Antituberculous agent

FIELD: pharmaceutical industry.

SUBSTANCE: invention provides composite therapeutical agent exhibiting antituberculous effect and made in the form of solid dosage form containing as active principle combination of lomefloxacin, isoniazid, pyrazinamide, ethambutol hydrochloride, and pyridoxine hydrochloride plus auxiliaries.

EFFECT: increased assortment of antituberculous drugs.

4 cl, 1 tbl, 4 ex

 

The invention relates to medicine, specifically to a combined anti-TB drugs, and can be used for treatment of tuberculosis.

In the standard chemotherapy of tuberculosis as the primary and most effective anti-TB drug isoniazid is used - isonicotinic acid hydrazide (Mashkovsky PPM Medicines, Vol.2, ed. 12-e, M, 1993, s). Featuring high therapeutic activity of isoniazid and has a strong toxic effect. But its major drawback is the rapid development of drug resistance of Mycobacterium tuberculosis, which significantly reduces its effectiveness. Resistance of Mycobacterium tuberculosis to isoniazid develops in 70% of patients and 30% of patients become chronic patients.

In the terms developed in Russia in recent years, TB epidemic has changed dramatically during TB infection, the structure of the clinical forms. The problem in the clinic of tuberculosis has been a sharp increase in the number of patients with drug-resistant Mycobacterium tuberculosis. In this regard, there is need to assign combinations of 4 or more anti-TB drugs. However, combination therapy of TB patients because of the complexity and duration of selection of effective drugs, and that the same course of therapy, carry out his or irregularly, or not getting to the end, which causes a return of the disease, the rapid emergence of secondary drug resistance. Therefore, the world Health Organization (who) recommends the rejection of mono - and combined therapy and necessitates the use of combined anti-TB drugs in a single dosage form.

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

In the patent of Russian Federation №2195937, 2003 proposed combined antituberculosis drug containing as an active start to the combination of isoniazid, rifampicin, pyrazines is Yes, ethambutol and pyridoxine, and as excipients metozel methyl cellulose ethers containing 14-30% metaxylene groups (prototype).

However, the 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 the development of highly effective anti-tuberculosis drugs, which has 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 the combination of lomefloxacin, isoniazid, pyrazinamide, ethambutol hydrochloride, pyridoxine hydrochloride, and pharmaceutically acceptable excipients, the following ratio of ingredients of the current starters, parts by weight:

Lomefloxacin 1,0

Isoniazid from 0.2 to 1.25

Pyrazinamide is 1.35-2,75

Ethambutol hydrochloride 1,4-3,3

Pyridoxine hydrochloride 0,01-1,0

The proposed combination of active ingredients is new for combined anti-TB drugs, are chosen empirically and allows to obtain a technical result that is appropriate to the task.

The use of the claimed combination of active ingredients in the specified ratio significantly increases antimicrobial activity against drug-resistant Mycobacterium tuberculosis, and the inclusion of lomefloxacin - fluoroquinolone with anti-TB activity and a broad spectrum of antimicrobial action on non-specific pathogenic flora gives the opportunity to apply a new tool for the treatment of severe progressive forms of tuberculosis.

Tuberculous process is often accompanied by metabolic vitamins, primarily pyridoxine, plays a crucial role in the metabolism of the essential amino acids tryptophan and methionine, and cysteine, glutamic and other amino acids that causes pain is the second physiological damage to the protective reactions of an organism of the patient. Disorders of vitamin metabolism may be due to direct antivitamins the action of some anti-TB drugs. These include structural analogs of pyridoxine and nicotinic acid. Antivitamins the effect of these drugs is one of the reasons for their toxic and toxic or allergic effects on the body. At the same time, it is known that the biological antagonism between metabolites of vitamins, particularly pyridoxine hydrochloride, and its structural analogues with anti-TB activity, primarily isoniazid and/or pyrazinamide, at their simultaneous introduction reduces the effectiveness of anti-TB drugs.

However, 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. In vitro experiments conducted on the test culture H37RV laboratory strain of M. tuberculosis, which were grown for 2 weeks in liquid nutrient medium Shkolnikova with the addition of various concentrations of the drugs. All cultivation of drugs and nutrient medium were prepared in accordance with the requirements of the Pharmacological Committee (Guidance on experimental (preclinical) study of new pharmacological substances is STV, M, 2000). The viability of Mycobacterium tuberculosis after exposure to the drug was assessed by their ability to growth on löwenstein-Jensen medium (after removal of the drug by laundering saline solution). Minimum total bactericidal concentration (SBC) of the drug was determined by the absence of crop growth. Noted a significant increase in the bactericidal activity of the new drug compared with the prototype. So, msbk the claimed means of 0.125 µg/ml (applicable beginning, the prototype - 0.5 μg/ml), at a concentration of 0.1 μg/ml (at the current early) growth of CFU (colony forming units) after 2-week incubation, the culture of mycobacteria from a new drug 2.8 times lower than that of the prototype, and at a concentration of 0.05 mg/ml (at the current beginning) is 1.5 times lower. Experimental in vivo studies were performed on mice that were infected with a culture of Mycobacterium tuberculosis isolated from a patient with multidrug resistance. The results were evaluated by Visavuori colonies of Mycobacterium tuberculosis from the lung tissue of mice (CFU/g of tissue) on löwenstein-Jensen medium. Studies show that the proposed TB composition is characterized by a significant increase in antimicrobial activity against multidrug-resistant culture mycobacteria the TB compared with the prototype and plain products, as isoniazid, pyrazinamide, ethambutol hydrochloride, or lomefloxacin entered into effective therapeutic doses.

The study of the toxicity of the new drug showed that after two weeks intragastric administration to rats at a dose of 500 mg/kg (at the current beginning) Hematology (red blood cells, hemoglobin, leukocytes, reticulocytes, platelets) and biochemical (total lipids and glucose) blood parameters as indicators of toxicity did not differ from the control. Not marked structural abnormalities in organs and tissues, not found irritating new composition to the mucous membrane of the gastrointestinal tract.

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. As auxiliary substances may be used substances commonly used in the pharmaceutical industry for the production of solid dosage forms, for example, starch, sugar, cellulose and its derivatives, gelatin, polyvinylpyrrolidone, polyethylene oxide, calcium phosphate, lubricants, spaceways the th agent, as nutriceuticals, esters of polyoxyethylenesorbitan and fatty acids (twins), esters sorbitan and fatty acids (spany), preferably starch, including modified, lactose, microcrystalline cellulose, nutritionstrategywales, polyvinylpyrrolidone, lubricant. Examples of the latter 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. 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 derivative of cellulose, for example, oksipropilmetiltselljulozy, or ready-mix brand "Opadry".

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

The invention is illustrated by the following examples (see Table), which are only illustrative but not restrictive.

Example 1. Lomefloxacin 200 mg (1 M.Ch.), isoniazid - 135 mg (0,675 M.Ch.), pyrazinamide - 370 mg (1,85 M.Ch.), ethambutol hydrochloride 325 mg (1,625 M.Ch.), pyridoxine hydrochloride, 10 mg (0.05 M.Ch.), excipients - 90 mg, including nutritionstrategywales - 55,0 mg polyvinylpyrrolidone 10.0 mg, polyethylene glycol, 5 mg, Aerosil - 10.0 mg, magnesium stearate - of 10.0 mg Average weight of tablets 1130,0 mg (the number of ingredients in mg is indicated per 1 tablet). The mixture lomefloxacin (as hydrochloride), isoniazid, pyrazinamide and ethambutol hydrochloride hydrate 8% aqueous solution of polyvinylpyrrolidone, which is added polyethylene glycol, until smooth. The mixture granularit and dried to a residual moisture content of 1.0%. Dry granules are milled, mixed with pyridoxine hydrochloride, metrictosaesocketsizes.html, Aerosil and magnesium stearate and tabletirujut. The obtained kernel with an average weight of 1130 mg cause film-forming composition on the basis of ready-mix brand Opadry to obtain a film of satisfactory size. Get coated tablets are light brown color with an average weight 1187 mg

Example 2. Lomefloxacin 200 mg(1 M.Ch.), isoniazid - 40 mg (0.2 M.Ch.), pyrazinamide - 550 mg (2,75 M.Ch.), ethambutol hydrochloride, 280 mg (1,4 M.Ch.), pyridoxine hydrochloride, 30 mg (0.15 to M.Ch.), excipients (starch - 25.0 mg, microcrystalline cellulose - 85,0 mg, polyvinylpyrrolidone - 15,0 mg, Aerosil - 10.0 mg, talc - 15,0 mg, calcium stearate - 10,0 mg Average weight of tablets 1260,0 mg (the number of ingredients in mg is indicated per 1 tablet).

A mixture of lomefloxacin, isoniazid, pyrazinamide and ethambutol hydrochloride with microcrystalline cellulose and part of the starch (70%) granularit using a solution of polyvinylpyrrolidone in aqueous alcohol, and dried. Dry granules are milled, mixed with pyridoxine hydrochloride, balance of starch, Aerosil, talc and calcium stearate and tabletirujut.

Example 3. Lomefloxacin - 100 g (1 M.Ch.), isoniazid 120 g (1,2 M.Ch.), pyrazinamide - 135 g (1,35 M.Ch.), ethambutol hydrochloride - 330 g (3,3 M.Ch.), pyridoxine hydrochloride, 100 g (1.0 M.Ch.), excipient is starch - 20,0 g, lactose - 20,0 g, microcrystalline cellulose - 65.0 g, silica - 5,0, Microcrystalline cellulose and silicon dioxide are mixed to obtain a pre-mixture. This mixture, in turn, is mixed with lomefloxacin, isoniazid, pyrazinamide, ethambutol hydrochloride, pyridoxine hydrochloride, lactose and starch. The mixture is filled solid desire the new capsules of suitable size, using conventional machine for filling capsules.

Example 4. Lomefloxacin - 50.0 g (1 M.Ch.), isoniazid - 33,75 g (0,675 M.Ch.), pyrazinamide - of 92.5 g (1,85 M.Ch.), ethambutol hydrochloride an 81.25 g (1,625 M.Ch.), pyridoxine hydrochloride 0.5 g (0,01 M.Ch.), excipients polyvinylpyrrolidone - 10.3 g, corrigent taste (Matricaria) and 9.8 g, flavor - 10.0 g, manitol - to 344.4 g, nutriceuticals - 17,5, Moistened with a solution of polyvinylpyrrolidone mixture of the remaining ingredients, granularit on the device for producing granules and dried. Receive granules for the preparation of water-dispersible suspension oral administration.

Table
IngredientsContent parts by weight
 Examples
 1234
Lomefloxacin1,01,01,01,0
Isoniazid0,6750,21,20,675
Pyrazinamide1,852,751,351,85
Ethambutol hydrochloride1,6251,43,31,625
Pyridoxine hydrochloride0,050,151,00,01
Excipients0,450,81,1to 7.84

1. Anti-tuberculosis drug in the form of a solid dosage form comprising a therapeutically effective amount of the current to the beginning, which contains a combination of lomefloxacin, isoniazid, pyrazinamide, ethambutol hydrochloride and pyridoxine hydrochloride, and pharmaceutically acceptable excipients, the following ratio of ingredients of the current starters, parts by weight:

Lomefloxacin 1,0,

Isoniazid 0.2 to 1.25 and

Pyrazinamide is 1.35-2,75,

Ethambutol hydrochloride 1,4-3,3,

Pyridoxine hydrochloride 0,01-1,0

2. TB tool according to claim 1, characterized in that it is made in tablet form.

3. TB tool according to claim 2, characterized in that it contains as excipients polyvinylpyrrolidone, polyethylene glycol, nutritionstrategywales, Aerosil, magnesium stearate.

4. TB tool according to claim 2 or 3, characterized in that it has a shell.



 

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