Title of Invention	"A PROCESS OF STABILLZING BUPROPION HYDROCHLORIDE SOLID DOSAGE FORMS"
Abstract	The present invention relates to a process for stabilizing bupropion hydrochloride solid dosage form using Glucono delta lactone or corresponding open chain hydroxy acid derivative.

Full Text

The present invention relates to a process preparation of stable bupropion hydrochloride solid dosage form using Glucono delta lactone or corresponding open chain hydroxy acid derivative. Bupropion hydrochloride is a well-known antidepressant and a non-nicotine aid to smoking cessation. GLAXOSMITHKLINE sells it in United States as WELLBUTRIN®; (bupropion hydrochloride immediate release tablets), WELLBUTRIN® SR and ZYBAN® SR (bupropion hydrochloride sustained release tablets). Bupropion hydrochloride is a water-soluble, crystalline solid, which is highly hygroscopic and susceptible to decomposition. Because of the drug's instability, researchers working in this field have tried a number of different approaches to improve the storage stability of the drug in the formulation. Prior art patents variously cover use of organic acids, carboxylic acids, dicarboxylic acids, inorganic acids, acid salts of an amino acids, sodium metabisuifite and sodium bisulfate as stabilizers for bupropion compositions. These prior art patents describe the use of L-cysteine hydrochloride, glycine hydrochloride, malic acid, sodium metabisulphate, citric acid, tartaric acid, L-cystine dihydrochloride, oxalic acid, succinic acid, fumaric acid, phthalic acid, hydrochloric acid, phosphoric acid, nitric acid and sulphuric acid as stabilizers in particular. Inventors of the present invention have discovered a novel process to stabilize bupropion hydrochloride solid dosage forms with Glucono delta lactone or corresponding open chain hydroxy acid derivative. Glucono delta lactone can be added as such or in the form of corresponding open chain hydroxy acid derivative. Glucono delta lactone is a crystalline compound, which hydrolyses to the corresponding open chain hydroxy acid derivative upon contact with moisture. Accordingly, present invention discloses a process for preparation of stable bupropion hydrochloride solid dosage forms by a) blending glucono delta lactone or corresponding open chain hydroxy acid derivative with bupropion hydrochloride in a weight ratio of 0.02:1 to 1:1 and optionally other pharmaceuticaily acceptable excipients like rate controlling polymers, diluent, binders, disintegrants, lubricants and glidants as described herein; b) shaping the above blend into a solid dosage form. The stable solid dosage form of bupropion hydrochloride as defined herein include solid dosage form of bupropion hydrochloride which contain at least 80% of undegraded bupropion hydrochloride after storage for three months at 40°C and 75% relative humidity. For the purpose of the present invention, the term "bupropion hydrochloride" refers to the hydrochloride salt of m-chloro-a- (t-butylamino) propiophenone. The amount of bupropion hydrochloride may vary from 25 to 500 mg. Glucono delta lactone as described above can be added as such or as corresponding open chain hydroxy acid derivative i.e. gluconic acid. Addition of Gluono delta lactone is preferred due to ease of handling, sweet taste & high aqueous solubility. These stabilizers can be easily used in compositions prepared by wet granulation as well as dry granulation methods. These stabilizers can be used in a concentration, which can effectively retain at least about 80% of the potency of bupropion hydrochloride in bupropion hydrochloride solid dosage forms after storage for three months at 40°C and 75% relative humidity. Amount of glucono delta lactone or its corresponding open chain hydroxy acid derivative w.r.t. bupropion hydrochloride may vary in a weight ratio of 0.02:1 to 1:1. Preferably it is about 0.02:1 to 0.5:1. Solid dosage forms of the present invention include tablets, caplets, capsules and granulates. Immediate release, modified release and extended release profiles are also included. The stabilized dosage forms of bupropion hydrochloride can be conveniently prepared by any of the methods known to the one skilled in the art. For tablets, the method of choice can be wet granulation, dry granulation or direct compression. These methods include the basic step of intimately mixing the stabilizer with bupropion hydrochloride along with other pharmaceutlcally acceptable excipients and shaping the product into a solid dosage form. Alternatively, the stabilizer (either complete/part) may also be added in granulating fluid during wet granulation. The pharmaceutical acceptable excipients of the present invention may be selected from rate controlling polymers (depending upon the choice whether an instant or sustained release composition is needed), coating polymers, diluent, binders, disintegrants, lubricants, glidants and coloring agents compatible with bupropion hydrochloride. For the present invention, release rate-controlling polymers may be selected from any such pharmaceutically acceptable excipients, which can control the rate of release of the active ingredient. Preferably such release rate-controlling polymers can be selected from the group consisting of cellulose derivatives, acrylates, methacrylates, polyvinlyacetate/povidone mixture, polyethylene oxides, starch and their derivatives, gums, alginates, carbohydrate based polymers, polysaccharides or combinations thereof. Cellulose derivative can be selected from the group consisting of ethyl cellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropyl methylcellulose and sodium carboxymethylcellulose of different degree of substitution and molecular weights. These release rate-controlling polymers can be used alone or in combination. Various degrees of substitution and/or different molecular weights corresponding to a different degree of viscosity can be used as suitable cellulose based rate-controlling system. Rate controlling polymer can be used in a concentration of 5% to 60% of the tablet weight depending on the polymer used. The use of hydroxypropyl methylcellulose (HPMC), hydroxypropylcellulose, polyvinyl acetate/povidone mixture or Carboxyvinyl polymers such as Carbopol® are preferred. Upon hydration, these polymers swell to form a gelatinous barrier, through which either the drug may diffuse out or be released by erosion of the barrier or a combination of erosion and diffusion. Diluents of this invention may be selected from any such pharmaceutically acceptable excipients, which give bulk to the composition and improve compressibility. Preferably those diluents may be selected from starch or its derivatives, microcrystalline cellulose, lactose, glucose, mannitol, alginates, alkali earth metal salts, dicalcium phosphate, glyceryl monostearate, polyvinyl acetate/povidone mixture or polyethylene glycols. Binders of this invention may be selected from any such pharmaceutically acceptable excipients, which have cohesive properties to act as a binder. Preferably those excipients are starch, gelatin, highly dispersed silica, mannitol, lactose, polyethylene glycol, polyvinylpyrrolidone, cross-linked polyvinylpyrrolidone, cross-linked carboxymethylcellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose and natural or synthetic gums. The disintegrant of the present invention may be selected from sodium starch glycolate, carboxy methylcellulose, croscarmellose sodium and crospovidone or combination thereof. Lubricants of the present invention may be selected from talc, stearic acid, magnesium stearate, other alkali earth metal stearate like calcium, zinc etc., sodium lauryl sulphate, hydrogenated vegetable oil, sodium benzoate, sodium stearyl fumarate, glyceryl monostearate and PEG 4000. Glidants of the present invention may be selected from colloidal silicon dioxide and talc. The stability of bupropion hydrochloride compositions was tested after storage for four to twelve weeks at 40°C and 75% relative humidity. Bupropion hydrochloride compositions containing stabilizers of the present invention stored under these conditions retain at least 80% of bupropion hydrochloride in the composition. In many instances, the formulations of the present invention retain more than 85% of bupropion hydrochloride in the composition. The present invention is further illustrative by, but is by no-means limited to, the following examples: EXAMPLES 1 &2: Bupropion hydrochloride 150-mg formulations (Table Removed) The above bupropion hydrochloride formulations were prepared using the following process; 1. Bupropion hydrochloride, Hydroxypropyl cellulose, Microcrystalline cellulose, Polyvinlyacetate/Povidone mixture (in example 2) were mixed in a blender. 2. The blend of step 1 was granulated with an aqueous solution of Glucono delta lactone. 3. Granules were dried & sized accordingly. 4. Granules were lubricated with stearic acid & compressed to form tablets. Example-3 (Table Removed) Process; 1. Bupropion hydrochloride, Hydroxypropyl cellulose, a part of Glucono delta lactone & microcrystalline cellulose were mixed in a blender. 2. Aqueous solution of the remaining quantity of glucono delta lactone was used to granulate the blend of step 1. 3. The wet mass was dried in the fluid bed dryer & the granules sized. 4. Granules were lubricated with stearic acid & compressed into tablets. Product stability data were obtained for the above formulation by storage at 40°C, 75% relative humidity for 3 months. Potency was determined using HPLC. Product stability data for 3 months are presented in Table 1. Table 1: Comparative stability of Bupropion hydrochloride tablets prepared as per the composition of Examples-1 - 3 vs commercially available bupropion hydrochloride takblets (WELLBUTRIN SR ®). (Table Removed) RH = Relative Humidity * % of added quantity The tablets of examples 3 were able to retain more than 80% of the potency of bupropion hydrochloride at the end of 3 months period i.e. 89.9%. The tablets of example 1 also retained more than 80% potency at the end of 3 months period. The above data clearly indicates that Glucono delta lactone in a ratio of about 0.28:1 by weight of bupropion hydrochloride effectively stabilizes bupropion hydrochloride tablets. Also, the ratio of 0.02:1 gave stable tablets of bupropion hydrochloride. WE CLAIM: 1. A process for preparation of stable bupropion hydrochloride solid dosage forms by a) blending glucono delta lactone or corresponding open chain hydroxy acid derivative with bupropion hydrochloride in a weight ratio of 0.02:1 to 1:1 and optionally other pharmaceutically acceptable excipients like rate controlling polymers, diluent, binders, disintegrants, lubricants and glidants as described herein; b) shaping the above blend into a solid dosage form. 2. The process according to claim 1 wherein the rate controlling polymer may be selected from the group consisting of cellulose derivatives, acrylates, polyvinyl acetate / povidone mixture, polyethylene oxides, starch and their derivatives, gums, alginates, carbohydrate based polymers, polysaccharide or combinations thereof. 3. The process according to claim 2 wherein the cellulose derivative is selected from the group consisting of ethyl cellulose, hydroxypropylcellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose or a mixture thereof. 4. The process according to claim 3 wherein the cellulose derivative is hydroxypropylcellulose. 5. The process according to claim 1 wherein the diluent is microcrystalline cellulose. 6. The process according to claim 1 wherein the binder is selected from the group consisting of starch, gelatin, highly dispersed silica, mannitol, lactose, polyethylene glycol, polyvinylpyrrolidone, cross-linked polyvinylpyrrolidone, cross-linked carboxymethylcellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose and natural or synthetic gums. 7. The process according to claim 1 wherein the disintegrant is selected from the group consisting of sodium starch glycolate, carboxy methylcellulose, croscarmellose sodium and crospovidone or combination thereof. 8. The process according to claim 1 wherein the lubricant is stearic acid. 9. The process according to claim 1 wherein the glidant is selected from colloidal silicon dioxide and talc. 10. A process for stabilizing bupropion hydrochloride solid dosage forms substantially as described and illustrated by the examples herein.

Documents:

1156-del-2002-abstract.pdf

1156-del-2002-claims(cancelled).pdf

1156-del-2002-claims.pdf

1156-del-2002-complete specification(granted).pdf

1156-del-2002-correspondence-others.pdf

1156-del-2002-correspondence-po.pdf

1156-del-2002-description (complete).pdf

1156-del-2002-form-1.pdf

1156-del-2002-form-2.pdf