EA013645B1 - Sustained release solid pharmaceutical composition of 1-(2,3,4-trimethoxybenzyl)piperazine and a method for the preparation thereof - Google Patents

Abstract

The inventive sustained release solid pharmaceutical composition comprises an 1-(2,3,4-trimethoxybenzyl) piperazine active substance or the pharmaceutically acceptable salt thereof combined with at least one type of polyethylene oxide, at least one type of lubricating agent and one or several pharmaceutically acceptable excipients.

Description

The present invention relates to the field of improving solid pharmaceutical compositions with sustained release of the active ingredient 1- (2,3,4-trimethoxybenzyl) piperazine.

The active ingredient 1- (2,3,4-trimethoxybenzyl) piperazine belongs to the chemical class of piperazine compounds and has the following formula:

1- (2,3,4-Trimethoxybenzyl) piperazine is a compound that, by maintaining the energy metabolism of cells exposed to hypoxia or ischemia, eliminates a decrease in intracellular levels of adenosine triphosphate (ATP). In accordance with this, 1- (2,3,4-trimethoxybenzyl) piperazine provides the functioning of ion pumps and potassium-sodium transmembrane flows, and also supports cell homeostasis. Thus, 1- (2,3,4-trimethoxybenzyl) piperazine has a myocardial and cerebral antitoxic effect through its effect on energy metabolism. This effect may be associated with inhibition of lipid oxidation and increased glucose oxidation.

Currently, 1- (2,3,4-trimethoxybenzyl) piperazine is mainly used in pharmaceutical compositions that have an anti-angina effect and are intended for the treatment of patients suffering from angina pectoris, including angina pectoris, true dizziness, vestibular syndrome, as well as treatment of induced cyclosporine nephropathy.

In general, 1- (2,3,4-trimethoxybenzyl) piperazine is used in the form of a pharmaceutically acceptable salt of the active ingredient, in particular 1- (2,3,4-trimethoxybenzyl) piperazine dihydrochloride.

Dihydrochloride of 1- (2,3,4-trimethoxybenzyl) piperazine is rapidly absorbed and excreted from the body, its half-life in plasma is less than 6 hours. For this reason, various compositions based on 1- (2,3,4 -trimethoxybenzyl) piperazine, which have a delayed effect.

European patent application EP 673649 respectively describes a composition based on 1- (2,3,4-trimethoxybenzyl) piperazine with a delayed action, in which the sustained release of 1- (2,3,4-trimethoxybenzyl) piperazine is made possible by a combination of a polymer which is insoluble in water, such as ethyl cellulose or polymethacrylate, with a plasticizing agent. Plasticizing agents that have good water permeability are those with which a uniform release of 1- (2,3,4-trimethoxybenzyl) piperazine was obtained. In accordance with European patent application EP 673649, the combination of a polymer that is insoluble in water with a plasticizing agent makes it possible to obtain a relatively permeable film that allows uniform release of the active ingredient.

The examples given for the purpose of illustration demonstrate tablets that include a combination of an insoluble ethyl cellulose polymer and a plasticizing agent of acetyl tributyl citrate.

The tablets described in European patent application EP 673649, obtained using the wet granulation process.

After the wet granulation step, the step of compacting the mixture of the active ingredient and the filler is carried out to obtain a tablet, which is exposed to a lubricating agent before coating using a solution or suspension comprising a combination of the selected water-insoluble polymer and a plasticizing agent, so that a good coating of the tablet with a polymer film is achieved, providing a controlled release of 1- (2,3,4-trimethoxybenzyl) piperazine.

The French patent application published under the number EB 2818549, describes compositions for the controlled release of 1- (2,3,4-trimethoxybenzyl) piperazine, where the control of the release of the active ingredient is obtained using polymers from the polymethacrylate group, which have plasticity properties, without the addition of plasticizing agent.

The polymethacrylates described in the French patent application are Eibgye polymethacrylates. The pharmaceutical compositions described in French patent application EB 2818549 are prepared by preparing a thermoplastic mixture of the active ingredient and polymethacrylate (s), followed by the step of co-extrusion or co-injection.

European patent application EP 1108424 describes sustained release pharmaceutical compositions of 1- (2,3,4-trimethoxybenzyl) piperazine in which the active ingredient is incorporated into a hydrophilic matrix, which consists of a polymer based on a cellulose derivative, in particular cellulose ether, such like hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxymethyl cellulose, methyl cellulose and hydroxypropyl methyl cellulose.

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The pharmaceutical compositions described in European patent application EP 1108424 are obtained using a process comprising the step of granulating 1- (2,3,4-trimethoxybenzyl) piperazine and a binding agent using wet granulation, after which the resulting granulate is mixed with hydroxypropyl methylcellulose before the steps lubrication and sealing.

Some pharmaceutical compositions for the controlled release of 1- (2,3,4-trimethoxybenzyl) piperazine, which are described in the prior art, allow the active ingredient to be released continuously over a period of time and accordingly have satisfactory pharmacokinetic characteristics, in particular with respect to the dissolution profile ίη νίίτο.

However, from the point of view of the therapeutic value of 1- (2,3,4-trimethoxybenzyl) piperazine in the prior art, there is a need for new pharmaceutical compositions with sustained release of 1- (2,3,4-trimethoxybenzyl) piperazine, which has good pharmacotechnical characteristics, in in particular with respect to the dissolution profile of ίη νίίτο, which are at least as satisfactory as those already proposed.

In addition, in the prior art there is a need for new pharmaceutical compositions for the controlled release of 1- (2,3,4-trimethoxybenzyl) piperazine, which can be obtained using processes that are simpler and less difficult than the processes used for obtaining known compositions.

The present invention provides novel pharmaceutical compositions for sustained release of 1- (2,3,4-trimethoxybenzyl) piperazine having pharmacotechnical characteristics that are at least as satisfactory as those for known controlled release pharmaceutical compositions 1- (2 , 3,4-trimethoxybenzyl) piperazine, and which can be obtained using a simple and inexpensive process.

The present invention relates to a sustained release pharmaceutical composition which comprises the active ingredient 1- (2,3,4-trimethoxybenzyl) piperazine or a pharmaceutically acceptable salt of 1- (2,3,4-trimethoxybenzyl) piperazine in combination with at least one polyethylene oxide and at least one lubricant, optionally in combination with one or more pharmaceutically acceptable excipients.

In accordance with the invention, it was unexpectedly shown that a solid pharmaceutical composition with prolonged release of 1- (2,3,4-trimethoxybenzyl) piperazine can be obtained when 1- (2,3,4-trimethoxybenzyl) piperazine is combined with at least one polyethylene oxide and at least one lubricant.

In particular, it was shown in accordance with the invention that a combination of 1- (2,3,4-trimethoxybenzyl) piperazine or a pharmaceutically acceptable salt of 1- (2,3,4-trimethoxybenzyl) piperazine with at least one polyethylene oxide and at least with a single lubricant makes it possible to obtain a solid pharmaceutical composition whose pharmacotechnical characteristics, including the ίη νίίτο release profile of the active ingredient and the ίη νίνο pharmacokinetic profile, are similar or even identical with some pharmacists eskimi formulations with sustained release of 1- (2,3,4-trimethoxybenzyl) piperazine hydrochloride, which is already available on the market.

In addition, as will be described in more detail later in this description, the new solid pharmaceutical compositions of the invention for the sustained release of 1- (2,3,4-trimethoxybenzyl) piperazine can be prepared using a simple direct compression process of a mixture of the active ingredient and excipients which does not require a granulation step, be it dry or wet granulation, and also does not require an extrusion step or, alternatively, injection under pressure.

Polyethylene oxide is a compound having the following formula:

where η is an integer that can vary significantly, for example, from 10 ² to 10 ⁶ .

It has been shown that for the production of solid pharmaceutical compositions in accordance with the invention, which have good sustained release characteristics of 1- (2,3,4trimethoxybenzyl) piperazine, the best results were obtained using high molecular weight polyethylene oxide, preferably polyethylene oxide, for which the η value fluctuates from 10 ⁴ to 5 x 10 ⁵ .

Preferably, polyethylene oxide is used having a molecular weight that ranges from 100,000 to 10,000,000, more preferably from 1,000,000 to 10,000,000, and even more preferably from 4,000,000 to 10,000,000.

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As an illustration, polyethylene oxide having a molecular weight that ranges from 6,000,000 to 8,000,000, for example, approximately 7,000,000, can be used. In particular, polyethylene oxide, a solution of which having a concentration of 1 wt.%, Has a viscosity at 25 ° C. of from 7500 to 10,000 mPa, can be used. / s inclusive (standard unit: MPa / s).

Preferably, the sustained release pharmaceutical composition 1- (2,3,4-trimethoxybenzyl) piperazine according to the invention comprises from 5 to 80% by weight of polyethylene oxide, based on the total weight of the composition.

Preferably, the solid pharmaceutical composition according to the invention comprises from 20 to 50% by weight of polyethylene oxide with respect to the total weight of the composition.

When the content of polyethylene oxide is less than 5% by weight relative to the total weight of the composition, the active ingredient 1- (2,3,4-trimethoxybenzyl) piperazine is released rapidly, which leads to other disadvantages regarding the short half-life in the body. When the content of polyethylene oxide exceeds 80 wt.%, The release of the active ingredient 1- (2,3,4-trimethoxybenzyl) piperazine significantly slows down, which leads to other disadvantages due to the fact that the concentration of 1- (2,3,4-trimethoxybenzyl) piperazine or a pharmaceutically acceptable salt of the active ingredient in the blood plasma is insufficient for optimal therapeutic efficacy.

According to a preferred embodiment of the solid pharmaceutical composition according to the invention, this composition comprises from 33 to 41% by weight of polyethylene oxide with respect to the total weight of the composition.

By way of illustration, a solid, sustained release pharmaceutical composition of 1- (2,3,4-trimethoxybenzyl) piperazine according to the invention comprises 37% by weight of polyethylene oxide based on the total weight of the composition.

In some embodiments of the composition in accordance with the invention, a combination of several polyethylene oxides, for example 2, 3, 4 or 5 polyethylene oxides, which have different molecular weights within the molecular weight range of the polyethylene oxides defined herein, may be used.

It has been shown that the production of the pharmaceutical composition according to the invention using polyethylene oxide was much better than using other water-soluble polymers, in particular a polymer based on a cellulose derivative such as hydroxypropyl cellulose.

It was also shown that the use of one or more polyethylene oxides did not require the addition of a plasticizing agent.

As already mentioned, a solid pharmaceutical composition in accordance with the invention may also include, in addition to the active ingredient, which is associated with at least one polyethylene oxide and at least one lubricating agent, one or more pharmaceutically acceptable excipients.

Preferably, the lubricant is selected from magnesium stearate, calcium stearate, zinc stearate, talc, sodium stearyl fumarate, magnesium silicate, calcium silicate, tribasic calcium phosphate, stearic acid, sodium benzoate, hydrogenated vegetable oils, glyceryl behenate, light mineral oil and polyethylene oils.

Preferably, when the composition includes one or more agents that increase the fluidity. Among the flow improvers, colloidal silica, silicon dioxide, magnesium silicate, calcium silicate and talc may be mentioned; however, colloidal silica and talc are preferred.

The flow agent (s), in particular, are used in combination with 1- (2,3,4-trimethoxybenzyl) piperazine or a pharmaceutically acceptable salt of 1- (2,3,4-trimethoxybenzyl) piperazine to obtain a solid base a powder material in which 1- (2,3,4-trimethoxybenzyl) piperazine is uniformly distributed and which has good flow properties.

Advantageously, the composition according to the invention comprises one or more binding agents.

Preferably, the binding agents are selected from polyvinylpyrrolidone, a copolymer of polyvinylpyrrolidone-vinyl acetate, gum arabic, hydrocolloids, microcrystalline cellulose, dextrins, gelatin, glucose, guar gum, starch, pregelatinized starch, maltose, and maltodeut, as well as maltodet and maltode.

Hydrocolloids may be selected from alginic acid, a salt of alginic acid such as sodium alginate, an alginic acid derivative, carrageenan, and carrageenan derivatives.

The binding agent (s), in particular, makes it possible to obtain the final pharmaceutical composition, in particular in the form of a tablet having good mechanical properties, especially having good disintegration characteristics.

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Preferably, the composition according to the invention further comprises one or more diluents.

The diluents are preferably selected from lactose, including lactose monohydrate, microcrystalline cellulose, pulped cellulose, dicalcium phosphate, sucrose, starch and derivatives of starch, carbonates, including calcium or sodium carbonate, or magnesium, bicarbonates, including calcium or sodium bicarbonate, mannitol, sucrose, xylitol, sorbitol, maltose, glucose, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulfate, dextrate, dextrin, fructose, kaolin, lactitol, dextrose, glyceryl palmitostear one hydrogenated vegetable oil type I, as well as mixtures thereof.

The diluent (s) in particular makes it possible to obtain a final pharmaceutical composition of controlled volume or size in which the various active ingredients and other excipients are uniformly distributed.

The invention also relates to a solid pharmaceutical composition with prolonged release of 1- (2,3,4-trimethoxybenzyl) piperazine, characterized in that it includes:

a) from 10 to 20% by weight of 1- (2,3,4-trimethoxybenzyl) piperazine or a pharmaceutically acceptable salt of 1- (2,3,4-trimethoxybenzyl) piperazine;

b) from 5 to 80 wt.% polyethylene oxide (s);

c) from 0.5 to 5 wt.% one or more lubricants and

b) from 0 to 85 wt.% of the additional filler (s) (weight percent are calculated in relation to the total weight of the composition).

The invention also relates to a solid pharmaceutical composition with prolonged release of 1- (2,3,4-trimethoxybenzyl) piperazine, characterized in that it includes:

a) from 15 to 20% by weight of 1- (2,3,4-trimethoxybenzyl) piperazine or a pharmaceutically acceptable salt of 1- (2,3,4-trimethoxybenzyl) piperazine;

b) from 20 to 50 wt.% polyethylene oxide (s);

c) from 0.5 to 5 wt.% one or more lubricants and

b) from 30 to 65 wt.% of the additional filler (s) (weight percent are calculated in relation to the total weight of the composition).

The invention also relates to a solid pharmaceutical composition with prolonged release of 1- (2,3,4-trimethoxybenzyl) piperazine, characterized in that it includes:

a) 17.5% by weight of 1- (2,3,4-trimethoxybenzyl) piperazine or a pharmaceutically acceptable salt of 1- (2,3,4-trimethoxybenzyl) piperazine;

b) 37% by weight of polyethylene oxide (s);

c) 1 wt.% of one or more lubricants and

b) 44.5% by weight of the additional filler (s) (weight percentages are calculated in relation to the total weight of the composition).

As mentioned herein, the presence of polyethylene oxide in combination with 1- (2,3,4-trimethoxybenzyl) piperazine or a pharmaceutically acceptable salt of 1- (2,3,4-trimethoxybenzyl) piperazine does not require the presence of a plasticizing agent in order to obtain desired pharmacotechnical characteristics.

In addition, as illustrated in the examples, the use of a polymer based on a cellulose derivative, in particular hydroxypropyl cellulose, does not allow the production of a solid pharmaceutical composition with sustained release of 1- (2,3,4-trimethoxybenzyl) piperazine having pharmacotechnical characteristics, in particular ίη release profile νίίτο 1- (2,3,4-trimethoxybenzyl) piperazine, as required. When using hydroxypropyl cellulose, the release of 1- (2,3,4-trimethoxybenzyl) piperazine is too fast.

In addition, it is preferable when the pharmaceutical composition in accordance with the invention does not contain a polymer based on a cellulose derivative.

In general, a solid pharmaceutical composition in accordance with the invention includes (1) the active ingredient 1- (2,3,4-trimethoxybenzyl) piperazine or a pharmaceutically acceptable salt of 1 (2,3,4-trimethoxybenzyl) piperazine, (s) at least , one polyethylene oxide, (ίίί) at least one flow agent, (ίν) at least one binding agent, (ν) at least one diluent, and (νί) at least one lubricant.

According to a preferred embodiment, the solid pharmaceutical composition according to the invention comprises excipients other than polyethylene oxide, in particular from 2 to 10% by weight of one or more flow agents, from 50 to 97% by weight of one or more diluents, from 0 5 to 5 wt.% Of one or more binding agents and from 0.5 to 5 wt.% Of one or more lubricants, weight percentages are expressed in relation to the total weight of fillers other than polyethylene oxide.

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A solid pharmaceutical composition in accordance with the invention may also contain one or more colorants, the level of which generally does not exceed 1 wt.% With respect to the total weight of the composition and often is less than 0.5 wt.% With respect to the total weight of the composition.

Preference is given to using colloidal silica and / or talc as a flow agent.

Preference is given to using lactose monohydrate as a diluent.

Preference is given to using polyvinylpyrrolidone, also called povidone, as a binding agent.

Preference is given to using magnesium stearate as a lubricant.

In a particular embodiment of the solid pharmaceutical composition according to the invention, a composition combining a diluent and a binding agent is used, such as a composition sold under the name ΤυΌΙΡΚΕδδ® by the company VL8P RNLAML and which comprises 96.5% by weight of lactose monohydrate and 3.5% by weight povidone in relation to the total weight of the specified composition, combining the diluent and a binding agent.

According to a preferred embodiment, a sustained release pharmaceutical composition of 1- (2,3,4-trimethoxybenzyl) piperazine is characterized in that it includes:

a) 17.5% by weight of 1- (2,3,4-trimethoxybenzyl) piperazine or a pharmaceutically acceptable salt of 1- (2,3,4-trimethoxybenzyl) piperazine;

b) 37% by weight of polyethylene oxide (s);

c) 0.2 wt.% anhydrous colloidal silica;

b) 40.63 wt.% lactose monohydrate;

e) 1.47 wt.% polyvinylpyrrolidone;

1) 1 wt.% Magnesium stearate;

d) 2 wt.% talc and

I) 0.2 wt.% Dye (weight percentages are calculated with respect to the total weight of the composition).

The 1- (2,3,4-trimethoxybenzyl) piperazine used in the pharmaceutical composition of the invention is preferably in the form of dihydrochloride.

Preference is given to using low particle size 1- (2,3,4-trimethoxybenzyl) piperazine dihydrochloride powder so that the active ingredient is homogeneously distributed in the final pharmaceutical composition. Preferably, 1- (2,3,4-trimethoxybenzyl) piperazine dihydrochloride powder is used, the average particle diameter of which varies from 5 to 30 μm, more preferably from 10 to 20 μm, measured using the dry particle size determination method as described in the examples.

The solid pharmaceutical composition according to the invention is preferably in tablet form.

By using a combination of the active ingredient and excipients contained in the pharmaceutical composition according to the invention, the final tablet formulation can actually be easily obtained using a simple direct compression process of the mixture of the active ingredient and excipients, the pharmacotechnical characteristics of which are optimal.

Preferably, each tablet comprises from 31.5 to 38.5 mg of 1- (2,3,4-trimethoxybenzyl) piperazine dihydrochloride, more preferably from 34 to 36 mg.

Preferably, each tablet has a weight that ranges from 180 to 220 mg, more preferably from 195 to 205 mg.

Such tablets are acceptable to meet the needs of some patients.

In addition, when using a new combination of the active ingredient and excipients of the solid pharmaceutical composition according to the invention, it is possible to obtain tablets which have the ability to disintegrate over a period of time of more than 60 minutes.

When using the solid pharmaceutical composition in accordance with the invention, it is also possible to obtain tablets that have a tensile strength that ranges from 30 to 120 N, more preferably from 60 to 90 N.

In addition, tablets that can be prepared using the solid pharmaceutical composition of the invention may have a ίη νίίτο dissolution profile as well as a ίη νίνο pharmacokinetic profile for 1- (2,3,4-trimethoxybenzyl) piperazine or a pharmaceutically acceptable salt 1 - (2,3,4-trimethoxybenzyl) piperazine, which is very satisfactory, taking into account the desired objectives of a sustained release of the active ingredient, thus demonstrating good therapeutic efficacy.

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In accordance with this, when using the solid pharmaceutical composition in accordance with the invention, it is possible to obtain tablets that have the following ίη νίίτο dissolution profile of 1- (2,3,4-trimethoxybenzyl) piperazine in a buffer solution with a pH of 1.2:

the release of 35 to 65% of the total 1- (2,3,4-trimethoxybenzyl) piperazine 120 minutes after the start of the study;

the release of 65 to 85% of the total 1- (2,3,4-trimethoxybenzyl) piperazine within 240 minutes after the start of the study;

a release of more than or equal to 85% of the total 1- (2,3,4-trimethoxybenzyl) piperazine 600 minutes after the start of the study.

When using the solid pharmaceutical composition in accordance with the invention, it is possible to obtain 1- (2,3,4-trimethoxybenzyl) piperazine tablets which have a ίη νίνο pharmacokinetic profile, as described below:

preferably, when the 1- (2,3,4-trimethoxybenzyl) piperazine tablet according to the invention has a ίη νίνο pharmacokinetic profile characterized by an area under the plasma concentration curve from 0 to infinity (AIS _0- „) from 600 to 1170 ng- h / ml;

preferably, when the tablet 1- (2,3,4-trimethoxybenzyl) piperazine in accordance with the invention has a ίη νίνο pharmacokinetic profile, characterized by a maximum plasma concentration (Stax) of from 40 to 110 ng / ml;

preferably, when the tablet 1- (2,3,4-trimethoxybenzyl) piperazine in accordance with the invention has a ίη νίνο pharmacokinetic profile characterized by a T _max value of from 2 to 6 hours; a person skilled in the art will understand that the T _max value is the time required to obtain the maximum concentration of the active ingredient in the blood plasma;

it is preferable that a tablet of 1- (2,3,4-trimethoxybenzyl) piperazine in accordance with the invention has a ίη νίνο pharmacokinetic profile characterized by a half-life in plasma (ί _1/2 ) of 4.5 to 10 hours.

The invention also relates to a method for producing a sustained release tablet of 1- (2,3,4-trimethoxybenzyl) piperazine, which comprises the step of preparing a mixture of 1- (2,3,4-trimethoxybenzyl) piperazine or a pharmaceutically acceptable salt of 1- (2,3 , 4-trimethoxybenzyl) piperazine with at least one polyethylene oxide, at least one lubricant and, optionally, one or more other pharmaceutically acceptable excipients, and then the step of preparing the tablet by directly compressing the mixture obtained in the previous step.

In particular, the invention relates to a method for producing a sustained release tablet of 1- (2,3,4-trimethoxybenzyl) piperazine, which comprises the following steps:

a) obtaining a mixture of the following components:

at least a portion of the total amount of 1- (2,3,4-trimethoxybenzyl) piperazine or a pharmaceutically acceptable salt of 1- (2,3,4-trimethoxybenzyl) piperazine and at least one flow agent;

b) adding to the mixture obtained in step a):

optionally, amounts of 1- (2,3,4-trimethoxybenzyl) piperazine or a pharmaceutically acceptable salt of 1- (2,3,4-trimethoxybenzyl) piperazine, which is necessary to obtain a total amount of the active ingredient of at least one polyethylene oxide, at least at least one binding agent, at least one diluent, optionally at least one dye to obtain a mixture of these various components;

c) adding to the mixture obtained in step b):

at least one lubricant, at least one antistatic agent;

ά) obtaining tablets using direct compression of the mixture obtained in step c).

The invention also relates to a method for producing a sustained release tablet of 1- (2,3,4-trimethoxybenzyl) piperazine, which comprises the following steps:

a) obtaining a mixture of the following components:

at least a portion of the total amount of 1- (2,3,4-trimethoxybenzyl) piperazine or a pharmaceutically acceptable salt of 1- (2,3,4-trimethoxybenzyl) piperazine and anhydrous colloidal silica;

b) adding to the mixture obtained in step a):

optionally, an amount of 1- (2,3,4-trimethoxybenzyl) piperazine or a pharmaceutically acceptable salt of 1- (2,3,4-trimethoxybenzyl) piperazine, which is necessary to obtain a total amount of the active ingredient of at least one polyethylene oxide, polyvinylpyrrolidone,

- 6 013645 lactose monohydrate, optionally at least one dye, to obtain a mixture of these various components;

c) adding to the mixture obtained in step b):

talc, magnesium stearate;

g) obtaining a tablet by direct compression of the mixture obtained in step c).

In some embodiments of the methods defined herein above, in step a), a third of the total amount of 1- (2,3,4-trimethoxybenzyl) piperazine or a pharmaceutically acceptable salt of 1- (2,3,4-trimethoxybenzyl) piperazine is administered and then in step b), the remaining two-thirds of the total amount of 1- (2,3,4-trimethoxybenzyl) piperazine or a pharmaceutically acceptable salt of 1- (2,3,4-trimethoxybenzyl) piperazine are added.

The 1- (2,3,4-trimethoxybenzyl) piperazine used in the methods defined in this invention above is preferably in the form of dihydrochloride.

The invention also relates to a tablet with a prolonged release of 1- (2,3,4-trimethoxybenzyl) piperazine, which is obtained in accordance with any of the processes defined above, while this tablet is characterized in that it has the following characteristics:

includes from 31.5 to 38.5 mg of 1- (2,3,4-trimethoxybenzyl) piperazine dihydrochloride, more preferably from 34 to 36 mg;

has a weight that ranges from 180 to 220 mg, more preferably from 195 to 205 mg;

has a disintegration time of more than 60 minutes;

has a tensile strength that ranges from 30 to 120 N, more preferably from 60 to 90 N.

A sustained release tablet of 1- (2,3,4-trimethoxybenzyl) piperazine, which is obtained in accordance with any of the methods defined above, in particular, characterized in that it has the following ίη νίΐτο dissolution profile 1- (2,3, 4-trimethoxybenzyl) piperazine in a buffer solution with a pH of 1.2:

the release of 35 to 65% of the total 1- (2,3,4-trimethoxybenzyl) piperazine 120 minutes after the start of the study;

the release of 65 to 85% of the total 1- (2,3,4-trimethoxybenzyl) piperazine within 240 minutes after the start of the study;

a release greater than or equal to 85% of the total 1- (2,3,4-trimethoxybenzyl) piperazine 600 minutes after the start of the study.

A sustained release tablet of 1- (2,3,4-trimethoxybenzyl) piperazine, which is obtained using one of the methods defined above, in particular, is characterized by having a ίη νίνο pharmacokinetic profile defined by at least one of the following parameters or a combination of the following parameters:

it is preferable that a 1- (2,3,4-trimethoxybenzyl) piperazine tablet according to the invention has a ίη νίνο pharmacokinetic profile characterized by an area under the plasma concentration curve from 0 to infinity (LIS _0-M ) from 600 to 1170 ng- h / ml;

preferably, when the tablet 1- (2,3,4-trimethoxybenzyl) piperazine in accordance with the invention has a ίη νίνο pharmacokinetic profile, characterized by a maximum plasma concentration (Stax) of from 40 to 110 ng / ml;

preferably, when the tablet 1- (2,3,4-trimethoxybenzyl) piperazine in accordance with the invention has a ίη νίνο pharmacokinetic profile characterized by a T _max value of from 2 to 6 hours; a person skilled in the art will understand that the T _max value is the time required to obtain the maximum concentration of the active ingredient in the blood plasma;

it is preferable that a tablet of 1- (2,3,4-trimethoxybenzyl) piperazine in accordance with the invention has a ίη νίνο pharmacokinetic profile characterized by a half-life in plasma (ΐ _1/2 ) of 4.5 to 10 hours.

In general, tablets according to the invention include tablets that are not film coated.

However, in some embodiments, a film coating may be provided if it does not modify the pharmacotechnical characteristics, in particular ίη νίΐτο of the dissolution profile of 1- (2,3,4trimethoxybenzyl) piperazine as compared to tablets not coated with a film.

The invention is also illustrated by the figures and examples set forth below.

FIG. 1 shows the dissolution curves of ίη νίΐτο of 1- (2,3,4-trimethoxybenzyl) piperazine obtained using a sustained release tablet of 1- (2,3,4-trimethoxybenzyl) piperazine for three different production batches.

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The ordinate indicates the percentage of 1- (2,3,4-trimethoxybenzyl) piperazine released into the solution compared to the initial amount of 1- (2,3,4-trimethoxybenzyl) piperazine contained in the tablet.

The abscissa shows the dissolution time, expressed in minutes.

FIG. 2 shows a comparison of the dissolution curves of a tablet that includes hydroxypropyl cellulose (composition No. 1) and 1- (2,3,4-trimethoxybenzyl) piperazine tablets according to the invention (composition No. 2).

The ordinate indicates the percentage of 1- (2,3,4-trimethoxybenzyl) piperazine released into the solution compared to the initial amount of 1- (2,3,4-trimethoxybenzyl) piperazine contained in the tablet.

The abscissa shows the dissolution time.

FIG. 3 shows the ίη νίνο pharmacokinetic profile of 1- (2,3,4-trimethoxybenzyl) piperazine.

The ordinate shows the concentration of 1- (2,3,4-trimethoxybenzyl) piperazine in blood plasma, expressed in ng / ml.

The abscissa shows the release time of 1- (2,3,4-trimethoxybenzyl) piperazine.

Examples

Example 1. A method for producing a sustained release pharmaceutical composition which comprises 1- (2,3,4-trimethoxybenzyl) piperazine dihydrochloride.

A. Products.

1- (2,3,4-Trimethoxybenzyl) piperazine dihydrochloride.

1- (2,3,4-Trimethoxybenzyl) piperazine dihydrochloride is sold by ΟΒΟΑδΥΝΤΗ or by CHEM1. The active ingredient is in the form of small crystals having an average particle diameter that varies from 11.828 to 16.056 microns, depending on the batch, with a unimodal distribution in the analysis using the dry particle size method using a laser using the сδΤΕΒδΙΖΕΒ® 2000 device, which is sold MAYUEKI company equipped with the δΟΊΡΟΟΟΌ 2000 device and provided with the ΜΑδΤΕΒδΙΖΕΒ® 2000 program, version 3.01 in accordance with the following method.

Static diffraction / scattering of light.

Options:

measuring range from 0.020 to 2000 μm, the required sample weight from 20 to 100 mg, the dispersion of the powder was dispersed using a UeShip device at a pressure of 2 bar

8C1COSSO 2000 percent fluctuation 70%

Anhydrous colloidal silica [European Pharmacopoeia (0434)].

The filler is used as an agent to increase the fluidity in formulations studied in order to ensure a good distribution of the active ingredient in the mixture intended for compaction.

Anhydrous colloidal silica is sold by ΌΕΟϋδδΑ under the trade name Aegoky® 200.

Any other material of equivalent quality supplied may replace it.

Polyethylene oxide.

This component is a water-soluble non-ionic polymer sold under the name ΡΟΕΥΟΧ ™ by ΌΟ \ ν. It acts as an agent to slow release. This filler also has good direct compression properties. It meets USP specifications (polyethylene oxide).

The ΡΟΕΥΟΧ ™ \ νδΡ 303 used is a high molecular weight filler (# 7000000). Its viscosity at 25 ° C in a 1% solution is from 7500 to 10,000 MPa / s.

Any other material of equivalent quality supplied may replace it.

Povidone [European Pharmacopoeia (0685)].

Povidone intended for the composition of the final product, in a concentration of 1.47%, is administered in the form of LIBERGE88® ΕΟΕ (see below), where it acts as a binding agent.

The povidone used is sold by ΒΑδΡ (BiFrge55® PFU). Any other material of equivalent quality supplied may replace it.

Lactose Monohydrate [European Pharmacopoeia (0187)].

This filler at a concentration of 40.63% acts as a diluent in the composition. It is administered in the form of LIBERGE88® ΕΟΕ (see below). Any other material of equivalent quality supplied may replace it.

- 8 013645

LIBERGE88® LCE.

This filler sold by ΒΑ8Ε is a direct compression agent. It consists of 96.5% lactose monohydrate and 3.5% povidone, both meeting the requirements of the European Pharmacopoeia. It combines its activities as a diluent and a binding agent. Any other material of equivalent quality supplied may replace it.

Magnesium Stearate [European Pharmacopoeia (0229)].

This vegetable filler in a concentration of 1% in the total mixture is used as a lubricant.

The magnesium stearate used for the development process is supplied by OnaggesT. Any other material of equivalent quality supplied may replace it.

Talc [European Pharmacopoeia (0438)].

This filler at a concentration of 2% in the total mixture is used as an anti-sticking agent and a flow agent.

The talcum used for the development process is supplied by b / eias. Any other material of equivalent quality supplied may replace it.

Dye.

The colorant is selected from Pigment Blend PB 23028, orange, which is sold by SOXOXOC lactose monohydrate [European Pharmacopoeia (0187)];

quinoline yellow (E104); Cochineal Red A (E124);

yellow orange 8 (E110).

Any other material of equivalent quality supplied may replace it.

B. Equipment.

All equipment is provided in accordance with the procedures carried out at the place of receipt and complies with the Rules for the Organization of Production and Quality Control of Medicines: СМА flask ΚΌΒΟΤΑΙΝΕΒ of acceptable capacity (or equivalent);

СМА mixer ΚΌΒΟΤΑΙΝΕΒ acceptable power (or equivalent); rotary tabletting machine ΕΕΤΤΕ (its equivalent);

Center punch: cylindrical 8P8;

stainless mesh strainer hole size: 0.800 mm.

C. Description of the manufacturing process.

All stages carried out in the production process were carried out in accordance with the Rules for the organization of production and quality control of medicines.

Preliminary stage: equipment - raw materials - documentation.

Checked the cleanliness of equipment and workplace;

conformity of production documentation;

compliance of source materials.

Weighed procedures were carried out.

Stage a). Premixing.

About one third of the amount of 1- (2,3,4-trimethoxybenzyl) piperazine dihydrochloride was pre-mixed with an equivalent volume of anhydrous colloidal silica in the flask by inverting it (or otherwise). Stirring was carried out until the mixture became homogeneous.

The pre-mixture was sieved through a 0.8 mm sieve. Checked for the absence of lumps and lumps.

Stage b). Mixing.

LiFrgeck® (or its equivalent) was introduced (a mixture of lactose monohydrate and povidone K30), the residue of 1- (2,3,4-trimethoxybenzyl) piperazine dihydrochloride and a dye (if necessary, previously sieved through a sieve with a hole size of 0.8 mm) into the mixer.

A preliminary mixture of the active ingredient / anhydrous colloidal silica was added. All polyethylene oxide was introduced.

The mixture was stirred for approximately 15 minutes at a speed of approximately 10 rpm. Step c). The final mixture.

Magnesium stearate and talc were added, previously sieved through a sieve with a hole size of 0.8 mm, into the mixer.

The mixture was stirred for approximately 5 minutes at a speed of approximately 10 rpm.

- 9 013645

Stage 6). Pressing.

The tablet machine was equipped with acceptable cylindrical punches with a diameter of 8 mm.

The machine was adjusted in such a way as to obtain tablets corresponding to the desired characteristics.

The final mixture was pressed.

Additional stage. Packaging.

The tablets were packaged in thermoformed RUS / RUES / aluminum blister packs. Ό. Qualitative and quantitative composition of the final composition.

The qualitative and quantitative composition of the final composition in relation to the active ingredient and excipients is given in detail in table. one.

Table 1

Component Name The roar nature Industrial recipe (kg / batch) Percent For one tablet (mg / tablet) Active ingredient • Dihydrochloride 1 (2,3,4trimethoxybenzyl) piperazine Fillers Anhydrous Colloidal Silica Polyethylene Oxide Lactose Monohydrate * Povidone * Magnesium stearate Talc Orange dye 17.50 0.20 37.00 40.63 1.47 1.00 2.00 0.20 35.00 0.40 74.00 81.26 2.94 2.00 4.00 0.40 105.00 1.20 222.00 243.78 8.82 6.00 12.00 1.20 Theoretical weight 200.00 mg 600.00 kg

References to Standards

Europe. Farm. (1741)

Europe. Farm. (0434)

Inside, Art. pharmacopeia for lek. funds of Europe. Farm.

(0187) Europe. Farm.

(0685) Europe. Farm.

(0229) Europe. Farm, (0438) Inside, Art. pharmacopeia for lek. * Li61rge88® LCE agents: lactose monohydrate 96.5 ± 2%;

povidone 3.5 ± 0.5%.

- 10 013645

Example 2. Pharmacotechnical characteristics of the composition in the form of tablets in accordance with the invention.

A. Ways.

Various methods for analyzing the pharmacotechnical characteristics of a tablet composition in accordance with the invention are detailed in table. 2 presented below.

table 2

Study Link Requirements CHARACTERISTICS Appearance - Round pill Colour - Orange STUDY Water content Average weight Inside, Art. pharmacopeia for lek. facilities * <5.0% 194.0 to 206.0 mg Weight uniformity Tensile strength Europe. Headlights. (2.9.5) Europe. Farm. (2.9.8) according to Europe. Farm. from 60 to 90 N Disintegration Europe. Farm. (2.9.1) > 60 minutes Brittleness Europe. Farm. (2.9.7) <1.0% Uniformity of active ingredient composition ** Europe. Farm. (2.9.6) according to Europe. Farm. Ιη νίΐΓΟ dissolution in buffer with pH 1.2 The copy below from 35% to 65% release in 120 minutes 65% to 85% release in 240 minutes £ 85% release in 600 minutes IDENTIFICATION AND ANALYSIS Active Ingredient Identification (HPLC) Prescribe presented below The release time for the sample is identical to the standard release time. The average content of active ingredient (HPLC) The copy below 33.25 to 36.75 mg

* Determined when using a sample weighing 3 g ± 5% using an electronic analyzer of water content such as MA 30 (or equivalent) at 100 ° C for 15 minutes ** This analysis is not mandatory in accordance with the European Pharmacopoeia, since the amount of active substance per tablet is more than 2 mg and more than 2% of the weight of the tablet; however, the analysis is carried out in pilot batches in order to verify that the distribution of the active substance in tablet samples taken at different times is appropriate.

Dissolution Analysis ίη νίΐτο.

Equipment.

Bo1a \ AT7 with rotating blades.

Spectrophotometer type Regkt E1tabba 20.

Working conditions:

Dissolution medium: buffer with a pH of 1.2 (Pharmacopoeia).

Amount of dissolution medium per flask: 1000 ml.

The speed of rotation of the blades: 50 rpm

Bath temperature: 37 ± 0.5 ° C.

Number of flasks: 6.

Number of units per flask: 1.

- 11 013645

Optical path circulation quartz cell: 1 cm.

Wavelength: 233 nm.

Sampling time: 15, 30, 60, 120, 180, 240, 360, 480, 600, 720, 840 min.

Peristaltic pump speed: 30 rpm

Standard reference solution.

When using a calibrated 500 ml flask (class A), 17.5 mg of accurately measured 1- (2,3,4-trimethoxybenzyl) piperazine was dissolved in the dissolution medium and adjusted to the mark using the same solvent.

Identification and method for evaluating the active ingredient.

Equipment.

HPLC system: HP 1100, LD1sp1.

Data Acquisition Software: LDC. Adyep !.

Working conditions.

Column type: Some 100 C18 5 μm, 150x4.6 mm, maintained at 40 ° C.

Wavelength: 240 nm.

Injection volume: 20 μl.

Retention time: approximately 10 min.

Run time: 15 min.

Flow rate: 1.2 ml / min.

Mobile phase:

2.87 g / l sodium heptanesulfonate solution adjusted to pH 3.0 with diluted H ₃ PO ₄ I 500 ml

Methanol 500 ml

Standard reference solution.

In a 50 ml calibrated flask (class A), 35 mg of precisely measured 1- (2,3,4-trimethoxybenzyl) piperazine in water I was dissolved and adjusted to the mark using the same solvent.

1.0 ml of the resulting solution was taken, introduced into a calibrated 10 ml flask (class A) and adjusted to the mark using the mobile phase.

B. Results.

The results of the analysis of the pharmacotechnical characteristics of the composition obtained in accordance with example 1 are detailed in table. 3.

Table 3

Research Party number 1 Party number 2 Party number 3 Average weight (mg) 200.4 mg 200.7 mg 199.3 mg Weight uniformity Compliant Compliant Compliant Disintegration 3 hours * 50 minutes, 32 sec > 60 minutes > 60 minutes Brittleness (%) <0.01 <0.01 0.04 Tensile strength (N) 87 87 91 Uniformity of active ingredient content Compliant Compliant Compliant The average content of active ingredient (HPLC) Ιη νΐίΓΟ dissolution in a buffer with a pH of 1.2 34.37 mg 34.85 mg 34.14 mg 35% to 65% release within 120 minutes 46.35% 43.15% 46.80% 65% to 85% release within 240 minutes 73.06% 70.12% 73.45% > 85% release in 600 minutes 100.45% 99.29% 102.25%

- 12 013645

The results of studies conducted on tablets made from samples of the mass product of each of the 3 tested batches were satisfactory:

average weight and weight uniformity were in compliance;

disintegration occurred after more than 60 minutes;

fragility was less than 1%;

tablet breaking for strength met the requirements (batch 4003 deviated only 1 N from the expected characteristics);

the uniformity of the content of the active ingredient met the requirements with a coefficient of variation of less than 5%;

ίη νίίτο dissolution in a buffer with a pH of 1.2 met the requirements for each time period; the average content of the active ingredient met the requirements.

In addition, these results are reproducible for 3 batches of the study.

Comparison of ίη νίίτο dissolution profiles of batches 1, 2 and 3 described in Table. 3, shown below, is shown in FIG. 1. The comparison results show a very high reproducibility of the dissolution characteristics of ίη νίίτο for each batch.

Example 3. A comparative study of dissolution profiles ίη νίίτο.

In this example, the ίη νίίτο dissolution profiles of two compositions were compared: composition No. 1, which includes hydroxypropyl cellulose, and composition No. 2, comprising the composition in accordance with the invention, respectively.

Compositions No. 1 and 2 had compositions detailed in table. 4.

Table 4

Components Composition Number 1 No. 2 (in accordance with the invention) % mg / tablet % mg / tablet 1 - (2,3,4-trimethoxybenzyl) piperazine 17.50 35.00 17.50 35.00 Anhydrous Colloidal Silica 0.20 0.40 0.20 0.40 Hydroxypropyl cellulose Poly ethylene oxide 37.00 74.00 - • - 37.00 74.00 EiFrzezz® 42.10 84.20 42.10 84.20 Magnesium stearate 1.00 2.00 1.00 2.00 Talc 2.00 4.00 2.00 4.00 Dye (pigment mixture 23028) 0.20 0.40 0.20 0.40 Theoretical tablet weight (mg) 200.00 200.00

Only composition No. 2 consisted of a composition in accordance with the invention. Composition No. 1 consisted of a composition that included hydroxypropyl cellulose rather than polyethylene oxide.

FIG. 2 shows a comparison of the dissolution profiles of ίη νίίτο between composition No. 1, which includes hydroxypropyl cellulose, and composition No. 2 in accordance with the invention.

The results of comparative studies showed the following:

composition No. 1, which includes hydroxypropyl cellulose, has a dissolution profile ίη νίίτο, which differs from that for composition No. 2 in accordance with the invention;

composition No. 2 in accordance with the invention has a dissolution profile ίη νίίτο, which makes it possible to obtain ίη νίνο pharmacokinetic profile (C _max , LIS, T _max and ί ₁₂ ), as described in example 4.

Example 4. The study of ίη νίνο dissolution profiles of the tablets of the pharmaceutical composition in accordance with the invention.

In this example, the pharmacokinetic characteristics of the 1- (2,3,4-trimethoxybenzyl) piperazine dihydrochloride tablet obtained in accordance with Example 1 were studied.

A. Method of analysis ίη νίνο pharmacokinetic data.

The level and extent of absorption of 1- (2,3,4-trimethoxybenzyl) piperazine dihydrochloride was evaluated after administration of the tablet composition of the invention that contains 35 mg of active ingredient.

The following pharmacokinetic values were determined:

the value of the area under the concentration curve in the blood plasma from 0 to infinity (AIS _0-M );

the value of the maximum plasma concentration (C _max );

ίη νίνο pharmacokinetic profile characterized by the value of T _max ;

plasma half-life (ί _1/2 ).

- 13 013645

This study was carried out as a double-blind study, which consisted of two phases of treatment for 48 hours in each case. Individuals were randomly assigned to different groups.

For this study, sequential administrations of a composition according to the invention were separated by periods of at least 7 and at most 14 days.

Individuals participating in the study were present for at least 11 hours before the administration of one of the compositions, and their presence continued for the next 24 hours.

The study was performed on 26 healthy men and women in order to conduct a study using at least 24 individuals that can be evaluated.

The test product consisted of modified release tablets containing 35 mg of 1- (2,3,4-trimethoxybenzyl) piperazine dihydrochloride as described in this patent, in particular in Example 1.

Individuals received a single oral dose of 35 mg of 1- (2,3,4-trimethoxybenzyl) piperazine dihydrochloride (1 modified release tablet) per treatment phase.

For treatment, 18 samples were collected with a volume of 10 ml of venous blood in heparinized glass tubes taken over a period of 48 hours. The total volume of blood collected from the individual did not exceed 380 ml, which excluded the repetition of studies in the laboratory (180 ml of blood was collected during treatment phases and 21 ml of blood were collected for laboratory studies before and after the study).

Samples of 10 ml of venous blood from each individual were collected in heparinized glass tubes, in particular, before oral administration of a tablet of the test composition in accordance with the invention, as well as at time points 1, 2, 3, 4, 4,5, 5, 5, 5, 6, 7, 8, 10, 12, 16, 24, 30, 36, and 48 hours after oral administration of the tablet.

The concentration of 1- (2,3,4-trimethoxybenzyl) piperazine dihydrochloride, expressed in ng / ml, was measured in each of the blood samples taken.

Statistical analysis of the parameters C _max , LIS (0-o>) and ΐ _1/2 included analysis of variance after the logarithmic transformation of the data. 90% confidence intervals were also calculated for each time point.

B. Results.

The data obtained during the study showed that 1- (2,3,4-trimethoxybenzyl) piperazine dihydrochloride tablets obtained in accordance with Example 1 have the following pharmacokinetic characteristics ίη νίνο:

the value of the area under the concentration curve in the blood plasma from 0 to infinity (LiC _0- „) ranged from 600 to 1170 ng-h / ml;

maximum plasma concentration (C _max ) ranged from 40 to 110 ng / ml;

the value of T _max ranged from 2 to 6 hours;

plasma half-life (ί _1/2 ) ranged from 4.5 to 10 hours

The ίη νίνο release profile of 1- (2,3,4-trimethoxybenzyl) piperazine dihydrochloride is shown in FIG. 3.

Claims (27)

CLAIM 1. A sustained release solid pharmaceutical composition which includes the active ingredient 1- (2,3,4-trimethoxybenzyl) piperazine or the pharmaceutically acceptable salt 1 (2,3,4-trimethoxybenzyl) piperazine, in combination with at least one polyethylene oxide, containing in an amount of from 5 to 80 wt.% polyethylene oxide (s) relative to the total weight of the composition and with at least one lubricating agent, optionally in combination with one or more pharmaceutically acceptable excipients. 2. The pharmaceutical composition according to claim 1, characterized in that the polyethylene oxide (s) have (have) a molecular weight that ranges from 100,000 to 10,000,000. 3. The composition according to claim 1 or 2, characterized in that it comprises from 20 to 50 wt.% Polyethylene oxide (s) in relation to the total weight of the composition. 4. Composition according to one of claims 1 to 3, characterized in that the lubricating agents are selected from magnesium stearate, calcium stearate, zinc stearate, talc, sodium stearyl fumarate, magnesium silicate, calcium silicate, tribasic calcium phosphate, stearic acid, sodium benzoate , hydrogenated vegetable oils, glyceryl behenate, light mineral oils and polyethylene glycol. 5. Composition according to one of claims 1 to 4, characterized in that it additionally includes one or more flow enhancing agents. 6. The composition according to claim 5, characterized in that the agents that increase the fluidity, are you - 14 013645 branes from colloidal silica, talc, silica, magnesium silicate and calcium silicate. 7. Composition according to one of claims 1 to 6, characterized in that it additionally includes one or more binding agents. 8. A composition according to claim 7, characterized in that the binders are selected from polyvinylpyrrolidone, polyvinylpyrrolidone-vinyl acetate copolymer, gum arabic hydrocolloid microcrystalline cellulose, dextrin, gelatin, glucose, guar gum, starch, pregelatinized starch, maltose, maltodextrin, and mixtures thereof. 9. Composition according to one of claims 1 to 8, characterized in that it additionally includes one or more diluents. 10. The composition according to claim 9, characterized in that the diluents are selected from lactose, including lactose monohydrate, microcrystalline cellulose, powdered cellulose, dicalcium phosphate, sucrose, starch or a derivative of starch, carbonates, including calcium carbonate, sodium or magnesium, bicarbonates, including calcium bicarbonate or sodium, mannitol, sucrose, xylitol, sorbitol, maltose, glucose, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulfate, dextrate, dextrin, fructose, kaolin, lactitol, de strozy, glyceryl palmitostearate, hydrogenated vegetable oil type I, as well as mixtures thereof. 11. Composition according to one of claims 1 to 10, characterized in that it includes: a) from 10 to 20 wt.% 1- (2,3,4-trimethoxybenzyl) piperazine or a pharmaceutically acceptable salt 1- (2,3,4-trimethoxybenzyl) piperazine; b) from 5 to 80% by weight of polyethylene oxide (s); c) from 0.5 to 5 wt.% one or more lubricating agents and b) from 0 to 85 wt.% additional (s) of filler (s) (effective percent are calculated relative to the total weight of the composition) 12. Composition according to one of claims 1 to 11, characterized in that it includes: a) from 15 to 20% by weight of 1- (2,3,4-trimethoxybenzyl) piperazine or the pharmaceutically acceptable salt of 1- (2,3,4-trimethoxybenzyl) piperazine; b) from 20 to 50% by weight of polyethylene oxide (s); c) from 0.5 to 5 wt.% one or more lubricating agents and b) from 30 to 65 wt.% additional (s) of filler (s) (weight percentages are calculated relative to the total weight of the composition). 13. Composition according to one of claims 1 to 12, characterized in that it includes: a) 17.5% by weight of 1- (2,3,4-trimethoxybenzyl) piperazine or the pharmaceutically acceptable salt of 1- (2,3,4-trimethoxybenzyl) piperazine; b) 37% by weight of polyethylene oxide (s); c) 1% by weight of one or more lubricating agents and b) 44.5 wt.% additional (s) filler (s). 14. Composition according to one of claims 1 to 13, characterized in that it includes: a) 17.5% by weight of 1- (2,3,4-trimethoxybenzyl) piperazine or the pharmaceutically acceptable salt of 1- (2,3,4-trimethoxybenzyl) piperazine; b) 37% by weight of polyethylene oxide (s) and c) 0.2 wt.% anhydrous colloidal silica; b) 40.63% by weight of lactose monohydrate; e) 1.47% by weight of polyvinylpyrrolidone; ί) 1 wt.% magnesium stearate; d) 2 wt.% talc and d) 0.2 wt.% of the dye (weight percentages are calculated relative to the total weight of the composition). 15. Composition according to one of claims 1 to 14, characterized in that it is presented in the form of tablets. 16. The composition according to claim 15, characterized in that each tablet comprises from 31.5 to 38.5 mg of 1- (2,3,4-trimethoxybenzyl) piperazine dihydrochloride, more preferably from 34 to 36 mg. 17. The composition according to claim 16, characterized in that it has a weight that ranges from 180 to 220 mg, more preferably from 195 to 205 mg. 18. Composition according to one of claims 15-17, characterized in that the tablet disintegration time is more than 60 minutes. 19. Composition according to one of claims 15-18, characterized in that the tensile strength of the tablet is from 30 to 120 N, more preferably from 60 to 90 N. 20. Composition according to one of claims 15-19, characterized in that the tablets have the following ίη νίίτο dissolution profile of 1- (2,3,4-trimethoxybenzyl) piperazine in a buffer solution with a pH of 1.2: release from 35 to 65% of the total 1- (2,3,4-trimethoxybenzyl) piperazine within 120 minutes after the start of the study; release from 65 to 85% of the total 1- (2,3,4-trimethoxybenzyl) piperazine over - 15 013645 240 min after the start of the study; the release is greater than or equal to 85% of the total 1- (2,3,4-trimethoxybenzyl) piperazine 600 minutes after the start of the study. 21. Composition according to one of the claims 15-20, characterized in that the tablets have a фарη νίνο pharmacokinetic profile, determined by at least one of the following parameters or a combination of these parameters: the area under the plasma concentration curve from 0 to infinity (LIS _0-M ) ranges from 600 to 1170 ng-h / ml; the maximum concentration in the blood plasma (Stax) ranges from 40 to 110 ng / ml; the value of T _max is from 2 to 6 hours and the half-life in blood plasma (ί _1/2 ) is from 4.5 to 10 hours. 22. The method of obtaining tablets with prolonged release of 1- (2,3,4-trimethoxybenzyl) piperazine, which includes the step of obtaining a mixture of 1- (2,3,4-trimethoxybenzyl) piperazine or a pharmaceutically acceptable salt 1- (2,3,4 -trimethoxybenzyl) piperazine with at least one polyethylene oxide, at least one lubricating agent and, optionally, one or more other pharmaceutically acceptable excipients, and then the step of preparing a tablet using direct compression of the mixture obtained in the previous step. 23. The method according to claim 22, characterized in that it comprises the following steps: a) obtaining a mixture of the following components: at least part of the total amount of 1- (2,3,4-trimethoxybenzyl) piperazine or a pharmaceutically acceptable salt of 1- (2,3,4-trimethoxybenzyl) piperazine and at least one flow agent; b) adding to the mixture obtained in step a), optionally, the amount of 1- (2,3,4-trimethoxybenzyl) piperazine or a pharmaceutically acceptable salt of 1- (2,3,4-trimethoxybenzyl) piperazine, which is necessary to obtain the total the amount of active ingredient; at least one polyethylene oxide; at least one binding agent; at least one diluent; optionally at least one dye; to obtain a mixture of these various components; c) adding to the mixture obtained in step b) at least one lubricating agent; at least one antistatic agent; b) obtaining a tablet using direct compression of the mixture obtained in step c). 24. The method according to one of paragraphs.22 and 23, characterized in that it includes the following steps: a) obtaining a mixture of the following components: at least part of the total amount of 1- (2,3,4-trimethoxybenzyl) piperazine or the pharmaceutically acceptable salt of 1- (2,3,4-trimethoxybenzyl) piperazine and anhydrous colloidal silica; b) adding to the mixture obtained in step a), optionally, the amount of 1- (2,3,4-trimethoxybenzyl) piperazine or a pharmaceutically acceptable salt of 1- (2,3,4-trimethoxybenzyl) piperazine, which is necessary to obtain the total the amount of active ingredient; at least one polyethylene oxide; polyvinylpyrrolidone; lactose monohydrate; optionally at least one dye; to obtain a mixture of these various components; c) adding talc to the mixture obtained in step b); magnesium stearate; b) obtaining a tablet using direct compression of the mixture obtained in step c). 25. The method according to one of claims 22 and 24, characterized in that: a) a third of the total amount of 1- (2,3,4-trimethoxybenzyl) piperazine or a pharmaceutically acceptable salt of 1- (2,3,4- trimethoxybenzyl) piperazine, and then administered in step b) the remaining two thirds of the total amount of 1- (2,3,4-trimethoxybenzyl) piperazine or a pharmaceutically acceptable salt 1- (2,3,4-trimethoxybenzyl) piperazine. 26. The method according to one of paragraphs.22-25, characterized in that the pharmaceutically acceptable salt 1- (2,3,4-trimethoxybenzyl) piperazine consists of 1- (2,3,4-trimethoxybenzyl) piperazine dihydrochloride. - 16 013645 27. Tablet with prolonged release of 1- (2,3,4-trimethoxybenzyl) piperazine, obtained using the method according to one of p-26, characterized in that it has the following characteristics: it contains from 31.5 to 38.5 mg of 1- (2,3,4-trimethoxybenzyl) piperazine dihydrochloride, more preferably from 34 to 36 mg; it has a weight that ranges from 180 to 220 mg, more preferably from 195 to 205 mg; it has a disintegration time of more than 60 minutes; it has a tensile strength that ranges from 30 to 120 N, more preferably from 60 to 90 N.