CS199128B1 - Stimulator of gastric secretion - Google Patents

Description

The invention relates to the field of medicine and relates to targeted formulations which selectively stimulate gastric secretion. Gastric secretion inhibitors are used to investigate gastric secretion as a diagnostic test in a variety of diseases: hyper- and hypoacid gastritis, ulcus ventriculi et duodenum (peptic ulcers), pernicious anemia, gastric tumor.

At present, either food stimulation or medical (chemical) stimulation is used to investigate the secretory capacity of the stomach. Stimulation by food, despite its simplicity and safety, cannot fulfill the basic diagnostic task - to determine the relationship between the functional state of the gastric mucosa and pathological-morphological changes, because the results are disturbed by external and internal factors (food quality and composition, psychological state of the patient, laboratory environment) and probing procedure). In addition, food stimulation does not allow the maximum degree of hydrochloric acid secretion in the stomach to be achieved and therefore leads to frequent diagnostic errors. For this reason, chemical secretion stimulators have been proposed.

Histamine, gastrin preparations (Pentagastrin) and Histalog (an analogue of histamine) are currently used as chemical (medicament) stimulators of gastric secretion. Histamine has insufficient selective effect and causes in patients beside the stomach

199 128 secretions still have a number of side effects such as redness of the skin, nausea, vomiting, headache, dizziness, bronohial spasms, edema of the vocal ligaments, hypotonia and shock conditions.

These side effects cannot be completely eliminated by the usual administration of traditional antihistamines (H 2 -antagonists such as Mepyramine, Tavegil, Suprastin). Therefore, histamine is administered in the so-called histamine test only in individual cases and during hospitalization.

Another chemical secretion stimulator, Pentagastrin, a synthetic analogue of gastrin hormone, is generally tolerated by patients without complications at first use and may produce a maximum degree of secretion at a sufficient dose. However, due to its polypeptide properties, there is a risk of allergic and anaphylactic reactions when repeatedly administered. In addition, the duration of action at a single dose of preparation is not long. A long-term drip infusion, which can only be performed during hospitalization, is necessary for an objective evaluation of the maximum excretion of hydrochloric acid per hour. A certain obstacle to the wider use of Pentagastrin is its relatively high cost.

Recently, synthetic analogs of hiatamine have attracted the attention of gastroenterologists, of whom Histalog (Betasol from Eli Lilly, USA) is the most widespread in clinics. It is a pyrazole analog of histamine: 3- (S) - [(1-aminoethyl) -pyrazole. Histalog loads 70 times less the circulatory system (hypotonia) than histamine, while its stimulating effect of gastric secretion is only 70 times weaker than hiatamine. When parenteral administration of Histalog to the patient at a dose of 1 to 5 mg / kg, the secretion response of the stomach reaches its maximum value and side effects occur far more rarely and therefore the preparation has reached widespread in clinics. The selective mechanism of action of Histalog on the stomach has not yet been sufficiently clarified. This effect is believed to be associated not only with gastric receptor selectivity but also with its ability to secrete endogenous histamine.

According to the most recent ideas, the effect of histamine on various physiological systems of the body takes place via specific recipes.

The existence of two types of histamine receptors H ^ and Hg has been demonstrated experimentally. The secretion cells of the stomach which produce hydrochloric acid are stimulated by Hg receptors. Since histamine acts to the same degree on the H 2 - and H 3 -receptors, SKP (USA) has developed substances that have a relatively selective effect on H 3 -receptors that have the ability to induce Hg-histamine effects, especially gastric aecretion, with substantially attenuated side effects. effects from H 1 -receptors. These compounds are direct histamine analogs, 5-alkyl-4- (2-aminoethyl) -imidazole derivatives. According to animal pharmacological research, 5-methylhistamine and its closest analogs are the most promising in clinical practice. Experimental tests on the pharmacological properties of these substances have been continued, but no data have yet been published in the scientific medical literature on the clinical use of these substances as diagnostic stimulators of gastric secretion. Therefore, it is difficult to evaluate the practical value of these compounds. All the aforementioned chemical emulators of gastric secretion, such as histamine, Pentagastrin,

Histalog and 5-menthylhistamine, however, have one basic disadvantage that in clinical practice they can only be administered parenterally (intramuscularly, intravenously, subcutaneously) as they are inactivated by gastrointestinal and hepatic fermentation and the secretory effect does not occur. This circumstance substantially limits the extent of their further spread in medical practice, since injections are required to cause pain and agitation in patients. In addition, injections are associated with the need for sterile instruments and appropriately qualified medical staff.

It is an object of the present invention to provide a new chemical stimulator of gastric secretion with selective action on the Hg-receptors of secretory cells, which will not have the side effects of histamine and induce maximal gastric secretion not only during parenteral administration but also oral administration.

This object was achieved by the finding of a new gastric secretion stimulator which according to the invention contains as active ingredient 2-amino-5- (2-aminoethyl) -1,3,4-thladiazole in the form of a salt with a pharmaceutically acceptable acid and a suitable a pharmaceutical carrier.

Either water (in ampoules for parenteral administration) or a pharmacologically neutral tablet filler are used as carriers for the active ingredient. The active ingredient content for a single parenteral injection or for a given dose is 50 to 200 mg.

The proposed preparation is hereinafter called Thidasin.

Thidasin is a highly active selective pharmacological stimulator of gastric secretion and has a number of important advantages over known pharmaceuticals with the same effect as histamine, histalog, 5-methylhistamine and pentagastrin, which will be shown in the results of comprehensive pharmacological and clinical pharmacology tests.

The detailed description provides data on the pharmacological and clinical trials of Thidasin, where the active substance was used in the form of hydro-chloride.

Effect of Thidasin on gastric secretion

Animal tests were performed to compare properties with hietamine and histolog.

In chronic experiments, male males with gastric fistula were used after 18 hours of fasting.

(a) Intramuscular use

Thidasin was administered intramuscularly at intervals of 40 minutes at increasing doses (0.05-0.08 - 0.1-0.2 mg / kg or more) until maximum secretion was achieved. Gastric juice was titrated to acid content and protaolytic activity was determined. Hydrochloric acid production was calculated in milliequivalents (niEq) and pepsin in milligrams. The results of the experiments showed that Thidasin can induce a maximum degree of hydrochloric acid secretion in the stomach of the pe. Intramuscular administration is minimal

188128 effective dose 0.05 mg / kg, maximum 3.0 mg / kg. The hourly output of hydrochloric acid at maximum secretion was 24 mEq per hour, pepsin 110 mg / hour.

In control experiments, dogs were given analogous doses of hlstamine hydrochloride or Hlatalog. A total of 55 experiments were performed. The results, which are arranged in the form of cumulative dose-effect curves, allow comparison of activities (pDg) between substances and Hg-receptors, respectively: hletamine 6.40, Thidasin 3.86, Hiatalog 3.63.

b) Oral administration

In a separate series of 20 experiments, dogs were administered Thidasin at a dose of 100 mg per animal. A maximum gastric secretion (26 mEq / hour) was observed after a flight time of 20 to 30 minutes. Administration of hlstamline at doses of 10 and 20 mg and Histalog at doses of 50 and 100 mg did not cause any gastric secretion in dogs.

This suggests that Thidasin can induce maximal gastric secretion in both parenteral and psoral administration. This is a significant difference compared to histamine and histolog.

Male rats (250-300 g) were used in twenty experiments according to the Shay method. The pylorus of the stomach was ligated for two hours by decapitation of the animals. Gastric juice volume and pH were then examined. One experimental group of animals was administered intramdominally Thidasin at a dose of 8 mg / kg. As a result, it was found that administration of the preparation increased more than three times the production of hydrochloric acid in the stomach after ligation of pyloric.

In the control group, the pH of the gastric juice was 2.2 and the production of hydrochloric acid per animal was 0.12 mEq on average; in the experimental group, the pH of gastric juice was 1.6 and the production of hydrochloric acid was 0.41 niEq.

Effect of Thidasin on blood pressure

In nine cats (2.5-4.0 kg) of narcotized urethane-chloralose mixtures (60 mg / kg chloralose, 600 mg / kg urethane), blood pressure in the artery oarotis oommunis by a mercury manometer was registered. An intravenous administration of 0.1 mg / kg of Thidasin in addition to lowering blood pressure from baseline by 4.00 kPa, administering the same dose of hietamine by 13.33 kPa and Histalog by 4.00 kPa. No hypotensive effect was observed when the dose of Thidasin was reduced to below 0.1 mg / kg.

In experiments on 18 rabbits (2.5 to 3.5 kg) with carotid artery artery present in the skin lobe, the preparations were injected intravenously. The 0.1 mg / kg dose of Thidasin reduced blood pressure by 1.60 kPa, the equimolar dose of hietamine by 5.33 kPa and Histalog by 2.00 kPa.

Effect of Thidasin on the H- and Hg-receptors of isolated organs

Contractions of the isolated guinea pig ileum stripe were registered with increasing concentrations of Thidasin, hietamine, and Histalog and displayed by dose-effect curves. Affinities (pDg) for H 1 -receptors were found: histamine-6.73, tas 128

Histalog - 4.23, Thidasin - 3.4.

Contractions of the isolated uterine horn of rats treated with acetylcholine at a concentration of 1 were registered on a strip of paper. Mol ”** Mol. The spasmolytic effect of the preparation at standard concentrations on these contractions was investigated. The histamine effect was taken as 100%. The spasmolytic effect of Thidasin on Hg-receptors was 15%, of Histalog 16%.

To determine the effect of the preparation on Hg-receptors, isolated guinea pig atrium was used and rhythm frequency was determined, and cumulative dose-effect curves were drawn and affinity (pDg) for receptors calculated. The affinities (pDg) for histamine were 6.64, for Histalog 4.80 and for Thidasin 5.10.

Attempts to inhibit the action of Thidasin by H1- and Hg-receptor antagonists

The effect of blockade of action on H1- and Hg-reeeptors was investigated in 30 guinea pigs which were shocked by intravenous administration of 190 mg / kg of Thidasin. When 0.05 mg / kg of the H 1 -antagonist (Tavegil) was pre-administered, the exit of the animals was prevented in 90% of the cases.

In experiments in 6 dogs, intramuscular administration of 2 mg / kg Thidasin induced maximal gastric secretion. The effect on secretion was completely eliminated by prior administration of the Hg-reoeptor antagonist at a dose of 30 mg / kg Metiamide.

In six cat experiments, hypotension was induced by intravenous administration of 2 mg / kg Thidasin. The pre-treatment of two histamine antagonists, 0.05 mg / kg Tavegil (H 1 -receptors) and 40 mg / kg Metiamide (Hg-receptors) prevented this reaction.

After carrying out a special test program, the acute and chronic toxicity of Thidasin and its effects on the functions of various organs and animal systems were investigated. Table 1 generalizes the results of these tests.

Table 1

Common number The name of the test Results Checklist skuDina Pokusná skuDina 1 2 3 4 AND. Acute toxicity mg / kg male mice 18.0 to 21.0 g i.p. 1000 male rats 200-250 g i.p. 1000 guinea pigs 280 to 350 g i.p. 360 guinea pigs 200 to 250 g i.p. 190

(B)

Chronic toxicity of guinea pigs weighing 200-250 g

1. intramuscular 20 mg / kg (0.1 LD, jq)

Thidasin daily, 10 days average weight in control group in g average weight in test group in g

2. Hematology (at the beginning and at the end of the experiment) hemoglobin,% in the control group in the experimental group leukooyty, in the control group in the experimental group erythrooys, in miles, in the control group in the experimental group sedimentation, mm in the experimental group leukooyty - budget blood clotting

3. Electrocardiogram at the beginning and end of the experiment

C. Locally irritant effect of 1 to 5% solutions (guinea pigs, rabbits) intramuscularly intravenously orally eubcutaneously on the conjunctiva

D. Allergic effect (Arthus-Sacharow phenomen) of male rabbits weighing 3.0 kg per day, 6 to 7 days:

in the test group subcutaneously, 0.1 ml of a 1% solution in the control group, 0.1 ml of normal horse serum

E. Effect on depth and frequency of respiration (rabbits, cats)

0.1 to 0.2 mg / kg l.v. respiratory rate per minute amplitude of respiratory movements, mm

230.8 i 52 220.0 i 58

260.3 i 51

252.3 - 50

13.8 - 0.4

11.8 Í 0,1

10920 - 702 11360 i 900 3,79 i 0,1 3,75 i 0,1 without special changes without changes without substantial changes

11.9 - 0.3 12.4 i 0.3

10070 and 610

9500 i 835 3,46 í 0,1 3,93 i 0,1 negative reaction negative reaction necrosis, separation of affected areas

90.0 0,2 0.2 220 0,3 0.3

85.0 i 0.4 180 - 0.1

Ί

0.1 to 0.2 mg / kg l.m, respiratory rate per minute respiratory amplitude, mm mg / kg i, v, respiratory rate per minute respiratory motion amplitude, mm mg / kg l.v, respiratory rate per minute respiratory motion amplitude, mm

79.0 2,0 2.0 78.0 - 2.3

160.0 -6.2 160.0 - 10.1

120 - 10.0 85.0 i 6.0

10.0 i 0.8 14.0-0.4

100.0 - 8.0 85.0 - 10.0

110.0 i 7.0 140 i 20.0

Chronic toxicity of male dogs weighing 22 to 25 kg, 3 animals

Orally, 200 mg (in gelatin capsules) daily, 10 days, 1 control daily, 1 control dog

Animal behavior, food reflexes

Weight at the beginning and at the end of the experiment

Functions of cardiovascular system

a) Electrocardlogram at the beginning and at the end of the experiment P-P, PQ, QRST, T without changes without change without substantial changes

-Ρ '-Q

RST of the whole heart cycle, heart rate indicator, part of the ECG, shows atrial waking time cardiac part of the ECG, the so-called ventricular complex, shows the time of waking in the heart ventricles and heart rate recovery (T-wave) characterizes myocardial repolarization intensity

b) Phonocardiogram at the beginning and at the end of the experiment

c) Blood pressure testing at the beginning and at the end of the experiment no variations in height and tone duration and no disturbances in ECG synchronization occurred within the limits of the physiological standard 14.67 to 18.67 kPa

199129

5 · Liver function

(a) bilirubin content, mg% at the start of the experiment

Day 5 of experiment Day 10 of experiment

(b) the glutamine-alanine-transaminase content in units at the start of the experiment

Day 5 of experiment Day 10 of experiment

c) Mobility of serum proteins

1) sublimate assay at the beginning of the experiment on day 5 of the experiment

Day 10 of experiment

2) Thymol turbidity reaction at the beginning of the experiment

Day 5 of experiment Day 10 of experiment

6. Urine examination, volume, specific gravity, protein, sediment microscopy (dogs, guinea pigs) (water load on the day of examination was 5% of the animal's weight) at the beginning of the experiment Day 5 Experiment Day 10

7. Histology of examination of internal organs (dogs, guinea pigs) Day 10 of the experiment (micro-cut preparations of liver, kidney, adrenal gland, thyroid gland)

0.15

0.15

0.15

0.16

0.15

0.15

30

30

35,5 32

1.0 1.0

1.0 i, o

1.0 1.1 no significant changes in diurese and in urine composition no microscopic changes in organs compared to control organs

The results of pharmacological testing of gastric secretion by Thidasin compared to known preparations lead to the following conclusions:

1. In animal experiments, Thidasin can induce maximal secretion of hydrochloric acid in the stomach to the same degree as histamine and Histalog.

2. Unlike histamine and Hlstalog, the maximum secretion rate can be achieved.

^ 17 '

Chronic toxicity values found at

Thidasin in both parenteral and oral administration, which is a significant advantage over known analogues.

3. Comparison of the effects of Thidasin on the H1- and Hg-receptors in various objects showed that the affinity between the preparation and the Hg-receptors is stronger than between the preparation and the H? -Receptors and the selectivity of Thidasin effect is higher than that of Histalog.

4. Thidasine at doses (3 mg / kg) that induce maximal gastric secretion in dogs has no significant effect on blood pressure, heart rate rhythm and overall animal behavior. Thidasin has a large theraupeutic breadth, as evidenced by the ratio

The 1000 two animal species indicate that the preparation at doses of 1/10 LD ^ q does not significantly affect the growth and development of the animals, blood composition and blood count and the function of the various internal organs, and does not lead to any pathological changes in vital animal organs.

Clinical trials of Thidasin as a diagnostic tool for gastric secretion testing in sick and healthy subjects were performed in 650 patients. The possibility of performing maximum and maximum tests in parenteral and oral administration of the preparation was tested in comparison with histamine and Pentagastrin. Particular attention was paid to the registration of side effects and the reproducibility of secretion results in repeated trials.

Tables 2, 3, 4 and 5 show some accumulated generalized values.

Table 2

Effect of maximum doses of Thidasin on gastric secretion values in middle-aged patients

Preparation

No. Issue / h HCl Concentration HCl Gastric meaq / h_mEq / l_first ml / hour_hour 1.hour * 2.hour 1.hour * 2.hour% 1.hour * 2.hour%

Thidasin (1 mg / kg) orally 13 4.3 21.6 +402.3 33.3 103.2 +209.9 102.1 227.9 +123 Thidasin (1 mg / kg) subcutaneously 11 8.2 18.3 +471.9 43.9 100.8 +129.6 87.0 200.5 +130,5 Pentagastrin 6 mg / kg 15 Dec 3.7 16.5 +345.9 35.3 94.0 +166.3 106.3 174.0 +63.7

x 1st hour of investigation (basal secretion)

2.hour examination (secretion after administration of the preparation)

18912B

Table 3

Comparison of gastric secretion using Thidaain (parenteral) at 1.5 mg / kg and a simple histamine test (0.01 mg / kg) in 20 patients

Values Total acidity Free acid Release Maximum expenditure Total acci- (units) (units) mEq / hr HCL mEq HCl stimulation dity for basel secretion Histamine Thidasin Histamine Thidasin Histamine Thidasin Histamine Thidasin Histamine Thidasin 92.0 + 23 90.3 + 22 81.7 + 21 77.0 + 20 12.0 + 0.4 12.2 + 0.7 8.8 + 0.2 8.9 + 0.3 2.52 + 0.12 2.54 + 0.09 p> 0.05 ^ 0.05 5> 0, O5 f0.05 ? 0.05

Table 4

Reproducibility of secretion results after administration of Thidasin and histamine in paired experiments according to total acidity values.

Number of observations in each group of 10 persons

Benefits

\ nre claw Thidasin Basel secretion Histamine N. 1.5 mg / kg orally 0.7 mg / kg subcutaneously 0.01 mg / kg subcutaneously «Difference * (fluctuations) 0-22 15-42 0-62 0-53 % difference on average 7.5 31 42 33

x)% difference is the ratio of the difference in the total acidity value at the first and second examinations of one and the same patient to the higher of both values.

189128

Table 5

Comparison of the effect of Thidasin, histamine and Pentagastrin on the most important values of gastric secretion in patients with duodenal ulcer

Secretion values Thidasin Histamine Pentagastrin 1 hour* 2.hodina 1.hodlna * 2.hodina l.hodina * 2.hodina mEq / hr 7,25-09 23.9-1.8 7.0 ± 1.2 19, A, 6 7.4-0.8 24.8 ^ 1.5 dispensing pepsin units / hour 4,0-0,7 17.8 ± 2.3 3.7-1.2 4.8 ± 3.0 3,3-0,8 19,3-3,8 chimosine release units / hour 17.3-0.3 218.2-4.0 16.0 ^ 0.008 39.14-2.8 16.4-0.04 157.3 ± 5.9

x) 1st lesson - basal reaction

The results of the experiments showed that, at adequate doses, the secretory efficacy of Thidasin was the same as that of histamine and Pentagastrin. In contrast to the latter two preparations, Thidasin can be administered equally well both orally in the form of tablets or probes in the form of solutions, as well as parenterally, intramuscularly or subcutaneously. Both submaximal and maximal secretion assays can be performed with Thidasin. In all cases, the use of Thidasin is not accompanied by any significant side effects that are characteristic of the hlstamine test and therefore does not require prior administration of antihistamine preparations. The oral administration of Thidasin is convenient, simple and can be done under outpatient conditions.

Clinical observations have confirmed experimental results and have shown that Thidasin is a selective gastric secretion stimulator almost free of side effects which, compared to analogous known agents (histamine, gastrin), has substantial advantages, although it can be administered orally, has a significant selective effect, is safe and convenient in clinical use. Based on the results of clinical observations, effective doses of the preparation for submaximal and maximal secretion tests have been determined using different routes of administration.

Table 6 contains relevant data.

Table 6

A. Doses for submaximal secretion tests

Way administration Hlstamin- diohloride mg / kg Histalog (Betasol) mg / kg Thidasln mg / kg Subcutaneously or intramuscularly 0.008 0.9 0.8 Per orally - - 1.5 B. Benefits for maximum secretion tests Way administration Histamine- dichlorld mg / kg Histalog (Betasol) mg / kg Thidasln mg / kg Subcutaneously or intramuscularly 0,025 1.7 1.6 Ferorally - - 2,0

Active ingredient, namely 2-amino-5- (2-aminoethyl) -1,3,4-thladiazole of the formula

S nh ₂ nh ₂ ch ₂ ch ₂ - C is a known substance (Maeaki Outa: J. Pharm. Soc. Japan., 72.

1636-1639 (1952).

The hydrochloride of this compound is a white, crystalline powder with a yellowish shade, slightly hygroscopic, mp 238 ° C (dec.), Melting point 237 ° C (dec.). The powder dissolves slightly in water, aqueous solution It is colorless, transparent and stable for a long time. A solution of the substance in 0.01 M hydrochloric acid concentration of 10 ^-4 mol charakteri8kioké has an absorption spectrum in the UV e maximum at 245-1 nm.

Example 1

Preparation of 2-amino-5- (2-aminoethyl) -1,3,4-thladiazole di- and monohydrochloride a) Preparation of 2-amino-5- (2-phthalimidoethyl) -1,3,4-thiadiazole.

189128 g of 1- (2-phthalimidopropionyl) -thiosemylcarbazide was dissolved in 45 ml of 96% sulfuric acid with stirring and heated to 100 ° C for 5-10 minutes. The solution was cooled, poured with stirring on battered ice and neutralized with 20% sodium hydroxide solution to pH 8-9. The precipitate was filtered off and washed with water on the filter until the inorganic salts were completely removed. Yield 18.5 g (90%), mp 229-231 ° C (dec.) (Aqueous dioxane). According to literature data, the melting point is 226-227 ° C.

For ^C i2 ^H 10 ^N 4 ° 2 ^S Calculated: 52.54% C, 3.67% H, 20.43% N, 11.69 S;

Found: C 52.31, H 3.82, N 20.24, 11.67 S.

The starting 1- (2-phthalimidoproplonyl) -thiosemicarbazide can be prepared by a method described in the literature (Masaki Outa: J. Pharm. Soc. Japan., 72, 1636-1639, 1952).

b) Preparation of 2-amino-5- (2-aminoethyl) -1,3,4-thiadiazole dihydro chloride

17.8 g of 2-amino-5- (2-phthalimidoethyl) -1,3,4-thiadiazole, 3.25 g of hydrazine hydrate and 130 ml of alcohol are heated at reflux for 3 hours. The alcohol was evaporated in vacuo; 150 ml of water and 25 ml of 20% hydrochloric acid are added to the residue, heated for 30 minutes, after cooling, the phthalhydraaid residue is filtered off and rinsed on the filter with water. The aqueous solution is evaporated on a steam bath, the residue is dissolved in 70 ml of cold water, treated with neutral charcoal and filtered. Evaporate the filtrate to dryness on a steam bath. Yield 14 g (100%), mp 238 ° C (dec.) (Aqueous methanol-acetone). According to literature data, the melting point is 237 ° C (dec.).

For C ^ HHgN ^S. H, 4.64; N, 25.80; S, 14.77; Cl, 32.66;

Found: C, 22.03; H, 4.64; N, 25.81; S, 15.00; Cl, 32.25.

c) Preparation of 2-amino-5- (2-aminoethyl) -1,3,4-thiadiazole monohydrochloride

To a suspension of 1.09 g of 2-amino-5- (2-aminoethyl) -1,3,4-thiadiazole dihydrochlaride in 10 ml of pure alcohol is added 0.8 ml of distilled triethylamine. The mixture was stirred for 1 hour, the residue was filtered and washed with alcohol. Yield 0.9 g (100%), mp 202-203 ° C.

For Ο ₄ ΗθΝ ₄ H .HCl calculated: 19.63% Cl;

found: 19.26% Cl.

Example 2

Preparation of a solution of 2-amino-5- (2-aminoethyl) -1,3,4-thiadiazole for injection or per os.

The formulation in the form of a 5% aqueous solution at a dose of 0.8 to 2 mg / kg body weight of the patient is administered subcutaneously or intramuscularly, or at a dose of 1.5 to 2.0 mg / kg body weight of the patient orally.

Because the 2-amino-5- (2-aminoethyl) -1,3,4-thiadiazole dihydrochloride solutions react strongly with acid, they are neutralized beforehand with sodium hydroxide solution to pH 6-7, whereby the compound is converted to the monohydrochloride.

To prepare 1 liter of a 5% preparation solution, dissolve 50 g of 2-amino-5- (2-aminoethyl) 1,3,4-thiadlazole dihydrochloride in 900 ml of water for injection, add 30% sodium hydroxide solution to pH 6 to 7 and make up to 1 liter with water. The solution is filtered, dispensed into 1 ml neutral glass vials and steam sterilized at 100 ° C for 30 minutes.

Sodium nitrite on a hot, hydrochloric acid solution of the preparation (nitrite ion reduction according to the iodine-starch indicator) or a positive reaction on chlorine ions may be used as an assay for the identity of the preparation.

The identity of the preparation can also be tested by UV-spectroscopy, where the absorption maximum appears at 245-1 nm.

The quantitative determination can be performed spectrophotometrically according to the optical absorbance of the test solution, or by titrimetric determination of chlorine ions,

Keep the ampoules in a place protected from light.

Example 3

Preparation of the preparation in the form of tablets.

To prepare tablets weighing 0.15 g each, 0.05 g of 2-amino-5- (2-aminoethyl) 1,3,4-thiadlazole dihydrochloride is mixed with a filler and the tablets are made. The filler has the following composition: Sugar 0.0535 g; starch 0.0425 g; talc 0.003 g; Calcium stearate 0.001 g. Identity and quantitative assays are the same as in Example 2. The tablets are stored in a dry place.

Claims (5)

A gastric secretion stimulator comprising an active ingredient and a pharmaceutical carrier, characterized in that it comprises 2-amino-5- (2-aminoethyl) -1,3,4-thiadiazole in the form of a salt with a pharmaceutically acceptable acid. Stimulator according to claim 1, characterized in that it contains water as the carrier. 3. Stimulator according to claim 1, characterized in that it comprises a mixture of solid fillers as carrier. 4. A stimulator according to claims 1 and 2, characterized in that the content of active ingredient per injection for parenteral administration is 50 mg / ml. 5. Stimulator according to claims 1 and 3, characterized in that the active ingredient content per tablet is 0.05 g.