BG65773B1 - Orally applicable tablet matrix for sustained release of trimetazidine - Google Patents

Abstract

The invention relates to a tablet matrix allowing sustained release of trimetazidine or its pharmaceutically acceptable salt after oral administration, characterized by that the sustained release is controlled through the use of a cellulose derivative polymer.

Description

Technical field

The present invention relates to a matrix tablet that permits the sustained release of trimethazidine, or an additional salt thereof, with a pharmaceutically acceptable acid after oral administration.

BACKGROUND OF THE INVENTION

Trimetazidine, or 1- (2,3,4-trimethoxybenzyl) piperazine, is a compound that prevents intracellular adenosine triphosphate (ATP) collapse by maintaining the energy metabolism of a cell exposed to hypoxia or ischemia. Thus, it ensures the functioning of ion pumps and sodium-potassium transmembrane transfer and maintains cellular homeostasis.

Trimetazidine dihydrochloride is currently used as a therapeutic agent for the prophylactic treatment of chest frog crises, for choreoretinal attacks, and for the treatment of vascular vertigo (Meniere's vertigo and tinnitus).

To date, trimethazidine dihydrochloride has been administered orally at a dosage of 40 to 60 mg daily, in the form of tablets containing 20 mg of the active substance or in the form of drinking solutions containing 20 mg of the active substance per milliliter. These two dosage forms are rapidly releasing forms. FR 2 490 963 describes a fast release tablet form. Trimetazidine dihydrochloride is rapidly absorbed and eliminated by the body and its plasma half-life is less than 6 hours, which means that the administration of the active substance should be divided into 2 or 3 doses daily to ensure sufficient plasma levels. Most often, the dosage regimen requires the administration of three tablets a day during treatment. Repeated daily intake of the drug poses risks of omission from both active and adult patients who take additional medicines.

Due to their rapid absorption and 6-hour plasma half-life, these rapidly releasing forms lead to low blood levels by the time of next intake. The importance of maintaining effective myocardial protection throughout the 24-hour period, and especially in the early morning when the consequences of ischemia are most serious, is known. As full day coverage cannot achieve full day coverage, the applicant has developed a delayed release formulation that allows perfect 24/7 coverage and provides sufficient blood levels between two doses while maintaining a large plasma peak after any application to maintain the efficacy of trimethazidine and, accordingly, the energy metabolism of cells exposed to hypoxia or ischemia and to avoid a decrease in intracellular ATP levels.

This form also avoids peripheral vasodilator effects while stabilizing blood circulation and tensile effects.

The new formulation according to the invention accordingly allows the positive characteristics of the formulation described in FR 2 490 963 to be retained, allowing for better daytime coverage, which in turn leads to a better drug intake scheme and continuous protection .

In particular, the present invention relates to a tablet matrix that enables the sustained release of trimethazidine or a pharmaceutically acceptable salt thereof by oral administration, and which consists of a hydrophilic matrix, characterized in that the sustained release is controlled by use of cellulose derivative polymer.

This matrix tablet, preferably administered twice daily, allows for the delayed release of the active ingredient to achieve a high peak plasma retention for each administration. It ensures that plasma levels in humans are higher than 70 µg / Ι after each administration and maintained at one plasma level higher than or equal to 40 µg / следва until the next administration, which was not provided in the case of the tablet,

65773 Bl described in FR 2 490 963 when administered three times daily.

Of the cellulose derivatives used in the matrix according to the invention, cellulose ethers such as hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxymethyl cellulose, methyl cellulose and hydroxypropyl methylcellulose may be mentioned.

A preferred cellulose derivative is hydroxypropyl methylcellulose. The percentage of cellulose derivative polymer is 25 to 50% of the total weight of the tablet.

Hydroxypropyl methylcellulose having a viscosity of 100 to 100,000 cP can be used. The viscosity is preferably 4,000 cP.

Various excipients are added to the hydrophilic matrix, for example, binders, diluents, lubricants and flowing agents. Of the binders, polyvidone is preferably used. The percentage of polyvidone is 3 to 12% of the total weight of the tablet. Preferably used by the diluents is calcium hydrophosphate dihydrate, which provides better fluidity and compressibility than other diluents, such as lactose monohydrate. The percentage of calcium hydrophosphate dihydrate is 25 to 75% of the total weight of the tablet.

Of the lubricants, magnesium stearate, stearic acid, glycerol behenate and sodium benzoate may be mentioned without limitation. A preferred lubricant is magnesium stearate. Finally, colloidal silicon is used as the preferred flowing agent.

The trimethazidine used in the tablet-matrix according to the invention is preferred in the dihydrochloride form.

The percentage of trimethazidine dihydrochloride is from 15 to 30% of the total weight of the tablet, preferably from 15 to 18%.

One of skill in the art will appreciate that the releasing kinetic properties of the matrix tablets will depend on the nature and amount of the main component of the matrix - in this case, the cellulose derivative.

It has surprisingly been found that the releasing kinetic properties of the tablet matrix according to the invention are not affected by either the amount or the quality of the cellulose derivative.

Different forms obtained using hydroxypropyl methylcellulose with different viscosity on the one hand, and different amounts of the same quality hydroxypropyl methylcellulose, on the one hand, have shown equivalent releasing kinetic properties. This suggests that there is a specific synergy between the cellulose derivative and trimethazidine.

The present invention also relates to a process for preparing a tablet matrix. The matrix tablet may be prepared by wet granulation followed by compression, by dry granulation followed by compression, or by direct compression. The preferred preparation method is wet granulation followed by compression.

Wet granulation is represented by mixing trimethazidine, polyvidone and diluent and moistening the mixture. This first step allows the creation of a hydrophilic environment around the active substance, which is useful for its dissolution and also allows for a single unit dose.

In the second step, the pre-formed granulate is mixed with the cellulose derivative. The lubricant and the flowing agent are added to the mixture.

The third step is compression of the previously obtained lubricant mixture.

The tablets thus obtained can be coated according to conventional wrapping technology.

The following exemplary embodiments illustrate the invention without limiting it in any way. The matrix tablets described in the exemplary embodiments were prepared in one of the following ways.

Step A. Mixing of trimethazidine, polyvidone and calcium hydrophosphate dihydrate, moistening the mixture by using sufficient amount of purified water, granulating and drying the granules.

Step B. Mixing the granule obtained in Step A with hydroxypropyl methylcellulose.

Step C. Lubrication of the mixture obtained in Step B with magnesium stearate and colloidal silicon.

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Step D. Compression of the lubricant mixture obtained in Step C on rotary tablet machines to obtain tablets having a strength of 40 to 160 N, measured by diameter fracture.

Examples of carrying out the invention

Example 1. Forms of tablet matrix, co-

Table 1: Uniform form for 3 types of tablets

Composition Quantity (td) Fi f ₂ F ₃ Trimetazidine dihydrochloride 60 30 35 Hydroxypropyl methylcellulose 112 74 74 Polyvidone 13.3 8.7 8.7 Calcium hydrophosphate dihydrate 92 85.9 80.9 Magnesium stearate 2.2 1 1 Colloidal silicon anhydrous 0.5 0.4 0.4 Total mass of the tablet 280 200 200

Example 2.

Example 2 showed that different amounts of hydroxypropyl methylcellulose did not affect the kinetic dissolution properties of the tablet.

Table 2: Uniform Form / different amounts of HPMC

Composition Quantity (td) F < F ₆ Trimetazidine dihydrochloride 35 35 Hydroxypropyl methylcellulose 54 94 Polyvidone 10.1 7.3 Calcium hydrophosphate dihydrate 99.5 62.3 Magnesium stearate 1 1 Colloidal silicon anhydrous 0.4 0.4 Total mass of the tablet 200 200

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Table 3 shows the percentages of compound released as a function of time for the F ₄ and F ₅ forms.

Table 3: Kinetic release properties

Time (h) Percentage of compound released (%) F _s 1 41 38 2 59 59 3 80 77 4 97 96

Example 3.

Example 3 shows that the different properties of hydroxypropyl methylcellulose do not affect the kinetic dissolution properties of the tablet.

Table 4: Forms / different qualities of HPMC

Composition Quantity (td) F ₃ f ₈ Ft Trimetazidine dihydrochloride 35 35 35 Hydroxypropyl methylcellulose 4000c 74 - - Hydroxypropyl methylcellulose 100 cP - - 74 Hydroxypropyl methylcellulose1 OOOOOP - 74 - Polyvidone 8.7 8.7 8.7 calcium hydrophosphate dihydrate 80.9 80.9 80.9 Magnesium stearate 1 1 1 Colloidal silicon anhydrous 0.4 0.4 0.4

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Table 5 shows the percent release of compound as a function of time for the forms F ₃ , F ₆ and F _? .

Table 5: Kinetic properties of released

Time (h) Percentage of compound released (%) Ez Is _in f ₇ 1 43 41 40 2 62 59 60 3 86 83 83 4 105 102 100

Example 4.

Plasma kinetic studies

Plasma kinetic studies were performed following the administration of a Form ₃ F tablet described in Example 1-12 to healthy volunteers.

The administration was for 4 days at a dosage of two tablets per day. The plasma kinetic properties of the Form F ₃ tablet were compared with those of the fast release tablet (IR) administered for 4 days at a dosage of three tablets per day.

The unitary form of a quick release tablet (IR) is as follows:

Trimetazidine dihydrochloride 20 mg Cornstarch 26 mg Mannitol 34 mg Polyvidone 4 mg Magnesium stearate 1 mg Talc 5 mg The average plasma concentration is above-

ceilings in Figure 1.

Figure 1. Plasma kinetics of trimethazidine

Mean plasma concentrations of trimethazvdine (in microg / Ι) after oral administration of the F ₃ form and rapid release form of 12 healthy volunteers

Figure 1: Plasma kinetics of trimethazidine

Mean plasma concentrations of trimethazidine (in µg / l) after oral administration of the F3 form and rapid-release form of 12 healthy volunteers

Time (h)

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This curve clearly indicates that the F, formulation permits a delayed release of trimethazidine, maintaining a high plasma peak for each administration.

The plasma level observed after each administration is close to 90 µg / Ι and hardly different from that obtained with the fast release form. At the end of 24 hours, the plasma level is higher than 40 µg / Ι, whereas with the fast release form, it is only about 25 µg / l.

Claims (14)

Claims A sustained release tablet of trimethazidine or a pharmaceutically acceptable salt thereof, characterized in that the sustained release is controlled by using a cellulose derivative polymer selected from hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxymethylcellulose, methylcellulose and methylcellulose. Matrix tablet according to claim 1, characterized in that the percentage of cellulose derivative is from 25 to 50% of the total weight of the tablet. Matrix tablet according to claim 1, characterized in that it also contains a binder, diluent, lubricant and a flowing agent. Matrix tablet according to claim 3, characterized in that the binder is polyvidone. 5. Tablet matrix according to claim 4, characterized in that the percentage of polyvidone is from 3 to 12% of the total weight of the tablet. Matrix tablet according to any of claims 3,4 or 5, characterized in that the diluent is calcium hydrophosphate dihydrate. 7. Tablet matrix according to claim 6, characterized in that the percentage of calcium hydrophosphate dihydrate is from 25 to 75% of the total weight of the tablet. 5 Matrix tablet according to any one of claims 3 to 7, characterized in that the lubricant is magnesium stearate and the flowing agent is anhydrous silica gel. The tablet matrix of claim 1, wherein the trimethazidine is in the dihydrochloride form. The tablet matrix according to claim 9, characterized in that the percentage of trimethazidine dihydrochloride is from 15 to 30% of the total weight of the tablet. 11. Tablet matrix according to claim 9 or 10, characterized in that the percentage of trimethazidine dihydrochloride is 17.5% of the total weight of the tablet. Matrix tablet according to any one of claims 1 to 11, characterized in that it contains 35 mg trimethazidine dihydrochloride, 74 mg hydroxypropyl methylcellulose, 8.7 mg polyvidone, 80.9 mg calcium hydrophosphate dihydrate, 1 mg magnesium stearate and 0.4 mg anhydrous silica gel. 13. A process for preparing a tablet matrix according to any one of claims 1 to 12, characterized in that the wet granulation is carried out by mixing trimethazidine, polyvidone and the diluent and the mixture is moistened; the granulate thus obtained is mixed with the cellulose derivative; a lubricant and a flowing agent are added; the resulting mixture is compressed. A matrix tablet according to any one of claims 1 to 12 for use in the prophylactic treatment of angina, choreoretinal attacks and for the treatment of vertigo of vascular origin.