Note: Descriptions are shown in the official language in which they were submitted.
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Nutritional composition for use to treat or prevent pregnancy related
conditions
Technical field of the invention
The present invention relates to a maternal compositions comprising, with
respect to the total fatty
acid concentration, more than 50wt% of long chain fatty acids and 50wt% or
less of medium chain
fatty acids, for use to treat or prevent acid reflux, nausea or vomiting,
gestational diabetes mellitus,
and/or a condition associated with any of the foregoing in a pregnant subject
and/or its offspring.
Background of the invention
Nausea and vomiting, acid reflux, and indigestion are all common
gastrointestinal conditions
affecting pregnant mammals. The seriousness of these conditions can range from
the somewhat
benign and merely uncomfortable, to the severe and in rare cases life-
threatening. Depending on the
severity, the aforementioned conditions may not only be a threat to the health
and wellbeing of the
pregnant mammal, they may even pose a threat to the healthy development of her
offspring.
During pregnancy a variety of physiological changes occur that are thought to
contribute to the
pathophysiology of the aforementioned conditions. However, changes leading to
disturbances in
gastric motility, and more particularly prolonged gastric emptying rates, are
thought to be of
particular relevance for these conditions (Prolonged gastric emptying rates
increase the risk of GER
(0mOr 0, Erd&gan M, Ozkilic H, Yilmaz C, Mol Imaging Radionucl Ther. 2014),
nausea and vomiting
(Stein 131-, Everhart KK, Lacy BE. Curr Treat Options Gastroenterol. 2014)). A
fast emptying of the
gastric contents after a meal can prevent or alleviate both acid reflux and
nausea/vomiting.
Accordingly, compositions that can improve gastric motility, and in particular
accelerate gastric
emptying rates, are of great interest to the maternal health and wellness
industry.
There are a variety of pharmacological compositions that can accelerate
gastric emptying rates and
thereby may be used to treat or prevent the aforementioned conditions.
However, because of the
fear of effecting the health of their offspring, mothers and their physicians
are generally against the
use of pharmacological therapies during pregnancy.
Accordingly, there is a need for non-pharmaceutical compositions that can
accelerate gastric
emptying rates and which may therefore be used to treat and/or prevent nausea
and vomiting, acid
reflux, and indigestion in a pregnant subject.
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The inventors have found that a maternal composition comprising, with respect
to the total fatty acid
concentration, more than 50 wt% of long chain fatty acids and 50 wt% or less
of medium chain fatty
acids, is emptied rapidly from the stomach and may be used to accelerate
gastric emptying. This is
particularly in comparison to a composition comprising more than 50 wt% of
medium chain fatty
acids and 50 wt% or less of long chain fatty acids. This is surprising given
that the prior art teaches
that long chain fatty acids slow gastric emptying whereas medium chain fatty
acids have no effect on
gastric emptying (Kossena GA, Charman WN, Wilson CG, O'Mahony B, Lindsay B,
Hempenstall JM,
Davison CL, Crowley Pi, Porter C. J.Pharm Res. 2007 Nov;24(11):2084-96). The
inventors have also
found that a composition in accordance with the invention increases expression
of fibroblast growth
factor 19 (hereinafter FGF19) in subjects.
Summary of the invention
The invention is set out in the claims. A maternal composition comprising,
with respect to the total
fatty acid concentration, more than 50 wt% of long chain fatty acids and 50%
or less of medium chain
fatty acids, is emptied rapidly from the stomach and may be used to accelerate
gastric emptying and
to increase the expression of FGF19 in a subject, and accordingly, may be used
to treat and/or
prevent nausea or vomiting, acid reflux, indigestion and gestational diabetes
in a pregnant subject
e.g. a pregnant cat, dog or human.
A maternal composition in accordance with the invention comprising, with
respect to the total fatty
acid concentration, less than 5 wt% of medium chain fatty acids, may be
particularly effective. As
might a maternal composition in accordance with the invention comprising long
chain fatty acids
selected from the groups consisting of; myristic acid, palmitic acid,
palmitoleic acid, stearic acid, oleic
acid, linoleic acid, alpha-linoleic acid, arachidic acid, eicosenoic acid, and
combinations thereof.
Because of the increased absorption of fatty acids when they are in the form
of triglycerides, it may
be preferable that each type of long chain and/or medium chain fatty acid
comprised in a maternal
composition of the invention is mainly e.g. at least 98%, 99%, or 99.5%, in
the form of triglycerides.
Palmitic acid, in particular in the sn 1 or 3 triglyceride form, is known to
cause and/or exacerbate
constipation. Accordingly, a maternal composition of the invention having a
low palmitic acid
concentration, in particular in the sn 1 or 3 triglyceride form, of no more
than 14%, more particularly
no more than 7%, or those that are free from palmitic acid, in particular in
the sn 1 or 3 triglyceride
form, may also be used to treat or prevent constipation.
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A maternal composition in accordance with the invention may be particularly
effective at treating or
preventing nausea or vomiting, acid reflux, indigestion, gestational diabetes,
and/or constipation in a
pregnant subject if used in conjunction or combination with ingredients known
to be useful in the
treatment or prevention of these conditions e.g. Vitamin B6 ginger or extracts
thereof.
A maternal composition in accordance with the invention may be administered
enterally to a
pregnant subject before and/or during pregnancy and/or during lactation,
administration may be at
any time of the day or night and may be before eating.
A maternal composition in accordance with the invention may be administered in
the form of a fat
blend e.g. an encapsulated fat blend or alternatively it may be administered
in the form of a
powdered nutritional composition to be reconstituted in for example milk,
juice or water, a food
product, a drink, a nutritional supplement such as a powdered nutritional
supplement to be sprinkled
on food or mixed in an aqueous medium for example milk, juice or water, or a
nutraceutical.
As stated herein, nausea or vomiting, acid reflux, indigestion and gestational
diabetes are associated
with a variety of conditions affecting a pregnant subject and/or their
offspring e.g. dehydration,
electrolyte imbalances, nutritional deficiencies, likelihood of having a small
for gestational age baby,
venous thromboembolism, pulmonary embolism and preeclampsia macrosomia, birth
injury to the
mother or infant, shoulder dystocia, premature delivery, and caesarian
delivery (hereinafter C-
section) ,developing type ll diabetes immediately after pregnancy and later in
life for the mother,
infants developing an impaired glucose tolerance and/or suffering from excess
weight/adiposity and
associated metabolic disorders e.g. type II diabetes and obesity, depression,
bipolar disorder, and
anxiety immediately after birth or later in life. Accordingly, by treating or
preventing nausea or
vomiting, acid reflux, indigestion, constipation, and gestational diabetes in
said pregnant subjects,
the composition of the invention may also be used to treat or prevent these
associated conditions in
said pregnant subject or their offspring.
Brief description of the figures
Figure 1 shows an overview of the study described in Example 1.
Figure 2 shows the results for measurements of gastric emptying. M= Meal (see
Table 1 and Tables 2
to 6 for composition); * indicates P<0.0001; ** indicates P=0.0003. half time
(t50/min)
Figure 3 shows the results for measurements of FGF 19 in blood samples taken
during experiment
described in Example 1. M= Meal (see Table 1 and Tables 2 to 6 for
composition); ** indicates P=
0.001. Area over baseline (A0B), (picogram/mL min).
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Figure 4 shows the results for measurement of bile acids in blood samples
taken during experiment
described in Example 1. Area over baseline (A0B), (micromole/L min). *
indicates P=0.9; ** indicates
P= 0.3; *** indicates P=0.0003; **** indicated P=0.0001.
The present invention will now be described in more detail.
Detailed Description
As stated herein above, the inventors have found that a maternal composition
comprising, with
respect to the total fatty acid concentration, more than 50% of long chain
fatty acids and 50% or less
of medium chain fatty acids, is emptied rapidly from the stomach and may be
used to accelerate the
gastric emptying rate.
Since, decreased gastric motility, and in particular prolonged gastric
emptying, is thought to be a
contributing factor for a variety of conditions affecting pregnant subjects
i.e. acid reflux, nausea or
vomiting, and indigestion. It follows that a composition that is rapidly
emptied from the stomach and
that may therefore stimulate and/or accelerate gastric emptying, may be used
in the treatment or
prevention of one or more of these aforementioned conditions and a condition
associated therewith
in a pregnant subject and/or its offspring.
A composition is considered to be rapidly emptied from the stomach if 50% of
the consumed
composition is emptied within 350 to 550mins, more particularly 400 to
500mins.
The time when half of a composition is emptied from the stomach is referred to
as T50meas.
The gastric emptying time of a composition can be measured by methods well
known to the skilled
person. One such method is laid out herein in example 1.
A further advantage of maternal compositions in accordance with the invention
is that they were
also found to increase the secretion of bile acid and the expression of FGF-
19.
FGF-19 is an intestinal hormone that can exert beneficial effects on glucose
metabolism by increasing
insulin sensitivity and inducing glycogen synthesis. Circulating levels of FGF-
19 have been found to be
reduced in pregnant subjects suffering from Gestational Diabetes Mellitus
(hereinafter GDM) and to
be inversely correlated with insulin resistance in this population (Wang,
2013). Increasing circulating
levels of FGF19 has been proven a useful mean to prevent and to treat insulin
intolerance and type 2
diabetes (Shaap et al, 2012) A composition that increases circulating FGF-19
levels may therefore be
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used to treat or prevent GDM or a condition associated therewith in a pregnant
subject and/or its
offspring.
Accordingly, in a first aspect of the present invention there is provided a
maternal composition
comprising, with respect to the total fatty acid concentration, 50 wt% or more
of long chain fatty
acids and less than 50 wt% of medium chain fatty acids, for use to treat or
prevent acid reflux,
nausea or vomiting, indigestion, and/or gestational diabetes mellitus, and/or
a condition associated
with any of the foregoing in a pregnant subject and/or its offspring.
The term "subject" as used herein refers to a mammal and more particularly a
cat, a dog or a human.
The term "treat" as used herein also encompasses amelioration and/or
alleviation of a condition e.g.
the symptoms of a condition.
The term "nausea and vomiting" as used refers to any nausea and vomiting
experienced in
pregnancy. It includes Hyperemesis grayidarum (HG). HG is the most severe form
of nausea and
vomiting in pregnancy and it effects between 0.5- 2% of of pregnant women. HG
may be defined as
severe and persistent nausea and vomiting, and may lead to weight loss greater
than 5% of pre-
pregnancy weight, dehydration, electrolyte imbalances, and nutritional
deficiencies, typically
requiring hospitalisation.
Depending on the severity, nausea or vomiting may lead to a reduction in
maternal weight gain
throughout pregnancy, which may result in suboptimal fetal outcomes. Also,
women who suffer from
extreme nausea and vomiting (such as HG) can be at higher risk of having small
for gestational age
babies and premature births. Nausea or vomiting, in particular HG, is also
known to be a risk factor
for venous thromboembolism, pulmonary embolism and preeclampsia. Furthermore,
in utero
exposure to nausea or vomiting, in particular HG, has been associated with an
increased risk in the
offspring for depression, bipolar disorder, and anxiety in adulthood.
The term "GDM" as used herein refers to any degree of glucose intolerance with
onset or first
recognition during pregnancy.
Whether or not a mammal has an impaired glucose tolerance may be determined by
measuring its
fasting glucose plasma concentration, or by carrying out an oral glucose
tolerance test (OGTT). The
skilled person will be familiar with these tests and the criteria for
diagnosing an impaired glucose
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tolerance and hence GDM. According to the criteria set out in the National
Academy of clinical
biochemistry (NACB) guidelines, published by the American Association for
clinical chemistry (AACC),
a pregnant human subject is considered as having an impaired glucose tolerance
if their fasting
plasma glucose concentration equates to 5.1mmol/L or more, or if their blood
glucose concentration
equates to less than 10 mmol/L 1hour after a 75gram glucose drink, or less
than 8.5 mmol/L 2 hours
after a 75gram glucose drink.
GDM may increase the risk of a number of maternal-fetal conditions, including
macrosomia, birth
injury to the mother or infant, shoulder dystocia, premature delivery, and
caesarian delivery
(hereinafter C-section). Mothers suffering from GDM also have an increased
risk of developing type ll
diabetes immediately after pregnancy and later in life, and the offspring of
mothers suffering from
GDM have an increased risk of developing an impaired glucose tolerance and/or
suffering from
excess weight/adiposity and associated metabolic disorders e.g. type II
diabetes and obesity later in
life.
The term "acid reflux" as used refers to a condition wherein acid comes up
from the stomach into
the esophagus, it is also referred to a Gastroesophageal reflux (GER) and in
severe cases to a
gastroesophageal reflux disease (GERD).
The term "indigestion" as used refers to a condition wherein digestion is
impaired in a subject. It is a
medical condition characterized by chronic or recurrent pain in the upper
abdomen, upper
abdominal fullness and feeling full earlier than expected when eating. It can
be accompanied by
bloating, belching, nausea.
The term "Medium chain fatty acids" as used herein refers to n-carboxylic
acids of saturated linear
aliphatic chains comprising 6-12 carbon atoms, and derivatives thereof. Any
reference to a specific
medium chain fatty acid is also a reference to any derivative thereof.
The term "Long chain fatty acids" as used herein refers to n-carboxylic acids
of saturated linear
aliphatic chains comprised of 13 or more, more particularly 13 to 22, carbon
atoms, and derivatives
thereof. Any reference to a specific long chain fatty acid is also a reference
to any derivative thereof.
Non limiting examples of derivatives of medium and/or long chain fatty acids
include phospholipids,
triglycerides, diglycerides, and monoglycerides.
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The maternal composition of the invention may comprise long chain fatty acid
in any concentration
in the range of 50 to 100 wt% with respect to the total fatty acid content
e.g.50 -60 wt%, 50-70 wt%,
60-80 wt%, 60-90 wt%, 95-100 wt%.
The maternal composition of the invention may comprise medium chain fatty
acids in any
concentration less than 50 wt%, with respect to the total fatty acids, e.g. in
the range 0-49.99 wt%,
10-40 wt%, 5-30 wt%, 12-45 wt%.
In an embodiment the composition of the invention is free or substantially
free from medium chain
fatty acids. By substantially free is meant that the composition comprises up
to 5%, up to 2% or up to
1% of medium chain fatty acids.
Any long chain fatty acid that is suitable for ingestion by the pregnant
subject may be used in the
composition of the invention.
Non limiting examples of suitable long chain fatty acids include; myristic
acid, palmitic acid,
palmitoleic acid, stearic acid, oleic acid, linoleic acid, alpha-linoleic
acid, arachidic acid, eicosenoic
acid, and combinations thereof.
Any medium chain fatty acid that is suitable for ingestion by the pregnant
subject may be used in the
composition of the invention.
Non limiting examples of suitable medium chain fatty acids include; caproic
acid, caprylic acid,
decanoic acid, dodecanoic acid, and combinations thereof.
In a particular embodiment of the invention the long and/or medium chain fatty
acids comprised in
the maternal composition of the invention are mainly in the form of
triglycerides.
By mainly is meant at least 98 wt%, more particularly at least 99.5wt%, even
more particularly more
than 99.5 wt%.
The long and medium chain fatty acids comprised within the maternal
compositions of the invention
may be saturated, unsaturated or polyunsaturated.
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Examples of unsaturated fatty acids include oleic acid, as well as
polyunsaturated fatty acids (PUFAS),
for example linoleic acid, alpha-linoleic, arachidonic acid, docohexaenoic
acid, and/or eicosenoic acid
Examples of polyunsaturated fatty acids include alpha-linolenic acid (ALA)
18:3, stearidonic acid
(SDA) 18:4, eicosatrienoic acid (ETE) 20:3, n-3 eicosatetraenoic acid (ETA)
20:4, eicosapentaenoic acid
(EPA) 20:5, n-3 docosapentaenoic acid (DPA) 22:5, docosahexaenoic acid (DHA)
22:6, linoleic acid
18:2, gamma-linolenic acid (GLA) 18:3, n-6 eicosadienoic acid 20:2, dihomo-
gamma-linolenic acid
(DGLA) 20:3, arachidonic acid (AA or ARA) 20:4, n-6 docosadienoic acid 22:2,
and docosapentaenoic
acid 22:5.
In a particular embodiment the composition of the invention comprises at least
one unsaturated
fatty acid, mainly in the form of triglycerides, in an amount of at least 15
wt%, at least 20 wt%, at
least 35 wt%, at least 38 wt%, 40 wt % to 90 wt%, 50 wt% to 80 wt%, 50 wt% to
75 wt%, 50 wt% to
70 wt %, 55 wt% to 70 wt %, with respect to the total fatty acid
concentration.
In another embodiment of the invention, the maternal composition of the
invention comprises at
least one polyunsaturated fatty acid (PUFA), the PUFA(s) being present in an
amount generally of at
least 8 wt%, or 10 wt%, with respect to the total fatty acid concentration.
The presence of PUFAs is especially advantageous for several key health
benefits such as cognitive
benefits, visual and cognitive development, anti-inflammatory properties, as
it is known in the art.
It may particularly beneficial if the maternal composition of the invention
comprise PUFAs selected
from the group consisting of alpha-linolenic acid, and/or linoleic acid, which
are essential fatty acids,
and /or docosahexanoic acid (DHA, C22:6) and/or arachidonic acid (ARA, C20:4)
which are known for
their health benefits with respect to cognition for example.
Essential fatty acids are fatty acids that must be ingest because the body
requires them for good
health but cannot synthesise them.
In a particular embodiment the maternal composition of the invention comprise
linoleic and/or alpha
linoleic acid, in particular in a total combined concentration, with respect
to the total fatty acid
concentration, in the range of 10 to 15 wt%, 12 to 14 wt%, 12.5 to 13.9 wt%.
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In another embodiment of the present invention the maternal composition of the
invention
comprises palmitic acid, more particularly in the sn 1 or 3 triglyceride form,
in an amount in the
range of not more than 14 wt%, more particularly not more than 7 wt%, 6 wt%, 5
wt%, 4 wt%, 3 wt%,
2 wt%, with respect to the total fatty acid content.
Palmitic acid, in particular in the sn 1 or 3 triglyceride form, is released
as a free fatty acid during
digestion and can form soaps with calcium that are not digested. These are
excreted and make the
stool consistency harder. Thus, reducing the amounts of the palmitic acid, in
particular in the sn 1 or
3 triglyceride form, can help to prevent or alleviate constipation.
11%- 38% of pregnant women experience constipation. Constipation is described
as infrequent
bowel movements or difficult evacuation.
In another embodiment of the present invention the maternal composition is
free from palmitic acid,
in particular the sn 1 or 3 triglyceride form.
In further embodiments of the present invention the maternal composition
comprises, with respect
with the total fatty acid content, the following medium and/or long chain
fatty acids:
caprioic acid (hexanoic acid) in a concentration in the range of 0 to 1 wt%
e.g 0.05 to 0.5 wt%, 0.05 to
0.4 wt%, 0.06 to 0.4 wt%, or 0.07 to 0.3 wt%; and/or
caprylic acid (octanoic acid) in a concentration in the range of 0 to 10 wt%
e.g. 2 to 8 wt%, 1.55 to 2
wt%, 1.6 to 2 wt%, 1.65 to 2 wt%, 1.7 to 2 wt%; and/or
decanoic acid in a concentration in the range of 0 to 10 wt% e.g. 0 to 1.8
wt%, 0.1 to 1.8 wt%, 1 to
1.7wt%, 1 to 1.5wt% or 1.2 to 1.8 wt%; and/or
dodecanoic acid in a concentration in the range of 0 to 12.0 wt% e.g. 0 to 10
wt%, 0 to 8 wt%, 0 to 6
wt%, 0 to 4 wt%, 1 to 12 wt%, 2 to 12 wt%. 4 to 12 wt%, 6 to 12 wt%, 8 to 12
wt%, 10 to 12 wt%.
myristic acid in a concentration in the range of 0 to wt% e.g 0.05 to 0.5 wt%,
0.05 to 0.4 wt%, 0.06 to
0.4 wt%, or 0.07 to 0.3 wt%; and/or
palmitic acid in a concentration in the range of 0 to 5 wt% e.g. 2 to 4 wt%, 2
to 3.5 wt%, 2.3 to 3.4
wt% and/or
palmitoleic acid in a concentration in the range of 0 to 1 wt% e.g 0.05 to 2
wt%, 0.05 to 1.5 wt%, 0.05
to 0.12 wt%; and/or
stearic acid in a concentration in the range of 0 to 3 wt% e.g. 1 to 3 wt%, 1
to 2.5 wt%, 2.51 to 1.04
wt%; and/or
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oleic acid in a concentration in the range of 0 to 70 wt% e.g. 10 to 70 wt%,
10 to 60 wt%, 10 to 50
wt%; and/or
linoleic acid in a concentration in the range of 9 to 11 wt%, 10 to 10.5wt%;
and/or
alpha-linoleic acid in a concentration in the range of 2 to 5 wt%, 2 to
3.5wt%, 2.2 to 3.2 wt%; and/or
arachidic acid in a concentration in the range of 0.1 to 0.5 wt%, 0.1 to 0.5
wt%, 0.2 to 0.31wt%;
and/or
eicosenoic acid in a concentration in the range of 0.5 to 1 wt%, 0.5 to
0.6wt%, 0.51 to 0.57wt%;
and/or any combination thereof.
The maternal composition of the invention may be employed in any effective
dose that provides a
benefit with respect to the treatment or prevention of, GDM and a condition
associated therewith in
a pregnant subject and/or its offspring.
An effective dose may be any dose that improves, by any degree, acid reflux,
nausea or vomiting,
indigestion, constipation and/or gestational diabetes mellitus i.e. an
impaired glucose intolerance, in
a pregnant subject.
It is well within the purview of the skilled person to determine an effective
dose. Typically, an
effective dose will depend on the type, age, size and health status of the
subject, on the subject's
lifestyle, as well as on its genetic heritage.
A particularly useful dose may be a dose equating to 100mg to 500mg, 200 to
350mg, or 200mg to
300mg of the total fatty acids comprised in the maternal composition.
The term "dose" as used herein refers to a daily quantity of the maternal
composition that is
administered to a subject before pregnancy i.e. a subject intending to get
pregnant, and/or during
pregnancy i.e. to a pregnant subject, and/or during lactation.
The daily quantity or dose may be administered all at once or it may be spread
out over several
administrations throughout a day. The dose may be by administered by any known
method, in
particular enterally e.g. orally.
The dose may be administered at any time of the day or night. However,
depending on the condition
to be treated, it may be beneficial to administer the dose at a particular
time e.g. for nausea
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and/vomiting it may be beneficial to administer the dose in the morning or
anytime during the day
before eating, for acid reflux and indigestion it may be beneficial to
administer the dose in the
evening, before going to bed, or anytime during the day before eating, and for
GDM it may be
beneficial to administer the dose during the day before eating.
If a composition is administered before eating it may be administered 2 hours,
1 hour, 30mins,
20mins, 10mins or 5 mins before eating.
If a maternal composition of the invention is administered to a subject
desiring to get pregnant it
may for example be administered during at least 1, 2, 3 or 4 months preceding
the pregnancy or
desired pregnancy. If administered to a pregnant subject, it may be
administered throughout or
partially throughout the pregnancy e.g. for at least 4, at least 8, at least
12, at least 16, at least 20, at
least 24, at least 28, or at least 36 weeks depending on the gestational
period of the subject. If
administered during lactation it may be administered throughout or partially
throughout the
lactation period of said subject.
Since nausea or vomiting is more prevalent in the first and second trimester
of pregnancy,
administration may be particularly beneficial in the first and/or second
trimester of pregnancy to
treat and/or prevent this condition.
Since acid reflux and indigestion are more prevalent in second and third
trimester of pregnancy,
administration may be particularly beneficial in the second and third
trimester of pregnancy to treat
and/or prevent one or more of these conditions.
Since the risk of GDM increases in the second and third trimester of
pregnancy, administration may
be particularly beneficial in the second and third trimester of pregnancy to
treat and/or prevent this
condition.
The maternal composition of the invention may be a fat blend that consists
solely of fat. Alternatively
the maternal composition may comprise other ingredients commonly used in
maternal compositions
e.g. the composition may further comprises a protein source e.g. dried milk or
dried skimmed milk,
and a carbohydrate source e.g. sucrose and/or maltodextrin, possibly together
with lecithin, soya
lecithin and/or a bulking agent. The compositions of the invention may also
comprise probiotics,
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prebiotics and vitamins and minerals. For example, vitamins and minerals
recommended by a
governmental body, such as USRDA, for supplementation in pregnancy e.g.
calcium, magnesium,
phosphorus, iron, zinc, copper, iodine, selenium, vitamin A or retinol
activity equivalent (RAE) e.g.
beta carotene or a mix of carotenoids, Vitamin C, Vitamin B1, niacin, folic
acid, biotin, Vitamin E. Non
limiting examples of other possible ingredients include: other nutrients, for
instance, selected from
the group of lipids e.g. Short chain fatty acids , carbohydrates, and protein,
micronutrients (in
addition to those set out above), or pharmaceutically active agents;
conventional food additives such
as anti-oxidants, stabilizers, emulsifiers, acidulants, thickeners, buffers or
agents for pH adjustment,
chelating agents, colorants, excipients, flavor agents, osmotic agents,
pharmaceutically acceptable
carriers, preservatives, sugars, sweeteners, texturizers, emulsifiers, water
and any combination
thereof.
The maternal composition may also alternatively or additionally contain
glucose syrup, milk fat,
magnesium citrate, choline salts and esters, prebiotic fibers, and/or ascorbyl
palmitate. Flavor
compounds, such as cocoa powder or honey, for example, may be added to provide
taste variations.
It may be particularly beneficial if the maternal composition includes other
ingredients known to be
useful in the treatment of nausea or vomiting, acid reflux, indigestion and/or
GDM e.g. Vitamin B6
ginger or extracts thereof are known to be used to treat or prevent nausea and
vomiting.
The maternal compositions of the invention may be administered in any form
suitable for ingestion
by the subject e.g. it can be in the form of a powdered nutritional
composition, a food product, a
drink, a nutraceutical, a nutritional supplement e.g. a powdered nutritional
supplement e.g. to be
sprinkled on food or mixed in a medium e.g. water or juice, or milk.
Non limiting examples of food products include cereal-based products, yogurts
or other milk-derived
products and bars.
Nutritional supplements can for example be provided in the form of a pill, a
tablet or a powder
supplement that can for example be mixed in a medium e.g. water, milk or
juice, or sprinkled on
food.
Powdered nutritional supplements that can for example be sprinkled on food or
mixed in a medium
e.g. water, juice or milk, are currently well accepted by consumers.
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As stated hereinabove, nausea and vomiting and/or acid reflux and/or
indigestion and/or GDM are
associated with a variety of conditions that may affect the pregnant subject
and/or its offspring.
Nausea or vomiting, acid reflux, indigestion, and/or GDM is considered as
being associated with a
condition if it increases the risk of a subject having or developing that
condition during pregnancy,
during birth, after birth or later in the life of said pregnant subject or its
offspring.
As used herein later in life may refer to up to 1 year after birth, up to 5
years after birth, up to 10
years after birth or 20years and beyond after birth.
Non limiting example of conditions effecting the pregnant subject that are
associated with nausea
and vomiting include; dehydration, electrolyte imbalances, nutritional
deficiencies, venous
thromboembolism, pulmonary embolism and preeclampsia, premature delivery,
depression, bipolar
disorder, and anxiety.
Non limiting example of conditions effecting the offspring of pregnant
subjects that are associated
with nausea and vomiting include; infants being small for their gestation age
or suffering from
depression, bipolar disorder, and anxiety later in life.
Non limiting example of conditions effecting the pregnant subject that are
associated with GDM
include; macrosomia, birth injury, premature delivery, caesarian delivery
(hereinafter C-section),
developing type ll diabetes immediately after pregnancy and later in life.
Non limiting example of conditions effecting the offspring of pregnant
subjects that are associated
with GDM include; macrosomia, birth injury, shoulder dystocia, premature
delivery, developing an
impaired glucose tolerance and/or suffering from excess weight/adiposity and
associated metabolic
disorders e.g. type II diabetes and obesity later in life.
In another aspect of the invention there is provided a nutritional composition
in accordance with the
invention for use in the manufacture of a medicament for use in the treatment
or prevention of
nausea or vomiting, acid reflux, indigestion, and/or GDM and a condition
associated with any of the
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foregoing in a pregnant subject and/or its offspring, wherein said medicament
is administered to said
subject before and/or during pregnancy and/or during lactation
In another aspect there is provided a method of treating and or preventing
nausea or vomiting, acid
reflux, indigestion, and/or GDM and a condition associated with any of the
foregoing in a pregnant
subject and/or its offspring comprising administering a maternal composition
in accordance with the
invention before and/or during pregnancy and/or during lactation.
The present invention will now be described in further details by the way of
the following examples.
Examples
Example 1
A cross-over study was designed where each subject received all test meals.
Subjects were randomly
assigned to one of 10 possible randomized sequences of the 5 test products.
Each subject received
the 5 study products during 5 different visits, separated by at least 1-week
washout, and at most 4
weeks. Each visit spread over two days (D-1 and DO):
= Day -1 for getting standardized meals
= Day 0 for:
¨ Baseline plasma samples
¨ Study product intake
¨ Plasma samples ¨ Breath samples
The subjects were healthy males from 20 to 40 years old with a BMI of 19 to
24.9 kg m-2, and which
had a normal fasting glycemia.
Study description
The five study products contained the same amount of maltodextrins and whey
protein, but differed
in their fatty acid composition. All study products contain a third of each
subject's daily energy
requirement, as determined by the Harris Benedict equation multiplied by a
factor 1.5 to account for
physical activity.
1. Maltodextrin (43% TEI)+whey proteins (WP, 12% TEI)
2. Maltodextrin (43% TEI)+WP (12% TEI)+MUFA (39% TEI)+PUFA (6% TEI)
3. Maltodextrin (43% TEI)+WP (12% TEI)+MUFA (27% TEI)+MCT (12% TEI)+PUFA
(6%
TEI)
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4. Maltodextrin (43% TEO+ WP (12% TEI)+MUFA (12% TEI)+MCT (27% TEI)+PUFA
(6%
TEI)
5. Maltodextrin (43% TEI)+WP (12% TEI) + MCT(39% TEI)+PUFA (6% TEO.
(TEI= total energy intake; WP= whey proteins; MUFA= Monounstaturated fatty
acids;
PUFA=Polyunsaturated fatty acids; MCT=medium chain triglycerides) See also
Table 1 for
composition of meals.
100 mg of 13C-octanoate (Eurisotope, St Aubin, France) was added to each study
product to monitor
gastric emptying.
Table 1: Fatty acid profile of study products
Meals are per-subject isocaloric, except for M1 which is the fat-free
reference diet and has similar
carbohydrate and protein content to the other meals, but no lipid. All other
meals one third of each
subject's daily energy requirement, M2 and M3 are dominated by oleic acid, M4
and M5 by MCT.
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Table 1
Meal 2 Meal 3 Meal 4 Meal 5
Total Fatty acid methyl esters 90.24 91.53 85.21 87.30
(FAME) (g/100g fat)
Saturates (g/100g product) 0.90 2.50 6.4 8.10
Mono unsaturates (g/100g 8.60 7.40 2 1.30
product)
Poly unsaturates (g/100g product) 1.60 1.80 1.4 1.30
(g/100g fat)
C6:0, Hexanoic 0.00 0.00 0.00 0.00
C8:0, Octanoic 0.00 7.31 29.04 35.53
C10:0, Decanoic 0.00 5.57 22.34 27.07
C12:0, Dodecanoic 0.00 0.09 0.21 0.18
C14:0, Myristic 0.06 0.07 0.07 0.05
C16:0, Palmitic 3.61 3.34 2.33 2.11
C16:1 n-7, Palmitoleic 0.12 0.12 0.05 0.00
C18:0, Stearic 2.51 2.13 1.08 1.04
C18:1 n-9, Oleic 69.13 57.18 17.11 10.24
C18:2 n-6, Linoleic 10.49 10.67 10.15 9.40
C18:3 n-3, alpha-Linoleic 2.26 3.20 2 1.07
C20:0, Arachidic 0.31 0.31 0.14 0.09
C20:1 n-9, Eicosenoic 0.51 0.57 0.25 0.06
Total MCT 0.00 12.97 51.59 62.78
Total essential FA 12.75 13.87 12.15 10.47
Total LCFA 88.94 77.52 33.11 24.01
Table 2 Composition of Meal 1 (M1)
Lipid % of TEl Amount Amount
compositio per diet per 100g
n (% final oil (8) (m/m)
mix)
Meal 1
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maltodextrin (2--3 wt% water) 43 107,50 24,57
Whey protein 12 30,00 6,86
Water to add 300,00 68,57
Total without additives (kg) 437,50 100,00
TS final beverage (% m/m) 31%
Masking LG 0,19
Stevia 0,01
Strawberry aroma 0,08
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Table 3: Composition of Meal 2 (M2)
Lipid % of Amount per Amount per
composition TEl diet (g) 100g (m/m)
(% final oil
mix)
Meal 2
maltodextrin 43 107,50 24,57
Whey protein 12 30,00 6,86
MCT 40% emulsion incl. Citrem 0,00 0,00
lipids 0 0 0,00 0,00
emulsion water 0,00 0,00
Soybean oil 40% emulsion incl. 0,00 0,00
Citrem
lipids 0 0 0,00 0,00
emulsion water 0,00 0,00
Canola oil 40% emulsion incl. 37,50 8,57
Citrem
lipids 30 14 15,00 3,43
emulsion water 21,00 4,80
High oleic sunflower oil 40% 87,50 20,00
emulsion incl. Citrem
lipids 70 32 35,00 8,00
emulsion water 49,00 11,20
Total Citrem (4% m/m emulsion) 5,00 1,14
Water to add 175,00 40,00
Total without additives (kg) 437,50 100,00
TS final beverage (% m/m) 43%
Masking LG 0,19
Stevia 0,018
Strawberry aroma 0,08
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Table 4: Composition of Meal 3 (M3)
Lipid % of TEl Amount Amt per
compositio per diet (g) 100g
n (% final oil (m/m)
mix)
Meal 3
maltodextrin 43 107,50 24,57
Whey protein 12 30,00 6,86
MCT 40% emulsion incl. Citrem 20,00 4,57
lipids 16 7,2 8,00 1,83
emulsion water 11,20 2,56
Soybean oil 40% emulsion incl. Citrem 0,00 0,00
lipids 0 0 0,00 0,00
emulsion water 0,00 0,00
Canola oil 40% emulsion incl. Citrem 52,50 12,00
lipids 42 18,9 21,00 4,80
emulsion water 29,40 6,72
High oleic sunflower oil 40% emulsion incl. 52,50 12,00
Citrem
lipids 42 19 21,00 4,80
emulsion water 29,40 6,72
Total Citrem (4% m/m emulsion) 5,00 1,14
Water to add 175,00 40,00
Total without additives (kg) 437,50 100,00
TS final beverage (% m/m) 43%
Masking LG 0,19
Stevia 0,01
Strawberry aroma 0,08
Table 5: Composition of Meal 4 (M4)
Lipid % of TEl Amount Amount
composition per diet per
(% final oil (g) 100g
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mix) (m/m)
Meal 4
maltodextrin 43 107,50 24,57
Whey protein 12 30,00 6,86
MCT 40% emulsion incl. Citrem 83,75 19,14
lipids 67 30,15 33,50 7,66
emulsion water 46,90 10,72
Soybean oil 40% emulsion incl. Citrem 22,50 5,14
lipids 18 8,1 9,00 2,06
emulsion water 12,60 2,88
Canola oil 40% emulsion incl. Citrem 18,75 4,29
lipids 15 6,75 7,50 1,71
emulsion water 10,50 2,40
High oleic sunflower oil 40% emulsion incl. 0,00 0,00
Citrem
lipids 0 0 0,00 0,00
emulsion water 0,00 0,00
Total Citrem (4% m/m emulsion) 5,00 1,14
Water to add 175,00 40,00
Total without additives (kg) 437,50 100,00
TS final beverage (% m/m) 43%
Masking LG 0,19
Stevia 0,01
Strawberry aroma 0,08
Table 6: Composition of Meal 5 (M5)
Lipid % of TEl Amount Amount
composition per diet per
(% final oil (g) 100g
mix) (m/m)
Meal 5
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maltodextrin 43 107,50 24,57
Whey protein 12 30,00 6,86
MCT 40% emulsion incl. Citrem 97,50 22,29
lipids 78 35,1 39,00 8,91
emulsion water 54,60 12,48
Soybean oil 40% emulsion incl. Citrem 27,50 6,29
lipids 22 10 11,00 2,51
emulsion water 15,40 3,52
Canola oil 40% emulsion incl. Citrem 0,00 0,00
lipids 0 0 0,00 0,00
emulsion water 0,00 0,00
High oleic sunflower oil 40% emulsion incl. 0,00 0,00
Citrem
lipids 0 0 0,00 0,00
emulsion water 0,00 0,00
Total Citrem (4% m/m emulsion) 5,00 1,14
Water to add 175,00 40,00
Total without additives (kg) 437,50 100,00
TS final beverage (% m/m) 43%
Masking LG 0,19
Stevia 0,01
Strawberry aroma 0,08
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Study
On the day of the kinetic, the participants came fasted. There were no other
diet restrictions.
The beverage was served at room temperature in an opaque cup with a cover to
be consumed orally
within 5-10 minutes.
Blood samples were drawn time points starting from 1 hr before intake of the
beverage, and during
the 4 hours of the study (See further figure 1 for overview of study).
Gastric emptying
In brief, 100 mg of 13C-octanoate was dissolved into the test meals on the
evening preceding the test
to ensure complete homogeneous dissolution of the tracer. On the day of the
metabolic
investigation, wwo baseline breath samples were collected in 3 glass
vacutainers at times -30 and -15
min prior to the meal ingestion. All test meals were ingested in less than 10
minutes, and time zero
was defined as the end of food ingestion. Breath samples were collected at
times 15, 30, 45, 60, 75,
90, 105, 120, 150, 180, 210 and 240 minutes using Easy Sampler Device and
Crimp Tubes from
QuinTron (Milwaukee, Wisconsin, USA)
Breath 13CO2 samples were analyzed for 13C enrichment using an isotope ratio
mass spectrometer
(IRMS, Delta V Advantage, Thermo, Bremen, Germany) device hyphenated to a gas
chromatography
system (GC Trace, Thermo, Bremen, Germany). The analyses were performed to
assess the
13CO2/12CO2 ratio (expressed as 613C, %o). CO2 standard gas was calibrated
against international
standard allowing 13C/12C ratio to be quoted against the Vienna Pee De
Belemnite (VPDB).
Data were transformed using non linear equations according to Ghoos et al (2)
using the R software
to calculate non-linear curve fitting. The parameter T50Meas is derived from
these equations and
represents the time in minutes when half of the stomach's content has been
emptied.
See also Figure 2 for results.
FGF-19
FGF-19 (fibroblast growth factor 19) is an intestinal hormone which can reduce
the risk of hepatic
steatosis and cholestasis, and promote liver growth. Intestinal FGF19 can
exert beneficial effects on
glucose metabolism, by increasing insulin sensitivity and inducing glycogen
synthesis. This hormone
can also promote protein synthesis, and lead to growth of lean body mass
FGF19 was measured by [LISA using commercial kit from R&D Systems.
The results show FGF-19 is more stimulated in M3 and M2, i.e. those meals
which are have low or no
MCT content induce significantly higher levels of FGF_19 as compared to
controls. The meals M4 and
M5 were not significantly different from control.
See also Figure 3.
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Creaming experiments
Experiments were performed to validate the gastric emptying method.
Method: Samples of each test product (M1- M5) were mixed in equal proportion
with simulated
gastric juice, which consisted of 2 mg/mL NaCI and 4.5 mg/mL pepsin at 37 C
and a pH of 1.9. The
physical distribution of fat throughout each mixture was assessed by measuring
optical turbidity as a
function of sample height (every 30 um) over time at 37 C using a TurbiscanTm
LAB.
The results are presented below in Table 7. Meal 3 was diluted to test how
sstable it was (Meal 3 (-
10%)).
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Table 7: In vitro meal coagulation test results
Meal Mixing ratio Creaming rate Cream layer height
(meal to SGF) (% of total sample
height)
Meal 2 1:1 ¨ 50 urn min-1 96.5%
Meal 3 1:1 ¨ 1000 urn min-1 61.9%
Meal 3 - 10% 9:1 ¨ 10 urn min-1 100%
Meal 4 1:1 ¨ 300 urn min-1 74%
Meal 5 1:1 ¨ 50 urn min-1 93.3%
Conclusions: Meals 2 and 5 displayed no phase separation. Meals 3 and 4
displayed modest
creaming, which was due to fat particle aggregation. Such separation in the
stomach will be relatively
minor and have only a modest effect on gastric emptying. No effect on gastric
empting is anticipated
for Meals 2, 4, 5.
Example 2A:
Table 8: Example of a lipid blend according to the invention
Ingredients Variant 1: No Milk Fat
MCT Oil -
Palm Olein -
Milk Fat -
Betapol-55 15.00
Coconut Oil 20.00
Canola Oil 32.21
Sunflower Oil 16.17
High Oleic Sunflower Oil 14.38
ARASCO/DHASCO 1:1 1.00
ARASCO/DHASCO 2:1 1.25
Palmitic Acid (% of total fat) 8.10
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Palmitic Acid sn-2 (% of palmitic acid) 27.30
Palmitic Acid sn-1,3 (% of palmitic 72.70
acid)
Palmitic Acid sn-2 (% of total fat) 2.20
Palmitic Acid sn-1,3 (% of total fat) 5.90
Example 26:
Table 9: Example of lipid blend according to the invention
Ingredients Variant 2: No Betapol-55
MCT Oil -
Palm Olein -
Milk Fat 15.00
Betapol-55 0.00
Coconut Oil 20.00
Canola Oil 22.87
Sunflower Oil 18.28
High Oleic Sunflower Oil 21.59
ARASCO/DHASCO 1:1 1.00
ARASCO/DHASCO 2:1 1.25
Palmitic Acid (% of total fat) 7.80
Palmitic Acid sn-2 (% of palmitic acid) 20.30
Palmitic Acid sn-1,3 (% of palmitic 79.70
acid)
Palmitic Acid sn-2 (% of total fat) 1.60
Palmitic Acid sn-1,3 (% of total fat) 6.20
25
