CH638975A5 - DRUG COMPOSITION FOR THE TREATMENT OF GASTRO-DUODENAL ULCERS. - Google Patents

Description

The present invention relates to a drug composition for the healing treatment of gastric ulcers and duodenal ulcers.

We currently know several types of antiulcer compounds which have quite different modes of action, for example antacid agents which are intended to neutralize excess hydrochloric acid and thus reduce gastric hyperchlorhydria, protectors of the gastric mucosa exerting a dressing and / or absorption effect of H + ions, as well as spasmolytics having above all anticholinergic properties, in particular for reducing the tone and motility of smooth muscles, for reducing gastric secretion, etc. There are of course also numerous compositions containing a combination of the different types of antiulcer drugs. In addition, healing agents have already been used in such compositions, but the results obtained have so far proved unsatisfactory.

This is why the aim of this invention consists in providing a new medicinal composition for the treatment of peptic ulcers which acts essentially by scarring of the mucous membranes.

The object of this invention, aimed at achieving the above object, consists of a composition which is characterized in that it comprises, in addition to antacid and gastric secretion inhibitor compounds, as well as excipients or of pharmaceutically acceptable carriers, at least one healing agent for the peptic mucosa and a carbonic anhydrase inhibitor.

As antacid agents and inhibitors of gastric secretion, use will preferably be made, in the composition according to the invention, of sodium hydrogencarbonate (basifying), of colloidal aluminum hydroxide which has a high binding power. hydrochloric acid, potassium hydrogen carbonate also useful for its action on the hydro-electrolyte balance, as well as basic bismuth carbonate and basic magnesium carbonate.

The preferred healing agent which can be used in this composition is allantoin or ureido-5-hydantoin, to which calcium pantothenate can be added, for example. It should be noted that, if the healing action for example of allantoin is known per se, in particular in the case of cosmetic compositions applicable topically, it has not so far been proposed to use it to act on the gastric and duodenal mucosa in drug compositions to be ingested.

But what the invention further provides and which was not within the reach of those skilled in the art, is the observation that this healing action of allantoin for example is favored, increased, in a completely unexpected by the presence of a carbonic anhydrase inhibitor compound, which exerts on the healing agent a very important synergistic effect within the framework of its action on the gastric or duodenal mucosa.

Carbonic andhydrase inhibitor compounds are usually used primarily for the treatment of glaucoma due to their diuretic activity. Among these compounds, the one which is preferably used in the composition according to the invention is acetazolamide or 5-acetamido-1,3,4-thiadiazole-2-sulfonamide.

The composition according to the invention is preferably presented in the form of a powder. The excipients that can be used generally consist of gelatin, which also acts to promote healing, and talc.

As regards the preferred proportions of the various constituents of the composition, the respective contents in% by weight relative to the total weight of the composition are as follows:

Acetazolamide 5-15%

Allantoin approx. 2%

Pantothenate of Ca approx. 4%

NaHC03 8-15%

Al (OH) 3 12-20%

KHC03 5-12%

Basic carbonate from Bi approx. 20%

Basic carbonate of Mg approx. 15%

The example which follows and which is intended to illustrate the present invention relates respectively to a particular and preferred formulation of the composition, to the results of toxicity and antiulcer efficacy tests, as well as to a mode of therapeutic administration of the composition.

Example

The following formulation constitutes a preferred example of the composition according to the invention:

Acetazolamide

0.200-0.400 g

Allantoin

0.050 g

Pantothenate of Ca

0.100 g

Basic carbonate of Bi

0.450 g

Mg basic carbonate

0.350 g

Na bicarbonate

0.100 g

K bicarbonate

0.250 g

Al colloidal hydroxide

0.450 g

Excipients (gelatin, talc, etc.) q.s. ad

2.5g

The acute toxicity of the composition indicated in the example was

studied in Wistar WU rats about 6 weeks old and weighing between 140 and 160 g.

The composition, mixed with 1% Tween 80 in distilled water, was administered per os (gastric tube), to 10 males and 10 females for doses of 2, 4 and 8 g / kg (volume of 20 ml / kg), and to 20 males and 20 females for a dose of 16 g / kg (administered twice 8 g / 20 ml / kg at 1 hour intervals). At the time of the administration of the product, the animals had been fasting since 17 h.

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638,975

After this treatment, and for 7 d, none of the animals died, which indicates that the composition according to the invention and non-toxic up to 16 g / kg orally, a dose which is very high since it corresponds at 120 g for a man, while the therapeutic dose is only around 5 to 10 g.

The antiulcer effect of the composition mentioned in the example has been studied with respect to acute experimental ulcers caused by reserpine (5 mg / 10 ml / kg, intraperitoneally) (Serpasil from Ciba AG) in Wistar WU rats about 7 weeks old and weighing between 160 and 180 g.

Doses of 2, 4 and 6 g / kg of the test composition were administered to the fasted rats for 48 h, water ad libitum, simultaneously with the ulcerogenic agent but per os (gastric tube) in a volume of 30 ml / kg of a 1% Tween 80 aqueous solution.

Approximately 18 h after administration of the ulcerogenic agent and the treatment composition, a macroscopic examination of the open stomachs along the large curvature and spread was performed.

Ulcers produced experimentally by this method usually appear in the glandular part of the stomach. Then a rating is assigned according to the observations made and on the basis of the following scale:

0 = no lesions

1 = hemorrhagic range

2 = 1 to 5 small ulcers (less than 3 mm)

3 = more than 5 small ulcers or 1 large ulcer

4 = several large ulcers

5 = perforated ulcer

Then, the ulceration index (IU) is calculated based on the following equation:

, _ sum of quotes x% of frequency number of animals

As a result of the tests carried out, the three doses administered are effective and make it possible to very significantly stop the lesions produced by reserpine.

Indeed, at a dose of 6 g / kg, the ulceration index is 10 with 20% of animals with ulcers. At a dose of 4 g / kg, the index is 18 with 30% of ulcerated animals and, at 2 g / kg, the index is 36 with 40% of ulcerated animals. The antiulcer effect is therefore very powerful since, by assigning the value 100 to the lesions created in the controls, we obtain, at the three doses of 6.4 and 2 g / kg, respectively 96, 93 and 86% of protection.

The antiulcer effect of the composition mentioned in the example has also been studied with respect to acute experimental ulcers caused by Phenylbutazone in Wistar WU rats aged approximately 10 weeks and weighing between 200 and 220 g (10 rats per treatment group).

Phenylbutazone was administered daily for 4 days per os (gastric tube) at a dose of 100 mg / kg (in aqueous solution of Tween 80 at 1%; volume administered = 10 ml / kg) to rats placed on the water diet approximately. 6 p.m. before the first administration. As expected, phenylbutazone proved to be very ulcer-causing, since 100% presented with serious ulcers (ulceration index on average of 290 out of a maximum of 300).

In parallel, the composition to be tested was administered to rats at a dose of 6 g / kg (in aqueous solution of Tween 80 at 1%;

administered volume = 20 ml / kg) orally (gastric tube), approximately 1 hour before phenylbutazone. Similarly, a reference product, Cimetidine, was administered to rats under the same conditions as the composition to be tested (except that the volume administered was 10 ml / kg).

In general, it should be noted that the respective doses administered were adjusted every day because of the weight loss of the rats due to the prolonged fast.

Then, on the fourth day, 6 hours after the last administration, a microscopic examination of the open stomachs was carried out along the large curvature and spread out, and a score was assigned according to the observations made and on the basis of the next scale:

0 = no ulcer

1 = 1-2 ulcers

2 = 3-4 ulcers

3 => 4 ulcers

Finally, the ulceration index (IU) was calculated based on the above mentioned equation, and the results obtained are mentioned below:

% of

Index

ulcerated ulcerating rats

Rats processed only by

phenylbutazone

100

290

Cimetidine treated rats

100

230

Rats processed by the composition

according to the invention

0

0

It emerges from these results that the composition according to the invention has an antiulcer efficacy in rats of 100% at a dose of 6 g / kg, a dose provided for in human therapy, while cimeti-dine, administered at 50 mg / kg , only reduces the severity of ulcers caused by the administration of phenylbutazone by approximately 20%.

For the treatment of gastric or duodenal ulcers, the patient should be administered, depending on the importance of the gastric acidity and the weight of this patient, from 2 to 4 doses / d, each dose containing 2.5 g of the powder composition described in the example. Each 2.5 g dose, contained for example in the form of a powder in a sachet, must be diluted in a glass of water (30 ml) to form a milky suspension to be ingested approximately 30 min to 2 h after the meal.

After about 3 to 5 d, the inhibitory effect appears in the gastric mucosa and the pain disappears. After 5 to 10 d of continuous treatment, the secretion of gastric acid is markedly reduced, a hypo- or anachlorhydric posthistamine or insulin action acting throughout the duration of the treatment. This leads to optimal conditions for the healing of ulcerative niches. In addition, the Na and K salts keep diuresis, blood pH and hydro-electrolyte balance within normal limits. Finally, after 10 to 12 d for a gastric ulcer and 21 to 25 d for a duodenal ulcer, scarring is effective. In some cases, treatment with a reduced dose (2.5 g / d) for 1-2 weeks may be continued.

The only contraindications known to date for the composition according to the invention are severe hepatic or renal insufficiency, as well as intolerance to sulfonamides.

Thus, the composition according to the invention has the advantage, compared with known drugs, of simultaneously creating the optimal conditions for the healing of gastric and duodenal ulcers, namely in particular:

- decrease in the hydrochloric acid secretion of the parietal cells by blocking the intimate biochemical intracellular mechanism;

- neutralizing in the gastric cavity of the residual hydrochloric acid, and

- stimulation of mucosal healing by the presence, in addition to healing agents, of a carbonic anhydrase inhibitor.

Carbonic anhydrase is an enzyme found in the gastric mucosa which is an important factor in the production of hydrochloric acid. An oral treatment for example with acetazolamide therefore decreases to a large extent the activity of carbonic anhydrase, thus inhibits the production of H + ions, and simultaneously increases the secretion of the gastric mucosa, which tends to favor healing, under the effect of healing agents, of the ulcerated mucosa.

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Claims (10)

638,975 1. Drug composition for the treatment by cicatrization of peptic ulcers, characterized in that it comprises, in addition to antacid compounds and inhibitors of gastric secretion, as well as excipients or carriers acceptable from the pharmaceutical point of view , at least one healing agent of the peptic mucosa and a carbonic anhydrase inhibitor. 2. Composition according to claim 1, characterized in that the healing agent is 5-ureidohydantoin or allantoin. 2 3. Composition according to Claim 2, characterized in that it contains, as second healing agent, Ca pantothenate. 4. Composition according to one of claims 1 to 3, characterized in that the carbonic anhydrase inhibitor is acetazola-mide or 5-acetamido-l, 3,4-thiadiazole-2-sulfonamide. 5. Composition according to claim 2, characterized in that it contains approximately 2% by weight of allantoin. 6. Composition according to claim 4, characterized in that it contains from 5 to 15% by weight of acetazolamide. 7. Composition according to one of claims 1 to 6, characterized by the fact that it comprises colloidal Al hydroxide, bi-hydrogen carbonate, Mg hydrogen carbonate, Na bicarbonate and baking soda. 8. Composition according to one of claims 1 to 7, characterized in that it is in the form of an ingestible powder. 9. Composition according to Claim 8, characterized in that it contains, as excipients, gelatin and talc. 10. Composition according to claim 8, characterized in that the powder is packaged in sachets each containing 2.5 g of the composition.