RU2504376C1 - High-stable pharmaceutical formulation of lyophilisate of 3-oxypyridine and methylpyridine derivatives and pharmaceutically acceptable salts thereof - Google Patents

Abstract

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmacology, pharmaceutics and medicine, more specifically to a new generation of high-stable dosage forms prepared with using the process of sublimation in a specific mode with a composition containing no stabilising agents reducing the width of therapeutic action of finished dosage form substantially. The invention concerns the pharmaceutical composition for injections and infusions containing 3-oxy- and methylpyridine derivatives and pharmaceutically acceptable salts thereof as an active ingredient, sodium chloride or potassium chloride as an additive agent, in the form a lyophilisate. The process involves the sublimation followed by the vacuum dewatering for at least 64 hours.

EFFECT: pharmaceutical composition possesses high stability for the whole shelf-life as opposed to all known pharmaceutical formulations of these compounds; it preserves pharmacological activity and enables dissolving the composition immediately before use and reducing a risk of the negative effect of the thermal sterilisation of aqueous solutions.

2 cl, 7 ex, 2 tbl

Description

FIELD OF THE INVENTION

The invention relates to the field of pharmacology, pharmaceuticals and medicine, specifically to a new generation of highly stable dosage forms obtained using the sublimation process in a specific mode, for the prevention and treatment of various diseases of the cerebrovascular system. 3-hydroxy- or methylpyridines and their derivatives are heteroaromatic phenols, compounds that effectively regulate the processes of oxidation and peroxidation. They are structural analogues of vitamin B6 (pyridoxole, pyridoxal and pyridoxamine), which play an important role in the life of the body. Aqueous solutions of drugs of these substances have a wide range of pharmacological effects, a sufficiently wide breadth of therapeutic effect, low toxicity and have found effective use in clinical practice in various fields of medicine.

The structural features of chemical substances play an important role in the formation of the pharmacological effect of active substances, in particular, the maintenance of pharmacophores in an active state, since a change in their position or the formation of additional bonds can change the spectrum of activity manifested by a substance. Therefore, various groups in the derivatives of 3-hydroxy and methylpyridines (unequal radicals in different positions of the pyridine ring: methylbenzyl substituted derivatives of 3-hydroxypyridines, phenylethyl substituted, isothiuronium substituted, adamantyl derivatives of pyridine, aminophenyl derivatives of 3-hydroxypyridines possess different properties of 3-hydroxypyridines) varying degrees of antioxidant activity. Alkyl substituted 3-hydroxypyridines proved to be effective membrane stabilizers in mechanical trauma, while aryl substituted and aminomethyl derivatives of 3-hydroxypyridines are less active. Replacing the OH group with an NH ₂ group or a hydrogen atom leads to a significant loss of biological activity, which indicates the decisive role of the hydroxyl radical in stabilizing the biological effect. 2-tert-butyl-6-methyl- and 2-ethyl-6-methyl-3-hydroxypyridines additionally have antitumor activities. The addition of antioxidants to such active compounds as metabisulfite in a ratio of 5-6: 0.05-1.25, which is about 1-20% of the total mass of the active substance, requires thorough studies of the general and chronic toxicity of the finished dosage form. Moreover, the permissible value of metabisulfite for different Pharmacopoeias should not exceed 0.1-2%, as well as the creation of an evidence base for the comparative effectiveness of an aqueous solution and 3-hydroxy- and methylpyridines and their derivatives, pharmaceutically acceptable salts, which are completely absent. The lability in color of aqueous solutions, according to the studies, is apparently more associated with the use in the technological process of finished dosage forms of derivatives of 3-hydroxypyridines, in particular 2-ethyl-6-methyl-3-hydroxypridine succinate, thermal sterilization at 121 ° C for 1 hour, given that the melting point of the active substance is about 114 ° C.

From the analysis of the above information materials, the purpose of the present invention is formulated naturally, namely: the creation of a stable pharmaceutical composition based on substances of derivatives of 3-hydroxy- or methylpyridines and their pharmaceutically acceptable salts, which allows to reduce the risk of impairing the quality of the manufactured medicinal product, increase storage stability and fully eliminate the problems associated with thermal sterilization of aqueous solutions.

The level of technology.

Known pharmaceutical formulations based on 3-hydroxypyridine containing 2-ethyl-6-methyl-3-hydroxypyridine hydrochloride (emoxypine) (RF patent No. 2070010) and 3- (N, N-dimethylcarbomoyloxy) -2-ethyl-6-methylpyridine succinate (RF patent No. 2095350) prepared by extempore in the experiment, without a description of the method for producing the finished dosage form and without studies of the finished dosage form.

Known means of antioxidant protection of eye tissues, containing emoxipin 4.5-16.0, pyridoxine hydrochloride 3.0-10.0 and polyethylene glycol, glycerin, or a combination of 3.0-5.0, the polymer is bio-soluble 69.0-89 , 5, characterized in that it is a biocompatible polymer with a hydrophilic plasticizing additive (RF patent No. 2070010), ointments for the treatment of thrombophlebitis: emoxipin and hydrophilic base (RF patent No. 2058775), 2-ethyl-6-methyl-3-hydroxypyridine succinate in various dosage forms: solutions for injection, granular powders, capsules, tablets for oral use, gels, dressings (RF patents No. 2065299, 2144822, 2145855, 2149648, 2293558, 2205640, patent application 2006111065). The need for injectable forms is explained by the use of these compounds in acute cerebrovascular accidents and other conditions requiring high doses of drugs in the blood.

An injectable form of 2-ethyl-6-methyl-3-hydroxypyridine succinate is known as a 5% aqueous solution. The composition contains 5 g of water for injection up to 100 ml (Mashkovsky M.D. Medicines. Ed. 13, 1997, v. 2, p .97). The disadvantage of this dosage form is unstable quality, in particular, the color of the solution (corresponds to the color standard 66, GF XI, issue 1, p.194). Also described is a pharmaceutical composition for injection (RF patent No. 2205640) based on an aqueous solution of 2-ethyl-6-methyl-3-hydroxypyridine succinate, which additionally contains succinic acid as a stabilizer in the following ratio, wt.%: 2-ethyl- 6-methyl-3-hydroxypyridine succinate - 5.0-6.0, succinic acid - 0.5-5.0, trilon B - 0.0-0.2 and water for injection - up to 100.0, by the Patent RF №2205640, it was found that, for example, the additional introduction of sodium sulfite, Trilon B, or a combination thereof, does not improve the quality of repair. And finally, a pharmaceutical composition containing an aqueous solution of 2-ethyl-6-methyl-3-hydroxypyridine succinate, sodium metabisulfite in the following ratio, wt.%: 2-ethyl-6-methyl-3-hydroxypyridine succinate - 5.0- 6.0, sodium metabisulfite - 0.05-1.25 and water for injection up to 100.0 (RF patent No. 2380089, adopted as a prototype). As a result, the form of 2-ethyl-6-methyl-3-hydroxypyridine succinate (mexidol) produced today contains 100 g of the drug containing 2 g of metabisulfite, which, with the recommended maximum single use of up to 8 ampoules, leads to the simultaneous administration of 16 mg of metabisulfite and exceeds all recommendations for the safe use of metabisulfite in foods, not to mention injectable forms.

Typically, antioxidants are used in very small quantities, which are considered harmless to the body. So, ascorbic acid is used in a concentration of from 0.02 to 0.1%, sodium bisulfite in a concentration of 0.1-0.15%, thiourea in a concentration of 0.005%, esters of ascorbic acid in a concentration of from 0.01 to 0.075 % etc. However, the use of stabilizers requires caution both regarding their possible effect on the physiological processes of the body, and on the activity of the drugs themselves. For example, there is evidence that many of the stabilizers used in parenteral drugs have a negative effect on the vital functions of the human body, in particular, sulfites. In this regard, it is absolutely necessary to study physical methods of stabilization and increase the level of pharmaceutical technology with the aim of the possible use of more advanced methods to increase the resistance of drugs [Azhgikhin I.S. Technology of drugs. 2nd edition rev. and add. - M.: Medicine, 1980 - 440 p.]. It was shown that the inclusion of metabisulfite, for example, in the dosage form of noshpa (drotaverine hydrochloride) reduces the half-lethal dose to a half-lethal dose (LD ₅₀ ) for injection for metabisulphite equal to 115 mg / kg of animal weight, which corresponds to the second class of toxicity and safety: highly toxic substances with LD ₅₀ to 200 mg / kg.

Disclosure of the invention.

Using the invention for the first time will provide the following technical result: to create a stable pharmaceutical form of 3-hydroxy- and methylpyridines or their derivatives for injection, which in terms of stability, preservation of pharmaceutical activity and toxicological properties significantly exceeds existing analogues.

1. To create a stable form with a breadth of therapeutic effect, not different from unstable aqueous compounds,

2. Do not conduct special studies on the interaction of drugs of 3-hydroxy- and methylpyridines and their derivatives with stabilizers, such as metabisulfite and trilon B, with other dosage forms that are acceptable for simultaneous use,

3. Exclude the autoclaving procedure at 122 ± 1 ° C for 8 minutes (thermal sterilization) for pharmaceutically active substances with a melting point close to or even higher, as in the case of 2-ethyl-6-methyl-hydroxypyridine succinate, the autoclaving temperature,

4. Limit the use of stabilizers to create stable forms and thereby the risk of increased complications with increasing doses of the drug administered,

5. Increase storage capacity (shelf life of activity and sterility) in comparison with liquid forms of preparations of 3-hydroxy- and methylpyridines and their derivatives (pharmaceutically acceptable salts).

The described technical result is achieved by a system of technological solutions and the creation of an economical technology for the production of high-quality lyophilized-dried preparations that meets the requirements of the USSR State Pharmacopoeia of the XIth edition for lyophilized-dried preparations “dry injections”. The claimed composition is obtained by the following methods: 2-10% aqueous or with 0.02-0.9% sodium or potassium chloride, substances of derivatives of 3-hydroxy and methylpyridines and their pharmaceutically acceptable salts, in compliance with sterility requirements, are poured into ampoules or vials of a pharmaceutical solution sublimation of the substance, followed by freezing in the temperature range from - 41-50 ° C and vacuum dehydration of the vacuum (less than 0.001 mbar). The freeze drying process is at least 64 hours. Compliance with the developed lyophilization regime allows us to comply with the condition: the lyophilisate, when diluted with water or infusion fluids, retains the characteristic properties of the drug and specific activity, uniformity in height and residual moisture of the total dry residue. The resulting lyophilisate is highly stable when diluted with infusion solutions and can be stored for at least 3 years (shelf life of 5 years).

The composition of a sterile solution for sublimation includes the following ingredients, in the following mass ratio. %

Active substance - 1.0-20.0

Sodium chloride or potassium chloride - 0.01-0.9

Water for injection - the rest

The active substance contains 3- (N, N-dimethylcarbomoyloxy) -2-ethyl-6-methylpyridine succinate, 3-methylpyridine succinate, 2-ethyl-6-methyl-3-hydroxypyridine hydrochloride, 2-ethyl-6-methyl nitroxy succinate -3-hydroxypyridine, 3-hydroxypyridine oxalate, 6-trichloromethyl -2-chloropyridine (nitrapyrin), 3-hydroxypyridine malonate, 2-ethyl-6-methyl-3-hydroxypyridine succinate.

A very slow removal of moisture during the sublimation process and a standard residual moisture content of up to 10% makes it possible to obtain stable lyophilizates when they are diluted with injection solutions with a low content of inorganic salt, which ensures the stability of the lyophilizate in the finished dosage form and avoid exposure to high temperatures. Techniques have been developed to intensify the freeze-drying process using regulation of the freezing, heat supply and controlled vacuum modes and providing a significant economic effect.

From the point of view of the widespread use of such a lyophilized composition in clinical practice, it is necessary to optimize the process of re-dissolution of the lyophilizate so that it does not require the use of special equipment (for example, a shaker) and can be easily carried out by medical staff.

The proposed ratio of the components is optimal, found experimentally and provides improved stability parameters of the drug compared to the prototype: improved color solution, stable quality of the drug for 3 years or more and the target therapeutic effect.

The implementation of the invention

Example 1. In a pre-sterilized measuring cup with a capacity of 1.0 l load 950 ml of water for injection. Water is sparged with nitrogen NSP for 10 minutes. Then, with stirring, 100 mg of sodium chloride and 50.0 g of derivatives of 3-hydroxypyridines or 3-methylpyridines and their pharmaceutically acceptable salts are added. After dissolution, the volume is adjusted to 1.0 L with water for injection, the solution is transferred to a closed sterile filtration system and filtered through a prefilter with a pore diameter of 0.4 μm and a sterile filter with a pore diameter of 0.22 μm, poured into a ampoule or vial in a stream of nitrogen, sealed in a stream of nitrogen, under aseptic conditions. The resulting ampoules or vials containing a colorless, clear solution are transferred to a TG-50 type freeze dryer and sublimated in the mode described above. After completion of the lyophilization process, the preparation is sealed or covered with a flip-top lid. The resulting finished dosage form is stable throughout the entire shelf life. The drug is dissolved with water for injection in a volume of 2-4 ml minimum (with intravenous infusions up to 100 ml of physiological saline or with a solution of glucose, dextrose). The resulting solution upon reconstitution is transparent. The dosage form is stable during storage for 5 years.

Thus, in the framework of the invention, a lyophilized form containing derivatives (salts) of 3-hydroxy- and methylpyridines in high concentration without the use of organic or inorganic cryostabilizers is created. significantly reducing the range of therapeutic effects with intravenous administration to the patient. This lyophilisate is stable when diluted with infusion solutions. In this case, lyophilizates upon reconstitution in water or infusion fluid retain the pharmacological activity of aqueous solutions of these properties compounds. Reconstitution of the lyophilisate occurs without the use of special equipment.

According to the method, a composition of the following composition is obtained, wt.%:

Derivatives of 3-hydroxypyridine and its salts - 1.0-20.0

Sodium chloride - 0.01-0.9

Water for injection - the rest

Derivatives of 3-methylpyridine and its salts - 1.0-20.0

Sodium chloride - 0.01-0.9

Water for injection - the rest

Example 1. A lyophilisate is prepared based on 10.0 g of 3-methylpyridine and 0.3 g of sodium chloride dissolved in 1.0 l of water for injection. Ampoules containing a clear, colorless solution are obtained and sublimation is carried out. After 72 hours, a lyophilisate (white column about 1.8 cm high in 5 ml) is obtained and sealed. The drug is stable over the entire shelf life, stable during storage for at least 3 years, corresponding to the requirements of a pharmaceutical agent for injection. After dissolving in water for injection, a clear solution is obtained that meets the requirements of a pharmaceutical agent for authenticity and quantitative composition.

According to the method, a composition of the following composition is obtained:

3-methylpyridine succinate 1,0 Potassium chloride 0,03 Water for injections Rest

Example 2. Obtained analogously to example 1. Obtain a lyophilisate based on 10.0 g of 2-ethyl-6-methyl-3-hydroxypyridine hydrochloride and 0.1 g of sodium chloride dissolved in 1.0 l of water for injection. Ampoules containing a clear, colorless solution are obtained and sublimation is carried out. After 72 hours, a lyophilisate (white column about 1.8 cm high in 5 ml) is obtained and sealed. The drug is stable over the entire shelf life, stable during storage for at least 3 years, corresponding to the requirements of a pharmaceutical agent for injection. After dissolving in water for injection, a clear solution is obtained that meets the requirements of a pharmaceutical agent for authenticity and quantitative composition.

According to the method, a composition of the following composition is obtained:

2-ethyl-6-methyl-3-hydroxypyridine hydrochloride 1,0 Sodium chloride 0.01 Water for injections Rest

Example 3. Obtained analogously to example 1. Obtain a lyophilisate, based on the preliminary dissolution of 20.0 g of 3- (N, N-Dimethylcarbamoyloxy) -2-ethyl-6-methylpyridine succinate and 0.2 g of sodium chloride in 1.0 l of water . Ampoules containing a clear, colorless solution are obtained and sublimation is carried out. After 72 hours, a lyophilisate (white column about 1.8 cm high in 5 ml) is obtained and sealed. The drug is stable over the entire shelf life, stable during storage for at least 3 years, corresponding to the requirements of a pharmaceutical agent for injection. After dissolving in water for injection, a clear solution is obtained that meets the requirements of a pharmaceutical agent for authenticity and quantitative composition.

By the method receive a composition of the following composition, mass. %:

3- (N, N-Dimethylcarbamoyloxy) -2-ethyl-6-methylpyridine succinate - 2.0 g

Sodium chloride - 0.02 g

Water for injection - the rest

Example 4. Obtain analogously to example 1. Obtain a lyophilisate, based on the preliminary dissolution of 20.0 g of nitroxysuccinate 2-ethyl-6-methyl-3-hydroxypyridine and 0.2 g of sodium chloride in 1.0 l of water. Ampoules containing a clear, colorless solution are obtained and sublimation is carried out. After 72 hours, a lyophilisate (white column about 1.8 cm high in 5 ml) is obtained and sealed. The drug is stable over the entire shelf life, stable during storage for at least 3 years, corresponding to the requirements of a pharmaceutical agent for injection. After dissolving in water for injection, a clear solution is obtained that meets the requirements of a pharmaceutical agent for authenticity and quantitative composition.

By the method receive a composition of the following composition, mass. %:

2-ethyl-6-methyl-3-hydroxypyridine nitroxysuccinate - 2.0 g

Sodium chloride - 0.02 g

Water for injection - the rest

The present invention and the achievement of the claimed technical result is confirmed by the results of the following studies to maintain stability, pharmacological activity and toxic properties of drugs and is illustrated by the following examples.

Example 5. Experimental studies were performed on 60 white outbred female rats weighing 150-180 g. Animals were kept under standard vivarium conditions of 10 animals per cage. The diet of rats consisted of a standard granular feed, which they received 1 time per day. 24 hours before the experiment, the feeding of animals in free water mode was stopped. The calculation of LD _{50 was} carried out using the express method according to V. B. To Prozorovsky [Prozorovsky VB, Prozorovskaya MP, Demchenko VM The express method for determining the average dose efficiency and its errors // Pharmacology and Toxicology, 1978, - p.497-502]. LD ₅₀ for oral administration of 3-hydroxy and methyl derivatives and their pharmaceutically acceptable salts was calculated on the basis of published data on the effective therapeutic doses of the test objects and the coefficient of conversion of dose from person to rat, equal to 5.9. The objects of study were introduced at a fixed time of day. In control experiments, animals were injected with physiological saline, the volume of which was equivalent to the amount administered in the experimental groups. Given that the objects of study are mainly used for intravenous administration, this route of administration was also chosen as the main one in the experiment, a placebo in the form of a 0.9% NaCl solution was administered to the control group.

Table 1 Comparison of acute toxicity (LD ₅₀ , mg / kg) of various dosage forms of 3-hydroxy and methylpyridines and their derivatives, determined in rats. A drug Water solution Metabisulfite, 0.2% Lyophilic forms 3-hydroxypyridine oxalate Intraperitoneally 295.6 214.2 310.3 6-Trichloromethyl-2-chloropyridine (nitrapyrin) 240 g / l Intraperitoneally 1261.9 899.7 1312.7 3-hydroxypyridine malonate Intraperitoneally 893.0 Emoxipin Intravenously 233.5 233.5 Intraperitoneally 241.3 198.1 Mexidol Intravenously 244.1 186.23 305.4 Intraperitoneally 808.7 599 2-methyl-6-ethylpyridine Intraperitoneally 1296 899 1296 3- (N, N-dimethylcarbamoyloxy) -2-ethyl-6-methylpyridine succinate 20 g per 1 liter Intravenously 160.1 127.9 173.6 Intraperitoneally 175.5 Note: Toxicity and hazard class - respectively, the ability of the drug to cause poisoning and the degree of this ability. According to the degree of toxicity, substances are divided into 4 hazard classes. First: potent toxic substances, LD ₅₀ less than 1 mg of the drug per 1 kg of body weight. Second: highly toxic substances with LD ₅₀ to 200 mg / kg. Third: medium toxic substances with LD ₅₀ from 200 to 1000 mg / kg. Fourth: low-toxic substances with LD ₅₀ more than 1000 mg / kg. * - used a registered solution of emoxipin manufactured in Belarus with hydrochloric acid and water for injection (aqueous solution) and emoxipin. Russia with anhydrous sodium sulfite, sodium benzoate, monosubstituted potassium phosphate, disubstituted sodium phosphate, methyl cellulose (“+ metabisulfite”).

Characterizing the terminal stage of intoxication in the determination of LD50, it should be noted that the death of experimental animals in the vast majority of cases (8 out of 10) occurred within the first 20 minutes after the administration of all the studied substances. Consequently, acute mortality was 96.36%. In this case, the animal first showed signs of lethargy, turning into increased motor activity, after which there was a loss of posture, cramps, more pronounced on the hind limbs, and death. Only in 2 cases out of 55 did animals die on the second and third day, i.e. deaths with a significant latent period were observed in 3.64% of cases, and the clinical picture of the terminal stage of intoxication was similar to that described above. The registered clinical picture of the terminal stage of intoxication may indicate the primary toxic effect of the test substances on the central nervous system.

Example 6. A study of the stability of drugs by the method of “accelerated aging”. Samples of the preparations were stored at 55 ° C.

table 2 The results of the analysis of aging of various preparations of 3-hydroxy- and methylpyridines and their derivatives (pharmaceutically acceptable salts) for intravenous and intramuscular administration by the method of “accelerated aging” at 55 ° C. No. Dosage form Shelf life at 55 ° C Equivalent. storage period in conventional units Description Color Note one 3-hydroxy-6-methyl-2-ethylpyridine hydrochloride (emoxypine) 10 mg in 1 ml with sodium sulfite anhydrous, sodium benzoate, potassium phosphate monosubstituted, sodium phosphate disubstituted, methyl cellulose, water d / i. 46 days 1 year Transparent Colorless 3 years Colorless 138 276 5 years Transparent Colorless Colorless Amount of substance below the lower limit in the ampoule 2 Emoksipin rr d / in. 1% amp. 1 ml, No. 10 - 10 g per 1 liter. Other ingredients: hydrochloric acid 0.1 M - 20 ml, water for injection up to 1 liter. 46 days 1 year Transparent Colorless or not more intense 3 years Light yellow 138 6b 276 5 years Transparent green More intense 3 2-ethyl-3-methyl-6-hydroxypyridine succinate aqueous solution 50 g per 1 l 46 days 1 year Transparent slightly yellow Transparent green Colorless or not more intense 3 years 138 6b 5 years 276 more intense four 2-ethyl-3-methyl-6-hydroxypyridine succinate 50 g +1 g metabisulfite per 1 l 46 days 1 year Transparent Colorless 3 years Colorless 138 Amount of substance below the lower limit in the ampoule 5 years Transparent Colorless 276 Colorless 3 2-ethyl-3-methyl-6-hydroxypyridine lyophilisate succinate 50 g +5 g sodium chloride + water 46 days 1 year White lyophilized powder Colorless, transparent upon dissolution Preservation of the column and the amount of substance 3 years 138 276 5 years 5 3- (N, N-dimethylcarbamoyloxy) -2-ethyl-6-methylpyridine succinate 46 days 1 year Transparent Colorless 2 years Colorless 92 Amount of substance below the lower limit in the ampoule 136 3 years Transparent Colorless or slightly yellow Light yellow 6 3- (N, N-dimethylcarbamoyloxy) -2-ethyl-6-methylpyridine succinate 46 days 1 year White lyophilisir. powder White Transparent upon dissolution Preservation of the column and the amount of substance 3 years 138 276 5 years

The data obtained confirm the increase in stability in the case of the invented lyophilic forms of preparations based on derivatives of 3-hydroxy- and methylpyridines and their pharmaceutically acceptable salts.

Example 7. A comparative study of the pharmacological activity of the invented stable lyophilic forms of drugs based on derivatives of 3-hydroxy and methylpyridines and their pharmaceutically acceptable salts in their ability to increase the body's resistance to hypoxia. The study was conducted on white rats weighing 180-22 g. Acute hypobaric hypoxia was reproduced by raising animals in a flow chamber to a height of 11000 m at a speed of 50 m / s. Rat lifespan was evaluated at altitude (Wl) until a second agonal inhalation. All test dosage forms were administered intraperitoneally 15 minutes before simulated hypoxia: 2% aqueous solution of 3- (N, N-dimethylcarbamoyloxy) -2-ethyl-6-methylpyridine succinate at a dose of 20 mg / mass, lyophilisate 3- (N, N- dimethylcarbamoyloxy) -2-ethyl-6-methylpyridine succinate at a dose of 20 mg / kg weight, 5% aqueous solution of 2-ethyl-3-methyl-6-hydroxypyridine succinate - 100 mg / kg and lyophilisate 2-ethyl-3-methyl- 6-hydroxypyridine succinate at a dose of 100 mg / kg animal weight. It was shown that the lifetime increased under the influence of drugs by 215, 250, 145 and 140%, respectively. The data obtained confirm the conclusion about the preservation of pharmacological activity in the obtained lyophilic forms.

Thus, the developed pharmaceutical composition has high storage stability for 5 years, high pharmacological activity and allows the dissolution of the substance immediately before use and significantly reduces the risk of negative interactions with the drugs used simultaneously.

Claims (2)

1. A pharmaceutical composition for injection containing derivatives of 3-hydroxy- or methylpyridines, or their pharmaceutically acceptable salts, as an active ingredient, characterized in that it is in the form of a stable lyophilisate and contains the active component, sodium or potassium chloride as an auxiliary substance, water for injection in the following ratio, wt.%:
Derivatives of 3-hydroxy- or methylpyridines, or their pharmaceutically acceptable salts 7.0-20.0 Sodium chloride or potassium chloride 0.01-0.9 Water for injections Rest,
while the composition does not contain stabilizers such as metabisulfite, sodium bisulfite, Trilon B and obtained by freeze-drying by sublimation, followed by vacuum dehydration for at least 64 hours 2. The pharmaceutical composition according to claim 1, characterized in that the active substance contains: 3- (N, N-dimethylcarbomoyloxy) -2-ethyl-6-methylpyridine succinate, 3-methylpyridine succinate, 2-ethyl-6-methyl -3-hydroxypyridine hydrochloride, nitroxysuccinate 2-ethyl-6-methyl-3-hydroxypyridine, 3-hydroxypyridine oxalate, 6-trichloromethyl-2-chloropyridine (nitrapyrin), 3-hydroxypyridine malonate, 2-ethyl-6-methyl-3- hydroxypyridine succinate.