Pharmaceutical composition possessing cerebrovasodilating and nootropic activity

FIELD: medicine, neurology, chemical-pharmaceutical industry, pharmacy.

SUBSTANCE: invention relates to a pharmaceutical composition as a solid medicinal formulation possessing cerebrovasodilating and nootropic activity and comprising vinpocetin and piracetam as active components. The composition possesses high effectiveness in more low doses due to synergetic effect and possesses high bioavailability.

EFFECT: valuable medicinal and pharmaceutical properties of composition.

3 cl, 9 tbl

 

The invention relates to medicine, specifically to a pharmaceutical composition having cerebrovasculature and nootropic activity.

Widespread in medical practice has received 3α,16α)-Bornemann-14-carboxylic acid ethyl ester (Vinpocetine), used in violation of cerebral circulation of different origin [ND 42-9175-98. Vinpocetine]. It is used as a known cerebrovasculature tool: improves cerebral blood flow, causes a small decrease in systemic arterial pressure, increasing the cerebral blood vessels, increased blood flow and improved oxygen supply to the brain and glucose. Increases the resistance of brain cells to hypoxia, facilitating transport of oxygen and substrates of energy supply to the tissues (due to the reduced affinity to him erythrocytes, increasing uptake and metabolism of glucose, switching it into energetically more favorable aerobic). Improves microcirculation in the brain by reducing platelet aggregation, reducing blood viscosity, increase erythrocyte deformability.

Known solid dosage form of Vinpocetine in the form of tablets, including Vinpocetine and excipients, M.Ch.: Vinpocetine 1,0; colloidal silicic acid 0,25; starch 19,25; La the Tosa 28,0; talc 1,0; magnesium stearate 0,5 (EP 0305181, 1989). The drug has a low ratio of active substance to the target additives, which leads to an increase in the duration of treatment and the introduction into the organism of a large number of adverse effects on the body talc.

Well-known drug of Vinpocetine in the form of tablets containing (machine hours): Vinpocetine 1,0; lactose 22,8; microcrystalline cellulose 2,7; stearate 0,54 (EP 0689844, 1996). This dosage form is characterized by a slow release of Vinpocetine (less than 20% within one hour).

Well-known drug for improvement of brain blood circulation Vinpocetine-acre tablets (RF patent 2155039, 2000). It is made in pill form and contains as active substance Vinpocetine, as well as pharmaceutically acceptable excipients starch, lactose, salt of stearic acid and silicon-containing compound (Aerosil) in the following ratio of ingredients, parts by weight: Vinpocetine 1,0; Aerosil 0,3-3,64; starch 4,3-12,4; salt of stearic acid of 0.05-0.2.

Well-known drug for improvement of brain blood circulation Tablet Vinpocetine 0.005 g [VFS 42-2937-99. Tablet Vinpocetine 0.005 g]. It contains Vinpocetine 0,0050 g and auxiliary substances (milk sugar 0,1965; Aerosil 0,0010; potato starch 0,0400; talc 0,0050; magnesium stearinovokisly 0,0025).

For more than 20 is the courthouse square, registered in Russia under 6 trade names, dosage form substance of Vinpocetine are tablets or perfusions [Register of medicines of Russia (RLS 2001). - M.: "radar", 2000]. They are all more or less are typical for a tablet form noted deficiencies and implement only the inherent substance of Vinpocetine mechanisms of pharmacological action.

Known 2-oxo-1-pyrrolidineethanol (piracetam), which has a neuroprotective effect at very low toxicity: has a positive effect on metabolic processes of the brain, improves integrative brain activity, improves microcirculation, without vasodilating action, exerts a protective effect in the brain damage caused by hypoxia, intoxication, an electric shock, increases mental activity, enhances cerebral blood flow, does not have a sedative, stimulating effect [FS 42-1943-99 Piracetam].

In Russia registered more than 150 drugs piracetam with 16 trade names.

Known drug Piracetam 0.4 g capsules [VFS 42-8449-98. Piracetam 0.4 g capsules]. It contains 1 capsule: piracetam 0.4 g of calcium stearate 0,0043 g magnesium carbonate basic to the mass of capsules, 0,43

It is known that piracetam increases the efficiency which you increased cerebral blood flow of funds [Register of medicines of Russia (RLS 2001). M: "radar", 2000].

The objective of the invention is to create a new combined drug in solid dosage form that has both cerebrovasculature and nootropic activity, increase the efficiency of the active substances in the composition in the treatment of these diseases, facilitating storage and transport.

The problem is solved in that the pharmaceutical composition in the form of solid dosage forms with cerebrovasculature and nootropic activity, contains as active ingredients Vinpocetine and piracetam and pharmaceutically acceptable carriers in the following active ingredients:

Vinpocetine0,0045-0,0150
piracetam0,36-1,2

The content of Vinpocetine and piracetam based on 100 wt.% the whole composition is: Vinpocetine of 0.29 and 2.83 wt.%, piracetam 75,4-to 77.7 wt.%, the rest of pharmaceutically acceptable carriers and excipients.

As pharmaceutically acceptable carriers and excipients may be, for example, used the lactose (sugar of milk), stearic acid and its salts, preferably calcium or magnesium, crystalline sorbitol, polyvinylpyrrolidone, sodium lauryl sulfate, made in the derivative of cellulose and other pharmaceutically suitable carriers and excipients.

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

Capsules get on the next technology. For example, powders of Vinpocetine, piracetam, milk sugar mix thoroughly for 20-30 minutes, add salt stearic acid and stirred for further 20 minutes the resulting mixture is Packed in hard gelatin capsules. The contents of capsules, powder white or almost white has flowability 8,7±0.6 g/s and bulk density 778±18 kg/m3.

The obtained capsules were tested for authenticity and other requirements under the global Fund XI. So uniformity of dosage was 7.5% (at the rate of 10.0%), raspadaemost 9.5 to 18 minutes (at a rate of not more than 30 min), release 45 min 81-88% (at a rate of not less than 75%).

A method of obtaining a pharmaceutical composition of the present invention in the form of tablets includes the stage of mixing the current start with the basic fillers, wet and dry granulation, dry dusting granulate and tableting. Raspadaemost tablets was less than 3 minutes (up to 15 min), the solubility is more than 80 wt.% for 30 minutes (a rate of not less than 75 wt.% 45 min), strength 108-109 N, a friability of less than 1 wt.% (normal up to 3 wt.%).

In foreign pharmacopoeias same pharmaceutical composition is not described, developed on the basis of the data is received at the analysis of the pilot scale batches of the drug, accumulated Canonpharma production" and the basis of regulations on the production of drugs. This composition allows to increase the effectiveness of therapeutic treatment of the patient due to the selected quantities of the active ingredients and the wide possibilities for varying the ratio between them, as well as a synergistic effect.

According to the invention Canonpharma production is developed, registered and approved for medical use in pharmaceutical drug WinPatrol (registration No. 002632/01 - 2003).

Pharmaceutical drug WinPatrol contains as active ingredients of Vinpocetine 0.005 g, piracetam and 0.4 g and excipients lactose and calcium stearate. The drug is made in the form of capsules.

The invention is illustrated by the following examples (table. 1-4).

Table 1

The compositions made in the form of capsules
no versionIngredientsNo. composition and content of the ingredients in the capsule, g
1234
Vinpocetine0,00450,00450,00550,0055
IPiracetam0,36000,44000,36000,4400
Lactose0,09900,12100,09900,1210
Calcium stearate0,00450,00550,00450,0055
5678
Vinpocetine0,00450,00450,00550,0055
IIPiracetam0,36000,44000,36000,4400
Sorbitol crystalline0,06600,08000,06600,0800
Polyvinylpyrrolidone0,03300,04000,03300,0400
A mixture of magnesium stearate with sodium lauryl (80:20, wt.%)0,00320,00380,00320,0038
9101112
Vinpocetine0,00560,00560,0150 0,0150
IIIPiracetam0,45001,20000,45001,2000
The methylcellulose0,06200,16000,06200,1600
Kollidon CL0,02100,03300,02100,0330
Stearic acid0,00100,00300,00100,0030

Table 2

The compositions made in tablet form
no versionIngredientsNo. composition and content of the ingredients in the tablet, g
13141516
IIIVinpocetine0,00560,00560,01500,0150
Piracetam0,45001,20000,45001,2000
Sorbitol crystalline0,12000,18000,12000,1800
A mixture of polyvinylpyrrolidone:
- kollidon 300,05600,15000,05600,1500
- kollidon CL0,02200,03300,02200,0330
Magnesium stearate0,00120,00360,00120,0036

Table 3
no songsIndex
Raspadaemost, minSolubility % for 30 minutes (a rate of 75% in 45 min)Strength, NAbrasion, wt.%
11673,0--
21871,4--
31870,8--
41771,5--
510,072,8--
610,073,5--
79,574,8- -
89,573,2--
910,574,1--
1010,073,8--
1110,572,5--
1210,574,0--
132,582,91080,1
142,584,81090,13
152,087,51080,12
162,584,8108,50,2

Table 4

The results of the analysis of model mixtures of WinPatrol according to the invention capsules
No. n NameInherent in the model mixture per capsule, gDefined
Of Vinpocetine, gRelative error, %
Vinpocetine0,00500,004936-1,26
1 Piracetam0,40000,4093+2,32
Fillersbefore mass 0,5200
Vinpocetine0,00540,00530-1,84
2Piracetam0,37000,3611-2,41
Fillersbefore mass 0,5200
Vinpocetine0,00460,00471+2,37
3Piracetam0,43000,4215-1,98
Fillersbefore mass 0,5200
Vinpocetine0,00500,00493-1,39
4Piracetam0,43000,4431+3.04 from
Fillersbefore mass 0,5200
Vinpocetine0,00460,0472+2,67
5Piracetam0,4000,3928-1,81
ÈA; Fillersbefore mass 0,520
Vinpocetine0,00500,00492-1,58
6Piracetam0,43000,4176-2,88
Fillersbefore mass 0,520
Vinpocetine0,00460,00466+1,21
7Piracetam0,4000,4108+2,69
Fillersbefore mass 0,520

Notes:

1. Model mixtures were prepared based on 10 capsules.

2. The proposed definition of authenticity of Vinpocetine in the combined drug by HPLC simultaneously with the determination of its quantitative content in the product. The same method conduct the validation of piracetam (PL. 5).

Table 5

Study release Vinpocetine from WinPatrol according to the invention capsules
the number of seriesThe content of Vinpocetine in the capsule, g The amount of xanthones
15 min30 min45 min
g%g%g%
0107010,005220,0026150,00,0037371,50,00437is 83.8
0207010,005150,0024848,10,0036170,10,0043584,5
0307010,004910,00224of 45.70,0034570,30,00431of 87.8
0407010,005020,0022244,30,0034668,90,0040680,9
0507010,004960,0024950,20,0036774,00,0041182,8
The average value %47,7±2,571,00±2,084,0±3,2

A study was conducted of the effectiveness of the drug WinPatrol on the subject of the synergism of the claimed pharmaceutical compositions of Vinpocetine and piracetam.

Feature a discuss edavanna sick.

In a study of the effectiveness of the drug WinPatrol were included 90 participants (48 men and 42 women) aged from 42 to 70 years (mean age of 56.2 years) in accordance with the criteria of inclusion and exclusion (table 6).

Table 6

Criteria for inclusion and exclusion of studies
Criteria for inclusion in the study
Early recovery period of ischemic stroke (from 4 weeks to 6 months)
Age from 40 to 70 years
Exclusion criteria from the study
The presence of severe somatic pathology
Pronounced cognitive and emotional-volitional disorders
Expressed speech disorders
The use of up to 3 months from the start of the study drugs included Vinpocetine and piracetam

72 patient suffered an ischemic stroke in the carotid pool, 18 patients in the vertebral-basilar pool. Time from stroke corresponded to the early recovery period (4 weeks to 6 months). Causes of cerebrovascular disorders were Atheros Eros cerebral or precerebral arteries, hypertensive heart disease, heart rhythm disorder, or a combination thereof. In all patients the diagnosis of cerebral stroke was confirmed by computer tomografia or a magnetic resonance tomografia.

Patients received a standardized 3-week course of therapy, differing in only one component:

group 1 (main) consisted of 30 patients (17 men and 13 women, mean age of 55.9±3.4 years)who received 2 capsules of WinPatrol 3 times a day, oral;

Comparison group:

group 2, 20 patients (10 women and 10 men, mean age of 56.4±3.2 years) received only Vinpocetine dose of 30 mg/day, oral;

3 the group of 20 patients (9 women and 11 men, mean age 53,1±3.1 years) received only piracetam dose of 1600 mg/day, oral;

4 the group of 20 patients (10 men and 10 women, mean age 57,0±2.3 years) received Vinpocetine dose of 30 mg/day and piracetam dose of 1600 mg/day, oral.

Research methods

All patients on the 1st and 21st day of the study were used to assess neurological and neuropsychological status. In the study of neurological status was carried out score the severity of subjective symptoms: headache, dizziness, tinnitus, sleep disorders, fatigue and reducing the memory. To use this 5-step score rating the scale with standardized criteria for assessing the severity of each subjective symptom (from 0 (no disturbance) to 4 (serious violations)). For attention assessment used a sample of Bourdon. The dynamics of the levels of depression, anxiety and hypochondria were investigated by using the scale Beck, tests Spielberg and Sheehan.

The results and discussion.

From the study were excluded 2 patients of the main group and 6 from the comparison groups. The reason in most cases was the need for correction of standard therapy, unrelated to the development of side effects. Only 5% of patients receiving WinPatrol, was marked by the appearance of pain in the stomach and dyspeptic phenomena, while similar complaints were noted in 20% of patients 4 comparison group receiving both Vinpocetine and piracetam. This is probably due to the mechanical effect of increased number of tablets.

On the background of therapy positive dynamics of the patient in the form of a regression of subjective symptoms (table 7).

Table 7

Dynamics of the average score in the severity of subjective symptoms
Group 1Group 2Group 3Group 4
toaftertoafterto aftertoafter
Headache2,11,4*2,01,61,91,62,11,5*
↓ 33%↓ 29%
Dizziness1,60,9*1,51,0*1,61,31,51,1*
↓ 44%↓ 33%↓ 27%
The noise in my head1,20,91,30,91,31,01,31,0
Fatigue2,31,4*2,01,52,21,4*2,11.4*
↓ 39%↓ 36%↓ 33%
memory loss 1,81,2*1,81,51,91,3*1,71,2*
↓ 33%↓ 32%↓ 29%
Insomnia1,60,9*1,71,1*1,61,21,50,9*
↓ 44%↓ 35%↓ 40%
*- the differences before and after treatment are significant (p<0,05)

In the main group (receiving WinPatrol) showed a significant (p<0.05) decrease as the average rating score for the assessment of severity of headache, dizziness, reduced memory and tiredness, and the number of patients with assessment for this indicator exceeded one point, i.e. the complaint absent or rarely bother. In this group showed a significant difference in the distribution of patients according to the severity of complaints from 0 to 4 for the symptoms of: headache, dizziness, and fatigue (p<0,05). In the comparison group occurred is the Eney a clear positive trend status.

The validation results of the attention of the examined patients are presented in table 8.

Table 8

The dynamics of the recovery of attention
IndexGroup 1Group 2Group 3Group 4
toaftertoaftertoaftertoafter
Productivity114to 135.2*136,8149150,3156142151
attention↑ 19%
Indicator accuracy0,820,93*0,880,900,890,920,870,91
↑ 13%
The productivity indicator645697,5*660675667,5690658669
attention↑ 8%
* - the differences before and after treatment are significant (p<0,05)

As can be seen from the data presented in the table, in patients with initial significant disorder of attention, manifested instability and exhaustion, until no concentration on any activity. After treatment indicators tended to improve, but did not reach normal values. This difference was significant only in patients of the main group.

Table 9

Dynamics neuropsychological indicators
IndexGroup 1Group 2Group 3Group 4
toaftertotoaftertoafter
Anxiety32,717,6*30,126,530,022,3*31,524,7*
↓ 46%↓ 26%↓ 22%
Depression21,120,217,815,319,317,618,116,5
Hypochondria3823*4235*36343936
↓ 40%↓ 16%
* - the differences before and after treatment are significant (p<0,05)

As a result of the treatment of changes in indicators of psychological status of all studied patients (table). A significant decrease of anxiety level on the test Spielberg noted in patients 3 and 4 groups, however, the figures obtained before and after treatment were consistent with a moderate level of anxiety (21-40 points). In the group of patients receiving WinPatrol, averages those is that Spielberg after treatment began to correspond to an insignificant level alarm (17.6 points). Depression scale Beck under the influence of the spent course of treatment tended to decrease, however, it is significant differences in any of the groups is not observed. Maximum changes in indicators of somatization anxiety (hypochondria) test Sheehan noted in the groups of patients receiving WinPatrol and Vinpocetine.

Thus, on a background of reception of WinPatrol positive dynamics of the main neurological and neuropsychological parameters was observed already after 3 weeks. The course of Vinpocetine or piracetam version monotherapy led to changes in some indicators. The application of a combination of Vinpocetine and piracetam (group 4) showed a similar trend of indicators compared with the dynamics in patients of the main group), but much less pronounced and not always reaching sustainable reliable differences from the figures before treatment. Dynamic monitoring of the status of patients with early recovery period of ischemic stroke allowed to objectify clinical value combination of metabolic and vasoactive therapy in a combined drug. Drug WinPatrol enhances the metabolism of the brain as expense attributable to the actions nootropic component (piracetam), and by increasing blood flow and microcirculation (de is the effect of Vinpocetine). Patients reported good tolerability and a more convenient form using one tablet WinPatrol compared with two pills nootropic and vasoactive drugs.

1. Pharmaceutical composition in the form of solid dosage forms with cerebrovasculature and nootropic activity, containing Vinpocetine and piracetam as an active ingredient and pharmaceutically acceptable carriers, the content of active ingredients is, g:

Vinpocetine0,0045-0,0150
Piracetam0,36-1,2

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 tablet form.



 

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