RU2613019C1 - Pharmaceutical composition for parenteral administration of 2-ethyl-6-methyl-3-hydroxypyridine succinate and method of producing said composition - Google Patents

Abstract

FIELD: pharmaceutics.

SUBSTANCE: invention relates to chemical-pharmaceutical industry and medicine and describes a method for preparing the composition for parenteral administration, containing (wt%): 2-ethyl-6-methyl-3-hydroxypyridine succinate as an active component – 4.0–6.0; stabilizer – sodium metabisulphite – 0.015–0.045 and water as a solvent – up to 100. Invention can be used in medicine as a drug for treating and preventing various diseases and pathological conditions of a human body.

EFFECT: composition is characterized by stability for three years, low toxicity, comparable with the solution of 2-ethyl-6-methyl-3-hydroxypyridine succinate without stabilizers, allows to implement the therapeutic action of the active substance without undesired secondary pharmacological activity of excipients.

1 cl, 6 ex, 2 tbl

Description

The invention relates to the pharmaceutical industry and medicine and describes a composition with 2-ethyl-6-methyl-3-hydroxypyridine succinate for parenteral administration, containing mainly 2-ethyl-6-methyl-3-hydroxypyridine succinate as an active ingredient, sodium stabilizer metabisulfite and water as a solvent. The invention can be used in medicine as a medicine for parenteral administration of 2-ethyl-6-methyl-3-hydroxypyridine succinate for the treatment and prevention of various diseases and pathological conditions of the human body. The composition has high stability, low toxicity, convenient and safe for clinical use.

It is known that 2-ethyl-6-methyl-3-hydroxypyridine succinate (ethylmethylhydroxypyridine succinate, trade name Mexidol® and others) is widely used in medicine as an antioxidant and antihypoxic agent, characterized by a wide spectrum of pharmacological action and high efficiency. The use of 2-ethyl-6-methyl-3-hydroxypyridine succinate as a nootropic and tranquilizing agent (Pat. RU 2065299), anti-ischemic and anti-atherosclerotic agent (Pat. RU 2144822), antianginal (Pat. RU 2168993), hepatoprotective (Pat. RU 2189817), antibacterial (Pat. RU 2157686) funds, etc.

Known compositions based on 2-ethyl-6-methyl-3-hydroxypyridine succinate in the form of various dosage forms: solution for parenteral administration (Order of the Ministry of Health of the Russian Federation dated 12/31/1996 No. 432 "Solution of Mexidol® 5% for injection"), tablets (Order Ministry of Health of the Russian Federation dated 01.26.1998 No. 21 “Mexidol® coated tablets, 0.125 g”), capsules (Pat. RU 2144822, 2145855), dressings (Pat. RU 2149648), etc.

As a consequence of the relatively low bioavailability of the preparations for oral administration, drugs for injection are of particular interest, in particular for intensive care of patients.

Injectable medicines for use in clinics account for about 40%. Compared to other drugs, injection drugs have several advantages:

- speed of action, especially with intravenous administration;

- the possibility of introducing a medicinal substance to a patient in an unconscious state;

- accuracy of dosage of a drug substance.

The number of drugs for parenteral administration in recent years is constantly growing, this method provides a very fast, almost immediate effect of drugs.

Thus, a solution of 2-ethyl-6-methyl-3-hydroxypyridine succinate for parenteral administration is of particular interest. However, a number of disadvantages inherent in the active substance are known, namely: high reactivity associated with pronounced reducing properties. This circumstance determines the unstable quality of the finished dosage form due to the possibility of redox reactions with a parallel increase in the content of impurities and the color of the solution.

Stabilization of a solution of 2-ethyl-6-methyl-3-hydroxypyridine succinate is achieved in several ways - technological, chemical, etc. It is well known that in the industrial production of injection forms, in order to exclude contact of labile drugs with air oxygen, inert gas, such as nitrogen, is used. or carbon oxide (IV). This method is common in the production of solutions of 2-ethyl-6-methyl-3-hydroxypyridine succinate and can increase the stability of the finished dosage form.

A known method of stabilizing a solution of 2-ethyl-6-methyl-3-hydroxypyridine succinate by adding succinic acid and Trilon B (Pat. RU 2205640):

2-ethyl-6-methyl-3-hydroxypyridine succinate 5.0-6.0 Succinic acid 0.5-5.0 Trilon B 0,0-0,2 Water for injections up to 100.0

In sterile water for injection, 2-ethyl-6-methyl-3-hydroxypyridine succinate and succinic acid are dissolved at a temperature of 30-35 ° C, after dissolution, the volume is adjusted to 1.0 l with sterile water for injection. The solution is filtered through a filter with a pore diameter of 0.22 μm, poured into 2 ml ampoules and sterilized at a temperature of 100 ° C for 30 minutes. Get 490 ampoules containing a colorless transparent solution, stable during storage for 2 years, corresponding to the requirements of regulatory documentation for the drug.

In this case, stabilization of the finished dosage form is achieved by reducing the degree of hydrolysis of the active substance due to succinic acid, as well as by binding heavy metal ions present in the system using Trilon B (an indirect antioxidant), which are known to be catalysts for redox reactions.

Among the disadvantages of the composition, a significant content of auxiliary substances, which are not indifferent to the body and have their own pharmacological effects, should be noted. Prolonged parenteral administration of Trilon B into the body, given its pronounced ability to complex with metal cations, does not exclude the occurrence of trace elements deficiency.

As the closest analogue of the prototype, the method of stabilization of a solution of 2-ethyl-6-methyl-3-hydroxypyridine succinate by adding direct sodium antioxidant metabisulfite (Pat RU 2380089):

2-ethyl-6-methyl-3-hydroxypyridine succinate 5.0-6.0 Sodium metabisulfite 0.05-1.25 Water for injections up to 100.0

To obtain a solution, water for injection is sparged with nitrogen NSP for 10 minutes. Then, sodium metabisulfite and 2-ethyl-6-methyl-3-hydroxypyridine succinate are added with stirring. The solution is filtered through a filter with a pore diameter of 0.22 μm, poured in a stream of nitrogen into 2 ml ampoules of light-proof glass, sealed in a stream of nitrogen and sterilized by autoclaving at 122 ± 1 ° C for 8 minutes.

Metabisulfite used in the well-known sodium solution is widely used in various industries, as well as in the pharmaceutical industry, with the aim of stabilizing readily oxidizing substances (Ultracain, Adrenaline, Dexamethasone, Aminazine, No-shpa, Metadoxil, etc.) due to the pronounced regenerative properties (Drug Register Russia, 2009).

However, this adjuvant, when introduced into the body, has certain disadvantages, namely the ability to cause allergic reactions up to anaphylaxis (Am. J. Hosp.Pharm., 1985, Oct., 42 (10): 2220-2226; J. Allergy Clin. Immunol., 1983, May 71 (5): 487-489; J. Toxicol. Clin. Toxicol. 1992, 30 (4): 597-606), urticaria (Ann. Allergy, 1993, Sep. 71 (3): 230-232), bronchospasm (Ann. Allergy, 1985, Feb. 54 (2): 115-121), dyspeptic symptoms (CMAJ., 1985, Nov., 1, 133 (9): 865-867, 880) and others. In this regard, the urgent issue of choosing the minimum amount of this auxiliary substance in the drug, allowing one whose chemical stability of the system over the estimated shelf life, but at the same time characterized by the absence of adverse effects on the human body.

The problem is solved by creating a pharmaceutical composition for parenteral administration containing 2-ethyl-6-methyl-3-hydroxypyridine succinate of the following composition (wt.%):

2-ethyl-6-methyl-3-hydroxypyridine succinate 4.0-6.0 Sodium metabisulfite 0.015-0.045 Water for injections up to 100.0

and a method for producing the proposed composition, which is implemented as follows: sodium metabisulfite and 2-ethyl-6- are added to water for injection, purified through a system of membrane filters with pore sizes of 0.1-1 μm and saturated with nitrogen for 10-30 minutes methyl 3-hydroxypyridine succinate, stirred until dissolved, the solution is purified by filtration through a membrane filter with a pore size of 0.22-0.45 μm, the resulting solution is bottled in a stream of nitrogen into ampoules, sterilized at a temperature of 100-130 ° C until sterile solution. In this case, the filling is carried out in glass ampoules of colorless or light-protective glass with a volume of 1-10 ml.

Technical result: composition with 2-ethyl-6-methyl-3-hydroxypyridine succinate for parenteral administration, which is characterized by stability for three years, low toxicity comparable to a solution of 2-ethyl-6-methyl-3-hydroxypyridine succinate without stabilizers, allows you to realize the therapeutic effect of the active substance without undesirable side pharmacological activity of excipients, convenient and safe for clinical use.

The preparation of the proposed composition is described in the following examples.

Example 1

In a sterilized glass container with a capacity of 2.0 l to 1.8 l of water for injection, purified through a system of membrane filters with pore sizes of 0.1 μm and saturated with nitrogen for 15 minutes, 0.9 g of sodium metabisulfite and PO g 2- are added ethyl 6-methyl-3-hydroxypyridine succinate and stirred until dissolved, followed by bringing the total volume to 2.0 L. The solution is cleaned of mechanical impurities by filtration through a Millipore HAWG047S6 membrane filter with a pore size of 0.45 μm and bottling is carried out in a stream of nitrogen into 1 ml ampoules of light-protective glass. Sterilization is carried out at 120 ± 1 ° C for 8 minutes. The result is 1950 ampoules (taking into account losses) containing a composition for parenteral administration that meets the requirements of regulatory documentation for 3 years and has the following composition (wt.%):

2-ethyl-6-methyl-3-hydroxypyridine succinate 5.5 Sodium metabisulfite 0,045 Water for injections up to 100.0

Example 2

Similarly to Example 1 using a 630 L reactor, adding 0.2 kg of sodium metabisulfite, 25 kg of 2-ethyl-6-methyl-3-hydroxypyridine succinate, bringing the total volume of the mixture to 500 L with water for injection, previously purified by filtration using a membrane cartridge-type filter unit with a fluoroplastic filter element with a pore diameter of 1.0 μm and saturated with nitrogen for 30 minutes Sterilizing filtration is carried out on a cartridge-type unit with a pore diameter of 0.22 μm. Bottling is carried out in ampoules of colorless glass with a volume of 2 ml, sterilized at a temperature of 100 C. 246,000 ampoules are obtained (taking into account losses) containing a composition for parenteral administration that meets the requirements of regulatory documents for 3 years and has the following composition (wt.%):

2-ethyl-6-methyl-3-hydroxypyridine succinate 5,0 Sodium metabisulfite 0,040 Water for injections up to 100.0

Example 3

Similarly to Example 1, using a 120 liter reactor, adding 0.015 kg of sodium metabisulfite, 4 kg of 2-ethyl-6-methyl-3-hydroxypyridine succinate, bringing the total volume of the mixture to 100 liters with water for injection, previously purified by filtration using a membrane filter unit cartridge type with a fluoroplastic filter element with a pore diameter of 0.45 μm and saturated with nitrogen for 10 minutes Sterilizing filtration is carried out on a cartridge-type unit with a pore diameter of 0.22 μm. Bottling is carried out in ampoules of colorless glass with a volume of 10 ml, sterilized at a temperature of 130 ° C. Receive 9850 ampoules (taking into account losses) containing a composition for parenteral administration, corresponding to the requirements of regulatory documentation for 3 years and having the following composition (wt.%):

2-ethyl-6-methyl-3-hydroxypyridine succinate 4.0 Sodium metabisulfite 0.015 Water for injections up to 100.0

Example 4

The study of the stability of solutions. To study stability, experimental series of the preparation containing sodium metabisulfite in the following concentrations were prepared and stored in vivo in the following concentrations: 0.01 g / 100 ml; 0.015 g / 100 ml; 0.030 g / 100 ml; 0.045 g / 100 ml; 0.06 g / 100 ml; 0.1 g / 100 ml. During storage, samples were taken and a full analysis was conducted for compliance with regulatory requirements. The stability data for solutions of 2-ethyl-6-methyl-3-hydroxypyridine succinate with different sodium metabisulfite content are given in Table 1. It was found that during storage, a decrease in the stabilizer content in the preparation was observed, and a solution having an initial concentration of sodium metabisulfite 0, 01 g / 100 ml, did not possess the necessary stability for 3 years. Thus, it was found that the minimum concentration of sodium metabisulfite, ensuring the stability of the finished drug for 3 years, is 0.015 g / 100 ml.

Example 5

The acute toxicity of experimental samples of the finished drug was studied (a drug with a concentration of sodium metabisulfite of 0.01 g / 100 ml was not tested due to the instability of the solution). It was found that the preparation containing 0.015 g / 100 ml, 0.030 g / 100 ml and 0.045 g / 100 ml sodium metabisulfite did not exhibit toxicity and did not statistically differ from the solution of 2-ethyl-6-methyl-3-hydroxypyridine succinate without or stabilizers. The results of the study of the acute toxicity of solutions of 2-ethyl-6-methyl-3-hydroxypyridine succinate with various sodium metabisulfite content are shown in Table 2. Starting from a concentration of 0.060 g / 100 ml and then there was a significant increase in acute toxicity of the finished drug.

Example 6

The study of the pharmacokinetics of the composition obtained in accordance with Example 1 was carried out on chinchilla rabbits (body weight 3.0-4.0 kg). The drug was administered once at a dose of 50 mg / kg intramuscularly. For comparison, a parallel experiment was carried out using a solution of 2-ethyl-6-methyl-3-hydroxypyridine succinate without any stabilizers. The concentration of the drug in blood plasma was determined after 1; 2.5; 5; 10; fifteen; twenty; thirty; 45; 60; 90; 120; 150 and 180 minutes after drug administration by high performance liquid chromatography on a Beckman computerized system (USA). Chromatography conditions: stationary phase — Luna column (Phenomenex) with 18 (2) reverse phase sorbent (4.6 × 250 mm; 5 μm); the mobile phase is methanol: citrate phosphate buffer (pH 5.0) (1.5: 5); the speed of the mobile phase is 1 ml / min; detection - 296 nm; the chromatograph loop volume is 200 μl. Chromatographed at room temperature (22-23 ° C). Under these conditions, the retention time of 2-ethyl-6-methyl-3-hydroxypyridine succinate was 5.6 minutes.

Quantitative assessment in both cases was carried out according to direct calibration using the areas of chromatographic peaks of 2-ethyl-6-methyl-3-hydroxypyridine succinate. The main pharmacokinetic parameters were calculated by a model-independent method using the M-IND software package.

The obtained experimental data were subjected to mathematical statistical processing using the program Statistica v 6.0.

When i / m administration, the drug was determined in blood plasma for 2-2.5 hours after administration. The time to reach the maximum concentration T _max is 2.5-5 minutes. Stach with a dose of 50 mg / kg is 22.5-27.0 μg / ml. The drug retention time (MRT) is 18-25 minutes. The pharmacokinetic parameters of the studied composition and 2-ethyl-6-methyl-3-hydroxypyridine solution did not statistically differ without any stabilizers.

Thus, the presented data on pharmacokinetics allow us to conclude that the pharmacokinetic parameters inherent in the active substance in the composition of the new composition are preserved in the absence of side effects inherent in the compositions known from the prior art.

Table 1 Exp. series Shelf life, months Description Authenticity Transparency Color pH Foreign matter Sterility Pyrogenicity quantitation B / color, transparent liquid Qualitative reactions, TLC, UV spectrum Must be transparent (GF XI, issue 1, p.198) It is not painted more intensely than the standard Y ₇ (OFS 42-0022-04) From 4.0 to 5.0 (potentiometric, GF XI, issue 1, p.113) Impurity stain is allowed, not more than 0.5% (TCX) Must be sterile (GF XI issue 2, p. 187) Must be pyrogen-free (GF XI, issue 2, p. 183) The content of ethylmethylhydroxypyridine succinate in 1 ml of the drug: from 0.045 to 0.055 g The sodium content of metabisulfite in 1 ml of the drug, g (iodimetry) one 2 3 four 5 6 7 8 9 10 eleven 12 010506E 0 Acc. Acc. Acc. Acc. 4.49 Absent Sterile. Acc. 0,0515 0.0001 010506E 12 Acc. Acc. Acc. Acc. 4,50 Absent Sterile. Acc. 0.0510 0.00006 010506E 24 Acc. Acc. Acc. Acc. 4.45 Absent Sterile. Acc. 0,0507 - 010506E 36 Not acc. Acc. Acc. Not acc. 4.40 Absent Sterile. Acc. 0,0493 - 020506E 0 Acc. Acc. Acc. Acc. 4.43 Absent Sterile. Acc. 0.0510 0.00015 020506E 12 Acc. Acc. Acc. Acc. 4,57 Absent Sterile. Acc. 0,0506 0.00012 020506E 24 Acc. Acc. Acc. Acc. 4.60 Absent Sterile. Acc. 0,0504 0.00011 020506E 36 Acc. Acc. Acc. Acc. 4.64 Absent Sterile. Acc. 0,0504 0.00009 030506E 0 Acc. Acc. Acc. Acc. 4.45 Absent Sterile. Acc. 0,0520 0,00030 030506E 12 Acc. Acc. Acc. Acc. 4,51 Absent Sterile. Acc. 0,0518 0,00028 030506E 24 Acc. Acc. Acc. Acc. 4,56 Absent Sterile. Acc. 0,0515 0,00025 030506E 36 Acc. Acc. Acc. Acc. 4.65 Absent Sterile. Acc. 0,0514 0.00018 040506E 0 Acc. Acc. Acc. Acc. 4.42 Absent Sterile. Acc. 0.0510 0,00046 040506E 12 Acc. Acc. Acc. Acc. 4.60 Absent Sterile. Acc. 0,0516 0,00038 040506E 24 Acc. Acc. Acc. Acc. 4.64 Absent Sterile. Acc. 0,0511 0,00028 040506E 36 Acc. Acc. Acc. Acc. 4.68 Absent Sterile. Acc. 0,0508 0,00021 050506E 0 Acc. Acc. Acc. Acc. 4,56 Absent Sterile. Acc. 0,0504 0,00060 050506E 12 Acc. Acc. Acc. Acc. 4.49 Absent Sterile. Acc. 0,0503 0,00053 050506E 24 Acc. Acc. Acc. Acc. 4.49 Absent Sterile. Acc. 0,0501 0,00051 050506E 36 Acc. Acc. Acc. Acc. 4,52 Absent Sterile. Acc. 0,0502 0,00049 060506E 0 Acc. Acc. Acc. Acc. 4.45 Absent Sterile. Acc. 0,0513 0.00100 060506E 12 Acc. Acc. Acc. Acc. 4.48 Absent Sterile. Acc. 0,0514 0,00094 060506E 24 Acc. Acc. Acc. Acc. 4.46 Absent Sterile. Acc. 0.0510 0,00085 060506E 36 Acc. Acc. Acc. Acc. 4.40 Absent Sterile. Acc. 0,0511 0,00069

table 2 Exp. series The sodium content of metabisulfite in 1 ml of the drug, g The death rate of animals * after intravenous administration of the drug in doses (mg / mouse): Estimated values (mg / mouse) 2.5 3.0 3,5 4.0 4,5 - 0 0/10 0/10 1/15 6/10 9/10 LD ₁₀ = 3.42 LD ₁₆ = 3.52 LD ₈₄ = 4.31 LD ₅₀ = 3.90 (3.72 ÷ 4.07) 020506E 0.00015 0/10 0/10 1/15 6/10 9/10 LD ₁₀ = 3.42 LD ₁₆ = 3.52 LD ₈₄ = 4.31 LD ₅₀ = 3.90 (3.72 ÷ 4.07) 030506E 0,00030 0/10 0/10 1/15 7/10 9/10 LD ₁₀ = 3.39 LD ₁₆ = 3.49 LD ₈₄ = 4.24 LD ₅₀ = 3.85 (3.69 ÷ 4.01) 040506E 0,00045 0/10 0/10 1/15 8/10 9/10 LD ₁₀ = 3.37 LD ₁₆ = 3.46 LD ₈₄ = 4.17 LD ₅₀ = 3.80 (3.65 + 3.94) 050506E 0,00060 0/10 0/10 1/15 9/10 10/10 LD ₁₀ = 3.18 LD ₁₆ = 3.28 LD ₈₄ = 4.05 LD ₅₀ = 3.65 (3.47 ÷ 3.83) 060506E 0.00100 0/10 1/10 6/15 9/10 10/10 LD ₁₀ = 2.95 LD ₁₆ = 3.07 LD ₈₄ = 4.03 LD ₅₀ = 3.52 (3.23 ÷ 3.72)

Claims (2)

1. A method of obtaining a pharmaceutical composition for parenteral administration containing 2-ethyl-6-methyl-3-hydroxypyridine succinate 4.0-6.0 wt.%, Sodium metabisulfite 0.015-0.045 wt.%, Water for injection up to 100.0 wt.%, characterized in that in water for injection, purified through a system of membrane filters with a pore size of 0.1-1.0 μm, saturated with nitrogen for 10-30 minutes, add sodium metabisulfite and 2-ethyl-6-methyl -3-hydroxypyridine succinate, stirred until dissolved, the solution is purified by filtration through a membrane filter with a pore size of 0.22-0.45 μm, ny filling the resulting solution in a nitrogen stream in ampoules, sterilized at a temperature of 100-130 ° C to obtain a sterile solution. 2. The production method according to claim 1, characterized in that the filling is carried out in glass ampoules of colorless or light-protective glass with a volume of 1-10 ml.