FR2512344A1 - Stable antacid suspension of aluminium and/or magnesium hydroxide(s) - prepd. by mixing powdered prod. with water, fragmenting and dispersing to give particle size of 5-10 microns - Google Patents

Abstract

Process for the preparation of a stable suspension of aluminium hydroxide and/or magnesium hydroxide, as active antacid agent, by mixing the aluminium hydroxide and/or magnesium hydroxide in powder form with water and then mechanically fragmenting and dispersing the mixture, until the mean particle size is of the order of 5-10 microns. Used for treatment of gastric hyperactivity. The present invention provides a high concentration neutralising suspension, having a creamy consistency, which is suitable for oral administration and has particles of sufficiently small and homogeneous size to give a dispersion having an active total surface adequate for gastric purposes and has an alkalinising capacity which is constant and measurable. The neutralising capacity is at least four times that of comparable products prepared as gels and is superior to that of concentrated gels, thus allowing smaller amounts of product to be used.

Description

 The present invention relates to a method of manufacturing a stable suspension of aluminum hydroxide and / or magnesium hydroxide for use as an active agent in Antacida.

 Antacida are drugs for the treatment of gastric hyperacidity, which have the effect of neutralizing gastric acids. The majority of known drugs of this kind consist of combinations of suspensions of gels of aluminum hydroxide and hydroxide of magnesia, sometimes accompanied by other alkaline salts, for example carbonates It is also known to partially replace these hydroxides by gels of other alkaline salts of alumina or magnesia.

 Until around 1970, such gels or combinations of gels offered relatively weak alkalizing capacity, which resulted in patients suffering from acute gastritis or peptic ulcers having to consume it. daily very high amounts, up to 200 ml or even more per day. During the years which followed, one sought to make these treatments less tiring, and unpleasant by concentrating these alkalizing remedies, either by concentration of the gels by partial elimination of their water content, or by replacing part of the gels by dry forms of these salts, whose alkalizing capacity per gram is much higher.

We thus arrived at alkalizing capacities measured "in vitro", of more than 40 milliequivalents of hydrochloric acid per 5 milliliters of preparation, compared to alkalizing capacities of 10 to 15 milliequivalents for older preparations, so therefore, to reduce approximately three times the volume of Antacida for the same alkalizing action. Both the studies comparing the "in vitroX" measures with those "in vivo" and the studies comparing the therapeutic effect of Antacida at different concentrations confirm that the therapeutic effect, therefore "in vivo", per milliliter of these
Antacida concentrates is also about triple that of older, less concentrated preparations.

 However, these more concentrated Antacida have certain drawbacks: on the one hand the cost price of gels per milliequivalent of antacid capacity is significantly higher than that of the dry forms of these same alkaline salts, whether these are in the form of powders or dried and ground gels, and the cost price per milliequivalents of antacid capacity of concentrated gels is even higher than that of non-concentrated gels; on the other hand, the preparations containing the dry forms of these alkaline salts have the disadvantage of leaving in the mouth a strongly unpleasant earthy sensation due, at least in part, to the average size of the particles and to the diversity of the sizes of the particles.

Tests have also been carried out by incorporating dry forms composed of particles of average size already reduced to 5 to 10 on average, compared to a usual average size of 30 to 50 for pharmaceutical use. This reduction in average particle size is obtained either by sieving or by micronization, which in both cases increases the cost price and in the latter case can also reduce the antacid capacity of the salts due to their heating during micronization. In addition,
Antacida containing such medium-sized salts thus reduced have the same disadvantage of leaving an earthy sensation in the mouth, although to a lesser degree.

 The dry forms of the alkaline salts are also sold in powder sachets, the effect being substantially the same as that of the suspensions, and especially in the form of tablets which constitute a convenient pharmaceutical presentation. These tablets are however less effective because of too large particles after disintegration in the stomach, which results in gastric dispersion and a total of active surface of the salts very insufficient.

 The method according to the invention makes it possible to obtain a neutralizing suspension of the gastric acidity, at high concentration, with a creamy consistency, for oral application, consisting of particles which are sufficiently small and homogeneous for a dispersion and an active total surface adequate at the gastric level. and whose alkalizing capacity can, if desired, be constant and titratable.

 The process according to the invention is characterized in that powdered alumina and / or magnesia hydroxide is mixed with water and that this mixture is mechanically dispersed and fragmented up to the obtaining an average particle size of the order of 5 to ro L.

 The aqueous mixture of aluminum hydroxide and / or magnesia is advantageously dispersed at high pressure, by means of a high-pressure homogenizer subjecting the mixture to the action of about 20,000 vibrations per second. The number of passages in such a homogenizer and the magnitude of the pressure depend above all on the particle size of the starting material.

Thus, for example, for a particle size of the starting material of approximately 30, two passages are sufficient, while for a particle size of approximately 50)>, three passages are necessary. The pressure can be increased as and when it passes to make optimal use of the fragmentation, dispersion and homogenization effect of the device. It has been found that for starting material from 30 to 50 / U the pressure to be applied in the second compression chamber of the homogenizer can go up to 500 kgs / cm2 from the second pass, but that it must be less than this maximum during the first pass. The pressure in the first compression chamber will be lower than that applied in the second, thus achieving an average particle size of between 5 and 10 μm for the homogenized suspension.

 On the other hand, the alkalizing powders being abrasive, it is desirable to equip the homogenizing apparatus with ceramic impact rings and tungsten / carbide pressure valves, so as to avoid premature wear of these parts .

 So that the passages in the homogenizer are carried out without problems due to the deposition and accumulation of particles at the outlet or at the inlet of the compression chambers, viscosity modulators must be incorporated before the first passage through the device.

The other additives commonly used for Antacida, such as preservatives and flocculants, as well as possibly other active substances having complementary therapeutic effects, can be incorporated at the same time or between passages or possibly even at the end of manufacturing. The duration of the passages will vary depending on the total mass to be treated.

 It is also possible to replace the hydroxide of alumina and / or of magnesia, used as starting material, partially by the usual gels and at least in part by powders or gels dried and ground of other alkalizing salts.

 On the other hand, it should be noted that according to current manufacturing methods, the alkalizing capacity of these salts, whatever their physical state, dry or in gels, varies substantially from one batch to another, which has as a consequence of similar variations in the basifying capacity of the preparations which incorporate them. However, thanks to the high average basifying capacity per gram of the dry forms of these salts, the process according to the invention also makes it possible to establish the formula not in quantities absolute of the alkalizing salts, but in milliequivalents of hydrochloric acid, that is to say in variable quantities of these materials, determined according to the variations in their alkalizing capacity from one batch to another, so as to obtain that each batch of the Antacidum thus produced has an equal alkalizing capacity and can be titrated "in vitro" with variations of less than + 5%.

We also note that the action of vibrations in the homogenizer, of the order of 20,000 vibrations per second, has a favorable effect on the texture of
Antacida thus treated, which in the mouth then leaves a perfectly creamy sensation, contrary to the earthy impression left by the non-homogenized preparations, but incorporating from the start alkalizing salts in dry form composed of particles previously reduced to 5 to 10 on average .This advantageous result therefore appears not only to the reduction in the average size of the particles, obtained thanks to the passages by a homogenizer, but also to the reduction in the diversity of the sizes of the particles, so that the major part of the antacid salts in suspension, namely more than 80%, are present in particles of substantially the same size from 5 to 15 and finally to the fact that we observe under the microscope that in the suspensions ions thus treated the larger particles show more rounded shapes , with fewer acute angles, than for untreated suspensions.

 From an economic point of view, it can also be considered as a non-negligible advantage that the powdered alumina and / or magnesia hydroxide, as used in the process according to the invention, is considerably cheaper than dry micronized or sieved powders or gels, which also have the disadvantage of being highly contaminated by bacteria.

100 ml of suspension produced by the process according to the invention and which can be used directly as Antacida, for example have the following composition 1) Dried alumina hydroxide
and reduced to powder: 12 g
Magnesium hydroxide gel
dried and reduced to powder: 13.3 g
Dimethylpolysiloxane: 1.5 g
Potassium biphosphate: 0.15 g
Alcohol (96%): 5 ml
Tragacanth: 0.3 g
Tween 80: 0.2 g
Nipagin: 0.12 g
Nipasol: 0.02 g
Benzoic acid: 0.3 g
Sweetener: 0.008 g
Genulacta: 0.3 g 2) Magnesium hydroxide gel
dried and reduced to powder: 5.5 g
Magnesium hydroxide gel
at 26% equivalent to 7.8 g of
dried powder: 30 g
Desiccated alumina hydroxide
and reduced to powder: 8 g
10% alumina hydroxide gel
of A1203 eq. 4 g powder
parched: 26.1 g
Dicyclomine hydrochloride: 0.125 g
Alcohol (96%): 5 ml
Tragacanth: 0.3 g
Tween 80: 0.2 ml
Nipagin: 0.12 g
Nipasol: 0.02 g
Benzoic acid: 0.3 g
Sweetener: 0.008 g
As homogenizers, it is possible to use, for example, the devices marketed by the American firm.
GAULIN Corporation.

 The neutralizing capacity of the products obtained by the process according to the invention can be at least 4 times greater than that of comparable products manufactured on the basis of non-concentrated gels and even greater than that obtained with concentrated gels. This technical characteristic does not only have an economic consequence but also proves to be particularly advantageous from a medical point of view, because on the one hand, a smaller quantity of drug is necessary to obtain the same therapeutic effect. and, on the other, that it is thus possible to manufacture a suitably concentrated Antacidum having an antacid therapeutic action known to the attending physician and constant from one batch to another.

Claims (8)

 1. Method for manufacturing a stable suspension of alumina hydroxide and / or magnesia as an active agent of Antacida, characterized in that powdered alumina hydroxide and / or magnesia hydroxide is mixed , with water and this mixture is mechanically dispersed and fragmented until an average particle size of the order of 5 to 10 is obtained  2. Method according to claim 1, characterized in that the aqueous mixture of alumina hydroxide and / or magnesia is fragmented and dispersed under high pressure.  3. Method according to claim 2, characterized in that fragmenting and dispersing said aqueous mixture in a high pressure homogenizer producing about 20,000 vibrations per second.  4. Method according to claim 3, characterized in that the said mixture is dispersed and dispersed in several passes in the homogenizer, increasing the pressure on each pass.  5. Method according to claim 4, characterized in that the said mixture is dispersed and dispersed under 2 pressures between 50 and 500 kg / cm2  6. Method according to any one of claims 1 to 5, characterized in that add to said mixture, before the fragmentation and mechanical dispersion, viscosity modulating additives.  7. Method according to any one of claims 1 to 6, characterized in that one adds to the said mixture, before, during or after the fragmentation and mechanical dispersion, the other usual additives for a Antacidum.  8. Method according to claim 1, characterized in that at least in part, as powdered alumina and / or magnesia hydroxide, powders or gels dried and reduced to powder of these hydroxides.