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:
NOVEL SUSTAINED RELEASE PHARMACEUTICAL COMPOSITION OF BUPROPION
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 a novel sustained release pharmaceutical composition of bupropion or salts thereof with improved stability wherein the composition comprises of granules of bupropion prepared by non-aqueous granulation method. The granules are mixed with a rate-controlling polymer along with other pharmaceutical^ acceptable excipients and then compressed to tablets.
The following specification particularly describes the invention and the manner in which it is to be performed.
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4. DESCRIPTION
The present invention provides a sustained release pharmaceutical composition of bupropion or salts thereof wherein the said composition is prepared by granulating bupropion or salt thereof by non-aqueous granulation method using a non-aqueous solvent having suitable binder. The granules so obtained are mixed with a rate-controlling polymer and other pharmaceutically acceptable excipients. This blend of granules with the rate-controlling polymer may be compressed to tablets.
Bupropion hydrochloride, an antidepressant of the aminoketone class, is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitor, or other known antidepressant agents. Its structure closely resembles that of diethylpropion; it is related to phenylethylamines. It is designated as (±)-1-(3-chlorophenyl)-2-[(1,1 dimethylethyl)amino]-1- propanone hydrochloride (Formula I). Bupropion hydrochloride powder is white, crystalline and highly soluble in water. It has a bitter taste and produces the sensation of local anesthesia on the oral mucosa. Bupropion is highly hygroscopic and susceptible to decomposition.

U.S Patent Nos. 3,819,706 (706) discloses the compound Bupropion and its salts thereof. US patent no. 3,885,046 ('046) discloses pharmaceutical composition comprising the compound Bupropion and its salts thereof suitable for use in the treatment of the depressed state.
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US patent no. 5,427,798 (798) discloses controlled sustained release tablet comprising bupropion hydrochloride and hydroxypropyl methyiceliulose. The method disclosed in this patent uses granulating solution having cysteine hydrochloride or glycine hydrochloride, dissolved in water which is sprayed on the blended powder of drug with the excipient.
US patent no. 6,143,327 ('327) and US patent no. 6,096,341 ('341) disclose a delayed release coated tablet comprising a core of bupropion hydrochloride and conventional excipients, which is further coated once or twice with rate controlling polymers.
US patent no. 6,652,882 ('882) discloses a controlled release pharmaceutical formulation of bupropion hydrochloride comprising an uncrosslinked polymer and crosslinked insoluble polymer.
US patent no. 6,238,697 ('697) discloses a method for tableting bupropion hydrochloride by direct compression.
Several other pharmaceutical compositions of bupropion have been disclosed in the prior art such as US Patent No 6,033,686, 6,893,660, 6,306,436, 6,210,716, 6,333,332, and 6,242,496.
US application no. 2003044462 discloses a pharmaceutical composition in solid form comprising bupropion hydrochloride and an effective amount of carboxyvinyl polymer as the sole stabilizing agent and the sole controlled release material.
US application no 2006020040 disclose a solid dosage form of bupropion hydrochloride; and a stabilizer, wherein the stabilizer comprises glucono delta lactone or its corresponding open chain hydroxy acid derivative.
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US application no. 2006099260 discloses a pharmaceutical composition, comprising: a core comprising bupropion; and a coating comprising a pharmaceutical^ acceptable pH-independent polymer and a surfactant.
US application no. 2005112198 discloses a pharmaceutical solid dosage form comprising buproprion hydrochloride and at least one member of the group consisting of: butylated hydroxyanisole, butylated hydroxytoluene and an ion exchange resin.
PCT application no. W099/33457 describes bupropion hydrochloride formulations containing dicarboxylic acids as stabilizing agents. PCT Application WO2005039481, WO2005049003 disclose an oral drug delivery system comprising bupropion.
It is well known in the prior art that the sustained release pharmaceutical composition of bupropion or its salts thereof is prepared by wet granulation using aqueous media or direct compression wherein the pharmaceutical compositions comprise a stabilizing agent. The present inventors while working on sustained release formulations of bupropion have surprisingly found a novel sustained release pharmaceutical composition of bupropion, comprising granules of bupropion or salts thereof, in admixture with pharmaceutically acceptable excipients wherein the granules are prepared by non-aqueous granulation method to minimize the contact of bupropion with water.
In one of the aspects of present invention there is provided, a sustained release pharmaceutical composition of bupropion or salts thereof, which comprises of granules of bupropion or salts thereof, in admixture with a rate controlling polymer and pharmaceutically acceptable excipients wherein the granules are prepared by non-aqueous granulation method.
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In yet another aspects of present invention there is provided, a process for preparing a sustained release pharmaceutical composition of bupropion or salts thereof which comprises of
a. preparing the granules of bupropion or salts thereof along with
pharmaceutically acceptable excipients,
wherein the granules are prepared by non-aqueous granulation method,
b. mixing the granules with a rate controlling polymer along with
pharmaceutically acceptable excipients.
In yet another aspect of present invention there is provided, a sustained release pharmaceutical composition of bupropion or salts thereof which comprises of
a. preparing the granules of bupropion or salts thereof along with
pharmaceutically acceptable excipients,
wherein the granules are prepared by non-aqueous granulation method,
b. mixing the granules with a rate controlling polymer along with
pharmaceutically acceptable excipients,
wherein 35% or less amount of bupropion is released within first hour and about 70% or more amount of bupropion is released in 12 hours when drug release is measured in a USP Type II apparatus at 50 rpm and using water as drug release medium at 37°C±2.
The sustained release pharmaceutical composition of bupropion or salts thereof comprises of bupropion and a rate-controlling polymer along with pharmaceutically acceptable excipients. The sustained release composition can be prepared by non-aqueous granulation method. Non-aqueous granulation method helps to improve the stability of water sensitive drugs. Thus, it may improve the shelf life of the pharmaceutical composition containing bupropion by reducing the water content. Non-aqueous granulation method comprises of granulating the powder blend of bupropion or salts thereof and buffering agent along with suitable pharmaceutical excipients with an organic solvent having a binder.
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Bupropion or salts thereof, and other pharmaceutically acceptable excipients are sifted and blended thoroughly. This powder blend may be granulated by using non-aqueous solvent having a suitable binder. The granules are dried and passed through the suitable sieve. The granules so obtained are mixed with a rate controlling polymer and extragranular material. The extragranular material may comprise diluent, filler, binder, lubricant and glidant. The granules along with the extragranular material may be compressed to form a tablet. The tablets can be optionally coated with a non-functional coating.
The sustained release dosage form of bupropion or salts thereof exhibits a drug release of about 35% or less in first hour and about 70% or more within next 12 hours when drug release studies are carried out in USP Type II apparatus at 50 rpm and using water as drug release medium at 37°C±2.
The pharmaceutically acceptable rate controlling polymers can be selected from a group comprising of one or more of carbohydrate gum, polyuronic acid salts, cellulose ethers, acrylic acid polymers and mixtures thereof. Suitable carbohydrate gums include one or more of xanthan gum, tragacanth gum, gum karaya, guar gum, acacia, gellan, locust bean gum and other carbohydrate gums having similar properties. Suitable polyuronic acid salts include one or more of alkali metal salts of alginic acid or pectic acid and mixtures thereof. Suitable alkali metal salts of alginic acid that may be used include one or more of sodium alginate, potassium alginate, ammonium alginate and other suitable alkali metal salts of alginic acid. Suitable cellulose ethers include one or more of hydroxypropyl methyl cellulose (HPMC), hydroxypropyl cellulose (HPC) 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.
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Additionally the sustained release pharmaceutical composition may comprise a buffering agent. Bupropion is highly hygroscopic and susceptible to decomposition. Because of the drug's instability, a relatively low pH environment has proven effective in stabilizing bupropion. Therefore a buffering agent can be added in the pharmaceutical composition to achieve the desired pH, thereby improving the shelf life of bupropion. A buffering agent can be one or more selected from a group of ammonium chloride, ammonium nitrate, ammonium acetate, potassium dihydrogen phosphate, ammonium hydrogen phosphate and the like.
The non-aqueous solvent can be one or more selected from a group of isopropanol, acetone, dichloromethane, chloroform, n-propanol and the like.
Pharmaceutically acceptable excipients can be diluent, filler, binder, lubricant, glidant and the like. Suitable binders may be one or more selected from a group of starch, sugars, gums, low molecular weight hydroxypropylmethyl cellulose, polyvinyl pyrrolidone and hydroxypropyl cellulose and the like. Suitable fillers may be one or more of lactose, dicalcium phosphate, microcrystalline cellulose, mannitol and the like. Suitable lubricants may be one or more talc, magnesium stearate, polyethylene glycol, hydrogenated vegetable oils, stearic acid, sodium stearyl fumarate and sodium benzoate and the like. Suitable glidants may be one or more of, colloidal silicon dioxide, talc, magnesium stearate and the like.
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.
Examples 1 The sustained release pharmaceutical composition of bupropion hydrochloride is provided in Table 1.
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Table 1
S.No. Ingredients mg/Tab
1 Bupropion.HCI 150
2 Ammonium Chloride 4.00
3 Mannitol 55.00
4 Polyvinyl pyrrolidone 8.00
5 Isopropanol q.s.
Extragranular
1 Hydroxypropyl cellulose 120.00
2 Avicel 55.00
3 Stearic Acid 4.00
4 Talc 4.00
Film coating
1 Opadry Purple 8.00
2 Isopropyl alcohol q.s.
3 Purified water q.s.
Procedure:
The pharmaceutical composition is prepared by sifting the accurately weighed amount of Bupropion hydrochloride and Mannitol. Ammonium chloride is weighed and triturated. The ammonium chloride triturate is mixed thoroughly with bupropion and mannitol in RMG. PVP is dissolved in isopropanol and added to RMG to prepare the granules. The granules are dried and mixed with the extragranular material. The granules are then compressed to tablets. The tablets are then coated with a coating solution of Opadry Purple in mixture of isopropyl alcohol and water (70: 30 v/v).
Table 2 provides the drug release data of the tablets prepared as per the Formula provided in Table 1. For determination of drug release rate, 900 ml of water as drug release medium using USP Type 2 Apparatus (rpm 50) was used.
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Table 2: Drug release data in Water

Time (hr) Cumulative Percent Drug Released
0 0
0.5 22
1 33
2 46
3 54
4 61
6 62
8 69
10 71
12 71
Example 2
The sustained release pharmaceutical composition of bupropion hydrochloride is provided in Table 3.

Procedure:

S.No. Ingredients mg/Tab
1 Bupropion.HCI 150
2 Ammonium Nitrate 4.00
3 Mannitol 55.00
4 Polyvinyl Pyrrolidone 8.00
5 Isopropanol q.s.
Extragranular
1 Hydroxypropyl cellulose 120.00
2 Avicel 55.00
3 Stearic Acid 4.00
4 Talc 4.00
Film coating
1 Opadry Purple 8.00
2 Isopropyl alcohol q.s.
3 Purified water q.s.

The pharmaceutical composition is prepared by sifting the accurately weighed amount of Bupropion hydrochloride and Mannitol. Ammonium nitrate is weighed and triturated. The ammonium nitrate triturate is mixed thoroughly with bupropion
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and mannitol in RMG. PVP is dissolved in isopropanol and added to RMG to prepare the granules. The granules are dried and mixed with the extragranular material. The granules are then compressed to tablets. The tablets are then coated with a coating solution of Opadry Purple in mixture of isopropyl alcohol and water (70: 30 v/v).
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WE CLAIM:
1. A sustained release pharmaceutical composition of bupropion or salts thereof, which comprises of granules of bupropion or salts thereof, in admixture with a rate controlling polymer and pharmaceutically acceptable excipients wherein the granules are prepared by non-aqueous granulation method.
2. A process for preparing a sustained release pharmaceutical composition of bupropion or salts thereof which comprises of
a. preparing the granules of bupropion or salts thereof along with
pharmaceutically acceptable excipients, wherein the granules are
prepared by non-aqueous granulation method,
b. mixing the granules with a rate controlling polymer along with
pharmaceutically acceptable excipients.
3. A sustained release pharmaceutical composition of bupropion or salts thereof which comprises of
a. preparing the granules of bupropion or salts thereof along with
pharmaceutically acceptable excipients, wherein the granules are
prepared by non-aqueous granulation method,
b. mixing the granules with a rate controlling polymer along with
pharmaceutically acceptable excipients,
wherein 35% or less amount of bupropion is released within first hour and about 70% or more amount of bupropion is released in 12 hours when drug release is measured in a USP Type II apparatus at 50 rpm and using water as drug release medium at 37°C±2.
4. A sustained release pharmaceutical composition of claims 1 to 3 wherein about 50 mg to 300 mg of bupropion or salt thereof is present.
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5. A sustained release pharmaceutical composition of claims 1 to 3 wherein bupropion or salt thereof is bupropion hydrochloride.
6. A sustained release pharmaceutical composition of claims 1 to 3, a rate-controlling polymer is hydroxy propyl cellulose.
7. A sustained release pharmaceutical composition of claims 1 to 3, the sustained release pharmaceutical composition comprises a buffering agent.
8. A sustained release pharmaceutical composition of claims 1 to 3 wherein non-aqueous granulation method comprises a granulating solution of polyvinyl pyrrolidone in isopropanol.
9. A sustained release pharmaceutical composition of claims 1 to 3 is in the form of tablet, capsule, granules, pellets meant for oral administration.