RU2487702C2 - Medicine for treating tuberculosis - Google Patents

Abstract

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutical industry and medicine, particularly it is used for treating various forms and localisation of tuberculosis.

EFFECT: medicine under the present invention containing sodium aminosalicylate and dextran, and provides the effective treatment of multidrug-resistant pulmonary tuberculosis.

3 ex, 2 tbl

Description

The invention relates to the field of pharmaceutical industry and medicine and can be used as an anti-tuberculosis drug.

Over the past 10 years, a rather tense epidemiological situation has persisted in tuberculosis, characterized by an increase in the severity of the clinical course of the disease and an increase in the number of drug-resistant forms of tuberculosis. Drug resistance of the causative agent of tuberculosis is one of the most serious clinical and epidemiological problems of modern medicine. Patients with resistant forms of tuberculosis are epidemiologically more dangerous due to high virulence, a longer duration of bacterial excretion and, consequently, a greater possibility of transmission of infection. It is multiresistant strains of mycobacterium tuberculosis that cause outbreaks of tuberculosis, characterized by rapid progression of the process and extremely high mortality. Many researchers note a high level of contagiousness in patients with multidrug-resistant forms of tuberculosis. It can be concluded that drug-resistant forms of tuberculosis are currently the most dangerous source of tuberculosis infection and largely determine the level of disability and mortality from tuberculosis [1, 2].

Para-aminosalicylic acid and its sodium salt have bacteriostatic activity against tuberculosis mycobacteria and are among the main anti-TB drugs. In accordance with the current World Health Organization classification of drugs used to treat multidrug-resistant tuberculosis, para-aminosalicylic acid sodium salt (PASK-Na), like other PASK drugs, belongs to the so-called reserve drugs or second-line drugs. The most important feature of sodium aminosalicylate is its pronounced ability to slow down the inactivation of other anti-TB drugs in the body, as well as slow down the development of drug resistance to them [3, 4].

PASK group drugs are available in the following dosage forms: granules; pills; coated tablets; enteric-coated tablets; solution for infusion.

Known analogues of the claimed invention. Russian patent 2248797, 2004 [5] claims an anti-tuberculosis pharmaceutical composition comprising, as an active ingredient, the paraaminosalicylic acid sodium salt and target additives. The pharmaceutical composition is in the form of a solid dosage form - coated tablets. The disadvantage of the invention is the large number and high concentration of excipients that make up the composition.

Russian patent 2003133171, 2003 [6] describes a preparation for the treatment of tuberculosis containing sodium para-aminosalicylate, anhydrous sodium sulfite, water for injection and a stabilizer disodium salt of ethylenediaminetetraacetic acid.

Known 3% aqueous solution of sodium PASK in bottles of 250 and 500 ml [7]. The solution contains a large amount of preservative stabilizer rongolita.

Also an analogue of the claimed invention is the drug Pasconate manufactured by Yuria-Farm LLC (Ukraine), which is a 3% aqueous solution of PASK sodium in glass bottles of 100, 200 and 400 ml, stabilized with sodium pyrosulfate and disodium salt of ethylenediaminetetraacetic acid. Shelf life - 1.5 years at a temperature of +4 to + 15 ° C [8].

PASK-Na aqueous solutions are extremely unstable, as a result of oxidative decarboxylation of PASK, toxic m-aminophenol is formed, which quickly turns into brown colored toxic products. Aqueous PASK sodium solutions cannot withstand thermal sterilization at a temperature of 120 ° C.

A common disadvantage of aqueous solutions of sodium amnosalicylate is the presence of stabilizers, storage conditions and a short shelf life.

The prototype of the claimed funds is lnofilizat for the preparation of a solution for infusion PAS-Fatol N [9]. The medicine is presented in the form of a set of two glass bottles with a capacity of 500 ml, in one bottle - 13.49 g of sodium PASK dihydrate, in the other - 500 ml of water for injection. Immediately prior to intravenous administration using a transport cannula, water for injection is sterilely introduced into a bottle of sodium PASC dihydrate, the powder is dissolved by shaking until a clear, infusion solution is obtained.

The objective of the invention is the creation of a stable and effective anti-TB drug. The problem is solved in that the inventive tool further comprises dextran with a molecular weight of 12500-70000. Dextran is a water-soluble, high molecular weight glucose polymer. In addition, dextran is used as a stabilizer, a prolonger of the action of drugs.

The inventive tool has the following composition, g:

sodium aminosalicylate 2.0-14.0 molecular weight dextran 12500-70000 0.1-14.0

The inventive tool is a porous mass, or a powder of white, or white with a yellowish, or white with a pinkish tint, or yellow, readily soluble in water, sparingly soluble in alcohol.

An anti-tuberculosis drug is obtained by freeze drying an aqueous solution of sodium aminosalicylate and dextran with a molecular weight of 12500-70000. The preparation of the solution consists in dissolving the calculated amount of sodium amnosalicylate and dextran in water for injection and adjusting the pH to 6.0-8.0. Dextran can be administered in the form of 6% and 10% ready-made solutions. Before bottling, preliminary and sterilizing filtration is carried out, due to which the solution is cleaned of mechanical impurities.

Example 1. 600 ml of water for injection, 200 g of sodium aminosalicylate are added to a container and mixed until the substance is completely dissolved. After that, 140 g of dextran with a molecular weight of 12500-70000 is introduced into the solution, stirred until complete dissolution. Then adjust the pH to 6.0-8.0. Bring the volume of the solution with water for injection to 1 l, mix. The resulting solution is filtered through sterilizing filters and poured into 10 ml glass bottles for blood, transfusion and infusion preparations and freeze-dried. Get the drug of the following composition, g:

sodium aminosalicylate 2.0 molecular weight dextran 12500-70000  14.0

Example 2. It differs from example 1 in that 300 g of sodium aminosalicylate and 300 g of dextran with a molecular weight of 12500-70000 are added to the container. The resulting solution is poured into 20 ml glass bottles for blood, transfusion and infusion preparations. Get the drug of the following composition, g:

sodium aminosalicylate 6.0 molecular weight dextran 12500-70000 6.0

Example 3. It differs from example 1 in that 560 g of aminosalicylate sodium and 4 g of dextran with a molecular weight of 12500-70000 are introduced into the container. The resulting solution is poured into 25 ml glass bottles for blood, transfusion and infusion preparations. Get the drug of the following composition, g:

sodium aminosalicylate 14.0 molecular weight dextran 12500-70000 0.1

Conducted stability studies showed that the drug obtained in this way is stable and retains its initial values for 4 years.

A preclinical study of the general toxic, locally irritating, allergenic effects of the claimed drug.

The quantitative parameters of toxicity of the samples of the claimed funds. Lethal, maximally tolerated, toxic and non-toxic doses of samples were established upon intravenous administration to non-linear mice. The LD50 value for intravenous administration to mice is 3200 mg / kg (2782.6-3680.0 mg / kg) at p = 0.05. LD ₁₀ was 2500 mg / kg (2192.98-2850.0 mg / kg), LD ₉₀ - 3800 mg / kg (3333.3-4332.0 mg / kg) at p = 0.05. The indices LD ₁ - 2150 mg / kg, LD ₁₆ - 2600 mg / kg, LD ₈₄ - 3650 mg / kg are determined. The range of lethal doses of LD ₈₄ / LD ₁₆ was 1.15.

Estimated changes in urine, hematological parameters and changes in body weight of animals in dynamics.

When weighing 7 and 14 days after a single intravenous injection of a sample of the finished dosage form (GLF) of sodium aminosalicylate with dextran in doses of 2200, 2500 and 3100 mg / kg, an increase in body weight of mice was noted. The data are presented in table 1.

Table 1 Dynamics of body weight of mice after a single intravenous administration of lyophilized PASK with dextran Daily dose, mg / kg Body weight g initially in 7 days after 14 days 2200 19.0 ± 0.89 21.0 ± 0.63 21.8 ± 0.86 2500 19.6 ± 1.03 21.3 ± 2.19 23.0 ± 1.53 3100 17.7 ± 2.03 18.5 ± 2.50 19.5 ± 2.50

Evaluation of hematological parameters showed that with the introduction of the test sample at a dose of 2500 mg / kg, the hemoglobin level was 157.4 ± 4.2 g / l, the number of red blood cells was 5.66 ± 0.08 · 10 ¹² / l; color indicator - 0.83 ± 0.02; the number of leukocytes is 9.7 ± 1.8 · 10 ⁹ / l. The same indicators with the introduction of the test sample at a dose of 3100 mg / kg were found equal in surviving animals (table 2).

table 2 Hematological parameters after a single intravenous administration of lyophilized PASK with dextran to mice Dose mg / kg Hemoglobin, g / l Erythrocytes, 10 ¹² / l CPU White blood cells, 10 ⁹ / L 2500 157.8 5.50 0.86 7.45 149.9 5.69 0.79 13.3 164.4 5.78 0.85 8.4 Mean (X ± s _x ) 157.4 ± 4.2 5.66 ± 0.08 * 0.83 ± 0.02 9.7 ± 1.8 3100 149.9 5.86 0.77 9.05 147.2 5.87 0.75 7.0 Mean (X ± s _x ) 148.6 ± 1.35 5.87 ± 0.005 * 0.76 ± 0.07 8.0 ± 1.03 * The differences with the control are significant, p <0.05

Significant differences in the urine analysis indices in animals of the placebo group and in mice that were administered the finished dosage form of PASK with dextran at doses of 2200 and 2500 mg / kg were also not detected.

The local irritating effect of the claimed drug was evaluated under conditions of a single administration to mice in the tail vein and prolonged administration to rabbits in the ear vein.

In mice that were injected with sodium PASK GLF in high (toxic) doses, local irritating effects were observed at the injection site. The effect was dose-dependent: when injected at a dose of 2600 mg / kg, the local irritant effect was less pronounced than when administered at doses of 2975-3100 mg / kg (p> 0.05).

It was found that the local irritating effect of PFASK GLF, which includes dextran, is significantly less pronounced than that of PASK GLF without adding dextran.

With the introduction of PASK GLF for a duration of 2 weeks and 3 weeks at a therapeutic dose (200 mg / kg), signs of local irritation at the injection site (rabbit ear vein) were not established.

An allergenic effect (epicutaneous effect and conjunctival staging) was evaluated.

Under the conditions of staging a conjunctival test, it was found that in all periods of observation, differences between the average values (in points) of assessing the condition of the left eye and the right eye of animals were not detected, i.e. placebo and GLF samples have a comparable effect on eye tissue. Sodium PASK GLF does not have any significant local irritating effect and does not cause hypersensitivity reactions after 15 minutes and 24 hours after instillation.

Under conditions of a single sensitization by intravenous administration of the claimed agent in a therapeutic dose, the possible allergenic effect of the test samples was evaluated. It is shown that the anti-tuberculosis drug does not have an allergenic effect. The condition of the skin of the ear did not change in any case 15 minutes and 24 hours after the application of the samples. Thus, the claimed anti-tuberculosis drug does not have an allergenic effect.

The inventive tool is used in various forms and localization of tuberculosis. Most often, PASK is prescribed for patients with multidrug resistance to other anti-TB drugs.

To prepare an infusion solution, the contents of a bottle containing PASK sodium salt and dextran with a molecular weight of 12500-70000 are dissolved in an appropriate amount of water for injection. It is necessary to achieve complete dissolution of the contents of the bottle. Freshly prepared solutions should be used.

For intravenous injections, 3% and 6% solutions of the drug are used. The drug can be administered using an injection pump with a controlled flow. Intravenously administered dropwise. The introduction begins with 30 drops of the solution per minute and, in the absence of local and general reactions, after 15 minutes the infusion rate is increased to 40-60 drops per minute. At the first infusion, no more than 200 ml of the solution is administered, and in the absence of side effects - 400 ml of the solution. Infusions are made 5-6 times a week or every other day, alternating with the intake of PASK sodium salt inside.

The dose of PASK sodium salt for adults is 10-12 g per day, for children - 0.2 g / kg per day (the maximum daily dose for children is 10 g). Depleted, elderly patients and with poor tolerance are prescribed at a dose of 6 g / day.

Information sources

1. Skryagina E.M. // Drug resistance of Mycobacterium tuberculosis in the Republic of Belarus // Mat. Anniversary. Sessions: 80th anniversary of the Central Research Institute of Tuberculosis, Russian Academy of Medical Sciences // M. Medical Life, 2001, p. 222-223.

2. Korovkin B.C. // The effectiveness of the treatment of patients with tuberculosis, emitting drug-resistant MBT // Mat. Anniversary. Sessions: 80th anniversary of the Central Research Institute of Tuberculosis RAMS // M., Medical Life. 2001 .-- S.178-179.

3. Tuberculosis Handbook. // Geneva. WHO.// 1998; p.222. WHO / TB / 98.253.

4. Treatment of Tuberculosis: Guidelines for National Programs. 2nd Ed. Geneva // WHO. 1997; p.78. // WHO // TB97.220

5. RU No. 2248797 dated February 9, 2004.

6. RU No. 2003133171 of 11/14/2003.

7. M.D. Mashkovsky. Medicines - M., "Medicine", 2000 (fourteenth edition), p.185-186.

8.http: //www.uriafarm.com.ua.

9.http: //www.switch-spb.ru/pas fatol.php. (prototype).

Claims (1)

The drug for the treatment of tuberculosis in the form of a lyophilized powder, which contains sodium aminosalicylate and dextran with a molecular weight of 12500-70000 in the following ratio of components, g:
sodium aminosalicylate 2.0-14.0 dextran 0.1-10.0
obtained by freeze drying a solution having a pH of 6.0-8.0.