Combined antituberculous composition
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
The invention relates to medicine, specifically to a combined anti-TB drugs, and can be used to treat various forms of tuberculosis.
Despite significant progress in many areas of medicine, including the treatment of tuberculosis, the incidence of TB remains extremely high. The main problem of reducing the effectiveness of treatment of TB patients is the rapid development of drug-resistant TB, the limited Arsenal of anti-TB drugs, the decline in the immune status of patients with tuberculosis.
According to official statistics in Russia, currently the rate of clinical cure new TB cases remains relatively low (Shilov MV TB in Russia in 2008 / Mvila - Moscow, 2008).
Treatment of a TB patient should be integrated and strictly individual on the basis of the principles of evidence-based medicine and should be long-term to get the maximum positive result, including the full clinical cure, if you have in mind a group of new cases (Mishin VY Treatment of patients with pulmonary tuberculosis. // Educational-methodical manual for doctors. - M: MOSCOW. - 2006. - 120 C.).
Individual set methods cured the I for each patient chooses a doctor, and this includes: defining the organizational forms of treatment (inpatient, health, outpatient), the combination of anti-TB drugs and the definition of the chemotherapy regimen, taking into account regional and individual drug sensitivity of the office, the choice 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 Ross. 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).
Chemotherapy of tuberculosis is causal (specific) therapy of patients with optimal combination of anti-TB drugs (hereinafter PTP), which aimed at the destruction of mycobacterial population (bactericidal effect) or suppression of its reproduction (bacteriostatic effect) (Khomenko A.G. Chemotherapy of pulmonary tuberculosis. - M - 1980. - 279 S.).
Only when the destruction of the office or suppressing their multiplication is possible to run adapt the ionic mechanisms aimed at the elimination of the clinical manifestations of the disease, resorption of inflammatory changes in the lungs, the activation of reparative processes, restoration of damaged morphological structures and restoration of functional disorders of organs and systems in the body of the patient, i.e. to create conditions for full clinical cure (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 Russian Federation according to the Ministry of health of the Russian Federation No. 109 of 21 March 2003 for the treatment of new TB cases used anti-TB drugs, which are divided into main and backup. Basic drugs: isoniazid, rifampicin, pyrazinamide, ethambutol, streptomycin. Reserve drugs: protionamide (ethionamide, kanamycin, amikacin, capreomycin, cycloserine, rifabutin, PASK, fluoroquinolones.
Anti-TB drugs of the main series are more efficient, have high bactericidal activity against Mycobacterium tuberculosis (hereinafter the office). However, their long-term use, which is required for treatment of tuberculosis for several months developing the sustainability office. For the treatment of drug-resistant TB using backup TB preparation is you.
p-Aminosalicylic acid and its sodium salt (hereinafter PAS) has bacteriostatic activity against the office and refers to the reserve antituberculosis drugs. On tuberculostatic activity PASK inferior to isoniazid and other drugs the main series, but it works for mycobacteria are resistant to the above-mentioned drugs. (Mashkovsky PPM, Medicines. - M.: Medicine, 1993, Vol.2, s-367, 372).
The most convenient form of PAS for the treatment of patients with tuberculosis should recognize the tablet.
In U.S. patent 2676902, 1954 declared composite product for the treatment of tuberculosis, which contains a PAS or its nontoxic salt and adjuvant - p-(di-n-propylsulfonyl)benzoic acid. The invention solves the problem of reducing the side effects from taking large quantities of PAS, which are necessary for the treatment of tuberculosis.
To prevent the development of drug resistant mycobacteria in the treatment of tuberculosis have gone two ways: create a combined dosage forms with fixed doses of anti-TB drugs, including drugs of different groups, or the patient is given simultaneously the combination of anti-TB drugs of different classes.
Researchers have proposed a number of other approaches to improve efficiency the efficiency of treatment outcome, including various methods of immunomodulation and immunotherapy. During research it was found that the appointment of preparations containing zinc, 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 of treatment of pulmonary tuberculosis, including 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 2,30-3.5 mg/kg two to three times the ingestion rate 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 contains 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 M. tuberculosis is uleta were 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.
In the patent of Russian Federation №2195937, 2003 proposed combined antituberculosis drug containing as an active start to the combination of isoniazid, rifampicin, pyrazinamide, ethambutol and pyridoxine, and as excipients metozel methyl cellulose ethers containing 14-30% metaxylene groups.
Known drug analogues has some weaknesses. During the course of use of the above drugs, there are marked toxic effect and the occurrence 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 TB efficiency and causes a return of the disease, and the development of secondary drug resistance.
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 to create what the new anti-tuberculosis drugs with high antibacterial activity against drug-resistant Mycobacterium tuberculosis, which toxic side effects are minimized, which will expand the range of anti-TB drugs.
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 PAS and zinc-containing compounds and pharmaceutically acceptable excipients.
According to the invention as the beginning of the current composition includes a combination of PAS and zinc-containing compound. The proposed combination of active ingredients is new for combined anti-TB drugs and found empirically.
In the framework of the present invention PASK means p-aminosalicylic acid or its salt, preferably the sodium salt, which has other names - para-aminosalitsilata sodium or aminosalitsilata sodium. As the zinc-containing compound is preferably used zinc salts, preferably zinc sulfate.
The preferred number of PAS and zinc-containing compounds (in terms of elemental zinc) is, parts by weight:
PAS - 500-2000
(in terms of elemental zinc) - 0,75-3,0.
When the zinc-containing compounds used zinc sulfate, then p is edocfile number is:
- 3,3-of 13.2 parts by weight, if the zinc sulfate is introduced into the composition in the form of heptahydrate, or a 2.0 parts by weight of 8.25, if the zinc sulfate is introduced into the composition in the form of monohydrate. It is most preferable to use zinc sulfate in an amount equivalent to 1.5 parts by weight of elemental zinc per 1000 parts by weight of the PAS.
The use of the claimed combination of active ingredients provides a synergistic effect, which consists in a significant increase in antimicrobial activity against drug-resistant Mycobacterium tuberculosis, and the inclusion of zinc sulfate gives the opportunity to apply a new tool for the treatment of drug-resistant 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 the composition has an impact on drug-resistant strains of Mycobacterium tuberculosis.
Studies (in vitro) has allowed the study of microbiological methods bacteriostatic and bactericidal activity of the new comprehensive anti-tuberculosis drugs (hereinafter - PAS ZINC) against M. tuberculosis laboratory strain H37Rv, the office MDR-strains and the office of the XDR strains. Definition antimycobacterial of action of the drug was carried out in accordance with the "Guide poeksperymentujmy (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. Clinical strains were characterized in respect of PTP as a steady and marked MDR-strain-1 and MDR-strain-2, and XDR-strain-1 and XDR-strain-2.
MDR strains 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 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 for the culture of selected strains of Mycobacterium tuberculosis were grown for 21 days on nutritionally dense löwenstein-Jensen (international standard). From the grown culture was preparing a suspension of Mycobacterium corresponding to V standard optical density (5×108million microbial cells in 1 ml). The prepared suspension was seeded with 0.2 ml tubes containing 2 ml of liquid nutrient medium Shkolnikova containing the studied compounds at appropriate concentrations from 500,0 to 0.39 µg/ml (12 dilutions). The concentration of drugs in test tubes was achieved by serial dilution method.
After 14 days of incubation in liquid medium at 37°C. the tubes cent who were fugereville for 15' at 3000 rpm, the supernatant was decanted, and the residue was suspensively in 0.8 ml sterile 0.9% NaCl and were seeded at 0.2 ml in two test tubes with a dense nutrient medium f-2. Growth of mycobacteria in a dense environment was taken into account through 21, 42 and 70 days of culturing in an incubator at 37°C. the Control were tubes with the sowing of the test strains not exposed to study drugs and their mixtures.
When detecting the growth of colonies of the office on a nutrient medium from cultures did swabs and painted them according to the method of Zn-staining (light microscopy). This procedure was carried out to confirm if it is Mycobacterium tuberculosis, and not third-party flora in this particular case.
Minimum inhibitory concentration 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.
In accordance with the work plan, the first viewing and recording the data in the experimental and control tubes was performed for 21 days from the time of sowing, and at 42 and 70 days, respectively.
The results of a comparative study of the bacteriostatic and bactericidal activity of the inventive integrated drug against mikeb is Cheri resistant tuberculosis MDR-and XDR strains-strains showed on the example of the combination of PAS and zinc sulfate, the new composition has a high inhibitory effect at low concentrations of 12.5 μg/ml Bactericidal effect observed at a concentration in a nutrient medium to 18.7 ág/ml
Thus, the new complex drug PAS ZINC has against Mycobacterium tuberculosis clinical MDR-and XDR strains-strains high inhibitory activity at low concentrations of 12.5 μg/ml Bactericidal effect, the most desirable when creating new medicines, observed at a concentration of PAS ZINC in the medium to 18.7 ág/ml
Experimental in vitro studies conducted with the purpose of studying specific activity against M. tuberculosis strain H37Rv (ILO) drug PAS ZINC on the model exudative necrotic TB mice. To accomplish the objectives were defined the following objectives: to determine the average life of animals after infection with a lethal dose of the office in different experimental groups of animals; to study the microbiological method in vivo bactericidal and bacteriostatic activity of the investigational product; 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 the system is Birmingham in vivo studies were performed on inbred male mice of the AKR, obtained from the vivarium of the state of research RAMS. Mice weight - 22-23 grams. Mice were infected by intravenous M. 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. Cups were cultured 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) - 10 pieces; infected mice receiving intragastric drug PAS ZINC at a dose of 200 mg/kg 10 pieces; infected mice receiving intragastric drug PAS ZINC at a dose of 1000 mg/kg - 10 pieces; infected mice receiving intragastric PAS at a dose of 1000 mg/kg - 10 PCs
The tested drugs were injected intragastrically daily (except weekends), within 2 months, the next day after infection, pre-dissolve the water. The amount of administered drug 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) of M. tuberculosis (MBT) 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, prepared a series of 10-fold dilutions 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 suspensions of lung cells were incubated for 21 days at 37°C, and then counted the number of colonies on plate and determined the number of CFU of bacteria in the lungs by the formula: Nlay down=2N1×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 the tubercle bacilli is ERI bodies (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, survival after lethal doses of infection was 35,7±0,26 days. Mice treated with PAS at a dose of 1000 mg/kg, lived and 62.6±0.57 days; PAS ZINC at a dose of 200 mg/kg of 85.7±1,7; PAS ZINC at a dose of 1000 mg/kg to 100.7±0.33 days.
According to the data obtained, the number of inoculated CFU office from the lungs of animals treated with PAS at a dose of 1000 mg/kg was 10 times higher (8,3±0,78)×108)than in the group of animals treated with PAS ZINC at a dose of 200 mg/kg (9,2×0,8)×107. Differences between groups of animals treated with PAS ZINC in doses of 200 and 1000 mg/kg, were insignificant [(9,2±0,8)×107and (2,0±0,3)×107respectively.
Intravenous office in mice developing exudative-necrotic inflammatory process affecting various parenchymal organs. Control animals die from the generalized tuberculosis in 36 days. 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 polymorphonuclear leukocytes (PAL). Around the vessels are formed of cellular infiltrates consisting of mono - and polynuclear; the number varies in different organs.
Especially large pneumonic is okusi 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 of cellular infiltrates occupy up to 70% histological slice; their composition is 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 g is patcito, 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 mice treated with PAS at a dose of 1000 mg/kg and PAS ZINC at a dose of 200 mg/kg, morphological picture of parenchymatous organs close and not significantly different from control animals.
In mice treated with PAS ZINC at a dose of 1000 mg/kg, air pulmonary parenchyma is at least 50-55%, and cellular infiltrates - no more than 35-40% of the area histological slice. In the composition of the infiltrates significantly increases the number of monocytes and lymphoid elements of various degrees of maturity, whereas the incidence of PC and PAL significantly lower than in the other treatment groups. Marked cellular elements retain structural integrity, necrosis is not expressed. Destructive changes of hepatocytes in mice treated group PASK ZINC at a dose of 1000 mg/kg, expressed to a lesser extent than in the other groups, although the effects of protein malnutrition persist. In the periportal zone defined small cell infiltrates containing dinnye of PAL.
In the spleen there is a proliferation of lymphoid elements, the structure of the follicles is restored. In the red pulp is a lot of macrophage elements, whereas PAL determined relatively rare.
Thus, histological examination of parenchymatous organs of mice with a model of exudative-necrotic tuberculous inflammation showed a pronounced positive effect of the drug PAS ZINC at a dose of 1000 mg/kg on the dynamics of the healing process of necrosis, restoration of structural and functional features of the lungs, liver and spleen. The drug helped to get a more pronounced reduction in the area of inflammatory process, reducing its activity in comparison with the traditional form of PAS used in the same dose.
Thus, statistically significant increase in the average lifespan of mice treated with therapy drug PAS ZINC, compared with drug PASK, with dose-dependent effect; also have a bacteriostatic effect of the drug PAS ZINC in vivo against M. tuberculosis H37Rv in acute models of exudative necrotic TB exceeding the bacteriostatic effect of the drug the PAS 10 times; it is shown that the prolonged administration of the drug the PAS ZINC at a dose of 1000 mg/kg activates proliferation of lymphoid elements in the spleen and significantly increases the frequencies of the identification of monocytes and lymphoid elements in the lungs, and also have a pronounced positive effect of the drug PAS ZINC at a dose of 1000 mg/kg for the restoration of structural and functional features of the lungs, liver and spleen from infected mice.
Thus, on the basis of the results of biological studies the conclusion can be made about the high therapeutic efficacy of new drugs and its application as a drug.
The proposed remedy is carried out in a variety of solid dosage forms - tablets, capsules, granules, powders. Obtaining the claimed combination compositions 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.
Examples of zinc-containing compounds are salts of zinc sulfate, aspartate, hyaluronate, glycerin, picolinate, citrate, acetate, most preferably zinc sulfate. As auxiliary substances may be used substances commonly used in the pharmaceutical industry for the production of solid dosage Faure is, for example, 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, nachrichtenanbieter-cellulose, polyvinylpyrrolidone, lubricant. Examples of the latter include stearic acid and/or its salt is 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. 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. Para-aminosalitsilata you can enter into the composition in the form of a dihydrate.
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 based on a copolymer of methacrylic acid with ethyl what relatum or ready-mix brand "Acryl-Eze".
Preferably the effective beginning of the claimed composition to use a combination of sodium para-aminosalitsilata and zinc sulfate. In the framework of this invention, the term zinc sulfate means as sulfate ZnSO4and its hydrates, for example heptahydrate or monohydrate.
Preferred amounts of the ingredients of the current start - parameters aminosalitsilata sodium and zinc sulfate in a single dose - for parameters aminosalitsilata sodium from 500 mg to 2000 mg, more preferably 1000 mg, zinc sulfate (in terms of elemental zinc) from 0.75 mg to 3.0 mg, more preferably 1.5 mg, which corresponds 4,12 mg monohydrate or 6.6 mg of the heptahydrate.
Obtaining the claimed composition is illustrated by the following example.
Example 1. Pre-sifted powder sodium aminosalitsilata parameters, sorbitol, sodium carboxymethyl amylum and parts of polyvinylpyrrolidone mix until smooth, granularit aqueous solution of the rest of the polyvinylpyrrolidone brand Kollidon, which also dissolved citric acid and polyethylene glycol (PEG 6000), dried and conduct dry granulation. To ground the granulate is added zinc sulfate as monohydrate, colloidal silicon dioxide and a salt of stearic acid (calcium stearate) and ready weight tabletirujut. Poluchatelej with an average weight of 1,200, The content of matrilineality in one tablet (HPLC) - 1000,0 mg, zinc (UV spectrometry) - 1,50 mg or in terms of the zinc sulfate - 4,12 mg strength - 250 N.
The obtained tablets applied film-forming composition based on the finished composition Acryl-Eze. Layering is produced to obtain a satisfactory film thickness. The obtained tablets with an average weight 1,320 g satisfy regulatory requirements in the pharmaceutical agent. Dissolution, % release aminosalitsilata parameters of sodium in the medium - phosphate buffer solution with pH 7.4 after 45 minutes (UV-spectrometry) - 99. The resulting tablets have a shelf life of more than 2 years.
1. TB composition comprising a therapeutically effective amount of the current to the beginning, which contains a combination of PAS and zinc sulfate.
2. TB composition according to claim 1, characterized in that it contains as PASK sodium para-aminosalitsilata.
3. TB composition according to claim 2, characterized in that it contains the ingredients of the current start in the following ratio, parts by weight:
|Zinc sulfate (in terms of elemental zinc)||0,75-3,0|
4. TB composition according to claim 3, characterized by the fact that made in the form of solid dosage forms.
5. TB composition according to claim 4, characterized by the fact that made in the form of tablets.
6. TB composition according to claim 5, characterized in that it has a shell.
7. TB composition according to claim 6, characterized in that it has a film shell.
8. TB composition according to any one of claim 2 to 7, characterized in that it contains ingredients beginning of the current in a single dose in the next number, mg:
|Zinc sulfate (in terms of elemental zinc)||0,75-3,0|
9. TB composition according to any one of claim 2 to 7, characterized in that it contains ingredients beginning of the current in a single dose in the next number, mg:
|Zinc sulfate (in terms of elemental zinc)||1,5|
SUBSTANCE: in capsule, in accordance with the invention, at least, one hollow space is surrounded by wall. At least, part of wall includes polymer mixture, which contains, at least, one adsorbent. Polymer mixture contains, at least, thermoplastic material, preferably polyolefin, more preferably, polyethylene or polypropylene. Adsorbent is selected from group, consisting of silica gels, zeolites, alumosilicates, molecular sieves, active coal, oxides of alkali-earth metals, calcium sulfate. Capsule is intended for packing compositions for inhalation.
EFFECT: invention allows to prolong stability of medication compositions.
28 cl, 8 dwg
FIELD: medicine, pharmaceutics.
SUBSTANCE: invention relates to chemical-pharmaceutical industry and medicine, in particular to composition, which possesses bacteriostatic and bactericidal action and is intended for treatment of tuberculosis diseases. Pharmacological composition with anti-tuberculosis action contains active substances - anti-tuberculosis medications (ethambutol, isoniazid, rifampicin, pirazinamide) and as potentiating agent of synergetic action, enhancing impact of chemical preparations, stabilised nanoparticles of silver.
EFFECT: invention possesses properties allowing to inhibit medication-resistant strains of tuberculosis mycobacteria.
5 ex, 1 tbl
SUBSTANCE: invention refers to medicine, particularly to phthisiology, and can be used in treating tuberculosis by antituberculous preparations (ATP). That is ensured by chemotherapy supplemented with daily introduction of the preparation taurin for at least 2 months.
EFFECT: method provides good tolerance to dosages of primary and reserve ATP required for therapy in various clinical forms of tuberculosis, reducing or eliminating various adverse reactions of therapy.
4 cl, 5 ex
FIELD: medicine, pharmaceutics.
SUBSTANCE: invention relates to prophylactic agent for skin, having antituberculous effect, which includes the following active substances - 0.50-0.75 wt % of streptomycin and 7.0-10.0 wt % of stabilised sol of silver nanoparticles, and also polyethylene oxides (PEO) of brands 400 and 1500 as the base.
EFFECT: invention provides a synergetic effect, which shows in ability to suppress antibiotic-resistant strains of microorganisms, including mycobacteria of tuberculosis, and in improvement of bactericide properties of proposed agent.
1 tbl, 5 ex
FIELD: medicine, pharmaceutics.
SUBSTANCE: invention relates to chemical-pharmaceutical industry, namely to creation of antituberculous composite medication, which contains isoniaside and individual glycoside of plant Stevia rebaudiana - stevioside or steviolbioside or mixture of said plant glycosides, which represent sweetener.
EFFECT: medication reduces toxicity of antituberculous medication isoniaside.
FIELD: medicine, pharmaceutics.
SUBSTANCE: invention relates to chemical-pharmaceutical industry and medicine and deals with composition for treatment of different forms and locations of tuberculosis. Claimed composition consists of sodium aminosalicylate and polyvinylpyrrolidone with molecular weight 8000-60000.
EFFECT: composition possesses high bioavailability and reduced local-irritate action of sodium aminosalicylate.
3 ex, 1 tbl
SUBSTANCE: invention refers to new derivatives of dihydro-pyrroloquinoline of formula I where values of R1, R2, R3a and R3c radicals are specified in cl. 1 of the patent claim. Also the invention refers to a method for making the compound of formula I, to its application, a composite product based on the compound of formula I and a general antimicrobial agent and a pharmaceutical composition based on the compound of formula I.
EFFECT: there are prepared new derivatives of dihydro-pyrroloquinoline exhibiting antibacterial activity.
26 cl, 4 dwg, 11 ex
SUBSTANCE: invention relates to novel quinoline derivatives of general formula II, where R1 denotes halogen, R2 denotes halogen, R3 denotes hydroxy, R4, R5 denote C1-C3-alkyl, R6 denotes aryl, R7 denotes aryl, n=1 or 2, as well as to pharmaceutically acceptable acid or base addition salts thereof, having activity towards mycobacteria. The invention also relates to a method for synthesis of formula II compounds.
EFFECT: obtaining novel quinoline derivatives with useful biological activity.
3 cl, 4 tbl, 5 ex
FIELD: medicine, pharmaceutics.
SUBSTANCE: invention relates to medicine, namely to chemical-pharmaceutical industry and deals with antituberculosis medication active with respect of drug-resistant strains of tuberculosis mycobacteria. Medication of synergic action contains antituberculosis chemical preparation - isoniaside and silver nanoparticles as potentiating agent, enhancing action of chemical preparation.
EFFECT: invention possesses ability to inhibit drug0resistant strains of tuberculosis mycobacteria and can be used for creation of novel medications for treatment of drug-resistant tuberculosis.
1 tbl, 7 ex
FIELD: medicine, pharmaceutics.
SUBSTANCE: invention relates to field of pharmacology and medicine, namely to new generation of antimicrobial D-cycloserin-based medications of regulated action. Described is medication of anti-microbial action with prolonged release into target organs, characterised in that it represents stable nanoparticles and includes D-cycloserin, PLGA 50/50, D-mannit and polyvinyl alcohol, with the following component ratio, wt %: D-cycloserin from 1 to 15; PLGA 50/50 from 20 to 40; D-mannit from 5 to 40; polyvinyl alcohol from 5 to 15. Described medication has considerably lower neurotoxicity and is able to produce bactericidal effect with respect to Mycobacterium tuberculosis, without producing toxic effect and possessing high therapeutic efficiency.
EFFECT: application of elaborated medication allows to achieve highly selective dosed release of active substance into target organs-cells (macrophages).
5 ex, 1 tbl
FIELD: medicine, pharmaceutics.
SUBSTANCE: invention relates to pharmacy, namely to creation of complexes for treatment of chronic fatigue syndrome (CFS). Four naturopathic complexes for CFS treatment contain herbal mixtures and homeopathic medications.
EFFECT: intake of naturopathic complexes ensures high therapeutic effect throughout the treatment without negative side effects and disease recurrences.
5 cl, 4 ex
FIELD: medicine, pharmaceutics.
SUBSTANCE: invention refers to chemical and pharmaceutical industry, notably to development of capsule with turgescent coating made of agar-agar with or without addition of water-soluble biologically active compounds, filled with oily solutions of oil-soluble vitamins and/or herbal oily extracts and/or fatty oils or fatty oils mixtures. Solution for encapsulation is prepared in the following manner: plastifier is added to water, stirred till complete dissolution, then agar-agar is added and left to turgesce at 15-40°C during 0.1-10 hours, preferably about 0.5-2 hours; then obtained mixture is stirred at 70-99°C, preferably at 80-98°C, most preferably at 95°C till mixture will become homogenous and transparent. Then capsules are manufactured as follows: solution is delivered in extruder which extrudes capsules at 77-99°C, preferably at 82-90°C, most preferably at 86°C; extruding rate is 1-10 capsules per second, preferably 3-6 capsules per second, cooling fluid's temperature is 3-15°C. Higher density of capsule agar covering is achieved by subsequent exposure to solution of polyol during 0.1-30 minutes, preferably 0.5 minutes, then to ethanol, preferably 95%, during 1-20 minutes, preferably 5 minutes.
EFFECT: capsules are resistant to temperature and humidity gradients, free of animal proteins thus excluding prionic infections.
16 cl, 27 ex
FIELD: medicine, veterinary science.
SUBSTANCE: invention is related to veterinary science. Method for production of complex preparation for prophylactics and treatment of metabolic derangements, microelementoses, improvement of animal organism resistance includes mixing of water-soluble salts of metals - stimulators of iron, zinc, copper, cobalt with sodium nucleinate as immunostimulant, succinic acid and methionine at the following ratio of components, in the following amounts, g/l: Succinic acid 10.0; Iron sulfate 2.0; Copper sulfate 0.1; Cobalt sulfate 1.0; Zinc sulfate 0.1; Sodium nucleinate 10.0; Methionine 10.0; Water for injections up to 1000 ml and pH of 6.8-7.0.
EFFECT: invention provides for production of efficient preparation for parenteral introduction for prophylactics and treatment of metabolic derangements, microelementoses, improvement of animal organism resistance.
4 tbl, 3 ex
SUBSTANCE: invention relates to chemical-pharmaceutical industry, namely to creation of medication for treatment and prevention of oncologic diseases. Medication represents tabletted form and contains calcium carbonate, vitamin D3, zinc oxide, Ca41Cl2 with induced activity 0.1 microcurie, vitamin E.
EFFECT: medication has anti-tumour action, increases efficiency of oncologic disease treatment.
SUBSTANCE: immunocorrecting preparation contains levamisole, vitamins, microelements and bentonite clay in the following ratio, g/kg: levamisole -75-80; vitamin A - 0.35-0.40; vitamin C - 0.2-0.3; zinc - 9.0-10.0; copper - 0.5-0.6; iron - 1.5-2.0; selenium - 0.03-0.04; bentonite clay - the remaining part. Application of claimed preparation by adding to animal and poultry forage produces expressed stimulating impact on immunocompetent systems of organism, which, in its turn, contribute to enhancement of protective functions of organism and increase of animal productivity and safety.
EFFECT: preparation can be used for stimulation of antibody-formation during vaccine prophylaxis of farm animals and poultry.
3 tbl, 3 ex
SUBSTANCE: invention refers to chemical-pharmaceutical industry and medicine, namely to pharmaceutical compositions for the oral medical products applied in the integrated treatment of menopause osteoporosis in women. There is offered pharmaceutical composition which contains one or more active substances mainly with different therapeutic modalities providing intensified osteogenesis or decreased bone resorption, an element-vitamin complex containing elements in the form of physiologically acceptable compounds, providing intensified bone formations and decreased bone resorption, and the vitamins intensifying therapeutic action of the active substances and ensuring intensified bone formation and decreased resorption, and an excipient in the form of one substance or mixed substances which is monoexcipient or one component of the excipient.
EFFECT: higher effectiveness of the composition.
6 cl, 13 tbl, 8 ex
SUBSTANCE: invention concerns medicine and biology, particularly biological preparations, and can find application in treatment of wounds, burns, tumours and correction of metabolic processes. The problem whereat the declared invention aims, is improving the clinical effectiveness for wide spectrum of inflammatory diseases, particularly, reduced time for achievement of medical effect and/or prolongation of remission periods and increased resistance of the patients to infections. The task in view is solved by that a biologically active preparation represents a suspension of particles of powdered copper, iron and zinc made of the alloy exposed to the plasma flux at temperature 5000-6000°K, in 0.9% NaCl solution in the weight ratio Cu:Fe:Zn=60:15:25, dispersion of particles 180-220 nm and concentration of the suspension equal of 10 mg/ml.
EFFECT: improved bactericidal effect of the preparation, reduction of pyoinflammatory processes in short terms and early activation of the patients.
1 cl, 2 tbl
SUBSTANCE: invention refers to medicine, namely to pharmaceutical compositions and aims at treatment and prevention of oncologic diseases. Amount of components of a liquid agent by weight is as follows: lemon juice 1000-1100 ml; fructose 1000-1100 g; 40% ethyl alcohol 500-550 ml; calcium chloride 35-55 g; calcium chloride (calcium-41) 0.05-5 mg; zinc oxide 1-12 g; colecalciferol (vitamin D3) 0.15 mg (6000 ME).
EFFECT: there is presented agent for treatment and prevention of oncologic diseases and method of application thereof.
4 cl, 2 ex
SUBSTANCE: invention concerns medicine, namely oncology and can be used for therapy of tumours. The method involves introduction in tumour tissue of octacarboxyphthalocyanine metal - octasodium salts of zinc octacarboxyphthalocyanine in a dose 10-150 mg/kg 1-3 hours prior to ultrasonic irradiation wherein tumour tissue is heated up to temperature 36-42°C.
EFFECT: application of the invention allows inhibiting growth of tumour cells due to solid-state sonic sensitisation with exposure of octacarboxyphthalocyanine metal and ultrasound.
3 tbl, 2 dwg, 22 ex
SUBSTANCE: invention refers to pharmaceutical industry, particularly to an agent for treating skin allergosis. The agent for treating skin allergosis, containing talc, starch and zinc oxide as a base, and s a reactant - dissolved dry extract of herbal raw material - nettle leaves, birch leaves, cowberry leaves, knotgrass herb, violet herb, licorice root, hop collective fruits in 40% ethanol in the ratio 1:3. Herewith the total extract is made by mixing powdered dry aqueous extracts of herbal raw material taken in equal quantities, in certain relation of components.
EFFECT: mentioned agent has the evident therapeutic effect in treating skin manifestations of allergic reactions of various aetiologies.
FIELD: medicine, pharmaceutics.
SUBSTANCE: invention refers to medicine. Substance of the method consists in the fact that oral cavity sanation is followed with removing nidi of a persistent infection. Further, antiseptic preparation of the oral cavity with Malavite solution after each meal, the persistent nidi are treated with Zovirax ointment 5 times a day every 4 hours in the course of 5 days. Imudon is prescribed by one tablet 6 times a day for 10 days, as well as Leukinferon 10000 ME or Cycloferon by 0.25 g are introduced intramuscularly according to the schedule on 1st, 3rd, 5th, 7th, 9th, 11th, 15th days. Tisol application is prescribed for an area of enlarged salivary gland two times a day for 14 days; herewith, a subclinical form of the disease requires the administration of acyclovir and imudon preparations, while in manifested form of the disease, famvir or acyclovir 0.2 g 5 times a day for 10 days are prescribed.
EFFECT: method of treating sialodenitis is offered.