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 A NON SWELLABLE 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 pharmaceutically acceptable excipient which is further coated with one or more release-controlling layer(s) wherein the said inert core is water insoluble and water non-swellable.
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 pharmaceutically acceptable excipient which is further coated with one or more release-controlling layer(s) wherein the said inert core is water insoluble and water non-swellable.
Metoprolol is a beta 1-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.

OH
OCH2CHCH2NHCH{CH3)g
6
CH2CH2OCH3

COOH
I * CH2
COOH

FORMULA I
U.S Patent Nos. 4,927,640 and 4,957,745 provides a controlled release preparation containing a number of beads comprising insoluble cores coated with metoprolol. Insoluble cores, such as glass and silicon dioxide are used.
U.S Patent Application 20050008701 provides 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.
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PCT Patent Application WO2005084636 provides oral controlled-release pharmaceutical composition of metoprolol succinate comprising a water-soluble, water swellable or water-insoluble inert core.
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 spheres when coated with water insoluble polymer ethylcellulose in admixture with pharmaceutically acceptable excipients, can be used as an inert core. The formed inert core was found to be water insoluble and non-swellable. The inert core is coated with one or more drug layers, which is further coated with one or more release controlling layers followed by coating with non-functional coat 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 said inert core is insoluble and non-swellable and comprises of microcrystalline cellulose spheres coated with a pharmaceutically acceptable polymer in admixture with pharmaceutically acceptable excipients.
Microcrystalline cellulose spheres are water swellable however the present invention provides a non-swellable inert core that is prepared by coating microcrystalline cellulose spheres with ethylcellulose in admixture with plasticizer, anti-adherent and suitable solvent. Also the inert core of present invention is water insoluble. The inert core is prepared by dissolving ethylcellulose in suitable solvent followed by adding triethyl citrate and talc and then coating microcrystalline
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cellulose spheres with it in fluid bed processor at optimum parameters. The inert core can be used to prepare immediate release, extended release, controlled release or sustained release dosage forms of various categories of drugs.
The various categories of drugs comprises one or more of lansoprazole, pantoprazole, metoprolol, propranolol, diltiazem, tamsulosin, diclofenac, itraconazole, venlafaxine, tolterodine and pharmaceutically acceptable salts or derivatives thereof.
The phrase "inert core," as used herein, includes core that is water insoluble and non-swellable.
The phrase "solid oral dosage form," as used herein, refers to tablets, capsules, pellets, sachets and like.
The phrase "insoluble," as used herein, refers to inert core, which does not dissolve in water.
The phrase "non-swellable," as used herein, refers to inert core having % swelling of 20 % or less in purified water, after 24 hours.
The pharmaceutically acceptable polymer comprise of one or more of acrylic polymers or copolymers, ethylcellulose and like.
The pharmaceutically acceptable excipients comprise one or more of plasticizers, anti-adherent, aqueous or non-aqueous solvents and the like. Suitable plasticizers include one or more of diethyl phthalate, triethyl citrate, acetyl tributyl citrate, dibutyl phthalate, triacetin, propylene glycol, polyethylene glycol and the like. Suitable anti-adherent includes one or more of talc. Suitable solvents include one or more of dichloromethane, acetone, ethanol, methanol, isopropyl alcohol, water or mixture thereof.
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In yet another aspect of the present invention there is provided an extended release dosage form of metoprolol or salt thereof comprising plurality of beads comprising
a) water insoluble and water non-swellable inert core;
b) one or more drug layers comprising metoprolol or salt thereof in admixture with pharmaceutically acceptable excipients;
c) one or more pharmaceutically acceptable rate controlling polymer surrounding one or more drug layers; and
d) optionally one or more non functional coating surrounding the one or more polymeric coatings
In yet another aspect of the present invention there is provided an extended release dosage form of metoprolol or salt thereof comprising plurality of beads wherein the said dosage form comprise water insoluble and water non-swellable inert core, the inert core is further coated with metoprolol or salt thereof which is further coated with one or more pharmaceutically acceptable rate-controlling polymer.
The extended release dosage form comprises metoprolol as an active ingredient, which is present in the form of metoprolol succinate. The extended release dosage form of metoprolol succinate is prepared using a water insoluble and water non-swellable inert core wherein an inert core comprises of microcrystalline cellulose spheres coated with water insoluble polymer ethylcellulose in admixture with plasticizer, anti-adherent and solvent. The inert core is being prepared by dissolving ethylcellulose in suitable solvent followed by adding triethyl citrate and talc and then coating microcrystalline cellulose spheres with it in fluid bed processor at optimum parameters. The inert core is 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 polymeric coat wherein
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pharmaceutically acceptable rate controlling polymer and opadry is dissolved in a suitable solvent. The polymer-coated pellets are further coated with non-functional coating comprising Polyethylene glycol (PEG). The PEG coated pellets are further blended in suitable blender with pharmaceutical^ acceptable excipients selected from the group comprising of filler, superdisintegrant, lubricant, glidant, cushioning agent and the like. The obtained blend can be optionally compressed to form tablet using suitable tooling or filled into capsule.
The pharmaceutically acceptable excipients can be filler, binder, disintegrant, lubricant, glidant, cushioning agent and the like.
The filler may be one or more of Avicel PH 101, Avicel PH 102, lactose, Prosolv SMCC 90 and dicalcium phosphate. The binder may be one or more of hydroxypropyl methylcellulose, povidone, hydroxypropyl cellulose, ethylcellulose or mixtures thereof. Disintegrant 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. Cushioning agent may be one or more of PEG, colloidal silicon dioxide and the like.
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, ethyl cellulose, 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.
Non-functional coating include one or more of Polyethylene glycols (PEGs), colloidal silicon dioxide and the like
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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.
EXAMPLE 1
Table 1: Table showing % swelling in coated and uncoated microcrystalline pellets (Celphere CP 203 and Celphere CP 305)

S.No. Celphere Type Initial volume (mL) Volume after 24 hrs (mL) % Swelling
1. Uncoated Celphere CP203 4 6 50
2. Coated* Celphere CP203 4 4.7 17.5
3. Uncoated Celphere CP305 4 6.2 55
4. Coated* Celphere CP305 4 4.6 15
* Ethylcellulose coat that is 15% of the uncoated Celphere CP 203 & Celphere CP 305
Procedure: All coated and uncoated Celphere pellets were separately put in measuring cylinder occupying 4 ml volume. To each cylinder was added 4 ml water and was kept for 24 hr period at controlled room temperature. After 24 hrs increase in the volume was measured and % swelling was calculated. The coated Celphere CP 203 and CP 305 showed % swelling of 20% or less in 24 hrs.
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EXAMPLE 2
Table 2: Composition of Metoprolol succinate Extended Release tablets.

S.No. Ingredients mg/Tablet
Stage 1: Seal Coating
1. Celphere CP 305 43.5
2. Ethylcellulose 50cps 4.94
3. Triethyl citrate 0.494
4. Talc 1.087
Stage 2: Drug Layering
5. Metoprolol Succinate 190
6. Opadry Clear 19
Stage 3: Extended Release Coating
7. Ethylcellulose 14.5
8. Opadry Clear 3.63
Stage 4: PEG Coating
9. PEG Coating 27.715
Stage 5: Blending and Compression
10. PEG coated pellets 304.8
11. Prosolv SMCC 90 517.72
12. Croscarmellose NA 70
13. PEG 6000 104.28
14. Sodium stearyl fumarate 3.2
Total Tablet Weight 1000
Procedure: Ethylcellulose was dissolved in a suitable solvent and to it and triethyl citrate and talc were added. Celphere CP 305 spheres were coated in fluid bed processor at optimum parameters with the above prepared mixture to get seal coated pellets. Metoprolol succinate and opadry clear were dissolved in suitable solvent and seal coated pellets were coated with it in fluid bed processor at
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optimum parameters. Ethylcellulose and opadry clear were dissolved in suitable solvent and drug layered pellets were coated with it in fluid bed processor at optimized parameters. The polymer coated pellets were then coated with PEG in suitable solvent followed by blending the PEG coated pellets with presifted Prosolv SMCC 90, croscarmellose sodium, PEG 6000 in suitable blender. The obtained blend was lubricated with presifted Sodium stearyl fumarate and compressed to form tablets using suitable tooling.
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WE CLAIM:
1. An inert core for preparation of solid oral dosage form wherein the said inert core is insoluble and non-swellable and comprises of microcrystalline cellulose spheres coated with a pharmaceutically acceptable polymer in admixture with pharmaceutically acceptable excipients.
2. An inert core as per claim 1, wherein pharmaceutically acceptable polymer is ethylcellulose
3. An extended release dosage form of metoprolol or salt thereof comprising plurality of beads comprising

a) water insoluble and water non-swellable inert core;
b) one or more drug layers comprising metoprolol or salt thereof in admixture with pharmaceutically acceptable excipients;
c) one or more pharmaceutically acceptable rate controlling polymer surrounding one or more drug layers; and
d) optionally one or more non functional coating surrounding the one or more polymeric coatings.

4. An extended release dosage form of metoprolol or salt thereof comprising plurality of beads wherein the said dosage form comprise water insoluble and water non-swellable inert core, the inert core is further coated with metoprolol or salt thereof which is further coated with one or more pharmaceutically acceptable rate-controlling polymer
5. An extended release dosage form as per claim 3 and 4, wherein water non-swellable inert core has % swelling of 20 % or less, after 24 hours.
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6. An extended release dosage form as per claim 3 and 4, wherein pharmaceutical^ acceptable rate controlling polymer is selected from a group comprising of cellulose ethers or acrylic acid polymers.
7. An extended release dosage form as per claim 3, wherein non-functional coating comprise Polyethylene glycol.
8. An extended release dosage form as per claim 3 and 4, wherein dosage form is pellet, capsule, sachet, tablet
9. An inert core as per claim 1 and an extended release dosage form as per claim 3, wherein pharmaceutically acceptable excipient is selected from a group comprising of binder, plasticizer, anti-adherent.
Dated this 29th day of September, 2006
For Wockhardt Limited
UUbJs,
(Mandar Kotygule) Authorized Signatory
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