TECHNICAL FIELD OF THE INVENTION
The present invention relates to new solid pharmaceutical compositions for the controlled release of trimetazidine suitable for once-daily dosing.
BACKGROUND
Trimetazidine [1-(2,3,4-trimethoxybenzyl piperazine] is a 3-ketoacyl-coenzyme A thiolase inhibitor with a cytoprotective effect, which by preserving the energy metabolisms of the cell exposed to the hypoxia or ischaemia, avoids the collapse of the intracellular rate of adenosine triphosphate (ATP). Thus it ensures the functioning of the ion pumps and the sodium-potassium transmembrane flux and maintains the cellular homeostasis.
Trimetazidine dihydrochloride is used therapeutically in the long-term treatment of angina pectoris. It is freely soluble in water and has two pKa values 4.32 and 8.95. Trimetazidine dihydrochloride is administered orally in doses of 40 to 60mg daily in divided doses as an immediate release preparation. It is quickly absorbed and eliminated by the organism with plasma half-life of around 6.0 +/- 1.4 hours and Tmax of around 1.8 +/- 0.7 hours. Since it has a shorter plasma half life, in practice 20mg preparation is given twice or thrice a day in order to ensure relatively constant plasma levels.
Servier had developed a modified-release dosage form containing 35mg for twice-daily administration, marketed under the brand name "VASTAREL MR". This dosage form was bioequivalent to the 20mg conventional thrice-a-day formulation of trimetazidine hydrochloride. The modified-release formulation is based on a hydrophilic matrix that utilizes polymers which swell in contact with gastrointestinal fluids to form gels. This formulation has been covered by Servier in a patent published as EP 1108424, which discloses a matrix tablet enabling prolonged release of trimetazidine comprised of cellulose derivative polymers.
The formulation described releases more than 90% of the drug in-vitro within a period of 4 hours.
European patent EP 0673649 also assigned to Servier describes pharmaceutical compositions for the prolonged release of trimetazidine wherein prolonged release is ensured by the reservoir system. The composition is prepared by compression of the active ingredient mixture and excipient, which are then coated with an insoluble polymer.
The prior art describes the use of hydrophilic polymers for controlling the release of trimetazidine from the controlled release pharmaceutical compositions. However for water-soluble salts such as hydrochloride salt of trimetazidine, it may result in burst release or dose dumping.
Although water-insoluble polymers have been employed as a coating polymer in reservoir systems, these systems produced a release profile where trimetazidine hydrochloride is not available for immediate absorption and pharmacological action. Other factors such as complexity of process, need for specialized equipment, incomplete release, etc. may also limit its use.
The PCT application WO 03043610 filed by Themis Laboratories, discloses a process for manufacturing microbeads, which enable "once a day" dosing for 60 mg dose of trimetazidine dihydrochloride per unit dose. The application further provides dissolution rates at different time periods which correspond to 24 hours therapeutic blood levels. Further, it discloses the dissolution rate to be not less than 65% w/w in 6 hours.
The European patent application EP 1195160 filed by USV, discloses a sustained release dosage form of trimetazidine that releases more than 90% of the drug in-vitro within a period of about 6 hours to about 8 hours.
A controlled in vitro release of trimetazidine is of at most importance in the context of in vivo drug profiles. Drug absorption from a solid dosage form following oral administration depends on the release of the drug substance from the drug product, the dissolution or solubilization of the drug under physiological conditions, and the permeability across the gastrointestinal tract. Because of the critical nature of the first two of these steps, in vitro dissolution may be relevant to the prediction of in vivo performance.
Therefore, taking into account the great therapeutic interest of trimetazidine, there exists a need in the state of the art for new pharmaceutical compositions for "once a day" dosing of trimetazidine, prepared by a simpler process that is cost-effective and yields a formulation with pH independent release of trimetazidine for at least 16 hours without any lag period.
The present invention provides new solid pharmaceutical compositions for the controlled release of trimetazidine suitable for once-daily dosing, in which the formulation exhibits a controlled in vitro release of trimetazidine in phosphate buffer at pH 6.8 of not less than about 75% after 16 hours when measured using USP Apparatus I at 100 rpm, thereby decreasing the incidence and severity of burst release or dose dumping. The pharmaceutical composition of the present invention uses a cost effective and rapid operation process.
SUMMARY
In one general aspect there is provided a pharmaceutical composition for controlled release of trimetazidine comprising:
(a) therapeutically effective amount of trimetazidine or its pharmaceutically acceptable salts,
(b) atleast one hydrophobic material, and
(c) one or more rate controlling polymer selected from a water-insoluble polymer, water-soluble polymer or water-swellable polymer,
wherein the composition exhibits in vitro release of trimetazidine or its pharmaceutically acceptable salt in phosphate buffer at pH 6.8 of not less than about 75% after 16 hours.
Controlled release compositions of trimetazidine suitable for once-daily dosing, contain less than about 100mg of trimetazidine.
Preferably the compositions contain about 50mg to about 80mg of trimetazidine. Particularly, controlled release compositions of trimetazidine suitable for once-daily dosing contain about 70mg of trimetazidine.
Controlled release formulations of the present invention comprise about 5 to 50% by weight of trimetazidine.
Examples of hydrophobic material include but are not limited to, one or more of fatty acids, long chain fatty alcohols, vegetable oil and glycerides of C6-C-18 fatty acids or mineral oil or mixtures thereof. The hydrophobic materials may comprise about 5 to about 90% by weight of the formulation. Particularly the hydrophobic materials may comprise about 20 to about 60% by weight of the formulation.
Examples of water-insoluble rate controlling polymers include but are not limited to, one or more of ethyl cellulose, cellulose acetate, cellulose acetate phthalate, cellulose acetate trimellitate, co-polymers of acrylate or methacrylate having a low quaternary ammonium content, poly vinyl acetate, or mixtures thereof. Particularly the water-insoluble polymers are ethyl cellulose, acrylic acid polymers or a combination of the two. The water-insoluble polymers may comprise about 5 to about 90% by weight of the formulation. Particularly the water-insoluble polymers may comprise about 20 to about 60% by weight of the formulation.
Examples of water soluble or swellable rate controlling polymers include but are not limited to, hydrxopropyl methylcellulose, hydroxypropyl cellulose, hydroxypropyl ethylcellulose, hydroxyethylcellulose, methylcellulose, xanthum gum and polyethylene oxide. The water soluble or swellable polymers may comprise about 5 to about 90% by weight of the formulation. Particularly the water soluble or swellable polymers may comprise about 7% to about 60% by weight of the formulation.
The controlled release composition may further comprise one or more pharmaceutically acceptable excipients selected from binders, fillers, disintegrants, lubricants, glidants, coloring agents and flavoring agents.
In another aspect there is provided a process for preparing a pharmaceutical composition for controlled release of trimetazidine comprising the steps of:
(a) dispersing trimetazidine in a molten mass of atleast one hydrophobic material;
(b) milling the material of step (a);
(c) mixing/blending the material of step (b) with a rate controlling polymer and other extragranular excipients;
(d) compressing the blend of step (c) into tablets or filling into capsules;
wherein the composition exhibits in vitro release of trimetazidine in phosphate
buffer at pH 6.8 of not less than about 75% after 16 hours.
The rate controlling polymer may be selected from water insoluble polymer alone or in combination with water soluble or swellable polymer.
More particularly the rate controlling polymer comprises ethyl cellulose either alone or in combination with xanthan gum. Particularly the polymer comprises about 20 to about 60% by weight of the formulation.
In yet another aspect there is provided a process for preparing a pharmaceutical composition for controlled release of trimetazidine comprising the steps of:
(a) dispersing trimetazidine in a molten mass of atleast one hydrophobic material;
(b) milling the material of step (a);
(c) mixing/blending the material of step (b) with rate controlling polymer comprising ethyl cellulose and xanthan gum; and other extragranular excipients;
(d) compressing the blend of step (c) into tablets or filling into capsules;
wherein the composition exhibits in vitro release of trimetazidine in phosphate
buffer at pH 6.8 of not less than about 75% after 16 hours.
Embodiments of the controlled release composition of the present invention may include one or more of the following features. For eg., the composition may be in the form of matrix-type dosage form, multiple unit dosage form, an osmotic dosage form or combinations of one or more dosage forms.
In one embodiment the controlled release pharmaceutical composition may be prepared as a combination of reservoir type and matrix type formulations which include controlled release coatings on controlled release matrices in which the active is uniformly dispersed.
In another embodiment, the composition is optionally coated with one or more layers comprising film forming agents and/or pharmaceutically acceptable excipients.
The details of one or more embodiments of the inventions are set forth in the description below. Other features, objects, and advantages of the invention will be apparent from the description and claims.
DESCRIPTION
The present invention relates to controlled release compositions of trimetazidine suitable for once-daily dosing, containing less than about 100mg of trimetazidine.
Preferably the compositions contain about 50mg to about 80mg of trimetazidine. Particularly, controlled release compositions of trimetazidine suitable for once-daily dosing contain about 70mg of trimetazidine.
Trimetazidine used herein should be understood as the base or any of its pharmaceutically acceptable salt thereof. Particularly, the salt is dihydrochloride. Controlled release formulations of the present invention comprise about 5 to 50% by weight of trimetazidine.
The term "controlled-release", as used herein, includes any type of controlled-release including prolonged release, sustained release, modified release and extended release.
The pharmaceutical compositions of the present invention can be administered orally in the form of tablets, such as monolithic tablets, tablet in a tablet, bilayered or multilayered tablets. The composition may also be in the form of capsules containing pellets, beads granules, multiparticulates, tablets, powder or osmotic dosage forms comprising a core covered with a semipermeable membrane containing one or more additional immediate release layers, and various other controlled release compositions known to a person skilled in the art.
The controlled release compositions of the present invention allow for highly reproducible release in vivo as the entire dosage form hydrates uniformly on contacting the gastrointestinal fluids. The controlled release compositions can be tailored to extend the release and absorption of the pharmaceutical active ingredient for up to about 2 hours to about 24 hours.
Examples of hydrophobic materials useful in the present invention include fatty acids such as stearic acid; long chain fatty alcohols such as, stearyl alcohol, cetyl alcohol, carnuba wax, beeswax and white wax. Examples of oils include vegetable oil and glycerides of C6-C18 fatty acids or mineral oil. The hydrophobic materials may comprise about 5 to about 90% by weight of the formulation. Particularly the hydrophobic materials may comprise about 7% to about 60% by weight of the formulation.
Examples of water-insoluble polymers include but are not limited to, one or more of ethyl cellulose, cellulose acetate, cellulose acetate phthalate, cellulose acetate trimellitate, co-polymers of acrylate or methacrylate having a low quaternary ammonium content, poly vinyl acetate, or mixtures thereof. Particularly the water-insoluble polymers are ethyl cellulose, acrylic acid polymers or a combination of the two. The water-insoluble polymers may comprise about 5 to about 90% by weight of the formulation. Particularly the water-insoluble polymers may comprise about 20 to about 60% by weight of the formulation.
Examples of water soluble or swellable polymers include but are not limited to, hydrxpropyl methylcellulose, hydroxypropyl cellulose, hydroxypropyl ethylcellulose, hydroxyethylcellulose, methylcellulose, xanthum gum and polyethylene oxide. The water soluble or swellable polymers may comprise about 5 to about 90% by weight of the formulation. Particularly the water soluble or swellable polymers may comprise about 7 to about 60% by weight of the formulation.
The controlled release composition may further comprise one or more pharmaceutically acceptable excipients.
The pharmaceutically acceptable excipients are those known to the skilled in the art and may be selected from binders, fillers, disintegrants, lubricants, glidants, coloring agents and flavoring agents.
Examples of binders include, but are not limited to, methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, gelatin, gum Arabic, ethyl cellulose, polyvinyl alcohol, pregelatinized starch, agar, tragacanth, sodium alginate and propylene glycol.
Controlled release formulations formed from such polymer blends, typically provide outstanding controlled-release performance, eliminating the potential performance variations. These formulations overcome the problems such as non-utilization of the total amount of drug and rapid drug release, due to independent usage of water-insoluble and water-soluble or water-swellable polymer respectively.
Examples of fillers or diluents include, but are not limited to, corn starch, lactose, white sugar, sucrose, sugar compressible, sugar confectioners, glucose, sorbitol, calcium carbonate, calcium dihydrogen phosphate dihydrates, calcium phosphate-dibasic, calcium phosphate-tribasic, calcium sulfate, microcrystalline cellulose, silicified microcrystalline cellulose, cellulose powdered, dextrates, dextrins, dextrose, fructose, kaolin, lactitol, mannitol, starch and starch pregelatinized.
Particularly, the fillers comprise microcrystalline cellulose, calcium dihydrogen phosphate dihydrate or a mixture of both.
Particularly formulations containing a mixture of microcrystalline cellulose and calcium dihydrogen phosphate dehydrate typically provide outstanding controlled-release performance for 24 hours.
Examples of disintegrants include, but are not limited to, starch, cross-linked carboxy methyl cellulose sodium, cross-linked polyvinyl pyrrolidone, sodium starch glycolate and low substituted hydroxy propyl cellulose.
Examples of lubricants and glidants include, but are not limited to, colloidal anhydrous silica, stearic acid, magnesium stearate, calcium stearate, talc, hydrogenated castor oil, sucrose esters of fatty acids, microcrystalline wax, yellow beeswax and white beeswax.
The coloring agents and flavoring agents of the present invention may be selected from any FDA approved colors and flavors for oral use.
The controlled release formulations of the present invention can be compressed into tablets or filled into capsules. Particularly tablets are compressed using direct compression.
The controlled release formulations of the present invention can optionally be coated with one or more layers comprising film forming agents and/or pharmaceutically acceptable excipients.
Coating may be performed by applying one or more film forming polymers with or without other pharmaceutically inert excipients. This may be done as a solution or suspensions using any conventional coating technique known in the prior art, such as spray coating in a conventional coating pan or fluidized bed processor, or dip coating.
Suitable film forming polymers include one or more of ethylcellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, methylcellulose, carboxymethylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, cellulose acetate, hydroxypropyl methylcellulose phthalate, cellulose acetate phthalate, cellulose acetate trimellitate, waxes, methacrylic acid polymers such as Eudragit® RL and RS, and mixtures thereof. The coating can also be performed using any commercially available ready to coat preparations such as opadry-AMB, opadry-white, opadry-clear, etc.
Suitable solvents used for making a solution/suspension of film forming polymer include one or more of methylene chloride, isopropyl alcohol, acetone, methanol, ethanol, water and mixtures thereof.
The present invention is illustrated below by reference to the following examples.
EXAMPLE 1
Controlled release tablets of trimetazdine dihydrochloride

(Table Removed)
Process:
1. Trimetazidine hydrochloride was dispersed in a molten mass of carnauba wax and stearic acid.
2. Dispersion of step 1 was stirred till it cooled.
3. Material of step 2 was milled and blended with ethyl cellulose; xanthan gum; microcrystalline cellulose; colloidal silicon dioxide & magnesium stearate.
4. Material of step 3 was compressed into tablets.
EXAMPLE 2
Controlled release capsules of trimetazdine dihydrochloride
Blend of step 3 of example 1 was filled into capsules.
EXAMPLE 3
Controlled release tablets of trimetazdine dihydrochloride

(Table Removed)
Process:
1. Trimetazidine hydrochloride was dispersed in a molten mass of carnauba wax and stearic acid.
2. Dispersion of step 1 was stirred till it cooled.
3. Material of step 2 was milled and blended with ethyl cellulose; xanthan gum; microcrystalline cellulose; calcium dihydrogen phosphate dehydrate; colloidal silicon dioxide & magnesium stearate.
4. Material of step 3 was compressed into tablets.
5. Tablets of step 4 were coated with the coating composition.
EXAMPLE 4
Controlled release capsules of trimetazdine dihydrochloride
Blend of step 3 of example 3 was filled into capsules.
The controlled release formulations prepared according to the present invention were subjected to in vitro drug release test which utilizes the United States Pharmacopea (USP) Apparatus 1 (rotating basket) at 100 rpm with 500 ml of phosphate buffer at pH 6.8 and 37°C. The results of the study are given in Table
1.
Table 1: Drug Release (DR) of Trimetazidine CR compositions prepared as per present invention in Phosphate buffer pH 6.8, 500 ml, USP 1 at 100 rpm.

(Table Removed)
In vivo bioequivalence study
In vivo performance of a single dose of trimetazidine controlled release formulations administered once daily (OD) were evaluated with respect to three doses of VASTAREL 20 mg tablets (Immediate release product of trimetazidine) administered thrice daily and two doses of VASTAREL MR 35 mg tablets (Modified release product of trimetazidine) administered twice daily under fasting and fed conditions in healthy male volunteers. Pharmacokinetic parameters Cmax (Peak serum concentration); AUCt(Area under the plasma concentration vs. time curve); & AUCinf (Area under the plasma concentration vs. time curve upto infinity) were calculated from the data obtained. The results of the study are given in Table 2 & 3.
Table 2: Pharmacokinetic data for controlled release (CR) formulations prepared as per present invention. Once daily vs. three doses of VASTAREL 20 mg tablets (containing trimetazidine 20 mg) administered thrice daily:

(Table Removed)
Table 3: Pharmacokinetic data for controlled release formulations prepared as per present invention. Once daily vs. two doses of VASTAREL MR 35 mg tablets (containing trimetazidine 35 mg) administered twice daily:

(Table Removed)
While there has been shown and described what are the preferred embodiments of the invention, one skilled in the pharmaceutical formulation art will appreciate that various modifications in the formulations and process can be made with out departing from the scope of the invention as it is defined by the appended claims.

WE CLAIM:
1. A pharmaceutical composition for controlled release of trimetazidine
comprising:
(a) therapeutically effective amount of trimetazidine or its pharmaceutically acceptable salts,
(b) atleast one hydrophobic material and
(c) one or more rate controlling polymer selected from a water-insoluble polymer, water-soluble or water-swellable polymer,
wherein the composition exhibits in vitro release of trimetazidine in phosphate buffer at pH 6.8 of not less than about 75% after 16 hours.
2. The pharmaceutical composition according to claim 1, wherein the in vitro release is measured by a drug release test which utilizes the United States Pharmacopoeia (USP) Apparatus 1 (rotating basket) at 100 rpm with 500 ml of phosphate buffer at pH 6.8 and 37°C.
3. The pharmaceutical composition according to claim 1, wherein the hydrophobic material comprises fatty acids, long chain fatty alcohols, vegetable oil and glycerides of C6-C18 fatty acids or mineral oil or mixtures thereof.
4. The pharmaceutical composition according to claim 1, wherein the water-insoluble polymer comprises one or more of ethyl cellulose, cellulose acetate, cellulose acetate phthalate, cellulose acetate trimellitate, copolymers of acrylate or methacrylate having a low quaternary ammonium content, poly vinyl acetate, or mixtures thereof.
5. The pharmaceutical composition according to claim 1 wherein the water soluble or swellable polymers comprises one or more of hydrxpropyl methylcellulose, hydroxypropyl cellulose, hydroxypropyl ethylcellulose, hydroxyethylcellulose, methylcellulose, xanthum gum and polyethylene oxide or mixtures thereof.
6. The pharmaceutical composition according to claim 1, wherein the composition further comprises pharmaceutically acceptable excipients selected from one or more of fillers, binders, disintegrants, lubricants, glidants, coloring agents and flavoring agents.
7. A process for preparing a pharmaceutical composition for controlled release of trimetazidine according to claim 1 comprising the steps of:

(a) dispersing trimetazidine in a molten mass of atleast one hydrophobic material;
(b) milling the material of step (a);
(c) mixing/blending the material of step (b) with a rate controlling polymer and optionally other extragranular excipients;
(d) compressing the blend of step (c) into tablets or filling into capsules;
wherein the composition exhibits in vitro release of trimetazidine in
phosphate buffer at pH 6.8 of not less than about 75% after 16 hours.
8. The process according to claim 7, wherein the tablet is a single monolithic matrix, bilayered, core coated or tablet in a tablet and the capsules contain pellets, beads, granules, multiparticulates, tablets or powder.
9. The pharmaceutical composition according to the preceding claims, wherein the composition is further coated with one or more layers comprising film forming agents and/or pharmaceutically acceptable excipients.
10. A pharmaceutical composition for the controlled release of trimetazidine substantially as described herein.