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:
PHARMACEUTICAL COMPOSITION COMPRISING BUPROPION OR SALT THEREOF AND ESTER AS STABILIZER
2. APPLICANT (S)
(a) NAME: WOCKHARDT LTD.
(b) NATIONALITY: INDIAN
(c) ADDRESS: Wockhardt Limited, D4-MIDC Area, Chikalthana,
Aurangabad - 431 210 (M.S.) INDIA.
3. PREAMBLE TO THE DESCRIPTION
The present invention provides stabilized pharmaceutical composition comprising bupropion or salt thereof and stabilizing agent along with other pharmaceutically acceptable excipients wherein the said stabilizing agent is selected from a group of esters.
The following specification particularly describes the invention and the manner in which it is to be performed.

4. DESCRIPTION
The present invention provides stabilized pharmaceutical composition comprising bupropion or salt thereof and stabilizing agent along with other pharmaceutically acceptable excipients wherein the said stabilizing agent is selected from a group of esters.
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.


FORMULA I
U.S Patent Nos. 3,819,706 and US patent no. 3,885,046 disclose the compound Bupropion and its salts thereof. Bupropion hydrochloride is a water-soluble, highly hygroscopic, crystalline and susceptible to decomposition. Because of the drug's instability, the shelf life of bupropion formulations has proved to be problematic, and a number of different approaches have been tried to improving the storage stability of the drug.
For example, U.S. Patent Nos. 5,541,231, 5,763,493, 5,358,970, 5,427,798 and 5,731,000, 6,333,332, 6,221,917, 6,194,002 describe stabilized bupropion


hydrochloride formulations that use an organic acid, a carboxylic acid, an amino acid salt (e.g., cysteine hydrochloride, glycine hydrochloride, and cysteine dihydrochloride), or sodium metabisulfite as a stabilizer.
U.S. Patent no. 5,968,553 describes bupropion hydrochloride formulations containing dilute inorganic acids as stabilizers including hydrochloric acid, phosphoric acid, nitric acid, and sulfuric acid.
US Patent no. 5,541,231 discloses the use of ascorbic acid or isoascorbic acid to stabilize the bupropion pharmaceutical compositions. US patent no. 6,221,917 discloses the use of dicarboxylic acid to stabilize the bupropion pharmaceutical compositions.
US Patent no. 6,482,987 discloses a method for preparing a stable composition of bupropion hydrochloride by dry blending bupropion hydrochloride and solid stabilizer.
US Patent no. 6,238,697 discloses a method for preparing a stable composition of bupropion hydrochloride by direct compression of bupropion hydrochloride and other excipients.
US Patent no. 6,893,660 describes a method for stabilizing bupropion formulation by adding a sealing component in the excipients to form a sealed excipient component.
US Patent no. 6,306,436 discloses a pharmaceutical composition of bupropion that is free of added acid. US patent no 6,652,882 disclose a controlled release pharmaceutical formulation of bupropion comprising an uncrosslinked polymer and crosslinked insoluble polymer. US patent no 6,210,716 discloses a controlled release dosage form of bupropion hydrochloride.


US Patent no. 6,096,341, 6,033,686 and 6,143,327 disclose a delayed release coated tablet comprising a core of bupropion hydrochloride and conventional excipients, free of stabilizer and coating.
US patent no 6,333,332 discloses a pharmaceutical composition comprising bupropion hydrochloride and a pharmaceutical^ acceptable stabilizer.
US patent no 6,242,496 disclose a method for stabilizing bupropion by using a stabilizer wherein said stabilizer has solubility in water at 20°C of less than 10 g stabilizer/100 g water and has an aqueous suspension pH of about 0.9 to about 4.0 at a concentration of about 6% w/w.
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.
US application no. 2006099260 discloses a pharmaceutical composition, comprising: a core comprising bupropion; and a coating comprising a pharmaceutically acceptable pH-independent polymer and a surfactant.
US application no. 2005112198 discloses a pharmaceutical solid dosage form comprising bupropion 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 from the prior art that a relatively low pH environment has proven effective in stabilizing bupropion. The use of acidic materials in pharmaceutical formulations requires specialized procedures and equipment. Therefore, it would be desirable to produce a stabilized bupropion hydrochloride formulation without the use of acid stabilizers.
The present inventors while working on pharmaceutical compositions of bupropion have surprisingly found that pharmaceutical compositions comprising bupropion or salts thereof can be stabilized by adding an effective stabilizing amount of a stabilizing agent wherein the said stabilizing agent is selected from a group of esters. The essence of this invention is the stabilizing agent capable of maintaining acidic pH of less than 6 around the bupropion particles, which prevents the degradation of bupropion.
In one of the aspects of present invention there is provided, a stabilized pharmaceutical composition comprising bupropion or salts thereof and stabilizing agent in an effective stabilizing amount wherein the said stabilizing agent is selected from a group of esters.
In yet another aspect of the present invention there is provided, a method of stabilizing bupropion or salts thereof in a pharmaceutical composition wherein said method comprises the step of adding an effective amount of a stabilizing agent wherein the said stabilizing agent is selected from a group of esters.
The term "stabilized pharmaceutical composition" herein refers to a pharmaceutical composition that contains at least about 80% of bupropion after three months of storage at 40°C and 75% relative humidity.

The "effective stabilizing amount" herein refers to that amount of stabilizing agent, which is capable of preventing the degradation of bupropion by maintaining a pH of less than 6 around bupropion particles in stored conditions thereby providing stable pharmaceutical compositions.
The "stabilizing agent" is pharmaceutical^ acceptable substance, selected from a group of esters wherein the said esters is capable of preventing the degradation of bupropion by maintaining a pH of less than 6 around the bupropion particles. The pharmaceutical composition of the present invention comprises esters in a percentage ranging between 0.001 and 5% w/w of bupropion. Bupropion is highly hygroscopic drug and susceptible to decomposition. A relatively low pH environment has proven effective in stabilizing bupropion. Because of this, a stabilizing agent is added in bupropion containing pharmaceutical composition so that the pH around the particles of bupropion is maintained less than 6. This leads to prevent the degradation of bupropion thereby improving the shelf life of the composition.
Esters are a class of chemical compounds having the following functional group:
R-C(=0)-0-R
Wherein R may be same of different selected from a group comprising alkanes, alkyne, alkene, aromatic rings. Esters consist of an inorganic or organic acid in which at least one -OH (hydroxy) group is replaced by an -O-alkyl (alkoxy) group. The most common type of esters are carboxylic acid esters (R-C(=O)-O-R), other esters include phosphoric acid, sulfuric acid, nitric acid, and boric acid esters. Cyclic esters are called lactones. Organic esters may be one or more selected from a group of dibutyl phthalate, triethyl citrate, acetyltributyl citrate, ascorbyl palmitate, benzyl benzoate, butyl stearate, cetyl palmitate, dibutyl sebacate, diethyl phthalate, diisopropyl adipate, diisopropyl adipate, diisopropyl dimerate, dimethyl phthalate, dioctylphthalate, ethyl acetate, ethyl oleate, isopropyl isostearate, isopropyl myristate, lysine acetate, methyl salicylate, methyl stearate, octyl hydroxystearate, oleyl oleate, polyvinyl acetate, polyvinyl acetate


phthalate, propyl gallate, sorbitan monooleate, sorbitan monopalmitate, sorbitan monostearate, sorbitan trioleate and the like. Inorganic esters may be one or more selected from a group of trimethyl borate, tri-n-butyl borate, tricyclohexyl borate, tridodecyl borate, tri-p-cresyl borate, methyl phosphate, dimethyl phosphate, diethyl phosphate, ethyl phosphate, diethyl sulphate, methyl sulphate, dimethyl sulphate and the like.
The pharmaceutical composition of bupropion or salts thereof can be prepared by conventional methods of preparation like aqueous or non-aqueous wet granulation, direct compression, melt granulation or dry granulation.
The powder blend of bupropion and stabilizing agent along with intragranular pharmaceutically acceptable excipients may be granulated by using nonaqueous solvent having a suitable binder. The granules are dried and passed through the sieve. The granules so obtained may be mixed with extragranular pharmaceutically acceptable excipients. The granules may be formulated as tablet, capsule, powder, sachets, granules, pellets and the like. The finished dosage form may be optionally coated with a functional and/or non-functional coating.
The non-aqueous solvent can be one or more selected from a group of isopropanol, acetone, methylene chloride, chloroform, n-propanol and the like.
The pharmaceutical composition of this invention contains 25 mg to 500 mg of bupropion hydrochloride.
The "pharmaceutical composition" comprises bupropion or salt thereof and a stabilizing agent wherein pharmaceutical composition can be an immediate release form, sustained release form or delayed release form. The pharmaceutical composition may further comprise a suitable pharmaceutically


acceptable rate-controlling polymer along with pharmaceutical^ acceptable excipients.
The pharmaceutical^ 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.
Pharmaceutically acceptable excipients present as extragranular or intragranular 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, polyvinylpyrrolidone 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, calcium Stearate, glyceryl behenate 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, calcium stearate and the like. Suitable disintegrant may be one or more of starch, croscarmellose sodium, crospovidone, sodium starch glycolate 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.
Example 1
The pharmaceutical composition of bupropion hydrochloride is provided in Table 1.

S.No. Ingredients mg/Tablet
I
1 Bupropion Hydrochloride 150.00
2 Ammonium Chloride 4.00
3 Hydroxypropyl cellulose 50
4 Triethyl Citrate 4.0
5 Isopropyl alcohol q.s.
6 Purified water q.s.
Granul es Coating
7 Hydroxypropyl cellulose 9.0
8 Isopropyl alcohol q.s.
9 Purified water q.s.
Extragranular
10 Perlitol SD 46.0
11 Microcrystalline cellulose 110.0
12 Stearic Acid 12
13 Glyceryl Behenate 12
14 Magnesium Stearate 3
Core Tab wt 400.0
Film coating
15 Opadry Purple 10
16 Isopropyl alcohol q.s.
17 Purified water q.s.


Coated Tab wt. 410.0

Procedure:
Bupropion hydrochloride, ammonium chloride and part of hydroxypropyl cellulose are sifted and added to Rapid Mixer Granulator (RMG). Remaining part of hydroxy propyl cellulose is dissolved in water and isopropyl alcohol followed by the addition of triethyl citrate. The blend in RMG is granulated by the addition of hydroxy propyl cellulose, dissolved in water, isopropyl alcohol and triethyl citrate. The granules so obtained are dried and sieved. The obtained granules are further coated using hydro-alcoholic solution of HPC. Extragranular material Perlitol SD, microcrystalline cellulose, stearic acid, glyceryl behenate and magnesium stearate are sifted and mixed with the granules in double cone blender. This blend is then compressed to tablets using appropriate tooling. The tablets are coated with Opadry purple dispersion in isopropyl alcohol and purified water.


WE CLAIM:
1. A stabilized pharmaceutical composition comprising bupropion or salts thereof and stabilizing agent in an effective stabilizing amount wherein the said stabilizing agent is selected from a group of esters.
2. A method of stabilizing bupropion or salts thereof in a pharmaceutical composition wherein said method comprises the step of adding an effective amount of a stabilizing agent wherein the said stabilizing agent is selected from a group of esters.
3. The stabilized pharmaceutical composition and method of stabilization according to claim 1 and 2, the stabilized pharmaceutical composition of bupropion or salts thereof, is such that at least about 80% of the potency of bupropion is maintained after storage for at least three month at 40°C and 75% relative humidity.
4. The stabilized pharmaceutical composition and method of stabilization according to claim 1 and 2, the ester is an organic ester and/or inorganic ester.
5. The stabilized pharmaceutical composition and method of stabilization according to claim 1 and 2, the organic ester is triethyl citrate.
6. The stabilized pharmaceutical composition and method of stabilization according to claim 1 and 2, the pharmaceutical composition is an immediate release, delayed release and sustained release dosage form.
7. The stabilized pharmaceutical composition and method of stabilization according to claim 1 and 2, about 50 mg to 300 mg of bupropion or salt thereof is present.


8. The stabilized pharmaceutical composition and method of stabilization according to claim 1 and 2, bupropion or salt thereof is bupropion hydrochloride.
9. The stabilized pharmaceutical composition and method of stabilization according to claim 1 and 2, the pharmaceutical^ acceptable excipients are diluent, filler, binder, lubricant, glidant and the like.
10. The stabilized pharmaceutical composition and method of stabilization according to claim 1 and 2, the pharmaceutical composition is in the form of tablet, capsule, granules, pellets meant for oral administration.





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