RU2523792C9 - Drug preparation for treating tuberculosis - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: drug preparation for treating tuberculosis contains an active substance isoniaside, and a pharmaceutical carrier tiozol gel with the isoniaside concentration of 5.7-54.5 wt % and the tiozol gel concentration of 45.5-94.3 wt %.

EFFECT: higher clinical effectiveness in tuberculosis and lower toxicity.

2 cl, 2 tbl

Description

The invention relates to medicine, namely to medicines for the treatment of tuberculosis.

A significant increase in the incidence and mortality from tuberculosis determines the relevance of the problem of the search for new drugs with anti-tuberculosis activity. A limited set of effective anti-TB drugs and the natural selection of microorganisms have led to the spread of resistant forms of Mycobacterium tuberculosis (MBT) to anti-TB drugs and an increase in the number of patients with drug-resistant forms of tuberculosis.

Currently, the main chemotherapeutic agent used to treat tuberculosis is isonicotinic acid hydrazide (isoniazid).

Mycobacteria of the human species are more sensitive to isoniazid. It most actively acts on rapidly multiplying mycobacteria, less active in relation to slowly multiplying. The drug in high concentrations can have a bactericidal effect on mycobacteria. Active against intracellular and extracellularly located mycobacteria. Isoniazid does not inhibit the development of other microorganisms.

Isoniazid has a number of side effects.

Long-term use of isoniazid in some patients causes the development of severe side effects: polyneuritis, drug arthritis and lupus-like syndromes of varying severity.

The appointment of isoniazid and its derivatives is contraindicated in patients with epilepsy, coronary heart disease, cardiovascular failure, with diseases of the central and peripheral nervous system, as well as the liver and kidneys, in violation of their functions.

One of the main problems of chemotherapy for tuberculosis is overcoming the resistance of the pathogen to the effects of chemotherapeutic agents.

In practice, these approaches make it possible to achieve positive results in a relatively short period of time: increasing the dose of isoniazid and its derivatives is hampered by their high toxicity, other methods of administration are little used in modern treatment practice. And their use is also justified until the pathogen resistance to one or more of the newly prescribed drugs, since the development of drug resistance occurs gradually as a result of the selection of resistant mutants in the patient's body.

One of the ways to prevent the development of resistant forms of Mycobacterium tuberculosis (MBT) to drugs and reduce side effects is the creation of combined drugs, the study of their tuberculostatic activity, methods of administration in treatment.

Known drugs containing isoniazid as the anti-tuberculosis drug (the most effective drug for treating tuberculosis), which are used injection and oral (per os). (RU No. 2207127, No. 2406518, No. 2434632, No. 2146130, No. 2417087, No. 2354378, US No. 2596069). With prolonged treatment with these drugs, a pronounced toxic effect is observed and side effects are manifested.

A drug is known that has an anti-tuberculosis effect, including active substances - isoniazid, fluorouracil, and a pharmaceutical carrier (patent RU No. 2211035, op. 2003). The composition is made in the form of a solution and is administered intramuscularly or intravenously.

The disadvantages of this drug include the previously described adverse side effects of isoniazid. Fluorouracil is a specific anticancer drug, has low tuberculostatic activity, and is highly toxic.

The introduction of a drug in the form of injections intramuscularly or intravenously negatively affects the gastrointestinal tract and liver and, in addition, is painful and traumatic.

The closest analogue adopted for the prototype is a drug with anti-tuberculosis action, including the active substance - isoniazid and a pharmaceutical carrier (MD Mashkovsky. Medicines, 1988). The pharmaceutical carrier may be in the form of a solvent (ioniazide for injection) or a vehicle (tablets of ioniazide).

The disadvantages of the drug include high toxic effects and the occurrence of side effects.

The administration of the drug per os, as well as when administered as an injection, negatively affects the gastrointestinal tract and liver of patients.

These shortcomings reduce the effectiveness of the treatment of tuberculosis.

The problem to which the invention is directed, is to increase the effectiveness of the treatment of tuberculosis and reduce the toxic effects of the anti-TB drug.

To solve the problem in a drug for the treatment of tuberculosis, including the active substance isoniazid and a pharmaceutical carrier, according to the invention, the drug tizol gel is used as a pharmaceutical carrier, while the drug is applied percutaneously to the projection of the affected organ.

The composition of the drug, wt.%:

isoniazid - 5.7-54.5; tizol gel - 45.5-94.3.

The drug tizol gel - P No. 001667 / 01-010807, developed and manufactured by OLIMP LLC, Yekaterinburg, is a gel for external and local use, it is a titanium glycerol solvate complex. Tizol is a safe non-toxic gel, has a high penetrating ability, creates the necessary concentration of the active substance in the affected tissues. As a metal complex compound, tizol has anti-inflammatory and antiseptic effects, microbiological purity and self-sustaining sterility. Within 20-30 minutes, tizol is absorbed through the skin or mucous membrane, distributed in the subcutaneous tissue and underlying tissues. Tizol is not metabolized in body tissues, excreted unchanged in urine, bile, in small quantities through the skin and mucous membranes for 20-24 hours. Not cumulated in the body.

The use of the claimed anti-tuberculosis drug, including isoniazid and tizol, allows percutaneous, application administration of the indicated drug on the projection of the affected organ, which excludes the toxic effect of the anti-tuberculosis drug of the proposed drug on the gastrointestinal tract and liver.

The maximum concentration of an anti-TB drug in blood serum is achieved in a short period of time - after 1.5 hours and lasts up to 8 hours, which reduces the side effects of isoniazid.

The study of the therapeutic effect of tisol with isoniazid was carried out on guinea pigs for two months. Infected animals were divided into three experimental groups (treatment with tizol + isoniazid) and two control groups (treatment with isoniazid per os and without treatment).

In each group there were 7 guinea pigs.

Guinea pigs were infected with 0.001 mg of Mycobacterium tuberculosis culture laboratory strain H ₃₇ Rv. A suspension of culture in physiological saline in a volume of 0.5 ml was injected subcutaneously into the inguinal region of guinea pig. Treatment of infected animals began the day after infection and lasted 2 months.

Tizol with isoniazid was daily injected through the skin by applying a thin layer of applications to the projection of the lung (onto the chest and back of the animal).

Experienced groups

In the I group of animals, a drug of the composition was applied, wt.%:

Isoniazid - 54.5

Tizol gel - 45.5

In the II group of animals, a drug of the composition was applied, wt.%:

Isoniazid - 37.5

Tizol gel - 62.5

In the III group of animals, a drug of the composition was applied, wt.%:

Isoniazid - 5.7

Tizol gel - 94.3

Control groups

Group IV animals received treatment with isoniazid per os 10 mg per 1 kg of body weight.

Group V animals did not receive treatment.

During the experiment, the following parameters were evaluated:

- the dynamics of the weight of animals,

- visual assessment of organs and tissues,

- assessment of organ damage by the index of damage (lung, spleen).

The index of damage to internal organs was calculated by the number of detected foci of tuberculosis infection in the parenchymal organs in the control and experimental groups.

In the control group V, untreated animals died within two months from generalized tuberculosis. The index of damage to internal organs was 4.0.

Group I of experimental animals was slaughtered after a month of treatment with the claimed drug - tizol with isoniazid. The index of damage to internal organs was 1.8, which characterizes the preservation of the tuberculosis process, but its decrease compared with the control group V (index of damage 4.0).

The II and III group of animals was killed after 2 months of treatment with a drug containing tizol and isoniazid. The index of damage to the internal organs of animals was 1.4 (group II) and 1.38 (group III), which characterizes a decrease in the tuberculosis process.

Group IV animals were killed after 2 months of treatment with isoniazid per os. The index of damage to internal organs was 1.8. This indicator indicates that the treatment process of the claimed drug is more effective than treatment with isoniazid per os for 2 months of treatment.

When comparing the indices of damage to the internal organs of guinea pigs, the high therapeutic effect of a drug containing tizol with isoniazid in the treatment of experimental tuberculosis by percutaneous application to the projection of the affected organ for two months is revealed.

An important indicator of the effectiveness of treatment is the difference in the weight of guinea pigs at the beginning and end of the experiment. Data on changes in the weight of animals are presented in table 1.

From the data of the table it follows that the control group V of untreated animals lost weight for two months, and by the end of the experiment their weight decreased by an average of 85 grams (25%).

The weight of animals treated for 2 months increased in all experimental groups (I, II, III groups), on average by 360-400 grams (109-112)%.

From the obtained data on the change in animal weight, a positive therapeutic effect is noted in the treatment of experimental tuberculosis with the drug tizol with isoniazid (I, II, III group), while in the treatment of animals with isoniazid per os (IV group), the weight increased only by 97%, which confirms reduction of the toxic effect of isoniazid with percutaneous application method of administration of the claimed drug.

In all the studied animals of various experimental groups (table 2), macroscopically lesions were not detected in the internal organs, with the exception of the lungs - in some cases they were enlarged, low-air, yellowish-gray in color (group I).

As can be seen from table 2, in this case macrophage-desquamative interstitial pneumonia was detected with the formation of multiple lymphoid follicles in the lung tissue, which has a non-specific character - there are no characteristic histological signs of tuberculosis - granulomas with necrosis, which confirms the absence of tuberculosis.

According to the results of a macroscopic study of animals during autopsy, the following changes were noted: in the control group V, specific tuberculous changes were expressed at the injection site (in the inguinal lymph nodes), lungs, liver, and spleen were affected. In the experimental groups (I, II, III groups) in guinea pigs treated with the claimed drug - tizol gel with isoniazid and treated with isoniazid per os (group IV), there were no visible tuberculous lesions of the lungs, liver and spleen, inguinal lymph nodes were not enlarged .

table 2 Comparative pathomorphological data on the effectiveness of treatment of experimental tuberculosis in guinea pigs with the claimed medicinal product - tizol with isoniazid with its transdermal administration by applications on the projection of the affected organ Group Tizol gel, wt.% Isoniazid, wt.% Lungs Liver Spleen VGLU I 45.5 54.5 Macrophage-desquamative interstitial pneumonia with the formation of lymphoid follicles mixed with eosinophils Small infiltrates
around central
veins Moderate follicular
hyperplasia Moderate follicular hyper
plasma II 62.5 37.5 Lean lymphocytic histiocytic infiltrates Small infiltrates around the central veins - Moderate follicular hyperplasia Moderate follicular hyperplasia III 94.3 5.7 Lean lymphocytic histiocytic infiltrates - - Moderate follicular hyperplasia IV - Per os 10 mg per 1 kg of body weight Lean lymphocytic histiocytic infiltrates - Moderate follicular hyperplasia Moderate follicular hyperplasia V counter role - Untreated Productively necrotic nature of tuberculosis changes - -

The data in table 2 show that lymphocytic-plasmacytic infiltrates were observed in the lungs, but they were mild (perivascular accumulations, small focal infiltrates). The weakest inflammatory reaction in the lungs was detected in group II and group III.

The data in table 2 confirm that the drug when the content of the components, wt.%:

 Isoniazid - 5.7-54.5

 Tizol gel - 45.5-94.3

 allows to achieve a therapeutic effect in the treatment of experimental tuberculosis and to reduce the toxic effect of the claimed drug when it is administered percutaneously by applications on the projection of the affected organ compared to the generally known per os administration method, by eliminating the direct effect of the claimed drug on the gastrointestinal tract and liver.

Claims (2)

1. A drug for the treatment of tuberculosis, comprising the active substance isoniazid and a pharmaceutical carrier, characterized in that the drug is tizol gel, and the drug is applied percutaneously to the projection of the affected organ. 2. The drug for the treatment of tuberculosis according to claim 1, characterized in that the content of the components is, wt.%:
Isoniazid - 5.7-54.5;
Tizol gel - 45.5-94.3.