RU2755094C1 - Dosage form for injection in form of solution and stabilizer for its preparation - Google Patents

Abstract

FIELD: pharmaceuticals.

SUBSTANCE: group of inventions relates to the field of chemical and pharmaceutical industry and medicine, namely to the dosage form of an antioxidant and antihypoxic agent in the form of a solution for injection, characterized by the fact that it includes 2-ethyl-6-methyl-3-hydroxypyridine succinate, a stabilizer representing 2-hydroxy-2-propanesulfonic acid monosodium salt and water for injection with the following content of components in wt. %: 2-ethyl-6-methyl-3-hydroxypyridine succinate 2.0-15.0; 2-hydroxy-2-propanesulfonic acid monosodium salt 0.01-0.4; water for injection being the rest. The use of 2-hydroxy-2-propanesulfonic acid monosodium salt as a stabilizer of a solution for injection containing 2-ethyl-6-methyl-3-hydroxypyridine succinate is also presented.

EFFECT: expansion of the arsenal of medicines with improved quality indicators: high stability and lower toxicity.

3 cl, 20 tbl

Description

The invention relates to the pharmaceutical industry and medicine. The invention can be used as a drug in the form of an injection solution containing 2-ethyl-6-methyl-3-hydroxypyridine succinate for the treatment and prevention of various diseases and pathological conditions of the human body.

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

- heart failure;

- ischemic heart disease as part of complex therapy;

- acute disorders of cerebral circulation;

- consequences of acute disorders of cerebral circulation, incl. after transient ischemic attacks, in the phase of subcompensation as preventive courses;

- minor craniocerebral trauma, consequences of craniocerebral trauma;

- encephalopathy of various origins (discirculatory, dysmetabolic, post-traumatic, mixed);

- syndrome of vegetative dystonia;

- mild cognitive disorders of atherosclerotic genesis;

- anxiety disorders in neurotic and neurosis-like states;

- relief of withdrawal symptoms in alcoholism with a predominance of neurosis-like and vegetative-vascular disorders, post-withdrawal disorders;

- conditions after acute intoxication with antipsychotic drugs;

- asthenic conditions, as well as for the prevention of the development of somatic diseases under the influence of extreme factors and loads;

- exposure to extreme (stress) factors; and prevention:

- exacerbations of heart failure;

- exacerbations of coronary heart disease.

Known compositions based on 2-ethyl-6-methyl-3-hydroxypyridine succinate in the form of various dosage forms: solution for parenteral administration, tablets, capsules (RU 2419432, RU 2144822, RU 2145855), dressings (RU 2149648), etc.

The multifaceted use of 2-ethyl-6-methyl-3-hydroxypyridine succinate requires the creation of dosage forms with different rates of absorption, penetration of the active substance into the blood and maintaining its active concentration in the blood (from the fastest possible in emergency situations to prolonged with long-term treatment).

As a consequence of the relatively low oral bioavailability of drugs, drugs for injection are of particular interest, in particular, for intensive care of patients. To ensure maximum bioavailability of the active substance, accurate dosage, as well as intensive care of patients in cases where it is necessary to quickly create high concentrations of the drug in the blood, dosage forms for injection are most preferred.

Injectable drugs for use in clinics account for about 40%. Compared to other drugs, injectables have a number of advantages:

- speed of action, especially when administered intravenously;

- the possibility of administering a medicinal substance to an unconscious patient;

- the accuracy of the dosage of the medicinal substance.

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

Thus, a solution of 2-ethyl-6-methyl-3-hydroxypyridine succinate for injection is of particular interest. At the same time, 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. nitrogen or carbon oxide (IV). This method is generally accepted in the production of solutions of 2-ethyl-6-methyl-3-hydroxypyridine succinate and allows to 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 stabilizers with antioxidant properties, which is used as a salt selected from the group of sulfite stabilizers-antioxidants: sodium or potassium disulfite (metabisulfite), sodium or potassium sulfite , sodium or potassium hydrosulfite, sodium or potassium thiosulfate (see RU 2635759).

The closest analogue is the pharmaceutical composition described in RU 2419432, which has the following composition, wt. %:

2-ethyl-6-methyl-3-hydroxypyridine succinate 4.0-6.0 sodium metabisulfite 0.015- .045 water for injections up to 100.0

Used in the known solution of sodium metabisulfite is widely used in various industries, as well as in the chemical-pharmaceutical industry in order to stabilize easily oxidizing substances due to pronounced reducing properties. However, although the description of this solution indicates that the resulting solution is stable and has low toxicity, it is insufficient. So, it is known from the prior art that this excipient, when introduced into the body, has certain disadvantages, namely the ability to cause allergic reactions up to anaphylaxis, urticaria, bronchospasm, dyspeptic symptoms, etc. (M.N. Lessof, Adverse Reactions to Food Additives ).

In this regard, the issue of choosing a stabilizer in a medicinal product is relevant, which makes it possible to achieve the chemical stability of the system during the entire expected shelf life, but at the same time is characterized by a low risk of negative impact on the human body.

The objective of the invention is to develop a new injection form based on 2-ethyl-6-methyl-3-hydroxypyridine succinate with low toxicity.

The problem is solved by the composition of the dosage form for injection in the form of a solution, including 2-ethyl-6-methyl-3-hydroxypyridine succinate, a stabilizer, which is 2-hydroxy-2-propanesulfonic acid monosodium salt and water for injection with the following content of components in wt. %:

2-ethyl-6-methyl-3-hydroxypyridine succinate 2.0-15.0 2-hydroxy-2-propanesulfonic acid monosodium salt 0.01-0.4 water for injections rest

As a suitable antioxidant stabilizer, 2-hydroxy-2-propanesulfonic acid monosodium salt (Sodium acetone disulfite, CAS 540-92-1) was chosen having the following structural formula:

It was unexpectedly found that in the case of using acetone disulfite as an antioxidant of sodium, instead of sodium metabilfite used in the prototype, it is possible to improve antioxidant properties, as well as antimicrobial, and at the same time significantly reduce toxicity. The results of testing various antioxidants as stabilizers for parenteral solutions are presented in Table 1.

Sodium acetone disulfite can be used in an amount of up to 4 mg per unit dosage form in the form of 1 ml of solution.

Preferably, sodium acetone disulfite is contained in the solution for injection in an amount of 0.01-0.4 wt. %, most preferably 0.04 to 0.4 wt. %.

2-ethyl-6-methyl-3-hydroxypyridine succinate is contained in the solution for injection in an amount of 2-15 wt. %, most preferably 5 wt. %.

The invention allows to expand the arsenal of medicines with improved quality indicators. EFFECT: high stability and lower toxicity.

The possibility of carrying out the invention can be demonstrated by the examples presented below. Examples of formulations for injection solutions are shown in Tables 2-12.

Solutions for injection can be prepared in the following ways.

While stirring water for injection, 2-ethyl-6-methyl-3-hydroxypyridine succinate, sodium acetone disulfite are introduced into it. After complete dissolution, the solution is bubbled with nitrogen for 60 minutes. Next, the solution is packed into pre-sterilized ampoules and the solution in ampoules is sterilized by autoclaving (sterilization with saturated steam under pressure) at a temperature of 120-122 ° C under a pressure of 120 kPa for 45 minutes or at a temperature of 130-132 ° C under a pressure of 200 kPa for 20 min.

Table 13 shows the studied formulations with different contents of sodium acetone disulfite and 2-ethyl-6-methyl-3-hydroxypyridine succinate. Experimental data for studying their stability are presented in Tables 14-20.

The conducted studies of the stability and quality of the obtained solutions allow us to conclude that the solutions are stable during the entire shelf life with the preservation of the necessary quality characteristics. At the same time, the stabilizer used has not only reduced toxic properties, but also antimicrobial effect.

Thus, it was found that 2-hydroxy-2-propanesulfonic acid monosodium salt (Sodium acetone disulfite) can be effectively used as a stabilizer for injection solutions containing 2-ethyl-6-methyl-3-hydroxypyridine succinate.

Claims (4)

1. A dosage form of an antioxidant and antihypoxic agent in the form of a solution for injection, characterized in that it includes 2-ethyl-6-methyl-3-hydroxypyridine succinate, a stabilizer, which is 2-hydroxy-2-propanesulfonic acid, monosodium salt and water for injection with the following content of components in wt. %: 2-ethyl-6-methyl-3-hydroxypyridine succinate 2.0-15.0 2-hydroxy-2-propanesulfonic acid monosodium salt 0.01-0.4 water for injections rest 2. The dosage form according to claim 1, characterized in that it contains 2-hydroxy-2-propanesulfonic acid monosodium salt in an amount of 0.04-0.4 wt. %. 3. The use of 2-hydroxy-2-propanesulfonic acid monosodium salt as a stabilizer for an injection solution according to claim 1, containing 2-ethyl-6-methyl-3-hydroxypyridine succinate.