Title of Invention

MATRIX TABLET ENABLING THE PROLONGED RELEASE OF TRIMETAZIDINE AFTER ADMINISTRATION BY THE ORAL ROUTE

Abstract

"MATRIX TABLET ENABLING THE PROLONGED RELEASE OF TRIMETAZIDINE AFTER ADMINISTRATION BY THE ORAL ROUTE." The present invention relates to a matrix tablet enabling the prolonged release of trimetazidine or an addition salt thereof with a pharmaceutically acceptable salt, after administration by the oral route, characterised in that the prolonged release is controlled by the use of a cellulose derivative polymer

Full Text

FORM 2 THE PATENTS ACT 1970 [39 OF 1970] & THE PATENTS RULES, 2003 COMPLETE SPECIFICATION [See Section 10; rule 13] "MATRLX TABLET ENABLING THE PROLONGED RELEASE OF TRIMETAZIDINE AFTER ADMINISTRATION BY THE ORAL ROUTE." LES LABORATORIES SERVIER, of 12 place de la Defense, 92415 Courbevoie Cedex, France, The following specification particularly describes and ascertains the nature of this invention and the manner in which it is to be performed: ORIGINAL 1060/MUM/2000 23-11-2000 GRANTED 22-8-2007 The present invention relates to a matrix tablet enabling the prolonged release of trimetazidine, or an addition salt thereof with a pharmaceutically acceptable acid, after administration by the oral route. Trimetazidine, or 1-(2,3,4-trimethoxybenzyl)piperazine, is a compound which, by maintaining the energy metabolism of a cell exposed to hypoxia or ischaemia, avoids the collapse of the intracellular level of adenosine triphosphate (ATP). It thus ensures functioning of the ion pumps and sodium-potassium transmembrane flows and maintains cellular homeostasis. Trimetazidine dihydrochloride is currently used therapeutically for the prophylactic treatment of angina pectoris crisis, in chorioretinal attacks and for the treatment of vertigo of vascular origin (Meniere's vertigo, tinnitus). Trimetazidine dihydrochloride has, until now, been administered by the oral route at doses of from 40 to 60 mg/day, in the form of tablets containing 20 mg of active ingredient or a drinkable solution containing 20 mg of active ingredient per ml. Those two forms are immediate-release forms. Patent FR 2 490 963 describes the immediate-release tablet form. Trimetazidine dihydrochloride is rapidly absorbed and eliminated by the body, its plasma half-life being less than 6 hours, which means that administration of the active ingredient has to be split into 2 or 3 administrations per day in order to ensure sufficient plasma levels. The dosage regimen most frequently required during treatments is three tablets per day. Multiple daily administrations bear the risk of being forgotten both by patients leading an active life and by elderly patients already taking a number of medications. Because of the rapid absorption and the 6-hour half-life, such immediate-release forms result in low levels in the blood by the time of the next administration. It is known to be important to maintain effective myocardial protection throughout the 24-hour period and especially in the early morning when the consequences of ischaemia are most serious. Because complete coverage of the day is not achieved with the immediate-release form, the Applicant has developed a prolonged-release form enabling perfect 24-hour coverage, ensuring a sufficient level in the blood between two administrations whilst retaining a large plasma peak after each administration so as to maintain the efficacy of the trimetazidine, maintaining the energy metabolism of a cell exposed to hypoxia or ischaemia and avoiding the lowering of the intracellular level of ATP. It also allows peripheral vasodilator effects to be avoided, while stabilising blood flow rates and tensional effects. The new formulation according to the invention accordingly allows the positive characteristics of the formulation described in patent FR 2 490 963 to be retained while enabling better coverage of the day, which leads to better compliance and permanent protection. The present invention relates more especially to a matrix tablet which enables the prolonged release of trimetazidine, or a pharmaceutically acceptable salt thereof, after administration by the oral route and which is composed of a hydrophilic matrix characterised in that the prolonged release is controlled by the use of a cellulose derivative polymer. This matrix tablet, administrable preferably twice a day, enables prolonged active ingredient release to be obtained whilst retaining a large plasma peak on each administration. It allows plasma levels greater than 70 pg/1 to be obtained in humans after each administration and a plasma level greater than or equal to 40 fag/1 to be maintained until the next administration, which was not the case with the tablet described in patent FR 2 490 963 when administered 3 times per day. Among the cellulose derivatives used in the matrix according to the invention, there may be mentioned, more especially, cellulose ethers such as hydroxypropylcellulose, hydroxyethylcellulose, hydroxymethylcellulose, methylcellulose and hydroxypropyl methylcellulose. The cellulose derivative is preferably hydroxypropyl methylcellulose. The percentage of cellulose derivative polymer is from 25 to 50 % of the total mass of the tablet. Hydroxypropyl methylcelluloses that have a viscosity of from 100 cP to 100 000 cP may be used. The preferred viscosity is 4 000 cP. Various excipients are added to the hydrophilic matrix, for example binders, diluents, lubricants and flow agents. Among the binders, polyvidone is preferably used. The percentage of polyvidone is from 3 to 12 % of the total mass of the tablet. Among the diluents, calcium hydrogen phosphate dihydrate is preferably used, which provides better fluidity and better compressibility than other diluents such as lactose monohydrate. The percentage of calcium hydrogen phosphate is from 25 to 75 % of the total mass of the tablet. Among the lubricants, there may be mentioned, without implying any limitation, magnesium stearate, stearic acid, glycerol behenate and sodium benzoate. The preferred lubricant is magnesium stearate. Finally, colloidal silica is preferably used as flow agent. The trimetazidine used in the matrix tablets according to the invention is preferably in the dihydrochloride form. The percentage of trimetazidine dihydrochloride is from 15 to 30 % of the total mass of the tablet, preferably from 15 to 18 %. The person skilled in the art will generally consider the release kinetics of matrix tablets to be dependent on the nature and amount of the basic component of the matrix - in this case, namely, the cellulose derivative. It now appears, surprisingly, that the release kinetics of the matrix tablet according to the invention are influenced neither by the amount nor by the grade of the cellulose derivative used. Various formulations produced using, on the one hand, hydroxypropyl methylcelluloses of different viscosities and, on the other hand, variable amounts of the same grade of hydroxypropyl methylcellulose have exhibited equivalent release kinetics, which implies that there exists a specific synergy between the cellulose derivative and the trimetazidine. The present invention relates also to a process for the preparation of the matrix tablet. The matrix tablet may be prepared by wet granulation followed by compression, by dry granulation followed by compression, or by direct compression. The preparation process is preferably wet granulation followed by compression. The wet granulation is performed by mixing the trimetazidine, the polyvidone and the diluent, and then wetting that mixture. That first step enables a hydrophilic environment to be created around the active ingredient, which is beneficial for its dissolution, and also enables a unit dose that is as uniform as possible to be obtained. In a second step, the previously obtained granulate is mixed with the cellulose derivative. The lubricant and the flow agent are then added to the mixture. The third step is compression of the lubricated mixture previously obtained. The tablets thus formed are then, if desired, coated according to a conventional coating technique. The following Examples illustrate the invention but do not limit it in any way. The matrix tablets described in the Examples were prepared in the following manner : - Step A : Mixture of trimetazidine, polyvidone and calcium hydrogen phosphate dihydrate, then wetting of the mixture using a,sufficient amount of purified water, granulation and then drying of the granulate. - Step B : Mixture of the granulate obtained in Step A with hydroxypropyl methylcellulose. - Step C : Lubrication of the mixture obtained in Step B with magnesium stearate and colloidal silica. - Step D : Compression of the lubricated mixture obtained in Step C on a rotary tablet machine so as to obtain tablets having a hardness of about from 40 to 160 N, measured by breaking across a diameter. EXAMPLE 1 ;-: Formulations of different matrix tablets containing various amounts of trimetazidine Table 1 : Unitary formulae for 3 types of tablet Compound Amount (mg) F, F2 F3 Trimetazidine dihydrochloride 60 30 35 Hydroxypropyl methylcellulose 112 74 74 Polyvidone 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 mass of the tablet 280 200 200 EXAMPLE 2 : Example 2 shows that different amounts of hydroxypropyl methylcellulose do not have an influence on the dissolution kinetics of the tablet. Table 2 : Unitary formulae / variable amounts ofHPMC Compound Amount (mg) F4 F5 Trimetazidine dihydrochloride Hydroxypropyl methylcellulose Polyvidone Calcium hydrogen phosphate dihydrate Magnesium stearate Anhydrous colloidal silica 35 54 10.1 99.5 1 0.4 35 94 7.3 62.3 1 0.4 Total mass of the tablet 200 200 Table 3 shows the percentages of compound released as a function of time for the formulations F4 and F5. Table 3 : Release kinetics Time (h) Percentage of compound released (%) 1 2 3 4 F4 F5 41 59 80 97 38 59 77 96 EXAMPLE 3: Example 3 shows that different grades of hydroxypropyl methylcellulose do not have an influence on the dissolution kinetics of the tablet. Table 4 : Formulations / variable grades ofHPMC Compound Amount (mg) F3 F6 F7 Trimetazidine dihydrochloride Hydroxypropyl methylcellulose 4000 cP Hydroxypropyl methylcellulose 100 cP Hydroxypropyl methylcellulose 100 000 cP Polyvidone Calcium hydrogen phosphate dihydrate Magnesium stearate Anhydrous colloidal silica 35 74 8.7 80.9 1 0.4 35 74 8.7 80.9 1 0.4 35 74 8.7 80.9 1 0.4 Table 5 shows the percentages of compound released as a function of time for the formulations F3, F6 and F7. Table 5 : Release kinetics Time (h) Percentage of compound released (%) 1 F3 F6 F7 43 41 40 2 62 59 60 3 86 83 83 4 105 102 100 EXAMPLE 4 : Plasma kinetics study The plasma kinetics were studied after administration of the matrix tablet of formulation F3 described in Example 1 to 12 healthy volunteers. Administration was carried out for 4 days at the rate of two tablets per day. The plasma kinetics of the tablet of formula F3 were compared to those of an immediate-release (IR) tablet administered for 4 days at the rate of three tablets per day. The unitary formulation of the immediate-release (IR) tablet is as follows : Trimetazidine d (hydrochloride 20 mg Mainstarch 26 mg Mannitol 34 mg Polyvidone 4 mg Magnesium stearate 1 mg Talc 5 mg The average plasma concentration is given in Figure 1. We claim: 1. Matrix tablet for the prolonged release of trimetazidine or a pharmaceutically acceptable salt thereof, characterised in that the prolonged release is controlled by the use of a cellulose derivative polymer. 2. Matrix tablet as claimed in claim 1, wherein the cellulose derivative polymer is a hydroxypropyl methylcellulose. 3. Matrix tablet as claimed in either claim 1 or claim 2, wherein the 11 percentage of ceillulose derivative is from 25 to 50 % of the total mass of the tablet. 4. Matrix tablet as claimed in claim 1, wherein it also comprises a binder, a diluent, a lubricant and a flow agent. 5. Matrix tablet as claimed in claim 4, wherein the binder is polyvidone. 6. Matrix tablet as claimed in claim 5, wherein the percentage of polyvidone is from 3 to 12 % of the total mass of the tablet. 7. Matrix tablet as claimed in any one of claims 4, 5 or 6, wherein the diluent is calcium hydrogen phosphate dihydrate. 8. Matrix tablet as claimed in claim 7, wherein the percentage of calcium hydrogen phosphate dihydrate is from 25 to 75 % of the total mass of the tablet. 9. Matrix tablet as claimed in any one of claims 4, 5, 6, 7 or 8, wherein the lubricant is magnesium stearate and the flow agent is anhydrous colloidal silica. 10. Matrix tablet as claimed in claim 1, wherein the trimetazidine is in the dihydrochloride form. 11. Matrix tablet as claimed in claim 10, wherein the percentage of trimetazidine dihydrochloride is from 15 to 30 % of the total mass of the tablet. 12. Matrix tablet as claimed in either claim 10 or claim 11, wherein the percentage of trimetazidine dihydrochloride is 17.5 % of the total mass of the tablet. 13. Matrix tablet as claimed in any one of claims 1 to 12, wherein it contains 35 mg of trimetazidine dihydrochloride, 74 mg of hydroxypropyl methylcellulose, 8.7 mg of polyvidone, 80.9 mg of calcium hydrogen phosphate dihydrate, 1 mg of magnesium stearate and 0.4 mg of anhydrous colloidal silica. 14. Process for the preparation of a matrix tablet as claimed in any one of claims 1 to 13, wherein: - wet granulation is carried out by mixing trimetazidine, polyvidone and the diluent and then wetting that mixture, - the granulate thus obtained is mixed with the cellulose derivative, - the lubricant and the flow agent are then added, - the previous mixture is then compressed. Dated 23rd day of November 2000. (HRISHIKESH RAY CHAUDHURY) OF REMFRY & SAGAR ATTORNEYS FOR THE APPLICANTS

Documents:

1060-mum-2000-abstract(22-8-2007).doc

1060-mum-2000-abstract(22-8-2007).pdf

1060-mum-2000-cancelled pages(22-8-2007).pdf

1060-mum-2000-claims(granted)-(22-8-2007).doc

1060-mum-2000-claims(granted)-(22-8-2007).pdf

1060-mum-2000-correspondence(22-8-2007).pdf

1060-mum-2000-correspondence(ipo)-(1-9-2006).pdf

1060-mum-2000-drawing(22-8-2007).pdf

1060-mum-2000-form 1(22-8-2007).pdf

1060-mum-2000-form 1(9-1-2002).pdf

1060-mum-2000-form 13(22-8-2007).pdf

1060-mum-2000-form 18(21-12-2005).pdf

1060-mum-2000-form 2(granted)-(22-8-2007).doc

1060-mum-2000-form 2(granted)-(22-8-2007).pdf

1060-mum-2000-form 3(22-8-2007).pdf

1060-mum-2000-form 3(23-11-2000).pdf

1060-mum-2000-form 5(22-8-2007).pdf

1060-mum-2000-form 6(9-1-2002).pdf

1060-mum-2000-petition under rule 137(22-8-2007).pdf

1060-mum-2000-petition under rule 138(23-8-2007).pdf

1060-mum-2000-power of authority(22-8-2007).pdf

1060-mum-2000-power of authority(4-4-2001).pdf

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