RU2235537C1 - Method for treating tuberculosis - Google Patents

Abstract

FIELD: medicine, phthisiology.

SUBSTANCE: one should introduce by inhalation a preparation containing the mixture of rifampicin and polyvinylpyrrolidone at 1 : (3-9) ratio. The present innovation increases efficiency of therapy at applying minimal dosages of rifampicin, the action of which is increased due to combination with polyvinylpyrrolidone at certain ratio.

EFFECT: higher efficiency of therapy.

3 cl, 3 ex, 1 tbl

Description

The invention relates to medicine, namely to methods for treating tuberculosis.

It is known that in the treatment of various forms of tuberculosis, drugs are used that act on tuberculosis microbacteria, inhibiting their reproduction and reducing their virulence. In particular, it is proposed to use methyluracil in the treatment of tuberculosis in combination with conventional complex therapy (antibacterial, detoxification) and vitamins, which gives positive results in the treatment of tuberculosis. (Problems of tuberculosis, 1993, N 6, Kozlenko LS. A way to rationalize the treatment of patients with pulmonary tuberculosis in a hospital, p.52-53).

Methyluracil has an anti-inflammatory effect, accelerates cell regeneration processes, stimulates leukopoiesis, is an immuno-stimulant. However, when using it, it is not possible to achieve complete closure of the decay cavity, in particular, with destructive pulmonary tuberculosis, that is, the activity of methyluracil is not high enough, even when it is used in large quantities. (Gracheva MP Phagocytic activity of alveolar macrophages of rabbits with tuberculous inflammation and under the influence of anti-TB drugs. Dissertation. Moscow, 1983). So, the usual dosage of methyluracil is 0.5 g 3 times a day, that is, during the day the patient receives 1.5 g of the drug. Such a dose, taking into account the intake of essential drugs, is quite significant, and the desired therapeutic effect is absent. In addition, the method of administration of methyluracil is limited. It can be used only orally.

Antibiotics have the highest bacteriostatic activity. The generally accepted traditional antibacterial therapy involves the use, as a rule, of the following drugs: tubazide (isoniazid), rifampicin and streptomycin (Mashkovsky MD Medicines. M: Medicine, 1993, v.2, p. 366-367; The problem of tuberculosis , 1993, N 2. - M .: Medicine, p. 34-36; Ursov I.G., Borovinsky A.I., Fedorova T.A., Fomintseva O.A., Zyryanova T.V. The concept of accelerated change destructive pulmonary tuberculosis). However, their use, as a rule, is either not effective enough, or requires the use of large doses of antibiotics, which negatively affects the state of other body systems.

Closest to the claimed invention is a method of treating tuberculosis with rifampicin, which is administered orally in the form of capsules in a daily dose of 150 mg. To reduce the rate of excretion of rifampicin from the body with urine, the drug is administered with pyrazinamide (GB Sokolova et al. Antibiotics and chemotherapy, 2000, 45, No. 9, pp. 30-37).

The disadvantage of this method is the lack of effectiveness of rifampicin, due, in particular, its introduction into the body through the gastrointestinal tract. The use of rifampicin in the form of an aerosol is ineffective due to its low solubility in water (2 mg / ml), which does not allow it to be administered in sufficiently high doses.

The challenge facing the authors was to create a method of treating tuberculosis with rifampicin based on its aerosol administration.

This problem was solved by inhalation of an aerosol preparation containing a mixture of rifampicin with polyvinylpyrrolidone in a ratio of 1: (3-9) daily. The treatment time is set individually depending on the condition of the patient. The average treatment time is 30-40 days, 15-20 minutes daily.

Using a drug with a rifampicin content of less than 10% reduces the effectiveness of treatment and requires the introduction of large quantities of the drug. At a concentration of rifampicin in the mixture of more than 25%, the fraction of fine particles in the preparation drops by 3-5 times, which does not allow the drug to be injected into the lungs in the required volumes and reduces the effectiveness of the treatment.

To obtain the preparation, as a rule, a mixture of ingredients of a certain composition is prepared and ground in a jet mill or other standard method to obtain particles less than 10 microns (optimally less than 5 microns). It is possible to dissolve the ingredients in a phosphate buffer solution, followed by obtaining a powdery preparation by spray or freeze-drying. With this production technology, the mixture may additionally contain 2-5 wt.% Sodium phosphates.

Example 1. 2.0 g of rifampicin and 8 g of polyvinylpyrrolidone were loaded into a flask and filled with 92 ml of phosphate buffer solution (pH 7.4). The mixture was stirred for 5 hours at a temperature of 60 ° C, filtered through a paper filter and dried by freeze-drying. The obtained powder after grinding contained 90.5% of the mass with a particle size of less than 10 microns.

Evaluation of the effectiveness of the method was carried out on 207 white outbred mice - males with generalized tuberculosis caused by the introduction of M. Bovis 8 culture into a lateral tail vein at a dose of 0.1 mg in 2 ml of physiological saline. In experiments on mice, 2 series of experiments were carried out using dry (SA) and drip-liquid (VA) aerosols.

A preparation containing 15 wt.% Rifampicin, 81 wt.% Polyvinylpyrrolidone, 3.3 wt.% Sodium phosphate disubstituted and 0.7 wt.% Sodium phosphate monosubstituted was administered daily for 30 days for 15 minutes at doses of 2 and 10 mg / kg for CA; 5 and 10 mg / kg for FA.

As a control, we used mice that did not receive the drug, who received rifampicin orally and VA with rifampicin at a dose of 10 mg / kg.

The effectiveness of treatment of the tuberculosis process was evaluated according to the results: dynamics of the body weight of mice; animal survival; macroscopic examination of the lungs and spleen with the calculation of the mass fraction (coefficient) of the lungs and spleen in the body; lung lesion index; sowing mycobacteria from the spleen.

The lung lesion index was calculated in accordance with the number and severity of foci of specific inflammation detected by macroscopic examination. Moreover, single submiliary foci were estimated at 0.5 points; numerous (no more than 20) - 1.5 points; single miliary - in 1.75 points; numerous merging submillion single millionths - 2.0 points, millionths (no more than 10) and 2.25 points, numerous millionths merging - 2.75 points, the presence of small caseous necrotic tricks - 3.0 points; extensive caseosis - 4.0 points; continuous lung damage - 5.0 points. In cases of serous impregnation of lung tissue, 0.25 to 1.0 points were added to the calculated lesion index, depending on the area of the lesion.

For bacteriological studies, dosed inoculation of the spleen tissue homogenate was carried out on a dense Levenshtein-Jensen nutrient medium. Growth massiveness of Mycobacterium tuberculosis (MBT) was evaluated after three weeks of incubation of spleen cultures (37 ° C) and expressed in colony forming units — CFU. The following colony counting technique was used: when registering up to 50 colonies, their total number was given; with growth by 1/3 of the test tube, the number of colonies was taken as 100 CFU; with an increase of 2/3 tubes - for 200 CFU; with continuous growth of colonies - for 300 CFU.

Statistical processing of the results was carried out according to the Student-Fisher parametric test and the non-parametric Wilkinson-Mann-Whitney test using the U criterion.

Comparative data on the effectiveness of different rifampicin preparations are given in the table. The research results indicate a high effectiveness of the treatment according to the claimed method, and higher results were obtained using dry aerosol.

The differences are apparently due to the good adhesion of the dry aerosol particles to the mucous membranes of the lung tissue, which ensures their easy phagocytosis by alveolar macrophages, where the pathogen can multiply, thereby ensuring a higher concentration of the antibiotic in the affected area. When using VA, the antibiotic enters the cell through diffusion, which does not allow reaching comparable concentrations in the cell with CA.

Example 2. 1.0 g of rifampicin and 9 g of polyvinylpyrrolidone were loaded into a flask and filled with 92 ml of water. The mixture was stirred for 5 hours at a temperature of 60 ° C, filtered through a paper filter and dried using freeze-drying. The obtained powder after grinding contained 85% of the mass with a particle size of less than 5 microns. When administered by inhalation under the conditions of Example 1 at a dose of 5 mg / kg with a 100% survival rate of mice, the weight gain of the mice was 16.6%, and MBT from the spleen was seeded 12.4 ± 0.6 CFU.

Example 3. 2.5 g of rifampicin and 7.5 g of polyvinylpyrrolidone were loaded into a flask and filled with 92 ml of water. The mixture was stirred for 5 hours at a temperature of 60 ° C, filtered through a paper filter and dried using freeze-drying. The resulting powder contained 75% by weight with a particle size of less than 10 microns. When administered by inhalation under the conditions of Example 1 at a dose of 5 mg / kg with a mouse survival rate of 100%, the weight gain of the mice was 11.6%, and the MBT inoculation from the spleen was 32.7 ± 0.9 CFU.

The experiments showed that when using the inventive preparation, the therapeutic dose is reduced at least 5 times in comparison with traditional methods of its administration.

Claims (4)

1. A method of treating tuberculosis by introducing into the body a mixture of substances containing rifampicin, characterized in that as a mixture, an inhalation preparation containing a mixture of rifampicin with polyvinylpyrrolidone in a ratio of 1: (3-9) is administered. 2. The method according to claim 1, characterized in that the mixture additionally contains 3-5 wt.% Sodium phosphate. 3. The method according to claims 1 and 2, characterized in that the drug is administered daily with an inhalation time of 15-20 minutes. 4. The method according to claims 1 to 3, characterized in that the drug is administered within 30-40 days.