HU196711B - Process for producing long-acting, gastric acid neutralizing pharmaceutics with high acid-binding capacity and increased bioavailability - Google Patents

Abstract

Prodn. of pharmaceutical prepns. of high acid neutralising capacity, of increased bioavailability and of delayed action and in given cases characterised by other actions in the gastrointestinal tract, esp. laxative action, comprises mixing 100 pts. wt. of a powdered basic magnesium cpd. or a powdered mixt. of basic magnesium cpds. and basic Al cpds. with 2-2500 pts. wt. of an in water-swelling, dry or in water swollen organic acid of polymeric character, pref. cellulose-glycolic acid, starch-glycolic acid or polymerised acrylic and/or methacrylic acids, then mixing this powder with 50-500 pts. wt. of water, allowing the mixt. to react at 20-80 deg.C for 1-24 hrs., granulating and drying the granules and after addn. of 5-60 pts. wt. of a smoothing agent and/or other pharmaceutical excipients, esp. colloidal silicic acid, PVA, sodium saccharimide and/or other flavouring or perfuming agents, prepg. tablets or other solid pharmaceutical prepns. or prepg. liquid suspensions from the mixt. contg. basic active ingredients and organic acids of polymeric character, by addn. of water and then the excipients.

Description

FIELD OF THE INVENTION The present invention relates to novel novel high-acid binding capacity, long-acting, high bioavailability, steroidal acid binding agents and, optionally, other gastrointestinal, e.g.

The clinical practice of drug therapy in recent years has widely demonstrated that besides acid secretion reducing agents, the so-called classical gastric acid neutralizing drugs, which act by selective inhibition of histamine H ₂ receptors. anracids continue to play a very important role in the therapy of hyperacid states and gastric ulcers. This is primarily due to the fact that on the one hand antacids show significantly less side effects and on the other hand well-formulated and properly administered antacids can fully meet therapeutic needs and lead to reliable therapeutic results. Therefore, considerable efforts have been made in recent years in this area of pharmaceutical research to develop antacids with high bioavailability.

Bioavailability of antacid activity, effect of the agent on gastric juice pH, and time course of this effect according to the Rosett-Rice test (cf. NE Rossett, ML Rice, Gastroenterology 26, 940 (1954)) It can be characterized. In conventional antacid formulations, the mode of action and its course of action generally follow the curve I, which shows that, after administration of the agent, the pH of the hyperacid gastric juice is, for a relatively short period, not only within the optimal range of 3-5, but it rises well above that. The antacid activity above A in the optimal pH range (3-5) of the activity area below curve 1 is useless and even harmful to the body (due to the loss of pepsin function and the so-called rebound effect in reactive hydrochloric acid production). ). To overcome this disadvantage, antacid formulations with controlled release rate (retarded), in which the pH of the gastric juice is kept within the optimum pH range for a prolonged period, but not for a sudden and unnecessarily large increase in pH, have been used. Thus, the antacid activity of the agent is fully bioavailable, as shown in Figure II, Figure 1. curve.

Among the currently used antacid agents, non-systemic antacids, i.e. formulations containing basic active substances whose cation is eliminated from the body in the form of poorly soluble salts of the intestine, are predominantly used, such as the magnesium cation, which is largely eliminated from the body when converted to poorly soluble magnesium carbonate.

Many attempts have been made in recent years to improve antacid formulations containing these types of active ingredients, in particular to increase acid-binding capacity, prolong the duration of action, improve the taste of the formulation or improve or improve the yield by pharmaceutical technology. Thus, U.S. Pat. U.S. Pat. No. 4,123,125 discloses the preparation of an easy-to-handle, pleasant-tasting antacid composition which can be converted into a suspension prior to ingestion.

A remarkable new technical solution is proposed in U.S. Patent No. 3,843,778, which discloses a coating of the antacid-containing particles with a hydrocarbon-type oil, which then forms a slurry or tablet. The product thus obtained is tasteless and may be flavored with any flavoring agent.

Various new procedures have also been proposed to increase the duration of action. An extended-acting multilayer tablet formulation is described, for example, in U.S. Patent No. 6,210,063. However, the process described there is mainly suitable for the preparation of formulations in which the active ingredient is contained per tablet. its amount does not exceed 300 mg. However, the amount of active ingredient in an anticidal composition often reaches, or even exceeds, 800 mg, so that this method is unsuitable for the preparation of prolonged-release anticidal tablets.

Inventors of the present invention are described in U.S. Patent No. 167,604. U.S. Patent No. 4,198,125 to Achar, et al., discloses a process for preparing controlled-release tablets wherein the controlled HLB (hydrophilic) containing a special hydrophobic component (e.g., stearic acid) and two different emulsifiers as a hydrophilic component for granulating a powder mixture containing the active ingredient emulsion was used.

The same authors in U.S. Pat. No. 179,474. U.S. Patent No. 4,463,500 discloses a process for the preparation of a controlled-release, sustained release solid pharmaceutical composition comprising the step of forming an amphoteric gelling agent, e.g. When dry powdered tragacanth and / or carboxymethylcellulose are added, a portion of this amphoteric gelling agent may be added prior to granulation to the active ingredient / carrier mixture. The particles of such formulations adhere to the gastric wall by the action of an amphoteric gelling agent, providing an antacid in the stomach for a longer period of time than usual, thus providing a sustained action.

A new technical solution for the manufacture of tablet-form pharmaceuticals has been the so-called. liquid wafer drug tablets that disintegrate immediately when placed in the oral cavity, usually causing a chilling sensation and ample saliva. As a result, the disintegrated drug can be easily and quickly swallowed with plenty of saliva, no need for water to ingest, which not only increases patient comfort, but also allows rapid ingestion of the drug in any situation, such as traveling or other uncomfortable conditions.

A process for the preparation of liquid wafer tablets which can be successfully used in the field of antacids is the process developed by Harden (British Patent No. 1,601,833), in which the sodium salt of an organic polymer is used as a special active disintegrant in aluminum and magnesium They applied. Its high swelling capacity plays an essential role in achieving the desired physical properties of the tablet. However, a particularly desirable time-delayed effect for antacid formulations has not yet appeared to be achieved with such immediate disintegrating liquid wafer formulations. There is no example in the prior art to realize the liquid wafer nature and the time-delayed effect within the same formulation, and even the luiquid wafer nature, which includes the requirement for rapid disintegration, has generally been considered inconsistent with the various embedding and coating operations required to achieve sustained release. using slow-dissolving, non-swellable excipients or greasy embedding materials.

The present invention is based on the surprising discovery that the sustained acid-binding effect and the liquid wafer nature can be achieved within a single formulation by a single technological operation, even by providing a high acid-binding capacity per dosage unit of the formulation, a normal tablet size. mass. According to the present invention, this object is achieved by contacting a highly basic magnesium compound or magnesium and aluminum compounds as the antacid agent and contacting it with a weak organic acid of a polymeric nature in an aqueous medium. The polymer then reacts with the basic metal compound to produce a highly swellable product which is then converted into a tablet for oral administration in a conventional manner. In said composition, said high-swelling product provides, on the one hand, rapid disintegration of the tablet upon ingestion and thus a liquid wafer character, and on admission to the stomach adheres to the stomach wall and reacts slowly with a stomach acid stronger than the polymeric acid component. It is understood that the pH increase caused by the OH 'flux produced by the composition can be controlled to the desired extent, mainly due to the viscosity-increasing and thus diffusion-reducing effect of the polymeric acids.

Another important advantage of the process according to the invention is that in the composition, while maintaining the liquid wafer nature and high acid-binding effect, the time-delayed effect can be combined with the rapid onset of action. This can be achieved according to the invention by mixing the basic magnesium compound (or a mixture of basic magnesium and aluminum compounds) with a stoichiometric equivalent of a weak acid of polymeric nature and subjecting the powder mixture to standard wet granulation.

Under these conditions, only a portion of the antacid reacts with the polymeric acid, the initial specific acid-binding capacity of the substance is only slightly reduced, and the high swelling product resulting from the reaction of some of the antacid with the polymeric acid is sufficient to disintegrate the tablet however, the unreacted portion of the antacid is capable of rapid acid binding immediately. Thus, when the tablet is taken, this unreacted portion, which is considered to be the stoichiometric excess of the antacid, provides the initial rapid acid binding effect. faecal release (the fast-release, fast-acting portion, while the other portion of the antacid reacted with the weak organic acid of the polymer provides the slow-release, sustained-release portion of the stomach with the stronger gastric acid; within the usual dose.

Thus, in this particularly preferred embodiment of the process according to the invention, liquid wafer-like antacids having an immediate onset of action and a prolonged action, having an immediate onset of action, can be prepared in a simple manner by optimizing the bioavailability, high acid-binding capacity, and the extent of the time-delayed effect can be varied within a wide range by varying the ratio of the ratio of antacid active ingredient to polymeric organic acid.

It follows from the above that when the basic antacid and the polymeric organic acid are used in chemically equivalent amounts or the polymeric organic acid is used in excess of the basic antacid, so that the total amount of the basic antacid can react with the polymeric organic acid, then, in the antacid formulation containing such an active ingredient, only the sustained action is present without the immediate action component. On the other hand, when a very large excess of polymeric organic acid (e.g. 1 to 30 parts by weight of magnesium oxide) is used, the swelling and water retention properties of the polymeric organic acid (e.g., cellulose glycolic acid) are very high. The oulk has a laxative effect so that an intestinal liquid wafer-type laxative composition can be produced by increasing the weight of the stool.

The present invention thus provides a method of preparing gastric acid neutralizing agents with high acid binding capacity, prolonged duration of action, increased bioavailability and optionally, e.g. 2 to 2500 parts by weight of a pharmaceutically acceptable water-swellable polymeric organic acid, the granulate then moistened with 50 to 5 000 parts by weight of water, and the dried particulate material, optionally 5 to 60 parts by weight of a smoothing agent and / or other pharmaceutical excipient. colloidal silicic acid, polyvinylpyrrolidone, saccharimide sodium and / or other flavoring or flavoring additives, to form tablets or other solid g or a powder mixture containing the basic active ingredient and the polymeric organic acid by adding water and optionally said excipients to a liquid suspension.

The basic magnesium compound used in the process of the invention is preferably magnesium oxide, magnesium hydroxide or basic magnesium carbonate, and optionally aluminum hydroxide as the basic aluminum compound. Organic polymers containing free carboxylic groups capable of swelling with water as the organic acid polymer, such as cellulose glycolic acid (carboxymethylcellulose H), carbonic glycolic acid (carboxymethyl starch H), carboxypolymethylone (e.g. Carbopo) 940 ), polymers of acrylic acid and methacrylic acid (such as compositions containing acrylic acid and methacrylic acid polymers known under the trade name Eudragit, in particular Eudragit L 100-55, also used as pharmaceutical excipients). As mentioned above, the polymer is a weak organic acid

(a) in the case of a sustained release preparation alone, in an amount sufficient to react with the total amount of the basic substance,

(b) in the case of combined immediate and extended release formulations, in smaller quantities, according to the desired proportions of the two types of effect,

(c) in the case of preparations for use as a laxative in bulls. The most preferred amount to be used is determined by the number of reactive basic groups of the basic material and the free carboxyl groups of the organic acid of the polymer.

The water-swellable polymeric nature of a weak organic acid used in the process of the present invention to provide sustained watering of a basic magnesium or aluminum compound is based on the fact that the viscosity of these materials is strongly In the presence of swellable polymer, the organic acid salt of an organic acid with a basic substance forms a highly viscous, highly adherent mass in the stomach from which gastric acid can slowly dissolve the basic active ingredient. This property of swellable polymeric organic acids can be experimentally demonstrated: Figure 2 shows the pH dependence of the viscosity of a 1% aqueous dispersion of Eudragit L 100-55. It can be seen that the viscosity of the initially low-viscosity acid dispersion during salt formation with increasing amounts of sodium hydroxide reaches a maximum at steady-state viscosity after repeated measurements, both after initial and gel breakdown, and then (not under physiological conditions). decreases again to very high pH values. Viscosity maxima at weakly alkaline pH can also be achieved by imaging with basic magnesium compounds.

This property of water-swellable polymeric weak organic acids is also present in the process of the present invention: the highly viscous, highly adhesive polymer with increased viscosity through magnesium ·

In preparing the compositions of the present invention, the basic compound reacts with the organic acid of the swellable polymer in the presence of water and the reaction takes time. Therefore, it is preferable to allow the mixture of the basic material and the organic acid of the swellable polymer to stand for a while before granulating the wet mass, so that there is sufficient time for the organic acid to swell and react with the basic compound.

This object, to facilitate the reaction of the basic compound with the polymeric acid, in another preferred embodiment of the process, may be achieved by first swelling the polymeric organic acid with water and then mixing the basic compound with the swollen material. Depending on the desired composition, additional basic compound and / or additional water may then be added to the resulting mixture, and the resulting wet mass will then be granulated.

Prior to compression into dry granules into tablets or other solid preparations, if desired, various excipients customary in the pharmaceutical art, in particular flavor enhancers and / or flavoring agents such as mammoth, xylitol and / or essential oils, tablet disintegrating agents such as polyrin and crosslinking agents, add.

The compositions of the invention may also be prepared in the form of a liquid suspension. Thus, the mixture of the basic compound and the polymeric acid is converted into a slurry with larger amounts of water instead of granulation, and then diluted, if appropriate, with additional water, preferably by the addition of a preservative such as sodium benzoate, or other physiologically beneficial products such as antacid. up.

Practical embodiments of the process of the invention are illustrated by the following examples.

Example 1

500 g of magnesium oxide and 50 g of dry powder acrylic acid polymer (Carbopol 940) are mixed, homogenized and 600 g of deionized water are added to the 0.5 mm mesh screen. The kneaded wet mass was allowed to stand at room temperature for 24 hours, then granulated by passing through a 2 mm mesh sieve and the granulate was dried. To the dry granulate of the sieve with a mesh size of 1.2 mm, 170 g of mandit, 23.5 g of cross-linked polyvinylpyrrolidone (trade name Polyplasdon XL), 2 g of hydrophobized colloidal silica (formulation Aerosil R 972) and 1.5 g of saccharimide sodium are mixed. and this mixture is compressed into 0.75 g individual tablets.

The time-elongated effect of the antacid composition thus produced is illustrated in Figure 3 with respect to the pharmacological grade magnesium oxide. Figure 3 shows that in an acidic medium of constant pH 3 at 37 ° C and stirred at 300 rpm for almost 120 minutes, the preparation of Example 1 containing the same amount of magnesium oxide was neutralized for almost 120 minutes. does not end after.

EXAMPLE 2 g Cellulose glycolic acid (carboxymethyl cellulose H prepared by precipitation of 20% hydrochloric acid alcohol in alcohol of a grade of carboxymethyl cellulose sodium according to the specifications of the Hungarian Pharmacopoeia) with 100 g of deionized water at 40 ° C. After stirring for 2 hours, 500 g of magnesium oxide and 700 g of water are added and the whole is kneaded. The wet mass is granulated as described in Example 1 and further processed into tablets.

Example 3

A powder mixture of 700 g of basic magnesium carbonate and 50 g of acrylic acid-methacrylic acid polymerizate (Eudragit L 100-55) is moistened with 700 g of water and kneaded until homogeneous. The wet mass is

Treat and granulate as described in Example 1, then add 200 g of mannitol, 42.5 g of cross-linked polyvinylpyrrolidone (Kollidon CL), 2.5 g of hydrophobic colloidal silica (Aerosil R 972), 2.5 g to the dry granulate. saccharimide sodium was mixed and compressed into tablets weighing 1 g each.

Example 4

To a dry powder mixture of 150 g of magnesium oxide and 50 g of acrylic acid methacrylic acid polymer (Eudragit L 100-55) is added 600 g of deionized water and a homogeneous dispersion is prepared by stirring. Allow to stand for two hours, stirring occasionally. Then, 350 g of magnesium hydroxide / aluminum hydroxide combined dry gel was mixed and the resulting wet mass was further processed into 0.75 g individual tablets as described in Example 1.

1-4. The antacid tablets prepared according to Example 1b have an acid-binding capacity in vitro of 17.5-25 mmol of hydrochloric acid measured in a batch at 37 ° C and 300 rpm with magnetic stirring. This acid-binding value of these tablets over a period of 90-160 minutes they make it. The neutralization curves of the compositions of each example, as measured above, are illustrated in Figure 4. Figure 4 shows that Figure 2-4. Examples 1 to 4 include the use of magnesium oxide and the like. for basic magnesium carbonate drugs, results similar to those obtained by the procedure of Example 1 (cf. the first figure) can be achieved by controlling the rate of drug release and the rate of drug release.

Example 5

To the dispersion prepared in Example 4 was added 0.05% sodium benzoate. The preserved suspension thus prepared may be used, either directly or after further dilution with water, in the form of liquid pharmaceutical compositions or other compositions for physiologically advantageous use.

Example 6 To a mixture of g of magnesium oxide and 95 g of powdered cellulose glycolic acid (carboxymethyl cellulose-H) was added 2.5 J of deionized water. The mixture was allowed to stand for 2 hours and then granulated by passing through a 2 mm mesh screen. The granules were dried at a temperature not exceeding 60 ° C and then granulated through a 1.2 mm mesh screen.

The granular product thus obtained has an extremely high swelling capacity and the dry material swells to about 30 times the volume in aqueous medium. The product is used for both liquid wafer tablets and so-called "wafer" tablets. The bulls are capable of producing an effective laxative because of their high water retention capacity.

Claims (8)

Claims A process for the preparation of high acid binding capacity, time effective action, increased bioavailability of gastric acid neutralizing agents and, optionally, other particularly useful laxative magnesium oxide in the gastrointestinal tract, characterized in that it contains 100 parts by weight of magnesium oxide and From 2 to 2500 parts by weight of a pharmaceutically acceptable, water-swellable, dry or water-swellable polymeric organic acid, preferably cellulose glycolic acid, starch glycolic acid or acrylic acid and / or methacrylic acid After mixing 50 to 500 parts by weight of water, the mixture is allowed to react for 1 to 24 hours at 20 to 80 ° C and then granulated. and converting the dried particulate material into tablets or other solid pharmaceutical formulations, optionally by adding 5 to 60 parts by weight of a smoothing agent and / or other pharmaceutical excipients, in particular colloidal silicic acid, polyvinylpyrrolidone, saccharimide sodium and / or other flavoring or perfuming additives, or the mixture of the basic active ingredient and the polymeric organic acid is made into a liquid suspension by the addition of water and optionally said excipients. Process according to claim 1, characterized in that the organic acid is swelled with at least an equal weight of water, preferably for at least one hour, and then mixed with the basic magnesium compound or a mixture of the basic magnesium compound and the basic aluminum compound. Process according to claim 1 or 2, characterized in that the polymeric organic acid is first swollen with a portion of water, the basic magnesium and optionally aluminum compound and a further portion of the water are mixed with the swollen polymeric organic acid and granulating the wet mass. 4. A process according to claim 1, wherein the basic magnesium and optionally aluminum compound or a portion thereof and the polymeric organic acid are mixed with a sufficient amount of water to form a liquid dispersion, and then the basic magnesium and optionally aluminum compound is added to the dispersion. and the resulting wet mass is granulated. 5. The process of claim 1, wherein the basic magnesium and optionally aluminum compound and the polymeric organic acid are mixed with a sufficient amount of water to form a liquid dispersion, and the resulting aqueous dispersion, optionally after further dilution with water, is a preservative. and / or to form a liquid composition by the addition of a taste enhancer or other excipient. 6. A process according to any one of claims 1 to 3, characterized in that the granulated mixture is. to the lozenge is added in an amount of from 1 to 6% by weight, with a swelling aid of 5 to 100 ml / g, preferably cross-linked polyvinylpyrrolidone, and 1 to 20% by weight of polymeric organic acid, preferably carboxypolymethylene. A process according to any one of the preceding claims for the preparation of a sustained release gastric acid neutralizing composition, characterized in that: 196,711 is applied in an amount sufficient to react with at least the total amount of the basic active ingredient of the organic polymeric acid. 5 8. A process for preparing a combined, immediate onset and sustained release gastric acid neutralizing composition according to any one of claims 1 to 3, wherein the basic magnesium and optionally aluminum compounds are used in an amount greater than necessary to react with the total amount of organic polymeric acid.