Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
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The present invention relates to a gastric acid neutralizing agent
in the form of a solution, a process for its preparation, and a method for
neutralizing gastric acid in mammals, including man.
The object of the present invention is to obtain a gastric acid `~
neutralizing solution which gives a fast reaction with an acid, has a high
acid neutralizing capacity, is not absorbed and does not give pharmacologically
systemic effects9 is well tolerated, does not have an u~pleasant ~aste and has
a good consistency.
An antacid ought to ha~e, among other properties, high reaction
speed with diluted acid and a high acid-binding capacity. Hitherto known
antacid preparations, which fulfill this requirement to the very best contain
aluminum hydroxide or related compounds, alone or in combination with magnes-
ium salts. Aluminum hydroxide and related compounds have the advantage of
reacting relatively quickly with acids at a lower pH. The reaction stops,
however, when the pH-value rises to about 4. Other compounds which have been
used to a relatively large extent as antacids are magnesium silicate and
calcium carbonate. These two compounds buffer at a somewhat higher pH-value
than the aluminum and they are partly resorbed. Other magnesium compounds,
such as the hydroxide and the carbonate, are only used to a limited extent as
such. They are, however, often combined with aluminum hydroxide depending on
the fact that the compounds themselves give a strong laxative effect which is
neutralized by the combination with aluminum hydroxide. Sodium bicarbonate is
a completely water-solublecompound which has been used to a certain extent as
an antacid, as well. This compound, however, raises the pH-value to above the
neutral point, which may stimulate an increased secretion of gastric acid.
Furthermore, it is completely resorbed and may create alkalose.
Most of the antacid active compounds hitherto used are thus compounds
; which are difficult to dissolve in water, but which dissolve in gastric juice
while reacting with hydrochloric acid, The reaction is not instantaneous, as
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the reaction between an acid and a ~ase in a solution. At the reaction
between a solid and a liquid phase, which is the case hereby, the reaction
speed depends on, among other things, the particle size ~or more correctly
the contact surface between the phases), the solubility of the solid phase,
the crystal structure, possible hydralation etc. It is a well known clinical
observation that a liquid preparation of e.g. aluminum hydroxide gives better
effect than tablets (e.g. Krantz and Carr, Pharmacol. Principles Med. Practic.
Williams and Wilkins, Baltimore 1961, page 391). One of the most important
reasons or this being the case is that the liquid preparations react faster
with acid than tablets ~Sjogren, ~arm, Revy. 62, 735, 1963).
These hitherto known and used antacids containing a combination of
Al- and Mg-salts do, however, show certain drawbacks as bad taste and chalky
consistency, and a relatively slow reactivity with acid. Another drawback
using this type of antacids is that an increase of the pH of the urine may
occur~ which leads to a faster secretion of acidic therapeutic agents which
may be administered simultaneously. Interaction with other drugs as anti-
cholinergic agents and tetracyclines in the gastrointestinal tract may occur
as well so that the latter are resorbed to a less degree than intended.
; It has now surprisingly been found possible to overcome above draw-
2G backs by means of the present invention which in one aspect provides a process
for the preparation of a clear aqueous solution of a gastric acid neutralizing
antacid agent in liquid form and containing a polyethyleneimine, which com-
prlses admlxing an aqueous solution of a polyethyleneimine with at least one
taste improving acid selected from the group alginic acid, polygalacturonic
acid, galacturonic acid, pectin, tannic acid, arabic acid, galactaric acid,
; and glutaric acid and, in order to change pH, adding at least one acid select-
ed from the group consisting of tartaric acid, fumaric acid, phosphoric acid,
acetic acid, citric acld, succinic acid, and malic acid in such an amount
that pH of the aqueous solution is 4 to 11.
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In another aspect the lnvention provides a clear aqueous solution
of a gastric acid neutralizing antacid agent in liquid form which comprises
an aqueous solutlon of a water-soluble polyeth~leneimine, at least one taste
improving acid selected from the group consisting of alginic acid, poly-
galacturonic acid, galacturonic acid, pectin, tannic acid, arabic acid,
galactaric acid, and glutaric acid, and at least one acid selec~ed from the
group consisting of tartaric acid, fumaric acid, phosphoric acid, acetic acid,
citric acid, succinic acid, and malic acid, the latter in such an amount that
pH is 4 to 11.
According to a preferred embodiment a water-soluble polyethylene-
:. :
imine is used having a molecular weight of 500 to 5000, and preferably, a
viscosity of about 200 cps as a 50% aquec~us solution.
According to a further preferred embodiment the aqueous solution
contains up to 60% by weight of the polyethyleneimine when a solution intended
to be diluted before use is prepared. Preferably the aqueous solution con-
tains 10 to 40% by weight of the polyethyleneimine when a solution intended
Eor direct administration is prepared.
According to a further aspect of the invention this also relates to
a method for treatment of hyperacidity and ulcer disease by administering an
effective amount of an agent according to the above given definitions includ-
ing preEerred embodiments.
The agent as prepared has the ability of neutralizing the acid oE
the gastric juice in the stomach to a desired pH without giving any unsuit-
able side effects.
The polyethyleneimines used, according to the present invention,
are water-soluble polyethyleneimines o~ the formula
2N CCH2C1-121, -`)X- (cH2cH2l~H~
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of which suitable qualities are sold under the trade marks G35 and G50 by
BASF (Badische Anilin und Soda Fabriken) Federal Republic o~ Germany, and
under the trade marks PEI 6~ PEI 12 and PEI 18 by Dow Chemicals, USA.
In order to obtain a gastric acid neutralizing agent such poly-
ethyleneimines, however, must be provided with at least one organic acid for
pH-decreasing purposes. The acid is selected from the group consisting o~
tartaric acid, fumaric acid, phosphoric acid, citric acid, acetic acid,
succinic acid and malic acid, and is preferably citric acid~ acetic acid,
succinic acid or malic acid. ;
~n order to improve palatability the acid-polyaIkyleneimine solu-
tion has further to be provided with at least one taste-improving acid
selected from the group consisting of al~inic acid, polygalacturonic acid,
galacturonic acid, pectin, tannic acid, arabic acid, galactaric acid and
glutaric acid. Preferably, alginic acid, polygalacturonic acid, galacturonic
acid or pectin are used. The amount of-taste-improving acid is l -lO, pre-
ferably l-5 % of the weight of the agent
In order to get good palatability a preferred embodiment of the
invention comprises adding the polyethyleneimine as an aqueous solution to a
solution of the taste-improving acid, whereupon the pH-regulating acid is
added until desired pH is reached.
The invention ~ill be described more in deta:il be]ow with reference
to the Examples gi~en, however, without being restricted thereto.
Example 1
Polyethyleneimine 100% ~(~35, BASF) 250 g
Alginic acid 20 g
Citric acid lO0 g
Water ad1000 g
The alginic acid was dissolved in 380 mls of water~ Then the poly-
ethyleneimine was added as a 50~ aqueous solution. After careful stirring the
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pH value was adjusted to 7.3 by adding the citric acid. The resulting solu-
tion was a clear, light yellow solution.
Example 2
Polyethyleneimine 100~ (G35, BASF) 250 g
Galacturonic acid 20 g
Acetic acid 160 g
Water ad 1000 g ;
The galacturonic acid was dissolved in 320 mls of water, whereupon
the polyethyleneimine was added as a 50~ solution. After careful mixing the
10 acetic acid was added~ whereby a clear, faintly orange solution having a pH
of 7O5 was obtained.
Example 3
Polyethyleneimine G35, 100%240 g
Polygalacturonic acid 16 g
Phosphoric acid 200 g
Water ad 1000 g
The preparation was prepared in accordance with Exiample 1, above,
whereby final pH of 6.0 was obtained.
Example 4
Po]yethyleneimine G35 210 g
Polygalacturonic acid 14 g
Phosphoric acid 205 g
Acetic acid go g
Water ad 1000 g
The preparation was prepared in accordance with Example 1 above,
whereby a final pH of 5.0 was obtained.
Example 5
Polyethyleneimine (100%)250 g -~
` Pectin 20 g
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Acetic acid 150 g
Water ad 1000 g
The preparation was prepared in accordance with Fxample 1 above.
pH was about 7.
xample 6
Polyethyleneimine (100%)230 g
Arabic acid 13 g
Phosphoric acid 230 g ~-
Water ad 1000 g
The preparation was prepared in accordance with Example 1 above.
Final pH was 6.4.
Example 7
Polyethyleneimine (100%)26Q g
Tannic acid 17 g
Acetic acid 130 g
Water ad 1000 g
The preparation was prepared in accordance with Example 1 above.
Final pH was 7.6
Example 8
Polyethyleneim:ine 2S0 g
Alginic acid 17 g
Succinic acid 170 g
Water ad 1000 g
The preparation was prepared :in accordance with Example 1 above.
Final pH is 7.1.
Example 9
Polyethyleneimine (100~)250 g
Galactaric acid 17 g
Acetic acid `130 g
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Water ad 1000 g
The preparation was prepared in accordance with Example 1 above.
Final pH was about 7.S.
ample 10
Polyethyleneimine (100%~ 250 g
Glutaric aeid 17 g
Acetie acid 130 g
~ater ad 1000 g
The preparation was prepared in accordance with Example 1 above.
10 Final pH was about 7.5.
Example 11
Polyethyleneimine (lOO~o) 250 g
Alginic acid 20 g
Malie aeid 170 g
Water ad 1000 g
The preparation was prepared in aecordanee with Example 1 above.
Final pH was about ?.30 Fumaric acid and tartaric acid may be used as well.
Example 12
Polyethyleneimine (100%) 250 g
Polygalaeturonic aeid50 g
Alginie acid 25 g
Phosphorie aeid 100 g
Water ad 1000 g
The preparation was prepared by dissolving polygalaeturonie aeid and
alginle aeid in 325 mls of water. Polyethyleneimine was then added as a 50%
aqueous solution. After thorough stirring phosphorie aeid was added. Final
pH 7.5~
Example 13
Polyethyleneimine (100%) 250 g
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Alginic acid S0 g
Arabic acid 25 g
Succinic acid 80 g
Water ad 1000 g
Alginic acid and arabic acid were dissolved in 345 ~ls of water.
Polyethyleneimine was then added as a 50~ aqueous solution. AXter thorough
stirring succinic acid was added. Final pH 7.6.
Example 14
Polyethyleneimine (100%) 250 g
Alginic acid 30 g
Galactaric acid 30 g
Phosphoric acid 100 g
Water ad 1000 g ~
The preparation was prepared in accordance with Examples 12-13 above. ;
The final pH obtained was 7.6.
The acid neutralizing capacities of the preparations above are
40-50 mls of 0.1 N HCl/g of 25% aqueous solution of polyethyleneimine. The
reaction is finished within 1-2 min.
The daily dose of a preparation according to the invention depends
rery much on the degree of hyperacidity the patient is suffering from. Normal
cases~ however~ require a~ amoun* of 8 to 40 g/24 hrs of the preparation when
the preparation contains 25% of the polyethyleneimine. Single doses are 2-4
g, which are administered 4 to 10 times/24 hrs. Specific weight of the
preparations above is about 1.25 g/ml.
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