HU203966B - Process for producing orally administrable pharmaceutical compositions in the form of ointment, having gastric acid binding effect - Google Patents

Abstract

A medicinal prepn. for oral consumption to neutralise gastric acids contains in addn. to antacids a gel forming cpd. and other conventional additives. The gel form, paste-like mixt. is pref. filled in tubes. The administration of the gel form antacid is simple and convenient and in comparison with other prods. regulate gastric pH more advantageously and evenly

Description

SUMMARY OF THE INVENTION The present invention relates to the manufacture of pharmaceutical compositions for oral administration in the form of an ointment having an antacid effect.

It is known that hyperacidity, acute and chronic gastritis and gastric and duodenal ulcers, which are often a consequence of these and are associated with other medical conditions, are extremely common,

Due to the widespread nature of the disease, it has a high degree of gastric acid-binding effect. antacid is on the market. For example, the 1983 edition of Rote Liste lists 85 different antacids.

Antacids generally contain basic aluminum, magnesium, potassium, sodium, calcium and bismuth compounds as the active ingredient, most often: aluminum hydroxide, magnesium hydroxide, magnesium carbonate, calcium carbonate, sodium bicarbonate, magnesium trisilicate, bismuth carbonate, bismuth nitrate, etc. The formulations are generally available in tablet or suspension form, however, it is also known to formulate the antacids in powder, capsule, granule and solution form.

Antacid formulations may contain, in addition to the acid-binding agent, other therapeutically active substance (s), in particular sedative, antispasmodic, hydrochloric acid antiinflammatory agents, enzymes, antiflatulants, antifouling agents, and the like. Another reference in the literature on antacids is the PDR Physicians Desk Reference Book.

The following antacids are most commonly used in Hungary: Nilacid tablets (manufactured by Chinoin), Acidex tablets (manufactured by EGIS), Almagel suspension (manufactured by Pharmachim Bulgaria), Gelusil suspension (manufactured by Gödecke-Parke Davis) , Tisacid tablets (manufactured by Alkaloid).

Antacids are usually taken by patients on a regular basis over a long period of time, so convenient, uncomplicated, easy administration, good taste, and the lowest dose are very important.

However, known formulations on the market do not satisfy these requirements satisfactorily. The disadvantage of the tablet is that it has to be chewed and cannot be swallowed without water. A patient suffering from stomach acid overload suddenly - e.g. on the street, on the means of transport - you can't get water, so taking a tablet is a big problem. A further disadvantage is that the original gel structure of the acid-binding agent (s) is severely damaged during tabletting and compression operations. Even a thoroughly chewed tablet does not have the finest distribution or surface necessary for a quick and good effect when ingested in the stomach.

Suspension formulations, although they overcome the above-mentioned drawbacks of the tablet, however, present problems in other directions. Physical instability, sedimentation, or overgrowth is a constant difficulty in using suspension products. Suspensions form precipitates, which makes it difficult to achieve constant dose and constant dosage. The suspensions should be shaken frequently before use for prolonged periods. A further disadvantage is the large volume, which is particularly unfavorable due to the field of application of antacids, since the patient carries his antacid drug constantly on the street and during transport.

No. 248,740. U.S. Pat. No. 4,882,093, discloses aluminum hydroxide gelled with hydroxyalkylcellulose, which is used as an aqueous suspension or dried powder. No mention is made of antacid ointments. The powders and aqueous suspensions described herein have an antacid content of only 0.5-8% by weight, as opposed to 20-40% antacid content of the ointments of the present invention.

No. 58,105,914. According to Japanese Patent Application Laid-Open Patent Application (C.A. 99110790), magnesium aluminum metasilicate is treated with gelatin and cross-linked polyacrylic acids, and the resulting gel is freeze-dried and powdered. There was no reference to making ointments. The Japanese patent application also provides for the preparation of antacid formulations with delayed release.

In contrast, one of the most important requirements for the compositions of the present invention is the rapid onset of action.

No. 8,126,810. According to Japanese Patent Application Laid-Open Japanese Patent Application (C.A. 94 214634z), a gel comprising aluminum magnesium carbonate, gelatin and mannitol is prepared and tabletted after powdering. The solid compositions thus prepared provide slow release. The composition of the present invention differs fundamentally from the teachings of the aforementioned Japanese Patent Application, both in nature (ointment) and mode of action (rapid release).

No. 2,009,597. In British Patent No. 4,892,858,583, an antacid is mixed with sucrose, agar and water-insoluble alginate in an aqueous medium, then the resulting liquid dispersion is cured under cooling and finally the resulting solid is individually cut and packaged. The solid preparation thus prepared has an antacid content of 13-17% by weight.

SUMMARY OF THE INVENTION It is an object of the present invention to provide antacid formulations which are easy and convenient to use, in a form suitable for non-settling, rapid onset and prolonged action in the stomach, by eliminating the drawbacks of known antacid formulations.

It has been found that the above requirements are excellent in the preparation of anticidal compositions having a consistency and shape similar to the ointment formulations normally intended for external use.

SUMMARY OF THE INVENTION The present invention relates to a process for the preparation of a pharmaceutical composition having an gastric acid-binding, orally administrable ointment form, comprising

EN 203 966 Β tacid is mixed with a naturally occurring macromolecular hydrophilic colloid, a semi-synthetic macromolecular substance and / or synthetic hydrophilic polymer and optionally other conventional pharmaceutical excipients and optionally other pharmaceutical active ingredients to form an ointment and form a suitable ointment. preferably in a tube, wherein the antacid is used in an amount of 20-40% by weight of the total ointment and 0.0510% by weight of the substance capable of forming an ointment consistency.

The antacid ointments of the present invention have great advantages over known antacid forms. 15

As opposed to non-water swallowable and chewable tablets, the ointment of the present invention can be swallowed immediately and easily, even in the most uncomfortable situations (e.g., on public transport or lying down) orally without water. The original colloidal gel structure of the active ingredients is not damaged during the manufacturing process. When the ointment is used, the active ingredient is immediately distributed in the stomach in a finely divided and large surface area so that it can act immediately. The spreading capacity of the ointment is far superior to e.g. the shape of the tablet.

A further advantage of the ointment is that it can be used to deliver mucus and other excipients to the stomach in an amount that is not possible with other conventional dosage forms. These substances enter the stomach to form a protective coating on the mucous membrane, which is beneficial.

Ointments obtainable by the process of the present invention do not exhibit such frequent sedimentation and / or excess viscosity of the suspensions, thus requiring prolonged agitation of the formulation prior to use, as in the case of suspensions.

Another advantage of the composition of the present invention is the convenient storage. The composition can be stored in a small space, which is advantageous for the manufacturing company on the one hand in reducing transport costs and, on the other hand, it is very advantageous for the patient, as mentioned above, to keep the antacid in the patient. ointment e.g. It can be advantageously prepared in a 50 g tube, which is pocket, purse, etc. it fits comfortably and can be taken out at any time. A 50 g tube (about 60-70 g total weight) will hold approx. Contains 35 to 40 doses of active ingredient. At the same time 50 a volume of 170 ml of liquid corresponding to 34 doses of the Almagel suspension is approx. It is available in bottles of 450 g total weight.

A further advantage of the compositions of the present invention is that the system is more blocked from light and air than the known antacid formulations and therefore the active ingredients and excipients are less subject to chemical degradation and complete system microbiological contamination and infection, such as. suspensions, vitreous preparations. 60

In selecting the composition of the antacid ointments obtainable by the process of the present invention, the following main aspects are considered:

1. Adequate acid binding.

2. The calculated dose of the composition should increase the pH of the stomach to an appropriate level at which pepsin activity is not completely inhibited but only reduced.

3. Do not induce undue excessive pH increase (do not raise pH above -4.2).

4. Make your initial impact fast enough.

5. After its rapid onset of action, maintain its effectiveness for a prolonged period of time or achieve the desired effect during normal gastric digestion.

The antacid ointments obtainable by the process of the present invention meet the above requirements as further demonstrated.

The compositions of the present invention are preferably potassium oleate, sodium polyhydroxyaluminum monocarbonate as the antacid active ingredient. phthalate, sodium aluminum carbonate, sodium citrate, ». potassium citrate, sodium bicarbonate, sodium carbonate, sodium tartrate, ammonium oleate, líti- _ς he um carbonate, disodium monohydrogen phosphate ,,, aluminum hydroxide, aluminum magnesium silicates 1 '* Tot , aluminum dimagnesium trisilicate, aluminum glycinate, aluminum glycinate dihydroxide, aluminum; um bismuth hydroxide carbonate, aluminum magnesium hydroxide carbonate, magnesium trisilicate, basic magnesium carbonate, magnesium carbonate, magnesium hydroxide, magnesium oxide, magnesium carbonate , (basic) bismuth gallate, (basic); | bismuth salicylate, bismuth aluminate, (basic) bis. mutated nitrate, (basic) bismuth carbonate, calcium *. , carbonate, calcium citrate, calcium lactate, and / or calcium phosphate.

Particularly preferred antacid agents are aluminum hydroxide, aluminum magnesium hydroxide, magnesium hydroxide, magnesium trisilicate, bismuth subnitrate and / or sodium bicarbonate.

The formulations may be formulated with a macromolecular hydrophilic colloid of natural origin, or a semi-synthetic macromolecular gelling agent and / or synthetic hydrophilic polymer, which is capable of forming an ointment consistency.

Preferred macromolecular hydrophilic colloids of natural origin are gum arabicum, tragacanth gum, starch, pectin, alginic acid or alginate, carrageenan, xanthan gum (from Kelelt) and / or guar gum (MEYPRO-like substance, preferably carboxymethyl guar). propyl guar or a mixture thereof or cationic guar).

For this purpose, 0.5 to 5.0% by weight of gum arabicum, preferably 0.8 to 2.0% by weight, based on the total weight of the composition; 0.1-5.0 weight #

preferably 0.4-2.0% by weight of tragacanth gum; 0.5

5.0 wt.% - preferably 0.5-2.0 wt.% - hard

HU 203 966 Β; 0.5-5.0% by weight, preferably 0.5-2.0% by weight of pectin; 0.05 to 10% by weight, preferably 0.5 to 1.5% by weight

- alginic acid or alginate; 0.1-5.0% by weight, preferably 0.5-1.5% by weight, of carrageenan; 0.05-5.0% by weight preferably 0.2-1.0% by weight - xanthan gum (from Kelta) and / or 0.1-10% by weight - preferably 0.4-2.0% by weight

- Guar gum (Meypro type) is used.

Preferably the semisynthetic macromolecular material is methylcellulose, carboxymethylcellulose, hydroxypropylmethylcellulose, propylene glycol ester of alginic acid (Mannucol) and / or ultraamylopectin.

Particularly preferred for this purpose is methyl cellulose in an amount ranging from 0.1 to 7.0% by weight, preferably 0.5 to 2.5% by weight, depending on the viscosity of the materials; 1.0-7.0% by weight

preferably from 1.5 to 3.0% by weight of carboxymethylcellulose; 0.1 to 10% by weight, preferably 0.5 to 5.0% by weight, of hydroxypropylmethylcellulose; 0.5-5.0% by weight, preferably 1.0-3.0% by weight, of propylene glycol ester of alginic acid and / or 0.1-5.0% by weight, preferably 0.2-1.5% by weight

ultraamylopectin may be used.

The synthetic hydrophilic polymer is preferably polyvinylpyrrolidone, polyvinylpolypyrrolidone and / or carboxyvinyl polymer (Caibopol).

For this purpose, 1-10%, particularly preferably 3-7% polyvinylpyrrolidone or polyvinylpolypyrrolidone and / or 1.0-10% by weight, preferably 2.0-5.0% by weight, of carboxyvinyl polymer (Carbopol) may be used.

The compositions of the present invention may contain xanthan gum (from Kelelt), Mypro-type guar, ultraamylopectin, carboxyvinylpolymer (Carbopol) and / or polyvinylpolypyrrolidone (PVPP) as the ointment consistency forming agent.

The compositions may, if desired, also contain further pharmaceutical excipients, e.g. preservatives, flavor additives, etc.

Preferably, the preservative is p-hydroxybenzoic acid methyl, ethyl, propyl or butyl ester, glycerol, sorbic acid, sorbates, benzoic acid or its salts such as sodium benzoate or propylene glycol.

For this purpose, preferably, 0.05 to 1.25% by weight, preferably 0.08 to 0.25% by weight, of the ρ-hydroxybenzoic acid methyl, ethyl, propyl or butyl ester, based on the total weight of the composition; 0.5 to 10% by weight, preferably 25% by weight, of glycerol; 0.01 to 2% by weight sorbic acid or sorbate, preferably 0.11.0% by weight; Benzoic acid in an amount of 0.1-5.0% by weight, preferably 0.2-1.0% by weight; 0.01 to 2.0% by weight, preferably 0.1 to 1.0% by weight, of sodium benzoate; and / or 0.1 to 10.0% by weight, preferably 2.0 to 5.0% by weight, of propylene glycol may be used.

Sweetening agents and / or flavoring agents may generally be used as flavor enhancers. The sweetening agent is preferably xylitol, sorbitol, saccharin, saccharin sodium, sodium cyclamate and / or aspartame, while the flavoring agent is preferably menthol, vanillin, peppermint oil, anise oil, lemon oil or other known flavoring substances or mixtures thereof.

Sodium bicarbonate, sodium citrate or disodium hydrogen phosphate may be added to the pharmaceutical compositions of the present invention to enhance the appropriate rapid onset of action. Sodium bicarbonate has proved particularly advantageous for this purpose.

They may also contain local anesthetics (eg oxetacaine, novocaine, norcaine, etc.) to reduce severe pain in acute conditions.

According to a preferred embodiment of the process according to the invention, the ointment consistency-forming material is swollen in water, the water-soluble components are dissolved in another apparatus, the two mixtures or solutions are mixed together and the solid, if necessary, powdered active ingredient or drugs; the above operations may be carried out in any order.

Advantageously, a solution of the water-soluble components is added to the swelling ointment consistency forming agent and then the powdered solid active ingredient (s) is added.

However, in the production process, different order of addition or use of the components is also possible. so e.g. the powdered solid components may be added to a mixture of the ointment consistency-forming material with water or an aqueous solution of the water-soluble components, or both, before mixing the two aqueous phases.

According to a particularly preferred embodiment of the process of the present invention, xanthan gum (from Celtic), Meypro-type guar, ultra-amylopectin, carboxyvinyl polymer (Carbopol), polyvinylpyrrolidone and / or polyvinylpolypyrrolidone (PPVP) in water, to the resulting mica-like substance is added an aqueous solution of water-soluble components, in particular methyl or propyl p-hydroxybenzoate, sodium cyclamate, sorbitol, glycerol, sodium bicarbonate, sodium benzonate, saccharin sodium and / or propylene glycol. followed by addition of powdered aluminum hydroxide, magnesium trisilicate, magnesium oxide, magnesium hydroxide and / or bismuth subnitrate.

The ointment obtainable by the process of the invention may be filled into containers commonly used in ointment formulations. For this purpose, e.g. tubes for ointments may be used. The ointment may be dispensed with a specially trained adapter screwed into the mouth of the tube, e.g. plastic dosing spoons can also be screwed into the mouth of the tube. Dosing is even easier with a "graduated" plastic dosing spoon or plate, which can be placed next to the tube in the wallboard. Additionally, trough-shaped, graduated plastic rods may be used. The advantages of the ointment of the present invention over known antacid formulations can be demonstrated by the following comparative experiments:

/. Constant pH method

The preparation is measured at 37 ° C in a pH 3.0 solution and then 1 N hydrochloric acid is added dropwise over time.

EN 203 966 Β so that the pH of the solution remains unchanged. A good formulation has a long in vitro acid neutralization time. The method is expected to provide a correlation between in vitro and in vivo results. No. 1 Fig. 3A shows the acid neutralization curve of Antacid gel, Nilacid tablet and Acidex tablet. Antacid ointment and Nilacid tablets gave practically the same result Acidex tablets show very poor acid retention.

2. Modified Rosett-Rice test

The preparation to be examined is diluted with 0.1N hydrochloric acid and 0.1N hydrochloric acid is added every minute while the pH of the solution is adjusted after each dose of hydrochloric acid.

Requirement: The pH of the solution should be maintained at pH 3.04.2 for a long time. The results are shown in Figure 2 and Table 1 below:

Table 1

Drink Nilacid tabl. PH Antacid ointment, PH Acidex tabl. pH 10 ' 7.30 3.47 3.09 20 ' 7.20 3.50 3.12 30 ' 6.90 3.50 2.90 40 ' 6.58 3.50 2.65 50 ' 6.24 3.50 2.43 60 ' 5.89 3.30 2.22 70 ' 5.50 3.10 2.03 80 '' 5.10 3.00 1.86 90 ' 4.50 2.80 1.66

The best of the three formulations is the Antacid ointment with a nearly constant pH of approx. 1.5 hours.

3. Investigation of pH adjustment

Ph. Hg. VII. As described in the article on aluminum hydroxide, the formulation sprayed with 0.05N hydrochloric acid is kept at 37 ° C and the pH of the solution is measured after 10, 15, 20 minutes.

Table 2

Time Nilacid tabl. pH antacid ointment pH Acidex tabl. PH regulation AlHOj to pH Tisacid tabl. 10 ' 2.83 3.0 1.75 min. 1.80 3.3 15 ' 4.77 3.2 1.87 min. 2.40 3.5 20 ' 5.67 3.26 1.97 min. 3,0max. 4.2 4.0

4. Examination of acid binding capacity

Ph. Hg. VII. according to the requirement described in the article on aluminum hydroxide, min.

220 ml 0.1 N HCV1 g A1 (OH) ₃ Nilacid tablets: 212 ml 0.1 n HCl / 1 g Antacid ointment: 224 ml 0.1 n HCl / 1 g Acidex tablets: 170 ml 0.1 n HCl / 1g

Comparing the three formulations in the tests described in sections 3 and 4, the acid binding capacity of Nilacid tablets and Antacid ointments per g is practically the same, and significantly lower than that of Acidex tablets.

5. The pH-raising and acid-binding capacity of some known domestic and foreign tablets and suspension formulations compared to our new ointment formulations

Requirement for pH lifting capacity:

Ph. Hg. VII. BP.86 10'min. 1.8 10 'min 1.8 15'min. 2.4 15'min. 2.3 20 'min 3.0 20 'min, 3.0 max. 4.2 max, 4.0

Requirements for acid-binding capacity:

Ph. Hg. VII: min. 220 ml 0.1 N HCl / 1 g active ingredient

Table 3

Ph raise 10 ' 15 ' 20 ' acid Binding ♦ Nilacid tablets 2.83 4.77 5.67 212 ♦ Almagel suspension (Phannachim, Bulgaria) 4.34 4.48 4.60 481.8 Gelusil suspension (Gödecke-Parké Davis) 1.85 1.85 1.88 152.0 Acidex Tablets (BP80) 1.75 1.87 1.97 170 Ointment No. example 2.34 2.91 3.25 237.96 Ointment No. 4 example 2.27 2.86 3.24 232.65 Ointment No. 5 example 2.09 2.67 3.02 232.3

'The essential requirement - the various pharmacopoeia agree - that the pH should not exceed 4.0-4.2! It is important from a physiological point of view that the pH of the stomach remains within a weakly acidic range. Thus, the symptoms of 'heartburn' are eliminated, but there is no increased acid production. The gastric contents above pH = 4 stimulate the acid producing glands to produce more acid.

HU 203 966 Β

Based on this result, Nilacid tablets and Almagel suspension as antacid preparations are not considered to be up-to-date. An important requirement of the advanced formulation is that it does not cause post-secretion (no rebound effect!). 5

From the above tables it can be seen that the ointments according to the invention have a significantly better pH shift than the known formulations. The ointment produced by the process of the invention causes the pH to rise steadily within the desired favorable range, the composition 10 to produce the desired effect within a very short time, the pH to be raised evenly, and not to exceed the permissible value of 4.0. Of the known tablets, the use of Nilacid causes the pH to rise rapidly and well above the upper limit of tolerance. Known suspension formulations behave similarly.

6. The following experiments investigated the behavior of different antacid formulations when added to hydrochloric acid:

During the experiment, 100 ml of 0.1N hydrochloric acid was poured into a 300-400 ml Elenmayer flask. One tablet of test substance, 5 to 5 ml of suspension, and 1.5 to 1.5 g of gel are added to the hydrochloric acid for each dose of active ingredient. Occasionally, the contents of the flask - approx. Shake by hand every 5 minutes while standing.

Acidex tablets do not change or swell within 24 hours. Above the tablet, the hydrochloric acid remains crystal clear.

The Nilacid tablet swells slowly, shaking slowly after 15 minutes, but when shaking stops, it will settle to the bottom of the flask immediately. The hydrochloric acid 35 remains crystal clear over the tablet.

After shaking for 15 minutes, the Gelusil suspension drops into drops and settles on the bottom of the flask. Droplets shake to the surface as a result of shaking, but immediately stop shaking. 40 The hydrochloric acid remains completely pure over the product.

The Almagel suspension is ca. After 10 minutes of shaking it behaves similarly to Gelusil, but over the droplets the hydrochloric acid becomes slightly opalescent.

The ointment according to the invention is immediately distributed after the first few minutes of shaking (within 5 minutes).

Loosely curled up in hydrochloric acid makes it opalescent. Even when shaking stops, the hydrochloric acid does not clear and very little material settles at the bottom of the flask, but when shaken, it is loosely agitated and agitated for approx. It does not settle again for 10-60 minutes.

The above experiment clearly demonstrates that the active ingredient is more readily and more readily accessible and more reactive to hydrochloric acid in the compositions of the present invention than in the known antacid tablets and suspensions.

Further details of the process are set forth in the following examples, without limiting the invention to the examples. 60

Example 1

We have prepared the following ointment:

Component Quantity, g (% by weight)

Aluminum hydroxide 16.31

Magnesium trisilicate 7.83

0.40 for ultramilopectect

Sorbitol (70%) 14.0

Sodium bicarbonate 2.60

Nipagin M (Methyl p-hydroxybenzoate) 0.10

Sodium cyclamate 0.44

Peach aroma 0.09

Lemon aroma 0.09

Distilled water gives -100.0 g

The ointment is prepared as follows:

Ultra-amylopectin is present in about half of the distilled water.

Dissolve at 0 ° C (leave to stir occasionally). In the other part of the water, approx. Dissolve Nipagin M and sodium cyclamate at 80 ° C. After cooling, the sorbitol is added and the mixture is added to the swollen mucus (ultraamylopectin) in portions with constant stirring. The premixed and homogenized powdered aluminum hydroxide, magnesium trisilicate and sodium bicarbonate are then added in portions with constant stirring, followed by the addition of peach aroma and lemon aroma to a high speed stirrer colloid (eg Ultratur). pass through for final homogenization and then fill into tubes in an ointment filling machine.

Example 2

The following composition ointment:

component

Aluminum hydroxide Magnesium hydroxide from Oxetacain Celtic

Nipagin M (amount of p-hydroxybenzoic acid, g (% w / w)

16.31

6.00

0.20

0.50 (ethyl ester) 0.10

Sodium cyclamate 0.44

Peach aroma 0.09

Lemon aroma 0.09

Glycerin 7.00

Sorbitol (70%) 7.0

Distilled water gives 100.0 g

The ointment is prepared as follows:

The Keltrolt is pre-drained for approx. It is dispersed in half heated to 80 ° C and with a high speed stirrer (e.g. Ultratunax type) for approx. Stir for 15-20 minutes. The mixture is left to cool while stirring from time to time. The remainder of the water is dissolved in Nipagin M, sodium cyclamate at about 80 ° C, and after cooling

Add sorbitol and glycerol. The resulting mixture was poured from Celtic to gel and stirred manually. Powdered oxetacal, aluminum hydroxide and magnesium hydroxide are then added successively in small portions.

Example 3

We prepare ointments with the following composition:

Component Quantity, g (% by weight)

Aluminum hydroxide 16.31

Bismuth Subnitrate 3.00

Sodium bicarbonate 2.00

Carbopol934P 1.00

Sodium benzoate 1.00

Sorbitol (70%) 14.00

Saccharin Sodium 0.02

Anise Saroma 0.400

Distilled water gives 100.0 g

The ointment is prepared as follows: _

The water is approx. Half was heated to 80 ° C and Carbopol 934 P was added with rapid stirring and stirred until cooled. After standing for one day, add, if necessary, a filtered solution of sodium bicarbonate, sodium benzoate, saccharine sodium and solybite in water. To the gel so prepared, and passing it through a colloidal mill if necessary.

Example 4

We prepare ointments with the following composition:

Component Quantity, g (% by weight)

Aluminum hydroxide 16.31

Magnesium trisilicate 7.83

Oxetacain 0.20

Meypro-guar (guar gum CS AAM100) 1.00 p-hydroxybenzoic acid methyl ester 0.015 enecarbonate 2.00

Sorbitol (70%) 14.00

Sodium bicarbonate 2.60

Sodium cyclamate 0.44

Lemon aroma 0.09

Peach aroma 0.09

Distilled water gives 100.0

The ointment is prepared as described in Example 1.

Example 5

Component Quantity, g (% by weight)

Aluminum hydroxide 23.49

Magnesium trisilicate 70.83

0.40 for ultramilopectect

Meypro-guar 0.70

Nipagine M (methyl p-hydroxybenzoic acid methyl ester) or p-hydroxybenzoic acid butyl ester 0.10

Sorbitol (70%) 14.0

Sodium cyclamate 0.44

Raspberry aroma 0.20

Distilled water gives 100.0 g

The ointment is prepared as described in Example 1. The two ointments are co-swollen with water in a consistency-forming substance (ultaamylopectin and Meypro-guart).

Example 6

We prepare ointments with the following composition:

Component Quantity, g (% by weight)

Aluminum magnesium hydroxide carbonate hydrate 30.0

PVPP (polyvinylpolypyrrolidone) .1.0

Meypro-guar 0.4

Glycerin 3.5

Sorbitol (70%) 7.0

Propylene glycol 3.5

Saccharin Sodium 0.03

Vanilla 0.05

Distilled water gives 100.0 g

The ointment is prepared as follows:

Meypro-guart and polyvinylpolypyrrolidone (PVPP) are present in water at ca. half at room temperature. In the other half of the water, the saccharin sodium and vanillin are dissolved, and glycerol, sorbitol and propylene glycol are added at room temperature. The resultant mixture is added in portions capable of forming a swollen ointment consistency under constant agitation.

The active ingredient is added in small portions under constant stirring, and the finished ointment is then passed through a colloidal mill or three-roll mill, if necessary.

Claims (22)

PATENT CLAIMS CLAIMS 1. A process for the preparation of a pharmaceutical composition for oral administration in the form of an enteric ointment having an antacid active ingredient which is capable of forming an ointment consistency with a naturally occurring macromolecular hydrophilic colloid, a semisynthetic macromolecular and / or synthetic hydrophilic polymer. mixed with other therapeutic agents and formulated in an ointment, while the antacid is 20 to 40% by weight of the total weight of the ointment and 0.05 to 10% by weight of the ointment consistency material is used. 2. A process according to claim 1 wherein the antacid is a basic alkali metal and / or alkaline earth metal and / or bismuth compound. 3. A process according to claim 2 wherein the antacid is potassium oleate, sodium polyhydroxyaluminum monocarbonate, sodium aluminum carbonate, sodium citrate, potassium citrate, sodium bicarbonate, sodium carbonate, tartarate, ammonium oleate, lithium carbonate, disodium monohydrogen phosphate, aluminum hydroxide, aluminum magnesium silicate, aluminum dimagnesium trisilicate, aluminum dihydrogen aluminate, aluminate glycate, -magnesium hydroxide carbonate, magnesium trisilicate, basic magnesium carbonate, magnesium carbonate, magnesium hydroxide, magnesium carbonate, basic bismuth gallate, basic bismuth salicylate, bismuth aluminate , basic bismuth carbonate, calcium carbonate, calcium citrate, calcium lactate and / or calcium phosphate. 4. A process according to claim 3 wherein the antacid is aluminum hydroxide, aluminum magnesium hydroxide, magnesium hydroxide, magnesium trisilicate, bismuth subnitrate and / or sodium bicarbonate. The process according to claim 1, wherein the antacid is present in an amount of 20-30% by weight, preferably 22-27% by weight, of the total composition. The process according to claim 1, wherein the ointment-forming material is present in an amount of 0.1 to 5% by weight, preferably 0.4 to 3% by weight, based on the total weight of the ointment. 7. The process according to claim 1, wherein the macromolecular hydrophilic colloid of natural origin is gum arabicum, tragacanth gum, starch, pectin, alginic acid or water soluble alginate, carrageenan, xanthan gum and / or guar gum, preferably coboxymethyl-. guar, hydroxypropyl guar or a mixture thereof or cationic guar. The process according to claim 7, characterized in that 0.55.0% by weight of the composition, preferably 0.8-2.0% by weight, of gum arabicum; 0.1 to 5.0% by weight, preferably 0.4 to 2.0% by weight, of tragacanth gum; 0.5-5.0% by weight of starch, preferably 0.52.0% by weight; 0.5 to 5.0% by weight, preferably 0.5 to 2.0% by weight, of pectin; 0.05 to 10% by weight, preferably 0.5 to 1.5% by weight, of alginic acid or water-soluble alginate; 0.1-5.0% by weight, preferably 0.5-1.5% by weight of carrageenan; 0.05-5.0% by weight of xanthan gum, preferably 0.2-1.0% by weight, and / or 0.1-10% by weight, preferably 0.4-2.0% by weight of guar gum. The process according to claim 1, wherein the semisynthetic macromolecular material is methylcellulose, carboxymethylcellulose, hydroxypropylmethylcellulose, propylene glycol ester of alginic acid and / or ultraamylopectin. The process according to claim 9, characterized in that - in an amount dependent on the viscosity of the materials 0.1 to 7.0% by weight, preferably 0.5 to 2.5% by weight, of methylcellulose; 1.0-7.0% by weight carboxymethylcellulose, preferably 1.5-3.0% by weight; 0.1 to 10% by weight, preferably 0.5 to 5.0% by weight, of hydroxypropylmethylcellulose; 0.5-5.0% by weight, preferably 1.0-3.0% by weight of propylene glycol ester of alginic acid and / or 0.1-5.0% by weight preferably 0.2 to 1.5% by weight of ultraamylopectin. The process according to claim 1, wherein the synthetic hydrophilic polymer is polyvinylpyrrolidone, polyvinylpolypyrrolidone and / or carboxyvinyl polymer. The process according to claim 11, characterized in that 1.0 to 10.0% by weight of polyvinylpyrrolidone or polyvinylpolypyrrolidone and / or 1.0 to 10.0% by weight, preferably 2.0 to 10% by weight, preferably 5.0% by weight using a Kaibox vinyl polymer. 13. A process according to any one of claims 1 to 3, wherein the gelling agent is selected from the group consisting of xanthan gum, Meypro-type guar, ultraamylopectin, carboxyvinyl polymer and / or polyvinylpolypyrrolidone. 14. A process according to any one of claims 1 to 3, wherein the other pharmaceutical excipient is a preservative or a flavor enhancer. 15. The process according to claim 14, wherein the preservative is methyl, ethyl, propyl or butyl ester of ρ-hydroxybenzoic acid, glycerol, sorbic acid, sorbate, benzoic acid or salts thereof, e.g. sodium benzoate or propylene glycol. Process according to claim 15, characterized in that, based on the total weight of the composition, 0.051.25% by weight, preferably 0.08-0.25% by weight, of p-hydroxybenzoic acid methyl, ethyl, propyl or butyl ester; 0.5 to 10% by weight, preferably 2 to 5% by weight, of glycerol; 0.01 to 2% by weight sorbic acid or sorbate, preferably 0.1 to 1.0% by weight; From 0.1 to 5.0% by weight, preferably 0.21.0% by weight, of benzoic acid; 0.01 to 2.0% by weight, preferably 0.1 to 1.0% by weight, of sodium benzoate; and / or 0.1 to 10% by weight, preferably 2.0 to 5.0% by weight, of propylene glycol. 17. The method of claim 14 wherein the flavor enhancer is a sweetener and / or a flavoring. 18. The process of claim 17 wherein the sweetener is xylitol, sorbitol, saccharin, saccharin sodium, sodium cyclamate and / or aspartame. 19. The process of claim 17, wherein the flavoring agent is menthol, vanillin, peppermint oil, anise oil, lemon oil, or other known flavoring compounds or mixtures thereof. HU 203 966 Β 20. A process according to any one of claims 1 to 6, wherein the gelling agent is swelled in water, the water-soluble components are dissolved in water in another apparatus, the two mixtures or solutions are mixed and the solid powdered active ingredient or agents are added. 21. The method of claim 20, wherein the swollen gelling agent is added to a solution of the water-soluble components and then added to the powdered solid carrier or carriers. 22. The process of claim 1, wherein the xanthan gum, Meypro-type guar, ultraamylopectin, carboxyvinyl polymer (Carbopol), polyvinylpyrrolidone and / or polyvinylpolypyrrolidone are swollen in water, and the water-soluble component is added to the resulting mucilageous gel. an aqueous solution of hydroxybenzoic acid methyl or propyl ester, sodium cyclamate, dispersants, glycerol, sodium bicarbonate, sodium benzoate, saccharin sodium and / or propylene glycol, followed by addition of powdered aluminum. hydroxide, magnesium trisilicate, magnesium oxide, magnesium hydroxide and / or bismuth sub-nitrite