EA024773B1 - Liquid pharmaceutical composition, comprising hydroxybutanedioate 2-ethyl-6-methyl-3-hydroxypyridine - Google Patents

Abstract

The invention relates to a liquid pharmaceutical composition stable in storing, having an antihypoxic, stress-protective, nootropic, anticonvulsant and anxiolytic activity. The composition comprises hydroxyburanedioate 2-ethyl-6-methyl-3-hydroxypyridine, mannitol and water for injections. The composition can be used in therapy of acute stroke, acute intoxication by antipsychotic preparations, reduction of abstinence syndrome in alcoholism without an additional dilution.

Description

The invention relates to a storage stable liquid pharmaceutical composition for intravenous and intramuscular administration of 2-ethyl-6-methyl-3-hydroxypyridine hydroxybutanedioate having anti-ischemic, cerebroprotective, neurotropic and lipid-regulating activities.

BACKGROUND OF THE INVENTION

2-Ethyl-6-methyl-3-hydroxypyridine hydroxybutanedioate - the substance described in RF patent No. 2377237, is an inhibitor of free radical processes, has a membrane protective, antihypoxic, nootropic, anticonvulsant, anxiolytic effect, increases the body's resistance to stress.

The drug Ethoxidol®, the active ingredient of which is 2-ethyl-6-methyl-3hydroxypyridine hydroxybutanedioate, has anti-ischemic properties, improves blood flow in the ischemic zone, limits the area of ischemic damage, detects hypolipidemic effect, reduces the content of total cholesterol and low density lipoproteins (Lp: / / dg18.go8t1P7Ygau.gi/1i81g1t$M2.a8rh1YKed=14400&rad=2&1=dg18U1e№).

The drug Ethoxidol® increases the body's resistance to various damaging factors, to oxygen-dependent pathological conditions (shock, hypoxia and ischemia, cerebrovascular accident, intoxication with alcohol and antipsychotics (antipsychotics)). Ethoxidol® improves cerebral metabolism and blood supply to the brain, improves microcirculation and rheological properties of blood, and reduces platelet aggregation. It stabilizes the membrane structures of blood cells (red blood cells and platelets) during hemolysis.

The mechanism of action of the drug is due to its antioxidant, antihypoxic and membrane protective action. It inhibits lipid peroxidation, increases the activity of superoxide oxidase, increases the ratio of lipid protein, reduces the viscosity of the membrane, increases its fluidity. It modulates the activity of membrane-bound enzymes (calcium independent phosphodiesterase, adenylate cyclase, acetylcholinesterase), receptor complexes (benzodiazepine, GABA, acetylcholine), which enhances their ability to bind to ligands, helps preserve the structural and functional organization of biomembranes, and improves neurotransmitter transport.

The preparation Ethoxidol® in the form of a solution for injection contains in addition to the active substance 2-ethyl-6-methyl-3-hydroxypyridine hydroxybutanedioate (ethylmethylhydroxypyridine manate) target additives: ацет-acetyl-b-glutamic acid, glycine, 2-dimethylaminoethanol and edetate (Trilon B). The drug is indicated for acute cerebrovascular accidents, dyscirculatory encephalopathy, autonomic dystonia syndrome, mild cognitive impairment in neurotic and neurosis-like conditions, relief of withdrawal symptoms in alcoholism with a predominance of neurosis-like and autonomic-vascular dysfunction, acute drugs.

The drug Ethoxidol® is prescribed intramuscularly and intravenously (in a jet or drip). Doses are selected individually.

In acute cerebrovascular disorders, Ethoxidol® is prescribed in the first 2-4 days intravenously (drip) at a dose of 200-300 mg, then 100 mg intramuscularly 3 times a day. In case of discirculatory encephalopathy, Ethoxidol® is prescribed intravenously in a stream or drop dose of 100 mg 2-3 times a day for 10-14 days.

With the infusion method of administration, the drug should be diluted in a 0.9% sodium chloride solution to achieve the required level of isotonicity of the solution. The need for additional dilution is worn to the disadvantages of the well-known drug Ethoxidol®.

Also known is a solid dosage composition in the form of a tablet containing the active substance ethyl methylhydroxypyridine malate and target additives (RF patent No. 2377237, 2009). However, such a dosage form is often not suitable for treating patients after a heart attack and stroke. In addition, the presence of sugars in the pharmaceutical composition is undesirable and even dangerous for patients with diabetes mellitus.

The objective of the invention is the creation of a stable liquid dosage form of ethylmethylhydroxypyridine malate, which does not require additional dilution during its use.

- 1,024,773

Description of the invention

The problem is solved by a pharmaceutical composition having antihypoxic stress-protective, nootropic, anticonvulsant and anxiolytic activity, which consists of 2-ethyl-6-methyl-3-hydroxypyridine hydroxybutanedioate and mannitol stabilizer in the following ratio of components, wt.%:

2-ethyl-6-methyl-3-hydroxy pyridine hydroxybutanedioate 0.05 - 0.5

Mannitol 2-15

Water for injection rest

The technical result of the invention is to create a stable infusion solution that does not require additional dilutions for its use in therapeutic practice.

Proposed for the introduction of the inventive infusion solution mannitol (Ό-mannitol) hexatomic hydrocarbon alcohol, which is widely used in the pharmaceutical and food industries. In modern medicine, mannitol is considered mainly as an intravenously administered osmotic diuretic, a means of eliminating fluid from the body. In pharmaceuticals, mannitol is often used as an auxiliary, inactive substance.

In the claimed composition of the infusion solution, mannitol acts as a stabilizer for the molecule of ethyl methylhydroxypyridine malate, protecting hydrogen bonds and preventing its destruction. In addition, having the properties of an osmotic diuretic, mannitol in the infusion solution can increase the volume of circulating blood, increasing the anticonvulsant effect of ethyl methyl hydroxypyridine malate.

The ratio of ethylmethylhydroxypyridine malate and mannitol, at which stabilization of the solution occurs, was found experimentally.

Examples

The invention is illustrated by the following examples.

Example 1

In 90 l of water for injection, saturated with nitrogen, at a temperature of 25-30 ° C, 5.0 kg of mannitol is dissolved with stirring, mixed. To the resulting solution was added 0.1 kg of ethyl methylhydroxypyridine malate and stirred for 30 minutes until complete dissolution with continuous bubbling with nitrogen. In the resulting solution, the pH is adjusted to a value of 3.5-5.5 with a solution of sodium hydroxide or hydrochloric acid, then the volume is adjusted to 100 l with water for injection, filtered and poured.

The resulting solution contains, wt.%: Ethylmethylhydroxypyridine malate - 0.1; mannitol - 5.0; water for injection - the rest.

Example 2

In a similar way, a solution is obtained that contains, wt.%: Ethylmethylhydroxypyridine malate - 0.05; mannitol - 2.0; water for injection - the rest.

Example 3

By the method described in example 1, get a solution that contains, wt.%: Ethylmethylhydroxypyridine malate - 0.5; mannitol - 15.0; water for injection - the rest.

The infusion solution of the present invention remains stable for 2 years and is completely ready for use in acute cerebrovascular accidents, acute intoxication with antipsychotic drugs, relief of withdrawal symptoms in alcoholism and other conditions in which it is indicated.

The table shows the results of the stability study of the solution of the present invention. The batch number corresponds to the number of the example in the description of the invention. In all cases, the solution was packaged in orange glass vials of 100 ml each. Vials were stored in a dark place at a temperature of 25 ± 2 ° C.

- 2 jupe

The results of the study of the stability of the solution

No. party and Description Authentic st Transparent nost Color Mechanical inclusion pH Foreign impurities,% Osmo lar nost Pyrogen nost Sterile nost Quantitative determination, mg Colorless or slightly painted transparent liquid Spectro a photo metric; TLC The drug must be transparent The color of the drug should not be more intense than the standard VU _b In accordance with the requirements of RD 501-98 From 3.5 to 5.5 TLC, any impurity - not more than 0.5%, in total - not more than 1.0% 222 to 350 mOsm / l A drug should be pyrogen-free nym A drug should be sterile nym Ethoxidol content in 1 ml should be from 0.9 to 1.1 At the time of bookmarking for storage one Colorless transparent liquid Confirm given Transparent ny Withstands Withstands 4.15 One <0.5; £ <0.5 306 Pyrogen free ny Sterile ny 1,02 2 Also Also Also Also Also 4.05 One <0.5; £ <0.5 312 - Also 0.99 3 · "· 5.1 One <0.5; £ <0.5 297 - h <- 1.06 After 6 months of storage ] Colorless transparent liquid Transparent ny Withstands Withstands 4.1 One <0.5; £ <0.5 1.00 2 Also Also Also Also 4.0 One <0.5; £ <0.5 - - - 0.98 3 - "- - "- - "- 5.1 One <0.5; £ <0.5 - - • 1.05 After 1 year of storage one Colorless transparent liquid Transparent ny Withstands Withstands 4.1 One <0.5; £ <0.5 1.01 2 Also Also Also Also 4.0 One <0.5; £ <0.5 - - - 0.98 3 -to- -to- - "- 5.2 One <0.5; £ <0.5 - 1.05 After 1.5 years of storage one Colorless transparent liquid Transparent ny Withstands Withstands 4.05 two <0.5 each; £ <1.0 1.00 2 Slightly painted transparent liquid Also Also Also 3.95 two <0.5 each; £ <1.0 0.96 3 Also - - "- - "- 5.2 two <0.5 each; £ <1.0 1,04 After 2 years x injured one Slightly painted transparent liquid Confirm given Transparent ny Withstands Withstands 4.0 two <0.5 each; £ <1.0 298 Pyrogen-free ny Sterile ny 0.98 2 Also Also Also Also Also 3.9 two <0.5 each; £ <1.0 308 Also Also 0.94 3 - "- 5.3 two <0.5 each; £ <1.0 294 1,02 After 2 years and 3 months of storage one Slightly painted transparent liquid Transparent ny Withstands Withstands 4.0 two <0.5 each; £ <1.0 0.96 2 Also - Also Also Also 3.9 two <0.5 each; £ <1.0 - * 0.94 3 - - "- - "- 5.3 two <0.5 each; £ <1.0 • 0.98

CLAIM

Claims (2)

CLAIM 1. Liquid pharmaceutical composition with antihypoxic stress-protective, nootropic, anticonvulsant and anxiolytic activity, consists of 2-ethyl-6-methyl-3-hydroxypyridine hydroxybutanedioate and mannitol stabilizer in the following ratio, wt.%: 2-ethyl-6-methyl -3-hydroxypyridine hydroxybutanedioate - 0.05-0.5; mannitol - 2-15; water for injection - the rest. 2. Liquid pharmaceutical composition according to claim 1, characterized in that it has the following ratio of components, wt.%: 2-ethyl-6-methyl-3-hydroxypyridine hydroxybutanedioate - 0.1; mannitol - 5; water for injection - the rest.