Coformulated antituberculous drug

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine, and concerns a coformulated drug exhibiting antituberculous action and representing a solid dosage form which contains as an active principle a formulation of rifampicin, isoniazid, pyrazinamide, and a zinc-containing compound, and pharmaceutically acceptable excipients. The zinc-containing compound is zinc salt, preferentially zinc sulphate.

EFFECT: pharmaceutical composition under the invention is characterised by high efficacy and provides synergetic antimycobacterial activity when using the formulation of rifampicin, isoniasid, pyrazinamide and zinc sulphate as an antituberculous drug as compared with a formulation of standard antituberculous drugs.

9 cl, 3 ex

 

The invention relates to medicine, specifically to a combined anti-TB drugs, and can be used in different modes of chemotherapy of tuberculosis.

Chemotherapy for more than 60 years, undoubtedly occupies a leading place in the treatment of tuberculosis as causal method, the essence of which consists in the elimination or suppression of the reproduction of Mycobacterium tuberculosis (MBT) in the body of the patient [Khomenko A.G. Chemotherapy of pulmonary tuberculosis. - M - 1980. - 279 S.]. Currently, however, the effectiveness of chemotherapy decreases, which is due to prolonged use of anti-TB drugs (PTP) and the growth of drug-resistant TB, including not only individual drugs, but their combination in the treatment of patients with pulmonary tuberculosis. An important factor is also the lack of new classes of anti-TB drugs.

With the onset of PTP in the 50-ies of XX century to the present time PTP was divided into main and backup.

The main anti-TB drugs are isoniazid, rifampicin, pyrazinamide, ethambutol and streptomycin is the most effective and bactericidal operating in the office of the medication with the lowest frequency of adverse effects. These drugs are used for treatment of new TB cases.

Group rezervujte are kanamycin (amikacin), capreomycin, protionamide, cycloserine, para-aminosalicylate acid (PAS). It is less effective drugs with bacteriostatic action, which is the replacement of the main anti-TB drugs in cases of detection of drug resistance or the emergence of fatal adverse reactions basic PTP [Mishin VY Treatment of patients with pulmonary tuberculosis. // Educational-methodical manual for doctors. - M: MOSCOW. - 2006. - 120 S.].

The development of resistance of mycobacteria is much slower in case of simultaneous use of several drugs. However, combination therapy of TB patients because of the complexity and duration of selection of effective drugs, as well as the duration of the course exercise therapy or irregularly, or not bring it to the end. This causes a return of the disease and the emergence of secondary resistance of Mycobacterium tuberculosis to drugs. Therefore, the world health organization (who) recommends the rejection of mono - and combined therapy and necessitates the use of combined anti-TB drugs at fixed doses in a single tablet. They provide the optimal therapeutic effect in the prevention of drug resistance arising in the case of monotherapy. They reduce the risk nekorrektnogo the dosing, simplify the practice of medicinal supplies, optimize direct, simply adhere to treatment.

Chemotherapy TB patient must be comprehensive and strictly individual. This combination of anti-TB drugs, and determine the mode of treatment, taking into account regional and individual drug sensitivity of the office, and the choice of pathogenetic methods aimed at normalization of the disturbed functions of the body, reducing the degree of inflammatory reaction, elimination of metabolic and immune disorders, as well as a means of stimulating therapy (Minicheva O.A., Skvortsova L.A., Pavlov M.V., Sapozhnikova, NV, Archakov LI, B. I. Vishnevsky Bacteriostatic activity of blood in patients with respiratory TB. // Mat. VIII Grew. Congress of TB. - M - 2007. - P.124; Mishin VY Optimization of treatment of new cases of pulmonary TB on the basis of the principles of evidence-based medicine // CONSILIUM medicum - 2008, No. 3. - P.20-25.)

In the standard chemotherapy of tuberculosis as the primary and most effective anti-TB drug isoniazid is used (Khomenko A.G. Chemotherapy of pulmonary tuberculosis. - M.: Medicine. - 1980. - 279 S.). Isoniazid has a high bactericidal effect on Mycobacterium tuberculosis, but has a strong toxic effect. But his main weeks the STATCOM is the rapid development of drug resistance of Mycobacterium tuberculosis, that greatly reduces its effectiveness. Resistance of Mycobacterium tuberculosis to isoniazid develops in 22,2-37,1% of patients and they move into the category of chronic patients [Filatova MS Peculiarities of the course and treatment of drug-resistant tuberculosis: author. dis ... Kida. honey Sciences. - M - 2004. - 25 S.].

In this regard, there is need to assign 4 or more anti-TB drugs. There are two ways to prevent the development of resistance of MTB to medicines:

- creation of drugs combined with fixed doses of drugs, including drugs of different groups;

- the patient receives simultaneously a combination of anti-TB drugs of different classes.

Researchers have proposed a number of other approaches to improve the effectiveness of treatment, including various methods of immunomodulation and immunotherapy. In studies it was found that the appointment of preparations containing zinc together with vitamin a, patients with tuberculosis of the lungs leads to rapid sputum conversion and improves radiographic indicators (Karyadi E, Mest CT, Schultnick M. et al. / A double blind, placebo-controlled study of vitamin A and zinc supplementation in persons with tuberculosis in Indonesia: effects on clinical response and nutritional status. Am J Clin Nutr. 2002; 75: 720-727).

In the patent of Russian Federation №2253460, 2005, the claimed method Leche is of tuberculosis, includes chemotherapy with combinations of anti-TB drugs on the basis of isoniazid or isoniazid and rifampicin, characterized in that it further prescribe zinc sulfate in a daily dose 2,30-3,50 mg/kg two to three times the ingestion, the rate of 21-28 days, which helped to shorten the duration of chemotherapy due to the clear anti-apoptotic action on T-lymphocytes.

In the patent of Russian Federation №2182483 features combined anti-tuberculosis drug, which consists of isoniazid and pyrazinamide or ethambutol hydrochloride. However, the presence in its composition of only two active components are not completely removes the above-mentioned disadvantages of combination therapy and requires the use of additional anti-TB drugs.

To reduce the development of drug resistance of Mycobacterium tuberculosis have been proposed multicomponent anti-TB drugs, containing three or more active substances. For example, in U.S. patent No. 5104875, 1992, describes pharmaceutical combined preparation containing rifampicin, Thiacetazone and, optionally, isoniazid or ethambutol.

Thus, well-known drugs - counterparts - has some significant drawbacks. So in exchange application of the above drugs, there are marked toxic effect in the incidence of side effects. In addition, in the known combined compositions of the mutual influence of ingredients leads to a significant reduction in the bioavailability of the beginning of the current, which degrades the anti-TB activity of combination and causes of relapse and the development of secondary drug resistance of Mycobacterium tuberculosis.

Thus, an important aspect in the selection of ingredients beginning of the current combined anti-TB drugs is based on their interaction and compatibility in the manufacturing process and storage.

The present invention is the development of highly efficient combined anti-TB compound, which has a high antimicrobial activity against Mycobacterium tuberculosis and minimal toxic side effects.

The problem is solved in that the proposed anti-TB means includes a therapeutically effective amount of the current to the beginning, which contains a combination of rifampicin, isoniazid, pyrazinamide, zinc-containing compound and pharmaceutically acceptable excipients. The preferred proportions of ingredients acting beginning is, parts by weight:

Rifampicin - 5-180,

Isoniazid - 5-150,

Pyrazinamide - 5-400,

Zinc is teramae connection

(in terms of elemental zinc) - 0,75-4,0.

The proposed combination of active ingredients is new for combined anti-TB drugs and is chosen empirically.

According to the invention as the beginning of the current composition includes a combination of rifampicin, isoniazid, pyrazinamide and zinc-containing compounds. As the zinc-containing compound is preferably used zinc salts, preferably zinc sulfate.

The use of the claimed combination of active ingredients in the specified ratio significantly increases antimicrobial activity against drug-sensitive M. tuberculosis, and the inclusion of zinc sulfate gives the opportunity to apply a new tool for the treatment of common forms of tuberculosis, complicated by pulmonary tissue destruction.

Biological studies in vitro and in vivo showed that the inventive composition has a high anti-TB activity and provides the most complete recovery of structural and functional features of the lungs and other parenchymatous organs.

The objective of the in vitro studies was the study of microbiological methods bacteriostatic and bactericidal activity of the new structure and its individual components against Mycobacterium tuberculosis (MB is) - laboratory strain H37Rv and clinical strains sensitive to PTP.

Definition antimycobacterial steps of the claimed combination was conducted in accordance with the "Manual on experimental (preclinical) study of new pharmacological substances", page 287-292, 2000

As biotests used laboratory strain of Mycobacterium tuberculosis H37Rv and clinical (wild) strains isolated from diagnostic material of pulmonary tuberculosis patients under treatment in the hospital of the research RAMS

In accordance with the work plan for the culture of selected strains of Mycobacterium tuberculosis were grown for 21 days on a dense nutrient medium Levinstein-Jensen (international standard). Growth of mycobacteria in a dense environment was taken into account and have registered through 21, 42 and 70 days of culturing in an incubator at 37°C. the Control were tubes with cultures of test strains not exposed to study drugs and their mixtures.

Minimum inhibitory concentrations of individual substances and mixtures was characterized by a significant decrease in the number of colonies on solid culture medium compared with the control. The minimum bactericidal concentration was determined as the concentration causing complete inhibition of growth of bacteria on solid nutrient medium.

Marked by considerably the th increased bactericidal activity of the new drug compared with the prototype. The study of the bacteriostatic and bactericidal activity of the new claimed composition against M. tuberculosis laboratory strain H37Rv and clinical, sensitive to drugs strains showed that this composition has a high inhibitory effect at a low concentration of 6.25 µg/ml Bactericidal effect is observed when the concentration of the composition in the medium to 18.7 ág/ml At the same time the study of the bacteriostatic and bactericidal concentrations mechanical mixture of products FC, similar in composition to the new structure against M. tuberculosis laboratory strain H37Rv and clinical, sensitive to drugs strains also showed high ingibiruet action at low concentrations. However, the value of MIC and MBC in this case, the above 11,46 µg/ml and 25.0 μg/ml, respectively. Thus, the new structure has against Mycobacterium tuberculosis clinical, sensitive to drugs strains, high inhibitory activity at low concentrations ~ of 6.25 µg/ml Bactericidal effect, the most desirable when creating new medicines, observed in its concentration in the medium in amounts to 18.7 ág/ml

Experimental in vivo studies carried out with the aim of studying the possible specific activity against .tuberculosis strain H37Rv (ILO) announced a new structure on the model exudative necrotic TB mice. To accomplish the objectives were defined the following tasks:

to determine the average life of animals after infection with a lethal dose of the office in different experimental animal groups;

- to study the microbiological method in vivo bactericidal and bacteriostatic activity of the investigated structure;

to assess morphological methods the nature of reparative processes in parenchymatous organs in the treatment of experimental tuberculosis of mice studied groups.

The determination of specific anti-TB activity in vivo studies were performed on inbred male mice of the AKR obtained from the vivarium of the state of research RAMS. The weight of mice 22-23 grams. Mice were infected by intravenous .tuberculosis strain H37Rv from the collection of the Institute Pasteur (France) in the lateral tail vein at a dose of 5×106CFU/mouse.

In preparative quantities of the office were obtained in the laboratory of immunogenetics SE the research RAMS. Aliquots (1 ml) was stored at - 70°C. For infection of mice, an aliquot was thawed, transferred to a phosphate buffer solution containing 0.025% Tween 80, and brought up to a concentration of 5×106CFU/ 0,5 ml To determine the number of CFU of bacteria in the resulting suspension was preparing a series of successive dilutions and 20 µl of each dilution were placed in a drop of a Petri dish with agar, Dubo. The Cup is cultivated at 37°C for 14 days to determine the concentration of MB in the infective material.

All experimental animals were divided into following groups:

- infected mice without treatment (control), infected mice receiving intragastric consisting of drugs isoniazid + rifampicin + pyrazinamide dose of 38 mg/kg;

- infected mice receiving intragastric declared ingredients: isoniazid + rifampicin + pyrazinamide + zinc sulfate at a dose of 38 mg/kg;

- infected mice receiving intragastric isoniazid at a dose of 38 mg/kg

The tested drugs were injected intragastrically daily (except weekends), within 2 months, two weeks after infection, pre-dissolved in water. Injected volume was 0.5 ml/mouse.

According to the program of study within two months after the start of treatment of the experimental animals were taken from experiment method of cervical dislocation to determine the number of colony forming units (CFU) .tuberculosis office (ILO) in the lungs of mice and histological examination of the tissues of the lung, liver and spleen.

To determine the number of bacteria (CFU office) in the lungs of infected mice lungs homogenized in 2 ml of physiological solution was prepared by serial 10-fold dilution of the original suspension in physiological solution and 50 μl of each dilution was placed on a Petri dish, covered with agar, Dubo. Petri dishes coated with what uspeniye lung cells were incubated for 21 days at 37°C, then counted the number of colonies on plate and determined the number of CFU of bacteria in the lungs by the formula: N=2Nl×R/0,1, where N is the number of colonies in the lungs.

Histological study of the pieces of lung, spleen and liver were fixed with 10% buffered formalin, were placed in paraffin, preparing histological sections, which were stained with hematoxylin and eosin.

The main indicators of resistance of the animal to the TB are term survival after infection, the ability to control the multiplication of bacilli in the organs (i.e. the number of mycobacteria, measured in CFU) and the degree of pathological changes in the lung tissue.

Mice of the control group not receiving any drugs, the average life after a fatal dose of infection was 28,2±0.44 days. Mice treated with the claimed composition isoniazid + rifampicin + pyrazinamide + zinc sulfate, and the combination of drugs isoniazid + rifampicin + pyrazinamide, and only one, isoniazid, at the time of slaughter and the whole experiment was still alive. According to the data obtained, the number of CFU office, sown from the lungs of mice treated with isoniazid and the combination of drugs isoniazid + rifampicin + pyrazinamide were approximately the same. However, in mice treated with the claimed composition was inoculated in 10 times smaller is e office than in mice of the above groups.

Intravenous office in mice developing exudative-necrotic inflammatory process affecting various parenchymal organs. Untreated animals die from the generalized tuberculosis in 1-2 months. By the time of his death in lung, liver and spleen observed the plethora, the sludge of erythrocytes in the blood vessels of medium and large caliber identified young and Mature forms of PAL (polymorphonuclear leukocytes). Around the vessels are formed of cellular infiltrates consisting of mono - and polynuclear; the number varies in different organs.

Especially large pneumonic foci are formed in the lungs, where, along with macrophages and lymphocytes are determined by the large accumulation of PAL. Among alveolar macrophages predominate lipobay, which on histological sections have foamy cytoplasm due to numerous granules neutral lipid. These cells are determined by the accumulation of the office. When the destruction of lipophages the office fall into vnutriarterialno the space around them concentrate of PAL. Therefore, the presence of foam cells (PC), especially destroyed their forms, reflects the activity of specific inflammation in mice, which is most pronounced in untreated animals. In the terminal period of the process cell infiltr what you take up to 70% histological slice; in their composition are determined by large accumulations PC, here are concentrated PAL forming zone of necrosis.

Edge sites alveoli partially or completely filled with edema fluid, contain fibrin and debris of the destroyed cellular elements.

In areas of the parenchyma preserving the air, millionarie septum thickened due to interstitial edema and infiltration of mono - and polynuclear. These cells are defined in the extended loops of the capillary network.

In the liver of untreated mice, in addition to the exudative reaction, the formation of perivascular infiltrates, pays attention to the development of degenerative changes of hepatocytes, especially expressed in the terminal period of inflammation. Cells of the hepatic beams have enlightened vacuolation the cytoplasm, often with signs of destruction. In areas of necrosis determined by PAL.

The spleen of control mice depleted lymphocytes, there has been a proliferation of stromal elements, the formation of diffuse mononuclear infiltrates, which are determined by PAL.

In all groups of experimental mice received a well-pronounced therapeutic effect. Almost all animals were observed almost complete restoration of structural and functional features of the lungs, liver and spleen. However, in all parenchymatous organ of the x remained plethora, signs of increased permeability of the microvasculature. They are maximally expressed in the lungs of animals treated group 2 months combination of drugs isoniazid + rifampicin + pyrazinamide, where the profiles of the blood vessels can be seen neutrophilic and eosinophilic leukocytes. Perivascular were located in small loose clusters of lymphocytes. Subpleural was thickening millionary partitions due to the swelling and moderate infiltration by mononuclear cells.

For animals treated with isoniazid, characterized by a more pronounced infiltration millionary partitions monocytes and lymphocytes, which may also form small perivascular infiltrates. However, in their composition, as well as in the Lumina of blood vessels, PAL not found.

The most nearly normal histological structure of the lungs and other parenchymatous organs were observed in animals treated group 2 month announced a combined composition. In this group of experimental animals in the lungs remained perivascular accumulations of lymphocytes in small numbers, mainly in the form of lymphonoduses. Individual animals have increased permeability of the microvasculature with the release of individual erythrocytes in vnutriarterialno space.

Thus, proceeding from the received Yes is the data it is possible to conclude that the claimed combined composition, has a more pronounced therapeutic effect than the combination of isoniazid and isoniazid + rifampicin + pyrazinamide, and provides the most complete recovery of structural and functional features of the lungs and other parenchymatous organs.

Thus, on the basis of the results of biological studies the conclusion can be made about the high therapeutic effectiveness of the new structure and its application as a drug.

The proposed remedy is carried out in a variety of solid dosage forms - tablets, capsules, granules, powders. As auxiliary substances may be used substances commonly used in the pharmaceutical industry for the production of solid dosage forms, such as starch, sugar, cellulose and its derivatives, gelatin, polyvinylpyrrolidone, polyethylene oxide, calcium phosphate, lubricant, wetting agent, as nutriceuticals, esters of polyoxyethylenesorbitan and fatty acids (twins), esters sorbitan and fatty acids (spany), preferably starch, including modified, lactose, microcrystalline cellulose, nutritionstrategywales, polyvinylpyrrolidone, lubricant. Examples of the latter Vlada stearic acid and/or its salts - calcium stearate, magnesium stearate, zinc stearate, talc, colloidal silica, Aerosil, polyethylene glycol, hydrogensource vegetable oil, liquid paraffin. The new composition may also contain flavoring agents, colorants and/or flavorings.

Preferably, the preparation is made in the form of pills, which can be a shell. The presence of the latter improves the appearance and organoleptic properties of the dosage form, protects it from mechanical damage. Preferably the shell is performed based on, for example, ready-mix brand "Opadry brown".

Preferred amounts of the ingredients beginning of the current in a single dose is: for rifampicin from 5 mg to 180 mg, more preferably 150 mg, isoniazid 5 mg to 150 mg, more preferably 75 mg, pyrazinamide from 5 mg to 400 mg, more preferably 400 mg, zinc-containing compounds (in terms of elemental zinc) from 0.75 mg to 4.0 mg, more preferably 4.0 mg, which corresponds to from 2.0 to 11.0 mg mg monohydrate zinc sulfate, more preferably 11.0 mg monohydrate zinc sulfate or 3,29 to 17.6 mg mg the heptahydrate zinc sulfate, more preferably to 17.6 mg heptahydrate zinc sulfate.

Examples of zinc-containing compounds are salts of zinc sulfate, aspartate, hyaluronate, glycerin, picolinate, citrate, azeta is, most preferably in the inventive compositions to use zinc sulfate. According to the invention the zinc sulfate can be introduced into the composition in the form of a hydrate, such as the heptahydrate or monohydrate, preferably in the form of a monohydrate.

Obtaining the inventive dosage forms can be carried out in accordance with known techniques for manufacturing solid dosage forms, for example, wet granulation, and then add to the dry granules with a lubricant, forming a final mixture of ingredients with the formation of the dosage forms of a given configuration and size and, if necessary, by drawing the shell.

The invention is illustrated by the following examples.

Example 1. Pre-sifted powders pyrazinamide, isoniazid, corn starch, microcrystalline cellulose colloidal anhydrous silica mix until smooth, granularit pre-cooked paste of corn starch and dried. Pre-sifted mixture of rifampicin, zinc sulfate monohydrate, starch of glycolate sodium, colloidal anhydrous silica with crosscarmelose sodium mixed with dried granules in a blender for 10 minutes, it adds a pre-sifted magnesium stearate and talc, mix in a blender 5 minutes Ready mass is tabletirujut. Get tablets with an average weight of 950 mg Content in one tablet (HPLC) rifampicin 150 mg, isoniazid 75 mg, pyrazinamide 400 mg zinc content (UV spectrometry) 4,00 mg or in terms of zinc sulfate to 12.7 mg, durability NLT 6 kg

The obtained tablets applied film-forming composition based on pre-prepared composition consisting of a "Opadry brown U", isopropyl alcohol, methylene chloride. Layering is produced to obtain a satisfactory film thickness. The obtained tablets with an average weight of 965 mg meet regulatory requirements in the pharmaceutical agent. The disintegration time 30 minutes

Example 2. Pre-sifted powders pyrazinamide, isoniazid, corn starch, microcrystalline cellulose colloidal anhydrous silica mix until smooth, granularit pre-cooked paste of corn starch and dried. Pre-sifted mixture of rifampicin, zinc sulfate monohydrate, starch of glycolate sodium, colloidal anhydrous silica with crosscarmelose sodium mixed with dried granules in a blender for 10 minutes, it adds a pre-sifted magnesium stearate and talc, mix in a blender 5 minutes Ready weight tabletirujut. Get tablets with an average weight of 1050 mg Content in od is the first tablet (HPLC) rifampicin 180 mg, isoniazid 150 mg, pyrazinamide 400 mg zinc content (UV spectrometry) 4,00 mg or in terms of zinc sulfate to 12.7 mg, durability NLT 6 kg

The obtained tablets applied film-forming composition based on pre-prepared composition consisting of a "Opadry brown U", isopropyl alcohol, methylene chloride. Layering is produced to obtain a satisfactory film thickness. The obtained tablets with an average weight 1071 mg meet regulatory requirements in the pharmaceutical agent. The disintegration time 30 minutes

Example 3. Pre-sifted powders pyrazinamide, isoniazid, corn starch, microcrystalline cellulose colloidal anhydrous silica mix until smooth, granularit pre-cooked paste of corn starch and dried. Pre-sifted mixture of rifampicin, zinc sulfate monohydrate, starch of glycolate sodium, colloidal anhydrous silica with crosscarmelose sodium mixed with dried granules in a blender for 10 minutes, it adds a pre-sifted magnesium stearate and talc, mix in a blender 5 minutes Ready weight tabletirujut. Get tablets with an average weight of 23.8 mg Content in one tablet (HPLC) 5 mg rifampicin, isoniazid, 5 mg, pyrazinamide 5 mg zinc content (UV-Spa is trometry) 0.75 mg, or in terms of zinc sulfate 2.4 mg, strength NLT 6 kg

The obtained tablets applied film-forming composition based on pre-prepared composition consisting of a "Opadry brown U", isopropyl alcohol, methylene chloride. Layering is produced to obtain a satisfactory film thickness. The obtained tablets with an average weight of 24.5 mg meet regulatory requirements in the pharmaceutical agent. The disintegration time 30 minutes

1. TB composition comprising a therapeutically effective amount of the current to the beginning, which contains a combination of rifampicin, isoniazid, pyrazinamide and zinc-containing compounds and pharmaceutically acceptable excipients.

2. TB composition according to claim 1, characterized in that it contains as a zinc-containing compound is a salt of zinc.

3. TB composition according to claim 2, characterized in that it contains as zinc salts zinc sulfate.

4. TB composition according to claim 3, characterized in that it contains the ingredients of the current start in the following ratio, parts by weight:

Rifampicin5-180
Isoniazid5-150
Feast is inamed 5-400
Zinc-containing compound
(in terms of elemental zinc)0,75-4,0

5. TB composition according to claim 4, characterized by the fact that made in the form of solid dosage forms.

6. TB composition according to claim 5, characterized by the fact that made in the form of tablets.

7. TB composition according to claim 6, characterized in that it has a shell.

8. TB composition according to any one of claims 4 to 7, characterized in that it contains ingredients beginning of the current in a single dose in the next number, mg:

Rifampicin5-180
Isoniazid5-150
Pyrazinamide5-400
Zinc sulfate (in terms of elemental zinc)0,75-4,0

9. TB composition according to any one of claims 4 to 7, characterized in that it contains ingredients beginning of the current in a single dose in the next number, mg:

Rifampicin150
Isoniazid75
Pyrazinamide400
Zinc sulfate (in terms of elemental zinc)4,0



 

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FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to field of medicine, namely to anti-tuberculosis composition. Claimed is pharmaceutical composition which includes sodium salt of para-aminosalicylic acid, zinc sulfate, sorbitol, polyvinylpyrrolodone, citric acid, stearic acid salt, sodium carboxymethyl starch, colloidal silicon dioxide and polyethylene glycol in amounts stated in invention formula.

EFFECT: pharmaceutical composition is characterised by high therapeutic activity, satisfactory technological characteristics and has storage term more than 2 years.

8 cl, 1 tbl, 1 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to field of chemical-pharmaceutical industry, namely to novel anti-tuberculosis medication. Claimed medication contains as active substance 4-thioureidoiminomethyperidinium perchlorate in effective and safe quantity and pharmaceutically acceptable auxiliary substances. Also claimed is method of its obtaining, which makes it possible to obtain target product with high yield. Novel medication, obtained by claimed method, possesses high tuberculostatic activity and low toxicity, preserves its stability in long-term storage.

EFFECT: invention can be used for treatment of all forms of pulmonary and extra-pulmonary tuberculosis, as well as in prophylaxis in composition of combined tuberculosis therapy.

12 cl, 8 tbl, 16 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to stable solid medication, containing olmesartan medoxomil and amlodipine or its pharmaceutically acceptable salt. Said solid medication is, in fact, free of reducing sugars. Stable solid medication optionally can additionally contain hydrochlortiazide or its pharmacologically acceptable salt. Medicinal form is intended for treatment or prevention of diseases caused by hypertension.

EFFECT: solid medicinal form in accordance with invention has improved solubility properties in comparison with lactose-containing composition.

42 cl, 2 dwg, 4 tbl, 2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention claims per oral drug form of neramexam with modified release, which is applied for long therapy of patients with such diseases and states as dimentia in Alzheimer's disease and neuropathic pain. Neramexane is dispersed inside hard matrix, which contains release-regulating filler. Filler is selected from copolymer of polyvinylpyrrolidone and vinyl acetate, hydroxypropylmethylcellulose. Hydroxypropylmethylcellulose is present in mixture with microsrystalline cellulose. Content of said filler is selected in such a way as to obtain profile of neramexan release in vitro, characterised by dissolution time of, at least, 1 hour for amount of neramexane, constituting 50 wt %.

EFFECT: profile of release ensures concentrations of neramexane in plasma with fluctuation index 0,4 or lower with introduction of matrix tablet of neramexane one time per day at steady state.

23 cl, 4 tbl, 7 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to chemical-pharmaceutical industry, namely to creation of pharmaceutical composition in form of hard peroral drug form for treatment of gastrointestinal tract diseases. Pharmaceutical composition contains the following ingredients: trimebutin maleate, lactose, colloidal silicon dioxide, talc, corn starch, magnesium stearate.

EFFECT: obtained pharmaceutical composition ensures high clinical effect.

5 cl, 2 ex, 1 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine, and consists in development of a new dosage of the preparation 6-methyl-2-ethyl-3-hydroxypyridine succinate providing modified release of an active substance. A unit dosage form contains 6-methyl-2-ethyl-3-hydroxypyridine succinate in amount 30.0-70.0 wt %, as a release modifier - cellulose derivatives and/or polyacrylic resins in amount 1.0-20.0 wt %, as an excipient - microcrystalline cellulose in amount 20.0-50.0 wt % and lubricants. The unit dosage form represents a tablet or a capsule consisting of a variety of small dense spheroids containing 6-methyl-2-ethyl-3-hydroxypyridine succinate as a major component. A combination of matrix and instant, coated and uncoated spheroids enables preparation of a drug in the various dosage forms with controlled release rate.

EFFECT: invention allows to produce the unit dosage forms of the preparation 6-methyl-2-ethyl-3-hydroxypyridine succinate for certain treatment regimens of various diseases.

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to pharmaceutical industry and solid dosage form of calcium atorvastatin. Solid dosage form consists of core containing the following components, wt %: calcium atorvastatin - 1.5-25; microcrystalline cellulose - 2-30; calcium carbonate - 5-30; croscarmellose sodium - 0.5-5; stearic acid and/or its salt - 0.5-1.04; lactose "Lactopress Spraydry" - balance; and shell containing the following components, wt %: polyethylene glycol - 6-28; titanium dioxide - 10-35; talc - 5-25; silicon emulsion - 0.05-4; dye - 0-3; polyvinyl alcohol - balance.

EFFECT: invention provides for production of calcium atorvastatin pills satisfying requirements of National pharmacopeia XI.

4 cl, 5 tbl

FIELD: medicine.

SUBSTANCE: invention concerns a solid oral dosage form composition containing therapeutically effective amount of aliskiren or its pharmaceutically acceptable salt in amount exceeding 46 wt %. The oral dosage form represents a tablet or a film-coated tablet. Aliskiren tablet is made by wet granulation with using mixed organic solvents or organic binding solutions.

EFFECT: elimination of aqueous granulation provides high stability of the dosage form of aliskiren and prolonged shelf-life.

18 cl, 2 ex

FIELD: food industry.

SUBSTANCE: present invention relates to gastral retentive composition containing active agent granulated together with the mixture of the first and the second gelatinating agents and mentioned composition production method the first gelatinating agent is a mixture of microcrystalline cellulose and sodium-carboxymethyl cellulose the second gelatinating agent is a compound with viscosity of 1% water solution which makes at least 600 centipoise at 25°C active agent is chosen from antibacterial compounds such as fluoroquinolones, antidiabetic compounds and antihypertensive medicinal agents.

EFFECT: invention provides gastral retentive composition with sustained release effect, which stays in stomach; medical agent has maximal absorption with improved therapeutic action there.

24 cl, 2 ex

FIELD: medicine.

SUBSTANCE: invention relates to pharmaceutical dosed form, which contains pharmaceutically active substance, unstable in presence of acid, which includes central nucleus, containing active substance and loosening agent, swelling coating, surrounding central nucleus, and enterosoluble coating, surrounding swelling coating. Swelling coating includes prolamin, preferably, zein. Pharmaceutically active substance includes benzimidazole, selected from omeprazole, lansoprazole, rabeprazole and pantoprazole.

EFFECT: invention ensures fast release of pharmaceutically active substance in medium, which has pH value at least 5.

33 cl, 12 ex

FIELD: medicine.

SUBSTANCE: according to the first version, an antiseptic ointment contains a base and an antiseptic agent in the form of an Ag+ or/and Cu2+ intercalated disperse bentonite powder which is produced by modification of Na+ preliminary enriched bentonite by aqueous solutions of silver nitrate or copper sulphate. A base is medical Vaseline or mixed medical Vaseline and lanolin and additionally contains a vegetable essential oil. The antiseptic ointment according to the second version contains a base and an antiseptic agent in the form of Ag+ or/and Cu2+ intercalated bentonite powders and a Zn2+ intercalated bentonite powder which is produced by modification of prepared raw Na+ enriched bentonite processed by solutions of inorganic salts of zinc chloride (ZnCl2) or zinc sulphate (ZnSO4), cleared from sodium salts and dispersion. A base is medical Vaseline or mixed medical Vaseline and lanolin and additionally contains a vegetable essential oil.

EFFECT: implementation of the invention provides producing ointments for outward application of prolonged antiseptic action with low cost of the active ingredients biologically compatible with various human and animal skin integuments.

8 cl, 5 ex

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