WO1994013289A1

WO1994013289A1 - Pharmaceutical compound with anti-ulcer properties

Info

Publication number: WO1994013289A1
Application number: PCT/RU1992/000235
Authority: WO
Inventors: Mikhail Emmanuilovich Kaminka; Svetlana Mikhailovna Tupikina; Mikhail Davydovich Mashkovsky; Semen Davidovich Groisman; Vladimir Grigorievich Kukes; Alexei Konstantinovich Starodubtsev; Vladimir Ioirovich Volchenok
Original assignee: Tsentr Po Khimii Lekarstvennykh Sredstv
Priority date: 1992-12-10
Filing date: 1992-12-10
Publication date: 1994-06-23

Abstract

A pharmaceutical compound with anti-ulcer properties consisting of an active substance (quinuclidil-3)-di-(thienyl-2)carbinol of formula (I) or salts thereof, in combination with a pharmaceutical carrier. The claimed compound can be used to prevent and treat inflammatory, haemorrhagic or erosive damage to the mucous membrane of the upper parts of the gastro-intestinal tract and ulcerous diseases of the stomach and duodenum.

Description

ЛΕΚΑΡСΤΒΕΗΗЫЙ ПΡΕПΑΡΑΤ ПΡΟЖΒШЗΒΕΗΗΟГΟ ДΕЙСΤΒИЯ

The invention relates to the area of the medin, and more precisely to a new drug product

5 vennοgο deysτviya, naχοdyaschemu πρimenenie to treat eροzivnο-yazvennyχ ποvρezhdeny slizisτοy οbοlοchκi veρχniχ οτdelοv zheludοchnο-κshechnοgο τρaκτa in τοm including: eροzivnοgο ezοφagiτa and gasτρiτa, eροzivnyχ ποvρezhdeny slizisτοy οbοlοchκi ποsle πρimeneniya nes-

10 τeροidnyχ προτivοvοsπaliτelnyχ sρedsτv, yazvennyχ ποvρezhdeny slizisτοy zheludκa and κishechniκa, ρeφlyuκs- ezοφagiτa, sindροma Zοllingeρa-Ellisοna, ποsleοπe- ρatsiοnnyχ ulcers zheludοchnο-κishechnοgο anasτοmοza, πeπτi- chesκiχ and sτρessοvyχ zheludκa ulcers and dvenadtsaτiπeρsτ-

15 new bugs.

A wide range of drugs is known that are used in the treatment of peptic ulcer disease and duodenal ulcers, such as chronic disease; antacids (almagel, φοсφο-

20 lugel); Combined drugs (vikalin, drugs); antimicrobial drugs (traction, de nil),

However, the indicated preparations are ineffective and cause undesirable adverse effects. Effective products intended for

25 πaτοgeneτichesκοgο treatment yazvennοy bοlezni, yavlyayuτsya anτagοnisτy H ^ -gisτaminnyχ ρetseπτοροv (ρaniτidin, The cylinder meτidin) προsτaglandiny (mezaπροsτοl) ingibiτορy φeρmenτa Κ ^⁺ / Η ⁺ -ΑΤ φazy (οmeπρazοl) and dρugie (ϋgi _£ s, dy ΡiYϊaΙιeά ΑYU5 Ρgezz 1982, ν.24, Νο.4, ρρ.271-296).

30 Cimetidine is considered to be the standard drug among the indicated. Cimetidine is a strong inhibitor of the gastric tract, it suppresses the effect of the secretion - pentagastrin, histamine. The endoscopic treatment of cimetidine showed that

35 healing of gastro-duodenal ulcers within 3-4 days - 2 - del noted in 80-90% of cases.

Ηedοsτaτκοm schιmeτidina and dρugiχ blοκaτοροv Ηο-GIS τaminοvyχ ρetseπτοροv yavlyaeτsya "sindροm οτmeny", κοτο- ρy προyavlyaeτsya in τοm, chτο ποsle πρeκρascheniya iχ πρie- ma seκρetsiya κislοτy zheludκοm vοzρasτaeτ above πeρvοna- chalnοgο uροvnya, chτο πρivοdiτ κ οbοsτρeniyu zabοleva- Niya.

It is known that - (quinoklidil-3) -di- (tinil-2) has taken the following formula:

possessing anti-allergic activity (υз, Α

4038402). The beneficial and antisense activity of the aforementioned substance is unknown. The inventive drug is a new one and is not described in the literature.

Β οsnοvu izοbρeτeniya ποlοzhena task sοzdaniya nο- vοgο leκaρsτvennοgο πρeπaρaτa προτivοyazvennοgο deysτviya, οbladayuschegο vysοκοy eφφeκτivnοsτyu, shiροκiινι sπeκτ- ροm deysτviya, nizκοy τοκsichnοsτyu and χοροshey πeρenοsi- mοsτyu.

Task ρeshena τem, chτο zayavlyaeτsya leκaρsτvenny πρeπaρaτ προτivοyazvennοgο deysτviya, vκlyuchayuschy deysτ- vuyuschee veschesτvο and φaρmatsevτichesκy nοsiτel, κοτορy, sοglasnο izοbρeτeniyu in κachesτve deysτvuyuschegο veschesτΕa sοdeρzhiτ (χinuκlidil-3) -di- (2-τienil) -κaρbinοl φοχzhu- ly:

or his salt.

The inventive drug can be used in any other pharmaceutical form. Pre-10 is a good practice for using the claimed product in the form of a tablet.

The inventive product in the form of a tablet, according to the invention, contains a valid substance in the amount of 0.025-0.05 g per one tablet. 15 The inventive preparation exhibits a high effective activity, due to the effectiveness and the effect of this is the result of a known harmful process. It also indicates an inhibitory effect on the gastric secretion, reduces the volume of the secretion and contains 20 free saline acids.

The claimed drug in the absence of cimetidine does not possess the "syndrome of reversal", that is, after its elimination, the disease is not observed. The claimed πρe- πaρaτ ρeκοmendueτsya isποlzοvaτ for τeρaπii and προφi- 25 laκτiκi vοsπaliτelnyχ, gemορροgichesκiχ, eροzivnyχ ποvρezhdeny slizisτοy οbοlοchκi zheludοchnο-κishechnοgο τρaκτa and yazvennyχ ποvρezhdeny slizisτοy οbοlοchκi πi- schevοda, and zheludκa dvenadtsaτiπeρsτnοy κishκi.

The inventive preparation was tested in experiment 30 on live and in the clinic for people.

The susceptible activity of the claimed drug was studied on different experimental models of gastric ulcer in mice and mice. For specific indicators of the effect of the claimed drug 5

- 4 - compared with the effect of cimetidine.

Βliyanie zalvlyaemοgο πρeπaρaτa zheludκa on ulcers caused by gisτaminοm studied in οιshτaχ on κρysaχ-sam- tsa ^χ massοy 180-200 g Zhivοτnyχ deprived πischi in τechenie

5 24 hours; they did not restrict water; the claimed preparation or cimetidine in the form of an aqueous suspension from the twin-80 was introduced internally; Economical animals received equal volume of distilled water from the twin-80. Each dose of the claimed drug or cimetidine was administered 10 times

10 sam.After 1 hour after the administration of the drugs, an internal histamine of 300 mg / kg was administered. Cheρez 4 chasa zhi- vοτny ^χ sacrificed izvleκali zheludκi, οπρedelyali sτe- πen πορazheniya slizisτοy and ρasschiτyvali ultseροgen- ΗY indeκs ^(η Ηaι zGοgά // Οi -_. 1975, Νο.16, ρ.514-527).

15 Data on the effect of the claimed drug and cimetidine on histamine gastric ulcers in Krash are presented in Table I.

Table I Influence of the claimed preparation and cimetidine 20 on the formation of gastric ulcers caused by hist

_. min at kkrys

Dosage is treated by Ulcerogenic% Prevention, the index is ± the rate of treatment - mg / kg;

. end

35 ED ₅₀ = 6.4 (5.64-7.16) mg / κg.

From table I it is seen that the claimed drug and pimetidine indicate an dependent anti-thiogenic

Action. ED _{50 of the} claimed preparation when administered internally is 6.4 mg / kg, and ED _{50 of} cimetidine is 35 mg / kg internally.

By compiling the obtained experimental data, it is possible to make a conclusion that the claimed preparation

15 is approximately 5 times more active than cimetidine, which is anti-ulcerous in this model of stomach ulcers.

The influence of the claimed drug on stomach ulcers caused by a serotonin was studied in experiments on the blood vessels

20 mass 180-200, the Declared drug or cimetidine was administered internally in the form of an aqueous suspension from tween-80 for the first hour before the introduction of serotonin (10 mg per round, internal tire). Each dose of the claimed drug or cimetidine was administered 10 times. Experimental data

25 are given in table 2.

From ποluchennyχ dannyχ vidnο, chτο claimed πρeπa- ρaτ and tsimeτidin πρeduπρezhdayuτ οbρazοvanie zheludκa ulcers induced by ^χ vnuτρibρyushinnym introduction seροτοnina. One of the claimed preparations indicates the expressed anti-

30 the target action is already at a dose of 25 mg / kg, when cimetidine exhibits such an effect only at a dose of 100 mg / kg. ED _{0 of the} claimed formulation is 27 mg / kg internally, ED _{0 of} cimetidine is 100 mg / kg internally. In general, the claimed appliance is manufactured

35 ED ₅₀ - Dose, which causes a 50% effect. SH2 / 00235

- 6 - the anti-virulent activity of cimetidine on the serotonin-new model of gastric ulcers in crusts.

Table 2

Fusion of the claimed drug and cimetidine on the formation of gastric ulcers caused by serotonin in the stomach

Dosage Treatment Ulcerogenic% Inductive maintenance, index + pause ulceration mg / kg prone to erosion

10 а π π κ κ н н 00 00 = 005

fifteen

20

25

The influence of the claimed drug on gastric ulcers caused by an inactive inflammatory disease was studied in experiments on the blood-groove

30 males weighing 140-160 g. They were deprived of food for 24 hours, they were not restricted to water. The inventive preparation or cimetidine was administered internally for I hour before the administration of the diluted drug (50 mg / kg of the drug). Each - 7 - for the declared drug or pimethidine, 10 doses were introduced. After 4 hours, animals were sacrificed and examined for the mucous membrane of the stomach, and the average number of ulcers in a group of 10 animals was calculated. The test data are presented in table 3.

Table 3 Influence of the claimed medication and cimetidine on gastric ulcer caused by dialysis. event, at

10 Preparation of Dosage Average number of ulcers% Disposal in a group of 10 doses of live mg / kg of lively + standardized ulcers due to an error of 0%

fifteen

20

25

From table 3 it is seen that the claimed preparation and

30 methidine is dependent on the formation of gastric ulcers caused by the introduction of a dilution of the disease in the stomach. For the preparation of ED _{50 of the} claimed medication (2 mg / kg) and cimetidine (28 mg / kg), you can conclude that the claimed medication is antiviral ΡСΤ / ΚШ2 / 00235

- 8 - methidine on this model of gastric ulcers in the region.

The gastrointestinal effect of the claimed drug for stomach ulcers caused by an absolute etal was studied. Experiments were carried out on white whales that were male 160 ^x 180 g in weight; they were deprived of food for 24 hours before the experiment and deprived of water for 18 hours. Ethnic java called the Begean Sh. , Bοηё, v. // rgos. 5οс. Ε ^χ ρ. Βϊοϊ. Άеά.-1981, ν.166 - Νο.З, ρ.394- 397. Absolute ethanol in volume I ml was injected into

10 dοκ cheρez 1.5 hours ποsle administration zayavlyaemοgο πρeπa- ρaτa tsimeτidina or even cheρez I hour zhivοτnyχ zabi- wali, izvleκali zheludοκ and izmeρyali length uchasτκοv ποvρezhdeniya in millimeτρa ^χ. The experimental data are presented in table 4.

15 Table 4 Influence of the claimed drug and cimetidine on ethanic ulcers in Krus

9 -

From table 4 it is visible that the claimed drug has the anti-pulsive effect (ED ₅₀ = 8 mg / kg), and cimetidine with this model turned out to be ineffective.

The effect of the claimed drug on gastric ulcers caused by indomethacin was also studied. Experience προвο-

10 Dili Bat ^χ -samtsaχ massοy 20-22 g πο meτοdu Βa- -ea Κ, 1 ?. , Βiskϊeu 0., З-Ггиϊе Ε. / Βτ ±. . Mar.- 1979-ν.66-Νο.1-ρ.154-156. People were deprived of food for 24 hours, they were not limited in water. Cimetidine or the claimed preparation was administered as an internal suspension

15 s with τwin-80. The domestic animals introduced the equal volume of distilled water from the twin-80. Each dose of drugs was given 10 animals. The test data are presented in table 5 _*

Table 5

20 Influence of the claimed drug and cimetidine on sores in mice

Dosage medication Average number of ulcers% Prevention, in a group of 10 life expectancy mg / kg of standard ± standard treatment

25th error and ulcers πο οτ- Ρ = 0.05 when worn for contact

thirty

35

- 10 -

Table 5 (continued)

Κaκ vidnο τablitsy of 5, ₅₀ ED 10 zayavlyaemοgο πρeπaρaτa sοsτavlyaeτ 9.5 mg / κg vnuτρ, τοgda κaκ tsimeτidina ED ₅₀ - 125 mg / κg vnuτρ, chτο svideτelsτvueτ ο τοm, chτο tsimeτidin weaker zayavlyaemοgο πρeπaρaτa πο anτiultse- ροgennοmu deysτviyu on mοdeli indοmeτatsinοvοy peptic ulcers in men. 15 Influence of the claimed drug on stomach ulcers caused by a rezepin was studied (in comparison with cimetidine) in experiments with male mice weighing 18–20. 20 mg / κg). After 18-24 hours, animals were slaughtered and examined the mucous membrane of the stomach (counting the number of erosions). The test data are presented in table 6.

Table 6 Influence of the claimed drug and cimetidine

25 mice ulcers

Delivered Doses Average%% Delivered, erosion on alternate samples mg / kg live (in case of ulcer, 10 times less than 5 days ago)

End - _% 18.3 ± 2.2 35 Declared 10 Ι 6.0 ± Ι, 9 12.6 - II

Table 6 π ο

5

10

As can be seen from Table 6, the claimed preparation (depending on which is available in mice

15 ulcers caused by rezerpinom, cimetidine in this experience does not show anti-ulcer activity.

There was a study of the effect of the claimed drug on stomach ulcers caused by the process of immobilization combined with cold. Experiences на ρ ο ο ο ο ο на на ο

20 people weighing 150-160 g. Animals were deprived of food for 24 hours, they were not restricted to water. Serious ulcers were caused by isobilization and exposure to cold (4-6 ° C) for 4 hours. The inventive drug was introduced internally for I hour before placing livestock in the

25th situation.

The test data are presented in table 7. - 12 -

Table 7 Influence of the claimed medication on acute gastric ulcers in

10

fifteen

ED ₅₀ = 16.0 (18.72-13.23)

Κaκ vidnο of τablitsy 7 claimed πρeπaρaτ (in zavisimοsτi οτ dοz) πρeduπρezhdaeτ οbρazοvanie ulcers are caused by a ^χ immοbilizatsiey sοcheτanii with χοlοdοm.

20 The effect of the claimed preparation and cimetidine on ^χ richest gastric ulcers caused by acetic LIQUID was studied in κρρысыс. 418-426). The drugs were injected into the stomach in a dose of 10 mg / kg one dose

25 in the course of 21 days, starting from the second day after the introduction of acetic acid. The results are presented in table 8. - thirteen -

Table 8 Influence of the claimed drug and cimetidine on the healing of a chronic gastric ulcer in the stomach caused by acetic acid _, _

5 Medication Dose Dose - Defeat of mucous membranes inside, scratch in m ^ per mg / kg body weight 7 days 14 days 21 days old

End - 18 56 ± 8, Ι 22.8 + 3.6 Ι3.2 ± 2.2 Yu The inventor declares 10 18 2Ι, 2 ± 3.426.4 + 1.12.0 + 0.44

Cimetidine 10 18 27.4 + 3.799.2 ± Ι, 65.0 + 0.65

As can be seen from table 8, the claimed preparation also, like cimetidine, accelerates the healing of the ulcerative 15 defect in comparison with the oncological group.

The study of the effect of the claimed preparation on the basal gastric section was carried out on male rats weighing 8–200 g. People were deprived of food for 24 hours, and were not restricted at all. Declare

20 cimetidine was administered internally as a suspension with the addition of tween-80 for 60 minutes before the cutter. Foreign animals were administered distilled water with the addition of tween-80 (4 drops of tween-80 per 10 ml of distilled water). Each doze declares

25 or cimetidine was administered as 10 animals. After an ethereal rush, they opened an abdominal cavity and put a ligature on the patient’s stomach. After 4 hours after the operation, the animals were killed, the stomach was removed, they shared its volume and the presence of a free salt

30 acids in the stomach, by spending 0.1 Η with a click. The content was expressed in milliliters 0.1 0,1 per 100 ml of gastric mixture. The results of the research are presented in Table 9. - 14 -

Table 9 Influence of the claimed drug and cimetidine on indices of the gastric section in russia

25 From table 9 it is visible that ED _{50 of the} claimed product, which reduces the content of free salic acid, makes 35.0 (19.0-51.6) mg / kg, and reduces the volume of the session - 30.0 (0.0) 0) mg / κg. For cimetidine, the corresponding ED ₅₀ values were 70.0 (38.0-102.0)

30 mg / kg and 96 (49.0-143.0) mg / kg.

The effect of the claimed drug on the gastric gland secretion stimulated by histamine, carbohydrate ^x- ray, pentagastrin, and insulin was studied. The results of ^χ research have shown that the claimed π

35 Possesses a high inhibitory activity and - 15 - all used types of stimulation of the gastric section in dogs (histamine, blood, insulin and pentagastric).

The study of the impact of the claimed pharmaceuticals (in

5 dose with cimetidine) on the activity of the pressure of the drug showed, that the claimed drug in the dose of 25 mg / kg reduces the activity of the pressure of the protein on 56.82, and cimetidine - on the average of $ 69-68. Β MORE THAN DOSES, the claimed medication fully suppresses the gastric secretion and

10 to investigate its effect on the activity of pressure of peptic acid in doses above 25 mg / kg was not possible.

In general, the above studies have shown that the claimed drug has a pronounced inhibitory effect on the acid-drug effect, the drug

15 Larger in the saline acid and potassium hydroxide range. The delivery of an active, claimed medication and cimetidine allows you to conclude that the claimed medication is superior to cimetidine and is more beneficial to

2 ₀ An experimental study of the harmlessness of the claimed product in experiments on mice and rattles is indicative of an increased transmittance.

Differences in visual sensitivity to the subject

25 I haven’t found out.

Sensitive differences in sensitivity to the claimed drug have not been identified.

The study of the toxicity of the claimed drug in the experiments on the shells of the general floor and the name of the

30 doses for 6 months seven times a week at a dose of 20 mg / kg (which is 10 times higher at a dose) and 2 mg / kg is not necessary. that the claimed preparation is exterminated

35 lively animals. The claimed invention does not indicate - 16 - impact on livelihoods, does not change hematologic indices, does not affect the biological indicators of physical and urinary dynamics, does not cause any changes.

5 The claimed drug, administered to doses in doses of 50, 20 and 2 mg / kg for 6 months seven times a week, did not show a local irritating effect on gastric mucosa.

10 There was a study of the pharmaceuticals of the claimed drug labeled with substance in a quinidine core. The results of the studies showed that with the introduction of the claimed preparation inside 25 mg / kg, it is rapidly absorbed from the gastrointestinal

15 of the transaction in the system distribution and distribution is shared by the other companies and companies. The separation of the radioactive products from the coffers makes 0.63 hours. In terms of the specific radioactivity, the studied regions are arranged in the following order: liver,

20 Ki, lungs, brain and blood. In addition, the maximum specific radioactivity is observed after 0.5-1 hours after the introduction of the claimed preparation. 16 16 hours after its introduction to the liver, handles and lungs, high levels of radioactivity are taken.

25 The transition from the elimination of radioactive products from Kruppa is 12.3 hours; the total clearance is 87.5 ml / hour.

Over 48 hours, $ 66.07 is withdrawn from the input of r-activity. The ugly essence of radioactive products is excreted with urine and calam in the same degree (in

30 in the amount of $ 49.8), and in the next 24 hours, mainly with urine.

As a result of the above studies, it was established that the claimed drug possesses a high anti-ulcerative activity and a widespread anti-disease

35 Generic Activities, By Acting On These Indicators - 17 - BLOCK

The receptor for cimetidine has a low toxicity; does not have expressed side effects; It does not possess an immune, allergenic, mutagenic sensitizing effect.

5 The inventive preparation was tested in a clinic for people with hepatic, erosive injuries of a mucous obstruction of the gastric tract; with the ulcerated niche of the stomach and duodenal ulcer. The prescriber appointed-

10 as a unit in tablets for use internally (content of the active substance 0.025-0.05 g) 2-4 times a day before meals. The treatment course was 2 to 6 years old and a systematic endoscopic compartment. "

15 Κlinichesκie isπyτaniya ποκazali, chτο πρeπaρaτ naibοlee zφφeκτiven πρi vοsπaliτelnyχ, gemορρagiches- κiχ, eροzivnyχ ^ οvρezhdeniyaχ slizisτοy οbοlοchκi zhe ludοchnο-κishechnο "gο τρaκτa and ulcer dvenadtsaτiπeρsτnοy κishκi;. Έφφeκτivnοsτ below πρi sφορmiροvavsheysya ulcerative

20 vein of the stomach with a size larger than ΙχΙ cm.

The indications for the use of the claimed drug are '.

25 hours; e |) οzivny (ulcerative) gasτρiτ, ulcerative ποv- ρezhdeniya slizisτοy οbοlοchκi zheludκa and κishechniκa, vοzniκayuschie in ρezulτaτe sτρessοvοgο vοzdeysτviya (τρavmy, οzhοgy and dρugοe) ρeφlyuκs-ezοφagiτ, sindροm Zοllingeρa-Ellisοna, ποsleοπeρatsiοnnye ulcers zheludοch-

30 non-intestinal anastomoses, gastric ulcers and duodenal ulcers.

The inventive preparation is manufactured by known methods.

The substance in question is claimed to be 35 (hiauklidil-3) -di- (thienyl-2) carbine or it may have been received by the following method. - 18 -

Eτilοvy eφiρ χinuκlidin-3-κaρbοnοvοy κislοτy πρivοdyaτ vο vzaimοdeysτvie with τienil-2-magniybροmidοm in sρede ορganichesκοgο ρasτvορiτelya πρi τemπeρaτuρe οτ -5 dο + Ι0 ^ο C 5 Ρeaκtsiοnnuyu weight vydeρzhivayuτ in τechenie 20 chasοv πρi κοmnaτnοy τemπeρaτuρe and 6 chasοv πρi κiπenii, οχ - crap and process acid, salami, salary.

The essential product separates, the acidic product is alkalized and processed, the refrigerant is removed and the target product is isolated.

The inventive device may be used in any other medicinal form, for example in the form of a tablet, a payment, capsules and other.

The inventive preparation is preferable to use 15 tablets for meals inside (containing 0.025 or 0.05 grams of the preparation) 2-4 times a day before meals (last).

The daily dose of the drug is up to 0.3 g; Acupuncture treatment οτ 2 to 6 weeks. 20 Prophylactically or in a cost-effective manner, the claimed medication is prescribed

0.025-0.05 g 1-2 times a day (the last day - before bedtime).

If you are in danger of dryness, you may dry it. 25 The inventive drug should not be used for pregnancy, glaucoma, adenoma of the prostate gland.

The inventive product may be used in conjunction with alkalizing and enhancing substances (30 active sedative components do not amplify the claimed medicinal product).

It is not necessary to use it earlier than after 1-2 hours after using aluminum hydroxide, magnesium hydroxide and other similar substances, which absorb the food from the stomach. 35 Declare to store in a dry place protected from light. - 19 -

The inventive drug is used in medicine for the treatment and treatment of erosion of the mucous membrane of the stomach and intestine, which develops due to the incidence of the disease.

5 hours; erosive gastritis, ulcerative disorders of the mucous membranes of the stomach and intestines, reflux esophagitis, Söllinger-Ellisen syndrome, is acute; gastric ulcers and duodenal ulcers.

The inventive product possesses a high active activity. Due to the efficiency and speed of the process, it eliminates the known preparation of cimetidine. It indicates an inhibitory effect on the biliary tract, reduces the content of free salt.

15th acid. The claimed preparation in the absence of cimetidine does not cause a disease after the treatment of it.

Claims

- 20 -

ПλΤΕΗΤΗΑЯ ΦΟΡΕШ

I. The medicinal product is a harmful activity, consisting of the active substance (chinuklidil-3) -di- (thienyl-2) carbule of the formula:

or his saline, and the pharmaceutical carrier. 2. Drug Administration πο π. I, in the form of 15 tablets, which contains a valid substance in the amount of 0.025-0.05 g per one tablet.