Anti-tuberculosis medication based on 4-thioureidoiminomethylpyridinium perchlorate, method of its obtaining and method of treatment

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

The technical field

The invention relates to the field of pharmaceutical industry, specifically to a new TB drug, which contains as active substance 4-theorieorientierte perchlorate in a therapeutically safe and effective amount, as well as pharmaceutically acceptable excipients. In addition, the invention relates to a method for producing the above-mentioned drugs (options) and the treatment of all forms of pulmonary and extrapulmonary tuberculosis, as well as prevention in the combination therapy of tuberculosis.

Prior art

Today there is an acute problem of mortality from tuberculosis (TB). According to the world health organization (who) in 2007, worldwide there were 9,27 million TB cases. This represents an increase from 9.24 million in 2006, 8.3 million cases in 2000 and 6.6 million cases in 1990, the Majority of suspected cases in 2007 occurred in Asia (55%) and Africa (31%), with a small proportion of cases in the Eastern Mediterranean Region (6%), European region (5%) and the Americas (3%). The first five countries in the total number of cases in 2007 were India (2.0 million), China (1.3 million), indone the Oia (0,53 million), Nigeria (0,46 million) and South Africa (0,46 million). According to estimates from 9,27 million cases of 1.37 million (15%) were HIV-positive; 79% of these HIV-positive cases were in the African region and 11% in South-East Asia.

Although the total number of TB cases in absolute terms, increased by the population growth, the number of such cases per capita falls. The rate of decline is slow, less than 1% per year. The frequency of such cases in the world in 2004 reached its peak and was 142 cases per 100,000 people. In 2007, this figure was approximately 139 cases per 100,000 people. The frequency of cases falling in five of the six who regions (the exception is the European region, in which the coefficients are almost stable).

In 2007, there were approximately 0.5 million TB cases multidrug-resistant (TB-MDR). On 27 countries (of which 15 were in the European region) account for 85% of such cases. The five countries with the largest number of cases of MDR-TB are India (131000), China ('s 112,000), Russian Federation (43000), South Africa (16000) and Bangladesh (15000). By the end of 2008, 55 countries and territories had reported at least one case of TB extensively drug-resistant (TB-XDR) [1].

The most important achievements the Oia in the treatment of patients with TB are associated with chemotherapy. Currently, the prior art it is known a large number of anti-tuberculosis drugs. The first chemotherapy appeared in the late 40-ies (streptomycin, sodium para-aminosalitsilata, tibon). Then were created ftivazid, isoniazid and new effective drugs, ethionamide, kanamycin, florimitsin, cycloserine, protionamide. This allowed to make the choice of chemotherapeutic agents, most indicated for the treatment of specific patients. Next came a very effective drugs - rifampicin, ethambutol, mycobutin. However, with the advent of new anti-TB drugs (PTP) is expanding the development of resistance of Mycobacterium tuberculosis (MBT) to them.

In the standard TB chemotherapy in the treatment of all forms) as the main and most effective anti-TB drugs are used isoniazid (isonicotinic acid hydrazide - GINK) [2], who adopted us as a prototype, and rifampicin [2, 3]. Isoniazid has a high therapeutic efficacy, however, is highly toxic (LD₅₀equal to 150 mg/kg), furthermore, when using this drug in the course of long-term treatment of the patient, as a rule, there are digestive disorders, kidney, neuro-psychiatric, hematologic, allergic reactions and toxic hepatitis. In addition to this is, its main drawback is the rapid development of drug resistance of Mycobacterium tuberculosis. Resistance of Mycobacterium tuberculosis to isoniazid develops in 70% of patients and 30% of patients become chronic patients. A semisynthetic antibiotic rifampicin also has high activity against the office and a strong toxic effect. In addition, its major drawback, as with isoniazid, is the rapid development of drug resistance of Mycobacterium tuberculosis, which significantly reduces its effectiveness. Resistance of Mycobacterium tuberculosis to rifampicin develops in 40-50% of patients. With the development of resistance to this antibiotic should be combined with other anti-TB drugs (streptomycin, isoniazid, ethambutol and other drugs [2]. In connection with the problem of development of resistance of Mycobacterium tuberculosis to available drugs arises the need to develop new anti-TB drugs and their combinations.

The authors of the present invention has set itself the task of developing a new highly effective drug with minimal toxic effects and stable during storage.

Detailed description of the invention

The problem is solved in that the authors of the present invention was RA who developed getting a new original TB drugs, including an active substance 4-theorieorientierte perchlorate in the safe and effective amount and a pharmaceutically acceptable excipient.

Get a 4-theorieorientierte perchlorate method that was previously developed by the authors of the present invention lies in the interaction of 4-pyridinediamine (in excess) with thiosemicarbazide in the presence of 48-55%perchloric acid in water-ethanol solution at 80-85°C [4].

According to the invention offer anti-TB medication contains the active substance in an amount of from 5.0 to 90.0% by weight of the dosage form, and pharmaceutically acceptable excipients in an amount of from 11.0 to 100.0% of the mass of the active substance. In terms of the mass of all dosage forms of anti-TB medication contains from 5.0 to 90.0 wt.% 4-theorieorientierte perchlorate by weight of the dosage form and a pharmaceutically acceptable auxiliary substances to 100 wt.%.

An effective amount of the active substance in the dosage form is from 5 to 1000 mg

It is preferable that the inventive anti-TB drug further comprises at least one anti-tuberculosis drug to achieve synergistic effects.

Drug as an additional anti-TB drugs can be one of such active substances as isoniazid, pyrazinamide, rifampicin, rifabutin, amikacin, ethambutol, the antibiotic is a fluoroquinolone or a combination of both.

Preferably, the drug can be manufactured in the form of tablets (enteric-soluble, modified release), combined tablets, capsules, pills, granules, coated tablets, suppositories, suspensions. Dosage forms can be made in the traditional way [5].

The tool according to the invention can be administered as usual oral or parenteral. The dosage depends on age, condition and weight of the patient, and the type of introduction.

Along with the active substance of the medicinal product may contain conventional excipients, adopted in the preparation technology of drugs, such as binders, fillers, preservatives, fluidity regulators, softeners, wetting, dispersing agents, emulsifiers, solvents, antioxidants and/or propellant, prolongator actions [6].

In one of the embodiments of the present invention is preferable as a target additives used sucrose, povidone, microcrystalline cellulose, silicon dioc the ID colloid, ethylcellulose, copolymers of methacrylic acid and ethyl acrylate, triethylcitrate, macrogol, talc, dye the iron oxide in the following ratio of components, % of active ingredient:

Sucrose - 3,1-50,4

Povidone - 0,9-14.4V

Microcrystalline cellulose - 1,1-18,0

Colloidal silicon dioxide is 0.2 - 3,6

Ethylcellulose - 0,2-3,6

The most common ways of obtaining tablets are three technological scheme: wet granulation, dry granulation and direct compression.

In accordance with the present invention, a method for obtaining a new TB drugs.

The closest in technical essence to the proposed object is a method of wet granulation, comprising the following steps: mixing ingredients, moisturizing, granulation, drying, dusting, tableting [7].

The method of obtaining the claimed medicinal product includes the following steps:

a) separately sieved powders 4-theorieorientierte perchlorate, colloidal silicon dioxide, crosspovidone, magnesium stearate, povidone, microcrystalline cellulose, hypromellose (hypromellose), hypromellose (hypromellose), talc, polyethylene glycol, propylene glycol, titanium dioxide, iron OK the IDA yellow;

b) in the reactor for the preparation of the humidifier download cold purified water and povidone, stirred for 30 minutes at 60°C to obtain a clear, homogeneous, pale yellow solution;

to obtain masses for tableting in the mixer load 4-theorieorientierte perchlorate and microcrystalline cellulose and stirred for 15 min, after mixing pour the humidifier, humidifying and mixing carried out for at least 15 minutes until a uniform distribution of the humidifier and smooth;

g) carry out wet granulation mass obtained in stage C);

d) the wet granules obtained in stage g), dried for 20 min at a pressure of 0.2 MPa and a temperature of 55±2°C to a residual moisture content of 1.0 to 2.0%;

e) carry out the dusting and dry granulation obtained in stage d) of the dried granulate, loading it into the hopper vibrating screens and then loading into the mixer, the dry granulate and obogrevateli (Aerosil, crosspovidone, magnesium stearate), avoiding dust, mix half finished within 15 minutes, you get a lot for tabletting;

g) obtained in stage e) mass tabletirujut on a tablet press;

C) on tablets-kernel is applied aqueous suspension of the film shell, consisting of a mixture of hypromellose, iron oxide W is logo, the macrogol, talc, propylene glycol and titanium dioxide, and get the claimed remedy.

The obtained tablets medicinal product according to the invention is coated from yellow to dark yellow, oval, biconvex. At the turn of the tablet from light yellow to yellow with a faint greenish tint.

The output stage is 99,47%. Thus, the method allows to obtain the claimed medicinal product with the highest possible output.

Also in accordance with the present invention proposed an alternative way to get a new TB drugs.

The closest in technical essence to the proposed object is the method of direct compression and wet granulation, comprising the following steps: mixing ingredients, moisturizing, granulation, rolling, and capacity of the granules, the coating film coating and drying [7].

An alternative way to get a new TB composition includes the following steps. Powder 4-theorieorientierte perchlorate is mixed with silicon dioxide colloidal, microcrystalline cellulose and ethylcellulose, moisturize 3,0-5,0% aqueous solution of povidone and 30,0-35,0% sugar syrup, granularit and running-obtained granules. Granules setpri 40-45°C. to a residual moisture content of 1.5 to 4.5%.

The coating on the granules kernel is applied in a known manner from a 20% aqueous solution of methacrylic acid and ethyl acrylate copolymer and suspensions of pigments, talc and dye iron oxide.

Also in accordance with the present invention claims a method for the treatment of all forms of pulmonary and extrapulmonary tuberculosis, as well as prevention in the combination therapy.

According to the claimed method, the drug of the present invention is applied orally or parenterally (subcutaneously, intravenously, intramuscularly, intraperitoneally), the frequency of reception - 1 time per day; single daily dose of 20 mg/kg (1200 mg/day); maximum single dose of 30 mg/kg (1800 mg/day).

To slow the development of resistance of Mycobacterium prescribed in conjunction with other anti-TB drugs or their combinations (isoniazid, pyrazinamide, rifampicin, rifabutin, amikacin, ethambutol, antibiotics, fluoroquinolone).

The biological activity of a medicinal product according to the invention

MATERIALS AND METHODS STUDY ANTITUBERCULOSIS ACTIVITY of a MEDICINAL product ACCORDING to the INVENTION

1. Evaluated in vitro (culture of microorganisms and methods)

Used strains of microorganisms:

1) laboratory test strains belonging to the Mycobacterium tuberculosis complex, obtained from the Federal Government-the military institution "research Institute of standardization and control of medical and biological preparations. Lautareasca", sensitive to existing anti-TB drugs:

- M. tuberculosis Erdman;

- M. tuberculosis H37Rv.

- M. tuberculosis Academia;

- M. bovis bovinus 8;

2) culture multidrug-resistant isolated from patients with newly diagnosed tuberculosis (14 strains):

No. 5419 Spbniif, resistance to isoniazid (10 mg/ml), rifampicin (40 µg/ml) and streptomycin (50 μg/ml);

No. 2483 Spbniif, resistance to isoniazid (1 μg/ml), rifampicin (40 µg/ml), streptomycin (5 and 10 µg/ml), rifabutin (40 µg/ml), ethambutol (2 μg/ml);

No. 3485 and No. 3589 Spbniif resistant to isoniazid (1 μg/ml), rifampicin (20 and 50 µg/ml), streptomycin (50 μg/ml), kanamycin (30 µg/ml), ethambutol (2 μg/ml), ciprofloxacin (30 mg/ml);

No. 3019 Spbniif, resistance to isoniazid (1 and 25 µg/ml), rifampicin (20 and 50 µg/ml), streptomycin, and kanamycin (30 and 50 µg/ml, respectively), ethionamide (30 μg/ml);

No. 3655 Spbniif, resistance to isoniazid (1 μg/ml), rifampicin (20 and 50 µg/ml), streptomycin (50 μg/ml), kanamycin and ethambutol (30 μg/ml);

No. 3689 Spbniif, resistance to isoniazid (1 μg/ml), rifampicin (20 and 50 µg/ml), streptomycin (50 μg/ml), kanamycin (30 µg/ml);

- No. 3910 Spbniif, resistance to isoniazid (1 μg/ml), rifampicin (20 and 50 µg/ml), streptomycin (50 μg/ml), kanamycin and ethionamide (30 μg/ml);

No. 1201 Spbniif, steadily the TB isoniazid (1 μg/ml), rifampicin (20 μg/ml), streptomycin (50 μg/ml), kanamycin (30 µg/ml), ethambutol (2 μg/ml);

No. 41 and No. 779 Spbniif resistant to isoniazid (1 μg/ml), rifampicin (20 and 50 µg/ml), streptomycin (50 μg/ml);

No. 1081 Spbniif, resistance to rifampicin (20 μg/ml), streptomycin (50 μg/ml);

No. 1719 and No. 1279 Spbniif resistant to isoniazid (1 μg/ml), rifampicin (20 μg/ml), streptomycin (50 μg/ml kanamycin and ethionamide (30 μg/ml);

3) non-specific microorganisms sensitive to antimicrobial agents (from the collection of the Federal state institution "St. Petersburg FIP University")

- gram-negative Bacillus - E. coli;

- gram positive cocci - Staphylococcus aureus, Streptococcus aureus, Corynebacterium pseudodiphtericum (diphtheroid).

Antibacterial activity of perozone studied the standard method twofold serial dilutions in nutrient media with respect to biological properties of the test strains:

- synthetic medium Sotona with 10% normal serum (M.);

- sugar broth (for gram-positive and gram-negative bacteria).

The microbial suspension was prepared ex tempore, the working concentration of 5×10⁶cells/ml

The range of the investigated doses perlson ranged from 100 to 0.19 µg/ml of each culture was performed according to 3 re-examination. Suspensions of test strains were made in 0.2 ml in the test and control tubes: mycobacterial suspension Metodologicheskie layers, a suspension of non-specific bacteria by the method of deep planting. The growth rate of non-specific microbes were taken into account in 24 hours, mycobacterial film in 7-10 days. The activity criterion was the minimum concentration means according to the invention in a nutrient medium, completely inhibiting the growth of microorganisms (MIC, μg/ml).

To simulate experimental tuberculosis used strain .bovis bovinus 8, sensitive to drugs.

Evaluation of therapeutic effect of the means according to the invention. Used the index of treatment efficiency IE (%) - equity as the differences in severity of TB infection in the control groups and in the groups of animals treated with the product according to the invention. The performance index was determined by the formula

where n_toand n_o- average values respectively in the control and experimental groups.

A positive value IE (plus effect) indicates the decrease in the prevalence or increase therapeutic activity of the composition of anti-TB drugs under the action of the means according to the invention.

A negative value IE (negative effect) indicates an increase of HIV prevalence, or the weakening of therapeutic action of the composition however, is under treatment under the influence of the means according to the invention.

When assessing the validity of the Comparators effects were calculated similarly and marked in accordance with generally accepted symbols (by the first letter of the drug).

The degree of connection variations in received therapeutic effects were determined by the correlation coefficient (r), quantitatively measured by the regression coefficients in y/X. this used the standard methods of calculating the student - Fisher.

2. Antibacterial activity means according to the invention in vitro

The results of a study of the impact tool according to the invention on the growth of standard test strains included in the Mycobacterium tuberculosis complex, sensitive to existing drugs, are shown in table 1.

As can be seen from table 1, the tool according to the invention inhibited the growth of test strains in the concentration range from 1.56 to 6.25 µg/ml Highest inhibitory activity tool according to the invention showed in relation to .bovis bovinus 8, the initial inhibition of growth (++) detected at a concentration of at 0.19 μg/ml, complete inhibition of growth (MIC) is at a concentration of 1.56 µg/ml of this weakening of the inhibitory effect of the strains was as follows:

- M. tuberculosis Erdman (MIC=3,125 mg/ml)

- M. tuberculosis H37RV u M tuberculosis "Academia" (MIC=at 6.25 µg/ml)

In order to identify the breadth of the spectrum of antibacterial activity perlson studied its action against gram-positive cocci (Staphylococcus aureus, Streptococcus aureus)and gram-positive and gram-negative rods (E. coli and diphtheroid). The results of the study are presented in table 2.

As can be seen from the table 2 data, the tool according to the invention even at high concentrations in the medium (100 μg/ml) had no effect on the growth of gram-positive and gram-negative cultures of microorganisms.

The inhibiting means according to the invention in relation to drug-sensitive Mycobacterium studied in 14 clinical isolates, of which 2 (14,3%) were resistant to 6 drugs (PTP), 7 (50%) 5 PTP, 1 (7,1%) - 4 PTP, 3 (21,4%) - 3 PTP, is 1 (7,1%) - to 2 PTP (table 3).

Testing has shown that the tool according to the invention inhibited the growth of all drug-resistant clinical isolates:

- 14,3% (2 strains) in the dose of 1.56 µg/ml;

- 50,0% (7 strains) in the dose of 3.125 mg/ml;

of 28.6% (4 strains) in a dose of 6.25 µg/ml;

at 7.1% (1) strain - at a dose of 50.0 mg/ml

It should be noted the effectiveness of the inhibitory effect of the means according to the invention against strains that are resistant to 5-6 TB drugs, where MICK for 88.8% of the crop was of 3.125 and 6.25 µg/ml

Thus, the results of in vitro studies established that the means according to the invention is:

- has a selective antimicrobial activity, acting only on the viability of Mycobacterium tuberculosis;

- possesses a strong anti-TB activity in sensitive and resistant strains of the office.

1.2. The effectiveness of monotherapy tool according to the invention in experimental tuberculosis in mice

The study was performed on 20 nonlinear white mice-males weighing 18-20 g Mice strain M. bovis bovinus 8 caused the clinical picture of generalized tuberculosis, on the 11th day after infection in the lungs visualized specific foci of inflammation. From that day on, experimental animals started introduction the study drug.

On the 52nd day after infection, the mortality in the control group (infected, untreated animals) accounted for 95.8% (table 4).

The tool according to the invention at a dose of 10 mg/kg reduced the mortality by 31.6%, and in doses of 20 mg/kg and 30 mg/kg - 73.9% and 97,5% respectively (see table 4). Protective effect means according to the invention is also manifested in the form of reduced loss of body weight the sick mice. In the dose of 10 mg/kg tool according to the invention reduced the drop weight is 5.3%, and in doses of 20 mg/kg and 30 mg/kg - 21.5% and 19.0% (see table 4).

Thus, the high protective and therapeutic indicators means according to the invention in terms of monotherapy mice with experimental tuberculosis characterize it as an effective antimycobacterial tool. These results are consistent with the ability of the tool according to the invention inhibit the growth of the test strain M. bovis bovinus in vitro (see table 1).

2. The effectiveness of monotherapy means according to the invention in experimental tuberculosis in rabbits

The study was performed on 18 rabbits male breed chinchilla infected marginal ear vein of the test strain of M. bovis bovinus 8. The tool according to the invention was introduced animals (n=6) on the day of infection at a dose of 20 mg/kg oral, course duration - 2 months.

Comparison group: infected untreated rabbits (control of infection, n=6) and infected treated with isoniazid (15 mg/kg, oral, n=6). The results of the experiment are presented in table 5.

As can be seen from table 5, the tool according to the invention is more effective than isoniazid, preventing the death of rabbits from TB infection to increase their body mass (average 77,17% against 74,67% for isoniazid).

2.1. The impact tool according to the invention for therapeutic effect of anti-TB drugs in experimental tuberculosis in mice

The study was performed on 250 nonlinear white mice-males. Evaluation of 6 combinations of means according to the invention (20 mg/kg, oral) anti-TB drugs (PTP)with different specific activity. In the comparison groups were simultaneously analyzed PTP in the medium therapeutic doses. Treatment was started in all groups on day 12 after infection on the background of a confirmed specific inflammatory PR the process in the lungs at autopsy of mice from the control group contamination. The results of the experiment were taken into account through 42 days (6 weeks) therapy.

The impact tool according to the invention for therapeutic effect of anti-TB drugs on the prevalence of bodies varied depending on the properties of the drugs used (table 6). Depending on the characteristics of the interaction with the tool according to the invention PTP divided into 3 groups.

Group 1. PTP showing synergene interaction with the tool according to the invention (increased therapeutic effect over all prevalence of bodies):

- Isoniazid - increased therapeutic activity on average by 13.9% with a variation of 3.6% (the reduction ratio of the mass of the liver) to 25% (decrease massiveness CFU in the spleen);

- Amikacin - increase efficiency on average 11,34% variation from 34.6 per cent (a decrease in the ratio of spleen weight, p<0,001) to 1.8% (decrease of the lung).

Group 2. PTP, which have therapeutic activity increases on most prevalence (three of five):

- Rifampicin - efficiency gains on to 9.66% by reducing the coefficients of the weight of the lungs (18.2%, p<0.05)and spleen (by 34.6%, p<0.01) and liver (1.6%) with the increase in the number of CFU 6.19%;

- Rifabutin - increase efficiency by 7.68% due to the reduction ratios of the masses of light (12.4%) and spleen (20.6%, p<0.05), and reduce Visavuori the office of the CE is esence (13.2%), but when this was raised with two parameters - the ratio of liver mass index and lung (0.4% and 7.4%, respectively);

- Ethambutol - efficiency gains on 11,44% due to the reduction ratios of the masses of the spleen (by 22.1%), liver (8.9%) and the number of CFU in the spleen (33.3%) with increasing index of the lungs and their weight (4.0 and 3.1%, respectively).

Group 3. Drugs that interact with the tool according to the invention primarily by the type of antagonism:

- Ofloxacin - efficiency decrease by 6.2% with a variation of the indicators from 4,65 to 11.9%, with the exception of the index of the lungs with positive therapeutic effect of 2.6%.

The state of phagocytic function TFM in the studied groups are presented in table 7. As the table shows, the average macrophage activity TFM monotherapy tool according to the invention was at the level of intact mice (132,41 against 154,97). The activating action of the means according to the invention is extended to those drugs, which would reduce the efficiency of phagocytosis when alone. Under the influence means according to the invention has registered the activation of phagocytosis in complex with 3 TB drugs: rifampicin - 1.4 times (71,43 to 99,12), rifabutin - 1.3 times (66,88 to 83,55), ooxacin - 1.2 times (95,14 to 111,66). Three PTP observed decreased activity of TFM when combined with the tool according to the invention. So, fall is their average macrophage activity on the background of the means according to the invention seen in isoniazid 1.2 times (with 77,66 to 66,54); the ethambutol - 1.3 times (from 106,35 to 81,95), amikacin - 2.8 times (with 193,42 to 68,29).

Morphological indicators in the context of monoplane six anti-TB drugs and composition tool according to the invention are shown in table 7. On set of test metrics tool according to the invention reduce the extent of affected lung tissue when combined with rifampicin - 16.9%with isoniazid - 10.1%, with ooxacin - 3,24%, with ethambutol - 3,19%, amikacin - 2.56%. The rising rates of lung damage was observed only with the joint purpose of a tool according to the invention with rifabutin (15.9%).

Classification of anti-TB drugs on the expression of therapeutic actions on the background of the means according to the invention, accounted for seven of the most informative tests established using correlation analysis, presented in table 8. Three songs with the greatest positive effect on the seven tests lesions (20 cases). Among the leaders of the composition rifabutin + tool according to the invention and rifampicin + tool according to the invention (7 cases each). Rarely, the composition amikacin + tool according to the invention (in 4 cases) and isoniazid + tool according to the invention (in 2 cases). Weak action is noted in the compositions of the means according to the invention with ooxacin and atmb what tol.

Summing up, it is safe to say that the tool according to the invention has a strong, highly selective inhibitory effect on the viability of Mycobacterium tuberculosis susceptible and resistant to existing drugs. The tool according to the invention is low toxic substance, no significant structural and functional disorders of vital organs and systems, as well as irritating to the mucous membranes of the gastrointestinal tract.

The tool according to the invention has moderate embryotoxicity, mainly with the introduction of it in the period of organogenesis, acts selectively, depending on individual susceptibility to it individuals. Teratogenic effects tool according to the invention shows only at the dose of 100 mg/kg (five times greater than therapeutic) with the introduction of the period of organogenesis in the form of increased Nisnevich anomalies of the skeleton, the deceleration of ossification of the sternum and the bones of the limbs, as well as edema and subcutaneous hemorrhages. Irregularities in the development of the placenta and changes in fo the formation of sex is not happening. The tool according to the invention with a long introduction animal does not violate the reproductive function, does not affect the development of offspring.

The tool according to the invention does not show allergenic, immunotoxic, mutagenic properties.

Thus, given the above experimental data can safely be noted that the technical result of the claimed invention lies in the creation of new drugs with enhanced tuberculostatic activity (200 times higher) and 2.4 times less toxicity compared to the drug of the prototype.

In addition, the tool according to the invention in combination with other anti-TB drugs (combination with rifabutin, rifampicin, isoniazid, amikacin and ethambutol) was increased therapeutic efficacy compared with monotherapy tool according to the invention.

Claimed the drug is stable in storage, does not change the appearance, physical characteristics and biological properties within 3 years.

The examples below illustrate (without limitation of the scope of claims), the most preferred embodiments of the invention, and confirm the possibility of obtaining the claimed medicinal product.

Example 1.

Drug, the implementation of the military in the form of tablets, has the following composition, and the ratio of components, wt.% (ratio of all components are given in terms of 100 wt.% core tablets).

Composition per tablet:

Tablets with modified release 100, 200, 400, 800, 1000 mg

Composition per tablet, mg:

Tablets, enteric-coated shell 200, 400, 500, 600, 800 mg

Composition per tablet, mg:

Example 2.

The drug is in the form of a solid dosage form coated pellets. The presence of a shell of the claimed composition gives the stability of the composition during storage, good appearance and improves organoleptic properties.

Pellets of a medicinal product according to the invention, coated

Composition per 100 g:

As the shell proposed the following composition at zootoxin and components wt.% from the pellet weight-kernel:

Methacrylic acid and ethyl acrylate copolymers - 3,0-4,0

Triethylcitrate - 0,8-1,8

Macrogol - 0,2-0,4

Talc - 0,9-1,3

The colorant iron oxide - 0,2-0,3

Example 3.

The drug is in the form of pills 100, 200, 300, 400 mg

Part one bean:

Example 4.

The drug is in the form of capsules, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg

Composition per capsule:

Example 5.

The drug is in suspension.

Powder 4-theorieorientierte perchlorate for preparation of oral suspension

bottles of 100 ml) 200 mg/5 ml, 300 mg/5 ml, 400 mg/5 ml

Composition per 100 ml:

All components and their ratio was found experimentally to be optimal, allowing for pharmaceutical anti-TB drug that meets the requirements of the state Pharmacopoeia.

Example 6.

The drug is in the form of rectal suppositories 50 mg, 100 mg, 200 mg, 300 mg

Example 7.

(Trust supplements: 4-theorieorientierte perchlorate was 44.5 wt.%)

The sifted powders 4-theorieorientierte perchlorate in the number 70,0, microcrystalline cellulose in an amount of 5.0 g of colloidal silicon dioxide in a quantity of 1.0 g of ethyl cellulose in an amount of 1.0 g is loaded into the mixer, stirred for 5-10 min at a speed of 25 Rev/min the resulting mixture is moistened with an aqueous solution of povidone, sucrose, obtained from 4.0 g of povidone, 14.0 g of sucrose and 28 ml of water, pass the wet mass through a granulator, wet granules practicing, increasing and dried at 40-45°C. until the moisture content of the granules of 1.5 to 4.5%. The obtained granules-kernel sift through a set of sieves with mesh size of 1.0 mm to 3.0 mm At the core of the granules ranging in size from 1.0 to 3.0 mm nano is Yat prepared by forming a suspension on the basis of copolymers of methacrylic acid.

0.85 grams of talc and 0.2 g of the dye of iron oxide is crushed with 0.2 g of macrogol and 5 ml of water to a creamy consistency and mixed with 3.0 g of methacrylic acid copolymer, dispersed in 15 ml of water. Applying a film coating on the granules-core lead after heating to 45-50°C with constant stirring and simultaneous drying with hot air to obtain a 100.0 g is evenly coated granules. The obtained pellets meet all the requirements of the state Pharmacopoeia.

Example 8.

(Trust supplements: 4-theorieorientierte perchlorate - of 11.0 wt.%)

Target take supplements in the same composition as in example 6, but in different quantities. The sifted powders 4-theorieorientierte perchlorate in an amount of 90.0 g of microcrystalline cellulose in a quantity of 1.0 g of colloidal silicon dioxide in an amount of 0.2 grams of ethyl cellulose in an amount of 0.2 g is loaded into the mixer, stirred for 5-10 min at a speed of 25 Rev/min the resulting mixture is moistened with an aqueous solution of povidone, sucrose, obtained from 0.8 g of povidone, 2.8 g of sucrose and 6 ml of water, pass the wet mass through a granulator, wet granules practicing, increasing and dried at 40-45°C. until the moisture content of the granules of 1.5 to 4.5%. The obtained granules-kernel sift through a set of sieves with mesh size of from 1.0 to 3.0 mm At the core of the granules ranging in size from 1.0 to 3.0 mm is applied to prepare the certain film-forming suspension on the basis of copolymers of methacrylic acid.

0.85 grams of talc and 0.2 g of the dye of iron oxide is crushed with 0.2 g of macrogol and 5 ml of water to a creamy consistency and mixed with 3.0 g of methacrylic acid copolymer, dispersed in 15 ml of water.

Applying a film coating on the granules-core lead after heating to 45-50°C, with constant stirring and simultaneous drying with hot air to obtain a 100.0 g is evenly coated granules. The obtained granules are red or yellow, round or irregular shapes meet all the requirements of the state Pharmacopoeia.

Example 9.

(Trust supplements: 4-theorieorientierte perchlorate - 100.0 wt.%)

Target take supplements in the same composition as in example 6, but in different quantities. The sifted powders 4-theorieorientierte perchlorate in an amount of 50.0 g of microcrystalline cellulose in the amount of 9.0 g of colloidal silicon dioxide in an amount of 1.8 g of ethyl cellulose in an amount of 1.8 g is loaded into the mixer, stirred for 5-10 min at a speed of 25 Rev/min the resulting mixture is moistened with an aqueous solution of povidone, sucrose, obtained from 7.2 g of povidone, 25,2 g sucrose and 50 ml of water, pass the wet mass through a granulator, wet granules practicing, increasing and dried at 40-45°C. until the moisture content of the granules of 1.5 to 4.5%. The obtained granules-kernel sift through a set of sieves with mesh size of the t 1.0 to 3.0 mm At the core of the granules ranging in size from 1.0 to 3.0 mm put the prepared film-forming suspension on the basis of copolymers of methacrylic acid. 0.85 grams of talc and 0.2 g of the dye of iron oxide is crushed with 0.2 g of macrogol and 5 ml of water to a creamy consistency and mixed with 3.0 g of methacrylic acid copolymer, dispersed in 15 ml of water.

Applying a film coating on the granules-core lead after heating to 45-50°C, with constant stirring and simultaneous drying with hot air to obtain a 100.0 g is evenly coated granules. The obtained pellets meet all the requirements of the state Pharmacopoeia.

Example 10.

Separately sieved powders 4-theorieorientierte perchlorate, silicon dioxide colloidal, crosspovidone, magnesium stearate, povidone, microcrystalline cellulose, hypromellose, talc, macrogol, propylene glycol, titanium dioxide, iron oxide yellow, taken in sufficient quantities according to example 1.

In the reactor for the preparation of the humidifier load estimated amount of cold purified water and povidone, stirred for 30 minutes at 60°C to obtain a clear, homogeneous, pale yellow solution. Loaded into the mixer estimated number 4-theorieorientierte perchlorate and microcrystalline cellulose is stirred for 15 min, after stirring download humidifier, humidifying and mixing carried out for at least 15 minutes until a uniform distribution of the humidifier and smooth. Perform wet granulation mass, the wet granulate is dried for 20 minutes at a pressure of 0.2 MPa and a temperature of 55±2°C to a residual moisture content of 1.0 to 2.0%. Exercise dusting and dry granulating the dried granulate, load it into the hopper vibrating screens and then loaded into the mixer, the dry granulate and obogrevateli (colloidal silicon dioxide, crosspovidone, magnesium stearate), avoiding dust, mix half finished within 15 minutes, you get a lot for tableting. The resulting mass tabletirujut on the tablet press.

On tablets-kernel is applied aqueous suspension of the film shell, consisting of a mixture of hypromellose, iron oxide yellow, macrogol, talc, propylene glycol and titanium dioxide and receive the medicinal product according to claim 1.

Example 11.

(Trust supplements: 4-theorieorientierte perchlorate - 20 wt.%)

The sifted powders 4-theorieorientierte perchlorate in the amount of 200.0 g of dry potato starch in an amount of 16.0 g of microcrystalline cellulose in the amount of 12.0 g of crosspovidone in the amount of 8.0 g of colloidal silicon dioxide in an amount of 2.0 g of magnesium stearate in the number is the amount of 2.0 g loaded into the mixer, stirred for 5-10 min at a speed of 50 rpm until a homogeneous distribution of the active ingredient in mass. The moisture content in the mixture of 1-3%. The resulting mass is loaded into the machine for encapsulation and fill the capsules. Capsules dedust and Packed in jars polymer or contour one-way packaging. Get 1000 capsules medicinal product according to the invention with a total mass content 240,0 g or 0.24 g ± 10% of each capsule with the content of the active ingredient 0.20 g ± 10%. The obtained capsules satisfy all the requirements of the pharmaceutical agent.

Example 12.

(Trust supplements: 4-theorieorientierte perchlorate - 33.3 wt.%)

Targeted supplements take in the same amount as in example 1, but instead of potato starch take corn, and the number of 4-theorieorientierte perchlorate - 180, Get 1000 capsules medicinal product according to the invention with a total mass content 240,0 g or 0.24 g ± 10% of each capsule with the content of the active ingredient 0.20 g ± 10%. The obtained capsules satisfy all the requirements of the pharmaceutical agent.

Example 13.

(Trust supplements: 4-theorieorientierte perchlorate - 9.1 wt.%)

Targeted supplements take in the same amount as in example 1, but instead of stearate and magnesium take calcium stearate, and the number of 4-theorieorientierte PE the chlorate - 220, Receive 1000 capsules medicinal product according to the invention with a total mass content 240,0 g or 0.24 g ± 10% of each capsule with the content of the active ingredient 0.20 g ± 10%. The obtained capsules satisfy all the requirements of the pharmaceutical agent.

Example 14.

Use the method of obtaining the suppository method of pouring. Calculate the quantity of ingredients to obtain 100 suppository. In the shredder download 4-theorieorientierte perchlorate in the amount of 5.0 g of β-cyclodextrin in an amount of 4.0 g of glycerol in the amount of 1.0 g and pulverized for 30 minutes. The resulting suspension is mixed in the reactor with 15.0 g suppozitornoj bases and macrogol heated to 45°C. the resulting concentrate is cooled and milled using a three-wheel of masseteric for 3 hours to obtain the desired degree of dispersion of the medicinal product according to the invention. The finished concentrate is mixed with 35,0 g suppozitornoj bases and macrogol at a temperature of 48°C until smooth and produce molding by pouring into molds and packaging suppository. Get 100 suppository that meets the requirements of: average weight and uniformity to the weight of 0.60 g ± 5%, the melting point is not higher than 37°C, the quantitative content of the 4-theorieorientierte perchlorate in suppositories- 0,05 (0,046-0,054).

Example 15.

Sifted p the Rosca 4-theorieorientierte perchlorate in the amount of 4.0 g, β-cyclodextrin in an amount of 0.40 g of povidone in the number of 1.40 g load in a ball mill and milled for 3 hours. To the resulting complex load sifted powders sucrose in the number of 3.95 g of citric acid in the amount of 0.20 g and vanillic fragrance in an amount of 0.01 g and pulverized for 1 hour. The ground mass of powder discharged into the mixer, it loads the silicon dioxide colloidal in the amount of 0.04 g and mixed for 5-10 min until homogeneous at a speed of 50 Rev/min the resulting mixture was Packed on the machine in the vials 10,0, Vials hermetically sealed with a lid and placed in a box with a measuring spoon 5 ml of the suspension Obtained meets the requirements of: the deviation of the mass of the bottle contents from 9.7 to 10.3 g, water content in the powder is not more than 2%, pH 5-8, the sedimentation stability of the suspension - not less than 24 hours.

For internal use powder dissolved in 90 ml of water to the mark and use a measuring spoon 5 ml on admission. 100 ml containing 20 doses of 200 mg of the active ingredient 4-theorieorientierte perchlorate.

Example 16.

Combined drug is in the form of capsules 100 mg + 100 mg, 150 mg + 200 mg (rifampicin + perlson)

Composition per capsule:

Sources of information

1. The report of the world health organization (who) in 2009 (found on the Internet at the address http://www.who.int/tb/publications/global_report/2009/key_points/ru/index.html).

2. Mashkovsky PPM "Drugs", Vol.2, Kharkov, Torching", 1997, SS-333, 341-342.

3. Khomenko A.G. "Chemotherapy of pulmonary tuberculosis". - M, Medicine, 1980. - 279 S.

4. RF patent №2265014 from 13.05.2004.

5. "Pharmaceutical technology. Technology of medicinal forms", 2nd ed., M., 2006.

6. Sucker et al.: Pharmazeutische Technologie, Thieme-Verlag, Stuttgard, 1991.

7. Technology of medicinal forms./Ed. by L.A. Ivanova. - M.: Medicine, 1991, vol. 2, p.142, p.223.

1. Anti-TB drug, which includes an active ingredient and pharmaceutically acceptable excipients, characterized in that the active substance it contains 4-theorieorientierte perchlorate in a therapeutically safe and effective amount.

2. Anti-TB drug according to claim 1, characterized in that it contains from 5.0 to 90.0 wt.% 4-theorieorientierte perchlorate by weight of the dosage form and a pharmaceutically acceptable auxiliary substances to 100 wt.%.

3. Anti-TB drug according to claim 1, characterized in that h is about as pharmaceutically acceptable auxiliary substances it contains sucrose, povidone, microcrystalline cellulose, colloidal silicon dioxide and ethylcellulose in the following ratio of ingredients, % by weight of the core tablet:

4. Anti-TB drug according to claim 1, characterized in that it is coated containing copolymer of methacrylic acid and ethyl acrylate, triethylcitrate, macrogol, talc, dye the iron oxide in the following ratio of ingredients, % by weight of the core tablet:

5. Anti-TB drug according to claim 1, characterized in that it additionally contains at least one anti-tuberculosis drug, the total content of which does not exceed a 90.0 wt.% by weight of the medicinal product according to claim 1.

6. Anti-TB drug according to claim 5, characterized in that as an additional drug it contains isoniazid, pyrazinamide, rifampicin, rifabutin, amikacin, ethambutol, the antibiotic is a fluoroquinolone or a combination of both.

7. Anti-TB drug according to claim 1, characterized in that it is made in the form of pills combined pills, capsules, pills, granules, coated tablets, suppositories, suspensions.

8. The method of obtaining anti-TB drugs according to any one of claims 1 to 7, comprising sieving and mixing powders of the active substance and the target additives, followed by pressing or moisture, the wet granulation mass, drying of the granulate, dry granulation, the powder, the formation of tablets of a nucleus with subsequent coating shell, characterized in that
a) as a method of obtaining mass is used for tabletting method of wet granulation;
b) as a method of obtaining cores tab is etoc used method of compression;
in) as a way of drawing of the method of application of the membrane in the form of water-soluble suspension.

9. The method of obtaining anti-TB drugs according to any one of claims 1 to 7, comprising mixing ingredients, moisturizing, granulation, breaking capacity granules, the coating film coating and drying, characterized in that
a) as a method of producing granules used method of increasing granules with a mixture of povidone and sugar syrup, followed by drying;
b) as a way of drawing of the method of application of the membrane in the form of water-soluble suspension.

10. The method of treatment and/or prevention of all forms of pulmonary and extrapulmonary tuberculosis, characterized in that carry out the administration of a medicinal product according to any one of claims 1 to 7 in therapeutically effective amounts.

11. The method according to claim 10, characterized in that the introduction of medicines carried out orally or parenterally.

12. The method according to claim 10, characterized in that the applied once daily administration of a medicinal product according to any one of claims 1 to 4 at a dose of 20 mg/kg