Means for treating irritated intestine syndrome cases with diarrhea predominance

FIELD: medicine.

SUBSTANCE: means has 0.001-0.05 mg of Ramozetron Hydrochloride as daily dose or equivalent molar quantity of Ramozetron or its other pharmaceutically permissible salt as active ingredient.

EFFECT: enhanced effectiveness of treatment.

12 cl

 

The technical field to which the invention relates.

The present invention relates to a medicine or, more specifically, to the treatment for irritable bowel syndrome with predominant diarrhea or to reduce the severity (facilitate) the symptom of diarrhoea in irritable bowel syndrome.

Background of invention

Chemical name ramosetron is (-)-(R)-5-[(1-methyl-1H-indol-3-yl)carbonyl]-4,5,6,7-tetrahydro-1H-benzimidazole.

Hydrochloride ramosetron available on the market as a means to reduce the severity of gastrointestinal symptoms (nausea and vomiting)associated with therapy anti-cancer drugs (such as cisplatin), and is normally administered to adults or oral 0.1 mg once daily, or intravenous 0.3 mg once daily (tablet "Nasea OD 0.1 mg, Injection Nasea OD 0.3 mg in JAPAN PHARMACEUTICAL REFERENCE PRODUCTS and ADMINISTRATION in JAPAN, fifth edition (1999), published by the International trade Association of Japanese medical products).

In EP-A-381422 revealed that the number of derivatives of tetrahydroindazole, including ramosetron and its pharmaceutically acceptable salts, has an antagonistic effect against T3receptors are antagonists NT3receptors). Based on this proposed action suppress vomiting caused by the contradictory, the same drug, such as cisplatin and radiation exposure, and prevention and treatment of migraine, headache mixed Genesis, trigeminal neuralgia, anxiety symptoms, abnormal gastrointestinal motility, peptic ulcers, irritable bowel syndrome, etc. and described that the usual clinical dose for adults is 0.1 to 10 mg by intravenous injection, and from 0.5 to 50 mg when administered orally, administered once or divided into several doses.

On the other hand, in WO 99/17755 described that the antagonist NTs receptors is effective in the treatment of women suffering from not causing constipation irritable bowel syndrome, and that therapeutically effective dose is in the range from 0.01 to 500 mg or, preferably, from 0.05 to 50 mg per day. More specifically, according to clinical studies, where from 1 to 8 mg alosetron was administered twice daily to patients suffering from not causing constipation irritable bowel syndrome in women, compared with placebo, there was significant improvement in relieving pain and discomfort, organisation of stools, frequency of contractions of the intestine and the ratio of the intervals between the need for emergency treatment, in men, compared with placebo, no improvement was noted, except for the organisation of the chair.

In addition, in WO 2002/007713 described in which the change of the antagonist NT 3receptor in the treatment of irritable bowel syndrome in men and women, when from 1 to 16 mg was administered three times a day.

Disclosure of inventions

The authors of the present invention have conducted intensive studies with the aim of creating new medicines for treatment of irritable bowel syndrome with predominant diarrhea, for which there was quite effective medicines. Conducted previously by the authors of the present invention, clinical studies, where hydrochloride ramosetron was administered twice daily to patients suffering from irritable bowel syndrome, could not confirm a significant therapeutic effect compared with placebo.

Subsequently, the authors of the present invention has arisen the concept that a therapeutically effective dose of ramosetron with irritable bowel syndrome can be significantly lower than from 0.1 to 0.3 mg, which currently is the dose means to reduce the severity of gastrointestinal symptoms associated with cancer therapy. Considering the above, was developed stable preparation containing a very small amount (0.001 to 0.01 mg) of hydrochloride ramosetron, and this preparation was used in a clinical study for 12 weeks in men and women suffering with what ndrama irritable bowel with the prevalence of diarrhea. The result was unexpectedly confirmed outstanding efficiency and thus was achieved the objective of the present invention.

Thus, the present invention relates to pharmaceutical compositions for the treatment of irritable bowel syndrome in men and women with predominant diarrhea containing from 0.001 to 0.05 mg of hydrochloride of ramosetron as a daily dose or an equivalent molar quantity of ramosetron or other pharmaceutically acceptable salt as an active ingredient, or it refers to a pharmaceutical composition for decreasing the intensity (facilitate) the symptom of diarrhoea in irritable bowel syndrome in men and women, containing from 0.001 to 0.05 mg of hydrochloride of ramosetron as a daily dose or an equivalent molar quantity of ramosetron or other pharmaceutically acceptable salt as an active ingredient.

Also the present invention relates to the use of hydrochloride ramosetron in a daily dose of from 0.001 to 0.05 mg, or ramosetron, or another pharmaceutically acceptable salt in equimolar amounts to produce (production) medicines for treatment of irritable bowel syndrome with predominant diarrhea in men and women, or it refers to the use of hydrochloride ramosetron in a daily dose of from 0.001 to 0.05 mg, or ramosetron or other pharmaceutically acceptable salt in equimolar amounts to produce drugs to reduce the severity of diarrhea among men and women, suffering from irritable bowel syndrome.

Also, this invention relates to a method of treatment prevailing in irritable bowel syndrome in men and women of diarrhea, including the introduction of the patient from 0.001 to 0.05 mg of hydrochloride of ramosetron as a daily dose or an equivalent molar amount of ramosetron or another pharmaceutically acceptable salt, or it relates to a method for reducing symptoms of diarrhea in irritable bowel syndrome in men and women, including the introduction of the patient from 0.001 to 0.05 mg of hydrochloride of ramosetron as a daily dose or an equivalent molar amount of ramosetron or another pharmaceutically acceptable salt.

In accordance with the present invention at the present time it is possible to provide an excellent tool for the treatment of irritable bowel syndrome with predominant diarrhea or means to reduce the severity of diarrhoea in irritable bowel syndrome with diarrhea independently for men and women.

As shown in the example test 1, which is below hydrochloride ramosetron was effective for patients suffering from irritable bowel syndrome with predominant diarrhea regardless of gender with a dose of 0.005 mg or 0.01 mg once a day. Since the introduction of 0.005 mg gave significant tera is efticiency effect in some cases, as with the introduction of 0.01 mg, in the future we can expect an effective dose, equal to half of this. Patients of example, test 1 was an adult Japanese and it is assumed that the optimal dose for children will be less, while often the optimal dose for Europeans and Americans is twice larger than for the Japanese. Therefore, although particularly preferred dose for hydrochloride ramosetron is in the range from 0.002 to 0.02 mg, probably, depending on the age differences between patients and race, for the treatment of irritable bowel syndrome with predominant diarrhea or reduce the severity of the symptom of diarrhoea in irritable bowel syndrome is a possible daily dose in the range from 0.001 to 0.05 mg

As described in EP-A-381422, clinical dose derived tetrahydroimidazo, including ramosetron, typically 0.1 mg or more per day, and has not been informed of any supposition, or the disclosure of that hydrochloride ramosetron demonstrates clinical benefit in a daily dose in the range from 0.002 to 0.02 mg in Addition, the present invention is better:

1) what superior means to reduce the severity of gastrointestinal symptoms associated with cancer therapy drugs, containing ramosetron how effective the effective ingredient and commercially available at the present time, a therapeutically effective dose which reduced from 1/5 to 1/50,

2) the drugs disclosed in WO 99/17755, that a sufficient therapeutic effect is achieved independently for men and women

3) what medications are disclosed in WO 2002/007713, that a sufficient therapeutic effect is achieved by introducing reduced from 1/50 to 1/500 dose once a day

and such benefits are not predictable on the basis of the above the previous level of technology.

The present invention will be now described below in more detail.

Ramosetron and its pharmaceutically acceptable salts are easily obtained by the method described in EP-A-381422 or similar to this method.

As to pharmaceutically acceptable salts ramosetron, its specific examples are salt of the mineral acid, such as hydrochloric acid, sulfuric acid, phosphoric acid and Hydrobromic acid; salts of organic acids such as acetic acid, oxalic acid, citric acid, maleic acid, malic acid, fumaric acid, tartaric acid and methanesulfonamide acid; and a salt of acidic amino acids such as glutamic acid and aspartic acid. Hydrochloride ramosetron is commercially available and the most preferred among them.

The medicine of this image is to be placed can be obtained as oral solid preparation, oral liquid medication or injectable in accordance with standard methods using organic or inorganic carrier, excipient and other additives that are suitable for oral or parenteral administration. Preferable to others are those that can be entered by the patient and are convenient for storage and carrying, more specifically tablets, soluble powders, granules, fine granules, capsules, pills, etc.

In the solid preparation as such, the active substance is mixed, with at least one inert diluent such as lactose, mannitol, glucose, microcrystalline cellulose, starch, polyvinylpyrrolidone or aluminate of metasilicate magnesium. The composition may contain, in accordance with generally accepted way, other additives, in addition to the inert diluent, comprising a binder such as hydroxypropylcellulose and gidroksipropilmetilzelluloza; lubricating substance, such as magnesium stearate, calcium stearate, polyethylene glycol, starch and talc; a disintegrator such as Cellulosics calcium; a stabilizer such as lactose; solvent additive, such as glutamic acid and aspartic acid; a plasticizer such as Tween 80 or triacetin; and coloring agents such as titanium oxide and sessions is on iron. Tablets and pills may be coated, if necessary, by the sugar-coated or substance, dissolving intragastrically or vnutriserdechno, such as sucrose, gelatin, agar, pectin, hydroxypropylcellulose and hypromellose.

Additionally, like the commercially available tablets "Nasea OD 0.1 mg, the drug may be a tablet, disintegrating in the mouth (intraoral). For example, intra-oral disintegrating tablet can be prepared in accordance with, for example, US 5466464, US 5576014, US 6589554, WO 2003/009831, WO 2002/092058 etc.

Since the drug of the present invention contains ramosetron in a very low dose, retrieving it using the method of stabilizing the temperature and humidity is especially preferred.

For example, stabilization of ramosetron temperature and humidity can be achieved by adding a specific compound having a carbonyl group. As regards the specific compound having a carbonyl group, its specific examples are aliphatic carboxylic acid (more specifically, saturated or unsaturated and linear or branched alifaticheskie mono-, di - or tricarboxylic acid or, in particular, aliphatic carboxylic acid having from 3 to 36 carbon atoms or its ester, hydroxycarbonate acid (more specifically, saturated eliminazione and linear or branched aliphatic, hydroximino-, di - or tricarboxylic acid or, especially, hydroxycarbonate acid having from 3 to 36 carbon atoms or its ester, an acid (dicarboxylic) acid, tolova acid, aromatic carboxylic compound (more specifically, an aromatic mono-, di - or tricarboxylic acid, which may be substituted by an alkyl group or a hydroxyl group having from 1 to 4 carbon atoms or, in particular, an aromatic carboxylic acid having from 7 to 20 carbons) or its ester and macromolecular substance having a carboxyl group, and such compounds can be used either individually, or jointly by two or more of them.

Especially in relation to specific substances with a carbonyl group, preferred are hydroxycarbonate acid and its ester, a macromolecular substance having a carboxyl group, an aromatic carboxylic substance or its ester and tolova acid; especially preferred are hydroxycarbonate acid or its ester, macromolecular substance having a carboxyl group, and an aromatic carboxylic substance or its ester; and more preferred are hydroxycarbonate acid or its ester and macromolecular substance having carboxyla the group.

In respect of aliphatic carboxylic acids, preferred are maleic acid, malonic acid, succinic acid and fumaric acid. As hydroxycarbonate acid are preferred tartaric acid, malic acid and citric acid, and most preferred are tartaric acid and citric acid. As the dicarboxylic acid are preferred glutamic acid and aspartic acid. As the aromatic carboxylic substance preferred are phthalic acid and propylgallate, and more preferred is propylgallate. In relation to macromolecular substance having a carboxyl group are preferred carboxymethyl cellulose and alginic acid, and more preferred is carboxymethylcellulose. As tolova acid are preferred ascorbic acid and altarboy acid, and more preferred is ascorbic acid.

Found that the above-mentioned carbonyl substance in the form of a hydrate or anhydride having no water of crystallization, such as a hydrate of citric acid and anhydride citric acid, also contributes to the stabilizing effect of the present invention, and the invention covers all hydrates, anhydrides and mixtures thereof. In relation degree is olymerization, molecular weight, etc. of macromolecular substances, despite the fact that these parameters are not particularly limited, but the average molecular weight of approximately 110000 or approximately 200,000 is preferred for carboxymethyl cellulose and alginic acid, respectively.

In relation to the input part of the amount of substance to stabilize ramosetron or its pharmaceutically acceptable salts are also no particular restrictions, because this number is the number to achieve stabilization. For example, from 0.01 to 90 wt.%, preferably from 0.01 to 50 wt.%. or more preferably, especially considering the manufacturer, from 0.1 to 10% of the composition.

Enter the number of ramosetron or its pharmaceutically acceptable salt can be respectively determined for each individual case: age, race, sex, etc. of the subject, taking into account the route of administration. In the case of single oral administration of hydrochloride ramosetron it is approximately from 0.001 to 0.05 mg per day, or, more preferably, from 0.002 to 0.02 mg per day for adults, and this oral administration is applied once daily after a meal.

As discussed above, for some human populations, which include Americans and Europeans, for the treatment of irritable bowel syndrome, localseo irritable bowel syndrome with predominant diarrhea, or reduce the severity of the symptom of diarrhoea in irritable bowel syndrome, the optimal daily dose of ramosetron (the number given in pure form) may be in the range from 0,0025 mg to 0.05 mg, or more suitable daily dose is in the range from 0,0025 mg to 0.02 mg or an equivalent molar quantities of pharmaceutically acceptable salts ramosetron.

As should be clear, recommended here as daily doses of the number of ramosetron or its pharmaceutically acceptable salt is administered within a 24-hour period, and the full amount can be entered with a single introduction (i.e. a single daily dose or multiple doses (i.e. two or more doses, administered over a 24-hour period, where the total number of multiple-dose is the daily amount in the range described here). As discussed earlier, a single injection may be convenient, at least in some circuits. therapeutic methods of the invention can also include measures to identify the subject in need of treatment of irritable bowel syndrome and/or alleviating or reducing the otherwise symptoms of diarrhea in irritable bowel syndrome. Defining, respectively, may include evaluation of the patient or the professional medical doctor and can be subjective (e.g. the R, review, opinion) or objective (e.g. measurable by using a test or diagnostic method).

Can be used in a variety of therapeutic regimes. For example, the patient may develop occasionally, i.e. in case of pain in irritable bowel syndrome ramosetron or its pharmaceutically acceptable salt can be entered in the number of daily doses, as described herein, during the period of time sufficient to relieve symptoms of irritable bowel syndrome, such as the introduction of ramosetron or its pharmaceutically acceptable salt in the number of daily doses, as described here daily for 7 days, 14 days, 21 days, 28 days, 6 weeks, 8 weeks, 12 weeks, 16 weeks or more, and this introduction cease until the patient again will not have the symptoms of irritable bowel syndrome. Alternative, the patient can proceed with a more prolonged therapy, i.e. unlimited or prolonged introduction (i.e., for example, 6, 9, 12 or 15 months) ramosetron or farmacevtichesky acceptable salt in the number of daily doses, as described here daily as a preventive therapy, eliminating or minimizing the cases of symptoms of irritable bowel syndrome. Can also be applied to other treatment methods.

Patients with irritable bowel syndrome with a prevalence of the diarrhoea was defined by Rome II Diagnosis Criteria, involving patients with irritable bowel syndrome in the phase of diarrhoea (D.A.Drossman et al., pages 351 to 432, Degnon Associates, McLean, 2000).

The best way of carrying out the invention

The present invention will now be described in more detail with reference to examples and examples, tests, although the present invention is not limited to these examples, etc.

Example 1

Hydrochloride ramosetron0,02 part
Lactose86 parts
Hydroxypropylcellulose3 parts
Tartaric acid1 piece
Yellow sesquioxide iron0.2 parts
The titanium oxide10 pieces
Light silicic acid anhydride0.3 part

Hydroxypropylcellulose (3 parts), 0,02 part of hydrochloride ramosetron and 1 part tartaric acid are dissolved in 35 parts of water with stirring using a magnetic stirrer and kneaded with 10 parts of titanium oxide and 0.2 parts yellow sesquioxide iron, using the apparatus for grinding and preparing the spray liquid (concentration of hydroxypropylcellulose: 8% wt.). Next, 86 parts of lactose is loaded into the granulator with the liquefied layer (Flow Coater; manufactured by Freund) and spray the liquids is sprayed with a speed of 5 g/min, carrying out granulation in the liquefied state. The granules are dried for 5 minutes at a flow of air having a temperature of 40°and then mixed with 0.3 parts of a light silicic acid anhydride to obtain the diluted powder.

Example 2

Hydrochloride ramosetron0,0008 part
Mannitol89 parts
Anhydride citric acid0.1 part
Maltose10 pieces
Red sesquioxide iron1 piece
Magnesium stearate1 piece

Maltose (10 parts), 0,0008 part of hydrochloride ramosetron, 0,1 parts anhydride citric acid and 1 part red sesquioxide iron suspended in 67 parts of water with stirring with a magnetic stirrer to obtain a sprayed liquid (concentration: 15% by weight). Next 89 parts mannitol loaded into a fluidized bed granulator (Flow Coater; production Freund) and the sprayed liquid is sprayed at a rate of 10 g/min, holding granulation liquid. After granulation, the granules are dried for 5 minutes at a flow of air having a temperature of 40°and then mixed with 1 part of magnesium stearate. The mixed powder is formed into tablets, in the amount of 120 mg per tablet, using R the operating tabletroute apparatus, getting a tablet with the original hardness of about 1 kPa. They keep for 18 hours at a relative humidity of 75%, and then for 4 hours at a relative humidity of 40%, receiving intraoral disintegrating tablets.

Example 3

Carry out the same method of production, as in example 2, except that the added amount of the anhydride citric acid replaced with 0.2 parts, receiving intraoral disintegrating tablets.

Example 4

Carry out the same method of production, as in example 2, except that the added amount of the anhydride citric acid substitute 0.5 parts, receiving intraoral disintegrating tablets.

Example 5

Hydrochloride ramosetron0,0008 part
Mannitol89 parts
Ascorbic acid0.2 parts
Maltose10 pieces
Red sesquioxide iron1 piece
Magnesium stearate1 piece

Maltose (10 parts), 0,0008 part of hydrochloride ramosetron, 0.2 parts of ascorbic acid and 1 part red sesquioxide iron suspended in 67 parts of water with stirring using a magnetic stirrer, and get sprayed liquid (conc who ntrace: 15% by weight). After that 89 parts mannitol loaded into a fluidized bed granulator (Flow Coater; production Freund) and the sprayed liquid is sprayed at a rate of 10 g/min, holding granulation liquid. After granulation, the granules are dried for 5 minutes at a flow of air having a temperature of 40°and then mixed with 1 part of magnesium stearate. The mixed powder is formed into tablets, in the amount of 120 mg per tablet using a rotary tabletroute apparatus, receiving the tablets with the original hardness of 1 kPa. They remain at 25°C for 18 hours at a relative humidity of 75%, and then at 30°C for 4 hours at a relative humidity of 40%, receiving intraoral disintegrating tablets.

Example 6

Spend the same method of production, as in example 5, except that the added amount of ascorbic acid replace 0.5 parts, receiving intraoral disintegrating tablets.

Example 7

Hydrochloride ramosetron0,0008 part
Mannitol88 pieces
Maltose10 pieces
Yellow sesquioxide iron1 piece
Anhydride citric acid0.2 parts
Magnesium stearate1 piece

Maltose (10 is t), 0,0008 part of hydrochloride ramosetron, 1 part red sesquioxide iron and 0.2 parts of anhydride citric acid are suspended in 67 parts of water with stirring using a magnetic stirrer, and get sprayed liquid (concentration: 15% by weight). Then, 88 parts of mannitol is loaded into the granulator fluidized bed (Flow Coater; production Freund) and the sprayed liquid is sprayed at a rate of 10 g/min, in air having a temperature of 50°and the cycle of spraying/drying/shaking for 15 seconds/15 seconds/10 seconds, respectively, conducting granulation liquid. After granulation, the granules are dried for 5 minutes at a flow of air having a temperature of 40°and then mixed with 1 part of magnesium stearate. The mixed powder is formed into tablets, in the amount of 120 mg per tablet using a rotary tabletroute apparatus, receiving the tablets with the original hardness of 1 kPa. They remain at 25°C for 18 hours at a relative humidity of 75%, and then at 30°C for 4 hours at a relative humidity of 40%, receiving intraoral disintegrating tablets.

Example 8

Hydrochloride ramosetron0,01 part
Avicel86 parts
Nizkozameshhennoj hydroxypropylcellulose10 h the values
Anhydride citric acid0.5 parts
Hydroxypropylcellulose3 parts
Magnesium stearate0.5 parts

Hydroxypropylcellulose (3 parts), 0.5 parts of anhydride citric acid and 0.01 part of hydrochloride ramosetron dissolved in 27 parts of water with stirring using a magnetic stirrer, and get sprayed liquid (concentration of hydroxypropylcellulose: 10% by weight). After that 86 parts of Avicel and 10 parts nitrosamines hydroxypropylcellulose loaded into the granulator fluidized bed (trade name: GPCG-5, production Powlex) and the sprayed liquid is sprayed at a rate of 100 g/min, holding granulation liquid. After granulation, the granules are dried at 40°C for 5 minutes, then stirred with 0.5 g of magnesium stearate. The mixed powder is formed into tablets, 100 mg per tablet using a rotary tabletroute the device.

Example 9

Hydrochloride ramosetron0.1 part
Lactose77 parts
Corn starch19 parts
Carboxymethylcellulose (CMC)5 pieces
Hydroxypropylcellulose3 parts
The MAG stearate is s 0.3 part

Hydroxypropylcellulose (3 parts) and 0.1 part of hydrochloride ramosetron dissolved in 35 parts of water with stirring using a magnetic stirrer, and get sprayed liquid (concentration of hydroxypropylcellulose: 8% by weight). After that 77 parts of lactose, 19 parts of corn starch and 5 parts of CMC is loaded into the granulator fluidized bed (trade name: Flow Coater, production Freund) and the sprayed liquid is sprayed at a rate of 10 g/min, holding granulation liquid. After granulation, the granules are dried for 5 minutes at a flow of air having a temperature of 40°and then mixed with 0.3 parts of magnesium stearate. The mixed powder is formed into tablets, 120 mg per tablet using a rotary tabletroute the device.

Example 10

Hydrochloride ramosetron0,0008 part
Mannitol89 parts
Propylgallate5 pieces
Maltose10 pieces
Magnesium stearate1 piece

Maltose (10 parts), 0,0008 part of hydrochloride ramosetron and 5 parts of propylgallate dissolved in 67 parts of water with stirring using a magnetic stirrer, and get sprayed liquid (concentration: 15% of the weight is). After that, 89 parts of mannitol is loaded into the granulator fluidized bed (Flow Coater, production Freund) and the sprayed liquid is sprayed, conducting granulation liquid. After granulation, the granules are dried for 5 minutes at a flow of air having a temperature of 40°and then mixed with 1 part of magnesium stearate. The mixed powder is formed into tablets, 120 mg per tablet using a rotary tabletroute the device.

The test example 1

A clinical study with patients suffering from irritable bowel syndrome with predominant diarrhea

Clinical research is being done using both of men and women suffering from irritable bowel syndrome (IBS) with the prevalence of diarrhea in accordance with the following conditions.

Subjects: patients suffering from IBS with the prevalence of diarrhea in accordance with the Rome II Diagnosis Criteria (D.A.Drossman and other, pages 351 to 432, Degnon Associates, McLean, 2000).

Number of patients: 418 patients.

Used medications and methods of administration: placebo and hydrochloride ramosetron administered orally for 12 weeks 0,005 mg or 0.01 mg per day.

The duration of the test: the observation period in one week and the period of treatment within 12 weeks.

The observed parameters:

1. The main observed parameters

(1) Overall assessment of the ease common symptoms of IBS (evaluation subjects

After completion of the treatment period start date introduction of the test drug is defined as the first day. Every week watching overall rating ease common symptoms of IBS, taking into account all the symptoms of IBS, taken into account by the subjects, compared to their condition in the period of observation, and record these observations in the patient diary. In particular, the Secretary General assessment of relief of common symptoms of IBS, as described below.

0 = complete relief

1 = significant relief

2 = some relief

3 = no change

4 = deterioration

Subjects with a score of 0 or 1 for two weeks or more, within four weeks poll on a monthly basis and calculate the monthly return estimation separately for each group, the host 0.005 mg and 0.01 mg and placebo hydrochloride ramosetron.

2. Additional monitored parameters

(1) Overall assessment of relief of abdominal discomfort/pain (score subjects)

After completion of the treatment period start date introduction of the test drug is defined as the first day. Every week watching the overall assessment of relief of abdominal discomfort/pain drug test, comparing with the state in the period of observation, and record these observations in the patient diary. In particular, the Secretary General assessment facilitate abdomina inogo discomfort/pain, as indicated below.

0 = complete relief

1 = significant relief

2 = some relief

3 = no change

4 = deterioration

(2) Overall score improve intestinal discomfort (score subjects)

After completion of the treatment period start date introduction of the test drug is defined as the first day. Every week watching the overall rating of improvement of intestinal discomfort, comparing with the state in the period of observation, and record these observations in the patient diary. In particular, the Secretary General assessment improve intestinal discomfort, as follows.

0 = complete relief

1 = significant relief

2 = some relief

3 = no change

4 = deterioration

(3) the Severity of abdominal discomfort/pain

During the period of the clinical trial (the observation period and the treatment period) subjects each day watching the severity of abdominal discomfort/pain and describe in the patient diary. Assessment of severity of abdominal discomfort/pain below

0 = absent

1 = mild

2 = moderately pronounced

3 = pronounced

4 = unbearable

(4) Oformlennoj (appearance) of stool

During the period of the clinical trial subjects every day describe oformlennoj (appearance) of stool in the diary of a patient, the using score (type) on the Bristol scale organisation of the chair. When during the day is celebrated multiple bowel movements or celebrate various oformlennoj (appearance) of stool in one of defecation, write only one form (appearance), which is more typical for a given day (or most concerned subject).

(5) the Frequency of contractions of the intestine (bowel)

During the period of the clinical trial subjects every day write down in the diary the patient's frequency of contractions of the intestine (bowel movements).

(6) the Urgency

During the period of the clinical trial subjects every day write down in the diary the patient, was there any urgent situation.

(7) a Sense of lack of bowel movements

During the period of the clinical trial subjects every day write down in the diary the patient, was there a feeling of insufficient reduction of the intestine (bowel movements).

As for (1) through (3) additional monitored parameters, they are counting on a monthly basis as well as the main observed parameters.

The results:

As for the final monthly evaluation of the Respondent to evaluate the overall ease common symptoms of IBS, it amounted to 26.9% in the placebo group. On the other hand, in the groups treated with 0.005 mg and 0.01 mg of the hydrochloride of ramosetron, monthly response assessment was 42,6% 43,0%, respectively, and more than 1% exceeded the response evaluation group, receiving placebo. The value of R for groups treated with 0.005 mg and 0.01 mg to the placebo group, was 0,0273 and 0,264 respectively. As for differences between the response estimates of the group receiving placebo and treated groups of 0.005 and 0.01 mg ramosetron, no marked differences between women and men.

As for the final monthly estimates of respondents in the overall assessment of relief of abdominal discomfort/pain and overall assessment of improvement of intestinal discomfort, in the groups treated with 0.005 mg or 0.01 mg of the hydrochloride of ramosetron, they were also better than in the placebo group, more than 10%.

Based on the above, confirmed therapeutic effect of 0.005 mg or 0.01 mg of the hydrochloride of ramosetron for patients suffering from irritable bowel syndrome with predominant diarrhea. Also confirmed that unlike alosetron described in WO 99/17755, hydrochloride ramosetron effective for men and women, and unlike drugs, are described in WO 2002/007713, it is effective when taken once a day.

Industrial applicability

In accordance with the present invention can be provided an excellent tool for the treatment of irritable bowel syndrome with predominant diarrhea or means to relieve irritable bowel syndrome, effective for men and women who.

1. Pharmaceutical composition for the treatment of irritable bowel syndrome in men with a predominance of diarrhoea containing from 0.001 to 0.05 mg of hydrochloride of ramosetron as a daily dose or an equivalent molar quantity of ramosetron, or other pharmaceutically acceptable salt as an active ingredient.

2. The pharmaceutical composition according to claim 1 for the treatment of irritable bowel syndrome in men with a predominance of diarrhoea containing from 0.002 to 0.02 mg of hydrochloride of ramosetron as a daily dose or an equivalent molar quantity of ramosetron, or other pharmaceutically acceptable salt as an active ingredient.

3. Pharmaceutical composition for decreasing the intensity of the symptom of diarrhoea in irritable bowel syndrome in men, containing from 0.001 to 0.05 mg of hydrochloride of ramosetron as a daily dose or an equivalent molar quantity of ramosetron, or other pharmaceutically acceptable salt as an active ingredient.

4. The pharmaceutical composition according to claim 3 to reduce the severity of the symptom of diarrhoea in irritable bowel syndrome in men, containing from 0.002 to 0.02 mg of hydrochloride of ramosetron as a daily dose or an equivalent molar quantity of ramosetron, or other pharmaceutically acceptable salt as an active ingredient is.

5. Application hydrochloride ramosetron in a daily dose of from 0.001 to 0.05 mg or ramosetron, or other pharmaceutically acceptable salt in equimolar amounts to obtain medication for the treatment of irritable bowel syndrome with predominant diarrhea in men.

6. Application hydrochloride ramosetron according to claim 5 in a daily dose of from 0.002 to 0.02 mg or ramosetron, or other pharmaceutically acceptable salt in equimolar amounts to obtain medication for the treatment of irritable bowel syndrome with predominant diarrhea in men.

7. Application hydrochloride ramosetron in a daily dose of from 0.001 to 0.05 mg or ramosetron, or other pharmaceutically acceptable salt in equimolar amounts to obtain medication to reduce the severity of diarrhea in men suffering from irritable bowel syndrome.

8. Application hydrochloride ramosetron according to claim 7 in a daily dose of from 0.002 to 0.02 mg or ramosetron, or other pharmaceutically acceptable salt in equimolar amounts to obtain medication to reduce the severity of diarrhea in men suffering from irritable bowel syndrome.

9. A method of treating irritable bowel syndrome in men with a predominance of symptoms of diarrhea, including the introduction of the patient from 0.001 to 0.05 mg of hydrochloride of ramosetron as a daily dose or EC is valentinovo molar number of ramosetron, or other pharmaceutically acceptable salt.

10. A method of treating irritable bowel syndrome in men with a predominance of symptoms of diarrhoea according to claim 9, including the introduction of the patient from 0.002 to 0.02 mg of hydrochloride of ramosetron as a daily dose or an equivalent molar amount of ramosetron, or another pharmaceutically acceptable salt.

11. The way to reduce the severity of the symptom of diarrhoea in irritable bowel syndrome in men, including the introduction of the patient from 0.001 to 0.05 mg of hydrochloride of ramosetron as a daily dose or an equivalent molar amount of ramosetron, or another pharmaceutically acceptable salt.

12. The way to reduce the severity of the symptom of diarrhoea in irritable bowel syndrome in men in claim 11, including the introduction of the patient from 0.002 to 0.02 mg of hydrochloride of ramosetron as a daily dose or an equivalent molar amount of ramosetron, or another pharmaceutically acceptable salt.



 

Same patents:

FIELD: medicine, pharmacy.

SUBSTANCE: invention relates to pharmaceutical compositions with anti-diarrheic effect. Pharmaceutical composition comprises the therapeutically effective amount of loperamide hydrochloride as an active component and special additives. Lactose, starch, aerosil, talk and stearate are used as special additives. Pharmaceutical composition is prepared in the form of solid gelatinous capsules. Loperamide capsules satisfy all requirement of the State Pharmacopoeia of XI Edition. Invention provides bioavailability of the pharmaceutical composition of loperamide capsules at the level 98.5%.

EFFECT: improved and valuable pharmaceutical properties of composition.

3 cl, 1 tbl, 3 ex

FIELD: veterinary science.

SUBSTANCE: the suggested preparation for treating diarrhea in farm animals youngsters contains bismuth salt in the form of bismuth-potassium ammonium citrate and, additionally, polyethylenoxide, moreover, preferably, it contains 1.5-2.5%-polyethylenoxide solution and 1.5-2.5%-bismuth-potassium ammonium citrate solution. The method for treating diarrhea deals with introducing the above-mentioned preparation once or twice daily for 1-2 d at the dosage of 1-75 ml/kg body weight. In young foxes it should be introduced at the dosage of 60-75 ml/kg body weight, in calves - at the dosage of 1-3 ml/kg body weight, in lambs - at the dosage of 2-3 ml/kg body weight. Application of the present complex preparation and therapeutic method enables to shorten terms of therapy by 1.5-2 times, decreases expenses for therapy by 3-5 times and provides decreased toxicological impact the preparation upon animal body.

EFFECT: higher efficiency of therapy.

6 cl, 3 ex, 2 tbl

The invention relates to pharmaceutical

The invention relates to new guanidinium heterocyclic compounds of the formula (I), where R1denotes H, alkyl or is absent when R1missing link (a) is a double bond, D represents CR2, R2selected from H, alkyl, halogen, or, when is a CR3D can be N, denotes NR9, CR3=CR8, CR3, S, where R9denotes H, alkyl, alkenyl or quinil and where R3and R8selected from H, alkyl, alkenyl, quinil or cyano, R4, R5, R6each independently selected from H, alkyl, alkenyl, quinil, cyano, halogen or NH-C(= NR10)OTHER11(guanidine), R10and R11selected from H, methyl and ethyl, and where only one of R1, R5and R6is guanidines, R7selected from H, alkyl, alkenyl, quinil and halogen
The invention relates to medicine, specifically to medicines antidiarrheal action

The invention relates to the field of organic chemistry and medicine and relates to new quinoline derivatives of General formula I, where R represents unsubstituted C1-C3-alkyl or C2-C3alkenyl; R1is cyano, which are agonists alpha-2-adrenergic receptors and can be used when obtaining drugs suitable for the treatment of nasal congestion, glaucoma, diarrhea, asthma

The invention relates to medicine, specifically to experimental physiology, pharmacology and pathophysiology related to the possibility of modeling violations of motor-evacuation function of the intestines - constipation

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel compounds of the formula (I): or its pharmaceutically acceptable salts that possess properties of CB2 receptors agonist and can be used in preparing drugs exerting analgesic effect, in particular, for pain treatment. In compound of the formula (I) R1 is chosen from group consisting of (C1-C6)-alkyl, (C3-C6)-cycloalkyl, (C3-C6)-cycloalkyl-(C1-C6)-alkyl, (C2-C6)-alkenyl, R42N-(C1-C6)-alkyl, R42NC(=O)-(C1-C6)-alkyl, R4O-(C1-C6)-alkyl, R4OC(=O)-(C1-C6)-alkyl, R4C(=O)-(C1-C6)-alkyl, R4C(=O)-NR4-(C1-C6)-alkyl, R42NSO2-(C1-C6)-alkyl, R42NC(=O)-NR4-(C1-C6)-alkyl, radicals phenyl-(C1-C6)-alkyl, heteroaryl-(C1-C6)-alkyl, heterocycloalkyl-(C1-C6)-alkyl, bicyclic heteroaryl-(C1-C6)-alkyl; Ar represents phenyl or pyridyl; R2 represents (C1-C6)-alkyl that is unsubstituted or substituted at 1-6 carbon atoms with one or more fluorine atom substitute or (C3-C6)-cycloalkyl; R3 is chosen from the following group consisting of: (a) , (b) , (c) , (d) , (e) , (f) , (g) , (h) , (i) , (j) and (k) ; R4 represents group chosen independently from group consisting of hydrogen atom (H), (C1-C6)-alkyl, (C2-C6)-alkenyl; groups R5 are chosen independently from group consisting of H, (C2-C6)-alkenyl; groups R6 are chosen independently from group consisting of H, (C1-C6)-alkyl, (C3-C6)-cycloalkyl, (C2-C6)-alkenyl, heterocyclyl, radical (C1-C3)-alkyl, phenyl, radical phenyl-(C1-C3)-alkyl, heteroaryl, radicals heteroaryl-(C1-C3)-alkyl, bicyclic heteroaryl and bicyclic heteroaryl-(C1-C3)-alkyl; R5 and R6 can be combined to form 5-7-membered heterocycle; X is chosen from group consisting of -C(R5)2-, -NR5-, C(=O)-, -CH2-CH2-, CH=CH- and -C(R)(R') wherein R and R' represent (C1-C6)-alkyl, -OR'' or H and R'' represents H; Y represents -CH or nitrogen atom and wherein heterocyclyl or heterocycloalkyl represent 5-6-membered ring comprising from 1 to 2 heteroatoms chosen from nitrogen (N) and oxygen (O) atoms that is unsubstituted or substituted with (C1-C6)-alkyl; heteroaryl represents heteroaromatic 5-6-membered ring comprising from 1 to 2 heteroatoms chosen from N, S and sulfur atom (S) that is unsubstituted or substituted with group chosen from group consisting of (C1-C6)-alkyl, nitro-group, halogen atom and acetoxymethyl; bicyclic heteroaryl represents 5-6-membered nitrogen-containing ring condensed with benzene ring. Also, invention relates to a pharmaceutical composition and a method for paintreatment.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

9 cl, 15 sch, 3 tbl, 130 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to alkylated (1H-benzimidazol-5-yl)-(-4-substituted phenyl)-amine derivatives, in particular compound of formula and pharmaceutically acceptable salts or solvates thereof, wherein R1, R2, and R9, are independently hydrogen, halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluorimethoxy, azido, etc.; R7 is optionally substituted C1-C10-alkyl, C3-C10-cycloalkyl, etc.; A is-OR3 or NR4R3; R8 is hydrogen, -Cl, -Br, -F, cyano, nitro, etc.; and meanings of the rest substituents are as defined in specification. Also disclosed is composition for MEK inhibition and uses of benzinidazole compounds.

EFFECT: new compounds with value biological properties.

32 cl, 56 ex

FIELD: medicine.

SUBSTANCE: the present innovation deals with applying a preparation for preventing and treating influenza that contains methyl-1-adamantyl-methylamine hydrochloride, 2-ethylthiobenzimidazole hydrobromide and a pharmaceutically acceptable filler; moreover, it is of high curative effect and, also, increases protective body functions, endurance and recovery period by not deepening pathogenetic mechanisms caused by influenza virus at the following ratio of ingredients, weight%: methyl-1-adamantyl-methylamine hydrochloride 5-15; 2-ethylthiobenzimidazole hydrobromide 15-50; a filler- the rest.

EFFECT: higher efficiency of prophylaxis and therapy.

1 cl, 5 ex, 1 tbl

FIELD: medicine, gastroenterology.

SUBSTANCE: at the background of aglutenic diet and complex therapy including antisecretory, antibacterial and enzymatic preparations one should introduce biologically active additives "Normoflorin Lacto" per 20 ml twice daily and "Normoflorin Bifido" per 20 ml once daily for the period of 28-30 d. The innovation enables to efficiently correct psychoemotional status in such category of patients due to simplifying the method of therapy at excluding side effects associated with applying psychotropic preparations.

EFFECT: higher efficiency of correction.

5 ex, 1 tbl

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to N3-alkylated benzimidazole derivatives for preparing a drug used in inhibition of MEK activity. Invention describes benzimidazole compound of the formula (I): and its pharmaceutically acceptable salts and solvates wherein R1, R2, R9 and R10 are chosen independently from hydrogen atom, halogen atom, trifluoromethyl group, difluoromethoxy-, trifluoromethoxy-, azido-group, -OR3, -C(O)R3, -C(O)OR3, -OC(O)R3, (C1-C10)-alkyl, (C3-C10)-cycloalkyl, (C3-C10)-cycloalkylalkyl wherein each alkyl and cycloalkyl moiety is substituted possibly with groups in the amount from one to five and chosen independently from halogen atom, trifluoromethyl group, difluoromethoxy-, trifluoromethoxy-group; R3 is chosen from hydrogen atom, trifluormethyl group, (C1-C10)-alkyl, (C3-C10)-cycloalkyl, (C3-C10)-cycloalkylalkyl wherein each alkyl and cycloalkyl group is substituted possibly with groups in the amount from one to five and chosen independently from halogen atom, trifluoromethyl group, difluoromethoxy-, trifluoromethoxy-group, -C(O)R', -C(O)OR', -OC(O)R' wherein R' is chosen independently from hydrogen atom, lower alkyl; R4 represents independently hydrogen atom or (C1-C6)-alkyl; R6 is chosen from trifluoromethyl group or (C1-C10)-alkyl, (C3-C10)-cycloalkyl wherein each alkyl and cycloalkyl moiety is substituted possibly with groups in the amount from one to five and chosen independently from halogen atom, trifluoromethyl group, difluoromethoxy-, trifluoromethoxy-group, -C(O)R', -C(O)OR', -OC(O)R', -OR'; R7 is chosen from (C1-C10)-alkyl, (C3-C10)-cycloalkyl, (C3-C10)-cycloalkylalkyl wherein each alkyl and cycloalkyl moiety is substituted possibly with groups in the amount from one to five and chosen independently from halogen atom, trifluoromethyl group, difluoromethoxy-, trifluoromethoxy-group, -C(O)R3, -C(O)OR3, -OC(O)R3, -SO2R6, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl; W is chosen from -C(O)OR3, -C(O)NR3R4, -C(O)NROR3, -C(O)R4OR3, -C(O)(C3-C10)-cycloalkyl, -C(O)(C1-C10)-alkyl. Also, invention describes compositions used for inhibition of MEK activity, using such compounds for preparing a drug used in inhibition of MEK activity and preparing a drug used in cancer treatment.

EFFECT: valuable medicinal and biochemical properties of compounds and composition.

17 cl, 10 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of thiophene of the general formula (I): , wherein R1 is chosen from group consisting of hydrogen atom (H), -C(O)R7, -CO2R7, -C(O)NR7R8, -C(O)N(R7)OR8, -C(O)N(R7)-R2-OR8, -C(O)N(R7)-Ph, -C(O)N(R7)-R-Ph, -C(O)N(R7)S(O)2R8, -R2-OR7, -R2-O-C(O)R7, -C(S)R7, -C(S)NR7R8, -C(S)N(R7)-Ph, -C(S)N(R7)-R2-Ph, -R2-SR7, -CN, -OR7 and Het wherein Het represents tetrazolyl; Q1 represent group of the formula: -(R2)a-(Y1)b-(R2)c-R3 wherein a, b and a are similar or different and each means independently 0 or 1, and at least one among a or b means 1; n means 0, 1, 2, 3 or 4; Q2 represents group of the formula: -(R2)aa-(Y2)bb-(R2)cc-R4, or two adjacent Q2 groups represent -OR7 and in common with carbon atoms to which they are bound form 5-7-membered heterocycle comprising 1 or 2 heteroatoms chosen from oxygen atom (O); R5 is chosen from group consisting of H, alkyl and -NR7R8, or their pharmaceutically acceptable salts and solvates. Compounds can be used in treatment of states mediated by Polo-like kinase and sensitive neoplasm. Also, invention describes a method for synthesis of these compounds and preparing pharmaceutical compositions based on thereof.

EFFECT: valuable medicinal properties of compounds and pharmaceutical compositions.

27 cl, 1 tbl, 199 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel derivatives of benzimidazole of the general formula (I): wherein A represents -CH2- or -C(O)-; Y represents -S- or -NH-; R1 and R2 represent independently hydrogen atom, (C1-C8)-alkyl, (C5-C9)-bicycloalkyl optionally substituted with one or some similar or different (C1-C6)-alkyl radicals, or radical of the formula -(CH2)n-X wherein X represents amino-group, (C3-C7)-cycloalkyl and other values of radicals also given in the invention claim; R3 represents -(CH2)p-W-(CH2)p'-Z3 wherein W3 represents a covalent bond, -CH(O)- or -C(O)-; Z3 represents (C1-C6)-alkyl, aryl radical, heteroaryl and other values of radical also; V3 represents -O-, -S-, -C(O)-, -C(O)-O-, -SO2- or a covalent bond; Y3 represents (C1-C6)-alkyl radical optionally substituted with one or some halogen-radicals, amino-group, di-((C1-C6)-alkyl)-amino-group, phenylcarbonylmethyl, heterocycloalkyl or aryl radicals; p, p' and p'' represent independently a whole number from 0 to 4; R4 represents radical of the formula: -(CH2)s-R''4 wherein R''4 represents heterocycle comprising at least one nitrogen atom and optionally substituted with (C1-C6)-alkyl or aralkyl, and other values of radicals given in the invention claim also. Also, invention relates to a pharmaceutical composition showing antagonistic property with respect to GnRH and based on these compounds. Also, using above proposed compounds for preparing a medicament is considered. Invention provides synthesis of novel compounds, preparing pharmaceutical composition and medicament based on thereof in aims for treatment of such diseases as endometriosis, fibroma, polycystic ovary, breast, ovary and endometrium cancer, gonadotropic hypophysis desensitization in medicinal stimulation of ovary in fertility treatment in females.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

18 cl, 2 tbl, 538 ex

FIELD: medicine, cardiology, pharmacy.

SUBSTANCE: invention relates to medicaments, namely, to using 2-[1-(1,1-dioxothietanyl-3)-benzimidazolyl-2-tho]acetic acid potassium salt of the formula: as a substance enhancing resistance of cardiac muscle against ischemia. Invention provides the stable cardioprotective effect in myocardium ischemia as compared with prototype (preparation obsidan).

EFFECT: enhanced effectiveness and valuable medicinal properties of agent.

4 tbl, 2 ex

FIELD: organic chemistry, crystallography.

SUBSTANCE: invention relates to a novel polymorphous crystalline form of 4-[2-[4-1-(2-ethoxyethyl)-1H-benzimidazol-2-yl]-1-piperidinyl]ethyl]-α,α-dimethylbenzeneacetic acid (bilastin). Invention describes polymorph (1) of bilastin with the following parameters of crystalline lattice according to data of X-ray diffraction analysis: crystalline system: monoclinic; space group: P2(1)c; crystal size: 0.56 x 0.45 x 0.24 mm; cell parameters: a = 23.38 (5) angstrem α = 90o; b = 8.829 (17) Å β = 90o; c = 12.59 (2) Å Y = 90o; volume: 2600 Å; Z, calculated density: 4, 1.184 mg/m3. Also, invention describes a method for preparing polymorph (1) of bilastin, a pharmaceutical composition comprising polymorph (1) and its using for treatment of histamine-mediated allergic responses and pathological processes in mammals and humans.

EFFECT: improved preparing method, valuable medicinal properties of polymorph.

7 cl, 3 dwg, 5 ex

FIELD: medicine, neurology, pharmacy.

SUBSTANCE: invention relates to an agent used in treatment of ischemic injuries in brain. Invention proposes an anxiolytic agent 5-ethoxy-2-[2-(morpholino)ethylthio]benzimidazole dihydrochloride (AFOBAZOL) that shows the expressed neuroprotective activity and can be recommended as an agent for treatment of ischemic insult and other ischemic brain injuries.

EFFECT: valuable medicinal properties of agent.

3 tbl

FIELD: chemical-pharmaceutical industry, medicine, pharmacy.

SUBSTANCE: invention relates to medicinal agents of prolonged effect used in treatment of arterial hypertension. Medicinal agent of prolonged effect used in treatment of arterial hypertension comprises indapamide, accessory substance represented by interpolymeric complex of polymethacrylic acid with polyethylene glycol or polypropylene glycol. The claimed invention provides preparing a stable and easily dosed medicinal formulation of prolonged effect.

EFFECT: improved and valuable medicinal properties of agent.

1 tbl, 3 ex

FIELD: chemical-pharmaceutical industry, pharmacy.

SUBSTANCE: invention relates to a solid standard dosed formulation comprising atorvastatin or its pharmaceutically acceptable salt and a vehicle, or combination of vehicles that comprises above 50 wt.-% of diluting agents and less 5 wt.-% of alkaline substance as an additive. Indicated diluting agent represents lactose monohydrate, anhydrous lactose, microcrystalline cellulose or sodium chloride. The solid standard dosed formulation represents a table or capsule that is made without granulation step. Invention provides preventing segregation during making the standard dosed formulation and to provides the high dosing precision of atorvastatin. Excluding the granulation step results to enhancing effectiveness in producing the standard dosed medicinal formulation and without decreasing the rate of production of composition.

EFFECT: improved and valuable properties of compositions.

5 cl, 1 dwg, 3 tbl, 7 ex

FIELD: medicine, surgery.

SUBSTANCE: method involves intravenous administration of 1% serotonin-adipinate solution diluted in 5-10 ml of physiological solution in the dose 0.1-0.2 mg/kg of body mass that is carried out immediately after elimination of acute intestinal obstruction. Then this solution is administrated into the damaged intestine mesentery. Method provides enhancing effectiveness of bowel ischemic damage correction based on elimination of smooth-muscle insufficiency of microcirculation channel of intestine. Invention can be used in surgery operation in case of acute intestinal obstruction accompanying with ischemic damage of bowel.

EFFECT: improved method of correction.

3 dwg, 3 ex

FIELD: medicine, pharmacy.

SUBSTANCE: invention relates to a pharmaceutical composition comprising enalapril maleate, lactose, potato starch, polyvinylpyrrolidone and magnesium stearate wherein a medium-molecular polyvinylpyrrolidone aqueous solution is used as polyvinylpyrrolidone, and the pharmaceutical composition comprises indapamide and aerosil additionally. The pharmaceutical composition is made as an enveloped-covered core in the following ratio of the core components, wt.-%: enalapril maleate is taken in the therapeutically effective dose; indapamide, 1.1-2.6; aerosil, 0.2-0.4; potato starch, 20.0-40.0; medium-molecular polyvinylpyrrolidone aqueous solution with the concentration 12%, 1.7-2.3; magnesium stearate, 0.8-1.0, and lactose, the balance. The claimed composition provides enhancing the hypotensive effect based on design of the composition comprising enalapril maleate and indapamide. The selected qualitative and quantitative composition excludes sticking tablet mass on equipment in tablets making process, loss of active substance and change of the ratio mass of components in ready tablets as compared to the measured one. Invention provides high strength and stability of tablets in storage.

EFFECT: improved and valuable properties of pharmaceutical composition, improved preparing method.

2 tbl

Up!