SK8632002A3 - Matrix tablet for sustained release of trimetazidine after oral administration - Google Patents

Abstract

The invention concerns a matrix object for prolonged release of trimetazidine or one of its additive salts to a pharmaceutically acceptable acid after oral administration, characterised in that the prolonged release is controlled by the use of a polymer derived from cellulose.

Description

Matrix tablet for prolonged release of trimethazidine after oral administration

Technical field

The present invention relates to a matrix tablet allowing sustained release of trimethazidine or a pharmaceutically acceptable acid addition salt thereof after oral administration.

Trimethazidine (1- (2,3,4-trimethoxybenzyl) piperazine) is a compound that, by maintaining the energy metabolism of cells exposed to hypotoxicity or ischemia, prevents the collapse of intracellular levels of adenosine triphosphate (ATP), thereby ensuring the functioning of ionic pumps and transmembrane penetration of sodium and potassium. .

BACKGROUND OF THE INVENTION

Trimethazidine dihydrochloride is currently used therapeutically for the prophylactic treatment of critical angina pectoris, in the case of chorioretinal attacks and for the treatment of dizziness of vascular origin (Meniere's disease, ear murmurs).

Up to now, the trimetazidine dihydrochloride has been administered orally at doses of 40 to 60 mg / day in tablets containing 20 mg of active ingredient or as an oral solution containing 20 mg of active ingredient / ml. Both forms are immediate release dosage forms. Patent FR 2,490,963 discloses an immediate release tablet form. Trimetazidine dihydrochloride is rapidly absorbed and rapidly eliminated from the body, with a plasma half-life of less than 6 hours, with the consequence that the administration of the active ingredient must be divided into 2 to 3 administrations per day to ensure sufficient plasma levels are maintained. . The most frequently required dosage regimen for treatment is three tablets per day. More frequent daily administration carries the risk that either an active lifestyle patient or elderly patients who are already taking multiple medicines will forget to take the medicine.

SUMMARY OF THE INVENTION

Due to the rapid absorption and the half-hour half-life, brothers of immediate release dosage forms result in low blood levels prior to further administration. It is known that it is important to maintain effective myocardial protection throughout the 24-hour period and especially in the early morning hours when ischemia has the most severe symptoms. Since immediate release dosage forms do not achieve complete coverage of daily use, the Applicant has developed a controlled release dosage form allowing perfect 24-hour coverage and ensuring sufficient blood levels between the two administrations while maintaining the efficacy of trimethazidine, maintaining a large plasma metabolism after each administration. cells exposed to hypoxia and ischemia and preventing a decrease in intracellular ATP levels.

It also allows the prevention of peripheral vasodilatory effects while stabilizing blood flow and tone.

The new formulation according to the invention also maintains the positive characteristics of the formulation described in patent FR 2,490,963, while allowing better coverage of daily needs, resulting in better compliance and durability.

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

This matrix tablet preferably administered twice daily allows for controlled release of the active ingredient, maintaining a large plasma peak after each administration. It allows to achieve levels above 70 pg / l in the patient's plasma after each administration and to maintain levels above 40 pg / l in the plasma until future administration, which is significantly different from that of the tablet of FR 2,490,963 administered three times a day.

Among the cellulose derivatives used in the matrix of the invention, mention may be made in particular of cellulose ethers such as hydroxypropylcellulose, hydroxyethylcellulose, hydroxymethylcellulose, methylcellulose and hydroxypropylmethylcellulose.

Preferably, the cellulose derivative is hydroxypropylmethylcellulose. The cellulose derivative polymer is 25 to 50% of the total weight of the tablet.

Hydroxypropylmethylcelluloses with a viscosity of from 100 cP to 100,000 cP can be used. The preferred viscosity is 4000 cP.

Various additives such as binders, diluents, lubricants and rheological additives are added to the hydrophilic matrix. Polyvidone is preferably used as a binder. The polyvidone content is 3-12% of the total tablet weight. The diluent used is preferably calcium hydrogen phosphate dihydrate, which exhibits better flowability and compressibility than other diluents, for example lactose monohydrate. The calcium hydrogen phosphate content is from 25 to 75% of the total weight of the tablet.

Among the lubricants, mention may be made, but not limited to, magnesium stearate, stearic acid, glyceryl behenate and sodium benzoate. A preferred lubricant is magnesium stearate. Finally, colloidal silicon dioxide is preferably used as the rheological additive.

The trimetazidine used in the matrix tablet of the invention is preferably in the form of the dihydrochloride.

The content of trimethazidine dihydrochloride represents 15 to 30% of the total weight of the tablet, preferably 15 to 18%.

The skilled person would surely assume that the release kinetics of the matrix tablets will depend on the nature and amount of the matrix constituent - which in this case is a cellulose derivative.

Surprisingly, however, it now appears that the release kinetics of the active ingredient from the matrix tablet of the invention are not affected by either the amount or the second cellulose derivative.

The various formulations prepared using, on the one hand, hydroxypropylmethylcellulose with different viscosities and, on the other hand, different amounts of the same type of hydroxypropylmethylcellulose showed the same release kinetics, leading to the conclusion that there is a specific synergism between the cellulose derivative and trimethazidine.

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

The wet granulation is performed by mixing trimethazidine, polyvidone and diluent and then wetting the mixture. The first step allows the formation of a hydrophilic environment around the active ingredient, which is useful for dissolution and also allows a maximum uniform unit dose.

In a second step, the granulate thus obtained is mixed with a cellulose derivative. Lubricant and rheological agent are then added to the mixture. The third step is the compression of the lubricated mixture obtained.

If desired, the tablets thus formed are then coated with conventional coating techniques.

The following examples illustrate the invention but do not limit it in any way. The matrix tablets described in the examples were prepared as follows:

- Step A: A mixture of trimethazidine, polyvidone and dibasic calcium phosphate dihydrate is prepared, followed by wetting the mixture with plenty of purified water, granulating and drying the granulate.

Step B: The granulate obtained in Step A is mixed with hydroxypropyl methylcellulose.

- Step C: Lubricate the mixture obtained in Step B with magnesium stearate and colloidal silicon dioxide as lubricants.

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Step D: Compress the lubricated mixture obtained in Step C on a rotary tablet press to obtain tablets with a hardness ranging from about 40 N to about 160 N when measuring refraction in the tablet diameter.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 shows the mean plasma concentrations of trimethazidine (in pg / L) after oral administration in the form of both F3 and IR (immediate release) to twelve healthy volunteers.

This curve clearly shows that the F3 dosage form allows for a controlled release while maintaining a large plasma peak after each administration.

The plasma level observed after each administration is about 90 pg / L and is practically not different from that obtained with the immediate release dosage form. At the end of 24 hours, the plasma level is greater than 40 pg / l, whereas in the immediate release formulation it is only about 25 pg / l.

DETAILED DESCRIPTION OF THE INVENTION

EXAMPLE 1

Formulations of different matrix tablets containing varying amounts of trimethazidine

Table 1: Unit compositions of 3 tablet types

compound Quantity (mg) Fiction f ₂ f ₃ trimetazidine dihydrochloride 60 30 35 hydroxypropyl methylcellulose 112 74 74 povidone 13.3 8.7 8.7 Calcium hydrogen phosphate dihydrate 92 85.9 80.9 Magnesium stearate 2.2 1 1 Anhydrous colloidal silica 0.5 0.4 0.4 Total weight of tablets 280 200 200

EXAMPLE 2

Example 2 shows that different amounts of hydroxypropylmethylcellulose do not affect the dissolution kinetics of the tablets.

Table 2: Unit compositions at varying amounts of HPMC

compound Quantity (mg) f ₄ f ₅ trimetazidine dihydrochloride 35 35 hydroxypropyl methylcellulose 54 94 povidone 10.1 7.3 Calcium hydrogen phosphate dihydrate 99.5 62.3 Magnesium stearate 1 1 Anhydrous colloidal silica 0.4 0.4 Total weight of tablets 200 200

Table 3 shows the percentage of compound released as a function of time for formulations F4 and F5.

Table 3: Release kinetics

Time (hours) Quantity of compound released (%) f ₄ f ₅ 1 41 38 2 59 59 3 80 77 4 97 96

EXAMPLE 3

Example 3 shows that different types of hydroxypropylmethylcellulose do not affect the dissolution kinetics of the tablets.

Table 4: Formulations / Different Types of HPMC

compound Quantity (mg) f ₃ f ₆ f ₇ Trimetazidine dihydrochloride 35 35 35 Hydroxypropylmethylcellulose 4000 cP 74 - - Hydroxypropylmethylcellulose 100 cP - - 74 Hydroxypropylmethylcellulose 100.000 cP - 74 - povidone 8.7 8.7 8.7 Calcium hydrogen phosphate dihydrate 80.9 80.9 80.9 Magnesium stearate 1 1 1 Anhydrous colloidal silica 0.4 0.4 0.4

Table 5 shows the percentages of compound released as a function of time for formulations F3, F6 and F7.

Table 5: Release kinetics

in Time (hours) Quantity of compound released (%) f ₃ f ₆ f ₇ 1 43 41 40 2 62 59 60 3 86 83 83 4 105 102 100

EXAMPLE 4 v

Plasma kinetics study

Plasma kinetics were studied after administration of the F3 matrix tablet described in Example 1 to twelve healthy volunteers. Administration was performed for 4 days at a dosage of two tablets daily. The plasma kinetics of the F3 type tablet were compared to the immediate release (IR) tablet kinetics administered 4 days at a dose of three tablets daily.

The unit formulation of an immediate release (IR) tablet is as follows:

trimetazidine dihydrochloride 20 mg Maize starch 26 mg mannitol 34 mg povidone 4 mg Magnesium stearate 1 mg talc 5 mg

The mean plasma concentration is shown in Figure 1.

Claims (17)

PATENT CLAIMS A matrix tablet for the sustained release of trimethazidine or a pharmaceutically acceptable salt thereof, characterized in that the sustained release is controlled by the use of a cellulose derivative polymer. Matrix tablet according to claim 1, characterized in that the cellulose derivative polymer is hydroxypropylmethylcellulose. Matrix tablet according to any one of claims 1 or 2, characterized in that the percentage of cellulose derivative represents 25 to 50% of the total weight of the tablets. Matrix tablet according to claim 1, characterized in that it also contains a binder, a diluent, a lubricant and a rheological agent. Matrix tablet according to claim 4, characterized in that the binder is polyvidone. Matrix tablet according to claim 5, characterized in that the percentage of polyvidone is from 3 to 12% of the total weight of the tablets. Matrix tablet according to any one of claims 4, 5 or 6, characterized in that the diluent is dibasic calcium phosphate dihydrate. The matrix tablet according to claim 7, characterized in that the percentage of dicalcium phosphate dihydrate is from 25 to 75% of the total weight of the tablet. A matrix tablet according to any one of claims 4, 5, 6, 7 or 8, characterized in that the lubricant is magnesium stearate and the rheological agent is anhydrous colloidal silica. The matrix tablet of claim 1, wherein the trimethazidine is in the form of the dihydrochloride. A matrix tablet according to claim 10, characterized in that the content of trimethazidine dihydrochloride is from 15 to 30% of the total weight of the tablet. Matrix tablet according to either of claims 10 or 11, characterized in that the content of trimethazidine dihydrochloride is 17.5% of the total weight of the tablet. Matrix tablet according to any one of claims 1 to 12, characterized in that it contains 35 mg of trimetazidine dihydrochloride, 74 mg of hydroxypropylmethylcellulose, 8.7 mg of polyvidone, 80.9 mg of calcium hydrogen phosphate dihydrate, 1 mg of magnesium stearate and 0.4 mg of colloidal silica. A matrix tablet according to claim 13, characterized in that it is administered twice a day. A matrix tablet according to claim 1, characterized in that it allows to achieve a plasma level of greater than 70 pg / L in humans after each administration and to maintain a plasma level of greater than or equal to 40 pg / L until the next administration. Process for preparing a matrix tablet according to any one of claims 1 to 13, characterized in that - wet granulation is performed by mixing trimethazidine, polyvidone and diluent and moistening the mixture, - the granulate thus obtained is mixed with a cellulose derivative, - then the lubricant and rheological agent are added, - the mixture obtained is pressed. A matrix tablet according to any one of claims 1 to 15 for use in the prophylactic treatment of angina, chorioretinal attacks and for the treatment of dizziness of vascular origin.