IE45208B1 - Neutralizing agent - Google Patents

Abstract

The invention is a gastric acid neutralizing antacid agent in liquid form which comprises an aqueous solution of a water-soluble polyethyleneimine, at least one taste improving acid selected from the group consisting of alginic acid, polygalacturonic acid, galacturonic acid, pectin, tannic acid, arabic acid, galactaric acid, and glutaric acid, and at least one acid selected 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, and a process for preparing the antacid agent. The antacid agent overcomes various disadvantages of previously known antacid agents containing aluminum hydroxide.

Description

The present invention relates to a gastric acid neutralising agent in the form of a solution, a process for its preparation, and a method for neutralizing gastric acid in mammals.

The present invention provides 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 effects, is well tolerated and is well tasting and has a good consistency.

An antacid ought to have, amongst other things, a high reaction speed with diluted acid and a high acid binding capacity. Hitherto Itnown antacid preparations, which fulful this requirement well contain aluminium hydroxide or related compounds, alone or in coiribination with magnesium salts. Aluminium hydroxide and related compounds have the advantage of reacting relatively fast with acids at a lower pH. The reaction stops, however, when the pH-value rises to about 4. Other compounds having been used to a relatively high extent as an antacid are magnesium silicate and calcium carbonate. Theee two compounds buffer at a somewhat higher pH-value than the aluminium compound and they are partly resorbed. Other magnesium compounds, as the hydroxide and the carbonate, are only used fo a limited extent as such. They are however, - 2 46208 often combined with aluminium hydroxide, in view of the fact that the compounds themselves give a strong laxative effect, which is neutralized by the combination with aluminium hydroxide. Sodium bicarbonate is a completely water soluble compound which has been used to a certain extent as 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 pf 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 momentaneous, unlike the reaction between an acid and a base in a solution.

In a reaction between a solid and a liquid phase, which is the case here, the reaction speed depends on, amongst other things, the particle size (or more correctly, the contact surface between the phases), the solubility of the solid phase, the crystal structure, possible hydration, It is a well known clinical observation that a liquid preparation of e.g. aluminium hydroxide, gives a better effect than tablets (e.g. Krantz and Carr, Pharmacol, Principles Med. Practic. WilL'iAms and Wilkins, Baltimore 1961, page 391).

One of the float important reasons for this being that the liquid preparations react faster with acid than do the S' tablets (Sjogren, Farm.Revy. ,t>2, 735, (L9S3).

These hitherto known and used antacids containing a combination of Al- and Mg-salts do, however, show certain drawbacks such as bad taste and chalky consistency, and a relatively slow reactivity with acid. Another drawback using these types of antacids is that an increase in the pH of the urine may occur, which leads to a faster secretion of acidic therapo-’tic agents xvhidi may be administered • * y. simultaneously. Interaction with other drugs, e.g. anticholinergic agents and tetracyclines, in the gastrointestinal tract saay occur as well, so that the.latter are reoorbad to a lesser degree than intended.

It has now surprisingly been found possible to overcome the above drawbacks of existing antacids by means of the present invention which provides a gastric acid neutralizing antacid agent in the form of an aqueous solution comprising a water soluble polyethyleneimine, at least one taste-improving acid which is alginic acid, polygalacturonic acid, galacturonic acid, pectin, tannic acid, arabic acid, galactaric acid, or glutaric acid, and at least one pH regulating acid which is tartaric acid, fumaric acid, phosphoric acid, acetic acid, citric acid, succinic -acid, or malic acid, the latter acid being present in such an amount that the pH of the solution is 4 to 11.

It is preferred to use a water soluble polyethylene imine having a molecular weight of 500 to 5000, and which, - 4 4S303 preferably, has a viscosity of about 200 cps when present in a 50% aqueous solution.

The aqueous solution may be prepared as a concentrate containing up to 60% by weight of polyethylene5 imine which can be diluted before use; the aqueous solution for direct administration should preferably contain 10 to 40% by weight of polyethyleneimine.

The gastric acid neutralizing agent of the invention may be prepared by a process wherein an aqueous solution of the polyethyleneimine is added to the tasteinproving acid and the pH regulating acid is then added to the mixture in an amount such that the pH of the aqueous solution is 4 to 11.

According to a further aspect of the invention, a method for treatment of hyperacidity and ulcer disease in mammals comprises administering orally an agent according to the present invention.

The agent as prepared has the ability of neutralizing the acid of the gastric juice in the stomach to a desired pH without giving anyunsuitable side effects.

The polyethyleneimines used in the present invention, are water soluble polyethyleneimines of the formula •*F· - 5 H2N-(CH2CH2N-)x-(CH2CH2NH)y- |Η2 -Νο£ which suitable qualities are sold under the marks G35 and G50 by BASF (Badische Anilin und Soda Fabriken), Federal Republic of Germany, and under the marks PEI 6, PEI 12 and PEI 18 by Itew chemicals, U.s.A.

The acid used to regulate the pH of the solution is preferably citric acid, acetic acid, succinic acid, or malic acid.

In order to improve palatability, it is preferred 10 to use alginic acid, polygalacturonic acid, galacturonic acid, or pectin as the taste improving acid. The amount of taste improving acid can be 1-10, and is preferably 1-5%. of the weight cf the agent.

In order to get the best palatability, it is 15 preferred to add the polyethyleneimine as an aqueous solution to a solution of the taste improving acid, whereupon the pH-regulating acid is added until the desired pH is reached.

The invention will be described more in detail 20 below with reference to the Examples given. - 6 48308 EXAMPLE 1 Polyethyleneimine 100% (G35, BASF) 250 Alginic acid 20 Citric acid 100 Water ad looo The alginic acid was dissolved in 380 mis. of water. Then the polyethyleneimine was added as a 50% aqueous solution. After careful stirring,the pH value was adjusted to 7.3 by adding the citric acid. The resulting solution was a clear, light yellow solution.

EXAMPLE 2 Polyethyleneimine 100% (G35, BASF) 250 g.

Galacturonie acid 20 g.

Acetic acid 160 g.

Wafer ad 1000 g.

The galacturonie acid was dissolved in 320 ml*, of water, whereut.·.·? tne polyethyleneimine was added ae a 50% solution. After careful mixing, the acetic acid was added, whereby a clear, faintly orange solution having a pH of 7.5 was obtained.

EXAMPLE 3 Polyethyleneimine G35, 100% 240 Polygalacturonie acid 16 Phosphoric acid 200 Water ad 1000 53θ8 The preparation is prepared in accordance with Example 1 above, the final pH vzas 6.0.

EXAMPLE 4 Polyethyleneimine G 35 210 g.

Poiygalaeturonic acid 14 g.

Phosphoric acid 205 g.

Acetic acid 90 g.

Water ad 1000 g.

The preparation was prepared in accordance with 10 Example 1 above, the final pH was 5.0.

EXAMPLE 5 Polyethyleneimine (100%) 250 g.

Pectin 20 g.

Acetic acid 150 g.

Water ad 1000 g.

The preparation is obtained in accordance with Example 1 above, the final pH was about 7.

EXAMPLE 6 Polyethyleneimine (100%) 230 g.

Arabic acid 13 g.

Phosphoric acid 230 g.

Water ad 1000 g.

The preparation is obtained in accordance with Example 1 above, the final pH was 5.4. - 8 40303 EXAMPLE 7 Polyethyleneimine (100%) Tannic acid Acetic acid Water The preparation ia obtained in Example 1 abc*·, the final pH was 7.6.

EXAMPLE 8 Polyethyleneimine Alginic acid Succinic acid Water The preparation is obtained in Example 1 above, the final pH was 7.1.

EXAMPLE 9 260 g. 17 g. 130 g. ad 1000 g. accordance with 250 g. 17 g. 170 g. ad 1000 g. accordance with Polyethyleneimine (100%) 250 g. Galactaric acid 17 g. Acetic acid 130 g. Water ad 1000 g.

The preparation is prepared in accordance with Example 1 above, the final pH was about 7.5.

EXAMPLE 10 Polyethyleneimine (100%) 250 Glutaric aeid 17 Acetic acid 130 Water ad 1000 - 9 The preparation is prepared in accordance with Example 1 above, the final pH was about 7.5.

EXAMPLE 11 Polyethyleneimins (100%) 250 g.

Alginic acid 20 g.

Malic acid 170 g.

Water ad 1000 g„ The preparation is prepared in accordance with Example 1 above, the final pH was about 7.3. Fumaric acid or tartaric acid may be used in place of the malic acid.

EXAMPLE 12 Polyethylaneimine (100%) 250 g.

Polygalacturonic acid 50 g.

Alginic acid 25 g.

Phosphoric acid 100 g.

Water ad 1000 g.

The preparation was prepared by dissolving polygalacturonic acid and alginic acid in 325 mis. of water. Polyethyleneixnine was then added as a 50% aqueous solution. After thorough stirring, the phosphoric acid v/as added. The final pH v/as 7.5. 4K308 EXAMPLE 13 Polyethyleneimi ne (100%) 250 g· Alginic acid 50 g· Arabic acid 25 g« Succinic acid 80 g· Water ad 1000 g. Alginic acid and arabic acid were dissolved in 345 mis. of weoer. Polyethy leneimir,e was then added as a 50% aqueous solution. After thorough stirring, succinic acid was added. The final pH was 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 was 7.6.

The acid neutralizing capacities of the preparations above are 40-50 mis. of 0.1N HCl/g. of 25% aqueous solution of polyethyleneimine. The reaction is finished with 1-2 minutes.

Ths daily dose of a preparation according to the invention depends very much on the degree of hyperacidity the patient is suffering. Normal cases, however, require an £SS°8 amount 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. The specific weight of the preparations above is about 1.25 g/ml.

Claims (11)

1. WE CLAIM

1. A gastric acid neutralizing antacid agent in the form of an aqueous solution comprising a water soluble polyethyleneimine, at least one taste-improving acid which is alginic acid, poiygalaeturonic acid, galacturonic acid, pectin, tannic acid, arabic acid, galactaric acid, or qlutaric acid, and at least one pH regulating acid which is tartaric ac.id, fumaric acid, phosphoric acid, acetic acid, citric acid, succinic acid, or malic acid, the latter acid being present in such an amount that the pH of the solution is 4 tc il.

2. An agent according to claim X wherein the polyethyleneimine is one having a molecular weight of 500 to 5000.

3. An rrtnt according to claim 1 or 2, wherein the polyethyleneimine is one that,in a 50% aqueous solution, gives a viscosity of about 200 cps.

4. An agent according to any one of the preceding claims in the form of a concentrate having a concentration of polyethyleneimine up to 60% by weignt and which can be diluted prior to administration.

5. An agent according to any one of claims 1-3 in the form of a solution ready for administration and having a concentration of polyethyleneimine of 10 to 40% by weight. - 13 e S 2 θ θ

6. An agent according to any one of the preceding claims, wherein the taste-improving acid is present in an amount of 1 to W by weight.

7. An agent according to claim 6 wherein the tasteimproving acid is present in an amount of 1-5½ by weight.

8. An agent according to claim 1 substantially as hereinbefore described with refererence to any one of the Examples.

9. A process for preparing an agent according to any one of the preceding claims wherein an aqueous solution of the polyethyleneimine is added to the taste-improving acid and the pH regulating acid is then added to the mixture in an amount such that the pH of the aqueous solution is 4 to 11.

10. A process according to claim 9 substantially as hereinbefore described with reference to any one of the Examples.

11. An agent obtained by a process according to claim 9 or 10.