Title of Invention

A PROCESS OF PRODUCING A SUSTAINED RELEASE TRIMETAZIDINE DIHYDRACHLORIDE COMPOSITION

Abstract

A process of producing a sustained release trimetazidine dihydrochloride composition which can be compressed. Trimetazidine dihydrochloride and hydrophobic polymer and/or other hydrophobic material are granulated by hot melt or extrusion followed by sizing and mixing with auxiliary substances. The dried granulated product may be compressed into tablets which may be coated with a film envelope for taste neutralization.

Full Text

FORM 2 THE PATENTS ACT 1970 As amended by the Patents (Amendment) Act 1999 COMPLETE SPEOMCATION (SEE SECTION 10) TITLE A process of producing a sustained release tiimetaadine dihydrfu:;hloride composition APPLICANTS USV Limited, BSD Marg, Govandi Station Road, Govsctidi, Mumbai 400088, Maliarashtra, India, an Indian company INVENTORS Under Section 28(2) Dr Gidwani Suresh Kumar, Singtiuikar Purashottam and Tewari Prashmit Kumar, dl Indian nationals and of USV Limited, BSD Marg, Govandi Station Road, Govandi, Mumbai 400088, Mdiarashtra, India This invention relates to a process of producing a sustained release trimetazidine dihydrochloride composition. This invention also relates to sustained release trimetazidine pharmaceutical compositions and sustained release matrix pharmaceutical compositions containing 60 mg of trimetazidine dihydrochloride and hydrocolioid forming materials and or hydrophobic pol^^Tners and or other hydrophobic materials as a retardant, which release trimetazidine in a sustained and reproducible manner over a prolonged period of time to achieve the sustained effect of trimetazidine over a 24 hour period after oral administration. Trimetazidine dihydrochloride [l-(2, 3, 4-trimethoxybenzyl)-piperazine dihydrochloride] composed of formula is freely soluble in water, about 80%. It has two pKa values 4.32 and 8.95. It regulates ionic and extra cellular exchanges, correcting the abnormal flow of ions across the cell membrane caused by ischemia and preventing cellular edema caused by anoxia. Thus it ensvires the function.! ng of the ion pumps and tJio sodium-potassium transmembrane flux and maintains the cellular homeostasis. Trimetazidine dihydrocliloride is used therapeutically, as a coronary vasodilator for the prophylactic treatment of anginal chest pain attack and during such attacks, during chorioretinal attacks as well as- for the treatment of giddiness of vascular origin (Vertigo of Maniere, acouphenous). 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 T max 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 but, due to the fact that it is absorbed quickly, these immediate release forms lead to maximum plasma levels immediately after administration and to a very low plasma level at the time of the next dose, r^sultinq in qreat differnncoG in peak and trough plar.ma levels at steady safe drug in the long treatment of chronic ischemic disorders. This compels the necessity of fabricating the immediate release dosage form into a sustained release once-a-day preparation for achieving regular and constant plasma levels, which is also favourable for compliance of the patient to his treatment. U.S. Patent 4,814,176 and U.S. Patent 4,755,544 by Makino, Yuji; Matugi, Hideo; Suzuki, Yoshiki; describes a sustained release preparation comprising a) chitin, chitosan or a mixture thereof or a) non-anionic cellulose ether, and b) anionic polymer compounds (Ganterz®) such as those having a carboxyl group, a sulfonic group or a group capable of providing the same. It mentions trimetazidine as one of the examples in the description which can be included in such systems but does not provide any detailed study on trimetazidine as a sustained release preparation. European Patent Application No. 0 673 649 by Huet de Barochez describes pharmaceutical compositions for the prolonged release of trimetazidine or of one of its pharmaceutically acceptable salts characterized in that prolonged release of trimetazidine is controlled by the use of a mixture of water insoluble polymer and a plasticizer coated on a reservoir system containing 80mg of trimetazidine dihydrochloride. However the in-vivo bioavailability study conducted on 12 volunteers shows steady state plasma concentration (Css) at around llGng/ml with 80mg dose. As reported in the literature, the maximum dose which usTially should be formulated in a sustained release dosage form should not exceed the total dose administered by conventional forms during the maintenance period. Optimization of sustained release dosage form design requires minimization of the total dose delivered and maximization of the duration of the drug release. However, European Patent Application No. 0 673 649 describes 80mg dose for prolonged release which is quite high compared to the total conventional dose, 40 to 60mg, in divided doses. In the present invention the same required steady state plasma concentration of trimetazidine can be achieved with just 60mg dose fabricated in a sustained release once-a-day matrix composition. Catherine Ilarpey, Pnncnle clauser, Claude I.abrid, vTcan-Lonis Froyria (Cardiovascular Drug Koviews, 19B0), determined the pharmacokinetic parameters after single and repeated doses of 20mq trimotazidine dihydrochloride. Their study shov/s steady state plasma concentration of 8 4.8 ± 14.8ng/ml with repeated b.l-d, and maximum plasma concentration C„,,., of 53.6 ± 9.0ng/ml v/ith single dose administration. Since a sustained release dosage form should give approximately the same steady state plasma concentration as that achieved with an immediate release dosage form, it has been decided to achieve Css around 84ng/ml with the sustained release compositions of the present invention. The present invention is based on the scientific calculation of the dose of trimetazidine dihydrochloride desired, based on the data available from in~vivo studies which are well documented in the scientific literature. The model used here is based on the mathematical equations provided by Dobrinska and Welling (1975) which give fairly accurate calculations about loading dose and maintenance dose for achieving sustained release effect. The dose of trimetazidi ne dihydrncliloridc is calculated bv considering the follov/ing phai-macokinetic values from the literature. Plasma concentration Css = 8'1ng/:iil Elimination half life t 1/2 - 6.0 honrs. Volume of distribution Vd = 294 litres. T max = 1.8 ± 0.7 hours. Using the Dobrinska and Welling model, the calculated loading dose is 15.87Cmg, the maintenance dose is 44.000mg and the total dose is 59.r;Bmg of trimetazidine dihydrochloride for achieving a sustained release effect for 2 4 hours. The object of the present invention is to prepare a composition containing 60mg of trimetazidine dihydrochloride by suitable technology shov/ing demonstrable release rate and facilitated in-vivo absorption for the desired period. The emphasis is to develop a simple monolithic system composed of hydrocolloid forming materials and/or hydrophobic polymers and/or other hydrophobic materials and other excipients with improved kineticr; of extended release doasge forms, and the simplest method producing it . According to the invention there is provided a process of producing a sustained release trimetazidine dihydrochloride composition comprising granulating trimetazidine dihydrochloride and hydrophobic material by hot melt granulation or by extrusion, sizing and mixing the granules with auxiliary substances. The monolithic (e.g. tablet form) sustained release system of the invention is a homogeneous system composed of active drug in an amount within the range of 8 to 50% by weight, preferably 10 to 30% by weight and one or more hydrocolloid forming materials arid/or one or more hydrophobic polymers and/or one or more other types of hydrophobic material in an amount within the range of about 20 to 80%) by weight, preferably 30 to 60%) by weight, based on the weight of the pharmaceutical composition. The hydrocolloid forming material which may be employed for the monolithic sustained release system in the present invention includes, but is not limited to : hydroxypropyl methyl cellulose (e.g. Methocel®), hydroxy propyl cellulose (e.g. Klucel®), polyethyleneoxide (average molecular weight 600,000 to 5,000,000); sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, calcium ammonium alginate, sodium alginate, potassium alginate, calcium alginate, propylene glycol alginate, alginic acid, polj^inyl alcohol, povidone, carbomer, potassium pectate, guar gum, xanthane gum. Mixtures of the hydrocolloid forming material may be employed in a weight ratio to another hydrocolloid forming material within the range of about 1: 0.1 io 0.1 : 1, preferably about 1 : 0.5 to 0.5 : 1 Hydrophobic polymers wliich may Ije employed for the monolithic sustained release syr-,tem in the present indention include, but are not 1 i [r i l;od to: stearic acid, glycerylmonostearate, glyceryl behenate, glyceryl monoolonte, glyceryl palmi tosl:oarnte, microcrystalline v;ax, stearyl alcohol, cetyl alcoliol , cetostearyl alcohol, hydrogenated castor oil, tristearin, waxes, polyvinyl alcohol, polyethylene powder, polyvinyl chloride, shellac, rosin, and the like. Mixtures of the hydrophobic polymer may bo employed in a weight ratio to another hydrophobic material within the range of about 1: 0.1 to 0.1 : 1, preferably about 1 : 0.5 to 0.5 : 1. Mixtures of hydrocolloid forming material with hydrophobic polymer and/or other hydrophobic material may also be used to produce pharmaceutical compositions according to the present invention and may be employed in the weight ratio ranging from 1 : 0.1 to 0.1 : 1, preferably 1 : 0.5 to 0.5 : 1 The pharmecutial composition according to the present invention may be used to produce commprossed tablets of any shape, preferably of round shape, and can be additionally provided v/ith a film coat of comjr.only used hydrophilic coating polymers. The film envelope used can be a taste neutralizing film forming agent, to v/hich dyes may optionally be added for elegance. The proportion by weight of the film envelope relative to the final tablet is in the usual range of 0.5 to 4.0% by weight, preferably 1.0 to 1.5% by weight. Film formers such as hydroxypropyl methylcellulose, hydroxypropyl cellulose, starch, cellulose derivatives and the like may be used. The monolithic composition according to the present invention can also be used to produce compressed slugs and filled into capsules. Auxiliary substances which may be employed for the monolithic sustained release system in the present invention include diluent, including but not limited to: dibasic calcium phosphate, tribasic calcium phosphate, calcium carbonate, lactose, etc.; binder including but not limited to: polyvinyl pyrrolidone, gelatin, gum acacia, Klucel EF (hydroxypropyl cellulose), carboxymethyl cellulose sodium, etc., glidants including but not limited to: colloidal silicone dioxide, talc, stnrch, and the like; lubricants including but not limited to: magnesium stonrate, zinc stearate, and the like. The pharmaceutical dosage form, such as tablet, according to the present invention, apart from active drug and hydrocolloid forming materials and/or hydrophobic polymers and or hydrophobic materials, may contain 10 to 70" by weight, preferably 20 to G0% by v/eight, of diluent; 1.0 to 15% by v.'olght of a binder, preferably 2.0 to 10% by weight; and up to 3.0% by weight of glidant, preferably 0.5 to 1.5% by weight; and up to 2.0% by weight of lubricants, preferably 0.5 to 1.0% by weight; each in relation to the weight of pharmaceutical composition. In the present invention the pharmaceutical composition, such as tablets, may be produced by dry mixing of active substance v/ith diluent, hydrocolloid forming agent and/or hydrophobic polymer and/or other hydrophobic material and, optionally, further auxiliary substances and granulating this mixture with aqueous or organic solution of the binder. This may be follov.'ed by drying and corivnrt.i ng it into qrnnuln ol 30^m to 2.0mm, pro fornbly l00μm to 1.0mm, by milling and sizing. Subsequently, other appropriate pharmaceutical auxiliary substances are admixed with the sized granules. In the present invention the pharmaceutical composition, such as tablets, may alternatively be produced by dry mixing of active substance, optionally further auxiliary substances, hydrophobic polymers and/or other hyd^opliol^ic material(s) and binder in an extruder. This mixture is extruded at a temperature of 40 to 120°C, preferably 60 to 90°C, in a simple extruder used for injection m.olding of plastics, followed by extrusion of the molted homogeneous mass with gradual cooling to room temperature and converting into granules of 30//[n to 2.0mm, preferably 100/im to 1.0mm, by milling and sizing. Subsequently, other appropriate pharmaceutical auxiliary substances are admixed with the sized granules. In the present invention the pharmace\itical composition, such as tablets, may alternatively be produced by dry mixing of active substance and optionally further auxiliary substance and granulating this mixt\]re with hydrnphobi.c polymers and/or other hydrophobic material (s) by a hot melt granulation technique using a jacketed rapid mixer granulnt-or at-, a temperature of 10 to I2n"c, preferably 60 to 80"C. TITIS is> foljov/ed by gradual cooling of the granulate mass to room temperature v;ith continuous mixing. The resulting mass is further granulated with aqueous or organic solution of the binder, followed by drying and converting it into granules of 30/xm to 2.0mm, preferably 100//m to 1.0mm, by milling and sizing. Subsequently appropriate other pharmaceutical auxilj.ary substances are admixed with the sjzed granules. The composition produced in this manner is subsequently processed in the usual manner to produce pharmaceutical dosage forms, such as by compression into tablets or by the filling of pressed slugs into capsules. The tablets can be coated with a film using standard coating processes and methods such as a conventional coating pan or fluid coating process. The sustained release tablets according to the present invention release trimetazidine dihydrochloride in a Controlled manner which provides an effect over a time period up to 24 hours, preferably over 18 hours as per the calculations. Useful trimetazidine sustained reJease formulations according to the invention show the following in-vitro drug release characteristics when tested in gastric fluid pH 1.2 for the first hour and then in phosphate buffer pH 6,8 USP. Example 1 : 600g of trimetazidine dihydrochloride, 1840g of Methocel E4M CR (HPMC), 2098g of anhydrous dibasic calcium phosphate were mixed and granxilated in a solution contaj.ning lOOg polyvinyl pyrrolidono dissolved in 2250ml of isopropyl alcohol. The resulting mass was dried at 45"C and the agglomerates were §.ized through a 2.4mm screen. These sized granules (4638g) were blended v/ith 14g of colloidal silicone dioxide and 40g of magnesium stearate and compressed into round tablets each contaj.ning 60mg of trimotazidJ ne d i hydrochlor ido . The i n-vi tro release of trimetazidine dihydrochloride from these tablets is shown in Figiire I of the accompanying drawings. In-vivo bioavailability study: In-vivo bioavailability studies v-ere carried o\it on 6 healthy human volunteers after oral administration of Trimetazidine SR tablets of Example 1 containing 60mg of trimetazidine dihydrochloride as per the present invention. The plasma trimetazidine concentration versus time over 24 hours is shown in Figure 3 of the accompanying drawings. Conclusion: Single dose In-vivo bioavailability study shov/s well sustained plasma levels of trimetazidine over 24 hours with around 20ng/ml plasma concentration of trimetazidine after 24 hours with maximum plasma concentration of 135ng/ml. Example 2 : 600g of trimetazidine dihydrochloride, 1840g of Methocel E4M CR (IIPMC), 2098g of anhydrous dibasic calcium phosphate were mixed and granulated in a solution containi.ng lOOg polyvinyl pyrrolidone dissolved in 2250 ml of isopropyl alcohol. The resulting mass was dried at. 4 5°C and t,ho. aaql omerai-or, v/oro sizod t.hroxicjK a 2.4(131111 screen. These sized granmles M630g) were blended wi Lh 14g of colloidal silicone dioxide and 48g of magnesium stearate and compressed into compact slugs and filled into capsules, each containing 60mg of trimetazidine dihydrochloride. The in-vitro release of trimetazidine dihydrochloride from these tablets is shov/n in Figure 1 of the accompanying drawings. Example 3 : 600g of trimetazidine dihydrochlorido, 2000g of Klucel GF (HPC), 2098g of anhydrous dibasic calcium phosphate were mixed and granulated in a solution containing lOOg polyvinyl pyrrolidone dissolved in 2250 ml of isopropyl alcohol. The resulting mass was dried at 45°C and the agglomerates were sized through a 2.4mm screen. These sized granules (4798g) were blended with 14g of colloidal silicone dioxide and 48g of magnesium stearate and compressed into round tablets, each containing 60mg of trimetazidine dihydrochloride. The in-vitro release of trimetazidine dihydrochloride from these tablets is shown in Figure 1 of the accompanying drawings. Example 4 : 600g of trimetazidine dihydrochloride, 1500g of Methocel E4M CR (HPMC), 380g of carboxymethyl cellulose sodium and 2050g of anhydrous dibasic calcium phosphate were mixed and granulated in a solution containing lOOg polyvinyl pyrrolidone dissolved in 2250ml of isopropyl alcohol. The resulting mass v^as dried at 45°C and the agglomerates were sized through a 2.4mm screen. These sized granules (4630g) were blended with 14q of colloidal silicone dioxide and 48g of magnesium stcarate and compressed into round tablets, each containing 60mg of trimetazidine dihydrochloride. The in-vitro release of trimetazidine dihydrochloride from these tablets is shown in Figure 1 of the accompanying drawings. Example 5 : 360g of stearic acid was melted at 70°C. 600g of trimetazidine dihydrochloride and lOOOg of lactose monohydrate were mixed and heated to 70°C in a jacketed rapid mixer granulator and granulated with the above melted stearic acid at 70°C. After granulation, the granulated mass was mixed continuously with gradual cooling to room temperature. lOOg of shellac and 50g of polyvinyl pyrrolidone were dissolved in 250g of isopropyl alcohol. This solution was gradually added to the above trimetazidine stearic acid and lactose granulate and mixed till a dough mass formed. The resulting dough mass was dried at 45°C for 2 hours and then sized through 2.4mm screen to break the agglomerates. These sized granijles (2110g) were blended with lOg of colloidal silicone dioxide and 20g of magnesium stearate and compressed into round tablets each containing 60mg of trimetazidine dihydrochloride. The in-vitro release of trimetazidine dihydrochloride from these tablets is shown in Figure 2 of the accompanying drawings. Example 6 : 400g of glyceryl monostearate was melted at 60°C, 600g of trimetazidine dihydrochloride and lOOOg of lactose monohydrate were mixed and heated to 60°C in a jacketed rapid mixer granulator and granulated with the above melted stearic acid at 60°C. After granulation, the granulated mass was mixed continuously v/ith gradual cooling to room temperature. lOOg of shellac and 50g of polyvinyl pyrrolidone were dissolved in 250g of isopropyl alcohol. This solution was gradually added to the above trimetazidine stearic acid and lactose granulate and mixed till a dough mass formed. The resulting dough mass v/as dried at 45°C for 2 hours and then sized through a 2.4mm screen to break the agglomerates. These sized granules (2150g) were blended v/ith lOg of colloidal silicone dioxide and 20g of magnesium stearate and compressed into round tablets of each containing GOg of trimetazidino dihydrochloride. The in-vitro release of trimetazidine dihydrochloride from these tablets is shov;n in Figure 2 of the accoinpanying drawings. Example 7 : 120g of glyceryl monostearate v/as melted at 60"C- 600g of trimetazidine dihydrochloride was heated to 60°C in a jacketed rapid mixer granulator and granulated xvith the above melted glyceryl monostearate at 60°C. After granulation, the granulated mass was mixed continuously with gradual cooling to room temperature. The resulting granule mass was then sized through a 1.5mm screen to break the agglomerates. These sized granules (720g) were blended with 1650g of mothocel E4M-CR (HPMC), lOOOg of lactose monohydrate, lOg of colloidal silicone dioxide and 20g of magnesium stearate and compressed into round tablets each containing 60mg of trimetazidine dihydrochloride. The in-vitro release of trimotnzicl i ne dihyc'.rochloride from these tablets is shov/n in Figure 2 of the accompanying drawings. References : 1. Huet de Barochez, Bruno; [1995] ; European Patent 673 649 Al. 2. Makino, Yuji; Matugi, Hideo; Suzuki, Yoshiki; [1988] , U.S. Patent 4,755,544. 3. Makino, Yuji; Matugi, Hideo; Suzuki, Yoshiki; [1989] , U.S. Patent 4,814,176. 4. Yoshida Yoshiyuki; Kendo Seiji; Yamasaka Hiranojiyou; Okazawa Heiichi; [1986]; Japanese Patent JP 61212517A. 5. Huet de Barochez, Bruno; Genty Patric; Alain Cuine; [1995]; Japanese Patent JP 7258086A. 6. Catherine Harpey; Pascale Clauser; Claude Labrid; Jean-Louis Freyria; Cardiovascular Drug Reviews; 1989; 6 (4); 292 312. 7. Leon Lachman; Herbet Liberman; Joseph Kanig, The Theory and Practice of Industrial Pharmacy; Lea & Febiger Philadelphia U.S.A.; Third edition; 1987; 430 442. 8. Dobrinska, Welling, J. Pharm. Sciences 1975. We claim: 1. A process of producing a sustained release trimetazidine dihydrochloride composition comprising granulating trimetazidine dihydrochloride and hydrophobic material by hot melt granulation or by extrusion, sizing and mixing the granules with auxiliary substances. 2. A process according to claim 1 including the further step of compressing the dried granulated product into tablets. 3. A process according to claim 2, including the further step of coating the tablet with a film envelope for taste neutralization. 4. A process according to any one of claims 1 to 3, which comprises the addition of upto 2% by weight of lubricant, upto 5% by weight of glidant and upto 5% by weight of binder prior to compacting the product. Dated this 15* day of April 2002 (M A Jose) ofKhaitan & Co Agent for the Applicants

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