AU604721B2 - Proceeding for the production of pharmaceutical preparations of high gastric acid binding capacity, of retarded effect and of increased bioavailability - Google Patents

Description

Signed Status D eclarant's N am i. PCr

WORLD

INTERNATIONAL APPLICATION PUBI iPERATION TREATY (PCT) (51) International Patent Classification 4 I) International Publication Number: WO 88/ 00051 A61K 33/06, 9/22, 9/10 Al A61K 47/00 (43) International Publication Date: 14 January 1988 (14.01.88) (21) International Application Number: PCT/HU87/00026 (81) Designated States: AU, CH, DE, GB, JP, US.

(22) International Filing Date: 24 June 1987 (24.06.87) Published With international search report.

(31) Priority Application Numbers: 2643/86 2643/86 (32) Priority Dates: 24 June 1986 (24.06.96) 21 April 1987 2,O.4.87) This document contains the (33) Priority Country: HU amendments made under Section 49 and is correct for printing.

(71X72) Applicants and Inventors: RACZ, IstvAn [HU/HU]; NebAncsvirag u. 3, H-1165 Budapest PLACHY, JAnos [HU/HU]; Mandula u. 18, H-1025 Budapest SZENTMIKLOSI, Peter [HU/HU]; Rudas L. u. P -3 MR 1988 H-1064 Budapest (HU).

(74) Agent: PATENTBUREAU DANUBIA; Bajcsy Zsi- AUSTRALIAN linszky ut 16, H-1368 Budapest (HU).

2 9 JAN i988 PATENT

OFFICE

(54) Title: PROCEEDING FOR THE PRODUCTION OF PHARMACEUTICAL PREPARATIONS OF HIGH GAS- TRIC ACID BINDING CAPACITY, OF RETARDED EFFECT AND OF INCREASED BIOAVAILABILI-

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(57) Abstract Production of a new pharmaceutical preparation of high acid-binding capacity, of retarded effect, of increased bioavailability forneutralization of gastric acid and eventually to other pharmaceutical preparations acting in the gastrointestinal tract, first of all of laxative effect by mixIng 100 pars by mass of a powdered basic magnesium- compound or the powdered mixture of basic magrnsium compounds and basic aluminium compounds with 2-2500 parts of a dry or in water swollen organic acid of polymeric character and therapeutically acc:otable, e. g. cellulose-glycolic acid, starch-glycolic acid or polymer acrylic and/or methacrylic acid, letting this powdered mixture to stand for 1-24 hours at the temperature of 20-80 0 C after addition of 50-500 parts by mass of water and forming tablets or other pharmaceutical preparations, eventually after addition of 5-60 parts by mass of smoothing agents and/or other pharmaceutical excipients, or tansforming the mixture containing the basic active ingredients 'and the polymeric organic acid in liquid suspension by adding water and eventually excipients.

I4 K- WO88/00051 PCT/HU87/00026 PROCEEDING FOR THE PRODUCTION OF PHARMACEUTICAL PREPARATIONS OF HIGH GASTRIC ACID BINDING CAPACITY, I OF RETARDED EFFECT AND OF INCREASED BIOAVAILABILITY The invention relates to the production of a new pharmaceutical prep ra ion of high gastric acid binding capacity, of -ed effect and of high bioavailability and eventually to other pharmaceutical preparations acting in the gastrointestinal tract, for instance to laxative preparations of high swelling and water retaining capacity (the so called "bulk" laxative preparations).

The clinical experience of pharmacotherapy confirmed extensively in the last years that paralelly to the preparations reducing the gastric secretion by selective inhibition of the histamine-

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2 -receptors, the classical gastric acid neutralizing preparations, the so called antacids play also actually an important role in the therapeutics of hyperacid conditions and gastric ulcers. This fact is explained, first of all, by the data demonstrating that the antacid preparations provoke much less sie effects and, on the other hand, the well formulated and correctly dosed antacids meet with all the therapeutical demands and give reliable results. Therefore in this field of pharmaceutical investigations great efforts have been made in the last years for developing antacid preparations of high bioavailability.

The bioavailability, the activity of antacid drugs, their action on the pH value of gastric juice and the course of their effect asfunction of time may be characterized by the Rossett-Rice test Rossett, M. L. Rice: Gastroenterology, 26.

940(1954) ,as shown in Figure 1. For the classical antacid preparations the mode of action and its -NNT d jr WO 88/00051 PCT/HU87/000 26 WO 88/00051 -2course as function of time follow generally the Curve I.

It shows that after administration of the preparation the pH value of the-hyperacid gastric juice rises only for a short time, but not only to the optimal value of 3-5, but to much higher ones.

The area of activity below the Curve I is divided in two parts: the part A corresponding to the optimal pH-range and the area Are, corresponding to higher pH-values. This latter antacid activity is worthless, even harmful for the organism, due to the supression of the pepsin activity and to the so called "rebound effect", provoking reactive hydrochloric acid secretion. The elimination of these disadvantages has been intended by the application of antacid preparation of controlled dissolution rate preparations). Their application does not cause an unnecessary, sudden, high pH rise of short duration but they maintain the pH value for a long time in the optimal pH range, assuring the full biological availability of the antacid activity of the preparations, as shown by the Curve II in Figure 1.

Among the antacid preparations actually applied especially the non-systemic antacids prevail, id est, preparations containing active ingredients of basic character, whose cation is evacuated from the organism as a poorly soluble salt formed in the intestines and does not disturb the acid-base equilibrium, even in cases of long lasting administration. SuchAcation is magnesium, which is transformed in the bowels into the scarcely soluble magnesium carbonate and is evacuated from the organism in this form.

Many attempts have been made in the last A T Iti T 0- t* i y WO 88/00051 PCT/HU87/00026 -3years for the development of the preparations of this type, especially for increasing the acid- -binding capacity, the prolongation of the duration of their action, the improvement of the taste or for rendering more easy or comfortable the ingestion using pharmacotechnical methods. So, for instance, the US Patent Specification No 4,271,142 describes the mode of production of a- antacid preparation of simple handling and pleasant taste, which may be transformed in suspension in situ before ingestion.

The US Patent Specification No. 3,843,778 describes a notable new technical method. According to this invention the active antacid ingredient containing granules is providaed with an oily coatig of hydrocarbon type and these coated granules are used for the preparation of suspensions or tablets.

The product so obtained is tasteless and may be flavoured at discretion.

Various new proceedings have been proposed for increasing the duration of the action. For instance, the Swiss Patent Speification No 621,063 discloges a preparation of ed- action, consisting tablets of various layers, but the method there described is suitable, in. the first place, for preparatio s, whose active ingredient content is not to300 mg.

But in antacid preparations the amount of the active ingredient may reach and even pass over 800 mg and so this proceeding is not very sita le for the preparation of antacid tablets of ret effect.

The inventors of the present invention disclosed in the Hungarian Patent Specification No 167,604 a process for the production of tablets characterized by regulated dissolution rate of the

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1 n- 4/ i s ,i PCTIHU87/00 0 26 WO 88/00051 4active ingredients by using for the granulation of the powdered mixture containing the active ingredients and the excipients a special hydrophob 1.component stearic acid) and as a hydro- 2hil component an emulsion contaniin two different emulgators of regulated HLB jrb -i h balance) value.

The same authors, in the Hungarian Patent Specification No 179,474 disclosed a process for obtaining solid pharmaceutical preparations of regulated active agent dissolution rate and increased duration of action, consisting-a- the addition of an amphoteric gel-forming substance to the powder containing the active ingredients and the excipients, e. g. dry, powdered tragacanth gum and/ /or carboxymethylcellulose a fraction of this amphoteric gel-forming substance may be added to the mixture of the active ingredients and the excipients already before granulation. The granules of these preparations adhere to the gastric mural due to the effect of the amphoteric gel-forming substance and prolong the presence of antacid material in the stomach and so they exert a. et-arded action.

In the field of production of pharmaceutical preparations in the form of tablets a new technical process was developed by the invention of the so called "liquid wafer" type pharmaceutical tablets, which, when put into the oral cavity, disintegrate immediately, generally causing a cool sensation and provoking salivation. Consequently, the disintegrated tablet may be swollen easily, quickly and also without taking water. This fact is not only comfortable for the patients, but it renders also possible the ingestion of the drugs in any situation, for _V A4 K .7 7\~ S WO 88/00051 PCT/HU87/00026 instance during travelling or in other conditions, where comfort is absent.

In the field of antacid tablets the method disclosed by Harden (British Patent Specification No. 1,601,833) may be succesfully adapted, this invention proposes in addition to aluminium and magnesium hydroxides as active ingredients the application of the sodium salt of a2 organic pomneric acid, which is especially active im promoting the disintegration (Primojel). The great swelling capacity of this substance plays an important role in obtaining the desired physical properties of the pre aration.

For antacid preparations the r-a' ed- action is very desirable, but as far as here it has not been achieved with the "liquid wafer" preparations.

No references are found in the literature about the simultaneous obtentn 9f the "liquid wafer" character and the rt-rded action and generally, the "liquid wafer" character, expressing the postulate of rapid disintegration, is considered as incompatible with the different manipulations of embedding and coating and the pertinent application of slowly dissolving, hardly swelling excipieuts or greasy embedding matters.

The present invention is based on the sus-che-d release recognition of the surprising fact, thatthe re-Etded acid binding action and the "liquid wafer" character may be achieved in the very same preparation by a single technical operation, by assuring a high acid-binding capacity for each dosing unit having the mass of a normal tablet. This aim is achieved according to the present invention by using as the active antacid ingredient a highly basic magnesium compound or a mixture of basic magnesium and aluminium compounds and by contacting the I /VT O ZI Oy ;.gL I I- ~I PCT/HU87/0 0 02 6 WO 88/00051 6active ingredient in an aqueous medium with a weak organic acid of polymeric charachter. In this case the weak piymeric acid reacts with the basic metallic compound producing a substance of high swelling capacity, able to be formulated habitually as a preparation for oral administration, expediently as tablets. The product of high swelling capacity, incorporated into the preparation assures the rapid disintegration of the tablets after ingestion and hence, on the other hand, the "liquid wafer" character is present and on the other hand, when arriving into the stomach, the mass adheres to the gastric wall and reacts slowly with the gastric acid, a stronger one, than the polymeric acid cmponent incorporated in the tablets, assuring a retared acid -binding action of long term. It is evident, that the pH increasing due to OH- flow provided by the preparation because of the viscosity enhancing and therefore diffusion decreasing effect may be controlled according to the wanted level.

An additional important advantage of the process described in the present invention consists -i-the fact, that by pssuring at the same time the "liquid wafer" r -r e-and the high acid-binding capacity, the ~etaeaction may be combined with a prompt incipient action. It may be achieved according to the invention by mixing the basic magnesium compound (respectively the mixture of basic magnesium and aluminium compounds) with a amount less than stoichiometrically correspondent of the weak acid of polymeric character and this powder mixture is submitted to the habitual wet granulation process. Under these conditions only a fraction of the active antacid ingredient/s/ reacts A: 35 with the polymeric acid, the specific acid-binding N O e 'i i; WO88/00051 PCT/HU87/00026 -7capacity of the substance is reduced only partly, the product obtained by the reaction of a part of the antacid substance with the polymeric acid characterized by high swelling potency, is sufficient for assuring the sudden disintegration of the tablets and so far assuring the "liquid wafer" character. On the other hand, the non-reacted part of the antacid substance is suitable -e rapid acid- -binding. It means that when taking the tablet, that part of the antacid ingredient, which may be considered as a stoichiometrical excess, assures the prompt incipient acid-binding capacity, forming the "fast-releasing" fract .n and the other part of the active antacid inredient enters in reaction with the polymeric acid and supplies the slowly reacting fraction of the dose. This fraction reacts slowly with the stronger gastric hydrochloric acid, forming the "slowly-releasing" part of the active ingredient of the dose ingested in the very same preparation.

In the case of this especially advantageous variant of the execution of the process described in the present invention, "liquid wafer" type antacid preparations of high acid-binding capacity and of optimized bioavailability may be obtained by the simple and habitual process of granulation, which Scombines the prompt incipient action with a' 'w1!cve Sretrded one ad he relation of the prompt initial and of the c dc actions may be varied between wide limits by changing the ratio of the active antacid ingredient and the weak polymeric acid.

It may be deduced from the exposed facts, that when the basic active antacid ingredient and the polymeric organic acid are used in stoichiometric amounts or the polymeric organic acid is present in S 35 excess as compared with the active antacid ingredient, .o WO 88/00051 PCT/HU87/000 26 -8all the basic antacid ingredient reacts with the polymeric organic acid and the pharmaceutical preparation contains the active antacid ingr eien exclusively in this reacted form, only the rXtarded action will get across inAabsence of the promptly acting component. Inversely, when polymeric organic acid cellulose-glycolic acid) is applied in a very great excess for 1 mass unity of magnesium S30-50 mass unities), the so called "bulk" laxative action will prevail due to the high swelling and water-retaining capacity of this component. -Bythis way, when proceeding according to the process described in the present invention, a "liquid wafer" type laxative preparation may be obtained, which acts by increasing the mass of faeces.

-Th-at-mea-s-,--^-ha-t-he-tin-v-t-io-on-f-e-s-t-aprocess for the preparation of pharmaceutical preparations of high acid-binding capacity and, retarded action, with increased bioavailability and eventually exerting also other actions developed in the gastrointestinal tract, e.g. laxative effect, characterized by mixing 100 parts by'mass of a powdered basic magnesium compoundor a powder consisting of a mixture of basic magnesium compounds and basic aluminium compouns with 2-2500 parts by mass of a therapeutic ly acceptable, in water swelling organic acid f polymeric character and this powder mixtur granulated with 50-500 parts by mass of wate? even-tl-ly after addition of 5-50 parts by mas of a smoothing agent and/or other pharmaceutical excipients like colloidal silicic acid, p yvinyl-pyrrolidone, sodium saccharimide and/o other flavouring or perfuming agents and t lets or other solid pharmaceutical products forulated or the 8a Accordingly, this invention provides a process for the preparation of a pharmaceutical preparation of high gastric acid binding capacity, of increased bioavailability, and of delayed action in tablet or solid form, which comprises the steps of reacting 100 parts by weight of a powdered basic magnesium compound or a powdered mixture comprising a basic magnesium compound and a basic aluminum compound with 2 to 2500 parts by weight of a therapeutically acceptable, dry or water-swollen, water-soluble weak organic acid of polymeric character selected from the group consisting of cellulose-glycolic acid, starch glycolic acid, and polymerized acrylic or methacrylic acids to form a powdered composition having high swelling capacity; wetting the powdered composition with 50 to 500 parts by weight of water; maintaining the wet powdered composition at 20 to 0 C for 1 to 24 hours to permit an antacid and the 1 20 polymeric organic acid to react thereby giving the wet powdered composition a high swelling capacity and viscosity as well as ability to react slowly in the stomach with gastric acid to exert a sustained-release acid effect; 25 granulating the wet powdered composition treated during step and drying the granules; te) adding 5 to 50 parts by weight of a smoothing agent or other pharmaceutical excipients; and either preparing tablets or other solid 30 pharmaceutical preparations.

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C 0~ i i- I-* L 1~II~ 8b More preferably, the invention refers to a process for the preparation of pharmaceutical preparations of high acid-binding capacity and delayed action, with increased bioavailability and optionally exerting also other actions developed in the gastrointestinal tract, e.g. laxative effect, characterized by mixing 100 parts by mass of a powdered basic magnesium compound or a powder consisting of a mixture of basic magnesium compounds and basic aluminium compounds with 2-2500 parts by mass of a therapeutically acceptable, in water swelling organic acid of polymeric character and this powder mixture is granulated with 50-500 parts by mass of water, eventually after addition of 5-50 parts by mass of a smoothing agent and/or other pharmaceutical excipients like colloidal silicic acid, polyvinyl-pyrrolidone, sodium saccharimide and/or other flavouring or perfuming agents and tablets or other solid pharmaceutical products are formulated or the e 2

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f PCT/HU87/0 00 26 WO 88/00051 -9basic active ingredient and the polymeric organic acid containing powder mixture is transformed in a suspension by addition of water, eventually after addition of the mentioned excipients.

In the process described in the invention as basic magnesium compounds, first of all, magnesium Oyid e 'hycf fe L, magnesium Yhy ye or basic magnesium carbonate and as basic aluminium compound chiefly aluminium hydroxide may be used. As an in water swelling weak polymeric organic acid free carboxyl groups containing organic polymers may come in consideration, e. g. cellulose-glycolic acid (carboxymethylcellulose), starch-glycolic acid (carboxy- -methyl starch), carboxy-polymethylene (for instance the product known by its commercial name "Carbopol 940"), polymeric derivatives of acrylic and methacrylic acids, (especially the product "Eudragit L 100used also as pharmaceutical excipient).

The weak organic acid of polymeric character is used, as mentioned above, in the following manner: a/ in the amount sufficient for the complete reaction with the basic substance, when exclusively the production of a preparation of retarded action is aimed, b/ in less amounts, when preparations of combined prompt and retarded effect are aimed, in ratios corresponding to the obtention of the desired action, c/ in a considerable excess, when a preparation of "bulk" laxative effect is wanted.

In each case, the most convenient amount may be determined by taking into consideration the number of the reactive basic groups of the basic compounds, as well as the number of the free reactive groups of the polymeric organic acid.

-r 0AVs LM N 0 cnaracter seiecuea rrom -ne group consisting uo cellulose-glycolic acid, starch glycolic acid, and polymerized acrylic or methacrylic acids to fq~ia a /2 P7

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WO 88/ 0005 PCT/HU87/0 0 0 2 6 10 The action of the weak, .in water swezdalig organic acids of polymeric character, manifesting itself in the r dption of the liberation of the active ingredient, id est, of the magnesium or aluminium compounds, respectively, is based according to the present invention of the fact, that the viscosity of these substances increases considerably as a result of the reaction of salt formation with the basic compounds. The salt of the polymeric organic acid, swollen in the presence of water, obtained as a result of its reaction with the basic substance, forms in the stomach a very adhesive mass of high viscosity, from which the gastric hydrochloric acid only slowly dissolves the basic active ingredient. This quality of the polymeric organic acids able to swell in water may be demonstrated also experimentally.

Figure 2 shows the dependance of the viscosity of an 1 per cent aqueous dispersion of Eudragit L 100-55 on the pH-values. Evidently, the originally low viscosity of the acid dispersion is gradually increasing with salt formation in the presence of gradualr increasing amounts of sodium hydroxide, at weakly basic pH-values the initial viscosity, as well as the equilibrated viscosity obtained by the destruction of the gel structure and controlled by repeated measurements reaches a maximum and then it is decreasing at very high pH-values (not viable under physiological conditions). The maximum of viscosity at weakly basic pH-values may be produced also by salt formation with basic magnesium compounds.

This property of the weak organic acids of polymeric character, swelling in water prevails also in the process described in the present invention: the adhesive polymer of increased viscosity increases -r l t l ro v 1 11 the time of retention in the stomach of the basic antacid preparation as a result of the salt formation with magnesium and delays the liberation of the antacid active ingredient.

When the preparation is produced according to the present invention, the reaction of the basic compound with the swelling polymeric organic acid is carried out in the presence of water and some time is required for the completion of the reaction. The limits of this tine, depending on the different character of the compounds in the reaction, are from 1 to 24 hrs. Therefore it is advantageous to let the mixture of the basic substance and o of the swelling polymeric organic acid stand for some time before granulation of the wet mass occurs and to let time enough for the swelling of the polymeric acid, as well as 15 for its reaction with the basic compound.

This aim, the promotion of the reaction of the basic compound with the polymeric acid may be realized also by another advantageous mode of realization of the process: by letting the polymeric organic acid swell in water and by 20 adding afterwards the basic compound to the swollen material. In dependence of the desired composition of the Smixture an excess of the basic compounds and/or water may be added for obtaining the desired consistence, apt for granulation.

The dried granules can be used for different purposes. Due to the great swelling ability of the product, "liquid wafer" tablets can be produced with fast integration. In the other hand "bulk laxative" preparation can be formed when administered in higher dosage range based on the water retention effect. This product characterized by higher swelling ability needs less alkaline compound and more polymer organic acids, than the antar;A preparations.

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1 r~ii ~~i i 4 4* S. 4 i 1 1lla The dry granulated mass may be enriched eventually before compression of the tablets or its transformation in other solid preparations, by the addition of different excipients generally used in pharamaceutical practice, especially flavouring and/or perfuming agents, e.g.

mannitol, xylitol and/or essential oils, agents promoting the disintegration of the tablets, e.g. cross-linked polyvinylpyrrolidone and similar compounds.

The preparations corresponding to the present LCG/KJS:EK(12:4) i ,i P y WO 88/00051 PCT/HU87100026 12invention may be produced also as liquid suspensions.

In this case the mixture of the basic substance and of the polymeric acid is not granulated but transformed in suspension with an additional amount of water. This suspension eventually after dilution with more water and addition of preservative agents, e.g. sodium benzoate may be applied as an antacid preparation or elaborated to other physiologically useful products, e. g. to soft drinks with antacid effect.

The following examples illustrate suitable methods for the practical application of the present invention.

Example I ox de 500 g of magnesium oxyde and 50 g of dry, powdered polymerized acrylic acid (Carbopol 940) are mixed, homogenized and sieved through a sieve with openings of 0.5 mm. 600 g of deionized water is added to the sieved powder. The wet mass is kneaded together and let -4e- stand for 24 hours at room temperature and then passed through a sieve with ai opening of 2 mm. The granulated mass is dryed. 170 g.

of mannitol, 23.5 g of cross-linked polyvinyl-pyrrolidone (Polyplasdon XL), 2 g of hydrophobised colloidal silica acid (Aerosil R 972) and 1,5 g of sodium saccharimide are added to the mass. It is regranulated through a sieve with opening of 1.2 mm and using this mixture of 0.75 g individual mass is compressed.

The duration of the action of this antacid preparation so produced was compared with the action of magnesium oxyde of the purity prescribed in the pharmacopoeia and the result presented in Figure 3 was obtained. In acidic medium of constant pH 3.0 of 0 37 C temperature, stirred at 300 rpm, magnesium 9-ve produces almost instantaneous neutralization, rf 4\ IL _e -f Many attempts have been made in the last

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WO 88/00051 PCT/HU87/00026 13 but the preparation made according to Example 1, containing identical amounts of magnesium eo does not finish the neutralization process even in 120 minutes.

Example II g of cellulose-glycolic acid (carboxy- -methyl-cellulose) prepared from sodium carboxy- -methyl-cellulose (corresponding to the prescriptions of the VIth Hungarian Pharmacopoeia by precipitation with alcohol containing 20 per cent t of the most concentrated hydrochloric acid) is e to swell in 100 g of deionized water at 40 C0 for 2 hours, 500 g of magnesium -ye-and 700 g more of water are added and a homogeneous mass is produced.

Th wet mass is granulated and tablets are made as indicated in Example I, Example III A mixture of 700 g of powdered magnesium carbonate and of 50 g of powdered polymerized methecrylic acid (Eudragit L 100 55) is wetted with 700 g of deionized water and a homogeneous mass is produced. The wet mass is treated as described in Example I and is granulated and the dry granulate is enriched with 200 g of mannitol, 42.5 g of crosslinked polyvinyl-pyrrolidon) (KollidonC), 2.5 g of hydrophobized colloidal silica (Aerosil R 972), g of sodium saccharimide and tablets of 1 g individual mass are compressed.

Example IV oxide 150 g of magnesium -exye and 50 g of polymerized acrylic-methacrylic acid /Eudragit L 100 are powdered and 800 g of deionized water are added <3 e 6 e to the dry mixture. It is kle to stand for 2 hours with periodical stirring. Then 350 g of a mixture of magnesium hydroxide/aluminium hydroxide is added cnaracuerizeu oy reguiaau -u-Lb.-jwA-u.Luu'-auu in the form of a dry gel and the v mass so obtained is further processed as described in Example I for the production of tablets of 0.75 g individual mass.

The acid binding capacity of the tablets prepared as described in Example I to IV is equal to 17.5 25 meq of hydrochloric acid in a medium of pH 3.0 of 37 °C temperature, stirred at 300 rpm.

with a magnetic stirrer: these tablets reach the degree of neutralization in 90 160 minutes. The curves of neutralization of the preparations obtained according to the Examples I to IV produced by the described method are presented in Figure 4.

Example V 0,05 of sodium benzoate is added to the dispersion obtained as described in Example IV. The preserved suspension so prepared may be used as a liquid pharmaceutical preparation directly or diluted with water, or it can be used as a component of other preparations produced for physiologically advantageous purposes.

Example VI 1 of deionized water are added to a mixture of 90 g of magnesium -exde-and 950 g of cellulose-glycolic pcid (carboxy-methyl-cellulose).

The mixture is le~kto stand for 2 hours and it is then granulated using a sieve of openings of 2 mm.

The granules are dryed at a temperature not exceeding °C and regranulated using a sieve of openings of 1.2 mm.

The granulated product so obtained has an extraordinary swelling capacity. The dry mass is swelling in water and its volume increases about times. The product is suitable for the production of "liquid wafer" tablets and it may be used also as

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ll i l L the ingestion of the drugs in any situation, for I I ~Ir WO 88/00051 PCT/HU87/00026 15 a "bulk" laxative: that means, due to its great water retaining capacity it is suitable to produce an active laxative preparation.

Claims (9)

1. A process for the preparation of a pharmaceutical preparation of high gastric acid binding capacity, of increased bioavailability, and of delayed action in tablet or solid form, which comprises the steps of reacting 100 parts by weight of a powdered basic magnesium compound or a powdered mixture comprising a basic magnesium compound and a basic aluminum compound with 2 to 2500 parts by weight of a therapeutically acceptable, dry or water-swollen, water-soluble weak organic acid of polymeric character selected from the group consisting of 7ellulose-glycolic acid, starch glycolic acid, and polymerized acrylic or methacrylic acids to form a powdered composition having high swelling capacity; wetting the powdered composition with 50 to 500 parts by weight of water; *se maintaining the wet powdered composition at 20 to 80 0 C for 1 to 24 hours to permit an antacid and the polymeric organic acid to react thereby giving the wet powdered composition a high swelling capacity and viscosity as well as ability to react slowly in the stomach with gastric acid to exert a sustained-release acid effect; granulating the wet powdered composition treated during step and drying the granules; adding 5 to 50 parts by weight of a smoothing agent or other pharmaceutical excipients; and I j i excess as compared with the active antacid ingredient, *T 4 17 either prepa'ing tablets or other solid pharmaceutical preparations.

2. A process f6r the preparation of a pharmaceutical preparation of high gastric acid binding capacity, of increased bioavailability, and of delayed action in liquid form, which comprises the steps of reacting 100 parts by weight of a powdered basic magnesium compound or a powdered mixture comprising a basic magnesium compound and a basic aluminum compound with 2 to 2500 parts by weight of a therapeutically acceptable, dry or water-swollen, water-soluble weak organic acid of polymeric character selected from the group consisting of cellulose-glycolic acid, starch glycolic acid, and polymerized acrylic or methacrylic acids to form a powdered composition having high swelling capacity; wetting the powdered composition with 50 to 500 parts by weight of water; j maintaining the wet powdered composition at 20 to 80 0 C for 1 to 24 hours to permit an antacid and the polymeric organic acid to react thereby giving the wet powdered composition a high swelling capacity and viscosity as well as ability to react slowly in the stomach with gastric acid to exert a sustained-release acid effect; adding 5 to 50 parts by weight of a smoothing agent or other pharmaceutical excipients; and preparing liquid suspensions e nn" I I I F A^S i Y"roT O] 3 18

3. The process defined in claim 1 or 2 which comprises swelling the polymeric organic acid in at least the same weight of water for at least one hour and only afterwards mixing the water-swollen organic acid with the basic magnesium compound or with the mixture of the basic magnesium compound and the basic aluminum compound.

4. The process defined in claim 1 or 2 which comprises swelling the polymeric organic acid at first with a part of the water, mixing the water-swollen polymeric organic acid with the basic magnesium compound or with the mixture of the basic magnesium compound and the basic aluminum compound and with the remaining part of the prescribed amount of water and granulating the obtained wet mass.

The process defined in claim 1 or 2 which comprises wetting the basic magnesium compound or the mixture of the basic magnesium compound and the basic aluminum compound or a part of them and the polymeric organic acid with an amount of water sufficient to obtain a liquid suspension, adding supplementary amounts of the magnesium compound or the mixture of the magnesium compound and the aluminum compound to the dispersion and granulating the obtained mass.

6. The process defined in claim 1 or 2 which comprises wetting the basic magnesium compound or the mixture of the basic magnesium compound and the basic aluminum compound and the polymeric organic acid with an amount of water eIo sufficient to obtain a liquid dispersion, and adding a preserving agent, flavoring agent or other excipient to prepare a liquid preparation. o. A i I- 19

7. The process defined in claim 1 or 2 which comprises adding to the granulated wet powdered composition 1 to 6% by volume of an excipient of 5 to 100 ml/g swelling capacity having the ability to promote tablet disintegration, said excipient selected from the group which consists of a cross-linked polyvinylpyrrolidone and a polymeric organic acid in an amount of 1 to 20% by volume.

8. The process defined in claim 1 or 2 which comprises employing a polymeric organic acid in an amount at least sufficient for a complete reaction with the total amount of the basic active ingredient employed.

9. The process defined in claim 1 or 2 which comprises employing the basic magnesium compound or a mixture of the basic magnesium compound and the basic aluminum compound in excess as compared with the amount stoichiometrically equivalent to the polymeric organic acid. DATED this 10th day of September, 1990 ISTVAN RACZ, JANOS PLACHY and PETER SZENTMIKLOSI WATERMARK PATENT TRADEMARK ATTORNEYS, 2nd Floor, "The Atrium", 290 Burwood Road, Hawthorn, Victoria, 3122, AUSTRALIA. S LCG/KJS:EK(12:4) ["LTo