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 STABILIZER
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 stabilized pharmaceutical composition comprising bupropion or salt thereof and stabilizing agent along with other pharmaceutically acceptable excipients wherein the stabilizing agent is capable of maintaining a pH of less than 6 around bupropion particles.
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 stabilized pharmaceutical composition comprising bupropion or salt thereof and stabilizing agent along with other pharmaceutically acceptable excipients wherein the stabilizing agent is capable of maintaining a pH of less than 6 around bupropion particles.
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.

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
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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 stabile 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.
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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 pharmaceutically 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
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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 stabilizer is selected from a group of salts of organic acid and/or salts of inorganic bases. 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, wherein the stabilizing agent in an effective stabilizing amount is capable of maintaining a pH of less than 6 around the bupropion particle and the said stabilizing agent comprises one or more of salts of organic acid and/or salts of inorganic bases.
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 capable of maintaining a pH of less than 6 around the bupropion particles and the said stabilizing agent comprises one or more of salts of organic acid and/or salts of inorganic bases.
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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 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 "stabilizing agent" is pharmaceutically acceptable substance capable of preventing the degradation of bupropion by maintaining a pH of less than 6 around the bupropion particles. 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.
The stabilizing agent may be one or more salts of organic acid and salts of
inorganic base. Suitable salts of organic acids and salts of inorganic bases
include but not limited to ethylenediaminetetraaceticacid disodium salt,
ethylenediaminetetraaceticacid calcium disodium salt,
ethylenediaminetetraaceticacid dipotassium salt dihydrate,
ethylenediaminetetraaceticacid manganese disodium salt,
ethylenediaminetetraaceticacid copper disodium salt, potassium hydrogen
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tartrate, sodium citrate, sodium acetate, sodium fumarate, calcium oxalate, calcium alginate, ammonium chloride 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 having a pharmaceutically acceptable rate controlling polymer may be granulated by using non-aqueous 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 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 acirylic acid polymers include any
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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.

SN Ingredients mg/Tab
Intra granular
1 Bupropion HCI 150.00
2 Potassium Hydrogen Tartrate 12.00
3 Hydroxy Propyl Cellulose 60.00
5 Microcrystalline Cellulose 90.00
6 Isopropyl Alcohol q. s.

7 Methylene Chloride q. s.
Extragranular
8 Microcrystalline cellulose 62.00
9 Stearic Acid 12.00
10 Glyceryl Behenate 12.00
11 Magnesium Stearate 2.0
12 HPC Based coating (2 %) 8.00
Total 408.00
Procedure:
Bupropion hydrochloride, potassium hydrogen tartrate, hydroxypropyl cellulose, microcrystalline cellulose are mixed together followed by granulation with a mixture of isopropyl alcohol and methylene chloride. The granules so obtained are dried and mixed with weighed amount of extragranular excipients i.e. microcrystalline cellulose, stearic acid, glyceryl behenate and magnesium stearate. These granules are compressed to tablets using appropriate tooling. The tablets are coated with hydroxypropylcellulose based coating.
Example 2
The pharmaceutical composition of bupropion hydrochloride is provided in Table 2.
Table 2

S.No. Ingredients Mg/Tab
1 Bupropion. HCI 150.15
2 Ammonium chloride 4.00
3 Hydroxypropyl cellulose 50.00
6 Isopropyl alcohol q. s.
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Extragranular
7 Microcrystalline cellulose 159.85
8 Stearic Acid 12.00
9 Glyceryl Behenate 12.00
10 Magnesium Stearate 2.0
11 HPC L Based coating (2 %) 8.00
TOTAL 408.00
Procedure: Weighed accurately bupropion hydrochloride, ammonium chloride, and hydroxypropyl cellulose are mixed together followed by granulation with a mixture of isopropyl alcohol. The granules so obtained are dried and mixed with weighed amount of extragranular excipients i.e. microcrystalline cellulose, stearic acid, glyceryl behenate and magnesium stearate. These granules are compressed to tablets using appropriate tooling. The tablets are coated with hydroxypropylcellulose based coating.

WE CLAIM:
1. A stabilized pharmaceutical composition comprising bupropion or salts thereof and stabilizing agent, wherein the stabilizing agent in an effective stabilizing amount is capable of maintaining a pH of less than 6 around the bupropion particle and the said the stabilizing agent comprises one or more of salts of organic acid and/or salts of inorganic bases.
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 capable of maintaining a pH of less than 6 around the bupropion particles and the said stabilizing agent comprises one or more of salts of organic acid and/or salts of inorganic bases.
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 pharmaceutical composition is an immediate release, delayed release and sustained release dosage form.
5. 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.
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6. The stabilized pharmaceutical composition and method of stabilization according to claim 1 and 2, bupropion or salt thereof is bupropion hydrochloride.
7. 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.
8. 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.
Dated this 20 th day of April, 2007

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