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 WITH AN INERT CORE
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 an 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 one or more release-controlling layer(s).
The following specification particularly describes the invention and the manner in which it is to be performed.
4. DESCRIPTION
The present invention provides an 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 one or more release-controlling layer(s).
1

Metoprolol is a betal-selective (cardioselective) adrenoceptor-blocking agent It 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.
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
2

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. The water-soluble inert core comprises sugar sphere or salt, water insoluble inert core comprises silicon dioxide, small particles of glass, plastic resin particles or mixtures thereof and water swellable inert core comprises hydroxypropyl methylcellulose, microcrystalline cellulose, starch or mixture thereof.
Several other controlled release preparation containing an inert core are known in the prior art such as US Patent No 4,871,549, US Application No 20050266078, US Application No 20060003007, US Application No 20040228915.
It is well known in the prior art that sugar spheres, glass beads, silicon dioxide or methylcellulose can be used as an inert core. Present inventors while working on extended release formulations of metoprolol or salt thereof have surprisingly found that microcrystalline cellulose pellets (Celphere CP 203) that is water swellable, when coated with water insoluble polymer ethylcellulose (Ethocel) layer in admixture with pharmaceutical^ acceptable excipients selected from the group consisting of plasticizer and solvent, can be used as an inert core. This inert core is further coated with one or more drug layers, which is further coated with one or more release controlling layers to provide controlled release, sustained release or extended release dosage forms.
In one of the aspects of present invention there is provided an inert core for preparation of solid oral dosage form wherein the inert core comprises of microcrystalline cellulose spheres coated with a water insoluble pharmaceutical^ acceptable polymer, the inert core is further coated with pharmaceutical^ active ingredient and other pharmaceutical^ acceptable excipients which is then optionally coated with release controlling polymer layer(s).
3

The inert core also called as seal coat can be used to prepare immediate release, extended release, controlled release or sustained release dosage forms of various categories of drugs. The 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 prepared by dissolving Ethocel and triacetin in suitable solvent and then Celphere CP 203 is coated with it in fluid bed processor at optimum parameters. The inert core is further coated with a drug solution or suspension comprising drug, o pa dry and a 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 a suitable solvent
The 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.
In yet another aspect of the present invention there is provided an extended release dosage form of metoprolol or salt thereof which comprises of an inert core comprising of microcrystalline cellulose spheres coated with a polymer optionally having other pharmaceutically acceptable excipients, the inert core is further coated with metoprolol or salt thereof optionally having other pharmaceutically acceptable excipients, the drug coat is further coated with pharmaceutically acceptable rate-controlling polymer to impart desired release profile.
The extended release dosage form of metoprolol or salt thereof is prepared using an inert core wherein an inert core comprises of microcrystalline cellulose pellets (Celphere CP 203) that is water swellable, which is further coated with water insoluble polymer ethylcellulose (Ethocel) in admixture with plasticizer and solvent. The inert core is being prepared by dissolving Ethocel and triacetin in suitable
4

solvent and Celphere CP 203 is coated with it in fluid bed processor at optimum parameters. The inert core is further coated with a drug solution or suspension comprising drug, opadry 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 pharmaceutical^ acceptable rate controlling polymer is dissolved in a suitable solvent. The coated pellets are further blended in suitable blender with pharmaceutical^ 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 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.
Suitable acrylic acid polymers include any suitable polyacrylic acid polymers or carboxyvinyl polymers such as those available under the brand name Carbopol.
The pharmaceutically 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, 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
5

skilled in the art and are intended to be included within the scope of the present invention.
EXAMPLES
Table 1: Composition of Metoprolol succinate Extended Release tablets.

S.No. Ingredients mg/Tablet
Stage 1: Seal Coating
1. Celphere CP 203 43.50
2. Ethocel 2.18
3. Triacetin 0.22
Stage 2: Drug Layering
4. Metoprolol Succinate 190.00
5. OpadryYS-1R-7006 Clear 19.00
Stage 3: Extended Release Coating
6. Ethocel 27.32
7. OpadryYS-1R-7006 Clear 6.83
Stage 4 Blending and Compression
. 8. Extended Release Coated Pellets 289.05
9. AvicelPH101 332.49
10. AvicelPH102 110.82
11. Polyethylene Glycol 6000 133.90
12. Ac-di-sol 79.60
13. Aerosil 200 1.20
14. Magnesium stearate 2.94
Total 950.00
Procedure: Ethocel and triacetin was dissolved in a suitable solvent and Celphere CP 203 was coated in fluid bed processor at optimum parameters with the above mixture. Metoprolol succinate and opadry clear was dissolved in suitable solvent and seal coated pellets were coated with it in fluid bed processor at optimum parameters. Ethocel and opadry clear was dissolved in a suitable solvent and drug layered pellets were coated with it in fluid bed processor at optimized parameters. Avicel PH 101, Avicel PH 102, Polyethylene glycol 6000, Ac-di-sol (croscarmellose sodium) and Aerosil 200 were sifted through suitable mesh and then blended in suitable blender. Magnesium stearate was sifted through suitable mesh. The blend was lubricated and Extended Release coated pellets were transferred to blender and blended. The Pellets were compressed to form tablets using suitable tooling.
6

Table 2: Drug release data of Metoprolol succinate Extended Release tablets prepared as per the formula given in table 1.

Time (hour) % Drug released
0 0
1 13
2 23
4 41
8 66
12 84
16 92
20 97
For determination of drug release, USP Type 2 Apparatus, 50 rpm is used wherein 500 ml of phosphate buffer pH 6.8 is used as a medium.

WE CLAIM:
1. An inert core for preparation of solid oral dosage form wherein the core comprises of microcrystalline cellulose spheres coated with a water insoluble pharmaceutlcally acceptable polymer.
2. An inert core as per claim 1, wherein water insoluble pharmaceutlcally acceptable polymer is ethylcellulose.
3. An inert core as per claim 1 is further coated with pharmaceutlcally active ingredient and other pharmaceutlcally acceptable excipients, which is then optionally coated with release controlling polymers.
4. An inert core as per claim 3, wherein pharmaceutlcally active ingredient comprises one or more of lansoprazole, pantoprazole, metoprolol, propranolol, diltiazem, tamsulosin, diclofenac, itraconazole, venlafaxine, tolterodine and pharmaceutlcally acceptable salts or derivatives thereof.
5. An inert core as per claim 3, wherein pharmaceutlcally acceptable excipient is selected from a group comprising of polymer, plasticizer, binder and the like.
6. An extended release dosage form of metoprolol or salt thereof which comprises of an inert core comprising of microcrystalline cellulose spheres coated with a polymer optionally having other pharmaceutlcally acceptable excipients, the inert core further coated with metoprolol or salt thereof optionally having other pharmaceutical^ acceptable excipients, the drug coat is further coated with pharmaceutical^ acceptable rate-controlling polymer to impart desired release profile.
8

7. An extended release dosage form as per claim 6, wherein metoprolol is present in the form of metoprolol succinate.
8. An extended release dosage form as per claim 6, wherein rate-controlling polymer is selected from a group comprising of cellulose ethers or acrylic acid polymers.
9. An extended release dosage form as per claim 6, wherein extended release dosage form is pellet, capsule, sachet or tablet.
Dated this 28th day of March, 2006

9