The infusion solution of bradenton to improve cerebral circulation

 

The invention relates to the field of medicine and relates to an infusion solution for improving cerebral circulation. The invention consists in that the infusion solution BRADENTON contains Vinpocetine, ascorbic acid, benzyl alcohol, sodium sanitarily Piro, sorbitol, tartaric acid and water for injection at a specific ratio of ingredients. The invention provides improved efficiency at infringements of brain blood circulation. 3 tab., 4 Il.

The invention relates to the field of medicine and for the creation of an infusion solution for improvement of brain blood circulation on the basis of Vinpocetine.

Known liquid forms of the alkaloids, which are similar in structure with Vinpocetine (patent US 4923876).

The closest in technical essence and the achieved result is the invention according to patent EP 305181/1994, which describes a pharmaceutical composition containing as active ingredient Vinpocetine and excipients. The composition is made in the form of tablets. However, in the description of the patent lists the different fillers for liquid dosage forms.

The present invention is the creation of a domestic 0.5% pop, these BRAVINGTON containing Vinpocetine, ascorbic acid, benzyl alcohol, sodium sanitarily, pyro, sorbitol, tartaric acid and water for injection.

The solution contains the indicated ingredients in the following ratios, wt.%: Vinpocetine - 0,4-0,6 ascorbic Acid - 0,04-0,06 benzyl Alcohol - 0,9-1,1 Sodium sanitarily, pyro - 0,09-0,11 Sorbitol - 7,0-9,0 Acid wine - 0,4-0,6 Water for injection - the Rest of the Preparation of a 0.5% aqueous solution of "Bradenton" is as follows. For the preparation of 300 l of the solution "Bradenton" use: Vinpocetine (in terms of 100% substance) - 1.5kg
Ascorbic acid - 0.15 g
Benzyl alcohol - 3.0kg
Sodium sanitarily, pyro - 0.3 kg
Sorbitol - 24,0 kg
Acid wine - 1.5kg
1 M solution of sodium hydroxide to pH 3.5
Water for injection to 300,0 l
The invention is illustrated by the following example.

In a reactor with a capacity of 300 l pour 200 l of water for injection with temperature (202)oTo include the stirrer (speed from 1.67 to 2.50 with-1) (from 100 to 150 rpm), open the valve on the feed to the reactor sterile nitrogen and bubbled water for injection with nitrogen for 30 minutes Then when working constantly interfered with the IRTA and sodium semitecolo pyro. Ingredients contribute to the reactor with an interval of time sufficient for complete dissolution of the previous component.

The solution is stirred for 5 minutes Add the estimated number of Vinpocetine. Again stir the solution for 10 min, measure the pH of the prepared solution. Using a 1 M solution of sodium hydroxide to bring the pH of the prepared solution to a value of approximately 3.5.

Water for injection temperature (202)oTo bring the volume of solution in the reactor to 300,0 l, stirred for 3 minutes

Spend sterilizing filtration. The filling solution is carried out in a stream of nitrogen. Sealed ampoules sent to stage a "Package" and "Marking" of the finished product.

The active substance of the proposed means "Bradenton" a 0.5% solution for infusion is Vinpocetine.

In clinical practice Vinpocetine used for about 20 years. At the first stages of the study this biologically active compounds (Kakihana M. 1990, Kiss C., Karpati E. 1996, Bereczki D. 1999) identified five main actions:
1) selective increase of brain blood circulation, improve the utilization of oxygen in brain tissue,
2) increase the tolerance of the tissue of the brain) inhibitor of platelet aggregation.

Currently in experimental and clinical practice has fully proved the effect of Vinpocetine on such "anchor links" cerebrovascular activity, as
- metabolic,
- vasoactive,
- angioprotective,
- antiagregatnoe,
- membranotropic,
- antioxidant,
- nootropic.

One of the determinants of the biological activity of Vinpocetine is its ability to inhibit phosphodiesterase, resulting in the cells of the brain tissue, platelets, and smooth muscle elements of the vessels increases the concentration of cyclic adenosine monophosphate (AMP). Vasodilator action of Vinpocetine is associated with a direct relaxing effect on smooth muscles of vessels. Vazodilatiruyuschee action of Vinpocetine to a certain extent related to the blockade of calcium channels in the membranes of smooth muscle cells.

The positive effect from the use of Vinpocetine in the acute phase of cerebral circulation to a certain extent linked to the ability of the drug to counter the strengthening of hemostatic activation, stimulated, on the one hand, the shear stress of blood flow, especially in the presence of pathological ilen regulation, lipid composition and antioxidant blood system, as well as a powerful release tromboplasticheskoy compounds from damaged tissues of the brain.

By reducing the breakdown of carbohydrates, the increased concentration of zikloadenosinmonofosfat (C-AMP), adenosine triphosphate (ATP), neurotransmitters - serotonin, norepinephrine and dopamine in the brain tissue and improve blood circulation Vinpocetine has a positive nootropic effects (Pepeu G. 1985, Nicholson S. 1989, Kakihana et al. 1990, Stole S. 1999).

The accumulation of C-AMP causes the dilation of blood vessels, improving blood circulation, improving blood circulation in the tissues (H. Hidaka et al. 1990). Especially now affects the blood vessels of the brain, where it increases the supply of oxygen, improves the utilization of glucose, increases the concentration of ATP contributes to the increased levels of catecholamines (noradrenaline, dopamine, serotonin) in the brain tissue (Kanareikin K.). In addition, Vinpocetine has a marked effect on hemostasis - reduces platelet aggregation, increases prostacyclin-thromboxane ratio. In the vasodilator action of peripheral blood vessels Vinpocetine causes a small decrease or normalization of systemic blood pressure. Vinpocetine benefits brain vessels. It is also shown that Vinpocetine has stopped falling vascular hearing and toxic Genesis.

Vinpocetine is indicated for the treatment of neurological and psychiatric disorders associated with disorders of cerebral circulation: in the acute period of ischemic stroke (1-3 day on disease development), in the early recovery period after ischemic and hemorrhagic stroke, disorders of memory, dizziness, aphasia, hypertensive encephalopathy, vazovegetative the symptoms of the menopause. In ophthalmology Vinpocetine used in atherosclerotic and angiospastic changes net and vascular membranes, degenerative changes yellow spots, with secondary glaucoma associated with partial thrombosis of the vessels. Vinpocetine used for reducing vascular hearing or toxic origin and dizziness fin origin.

The drug is contraindicated in severe ischemic heart disease, arrhythmias, pregnancy and lactation. The injection solution is incompatible with heparin. Do not enter the drug under the skin and intramuscularly.

Side effects of the drug to lower blood pressure is the final circulation at 4766 patients (2309 men and 2457 women) aged 40 to 65 years old of them 1350 patients with initial presentation of inadequate, 2476 - TE 659 - ischemic stroke (AI), including 196 minor stroke, 281 - haemorrhagic stroke (GI). The comparison group consisted of 200 patients receiving therapy with other vasodilator.

In patients with stroke treatment with Vinpocetine started in the acute period of 1-3 day from the disease with intravenous injection at a dose of 10 mg, if tolerated, the dose was increased to 20 to 60 mg per day. The course was 12-16 introductions, then patients continued oral administration of the drug at a dose of 10 mg three times a day for months. In the early rehabilitation period was conducted maintenance treatment at a dose of 5 mg three times a day.

The average dose of Vinpocetine in the treatment of patients decompressional DE amounted to 20-30 mg, the drug was administered intravenously drip on 200-600 ml of physiological solution for 10-12 days, with subsequent transition to the oral ingestion of the drug by 5-10 mg 3 times a day for 4-6 weeks.

In the treatment of Dolny initial presentation of inadequate were used only by oral administration of Vinpocetine dose of 5-10 mg per day for 6-8 weeks.

In the course of treatment with Vinpocetine 4766 patients found that 4038 patients (84%) showed a good result in the form of subje is pokazateli additional examinations (blood pressure, the indices of coagulation, REG, EEG, psychological tests). In 677 patients (15%) showed a significant condition or lack of effect, in 51 cases (1%) the treatment was interrupted due to the manifestation of side effects.

The best clinical results observed in patients with initial presentation of inadequate and TE stage I, which according to clinical and laboratory examination after a month's course of monotherapy with Vinpocetine has come full normalization of hemodynamic parameters. Highly effective was the treatment of patients with DE stage II, pnmc with ischemic and hemorrhagic stroke at relatively mild and moderate disease. Not received a positive result or registered a slight improvement in patients TEH stage III, patients with severe hemorrhagic and ischemic stroke and acute focal lesions of the brain, which was confirmed in the process of conducting computer and magnetic resonance tomography.

According to the data obtained in clinics the Moscow region, the greatest clinical effect was achieved by intravenous drip of the drug with subsequent transition to his oral intake. In the case of the occurrence of side is Aulnay. This indicates the necessity of individual approach to the appointment of the drug to patients with a baseline arterial hypertension and patients of older age groups with severe cardiac pathology.

The mechanism of the clinical effect of Vinpocetine based on the restructuring of systemic hemodynamics in the direction of normokinetic, improving cerebral blood flow in the vessels of medium and large diameter, as well as in the area of arteriovenous flow, normalization rheological and coagulation properties of blood.

Studies conducted in patients of the main group and the comparison group receiving treatment of other cardiovascular drugs, revealed a stronger, more effective treatment with Vinpocetine compared to other drugs on the brain and systemic hemodynamics, blood clotting and clinical outcome.

Follow-up monitoring of patients of the main group and the comparison group showed a significant decrease in the number of patients with a progressive course of cerebrovascular disease in the group treated with Vinpocetine, compared with patients treated with other drugs. Protective effect of Vinpocetine on cerebral hemodynamics in securecaredental preparation for mass prevention of cerebrovascular diseases.

Ultraviolet (UV) spectrum of a solution of Vinpocetine should have two clearly pronounced maximum at 268 nm and 313 nm and at least two clear absorption at 243 nm and 291 nm.

For registration UV spectrum was used spectrophotometer "U1-trospec-II" produced by LKB Biochrom. For registration of the absorption spectra of drugs were diluted in the ratio of 1:900.

On the overview spectra (Fig.1 and 2) presents absorption spectra of drugs Bravington" (Fig. 1) and "reverse" company "Gedeon Richter" series A (Fig. 2) in the range from 200 to 380 nm. According to them, the most pronounced absorption maxima in regions respectively 260-280 nm and 305-325 nm and minima of the absorption at intervals 235-250 275-300 nm and nm.

A more detailed study of the absorption spectra in the range 240-380 nm showed that there are two clear absorption optical density at wavelengths 265-270 nm and 310-315 nm and at least two absorption optical density at intervals 240-245 nm and 290-295 nm, as the drug "Bradenton" (Fig.3), and "reverse" company "Gedeon Richter" (Fig.4).

Thus, it is shown that the spectrophotometric solution "Braginton" is almost identical to the solution of "reverse" production "Gedeon Richter".

Acute toxicity of the drug "s rats weighing 180-220 g The drug was administered intravenously and intraperitoneally. The maximum dose of the drug was calculated as follows.

On the basis of the maximum permissible volume injection (PL.1) and the concentration of the drug in the finished dosage form of 5 mg/ml, it is easy to calculate that the maximum achievable single dose for mice is 125 mg/kg intravenously and 250 mg/kg intraperitoneal injection. For rats, respectively, 50 and 125 mg/kg (table.2).

Thus, the introduction of the maximum achievable doses of the drug "Bradenton" and the comparison drug did not lead to a fatal outcome within at least 14 days. Given that therapeutic dose is 1 mg/kg, it is possible to conclude that the low toxicity of both drugs.

Subacute toxicity of the drug was studied in two species of laboratory animals: outbred mice weighing 18-22 g and outbred rats weighing 180-220, the Drugs were injected intravenously in amounts listed in table.3. Based on the fact that therapeutic dose of 1 mg/kg, and ten times therapeutic dose of 10 mg/kg, laboratory animals were divided into five groups:
Rats: Group 1 - the dose of 10 mg/kg and Group 2 - dose 1 mg/kg of the drug "Bradenton";
Group 3 - the dose of 10 mg/kg and Group 4 - dose 1 mg/kg prep is the SCP 1 - the dose of 10 mg/kg and Group 2 - dose 1 mg/kg of the drug "Bradenton";
Group 3 - the dose of 10 mg/kg and Group 4 - dose 1 mg/kg of the drug "reverse" company "Gedeon Richter";
Group 5 - intact animals, saline.

The duration of injection is 14-16 days, after which animals were determined the content of total protein, glucose, urea, activity albinterferon (ALT), asparaginases (ACT), alkaline phosphatase, hemoglobin concentrations, platelets and leukocytes, and also conducted a pathologic-anatomic dissection and subsequent preparation of histological preparations of the following organs: liver, kidney, thymus, brain, spleen.

During the whole time not a single fatal accident. Both of the drug in a dose of 1 mg/kg and at a dose of 10 mg/kg did not cause any visible signs of intoxication.

A comparative study of subacute toxicity "Bradenton" (experimental drug) and drug "reverse" the production company "Gedeon Richter" (drug comparison) found that such biochemical and hematological blood parameters, as the content of total protein, glucose, urea, activity of alanine (ALT) and aspartate (ACT) transaminase, activity of alkaline is the SCP animals receiving the experimental drug from the group of animals treated with the drug comparisons, as in a therapeutic dose and a 10-fold therapeutic dose in both species of experimental animals. In addition, the experiment shows that both drugs do not lead to significant changes of these parameters and compared with a control group of laboratory animals.


Claims

Infusion solution to improve cerebral circulation, containing Vinpocetine and excipients, characterized in that as auxiliary substances it contains ascorbic acid, benzyl alcohol, sodium sanitarily Piro, sorbitol, tartaric acid and water for injections in the following ratio of ingredients, wt. %:
Vinpocetine - 0,4-0,6
Ascorbic acid - 0,04-0,06
Benzyl alcohol - 0,9-1,1
Sodium sanitarily, pyro - 0,09-0,11
Sorbitol - 7,0-9,0
Acid wine - 0,4-0,6
Water for injection - Rest

 

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