Note: Descriptions are shown in the official language in which they were submitted.
CA 02466278 2004-05-06
WO 03/039556 PCT/GB02/04980
-1-
REHYDRATING FORMULATION
The present invention relates to an aqueous formulation for combatting
dehydration comprising a low concentration of galactose and a source of sodium
ions (eg a
sodium salt).
There are a number of circumstances in which a subject may suffer dehydration
and associated deficiencies such as loss of mineral salts. For example,
exercise acts to
deplete the body of fuel stores and increases the rate of perspiration causing
loss of water
and mineral salts. These losses can be significant if exercise is prolonged
and particularly
if ambient temperatures are moderate or high. Other circumstances which may
lead to
dehydration include excessive temperatures, nutritional deprivation, fever,
diarrhoea and
vomiting excess as a result of (for example) enterotoxin effects (eg cholera
typically in the
third world), viral effects (eg rotavirus typically in the developed world) or
post surgical
rest (eg when GI rest is important). Alternatively, the circumstances which
may lead to
dehydration may be self induced (eg through alcohol consumption). In extreme
cases, loss
of fluid and/or electrolytes may be clinically important or even life
threatening, in
particular in children and the elderly.
Humans do not function efficiently when dehydrated or when they are suffering
an
electrolyte imbalance. Rehydrating drinks containing inorganic salts and/or
high sugar (eg
glucose) content are well established in combatting these disorders. However
the
administration of glucose may lead to exaggerated insulin responses.
Galactose is a naturally occurring hexose for which worldwide demand is
negligible and reported uses scarce. Prior publications relating to galactose
include:
(1) WO-A-01/28360 (Marathade Ltd) discloses high energy multi-saccharide food
products
containing galactose and creatine for use in sport or to combat hunger or
fatigue;
(2) EP-A-0340491 (Biodyn Ag) discloses a foodstuff in which the saccharide
component is
primarily galactose;
CONFIRMATION COPY
CA 02466278 2004-05-06
WO 03/039556 PCT/GB02/04980
_2_
(3) WO-A-96/18313 (University of Nottingham) discloses formulations for
increasing
creatine uptake comprising creatine, insulin and a simple carbohydrate such as
galactose;
(4) WO-A-98/06418 (Mannatech, Inc) discloses dietary supplements comprising
galactose
for nutritional support and treating various disorders;
(5) US-A-5843921 (Childrens Hospital of Los Angeles) discloses formulations
for
treatment of diabetes comprising less than 3g per unit of simple sugars
including galactose;
(6) WO-A-96/08979 (Quadrant Holdings Cambridge Ltd) discloses sports beverages
comprising trehalose and galactose;
(7) WO-A-90/02494 (Svenslca Mejeriernas Riksforening Ekonomi AB) discloses a
sports
drink comprising galactose originating from a desalinated and hydrolised whey
concentrate;
(8) EP-A-349712 (Biodyn Ag) discloses foodstuffs containing a tooth protecting
amount of
galactose in the form of lactose hydrosylate; and
(9) EP-A-184121 (Biodyn Ag) discloses anti-caries additives for sucrose
foodstuffs
comprising galactose I.
US-A-5780094 (Marathade Limited) discloses a rehydrating sports drink
containing a high concentration of galactose and a proportion of glucose. The
absorption of
water in the intestine is efficient and effective when driven by sodium co-
transport
involving a high concentration of galactose and glucose. Galactose
advantageously effects
more rapid intestinal uptake of water than does glucose.
The present invention is based on the recognition that being physiologically
adapted to effectively metabolise galactose and glucose (the two constituent
sugars of
lactose in milk) children are able to exploit sodium co-transport for
effective rehydration
using a low concentration of galactose. In particular, the present invention
relates to an
improved rehydrating aqueous formulation comprising a low concentration of
galactose
and a sodium salt to combat dehydration resulting from (for example)
diarrhoea.
Thus viewed from one aspect the present invention provides an aqueous
formulation for combatting dehydration comprising galactose at a concentration
in the
range 25 to 135mM, a source of sodium ions and water.
CA 02466278 2004-05-06
WO 03/039556 PCT/GB02/04980
-3-
The aqueous formulation of the invention is generally more effective than a
conventional glucose-containing rehydrating solution in treating extreme
dehydration
which might otherwise be fatal to a child. Moreover galactose (unlike glucose)
does not
elicit a primary insulin response.
In a preferred embodiment, the concentration of galactose in the aqueous
formulation is in the range 25 to 130mM, preferably 37 to 120mM, more
preferably 40 to
120mM, especially preferably 45 to 90mM.
The source of sodium ions in the aqueous formulation of the invention is
typically
a sodium salt. Any physiologically tolerable sodium salt will suffice.
Examples include
sodium lactate, sodium chloride, sodium citrate, trisodium citrate, sodium
hydrogenphosphate, disodium hydrogen phosphate and sodium bicarbonate. The
counter
ion (eg chloride, bicarbonate, phosphate, hydrogenphosphate or citrate) may
provide
stability and buffering capacity and sodium citrate is advantageous for
acidosis associated
with diarrhoea of specific aetiology (eg viral). Sodium chloride is preferred.
The concentration of sodium ions may be adapted to facilitate sodium co-
transport
and replacement of electrolyte loss. In a preferred embodiment, the
concentration of
sodium ions in the aqueous formulation is in the range 25 to 100mM, preferably
30 to
90mM, particularly preferably 35 to 90mM, more preferably 45 to 90mM, yet more
preferably 60 to 90mM. For combatting dehydration as a symptom of severe
diarrhoea (eg
caused by enterotoxin effects), higher sodium concentrations are preferred (eg
80-90mM
such as about 90mM). For combatting dehydration as a symptom of less severe
diarrhoea
(eg caused by viral effects or when hypernatraemia is a risk), lower sodium
concentrations
are preferred.
An embodiment of the aqueous formulation further comprises one or more sources
of additional ions (eg potassium, magnesium, calcium or zinc) to
advantageously achieve
replacement of minerals which have been lost as a symptom of (for example)
diarrhoea.
The source of an additional ion is typically a salt (eg a mineral salt) such
as a chloride.
CA 02466278 2004-05-06
WO 03/039556 PCT/GB02/04980
-4-
Preferably the aqueous formulation comprises a source of potassium ions (eg a
potassium salt such as potassium chloride). The potassium salt serves to
replace electrolyte
loss. In a preferred embodiment, the concentration of potassium ions in the
aqueous
formulation is in the range 5 to 35mM, preferably 10 to 30mM, particularly
preferably 15
to 25mM, more preferably about 20 to 25mM.
An embodiment of the aqueous formulation of the invention further comprises
one
or more additional carbohydrates. In an embodiment of the invention, the one
or more
additional carbohydrates may be a digestible saccharide such as a digestible
saccharide
selected from one or more of the group consisting of monosaccharides,
disaccharides,
oligosaccharides and polysaccharides. These may be natural or synthetic
saccharides. For
example, the one or more additional carbohydrates may be selected from the
group
consisting of glucose, sucrose, dextrose, fructose, lactose and maltose.
Preferably the
additional carbohydrate is a monosaccharide, particularly preferably glucose.
In situations
where the osmolality of the aqueous formulation is important (eg where
hyperosmolar or
isomolar solutions are contra indicated), maltodextrin or higher
oligosaccharide may be
used in place of glucose.
In a preferred embodiment, the galactose and optionally one or more additional
carbohydrates of the aqueous formulation are present in a total amount
sufficient to meet
the carbohydrate requirements of sodium co-transport for effective
rehydration. In a
preferred embodiment, the total concentration of carbohydrate is in the range
50 to 300mM,
preferably 50 to 200mM, particularly preferably 55 to 175mM, more preferably
60 to
135mM, especially preferably 90 to 130mM.
In a preferred embodiment of the formulation, galactose and glucose are
present in
a total amount sufficient to meet the carbohydrate requirements of sodium co-
transport in
effective rehydration. Typically the ratio of molar concentration of galactose
and glucose is
in the range 0.6:1 to 1:0.6, preferably 0.8:1 to 1:0.8, particularly
preferably 0.9:1 to 1:0.9,
more preferably the molar concentration ratio is about 1:1.
CA 02466278 2004-05-06
WO 03/039556 PCT/GB02/04980
-5-
In a preferred embodiment, the concentration of glucose in the aqueous
formulation is in the range 30 to 135mM, preferably 35 to 130mM, particularly
preferably
37 to 120mM, more preferably 40 to 100mM, especially preferably 45 to 80mM.
In situations where the osmolality of the aqueous formulation is important (eg
where hyperosmolar or isomolar solutions are contra indicated), maltodextrin
or higher
oligosaccharide is preferably used in place of glucose. Thus the ranges of
preferred glucose
concentration may be satisfied by a concentration of an oligosaccharide with
an appropriate
chain length. For example, in place of glucose at 60mM, a maltodextrin of
average chain
length six could be used at l OmM.
A general purpose formulation might typically have a ratio of sodium ion
concentration:carbohydrate concentration of about 1:2 eg a concentration of
sodium ions of
about 60mM and galactose and glucose present at a total concentration of
120mM. Such a
formulation would be useful where the circumstance leading to dehydration is
diarrhoea as
a result of post surgical rest (eg when GI rest is important) or the
circumstance leading to
dehydration is self induced (eg through alcohol consumption).
The aqueous formulation of the invention may be administered by any convenient
route. Preferably the aqueous formulation is adapted for oral administration.
For example,
the aqueous formulation may be palatable and for this purpose may further
comprise
natural or synthetic flavourings such as fruit flavourings (eg blackcurrant,
strawberry,
apple, citrus, lemon, lime, orange or cranberry) or caffeine and sweeteners.
The aqueous formulation of the invention may further comprise physiologically
tolerable stabilisers, anti-oxidants (eg ascorbic acid) and preservatives (eg
sodium benzoate
or sorbic acid) as desired.
The administration dosage generally depends on the level of dehydration and
the
size and age of the subject. Generally it is advisable for the dose to be
equivalent to or
slightly greater than the actual or expected loss of bodily water and to be
administered at
CA 02466278 2004-05-06
WO 03/039556 PCT/GB02/04980
-6-
appropriate intervals. Typically a dose of aqueous formulation is in the range
100 to 250m1.
Citric acid may be added to the aqueous formulation for partial or total
replacement of citrate ion and for buffering purposes (typically to maintain
pH in the range
2 to 6). Where the source of sodium or other ions is a citrate salt and/or
citric acid is added,
the concentration of citrate ion in the aqueous formulation may be in the
range 5 to 30mM,
preferably 10 to 25mM, particularly preferably 10 to lSmM. A phosphate salt
may be used
as an alternative buffering agent.
Where the source of sodium (and optionally additional ions) is a chloride
salt, the
concentration of chloride ion in the aqueous formulation may be in the range
10 to 1 OOmM,
preferably 30 to 90mM, more preferably 40 to 85mM, especially preferably 45 to
80mM.
For combatting dehydration as a symptom of severe diarrhoea, higher chloride
concentrations are prefeiTed (eg 70-80mM such as about 80mM).
The aqueous formulation of the invention rnay be an aqueous solution, aqueous
dispersion or aqueous suspension. Preferably the aqueous formulation is an
aqueous
solution. Preferably the aqueous formulation (eg solution) is a reconstituent
aqueous
formulation (eg solution). For example, a reconstituent aqueous formulation of
the
invention may be reconstituted by the end user at the point of use from a
composition
comprising galactose and a source of sodium ions (and optionally one or more
sources of
additional ions and one or more additional caxbohydrates) by addition of a
suitable volume
of aqueous solvent (eg water).
Viewed from a further aspect the present invention provides a composition
formulable (eg dissolvable) in water to form an aqueous formulation as
hereinbefore
def ned, said composition comprising galactose, a source of sodium ions,
optionally an
additional carbohydrate and optionally a source of additional ions. For
example, the
composition comprises galactose in an amount sufficient to form a
concentration in the
range 25 to 135mM in a specified volume of aqueous solvent (eg water) and a
source of
sodium ions.
CA 02466278 2004-05-06
WO 03/039556 PCT/GB02/04980
The composition of the invention may be provided in any suitable solid or
liquid
form. For example, the composition may be provided in solid form such as
powdered (eg
effervescent or non-effervescent powdered) or tablet form or in liquid form
such as gel or
liquid concentrate form.
Viewed from a yet further aspect the present invention provides the use of
galactose and a source of sodium ions for the preparation of (A) an aqueous 25
to 135mM
galactose formulation for combatting (eg treating or preventing) dehydration
or (B) a
medicament formulabde (eg dissolvable in water) into an aqueous 25 to 135mM
galactose
formulation for combatting (eg treating or preventing) dehydration.
In a preferred embodiment of the use of the invention, the aqueous 25 to 135mM
galactose formulation is as hereinbefore defined.
In a preferred embodiment of the use of the invention, the medicament is a
composition as hereinbefore defined.
In a preferred embodiment, the present invention provides the use of galactose
and
a source of sodium ions for the preparation of (A) an aqueous 25 to 135mM
galactose
formulation for combatting dehydration and associated deficiencies or (B) a
medicament
formidable into an aqueous 25 to 135mM galactose formulation for combatting
dehydration and associated deficiencies. The associated deficiencies may be
mineral loss,
electrolyte imbalance, etc.
In a preferred embodiment, the present invention provides the use of galactose
and
a source of sodium ions for the preparation of (A) an aqueous 25 to 135mM
galactose
formulation for combatting dehydration in children (eg infants) or (B) a
medicament
formidable into an aqueous 25 to 135mM galactose formulation for combatting
dehydration in children (eg infants).
Preferably the dehydration and (where present) associated deficiencies are
symptoms of diarrhoea . The diarrhoea may be a result of (for example)
enterotoxin effects
CA 02466278 2004-05-06
WO 03/039556 PCT/GB02/04980
_g_
(eg cholera typically in the third world), viral effects (eg rotavirus
typically in the
developed world) or post surgical rest (eg when GI rest is important). The
concentration of
each component may be tailored to optimise treatment of dehydration and
associated
deficiencies caused by mild, moderate or severe diarrhoea. For combatting
dehydration as a
symptom of severe diarrhoea, higher sodium and chloride concentrations are
preferred.
Alternatively, the circumstances which may lead to dehydration may be self
induced (eg
through alcohol consumption).
In a preferred embodiment of the use of the invention, the dehydration or
associated deficiencies are life threatening.
Viewed from a still yet further aspect the present invention provides a method
for
combatting dehydration in a subject comprising the step of:
administering an effective dose of an aqueous formulation as hereinbefore
defined to the
subj ect.
Viewed from an even still further aspect the present invention provides a
method
for combatting dehydration and associated deficiencies in a subject comprising
the step of:
administering an effective dose of an aqueous formulation as hereinbefore
defined to the
subj ect.
Although the subject may be any age, preferably the subject is a child (eg an
infant). Preferably the dehydration and (where present) associated
deficiencies are
symptoms of diarrhoea (eg severe diarrhoea). The diarrhoea may be a result of
(for
example) enterotoxin effects (eg cholera typically in the third world), viral
effects (eg
rotavirus typically in the developed world) or post surgical rest (eg when GI
rest is
important). Alternatively, the circumstances which may lead to dehydration may
be self
induced (eg through alcohol consumption).
The present invention will now be described in a non-limitative sense with
reference to the following Example.
CA 02466278 2004-05-06
WO 03/039556 PCT/GB02/04980
-9-
Example
Nine reconstituent aqueous formulations A, A1 and B-H were prepared which had
the components and concentrations after reconstitution in water shown in Table
1:
Table 1
vubstanc~C~oricentra~ion
mM
A(Al) B C D E F G H
Galactose45(90) 60 80 40 45 45 75 55
Glucose 45(0) 60 80 40 45 45 75 55
Sodium 45 70 25 30 35 20 25 60
Chloride
Potassium25 20 20 15 20 25 20 20
Chloride
Trisodium10 10 10 10 15 13.3/ 0 10
Citrate/ 6.7
Citric
Acid
Sucrose 0 0 0 80 20 0 0 0
Fructose 0 0 0 1 2 0 0 0
Sodium 0 0 0 0 0 0 15 0
bicarbonate
A solid mixture of pre-weighed components was prepared such that the specified
concentrations were obtained when a certain proportion was dissolved in a
specified
volume of water. The unit volume of water added to reconstitute the
composition may be
up to 1000m1. Typically 250m1 would be appropriate and a single dose may be
made up of
one, two or three 250m1 unit volumes administered at appropriate intervals.
Each aqueous
formulation may be flavoured to be palatable as desired using lemon, lime,
blackcurrant,
orange, citrus or cranberry.
CA 02466278 2004-05-06
WO 03/039556 PCT/GB02/04980
-10-
The sodium concentration for compositions F, G and H are 60, 40 and 90mM
respectively and the chloride concentrations are 45, 45 and 80mM respectively.
Higher
sodium and chloride concentrations are desirable for effective treatment of
severe
diarrhoea. Thus compositions F, G and H are useful in the treatment of
moderate, mild and
severe diarrhoea respectively.
General purpose formulations I, J, K, L, M and N are shown in Table 2.
Table 2
;.substance . . ....
. '. ="~~centrat~0~..mM
', ..
I J K L M N
Galactose 120 120 60 60 60 60
Glucose - - 60 60 - -
Sodium 60 30 60 30 60 30
Chloride
Potassium 20 20 20 20 20 20
Chloride
Trisodium - 13.3/ - 13.31 - 13.3/
Citrate/ 6.7 6.7 6.7
Citric Acid
Maltodextrin0 0 0 0 10 10
(chain 6)
