U.S. patent application number 13/620216 was filed with the patent office on 2013-04-25 for nutritional composition comprising immunoglobulins and oligosaccharides.
This patent application is currently assigned to N.V. NUTRICIA. The applicant listed for this patent is Gunther Boehm, Johan Garssen, Laura M'Rabet, Raymonde Peter Peeters, Antony William Scammell, Bernd Stahl. Invention is credited to Gunther Boehm, Johan Garssen, Laura M'Rabet, Raymonde Peter Peeters, Antony William Scammell, Bernd Stahl.
Application Number | 20130102560 13/620216 |
Document ID | / |
Family ID | 34928473 |
Filed Date | 2013-04-25 |
United States Patent
Application |
20130102560 |
Kind Code |
A1 |
Boehm; Gunther ; et
al. |
April 25, 2013 |
NUTRITIONAL COMPOSITION COMPRISING IMMUNOGLOBULINS AND
OLIGOSACCHARIDES
Abstract
The present invention provides a method and composition for the
treatment and/or prevention of infection, said method comprising
orally administering a composition to a mammal, said composition
comprising a galactose containing indigestible oligosaccharide and
immunoglobulin from the milk or colostrum of hyperimmunized
cows.
Inventors: |
Boehm; Gunther; (Echzell,
DE) ; M'Rabet; Laura; (Amersfoort, NL) ;
Stahl; Bernd; (Rosbach-Rodheim, DE) ; Garssen;
Johan; (Nieuwegein, NL) ; Scammell; Antony
William; (Adelaide, AU) ; Peeters; Raymonde
Peter; (Adelaide, AU) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Boehm; Gunther
M'Rabet; Laura
Stahl; Bernd
Garssen; Johan
Scammell; Antony William
Peeters; Raymonde Peter |
Echzell
Amersfoort
Rosbach-Rodheim
Nieuwegein
Adelaide
Adelaide |
|
DE
NL
DE
NL
AU
AU |
|
|
Assignee: |
N.V. NUTRICIA
|
Family ID: |
34928473 |
Appl. No.: |
13/620216 |
Filed: |
September 14, 2012 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
11574123 |
Feb 22, 2007 |
8277835 |
|
|
PCT/NL2005/000612 |
Aug 24, 2005 |
|
|
|
13620216 |
|
|
|
|
Current U.S.
Class: |
514/54 |
Current CPC
Class: |
A23Y 2300/29 20130101;
A61P 1/00 20180101; A23L 33/12 20160801; A61P 43/00 20180101; A61P
31/00 20180101; A61K 39/42 20130101; A61P 31/14 20180101; A61P
11/00 20180101; A61P 31/18 20180101; A61K 35/741 20130101; A23V
2002/00 20130101; A23L 33/21 20160801; A61P 25/00 20180101; A23L
33/40 20160801; A61P 3/02 20180101; A61P 31/12 20180101; A61K
31/733 20130101; A61K 31/702 20130101; A61K 31/202 20130101; A61P
3/10 20180101; A61K 31/202 20130101; A61K 2300/00 20130101; A61K
31/702 20130101; A61K 2300/00 20130101; A61K 39/42 20130101; A61K
2300/00 20130101; A23V 2002/00 20130101; A23V 2200/324 20130101;
A23V 2250/28 20130101; A23V 2250/608 20130101; A23V 2250/304
20130101; A23V 2250/1642 20130101; A23V 2250/1882 20130101; A23V
2002/00 20130101; A23V 2200/3202 20130101; A23V 2200/3204 20130101;
A23V 2250/28 20130101; A23V 2250/608 20130101; A23V 2250/304
20130101; A23V 2250/1642 20130101; A23V 2250/1882 20130101; A61K
35/741 20130101; A61K 2300/00 20130101 |
Class at
Publication: |
514/54 |
International
Class: |
A61K 31/702 20060101
A61K031/702; A61K 31/202 20060101 A61K031/202; A61K 31/733 20060101
A61K031/733 |
Foreign Application Data
Date |
Code |
Application Number |
Aug 24, 2004 |
EP |
04077394.7 |
Claims
1. A method of reducing the incidence of respiratory tract
infection episodes comprising administering to an infant mammal in
need thereof a liquid infant formula composition supplemented with:
(a) 0.5-10 grams transgalactooligosaccharide per 100 grams dry
weight of the composition; and (b) 0.5-10 grams
fructopolysaccharide per 100 grams dry weight of the
composition.
2. The method of according to claim 1, wherein the composition is
supplemented with: (a) 2-5 grams transgalactooligosaccharide per
100 grams dry weight of the composition, and (b)1-5 grams
fructopolysaccharide per 100 grams dry weight of the
composition.
3. The method of according to claim 1, wherein the composition, as
a percentage of the total caloric value of the composition,
comprises: (a) 35-50% energy fat; (b) 7.5-12.5% energy protein; (c)
40-55% energy carbohydrate.
4. The method of according to claim 3, wherein at least 50%, by
weight, of the carbohydrate of the composition is lactose.
5. The method of according to claim 3, wherein the fat,
carbohydrate, or protein is of plant, non-human animal, bacterial,
or synthetic origin.
6. The method according to claim 1, wherein the composition
comprises indigestible dextrins, xylooligosaccharides,
arabinooligosaccharides, glucooligosaccharides,
mannooligosaccharides, fucooligosaccharides, fructans,
fructooligosaccharide, hydrolysed inulin, inulin, or lactose.
7. The method according to claim 6, wherein the composition
comprises a fructan, fructooligosaccharide, a hydrolysed inulin or
an inulin.
8. The method according to claim 1, wherein the composition
comprises a long chain polyunsaturated fatty acid (LC-PUFA).
9. The method according to claim 8, wherein the LC-PUFA is selected
from the group consisting of eicosapentaenoic acid (EPA, n-3),
docosahexaenoic acid (DHA, n-3) and arachidonic acid (AA, n-6).
10. The method according to claim 1, wherein the mammal is a
human.
11. The method according to claim 1, wherein the composition is
administered orally.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a division of U.S. patent application
Ser. No. 11/574,123, filed Feb. 22, 2007, which is the National
Phase of International Patent Application No. PCT/NL2005/000612,
filed Aug. 24, 2005, which claims priority from European Patent
Application No. 04077394.7, filed Aug. 24, 2004. The contents of
these applications are incorporated herein by reference in their
entirety.
FIELD OF THE INVENTION
[0002] The present invention provides a method for the prevention
and/or treatment of intestinal and/or respiratory tract infections,
said method comprising the administration of a nutritional
composition containing antibodies and indigestible
oligosaccharides.
BACKGROUND OF THE INVENTION
[0003] The respiratory tract and intestinal tract are common sites
for infection by pathogens. Despite the host organism often having
a functioning immune system, the respiratory and intestinal tract
frequently become infected because they are in direct contact with
the physical environment and are exposed to pathogenic
microorganisms (such as viruses, bacteria, protozoa, fungi, etc.)
that can be transmitted e.g. by touch, in the air and via food.
There are many microorganisms that cause illness in infants and
other individuals. For individuals whose immune systems are
compromised the risk of infection and serious illness is even
higher.
[0004] Respiratory syncytial virus (RSV) is the leading cause of
serious lower respiratory tract disease in infants and children.
Primary RSV infection occurs most often in children from 6 weeks to
2 years of age. RSV is estimated to cause as much as 75% of all
childhood bronchiolitis and up to 40% of all pediatric pneumonias.
Children at increased risk from RSV infection include preterm
infants and children with bronchopulmonary dysplasia, congenital
heart disease, congenital or acquired immunodeficiency and cystic
fibrosis. The fatality rate in infants with heart or lung disease
who are hospitalized with RSV infection is 3%-4%. Treatment options
for established RSV disease are limited. Severe RSV disease of the
lower respiratory tract often requires considerable supportive
care, including administration of humidified oxygen and respiratory
assistance.
[0005] Epidemiology studies also show that the incidence of asthma
and allergy in children up to 12 years of age is considerably
higher in children who have been hospitalized as infants with RSV
infection.
[0006] Acute otitis media (AOM) is the most frequent diagnosis in
physician offices among children 1-4 years of age. There is strong
correlation between the presence of virus in the nasopharynx and
the occurrence of otitis media; using sensitive molecular testing
methods (eg PCR), respiratory viruses have been detected in up to
90% of cases. RSV, adenoviruses and influenza virus are most
frequently seen; RSV accounts for 10-70% of viral isolations from
middle ear fluid. In a study of infants aged 2-24 months with
bronchiolitis, 86% had AOM; RSV was isolated from 71% of patients.
In a majority of cases, viral infection of the nasopharynx and
distal tubes cause Eustachian tube dysfunction, resulting in
transient negative middle ear pressure, thus facilitating secondary
viral or bacterial otitis media. The most common bacteria involved
in the mixed RSV-bacterial infections are Streptococcus pneumoniae
and Haemophilus influenzae. Further, there is evidence that
enhanced synthesis of proinflammatory cytokines and cell adhesion
molecules in the middle ear infected with RSV may contribute to the
inflammatory processes in otitis media.
[0007] RSV is also very prevalent in the elderly, and along with
influenza, a major cause of death. however, there is as yet no
vaccine available to prevent death caused by RSV.
[0008] Rotavirus infection can cause gastroenteritis. It most often
infects infants and young children. In children aged 3 months to 2
years, rotavirus is one of the most common causes of diarrhea, and
hospitalisations. Rotavirus leads to outbreaks of diarrhea during
the winter months and is particularly a problem in child-care
centers and children's hospitals. Almost all children have had a
rotavirus infection by the time they are 3 years old. Infected
infants may experience a spectrum of symptoms ranging from
vomiting, diarrhea, fever, dehydration and pain to more serious
long-term complications such as lactose malabsorption, carbohydrate
intolerance, early onset of protein intolerance and increased
susceptibility to other infections. Rotavirus is a major cause of
infant death in countries with poor public health systems.
[0009] Prevention of respiratory and intestinal infections has
proven difficult, with very few vaccines available to prevent
infections of the respiratory or intestinal tract, particularly in
relation to RSV and rotavirus. Prevention of RSV infection in
infants who are at high risk of death from RSV is attempted by the
regular intramuscular injection of a monoclonal antibody. This
monoclonal antibody has an effect in reducing the occurrence of
serious cases of RSV in at risk children. However, it is highly
invasive, very expensive, and only available to a small proportion
of people at risk from RSV infection and the ongoing illness that
can result.
[0010] Infants breast-fed with mother's milk have a reduced
occurrence and a reduced severity of respiratory tract and
intestinal tract infections. In the art, it is presently believed
that this reduced occurrence and severity is partly because
mother's milk contains immunoglobulin(s) with virus and/or other
microorganism neutralizing activity.
[0011] Treatment of intestinal and respiratory infection is often
difficult. Most cases are treated with palliative care only.
Treatment for rotavirus infection is limited to oral and/or
intravenous rehydration. Only a few effective drugs are available
for respiratory infection and often treatment requires pulmonary
administration of the drug. In young infants this leads to
significant stress. Therefore there is a need for further effective
agents that preferably can be administered without imposing stress,
or with at least decreasing the amount of stress imposed on infants
and children.
[0012] Some pathogens which gain entry to the body via the
intestinal and/or respiratory tract are associated with systemic
disease. For example, herpes virus can initially gain entry via the
respiratory tract before invading and residing in other parts of
the body to cause disease over time.
[0013] WO9613271 describes a composition for promoting
gastrointestinal health comprises an effective amount of a
beneficial human intestinal microorganism and an effective amount
of an immunoglobulin composition comprising concentrated
immunologically active immunoglobulins. Another composition for
restoring and maintaining gastrointestinal health comprises 40-60%
by weight of an immunoglobulin composition comprising concentrated
immunologically active immunoglobulins and 40-60% by weight of
soluble dietary fiber selected from inulin, fructooligosaccharides,
pectin, guar gum, and mixtures thereof.
SUMMARY OF THE INVENTION
[0014] In a multicentre clinical trial, the present inventors have
now surprisingly found that enteral administration a nutritional
composition containing galactooligosaccharides to infants can be
used to reduce the incidence and/or severity of infections,
particularly respiratory tract infections. The anti-infective
effects have not previously been described for galactose containing
soluble dietary fibers such as galactooligosaccharides (GOS).
[0015] Additionally, the present inventors have found that
galactooligosaccharides stimulate the immune system. These
observations have resulted in the hypothesis that the infection
reducing properties of galactose containing prebiotic components
(for example GOS) is the result of a combination of an improved
immune response and a positive stimulation of the intestinal
flora.
[0016] These insights in the mode of action of galactose containing
oligosaccharides have now resulted in the possibility to further
improve infant nutrition and have resulted in the development of
the present composition and the present methods to reduce
infections.
[0017] The present invention provides a composition that contains
galactose containing prebiotic components and one or more
immunoglobulins with activity against one or more pathogenic
micro-organisms, such as one or more pathogenic viruses, bacteria,
fungi, etc. Preferably the immunoglobulins are obtained from
mammalian colostrum or milk, produced by mammals treated with
antigens, e.g. cows hyperimmunized against one or more human
pathogens.
[0018] In particular, the combination of the immune-stimulatory
effects of the GOS in combination with the respiratory virus
neutralizing effects of the immunoglobulin provide an advantageous
combination for the treatment and prevention of respiratory tract
infection caused by viruses.
[0019] In a further preferred embodiment, the combination of the
Bifidobacteria stimulating effect, immune-stimulatory effect of
GOS, and virus neutralizing effects of the immunoglobulins is
particularly effective in the treatment and/or prevention of
intestinal infections, e.g. rotavirus infection.
[0020] The oligosaccharides and (one or more) specific
immunoglobulins act synergistically. The anti-rotavirus
immunoglobulin binds the rotavirus, which is subsequently
neutralized by the intestinal immune system.
[0021] The oligosaccharides stimulate the growth of
Bifidobacterium, which reduces rotavirus infection. Additionally
the oligosaccharides stimulate the reestablishment of a normal
intestinal flora during and after the rotavirus infection. This
reduces the severity and period of diarrhea, as well as the chances
for re-infection with a pathogen. Furthermore both ingredients can
be combined in infant nutrition, making additional intervention
unnecessary.
[0022] In a further preferred embodiment, the present invention
relates to a combination of one or more immunoglobulins, galactose
containing oligosaccharides and acid oligosaccharides. The acid
oligosaccharides prevent the adhesion of pathogens to the
epithelial cells, resulting in yet a further reduction of
infections (both incidence and/or severity of infection and/or
reinfections).
[0023] In a particular effective embodiment, the present invention
provides a composition comprising galactose containing
oligosaccharides, immunoglobulin with respiratory virus
neutralizing activity, and immunoglobulin with intestinal virus
neutralizing activity. The present composition can be easily made
by hyperimmunizing cows for both viruses and combining the mammary
secretion product with a galactose containing oligosaccharides.
[0024] The present compositions are particularly effective in
preventing and reducing infection in an infant without the need to
inject or administer orally multiple antigens by means of an active
vaccine, or to inject monoclonal antibodies. In fact preferably the
present composition is orally ingested and can be administered as a
food or a pharmaceutical preparation, preferably the present
composition is included in food compositions.
DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS
[0025] In one aspect the present invention provides a method for
the treatment and/or prevention of infection, said method
comprising administering a composition comprising: a galactose
containing indigestible oligosaccharide containing at least two
terminal saccharide units, wherein at least one terminal saccharide
unit is selected from the group consisting of glucose and
galactose; and at least one terminal saccharide is selected from
the group consisting of galactose and fucose; and immunoglobulin
having activity against one or more pathogenic microorganisms.
[0026] In a further aspect the present invention provides a
composition suitable for the treatment and/or prevention of
infection or disease comprising a galactose containing indigestible
oligosaccharide containing at least two terminal saccharide units,
wherein at least one terminal saccharide unit is selected from the
group consisting of glucose and galactose; and at least one
terminal saccharide is selected from the group consisting of
galactose and fucose; and an immunoglobulin having activity against
pathogenic microorganisms.
Oligosaccharides
[0027] The present invention comprises the administration of a
galactose containing indigestible oligosaccharide (GAL-oligo)
containing at least two terminal saccharide units, wherein at least
one terminal saccharide unit is selected from the group consisting
of glucose and galactose; and at least one terminal saccharide is
selected from the group consisting of galactose and fucose.
Preferably the saccharides of the GAL-oligo are .beta.-linked.
[0028] The term "terminal saccharide" refers to a saccharide, which
is bound to one other saccharide unit (e.g. galactose, glucose,
fructose or fucose). The present GAL-oligo preferably contains not
more than 4 terminal saccharides, preferably not more than 2.
[0029] The term "indigestible oligosaccharides" as used in the
present invention refers to saccharides which are not or only
partially digested in the intestine by the action of acids or
digestive enzymes present in the human upper digestive tract (small
intestine and stomach) but which are fermented by the human
intestinal flora.
[0030] In a preferred embodiment, the GAL-oligo contains at least
one terminal galactose and one selected from at least terminal
glucose and one terminal fucose. Even more preferably, the present
galactose containing indigestible oligosaccharide comprises at
least one terminal galactose and at least one terminal glucose.
Preferably the oligosaccharide consists of 2 terminal saccharide
units and 2 to 60 saccharide units in total.
[0031] Preferably the GAL-oligo is selected from the group
consisting of transgalactooligosaccharides,
galactooligosaccharides, lacto-N-tetraose (LNT),
lacto-N-neotetraose (neo-LNT), fucosyl-lactose, fucosylated LNT and
fucosylated neo-LNT. In a particularly preferred embodiment the
present method comprises the administration of
transgalactooligosaccharides ({galactose}.sub.n-glucose; wherein n
is an integer between 1 and 60, i.e. 2, 3, 4, 5, 6, . . . , 59, 60;
preferably n is selected from 2, 3, 4, 5, 6, 7, 8, 9, or 10).
Transgalactooligosaccharides (TOS) are for example sold under the
trademark Vivinal.TM. (Borculo Domo Ingredients, Netherlands).
Preferably the saccharides of the transgalactooligosaccharides are
.beta.-linked.
[0032] The present composition may be in powder or liquid form. The
present composition preferably comprises 0.1 to 12 grams of the
GAL-oligo per 100 gram dry weight of the composition, preferably
between 0.5 and 8 grams, more preferably between 1.0 and 7.5 grams.
After reconstitution of the powder in liquid and administration of
the liquid formula to the infant, these amounts of GAL-oligo
provide the desired effects without causing intestinal
discomfort.
Immunoglobulins
[0033] The present composition contains at least one immunoglobulin
having neutralizing activity against one or more pathogenic
microorganisms. The present immunoglobulin preferably has
neutralizing activity against one or more viruses, bacteria.
protozoa, parasites or prions. In a preferred embodiment the
immunoglobulin(s) have virus neutralizing activity.
[0034] When referring to "activity" or "neutralizing activity" of
an immunoglobulin, or a mixture of immunoglobulins (such as IgG and
IgA), reference is made to the ability of the immunoglobulin(s) to
bind the pathogen(s) against which the immunoglobulin was raised
and reduce it's harmful effects in vivo, particularly to bind the
antigens used for immunizing the animal. The activity can be tested
using in vitro or in vivo binding assays. A "specific
immunoglobulin" or "specific immunoglobulins" neutralizes one
pathogenic microorganism (e.g.
[0035] one virus or viral strain, one bacterial species or strain,
etc.), namely the one it/they was/were raised against.
[0036] Preferably the composition comprising an immunoglobulin (or
a mixture of immunoglobulins) having neutralizing activity against
one or more viruses that infect the respiratory tract (i.e. an
immunoglobulin having respiratory virus neutralizing activity)
and/or an immunoglobulin (or a mixture of immunoglobulins) having
neutralizing activity against one or more viruses that infect the
intestinal tract (an immunoglobulin having intestinal virus
neutralizing activity). More preferably the present composition
contains an immunoglobulin (or Ig mixture) capable of neutralizing
a virus selected from the group consisting of Myxovirus,
Orthomyxokvirus, Rhinovirus, Echoviruses, Coxsackieviruses,
Adenovirus, Respiratory Syncytial Virus (RSV), (human) Meta
pneumovirus (MPV), Coronavirus, Herpes virus, Measles virus,
Rotavirus, Calicivirus, Astrovirus and Cytomegalovirus. Most
preferably the composition comprising an immunoglobulin (or Ig
mixture) having respiratory syncytial virus neutralizing activity
and/or an immunoglobulin (or Ig mixture) having rotavirus
neutralizing activity.
[0037] Preferably the immunoglobulin is obtained or obtainable from
milk and/or colostrum from hyperimmunized mammals, preferably
hyperimmunized farm animals, most preferably hyperimmunized cows.
Preferably the immunoglobulin is obtained or obtainable from milk
from hyperimmunized cows. Methods for obtaining these
immunoglobulins from a hyperimmunised mammal are well known to the
skilled person and are for example described in GB1573995. The
immunoglobulin used in the present invention is preferably an
immunoglobulin mixture obtainable from hyperimmunized mammals. The
immunoglobulin mixture from hyperimmunized animals can be
differentiated from immunoglobulin mixtures from nonhyperimmunized
mammals, because these immunoglobulin mixtures have a higher
content of immunoglobulin directed to a specific microorganism,
e.g. virus, compared to immunoglobulin mixtures obtained from
normal milk. The immunoglobulin is preferably obtainable or
obtained from farm animals hyperimmunized with a respiratory virus
antigen and/or intestinal virus antigen., most preferably with both
a respiratory virus antigen and intestinal virus antigen. The
colostrum and the milk of these cows contain immunoglobulin with
respiratory virus neutralizing activity and immunoglobulin with
intestinal virus neutralizing activity. The immunoglobulin is
preferably obtainable or obtained from farm animals hyperimmunized
with a respiratory syncytial virus antigen and/or rotavirus
antigen, most preferably with both a respiratory syncytial virus
antigen and rotavirus antigen. In an alternative embodiment the
composition contains a mixture of milks and/or colostrums, wherein
at least one milk or colostrum contains immunoglobulin (or Ig
mixtures) having neutralizing activity against one or more viruses
that infect the respiratory tract and at least one milk or
colostrum which contains an immunoglobulin having neutralizing
activity against one or more viruses that infect the intestinal
tract. Hence, the present composition may be obtained from the
colostrum or milk of different animals, one set of animals
producing immunoglobulin against one or more respiratory viruses
and another set of animals producing immunoglobulin against one or
more intestinal viruses.
[0038] The immunoglobulin is preferably at least one or more
(mixtures) selected from the group consisting of IgM, IgY, IgG and
IgA,most preferably IgG and/or IgA. Preferably the present
composition contains IgG and IgA. Both classes are effective in
preventing the infection of epithelial cells by pathogenic
microorganisms, and both are found in colostrum and milk. Avian IgY
is also proven to be effective in preventing the infection of
epithelial cells by pathogenic microorganisms. Preferably the
present composition contains milk derived immunoglobulin(s),
wherein said milk is derived from hyperimmunised cows. Hence
preferably the weight ratio IgG/IgA is between 1 and 100.
[0039] The immunoglobulin is preferably obtained from at least one
dairy source selected from the group consisting of colostrum or
milk products, preferably fresh milk, fresh dairy products,
microfiltered milks with extended shelf life, whole colostrum
powder, skim colostrum powder, milk powder, colostrum protein
concentrate, milk protein concentrate milk protein isolate,
colostrum protein isolate whey protein concentrate and whey protein
isolate.
[0040] An infant receiving human breast milk as a substantial part
of their diet receives approximately 0.2 g to 2 g immunoglobulin
per day. The present method preferably comprises administering
between 0.05 gram immunoglobulin per kg body weight and 2 gram
immunoglobulin per kg body weight per day, more preferably between
0.1 grams/kg body weight and 1 grams/kg body weight immunoglobulin
per day.
[0041] The present composition, particularly the present infant
nutrition, contains between 0.25 wt. % and 5 wt. % immunoglobulin
based on dry weight of the present composition.
[0042] The present composition preferably contains at least 1 wt. %
immunoglobulin(s) having respiratory syncytial virus neutralizing
activity based on total weight of immunoglobulin, preferably at
least 2 wt. %, even more preferably at least 2.5 wt %. Preferably
not more than 90 wt. %. The present composition preferably contains
at least 1 wt. % immunoglobulin(s) having rotavirus neutralizing
activity based on total weight of immunoglobulin, preferably at
least 2 wt. %, even more preferably at least 2.5 wt %. Preferably
not more than 90 wt. %.
[0043] The weight ratio GAL-oligo: immunoglobulin in the present
composition is preferably between 0.01 and 100, more preferably
between 0.1 and 10.
[0044] The present composition preferably provides 0.1 to 30 g of
immunoglobulin(s) per day. When the composition is administered to
infant, it preferably provides 0.2 to 5 g of immunoglobulin per
day. When the composition is administered to adults it preferably
provides 0.5 to 15 g immunoglobulin per day.
[0045] In a further preferred embodiment the present composition
comprises an immunoglubolin having neutralizing activity against
one or more pathogenic microorganisms selected from the group
consisting of Helicobacter pylori, Enterotoxigenic Escherichia coli
(ETEC) and Shigella.
Digestible Galactose Saccharide
[0046] The present composition preferably comprises digestible
carbohydrate containing digestible galactose saccharide. The
composition contains at least 5 wt. % digestible galactose
saccharide based on total dry weight of the composition, said
saccharide being selected from the group consisting of galactose
and digestible galactose containing saccharide containing at least
two terminal saccharide units, wherein at least one terminal
saccharide unit is selected from the group consisting of glucose
and galactose; and at least one terminal saccharide is selected
from the group consisting of galactose and fucose. The preferred
composition used in the present method contains at least 5 wt %
digestible galactose saccharide based on total dry weight of the
present composition, preferably at least 10 wt. %, even more
preferably at least 25 wt. %.
[0047] The term "digestible galactose saccharide" as used in the
present invention refers to mono-, di-, tri- or polysaccharides
which are digested in the intestine of normal healthy human by the
action of acids or digestive enzymes present in the human upper
digestive tract (small intestine and stomach). Preferably lactose
is used in the present method.
[0048] Preferably the digestible galactose saccharide is lactose.
Preferably at least 50 wt % of the carbohydrate of the composition
used in the present method is lactose, preferably at least 75 wt.
%, even more preferably at least 90 wt. %. The term carbohydrate as
used herein refers to digestible carbohydrate, as is common
practice. The composition used in the present method preferably
contains at least 10 wt % lactose saccharide based on total dry
weight of the present composition, preferably at least 25 wt. %,
even more preferably at least 40 wt. %, most preferably at least 50
wt. %. In order to provide optimal nutrition to an infant, i.e. a
composition which is highly similar to human milk, the present
method preferably comprises the administration of a composition
comprising between 40 and 60 wt. % lactose based on total dry
weight of the composition.
[0049] In a further preferred embodiment the present invention
relates to the administration of about 2 to 50 grams lactose per
serving, preferably about 10 to 25 grams lactose per serving. A
serving is preferably between 5 and 500 ml, more preferably between
100 and 300 ml.
[0050] The weight ratio digestible galactose saccharide: galactose
containing indigestible oligosaccharide is preferably above 1, more
preferably above 5, even more preferably above 10. The ratio is
preferably below 1000, more preferably below 100.
Combinations of Oligosaccharides
[0051] In a particularly preferred embodiment the present method
comprises the administration of the present GAL-oligo and a second
indigestible oligosaccharides selected from the group consisting of
indigestible dextrins, xylooligosaccharides,
arabinooligosaccharides, glucooligosaccharides,
mannooligo-saccharides, fucooligosaccharides fructans--Levan-type
((.beta.-D-(2.fwdarw.6)-fructofuranosyl).sub.n
.alpha.-D-glucopyranoside) and fructans--Inulin-type
(.beta.-D-2.fwdarw.1)-fructofuranosyl).sub.n
.alpha.-D-glucopyranoside). Preferably the second oligosaccharide
is selected from the group consisting of inulin, hydrolysed inulin
and fructooligosaccharides.
[0052] The present composition preferably comprises between 0.5 and
12 grams of the second indigestible oligosaccharide, more
preferably between 1 and 8 grams of the second indigestible
oligosaccharide per 100 gram dry weight of the present composition.
The DP of the second oligosaccharide is preferably below 40, even
more preferably between 10 and 30.
[0053] Optimally, the present composition comprises between 1 and
12 grams water-soluble indigestible oligosaccharides in total (i.e.
with or without a second, third, etc water-soluble indigestible
oligosaccharide) per 100 gram dry weight of the present
composition, more preferably between 2 and 9 grams in total.
[0054] Preferably the weight ratios: [0055] a. (oligosaccharides
with DP 2 to 5): (oligosaccharides with DP 6 to 9); and [0056] b.
(oligosaccharides with DP 10 to 60): (oligosaccharides with DP 6 to
9) are both above 1.
[0057] Preferably both weight ratios are above 2, even more
preferably above 5.
[0058] The present method preferably comprises the administration
of 0.5 to 10 gram transgalactooligosaccharides with DP between 1
and 10 per 100 gram dry weight of the composition, more preferably
between 2 and 5 gram. The present invention preferably comprises
0.5 to 10 gram fructopolysaccharide with DP between 15 and 40 per
100 gram dry weight of the composition, more preferably between 1
and 5 gram. The term "fructopolysaccharide" refers to an
indigestible polysaccharide carbohydrate comprising a chain of at
least 10 .beta.-linked fructose units.
Acid Oligosaccharides
[0059] In a further preferred embodiment the second indigestible
oligosaccharide is an acid oligosaccharide. The term acid
oligosaccharide refers to oligosaccharides comprising at least one
acidic group selected from the group consisting of
N-acetylneuraminic acid, N-glycoloylneuraminic acid, free or
esterified carboxylic acid, sulfuric acid group and phosphoric acid
group. The acid oligosaccharide preferably is a polyhexose.
Preferably, at least one of the aforementioned acid groups is
situated at the terminal hexose unit of the acid oligosaccharide.
Preferably the acid oligosaccharide contains a carboxylic acid at
the terminal hexose unit, wherein said carboxylic acid group may be
free or esterified. Methods for the manufacture of esterified
pectin hydrolysates that can be suitably used in the present method
and composition are provided in WO 01/60378 and/or WO02/42484,
which are hereby incorporated by reference.
[0060] Preferably, the acid oligosaccharide has one, preferably
two, terminal uronic acid units, which may be free or esterified.
Preferably the terminal uronic acid unit is selected from the group
consisting of galacturonic acid, glucuronic acid, guluronic acid,
iduronic acid, mannuronic acid, riburonic acid and alturonic acid.
These units may be free or esterified. In an even more preferred
embodiment, the terminal hexose unit has a double bond, which is
preferably situated between the C.sub.4 and C.sub.5 position of the
terminal hexose unit. Preferably one of the terminal hexose units
comprises the double bond. The terminal hexose (e.g. uronic acid)
preferably has a structure according to Formula 1:
##STR00001## [0061] wherein; [0062] R is preferably selected from
the group consisting of hydrogen, hydroxy or acid group, preferably
hydroxy (see above); and at least one selected from the group
consisting of R.sub.2, R.sub.3, R.sub.4 and R.sub.5 represents
N-acetylneuraminic acid, N-glycoloylneuraminic acid, free or
esterified carboxylic acid, sulfuric acid group and phosphoric acid
group, and the remaining of R.sub.2, R.sub.3, R.sub.4 and R.sub.5
representing hydroxy and/or hydrogen. Preferably one selected from
the group consisting of R.sub.2, R.sub.3, R.sub.4 and R.sub.5
represents N-acetylneuraminic acid, N-glycoloylneuraminic acid,
free or esterified carboxylic acid, sulfuric acid group and
phosphoric acid group, and the remaining of R.sub.2, R.sub.3,
R.sub.4 and R.sub.5 represent hydroxy and/or hydrogen. Even more
preferably one selected from the group consisting of R.sub.2,
R.sub.3, R.sub.4 and R.sub.5 represents free or esterified
carboxylic acid and the remaining of R.sub.2, R.sub.3, R.sub.4 and
R.sub.5 represent hydroxy and/or hydrogen; and n is an integer and
refers to a number of hexose units (see also Degree of
Polymerisation, below), which may be any hexose unit. Suitably n is
an integer between 1-5000 representing the number of hexose units
said hexose units preferably being uronic acid, even more
preferably being galacturonic acid units. The carboxylic acid
groups on these units may be free or (partly) esterified, and are
preferably at least partly methylated.
[0063] Most preferably, R.sub.2 and R.sub.3 represent hydroxy,
R.sub.4 represent hydrogen and R.sub.5 represents free or
esterified carboxylic acid.
[0064] The acid oligosaccharide as used in the present method has a
degree of polymerisation (DP) between 1 and 5000, preferably
between 1 and 1000, more preferably between 2 and 250, even more
preferably between 2 and 50, most preferably between 2 and 10. If a
mixture of acid oligosaccharides with different degrees of
polymerisation is used, the average DP of the acid oligosaccharide
mixture is preferably between 2 and 1000, more preferably between 3
and 250, even more preferably between 3 and 50.
[0065] The acid oligosaccharides are preferably characterised by a
degree of methoxylation above 20%, preferably above 50% even more
preferably above 70%. Preferably the acid oligosaccharides have a
degree of methylation above 20%, preferably above 50% even more
preferably above 70%.
[0066] The acid oligosaccharide is preferably administered in an
amount of between 10 mg and 100 gram per day, preferably between
100 mg and 50 grams per day, even more between 0.5 and 20 gram per
day
Respiratory and Intestinal Tract Infections
[0067] The present invention provides a method for the treatment
and/or prevention of respiratory tract infection and/or intestinal
tract infections. The most common and serious respiratory and
intestinal infections in infants and young children are typically
caused by viral infection, however the invention is also suitable
for treating and/or prevention infection by other pathogenic
micro-organisms, such as but not limited to pathogenic bacteria,
protozoa, parasites, prions, fungi, etc. "Pathogenic
microorganisms" refer herein to microscopic or submicroscopic
organisms or agents, including viruses and prions, which are
capable of causing disease in humans. In a preferred embodiment the
present method provides a method for the treatment and/or
prevention of respiratory tract infection caused by Myxovirus,
Orthomyxokvirus, Rhinovirus, Echoviruses, Coxsackieviruses,
Adenovirus, Parainfluenzavirus, Respiratory Syncytial virus (RSV),
(human) Meta pneumovirus (MPV), Coronavirus, Herpes virus, Measles
virus, Cytomegalovirus, Histoplasma capsulatum, Coccidioides
immitis, Blastomyces dermatitidis, Cryptococcus Aspergillus,
Mucorales. The present method is particularly suitable for the
treatment and/or prevention of respiratory syncytial virus
infection and/or rotavirus infection.
[0068] In a preferred embodiment, the present method relates to the
treatment and/or prevention of respiratory tract infection disease,
preferably selected from the group consisting of tuberculosis,
bronchitis, bronciolitis, tracheitis, pneumonia, sinusinitis,
rhinitis, severe acute respiratory syndrome (SARS), croup
epiglottitis, histoplasmosis, coccidioidomycosis, blastomycosis,
cryptococcosis, aspergillosis, mucormycosis, lung abcess and otitis
media. In a particularly preferred embodiment the invention
provides a method for the treatment and/or prevention of viral
pneumonia and/or bronchitis. The present method is also suitable
for the treatment and/or prevention of symptoms of respiratory
tract infection selected from the group consisting of irritation in
the lungs, congestion in the lungs, excessive mucus production,
breathlessness (i.e. difficulty with breathing), particularly
breathlessness. The present method is also suitable for the
treatment and/or prevention of asthma.
[0069] In a further preferred embodiment the present invention
provides a method for the treatment and/or prevention of intestinal
tract infections, particularly gastroenteritis, more preferably
viral gastroenteritis. The present method is also suitable for the
treatment and/or prevention of symptoms and sequelae of viral
gastroenteritis selected from the group consisting watery diarrhea,
vomiting, fever, chills and abdominal pain. The present method is
also suitable for the treatment and/or prevention of more serious
long-term complications such as lactose malabsorption, carbohydrate
intolerance, early onset of protein intolerance and increased
susceptibility to other infections.
[0070] By preventing initial infection of the intestinal and
respiratory tract by pathogens that cause systemic disease, the
invention can also play a role in the prevention of systemic
disease including herpes simplex type I and II.
Treatment Group
[0071] The present method is particularly suitable for treatment
and/or prevention of respiratory and intestinal infections in
humans, preferably (healthy) children with the age between 0 and 10
years, preferably infants with the age between 0 and 4 years, and
more preferably infants under 1 year of age. The present method can
be advantageously used for the treatment and/or prevention of the
above mentioned disease, infection and symptoms in premature
infants (an infant born before 37 weeks gestation). Infants and
young children at high risk due to other health complications, or
due to their environment can also be suitably treated.
[0072] The present method is particularly suitable for the
treatment and/or prevention of respiratory and/or intestinal
infections in immunocompromised mammalian subjects, preferably
elderly (human above the age of about 60), subjects infected with
human immunodeficiency virus (HIV), subjects suffering from one or
more of the following diseases: nephrotic syndrome, multiple
myeloma, lymphoma, Hodgkin's disease, subjects which have undergone
organ transplantation, subjects with chronic illnesses of the hart,
kidney or lungs (especially chronic obstructive pulmonary disease
(COPD), lung emphysema, sarcoidosis, cystic fybrosis,
bronchiectasis, lung cancer, atelectasis, respiratory failure,
occupational lung diseases, asthma), diabetes and alcoholism. The
present method is advantageously used for the treatment and/or
prevention of patients with COPD, HIV infection and/or diabetes, as
these patients are often weakened by the disease.
[0073] In a further preferred embodiment, the present method
comprises the administration of the present composition to humans,
mostly hospitalized patients, that are on a ventilator or
artificial breathing machine, or in the intensive care unit, as
these patients are particularly vulnerable for viral
infections.
[0074] An aspect of the present invention therefore is the
prevention and/or reduction of occurrence and severity of a range
of illness which would ordinarily be expected to result from
infection of the intestinal tract. An aspect of the present
invention is to combine the immune stimulating effects of
indigestible oligosaccharides with immunoglobulin that can help
prevent the initial ingress and infection by pathogens which cause
systemic illness other than respiratory or intestinal illness.
Nutritional Formula
[0075] Drug treatment of respiratory tract infection in infants
with the age between 0 and 4 is often cumbersome because many of
the medicaments have to be administered via the pulmonary route.
There are no effective vaccines available to prevent respiratory
disease in this age group. Prevention by means of injectable
monoclonal antibodies is invasive, expensive and only partly
effective. The present invention provides a method for treatment
and/or prevention of respiratory infections comprising orally
administering a nutritional composition. Hence, the present method
also overcomes the problem of pulmonary or intramuscular
administration.
[0076] The nutritional composition suitable for use in the present
method preferably contains between 10 and 60 en % lipid, between 5
and 50 en % protein, between 15 and 90 en % carbohydrate. More
preferably the nutritional composition contains between 7.5 to 12.5
energy % protein; 40 to 55 energy % carbohydrates; and 35 to 50
energy % fat. (en % is short for energy percentage and represents
the relative amount each constituent contributes to the total
caloric value of the preparation).
[0077] The nutritional composition preferably also contains at
least one long chain polyunsaturated fatty acid (LC-PUFA)
preferably selected from the group consisting of eicosapentaenoic
acid (EPA, n-3), docosahexaenoic acid (DHA, n-3) and arachidonic
acid (AA, n-6), as these further reduce the respiratory tract
infections and/or symptoms thereof. Preferably the present
composition contains AA and DHA, even more preferably AA, DHA and
EPA. The present combination of indigestible oligosaccharide(s) and
LC-PUFA acts synergistically.
[0078] Preferably the present composition comprises at least 0.1
wt. %, preferably at least 0.25 wt %, more preferably at least 0.5
wt. %, even more preferably at least 0.75 wt. % LC-PUFA with 20 and
22 carbon atoms of the total fat content. The content of LC-PUFA
with 20 and 22 carbon atoms in the present composition, preferably
does not exceed 15 wt. % of the total fat content, preferably does
not exceed 10 wt. %, even more preferably does not exceed 5 wt. %
of the total fat content.
[0079] The EPA content preferably does not exceed 15 wt. % of the
total fat, more preferably does not exceed 5 wt. %, most preferably
does not exceed 1 wt. %, but is preferably at least 0.05 wt %, more
preferably at least 0.1 wt. % of the total fat. The DHA content
preferably does not exceed 10 wt. %, more preferably does not
exceed 5 wt. %, most preferably does not exceed 1 wt. %, but is at
least 0.1 wt % of the total fat. The present composition preferably
comprises at least 0.1 wt. % AA, even more preferably at least 0.25
wt. % AA, most preferably at least 0.5 wt. % AA based on total fat.
The AA content preferably does not exceed 5 wt. %, more preferably
does not exceed 1 wt. % of the total fat.
[0080] Composition suitable for administration to adults may
comprise increased amounts of LC-PUFA. The EPA content in this case
preferably does not exceed 15 wt. % of the total fat, more
preferably does not exceed 10 wt. %, but is preferably at least
0.05 wt %, more preferably at least 0.1 wt. % of the total fat. The
DHA content preferably does not exceed 15 wt. %, more preferably
does not exceed 10 wt. %, but is at least 0.1 wt % of the total
fat. The present composition preferably comprises at least 0.1 wt.
% AA, even more preferably at least 0.25 wt. % AA, most preferably
at least 0.5 wt. % AA based on total fat. The AA content preferably
does not exceed 15 wt. %, more preferably does not exceed 10 wt. %
of the total fat.
[0081] The present method does not include a method comprising the
administration of a composition consisting of human milk. Hence,
preferably the present method includes the administration of a
composition comprising a substance of non-human origin which is
preferably a nutritional substance suitable for oral administration
to a human, more preferably a fiber carbohydrate, fat and/or
protein of non-human origin, preferably from plant, animal,
bacterial or synthetic origin.
Pharmaceutical Formula
[0082] The present invention provides a method for treatment and/or
prevention of respiratory and/or intestinal infections comprising
orally administering a pharmaceutical composition with indigestible
oligosaccharides and immunoglobulin. Preferred pharmaceutical
formulations can be in liquid or solid form. Liquid form products
can include immunoglobulin that has been derived from colostrum,
milk or egg yolk by a number of methods to remove contaminating
bacteria and extend shelf life. A preferred method for removing
bacteria is by microfiltration. Solid form pharmaceutical
compositions include powders for reconstitution, tablets, chewable
tablets and capsules. A person skilled in the art can formulate
products including the invention to deliver the active ingredients
largely intact to certain parts of the intestine.
Probiotics
[0083] In a further preferred embodiment, the present method
comprises the administration of the above-described indigestible
oligosaccharide(s) and/or immunoglobulins ? and a probiotic.
Preferably the probiotic is selected from the group Lactobacillus,
Lactococcus, Bifidobacterium, Enterococcus, Propionibacterium,
Pediococcus, Bacillus and Streptococcus and more preferably from
the group consisting of Lactobacillus and Bifidobacterium. The
probiotic is preferably a non-pathogenic lactic acid-producing
bacterium. The combination of the present indigestible
oligosaccharide(s) and the probiotic bacteria acts
synergistically.
EXAMPLES
Example 1
Effectiveness of Transgalactooligsaccharides in Standard Infant
Formula's for Prevention of Respiratory Tract Infections in Infants
of the Age Until 1 Year
[0084] Method: A multicentre clinical trial was performed in Italy,
including 7 centers and 56 paediatricians. At the moment
breast-feeding was stopped, infants were divided into two groups.
The infants in Group A (n=69) were administered Nutrilon.TM. 1 or 2
supplemented with oligosaccharides to a final concentration of 0.36
g transgalactooligosaccharides/100 ml (Vivinal-GOS.TM.; Borculo
Domo Ingredients, Netherlands) and 0.04 g fructopolysaccharide/100
ml (Raftiline HP.TM., Orafti, Tienen, Belgium). The infants in
control group B (n=82) received standard Nutrilon.TM. 1 or 2.
Nutrilon 1.TM. contains 45 en % carbohydrate, 8 en % protein and 47
en % fat; about 97 wt % lactose based on total carbohydrate; 7.3
gram lactose per 100 ml; about 54 gram lactose per 100 gram dry
weight of the complete composition.
[0085] Nutrilon 2.TM. contains 47 en % carbohydrate, 10 en %
protein and 43 en % fat; about 96 wt % lactose based on total
carbohydrate; 7.9 gram lactose per 100 ml; about 54 gram lactose
per 100 gram dry weight of the complete composition.
[0086] Results: The age of the infants varied between 2 and 9
months and the infants were followed for 6 months. Both groups did
not show any difference in nutritional intake. In group A a total
number of 32 upper respiratory tract infection episodes was
observed. In control group B a total number of 60 upper respiratory
tract infection episodes was observed. Thus the incidence of upper
respiratory infection episodes was significant (p<0,01) lower in
group A vs group B.
Example 2
Immune Stimulatory Effect of Composition with Indigestible
Galactose Containing Oligosaccharides
[0087] Experimental setup: Diets comprising indigestible galactose
containing oligosaccharides were tested on the delayed-type
hypersensitivity (DTH) response by orally ingestion of diets
containing indigestible galactose containing oligosaccharides by
mice. The DTH is a parameter for Th1 immunological response and is
determined by measuring the increase in ear swelling after local
antigen challenge. For the DTH responses, mice were i.e. injected
with 25 .mu.l dialysed Influvac in both ears as a DTH
challenge.
[0088] Neutral oligosaccharide mixture (GF) containing
galactooligosaccharides (GOS) (Vivinal-GOS.TM.(Borculo Domo
Ingredients, Netherlands) and fructooligosaccharides (FOS)
(Raftiline HP.TM., Orafti, Tienen, Belgium) were used in a weight
ratio GOS:FOS of 9:1. Diets containing 1, 2.5 and 5 wt. % GF based
on total weight of the diet were tested.
[0089] Results: Administering diets with 1 or 2.5 wt. % GF induces
a statistically significant increase in the DTH (see Table 1).
These results are indicative for the immunestimulatory effects of
indigestible galactose containing oligosaccharides, which may even
be enforced by including of fructopolysaccharides.
TABLE-US-00001 TABLE 1 Wt % oligosaccharides in diet DTH response
(%) 0 (control) 100 1 wt % GF 132* 2.5 wt % GF 129* *indicates
significantly different (P < 0,05) from control
Example 3
Anti-Infective Composition
[0090] Infant formula with 40 en % lipid, 11 en % protein and 49 en
% carbohydrate containing: [0091] a. milk obtained from cows
hyperimmunized with rotavirus antigen and E. coli antigen and thus
containing immunoglobulin (IgG) having rotavirus neutralizing
activity, and activity against E. coli. [0092] b.
Transgalactoligosaccharides (Vivinal.TM. (Borculo Domo Ingredients,
Netherlands).) [0093] c. Lactose
Example 4
Anti-Infective Composition
[0094] Infant formula with 40 en % lipid, 11 en % protein and 49 en
% carbohydrate containing: [0095] a. milk obtained from cows
hyperimmunized with rotavirus antigen and respiratory syncytial
virus antigen, and thus containing immunoglobulin (IgG) having
rotavirus neutralizing activity and immunoglobulin (IgG) having
respiratory syncytial virus neutralizing activity. [0096] b.
Transgalactoligosaccharides (Vivinal.TM. (Borculo Domo Ingredients,
Netherlands).) [0097] c. Lactose
* * * * *