The present invention relates to a controlled release pharmaceutical dosage forms of trimetazidine and the process of preparation thereof, suitable for once-daily dosing.
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 20 mg 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 European 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 either hydrophilic polymers in the matrix system or insoluble polymer in the reservoir system 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 leading to side effects due to sudden increase of the drug in the blood concentration.
To develop the controlled release pharmaceutical dosage forms for water-soluble drugs or their salts with constant release rate has always been a challenge to the formulators. While various trimetazidine compositions are available commercially, there still exists a need for alternative controlled release pharmaceutical dosage forms that provide the constant release rate with the desired in-vitro and in-vivo release profiles and could be used for long term treatment of angina and ensure better patient compliance.
Our scientists have now discovered a gastro-retentive controlled release pharmaceutical dosage form of trimetazidine and process of preparation thereof suitable for once daily administration, so that the incidences of such side effects are lowered and the duration of efficacy of the trimetazideine is prolonged with the desired in-vitro and in-vivo release profile.
Summary of the Invention
Hence in one general aspect, there is provided a controlled release pharmaceutical dosage form of trimetazidine comprising;
(i) trimetazidine or its pharmaceutically acceptable salts;
(ii) one or more gel-forming materials; and
(iii) one or more gas generating materials.
In another general aspect, there is provided a controlled release pharmaceutical dosage of the trimetazidine comprising;
(i) trimetazidine or its pharmaceutically acceptable salts;
(ii) xanthan gum and/or polyethylene oxide; and
(iii) sodium bicarbonate and/or citric acid.
In another general aspect, there is provided a controlled release pharmaceutical dosage of the trimetazidine comprising from about 5% to about 50% of trimetazidine or its pharmaceutically acceptable salts, about 5% to about 50% of one or more gel-forming materials, about 0% to about 50% of one or more gas generating materials, by weight based upon the total weight of the dosage form.
In another general aspect, there is provided a controlled release pharmaceutical dosage of the trimetazidine comprising from about 5% to about 50% of trimetazidine or its pharmaceutically acceptable salts, about 5% to about 50% of the xanthan gum and/or polyethylene oxide, about 0% to about 50% of the sodium bicarbonate and/or citric acid, by weight based upon the total weight of the dosage form.
In another general aspect, there is provided a controlled release pharmaceutical dosage of the trimetazidine comprising from about 10% to about 30% of trimetazidine or its pharmaceutically acceptable salts, about 10% to about 40% of one or more the gel-forming materials, about 5% to about 40% of one or more gas generating materials, by weight based upon the total weight of the dosage form.
In another general aspect, there is provided a controlled release pharmaceutical dosage of the trimetazidine comprising from about 15% to about 25% of trimetazidine or its pharmaceutically acceptable salts, about 25% to about 35% of one or more the gel-forming materials, about 10% to about 25% of one or more gas generating materials, by weight based upon the total weight of the dosage form.
In another general aspect, there is provided a controlled release pharmaceutical dosage of the trimetazidine comprising from about 15% to about 25% of trimetazidine or its pharmaceutically acceptable salts, about 25% to about 35% of xanthan gum and/or polyethylene oxide, about 10% to about 25% of sodium bicarbonate and/or citric acid, by weight based upon the total weight of the dosage form.
In another general aspect there is provided a controlled release pharmaceutical dosage of the trimetazidine, wherein the dosage form has an in vitro trimetazidine
release in USP I apparatus at 100 rpm, in 500 ml 0.1 N hydrochloric acid or in 500 ml
of pH 6.8 phosphate buffer as follows:
between 0 and 40% after 2 hours;
between 40 and 60% after 4 hours;
between 50 and 75% after 6 hours;
between 60 and 85% after 8 hours;
between 70 and 95% after 12 hours; and
more than 80% trimetazidine released after 20 hours.
In another general aspect, there is provided a process for the preparation of a controlled release pharmaceutical dosage form of trimetazidine wherein the process comprises the steps of:
(i) blending trimetazidine or its pharmaceutically acceptable salts, one or more gel-forming materials, one or more gas generating materials with one or more pharmaceutically inert excipients, (ii) optionally granulating the blend of step (i),
(iii) compressing the blend/granules of steps (i) or (ii) into tablets using appropriate tooling.
In another general aspect, there is provided a process for the preparation of a controlled release pharmaceutical dosage form of trimetazidine wherein the process comprises the steps of:
(i) blending trimetazidine or its pharmaceutically acceptable salts, one or more gel-forming materials, one or more gas generating materials with one or more pharmaceutically inert excipients, (ii) optionally granulating the blend of step (i), (iii) filling the blend/granules of steps (i) or (ii) into capsules of suitable size.
In another general aspect there is provided a method of treating angina in mammals, which comprises administering to a mammal in need thereof, the controlled release pharmaceutical dosage form of trimetazidine.
The controlled release pharmaceutical dosage form of the present invention may be administered in combination with other cardio therapeutic agents.
Detailed Description of the Invention
The term "controlled release" as used herein, includes any type of controlled- release including prolonged release, sustained release, modified release and extended release.
The term "trimetazidine" as used herein includes trimetazidine as well as pharmaceutically acceptable salts, enantiomers, hydrates, solvates, metabolites, prodrugs or mixture thereof, in particularly trimetazidine dihydrochloride salt. Controlled release pharmaceutical dosage forms of trimetazidine contain less than about 100mg of trimetazidine, in particular, from about 50 mg to about 80 mg of trimetazidine, in particular, about 70 mg of trimetazidine. Controlled release pharmaceutical dosage forms of the present invention comprise from about 5% to about 50% of trimetazidine, in particular from about 10% to about 30%, in particular from about 15% to about 25%, by weight of trimetazidine, based upon the total weight of the dosage form.
In one of the object, the present invention relates to controlled release
pharmaceutical dosage of the trimetazidine having the desired in-vitro and in-vivo
release profiles. The pharmaceutical dosage form of the present invention has a
constant release for up to 24 hours, and thus is suitable for once-a-day
administration, making it more patient complaint. It further overcomes the problem of
dose-dumping due to burst release of the drug as mentioned in the prior arts. The
controlled release pharmaceutical dosage form of the present invention has an in
vitro trimetazidine release in USP I apparatus at 100 rpm, in 500 ml 0.1 N
hydrochloric acid or in 500 ml of pH 6.8 phosphate buffer as follows:
between 0 and 40% after 2 hours;
between 40 and 60% after 4 hours;
between 50 and 75% after 6 hours;
between 60 and 85% after 8 hours;
between 70 and 95% after 12 hours; and
more than 80% trimetazidine released after 20 hours.
The term "gel-forming material" as used herein forms a stable structure that entraps the generated gas. With the passage of time, the gel-forming material results in a hydrodynamically balanced system whereby the matrix is retained in the stomach for an extended period of time. Simultaneously, the gel-forming polymer which provides a tortuous diffusion pathway for the drug, thereby resulting in controlled drug release. Specific examples of gel-forming materials include, but not limited to, polyethylene oxide, poloxamers, guar gum, locust bean gum, xanthan gum, cyclodextrin, arabic gum, gellan gum, karaya gum, alginic acid, pectic acid, casein, tara gum, tamarind gum, tragacanth gum, pectin, glucomannan, ghatti gum, arabino galactan, furcelleran, pullulan, carrageenan, alginic acid, glucosamine, chitosan, colloidal silica, pregelatinized starch, hydroxypropyl methyl cellulose, hydroxy propyl cellulose, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, polyvinyl alcohol, derivatives thereof, and the like. These materials can be used alone or in any combination, in particular xanthan gum and/or polyethylene oxide. Controlled release pharmaceutical dosage form of the present invention comprises from about 5% to about 50%, in particular from about 10% to about 40%, in particular from about 25% to about 35%, by weight of the gel-forming material based upon the total weight of the dosage form.
The term "xanthan gum" as used herein, is a high molecular weight biosynthetic polysaccharide gum produced by a pure-culture aerobic fermentation of a carbohydrate with Xanthomonas campestris. It is also known as corn sugar gum and is extraordinarily enzymatically resistant.
The term "polyethylene oxide" as used herein is a non-ionic homopolymer of the formula -(-0-CH2-CH2-)n-, wherein n represents the average number of oxyethylene groups, n generally being from about 2,000 to about 100,000. It is a water soluble resin which is available as a white powder in several grades having different molecular weights which vary in viscosity profile when dissolved in water. Polyethylene oxide is commercially available under the trade name Polyox™ from Union Carbide Corporation. Further commercially available polyethylene oxide products have an average molecular weight of about 100,000 to about 10, 000,000. Polyethylene oxide used in the present invention comprises the molecular weight ranging from about 100000 to about 7000,000.
Since the polyethylene oxide and xanthan gum have complimentary physicochemical properties, the control of the release patterns of trimetazidine can be easily attained by changing the mixing ratio of two polymers. For example, polyethylene oxide is preferentially used for the purpose of increasing viscosity rather than the solubilization of trimetazidine, and xanthan gum is prefertially used for the purpose of forming gels, together with the solubiliation of trimetazidine. The weight ratio between polyethylene oxide and xanthan gum may be varied preferably in the range of 1:0.1 to 1:10, in particular 1:1 to 1:10.
The term "gas generating material" as used herein may consist of a single substance or a gas generating couple known to produce gas upon contact with gastric fluid. The gas generating material interacts with an acid source triggered by contact with water or simply with gastric fluid to generate carbon dioxide or sulfur dioxide that gets entrapped within the hydrated gel matrix of the gel-forming composition. Specific examples of the gas generating material include, but not limited to, carbonates such as calcium carbonate or sodium glycine carbonate; bicarbonates such as sodium hydrogen carbonate or potassium hydrogen carbonate; sulfites such as sodium sulfite, sodium bisulfite, or sodium metabisulfite; and the like. These salts can be used alone or in combination with an acid source as a couple. The acid source may be one or more of an edible organic acid, a salt of an edible organic acid, or mixtures thereof. Specific examples of organic acids include, but not limited to, citric acid or its salts such as sodium citrate or calcium citrate; malic acid, tartaric acid, succinic acid, glycolic acid, fumaric acid, maleic acid, or their salts; ascorbic acid or its salts such as sodium or calcium ascorbate; glycine, sarcosine, alanine, taurine, glutamic acid, and the like, in particular combination of sodium bicarbonate and/or citric acid. Although hydrochloric acid is present in gastric juice, it is included for patients with subacidity. The content of the acidic material can be controlled in such a manner that the final matrix tablet is naturally foamed in purified water and floats. Controlled release pharmaceutical dosage form of the present invention comprises from about 0% to about 50%, in particular from about 5% to about 40% by weight, in particular from about 10% to about 25% by weight of the gas generating material based upon the total weight of the dosage form.
Further since, the gel containing a polyalkylene oxide is highly elastic, it easily retains carbon dioxide generated from the tablet of the present invention. Accordingly the density of the matrix is lowered in few minutes to allow the rapid floating of the preparation. Accordingly when the gel is rapidly formed and foamed at the same time, the desired controlled release can be achieved in the floating state. If the foaming mechanism is too fast, the shape of the matrix may collapse before the formation of the gel. Meanwhile, if the foaming mechanism is too slow, the gel is adhered to the gastric mucosa and subsequent foaming of the gel causes no floating. This problem can be easily solved by the tablet of the present invention in which the gas generating material and the gel-forming materials containing a polyalkylene oxide are homogeneously dispersed.
The term "pharmaceutical dosage form" as used herein includes any conventional dosage form such as tablet, capsule, granule, pellet, spheroid, pills, sachet and the like
The controlled release pharmaceutical dosage form of the present invention may further comprise one or more pharmaceutically inert excipients selected from the group consisting of diluents, binders, lubricant/glidants and coloring agents.
Specific examples of diluents include, but not limited to, dicalcium phosphate, dihydrogen calcium phosphate, tribasic calcium phosphate, calcium carbonate, calcium sulphate, lactose, microcrystalline cellulose, kaolin, pregelatinized starch, and the like, or combination thereof.
Specific examples of binders include, but not limited to, polyvinylpyrrolidone, gelatin, polyvinyl alcohol, gum acacia, and the like or combination thereof. Part or whole of the binder may be present in the intragranular portion or may be added in the binder solution for granulation.
Specific examples of granulating fluid include acetone, ethanol, isopropyl alcohol, methylene chloride or combination thereof.
Specific examples of lubricants/glidants include, but not limited to, colloidal silicon dioxide, stearic acid, magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, talc, hydrogenated castor oil, sucrose esters of fatty acid, microcrystalline wax, yellow beeswax, white beeswax, and the like, or combination thereof.
Coloring agents includes any FDA approved color for oral use.
The controlled release pharmaceutical dosage form of the may be prepared by the conventional techniques known in the art such as wet granulation, dry granulation, direct compression or extrusion-spheronization or hot melt extrusion. The wet granulation process involves use of water or any other suitable granulating fluid. The dry granulation may involve use of roller compacter or any suitable technique.
The controlled release pharmaceutical composition of the present invention may be further coated with one or more non-functional coating layers, if desired, comprising film forming polymers with/without coating additives.
Coating additives may be selected from the group consisting of plasticizers, opacifiers, coloring agents, lubricants/glidants, and the like.
Examples of film-forming polymers include ethylcellulose, hydroxypropyl methylcellulose, hydroxypropylcellulose, methylcellulose, carboxymethyl cellulose, hydroxymethylcellulose, hydroxyethylcellulose, cellulose acetate, hydroxypropyl methylcellulose phthalate, cellulose acetate phthalate, cellulose acetate trimellitate; waxes such as polyethylene glycol; methacrylic acid polymers such as Eudragit ®; and the like. Alternatively, commercially available coating compositions comprising film- forming polymers marketed under various trade names, such as Opadry® may also be used.
Specific examples of plasticizers include, but not limited to, triethylcitrate, dibutylsebacate, acetylated triacetin, tributylcitrate, glyceroltributyrate, monoglyceride, rape oil, olive oil, sesame oil, acetyltributylcitrate, acetyltriethylcitrate, glycerin sorbitol, diethyloxalate, diethyl phthalate, diethylmalate, diethylfumarate,
dibutylsuccinate, diethylmalonate, dioctylphthalate and the like, or combination thereof.
Specific examples of opacifiers include, but not limited to, titanium dioxide, manganese dioxide, iron oxide, silicon dioxide, and the like, or combination thereof.
Coating may be performed by applying the coating composition as solution/suspension/blend using any conventional coating technique known in the prior art such as spray coating in a conventional coating pan or fluidized bed processor; dip coating or compression coating.
Examples of solvents used for preparing solution/dispersion of coating substances include methylene chloride, isopropyl alcohol, acetone, methanol, ethanol, water and the like.
In one of the embodiment, controlled release pharmaceutical dosage form of trimetazidine may be prepared by a process comprising the steps of:
(i) blending trimetazidine or its pharmaceutically acceptable salts, one or more gel-forming materials, one or more gas generating materials with one or more pharmaceutically inert excipients; (ii) granulating the blend of step (i) with the binder solution; (iii) compressing the granules of step (ii) into tablets using appropriate tooling;
and (iv) optionally coating the tablets of step (iii) with Opdary® dispersion.
In another embodiment, controlled release pharmaceutical dosage form of trimetazidine may be prepared by a process comprising the steps of:
(i) blending trimetazidine or its pharmaceutically acceptable salts, one or more gel-forming materials, one or more gas generating materials with one or more pharmaceutically inert excipients; (ii) compressing the blend of step (i) into tablets using appropriate tooling; and (iii) optionally coating the tablets of step (ii) with Opdary® dispersion.
In another embodiment, there is provided a method of treating angina in mammals, which comprises administering to a mammal in need thereof, the controlled release pharmaceutical dosage form of trimetazidine. The controlled release pharmaceutical dosage form of the present invention may be administered in combination with other cardio therapeutic agents.
The invention may be further illustrated by the following examples, which are for illustrative purpose only and should not be construed as limiting the scope of the invention in any way.
Example 1
(Table Removed )
Example 2
(Table Removed )
Procedure of Examples 1 and 2:
1. Ingredients 1-6 (ingredients 1-7 of example 2) were passed through suitable sieve and transferred into rapid mixer granulator and mixed.
2. Polyvinylpyrrolidone was dissolved in isopropyl alcohol under continuous stirring.
3. The premix of step 1 was granulated using binder solution of step 2.
4. The wet mass of step 3 was dried in a suitable dryer and milled using suitable screen and transferred into the blender.
5. Ingredients 9-10 (ingredients 10-11 of example 2) were sifted through suitable sieve and transferred into step 4 blender and blended.
6. Lubricated blend of step 5 was compressed using suitable punches.
7. Opadry® was suspended in purified water under continuous stirring.
8. Tablets of step 6 were coated using step 7 coating dispersion.
Example 3
(Table Removed )
Procedure of Example 3:
1. Trimetazidine dihydrochloride was passed along with xanthan gum through suitable sieve.
2. The ingredients 3-7 were passed through suitable sieve and all the sifted ingredients were transferred into the blender, and mixed for suitable duration.
3. Ingredients 8-9 were passed through suitable sieve and transferred into blend of step 3 and blended for suitable duration.
4. The blend of step 3 was compressed into tablets using suitable punches.
5. Opadry® was suspended in purified water under continuous stirring.
6. Tablets of step 4 were coated using step 5 coating dispersion.
In-vitro Dissolution study
In-vitro trimetazidine release from the tablet prepared as per the pharmaceutical composition of the examples 1 and 2 were determined by dissolution of trimetazidine using the USP I apparatus at 100 rpm, in 500 ml 0.1 N hydrochloric acid for 20 hours. The results of the release studies are represented below in the Table 1.
Table 1: In-vitro Trimetazidine release (USP I apparatus at 100 rpm, in 500 ml 0.1 N hydrochloric acid)
(Table Removed )
In-vitro trimetazidine release from the tablet prepared as per the pharmaceutical composition of the examples 1-3 were determined by dissolution of trimetazidine using the USP I apparatus at 100 rpm, in 500 ml of phosphate buffer of pH 6.8 for 20 hours. The results of the release studies are represented below in the Table 2.
Table 2: In-vitro Trimetazidine release (USP I apparatus at 100 rpm, in 500 ml of phosphate buffer of pH 6.8)
(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 dosage forms and process can be made without departing from the scope of the invention as it is defined by the appended claims.

WE CLAIM
1. A controlled release pharmaceutical dosage form of the trimetazidine
comprising;
(i) trimetazidine or its pharmaceutically acceptable salts; (ii) one or more gel-forming materials; and (iii) one or more gas generating materials.
2. The controlled release pharmaceutical dosage form of claim 1, wherein the
dosage form has in vitro trimetazidine release in USP I apparatus at 100 rpm,
in 500 ml 0.1 N hydrochloric acid or in 500 ml of pH 6.8 phosphate buffer as
follows:
between 0 and 40% after 2 hours;
between 40 and 60% after 4 hours;
between 50 and 75% after 6 hours;
between 60 and 85% after 8 hours;
between 70 and 95% after 12 hours; and
more than 80% trimetazidine released after 20 hours.
3. The controlled release pharmaceutical dosage form of claim 1, wherein the gel forming material is selected from the group consisting of polyethylene oxide, poloxamers, guar gum, locust bean gum, xanthan gum, cyclodextrin, arabic gum, gellan gum, karaya gum, alginic acid, pectic acid, casein, tara gum, tamarind gum, tragacanth gum, pectin, glucomannan, ghatti gum, arabino galactan, furcelleran, pullulan, carrageenan, alginic acid, glucosamine, chitosan, colloidal silica, pregelatinized starch, hydroxypropyl methyl cellulose, hydroxy propyl cellulose, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, polyvinyl alcohol, derivatives or combination thereof, and the like.
4. The controlled release pharmaceutical dosage form of claim 3, wherein the gel forming material is xanthan gum and/or polyethylene oxide.
5. The controlled release pharmaceutical dosage form of claim 1, wherein the gas generating material is selected from the group consisting of calcium carbonate, sodium glycine carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium sulfite, sodium bisulfite, sodium metabisulfite, citric acid or its salts such as sodium citrate or calcium citrate, malic acid, tartaric acid, succinic acid, glycolic acid, fumaric acid, maleic acid, ascorbic acid or its salts such as sodium or calcium ascorbate, glycine, sarcosine, alanine, taurine, glutamic acid, combinations thereof and the like.
6. The controlled release pharmaceutical dosage form of claim 5, wherein the gas generating material is sodium bicarbonate and/or citric acid.
7. The controlled release pharmaceutical dosage form of any of the preceding claims may further comprise one or more pharmaceutically inert excipients selected from the group consisting of diluents, binders, lubricant/glidants and coloring agents.
8. The controlled release pharmaceutical dosage form of any of the preceding claims wherein the pharmaceutical composition may be selected from the group consisting of tablet, capsule, granule, pellet, spheroid, pills, sachet and the like.
9. The controlled release pharmaceutical composition of any of the preceding claims, wherein the pharmaceutical composition is prepared by a process comprising the steps of:
(i) blending trimetazidine, one or more gel-forming materials, one or more gas generating materials with one or more pharmaceutically inert excipients,
(ii) optionally granulating the blend of step (i),
(iii) compressing the blend/granules of steps (i) or (ii) into tablets using appropriate tooling.
10. A controlled release pharmaceutical dosage form of trimetazidine and process of preparation thereof, as described and illustrated in the examples herein.