Combined antituberculosis drug (risoluto)

 

(57) Abstract:

The invention relates to the field of pharmacology and medicine and relates to a combined anti-TB drugs. The invention lies in the fact that combined antituberculosis drug contains rifampicin, ethambutol, isoniazid, pyrazinamid and pyridoxine at a certain ratio of components. The invention provides for increasing the effectiveness of therapy by simplifying the treatment process, overcoming resistance in a wide range of patients, improve the properties of the drug. 6 table.

The invention relates to the field of pharmacology and medicine, specifically to a new type of anti-TB drugs, containing a collection of medicinal substances in one tablet (capsule), designed primarily to overcome possible resistance of Mycobacterium tuberculosis to medicinal substances in a patient, to simplify the treatment procedure and, thus, to contribute to the implementation of treatment in full and, ultimately, to improve the effectiveness of the treatment.

Ordinary course of monotherapy tuberculosis is prescribed rifampicin or isoniazid. The preferred course combined terbiyesiz, usually add a fourth drug ethambutol. Medicines are prescribed by the attending physician, in doses and ratios depending on age, physiological characteristics, the nature of the disease, as well as, paradoxically, the availability of medicines in pharmacies, which is typical even for developed countries such as the USA or Italy.

Until recently, research in the field of therapy of tuberculosis walked in the direction of the search for new active principles and their combinations with known drugs (see, for example, Heb.Pat. 0650728, Pat. USA 5399558, Heb. Pat. 0398165, Pat. PCT WO 95/13807), or the creation of new dosage forms for such well-known drugs, such as isoniazid, rifampicin, ethambutol (see , for example, WO 88/06038, Pat. USA 5811088, Pat. Russia 93015116, 2143900, 94041109, 98100213).

However, they mostly never touched drugs combined, as they do not assume the presence of active components in a single tablet or other dosage form. Thus they are, as a rule, mono - or combination therapy.

Currently, the world Health Organization (who) recommends the rejection of mono - and from SOCOM, containing specially selected set of drugs at fixed doses in a single tablet, providing optimal therapeutic effect (Consilium Medicum 1999, so 2, S. 170-171. Remedium, 2000, 7,8)

The need for such a strategy is dictated by the fact that the combined therapy at the present time due to the increase in the percentage of patients with resistant strains includes three or more drugs, the treatment is on average 6-12 months. Diagnosis of clinically established within 3-6 weeks, on the identification of primary resistance (i.e. inefficiency originally prescribed course of treatment) also requires 3-6 weeks.

As a consequence of the above, for HIV patients receiving concomitant therapy often fails to timely perform tests for the selection of effective treatment, as they die from TB through 4-16 weeks after the clinical manifestations of this disease.

Typically, TB patients because of the complexity and duration of selection of effective drugs, as well as the course of therapy, realize it or not regularly, or not getting to the end, which causes a return of the disease, the emergence of secondary resistance to drug among the x problems (besides the selection of an effective composition of medicines, their ratios), such as the interaction of various drugs during the manufacturing process and storage, development of technological modes of production that are acceptable to all active principles, selection of common carriers engaged in, for example, targeted drug delivery for overcoming resistance to drugs in order to prolong the action, or solving other tasks.

In the case of combined anti-TB drugs on the basis of rifampicin on the recommendation of the who special attention should be paid to ensuring adequate bioavailability, which may be significantly decreased when creating new drugs combined, and even in the case of non-manufacturing technologies for known drugs combined. (Ibid.).

Thus, the known combined antituberculosis drug containing as an active beginning of a mixture of rifampicin, ethambutol and isoniazid in the ratio of 150:75:300 (mg) and 30-50 wt.% inert filler, which is used as chalk, soda, magnesium stearate (Reference Vidal, 2001, p. B-336), which is closest to the proposed invention, and so the single substances) rifampicin, ethambutol and isoniazid, the preparation exhibits a high therapeutic activity in a total dose of 140 mg/kg of body weight.

But long-term use, there are marked toxic effect.

Inventive task is to expand the Arsenal of combined anti-TB drugs, increasing their therapeutic efficacy, reduced toxic effects.

The objective is achieved by the fact that the proposed combined antituberculosis drug containing as an active start rifampicin, ethambutol, isoniazid and additionally pyrimid and pyridoxine, and as filler 2-15 wt.% metusela in the following ratio of components in medicinal mixture, mg:

Rifampin - 140 - 160

Ethambutol - 270 - 280

Isoniazid - 70 - 80

Pyrimid - 400

Pyridoxine - 10 - 15

The applicant selected set of drugs (rifampicin, ethambutol, isoniazid, pyrazine), which is used in the preferred course of combination therapy. This set also includes pyridoxine - the precursor to the formation of pyridoxal phosphate is one of the derivatives of vitamin b6.

Metacel is the brand name of the methyl esters of cellco curable molding and pelletizing. Methyl cellulose ethers are used as thickeners in a number of industries (textiles, typography, cosmetology, food industry to thicken juices, pastes and so on)

The applicant is unknown to the application of metusela as a carrier for the combined anti-TB drugs. The proposed combination of active principles and media, their ratio are new to combined anti-TB drugs, are chosen empirically and impact of the identified properties of the drug.

The applicant discovered unexpected (from the standpoint of prior art) the following properties of the proposed drug.

1. Data pharmakinetic rifampicin in the proposed drug showed that the maximum concentration is reached after 3-4 hours and is 7 g/ml, which is sufficient for the manifestation of high bacteriostatic effect. Curve pharmokinetic smoother, which is an advantage, because the high value of the bacteriostatic effect lasts longer. This proves that in this combined drug met the requirements of the who concerning the requirements bioavailability of rifampicin in combination protease (70 mg/kg of body weight of the animal), 2 times less prescribed therapeutic doses (used in the prototype - 140 mg/kg of body weight of the animal), showed the effectiveness of the treatment (80,1%), almost the same as in the prototype (82,6%). This indicates the presence of a synergistic effect of the components isobutane, possibly due to the reciprocal influence of the bacteriostatic effect and the overall toxicity of the drug with a long introduction, other possible interdependent processes in vivo (see, for example, Kiselev Century. And. Kanamycin sulfate inducer goes gene of Escherichia coli. Molecular genetics, Microbiology and Virology, 1989, 5, S. 41-43). Interestingly, the bacteriostatic effect in vitro, when it cannot be considered the General toxicity of the drug is achieved only when the same concentrations in the nutrient medium as isobutane and nutrient mixture on the prototype, and isoniazid, as the most active and widely used in the clinic tuberculosis drug.

3) the Study of hematological and biochemical parameters as indicators of toxicity with long-term administration isobutane shows that he has no toxic properties.

Active ingredients in the joint presence of stable production process is Anderton domestic equipment.

The invention is illustrated by the following examples: example 1 describes the compositions used in examples 2-5, example 2 describes the data on pharmokinetic rifampicin as part isobutane; example 3 is devoted to the description of chemotherapeutic effectiveness isobutane in conditions of experimental tuberculosis of mice; in example 4 shows the hematological and biochemical parameters as indicators of toxicity; example 5 is devoted to clinical therapy Isobutanol limited group of patients with a diagnosis of focal tuberculosis.

Example 1.

Obtaining compositions.

To 150 mg of rifampicin, 275 mg ethambutol, 75 mg isoniazid 400 mg of pyrimido, 10 mg pyridoxine was added 100 mg of metusela (corresponds to 10% of the total weight of the composition). The mixture was thoroughly mixed in the mixer for 15 min, dried in the dryer shelf type (Munsterman"), passed through a granulator RF-3056 and tabletirujut on a rotational tabletop press RTM-41.

The result is a composition of the following composition, which is used in examples 2-4, mg:

Isoniazid - 75

Rifampicin - 150

Ethambutol - 275

Pyrazinamid - 400

Pyridoxine - 15

So prepare ferritina part resolutely.

Determination of rifampicin in plasma of mice was performed using reversed-phase HPLC. This used the pump Gilson M302 (USA), a Rheodyne injector 7125i (USA) and a photometric detector Carlo Erba microUVIS20 (Italy). The analysis was carried out using a column Packed reversed-phase sorbent XTerra RP8H,6 mm (Waters, USA) using as mobile phase of 40% acetonitrile in 0.1 M ammonium acetate buffer solution, pH of 4.6, at a flow rate of 1.2 ml/min Detection was performed at 254 nm.

Samples for analysis were prepared by the following method: the blood plasma of animals was obtained after centrifugation at 2500 rpm for 20 min, then it was extracted with 5 volumes of a mixture l3:Meon=4:1, the extractant was dried in a stream of argon, the residue was dissolved in 0.2 ml of mobile phase.

The number of rifampicin in plasma samples was determined by the peak area corresponding to the time of the release of the antibiotic. For this purpose built calibration curve based on the results of HPLC analysis of an aliquot of a solution of rifampicin, prepared according to precise the sample substance. The data analysis are presented in table.1.

Example 3.

Chemotherapeutic efficacy isobutane in the conditions of the experiment the pilot playback hematogenous disseminated tuberculosis was carried out at 85 mice C57BL/6, laboratory animals were obtained from Central animal kennel RAMS. In the experience of the included mouse, the past quarantine, standardization by weight (20-25 g) and sex. Infection was performed two weeks virulent culture of M. tuberculosis H37Rv by intravenous (tail vein) injection of a suspension of Mycobacterium dose of 2-10 CFU (colony forming units) in 0.5 ml of saline. All experimental animals were divided into 5 groups depending on the chemotherapy regimen, and 17 individuals in each treatment group.

Treatment of animals was started 14 days after infection, when in the lungs was determined macroscopically multiple foci of tuberculosis infection.

Chemotherapy was administered every day (except Sunday) for 2 months. Drugs administered orally.

Macroscopic evaluation of the effectiveness of each regimen was expressed by a performance index that is measured by a special formula developed by Torgunova A. N. (see Methods of experimental chemotherapy (a Practical guide). Ed. 2nd edition, edited by G. N. Pershina. M.: Medicine, 1971).

Microbiological study included positive strokes is.N. (see Order 558 USSR Ministry of health, from 08.06.1978, M., 1978, guideline, Appendix 2).

1 month of treatment.

At macroscopic examination of the internal organs of mice not treated with chemotherapy (group 2) were found expressed signs of tuberculous inflammation (major foci of tuberculosis infection in the lungs). Index lesions of the internal organs of the mice in this group was 2.8 ED (see tab. 2).

Macroscopic picture of the internal organs of animals treated with a mixture of drugs on the prototype in the studied dose (group 3), corresponds to index lesion of 1.8 UNITS, i.e., in the lungs of experimental animals was determined by single foci of tuberculosis infection (see table.2).

Macroscopic examination of the internal organs of mice treated for 1 month risoluto (4) and (5 groups), also showed the presence of TB infection. The index lesion was 1.5 and 1.5 U, respectively.

The results of the examination and study of seed obtained from mice that participated in the experiment for 1 month showed the presence of mycobacteria in all studied parenchymatous organs (see table.3).

2 months of treatment.

When the macro is aniu experiment were found expressed signs of tuberculous inflammation (large necrotic foci of tuberculosis infection in the lungs). Index lesions of the internal organs of the mice in this group was 3.5 UNITS (see tab.3).

Painting defeat the parenchymatous organs of mice 3 groups close to the one in the 4th and 5th groups, the index lesion in these cases of 0.6, 0.5 and 0.7 IU, respectively, i.e., expressed foci of infection is not detected. The effectiveness of chemotherapy in these groups - 82,6, 85,7 and to 80.1%, respectively (see tab.2).

The decrease in therapeutic doses isobutane 2 times of the maximum led to the decrease in the efficiency of only 5.6%.

Examination of smears, fingerprints and seed in the groups receiving the drug mixture and risoluto within 2 months, revealed a significant positive effect of chemotherapy at a dose of 140,0 mg/kg the Results of microbiological studies parenchymatous organs showed sterilization of the material researched from Mycobacterium tuberculosis.

The dose isobutane 70 mg/kg data smears did not reveal the presence of bacilli in smears from pathological material, and the growth of mycobacteria in crops was negligible.

Data Visavuori mycobacteria from the spleen of infected animals reflect current chemotherapy in General. Results see table.4.

7colonies on your body mouse, indicating extensive process infectious lesion of the organs of the few surviving to the end of the experiment animals.

Thus, in the experimental studies found high chemotherapeutic efficiency (85,7%) new TB drug risoluto. Application of the test drug in half dose also gave very good results of therapeutic efficacy - of 80.1%, which will allow you to use risoluto for therapy in half dose and thus further reduce the toxic effects of treatment.

Example 4.

Toxic effects observed with long-term administration of anti-TB drugs.

The conditions of the experiment described in example 3.

The data are given in table.5 and 6.

Comparative study of hematological and biochemical the imps shows what risoluto, unlike the prototype, has no toxic properties (see tab.5 and 6), even at a dose of 140 mg/kg

Example 5.

Clinical therapy Isobutanol limited contingent of patients.

Used the composition of example 1 containing 20 mg of pyridoxine.

The group consisted of 5 patients who were prescribed treatment Isobutanol at a dose of 140 mg/kg / day, 3 weeks was conducted radiological, biochemical and hematological studies. In all cases there was a positive dynamics of complaints, including neurological symptoms, was not.

Combined antituberculosis drug containing as an active beginning of a mixture of rifampicin, ethambutol and isoniazid and inert filler, characterized in that it additionally contains pyrazinamide and pyridoxine, and as filler 2-15 weight. % metusela in the following ratio of components, mg:

Rifampicin - 140-160

Ethambutol - 270-280

Isoniazid - 70-80

Pyrazinamid - 400

Pyridoxine - 10-15

 

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