RU2413517C1 - Combined antituberculous composition - Google Patents

Abstract

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to an antituberculous composition which can represent a solid dosage form containing a therapeutically effective amount of an active principle - a combination of sodium paraaminosalicylate (PAS) and zinc sulphate.

EFFECT: invention provides a synergetic effect which consists in higher antimycobacterial activity and enabled therapy of drug resistant forms of tuberculosis complicated by pulmonary tissue destruction.

9 cl, 1 ex

Description

The invention relates to medicine, specifically to combination anti-TB drugs, and can be used to treat various forms of tuberculosis.

Despite significant success in many areas of medicine, including in the treatment of tuberculosis, the incidence of tuberculosis remains extremely high. The main problem of reducing the effectiveness of treatment for tuberculosis patients remains the rapid development of drug-resistant forms of tuberculosis, the limited arsenal of anti-TB drugs, and the decrease in the immune status of tuberculosis patients.

According to official statistics in Russia, at present, the clinical cure rate for newly diagnosed patients with tuberculosis remains at a rather low level (Shilova M.V. Tuberculosis in Russia in 2008 / M.V. Shilova - Moscow, 2008).

Treatment of a patient with tuberculosis must necessarily be comprehensive and strictly individual based on the principles of evidence-based medicine and should be carried out for a long time until the maximum positive result is obtained, including until complete clinical cure, if we keep in mind the group of newly diagnosed patients (V. Mishin. Treatment of patients with tuberculosis lungs // Teaching aid for doctors. - M: MGMSU. - 2006. - 120 p.).

An individual set of treatment methods for each patient is chosen by the attending physician, and this implies: determining the organizational form of treatment (inpatient, sanatorium, outpatient), choosing a combination of anti-TB drugs and determining the chemotherapy regimen taking into account the regional and individual drug sensitivity of the office, the choice of pathogenetic methods aimed at normalization of impaired body functions, a decrease in the degree of inflammatory reaction, elimination of metabolic and immune disorders, as well as stimulating therapy (Manicheva O.A., Skvortsova L.A., Pavlova M.V., Sapozhnikova N.V., Archakova L.I., Vishnevsky B.I. Bacteriostatic blood activity in patients with respiratory tuberculosis. // Mat. VIII Ross. Congress of TB doctors. - M. - 2007. - P.124 .; Mishin V.Yu. Optimization of treatment of newly diagnosed pulmonary tuberculosis patients based on the principles of evidence-based medicine // CONSILIUM medicum - 2008 / - No. 3. - С .20-25).

Tuberculosis chemotherapy is an etiotropic (specific) therapy for patients using the optimal combination of anti-TB drugs (hereinafter PTP), which is aimed at destroying the mycobacterial population (bactericidal effect) or suppressing its multiplication (bacteriostatic effect) (Khomenko A.G. Chemotherapy of pulmonary tuberculosis. - Moscow - 1980 .-- 279 p.).

Only when the MBT is destroyed or their reproduction is suppressed, it is possible to launch adaptive mechanisms aimed at eliminating the clinical manifestations of the disease, resolving inflammatory changes in the lungs, activating reparative processes, restoring damaged morphological structures, and restoring functional disorders of organs and systems in the patient’s body, i.e. to create conditions for complete clinical cure (V. Mishin. Optimization of treatment of newly diagnosed pulmonary tuberculosis patients based on the principles of evidence-based medicine // CONSILIUM medicum - 2008 / - No. 3. - P.20-25).

In the Russian Federation, according to the Order of the Ministry of Health of the Russian Federation No. 109 of March 21, 2003, anti-TB drugs are used to treat newly diagnosed tuberculosis patients, which are divided into main and reserve ones. The main drugs: isoniazid, rifampicin, pyrazinamide, ethambutol, streptomycin. Reserve preparations: protionamide (ethionamide), kanamycin, amikacin, capreomycin, cycloserine, rifabutin, PASK, fluoroquinolones.

Anti-TB drugs of the main series are more effective, have high bactericidal activity against tuberculosis mycobacteria (hereinafter referred to as the Office). However, with their prolonged use, which is required for the treatment of tuberculosis, the resistance of the office develops over several months. For the treatment of drug-resistant forms of tuberculosis, backup anti-TB drugs are used.

p-aminosalicylic acid and its sodium salt (hereinafter referred to as PASK) have bacteriostatic activity against MBT and belong to reserve anti-TB drugs. In terms of tuberculostatic activity, PASK is inferior to isoniazid and other mainstream anti-TB drugs, however, it acts on mycobacteria resistant to the above drugs. (Mashkovsky M.D., Medicines. - M.: Medicine, 1993, v. 2, p. 366-367, 372).

The most convenient form of PASK for the treatment of tuberculosis patients should be recognized as tablets.

US Pat. No. 2,676,902, 1954, claims a composite product for treating tuberculosis that contains PASK or a non-toxic salt thereof and an adjuvant, p- (di-n-propylsulfamyl) benzoic acid. The invention solves the problem of only reducing the side effects of taking large amounts of PASK, which are necessary for the treatment of tuberculosis.

In order to prevent the development of drug-resistant mycobacteria in the treatment of tuberculosis, they went in two ways: creating combined dosage forms with fixed doses of anti-TB drugs, which include drugs of various groups, or the patient is given a combination of different classes of anti-TB drugs at the same time.

Researchers have proposed a number of other approaches to improve the outcome of treatment, including various methods of immunomodulation and immunotherapy. Studies have shown that the administration of zinc-containing drugs to patients with pulmonary tuberculosis leads to accelerated sputum negation and improves radiological parameters (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 the Russian Federation No. 2253460, 2005, a method for treating pulmonary tuberculosis is claimed, including chemotherapy with combinations of anti-TB drugs based on isoniazid or isoniazid and rifampicin, characterized in that zinc sulfate is also prescribed in a daily dose of 2.30-3.5 mg / kg two or three times an oral course of 21-28 days, which allowed to reduce the duration of chemotherapy due to the pronounced anti-apoptotic effect on T-lymphocytes.

In the patent of the Russian Federation No. 2182483 a combined anti-tuberculosis drug is proposed that contains isoniazid and pyrazinamide or ethambutol hydrochloride. However, the presence in its composition of only two active ingredients does not completely remove the above-mentioned disadvantages of combination therapy and requires the appointment of other anti-TB drugs.

In order to reduce the development of drug resistance of tuberculosis mycobacteria, multicomponent anti-TB drugs containing three or more active substances have been proposed. For example, US Pat. No. 5,104,875, 1992, describes a pharmaceutical combination preparation containing rifampicin, thiacetazone and, optionally, isoniazid or ethambutol.

In the patent of the Russian Federation No. 2195937, 2003, a combined anti-tuberculosis drug is proposed containing, as an active principle, a combination of isoniazid, rifampicin, pyrazinamide, ethambutol and pyridoxine, and methocell, methyl cellulose ethers containing 14-30% methoxy groups as an excipient.

Known analog drugs have a number of disadvantages. With the course use of the above drugs, a pronounced toxic effect and the occurrence of side effects are observed. In addition, in the known combined formulations, the mutual influence of the ingredients leads to a significant decrease in the bioavailability of the active principle, which worsens the anti-tuberculosis efficacy and causes the return of the disease, and the development of secondary drug resistance.

Thus, an important aspect in the selection of the constituent ingredients of the active principle of combined anti-TB drugs is the consideration of their interaction and compatibility in the manufacturing and storage process.

The present invention is the creation of a new anti-tuberculosis drug with high antibacterial activity against drug-resistant mycobacterium tuberculosis, in which toxic side effects are minimized, which will expand the range of anti-TB drugs.

The problem is solved in that the proposed anti-tuberculosis agent includes a therapeutically effective amount of the active principle, which contains a combination of PASA and a zinc-containing compound and pharmaceutically acceptable excipients.

According to the invention, as an active principle, the composition comprises a combination of PASA and a zinc-containing compound. The proposed combination of active ingredients is new for combined anti-TB drugs and has been found experimentally.

In the framework of this invention, PASK means p-aminosalicylic acid or its salt, preferably a sodium salt, which has other names - sodium para-aminosalicylate or sodium aminosalicylate. As the zinc-containing compound, zinc salts, more preferably zinc sulfate, are preferably used.

The preferred amount of PASK and zinc-containing compounds (in terms of elemental zinc) is, parts by weight:

PASK - 500-2000

Zinc-containing compound

(in terms of elemental zinc) - 0.75-3.0.

When zinc sulfate is used as the zinc-containing compound, its preferred amount is:

- 3.3-13.2 parts by weight if zinc sulfate is introduced into the composition as heptahydrate, or 2.0-8.25 parts by weight if zinc sulfate is introduced into the composition as monohydrate. Most preferably, zinc sulfate is used in an amount equivalent to 1.5 parts by weight. elemental zinc per 1000 parts by weight PASK.

The use of the claimed combination of active ingredients provides a synergistic effect, consisting in a significant increase in antimicrobial activity with respect to drug-resistant mycobacterium tuberculosis, and the inclusion of zinc sulfate in the composition makes it possible to use a new drug for the treatment of drug-resistant forms of tuberculosis complicated by destruction of lung tissue.

Biological studies in vitro and in vivo showed that the claimed composition has a high anti-tuberculosis activity, while the composition also affects drug-resistant strains of mycobacterium tuberculosis.

In vitro studies have allowed the microbiological methods to study the bacteriostatic and bactericidal activity of a new complex anti-tuberculosis drug (hereinafter - PASK ZINC) in relation to Mycobacterium tuberculosis (MBT) laboratory strain H37Rv, MBT MDR strains and MBT XDR strains. The determination of the antimycobacterial effect of the drug was carried out in accordance with the "Guidelines for the experimental (preclinical) study of new pharmaceutical substances" p.287-292, 2000

The laboratory strain Mycobacterium tuberculosis H37Rv and clinical (wild) strains isolated from the diagnostic material of patients with pulmonary tuberculosis who are being treated in a hospital of the Central Research Institute of Medical Sciences, were used as biotests. Clinical strains have been characterized with respect to anti-TB drugs as resistant and designated MDR strain-1 and MDR strain-2, as well as XDR strain-1 and XDR strain-2.

MDR strain is resistant to S, H, R and sensitive to E, Kn, Z, Ofl, Et, Cs, Cp, Pas.

MDR strain-2 is resistant to S, H, R, E, Z and sensitive to Kn, Ofl, Et, Cs, Cp, Pas.

XDR strain-1 is resistant to S, H, R, E, Kn, Z, Ofl and sensitive to Et, Cs, Cp, Pas.

XDR strain-2 is resistant to S, H, R, E, Kn, Z, Ofl, Et and sensitive to Cs, Cp, Pas.

In accordance with the work plan, the culture of the selected strains of Mycobacterium tuberculosis was grown for 21 days in a dense Levenshtein-Jensen nutrient medium (international standard). A suspension of mycobacteria was prepared from the grown culture, corresponding to the V standard of optical density (5 × 10 ⁸ million microbial bodies in 1 ml). The prepared suspension was inoculated with 0.2 ml in test tubes with 2 ml of Shkolnikova's liquid nutrient medium containing the studied compounds in appropriate concentrations - from 500.0 to 0.39 μg / ml (12 dilutions). The required concentration of drugs in test tubes was achieved by serial dilution.

After 14 days of incubation in a liquid medium at 37 ° C, the tubes were centrifuged for 15 'at 3000 rpm, the supernatant was drained, and the precipitate was suspended in 0.8 ml of sterile 0.9% NaCl and 0.2 ml inoculated into two test tubes with dense nutrient medium F-2. The growth of mycobacteria in a dense medium was taken into account after 21, 42 and 70 days of cultivation in an incubator at 37 ° C. The control was tubes with inoculation of test strains not exposed to the studied drugs and their mixtures.

When revealing the growth of colonies of the office on a nutrient medium, cultures were swabbed and stained using the Ziehl-Nielsen method (light microscopy). The indicated procedure was carried out to confirm the presence of precisely mycobacterium tuberculosis, and not of an extraneous flora in this particular case.

The minimum inhibitory concentration was characterized by a significant decrease in the number of colonies in a dense nutrient medium compared with the control. The minimum bactericidal concentration was defined as the concentration causing a complete suppression of the growth of mycobacteria in a dense nutrient medium.

In accordance with the work plan, the first viewing and recording of data in experimental and control tubes was carried out on 21 days from the time of seeding, as well as on 42 and 70 days, respectively.

The results of a comparative study of the bacteriostatic and bactericidal activity of the inventive complex anti-tuberculosis agent against Mycobacterium tuberculosis resistant MDR strains and XDR strains showed by the example of a combination of PASA and zinc sulfate, that the new composition has a high inhibitory effect at a low concentration of 12.5 μg / ml. The bactericidal effect is observed at a concentration in the nutrient medium of 18.7 μg / ml.

Thus, the new complex preparation PASK ZINC has a high inhibitory effect at a low concentration of 12.5 μg / ml against Mycobacterium tuberculosis clinical MDR strains and XDR strains. The bactericidal effect, most desirable when creating new drugs, is observed at a concentration of PASK ZINC in the nutrient medium - 18.7 μg / ml.

Experimental in vitro studies have been carried out to study the specific activity of M. tuberculosis strain H37Rv (MBT) of PASK ZINC on a model of exudative necrotic tuberculosis in mice. To achieve this goal, the following tasks were identified: to determine the average life span of animals after infection with a lethal dose of MBT in various experimental groups of animals; to study the microbiological method in vivo bactericidal and bacteriostatic activity of the studied drug; evaluate morphological methods the nature of reparative processes in parenchymal organs in the treatment of experimental tuberculosis of mice of the studied groups.

The determination of specific anti-tuberculosis activity in the in vivo system was carried out on male inbred mice of the AKR line obtained from vivarium of the Central Scientific Research Institute of Cytology and Genetics, RAMS. The weight of the mice is 22-23 grams. Mice were infected by intravenous administration of M. tuberculosis strain H37Rv from the collection of the Pasteur Institute (France) into the lateral tail vein at a dose of 5 × 10 ⁶ CFU / mouse.

In preparative quantities, MBTs were obtained in the immunogenetics laboratory of the Central Research Institute of Cardiology, Russian Academy of Medical Sciences. Aliquots (1 ml) were stored at - 70 ° C. To infect mice, an aliquot was thawed, transferred to a phosphate-buffered saline containing 0.025% Tween 80 and adjusted to a concentration of 5 × 10 ⁶ CFU / 0.5 ml. To determine the number of CFU of mycobacteria in the resulting suspension, a series of serial dilutions was prepared and 20 μl of each dilution was placed dropwise into a Petri dish with Dubo agar. The cups were cultured at 37 ° C for 14 days to determine the concentration of MB in the infectious material.

All experimental animals were divided into the following groups: infected mice without treatment (control) - 10 pcs.; infected mice receiving intragastric drug PASK ZINK at a dose of 200 mg / kg - 10 pcs.; infected mice receiving intragastric drug PASK ZINK at a dose of 1000 mg / kg - 10 pcs.; infected mice receiving intragastric PASK at a dose of 1000 mg / kg - 10 pcs.

The test drugs were administered intragastrically, daily (except weekends), for 2 months, the day after infection, previously dissolved in water. The volume of drug administered was 0.5 ml / mouse.

According to the study program, two months after the start of treatment, part of the experimental animals was removed from the experiment by the cervical dislocation method to determine the number of colony forming units (CFU) of M. tuberculosis (MBT) in the lungs of mice and histological examination of lung, liver and spleen tissues.

To determine the number of mycobacteria (CFU MBT) in the lungs of infected mice, the lungs were homogenized in 2 ml of physiological saline, a series of 10-fold dilutions of the initial suspension in physiological saline was prepared, and 50 μl of each dilution was placed on a Petri dish coated with Dubo agar. Petri dishes coated with suspensions of lung cells were incubated for 21 days at 37 ° C, after which the number of colonies on the plate was counted and the number of CFU of mycobacteria in the lungs was determined by the formula: N _leg = 2N ₁ × P / 0.1, where N is the number of colonies in lungs.

For histological examination, pieces of the lung, spleen, and liver were fixed with 10% buffered formalin, embedded in paraffin, and histological sections were prepared, which were stained with hematoxylin and eosin.

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

In mice of the control group that did not receive any drugs, survival after a lethal dose of infection was 35.7 ± 0.26 days. Mice treated with PASK at a dose of 1000 mg / kg lived 62.6 ± 0.57 days; PASK ZINC at a dose of 200 mg / kg - 85.7 ± 1.7; PASK ZINC at a dose of 1000 mg / kg - 100.7 ± 0.33 days.

According to the data obtained, the number of seeded CFU of MBT from lungs of animals treated with PACK at a dose of 1000 mg / kg was 10 times higher (8.3 ± 0.78) × 10 ⁸ ) than in the group of animals treated with PACK ZINC at a dose of 200 mg / kg (9.2 × 0.8) × 10 ⁷ . The differences between groups of animals treated with PACK ZINC at doses of 200 and 1000 mg / kg were insignificant [(9.2 ± 0.8) × 10 ⁷ and (2.0 ± 0.3) × 10 ^7, respectively).

With intravenous administration of MBT, an exudative-necrotic inflammatory process develops in mice, affecting various parenchymal organs. Control animals die from generalized tuberculosis after 36 days. By the time of death in the lungs, liver and spleen, plethora, erythrocyte sludge is observed, young and mature forms of polymorphic nuclear leukocytes (PNL) are detected in large and medium caliber blood vessels. Around the vessels, cellular infiltrates are formed, consisting of mono- and polynuclear cells; the amount of the latter varies in different organs.

Especially large pneumonic foci are formed in the lungs, where, along with macrophages and lymphocytes, large accumulations of PNL are determined. Among alveolar macrophages, lipophages predominate, which have a foamy cytoplasm on histological sections due to the numerous granules of a neutral lipid. It is in these cells that MBT accumulations are determined. When lipophages are destroyed, MBTs enter the intraalveolar space, where PNPs are concentrated around them. Therefore, the presence of foam cells (PC), especially their destroyed forms, reflects the activity of specific inflammation in mice, which is most pronounced in untreated animals. In the terminal period of the process, cellular infiltrates occupy up to 70% of the histological section; In their composition, large accumulations of PCs are determined, and PNPs that form zones of necrosis are concentrated here.

Alveoli bordering with foci are partially or completely filled with edematous fluid, contain fibrin and fragments of destroyed cellular elements. In areas of the air-retaining parenchyma, the interalveolar septa are thickened due to interstitial edema and infiltration by mono- and polynuclear cells. The same 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, the development of dystrophic changes in hepatocytes, especially expressed in the terminal period of inflammation, draws attention. The cells of the liver beams have an enlightened vacuolated cytoplasm, often with signs of destruction. In areas of necrosis, PNLs are determined.

The spleen of control mice is depleted in lymphocytes, proliferation of stromal elements, and the formation of diffuse mononuclear infiltrates are observed, the composition of which is determined by PN.

In mice treated with PASK at a dose of 1000 mg / kg and PASK ZINC at a dose of 200 mg / kg, the morphological picture of parenchymal organs is similar and does not significantly differ from control animals.

In mice treated with PASC ZINC at a dose of 1000 mg / kg, the air pulmonary parenchyma is at least 50-55%, and cell infiltrates are not more than 35-40% of the area of the histological section. In the composition of infiltrates, the number of monocytes and lymphoid elements of varying degrees of maturity noticeably increases, while the frequency of detection of PK and PNL is significantly lower than in other therapeutic groups. Marked cellular elements retain structural integrity, necrosis zones are not expressed. Destructive changes in hepatocytes in mice of the group treated with PASK ZINC at a dose of 1000 mg / kg are less pronounced than in other groups, although the effects of protein dystrophy persist. In the periportal zone, small cellular infiltrates containing single PMNs are determined.

In the spleen, proliferation of lymphoid elements is noted, the structure of the follicles is restored. There are many macrophage elements in the red pulp, while PNPs are relatively rare.

Thus, a histological study of the parenchymal organs of mice with a model of exudative necrotic tuberculosis inflammation showed a pronounced positive effect of PASK ZINC at a dose of 1000 mg / kg on the dynamics of the healing processes of foci of necrosis, restoration of structural and functional features of the lungs, liver and spleen. The drug allowed to obtain a more pronounced reduction in the area of the inflammatory process, a decrease in its activity compared to the traditional form of PASK, applied in the same dose.

Thus, a significant increase in the average life span of mice treated with PASK ZINC was established compared with PASK, which has a dose-dependent effect; the bacteriostatic effect of PASK ZINC in vivo against M. tuberculosis H37Rv in the acute model of exudative necrotic tuberculosis was also found to be 10 times higher than the bacteriostatic effect of PASK; it was shown that prolonged administration of PASK ZINC at a dose of 1000 mg / kg activates the proliferation of lymphoid elements in the spleen and markedly increases the detection rate of monocytes and lymphoid elements in the lungs, as well as a pronounced positive effect of PASK ZINC at a dose of 1000 mg / kg on structural restoration -functional features of the lungs, liver and spleen in infected mice.

Thus, on the basis of the results of biological research, it can be concluded that the new drug is highly therapeutic and that it can be used as an anti-tuberculosis drug.

The proposed drug is performed in the form of various solid dosage forms - tablets, capsules, granules, powders. The preparation of the inventive combined composition can be carried out in accordance with known methods for the manufacture of solid dosage forms, for example, by wet granulation, followed by the addition of a lubricant to the dry granules, molding the final mixture of ingredients with the formation of a dosage form of a given configuration and size and, if necessary, coating.

Examples of zinc-containing compounds are zinc salts — sulfate, aspartate, hyaluronate, glycerate, picolinate, citrate, acetate, most preferably zinc sulfate. As auxiliary substances, substances commonly used in the pharmaceutical industry for the production of solid dosage forms can be used, for example, starch, saccharide, cellulose and its derivatives, gelatin, polyvinylpyrrolidone, polyethylene oxide, calcium phosphate, a lubricant, a wetting agent such as sodium lauryl sulfate, polyoxyethylene sorbitan esters and fatty acids (twins), esters of sorbitan and fatty acids (spana), preferably starch, including modified starch, lactose, microcrystalline chain cellulose, croscarboxymethyl cellulose sodium, polyvinylpyrrolidone, lubricant. Examples of the latter are stearic acid and / or its salts — calcium stearate, magnesium stearate, zinc stearate, talc, colloidal silicon dioxide, aerosil, polyethylene glycol, hydrogenated vegetable oil, liquid paraffin. The new composition may also contain flavors, colorants and / or flavors. According to the invention, zinc sulfate can be introduced into the composition in the form of a hydrate, for example heptahydrate or monohydrate, preferably in the form of a monohydrate. Para-aminosalicylate can be introduced into the composition as a dihydrate.

Preferably, the preparation is made in the form of a tablet, which may be coated. The presence of the latter improves the appearance and organoleptic properties of the dosage form, protects it from mechanical damage. Preferably, the shell is made on the basis of a copolymer of methacrylic acid with ethyl acrylate or a finished mixture of the Acryl-Eze brand.

It is preferable to use a combination of sodium para-aminosalicylate and zinc sulfate as the active principle of the claimed composition. As used herein, the term zinc sulfate means both ZnSO ₄ sulfate and its hydrates, for example heptahydrate or monohydrate.

The preferred amount of ingredients of the active principle - sodium para-aminosalicylate and zinc sulfate in a single dose is - for sodium para-aminosalicylate from 500 mg to 2000 mg, more preferably 1000 mg, for zinc sulfate (in terms of elemental zinc) from 0.75 mg up to 3.0 mg, more preferably 1.5 mg, which corresponds to 4.12 mg of monohydrate or 6.6 mg of heptahydrate.

The preparation of the claimed composition is illustrated by the following example.

Example 1. Pre-sifted powders of sodium para-aminosalicylate, sorbitol, sodium carboxymethyl starch and parts of polyvinylpyrrolidone are mixed to a homogeneous state, granulated with an aqueous solution of the rest of Collidon brand polyvinylpyrrolidone, in which citric acid and polyethylene glycol are also dissolved (PEG 6000), dried, dried . Zinc sulfate in the form of a monohydrate, colloidal silicon dioxide and a salt of stearic acid (calcium stearate) are added to the crushed granulate and the finished mass is tabletted. Tablets with an average weight of 1,200 g are obtained. The content of sodium aminosalicylate in one tablet (HPLC) is 1000.0 mg, the zinc content (UV spectrometry) is 1.50 mg or in terms of zinc sulfate is 4.12 mg, strength is 250 N .

A film-forming composition based on the finished Acryl-Eze composition is applied to the obtained tablets. Layering is carried out until a film of satisfactory thickness is obtained. The resulting tablets with an average weight of 1,320 g satisfy the regulatory requirements for a pharmaceutical agent. Dissolution,% release of sodium para-aminosalicylate in medium — phosphate buffer solution with a pH of 7.4 after 45 minutes. (UV spectrometry) - 99. The resulting tablets have a shelf life of more than 2 years.

Claims (9)

1. An anti-tuberculosis composition comprising a therapeutically effective amount of an active principle, which contains a combination of PASK and zinc sulfate. 2. The anti-tuberculosis composition according to claim 1, characterized in that it contains para-aminosalicylate as sodium PASK. 3. The anti-tuberculosis composition according to claim 2, characterized in that it contains the ingredients of the active principle in the following ratio, parts by weight:
Sodium paraaminosalicylate 500-2000 Zinc sulfate (in terms of elemental zinc) 0.75-3.0 4. The anti-tuberculosis composition according to claim 3, characterized in that it is made in the form of a solid dosage form. 5. The anti-tuberculosis composition according to claim 4, characterized in that it is made in the form of a tablet. 6. The anti-tuberculosis composition according to claim 5, characterized in that it has a shell. 7. The anti-tuberculosis composition according to claim 6, characterized in that it has a film membrane. 8. The anti-tuberculosis composition according to any one of claims 2 to 7, characterized in that it contains the ingredients of the active principle in a single dose in the following amount, mg:
Sodium paraaminosalicylate 500-2000, Zinc sulfate (in terms of elemental zinc) 0.75-3.0 9. The anti-tuberculosis composition according to any one of claims 2 to 7, characterized in that it contains the ingredients of the active principle in a single dose in the following amount, mg:
Sodium paraaminosalicylate 1000 Zinc sulfate (in terms of elemental zinc) 1,5