RU2491054C1 - Pharmaceutical composition for injections and method for its obtaining - Google Patents

Abstract

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to field of medicine and veterinary. Stable pharmaceutical composition for injections, contains water solution of 2-ethyl-6-methyl-3-oxypyridine succinate and auxiliary substance, and as auxiliary substance carbonic acid is applied, composition is obtained by mixing with the following component ratio (wt %): 2-ethyl-6-methyl-3-oxypyridine succinate 1-10; carbonic acid 0.01-0.5; water for injection to 100. Method of composition obtaining by i.1 is characterised by the fact, that filling and sealing ampoules on syringe filling machine is carried out in steam of carbonic acid, and sterilising filtration of 2-ethyl-6-methyl-3-oxypyridine succinate solution before filling is carried out under pressure of carbon dioxide.

EFFECT: pharmaceutical composition does not possess allergenic properties and is highly stable during entire normative storage term.

5 cl, 4 tbl, 8 ex

Description

FIELD OF THE INVENTION

The invention relates to the field of medicine and veterinary medicine, namely, to a pharmaceutical composition for injection based on 2-ethyl-6-methyl-3-hydroxypyridine succinate.

State of the art

Known injection form of 2-ethyl-6-methyl-3-hydroxypyridine succinate in the form of an aqueous solution with a concentration of the active substance of 5% [Mashkovsky MD Medicines Ed. 13, 1997, v.2, p.197]. The disadvantage of this form is the easy oxidation of the active substance, while its content decreases, and an intense yellow-brown color of the solution appears. Filling and sealing on syringe filling machines in a nitrogen stream, as is known from practical experience, does not completely protect against the presence of oxygen in the ampoule. Because nitrogen is lighter than air and practically insoluble in an aqueous solution, when blowing and sealing ampoules, including due to the turbulent flow arising, an insignificant amount of oxygen remains in the ampoules, which, nevertheless, is sufficient for the appearance of a clear color of the solution during thermal sterilization and storage; Moreover, since the amount of air in the ampoules is different, their staining is different, which leads to marriage in terms of the “heterogeneity of the series”.

In patent RU 2205640, publ. 06/10/2003, an additive was proposed as a stabilizer of succinic acid, but it greatly reduces the pH of the solutions, which leads to pain in injections and at the same time, protection against oxidation is insufficient. The optional Trilon B additive cannot protect against oxidation, as complexes of transition metals (iron, copper, etc.), as a rule, are active as catalysts for the oxidation of phenols [Karpov V.V., Hidekel M.L. Oxidation of some phenols by molecular oxygen in the presence of copper-containing complexes. JOKH Vol. 3, Issue 9, 1669-1674 (1967)].

Closest to the proposed solution, the composition described in patent RU 2380089, publ. 01/27/2010, its essence is the addition of a well-known stabilizer - sodium metabisulfite. Moreover, the oxidation and staining of a solution of 2-ethyl-6-methyl-3-hydroxypyridine succinate during storage is completely excluded. However, this solution has the disadvantage that sulfites are highly allergenic and also cause attacks of bronchial asthma in patients with appropriate bronchopulmonary pathology [see Special instructions for solutions in / in and / m administration of drugs Metadoxil and No-spa at http://www.webvidal.ru]. Due to the ability to cause fatal bronchospasm in asthmatics, sulfites and pyrosulfites as food stabilizers are prohibited or restricted for use in most countries [see E 226, E 227, E228 at http://www.procook.ru/articles.php?do=68]. Even the oral administration of sulfites and pyrosulfites with food and pharmaceuticals stimulates the development of allergic reactions, excretion of calcium from the body [Hugot D., Causeret J., Leclerc J. Effets d l'ingest on de sulfites sur 1'excretion du calcium chez Ie rat . Ann. Biol. Anim. Biochim. Biophys., 5, 53-59 (1965)], destroys thiamine, B ₁₂ , biotin, causing clinically pronounced vitamin deficiency [Bhagat B., Lockett MF The effect of sulphite in solid diets on the growth or rats. Food Cosmet. Toxicol., 2, 1-13 (1964); Shtenberg AJ, Ignat'ev AD Toxicological evaluation of some combinations of food preservatives. Food Cosmet. Toxicol., 8, 369-380 (1970); see Descriptions of preservatives E220-E228 at http://www.procook.ru/articles.php?do=68], damages the bronchopulmonary system, heart, kidneys, thyroid gland [Harmful substances in industry. Inorganic and organoelement compounds: Handbook. / Ed. prof. N.V. Lazareva, ed. 7th break and add. - L .: Chemistry, 1977, p. 65; Rehm HJ, Wittmann H. Beitrag zur Kenntnis der antimikrobiellen Wirkung der schwefligen Saure. II. Mitteilung. Die Wirkung der dissoziierten und undissoziierten Saure auf verschiedene Mikroorganismen. Z. Lebensin. Unters. Forsch., 120 (6), 465-478 (1963)], inhibits vital enzymes [Gunnison AF Sulfite toxicity. A critical review of in vitro and in vivo data. Food Cosmet. Toxicol., 19, 667-682 (1981); Pfleiderer G., Jeckel D., Wieland T. Uber die Einwirkung von Sulit aufeinige DPN hydrierende Enzyme, Biochem. Z., 328, 187-194 (1956)] has a mutagenic effect [Mukai F., Hawryluk I., Shapiro R. The mutagenic specifity of sodium bisulfite. Biochem. Biophys. Res. Commun. 39, 983-988 (1970); Hayatsu H., Miura A. The mutagenic action of sodium bisulfite. Biochem. Biophys. Acta, 39,156-160 (1970)]. Since injectable 2-ethyl-6-methyl-3-hydroxypyridine succinate is often used in large doses and for a long time [RU 2309664, publ. 11/10/2007; RU 2290930, publ. 01/10/2007; Reference VIDAL. Medicines in Russia: A Handbook. M .: AstraFarmService, 2011, p. B-856], the drawbacks of using sodium metabisulfite as a stabilizer for the injection form of the drug are obvious, because on the one hand, the induction of a fatal attack of bronchial asthma is possible, on the other hand, deepening and intensification of pathological changes in the cardiovascular system and kidneys, impaired thyroid function. In the clinical sense, the use of sulfites or pyrosulfites as stabilizers of 2-ethyl-6-methyl-3-hydroxypyridine succinate significantly narrows the scope of the highly effective drug, leaving a large contingent of patients without the necessary adequate therapy.

Disclosure of the invention.

The objective of the invention is to provide a storage stable injection form of 2-ethyl-6-methyl-3-hydroxypyridine succinate that does not contain allergenic stabilizers. The problem is solved in that carbon dioxide (CO ₂ ) is introduced into a solution of 2-ethyl-6-methyl-3-hydroxypyridine succinate in an amount of 0.01-0.5 wt.% (Readily soluble in aqueous solutions) and all processes are carried out (filtration filling, sealing) mainly in the atmosphere of carbon dioxide instead of nitrogen. Moreover, in the ampoule at the time of sealing, a “cushion” is formed from heavy carbon dioxide, which is partially released from the solution, which completely eliminates the “throwing” of oxygen at the time of filling and sealing. The method allows the use of syringe filling machines and high-performance vacuum filling machines.

At the same time, carbon dioxide, in contrast to sulfites, in the indicated concentrations (obtained during the process) is not only non-toxic, but, on the contrary, exhibits antihypoxic effect and stimulates respiration [M.D. Mashkovsky Medicines / Manual for doctors, Vol. 2. - 14th ed., Rev., Rev. and add. - M .: New Wave Publishing House LLC, 2000. - C.188]. To implement the invention, it is sufficient to replace the nitrogen in syringe filling machines with carbon dioxide (food grade), while the carbon dioxide content to stabilize the solution is sufficient in a minimum amount (see example 4). In addition, you can enter carbon dioxide during sterilizing filtration of the injection solution, as well as prepare the injection solution in water containing carbon dioxide - this reduces the likelihood of oxidation products appearing in intermediate operations and, in addition, excludes the growth of most aerobic microorganisms, which reduces the likelihood of endotoxins in solutions (pyrogens) [Luke E., Jager M. Preservatives in the food industry: Properties and applications. / Translation from German L.A. Sarafanova. Ed. 3rd - St. Petersburg: GIORD, 1998, pp. 70-71].

Thus, the proposed stable pharmaceutical composition for injection contains the following components (wt.%):

2-ethyl-6-methyl-3-hydroxypyridine succinate 1-10 carbon dioxide 0.01-0.5 water for injections up to 100

The maximum concentration of carbon dioxide in the range of 0.3-0.5 wt.% Is achieved by special technological methods (see examples 1-3) and reliably stabilizes the solution during storage. A carbon dioxide concentration of greater than 0.5 wt.% Is unattainable due to the limited solubility of carbon dioxide. A sufficient minimum concentration of carbon dioxide for the implementation of the claimed effect is achieved by carrying out the process of filling ampoules and sealing in a stream of carbon dioxide; while the concentration of carbon dioxide in the solution is not less than 0.01 wt.% (example 4).

The content of 2-ethyl-6-methyl-3-hydroxypyridine succinate in injection preparations for medical use is traditionally 5%, but other concentrations are convenient for use in veterinary medicine - from 1 to 2.5% (for the treatment of small pets) and 10% (for the treatment of productive animals - cattle, horses). Solutions with a concentration of more than 10% may crystallize upon cooling, which is unacceptable.

The process of dissolving the substance in water and saturation with carbon dioxide is more advantageous to carry out during cooling, while the solubility of carbon dioxide increases and its content in the finished solution increases, however, it is impossible to lower the temperature below 5 ° C, because crystallization begins on the walls of the reactor. For more concentrated solutions (with a concentration of over 5%) intended for veterinary medicine, it is convenient to heat the solution before sterilizing filtration, because this reduces viscosity and significantly speeds up the filtration process. However, heating above 30 ° C is unacceptable, because the solubility of carbon dioxide is greatly reduced, and difficulties arise when filling ampoules.

Previously, the use of carbon dioxide was practiced in the preparation of injectable forms of such drugs as the sodium salt of n-aminosalicylic acid and sodium ascorbate [I. Muravyov Textbook of technology of drugs and galenic drugs. - M .: Medgiz, 1961, p. 753, 754], but the application of this method to the preparation of a stable injection form of 2-ethyl-6-methyl-3-hydroxypyridine succinate is unknown.

Thus, the present invention eliminates the use of highly allergenic hazardous sulfites in the preparation of an injectable form of 2-ethyl-6-methyl-3-hydroxypyridine succinate and at the same time ensures high stability of the drug during storage.

The implementation of the invention.

Example 1. (Laboratory experience).

In a three-necked flask with a volume of 2 l, equipped with a paddle stirrer and a bubbler for supplying carbon dioxide, load 1900 ml of water for injection. Carbon dioxide (“food grade”) is bubbled through water for 15 minutes with the agitator turned on. Then, 100 g of 2-ethyl-6-methyl-3-hydroxypyridine succinate are added with stirring and stirred until dissolved, without stopping the flow of carbon dioxide. The resulting solution was poured into a 2 L volumetric flask, adjusted to the mark with distilled water, and stirred. After that, it is filtered through a package of membrane filters (0.45 and 0.22 μm), poured in a laminar cabinet in a stream of carbon dioxide into ampoules of light-protective glass, 2 ml each, sealed in a stream of carbon dioxide and sterilized by autoclaving at 122 ± 1 ° C in for 8 minutes. Received after viewing 993 ampoules on mechanical inclusions. The solution from the ampoules is analyzed for color (by absorbance at 400 nm), pH and the content of the bicarbonate ion after sterilization, after 1 year, 2 years and 3 years of storage under standard conditions. The content of the bicarbonate ion is determined nephelometrically by reaction with barium nitrate in an ammonia buffer medium (pH = 7-8).

Table 1 Quality indicators of the injection solution of 2-ethyl-6-methyl-3-hydroxypyridine succinate Period Optical density at λ = 400 nm (color) pH Bicarbonate content after sterilization 0.02 (better than standard Y7 according to GF XII) 4.45 0.08% (corresponds to the content of CO ₂ 0.058%) after 1 year 0,022 4,5 - after 2 years 0,031 4,5 - 3 years later 0.041 (at reference level Y7) 4,52 -

Example 2. (Syringe filling).

The solution for injection is prepared in an enameled reactor equipped with a paddle stirrer. 200 L of water for injection was charged into the reactor and, with stirring, 11.37 kg of 2-ethyl-6-methyl-3-hydroxypyridine succinate was stirred until dissolved. Then, the water for injection is adjusted to a total weight of 234.50 kg and further stirred for 10 minutes. A pressure of 3 atm (solution temperature 16-20 ° C) is created in the reactor by supplying carbon dioxide, it is held for 30 minutes and filtered through filters with pore sizes of 0.45 and 0.22 μm, immediately before dosing of 0.22 μm. After preparation of the solution, a sample is taken for analysis before filtration.

Filling and sealing of ampoules on a syringe filling machine is carried out in a stream of carbon dioxide. Use ampoules with a nominal volume of 2 ml of lightproof glass; secondary packaging - 5 ampoules per cartridge of polyethylene terephthalate or polystyrene; 2 cassettes per pack of cardboard (Armadin preparation). Get 100,000 ampoules of the drug. After storage under normal conditions for 3 years, the drug meets the requirements of ND. The bicarbonate ion content in the solution is 0.50%, which corresponds to a CO ₂ content _of 0.36%.

Table 2. Quality indicators of the drug "Armadin". No. p / p Name of indicator Allowable rate After ampoule After storage for 3 years one. Description Colorless or lightly colored clear liquid Colorless clear liquid Colorless clear liquid 2. Solution transparency The drug must be transparent Match. Match. 3. The color of the solution Must stand comparison with Y6 Match. Match. four. PH 4.0 to 5.0 4.42 4.45 5. Related impurities,% Each admixture is not more than 0.5 One trace impurity One trace impurity The amount of impurities is not more than 0.5 6. Mechanical inclusions Visible particles Lack of Match. Match. Invisible particles Particles ≥10 μm - not more than 6000 ≤25 microns not more than 600 per ampoule Match. Match. 7. Quantitative determination, g / ml 0.0475-0.0525 0,050 0,050 8. The content of bicarbonate ion in solution,% - 0.5 (corresponds to the CO ₂ content _of 0.36%) 0.5 (corresponds to the CO ₂ content _of 0.36%) 9. The optical density of the solution (at λ = 400 nm) - 0,021 0,023

Example 3. (vacuum filling).

The solution for injection is prepared in an enameled reactor equipped with a paddle stirrer. 200 l of water for injection are charged into the reactor and, with stirring, 11.37 kg of 2-ethyl-6-methyl-3-hydroxypyridine succinate is stirred until complete dissolution. Then add 23 L of water for injection, mix for 30 minutes and take a sample to determine the content of 2-ethyl-6-methyl-3-hydroxypyridine succinate. If the content is in the range of 0.0475-0.0525 g / ml, the reactor is shut down, food carbon dioxide is supplied to a pressure of 2.8-3 atm; then the solution is cooled to 5 ± 1 ° C by supplying a coolant to the reactor jacket; the pressure in the reactor is maintained by a periodic supply of carbon dioxide. At a temperature of 5 ± 1 ° C and a pressure of 2.8-3 atm, the solution is kept with stirring until the pressure drop ceases, and then it is transferred to a vacuum filling circuit through a system of sterilizing filters (0.45 and 0.22 μm). Filling is carried out on vacuum filling machines, while the vacuum is released by supplying carbon dioxide through the receiver-valve system. Ampoules are used from dark glass, with a volume of 2 ml. After filling, the ampoules are sealed and autoclaved at 122 ± 1 ° C for 8 minutes, then checked for leaks and mechanical inclusions. After rejection, 98,600 ampoules are obtained, which are stored in secondary packaging (see Example 2) under normal conditions for 3 years. After storage, the drug meets the requirements of ND. The bicarbonate ion content in the solution is 0.38%, which corresponds to a CO ₂ content _of 0.27%.

Table 3. Quality indicators of the injection solution of 2-ethyl-6-methyl-3-hydroxypyridine succinate. No. p / p Name of indicator Allowable rate After ampoule After storage for 3 years one. Description Colorless or lightly colored clear liquid Colorless clear liquid Colorless clear liquid 2. Solution transparency The drug must be transparent Match. Match. 3. The color of the solution Must stand comparison with Y6 Match. Match. four. pH 4.0 to 5.0 4.42 4.48 5. Related impurities,% Each admixture is not more than 0.5 Ots. Ots. The amount of impurities is not more than 0.5 6. Mechanical inclusions Visible particles Lack of Match. Match. Invisible particles Particles ≥10 μm - not more than 6000 ≤25 microns not more than 600 per ampoule Match. Match. 7. Quantitative determination, g / ml 0.0475-0.0525 0,050 0,050 8. The content of bicarbonate ion in solution,% - 0.38 (corresponds to the content of CO ₂ 0.27%) 0.38 (corresponds to the content of CO ₂ 0.27%) 9. The optical density of the solution (at λ = 400 nm) - 0,022 0,028

Example 4

The experiment is carried out similarly to experiment 2, but sterilizing filtration is carried out under nitrogen pressure; filling and sealing on a syringe filling machine is carried out in a stream of carbon dioxide. The content of bicarbonate ion in the solution is 0.14 (corresponds to the content of CO ₂ 0,01%). The color of the solution at the time of release is at the level of standard Y7, the optical density of the solution (at λ = 400 nm) is 0.041; after 3 years of storage, the color between the standard Y6 and Y7 (meets the requirements of regulatory documentation), the optical density of the solution (at λ = 400 nm) is 0.049.

Example 5

In a three-necked flask with a volume of 2 l, equipped with a paddle stirrer and a bubbler for supplying carbon dioxide and a thermometer, 1800 ml of water for injection is charged. Carbon dioxide (“food grade”) is bubbled through water for 15 minutes with the agitator turned on. Without stopping the supply of carbon dioxide, 200 g of 2-ethyl-6-methyl-3-hydroxypyridine succinate are introduced and mixed until dissolved. The solution was poured into a volumetric flask of 2L is brought to mark with distilled water and returned to the flask with stirrer, stirring and supplying the solution CO ₂ warmed to 30 ° C, which significantly reduces the viscosity and accelerates the process of sterilizing filtration. The resulting solution is filtered through a package of sterilizing filters (0.45 and 0.22 μm), poured in a laminar cabinet in a stream of carbon dioxide into 2 ml ampoules of light-proof glass, sealed in a stream of carbon dioxide and sterilized by autoclaving at 122 ± 1 ° C in for 8 minutes. Received after viewing the mechanical inclusion of 989 ampoules. The solution from the ampoules is analyzed for color (by absorbance at 400 nm), pH, and bicarbonate ion content. Immediately after manufacturing, the color is better than the standard Y6, the optical density of the solution (at λ = 400 nm) is 0.044; the content of bicarbonate ion in the solution is 0.014% (corresponds to the content of CO ₂ 0.01%), pH = 4.44. after 3 years of storage, pH = 4.48, color better than Y6 standard, optical density of the solution (at λ = 400 nm) 0.05. TLC analysis of specific impurities did not reveal a change in their content over the entire shelf life.

Example 6

Injectable 2-ethyl-6-methyl-3-hydroxypyridine succinate with a concentration of 1-2.5% is used in veterinary medicine, because provides ease of dosing when used in small pets.

The process is carried out as in example 2. In a reactor with a stirrer, 200 L of water for injection is placed and with the stirrer turned on, 2.345 kg of 2-ethyl-6-methyl-3-hydroxypyridine succinate are charged. The reaction mass is stirred until complete dissolution (visual control), add water to 234.5 kg; serves in the jacket of the reactor coolant for cooling. The reactor is sealed, carbon dioxide is supplied to a pressure of 3 atm; the mass is cooled to 5 ° C and stirred under these conditions until the pressure drop ceases. After that, the solution from the reactor under pressure of carbon dioxide is filtered through a package of sterilizing filters (0.45 and 0.22 μm), immediately before dosing through a 0.22 μm filter. Ampoules are filled using the syringe method under aseptic conditions; use 2 ml ampoules of lightproof glass. Get 100,000 ampoules of the drug. The color at the time of release is indistinguishable from water, the optical density at 400 nm is not determined, the content of the bicarbonate ion in the solution is 0.76% (corresponds to the CO ₂ content _of 0.51%). After three years of storage: color - better than standard Y7, optical density at 400 nm - 0.01.

Example 7. (prototype).

1900 ml of water for injection is loaded into a 2 liter glass. Water is sparged with nitrogen, TSP for 10 minutes, then 100 g of 2-ethyl-6-methyl-3-hydroxypyridine pharmacopoeial succinate and 10 g of sodium metabisulfite are added with stirring. After dissolution, the volume was adjusted to 1 liter with water for injection. The solution is filtered through a 0.22 μm filter, poured in a stream of nitrogen into 2 ml ampoules of light-protective glass, sealed in a stream of nitrogen and sterilized by autoclaving at 122 ± 1 ° C for 8 minutes. Get 980 ampoules, color - at the level of the standard Y7; the composition of the injection solution of 2-ethyl-6-methyl-3-hydroxypyridine succinate stabilized with metabisulfite:

2-ethyl-6-methyl-3-hydroxypyridine succinate 5 wt.% sodium metabisulfite 1 wt.% water for injections up to 100%

Example 8. (determination of allergenic activity).

To compare the allergenic properties of injection solutions of 2-ethyl-6-methyl-3-hydroxypyridine succinate obtained by the proposed method and the prototype, the study is carried out on guinea pigs - albinos. In the experiment, males 1 year old with a weight of 900-950 g are used. To study, take the ampoules obtained according to example 1 (the proposed pharmaceutical composition) and example 7 (prototype). For the experiment, take two groups of animals of 10 pieces each; the first group is administered the drug obtained according to example 1, the second group - the drug obtained according to example 7; the drug is administered in a volume of 1 ampoule (100 mg of active substance) to each animal (corresponds to the maximum dose for humans - 1000 mg / day). The first injection is done subcutaneously, then the next day, in the same amount intramuscularly in the thigh, and every other day, again intramuscularly (only three injections). After 15 days, the animals are injected intravenously; observe the condition of the animals and the number of dead animals during the day. The drug stabilized with metabisulfite causes death in most animals from anaphylactic shock (see Table 4), while the drug stabilized with carbon dioxide does not have allergic activity under experimental conditions.

Table 4. Allergenic properties of injectable forms of 2-ethyl-6-methyl-3-hydroxypyridine succinate. Parameter Carbon stabilized preparation (proposed pharmaceutical composition) The drug is stabilized by metabisulfite (prototype) The number of animals in the experience 10 10 The number of dead animals 0 7 Number of animals surviving, but with an allergic reaction 0 2 - oppressed, panting 1 - oppressed, on the skin of the urticaria, mucous membranes are inflamed.

Claims (5)

1. A stable pharmaceutical composition for injection containing an aqueous solution of 2-ethyl-6-methyl-3-hydroxypyridine succinate and an excipient, characterized in that carbon dioxide is used as an excipient, and the composition is obtained by mixing in the following ratio of components (wt. %):
2-ethyl-6-methyl-3-hydroxypyridine succinate 1-10 carbon dioxide 0.01-0.5 water for injections up to 100 2. The method of obtaining the composition according to claim 1, characterized in that the filling and sealing of the ampoules on a syringe filling machine is carried out in a stream of carbon dioxide. 3. The method according to claim 2, characterized in that the sterilizing filtration of a solution of 2-ethyl-6-methyl-3-hydroxypyridine succinate is carried out under pressure of carbon dioxide before filling. 4. The method according to claim 1, characterized in that the solution of 2-ethyl-6-methyl-3-hydroxypyridine succinate is prepared in carbonated water at a temperature of 5-30 ° C. 5. The method according to claim 4, characterized in that the ampoules are filled with a solution on a vacuum filling machine, while the vacuum is released during filling by supplying carbon dioxide.