Title of Invention	STABLE PHARMACEUTICAL COMPOSITIONS OF BETA ADRENORECEPTOR BLOCKER AND A CALCIUM CHANNEL BLOCKER
Abstract	The present invention discloses stable pharmaceutical compositions comprising pharmaceutically acceptable acid addition salt of vasodilator such as Amlodipine and acid addition salt of a synthetic beta-selective adrenoreceptor blocking agent Metoprolol Succinate formulated as oral solid dual release pharmaceutical compositions, useful for the treatment of various cardiovascular diseases. The manufacturing process for the preparation of said stable pharmaceutical compositions is disclosed herein.

Title of Invention

STABLE PHARMACEUTICAL COMPOSITIONS OF BETA ADRENORECEPTOR BLOCKER AND A CALCIUM CHANNEL BLOCKER

Abstract

The present invention discloses stable pharmaceutical compositions comprising pharmaceutically acceptable acid addition salt of vasodilator such as Amlodipine and acid addition salt of a synthetic beta-selective adrenoreceptor blocking agent Metoprolol Succinate formulated as oral solid dual release pharmaceutical compositions, useful for the treatment of various cardiovascular diseases. The manufacturing process for the preparation of said stable pharmaceutical compositions is disclosed herein.

Full Text	FORM 2 THE PATENT ACT 1970 (39 of 1970) & The Patents Rules, 2003 COMPLETE SPECIFICATION (See section 10 and rule! 3) 1. TITLE OF THE INVENTION: "Stable pharmaceutical compositions of beta adrenoreceptor blocker and a calcium channel blocker" 2. APPLICANT (S) (a) NAME: IPCA LABORATORIES LIMITED (b)NATIONALITY: an Indian Company incorporated under the Indian Companies ACT, 1956 (c) ADDRESS: 48, Kandivli Industrial Estate, Charkop, Kandivli (West) Mumbai - 400 067, Maharashtra, India. 3. PREAMBLE TO THE DESCRIPTION The following specification particularly describes the invention and the manner in which it is to be performed. Technical Field of the invention: The present invention relates to stable dual release pharmaceutical compositions used for the treatment of cardiovascular diseases like hypertension and chronic stable angina comprising a calcium channel blocker drug such as amlodipine and a synthetic beta-selective adrenoreceptor blocking agent such as metoprolol succinate in the form of an oral solid bilayered formulation and to a process for preparation thereof. The salt of metoprolol is provided with an extended release polymer base retardant coating and the salt of amlodipine either besylate or maleate is provided as an immediate release component. Background and Prior Art: Amlodipine besylate is long acting calcium channel blocker. Amlodipine besylate is chemically described as 3-ethyl-5-methyl-2-(2-aminoethoxymethyl)-4-(2-chlorophenyl)-l,4-dihydro-6-methyl-3,5-pyridinedicarboxylate benzenesulfonate. Its empirical formula is C20H25CIN2O5●C6H6O3S. It inhibits the transmembrane influx of calcium ions into vascular smooth muscles and cardiac muscles and hence useful in the treatment of angina and hypertension. Amlodipine besylate is commercially available as Norvasc (Pfizer) in the form of oral tablets in 2.5mg, 5mg and l0mg base preparations. The usual initial anti hypertensive oral dose of Amlodipine besylate is 5 mg once daily with a maximum dose of 10 mg once daily. Small, fragile or elderly individuals or patients with hepatic insufficiency may be 2.5 mg once daily and this dose may be used when adding Amlodipine besylate to other hypertensive Amlodipine is well absorbed in the gastrointestinal tract. After oral administration, absorption produces peak plasma concentrations between 6 and 12 hours. Absolute bioavailability has been estimated to be between 64% and 90%. The bioavailability of amlodipine is high in man corresponding to 97%. It is extensively converted to inactive metabolites via hepatic metabolism. US Patent Application No. 2003220312 describes co-administration or sequential administration of two compounds for treating a variety of circulatory disorders including 2 cardiovascular disorders, such as hypertension, congestive heart failure, myocardial fibrosis and cardiac hypertrophy. The first compound is characterized by a steroid type nucleus with an epoxy moiety attached to the nucleus and having competitive aldosterone receptor binding activity. The second compound is a calcium channel blocker, preferably, amlodipine besylate. Amlodipine is used in combination with statin compounds. This synergistic combination is useful for treating subjects suffering from angina pectoris, arteriosclerosis, combined hypertension and hyperlipidemia and for subjects with symptoms of cardiac risk Such pharmaceutical compositions of amlodipine and atorvastatin are described in patent CA2444554. The said patent also describes methods of preparing stable pharmaceutical compositions comprising atorvastatin and amlodipine, and a kit suitable for commercial sale. Metoprolol succinate is a beta-selective (cardioselective) adrenoreceptor blocking agent, for oral administration, available as extended release tablets to treat a heart condition called angina. Its chemical name is (±) l-(isopropylamino)-3-[p-(2-methoxyethyl) phenoxy]-2-propanol succinate (2:1) (salt). It reduces the oxygen demand to heart, slowing the heart rate, reducing cardiac output when at rest and on exercise and reduces systolic blood pressure. There have been controlled and sustained release metoprolol formulations already known which comprise of controlled release pellets, where each pellet acts as a separate drug delivery unit. But in order to obtain a desirable release of a drug, a considerable amount of experimentation needs to be done. So, in accordance with the present investigation, an extended release pharmaceutical formulation is devised to release the drug for upto 24 hours in a suitable controlled manner. EP 0293347 by Henry A. C. and Christina E. E. describes Metoprolol succinate as therapeutically active compound, and pharmaceutical preparation comprising it. The invention describes a core containing the therapeutically active compound, the core coated with a layer comprising an anionic polymer soluble, and a water insoluble polymer selected from the group of quaternary ammonium substituted acrylic polymers. 3 US Pat. No. 4871549 to Yoshio U et al., describes a time controlled explosion system comprising Metoprolol, a swelling agent such as a low substituted hydroxy propyl cellulose, sodium starch glycolate or carboxy methyl cellulose sodium, coated with a water-insoluble coating material so that drug release is caused by the explosion of the membrane after a definite time period. EP1110542 by Mccall Troy W and Bachiwal Anand R describes once-a-day oral dosage form of Metoprolol to be released over a period of 24 hours in the gastrointestinal tract. The sustained release matrix comprised of heterosaccharide derivatives of xanthan gum. However, none of the above patents deal with combination of an anti-hypertensive such as a beta-selective adrenoreceptor blocking agent and calcium channel blocker wherein the adrenoreceptor blocking agent is suitably formulated for extended release while the calcium channel blocker is incorporated suitably for immediate release. Thus there exists a need to introduce stable, cost effective pharmaceutical compositions having an additive effect in lowering blood pressure in hypertensive patients comprising dual effect thereby providing rapid effect of Amlodipine and an extended release of Metoprolol for 24 hours release. Object of the invention: The main object of the present invention is to provide stable dual release pharmaceutical compositions used for treatment of hypertension, chronic stable angina and other related cardiovascular diseases comprising combination of therapeutically effective amount of a synthetic beta-selective adrenoreceptor blocking agent Metoprolol succinate and a calcium channel blocking agent, Amlodipine either racemic or its enantiomer or its salts. Another object is to provide extended release of selective beta-adrenoreceptor blocker by using monolithic matrix that is combination of hydrophobic (carbomer) and hydrophilic (hydroxy propyl methyl cellulose) polymers, in an effective manner in extended release layer and immediate release of calcium channel blocking agent, thus providing two drugs 4 combination therapy to have additive effect in lowering blood pressure in hypertensive patients. Yet another object of the invention is to reduce the dose of one of the active ingredient by extending the drug release over a period of time. Summary of the invention: The present invention discloses stable pharmaceutical compositions comprising two active ingredients, formulated in a single dosage form providing different release profiles comprising dual release drug absorption system (Duredas) technology. The compositions involves use of disintegrants, which helps the immediate release of drug comprising calcium channel blocking agent and the use of monolithic matrix technique for extended release of an adrenergic blocking agent. The monolithic matrix comprises a combination of hydrophobic polymer preferably carbomer and hydrophilic polymer preferably hydroxypropyl methylcellulose, thereby facilitating extended release of adrenergic blocking agent, over a time period of up to 24 hours. The stable solid pharmaceutical compositions for oral administration comprises a calcium channel blocker such as Amlodipine and a synthetic adrenoreceptor blocking agent, such as Metoprolol succinate equivalent to Metoprolol tartarate; and pharmaceutically acceptable excipients. The amount of the said salts of Amlodipine is in range the of 2.5 tol5mg equivalent to Amlodipine free base and preferably 5mg and 2.5mg. The amount of Metoprolol succinate equivalent to Metoprolol tartarate is in the range of 12.5 mg to 200mg and preferably 50mg and 25mg. The compositions possess additive effect in lowering blood pressure in hypertensive patients. Detailed description of the invention: The present invention describes stable dual release pharmaceutical compositions for oral administration that comprises a dihydropyridine calcium channel blocker drug such as Amlodipine as an immediate release component and a synthetic beta-selective adrenoreceptor blocking agent such as Metoprolol succinate incorporated in an extended 5 release matrix using monolithic matrix technology, along with pharmaceutical^ acceptable excipients. Monolithic matrix technique includes use of combination of hydrophobic such as carbomer and hydrophilic polymers such as hydroxypropyl methylcellulose, thereby helps the extended release of drug over specific period of time. The drug is dispersed in a mixture of hydrophilic and hydrophobic matrix resulting in the initial dissolution of matrix polymer and then diffusion of the dissolved drug through the pores of the matrix before release. The invention further describes a process for preparation of dual release pharmaceutical compositions comprising bilayered tablets of two active ingredients such as Amlodipine besylate and Metoprolol succinate, formulated in a single dosage form providing different release profile using dual drug release absorption system (Duredas). The invention describes immediate release Amlodipine besylate equivalent to amlodipine free base and Metoprolol succinate equivalent to Metoprolol tartarate as an extended release component. The two drugs in combination therapy possess additive effect in lowering blood pressure in hypertensive patients. As described herein, "bilayer tablet" is a tablet which is made up of two or more distinct layers or discrete zones of granulation compressed together with the individual layers lying one on top of another. Bilayer tablets are generally prepared by compressing granules onto previously partially compressed granules. The bilayered tablets of the present invention provide dual release of the individual components wherein, an accurate dose of individual active is delivered. The process involves reduced manufacturing steps and manufacturing time. This process provides a cost effective formulation as conventionally there is always loss of 20-25 % at coating stage. Process I The process of preparation of dual release pharmaceutical composition comprises of; granulating metoprolol succinate equivalent to metoprolol tartarate together with selected 6 excipients by non-aqueous granulation process, blending the said granules of metoprolol succinate equivalent to metoprolol tartarate with lubricants and glidants; wherein carbomers are used both in granulation and blending stage; blending amlodipine besylate with disintegrants, lubricants and glidants and compressing the said two blends into bilayered tablet where each layer represents a blend comprising single active ingredient with excipients. Process II The process of preparation of dual release pharmaceutical composition comprises of; granulating metoprolol succinate equivalent to metoprolol tartarate together with selected excipients by non-aqueous granulation process, blending the said granules of metoprolol succinate equivalent to metoprolol tartarate, lubricants and glidants; wherein carbomers are used both in granulation and blending stage; granulating amlodipine besylate together with selected excipients by moist granulation process and blending the said granules of amlodipine besylate with disintegrants, lubricants and glidants and compressing the said two blends into a bilayered tablet where each layer represents blend comprising a single active ingredient with excipients. In one embodiment, the stable dual release pharmaceutical compositions comprises the following steps, (i) non-aqueous granulation of Metoprolol succinate and an extended release matrix comprising a hydrophobic polymer (carbomer) and hydrophilic polymer (hydroxypropyl methyl cellulose) along with selected excipients, (ii) direct compression of Amlodipine besylate together with selective excipients, (iii) compressing the steps of (i) and (ii) into two layer tablets characterized by the presence of the two drug substances in two different layers with or without coating. In another embodiment, the present invention provides the process for preparing the stable pharmaceutical compositions comprising; (i) Metoprolol succinate and an extended release matrix comprising a carbomer and hydroxypropyl methyl cellulose in amount from about 5% to 95% by 7 weight of the final product along with selected excipients, using non-aqueous granulation process; (ii) Amlodipine besylate together with selective excipients, using wet granulation process and (iii) lubricating the said granules and (iv) compressing the granules of (i) and (iii) into two layer tablets characterized by the presence of the two drug substances in two different layers, using standard compression tooling known in art with or without coating. Amlodipine may be in the form of racemic mixture or S (-) isomer or its salts. The said salts are Amlodipine besylate or maleate, preferably Amlodipine besylate. The dose range of amlodipine besylate equivalent to amlodipine free base in the said composition in the range of about 2mg to 15mg of base and dose range for Metoprolol succinate equivalent to Metoprolol tartarate in the range of about 12.5mg to 200mg. Most preferred dose range of Amlodipine besylate in the said composition is 5mg equivalent to Amlodipine free base and for Metoprolol succinate equivalent to Metoprolol tartarate is 50mg. The dual release drug absorption system comprising Amlodipine besylate equivalent to Amlodipine free base and Metoprolol succinate equivalent to Metoprolol tartarate in combination with pharmaceutically acceptable excipients selected from diluents, binders, flavors, preservatives, pH adjuster, alkalizing agent, disintegrating agents, film formers, lubricants and/or glidants and plasticizers either alone or in combination thereof. The said diluents are selected from the group consisting of microcrystalline cellulose, calcium phosphate, maize starch or their modified forms. The said diluents are used in the range of 5 to 95% of tablet weight. The said binders are selected from the group containing maize starch, polyvinylpyrrolidone. The said polyvinylpyrrolidone is used in the range of 3 to 15% and maize starch in the range of 2 to 10%. 8 The said disintegrants are selected from the group containing starch, derivative of starch, preferably sodium starch glycolate and croscarmellose sodium. The said glycolate is used in the range of 1-6% and croscarmellose sodium is used in the range 1-6%. The said lubricant and/or glidants are selected from the group containing magnesium stearate used in the range of 0.25% to 5% and colloidal silicon dioxide is used in the range of 0.1 % to 0.5%. The film formers are selected from group of polymers such as carbomer, which is used in the range of 5% to 10% and hydroxy propyl methyl cellulose which is used in the range of 0.45% to 1%. Monolithic matrix technique includes use of combination of hydrophobic preferably carbomer and hydrophilic polymers, thereby helps the extended release of drug over specific period of time. The drug to carbomer ratio may be e.g. from about 10:1 to about 1:12. More appropriately, the drug to carbomer ratio is from about 10:1.25 to about 1:12 by weight of final product. The preparation of the extended release layer is by compression and mixing of polymers. Carbomers are used both in granulation as well as mixing stages. By extended release it is meant for purposes of the present invention that the therapeutically active medicament is released from the formulation at an extended rate such that therapeutically beneficial blood levels (but below toxic levels) of the medicament are maintained over an extended period of time e.g., providing a 24 hour dosage form. Other miscellaneous auxiliaries required for processing the product and maintaining stability can also be used. The said stable compositions are preferably in the dosage form of tablets and bilayered tablets. The bilayer tablet may be film coated preferably with hydroxy propyl methyl cellulose, talc, titanium dioxide, polyethylene glycol 4000. 9 The said pharmaceutical compositions of Amlodipine besylate and Metoprolol succinate according to the invention is preferably in the solid dosage form, such as tablets, pills, granules, capsules or sachets, preferably tablets. The said compositions of Amlodipine besylate and Metoprolol succinate are physically and chemically stable over its shelf life period. The invention is more specifically explained by following examples. However, it should be understood that the scope of the present invention is not limited by the examples in any manner. It will be appreciated by any person skilled in this art that the present invention includes the following examples and further can be modified and altered within the technical concept of the present invention. Uncoated tablets Example 1: A) Metoprolol succinate granules: Contains 50mg metoprolol succinate equivalent of metoprolol tartarate along with the following excipients: Sr. No. Ingredient Qty % w/w of total weight 1 Metoprolol succinate 19.4% 2 Micro crystalline cellulose 8.97% 3 Carbomer 8.98% 4 Hydroxy propyl methyl cellulose (K15M) 24.9% 5 Polyvinylpyrrolidone (K30) 12.24% 6 Isopropyl alcohol qs 7 Hydroxy propyl methyl cellulose (K15M) 24.49% 8 Magnesium stearate 1.02% Preparation of metoprolol succinate granules: Metoprolol succinate, microcrystalline cellulose, carbomer, hydroxy propyl methyl cellulose were mixed geometrically after sifting through mesh 40. This blend was 10 granulated with mixture of polyvinylpyrrolidone and isopropyl alcohol using nonaqueous wet granulation. Granules were milled through mesh 8. Granules are dried at 40-50°C. Dried granules were sifted through mesh 20. It was then lubricated with magnesium stearate. Metoprolol succinate granules: Contains 25mg metoprolol succinate equivalent of metoprolol tartarate along with the following excipients: Sr. No. Ingredient Qty % w/w of total weight 1 Metoprolol succinate 12.9% 2 Micro crystalline cellulose 24.89% 3 Carbomer 21.6% 4 Hydroxy propyl methyl cellulose (K15M) 32.40% 5 Polyvinylpyrrolidone (K30) 6.80% 6 Isopropyl alcohol qs 7 Magnesium stearate 1.62% Tablets containing 25mg metoprolol succinate equivalent to metoprolol tartarate are similarly prepared. B) Amlodipine besylate: Contains 5mg of amlodipine base equivalent to the amlodipine along with the following excipients: Sr. No. Ingredient Qty % w/w of total weight 1 Amlodipine besylate 5.6% 2 Dicalcium phosphate granular 25.6% 3 Dicalcium phosphate anhydrous 27.6% 4 AvicelpH102 32% 5 Colloidal silicon dioxide 1.6% 6 Sodium starch glycolate 4.8% 7 Sunset yellow (lake) 1.6% 8 Magnesium stearate 1.3% 11 Prepartion of amlodipine besylate mix for direct compression: Amlodipine besylate, dicalcium phosphate anhydrous, dicalcium phosphate granular, Avicel pH 102, colloidal silicon dioxide, sodium starch glycolate sunset yellow (lake) were mixed geometrically after sifting through mesh 100. It was then lubricated with magnesium stearate. Example 2: A) Metoprolol succinate granules: Contains 50mg and 25mg metoprolol succinate equivalent of metoprolol tartarate along with the excipients and formulation same as example 1. B) Amlodipine besylate granules: Contains 5mg of amlodipine free base along with the following excipients Sr. No. Ingredient Qty % w/w of total weight 1 Amlodipine besylate 6.67% 2 Micro crystalline cellulose 33.18% 3 Dicalcium phosphate anhydrous 45.45% 4 Crosscarmellose sodium 2.73% 5 Maize starch 3.64% 6 Purified water qs 7 Sodium starch glycolate 5.45% 8 Colloidal silicon dioxide 1.36% 9 Magnesium stearate 1.02% 10 Sunset yellow (lake) 0.68% Preparation of amlodipine besylate granules: Amlodipine besylate, microcrystalline cellulose, dicalcium phosphate anhydrous, crosscarmellose sodium, sunset yellow (lake) were mixed geometrically after sifting through mesh 100. This blend was granulated with starch paste using moist granulation. Wet granules were milled through mesh 8. Granules are dried at 40-50°C Dried granules were sifted through mesh 20. Sodium starch glycolate and colloidal silicon dioxide were 12 sifted through mesh 40 and mixed with amlodipine besylate equivalent to amlodipine free base granules. It was then lubricated with magnesium stearate. Tablets containing 2.5mg amlodipine besylate equivalent to amlodipine free base are similarly prepared Coated tablets Example 3: A) Metoprolol succinate granules: Contains 50mg and 25mg metoprolol succinate equivalent of metoprolol tartarate along with the excipients and formulation same as example 1. B) Amlodipine besylate: Contains 5mg of amlodipine base along with the excipients and prepared as example 1 using direct compression method. Tablets containing 2.5mg amlodipine besylate are similarly prepared. The coating solution to be coated on the tablets has the following composition: Sr. No. Ingredient Qty % w/w of total weight 1 Hydroxy propyl methyl cellulose 2.06% 2 Poly ethylene glycol 400 0.04% 3 Talc 0.01% 4 Titanium dioxide 0.01% 5 Isopropyl alcohol qs 6 Methylene chloride qs There is a 2% weight gain by coating. The process of film coating comprises: Dispersing HPMC E5 in isopropyl alcohol (taken in suitable a stainless steel container) and stirring constantly for approximately 10 minutes. Add titanium dioxide, purified talc again under stirring for approximately 10 minutes. Further, adding methylene chloride 13 and polyethylene glycol 6000 under stirring for 10 minutes. Continue stirring for 30 minutes and pass the suspension through a bolting cloth, homogenized by passing through a homogenizer. This solution is used to coat tablet with conventional coater/auto-coater. Example 4: A) Metoprolol succinate granules: Contains 50mg and 25mg metoprolol succinate equivalent of metoprolol tartarate along with the excipients and formulation same as example 1. B) Amlodipine besylate: Contains 5mg of amlodipine base along with the excipients and prepared as example 2 using wet granulation method. Tablets containing 2.5mg amlodipine besylate equivalent to amlodipine free base are similarly prepared. The coating solution to be coated on the tablets remains same as example3 and the weight gain by coating is 2%. The pharmaceutical compositions of Amlodipine besylate and Metoprolol succinate are physically and chemically stable over its shelf life period. The stability data is as follows: 14 The sample comprising Metoprolol succinate + Amlodipine Tablets (25+2.5) mg. Each film coated bilayered tablet contains Metoprolol succinate USP 23.75mg equivalent to Metoprolol tartrate USP 25mg and Amlodipine besylate BP equivalent to Amlodipine 2.5 mg is stored at: 25 ± 2°C & 60 ± 5% RH. TEST SPECIFICATION BATCH NO. INITIAL AFTER 03 MONTHS APPEARANCE Orange - white, bilayered, oval shaped , Him coated tablets IN/MAT(25+2.5)06/05 Complies Complies IN/MAT(25+2.5)07/05 Complies Complies IN/MAT(25+2.5)08/05 Complies Complies DISSOLU HON Metoprolol Succinate 1Hr. :NMT25% 4Hrs.: 25-50% 8Hrs.: 45-75% 20Hrs. :NLT80% IN/MAT(25+2.5)06/05 14.33% 34.80% 63.19% 89.18% 15.20% 38.88% 62.03% 98.43% IN/MAT(25+2.5)07/05 21.20% 42.12% 67.98% 103.40% 15.42% 40.94% 65.23% 102.44% IN/MAT(25+2.5)08/05 - - 16.29% 40.78% 64.42% 98.69% Amlodipine Besylate NLT 70% in 60 min IN/MAT(25+2.5)06/05 89.92 % 92.15% IN/MAT(25+2.5)07/05 91.78% 97.27% IN/MAT(25+2.5)08/05 91.77% 91.55% ASSAY Metoprolol Succinate : 90%-110% IN/MAT(25+2.5)06/05 96.89% 101..25% IN/MAT(25+2.5)07/05 98.99 % 101.54% IN/MAT(25+2.5)08/05 98.16% 97.16% Amlodipine Besylate : 90%-110% IN/MAT(25+2.5)06/05 96.89% 96.74% IN/MAT(25+2.5)07/05 98.45% 96.98% IN/MAT(25+2.5)08/05 103.87% 99.19% 15 The sample comprising Metoprolol succinate + Amlodipine Tablets (25+2.5) mg. Each film coated bilayered tablet contains Metoprolol succinate USP 23.75mg equivalent to Metoprolol tartrate USP 25mg and Amlodipine besylate BP equivalent to Amlodipine 2.5 mg is stored at: 40 ± 2°C & 75 ± 5% RH. TEST SPECIFICATION BATCH NO. INITIAL AFTER 03 MONTHS APPEARANCE Orange - white, bilayered, oval shaped , film coated tablets MMAT(25+2.5)06/05 Complies Complies IN/MAT(25+2.5)07/05 Complies Complies IN/MAT(25+2.5)08/05 Complies Complies DISSOLU TION Metoprolol Succinate 1Hr. :NMT25% 4Hrs.: 25-50% 8Hrs.: 45-75% 20Hrs.: NLT 80% BM/MAT(25+2.5)06/05 14.33% 34.80% 63.19% 89.18% 19.92% 37.89% 60.06% 93.27% IN/MAT(25+2.5)07/05 21.20% 42.12% 67.98% 103.40% 23.21% 36.40% 58.67% 90.88% IN/MAT(25+2.5)08/05 15.98% 34.52 % 59.32 % 91.47% 14.96% 39.11% 61.35% 94.67% Amlodipine Besylate NLT 70% in 60 min IN/MAT(25+2.5)06/05 89.92 % 86.27% IN/MAT(25+2.5)07/05 91.78% 85.94% IN/MAT(25+2.5)08/05 91.77% 90.33% ASSAY Metoprolol Succinate : 90%- 110% IN/MAT(25+2.5)06/05 96.89% 98.99% lN/MAT(25+2.5)07/05 98.99 % 98.99% IN/MAT(25+2.5)08/05 98.16% 96..33% Amlodipine Besylate : 90%-110% lN/MAT(25+2.5)06/05 96.89% 104.94% IN/MAT(25+2.5)07/05 98.45% 95.67% IN/MAT(25+2.5)08/05 103.87% 101.51% 16 The sample comprising Metoprolol succinate + Amlodipine Tablets (50+5) mg. Each film coated bilayered tablet contains Metoprolol succinate USP 47.5mg equivalent to Metoprolol tartrate USP 50mg and Amlodipine besylate BP equivalent to Amlodipine 5 mg is stored at: 25 ± 2°C & 60 ± 5% RH. TEST SPECIFICATION BATCH NO. INITIAL AFTER 03 MONTHS APPEARAN CE Orange - white, bilayered, oval shaped , film coated tablets IN/MAT(50+5)07/05 Complies Complies IN/MAT(50+5)08/05 Complies Complies IN/MAT (50+5)09/05 Complies Complies DISSOLUTI ON Metoprolol Succinate 1Hr. :NMT25% 4Hrs.: 25-50% 8Hrs.: 45-75% 20Hrs.: NLT 80% IN/MAT(50+5)07/05 16.37% 36.10% 56.87% 96.34% 15.91% 42.10% 56.03% 90.74% IN/MAT(50+5)08/05 16.82% 46.52% 69.66% 99.25% 18.06% 44.98% 69.66% 100.84% IN/MAT (50+5)09/05 16.2% 39.5% 58.92 % 88.3 % 16.34% 37.99% 55.97% 82.88% Amlodipine Besyate NLT 70% in 60 min IN/MAT(50+5)07/05 94.84% 92.75% IN/MAT(50+5)08/05 94.06% 100.08% IN/MAT (50+5)09/05 97.83% 97.24% ASSAY Metoprolol Succinate :90%- 110% IN/MAT(50+5)07/05 99.27% 102.19% IN/MAT(50+5)08/05 99.19% 98.52% IN/MAT (50+5)09/05 99.27% 96.36% Amlodipine Besylate : 90%-110% IN/MAT(50+5)07/05 98.38% 100.35% CM/MAT(50+5)08/05 99.09% 99.21% IN/MAT (50+5)09/05 97.02% 98.01% The sample comprising Metoprolol succinate + Amlodipine Tablets (50+5) mg. Each film coated bilayered tablet contains Metoprolol succinate USP 47.5mg equivalent to Metoprolol tartrate USP 50mg and Amlodipine besylate BP equivalent to Amlodipine 5 mg is stored at: 40 ± 2°C & 75 ± 5% RH. 17 TEST SPECIFICATION BATCH NO. INITIAL AFTER 03 MONTHS APPEAR ANCE Orange - white, bilayered, oval shaped , film coated tablets IN/MAT(50+5)07/05 Complies Complies IN/MAT(50+5)08/05 Complies Complies IN/MAT (50+5)09/05 Complies Complies DISSOLU HON Metoprolol Succinate 1Hr. :NMT25% 4Hrs.: 25-50% 8Hrs.: 45-75% 20Hrs.: NLT 80% IN/MAT(50+5)07/05 16.37% 36.10% 56.87% 96.34% 15.37% 38.36% 55.46% 87.32% IN/MAT(50+5)08/05 16.82% 46.52% 69.66% 99.25% 17.33% 44.87% 90.31% 101.24% IN/MAT (50+5)09/05 16.2% 39.5% 58.92 % 88.3 % 18.04% 40.81% 61.89% 92.69% Amlodipine Besylate NLT 70% in 60 min IN/MAT(50+5)07/05 94.84% 87.68% IN/MAT(50+5)08/05 94.06% 102.04% IN/MAT (50+5)09/05 97.83% 97.41% ASSAY Metoprolol Succinate : 90%-110% IN/MAT(50+5)07/05 99.27% 100.80% IN/MAT(50+5)08/05 99.19% 99.30% IN/MAT (50+5)09/05 97.83% 97.43% Amlodipine Besylate : 90%-110% IN/MAT(50+5)07/05 98.38% 99.23% IN/MAT(50+5)08/05 99.09% 99.30% IN/MAT (50+5)09/05 97.02% 100.07% Bioavailability study is conducted of Metoprolol XL 50mg + Amlodipine 5 mg FDC manufactured by IPCA Laboratories Ltd. in comparison with, Seloken XL tablet containing Metoprolol XL 50mg manufactured by Astra Zenaca Pharma Ltd. and Amlogard tablet containing Amlodipine 5 mg manufactured by Pfizer in 12 healthy male, adult human volunteers under fasting condition in a randomized two-way complete crossover design. Values of Cmax, tmax, AUC o-t and AUC o-«> were comparable for the Reference and the Test preparation in the fasting state. Metoprolol XL was detected in plasma from 0.5 hour to about 72 hours in Reference preparation and Test preparation. Peak plasma levels of Metoprolol XL with the Reference preparations were achieved between 5 to 12 hours and with the Test preparations they are achieved between 2 to 12 hours. The mean peak plasma levels of Metoprolol XL with Reference preparation, Seloken XL tablet on the study day ranged between 32-292 ng/ml while with Test preparation ranged between 30-301 ng/ml. 18 On the basis of comparison of the AUCo-t for Metoprolol XL after single dose administration, the relative bioavailability of the Test preparation of Metoprolol XL 50 mg was 102.87 % of that of the Reference preparation, Seloken XL tablet. Amlodipine was detected in plasma from 0.5 hour to about 96 hours in Reference preparation and Test preparation. Peak plasma levels of Amlodipine with the Reference preparations were achieved between 5 to 16 hours and with the Test preparations they are achieved between 5 to 12 hours. The mean peak plasma levels of Amlodipine with Reference preparation, on the study day ranged between 2.01-3.94 ng/ml, while with Test preparation ranged 2.48-4.67 ng/ml. On the basis of comparison of the AUCo-t for Amlodipine after single dose administration, the relative bioavailability of the Test preparation of Amlodipine 5 mg was 99.37 % of that of the Reference preparation. Conclusion: On the basis of pharmacokinetic parameters, it can be concluded that the Test preparation of Metoprolol XL 50mg + Amlodipine 5 mg FDC tablets manufactured by IPCA Laboratories Ltd. is bioequivalent with the Reference preparation, Seloken XL tablet containing Metoprolol XL 50mg manufactured by Astra Zenaca Pharma Ltd. and Amlogard tablet containing Amlodipine 5 mg manufactured by Pfizer. It will be evident to those skilled in the art that the invention is not limited to the details of the foregoing illustrative examples and that the present invention may be embodied in other specific forms without departing from the essential attributes thereof, and it is therefore desired that the present embodiments and examples be considered in all respects as illustrative and not restrictive, reference being made to the appended claims, rather than to the foregoing description, and all changes which come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein. 19 We claim; 1. Stable bilayered tablet pharmaceutical compositions prepared with Duredas technology comprising a calcium channel blocker such as Amlodipine and a beta-selective adrenoreceptor blocking agent, such as Metoprolol, wherein Amlodipine is incorporated as an immediate release component and Metoprolol is incorporated as an extended release component comprising monolithic matrix technology; the said composition is prepared by a process comprising; a. granulating metoprolol succinate with pharmaceutically acceptable excipients by non-aqueous granulation process and blending the said granules of metoprolol succinate with disintegrants, lubricants and glidants; b. granulating amlodipine besylate with pharmaceutically acceptable excipients by wet granulation process and blending the granules with disintegrants, lubricants and glidants or blending the besylate salt of amlodipine with disintegrants, lubricants and glidants (dry granulation) and c. compressing the said two blends (a) and (b) into a bilayered tablet where each layer represents blend comprising a single active ingredient with excipients and d. coating the bilayer tablets. 2. Pharmaceutical compositions as claimed in claim 1, wherein the said Amlodipine is in the form of racemic mixture or S (-) isomer and salts such as besylate or maleate, preferably Amlodipine besylate in an amount equivalent to Amlodipine free base in the range of 2 to 15mg and preferably 5mg and 2.5mg. 3. Pharmaceutical compositions as claimed in claim 1, wherein the said Metoprolol salt is Metoprolol succinate in the range of 12.5 to 200mg equivalent to Metoprolol tartarate and preferably 50mg and 25mg. 20 4. Pharmaceutical compositions as claimed in claim 1, wherein Metoprolol succinate is incorporated as an extended release monolithic matrix comprising a polymer base retardant coating comprising a combination of hydrophobic polymer such as carbomer and a hydrophilic polymer such as hydroxypropyl methyl cellulose. 5. Pharmaceutical compositions as claimed in claim 1, wherein the pharmaceutically acceptable excipients are selected from diluents, binders, disintegrants, lubricants, glidants, flavors, alkalizing agents, preservatives, sweeteners, film formers and plasticizers either alone or in combination thereof. 6. Pharmaceutical compositions as claimed in claim 1 and 5, wherein the said diluents are selected from the group consisting of microcrystalline cellulose, calcium phosphate, maize starch or their modified forms used in the range of 5 to 95% of tablet weight. 7. Pharmaceutical compositions as claimed in claim 1 and 5, wherein the said binders are selected from the group containing maize starch, polyvinylpyrrolidone wherein preferred binder is polyvinylpyrrolidone used in the range of 3 to 15% and maize starch in the range of 2 to 10%. 8. Pharmaceutical compositions as claimed in claim 1 and 5, wherein the said disintegrants are selected from the group containing starch, derivative of starch and the preferred disintegrants are sodium starch glycolate used in the range of 1-6% and crosscarmellose sodium used in the range 1-6%. 9. Pharmaceutical compositions as claimed in claim 1 and 5, wherein the said lubricant and glidants are selected from the group containing magnesium stearate in the range of 0.25% to 5%, and colloidal silicon dioxide used in the range of 0.1% to 0.5% 21 10. Pharmaceutical compositions as claimed in claim 1 and 9, wherein the said film formers are selected from group of polymers such as carbomer used in the range of 5% to 10% and hydroxy propyl methyl cellulose used in the range of 0.45% to 1%. 11. Stable pharmaceutical compositions as claimed in any of the preceding claims 1 to 10 and their process of preparation as described herein with reference to the foregoing examples 1-4. Dated this 14,h day of December 2006 Dr. Gopakumar G. Nair Agent for the Applicant 22 Abstract: The present invention discloses stable pharmaceutical compositions comprising pharmaceutically acceptable acid addition salt of vasodilator such as amlodipine with acid addition salt of a synthetic beta-selective adrenoreceptor blocking agent metoprolol succinate formulated as oral solid dual release pharmaceutical compositions, useful for the treatment of various cardiovascular diseases. The manufacturing process for the preparation of said stable pharmaceutical compositions is disclosed herein.

Full Text

FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule! 3)
1. TITLE OF THE INVENTION:
"Stable pharmaceutical compositions of beta adrenoreceptor blocker and a calcium channel blocker"
2. APPLICANT (S)
(a) NAME: IPCA LABORATORIES LIMITED
(b)NATIONALITY: an Indian Company incorporated under the Indian Companies ACT, 1956
(c) ADDRESS: 48, Kandivli Industrial Estate, Charkop, Kandivli (West) Mumbai - 400 067, Maharashtra, India.
3. PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the invention and the manner in which it is to be performed.

Technical Field of the invention:
The present invention relates to stable dual release pharmaceutical compositions used for the treatment of cardiovascular diseases like hypertension and chronic stable angina comprising a calcium channel blocker drug such as amlodipine and a synthetic beta-selective adrenoreceptor blocking agent such as metoprolol succinate in the form of an oral solid bilayered formulation and to a process for preparation thereof. The salt of metoprolol is provided with an extended release polymer base retardant coating and the salt of amlodipine either besylate or maleate is provided as an immediate release component.
Background and Prior Art:
Amlodipine besylate is long acting calcium channel blocker. Amlodipine besylate is chemically described as 3-ethyl-5-methyl-2-(2-aminoethoxymethyl)-4-(2-chlorophenyl)-l,4-dihydro-6-methyl-3,5-pyridinedicarboxylate benzenesulfonate. Its empirical formula is C20H25CIN2O5●C6H6O3S. It inhibits the transmembrane influx of calcium ions into vascular smooth muscles and cardiac muscles and hence useful in the treatment of angina and hypertension.
Amlodipine besylate is commercially available as Norvasc (Pfizer) in the form of oral tablets in 2.5mg, 5mg and l0mg base preparations. The usual initial anti hypertensive oral dose of Amlodipine besylate is 5 mg once daily with a maximum dose of 10 mg once daily. Small, fragile or elderly individuals or patients with hepatic insufficiency may be 2.5 mg once daily and this dose may be used when adding Amlodipine besylate to other hypertensive
Amlodipine is well absorbed in the gastrointestinal tract. After oral administration, absorption produces peak plasma concentrations between 6 and 12 hours. Absolute bioavailability has been estimated to be between 64% and 90%. The bioavailability of amlodipine is high in man corresponding to 97%. It is extensively converted to inactive metabolites via hepatic metabolism.
US Patent Application No. 2003220312 describes co-administration or sequential administration of two compounds for treating a variety of circulatory disorders including
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cardiovascular disorders, such as hypertension, congestive heart failure, myocardial fibrosis and cardiac hypertrophy. The first compound is characterized by a steroid type nucleus with an epoxy moiety attached to the nucleus and having competitive aldosterone receptor binding activity. The second compound is a calcium channel blocker, preferably, amlodipine besylate.
Amlodipine is used in combination with statin compounds. This synergistic combination is useful for treating subjects suffering from angina pectoris, arteriosclerosis, combined hypertension and hyperlipidemia and for subjects with symptoms of cardiac risk
Such pharmaceutical compositions of amlodipine and atorvastatin are described in patent CA2444554. The said patent also describes methods of preparing stable pharmaceutical compositions comprising atorvastatin and amlodipine, and a kit suitable for commercial sale.
Metoprolol succinate is a beta-selective (cardioselective) adrenoreceptor blocking agent, for oral administration, available as extended release tablets to treat a heart condition called angina. Its chemical name is (±) l-(isopropylamino)-3-[p-(2-methoxyethyl) phenoxy]-2-propanol succinate (2:1) (salt). It reduces the oxygen demand to heart, slowing the heart rate, reducing cardiac output when at rest and on exercise and reduces systolic blood pressure. There have been controlled and sustained release metoprolol formulations already known which comprise of controlled release pellets, where each pellet acts as a separate drug delivery unit. But in order to obtain a desirable release of a drug, a considerable amount of experimentation needs to be done. So, in accordance with the present investigation, an extended release pharmaceutical formulation is devised to release the drug for upto 24 hours in a suitable controlled manner.
EP 0293347 by Henry A. C. and Christina E. E. describes Metoprolol succinate as therapeutically active compound, and pharmaceutical preparation comprising it. The invention describes a core containing the therapeutically active compound, the core coated with a layer comprising an anionic polymer soluble, and a water insoluble polymer selected from the group of quaternary ammonium substituted acrylic polymers.
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US Pat. No. 4871549 to Yoshio U et al., describes a time controlled explosion system comprising Metoprolol, a swelling agent such as a low substituted hydroxy propyl cellulose, sodium starch glycolate or carboxy methyl cellulose sodium, coated with a water-insoluble coating material so that drug release is caused by the explosion of the membrane after a definite time period.
EP1110542 by Mccall Troy W and Bachiwal Anand R describes once-a-day oral dosage form of Metoprolol to be released over a period of 24 hours in the gastrointestinal tract. The sustained release matrix comprised of heterosaccharide derivatives of xanthan gum.
However, none of the above patents deal with combination of an anti-hypertensive such as a beta-selective adrenoreceptor blocking agent and calcium channel blocker wherein the adrenoreceptor blocking agent is suitably formulated for extended release while the calcium channel blocker is incorporated suitably for immediate release.
Thus there exists a need to introduce stable, cost effective pharmaceutical compositions having an additive effect in lowering blood pressure in hypertensive patients comprising dual effect thereby providing rapid effect of Amlodipine and an extended release of Metoprolol for 24 hours release.
Object of the invention:
The main object of the present invention is to provide stable dual release pharmaceutical compositions used for treatment of hypertension, chronic stable angina and other related cardiovascular diseases comprising combination of therapeutically effective amount of a synthetic beta-selective adrenoreceptor blocking agent Metoprolol succinate and a calcium channel blocking agent, Amlodipine either racemic or its enantiomer or its salts.
Another object is to provide extended release of selective beta-adrenoreceptor blocker by using monolithic matrix that is combination of hydrophobic (carbomer) and hydrophilic (hydroxy propyl methyl cellulose) polymers, in an effective manner in extended release layer and immediate release of calcium channel blocking agent, thus providing two drugs
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combination therapy to have additive effect in lowering blood pressure in hypertensive patients.
Yet another object of the invention is to reduce the dose of one of the active ingredient by extending the drug release over a period of time.
Summary of the invention:
The present invention discloses stable pharmaceutical compositions comprising two active ingredients, formulated in a single dosage form providing different release profiles comprising dual release drug absorption system (Duredas) technology. The compositions involves use of disintegrants, which helps the immediate release of drug comprising calcium channel blocking agent and the use of monolithic matrix technique for extended release of an adrenergic blocking agent. The monolithic matrix comprises a combination of hydrophobic polymer preferably carbomer and hydrophilic polymer preferably hydroxypropyl methylcellulose, thereby facilitating extended release of adrenergic blocking agent, over a time period of up to 24 hours.
The stable solid pharmaceutical compositions for oral administration comprises a calcium channel blocker such as Amlodipine and a synthetic adrenoreceptor blocking agent, such as Metoprolol succinate equivalent to Metoprolol tartarate; and pharmaceutically acceptable excipients. The amount of the said salts of Amlodipine is in range the of 2.5 tol5mg equivalent to Amlodipine free base and preferably 5mg and 2.5mg. The amount of Metoprolol succinate equivalent to Metoprolol tartarate is in the range of 12.5 mg to 200mg and preferably 50mg and 25mg. The compositions possess additive effect in lowering blood pressure in hypertensive patients.
Detailed description of the invention:
The present invention describes stable dual release pharmaceutical compositions for oral administration that comprises a dihydropyridine calcium channel blocker drug such as Amlodipine as an immediate release component and a synthetic beta-selective adrenoreceptor blocking agent such as Metoprolol succinate incorporated in an extended
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release matrix using monolithic matrix technology, along with pharmaceutical^ acceptable excipients.
Monolithic matrix technique includes use of combination of hydrophobic such as carbomer and hydrophilic polymers such as hydroxypropyl methylcellulose, thereby helps the extended release of drug over specific period of time. The drug is dispersed in a mixture of hydrophilic and hydrophobic matrix resulting in the initial dissolution of matrix polymer and then diffusion of the dissolved drug through the pores of the matrix before release.
The invention further describes a process for preparation of dual release pharmaceutical compositions comprising bilayered tablets of two active ingredients such as Amlodipine besylate and Metoprolol succinate, formulated in a single dosage form providing different release profile using dual drug release absorption system (Duredas). The invention describes immediate release Amlodipine besylate equivalent to amlodipine free base and Metoprolol succinate equivalent to Metoprolol tartarate as an extended release component. The two drugs in combination therapy possess additive effect in lowering blood pressure in hypertensive patients.
As described herein, "bilayer tablet" is a tablet which is made up of two or more distinct layers or discrete zones of granulation compressed together with the individual layers lying one on top of another. Bilayer tablets are generally prepared by compressing granules onto previously partially compressed granules.
The bilayered tablets of the present invention provide dual release of the individual components wherein, an accurate dose of individual active is delivered. The process involves reduced manufacturing steps and manufacturing time. This process provides a cost effective formulation as conventionally there is always loss of 20-25 % at coating stage.
Process I
The process of preparation of dual release pharmaceutical composition comprises of;
granulating metoprolol succinate equivalent to metoprolol tartarate together with selected
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excipients by non-aqueous granulation process, blending the said granules of metoprolol succinate equivalent to metoprolol tartarate with lubricants and glidants; wherein carbomers are used both in granulation and blending stage; blending amlodipine besylate with disintegrants, lubricants and glidants and compressing the said two blends into bilayered tablet where each layer represents a blend comprising single active ingredient with excipients.
Process II
The process of preparation of dual release pharmaceutical composition comprises of; granulating metoprolol succinate equivalent to metoprolol tartarate together with selected excipients by non-aqueous granulation process, blending the said granules of metoprolol succinate equivalent to metoprolol tartarate, lubricants and glidants; wherein carbomers are used both in granulation and blending stage; granulating amlodipine besylate together with selected excipients by moist granulation process and blending the said granules of amlodipine besylate with disintegrants, lubricants and glidants and compressing the said two blends into a bilayered tablet where each layer represents blend comprising a single active ingredient with excipients.
In one embodiment, the stable dual release pharmaceutical compositions comprises the following steps,
(i) non-aqueous granulation of Metoprolol succinate and an extended release matrix comprising a hydrophobic polymer (carbomer) and hydrophilic polymer (hydroxypropyl methyl cellulose) along with selected excipients, (ii) direct compression of Amlodipine besylate together with selective excipients, (iii) compressing the steps of (i) and (ii) into two layer tablets characterized by the presence of the two drug substances in two different layers with or without coating.
In another embodiment, the present invention provides the process for preparing the stable pharmaceutical compositions comprising;
(i) Metoprolol succinate and an extended release matrix comprising a carbomer and hydroxypropyl methyl cellulose in amount from about 5% to 95% by
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weight of the final product along with selected excipients, using non-aqueous
granulation process;
(ii) Amlodipine besylate together with selective excipients, using wet granulation
process and
(iii) lubricating the said granules and
(iv) compressing the granules of (i) and (iii) into two layer tablets characterized by
the presence of the two drug substances in two different layers, using standard
compression tooling known in art with or without coating.
Amlodipine may be in the form of racemic mixture or S (-) isomer or its salts. The said salts are Amlodipine besylate or maleate, preferably Amlodipine besylate. The dose range of amlodipine besylate equivalent to amlodipine free base in the said composition in the range of about 2mg to 15mg of base and dose range for Metoprolol succinate equivalent to Metoprolol tartarate in the range of about 12.5mg to 200mg. Most preferred dose range of Amlodipine besylate in the said composition is 5mg equivalent to Amlodipine free base and for Metoprolol succinate equivalent to Metoprolol tartarate is 50mg.
The dual release drug absorption system comprising Amlodipine besylate equivalent to Amlodipine free base and Metoprolol succinate equivalent to Metoprolol tartarate in combination with pharmaceutically acceptable excipients selected from diluents, binders, flavors, preservatives, pH adjuster, alkalizing agent, disintegrating agents, film formers, lubricants and/or glidants and plasticizers either alone or in combination thereof.
The said diluents are selected from the group consisting of microcrystalline cellulose, calcium phosphate, maize starch or their modified forms. The said diluents are used in the range of 5 to 95% of tablet weight.
The said binders are selected from the group containing maize starch, polyvinylpyrrolidone. The said polyvinylpyrrolidone is used in the range of 3 to 15% and maize starch in the range of 2 to 10%.
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The said disintegrants are selected from the group containing starch, derivative of starch, preferably sodium starch glycolate and croscarmellose sodium. The said glycolate is used in the range of 1-6% and croscarmellose sodium is used in the range 1-6%.
The said lubricant and/or glidants are selected from the group containing magnesium stearate used in the range of 0.25% to 5% and colloidal silicon dioxide is used in the range of 0.1 % to 0.5%.
The film formers are selected from group of polymers such as carbomer, which is used in the range of 5% to 10% and hydroxy propyl methyl cellulose which is used in the range of 0.45% to 1%.
Monolithic matrix technique includes use of combination of hydrophobic preferably carbomer and hydrophilic polymers, thereby helps the extended release of drug over specific period of time. The drug to carbomer ratio may be e.g. from about 10:1 to about 1:12. More appropriately, the drug to carbomer ratio is from about 10:1.25 to about 1:12 by weight of final product. The preparation of the extended release layer is by compression and mixing of polymers. Carbomers are used both in granulation as well as mixing stages.
By extended release it is meant for purposes of the present invention that the therapeutically active medicament is released from the formulation at an extended rate such that therapeutically beneficial blood levels (but below toxic levels) of the medicament are maintained over an extended period of time e.g., providing a 24 hour dosage form.
Other miscellaneous auxiliaries required for processing the product and maintaining stability can also be used.
The said stable compositions are preferably in the dosage form of tablets and bilayered tablets. The bilayer tablet may be film coated preferably with hydroxy propyl methyl cellulose, talc, titanium dioxide, polyethylene glycol 4000.
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The said pharmaceutical compositions of Amlodipine besylate and Metoprolol succinate according to the invention is preferably in the solid dosage form, such as tablets, pills, granules, capsules or sachets, preferably tablets.
The said compositions of Amlodipine besylate and Metoprolol succinate are physically and chemically stable over its shelf life period.
The invention is more specifically explained by following examples. However, it should be understood that the scope of the present invention is not limited by the examples in any manner. It will be appreciated by any person skilled in this art that the present invention includes the following examples and further can be modified and altered within the technical concept of the present invention.
Uncoated tablets
Example 1:
A) Metoprolol succinate granules: Contains 50mg metoprolol succinate equivalent of metoprolol tartarate along with the following excipients:

Sr. No. Ingredient Qty % w/w of total weight
1 Metoprolol succinate 19.4%
2 Micro crystalline cellulose 8.97%
3 Carbomer 8.98%
4 Hydroxy propyl methyl cellulose (K15M) 24.9%
5 Polyvinylpyrrolidone (K30) 12.24%
6 Isopropyl alcohol qs
7 Hydroxy propyl methyl cellulose (K15M) 24.49%
8 Magnesium stearate 1.02%
Preparation of metoprolol succinate granules:
Metoprolol succinate, microcrystalline cellulose, carbomer, hydroxy propyl methyl cellulose were mixed geometrically after sifting through mesh 40. This blend was
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granulated with mixture of polyvinylpyrrolidone and isopropyl alcohol using nonaqueous wet granulation. Granules were milled through mesh 8. Granules are dried at 40-50°C. Dried granules were sifted through mesh 20. It was then lubricated with magnesium stearate.
Metoprolol succinate granules: Contains 25mg metoprolol succinate equivalent of metoprolol tartarate along with the following excipients:

Sr. No. Ingredient Qty % w/w of total weight
1 Metoprolol succinate 12.9%
2 Micro crystalline cellulose 24.89%
3 Carbomer 21.6%
4 Hydroxy propyl methyl cellulose (K15M) 32.40%
5 Polyvinylpyrrolidone (K30) 6.80%
6 Isopropyl alcohol qs
7 Magnesium stearate 1.62%
Tablets containing 25mg metoprolol succinate equivalent to metoprolol tartarate are similarly prepared.
B) Amlodipine besylate: Contains 5mg of amlodipine base equivalent to the amlodipine along with the following excipients:

Sr. No. Ingredient Qty % w/w of total weight
1 Amlodipine besylate 5.6%
2 Dicalcium phosphate granular 25.6%
3 Dicalcium phosphate anhydrous 27.6%
4 AvicelpH102 32%
5 Colloidal silicon dioxide 1.6%
6 Sodium starch glycolate 4.8%
7 Sunset yellow (lake) 1.6%
8 Magnesium stearate 1.3%
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Prepartion of amlodipine besylate mix for direct compression:
Amlodipine besylate, dicalcium phosphate anhydrous, dicalcium phosphate granular, Avicel pH 102, colloidal silicon dioxide, sodium starch glycolate sunset yellow (lake) were mixed geometrically after sifting through mesh 100. It was then lubricated with magnesium stearate.
Example 2:
A) Metoprolol succinate granules: Contains 50mg and 25mg metoprolol succinate
equivalent of metoprolol tartarate along with the excipients and formulation same as
example 1.
B) Amlodipine besylate granules: Contains 5mg of amlodipine free base along with the
following excipients

Sr. No. Ingredient Qty % w/w of total weight
1 Amlodipine besylate 6.67%
2 Micro crystalline cellulose 33.18%
3 Dicalcium phosphate anhydrous 45.45%
4 Crosscarmellose sodium 2.73%
5 Maize starch 3.64%
6 Purified water qs
7 Sodium starch glycolate 5.45%
8 Colloidal silicon dioxide 1.36%
9 Magnesium stearate 1.02%
10 Sunset yellow (lake) 0.68%
Preparation of amlodipine besylate granules:
Amlodipine besylate, microcrystalline cellulose, dicalcium phosphate anhydrous, crosscarmellose sodium, sunset yellow (lake) were mixed geometrically after sifting through mesh 100. This blend was granulated with starch paste using moist granulation. Wet granules were milled through mesh 8. Granules are dried at 40-50°C Dried granules were sifted through mesh 20. Sodium starch glycolate and colloidal silicon dioxide were
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sifted through mesh 40 and mixed with amlodipine besylate equivalent to amlodipine free base granules. It was then lubricated with magnesium stearate.
Tablets containing 2.5mg amlodipine besylate equivalent to amlodipine free base are similarly prepared
Coated tablets Example 3:
A) Metoprolol succinate granules: Contains 50mg and 25mg metoprolol succinate
equivalent of metoprolol tartarate along with the excipients and formulation same as
example 1.
B) Amlodipine besylate: Contains 5mg of amlodipine base along with the excipients and
prepared as example 1 using direct compression method.
Tablets containing 2.5mg amlodipine besylate are similarly prepared.
The coating solution to be coated on the tablets has the following composition:

Sr. No. Ingredient Qty % w/w of total weight
1 Hydroxy propyl methyl cellulose 2.06%
2 Poly ethylene glycol 400 0.04%
3 Talc 0.01%
4 Titanium dioxide 0.01%
5 Isopropyl alcohol qs
6 Methylene chloride qs
There is a 2% weight gain by coating.
The process of film coating comprises:
Dispersing HPMC E5 in isopropyl alcohol (taken in suitable a stainless steel container) and stirring constantly for approximately 10 minutes. Add titanium dioxide, purified talc again under stirring for approximately 10 minutes. Further, adding methylene chloride
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and polyethylene glycol 6000 under stirring for 10 minutes. Continue stirring for 30 minutes and pass the suspension through a bolting cloth, homogenized by passing through a homogenizer. This solution is used to coat tablet with conventional coater/auto-coater.
Example 4:
A) Metoprolol succinate granules: Contains 50mg and 25mg metoprolol succinate
equivalent of metoprolol tartarate along with the excipients and formulation same as
example 1.
B) Amlodipine besylate: Contains 5mg of amlodipine base along with the excipients and
prepared as example 2 using wet granulation method.
Tablets containing 2.5mg amlodipine besylate equivalent to amlodipine free base are similarly prepared.
The coating solution to be coated on the tablets remains same as example3 and the weight gain by coating is 2%.
The pharmaceutical compositions of Amlodipine besylate and Metoprolol succinate are physically and chemically stable over its shelf life period. The stability data is as follows:
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The sample comprising Metoprolol succinate + Amlodipine Tablets (25+2.5) mg. Each film coated bilayered tablet contains Metoprolol succinate USP 23.75mg equivalent to Metoprolol tartrate USP 25mg and Amlodipine besylate BP equivalent to Amlodipine 2.5 mg is stored at: 25 ± 2°C & 60 ± 5% RH.

TEST SPECIFICATION BATCH NO. INITIAL AFTER 03 MONTHS
APPEARANCE Orange - white, bilayered, oval shaped , Him coated tablets IN/MAT(25+2.5)06/05 Complies Complies
IN/MAT(25+2.5)07/05 Complies Complies
IN/MAT(25+2.5)08/05 Complies Complies
DISSOLU HON Metoprolol Succinate 1Hr. :NMT25% 4Hrs.: 25-50% 8Hrs.: 45-75% 20Hrs. :NLT80% IN/MAT(25+2.5)06/05 14.33% 34.80% 63.19% 89.18% 15.20% 38.88% 62.03% 98.43%
IN/MAT(25+2.5)07/05 21.20% 42.12% 67.98% 103.40% 15.42% 40.94% 65.23% 102.44%
IN/MAT(25+2.5)08/05 - - 16.29% 40.78% 64.42% 98.69%
Amlodipine Besylate NLT 70% in 60 min IN/MAT(25+2.5)06/05 89.92 % 92.15%
IN/MAT(25+2.5)07/05 91.78% 97.27%
IN/MAT(25+2.5)08/05 91.77% 91.55%
ASSAY Metoprolol Succinate : 90%-110% IN/MAT(25+2.5)06/05 96.89% 101..25%
IN/MAT(25+2.5)07/05 98.99 % 101.54%
IN/MAT(25+2.5)08/05 98.16% 97.16%
Amlodipine Besylate : 90%-110% IN/MAT(25+2.5)06/05 96.89% 96.74%
IN/MAT(25+2.5)07/05 98.45% 96.98%
IN/MAT(25+2.5)08/05 103.87% 99.19%
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The sample comprising Metoprolol succinate + Amlodipine Tablets (25+2.5) mg. Each film coated bilayered tablet contains Metoprolol succinate USP 23.75mg equivalent to Metoprolol tartrate USP 25mg and Amlodipine besylate BP equivalent to Amlodipine 2.5 mg is stored at: 40 ± 2°C & 75 ± 5% RH.

TEST SPECIFICATION BATCH NO. INITIAL AFTER 03 MONTHS
APPEARANCE Orange - white, bilayered, oval shaped , film coated tablets MMAT(25+2.5)06/05 Complies Complies
IN/MAT(25+2.5)07/05 Complies Complies
IN/MAT(25+2.5)08/05 Complies Complies
DISSOLU TION Metoprolol Succinate 1Hr. :NMT25% 4Hrs.: 25-50% 8Hrs.: 45-75% 20Hrs.: NLT 80% BM/MAT(25+2.5)06/05 14.33% 34.80% 63.19% 89.18% 19.92% 37.89% 60.06% 93.27%
IN/MAT(25+2.5)07/05 21.20% 42.12% 67.98% 103.40% 23.21% 36.40% 58.67% 90.88%
IN/MAT(25+2.5)08/05 15.98% 34.52 % 59.32 % 91.47% 14.96% 39.11% 61.35% 94.67%
Amlodipine Besylate NLT 70% in 60 min IN/MAT(25+2.5)06/05 89.92 % 86.27%
IN/MAT(25+2.5)07/05 91.78% 85.94%
IN/MAT(25+2.5)08/05 91.77% 90.33%
ASSAY Metoprolol Succinate : 90%- 110% IN/MAT(25+2.5)06/05 96.89% 98.99%
lN/MAT(25+2.5)07/05 98.99 % 98.99%
IN/MAT(25+2.5)08/05 98.16% 96..33%
Amlodipine Besylate : 90%-110% lN/MAT(25+2.5)06/05 96.89% 104.94%
IN/MAT(25+2.5)07/05 98.45% 95.67%
IN/MAT(25+2.5)08/05 103.87% 101.51%
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The sample comprising Metoprolol succinate + Amlodipine Tablets (50+5) mg. Each film coated bilayered tablet contains Metoprolol succinate USP 47.5mg equivalent to Metoprolol tartrate USP 50mg and Amlodipine besylate BP equivalent to Amlodipine 5 mg is stored at: 25 ± 2°C & 60 ± 5% RH.

TEST SPECIFICATION BATCH NO. INITIAL AFTER 03 MONTHS
APPEARAN CE Orange - white, bilayered, oval shaped , film coated tablets IN/MAT(50+5)07/05 Complies Complies
IN/MAT(50+5)08/05 Complies Complies
IN/MAT (50+5)09/05 Complies Complies
DISSOLUTI ON Metoprolol Succinate 1Hr. :NMT25% 4Hrs.: 25-50% 8Hrs.: 45-75% 20Hrs.: NLT 80% IN/MAT(50+5)07/05 16.37% 36.10% 56.87% 96.34% 15.91% 42.10% 56.03% 90.74%
IN/MAT(50+5)08/05 16.82% 46.52% 69.66% 99.25% 18.06% 44.98% 69.66% 100.84%
IN/MAT (50+5)09/05 16.2% 39.5% 58.92 % 88.3 % 16.34% 37.99% 55.97% 82.88%
Amlodipine Besyate NLT 70% in 60 min IN/MAT(50+5)07/05 94.84% 92.75%
IN/MAT(50+5)08/05 94.06% 100.08%
IN/MAT (50+5)09/05 97.83% 97.24%
ASSAY Metoprolol Succinate :90%- 110% IN/MAT(50+5)07/05 99.27% 102.19%
IN/MAT(50+5)08/05 99.19% 98.52%
IN/MAT (50+5)09/05 99.27% 96.36%
Amlodipine Besylate : 90%-110% IN/MAT(50+5)07/05 98.38% 100.35%
CM/MAT(50+5)08/05 99.09% 99.21%
IN/MAT (50+5)09/05 97.02% 98.01%
The sample comprising Metoprolol succinate + Amlodipine Tablets (50+5) mg. Each film coated bilayered tablet contains Metoprolol succinate USP 47.5mg equivalent to Metoprolol tartrate USP 50mg and Amlodipine besylate BP equivalent to Amlodipine 5 mg is stored at: 40 ± 2°C & 75 ± 5% RH.
17

TEST SPECIFICATION BATCH NO. INITIAL AFTER 03 MONTHS
APPEAR ANCE Orange - white, bilayered, oval shaped , film coated tablets IN/MAT(50+5)07/05 Complies Complies
IN/MAT(50+5)08/05 Complies Complies
IN/MAT (50+5)09/05 Complies Complies
DISSOLU HON Metoprolol Succinate 1Hr. :NMT25% 4Hrs.: 25-50% 8Hrs.: 45-75% 20Hrs.: NLT 80% IN/MAT(50+5)07/05 16.37% 36.10% 56.87% 96.34% 15.37% 38.36% 55.46% 87.32%
IN/MAT(50+5)08/05 16.82% 46.52% 69.66% 99.25% 17.33% 44.87% 90.31% 101.24%
IN/MAT (50+5)09/05 16.2% 39.5% 58.92 % 88.3 % 18.04% 40.81% 61.89% 92.69%
Amlodipine Besylate NLT 70% in 60 min IN/MAT(50+5)07/05 94.84% 87.68%
IN/MAT(50+5)08/05 94.06% 102.04%
IN/MAT (50+5)09/05 97.83% 97.41%
ASSAY Metoprolol Succinate : 90%-110% IN/MAT(50+5)07/05 99.27% 100.80%
IN/MAT(50+5)08/05 99.19% 99.30%
IN/MAT (50+5)09/05 97.83% 97.43%
Amlodipine Besylate : 90%-110% IN/MAT(50+5)07/05 98.38% 99.23%
IN/MAT(50+5)08/05 99.09% 99.30%
IN/MAT (50+5)09/05 97.02% 100.07%
Bioavailability study is conducted of Metoprolol XL 50mg + Amlodipine 5 mg FDC manufactured by IPCA Laboratories Ltd. in comparison with, Seloken XL tablet containing Metoprolol XL 50mg manufactured by Astra Zenaca Pharma Ltd. and Amlogard tablet containing Amlodipine 5 mg manufactured by Pfizer in 12 healthy male, adult human volunteers under fasting condition in a randomized two-way complete crossover design. Values of Cmax, tmax, AUC o-t and AUC o-«> were comparable for the Reference and the Test preparation in the fasting state.
Metoprolol XL was detected in plasma from 0.5 hour to about 72 hours in Reference preparation and Test preparation. Peak plasma levels of Metoprolol XL with the Reference preparations were achieved between 5 to 12 hours and with the Test preparations they are achieved between 2 to 12 hours.
The mean peak plasma levels of Metoprolol XL with Reference preparation, Seloken XL tablet on the study day ranged between 32-292 ng/ml while with Test preparation ranged between 30-301 ng/ml.
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On the basis of comparison of the AUCo-t for Metoprolol XL after single dose administration, the relative bioavailability of the Test preparation of Metoprolol XL 50 mg was 102.87 % of that of the Reference preparation, Seloken XL tablet.
Amlodipine was detected in plasma from 0.5 hour to about 96 hours in Reference preparation and Test preparation. Peak plasma levels of Amlodipine with the Reference preparations were achieved between 5 to 16 hours and with the Test preparations they are achieved between 5 to 12 hours.
The mean peak plasma levels of Amlodipine with Reference preparation, on the study day ranged between 2.01-3.94 ng/ml, while with Test preparation ranged 2.48-4.67 ng/ml. On the basis of comparison of the AUCo-t for Amlodipine after single dose administration, the relative bioavailability of the Test preparation of Amlodipine 5 mg was 99.37 % of that of the Reference preparation.
Conclusion: On the basis of pharmacokinetic parameters, it can be concluded that the Test preparation of Metoprolol XL 50mg + Amlodipine 5 mg FDC tablets manufactured by IPCA Laboratories Ltd. is bioequivalent with the Reference preparation, Seloken XL tablet containing Metoprolol XL 50mg manufactured by Astra Zenaca Pharma Ltd. and Amlogard tablet containing Amlodipine 5 mg manufactured by Pfizer.
It will be evident to those skilled in the art that the invention is not limited to the details of the foregoing illustrative examples and that the present invention may be embodied in other specific forms without departing from the essential attributes thereof, and it is therefore desired that the present embodiments and examples be considered in all respects as illustrative and not restrictive, reference being made to the appended claims, rather than to the foregoing description, and all changes which come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein.
19

We claim;
1. Stable bilayered tablet pharmaceutical compositions prepared with
Duredas technology comprising a calcium channel blocker such as
Amlodipine and a beta-selective adrenoreceptor blocking agent, such as
Metoprolol, wherein Amlodipine is incorporated as an immediate release
component and Metoprolol is incorporated as an extended release
component comprising monolithic matrix technology; the said
composition is prepared by a process comprising;
a. granulating metoprolol succinate with pharmaceutically acceptable
excipients by non-aqueous granulation process and blending the
said granules of metoprolol succinate with disintegrants, lubricants
and glidants;
b. granulating amlodipine besylate with pharmaceutically acceptable
excipients by wet granulation process and blending the granules
with disintegrants, lubricants and glidants or blending the besylate
salt of amlodipine with disintegrants, lubricants and glidants (dry
granulation) and
c. compressing the said two blends (a) and (b) into a bilayered tablet
where each layer represents blend comprising a single active
ingredient with excipients and
d. coating the bilayer tablets.
2. Pharmaceutical compositions as claimed in claim 1, wherein the said Amlodipine is in the form of racemic mixture or S (-) isomer and salts such as besylate or maleate, preferably Amlodipine besylate in an amount equivalent to Amlodipine free base in the range of 2 to 15mg and preferably 5mg and 2.5mg.
3. Pharmaceutical compositions as claimed in claim 1, wherein the said Metoprolol salt is Metoprolol succinate in the range of 12.5 to 200mg equivalent to Metoprolol tartarate and preferably 50mg and 25mg.
20

4. Pharmaceutical compositions as claimed in claim 1, wherein Metoprolol succinate is incorporated as an extended release monolithic matrix comprising a polymer base retardant coating comprising a combination of hydrophobic polymer such as carbomer and a hydrophilic polymer such as hydroxypropyl methyl cellulose.
5. Pharmaceutical compositions as claimed in claim 1, wherein the pharmaceutically acceptable excipients are selected from diluents, binders, disintegrants, lubricants, glidants, flavors, alkalizing agents, preservatives, sweeteners, film formers and plasticizers either alone or in combination thereof.
6. Pharmaceutical compositions as claimed in claim 1 and 5, wherein the said diluents are selected from the group consisting of microcrystalline cellulose, calcium phosphate, maize starch or their modified forms used in the range of 5 to 95% of tablet weight.
7. Pharmaceutical compositions as claimed in claim 1 and 5, wherein the said binders are selected from the group containing maize starch, polyvinylpyrrolidone wherein preferred binder is polyvinylpyrrolidone used in the range of 3 to 15% and maize starch in the range of 2 to 10%.
8. Pharmaceutical compositions as claimed in claim 1 and 5, wherein the said disintegrants are selected from the group containing starch, derivative of starch and the preferred disintegrants are sodium starch glycolate used in the range of 1-6% and crosscarmellose sodium used in the range 1-6%.
9. Pharmaceutical compositions as claimed in claim 1 and 5, wherein the said lubricant and glidants are selected from the group containing magnesium stearate in the range of 0.25% to 5%, and colloidal silicon dioxide used in the range of 0.1% to 0.5%
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10. Pharmaceutical compositions as claimed in claim 1 and 9, wherein the said film formers are selected from group of polymers such as carbomer used in the range of 5% to 10% and hydroxy propyl methyl cellulose used in the range of 0.45% to 1%.
11. Stable pharmaceutical compositions as claimed in any of the preceding claims 1 to 10 and their process of preparation as described herein with reference to the foregoing examples 1-4.
Dated this 14,h day of December 2006
Dr. Gopakumar G. Nair Agent for the Applicant
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Abstract:
The present invention discloses stable pharmaceutical compositions comprising pharmaceutically acceptable acid addition salt of vasodilator such as amlodipine with acid addition salt of a synthetic beta-selective adrenoreceptor blocking agent metoprolol succinate formulated as oral solid dual release pharmaceutical compositions, useful for the treatment of various cardiovascular diseases. The manufacturing process for the preparation of said stable pharmaceutical compositions is disclosed herein.

Documents:

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Patent Number

270910

Indian Patent Application Number

2057/MUM/2006

PG Journal Number

05/2016

Publication Date

29-Jan-2016

Grant Date

27-Jan-2016

Date of Filing

15-Dec-2006

Name of Patentee

IPCA LABORATORIES LIMITED

Applicant Address

48, KANDIVLI INDUSTRIAL ESTATE, CHARKOP, KANDIVLI(WEST), MUMBAI-400 067,

Inventors:

#	Inventor's Name	Inventor's Address
1	SENGUPTA, SUBHRANGSHU	B-401, Ganga Vasant Nagar, Thakur Village, Kandivli(E), Mumbai-400 101,
2	KADAM, SONAL	1,Nilkantha Sadan, Peru Baug, Aarey Road, Goregaon (E), Mumbai-400 063
3	BANSAL, YATISH KUMAR	Flat No.5, Siras Villa, Plot No.4, Sai Baba Park, Evershine Nagar, Malad(W), Mumbai-400 064
4	GODHA, PREMCHAND	Flat No.5, Siras Villa, Plot No.40, Sai Baba Park, Evershine Nagar, Malad(W), Mumbai-400 064,
5	BENDE, GIRISH	4/18, SHRADDHA GARDENS, CHINCHWAD, PUNE-411 033,

PCT International Classification Number

A61K31/00

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA