DE2505913A1 - MEDICINAL PRODUCT FOR THE ORAL TREATMENT OF NON-TUMOROUS GASTRODUODENAL DISEASES AND METHOD OF MANUFACTURING IT - Google Patents

Description

PATE ΓΜTAN WALTE

DR. ING. A. VAN DERWERTH DP. FRANZ LEATHER

C1934-1974) 8 MUNICH 80

LUCILE-CRAHN-STR 22 TEL. (089) 473947

Munich, February 11, 1975 TY 4038/2

Carlos Tyortyalian, 128 Vicente Lopez, Monte Grande, Argentina

Medicines for the oral treatment of non-tumorigenic Gastroduodenar complaints and method for their preparation

The invention relates to a medicament for the treatment of non-tumor-like complaints of the gastroduodenal area, especially in the case of hypersecretion and ulcers, and a method for producing such an agent.

Symptoms of the above-mentioned type mainly occur in the area of the stomach outlet (pylorus), in the small curvature of the stomach and in the duodenum, and they are generally associated with hyperacidity of the gastric fluid. These Complaints have a cyclical occurrence and they show up by pain and also every day during the

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critical period due to the occurrence of vomiting at some point after meals. In the event of from severe ulcers, the development of the damage or injury can lead to capillary bleeding that persists and go unnoticed, which can result in severe anemia, or break out suddenly and even can be fatal. In addition, the progression of the disease can lead to perforations, which allow gastric fluid to enter the abdomen, causing peritonitis (Peritonitis).

Apart from such serious predictions that require an immediate surgical intervention is required, these cyclical complaints are very bothersome to the patient, themselves when the disease is in the benign stage so that effective treatment is required and easy to perform and should have a rapid effect in order to bring rapid relief to the patient when the pain occurs. The treatment should also have a prophylactic effect, particularly in terms of reducing hypersecretion on preventing further development of the disease.

The classic treatment is to eat all of them Avoid foods that stimulate gastric secretion, especially meat, acids, raw vegetables or fruits, as well Tea and coffee, and it consists in the supply of medicines that neutralize gastric acid should, e.g. B. sodium bicarbonate to prevent ulcer formation, e.g. B. bismuth carbonate, and the hypersecretion should reduce, z. B. Atropine and Belladonna. Possess these latter drugs or preparations ■ However, unpleasant side effects, as they are also with the histamine

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Parathyroid extracts occur, often used for treatment applied to the pain.

However, these classic treatment methods bring certain complications and they use medicines, from some of which are costly, difficult to apply and, in the longer term, dangerous. ·

It would therefore be very beneficial to replace these products in whole or in part with a less expensive drug to be able to replace, which is harmless and easy to apply.

The object of the invention is to create such a medicament for the treatment of non-tumor-like complaints of the Gastroduodenal area, especially in cases of hypersecretion and ulcers, this drug taking the above should meet the specified criteria and must be effective.

This object is achieved by the medicament according to the invention dissolved, which is characterized in that it contains benzimidazole as an active ingredient. The preparation or that Medicinal product is preferably produced in dosed forms suitable for oral administration, preferably in Form of capsules, tablets or the like so that the active Component, that is, the Benzimidazql, can act directly on the gastric and duodenal mucous membranes against which it has a great affinity so that its secretions are inhibited.

Benzimidazole is a compound known per se that was synthesized for the first time more than a hundred years ago and which has a very stable molecule that is also resistant to the effects of temperature and pressure

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as against the action of concentrated sulfuric acid and concentrated hydrochloric acid as well as alkali compounds. The compound also has a biological one which is known per se Activity because of its chemical relationship to histamine and its occurrence in the vitamin Β, -p molecule where it is a bridge between the cobalt and one of the side chains with the interposition of an amino alcohol residue in this Chain forms.

It is also known that benzimidazole as well as addition derivatives and substitution derivatives thereof have different pharmacological properties:

- Anithistamine effect: substitution by basic groups has recently led, after numerous setbacks, to derivatives which have an advantageous activity on this Own territory;

- analgesic effect: derivatives known since 1957 have been subjected to clinical studies in humans, however, these were dropped because of the severe depressant effect on the respiratory system as a result of the injection;

-vasoactive activity: certain derivatives are vasoconstrictors, although others have vasodilatory activity, in particular in the coronary area. There are numerous publications about this and there have been both pharmacodynamic as well as clinical examinations. These derivatives also have sedative and anti-inflammatory activity and in certain cases also antispasmolytic activity Activity;

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- Common malaria activity: numerous derivatives have been synthesized in which antimalarial activity has been shown;

- Germicidal activity: certain derivatives "have a weak one tuberculostatic activity, others possess remarkable Antifungal activity with a spectrum better than that of griseofulvin and the blocking effect on the Protein synthesis is attributable, but this is due to the antagonistic action of adenine, guanine, nucleic acids and vitamin B ^, ~ can be inhibited;

- Antiviral activity: It is reported that certain halogen derivatives have an effect on the influenza virus;

- Antitumor activity: It has been shown to be certain, simple substituted derivatives are themselves able to inhibit the growth of experimental Ehrlich tumors.

The studies of known pharmacological properties of benzimidazole as well as studies in connection with the therapeutic application according to the invention for the control the gastric secretion have shown the harmlessness of this substance ". The lethal dose (LD [-q), determined according to the" up and down "method varies between 520 and 610 mg / kg after 30 days in mice.

Studies have also shown the selective affinity of benzimidazole shown for the gastric mucosa in mice and dogs as well as in humans, including the working methods of the Autoradiography and gamma scintillation applied and with Carbon-14 or iodine-131 labeled benzimidazole that is intraperitoneally or injected intravenously.

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In "both cases it was shown that the distribution of the labeled Compound was homogeneous 15 minutes after injection, but radioactivity in the majority after 3 hours the tissue was very low with the exception of the gastric contents and gastric area where the increase persisted and up to 6 hours was maintained but the compound disappeared over the next 24 hours.

These investigations actually showed in a convincing way that benzimidazole is easily and completely excreted, especially through the urine, and that it is not of any kind Has residual toxicity in both humans and animals, even at the concentrations found in the gastro-duodenal Mucous membranes were observed.

Further results carried out on mice and rats gave the following results:

a) Examination of the excretion of anti-saliva: EDc- ₀ > 100 mg / kg po

Saliva is excreted by subcutaneous injection of pilocarpine (a muscarinic, para-sympathicomimetic Drug) induced.

Eight mice weighing 22 to 28 g were used per group. Before starting the experiment, the mice were two hours left starving. After application of the test compound, the mice were anesthetized with urethane (1.92 g / kg i.p.). JO minutes after the oral and 15 minutes after the subcutaneous Application · the test compound was salivary by Injection of pilocarpine (0.25 mg / kg s.c.) induced. 15 minutes later the animals without saliva excretion (inhibited saliva excretion) were counted. The ED ^ Q value is called the Dose is defined at which saliva excretion is 50% of animals is prevented.

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In this way it was shown that benzimidazole had no effect on saliva excretion at doses "up to 100 mg / kg p.o. owns.

Id) Intestinal motility (activated charcoal meal test):

ED ^ ₀ > 100 mg / kg po

The intestinal motility in vivo was determined by oral administration an activated carbon mixture investigated. Palis the activated carbon If the appendix is not reached within a defined period of time, intestinal motility is considered to be inhibited.

Eight mice weighing 22 to 28 g were used per group. The animals were starved for 24 hours. 30 minutes after the oral or immediately after the subcutaneous application of the test compound, each mouse received via gastric tube 20 ml / kg of an activated carbon mixture. 2.5 hours later, the animals were sacrificed and the number of mice without activated charcoal im Appendix counted. The EDcQ value is defined as the dose in which 50% of the animals have an activated charcoal free: appendix own. .

In this way, benzimidazole has been shown to increase intestinal motility at doses up to 100 mg / kg p.o. not reduced.

c) In the Shay rat test (carried out according to the method by H. Shay et al., Arch. Surg. j? £ (194-9), p. 210) Benzimidazole has an ED ^ Q value of 52 mg / kg i.d. for the volume and from 42 mg / kg i.d. for acidity.

The therapeutic power of benzimidazole for The treatment of non-tumor-like complaints of the gastroduodenal area was further supported by clinical investigations

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shown. 220 patients who suffered from non-tumor gastroduodenal -suffered from oral discomfort, and of whom three with bleeding ulcers as a result of ingestion of synthetic, anti-inflammatory drugs and other substances that cause gastroduodenal ulcers were treated according to the invention. These patients received benzimidazole from 5 mg to 20 mg orally every six to eight Hours of positive results and no intolerance or any other side effects observed.

The invention therefore makes use of these properties selective affinity and the sustained concentration of Benzimidazole in the gastroduodenal mucosa to facilitate easy, and to provide beneficial treatment for non-tumorigenic ailments thereof, taking advantage of its Ability to inhibit secretions is exploited.

The indication of benzimidazole according to the invention is therefore new compared to its previously known therapeutic purposes, and it is additionally associated with a type and dosage of administration in which the greatest advantage is derived from the activity of the drug.

According to the invention, benzimidazole is preferably in the form of a crystalline powder contained within a dosage form suitable for oral administration, in particular a digestible capsule or other equivalent form suitable for oral administration (per os) is suitable, which makes its immediate effect and its selective concentration in the area of the mucous membranes treated with it should be supported. Any dosage form

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preferably contains a single dose of the benzimidazole to ensure efficient treatment for the Sufficient time that it remains in the area of these mucous membranes.

In practice it has been found that the required, daily Dose on the order of about 30 to 200 mg and preferably about 30 to 100 mg for an adult of normal weight and that the duration of action is better than six hours. The product is available for application in the form of dosage forms suitable for oral administration, preferably as capsules, prepared, each about 10 to 70 mg and preferably 10 to 30 mg of benzimidazole either neat Form or in a mixture with at least one auxiliary and / or Contains carrier, the recommended dosage being the administration of one dosage form provides approximately every eight hours.

The substance shows an effect three to five minutes after application, with the symptoms for a period at the end of this period Period of about six to eight hours will disappear.

As previously described, the active ingredient according to the invention can be used in oral dosage forms. Suitable dosage forms include capsules, tablets, coated tablets, Syrup, suspensions and the like. Such preparations can be inert binders, fillers, carriers or diluents contain. Additional auxiliaries such as flavorings, preservatives, stabilizers, emulsifiers, buffers and the like can be added in accordance with common pharmaceutical manufacturing practice. The carriers and diluents used can be organic or inorganic substances, e.g. B. water, gelatin,

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Lactose, starch, magnesium stearate, talc gum ara "bikum, Polyalkylene glycol and the like. A "preferred oral dosage form is capsules.

The above-mentioned dosage forms can according to per se known methods, d. H. in accordance with standard pharmaceutical manufacturing practice.

So z. B. Capsules are prepared, which 30 mg Benzimidazole together with other common ingredients, such as. B. talc and magnesium stearate.

It is of course possible that the benzimidazole also in other dosage forms and in other frequencies than previously mentioned, can be given, this being done by the doctor concerned with a view to the needs of the concerned Patient is set.

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Claims (5)

Claims Medicines for the oral treatment of non-tumorigenic Gastroduodenal complaints and especially hypersecretion and ulcers, characterized that there is benzimidazole as the active ingredient, optionally in addition to other usual ingredients, contains. 2. Medicament according to claim 1, characterized in that each dosage form contains about 10 to about 70 mg of benzimidazole contains. 3. Medicament according to claim 1 or 2, characterized in that that it is in the form of capsules. 4. Process for the preparation of a medicinal product for oral use Treatment of non-tumor gastroduodenal complaints and especially hypersecretion and ulcers, characterized in that benzimidazole as the active ingredient with a non-toxic, inert, solid or liquid carrier material and / or diluent which is suitable for oral administration, mixed will. 5. The method of claim 4, characterized in that from about 10 to about 70 mg of benzimidazole are used per unit dosage form. . 509 8 35/086 3