Note: Descriptions are shown in the official language in which they were submitted.
CA 02214343 1997-08-29
V4'O 96/27368 PCT/GB96/00358
-1-
LIQUID AQUEOUS PHARMACEUTICAL COMPOSITIONS COMPRISING SODIUM ALGINATE AND
POTASSIUM BICARBONATE
This invention relates to the preparation of
pourable liquid sodium alginate compositions and in
particular to the preparation of such compositions for
the treatment of reflux oesophagitis, gastritis,
dyspepsia or peptic ulceration, or for use as sustained
releasing compositions.
Reflux oesophagitis occurs when small amounts of
gastric juice, food and/or bile acids pass into the lower
part of the oesophagus and cause oesophageal inflammation
accompanied by pain which may manifest itself in the form
of heartburn.
One approach to the problem of reflux oesophagitis
has been to administer a preparation which on contact
with gastric acid generates a carbonated gelatinous foam
or raft which floats on the stomach contents. When
reflux occurs it is this raft which precedes the stomach
contents into the oesophagus, thus protecting the mucosa
from further irritation. Known preparations of this type
include solid preparations in the form of powder or
tablets containing alginic acid, sodium bicarbonate and
antacid materials or liquid preparations containing
sodium alginate, sodium bicarbonate and calcium carbonate
marketed under the name GAVISCON (TM Reckitt & Colman
Products Ltd). In our British Patent No. 1524740 we
describe such liquid preparations.
GB 1524740 specifies that sodium bicarbonate is used
as the effervescent agent to release carbon dioxide on
contact with stomach acid, and most similar liquid
products also use the sodium salt. Sodium bicarbonate is
CA 02214343 1997-08-29
WO 96/27368 PC'T/GB96/00358
-2-
generally the salt of choice for many reasons, including
its taste characteristics, its solubility and its general ~
pharmaceutical acceptability. Other bicarbonates, eg
potassium bicarbonate have been avoided in the past r
because of poor taste characteristics (brackish) and
because of potential cardiac problems in high dosages.
A current problem with liquid alginate products of
the above type is the size of the dose which must be
taken (up to 20 ml four times daily). This results in
large volumes of products which are not conveniently
portable and which take up a lot of space in pharmacies,
warehouses etc.
It is therefore an aim of the invention to provide
more concentrated products thereby reducing the
relative dosage volume.
On the one hand, we have found that merely doubling
the concentration of all ingredients in conventional
sodium alginate compositions leads to compositions which
are too thick to dispense from a bottle and may even be
too thick to comfortably swallow.
On the other hand we have found that reducing the
sodium bicarbonate concentrations in such products will
reduce the initial viscosity to apparently acceptable
levels at which pouring may be achieved. However if the
bicarbonate concentrations are reduced too far there will
be inadequate carbon dioxide production in the stomach,
which will lead to inadequate raft formation.
We have found moreover that the compositions having
high concentrations of sodium alginate and low
concentrations of sodium bicarbonate have a further
serious defect. Their pouring properties are lost if
CA 02214343 1997-08-29
WO 96/27368 PCT/GB96/00358
-3-
storage temperatures drop too low. Specifically, if
such compositions are stored at below 5°C for 48 hours
or more they will remain too thick to pour, even after
being restored to room temperature and vigorously shaken.
Temperatures of 5°C or lower are commonly encountered
when commercial products are stored for long periods in
warehouses or transported over long distances.
We have now unexpectedly found that using potassium
bicarbonate in the above compositions alleviates these
thickening problems.
According to the invention there is provided the use
of potassium bicarbonate for the preparation of an
aqueous pourable liquid composition comprising at least
8% w/w sodium alginate for use as a pharmaceutical.
Such aqueous pourable liquid compositions that
'result are pourable at room temperatures and furthermore
this property is regained upon warming following
prolonged storage below 5°C for up to six weeks or more
(although reasonably vigorous shafting may be required).
By pourable we mean that the compositions of the
2$ invention will flow evenly at room temperature (possibly
following reasonably vigorous shaking) such that doses of
for example 5 ml may be measured out with reasonable
accuracy. For example reproducible doses of as low as 5
ml may be dispensed from screw cap bottles having neck
diameters of 1.5 cm, or from squeezable plastic bottles
having dispensing outlets as small as 5 mm diameter.
Compositions of the invention, particularly those
according to the preferred embodiments are liquid, or
become liquid upon vigorous shaking, even after prolonged
storage under low temperatures.
CA 02214343 2005-12-30
25448-86
- 4 -
Whilst simple numerical viscosity is not an accurate
prediction of pourability in the compositions of the
invention, a rough guide is that compositions having a
viscosity of below 3500 mPa.s are preferred and more
preferably compositions having a viscosity of below 2000
mPa.s. For the: purposes of this rough test the samples
should be shaken vigorously before testing and viscosity
should be measured at a shear rate of lODs-1 in a Bob and
Cup Viscometer. Alternatively, to simulate vigorous
shaking, the samples may be sheared at 50Ds'1 iW a
viscometer before the viscosity is measured.
Sodium alginate mainly comprises the sodium salt of
alginic acid which is a mixture of polyuronic acids
composed of residues of D-mannuronic and L-guluronic
acids. It may be obtained from algae belonging to the
order Phaeophycae. Preferably, low viscosity grade
sodium alginate is used to prepare the compositions
according to the invention. These are grades of sodium
alginate for which the viscosity of a 10% weight/volume
aqueous solution, when determined on a Brookfield RVT
viscometer using spindle number 3 at 20 r.p.m. at 20°C,
falls within the range 200 - 1500 mPa.s. An example of a
suitable commercial grade of low viscosity sodium
alginate is Protanal*LFR 5/60 (Pronova Biopol).
Preferably the sodium alginate has a high guluronic
acid content. Guluronic acid content is expressed as gel
strength(G). High guluronic acid grades of sodium
alginate preferably have gel strengths of at least lOG.
The concentration of sodium alginate in compositions
produced according to the invention is higher than in
conventional compositions, i.e. at least 8% w/w.
Preferably the concentration is 8 to 14% w/v, more
*Trade-mark
CA 02214343 2005-12-30
25448-86
- 5 -
preferably 9 to 14% w/v, even more preferably 10 to 13%
w/v and most preferably 10 to 12% w/v.
The concentration of potassium bicarbonate in
compositions according to the invention is preferably 0.1
to 5% w/v, more preferably 0.5 to 5% w/v,~ even more
preferably 1 to 3% w/v and most preferably 1.5 to 3% w/v.
Compositions prepared according to the invention may
be used in the treatment of reflux oesophagitis,
gastritis, dyspepsia or peptic ulceration. They may also
be used as carriers of other active ingredients and so
act as sustaiYied release compositions, or compositions
delivering the actives specifically to the stomach
(targeted delivery).
Further according to the invention there is provided
the use of an orally effective amount of an aqueous
pourable liquid composition comprising
a) 8 to 14~ w/v low viscosity sodium alginate;
b) 0.1 to 5o w/v potassium bicarbonate
for the treatment of reflux oesophagitis, gastritis,
dyspepsia or peptic ulceration.
Further according to the invention there is
therefore provided a pharmaceutical composition for the
treatment of reflux oesophagitis, gastritis, dyspepsia or
peptic ulceration, or for use as a sustained releasing or
targeted delivery composition, in the form of an aqueous
pourable liquid comprising
a) 8 to 14 w/v low viscosity grade sodium alginate;
b) 0.1 to 5 w/v potassium bicarbonate.
CA 02214343 2005-12-30
25448-86
- 6 -
The compositions of the invention preferably also
comprise a suspending agent. Suitable suspending agents
include carrageenans, hypromellose, tragacanth, pectin,
S pre-gelatinised potato starch, sodium starch glycolate,
carbomer or mixtures thereof. Carbomer is a synthetic
high molecular weight polymer of acrylic acid cross
linked with either allyl esters of sucrose or
pentaerythritol. Suitable commercially available grades
of carbomer include Carbopol*934P or Carbopol*974P (BF
Goodrich).
For use in liquid products, carbomers must be
neutralised after being pre-dispersed in water. The
preferred neutralising agent is sodium hydroxide. The
concentration of carbomer is given as the total amount of
material used before neutralisation.
The choice of suspending agent and its concentration
will depend upon the amount and grade of sodium alginate
used in the compositions and upon the amount and type of
extra insoluble ingredients used. Preferably the
suspending agent is a carbomer. The preferred
concentration of suspending agent is 0.1 to 1% w/v, most
preferably 0.1 to 0.5% w/v.
The compositions of the present invention preferably
further comprise a source of divalent or trivalent metal
ions to strengthen the raft formed in the stomach. These
~ metal ions preferably become available when the
compositions reach the stomach but must not be available
before then or the compositions will gel too early.
Suitable metal ions are aluminium and, preferably,
calcium ions. Most preferably the compositions comprise
calcium carbonate.
*Trade-mark
CA 02214343 1997-08-29
WO 96/27368 PCT/GB96100358
_7_
The compositions of the present invention therefore
r preferably further comprise from 0.1 to 5°s w/v calcium
ions, most preferably 0.5 to 3~ w/v calcium carbonate.
Still further according to the invention, there is
provided a pharmaceutical composition for the treatment
of reflex oesophagitis, gastritis, dyspepsia or peptic
ulceration, or for use as a sustained releasing or
targeted delivery composition, in the form of an aqueous
pourable liquid comprising
a) 8 to 14 w/v low viscosity sodium alginate;
b) 0.1 to 5 w/v potassium bicarbonate;
c) 0.1 to 1% w/v carbomer, neutralised with
sodium hydroxide; and
d) 0 to 5o w/v, preferably 0.5 to 5o w/v, calcium
carbonate.
The compositions of the present invention preferably
comprise substantially no source of sodium ions other
than those provided by the sodium alginate and the sodium
hydroxide used to neutralise the carbomer. Most
preferably no sodium bicarbonate is added during the
manufacture of the compositions of the invention.
The compositions of the present invention may
further comprise preservatives to prevent contamination
and subsequent deterioration by micro-organisms.
Examples of suitable preservatives are methyl, ethyl,
propyl and butyl para-hydroxybenzoates and their salts,
which are preferably used in combination eg methyl and
propyl or ethyl and butyl.
W O 96!27368 CA 0 2 214 3 4 3 19 9 7 - 0 8 - 2 9 p~/GB96/00358
_g_
Preferred concentrations for the preservatives are
0.01 to 0.5% w/v. a
The compositions of the present invention may also
include one or more of the following ingredients,
colouring, sweetening, flavouring or pH adjusting
ingredients.
Where the compositions of the present invention are
intended for use as sustained releasing compositions they
will also contain active ingredients suitable for
sustained administration in the stomach.
Where the compositions of the present invention are
intended for use as targeted delivery compositions they
will also contain active ingredients suitable for
specific delivery to the stomach, for example local
antimicrobial agents.
The compositions of the invention may be prepared by
any conventional manufacturing process for compositions
of this type. Preferably the compositions are prepared
by the following process.
1) Dissolving the potassium bicarbonate in
approximately 60~ of the water to be used in the
composition and mixing in any of the preservatives,
sweeteners and crosslinking aids (if used).
2) Adding the sodium alginate and stirring until
dissolved.
3) Adding the suspending agents (if used). If the
suspending agent is carbomer it should be pre neutralised
with sodium hydroxide in approximately 30~ of the water
to be used in the compositions.
v
CA 02214343 1997-08-29
BVO 96/27368 PCT/GB961Q0358
-9-
4) Adding any flavourings or colouring agents and
adjusting the volume.
The process is preferably carried out at
approximately 20 to 25°C.
9
I
CA 02214343 2005-12-30
25448-86
- 10 -
The invention will now be illustrated by reference
to the following examples.
Exa le 1
Sodium alginate LFR 5/60 100 g
(Pronova Biopol*) '
Potassium bicarbonate 20 g
Calcium carbonate 20 g
Carbomer (Carbopol*974P) 1 g
Sodium hydroxide 0.3 g
Ethyl parahydroxybenzoate 2 g
Sodium butyl parahydroxybenzoate 0.2 g
Sodium Saccharin 2 g
Flavour 2 g
Deionised water to 1 litre
1. The carbomer was dispersed in 300 ml deionised water
in a first vessel and neutralised with the sodium
hydroxide.
2. In a second vessel the potassium bicarbonate, calcium
carbonate, preservatives and saccharin were mixed with
600 ml deionised water.
3. The sodium alginate was added to the second vessel and
stirred until fully dissolved.
4. The contents of the second vessel were added to the
contents of the first vessel and stirred until fully
dispersed.
5. The flavour was added and the volume adjusted to 1
litre by the addition of further deionised water. The
mixture was stirred until fully dispersed.
*Trade-mark
CA 02214343 2005-12-30
25448-86
- 11 -
ales 2 to 12
The following further Examples were all produced by
the method of Example 1.
2 3 4 5 6
Sodium alginate LFR
5/60 (Pronova 1008 1008 1008 1008 100g
Biopol:)
Potassium 20g 31g 31g 31g 31g
uicarbonate
Calcium carbonate 20g 32g 32g 32g 32g
Carbomer (Carbopol*
974P) 2g 2g 4g 6g lg
Sodium hydroxide 0.7g 0.7g 1.4g 2.1g 0:3g
Ethyl
parahydroxybenzoate 2g 2g 2g 2g 2g
Sodium butyl
parahydroxybenzoate 0.2g 0.2g 0.2g 0.2g 0.2g
Sodium Saccharin 2g 2g 2g 2g 2g
Flavour 2g 2g 2g 2g 2g
Deionised Water to 1 ltr 1 ltr 1 ltr 1 ltr 1 ltr
*Trade-mark
CA 02214343 2005-12-30
25448-86
- 12 -
7 8 9
Sodium alginate LFR 5/60
(Pronova Biopol*) 1008 1008 1008
Potassium bicarbonate 20g lOg 25g
Calcium carbonate 32g 32g 32g
Carbomer (Carbopol*974P) 2g 2g 2g
Sodium hydroxide 0.7g 0.7g 0.7g
Ethyl
parahydroxybenzoate 2g 2g 2g
Sodium butyl
parahydroxybenzoate 0.2g 0.2g 0.2g
Sodium saccharin 2g 2g 2g
Flavour 2g 2g 2g
Deionised Water to 1 ltr 1 ltr 1 ltr
*Trade-mark
CA 02214343 2005-12-30
25448-86
- 13 -
10 11 12
Sodium alginate LFR 5/60
(Pronova Biopol) 100g 100g 1008
Potassium bicarbonate 31g 31g 31g
Calcium carbonate 16g 8g 24g
Carbomer (Carbopol~' 974P) lg. lg lg
Sodium hydroxide 0.3g 0.3g 0.3g
Ethyl
parahydroxybenzoate 2g 2g 2g
Sodium butyl
parahydroxybenzoate 0.2g 0.2g 0.2g
Sodium saccharin 2g 2g 2g
Flavour 2g 2g 2g
Deionised Water to 1 ltr 1 Itr 1 ltr
Examples 2 to 12 may be repeated using 8 or 12% w/v
sodium alginate instead of 10%.
Examples 2 to 12 may further be repeated using 0.5, 4
or 5% w/v potassium bicarbonate.
*Trade-mark
CA 02214343 2005-12-30
25448-86
- 14 -
All of Examples 1 to l2 have the capability o~ being
stored for at least 48 hours below 4°C, and in the case
where a gel forms can be made pourable at room
temperature by reasonable shaking or stirring.
gxam~l_es 13-to 24
13 14 15 16
Sodium alginate LFR
5/60(Pronova Biopol) 100g 80g 1008 1008
Potassium
bicarbonate 20g 20g IOg I5
Calcium carbonate 20g 20g 20g 20g
Aluminium hydroxide - - - -
Carbomer (Carbopol* 4g 4g 4g 4g
974P)
Sodium hydroxide 1.4g 1.4g 1.4g 1.4g
Ethyl 2g 2g 2g 2g
parahydroxybenzoate
Sodium butyl 0.228 0.22g 0.228 0.228
parahydroxybenzoate
Sodium saccharin lg lg lg lg
Flavour 0.7g 0.7g 0.7g 0.7g
Deionised water to 1 ltr 1 ltr 1 ltr 1 ltr
*Trade-mark
CA 02214343 2005-12-30
25448-86
- 15 -
17 18 19 20
Sodium alginate LFR 5/60 100g 100g ~100g 1008
(Pronova Biopol)
Potassium bicarbonate 20g 20g 20g 20g
Calcium carbonate - - 20g 20g
Aluminium hydroxide - 20g - -
Carbomer (Carbopol*974P) 4g 4g 4g -
Sodium hydroxide 1.4g 1.4g 1.4g -
Ethyl
parahydroxybenzoate 2g 2g 5g 2g
Sodium butyl
parahydroxybenzoate 0.22g 0.22g 0.558 0.22g
Sodium saccharin lg lg lg lg
Flavour 0.7g 0.7g 0.7g 0.7g
Deionised water to 1 ltr 1 ltr 1 ltr 1 ltr
*Trade-mark
CA 02214343 2005-12-30
25448-86
- 16 -
21 22 23 24
Sodium alginate LFR 1208 I30g 100g 100g
5/60 (Pronova Biopol*)
Potassium bicarbonate 20g 20g 5g 50g
Calcium carbonate - - 20g 20g
Aluminium hydroxide - - -
Carbomer (Carbopol*974P) 4g 4g 4g 4g
Sodium hydroxide 1.4g 1.4g 1.4g I.4g
Ethyl 2g 2g 2g 2g
parahydroxybenzoate
Sodium butyl
parahydroxybenzoate 0.228 0.228 0.228 0.228
Sodium saccharin lg lg lg lg
Flavour 0.7g 0.7g 0.7g 0.7g
Deionised water to 1 ltr 1 ltr 1 ltr 1 ltr
Each of Examples 13 to 24 were manufactured by the
general method of Example 1 (taking into account changes
necessitated by the various formula differences).
Samples of each of Examples 13 to 24 were stored at 4°C
for 3 weeks and were all found to be easily pourable
*Trade-mark
CA 02214343 1997-08-29
W~ 96/27368 PCTlGB96100358
- 17-
following warming to room temperature and shaking.
a
s
