RU2466722C2 - Antituberculous drug - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention refers to an antituberculosis drug containing sodium aminosalicylate 2.0-14.0 g and chlorine ions 0.00020-0.00150 g.

EFFECT: preparing the stable and effective antibuberculosis drug.

3 ex

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, accordingly, 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].

In accordance with the modern classification of medicines proposed by the World Health Organization for the treatment of multidrug-resistant tuberculosis, the 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 a pronounced ability to slow down the inactivation of other anti-TB drugs in the body, as well as slow down the development of a drug to them Twain stability [3, 4].

PASK group drugs are available in the following dosage forms: granules, tablets, 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.

In the patent of Russia 2003133171, 2003 [6] A preparation for the treatment of tuberculosis is described, containing sodium paraaminosalicylate, anhydrous sodium sulfide, water for injection and a stabilizer of disodium salt of ethylenediaminotetraacetic 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 rongalita.

Also an analogue of the claimed invention is the drug Pasconate manufactured by Yuriya-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 ethnlendiaminetetraacetic 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 drawback of aqueous solutions of sodium aminosalicylate is the presence of stabilizers, storage conditions and a short shelf life.

The prototype of the claimed drug is a lyophilisate for preparing 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 additionally contains chlorine ions, part of the hydrochloric acid used to bring the pH of the solution to a physiological value of 6.0-8.0. This pH value is close to the blood pH value of 7.4. The tool has the following composition, g:

sodium aminosalicylate - 2.0-14.0 chlorine ions - 0,00020-0,0015

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

An anti-tuberculosis drug is obtained by freeze drying an aqueous solution of sodium aminosalicylate. The preparation of a solution of sodium aminosalicylate consists in dissolving the calculated amount of the substance in water for injection and adjusting the pH with a solution of hydrochloric acid to values of 6.0-8.0. Before bottling, preliminary and sterilizing filtration is carried out, due to which the solution is cleaned of mechanical impurities.

Example 1

900 ml of water for injection, 200 g of sodium aminosalicylate are added to the container and mixed until the components are completely dissolved. Then, the pH was adjusted to 6.0-8.0 with hydrochloric acid. 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 chlorine ions - 0,00020

Example 2

It differs from example 1 in that 300 g of aminosalicylate sodium are added to the container and 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 chlorine ions - 0,00085

Example 3

It differs from Example 1 in that 400 g of aminosalicylate is added to the container and the resulting solution is poured into 35 ml glass bottles for blood, transfusion and infusion preparations. Get the drug of the following composition, g:

sodium aminosalnicylate - 14.0 chlorine ions - 0.00150

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

On the basis of RUE Belmedpreparaty, a preclinical study of the general toxic, locally irritating, allergenic effect of the claimed drug was carried out.

Quantitative parameters of toxicity of sodium aminosalicylate samples for intravenous administration were determined. Lethal, maximally tolerated, toxic and non-toxic doses of samples were established upon intravenous administration to non-linear mice. The value of LD ₅₀ when administered intravenously to mice is 2650 mg / kg (2345.1-2994.5 mg / kg) at p = 0.05. LD ₁₀ (maximum tolerated dose, MTD) was 1950 mg / kg (1349.5-2817.8 mg / kg), LD ₉₀ - 3600 mg / kg (2491.35-5202.0 mg / kg) at p = 0.05. The indices LD ₁ - 1550 mg / kg, LD ₁₆ - 2100 mg / kg, LD ₈₄ - 3400 mg / kg are determined.

Changes in urine indices, hematologic indices, and changes in body weight of animals in dynamics were evaluated.

7 and 14 days after a single intravenous injection of a sample of GLF at a dose of 2600 mg / kg, an increase in the body weight of mice from 20.5 ± 0.72 g to 20.8 ± 1.1 g and 21.6 ± 1.5 g was noted, respectively. Against the background of the introduction of the test sample at doses of 2975 mg / kg and 3000 mg / kg in the surviving animals, body weight did not change significantly after 7 days after injection, a decrease in body weight was noted after 14 days (from 19.7 ± 0.62 g - initially up to 18.5 ± 3.5 g at the end of the observation period).

Analysis of the dynamics of hematological parameters showed that with the introduction of the test sample at a dose of 2600 mg / kg, the hemoglobin level was 156.7 ± 5.2 g / l, the number of red blood cells was 5.88 ± 0.23 · 10 ¹² / l, and the color indicator was 0.81 ± 0.05; the number of leukocytes - 6.19 ± 0.45 · 10 ⁹ / l. If a placebo was administered to mice intravenously, the hemoglobin level was found to be 155.4 ± 5.9 g / l, the number of red blood cells was 6.17: 1: 0.09 · 12 ¹² / l, the color index was 0.76 ± 0.02; the number of leukocytes is 8.31 ± 0.9 · 10 ⁹ / l. Differences in hematological parameters with those in the control group were statistically unreliable.

Significant differences in the urine analysis in placebo animals and in mice that were administered sodium PASK GLF at a dose of 2600 mg / kg were also not detected.

The local irritating effect of the claimed agent 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).

With the introduction of sodium PASK GLF 2 weeks and 3 weeks in a therapeutic dose (200 mg / kg), no signs of local irritation at the injection site (rabbit ear vein) were found.

Allergic effect (epicutaneous effect and conjunctival test) 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 irritant 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 1 bottle 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 V.S. // The effectiveness of the treatment of patients with tuberculosis, releasing drug-resistant MBT // Mat. Anniversary. Sessions: 80th anniversary of the Central Research Institute of Tuberculosis, Russian Academy of Medical Sciences // M. Medical Life, 2001, - p.178-179.

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

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

5. RU No. 2248797 dated 09.02.2004.

6. RU No. 2003133171 dated November 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)

Anti-tuberculosis drug based on sodium aminosalicylate, characterized in that it additionally contains chlorine ions in the following ratio of components, g:
sodium aminosalicylate 2.0-14.0 chlorine ions 0,00020-0,00150