FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule13)
1. TITLE OF THE INVENTION:
EXTENDED RELEASE DOSAGE FORM OF METOPROLOL OR SALT THEREOF
2. APPLICANT (S)
(a) NAME: WOCKHARDT LTD.
(b) NATIONALITY: INDIAN
(c) ADDRESS: Wockhardt Towers, Bandra-Kurla Complex, Bandra
(East), Mumbai-400 051.
3. PREAMBLE TO THE DESCRIPTION
The present invention provides extended release dosage form of metoprolol or salt thereof comprising an inert core coated with a solution or suspension of metoprolol or salt thereof in admixture with a binder and a solvent. The drug layer is further coated with extended release coat and colloidal silicon dioxide coat comprising of pharmaceutical^ acceptable excipient selected from the group consisting of one or more polymers, binder, solvent and the like. The colloidal silicon dioxide coat minimizes the crushing of pellets during tablet compression.
The following specification particularly describes the invention and the manner in which it is to be performed.

4. DESCRIPTION
The present invention provides extended release dosage form of metoprolol or salt thereof comprising an inert core coated with a solution or suspension of metoprolol or salt thereof in admixture with a coating mixture and a solvent. The drug layer is further coated with extended release coat and colloidal silicon dioxide (Aerosil 200) coat comprising of pharmaceuticafly acceptable excipient selected from the group consisting of one or more polymers, binder, solvent and the like. The colloidal silicon dioxide coat minimizes the crushing of pellets during tablet compression.
Metoprolol is a beta 1-selective (cardioselective) adrenoceptor-blocking agent that is commercially available in two salt forms; one of them is tartrate salt available as Lopressor® tablets and the other is succinate salt (Formula I) available as Toprol-XL® tablets. Metoprolol is chemically, (±) 1-(isopropylamino)-3-[p-(2-methoxyethyl) phenoxy]-2-propanol. Metoprolol succinate is indicated in the treatment of hypertension and angina pectoris.

U.S Patent Nos. 4,927,640 and 4,957,745 disclose a controlled release preparation containing a number of beads comprising insoluble cores coated with metoprolol. The beads have a high content of metoprolol in the range of 95-100% w/w of the soluble part of the bead. Insoluble cores, such as glass and silicon dioxide are used.
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U.S Patent No 5,001,161 discloses a pharmaceutical composition comprising metoprolol succinate together with a sustained release pharmaceutically acceptable carrier.
U.S Patent Application 20030185887 discloses a controlled or sustained release dosage formulation of propranolol where the inert core is coated with a solution of propranolol, water insoluble binder and filler. The active core so produced is further coated with a release-controlling layer.
U.S Patent Application 20050008701 discloses a controlled release pellet comprising water-soluble or water swellable inert core and a drug layer applied to it, alongwith a controlled release coating surrounding the drug layer
PCT Patent Application WO 2005084636 discloses oral controlled-release pharmaceutical composition of metoprolol succinate comprising a water-soluble, water swellable or water-insoluble inert core; one or more drug layers comprising metoprolol and one or more polymeric coatings surrounding the one or more drug layers and optionally, one or more non functional coatings (e.g. polyethylene glycol) surrounding the one or more polymeric coatings.
Several other controlled release/ extended release pharmaceutical compositions are known in the prior art such as US Patent No 5,399,362, US Patent No 5,399,358, US Patent No 5,707,656, US Patent No 5,709,882, US Patent No 4,871,549, US Application No 20020177579, US Application No 20040228915 and US Application No 20050266078.
It well known from the prior art that polyethylene glycol can be coated over the pellets to minimize crushing during compression, as it provides a cushioning effect. Present inventors while working on extended release formulations of metoprolol or salt thereof have surprisingly found that an extended release
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pellets of metoprolol or salt thereof when coated with colloidal silicon dioxide (Aerosil 200) crushing of pellets during tablet compression is minimized.
In one of the aspects of present invention there is provided a dosage form wherein the dosage form comprises of a core comprising of pharmaceutically active ingredient and pharmaceutically acceptable excipient or an inert core coated with pharmaceutically active ingredient and pharmaceutically acceptable excipient which is then optionally coated with pharmaceutically acceptable release controlling polymer which is then coated with colloidal silicon dioxide.
A dosage form comprising of core or an inert core can be used to prepare immediate release, extended release, controlled release or sustained release dosage forms of various categories of drugs. The inert core is being prepared by dissolving ethylcellulose (Ethocel) and triacetin in suitable solvent and then microcrystalline cellulose spheres (Celphere CP 203) are coated with it in fluid bed processor at optimum parameters. The inert core is further coated with a drug solution or suspension comprising drug, op a dry and suitable solvent, in fluid bed processor at optimum parameters. The drug layer is further coated in fluid bed processor at optimized parameters with an extended release coat wherein pharmaceutically acceptable rate controlling polymer is dissolved in suitable solvent. Mix 0 pa dry and colloidal silicon dioxide (Aerosil 200) in the suitable solvent and coat the extended release coated pellets with it in fluid bed processor at optimum parameters.
The pharmaceutically active ingredients comprises one or more of lansoprazole, pantoprazole, metoprolol, propranolol, diltiazem, tamsulosin, diclofenac, Itraconazole, Venlafaxine, Tolterodine and pharmaceutically acceptable salts or derivatives thereof.
In yet another aspect of the invention there is provided an extended release dosage form of metoprolol or salt thereof which comprises of a core comprising
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of metoprolol or salt thereof and pharmaceutical^ acceptable excipient or an inert core coated with metoprolol or salt thereof and pharmaceutically acceptable excipient which is then coated with pharmaceutically acceptable release controlling polymer to impart desired release profile and then coated with colloidal silicon dioxide.
The extended release dosage form of metoprolol or salt thereof is prepared using an inert core wherein an inert core comprises of Celphere CP 203 (microcrystalline cellulose pellets) that is water swellable, which is further coated with water insoluble polymer Ethocel (ethylcellulose) in admixture with plasticizer and suitable solvent. The inert core is being prepared by dissolving ethocel and triacetin in suitable solvent and then Cellphere CP 203 is coated with it in fluid bed processor at optimum parameters. The inert core is further coated with a drug solution comprising drug, opadry and suitable solvent in fluid bed processor at optimum parameters. The drug layer is further coated with an extended release coat and Aerosil coat in fluid bed processor at optimized parameters. The extended release coat is prepared by dissolving ethylcellulose and opadry in suitable solvent and then drug coated pellets are coated with it. The Aerosil coat is prepared by mixing Opadry and colloidal silicon dioxide (Aerosil 200) in suitable solvent and then coating the extended release coated pellets with it in fluid bed processor at optimum parameters. The coated pellets are further blended in suitable blender with pharmaceutically acceptable excipients selected from the group consisting of filler, superdisintegrant, lubricant, glidant and the like. The pellets are further compressed to form tablets using suitable tooling.
The pharmaceutically acceptable rate controlling polymers can be selected from a group comprising of one or more of cellulose ethers, acrylic acid polymers and mixtures, thereof.
Suitable cellulose ethers include one or more of hydroxypropyl methylcellulose, hydroxypropyl cellulose and other suitable cellulose ethers.
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Suitable acrylic acid polymers include any suitable polyacrylic acid polymers or carboxyvinyl polymers such as those available under the brand name carbopol.
The pharmaceutical^ acceptable excipients can be filler, binder, superdisintegrant, lubricant, glidant and the like. The filler may be one or more of Avicel PH 101, Avicel PH 102, lactose, and dicalcium phosphate. Superdisintegrant may be one or more of croscarmellose sodium, crospovidone and sodium starch glycolate lubricants may be one or more of magnesium stearate, calcium stearate, polyethylene glycol, hydrogenated vegetable oils, stearic acid, and sodium benzoate. The glidants may be one or more of colloidal silicon dioxide and talc.
While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present
invention.
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EXAMPLES
Table 1: Composition of Metoprolol succinate Extended Release tablets.

Stages Ingredients Example 1 mg/Tablet Example 2 mg/Tablet
Stage 1: Seal Coating Celphere CP 203 43.50 43.50
Ethocel 2.18 2.18
Triacetin 0.22 0.22
Stage 2: Drug Layering Metoprolol Succinate 190.00 190.00
Opadry YS-1R-7006 Clear 19.00 19.00
Stage 3: Extended Release Coating Ethocel 27.32 27.32
Opadry YS-1R-7006 Clear 6.83 6.83
Stage 4: Colloidal silicon dioxide Coating (Aerosil) Aerosil 200 ~ 19.25
Opadry YS-1R-7006 Clear — 2.14
Stage 5: Blending and Compressionr Extended Release Coated Pellets 289.05 ~
Aerosil Coated Pellets — 310.44
Avicel PH 101 332.49 321.55
Avicel PH 102 110.82 107.19
Polyethylene Glycol 6000 133.90 129.73
Ac-di-sol 79.60 77.11
Aerosil 200 1.20 1.14
Magnesium stearate 2.94 2.84
Total 950.00 950.00
Procedure: Ethocel and triacetin was dissolved in suitable solvent and Celphere CP 203 was coated with it in fluid bed processor at optimum parameters. Metoprolol succinate and opadry was dissolved in suitable solvent and seal coated pellets were coated with it in fluid bed processor at optimum parameters. Ethocel and opadry was dissolved in suitable solvent and drug-layered pellets were coated with it in fluid bed processor at optimized parameters. Opadry and Aerosil 200 (colloidal silicon dioxide) were added to suitable solvent and then extended release pellets were coated with it in fluid bed processor at optimum parameters in case of example 2. Avicel PH 101, Avicel PH 102, Polyethylene glycol 6000, Ac-di-sol (croscarmellose sodium) and Aerosil 200 were sifted
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through suitable mesh and then blended in suitable blender. Magnesium stearate was sifted through suitable mesh. The blend was lubricated in suitable blender. The Aerosil-coated pellets were transferred to suitable blender and blended. Pellets were compressed to form tablets using suitable tooling.
Table 2: Drug release data of Metoprolol succinate Extended Release tablets prepared as per the formula given in table 1.

Time (hour) Example 1 % Drug released Example 2 % Drug released
0 0 0
1 13 5
2 23 11
4 41 24
8 66 52
12 84 72
16 92 86
20 97 93
For determination of drug release, USP Type 2 Apparatus, 50 rpm is used wherein 500ml of phosphate buffer pH 6.8 is used as a medium.
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WE CLAIM:
1. A dosage form wherein the dosage form comprises of a core comprising of pharmaceutically active ingredient and pharmaceutically acceptable excipient or an inert core coated with pharmaceutically active ingredient and pharmaceutically acceptable excipient which is then optionally coated with pharmaceutically acceptable release controlling polymer which is then coated with colloidal silicon dioxide.
2. A dosage form as per claim 1, wherein pharmaceutically active ingredient comprises one or more of lansoprazole, pantoprazole, metoprolol, propranolol, diltiazem, tamsulosin, diclofenac, Itraconazole, Venlafaxine, Tolterodine and pharmaceutically acceptable salts or derivatives thereof.
3. A dosage form as per claim 1, wherein pharmaceutically acceptable excipient is selected from a group comprising of polymer, plasticizer, binder and the like.
4. A dosage form as per claim 1, wherein pharmaceutically acceptable release controlling polymer is selected from a group comprising of cellulose ethers or acrylic acid polymers.
5. An extended release dosage form of metoprolol or salt thereof which comprises of a core comprising of metoprolol or salt thereof and pharmaceutically acceptable excipient or an inert core coated with metoprolol or salt thereof and pharmaceutically acceptable excipient which is then coated with pharmaceutically acceptable release controlling polymer to impart desired release profile and then coated with colloidal silicon dioxide.
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6. An extended release dosage form as per claim 5, wherein metoprolol is present in the form of metoprolol succinate.
7. An extended release dosage form as per claim 5 is tablet.
Dated this 28th day of March, 2006