Antidepressive medicinal agents for parenteral using based on pirlindole sulfonate salts

FIELD: medicine, pharmacy.

SUBSTANCE: invention relates to new medicinal agents for parenteral using based on an antidepressant agent pirlindole salts. Agent comprises 2,3,3a,4,5,6-hexahydro-8-methyl-1H-pyrazino[3,2,1-j,k]carbazole (pirlindole) sulfonate salts as an active substance, such as methane sulfonate or benzene sulfonate. The composition for intravenous or intramuscular injection comprises additionally citric acid and water taken in the definite ratios. Invention provides preparing an agent possessing good tolerance, low toxicity and resistance in storage.

EFFECT: improved and valuable medicinal and pharmaceutical properties of agent.

2 cl, 1 tbl, 4 ex


The invention relates to medicine, namely to medicines for parenteral use on the basis of sulfate salts antidepressant pirlindola, and can be used in psychiatric practice for the treatment of patients with depression.

The pirlindola represents a 2,3,3A,4,5,6-hexahydro-8-methyl-1H-pyrazino [3,2,1-j,k]carbazole and is known as a highly effective antidepressant ("Register of medicines of Russia", 9th edition, 2002, page 681), and its salt is a hydrochloride, produced in Russia under the trade name pirazidol, widely used in psychiatric practice.

Traditional salt - pirlindola hydrochloride is sparingly soluble in water and therefore is still the drug was limited to only its oral form, namely tablets 0.025 and 0.05, (Medmaravis "Drugs", ed. XIV, Moscow, "New wave", 2000, vol. 1, p.95-96).

At the same time in the hospital in cases of acute and severe depressive conditions requiring rapid therapeutic effects, as well as in drug-resistant forms of depression required antidepressant funds in injectable forms for intramuscular and intravenous (parenteral) administration. The use of an injectable use of non-oral administration of the drug, for example in cases of difficulty is swallowing tablets some sick or contraindications to the ingestion gastro-intestinal tract.

The present invention is the creation of medicines for parenteral use based on water-soluble salts pirlindola with the necessary therapeutic activity, good tolerability, low toxicity, stability during storage.

According to the invention the problem is solved by using as the water-soluble salts pirlindola his sulphonate salt of structural formula I, specifically methane-sulfonate (nelfinavir) pirlindola (Ia) or benzosulfimide (besilate) pirlindola (IB).

The choice of these salts is carried out by chemical, pharmacological and pharmaceutical research a large group of newly synthesized salts of a number of pyrazinamidase.

Sulphonate salt pirlindola (methanesulfonate and bansilalpet) can be obtained on an industrial scale. Starting compound to obtain these salts: pirlindola hydrochloride, methanesulfonate (in the synthesis of methansulfonate), and benzosulfimide (in the synthesis of benzosulfimide) are available substances.

To obtain these salts pirlindola hydrochloride by treatment with an aqueous solution of ammonia at room temperature into a pirlindola base is extracted with methylene chloride, the extract washed with water (until athelney reaction in the wash water) and treated with charcoal at room temperature. The charcoal is filtered off, washed with methylene chloride and then the solvent is distilled off under vacuum. The oily residue pirlindola base is dissolved in isopropanol and the resulting solution under stirring and external cooling of the poured solution methansulfonate (or benzosulfimide) in isopropanol.

Source components and temperature cooked medicines are necessary and sufficient to obtain sulphonate salts pirlindola required quality.

The following examples illustrate the method of obtaining sulphonate salts pirlindola of pirlindola reasons:

Example 1. Getting methansulfonate

2,3,3A,4,5,6-hexahydro-8-methyl-1H-pyrazino[3,2,1-j,k]carbazole (pirlindola methansulfonate).

To a solution of 33.6 g pirlindola Foundation in 70 ml of isopropyl alcohol was added a solution of 15,86 g 98,69%methansulfonate in 27 ml of isopropyl alcohol with such speed that the temperature of the reaction mixture did not exceed 40°C. the Reaction mass was stirred at 25°1 hour, filtered, washed with cooled to 3±1°With (2 x 15 ml) of isopropanol and acetone (2×20 ml), dried and receive 45,3 g pirlindola methansulfonate, so pl. 257-259°C (from aqueous isopropanol). Output 93,6%.

Found %: With 59,31N 6.73N 8.41S 10.16C15H18N2·CH4About3S
Calculated %:With 59,60;N, 6.88;N 8.69;S 9.94.

Example 2. Getting benzosulfimide 2,3,3A,4,5,6-hexahydro-8-methyl-1H-pyrazino[3,2,1-j,k]carbazole (pirlindola of benzosulfimide).

To a solution of 8.7 g of benzosulfimide in 50 ml of methylene chloride is added a solution of 11.5 g pirlindola Foundation in 140 ml of methylene chloride at 20-25°C, kept at this temperature for 1 hour. The residue is filtered, washed with methylene chloride (2×25 ml), dried at 70°C to constant weight and get 15 g pirlindola of benzosulfimide, so pl. 238-239°C (from water). Yield 77%.

Found %:With 65,31N 6.22N 7.41S at 8.62C15H18N2·C6H6O3S
Calculated %:With 65,59;H 6.29;N, 7.28;S 8.34.

Received sulphonate salt pirlindola - methanesulfonate and bansilalpet is suitable for the preparation of injection solutions.

According to the invention for injecting use the tool, sostojashhee active ingredient, water for injection and citric acid in the following ratio of components:

Sulphonate salt pirlindola
(methanesulfonate or bansilalpet)10,0-15,0 g
Citric acid0,08-0,1 g
Water for injectionTo 1000 ml

Thus, the concentration of the active substance in the solution is 1.0 to 1.5%.

Components are selected in the result of experimental studies and provide stability of solutions for 2 years. While it is preferable to use a 1.25% solutions of sulfate salts pirlindola having a pH from 3.3 to 4.5.

Injection solution according to the invention can be prepared by dissolving citric acid in pre-probabtionary nitrogen water for injection and subsequent dissolution of sulfate salt pirlindola with constant stirring and bring to the desired volume with water for injection. The resulting solution is filtered and poured into ampoules under aseptic conditions.

The following examples illustrate the method of preparation of injection solution of sulfate salts pirlindola:

Example 1.

Pirlindola methanesulfonate 10.0 g
Citric acid0.08 g
Water for injectionTo 1000 ml

The method of preparing the inventive means:

In a glass container with a capacity of 1.5 liters, equipped with a stirrer and a bubbler, place 800 ml of water for injection, contribute 0.08 g of citric acid and stir until dissolved. To the resulting solution was added 10.0 g pirlindola methane-sulfonate and lead to its dissolution under stirring and barbatii nitrogen. The resulting solution was adjusted with water for injection to 1000 ml, mix thoroughly and carry out the determination of the pH value, which should be 3.5 and 3.6. The solution pirlindola methansulfonate subjected to sterilizing filtration, filled into ampoules and sealed in a stream of nitrogen.

Get the solution pirlindola methansulfonate for injection, representing a clear, slightly coloured, sterile liquid containing pirlindola methansulfonate 0.01 g/ml, citric acid 0,00008 g/ml.

Example 2.

Pirlindola bansilalpet10.0 g
Citric acid0.09 g
Water for injectionTo 1000 ml

Preparation of the solution is performed by a method similar to example 1.

Example 3.

Pirlindola methanesulfonate15.0 g
Citric acid0.1 g
Water for injectionTo 1000 ml

Preparation of the solution is performed by a method similar to example 1.

Example 4.

Pirlindola methanesulfonate12.5 g
Citric acid0.09 g
Water for injectionTo 1000 ml

Preparation of the solution is performed by a method similar to example 1.

The biological activity of sulfate salts pirlindola studied in comparison with pirlindola hydrochloride and imipramine hydrochloride.

The study is based on tests that characterize specific antidepressant activity, as well as the overall pharmacological effects (effects on the cardiovascular system, the gastrointestinal tract, food consumption).

The study was subjected to aqueous solutions of sulfate salts pirlindola and Comparators in different doses.

1. Antidepressant activity of sulfate salts pirlindola in experiments on outbred white mice and rats.

1.1. Impact on duration of immobilization test "despair".

1.2. The action of reserpine (blepharoptosia).

1.3. Effect for the e to the action of amphetamine ("group toxicity").

1.4. Action 1-DOPA (hyperthermia).

1.5. Action 5-oksitriptofana (5-AHP crystal growth; shaking of the head).

1.6. Action of clonidine (aggression).

1.7. Action tremorine (hypothermia).

The results of these studies are shown in table 1.

The table shows that pirlindola methanesulfonate reduces the immobilization time, providing an activating effect on animals in behavioral testing "despair", reduces depressive action of reserpine, strengthens the Central effects of amphetamine and 1-DOPA increases aggression caused by clonidine, has virtually no effect on the action tremorine.

The nature and power of these tests pirlindola methanesulfonate similar to pirlindola hydrochloride and, like the latter, has a number of differences from imipramine. Thus, in contrast to imipramine pirlindola methanesulfonate enhances the effects of 5-AHP crystal growth and clonidine already after a single dose (imipramine enhances the action of only a large dose of 5-AHP crystal growth 300 mg/kg, and enhanced activity of clonidine is observed only when multiple introductions imipramine), it also increases group toxicity of amphetamine, whereas imipramine in this test is not active.

A significant difference salts pirlindola from imipramine is the lack of anticholinergic actions (no impact on hypothermic the step tremorine).

1.8. The effect on the Pressor effects of norepinephrine and tiramina in anesthetized rats.

Found that the Pressor effect of norepinephrine (20 g intravenous (IV) under the influence of pirlindola methansulfonate in doses 1-3-5 mg/kg in practically did not change.

Table 1

Comparative antidepressant activity of salts pirlindola and imipramine.
Preparations and dose mg/kgReduction immobilization test "despair" seconds m±mReduction blepharoplasty caused by reserpine (2.5 mg/kg b) the points m±mThe reduction of group cohesion toxicity induced by amphetamine (7.5 mg/kg s/C) % mortalityStrengthening hyperthermia induced by 1-DOPA (200 mg/kg/b). Rectal temperature °With m±mStrengthening shaking of the head, 5-AHP crystal growth (50 mg/kg/b) % of mice with shakingIncreased aggression from the hydrochloride (20 mg/kg/b). The number of contractions 2 mice within 1 h m±mReducing hypothermia caused by tremorine (20 mg/kg s/C). Rectal temperature °With m±m
pirlindola0186±5,63,8±0,13036,6±0,25521±5,63,3± 0,24
hydrochloride5108±11*2,0±0,26*no effect37,4±0,2*it reinforces34,4±0,33*
* The difference with the control was statistically significant at P<0,05

Pressor effect of tiramina (0.4 mg/kg/under the influence pirlindola methanol-fonate dose of 1 mg/kg intravenous (IV) practically does not change, at a dose of 3 mg/kg - short-amplified ˜ 30%, in a dose of 5 mg/kg increases by 60% (within 30 to 90 minutes).

The increased Pressor response tiramina caused irreversible monoamine oxidase inhibitors (MAOIS) phenelzine and tranylcypromine 200-300% and occurs within a few hours.

Short-term and insignificant compared with these MAOIS an increased Pressor response to tyramine does salt pirlindola more secure against "cheese" effect (hypertensive reaction to a number of food and drugs, containing tyramine and other amines).

1.9. Effect on bioelectric activity of the brain.

Sulphonate salt pirlindola have an activating effect on the spontaneous electroencephalogram, the ascending activating system of the brain, functional mobility of cortical neurons differ from imipramine and remind phenelzine, although inferior to the latter the expression of the activating steps. At the same time sulphonate salt pirlindola, like imipramine, have a stimulating effect on the limbic system, while phenelzine reduces her anxiety.

The ability salts pirlindola to enhance effects of 1-DOPA, 5-AHP crystal growth, tiramina testifies to their inhibiting effect on the inactivation of monoamines by inhibiting the activity of monoamine oxidase (MAO). Inhibit the maintenance MAO activity salts pirlindola election (MAO type A) and reversible (short-term).

2. General pharmacological properties of sulfate salts pirlindola (experiments on cats and rats)

2.1. Effects on the cardiovascular system.

2.2. Effect on the gastrointestinal tract.

In these experiments established that salt pirlindola not have cardiotoxic effect, celebrated in imipramine and other tricyclic antidepressants. In experiments on rats found that salt pirlindola at a dose of 20 mg/kg/causes only a slow heart rate, while all animals maintained sinus rhythm. Imipramine at a dose of 20 mg/kg causes a disturbance of the cardiac rhythm and in 30% of cases of cardiac arrest.

Salt pirlindola less than imipramine, reduced basal gastric secretion, do not reduce the evacuation function of the gastrointestinal tract, do not affect food consumption.

Thus, it is shown that parenteral in equimolecular doses sulphonate salt pirlindola on pharmacological properties do not differ from pirlindola hydrochloride.

The study of the acute toxicity of sulfate salts pirlindola was conducted on white mice of both sexes weighing 16,0-18,0, For ampoule solution pirlindola methansulfonate (1,25%) LD50when administered intravenously was 75 (67÷93) mg/kg, with the introduction of under the skin 295 (256÷339) mg/kg, for pirlindola hydroch oride, accordingly, 67 (61÷74) mg/kg and 267 (236÷302) mg/kg, for imipramine hydrochloride, respectively, 40 (28÷56) mg/kg and 229 (176÷297) mg/kg

Thus, the toxicity of sulfonates pirlindola similar toxicity pirlindola hydrochloride and less toxicity imipramine hydrochloride

Pharmacokinetics study.

A study of the content pirlindola in the serum of rats after oral administration in the form of salts: methansulfonate and benzosulfimide. A statistically significant difference in the concentration value of the analyte in the serum, and the dynamics of its changes by oral administration of two different salts no. The drug is rapidly absorbed into the bloodstream and rapidly excreted. The maximum concentration in the blood is observed after 30 min after injection, the period of preliminary - 5.5 hours

Thus, when compared with traditional salt pirlindola hydrochloride sulfonate salt pirlindola (methanesulfonate or bansilalpet) have the advantage of physico-chemical properties, which allows to obtain drugs in the form of a solution for parenteral use.

Pharmacological study of sulfate salts pirlindola allows us to conclude that parenteral their activity on all pharmacological indices of antidepressant response in the experimental is NTE develops quickly and clearly expressed.

Injectable dosage form based on sulphonate salts pirlindola (methansulfonate or benzosulfimide) significantly extends the treatment of mental illness, including in cases when it is difficult to use pills.

On the basis of experimental data recommendations on the use of these tools according to the invention in clinical trials for treatment of depression.

The means according to the invention can be administered intravenously or intramuscularly.

When intravenous drip injection daily dose of 50-150 mg (2-6 capsules a 1.25% solution) diluted in 250-500 ml of 5% aqueous glucose solution.

Depending on the condition of the patient, efficacy and tolerability of the drug patients intravenous sulfate salts pirlindola is for 5-15 days followed by transfer to intramuscular injection.

The lack of effectiveness and lack of side effects daily dose can be increased to 200 mg (8 capsules of 1.25% solution).

Intramuscular tool administered 1-2 times per day in doses of 50-150 mg (2-6 capsules a 1.25% solution) within 2-3-5 days; if necessary with simultaneous appointment of the interior tablets pirazidola.

Clinical trials pirlindola methanesulfonate in the form of solution for injection of 1.25 confirmed his pronounced anti-depressive effect in good tolerability.

1. For the treatment of depression by parenterale introduction, characterized in that it contains as active ingredient salt pirlindola (methosulphate or bansilalpet), citric acid water for injections in the following ratio of ingredients, g/ml water:

Salt pirlindola (methanesulfonate or
Citric acidof 0.08 to 1.0
Water for injectionTo 1000 ml

2. The tool according to claim 1, which contains as an active ingredient pirlindola methanesulfonate in the following ratio of ingredients, g/ml water:

Pirlindola methanesulfonate12,5
Citric acid0,09
Water for injectionTo 1000 ml


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