37 2.3 Na (mg) 25 158 K (mg)
80 504 Cl (mg) 65 410 Ca (mg) 60 378 P (mg) 33 208 Mg (mg) 7 44 Mn
(.mu.g) 5 32 Se (.mu.g) 3 19 Vitamin A (.mu.g RE) 90 570 Vitamin D
(.mu.g) 1.5 9.5 Vitamin E (mg TE) 0.8 5.0 Vitamin K1 (.mu.g) 8 50
Vitamin C (mg) 15 95 Vitamin B1 (mg) 0.1 0.6 Vitamin B2 (mg) 0.1
0.6 Niacin (mg) 0.5 3.2 Vitamin B6 (mg) 0.06 0.4 Folic acid (.mu.g)
15 95 Pantothenic acid (mg) 0.8 5.0 Vitamin B12 (.mu.g) 0.2 1.3
Biotin (.mu.g) 2.0 12.6 Choline (mg) 15 95 Fe (mg) 1.0 6.3 I
(.mu.g) 15 95 Cu (mg) 0.06 0.4 Zn (mg) 0.9 5.7 BB536 (=ATCC
BAA-999, deposited 2.10.sup.6 cfu/g of powder by Morinaga, (sourced
from Morinaga Milk Industry, Co., Ltd, Tokyo, Japan) AND/OR AND/OR
Lactobacillus reuteri DSM 17938 10.sup.7 cfu/g of powder (sourced
from Biogaia - BioGaia AB, Sweden)
Example 3
[0062] An example of the composition of a follow up infant formula
for use according to the present invention is given below. This
composition is given by way of illustration only. The proteins of
the below composition are from whey and casein in a ratio of 50/50.
In an alternative, the proteins are from whey only or 70% (w/w)
from whey. In the below example 16% (w/w) of the carbohydrates are
rice carbohydrates (in a similar alternative example 25% of the
carbohydrates are rice carbohydrates). Prebiotics can be added
(e.g. GOS, 0.5 g/100 kcal) to the formulation.
TABLE-US-00003 Follow up infant formula For infants 6 to 12 months
Nutrient per 100 kcal per litre Energy (kcal) 100 670 Protein (g)
2.2 14.6 Fat (g) 3.7 31.6 Linoleic acid (g) 0.76 5.1
.alpha.-Linolenic acid (mg) 88 590 Lactose (g) 7.44 81.2
Maltodextrine (g) 2.1 14.2 Starch (g) 2.59 17.3 Prebiotic (100%
GOS) (g) 0.63 4.0 Minerals (g) 0.58 3.9 Na (mg) 39 158 K (mg) 113
760 Cl (mg) 73 490 Ca (mg) 105 700 P (mg) 66 440 Mg (mg) 11.4 76
Vitamin A (.mu.g RE) 90 570 Vitamin D (.mu.g) 1.5 9.5 Vitamin E (mg
TE) 0.8 5.0 Vitamin K1 (.mu.g) 8 50 Vitamin C (mg) 15 95 Vitamin B1
(mg) 0.1 0.6 Vitamin B2 (mg) 0.1 0.6 Niacin (mg) 0.5 3.2 Vitamin B6
(mg) 0.06 0.4 Folic acid (.mu.g) 15 95 Pantothenic acid (mg) 0.8
5.0 Vitamin B12 (.mu.g) 0.2 1.3 Biotin (.mu.g) 2.0 12.6 Choline
(mg) 15 95 Fe (mg) 1.0 6.3 I (.mu.g) 15 95 Cu (mg) 0.06 0.4 Zn (mg)
0.9 5.7 Lactobacillus reuteri DSM 17938 10.sup.7 cfu/g of powder
(sourced from Biogaia - BioGaia AB, Sweden) AND/OR AND/OR
Lactobacillus rhamnosus CGMCC 10.sup.6 cfu/g of powder 1.3724
AND/OR AND/OR BB536 (=ATCC BAA-999, deposited 10.sup.6 cfu/g of
powder by Morinaga, (sourced from Morinaga Milk Industry, Co., Ltd,
Tokyo, Japan)
Example 4
Effect of Probiotics on Sleep Quality
[0063] Stress administered to pregnant rats leads to sleep quality
alterations in the progeny (i.e. prenatal stress or PRS animals)
similar to those experienced by infants and children with perturbed
sleep patterns and by adults suffering from poor sleep quality and
insomnia. These alterations are characterized by a lighter sleep
and increased wake up episodes (i.e. increased amounts of REM
sleep, decreased amounts of NREM, and increased sleep fragmentation
(Dugovic, 1999)). This model has been used to test the efficacy of
probiotic administration on sleep quality.
[0064] PRS (i.e. progeny from dams submitted to restrain stress
during pregnancy) and control (i.e. progeny from undisturbed dams)
rats were implanted under deep anaesthesia with chronic electrodes
for polygraphic recordings of frontoparietal electroencephalogram
(EEG), electrooculogram (EOG), and nuchal electromyogram (EMG). All
electrodes were attached to a microconnector and fixed to the skull
with dental cement. EEG, EOG, and EMG activities were recorded on a
polygraph (EEG-4414 A/K; Nihon-Khoden) with an output connected to
a computer for on-line spectral analysis of the EEG. After surgery
for electrode implantation, the rats were individually housed in
Plexiglas cages (30 cm diameter, 40 cm high), and left undisturbed
for 2 weeks. The animals were then habituated to the sleep
recording procedure for the next 14 d. They received placebo or one
of two probiotics by gavage during this time. At the end of the
habituation period, sleep was recorded for a period of 24 hr,
beginning at the onset of the light phase. Polygraphic recordings
were visually scored by 30 sec epochs. Those epochs are classified
as being wake, NREM sleep, or REM sleep. The amount of time spent
in the three vigilance states and the number and duration of
episodes for each state were recorded. The following groups were
studied:
[0065] PRSr: PRS animals that received 1 ml/day of oil drops
containing 10.sup.9 cfu Lactobacillus reuteri DSM 17938 (BioGaia
Probiotic drops, BioGaia AB, Sweden).
[0066] PRSb: PRS animals that received 1 ml/day of saline solution
containing 10.sup.10 cfu Bifidobacterium longum NCC3001 (ATCC
BAA-999, initially provided by Morinaga Milk Industry Co. Ltd)
dissolved in saline
[0067] PRSp: PRS animals that received 1 ml/day of drops containing
the same oil carrier as the L. reuteri product but without the
probiotic.
[0068] Control: control animals that received 1 ml/day of drops
containing the same oil carrier as the L. reuteri product but
without the probiotic.
[0069] Results are shown in FIGS. 1 and 2. As expected, compared to
the Control group, the amount of time spent in quiet sleep (NREM,
FIG. 1B) was reduced and the time spent in active sleep (REM, FIG.
1C) was increased in PRSp animals, whereas the duration of the wake
state (FIG. 1A) was similar in both groups. The administration of
both probiotics normalized the duration of NREM and REM states
without affecting the duration of the wake state. Consistently, the
number of episodes over 24 hours of wake (FIG. 2A), NREM (FIG. 2B)
and REM (FIG. 2C) states was higher in PRSp than in Control
animals, which indicates increased sleep fragmentation and higher
number of wake up episodes in the PRSp group. Both probiotics
reduced the number of wake up episodes and sleep fragmentation to
Control levels.
[0070] In conclusion, the data indicate that probiotic
administration normalizes the sleep patterns and improves sleep
quality in the animal model. Better sleep quality likely resulted
in improved alertness during the wake state in the probiotic
groups, as suggested by the lower number and the increased duration
(data not shown) of the wake episodes in the probiotic groups
compared to the placebo PRS group.
* * * * *