EA009666B1 - Pharmaceutical composition exhibiting a cerebral vasodilatation and nootropic activity - Google Patents

Abstract

The invention relates to medicine, more specifically to a vinpocetine and pyracetam pharmaceutical composition which is embodied in the form of a solid dosage form and exhibits a cerebral vasodilatation and nootropic activity. The inventive vinpocetine and pyracetam composition is used in the form of ingredients and pharmaceutically acceptable carriers. Said composition contains 0.0045-0.150 g of vinpocetine and 0.36-1.2 g of pyracetam as active components and is efficient for therapeutic treatment due to a large possibility to modify the active component ratio thereof.

Description

The invention relates to the field of the chemical-pharmaceutical industry, specifically to a pharmaceutical composition having cerebro-vasodilating and nootropic activity.

Ethyl ether (vinpocetine), which is used for cerebrovascular diseases of various origins, is widely used in medical practice (3a, 16a) -eburnamenine-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 (Russian Drug Register (RLS 2002). M: RLS, 2002, p. 205).

Known solid dosage form of vinpocetine in the form of tablets, including vinpocetine and excipients, mh: vinpocetine - 1.0; colloidal silicic acid - 0.25; starch 19.25; lactose - 28.0; talc - 1.0; magnesium stearate - 0.5 (EP 0305181, 1989). The drug has a low ratio of active substance to target additives, which leads to an increase in the duration of the course of treatment and the introduction into the body of a large amount of talcum adversely affecting the body.

Known drug vinpocetine in the form of a tablet containing (mh): vinpocetine - 1.0; lactose 22.8; microcrystalline cellulose - 2.7; magnesium stearate - 0.54 (EP 0689844, 1996). This dosage form is characterized by a slow release of vinpocetine (less than 20% within an hour).

Known drug for improving cerebral circulation vinpocetine-acre tablets (RF patent 2155039, 2000). It is made in the form of tablets and contains vinpocetine as an active substance, and starch, lactose, stearic acid salt and silicon-containing compound (aerosil) as the pharmaceutically acceptable excipients in the following ratio of ingredients, parts by weight: vinpocetine - 1.0; Aerosil - 0.3-3.64; starch - 4.3-12.4; the stearic acid salt is 0.050.2.

For more than 20 drugs registered in the Russian Federation under 6 trade names, the dosage form of the substance of vinpocetine is tablets or solutions for infusion (Russian Drug Register (RLS 2001). M: RLS, 2000). All of them to a greater or lesser extent have the noted drawbacks characteristic of the tablet form and realize only pharmacological effects inherent in the substance of vinpocetine.

Known 2-oxo-1-pyrrolidinacetamide (piracetam), which has a nootropic effect with very low toxicity: it 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 in case of damage the brain caused by hypoxia, intoxication, electric shock, increases mental activity, enhances cerebral blood flow, does not have a sedative, psycho-stimulating effect (Re Histogram of Medicines of Russia (RLS 2001). M.: “RLS”, 2000, p. 678).

Known drug piracetam in capsules containing 0.4 g of piracetam in 1 capsule (Register of medicines of Russia (RLS 2001). M: "RLS", 2000, S. 678).

Known drug piracetam-richter in tablets containing 0.4 g of piracetam in 1 tablet (Vidal Handbook. Medicines in Russia: Handbook. M: AstraFarmServir, 2005, B-766).

The objective of the invention is the creation of a new combined preparation in solid dosage form having both cerebro-vasodilating and nootropic activity, increasing the effectiveness of the active substances in combination in the treatment of diseases caused by cerebrovascular disorders due to a synergistic effect.

The problem is solved in that the pharmaceutical composition in the form of a solid dosage form having cerebro-vasodilating and nootropic activity contains vinpocetine and piracetam and pharmaceutically acceptable carriers as active ingredients in the following content of active ingredients, g:

Vinpocetine 0.0045-0.0150

Piracetam 0.36-1.2

The content of vinpocetine and piracetam in terms of 100 wt.% Of the whole composition is vinpocetine - 0.29-2.83 wt.%, Piracetam - 75.4-77.7 wt.%, The rest are pharmaceutically acceptable carriers and excipients.

As pharmaceutically acceptable carriers and excipients, for example, lactose, stearic acid and its salts, preferably calcium or magnesium, crystalline sorbitol, polyvinylpyrrolidone, sodium lauryl sulfate, cellulose derivatives and other pharmaceutically acceptable carriers and excipients can be used.

According to the invention, the composition may be in the form of capsules and tablets, preferably

- 1 009666 in capsule form.

Capsules are prepared using the following technology. For example, powders of vinpocetine, piracetam, milk sugar are thoroughly mixed for 20-30 minutes, the stearic acid salt is added and mixed for another 20 minutes. The resulting mixture is Packed in hard gelatin capsules. The contents of the capsules is a white or almost white powder, has a flowability of 8.7 ± 0.6 g / s and a bulk density of 778 ± 18 kg / m ³ .

The resulting capsules were tested for authenticity and other requirements according to GF XI. So the dosage uniformity was 7.5% (with a norm of 10.0%), disintegration - 9.5-18 min (with a norm of not more than 30 min), release in 45 minutes - 81-88% (with a norm of at least 75% )

A method for preparing a pharmaceutical composition of the present invention in the form of tablets includes the steps of mixing the active principle with basic excipients, wet and dry granulation, dusting of dry granulate and tabletting. The disintegration of the tablets was less than 3 minutes (normal - up to 15 minutes), solubility - more than 80 wt.% For 30 minutes (norm at least 75 wt.% For 45 minutes), strength - 108-109 N, abrasion - less than 1 wt. % (normal to 3 wt.%).

In foreign pharmacopoeias, a similar pharmaceutical composition is not described, developed on the basis of data obtained by analyzing the pilot industrial series of the drug developed by ZAO Canonfarm Production and laid down in the basis of the regulation for the production of drugs. This composition allows to increase the effectiveness of therapeutic treatment of the patient due to selected amounts of active ingredients and wide possibilities for varying the ratio between them, as well as a synergistic effect.

According to the invention, Canonfarm Production CJSC developed, registered and approved for medical use the pharmaceutical preparation Vinpotropil (registration number 002632 / 01-2003).

The pharmaceutical preparation Vinpotropil contains 0.005 g of vinpocetine and 0.4 g of piracetam as active ingredients, as well as excipients lactose and calcium stearate. The drug is made in the form of capsules.

The invention is illustrated by the following examples.

Table 1 The composition of the compositions made in the form of capsules

Option No. Ingredients No. of composition and the content of ingredients in the capsule, g one 2 3 4 Vinpocetine 0.0045 0.0045 0.0055 0.0055 I Piracetam 0.3600 0.4400 0.3600 0.4400 Lactose 0,0990 0,1210 0,0990 0,1210 Calcium stearate 0.0045 0.0055 0.0045 0.0055 5 6 7 8 Vinpocetine 0.0045 0.0045 0.0055 0.0055 eleven Piracetam 0.3600 0.4400 0.3600 0.4400 Sorbitol Crystal 0.0660 0,0800 0.0660 0,0800 leaf Polyvinylpyr 0,0330 0,0400 0,0330 0,0400 roledon A mixture of magnesium stearate with sodium lauryl sulfate (80:20, in% of May.) 0.0032 0.0038 0.0032 0.0038 nine 10 AND 12 Vinpocetine 0.0056 0.0056 0.0150 0.0150 III Piracetam 0.4500 1,2000 0.4500 1,2000 Cellulose 0.0620 0.1600 0.0620 0.1600 Collidon Cb 0.0210 0,0330 0.0210 0,0330 Stearic acid 0.0010 0.0030 0.0010 0.0030 new

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table 2

The composition of the compositions made in the form of tablets

Ingredients No. of composition and content of ingredients in a tablet, g

III

thirteen 14 fifteen sixteen Vinpocetine 0.0056 0.0056 0.0150 0.0150 Piracetam 0.4500 1,2000 0.4500 1,2000 Sorbitol crystalline 0,1200 0.1800 0,1200 0.1800 chesky A mixture of polyvinyl pyrrolidones: - collidon 30 0,0560 0.1500 0,0560 0.1500 - collidon 0.0220 0,0330 0.0220 0,0330 Magnesium stearate 0.0012 0.0036 0.0012 0.0036

Table 3

Quality indicators of compositions No.

com position tions Disintegration, min Solubility,% in 30 min (norm 75% per 45 min) Strength, N Abrasion,% May. one sixteen 73.0 - - 2 eighteen 71,4 - - 3 eighteen 70.8 - - 4 17 71.5 - 5 10.0 72.8 - 6 10.0 73.5 - 7 9.5 74.8 - 8 9.5 73,2 - nine 10.5 74.1 - 10 10.0 73.8 - eleven 10.5 72.5 - 12 10.5 74.0 - thirteen 2,5 82.9 108 0.1 14 2,5 84.8 109 0.13 fifteen 2.0 87.5 108 0.12 sixteen 2,5 84.8 108,5 0.2

- 3 009666

Table 4 The results of the analysis of model mixtures of Vinpotropil according to the invention in capsules

ί

Name

Vinpocetine Piracetam Excipients

Vinpocetine Piracetam Fillers Vinpocetine Piracetam Fillers

Vinpocetine Piracetam Fillers Vinpocetine Piracetam Fillers Vinpocetine Piracetam Fillers Vinpocetine Piracetam Fillers

It is put in model mix on one capsule, g

0.0050

0.4000 to a mass of 0.5200

0.0054

0.3700 to a mass of 0.5200

0.0046

0.4300 to a mass of 0.5200

0.0050

0.4300 to a mass of 0.5200]

0.0046

0.400 to a mass of 0.520

0.0050

0.4300 to a mass of 0.520

0.0046 '

0.400 to a mass of 0.520

Determined by Vinpocetine, g

0,004936

0.4093

0.00530

0.3611

0.00471

0.4215

0,00493

0.4431

0.0472

0.3928

0,00492

0.4176

0.00466

0.4108

Relative: relative error,%

-1.26 +2.32

-1.84

-2.41

-1.39 +3.04 + 2.67

-1.81

Notes:

1. Model mixtures were prepared based on 10 capsules.

2. A determination is made of the authenticity of vinpocetine in a combined preparation by HPLC simultaneously with the determination of its quantitative content in the preparation. The same method is used to determine the authenticity of piracetam.

Table 5

Study of the release of vinpocetine from Vinpotropil according to the invention in capsules

Series No. The content of vinpocetine in capsule g The amount of xanthones 15 minutes 30 minutes 45 minutes G % g % g % 010701 0.00522 0,00261 50,0 0,00373 71.5 0,00437 83.8 020701 0.00515 0,00248 48.1 0,00361 70.1 0.00435 84.5 030701 0,00491 0.00224 45.7 0.00345 70.3 0.00431 87.8 040701 0,00502 0,00222 44.3 0,00346 68.9 0,00406 80.9 050701 0,00496 0,00249 50,2 0.00367 74.0 0.00411 82.8 Mean, % 47.7 ± 2.5 71.00 + 2.0 84.0 ± 3.2

A study was conducted on the effectiveness of the drug Vinpotropil for synergies of the claimed pharmaceutical composition of vinpocetine and piracetam.

Characteristics of the examined patients.

The study of the effectiveness of the drug Vinpotropil included 90 people (48 men and 42 women) aged 42 to 70 years (average age 56.2 years) in accordance with the inclusion and exclusion criteria (Table 6).

- 4 009666

Table 6 Criteria for inclusion and exclusion from the study

Study Criteria

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

The use of drugs, including vinpocetine and piracetam of the patient, suffered an ischemic stroke in the carotid pool within 18 months from the start of the study, and 18 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 the 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 a standardized 3-week course of therapy, differing only in one component.

The group (main) consisted of 30 patients (17 men and 13 women, average age 55.9 ± 3.4 years) who received 2 capsules of Vinpotropil 3 times a day orally;

Comparison groups.

Group - 20 patients (10 women and 10 men, average age 56.4 ± 3.2 years) received only vinpocetine at a dose of 30 mg / day orally;

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

Group - 20 patients (10 men and 10 women, average age 57.0 ± 2.3 years) received vinpocetine at a dose of 30 mg / day and piracetam at a dose of 1600 mg / day orally.

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 the 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)). To assess attention, a Bourdon test was used. The dynamics of the levels of depression, anxiety and hypochondria were studied using the Beck scale, tests of Spielberg and Sheehan.

Results and discussion.

2 patients of the main group and 6 people from the comparison groups were excluded from the study. The reason in most cases was the need for correction of standard therapy, not associated with the development of side effects. Only in 5% of patients receiving Vinpotropil, the appearance of pain in the stomach and dyspeptic symptoms was noted, while similar complaints were noted in 20% of patients in the 4 comparison groups who received vinpocetine and piracetam at the same time. This is probably due to the mechanical effect exerted by the increased number of tablets.

Against the background of the therapy, a positive dynamics of the patient's condition was noted in the form of a regression of subjective symptoms (Table 7).

- 5 009666

Table 7

Dynamics of the average score in the severity of subjective symptoms

Group 1 Group 2 Group 3 Group 4 before after BEFORE after BEFORE after before after Headache 2.1 1.4 ’ 2.0 1,6 1.9 1,6 2.1 1,5 ' 4 sz% 4 29% Dizziness 1,6 0.9 ’ 1,5 1, o ' 1,6 1.3 1,5 1,1 ' 4 44% 4 sz% 4 27% Noise in the head 1,2 0.9 1.3 0.9 1.3 1,0 1.3 1,0 Fatigability 2,3 1.4 ’ 2.0 1,5 2.2 1.4 ’ 2.1 1.4 ’ 4 39% 4 36% 4 sz% Decline 1.8 1.2 * 1.8 1,5 1.9 1.3 ’ 1.7 1.2 * of memory 4 sz% 4 32% 4 29% Sleep disturbance 1,6 0.9 ’ 1.7 1, G 1,6 1,2 1,5 4 44% 4 35% 4 40%

* - differences before and after treatment are significant (p <0.05)

In the main group (receiving Vinpotropil), there was a significant (p <0.05) decrease in both the average rating score for assessing the severity of headache, dizziness, memory loss and increased fatigue, as well as the number of patients whose assessments for this indicator exceeded one point, those. the complaint is absent or rarely bothers. In this group, a significant difference was revealed in the distribution of patients according to the severity of complaints from 0 to 4 for symptoms: headache, dizziness and fatigue (p <0.05). In comparison groups, there was a less distinct positive dynamics of the state.

The results of checking the attention of the examined patients are presented in table. 8. The dynamics of recovery of attention

Table 8

Index Group 1 Group 2 Group 3 Group 4 before after before after before after before after Attention Productivity 114 135.2 * 136.8 149 150.3 156 142 151 4 19% Performance accuracy indicator 0.82 0.93 * 0.88 0.90 0.89 0.92 0.87 0.91 7 13% Attention Productivity Index 645 697.5 * 660 675 667.5 690 658 669 Ϊ8%

* - differences before and after treatment are significant (p <0.05)

As can be seen from the data presented in the table, in patients, a significant

- 6 009666 structure of attention, manifested by instability and exhaustion, up to the impossibility of concentration on any type of activity. After the treatment, the indicators tended to improve, however, did not reach normal values. Moreover, the differences were significant only in patients of the main group.

Table 9

Dynamics of neuropsychological indicators

Index Group 1 Group 2 Group 3 Group 4 BEFORE after before after before after before after Anxiety 32,7 17.6 ' 30.1 26.5 30,0 22.3 ' 31.5 24.7 ’ _ 4 46% 4 26% 4 22% Depression 21.1 20,2 17.8 15.3 19.3 17.6 18.1 16.5 Hypochondria 38 23 ' 42 35 ' 36 34 39 36 ria 4 40% 4-16%

* - differences before and after treatment are significant (p <0.05)

As a result of the treatment, changes in the indicators of the psychological status of all the studied patients were noted (Table 9). A significant decrease in anxiety level according to the Spielberg test was observed in patients of groups 3 and 4, however, the obtained indicators before and after treatment corresponded to a moderate anxiety level (21-40 points). In the group of patients who received Vinpotropil, the average Spielberg test after treatment began to correspond to an insignificant level of anxiety (17.6 points). Beck indicators of depression under the influence of the course treatment had a tendency to decrease, however, no significant differences were observed in any of the groups. The maximum changes in the indicators of somatization of anxiety (hypochondria) according to the Sheehan test were noted in groups of patients receiving Vinpotropil and Vinpocetine.

Thus, against the background of taking Vinpotropil, the positive dynamics of the main neurological and neuropsychological parameters was noted after 3 weeks. The course of vinpocetine or piracetam in the monotherapy variant led to a change in only some indicators. The use of a combination of vinpocetine and piracetam (group 4) showed similar dynamics of the indicators (compared with the dynamics in patients of the main group), but much less pronounced and not always reaching a steady significant difference from the indicators before treatment. Dynamic monitoring of the condition of patients with an early recovery period of ischemic stroke made it possible to objectify the clinical value of a combination of metabolic and vasoactive therapy as part of one combined drug. The drug Vinpotropil enhances brain metabolism both due to the neurometabolic effect of the nootropic component (piracetam), and due to increased blood flow and microcirculation (the effect of vinpocetine). Patients noted a good tolerability of the drug and a more convenient form of using one tablet of Vinpotropil compared with two tablets of nootropic and vasoactive drugs.

Claims (3)

1. A pharmaceutical composition in the form of a solid dosage form having cerebro-vasodilating and nootropic activity, containing vinpocetine and piracetam as active ingredients and pharmaceutically acceptable carriers, while the content of active ingredients is vinpocetine 0.0045-0.0150 g, piracetam 0.36- 1.2 g 2. The pharmaceutical composition according to claim 1, characterized in that it is made in the form of a capsule. 3. The pharmaceutical composition according to claim 1, characterized in that it is made in the form of tablets.