RU2359669C1 - Pharmaceutical composition in form of solution for injections, possessing cerebrovasodilating and nootropic activity, and method of its reception - Google Patents

Abstract

FIELD: medicine, pharmaceutics.

SUBSTANCE: pharmaceutical composition on the basis of a Vinpocetine and Pyracetamum combination in the form of a solution for injections possessing cerebrovasodilating and nootropic activity and the method of its reception are offered. The solution contains 0.1-0.5 wt % of Vinpocetinum and 5-40 wt % of Pyracetamum and auxiliary substances.

EFFECT: maintenance of more expressed synergy at treatment of the diseases bound to acute or chronic insufficiency of a cerebral circulation in a combination to stability of the form.

12 cl, 4 ex, 3 tbl

Description

The invention relates to medicine, specifically to a pharmaceutical composition in the form of an injection solution having cerebro-vasodilating and nootropic activity.

Ethyl ether (vinpocetine), which is used for cerebrovascular diseases of various origins, is widely used in medical practice (3α, 16α) -ebournamenine-14-carboxylic acid. It is used as a well-known cerebrovasodilator: it improves cerebral blood circulation, causes a slight decrease in systemic blood pressure, dilates the blood vessels of the brain, increases blood flow and improves the supply of oxygen and glucose to the brain. Increases the resistance of brain cells to hypoxia, facilitating the transport of oxygen and energy supply substrates to tissues (due to a decrease in the affinity of red blood cells for it, increased absorption and metabolism of glucose, switching it to an energetically more favorable aerobic direction). Improves microcirculation in the brain by reducing platelet aggregation, lowering blood viscosity, increasing red blood cell deformability.

It is known that in neurological practice in acute focal ischemic disorders of cerebral circulation (in the absence of hemorrhage), vinpocetine preparations are used intravenously. Initially, 0.01-0.02 g (1-2 ampoules) are introduced into 500-1000 ml of isotonic sodium chloride solution (drop infusion). If necessary, repeated (3 times a day) slow drip infusions are prescribed, then they switch to taking the drug inside (Mashkovsky M.D. “Medicines”, M., Novaya Volna LLC, 2002, v. 1, p. 390-391).

The injectable form of vinpocetine is described in EP 0305181, publ. 03/01/1989, the composition of the known composition includes, wt.%:

Vinpocetine 1,2 Vitamin C 0.5 Sodium pyrosulfate 0.4 Wine acid 2,4 Benzyl alcohol 3,5 Propylene glycol 92

In patent RU 2212890, publ. 09/27/2003, an infusion solution for improving cerebral circulation of the following composition, wt.%:

Vinpocetine 0.4-0.6 Ascorbic acid 0.04-0.06 Benzyl alcohol 0.9-1.1 Sodium Pyrosulfate 0.09-0.11 Sorbitol 7.0-9.0 Tartaric acid 0.4-0.6 Water for injections Rest

From patent RU 2232579, publ. July 20, 2004, a solution of vinpocetine is known having the following composition, wt.%:

Vinpocetine 0.25-1.0 succinic acid 0.165-1.5 Sodium chloride 0.088-0.092 Sodium Pyrosulfate 0.2-0.5 Vitamin C 0.05-0.5 Water Up to 1000 ml

Known 2-oxo-1-pyrrolidinacetamide (piracetam), which has a nootropic effect with very low toxicity. Piracetam has a positive effect on the metabolic processes of the brain, improves the integrative activity of the brain, improves microcirculation, without exerting a vasodilating effect, has a protective effect on brain damage caused by hypoxia, intoxication, electroshock, increases mental activity, enhances cerebral blood flow, does not have sedative, psycho-stimulating effect.

Various dosage forms of piracetam are known, including a solution for injection containing 1 g of the active substance in an ampoule (Mashkovsky M.D. Medicines, M., 1993, part 1, p.135).

Known nootropic agent in the form of a solution for injection containing piracetam and excipients - orotic acid, ethanolamine, citric acid and water for injection (US 4990513, publ. 05.02.1991).

In patent RU 2224514, publ. 02/27/2004, a nootropic agent in the form of a solution for injection is described, containing, wt.%: Piracetam 15-25, sodium acetate (0.08-0.11), acetic acid (up to pH 5.8) and water (the rest) .

It is known that piracetam enhances the effects of enhancing cerebral circulation [Drug Register of the Russian Federation (RLS 2001). M .: "Radar", 2000].

In patent RU 2126250, publ. 02/20/1999, the combined use of vinpocetine and piracetam in the form of infusions is described, which is included in the method of treating psychopathological syndromes of the borderline level of vascular sclerotic genesis, including intravenous drip of antidepressants at a dose of 40-50 mg or tranquilizers at a dose of 5-10 mg in combination with angioprotectors (including vinpocetine) at a dose of 2.0 ml, nootropics (including piracetam) at a dose of 5.0-10.0 ml and physiological saline in an amount of 200.0 ml. This invention relates to the field of border psychiatry and is not the object of the same purpose as the claimed invention.

The inventive pharmaceutical composition having cerebrovasodilating and nootropic activity, is intended for therapeutic treatment of patients with cerebrovascular accident in the early recovery period of ischemic stroke. In addition, in the presented description of the known method, there is no relationship between the technical result of the invention and the separate use of a combination of vinpocetine and piracetam, since this combination is added to a tranquilizer or antidepressant. It is possible that the combination of vinpocetine and piracetam can only enhance the effect of psychotropic drugs (tranquilizers and antidepressants).

The closest analogue of the claimed invention is a pharmaceutical composition in the form of a solid dosage form having cerebrovasodilating and nootropic activity, developed by Canonfarm Production CJSC and disclosed in patent RU 2262931, publ. 10/27/2005. Known pharmaceutical composition contains vinpocetine and piracetam as active substances. Due to the synergistic effect achieved, the composition is highly effective at lower doses of active components and high bioavailability.

In accordance with the invention disclosed in RU 2262931, Canonfarm Production CJSC previously developed, registered and approved for medical use the pharmaceutical cerebrovasodilating and nootropic preparation Vinpotropil ^® (registration number 002632 / 01-2003), produced in the form of capsules.

Vinpotropil ^{® is} indicated for cerebrovascular insufficiency (recovery period of ischemic and hemorrhagic stroke), neurotic and mental disorders in patients with and without cerebrovascular insufficiency, discirculatory, hypertensive and post-traumatic encephalopathy, menopausal syndrome, vascular diseases of the eye, and decrease in acute pain and asthenic syndromes.

The use of a pharmaceutical preparation in injectable form has several advantages over other forms of use, namely: the faster action of the pharmaceutically active substance due to the direct injection of the drug into the patient’s blood, the absence of irritating effects of the drug on the organs of the gastrointestinal tract. In some cases, the use of an injection form of a pharmaceutical preparation is very effective in case of impossibility of its ingestion.

It was also unexpectedly discovered that the drug Vinpotropil ^® (solution for injection), with the introduction of the total dose of vinpocetine and the total dose of piracetam similar to that achieved with the oral administration of the drug Vinpotropil ^® (gelatin capsules), provides, with its continuous use for 3 weeks. 2 times a day (in accordance with the instructions for use), a more pronounced clinical improvement, manifested in a decrease in such subjective neurological symptoms as headache, dizziness, tinnitus, sleep disturbances, fatigue and memory loss.

In addition, the objective of the present invention is to expand the arsenal of combined drugs for the therapeutic treatment of patients with cerebrovascular accident in the early recovery period of ischemic stroke.

The technical result of the invention is to obtain a stable pharmaceutical composition in the form of a solution for injection, which has a more pronounced, compared to the prototype, cerebrovasodilating and nootropic activity due to the selection of qualitative and quantitative composition of the components.

The problem is solved in that the pharmaceutical composition in the form of a solution for injection, having cerebro-vasodilating and nootropic activity, contains effective amounts of vinpocetine and piracetam and auxiliary substances that provide not only the necessary solubility of the active substances in the injection solution, but also the stability of the solution during storage.

The solution of this problem was complicated by the fact that vinpocetine and piracetam have a significant difference in physicochemical properties, in particular in solubility parameters. Vinpocetine is practically insoluble in water, while piracetam has good solubility in water. In this regard, it was necessary to select the composition of the injectable form so that both vinpocetine and piracetam were present in an amount sufficient to provide a therapeutic effect, and also ensure the stability of the drug during storage.

The selection of the components of the pharmaceutical composition was carried out experimentally. The content of vinpocetine and piracetam in terms of 100 wt.% Of the whole composition is: vinpocetine - 0.1-0.5 wt.%, Piracetam - 5-40 wt.%, The rest are excipients. As auxiliary substances, acids (succinic, ascorbic or aminoacetic (glycine)) can be used, as well as various sodium salts - metabisulfite, chloride, acetate or succinate.

The pharmaceutical composition in accordance with the invention is prepared as follows: in a 1000 ml volumetric flask, weighed portions of pre-ground and sieved vinpocetine and piracetam, succinic acid, ascorbic acid (or glycine), sodium metabisulfite (or sodium succinate, or sodium chloride, or sodium acetate) are placed ), 400 ml of water for injection is added, the mixture is dissolved at room temperature, the pH is adjusted to a value of not more than 4.0 with a 0.1 M hydrochloric acid solution, the volume of the solution is adjusted with distillation water ovannoy to 1 liter stirred.

The finished solution is filtered through a Millipore filter (pore size 0.22 μm), poured into ampoules with a capacity of 5 ml, sealed and sterilized.

Examples 1-3 are illustrative, confirming the possibility of carrying out the invention, without limiting the scope of the claimed claims.

Example 1

In a 1000 ml volumetric flask, 2 g of vinpocetine and 160 g of piracetam (pre-ground and sifted powders), 15 g of succinic acid, 5 g of ascorbic acid (or glycine), 5 g of sodium metabisulfite are added, 400 ml of water for injection are added, the mixture is dissolved at room temperature, adjust the pH to not more than 4.0 with a 0.1 M hydrochloric acid solution, adjust the volume of the solution with distilled water to 1 L, mix, pour into 5 ml ampoules, seal and sterilize.

Example 2

2 g of vinpocetine and 400 g of piracetam (pre-ground and sieved powders), 4 g of succinic acid, 2 g of ascorbic acid, 2 g of sodium chloride are added to a 1000 ml volumetric flask, 400 ml of water for injection are added, the mixture is dissolved at room temperature, The pH is adjusted to a value of not more than 4.0 with a 0.1 M hydrochloric acid solution, the volume of the solution is adjusted to 1 liter with distilled water, mixed, poured into ampoules with a capacity of 5 ml, sealed and sterilized.

Example 3

In a 1000 ml volumetric flask, 2 g of vinpocetine and 200 g of piracetam (pre-ground and sifted powders), 0.8 g of succinic acid, 0.4 g of ascorbic acid, 0.4 g of sodium acetate are added, 400 ml of water for injection are added, Dissolve the mixture at room temperature, adjust the pH to not more than 4.0 with a 0.1 M hydrochloric acid solution, adjust the volume of the solution with distilled water to 1 L, mix, pour into 5 ml ampoules, seal and sterilize.

Example 4 shows the data of a comparative study of the effectiveness of the drug Vinpotropil ^® (solution for injection), obtained in accordance with the present invention, and the drug Vinpotropil ^® (gelatin capsules), obtained in accordance with RU 2262931, confirming the achievement of the specified technical result.

Example 4

Characteristics of the examined patients.

The study of the effectiveness of the drug Vinpotropil ^® included 160 people (87 men and 73 women) aged 40 to 74 years (average age 59.2 years) in accordance with the inclusion and exclusion criteria (Table 1).

Table 1 Study inclusion and exclusion criteria Criteria for inclusion in the study: Early recovery period of ischemic stroke (from 4 weeks to 6 months) Age from 40 to 70 years Study exclusion criteria: The presence of severe somatic pathology Pronounced cognitive and emotional-volitional disorders Pronounced speech impairment Use up to 3 months from the start of the study of drugs that included vinpocetine and piracetam

115 patients suffered an ischemic stroke in the carotid pool, 45 patients - in the vertebral-basilar pool. The periods from the development of a stroke corresponded to the early recovery period (from the 4th week to 6 months). The causes of cerebrovascular disorders were atherosclerosis of cerebral or precerebral arteries, hypertension, cardiac arrhythmias, or a combination thereof. In all patients, the diagnosis of cerebral stroke was confirmed by computed tomography or magnetic resonance imaging.

Patients received the same 3-week course of therapy, differing only in one component (8 groups):

Group I (20 patients, of which 12 men and 8 women, average age 55.9 ± 3.4 years), received 2 capsules of Vinpotropil ^® (5 mg / caps. Of vinopocetin, 400 mg / caps. Of piracetam) 2 p. / day, orally;

Group II (20 patients, of which 10 women and 10 men, average age 56.4 ± 3.2 years) received only vinpocetine at a dose of 20 mg / day, orally;

Group III (20 patients, including 9 women and 11 men, average age 53.1 ± 3.1 years) received only piracetam at a dose of 1600 mg / day, orally;

Group IV (20 patients, of which 10 men and 10 women, average age 57.0 ± 2.3 years) received vinpocetine at a dose of 20 mg / day and piracetam at a dose of 1600 mg / day, orally;

Group V (20 patients, of which 8 men and 12 women, average age 60.0 ± 3.3 years) received injections of the composition of vinpocetine and piracetam in accordance with the present invention (1 ml of the preparation according to the invention 2 r./day);

Group VI (20 patients, of which 10 men and 10 women, average age 64.0 ± 2.3 years) received 1 ml of a 0.5% solution of vinpocetine 2 r./day in the form of injections;

Group VII (20 patients, 11 of them men and 9 women, average age 63.7 ± 2.8 years) received 1 ml of a 40% solution of piracetam 2 r./day in the form of injections;

Group VIII (20 patients, of which 12 men and 8 women, average age 61.7 ± 4.3 years) received 1 ml of a 40% solution of piracetam 2 r. / Day and separately 1 ml of a 0.5% solution of vinpocetine 2 r. / day in the form of injections.

Research Methods:

All patients on the 1st and 21st day of the study evaluated the neurological and neuropsychological status. In the study of neurological status, a severity assessment of subjective symptoms was carried out: headache, dizziness, tinnitus, sleep disturbance, fatigue, and the degree of memory loss. To do this, we used 5-step score rating scales with standardized criteria for assessing the severity of each subjective symptom (from 0 (no violations) to 4 (gross violations)) (the results are presented in table 2). To assess attention, a Bourdon test was used (Table 3).

Results and discussion.

2 patients of the main group and 5 people from the comparison groups were excluded from the study, due to the need for correction of standard therapy, not associated with the development of side effects. In 5% of patients receiving Vinpotropil ^® in the form of a solution for injection, the appearance of pain in the stomach and dyspeptic symptoms was noted, while similar complaints were noted in 10-20% of patients of comparison groups I and IV.

table 2
Dynamics of the average score in the severity of subjective symptoms Group number I II III IV V VI VII VIII Before Before Before Before Before Before Before Before After After After After After After After After Headache 2,4 2.1 1.9 2,3 2.5 2.1 2.0 2,4 1,2 1.7 1,6 1.3 1,1 1,5 1,6 1,2 % meas. 50.0% * 19.0% * 15.8% 43.5% * 56.0% * 28.6% * 20.0% * 50.0% * Dizziness 1.9 1,6 1.7 1.9 1.8 1,6 1.8 1.8 1,0 1,2 1.4 1,2 0.8 1.4 1.4 0.9 % meas. 47.4% * 25.0% * 17.6% 36.8% * 55.6% * 12.5% 22.2% * 50.0% * Noise in the head 1,5 1,5 1.3 1,5 1.4 1,6 1.4 1.4 0.8 1,1 1,0 0.9 0.6 1,2 1,1 0.9 % meas. 46.7% * 26.7% * 23.1% * 40.0% * 57.1% * 18.8% * 21.4% * 35.7% * Fatigability 2.2 2.1 2.0 2.2 2,3 2.2 2.0 2.2 1,5 1.7 1.8 1,6 1,0 1.4 1,6 1.3 % meas. 31.8% * 19.0% * 10.0% 27.3% * 56.5% * 36.4% * 20.0% * 40.9% * Memory impairment 1.8 1.8 1.9 1.8 2.2 1.8 1.7 1.9 1.3 1,6 1.4 1.4 0.9 1.4 1,0 1,1 % meas. 27.8% * 11.1% 26.3% * 22.2% * 59.1% * 22.2% * 41.2% * 42.1% * Sleep disturbance 1.9 1,6 1.7 2.0 1,6 1.7 1,6 1.9 1,1 1,2 1.3 1.3 0.7 1,1 1,2 0.8 % meas. 42.1% * 25.0% * 23.5% * 35.0% * 56.3% * 35.3% * 25.0% * 57.8% * - differences before and after the course of treatment are significant (p <0.05)

From the data given in table 2, it can be seen that, although in the groups receiving vinpocetine and piracetam in capsules (as a combined preparation of Vinpotropil ^® or separately), as well as in the group receiving combination therapy, which included injections of piracetam and vinpocetine (at different points in time ), there was also a decrease in the average rating score for assessing the severity of headache, dizziness, noise in the head, sleep disturbances, memory loss and increased fatigue, the most distinct positive dynamics of pain GOVERNMENTAL observed in group V, receives an injection of vinpocetine and piracetam compositions according to the present invention.

The results of attention testing (attention productivity, performance accuracy indicator, attention productivity indicator) of the examined patients are presented in table 3.

Table 3
Attention recovery dynamics Indicator I II III IV V VI VII VIII Attention Productivity 130.3 135.2 133.6 142.1 137.8 133.5 129.0 139.7 155.3 140.1 145.2 150.0 176.4 147.1 149.8 158.1 % meas. 19.2% * 3.6% 8.7% 5.6% 28.0% * 10.2% 16.1% 13.2% Performance accuracy indicator 0.81 0.87 0.83 0.85 0.80 0.86 0.78 0.83 0.90 0.90 0.86 0.92 0.97 0.9 0.85 0.93 % meas. 11.1% 3.4% 3.6% 8.2% 21.3% * 4.7% 9.0% 12.0% Attention Productivity Index 640 630 650 655 646 636 650 630 688 659 671 683 700 670 680 680 % meas. 7.5% 4.6% 3.2% 4.3% 8.4% 5.3% 4.6% 7.9% * - differences before and after the course of treatment are significant (p <0.05)

From the data presented, it can be seen that patients initially had a significant disorder of attention, manifested by instability and exhaustion, up to the impossibility of concentrating on any type of activity. After the treatment, the indicators tended to improve, but did not reach normal values. Moreover, the differences were significant only in patients of the main group.

Thus, after a 3-week course of injections of the drug Vinpotropil ^® (solution for injection), a significantly more pronounced positive dynamics of the main neurological and neuropsychological parameters was observed in comparison with the same course of the drug Vinpotropil ^® (gelatin capsules), and with the course including the introduction either vinpocetine or piracetam (or their separate administration at different times). The closest results were obtained with the separate administration (at different points in time) of vinpocetine (as an injection) and piracetam (also as an injection), however, in comparison with these types of therapy, the drug Vinpotropil ^® (injection) obtained in accordance with the claimed invention, had an unexpectedly excellent cerebrovasodilating and nootropic effect in the early recovery period of ischemic stroke.

Claims (13)

1. A pharmaceutical composition having cerebro-vasodilating and nootropic activity, containing vinpocetine and piracetam in an effective amount and excipients, characterized in that it is made in the form of a solution for injection. 2. The pharmaceutical composition according to claim 1, characterized in that the content of vinpocetine is 0.1-0.5 wt.%. 3. The pharmaceutical composition according to claim 1, characterized in that the content of piracetam is 5-40 wt.%. 4. The pharmaceutical composition according to claim 1, characterized in that as auxiliary substances contains one or more acids selected from the group consisting of succinic acid, ascorbic acid or aminoacetic acid (glycine). 5. The pharmaceutical composition according to claim 1, characterized in that as auxiliary substances it contains one or more sodium salts selected from sodium chloride, sodium metabisulfite, sodium acetate and sodium succinate. 6. The pharmaceutical composition according to claim 4, characterized in that the succinic acid content is 0.1-1.5 wt.%. 7. The pharmaceutical composition according to claim 4, characterized in that the content of ascorbic acid is 0.1-1.5 wt.%. 8. The pharmaceutical composition according to claim 4, characterized in that the glycine content is 0.1 to 1.5 wt.%. 9. The pharmaceutical composition according to claim 5, characterized in that the sodium chloride content is 0.1-1.5 wt.%. 10. The pharmaceutical composition according to claim 5, characterized in that the sodium content of metabisulfite is 0.1 to 1.5 wt.%. 11. The pharmaceutical composition according to claim 5, characterized in that the sodium content of succinate is 0.1-1.5 wt.%. 12. The pharmaceutical composition according to claim 5, characterized in that the sodium acetate content is 0.1-1.5 wt.%. 13. A method of obtaining a pharmaceutical composition according to any one of claims 1 to 12, characterized in that
a) weighed portions of vinpocetine, piracetam, succinic acid or its pharmaceutically acceptable salt (in terms of succinic acid), ascorbic acid (or glycine), sodium metabisulfite (or sodium chloride, or sodium acetate) are crushed, sieved through a sieve and placed in a volumetric flask 1000 ml;
b) add 400 ml of water for injection;
c) dissolving the mixture at room temperature;
g) adjust the pH to a value of not more than 4.0 using a 0.1 M solution of hydrochloric acid;
d) adjust the volume of the solution with distilled water to 1 l;
e) mix;
g) poured into ampoules;
h) sealed;
i) sterilized.