RU2525433C2 - Medication vincamin in form of matrix tablets for improvement of cerebral circulation and method of its manufacturing - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention relates to field of medicine, namely to matrix tablets of vincamin, belonging to peripheral vasodilators and used as preparation improving cerebral circulation. Vincamin medication includes active substance vincamin and auxiliary substances magnesium stearate, lactose monohydrate, hypromelose, copovidone, silicon dioxide colloidal hydrophobic, silicon dioxide hydrophilic in amounts given in the invention formula.

EFFECT: invention provides prolonged release of vincamin from matrix tablets.

1 dwg, 2 tbl, 3 ex

Description

The invention relates to medicine, in particular to a solid dosage form - vincamine tablets related to peripheral vasodilators and used as a drug that improves cerebral circulation.

Vincamine structural formula

Chemical name: 13a-ethyl-2,3,5,6,12,13,13a, 13b-octahydro-12hydroxy-1H-indolo- (3,2,1-de) pyrido (3,2,1-ij) (1,5-naphthyridine-12-methyl carboxylic acid ester.

The empirical formula is: C ₂₁ H ₂₆ N ₂ O ₃ .

Molecular mass: 354.4.

Description: White crystalline powder. Almost insoluble in water, soluble in chloroform, sparingly soluble in ethanol and ether.

Vincamine preparations are taken to normalize and adapt cerebral circulation in accordance with the metabolic needs of the brain. Prescribe a drug to improve, regulate and maintain brain functions in conditions such as memory impairment, impaired concentration, diabetic angiopathy, atherosclerotic lesions of the cerebral vessels, post-traumatic craniocerebral disorders, after acute cerebrovascular accident, cerebral disturbances after cerebral ischemia hypertensive encephalopathy, impaired hearing and vision of vascular origin, impaired orientation in space and time, emotional disturbances, which are The consequences of various mental disorders.

Patents are known from the prior art: No. UA44193, А61К 36/00, А61Р 35/00, 04/03/2009, which describes a pharmaceutical composition that includes a small periwinkle (vincamine); US 3454583, 07/08/1969, C07D 295/03; C07D 461/00; C07D 471/14, which describes a new synthesis for the production of vincamine.

In patent FR 2253507, A 61 / K27 / 12, C07D 57/06, 1973, it is indicated that the vincamine retard dosage form has advantages over the single-release dosage form because vincamine quickly appears in the body after use and the maximum concentration of vincamine in the blood decreases after an hour. This patent proposes the most appropriate form, which allocates evenly vincamine for 8 hours. This dose is 40 mg of vincamine, which is contained in granules ranging in size from 20 microns to 80 microns, made for the slow release using the Precirol Gattefose glycerol palmitostearate esters. Such particles are compressed into tablets or packed into capsules.

However, no real technological indicators of this form were provided either by the manufacturing method or by the control method. In addition, examples of the use of such a drug are insufficient to create a dosage form for industrial manufacture.

Patent No. FR2313915 (A1), CORNEILLEGILBERT [FR], A61K 31/475, A61K 9 / 50K2, C07D 461/00, 1977, describes the vincamine retard form in the form of hard capsules. Vincamine release is presented that meets the following standards: less than 40% in 1 hour, less than 75% in 4 hours, more than 75% in 8 hours. The release in 1 hour is checked in artificial gastric juice with a pH of 1.5, and at the end of this first hour, the gastric juice is replaced and microbeads are placed in artificial intestinal juice with a pH of 7.2.

This dosage form corresponds to the well-known drug Oxybral on the pharmaceutical market, which offers a 30-minute release program - 30%, 30-70% in 2 hours, and at least 80% in 8 hours.

The disadvantages of this patent is that, firstly, the drug, which is offered in the form of hard capsules, consists of two types of pellets. Pellets are created by spraying a layer of vincamine on neutral balls of sugar, starch and other auxiliary substances, and then applying a protective layer containing at least two polymer components - gumilak, gelatin, cellulose derivatives, methacrylates, polyvinylpyrrolidone. The choice of polymer components provides different dissolution times for vincamine. A combination of two varieties of pellets provides a vincamine release program. This technology does not provide reliable indicators of the dissolution of vincamine, the solubility of which is highly dependent on the pH of the solution.

The second disadvantage is that the formation of a layer of vincamine and polymer materials on neutral balls requires the use of a significant amount of explosive organic solvents, i.e. Needs special technological equipment and appropriate organization of production.

Closest to the claimed invention is the retard form of vincamine in the form of tablets, in which to program the release of the active substance - vincamine - a mixture of Eudragite RL-PM and RS-PM in a ratio of 2: 1 and ethyl cellulose is used. As excipients, calcium phosphate, talc, magnesium stearate are used. The release program is defined in the Sartorius apparatus and depending on the amount of ethyl cellulose has the following indicators: for 1 hour 12-30%, for 2 hours 23-40%, for 3 hours 32-55%, for 4 hours 40-62%, for 6 hours 55-77% [DE 2707763, A61K 31/475, 1977].

Such a release program is not adjusted with in vivo data in humans; Sartorius devices are not official to determine this test. In addition, dissolution conditions (liquids and pH) were not determined. The disadvantage is that for the manufacture of this drug, vincamine with excipients is granulated with solutions of EudragiteRL-PM and RS-PM polymers in a ratio of 2: 1 or ethyl cellulose in an organic solvent - methylene chloride. This makes it impossible to use such technology in an industrial environment due to the use of explosive solvents.

The basis of the invention is the task of creating a vincamine drug in the form of matrix tablets to improve cerebral circulation, which would be more effective in the release of vincamine and would respond to a prolonged release of vincamine.

The second task, which is the basis of the invention, is the creation of an effective and simple method for the manufacture of a vincamine drug in the form of matrix tablets to improve cerebral circulation by improving and simplifying the process while reducing production time and using safe technology (without explosive solutions).

The problem is solved in that the drug vincamine in the form of matrix tablets for improving cerebral circulation, including the active substance - vincamine and excipient - magnesium stearate, according to the invention contains lactose monohydrate, hypromellose with viscosity, copovidone, silicon dioxide, colloidal hydrophobic, silicon dioxide the following ratio of components, wt.%:

Component Name Amount, % Vincamine 21.43-16.67 Lactose Monohydrate 31.86-34.55 Hypromellose 29.0-32.5 Copovidone 12.14-13.0 Silicon dioxide colloidal hydrophobic 0.5-0.6 Silicon dioxide hydrophilic 0.5-0.6 Magnesium stearate 2.8-3.3

The second task is solved by the fact that in the method of manufacturing a vincamine drug in the form of matrix tablets for improving cerebral circulation, comprising mixing the components, calibrating, pressing, according to the invention, vincamine, lactose monohydrate, hypromellose, copovidone, silicon dioxide, colloidal hydrophobic, silicon are loaded into the mixer dioxin, the loaded components are mixed, calibrated, mixed again, then magnesium stearate is added and mixed again before pressing.

In the prototype, the vincamine release program is provided by using a mixture of two oidragits and using a hydrophilic insoluble filler - calcium hydrogen phosphate dihydrate. Alcoholic polymer solutions during granulation contribute to better solubility of the active substance in water. And the polymer composition of these solutions provides a certain speed of this process.

In the claimed invention, an increase in solubility is provided by the use of a soluble filler — lactose monohydrate of a crystalline structure and two polymers — copovidone and hypromellose, the effect of which, according to published data, is achieved by complexing with vincamine. The possibility of such complexing with certain medicinal substances has been described for copovidone [Kollidon, BASF 2003 7 revisededition, p. 96-107, 238-240], but for vincamine having a complex chemical structure, such an interaction was not known. The provision of the necessary physical and mechanical properties in the tablet of the prototype is carried out by using talc and magnesium stearate. For the last thirty years, silicon dioxide has also been widely used for these purposes. Different solubility of vincamine substance depending on the pH of the medium showed that the most effective is the use of a mixture of equal parts of hydrophilic and hydrophobic silicon dioxide in an amount of from 1.5 to 2.0% and an increased amount of anti-adhesive substance - magnesium stearate. Despite the fact that all excipients used are widely known as fillers, their amount and ratio in this preparation were proved by experimental data and cannot be predicted at the current level of knowledge.

The proposed composition of excipients and their quantity make it possible to fulfill the second objective of the invention — production technology in the most simplified way by direct tabletting method, in which there is no preparation of a moisturizing solution, moistening, granulation, drying, that is, operations maximize the stability of the components. This direct tabletting method minimizes the manufacturing time, the destructive effect of technological operating modes, and is performed without the use of explosive organic solutions.

Specific examples of the drug are shown in table 1.

Table 1 Example 1 Example 2 Example 3 Component Name Amount, % Amount, % Amount, % Vincamine 18.75 21.43 16.67 Lactose Monohydrate 33.38 31.71 34.67 Hypromellose 31.25 29.64 32,5 Copovidone 12.5 12.86 12.22 Silicon dioxide colloidal hydrophobic 0.5 0.57 0.5 Silicon dioxide hydrophilic 0.5 0.57 0.5 Magnesium stearate 3.12 3.22 2.94 wt. % one hundred one hundred one hundred

The physico-mechanical properties and vincamine release are shown in Table 2.

table 2 Indicators The average weight of the tablet, mg 160 Solubility% less than 30% after 30 minutes, from 30 to 70% after 120 minutes, not less than 80% after 480 minutes Abrasion,% 0.06 Crush Resistance, N 81.7 Height mm 3.4 mm ± 0.2 mm Diameter mm 7.0 mm ± 0.2 mm

A comparison of the kinetics of the release of the active substance - vincamine and oxybral is shown in the graph.

The data presented indicate that the release of vincamine from the matrix solid medical form, namely tablets, corresponds to a prolonged release in capsules of the Oxybral comparison drug, that is, the amount of vincamine 30 mg, which passes into solution, is less than 30% after 30 minutes, from 30 to 70 % after 120 minutes, at least 80% after 480 minutes.

Claims (1)

Vincamine drug in the form of matrix tablets for improving cerebral circulation, including the active substance, vincamine and excipient magnesium stearate, characterized in that it contains lactose monohydrate, hypromellose, copovidone, silicon dioxide, hydrophobic colloid, hydrophilic silicon dioxide in the following ratio of components, wt.%:
Vincamine 21.43-16.67 Lactose Monohydrate 31.86-34.55 Hypromellose 29.0-32.5 Copovidone 12.14-13.0 Silicon dioxide colloidal hydrophobic 0.5-0.6 Silicon dioxide hydrophilic 0.5-0.6 Magnesium stearate 2.8-3.3

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