RU2247559C1 - Antituberculous agent - Google Patents

Abstract

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

Description

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

In standard chemotherapy for tuberculosis, isoniazid - isonicotinic acid hydrazide is used as the main and most effective anti-tuberculosis drug (Mashkovsky M.D. Medicines, vol. 2, ed. 12th, M., 1993, p. 367). Characterized by high therapeutic activity, isoniazid has a strong toxic effect. But its main drawback is the rapid development of drug resistance of Mycobacterium tuberculosis, which significantly reduces its effectiveness. Isoniazid resistance of mycobacterium tuberculosis develops in 70% of patients, and 30% of patients become chronic patients.

In the context of the tuberculosis epidemic that has developed in Russia in recent years, the course of tuberculosis infection and the structure of clinical forms have changed dramatically. A problem in the tuberculosis clinic was a sharp increase in the number of patients with drug resistance of mycobacterium tuberculosis. In this regard, there is a need for the appointment of combinations of 4 or more anti-TB drugs. However, with combined therapy, patients with tuberculosis, due to the difficulties and the duration of the selection of effective drugs, as well as the course of therapy themselves, either do it irregularly or do not finish it, which causes the disease to return and the secondary resistance to drugs to appear quickly. Therefore, the World Health Organization (WHO) recommends the abandonment of mono- and combination therapy and indicates the need to use combined anti-TB drugs in one dosage form.

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 components does not completely remove the above-mentioned disadvantages of combination therapy and requires the appointment of additional 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 a excipient (prototype )

However, well-known analogue 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 tuberculosis efficacy and causes the disease to return 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 objective of the present invention is to provide a highly effective anti-TB drug 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 drug includes a therapeutically effective amount of the active principle, which contains a combination of lomefloxacin, isoniazid, pyrazinamide, ethambutol hydrochloride, pyridoxine hydrochloride, and pharmaceutically acceptable excipients in the following ratio of active principle ingredients, parts by weight:

Lomefloxacin 1.0

Isoniazid 0.2-1.25

Pyrazinamide 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, selected experimentally and allows you to get a technical result that matches the task.

The use of the claimed combination of active ingredients in the indicated ratio significantly increases antimicrobial activity in relation to drug-resistant mycobacteria of tuberculosis, and the inclusion of lomefloxacin - fluoroquinolone, which has anti-tuberculosis activity and a wide spectrum of antimicrobial activity on nonspecific pathogenic flora, makes it possible to use a new agent for the treatment of acute progressive forms of tuberculosis.

The tuberculosis process is often accompanied by a violation of the metabolism of vitamins, primarily pyridoxine, which plays an important role in the exchange of the essential amino acids tryptophan and methionine, as well as cysteine, glutamine and other amino acids, which causes great damage to the physiological protective reactions of the patient's body. Violations of vitamin metabolism can also be caused by the direct anti-vitamin action of some anti-TB drugs. These include structural analogues of pyridoxine and nicotinic acid. The anti-vitamin effect of these drugs is one of the reasons for their toxic and toxic-allergic effects on the body. At the same time, it is known that biological antagonism between the metabolites of vitamins, in particular pyridoxine hydrochloride, and their structural counterparts with anti-tuberculosis action, primarily isoniazid and / or pyrazinamide, when administered simultaneously reduces the effectiveness of anti-TB drugs.

However, 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 experiments were performed on a H37RV test culture, a laboratory strain of M. tuberculosis, which was grown for 2 weeks in Shkolnikova's liquid nutrient medium with the addition of various drug concentrations. All dilutions of preparations and culture media were prepared in accordance with the requirements of the Pharmacological Committee (Guidelines for the experimental (preclinical) study of new pharmacological substances, M., 2000). The viability of Mycobacterium tuberculosis after exposure to the drug was evaluated by their ability to grow on Levenshtein-Jensen medium (after removing the drug by washing with saline). The minimum total bactericidal concentration (MSC) of the drug was determined by the absence of culture growth. A significant increase in the bactericidal activity of the new drug compared with the prototype was noted. So, the MSBC of the claimed drug is 0.125 μg / ml (according to the current principle, 0.5 μg / ml for the prototype), at a concentration of 0.1 μg / ml (current principle), the growth of CFU (colony forming units) after 2-week incubation culture of mycobacteria in the new drug is 2.8 times lower than that of the prototype, and at a concentration of 0.05 μg / ml (according to the current principle) - 1.5 times lower. In vivo experimental studies were performed on mice infected with a culture of tuberculosis mycobacteria isolated from a patient with multidrug resistance. The results were evaluated by seeding colonies of mycobacterium tuberculosis from lung tissue of mice (CFU / g of tissue) on Levenshtein-Jensen medium. Research data indicate that the claimed anti-tuberculosis composition is characterized by a significant increase in antimicrobial activity against a multiresistant culture of tuberculosis mycobacteria compared to the prototype and single drugs like isoniazid, pyrazinamide, ethambutol hydrochloride, or lomefloxacin, administered in effective therapeutic doses.

A study of the toxic effect of the new drug showed that after two weeks of intragastric administration to rats at a dose of 500 mg / kg (according to the current principle), hematological (red blood cells, hemoglobin, white blood cells, reticulocytes, platelets) and biochemical (total lipids and glucose) blood parameters as indicators of toxicity do not differ from control. No structural abnormalities in organs and tissues were noted, and the irritating effect of the new composition on the mucous membrane of the gastrointestinal tract was also not detected.

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. 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, esters polyoxyethylene sorbitan and fatty acids (twins), esters of sorbitan and fatty acids (spans), preferably starch, including modified starch, lactose, microcrystalline c llyuloza, natriykroskarboksimetiltsellyuloza, polyvinylpyrrolidone, a 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. 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 derivative of cellulose, for example, hydroxypropyl methylcellulose, or a ready-made mixture of the brand "Opadry".

The preparation of the claimed dosage form can be carried out in accordance with known methods for the manufacture of solid dosage forms, for example, by wet granulation followed by adding a lubricant to the dry granules, molding the final mixture of ingredients to form the dosage form of a given configuration and size, and, if necessary, coating .

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

Example 1. Lomefloxacin - 200 mg (1 m.h.), isoniazid - 135 mg (0.675 m.h.), pyrazinamide - 370 mg (1.85 m.h.), ethambutol hydrochloride - 325 mg (1.625 m. hours), pyridoxine hydrochloride - 10 mg (0.05 parts by weight), excipients - 90 mg, including croscarboxymethyl cellulose sodium - 55.0 mg, polyvinylpyrrolidone - 10.0 mg, polyethylene glycol - 5 mg, aerosil - 10 , 0 mg, magnesium stearate - 10.0 mg. The average tablet weight is 1130.0 mg (the number of ingredients in mg is indicated per 1 tablet). A mixture of lomefloxacin (as a hydrochloride), isoniazid, pyrazinamide and ethambutol hydrochloride is moistened with an 8% aqueous solution of polyvinylpyrrolidone, to which polyethylene glycol is added, until homogeneous. The mixture is granulated and dried to a residual moisture content of 1.0%. Dry granules are ground, mixed with pyridoxine hydrochloride, croscarboxymethyl cellulose sodium, aerosil and magnesium stearate and tableted. A film-forming composition based on the finished Opadry brand mixture is applied to the obtained cores with an average mass of 1130 mg until a satisfactory film is obtained. A light brown coated tablet with an average weight of 1187 mg is obtained.

Example 2. Lomefloxacin - 200 mg (1 m.h.), isoniazid - 40 mg (0.2 m.h.), pyrazinamide - 550 mg (2.75 m.h.), ethambutol hydrochloride - 280 mg (1 , 4 m.h.), pyridoxine hydrochloride - 30 mg (0.15 m.h.), 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.The average tablet weight is 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%) is granulated using a solution of polyvinylpyrrolidone in aqueous alcohol, and dried. The dry granules are ground, mixed with pyridoxine hydrochloride, starch residue, aerosil, talc and calcium stearate and tableted.

Example 3. Lomefloxacin - 100 g (1 m.h.), isoniazid - 120 g (1.2 m.h.), pyrazinamide - 135 g (1.35 m.h.), ethambutol hydrochloride - 330 g (3 , 3 mph), pyridoxine hydrochloride - 100 g (1.0 mph), excipients - starch - 20.0 g, lactose - 20.0 g, microcrystalline cellulose - 65.0 g, silicon dioxide - 5.0 g. Microcrystalline cellulose and silicon dioxide are mixed to obtain a preliminary mixture. This mixture, in turn, is mixed with lomefloxacin, isoniazid, pyrazinamide, ethambutol hydrochloride, pyridoxine hydrochloride, lactose and starch. The resulting mixture is filled in hard gelatin capsules of a suitable size using conventional capsule filling machines.

Example 4. Lomefloxacin - 50.0 g (1 m.h.), isoniazid - 33.75 g (0.675 m.h.), pyrazinamide - 92.5 g (1.85 m.h.), ethambutol hydrochloride 81 , 25 g (1.625 mph), pyridoxine hydrochloride 0.5 g (0.01 mph), excipients polyvinylpyrrolidone - 10.3 g, flavor flavoring (sodium saccharinate) - 9.8 g, flavor - 10 , 0 g, mannitol - 344.4 g, sodium lauryl sulfate - 17.5 g. A mixture of the remaining ingredients is moistened with a solution of polyvinylpyrrolidone, granulated in a granulate plant and dried. Granules are prepared for the preparation of a water-dispersible oral suspension.

Table Ingredients Content, parts by weight Examples 1 2 3 4 Lomefloxacin 1,0 1,0 1,0 1,0 Isoniazid 0.675 0.2 1,2 0.675 Pyrazinamide 1.85 2.75 1.35 1.85 Ethambutol hydrochloride 1,625 1.4 3.3 1,625 Pyridoxine hydrochloride 0.05 0.15 1,0 0.01 Excipients 0.45 0.8 1,1 7.84

Claims (4)

1. An anti-tuberculosis drug in the form of a solid dosage form, comprising a therapeutically effective amount of an active principle, which contains a combination of lomefloxacin, isoniazid, pyrazinamide, ethambutol hydrochloride and pyridoxine hydrochloride, and pharmaceutically acceptable excipients in the following ratio of active principle ingredients, parts by weight : Lomefloxacin 1.0, Isoniazid 0.2-1.25, Pyrazinamide 1.35-2.75, Ethambutol hydrochloride 1.4-3.3, Pyridoxine hydrochloride 0.01-1.0 2. The anti-tuberculosis drug according to claim 1, characterized in that it is made in the form of a tablet. 3. The anti-tuberculosis drug according to claim 2, characterized in that it contains polyvinyl pyrrolidone, polyethylene glycol, croscarboxymethyl cellulose sodium, aerosil, magnesium stearate as auxiliary substances. 4. The anti-tuberculosis drug according to claim 2 or 3, characterized in that it has a shell.