RU2578433C1 - Antituberculous pharmaceutical composition for parenteral use in small dosages volume - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention refers to medicine, more specifically to antituberculous pharmaceutical composition having high bioavailability and low toxicity, and is used for injection into the intravenous, intramuscular, subcutaneous and intraperitoneally in doses of small volume. Pharmaceutical composition contains as active substance therapeutically effective amount of sodium para-aminosalicylate, target additive-polyvinyl pyrrolidone, complexing agent and a stabilising substance in the following proportions, wt %:

para-aminosalicylate sodium 60-92; polyvinylpirrolydon 5-30; complexing agent 0.01-2; stabilizing agent 0.01-2; water to 100.

According to invention composition is obtained by dissolving sodium para-aminosalicylate, polyvinyl pyrrolidone, complexing and stabilising substances in a water system and further lyophilisation; as complexing agent used is a disodium salt of ethylenediaminetetraacetic acid (EDTA), and the stabilising substance - sodium metabisulphite (pyrosulphite).

EFFECT: invention enables to obtain stable antituberculous preparation on the basis of sodium paraaminosalicylic acid for irrigation injection and provides considerable reduction of dose of sodium paraaminosalicylic acid with provision of bioavailability equivalent large volumes of sodium paraaminosalicylic acid without PVP, enabling use of the preparation for injections in out-patient treatment, reducing systemic toxic effects.

3 cl, 2 tbl

Description

The invention relates to medicine, specifically to an anti-tuberculosis pharmaceutical composition having high bioavailability and low toxicity, and is used for injectable administration intravenously, intramuscularly, intraperitoneally and subcutaneously in small volume dosages.

It is well known to use para-aminosalicylic acid (PASK) and sodium para-aminosalicylate, the sodium salt of para-aminosalicylic acid (PASK-sodium), which are commonly used with other anti-tuberculosis drugs in the treatment of tuberculosis and are available as oral and parenteral drugs in the treatment of tuberculosis. In the first case, the drug exists in the form of enteric-coated tablets or granules, the maximum dose per day is 12 grams; in the second case, it is a sterile powder (lyophilisate) for the preparation of a solution for infusion. One such marketed drug is called Pas-Fatol Ν, where the active substance is 13.49 g, which is equivalent to 12 g of para-aminosalicylic acid.

The two most important issues addressed in the clinical pharmacology of Pas-Fatol Ν:

1) rather rapid formation of an inactive toxic metabolite in acidic conditions;

2) a short half-life in blood serum, which is 1 hour for free medication.

PASK and PASK-sodium have bacteriostatic activity against tuberculosis mycobacteria and are among the main anti-TB drugs. When taken orally, PASK is well absorbed and penetrates the blood serum and tissues of internal organs.

However, when using PASK, side effects may occur. The most commonly reported gastrointestinal upsets are: worsening or loss of appetite, nausea, vomiting, abdominal pain, diarrhea, or constipation. These phenomena usually decrease with a dose reduction or a short break in treatment, as well as with the use of targeted supplements.

The clinical use for intravenous injection of PASK-sodium and polyvinylpyrrolidone (PVP) is known (published in Dis Chest, 1954: 26, pp. 47-51). The article shows that such a combination leads to an increase in the level of active substance in the body, which is approximately two times higher and is maintained twice as long in the therapeutic range.

However, the article does not indicate how to obtain a stable preparation containing PASK sodium with PVP. The stability of the substance is one of the main problems, since PASK sodium is very easily oxidized, which leads to the formation of m-aminophenols, which are known to be highly toxic to the body.

A known method of producing porous microparticles (application WO 2007/086039, IPC A61K 9/16, published 02.08.2007), which includes the step-by-step combination of one or more organic substances with a volatile solvent and spray drying of the resulting system, which leads to the formation of porous particles an organic compound or a composite microparticle from combinations of organic compounds. Among the organic compounds used in this method, there may be one or more bioactive substances containing PASK and a pharmaceutically acceptable excipient containing PVP together with any auxiliary compound or combination with their participation. The present invention mainly focuses on the use of PASK when administered through the respiratory tract.

The preparation of complexes in solution between polyvinylpyrrolidone and p-aminobenzoic, benzoic, salicylic, p-hydroxybenzoic, m-hydroxybenzoic acids and phenobarbital is described (J. American Pharm. Ass. 1954, 43, 398-401 in the article "Study of the formation of possible complexes between macromolecules and specific pharmaceuticals. ”)

In another study (J. Pharm. Sci. 1968, 57, 832-35, “Dissolution of Salicylic Acid and Polyvinylpyrrolidone from Compressed Mixtures”), polyvinylpyrrolidone was shown to increase the solubility of salicylic acid.

Today, manufacturers supply PASK sodium for injection in large volumes of 500 ml, the so-called "large volume parenteral" (LVP). Such mixtures contain 10-12 g of active ingredient without PVP. For injection, the LVP preparation is diluted in saline or in water for injection in a volume of about 500 ml. One of the serious limitations of the use of LVP is that the patient must be hospitalized to administer the drug for at least 3-4 hours and, therefore, the drug cannot be used on an outpatient basis. Moreover, a large dose of sodium aminosalicylate in the amount of 10-12 g with a single application has more systemic toxic effects compared to the low dose used when using PASK-sodium in combination with PVP. Also, LVP can only be administered intravenously.

It follows from the above that a form of sodium para-aminosalicylate has not yet been obtained, which would be stable, have a small volume, and the introduction of which would not require hospitalization.

The objective of the invention is to obtain a stable form of an anti-tuberculosis drug based on PASK-sodium with a high bioavailability and low toxicity for injection in small doses.

The technical result is a significant reduction in the administered dose of PASK-sodium compared to the usual one with bioavailability equivalent to large volumes of PASK-sodium without PVP, the possibility of using the drug for injection in outpatient treatment, the reduction of systemic toxic effects, the stability of the drug for at least 3 years.

The problem is solved, and the technical result is achieved by an anti-tuberculosis pharmaceutical composition for parenteral use, comprising as the active substance a therapeutically effective amount of sodium para-aminosalicylate, the target additive is polyvinylpyrrolidone, a complexing substance and a stabilizing substance in the following ratio of components, mass. %:

sodium para-aminosalicylate 60-92 polyvinylpyrrolidone 5-30 complexing substance 0.01-2 stabilizing substance 0.01-2 water up to 100

According to the invention:

- the drug is obtained by dissolving sodium para-aminosalicylate, polyvinylpyrrolidone, complexing and stabilizing substances in the aqueous system and subsequent lyophilization;

- disodium salt of ethylenediaminetetraacetic acid (EDTA) is used as a complexing substance, and sodium metabisulfite (pyrosulfite) as a stabilizing substance.

The technical result is achieved due to the following.

The combination of the sodium salt of PASK and polyvinylpyrrolidone proposed in the invention provides high bioavailability, stability and low toxicity. The drug can be used on an outpatient basis in the form of ampoules for injection. The dilution time of this small-volume preparation is less than 1 minute, after which it can be used for parenteral administration in several ways: intravenously, intramuscularly, intraperitoneally and subcutaneously. Moreover, the transportation of such a medicine is much safer and easier than large volume drugs.

As a result of the studies conducted by the authors, it was found that the combination of PASA-sodium with PVP leads to a decrease in the level of m-aminophenol compared to a conventional solution of PASA-sodium. The solution of the mixture of sodium salt of PASK and PVP was kept at room temperature for 10 days, and then samples were taken at intervals of one day to analyze the level of m-aminophenol. A decrease in the level of m-aminophenol was observed compared to a conventional PASK sodium salt solution.

The stability of the mixture of the sodium salt of PASK and PVP in the powder (without drying) and in the lyophilized form was compared, respectively, with two forms (in powder and during lyophilization) of the pure sodium salt of PASK. The mixture was shown to be highly stable compared to pure PASK sodium.

Studies on accelerated degradation of the drug showed that the drug was stable for 3 years at 30 ° C and 65% relative humidity, while the content of m-aminophenol was not more than 0.25%.

None of the studies to date has data on obtaining a stable preparation based on sodium para-aminosalicylate for injection in small volumes, which allows us to conclude that the invention meets the criteria of "novelty" and "inventive step".

The claimed anti-tuberculosis composition is prepared as follows.

Complexing substance in an amount of 0.01-2 mass. % dissolved in water for injection. Polyvinylpyrrolidone in the amount of 5-30 mass. % and a stabilizing substance in an amount of 0.01-2 mass. % added to this solution. Bring the solution to pH = 6.5 by adding 0.1 N sodium hydroxide, then add PASK sodium in the amount of 60-92 mass. % and the pH is maintained between 8 and 9. The volume of the solution is adjusted to 100% and then lyophilized.

The dry preparation obtained according to the invention is dissolved in less than one minute in 10 ml of water for injection, after which the preparation can be administered to the patient immediately in several ways: intravenously, intramuscularly, intraperitoneally and subcutaneously. The solution is clear, not cloudy, the presence of solid particles in the acceptable pharmaceutical range for injection in small volumes.

Toxicity studies

Studies were performed on wistar rats (15 males and 15 females). A mixture of 25% PASA sodium and 3.5% PVP was compared with pure 25% PASA sodium and pure 3.5% PVP.

The results are presented in tables 1 and 2.

As can be seen from the table, the mixture of PASK-sodium and PVP does not exceed the toxicity of pure PASK-sodium and PVP.

Indications for the use of the drug are the most severe forms of multidrug-resistant tuberculosis, such as caseous pneumonia, disseminated and miliary forms of tuberculosis, etc. with inability to ingest the required amount of PAS-sodium, as well as extensive lung and pleural operations associated with tuberculosis .

Thus, the invention allows to obtain a stable anti-tuberculosis drug based on PASK-sodium for low-dose injections and provides a significant reduction in the administered dose of PASK-sodium with bioavailability equivalent to large volumes of PASK-sodium without PVP, the possibility of using the drug for injection in outpatient treatment, and reducing systemic toxic effects, drug stability for at least 3 years. Transportation of the drug is much safer and easier compared to conventional preparations containing PASK-sodium, since the dose of PASK-sodium required for treatment is contained in a smaller volume of the drug.

Claims (3)

1. An anti-tuberculosis pharmaceutical composition for parenteral use, comprising as the active substance a therapeutically effective amount of sodium para-aminosalicylate, the target additive is polyvinylpyrrolidone, a complexing agent and a stabilizing substance in the following ratio of components, mass. %:
sodium para-aminosalicylate 60-92 polyvinylpyrrolidone 5-30 complexing substance 0.01-2 stabilizing substance 0.01-2 water up to 100 2. The anti-tuberculosis pharmaceutical composition according to claim 1, obtained by dissolving sodium para-aminosalicylate, polyvinylpyrrolidone, complexing and stabilizing substances in the aqueous system and subsequent lyophilization. 3. The anti-tuberculosis pharmaceutical composition according to claim 1, characterized in that disodium salt of ethylenediaminetetraacetic acid (EDTA) is used as a complexing substance, and sodium metabisulfite (pyrosulfite) is used as a stabilizing substance.