U.S. patent application number 13/620442 was filed with the patent office on 2013-01-10 for liquid nucleotides/nucleosides-containing product.
This patent application is currently assigned to N.V. Nutricia. Invention is credited to Esther Jacqueline DE KORT, Martine Groenendijk, Robert Johan Joseph Hageman, Patrick Joseph Gerardus Hendrikus Kamphuis.
Application Number | 20130012469 13/620442 |
Document ID | / |
Family ID | 40094223 |
Filed Date | 2013-01-10 |
United States Patent
Application |
20130012469 |
Kind Code |
A1 |
DE KORT; Esther Jacqueline ;
et al. |
January 10, 2013 |
LIQUID NUCLEOTIDES/NUCLEOSIDES-CONTAINING PRODUCT
Abstract
The invention pertains to a liquid composition for preventing
and/or treating memory decline and/or cognitive dysfunction,
Alzheimer's, Parkinson's and/or dementia, said composition
comprising: (i) at least 50 mg nucleoside and/or nucleotide per 100
ml; (ii) between 0.2 and 10 grams protein per 100 ml; (iii) between
0.05 and 3 wt. % of thickener, based on total weight of the
composition. The thickener is preferably selected from the group
consisting of cellulose, xanthan gum, gellan gum, alginate, guar
gum, locust bean gum, gum karaya, gum tragacanth, carrageenan, and
mixtures thereof. The composition preferably has a loss factor tan
.delta. between 0.1 and 100, as measured at any strain in the range
of 1-100% at 0.1 Hz and 20.degree. C. It is particularly found that
a thickener selected from the group consisting of gellan gum,
xanthan gum and cellulose greatly reduces sedimentation.
Inventors: |
DE KORT; Esther Jacqueline;
(Wageningen, NL) ; Hageman; Robert Johan Joseph;
(Wageningen, NL) ; Groenendijk; Martine;
(Barendrecht, NL) ; Kamphuis; Patrick Joseph Gerardus
Hendrikus; (Utrecht, NL) |
Assignee: |
N.V. Nutricia
|
Family ID: |
40094223 |
Appl. No.: |
13/620442 |
Filed: |
September 14, 2012 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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12809418 |
Sep 15, 2010 |
8282965 |
|
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PCT/NL2008/050124 |
Mar 4, 2008 |
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13620442 |
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Current U.S.
Class: |
514/51 ; 514/43;
514/52 |
Current CPC
Class: |
A61K 35/60 20130101;
A61K 47/36 20130101; A61K 35/60 20130101; A61K 2300/00 20130101;
A23L 33/115 20160801; A23L 33/40 20160801; A23L 33/13 20160801;
A61K 47/42 20130101; A61K 47/38 20130101; A23L 33/17 20160801; A61K
31/7052 20130101; A61K 33/06 20130101; A61K 31/7052 20130101; A61K
31/7072 20130101; A61P 25/28 20180101; A23L 29/262 20160801; A61K
38/02 20130101; A23V 2002/00 20130101; A23L 29/269 20160801; A61K
31/7072 20130101; A61K 47/44 20130101; A23L 29/272 20160801; A61K
47/38 20130101; A23V 2002/00 20130101; A61P 25/00 20180101; A23V
2250/706 20130101; A23V 2250/7052 20130101; A23V 2250/1642
20130101; A23V 2250/1868 20130101; A23V 2250/708 20130101; A61K
2300/00 20130101; A61K 2300/00 20130101; A23V 2250/628 20130101;
A61K 38/02 20130101; A61K 33/06 20130101; A61K 9/0095 20130101;
A61K 47/36 20130101; A23V 2250/51082 20130101; A61P 25/16 20180101;
A61K 2300/00 20130101; A23V 2200/322 20130101; A23V 2250/714
20130101; A23V 2250/5114 20130101; A61K 2300/00 20130101; A23V
2250/72 20130101; A23V 2250/1608 20130101; A61K 2300/00 20130101;
A23V 2200/302 20130101; A23V 2250/712 20130101; A23V 2250/54252
20130101; A23V 2250/1612 20130101; A23V 2250/1614 20130101; A23V
2250/1588 20130101; A61K 2300/00 20130101; A23V 2250/187 20130101;
A23V 2250/702 20130101; A23V 2250/54246 20130101; A61K 2300/00
20130101 |
Class at
Publication: |
514/51 ; 514/43;
514/52 |
International
Class: |
A61K 31/7052 20060101
A61K031/7052; A61K 31/7072 20060101 A61K031/7072; A61P 25/16
20060101 A61P025/16; A61P 25/00 20060101 A61P025/00; A61P 25/28
20060101 A61P025/28 |
Foreign Application Data
Date |
Code |
Application Number |
Dec 20, 2007 |
EP |
07123811.7 |
Claims
1. A method for preventing and/or treating memory decline and/or
cognitive dysfunction, Alzheimer's, Parkinson's and/or dementia,
the method comprising administering to a person in need thereof a
composition comprising: (i) at least 50 mg nucleoside and/or
nucleotide per 100 ml of the composition; (ii) between 0.2 and 10
grams protein per 100 ml of the composition; and (iii) between 0.05
and 3 wt. % of thickener, based on total weight of the composition,
wherein the thickener is selected from the group consisting of
cellulose, xanthan gum and gellan gum, and mixtures thereof.
2. The method according to claim 1, wherein the thickener comprises
cellulose.
3. The method according to claim 1, wherein the composition
comprises a mixture of microcrystalline cellulose (MCC) and an
anionic polymeric polysaccharide.
4. The method according to claim 3, wherein the mixture comprises
0.05-1.0 wt % of the composition.
5. The method according to claim 3, wherein the anionic polymeric
polysaccharide is carboxymethyl cellulose (CMC).
6. The method according to claim 1, wherein the composition has a
loss factor tan .delta. between 0.1 and 100, as measured at any
strain in the range of 1-100% at 0.1 Hz and 20.degree. C.
7. The method according to claim 1, the composition having
shear-thinning and/or thixotropic properties.
8. The method according to claim 1, the composition further
comprising between 10 and 150 mg calcium per 100 kcal.
9. The method according to claim 1, the composition comprising
nucleotide, wherein the nucleotide provides at least 30 wt. % of
total phosphorus in the composition.
10. The method according to claim 8, wherein (a) nucleotide
provides at least 30 wt. % of total phosphorus in the composition
or (b) the composition comprises a weight ratio of protein to
calcium of at least 5.
11. The method according to claim 8, wherein the composition
comprises a weight ratio of protein to calcium of at least 10.
12. The method according to claim 1, wherein the composition has a
dry matter content between 10 and 40%.
13. The method according to claim 1, wherein the composition
comprises at least one cellulose selected from the group consisting
of high viscous cellulose and cellulose derivatives like
hydroxyethyl cellulose, hydroxypropyl methyl cellulose,
carboxymethyl cellulose, microcrystalline cellulose and methyl
cellulose.
14. The method according to claim 1, wherein the composition
comprises uridine monophosphate (UMP) in an amount of 0.08-3 g per
100 ml of the composition.
15. The method according to claim 1, wherein the composition
comprises 50 mg to 3 gram choline per 100 ml of the
composition.
16. The method according to claim 15, wherein the choline is in the
form of choline chloride.
17. A liquid composition comprising: (i) at least 50 mg nucleoside
and/or nucleotide per 100 ml of the composition; (ii) between 0.2
and 10 grams protein per 100 ml of the composition; and (iii)
between 0.05 and 3 wt. % of thickener, based on total weight of the
composition, wherein the thickener is selected from the group
consisting of cellulose, xanthan gum and gellan gum, and mixtures
thereof.
18. The liquid composition according to claim 14, wherein the
composition has a loss factor tan .delta. between 0.1 and 100, as
measured at any strain in the range of 1-100% at 0.1 Hz and
20.degree. C.
19. The liquid composition according to claim 14, comprising
between 10 and 150 mg calcium per 100 kcal.
20. The liquid composition according to claim 14, comprising
nucleotide, wherein the nucleotide provides at least 30 wt. % of
total phosphorus in the composition.
21. A nutritional composition comprising a nucleotide and a
thickener characterized in that the nucleotide provides more than
30 wt. % of the amount of phosphorous that is present in the total
composition, and the composition comprises 30 to 80 mg phosphorus
per 100 kcal.
22. The nutritional composition according claim 21, further
comprising protein and/or a mineral.
23. The nutritional composition according to claim 21, which has
been subjected to a ultra high temperature (UHT) treatment.
24. The nutritional composition according to claim 21, further
comprising intact protein.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a Divisional of U.S. patent application
Ser. No. 12/809,418, filed Sep. 15, 2010, which is the National
Phase of International Patent Application No. PCT/NL2008/50124,
filed Mar. 4, 2008, which claims priority from European Patent
Application No. 07123811.7, filed Dec. 20, 2007. The contents of
these applications are herein incorporated by reference in their
entirety.
FIELD OF THE INVENTION
[0002] The invention pertains to a liquid
nucleotides/nucleosides-containing nutritional product, preferably
a product containing uridine-containing nucleotides/nucleosides,
and its preparation, and to its use in improving neurodegenerative
disorders, preferably for combating memory decline and/or cognitive
dysfunction, Alzheimer's, Parkinson's and/or dementia, and for
promoting or supporting healthy brain function.
BACKGROUND OF THE INVENTION
[0003] Memory loss, dementia and reduced brain function are major
problems, particularly in elderly. Significant effort is put in the
treatment and/or prevention of these disorders related with
impaired nerve functioning. Persons older than 50 years of age are
particularly prone to developing such disorders.
[0004] WO-A-2006/031683 teaches to administer a composition
comprising a uridine in order to improve cognitive and neurological
functions in a subject. Uridine, in particular in the form of
uridine monophosphate (UMP), is a nutrient that increases synthesis
and release of neurotransmitters and membrane synthesis by neural
cells and brain cells. Nutritional products containing uridine and
high concentrations of macro- and micronutrients are administered
to elderly patients, with the aim to prevent memory decline.
[0005] However, when targeting this group of patients often
troubled by reduced appetite or disturbed eating behavior, such a
nutritional product needs to satisfy a number of requirements. It
should be readily consumable, thus avoiding an insufficient intake
of the active ingredients. For that purpose, it is strived for a
product that is desirably liquid with a sufficiently low viscosity
so it can be easily swallowed.
SUMMARY OF THE INVENTION
[0006] It is desirable to administer active ingredients to elderly
and Alzheimer patients in liquid form. Furthermore, it is highly
desirable to administer the active ingredients in a relatively
small dosage form such that the administration does not interfere
with normal nutritional intake. Additionally palatability is of
utmost importance to ensure compliance products need to be consumed
for many day, weeks, months or years.
[0007] Hence, based on the knowledge that nucleosides/nucleotides,
particularly uridine and/or cytidine-containing nucleotides, are
advantageously used by patients suffering from memory impairment,
the present inventors designed a liquid composition containing
uridine monophosphate suitable for administration to elderly and
Alzheimer patients, i.e. a liquid composition prepared by admixing
different ingredients including a large amount of uridine
monophosphate, proteins and preferably also minerals.
[0008] However, unexpectedly sediment was formed in the liquid
product after several weeks. Sediment is highly undesirable as it
reduces shelf life and palatability of the product, and may result
in intake of active ingredients at different concentrations. It is
the first time that this problem is recognized in the art for this
type of product, high in nucleotides and/or nucleosides.
[0009] The sediment was most probably caused by a combination of
the high concentrations of uridine phosphates and minerals in the
composition. Analyses for the sediment revealed that the sediment
contains high quantities of calcium, presumably in the form of an
insoluble organic salt, e.g. calcium citrate. Calcium citrate is
typically added to the composition to include advantageous amounts
calcium in the composition. Hence, it would be one solution to
reduce the calcium citrate addition or replace the calcium citrate
for a different calcium salt. However, this did not appear an
option. Addition of other calcium salts resulted in different
problems, e.g. addition of a soluble calcium salt resulted in
aggregation of proteins which is highly undesirable. Addition of
the (insoluble) calcium phosphate also was not an option as it
would result in an undesirable intake of phosphorus (i.e. the
nucleotides and often proteins already provide high amounts of
phosphorus). Reduction of calcium addition would result in an
unacceptable lack of calcium in the product. Hence, a particular
problem to be solved now was to prevent sediment formation while
maintaining palatability and liquidity of the product.
Additionally, the product showed a good homogeneity.
[0010] Surprisingly it was found that inclusion of a thickener,
preferably a thickener selected from the group consisting of
cellulose, xanthan gum, gellan gum, alginate, guar gum, locust bean
gum, gum karaya, gum tragacanth, carrageenan, and mixtures thereof,
especially cellulose, gellan gum and/or xanthan gum, provided an
advantageous solution to the problem. It was found that particle
formation and subsequent sedimentation was prevented if these
thickeners were added to the product. The inventors hypothesize
that due to the high viscosity at low shear rate the interactions
between minerals, and hence the ability to form sediment particles
is limited. Furthermore, the present stabilizer provides a low
viscosity when ingested, resulting in a good palatability and easy
ingestion for the elderly or Alzheimer or Parkinson patient. This
is due to the shear-thinning and/or thixotropic properties of the
product with these thickeners.
[0011] Hence the present inventors found that a liquid
nucleotide-containing nutritional product, in particular a product
which comprises a component which comprises a uridine nucleotide,
may be provided which is readily consumable and wherein settlement
of solids is reduced or even avoided by making use of thickeners,
preferably thickeners which demonstrate thixotropic or
shear-thinning behavior when added to a liquid. The nutritional
formula is pourable, yet is able to hold the nucleotides and
further components, among which choline salts, in suspension
without the formation of a sediment that is not readily
redispersible.
[0012] The present solution also works for liquid compositions that
contain nucleosides and/or nucleotides other than uridine
phosphates, particularly other nucleotides, e.g. cytidine
phosphates.
[0013] In a further aspect the present inventors found that in a
protein-containing composition the aforementioned nucleosides
and/or nucleotides, particularly nucleotides, can be suitably used
to reduce protein aggregation. Hence, the present invention also
provides a thixotropic and/or shear-thinning liquid comprising
nucleoside and/or nucleotide and protein, wherein the nucleoside
and/or nucleotide provides at least 25 wt. % of the total
phosphorus in the composition, preferably at least 30 wt. %.
[0014] In yet another aspect the invention pertains to a
nutritional composition comprising a nucleotide and a thickener
characterized in that the nucleotide provides more than 30 wt. % of
the amount of phosphorous that is present in the total composition,
and the composition comprises 30 to 80 mg phosphorus per 100 kcal.
The composition preferably comprises protein, preferably intact
protein, and/or one or more minerals.
DETAILED DESCRIPTION OF THE INVENTION
[0015] In one aspect the present invention provides a liquid
composition for preventing and/or treating neurodegenerative
disorders, preferably selected from the group consisting of memory
decline, cognitive dysfunction, Alzheimer's, Parkinson's and/or
dementia, said composition comprising: at least 50 mg nucleoside
and/or nucleotide per 100 ml; and between 0.2 and 10 grams protein
per 100 ml.
[0016] In a further aspect the present method provides a method for
the treatment and/or prevention of memory decline and/or cognitive
dysfunction, Alzheimer's, Parkinson's and/or dementia, said method
comprising the administration of a composition comprising: at least
50 mg nucleoside and/or nucleotide per 100 ml; and between 0.2 and
10 grams protein per 100 ml.
[0017] In yet a further aspect the present invention provides a
liquid comprising at least 50 mg nucleoside and/or nucleotide per
100 ml; and between 0.2 and 10 grams protein per 100 ml.
[0018] In still a further aspect, the present invention provides at
least 50 mg nucleoside and/or nucleotide per 100 ml, and between
0.2 and 10 grams protein per 100 ml.
[0019] The aforementioned liquid compositions are preferably
characterized by having a loss factor tan .delta. between 0.1 and
100, as measured at any strain in the range of 1-100% at 0.1 Hz and
20.degree. C.
[0020] The liquid composition is preferably characterized by having
(a) a nucleotide content providing at least 25 wt. % of the total
phosphorus in the composition, preferably at least 30 wt. % or (b)
a weight ratio of protein to calcium of at least 5, preferably at
least 10, more preferably at least 25.
[0021] In one aspect, the nucleotide present in the liquid
composition provides at least 25 wt. % of the total phosphorus in
the composition, preferably at least 30 wt %, more preferably at
least 35 wt. %, more preferably 40 to 90 wt. %, most preferably 50
to 85 wt. %.
[0022] The use of the present compositions in a method for
preventing and/or treating neurodegenerative disorders, preferably
selected from the group consisting of memory decline and/or
cognitive dysfunction, Alzheimer's, Parkinson's and/or dementia is
also provided.
[0023] In a further aspect the present invention provides a
nutritional composition comprising a nucleotide and a thickener
characterized in that the nucleotide provides more than 30 wt. %,
preferably 40-90, more preferably 50-85 wt. %, of the amount of
phosphorous that is present in the total composition, and the
composition comprises 30 to 80 mg phosphorus per 100 kcal.
Thickener
[0024] The present composition contains a thickener. Preferably the
present composition contains a thickener selected from the group
consisting of xanthan gum, gellan gum, cellulose, alginate, guar
gum, locust bean gum, gum karaya, gum tragacanth, carrageenan, and
mixtures thereof.
[0025] More preferably the present composition comprises a
thickener selected from the group consisting of xanthan gum, gellan
gum and cellulose. These thickeners preferably have shear-thinning
and/or thixotropic properties which are considered beneficial to
the product. It is even more preferred that the thickener is
selected from the group consisting of xanthan gum and cellulose.
Most preferably the present composition comprises cellulose.
According to a preferred embodiment, the present composition
contains at least 70 wt. % cellulose based on total weight of
thickener.
[0026] Preferably the present composition contains between 0.05 and
3 wt. % of one or more of the aforementioned thickeners, based on
total weight of the composition, preferably 0.1-2 wt. %, more
preferably 0.3-1 wt. %.
[0027] One of the preferred thickeners is the polysaccharide
xanthan gum. Its backbone consists of two .beta.-D-glucose units
linked through the 1 and 4 positions. The side chain consists of
two mannose and one glucuronic acid, so the chain consists of
repeating modules of five sugar units. The side chain is linked to
every other glucose of the backbone at the 3 position. About half
of the terminal mannose units have a pyruvic acid group linked as a
ketal to its 4 and 6 positions. The other mannose unit has an
acetyl group at the 6 positions. It is preferred to use xanthan gum
having pseudoplastic behaviour, and which is stable over a wide
range of temperatures and pH.
[0028] Gellan gum is a linear tetrasaccharide
4)-L-rhamnopyranosyl-(.alpha.-1.fwdarw.3)-D-glucopyranosyl-(.beta.-1.fwda-
rw.4)-D-glucuronopyranosyl-(.beta.-1.fwdarw.4)-D-glucopyranosyl-(.beta.-1.-
fwdarw.4)-D-glucopyranosyl-(.beta.-1.fwdarw. with O(2) L-glyceryl
and O(6) acetyl substituents on the 3-linked glucose. It is a
bacterial exopolysaccharide that is prepared commercially in a
manner similar to xanthan gum.
[0029] In a preferred embodiment, the composition comprises
cellulose. Preferably the present composition contains between 0.05
and 3 wt. % cellulose, based on total weight of the composition,
preferably 0.1-2 wt. %, more preferably 0.3-1 wt. %. Cellulose is a
linear homopolymer of anhydroglucose units linked together by
beta-D-1,4 glycosidic bonds. It is preferred to select cellulose
from the group consisting of high viscous cellulose and cellulose
derivatives like hydroxyethyl cellulose, hydroxypropyl
methylcellulose (HPMC), carboxymethyl cellulose (CMC),
microcrystalline cellulose (MCC) and methyl cellulose. It was found
that excellent results in terms of stability were obtained using
large amounts of the non-ionic cellulose ether microcrystalline
cellulose.
[0030] In this context it is important to differentiate between
slowing precipitation of already formed particles and/or viscosity
increase on the one hand, from a decrease in rate and/or prevention
of the formation of particles on the other hand. In the present
case, it is less important to stabilize already suspended
particles. After all, in such case the formation of precipitates
would still occur, since with time particles having a higher mass
will reach the bottom of the package. In order to solve the problem
of the invention, in a main aspect the thickener prevents and/or
reduces the formation of the particles, and thus decreases the
formation of a sediment on the bottom of a package.
[0031] Due to the limited water-solubility and/or disperability of
the non-ionic cellulose ether, it is preferred that the composition
of the invention further contains a respectable amount of an
anionic polymeric polysaccharide. In a preferred embodiment the
anionic polysaccharide is selected from the group consisting of
guar gum, carboxymethylcellulose, hemicellulose, pectin, alginate,
konjac flour, psyllium, gums from tragacanth, xanthan, karaya,
chia, wellan, ghatti or okra, or the hydrolysates of these oligo-
or polycarbohydrates, These anionic polysaccharides facilitate the
manufacture of a stable aqueous food product, in particularly a
heat treated or sterilized liquid product which comprises
nucleotides and one or more proteins. The anionic polymeric
polysaccharide, such as guar gum or an anionic cellulose, enhances
the stability of the aqueous system and prevents agglomeration of
cellulose. In one embodiment, it is preferred to use an anionic
cellulose, preferably carboxymethyl cellulose (CMC).
[0032] In a preferred embodiment, the liquid composition contains a
mixture of MCC and an anionic polymeric polysaccharide, preferably
CMC. The liquid composition preferably comprises 0.05-3.0 wt. % of
a mixture of microcrystalline cellulose (MCC) and an anionic
polymeric polysaccharide, based on the total weight of the
composition, preferably 0.3-1.0 wt. %. The relative weight ratio of
non-ionic cellulose to the anionic polymeric polysaccharide is
preferably at least 3:1, more preferably between 4:1 and 9:1. In
one embodiment, it is preferred that at least 70 wt. %, more
preferably 75-90 wt. % of the cellulose thickeners present in the
composition is provided by MCC. Often, MCC is marketed being coated
with CMC or cellulose gum. In the most preferred embodiment, the
remainder is formed from CMC. Suitable candidates are
Avicel-plus-BV2312 and Vivapur MCG591F, commercially available with
FMC biopolymers and Rettenmaier, respectively. Particularly good
results are reported for the latter of the two.
[0033] It is further found that optimal characteristics were
obtained with thickeners having a certain particle size. Preferably
the present thickener is a mixture of particles wherein at least 50
wt. % of the particles have a particle size between 20 and 200
micrometer. The bigger thickener particle sizes avoid sedimentation
to occur over longer time scales.
[0034] The inventors have discovered that the amount of the one or
more cellulose thickeners in the liquid composition is preferably
more than 0.05 wt. %, more preferably at least 0.1 wt. %, more
preferably at least 0.3 wt. %, based on the total weight of the
composition. It is believed that at these concentrations a weak
three-dimensional network is built which effectively holds the
components in the liquid matrix, the result being no sediment can
form. In order to control the viscosity of the composition, it is
preferred that the composition contains less than 1.0 wt. %, more
preferably less than 0.8 wt. % of the cellulose thickener(s).
[0035] Apart from the cellulose, gellan and/or xanthan thickeners,
it is preferred that the liquid nutritional composition is low in
other thickening agents, i.e. substances that are known to increase
the viscosity of a composition without substantially modifying its
other properties, such as taste. It is preferred that the
composition comprises less than 0.1 wt %, more preferably less than
0.05 wt. % of such other food thickeners, most preferably none at
all. In one embodiment, the weight ratio of thickeners other than
cellulose and xanthan over the sum of cellulose and xanthan
thickeners of the present invention is less than 0.1, preferably
less than 0.01, more preferably 0. More preferably, the weight of
thickeners other than cellulose over the sum of the weight
cellulose thickeners present in the composition is less than 0.1,
more preferably less than 0.01, most preferably 0.
Physical Characteristics
[0036] The composition is preferably characterized by its rheologic
behaviour. Thereto, viscosity measurements are performed using `cup
and bob` geometry or plate and cone geometry. A sample can be
suitably analysed by using a MCR 300 rheometer (Anton Paar Physica,
Graz, Austria).
[0037] Cup and bob viscometers work by defining the exact volume of
sample which is to be sheared within a test cell, the torque
required to achieve a certain rotational speed is measured and
plotted. There are two classical geometries in cup and bob
viscometers, known as either the "Couette" or "Searle"
systems--distinguished by whether the cup or bob rotates. Either
one may be used, to determine storage modulus G', loss modulus G''
and loss factor with strain between 1-100% at 0.1 Hz at 20.degree.
C. The loss factor tan .delta.=G''/G'. By measuring G' and G'' the
structure strength is thus evaluated. The storage modulus and the
loss modulus can be suitably determined using a DG 26.7 cup and
massive cylinder (Anton Paar Physica, Graz, Austria). These
amplitude sweep measurements can be carried out with a strain of
0.01-1000% and shear rate of 10 s.sup.-1. Samples are preferably
added to the cup at least 10 minutes before measurements are
started.
[0038] It is found that good results are obtained with G' being
larger than but close to G'', i.e. 0.1<tan .delta.<100. In
such case, sedimentation will be slowed down greatly or even
avoided. With larger values, consumers would appreciate an unwanted
"gel-like" taste, which may be described as a little bit sticky,
slippery or slimy. Best results are obtained with tan
.delta.<10, and more preferably tan .delta. is larger than 0.2.
The value for tan .delta. should be within the aforementioned range
at any strain between 1 and 100%, as measured at 0.1 Hz frequency
and at 20.degree. C. Within the range of 1-100% strain, an
substantially linear relationship is observed. For sake of
comparison, without the present thickeners G''>G', which
indicates a low viscosity product with little structural strength.
It has a pure liquid character and tan .delta.>1000.
[0039] Even more preferably, tan .delta. also remains within the
range of 0.1-100, preferably larger than 0.2, when measured
similarly, but at strain 100-1000%.
[0040] The composition for use according to the invention
preferably has a low viscosity, preferably a viscosity between 1
and 100 mPas measured at a shear rate of 100 sec.sup.-1 at
20.degree. C. High viscosities are to be avoided, since these often
are associated with unacceptable mouthfeel characteristics and
difficulty to be ingested by the target group, e.g. elderly and
Alzheimers patients. More preferably, the present composition is
preferably provided in the form of a drink capable of being
ingested through a straw which makes the product even easier to
ingest and improves compliance. In a preferred embodiment the
present composition has a viscosity of less than 80 mPas at a shear
rate of 100 per sec at 20.degree. C., more preferably of 1-40 mPas
at a shear rate of 100 per sec at 20.degree. C. These viscosity
measurements may be performed using plate and cone geometry. `Cone
and Plate` viscometers use a cone of very shallow angle in bare
contact with a flat plate. With this system the shear rate beneath
the plate is constant to a modest degree of precision and
deconvolution of a flow curve; a graph of shear stress (torque)
against shear rate (angular velocity) yields the viscosity in a
straightforward manner.
[0041] It is preferred that the present composition fulfils FSMP
guidelines, and hence contains significant amounts of minerals and
vitamins. Hence, typically the product has an osmolality of 300 to
800 mOsm/kg.
[0042] To prevent increased viscosity due to gelling of protein the
pH of the liquid is preferably kept around neutral, while for a
good palatability the pH is preferably slightly acidic. The liquid
nutritional composition preferably has a pH in the range of 5-7.5,
more preferably 6-7.
[0043] The liquid nutritional composition preferably has a dry
matter content in the range of 10-40 wt. %, more preferably 10-30
wt. %.
Nucleotides/Nucleosides
[0044] Preferably the present composition comprises nucleosides
and/or nucleotides, preferably nucleotides. Nucleotides add to the
phosphorus content and therefore cause similar problems if the
product in which these are included in high amounts also contain
protein and calcium. Nucleotides typically more effectively
absorbed by the body. The liquid composition preferably comprises
80-3000 mg nucleotide and/or nucleoside per 100 ml liquid product,
preferably 100-2000 mg nucleotide and/or nucleoside per 100 ml
liquid product, more preferably 200-1000 mg nucleotide and/or
nucleoside per 100 ml liquid product.
[0045] Preferably, the liquid composition is characterized by
comprising predominantly nucleotides over nucleosides. So the mass
ratio of nucleotides over nucleosides is preferably more than 2.0,
more preferably more than 4.0, most preferably more than 10.0, in
particular more than 20. These ratios are specifically preferred
for liquid products with pH between 2.0 and 8.0, more preferably
between 5-7.5, more preferably 5.5-7.5, most preferably 6-7.
[0046] The present inventors have found that the invention works
particularly well when the composition comprises uridine nucleotide
or uridine nucleoside, preferably uridine nucleotide, preferably at
least one uridine phosphate selected from uridine monophosphate
(UMP), uridine diphosphate (UDP and uridine triphosphate (UTP).
[0047] Also, the present composition preferably comprises cytidine
nucleotide or cytidine nucleoside, preferably cytidine nucleotide,
preferably at least one cytidine phosphate selected from cytidine
monophosphate (CMP), cytidine diphosphate (CDP) and cytidine
triphosphate (CTP).
[0048] Most preferably the present composition comprises UMP, as
UMP is most efficiently being taken up by the body. Additionally,
it was surprisingly found by the inventors that UMP contributes to
the product stability, since it binds calcium and thus reduces
calcium-induced protein aggregation even further.
[0049] Hence, inclusion of UMP in the present product enables a
high efficacy at the lowest dosage and/or the administration of a
low volume to the subject. Preferably at least 50 wt. % of the
uridine in the present composition is provided by UMP, more
preferably at least 75 wt. %, most preferably at least 95 wt. %.
The liquid composition preferably comprises 0.08-3 g uridine per
100 ml, preferably 0.1-2 g uridine per 100 ml day, more preferably
0.2-1 g uridine per 100 ml, wherein uridine is the cumulative
amount of uridine, deoxyuridine, uridine phosphates, uracil and
acylated uridine derivatives.
[0050] The present liquid composition preferably comprises 0.08-3 g
UMP per 100 ml liquid product, preferably 0.1-2 g UMP per 100 ml
liquid product, more preferably 0.2-1 g per 100 ml liquid product.
Preferably 1-37.5 mg UMP per kilogram body weight is administered
per day.
[0051] Preferably the weight ratio of uridine to cytidine is larger
than 1.0, more preferably at least 2.0, most preferably more than
5.0. The term cytidine as used herein relates to cytidine and/or
equivalent thereof. Although cytidine is a precursor of uridine,
which passes the blood brain barrier, it is more efficient and
effective to include uridine in the present composition.
[0052] In a further preferred embodiment the present composition
preferably does not contain high amounts of other nucleotides.
Hence, preferably the weight ratio adenosine/uridine in the present
composition is below 0.1, more preferably below 0.01, most
preferably 0. Preferably the weight ratio guanosine/uridine in the
present composition is below 0.1, more preferably below 0.01, most
preferably 0. Preferably the weight ratio of inosine to uridine in
the present composition is below 0.1, more preferably below 0.01,
most preferably 0.
Choline
[0053] The combination of uridine with choline is particularly
effective in improving neurodegenerative disorders, particularly in
improving membrane formation and memory function. Hence preferably
the present composition contains a component selected from the
group consisting of choline (including choline salts, e.g. choline
chloride), citicholine, cytidylcholine and phosphatidylcholine,
more preferably choline and/or phosphatidylcholine, more preferably
choline. Supplying choline with the diet increases the plasma
choline and thereby prevents or slows down membrane breakdown, and
increases new membrane synthesis. The use of the selected methyl
donors will increase the number of patients that respond to the
therapy. Especially elderly, in particular frail elderly, benefit
from the inclusion of the selected choline.
[0054] The inclusion of choline however provides additional
challenges with respect to sedimentation, as the further inclusion
of salts such as choline chloride further increases the risk of
sediment formation. It was found that also when choline (salt) was
included in the present composition with thickener, no sediment was
formed.
[0055] The present composition preferably comprises 50 mg to 3 gram
choline per 100 ml of the liquid formula, preferably 200 mg-1000 mg
choline per 100 ml. The choline composition is preferably comprises
choline chloride.
Minerals
[0056] To fulfil important nutritional requirements the present
liquid composition contains divalent cations, particularly calcium.
Preferably the present liquid composition contains 10-150 mg
calcium per 100 kcal, preferably 40-100 mg calcium per 100 kcal.
Alternatively or additionally, it is preferred for the liquid
composition to contain 10-150 mg calcium per 100 ml, more
preferably 40-100 mg calcium per 100 ml. The calcium causes
particular problem in aggregation of proteins. Hence, the present
composition preferably comprises an insoluble calcium source. In a
preferred embodiment, the calcium salt (s) used in the present
composition have a solubility below 0.15, more preferably below
0.1, even more preferably below 0.06 gram per 100 ml
(demineralised) water at 20.degree. C. and pH 7.
[0057] The calcium salt is preferably selected from the group
consisting of calcium carbonate, calcium sulfate, calcium citrate
(e.g. mono-calcium citrate or tri-calcium citrate), a calcium salt
coated with a substance which has limited solubility in water at pH
7 and is soluble at a pH below about 5 (hereafter referred to as
coated calcium salts) and mixtures thereof. Examples of coatings
and methods for the preparations of coated calcium salts are given
in W00/038829, the entire content of which is hereby incorporated
by reference. Preferably the present composition comprises calcium
citrate.
[0058] In certain embodiments, particularly for compositions
containing low amounts of nucleotides or nucleosides, it is be
desirable to add phosphate salts. The phosphate salt can be added
to provide the mineral requirements to a patient. Preferably the
present composition contains phosphate salts of sodium, potassium,
calcium and/or magnesium. The composition preferably comprises 30
to 80 mg phosphorus per 100 kcal.
LC-PUFA
[0059] The present composition preferably contains docosahexaenoic
acid (22:6 .omega.-3; DHA), and/or eicosapentaenoic acid (20:5
.omega.-3; EPA). The present liquid composition preferably contains
100-5000 mg (DHA+EPA) per 100 ml, more preferably 500-3000 mg per
100 ml. The present composition preferably contains a very low
amount of arachidonic acid (AA; 20:4 .omega.-6). The arachidonic
acid is believed to counteract the effects of the present
composition. The present subjects normally ingest sufficient and/or
biosynthesizes (precursors of) AA, and an excess daily dosage may
stimulate inflammatory responses, inhibiting daily activities.
Preferably the weight ratio DHA/AA in the present composition is at
least 5, preferably at least 10, more preferably at least 15. The
present method preferably comprises the administration of a
composition comprising less than 5 wt. % arachidonic acid based on
total fatty acids, more preferably below 2.5 wt. %. The ratio
omega-6/omega-3 fatty acids in the present product, is preferably
below 0.5, more preferably below 0.2.
Protein
[0060] The present composition comprises protein, preferably intact
protein. Proteins enable the manufacturing of palatable products.
Especially for elderly and AD patients benefit from the protein as
it strengthens the motor skills. Preferably the present composition
comprises milk protein. Preferably the present composition
comprises a protein selected from the group consisting of whey
protein, casein or caseinate. Preferably the present composition
comprises caseinate, more preferably the present composition
contains at least 70 wt. %, more preferably at least 90 wt. %
casein and/or caseinate based on total protein.
[0061] Preferably, the proteins are included in intact
(unhydrolyzed) form, in order to have a palatable product. Such
high molecular weight proteins increase the viscosity of the
heat-treated liquid product, compared to the hydrolyzed forms. The
present inventors were able to make an acceptable product, with
good palatability and limited viscosity, by applying the measures
according the invention, still avoiding precipitation.
[0062] Preferably the present composition contains between 0.2 and
7 gram protein per 100 ml, preferably, more preferably between 1
and 6 grams protein per 100 ml, most preferably between 2 and 5
grams protein per 100 ml.
Other Components
[0063] Preferably, the present composition preferably comprises
phospholipids, preferably 0.1-50 wt. % phospholipids based on total
weight of lipids, more preferably 0.5-20 wt. %, more preferably
between 1 and 5 wt. % based on total weight of lipids. Preferably
the present composition contains at least one selected from the
group consisting of phosphatidylcholine, phosphatidylethanolamine,
phosphatidylserine and phosphatidy-linositol. The total amount of
lipids is preferably between 10 and 30 wt. % on dry matter, and/or
between 2 and 6 g lipid per 100 ml for a liquid composition.
Inclusion of phospholipids beneficially improves membrane function,
thereby enabling an improved functioning of the different parts of
the brain that play a (main) role in the ability to perform daily
activities. Furthermore, the phospholipids improve stability of the
present product.
[0064] Advantageously the present composition contains digestible
carbohydrates. The digestible carbohydrates positively influence
the operational skills of the subject, and have an advantageous
effect over and above the effects for the present composition
containing uridine. The present composition preferably contains
between 1 and 50 gram digestible carbohydrates per 100 ml of a
liquid product, more preferably between 5 and 30 grams per 100 ml,
more preferably 10-30 grams carbohydrates/100 ml. The total amount
of digestible carbohydrates is preferably between 25 and 80 wt. %
on dry matter, preferably 40-80 wt. %.
[0065] Preferably the present composition contains organic acid(s),
preferably 0.5 to 10 wt. % organic acid based on total weight of
digestible carbohydrates, more preferably 1.5 to 6 wt. %.
Preferably the present composition contains citric acid, preferably
0.5 to 10 wt. % citric acid based on total weight of digestible
carbohydrates, more preferably 1.5 to 6 wt. %.
[0066] Persons suffering from neuropathies or neurological problems
often experience problems with eating. Their sensory capabilities
and/or control of muscles have become imparted, as well as, in some
instances, their ambition to apply proper eating habits. Part of
these patients may experience a general loss in appetite and a
relatively large part of this patient group became malnourished.
Preferably the product has an energy density of 0.8-4.5 kcal per g
of the composition, more preferably between 0.9 and 2.5 kcal per
ml.
[0067] Liquid nutritional products preferably have a long shelf
life. However, increasing shelf life by heat treatments often
results in destabilisation of the products and/or palatability,
leading to a product which is unacceptable. The present liquid
product can be subjected to a heat treatment without major adverse
side effects. Hence, the present liquid composition is preferably
heat-treated, more preferably the composition is subjected to a
sterilization process. In a preferred embodiment the present
composition is subjected to an ultra-high temperature treatment
(UHT-process). Such UHT-process is preferably applied in line, i.e.
before the liquid product is filled in the package of the sold
unit.
Application
[0068] The invention particularly pertains to the use of the
above-defined liquid composition for preventing and/or treating
neurodegenerative disorders, preferably selected from the group
consisting of memory decline and/or cognitive dysfunction,
Alzheimer's, Parkinson's and/or dementia. In the context of the
invention, "dementia" is especially understood "senile dementia".
Senile dementia or dementia is considered to comprise Alzheimer's
disease (AD). The invention also pertains to the use of the
aforementioned composition for promoting or supporting healthy
brain function.
[0069] The composition is particularly useful for the dietary
management of subjects suffering from neurodegenerative disorders,
preferably selected from the group consisting of memory decline
and/or cognitive dysfunction, Alzheimer's, Parkinson's and/or
dementia.
[0070] The present method preferably comprises the administration
of between 25 and 500 ml of the present composition, preferably
between 50 and 250 ml, preferably between 75 and 150 ml. Preferably
this is administered once a day. Relatively limited volumes are
easy to ingest by the target patients groups, e.g. elderly and AD
patients.
[0071] The invention also pertains to the treatment and/or
prevention memory impairment, particularly the treatment and/or
prevention of age-associated memory impairment (AAMI), Mild
Cognitive Impairment (MCI), significant episodic memory
impairments, prodromal dementia and/or prodromal Alzheimer, and/or
to treating elderly with memory and/or cognitive impairments, using
the aforedefined composition.
[0072] It is also an objective of the invention to provide a method
for preventing and/or treating one of the aforementioned disorders
or for supporting brain health in a subject in need thereof, by
administering to said subject the liquid composition as defined
above. The patient is preferably a person older than 50 years of
age.
Example 1
Sedimentation of the UMP-Containing Product without Thickener
[0073] A liquid formula containing per 100 ml: Energy 100 kcal
Protein 3.06 g (casein, whey 80/20) Carbohydrates 13.3 g
(maltodextrins, sucrose) Fat 3.73 g (fish oil, phospholipids)
comprising 0.96 g DHA and 0.24 g EPA; Uridine monophosphate 0.5 g
(disodium salt); Choline 0.32 g; Vitamin E 32 mg alpha-tocopherol
Vitamin C 64 mg Selenium 48 mcg; Vitamin B6 0.8 mg; Folic acid 0.32
mg; Vitamin B12 2.4 mcg; Magnesium 20 mg; Zinc 1.2 mg; Manganese
0.3 mg; Molybdenum 10 mcg; 0.1 g Na; 0.15 g K; 0.12 g Cl; 80 mg Ca;
70 mg P; 1.6 mg Fe; 27 mcg I; 0.18 mg Cu; 6.7 mcg Cr; 0.1 mg F;
0.16 mg vit A; 0.15 mg B1; 0.16 mg B2; 1.8 mg B3; 0.53 mg B5; 0.7
mcg D; 4.0 mcg biotin; and 5.3 mcg vitamin K; was tested for
sediment formation. Surprisingly the product was tested negative
for sediment formation after incubation at 0 months, minor sediment
formation after 1 month, significant sediment formation after two
months and high amounts of large sediment particles after 4 months
(see Table 1)
TABLE-US-00001 TABLE 1 Sediment formation Time (Visual after
sieving with (Months) Incubation temperature (.degree. C.) 150
micron sieve) 0 20 -- 1 37 +/- 2 20 + 4 37 ++ 5 37 ++
Example 2
Sedimentation of the UMP-Containing Product with Different
Concentrations of Thickener
[0074] The product described in example 1 was tested for sediment
formation using different concentrations of thickener
(Avicel-plus-BV2312 (mix of 85-92 wt. % cellulose gum and 8-15 wt.
% CMC). It was found that already relatively small amounts of the
thickener prevented sedimentation (see Table 2). Sedimentation was
evaluated using 150 micron sieve.
TABLE-US-00002 TABLE 2 Incubation Time temperature Concentration
thickener (w/w) (Months) (.degree. C.) 0.0% 0.10% 0.2% 0.3% 0.4%
0.5% 0 20 -- -- -- -- -- -- 1 37 ++ + -- -- -- -- 2 37 ++ + -- --
-- -- 4 20 ++ -- -- -- -- --
Example 3
A Liquid Formula with the Composition According to Example 1, and
0.4 g Vivapur MCG591F (Mix of 85-91 wt. % Cellulose Gum and 9-15
wt. % CMC) per 100 ml Water
[0075] The rheology properties of the thickener-containing formula
in terms of the loss factor tan .delta. was about 1, even after
several months. G' and G'' were between 10 and 10.sup.3. The
corresponding counterpart free from thickeners exhibited values of
10.sup.-3, 1 and 10.sup.4 for the storage modulus, loss modulus and
loss factor, respectively.
[0076] These numbers were roughly obtained over the whole range of
1-100% strain at 0.1 Hz and 20.degree. C., using a `cup and bob`
(cylinder geometry) Physica Couette-type viscometer (Physica US200,
USA).
[0077] The thickener-containing product was tested for the
formation of sediments over time. No sediment formation occurred
for an incubation period of 8 months (at 20.degree. C. and
37.degree. C.). This is indicative for the advantageous solution
the present invention provides.
* * * * *