Indian Patents. 209226:"STABILISED PHARMACEUTICAL COMPOSITION COMPRISING BUPROPION HYDROCHLORIDE AND METHOD FOR STABILISING BUPROPION HYDROCHLORIDE"

Title of Invention	"STABILISED PHARMACEUTICAL COMPOSITION COMPRISING BUPROPION HYDROCHLORIDE AND METHOD FOR STABILISING BUPROPION HYDROCHLORIDE"
Abstract	Applicants disclose a stabilized pharmaceutical composition in solid form comprising buproprion hydrochloride, an antidepressant and a stabilizer. Degradation of the buproprion hydrochloride in the formulation is inhibited to the extent that the pharmaceutical formulation will maintain at least 80% of its initial buproprion potency after one year.

Full Text	IA The present invention relates to pharmaceutical compositions comprising bupropion hydrochloricle and a pharmaceutically acceptable stabiliser mid methods of stabilizing bupropion hydrochloride in a pharmaceutical composition. Bupropion hydrochloride is a known amtidepressant sold in instant release tablet form under the brand name WELLBUTRINR. (Also see U.S. Patents 3,819,706 and 3,885,046; 1993 Physicians Desk Reference and the Merck Index. Eleventh Edition, Entry No. 1488. Bupropion hydrochloride is also useful as an anticholesterol agent, in suppressing prolacttn secretion, in preventing functional impairment and drowsiness seen upon administration of benzodiazepine, in the treatment or minimal bruin dysfunction, tardive dyskinesia, impaired mental alertness upon ingestion of ethanol and psychosexual dysfunction. While the instant release tablets currently sold are quite suitable for the indicated use, the method of manufacturing these is less than desirable based on cost as well as process conditions . The object of the present invention is to prevent (inhibit) the degradation of bupropion hydrochloric using stabilizer ingredients, thus allowing the preparation of pharmaceutical compositions such as instant and sustained release tablets and capsules which, from a cost of manufacture and processing standpoint, are much improved over those achievable in the past. The invention provides a pharmaceutical composition in solid form comprising bupropion hydrochloride and a pharmaceutically acceptable stabiliser in an effective stabilising amount, in which the composition contains at least 80% w/w of undegraded bupropion hydrochloride after storage for 6 weeks at 40°C and. 75% relative humidity, an aqueous solution of the stabiliser in a concentration of 6% W/W having a pH of 0.9 to 4, and the stabiliser being selected from an organic acid, a carboxylic acid, an acid salt of an amino acid and sodium metabisulphite; with the proviso that a sustained release tablet comprising (i) bupropion hydrochloride and hydroxypropyl methylcellulose, the amount of hydroxypropyl methylceliulose to the amount of bupropion hydrochloride being from 0.19 : 1 to 1.1 : 1, and (ii) glycine hydrochloride or cysteine hydrochloride, is excluded. The invention further provides a pharmaceutical composition in solid form comprising bupropion hydrochloride and a pharmaceutically acceptable stabiliser in an effective stabilising amount, in which the composition contains at least 80% wlw of undegraded bupropion hydrochloride after storage for 6 weeks at 50°C and 27% relative humidity, an aqueous solution of the stabiliser in a concentration of 6% wlw having a pH of 0.9 to 4, and the stabiliser being selected from an organic acid, a carboxylic acid other than ascorbic acid and isoascorbic acid, an acid salt of an amino acid and sodium metabisulphite. -2- The preferred pH of the aqueous solution of the stabilizer is 0.9 to about 2 and most preferably. Preferably the pharmaceutica! composition according to the present invention contains at least about 90% w/w of undegraded bupropion hydrochloride after storage for 6 weeks under the above conditions and more preferably 95% or even 98%. In an additional aspect, the amount of undegrade bupropion hydrochloride is greater than 80% of its labelled strength, and more preferably greater 'than 90% percent of the labelled strength after one year of storage under the humidity and temperature conditions usually encountered in pharmacies and medicine cabinets ie. room temperature and 35-60% humidity. Thus, when used in a pharmaceutical preparation for example, a tablet will still retain at least 80% of its potency and preferably at least 90% after one year of storage at room temperature (15-25°C (59-77°F)) at 35-60% humidity. For example if the tablet initially contains lOOmg bupropion hydrochloride (labeled amount) at time of preparation, after one year storage at least 80mg of undegraded bupropion hydrochloride will remain in the tablet. The amount of the stabiliser which may be used with the present invention may vary but preferably is about 2.7% to 27%, most preferably about 5% to 16.2% based on the label strength of bupropion. hydrochloride in the pharmaceutical formulation (composition) in solid form. For example if a formulation contains lOOmg of bupropion hydrochloride it would preferably contain-about 2.7 to 27g of stabilizer. Stabilizers of use in this invention include organic acids, carboxylic acids, acid salts of amino acids and sodium metabisulphite. Preferably, the acid salts of amino acids are hydrochloride salts such as cysteine hydrochloride, glycine hydrochloride or cystine dihydrochloride. Other, preferred examples ,of stabilisers according to the present invention include: ascorbic acid, malic acid, isoascorbic acid, citric acid and tartaric -3- acid. L-cysteine hydrochloride and glycine hydrochloride are the most preferred stabilisers. In the examples the cysteine hydrochloride is in the L form and NF and USP are designations for standards published in the National Formulary and US Pharmacopeia, respectively. The present invention extends to the use of combinations of stabilisers especially combinations of the aforementioned stabilisers. The pH of the aqueous solution of the stabilisers may be determined as follows: The stabiliser is weighed out to provide 3.75 grams thereof, (except for 3.34 grams of L-cystine dihydrochloride) and is then added to 60 grams of distilled water in a glass PyrexR beaker. The resulting mixture is stirred for approximately 5 minutes, using a stir plate and magnetic stir bar. The resulting solution or dispersion is examined using either a Orion Model 701A Ionalyzer^-, or an Accumet pH Meter Model 915. Solutions are stirred with a magnetic stir bar during analysis. Measurements of pH are performed in triplicate and the average thereof is used. Examples of forms of preferred solid pharmaceutical composition include a tablet or capsule. Such forms are prepared using standard procedures known in the art which involve admixing buproprion hydrochloride and the stabiliser with the tablet or capsule excipients. Such excipients may include, for example, microcrystalline cellulose, sodium starch glycolate and/or corn starch, talc, magnesium stearate and colloidal silicon dioxide. Caplets are tablets generally shaped in the form of capsules. Capsules of this invention are generally prepared by mixing the stabiliser with bupropion hydrochloride and other excipients and placing same in, e.g., a two-part hard gelatin capsule. Preferably the weight of the inactive ingredients is greater than about 1 lA times that of bupropion hydrochloride but less than about 4 times that of bupropion hydrochloride. The tablets or capsules of this invention generally contain 25mg to 500mg of bupropion hydrochloride and usually contain 50mg, 75mg, lOOmg or 150mg of bupropion hydrochloride. The amount of bupropion hydrochloride in solid form pharmaceutical -4- compositions e.g. tablets after storage, may be determined using standard procedures such as high performance liquid chromatography (HPLC). This invention is also directed to a new and improved method for stabilising the antidepressant bupropion hydrochloride to prevent the degradation thereof by admixing the stabiliser with bupropion hydrochloride. In this way a pharmaceutical composition is produced in which the bupropion hydrochloride is inhibited from degrading thus facilitating the storage of the composition over a prolonged period of time at room temperature i.e. under humidity and temperature conditions usually encountered in pharmacies and in medicine cabinets. The compositions according to the present invention include those suitable for oral, rectal, topical (including buccal and sublingual) or transdermal administration. The compositions may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing bupropion hydrochloride and the stabiliser into association with a carrier which constitutes one or more accessory ingredients. In general, the composistions are prepared by uniformly and intimately bringing bupropion hydrochloride and the stabiliser into association with a finely divided solid carrier and then, if necessary, shaping the product. Compositions of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets, tablets or lozenges, each containing a predetermined amount of bupropion hydrochloride and the stabiliser; as a powder or granules including microencapsulated or time-release forms. A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine, bupropion hydrochloride and the pharmaceutically acceptable stabiliser in a free-flowing form such as a powder or granules optionally mixed with a binder, disintegrant, lubricant, inert diluent, surface active agent or dispersing agent. Molded tablets comprising a mixture of the powdered bupropion hydrochloride and the stabiliser with any suitable carrier may be made by molding in a suitable machine. -5- Compositions suitable for rectal administration may be presented as a suppository with a conventional carrier such as cocoa butter, hydrogenated fats or hydrogenated fatty carboxylic acids. Compositions suitable for topical administration in the mouth, for example buccally or sublingually, include lozenges comprising bupropion hydrochloride and the stabiliser in a flavoured basis such as sucrose and acacia or tragacanth, and pastilles comprising the active compound in a basis such as gelatin and glycerin or sucrose and acacia. In addition to the aforementioned ingredients, the compositions of this invention may further include one or more accessory ingredient(s) selected as appropriate from diluents, buffers, flavouring agents, binders, disintegrants, surface active agents, thickeners, lubricants, preservatives (including antioxidants) and the like. The following examples are representative of the invention. In the examples, cysteine hydrochloride means L-cysteine hydrochloride. EXAMPLE 1 The formulation contained the following ingredients in the following amounts: Ingredient 100 mg potency 75 mg potency Weight (mg) per tablet Bupropion hydrochloride 100.00 75.0 Microcrystalline cellulose, NF 91.3 68.5 Sodium starch glycolate, NF 9.2 6.9 L-Cysteine hydrochloride, NF 5.0 3.8 Talc, USP 23.0 17.3 Magnesium stearate, NF 1.2 0.9 Colloidal silicon dioxide, NF 0.3 0.2 TOTAL 230.0mg 172.6mg -6- The powder ingredients were weighed out for a 120,000 tablet batch size for the lOOmg potency and a 160,000 tablet batch size for the 75mg potency. The bupropion hydro chloride, microcystalline cellulose and sodium starch glycolate were sifted through a 30 mesh Russell-Finex sifter. The sifted ingredients were blended for 15 minutes in a 3 cu. ft. slant-cone blender. The blended ingredients were granulated as follows: The cysteine hydrochloride was dissolved in 1.28kg of purified water using a Lightnin'R Mixer. This cysteine hydrochloride solution was added to 5.12 kg of SD3A alcohol (anhydrous) and mixed thoroughly using a Lightnin'^- Mixer. The blended ingredients were placed in a 3 cu. ft. Littleford Lodige granulator and ganulated using the cysteine hydrochloride solution. Mixing time was 3 to 5 minutes and chopper time was 3 to 5 minutes. Wetness was checked and additional 80% w/w SD3A alcohol (aqueous) solution was added to achieve appropriate massing. Clumps of wet granule were broken up by hand. Granule was dried in a WST-30 Glatt fluid-bed dryer until loss on drying (by Compu-Trac^-, 90°C) of granule was between 1 to 2%. Fluid-bed dryer parameters were set as follows: Inlet air temperature: 60°C. Air volume: 200-800 cu meter/hr Pre-heat temperature: 25°C. Dew point: 10°C. By-pass flap: 50% Shaker interval: 5 seconds every 2 minutes Dried granule was sifted through a 20 mesh Russell-Finex sifter. Talc (pre-sifted 60 mesh) was added to a small amount of dried granule, sifted through a 20 mesh Russell Finex sifter, added to a 3 cu. ft. slant-cone blender and blended with -7- the remainder of the granule for 5 minutes. Magnesium stearate and colloidal silicon dioxide was sifted together through a 30 mesh Russell-Finex sifter and blended in a table-top v-shell blender for 20 minutes. This magnesium stearate/colloidal silicon dioxide blend was then added to the dried granule in the 3 cu. ft. slant-cone blender and blended an additional 5 minutes. The lubricated granule was compressed on a rotary-type Manesty BetapressR in a controlled humidity environment of less than 30% relative humidity. Tablets were compressed at a compression weight of about 230mg for the lOOmg potency and about 172.6mg for the 75mg potency. Round, 7.8 mm, concave, plain punches were used for the lOOmg potency and round, 7.0 mm, concave, plain punches were used for the 75mg potency. Tablets were dedusted using a Manesty Tablet Deduster. A portion of tablets was film-coated using a compu-lab Acella - CotaR film-coater. The aqueous film coat OpadryR Red YS-1-1846 was used for the lOOmg potency and OpadryR Yellow YS-1-2186 for the 75mg potency (supplied by Colocon, Inc. of 415 Moyer Blvd, West Point, PA 19486. The Accela - Cota^- parameters were: Inlet air temperature: 50-80°C. Inlet air volume: 100-500 cfm Exhaust air temperature: 50-60°C. Tablets were coated to a weight gain of 1-5% based on the core tablet weight to achieve an acceptable color intensity. EXAMPLE 2 The procedure of Example 1 was repeated except that lubricant levels were changed, resulting in the following formulation: Ingredient lOOmg potency tablet Weight (mg) per tablet Bupropion hydrochloride 100.0 -8- Microcrystalline cellulose, NF 91.3 Sodium starch glycolate, NF 9.2 L-Cysteine hydrochloride 5.0 TaIc,USP 23.0 Magnesium stearate, NF 2.4 Colloidal silicon dioxide, NF 0.6 TOTAL 231.5 EXAMPLE 3 The procedure of Example 2 was repeated except; In order to achieve a 75mg potency, the tablets were compressed using 7.0mm, round, concave, plain punches and were not film-coated. Tablets had the resulting formulation: Ingredient 75mg potency tablet Weight (mg) per tablet Bupropion hydrochloride 75.0 Micro crystalline cellulose, NF 68.5 Sodium starch glycolate, NF 6.9 L-Cysteine hydrochloride 3.8 Talc,USP 17.3 Magnesium stearate, NF L8 Colloidal silicon dioxide, NF 0.5 TOTAL 173.8 EXAMPLE 4 Tablets are manufactured according to the following formulation: Ingredient 1 OOmg potency tablet Weight (mg) per tablet -9- Bupropion hydro chloride 100.0 Microcrystalline cellulose, NF 91.3 Sodium starch glycolate, NF 9.2 Glycine hydrochloride 5.0 Talc,USP 23.0 Magnesium stearate. NF 1.2 Colloidal silicon dioxide, NF 0.32 TOTAL 230.0MG Sufficient powder ingredients were weighed out to make approximately 24,000 tablets. The bupropion hydrochloride, microcrystalline cellulose and sodium starch glycolate were sifted through a 30 mesh Russell-Finex sifter. The sifted ingredients were blended for 15 minutes in a Patterson-Kelly (PK) v-shell blender. The blended ingredients were granulated as follows: A quantity of purified water, USP that equals approximately 25% of the total weight of granulating solvent needed to impart the desired granule wetness was weighed out. The glycine hydrochloride was dissolved in the purified water using a Lightnin'^- Mixer. The glycine hydrochioride solution was added to a quantity of SD3A alcohol, anhydrous, equal to the remaining 75% of the total weight of solvent needed to impart the desired granule wetness and mixed thoroughly using a Lightnin'^- Mixer. The blended ingredients were placed in a Hobart planetary mixer and granulated using the glycine hydrochloride solution. Mixing and time was approximately 3 to 5 minutes. Granulation wetness was checked and additional 75% w/w SD3A alcohol (aqueous) solution was added to achieve appropriate massing. Any clumps of wet granule were broken up by hand. Granule was dried in a Despatch Tray Oven to 50°C for approximately 4 hours until loss on drying (by Compu-TracR, 90°C) of granule was 1 to 2%. -10- Dried granule was sifted through a 20 mesh Russell-Finex sifter. Talc (pre-sifted 60 mesh) was added to a small amount of dried granule and sifted through a 20 mesh hand screen. This was added to the remainder of the granule and blended in a PK v-shell blender for 5 minutes. Magnesium stearate and colloidal silicon dioxide was sifted together through a 30 mesh hand screen, and blended in a PK v-shell blender for 15-20 minutes. This magnesium stearate/colloidal silicon dioxide blend was then added to the granule/talc blend in the PK v-shell blender and blended an additional 5 minutes. The lubricated granule was compressed on a rotary-type Manesty BetapressR in a controlled humidity environment of less than 30% relative humidity. Tablets were compressed at a compression weight of 230mg, using 7.8mm, round, concave, plain punches. EXAMPLE 5 The procedure of Example 4 is repeated except that the lubricant levels are changed resulting in the following formulation: Ingredient 1 OOmg potency tablet Weight (mg) per tablet Bupropion hydrochloride 100.0 Microcrystalline cellulose, NF 91.3 Sodium starch glycolate, NF 9.2 Glycine hydrochloride 5.0 Talc, USP 22.9 Magnesium stearate, NF 0.7 Colloidal silicon dioxide, NF 0.2 TOTAL 229.3mg Tablets are compressed at approximately 229.3mg. -11- EXAMPLF, 6 The procedure of Example 4 is repeated except that the lubricant levels are changed resulting in the following formulation: Ingredient 1 OOmg potency tablet Weight (mg) per tablet Bupropion hydrochloride 100.0 Micro crystalline cellulose, NF 91.3 Sodium starch glycolate, NF 9.2 Glycine hydrochloride 5.0 Talc,USP 10.9 Magnesium stearate, NF 1.1 Colloidal silicon dioxide, NF 0.2 TOTAL 217.7mg Tablets are compressed at approximately 217.7mg. EXAMPLE 7 The procedure of Example 4 was repeated except that the lubricant levels were changed resulting in the following formulation: Ingredient lOOmg potency tablet Weight (mg) per tablet Bupropion hydrochloride 100.0 Microcrystalline cellulose, NF 91.3 Sodium starch glycolate, NF 9.2 Glycine hydrochloride 5.0 Talc,USP 10.9 Magnesium stearate. NF 0.7 Colloidal silicon dioxide, NF 0.2 TOTAL 217.3mg -12- Tablets are compressed at approximately 217.3mg EXAMPLE 8 The procedure of Example 4 was repeated except magnesium stearate and colloidal silicon dioxide were replaced with sodium stearyl fumarate resulting in the following formulation: Ingredient lOOmg potency tablet Weight (mg) per tablet Bupropion hydrochloride 100.0 Microcrystalline cellulose, NF 91.3 Sodium starch glycolate, NF 9.2 Glycine hydrochloride 5.0 Talc,USP 10.9 Sodium stearyl fumarate 3.3 TOTAL 219.7mg Tablets are compressed at approximately 219.7mg EXAMPLE 9 The procedure of Example 4 was repeated except that the formulation is changed as follows: Ingredient 1 OOmg potency tablet Weight (mg) per tablet Bupropion hydrochloride 100.0 Microcrystalline cellulose, NF 68.8 Corn starch, NF 23.0 Sodium starch glycolate, NF 9.2 -13- Glycine hydrochloride 5.0 TaIc,USP 23.0 Magnesium stearate, NF 0.8 Colloidal silicon dioxide, NF 0.2 TOTAL 230.0mg Tablets are compressed at approximately 230.0mg. EXAMPLE 10 The procedure of Example 4 is repeated except sodium starch glycolate is replaced with crospovidone, resulting in the following formulation: Ingredient lOOmg potency tablet Weight (mg) per tablet Bupropion hydrochloride 100.0 Microcrystalline cellulose, NF 95.9 Crospovidone 4.6 Glycine hydrochloride 5.0 Talc,USP 23.0 Magnesium stearate, NF 1.2 Colloidal silicon dioxide, NF 0.3 TOTAL 230.0mg Tablets are compressed at approximately 230.0mg EXAMPLE 11 The procedure of Example 4 is repeated except that the formulation is changed as follows: Ingredient 1 OOmg potency tablet -14- Weight (mg) per tablet Bupropion hydrochloride 100.0 Microcrystalline cellulose, NF 68.8 Corn starch, NF 23.0 Sodium starch glycolate, NF 9.2 L-Cysteine hydrochloride 5.0 Talc,USP 23.0 Magnesium stearate, NF 1.2 Colloidal silicon dioxide, NF 0.3 TOTAL 230.5mg Tablets were compressed at approximately 230.5mg EXAMPLE 12 The procedure of Example 11 is repeated except that L-cysteine hydrochloride is replaced with glycine hydrochloride. EXAMPLE 13 The procedure of Example 4 is repeated except that the sodium starch glycolate and colloidal silicon dioxide are removed and the formulation follows: Ingredient lOOmg potency tablet Weight (mg) per tablet Bupropion hydrochloride 100.0 Microcrystalline cellulose, NF 71.0 Com starch, NF 22.0 L-Cysteine hydrochloride 5.0 Talc, USP 22.0 Magnesium stearate, NF 1.1 -15- TOTAL 221.1mg Tablets were compressed at approximately 221. lmg EXAMPLE 14 The procedure of Example 4 was repeated except that the sodium starch glycolate was removed and the formulation follows: Ingredient 1 OOmg potency tablet Weight (mg) per tablet Bupropion hydrochloride 100.0 Microcrystalline cellulose, NF 71.0 Corn starch, NF 22.0 L-Cysteine hydrochloride 5.0 Talc, USP 22.0 Magnesium stearate, NF 1.1 Colloidal silicon dioxide, NF 0.2 TOTAL 221.3mg Tablets were compressed at approximately 221.3mg. A portion of tablets was film-coated using a Compu-Lab Accela-CotaR film-coater. The aqueous film coat Opadry Red YS-1-1846 was used for the lOOmg potency. The Acella-CotaR parameters were: Inlet air temperature: 50-80°C. Inlet air volume: 200-1000 cfm Exhaust air temperature: 40-60°C. Exhaust air volume: 200-1000 cfin Tablets were coated to a weight gain of 1-5% over the core tablet weight to achieve an acceptable color intensity. 150MG CAPSULES -16- EX AMPLE 15 150mg capsules were prepared according to the following formulation and procedure: Ingredient Weight (mg) per capsule Bupropion hydrochloride 150.0 Micro crystalline cellulose, NF 106.5 Corn starch, NF 33.00 Talc,USP 33.00 L-Cystein hydrochloride 7.500 TOTAL 330.0mg A stock blend of bupropion hydrochloride, corn starch (purity 826) and microcrystalline cellulose (MCC) was prepared as follows: The above ingredients were sifted by hand through a 30 mesh screen. They were then blended in an Patterson-Kelly (P-K) v- shell blender for 10 minutes. The proper amount of cysteine hydrochloride was weighed out and added to 85% w/w SD3A alcohol (aqueous) solution. This mixture was vigorously mixed for approximately 5 minutes. It was then immediately added to the proper amount of the above mentioned stock blend and wet-granulated in a table-top Hobart mixer. The resulting wet granulation was screened by hand through a 16 mesh screen. The wet granule was dried in a tray oven at 50°C for 4 hours to obtain a loss on drying (LOD) of below 2% using a CompuTracR moisture analyser 90°C. (Upon standing the batches re-equilibrated to 2-3% LOD). The dried granule was sifted through a 16 or 30 mesh hand screen. The granule was lubricated with talc (sifted 60 mesh), in a P-K v-shell blender for 5 minutes. -17- Finished granule is encapsulated on a Chemi-Pharm manual capsule-filling machine Model No. 201, using size No. 1, white, opaque two part hard gelatin capsules. EXAMPLE 16 The procedure of Example 15 is repeated except cysteine hydrochloride was replaced with glycine hydrochloride. EXAMPLE 17 The procedure of Example 15 is repeated except cysteine hydrochloride was replaced with L-cystine dihydrochloride. EXAMPLE 18 The procedure of Example 15 is repeated except cysteine hydrochloride was replaced with tartaric acid. EXAMPLE 19 The procedure of Example 15 is repeated except cysteine hydrochloride was replaced with citric acid. EXAMPLE 20 The procedure of Example 15 is repeated except cysteine hydrochloride was replaced with malic acid. EXAMPLE 21 The procedure of Example 15 is repeated except cysteine hydrochloride is replaced with isoascorbic (erythorbic) acid. EXAMPLE 22 -18- The procedure of Example 15 is repeated except cysteine hydrochloride is replaced with ascorbic acid. EXAMPLE 23 The procedure of Example 15 is repeated except cysteine hydrochloride is replaced with sodium metabisulfite. CAPLETS EXAMPLE 24 The caplets were manufactured according to the following formulation: Ingredient lOOmg potency caplet (Core) Weight (mg) per caplet Bupropion hydrochloride 100.0 Microcrystalline cellulose, NF 274.0 Sodium starch glycolate, NF 15.00 L-Cysteine hydrochloride, USP 9.00 Talc, USP 12.00 Magnesium stearate, NF 4.00 CORE WEIGHT 414.0MG (Coating) OpadryRRed, YS-1-1846 12.00 Carnauba Wax, NF 0.04 TOTAL WEIGHT 426.0 Sufficient powder ingredients were weighed out to make a batch size of approximately 60,000 caplets. -19- The bupropion hydrochloride, microcrystalline cellulose and sodium starch glycolate were sifted through a 20 or 30 mesh Russell Finex sifter. The sifted ingredients were blended for 15 minutes in a 3 cu.ft. slant-cone blender. The blended ingredients were granulated as follows: A quantity of purified water, USP that equals approximately no more than 20% of the total weight of granulating solution needed to impart the desired granule wetness was weighed out. The cysteine hydrochloride was dissolved in the purified water using a mixer. The cysteine hydrochloride solution was added to a quantity of SD3A alcohol, anhydrous, equal to the remaining 80% (no less than) of the total weight of solution needed to impart the desired granule wetness and mixed thoroughly using a mixer. The blended ingredients were placed in a 3 cu.ft. Littleford LodigeR granulator and granulated using the hydroalcoholic cysteine hydrochloride solution. Mixing and chopper time was approximately 5-10 minutes. Wetness was checked and additional 80% w/w SD3A alcohol (aqueous) solution was added to achieve appropriate massing. Any clumps of wet granule were broken up by hand. Granule was dried in a WST-30 Glatt fluid-bed dryer until loss on drying (by Corripu- TracR, 90°C) of granule was 0.8-2.0%. Fluid-bed drying parameters were set as follows: Inlet air temperature: 60°C Air volume: 200-1200 cu meter/hr Dried granule was milled using a ComilR and appropriately sized screen. Talc (pre-sifted 60 mesh) was added to small amount of dried granule and mixed by hand. Magnesium stearate (pre-sifted) was added to a small amount of dried granule and mixed by hand. Both mixtures were sifted through a 16 mesh screen in a Russell Finex sifter. This sifted mixture was added to the remainder of the granule and blended in the 3 cu.ft slant-cone blender for 5 minutes. -20- The lubricated granule was compressed on a rotary-type Manesty BetapressR. Caplets were compressed at a compression weight of approximately 414 gm. using 6.5 x 14.5 mm concave, caplet punches containing a partial score-bar on the upper and lower punches. Caplets were dedusted using a Manesty Tablet Deduster. A portion of tablets was film-coated using a Compu-Lab Accela-CotaR film-coater. The aqueous film coat Opadry RedR YS-1-1846 was used. The Accela-CotaR parameters were: Inlet air temperature: 50-80°C. Inlet air volume: 100-500 cfm Exhaust air temperature: 40-60°C. Caplets were coated to a weight gain of 1-5% over the core tablet weight to achieve an acceptable color intensity. Caplets were coated with carnauba WELX to assist in packaging. Carnauba wax was added to the film-coated caplets wliich were rotated in the coating drum for approximately 5 minutes to distribute the wax. EXAMPLE 25 The procedure of Example 24 is repeated except: In order to achieve a 75mg potency, the caplets are compressed at a compression weight of approximately 310.5mg, using 5.9 x 13.1mm concave, caplet punches containing a partial score-bar on the upper and lower punches. The aqueous film coat OpadryR Yellow-Gold YS-1-2186 is for the 75mg potency. Caplets have the resulting composition: Ingredient 75mg potency caplet (Core) Weight (mg) per caplet Bupropion hydrochloride 75.00 Microcrystalline cellulose, NF 205.5 -21- Sodium starch glycolate, NF 11.25 Cysteine hydro chloride, USP 6.750 Talc, USP 9.00 Magnesium stearate, NF 3.00 CORE WEIGHT 310.5mg (Coating) Opadry Yellow, YS-1-2186 9.00 Camauba Wax, NF 0.03 TOTAL WEIGHT 319.5.0mg EXAMPLE 26 The procedure of Example 24 is repeated except: In order to achieve a 50mg potency, the caplets are compressed at a compression weight of approximately 207mg, using 5.1 x 11.4mm concave, caplet punches containing a partial scorebar on the upper and lower punches. The aqueous film coat Opadry^- White YS-1-7059 is used for the 50mg potency. Caplets have the resulting composition: Ingredient 50mg potency caplet (Core) Weight (mg) per caplet Bupropion hydrochloride 50.00 Microcrystalline cellulose, NF 137.0 Sodium starch glycolate, NF 7.50 Cysteine hydrochloride, USP 4.50 Talc, USP 6.00 Magnesium stearate, NF 2.00 CORE WEIGHT 207.0mg (Coating) Opadry WhiteR, YS-1-7059 6.00 Carnauba Wax, NF 0.02 -22- TOTAL WEIGHT 213.0mg EXAMPLE 27 The procedure of Example 24 is repeated except: The blended powders are granulated with 100% SD3A Alcohol. EXAMPLE 28 The procedure of Example 27 is repeated except: The cysteine hydrochloride is blended in dry with the other ingredients rather than adding it to the granulating solution. The level of cysteine hydrochloride is increased giving the caplets the following composition: Ingredient 1 OOmg potency caplet (Core) Weight (mg) per caplet Bupropion hydrochloride 100.00 Microcrystalline cellulose, NF 274.0 Sodium starch glycolate, NF 15.00 Cysteine hydrochloride, USP 18.00 Talc,USP 12.00 Magnesium stearate, NF 4.00 CORE WEIGHT 423.0mg (Coating) Opadry RedR, YS-1-1846 12.00 Camauba Wax, NF 0.040 TOTAL WEIGHT 435.0mg EXAMPLE 29 -23- The procedure of Example 24 was followed except: Glycine hydrochloride is used as the Stabiliser, giving the caplets the following composition: TOTAL WEIGHT 426.0mg EXAMPLE 30 The procedure of Example 24 was repeated except: The blended powders were granulated with 100% Isopropyl alcohol. We claim, 1. A pharmaceutical composition in solid form comprising bupropion hydrochloride and a pharmaceutically acceptable stabiliser in an effective stabilising amount, in which the composition contains at least 80% w/w of undegraded bupropion hydrochloride after storage for 6 weeks at 40°C and 75% relative humidity, an aqueous solution of the stabiliser in a concentration of 6% W/W having a pH of 0.9 to 4, and the stabiliser being selected from an organic acid, a carboxylic acid, an acid salt of an amino acid and sodium metabisulphite; with the proviso that a sustained release tablet comprising (i) bupropion hydrochloridE and hydroxypropyl methylcellulose, the amount of hydroxypropyl methylcellulose to the amount of bupropion hydrochloride being from 0.19 : 1 to 1.1 : 1, land (ii) glycine hydrochloride or cysteine hydrochloride, is excluded. 2. A pharmaceutical composition according to claim 1 wherein the carboxylic acid is ascorbic or isoascorbic acid. 3. A pharmaceutical composition in solid form comprising bupropion hydrochloride and a pharmaceutically acceptable stabiliser in an effective stabilising amount, in which the composition contains at least 80% wlw of undegraded bupropion hydrochloride after storage for 6 weeks at 50°C and 27% relative humidity, an aqueous solution of the stabiliser in a concentration of 6% wlw having a pH of 0.9 to 4, and the stabiliser being selected from an organic acid, a carboxylic acid other than ascorbic acid and isoascorbic acid, an acid salt of an amino acid and sodium metabisulphite. 4. A pharmaceutial composition according to any one of claims 1 to 3 wherein the aqueous solution of the stabiliser has a pH of 0.9 to 2. 5. A pharmaceutial composition according to claim 4 wherein the aqueous solution of the stabiliser has a pH of 1. 6. A pharmaceutial composition according to any one of claims 1 to 5 which contains at least 95% wlw of undegraded bupropion hydrochloride. 7. A pharmaceutical composition according to any one of claims 1 to 6, wherein the amount of stabiliser is 2.7% to 27% of the weight of bupropion hydrochloride in the composition. 25 8. A pharmaceutical composition according to claim 7, wherein the amount of stabiliser is 5% to 16.2% of the weight of bupropion hydrochloridel in the composition. 9. A pharmaceutical composition according to any one of claims I and 3 to 8, wherein the acid salt of the amino acid is cysteine hydrochloride, glycine hydrochloride or cystine dihydrochloride. 10. A pharmaceutical composition according to any one of claims 1 and 3 to 8, wherein the organic acid is tartaric acid, citric acid or malic acid. 11. A tablet or capsule comprising a composition according to any one of claims 1 to 10, wherein the amount of bupropion hydrochloride is 50, 75, 100 or 150mg. 12. A method of stabilising bupropion hydrochloride in a solid pharmaceutical composition, so that at least 80% w/w of bupropion hydrochloride is present in the undegraded form after storage for 6 weeks at 40°C and 75% relative humidity, wherein said method comprises mixing bupropion hydrochloridk with a stabilise, an aqueous solution of the stabiliser in a concentration of 6% w/w having a pH of 0.9 to 4, and the stabiliser being selected from an organic acid, a carboxylic acid, an acid salt of an amino acid and sodium metabisulfite. 13. A method as claimed in claim 12 wherein the carboxylic acid is ascorbic or isoascorbic acid. 14. A method of stabilising bupropion hydrochloride in a solid pharmaceutical composition, so that at least 80% wlw of bupropion hydrochloride is present in the undegraded form after storage for 6 weeks at 50°C and 27% relative humidity, wherein said method comprises mixing bupropion hydrochloride with a stabiliser, an aqueous solution of the stabiliser in a concentration of 6% wlw having a pH of 0.9 to 4, and the stabiliser being selected from an organjc acid, a carboxylic acid other than ascorbic acid or isoascorbic acid, an acid salt of an amino acid and sodium metabisulfite. 15. A method as claimed in any one of claims 12 to 14 wherein the aqueous solution of the stabiliser has a pH as defined in claim 4 or claim 5. 16. A method as claimed in any one of claims 12 to 15 wherein the composition contains at least 95% w/w of undegraded bupropion hydrochloride. 26 17. A method as claimed in any one of claims 12 or 14 to 16 wherein the acid salt of an amino acid or the organic acid is as defined in claim 9 or claim 10. 18. A method as claimed in any one of claims 12 to 17 wherein the amount of stabiliser is as defined in claim 7 or claim 8. 19. A method as claimed in any one of claims 13 to 18 wherein theftmount of bupropion hydrochloride is as defined in claim 1I. Applicants disclose a stabilized pharmaceutical composition in solid form comprising buproprion hydrochloride, an antidepressant and a stabilizer. Degradation of the buproprion hydrochloride in the formulation is inhibited to the extent that the pharmaceutical formulation will maintain at least 80% of its initial buproprion potency after one year.

Full Text

IA
The present invention relates to pharmaceutical compositions comprising bupropion hydrochloricle and a pharmaceutically acceptable stabiliser mid methods of stabilizing bupropion hydrochloride in a pharmaceutical composition.
Bupropion hydrochloride is a known amtidepressant sold in instant release tablet form under the brand name WELLBUTRINR. (Also see U.S. Patents 3,819,706 and 3,885,046; 1993 Physicians Desk Reference and the Merck Index. Eleventh Edition, Entry No. 1488. Bupropion hydrochloride is also useful as an anticholesterol agent, in suppressing prolacttn secretion, in preventing functional impairment and drowsiness seen upon administration of benzodiazepine, in the treatment or minimal bruin dysfunction, tardive dyskinesia, impaired mental alertness upon ingestion of ethanol and psychosexual dysfunction. While the instant release tablets currently sold are quite suitable for the indicated use, the method of manufacturing these is less than desirable based on cost as well as process conditions .
The object of the present invention is to prevent (inhibit) the degradation of bupropion hydrochloric using stabilizer ingredients, thus allowing the preparation of pharmaceutical compositions such as instant and sustained release tablets and capsules which, from a cost of manufacture and processing standpoint, are much improved over those achievable in the past.
The invention provides a pharmaceutical composition in solid form comprising bupropion hydrochloride and a pharmaceutically acceptable stabiliser in an effective stabilising amount, in which the composition contains at least 80% w/w of undegraded bupropion hydrochloride after storage for 6 weeks at 40°C and. 75% relative humidity, an aqueous solution of the stabiliser in a concentration of 6% W/W having a pH of 0.9 to 4, and the stabiliser being selected from an organic acid, a carboxylic acid, an acid salt of an amino acid and sodium metabisulphite; with the proviso that a sustained release tablet comprising (i) bupropion hydrochloride and hydroxypropyl methylcellulose, the amount of hydroxypropyl methylceliulose to the amount of bupropion hydrochloride being from 0.19 : 1 to 1.1 : 1, and (ii) glycine hydrochloride or cysteine hydrochloride, is excluded.
The invention further provides a pharmaceutical composition in solid form comprising bupropion hydrochloride and a pharmaceutically acceptable stabiliser in an effective stabilising amount, in which the composition contains at least 80% wlw of undegraded bupropion hydrochloride after storage for 6 weeks at 50°C and 27% relative humidity, an aqueous solution of the stabiliser in a concentration of 6% wlw having a pH of 0.9 to 4, and the stabiliser being selected from an organic acid, a carboxylic acid other than ascorbic acid and isoascorbic acid, an acid salt of an amino acid and sodium metabisulphite.

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The preferred pH of the aqueous solution of the stabilizer is 0.9 to about 2 and most preferably.
Preferably the pharmaceutica! composition according to the present invention contains at least about 90% w/w of undegraded bupropion hydrochloride after storage for 6 weeks under the above conditions and more preferably 95% or even 98%. In an additional aspect, the amount of undegrade bupropion hydrochloride is greater than 80% of its labelled strength, and more preferably greater 'than 90% percent of the labelled strength after one year of storage under the humidity and temperature conditions usually encountered in pharmacies and medicine cabinets ie. room temperature and 35-60% humidity. Thus, when used in a pharmaceutical preparation for example, a tablet will still retain at least 80% of its potency and preferably at least 90% after one year of storage at room temperature (15-25°C (59-77°F)) at 35-60% humidity. For example if the tablet initially contains lOOmg bupropion hydrochloride (labeled amount) at time of preparation, after one year storage at least 80mg of undegraded bupropion hydrochloride will remain in the tablet.
The amount of the stabiliser which may be used with the present invention may vary but preferably is about 2.7% to 27%, most preferably about 5% to 16.2% based on the label strength of bupropion. hydrochloride in the pharmaceutical formulation (composition) in solid form. For example if a formulation contains lOOmg of bupropion hydrochloride it would preferably contain-about 2.7 to 27g of stabilizer.
Stabilizers of use in this invention include organic acids, carboxylic acids, acid salts of amino acids and sodium metabisulphite. Preferably, the acid salts of amino acids are hydrochloride salts such as cysteine hydrochloride, glycine hydrochloride or cystine dihydrochloride. Other, preferred examples ,of stabilisers according to the present invention include: ascorbic acid, malic acid, isoascorbic acid, citric acid and tartaric

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acid. L-cysteine hydrochloride and glycine hydrochloride are the most preferred stabilisers.
In the examples the cysteine hydrochloride is in the L form and NF and USP are designations for standards published in the National Formulary and US Pharmacopeia, respectively.
The present invention extends to the use of combinations of stabilisers especially combinations of the aforementioned stabilisers.
The pH of the aqueous solution of the stabilisers may be determined as follows:
The stabiliser is weighed out to provide 3.75 grams thereof, (except for 3.34 grams of L-cystine dihydrochloride) and is then added to 60 grams of distilled water in a glass PyrexR beaker. The resulting mixture is stirred for approximately 5 minutes, using a stir plate and magnetic stir bar. The resulting solution or dispersion is examined using either a Orion Model 701A Ionalyzer^-, or an Accumet pH Meter Model 915. Solutions are stirred with a magnetic stir bar during analysis. Measurements of pH are performed in triplicate and the average thereof is used.
Examples of forms of preferred solid pharmaceutical composition include a tablet or capsule. Such forms are prepared using standard procedures known in the art which involve admixing buproprion hydrochloride and the stabiliser with the tablet or capsule excipients. Such excipients may include, for example, microcrystalline cellulose, sodium starch glycolate and/or corn starch, talc, magnesium stearate and colloidal silicon dioxide. Caplets are tablets generally shaped in the form of capsules. Capsules of this invention are generally prepared by mixing the stabiliser with bupropion hydrochloride and other excipients and placing same in, e.g., a two-part hard gelatin capsule.
Preferably the weight of the inactive ingredients is greater than about 1 lA times that of bupropion hydrochloride but less than about 4 times that of bupropion hydrochloride. The tablets or capsules of this invention generally contain 25mg to 500mg of bupropion hydrochloride and usually contain 50mg, 75mg, lOOmg or 150mg of bupropion hydrochloride. The amount of bupropion hydrochloride in solid form pharmaceutical

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compositions e.g. tablets after storage, may be determined using standard procedures such as high performance liquid chromatography (HPLC).
This invention is also directed to a new and improved method for stabilising the antidepressant bupropion hydrochloride to prevent the degradation thereof by admixing the stabiliser with bupropion hydrochloride. In this way a pharmaceutical composition is produced in which the bupropion hydrochloride is inhibited from degrading thus facilitating the storage of the composition over a prolonged period of time at room temperature i.e. under humidity and temperature conditions usually encountered in pharmacies and in medicine cabinets.
The compositions according to the present invention include those suitable for oral, rectal, topical (including buccal and sublingual) or transdermal administration.
The compositions may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing bupropion hydrochloride and the stabiliser into association with a carrier which constitutes one or more accessory ingredients. In general, the composistions are prepared by uniformly and intimately bringing bupropion hydrochloride and the stabiliser into association with a finely divided solid carrier and then, if necessary, shaping the product.
Compositions of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets, tablets or lozenges, each containing a predetermined amount of bupropion hydrochloride and the stabiliser; as a powder or granules including microencapsulated or time-release forms.
A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine, bupropion hydrochloride and the pharmaceutically acceptable stabiliser in a free-flowing form such as a powder or granules optionally mixed with a binder, disintegrant, lubricant, inert diluent, surface active agent or dispersing agent. Molded tablets comprising a mixture of the powdered bupropion hydrochloride and the stabiliser with any suitable carrier may be made by molding in a suitable machine.

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Compositions suitable for rectal administration may be presented as a suppository with a conventional carrier such as cocoa butter, hydrogenated fats or hydrogenated fatty carboxylic acids.
Compositions suitable for topical administration in the mouth, for example buccally or sublingually, include lozenges comprising bupropion hydrochloride and the stabiliser in a flavoured basis such as sucrose and acacia or tragacanth, and pastilles comprising the active compound in a basis such as gelatin and glycerin or sucrose and acacia.
In addition to the aforementioned ingredients, the compositions of this invention may further include one or more accessory ingredient(s) selected as appropriate from diluents, buffers, flavouring agents, binders, disintegrants, surface active agents, thickeners, lubricants, preservatives (including antioxidants) and the like.
The following examples are representative of the invention.
In the examples, cysteine hydrochloride means L-cysteine hydrochloride.
EXAMPLE 1 The formulation contained the following ingredients in the following amounts:

Ingredient 100 mg potency 75 mg potency
Weight (mg) per tablet
Bupropion hydrochloride 100.00 75.0
Microcrystalline cellulose, NF 91.3 68.5
Sodium starch glycolate, NF 9.2 6.9
L-Cysteine hydrochloride, NF 5.0 3.8
Talc, USP 23.0 17.3
Magnesium stearate, NF 1.2 0.9
Colloidal silicon dioxide, NF 0.3 0.2
TOTAL 230.0mg 172.6mg

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The powder ingredients were weighed out for a 120,000 tablet batch size for the lOOmg potency and a 160,000 tablet batch size for the 75mg potency.
The bupropion hydro chloride, microcystalline cellulose and sodium starch glycolate were sifted through a 30 mesh Russell-Finex sifter.
The sifted ingredients were blended for 15 minutes in a 3 cu. ft. slant-cone blender. The blended ingredients were granulated as follows:
The cysteine hydrochloride was dissolved in 1.28kg of purified water using a Lightnin'R Mixer. This cysteine hydrochloride solution was added to 5.12 kg of SD3A alcohol (anhydrous) and mixed thoroughly using a Lightnin'^- Mixer. The blended ingredients were placed in a 3 cu. ft. Littleford Lodige granulator and ganulated using the cysteine hydrochloride solution. Mixing time was 3 to 5 minutes and chopper time was 3 to 5 minutes. Wetness was checked and additional 80% w/w SD3A alcohol (aqueous) solution was added to achieve appropriate massing.
Clumps of wet granule were broken up by hand.
Granule was dried in a WST-30 Glatt fluid-bed dryer until loss on drying (by Compu-Trac^-, 90°C) of granule was between 1 to 2%. Fluid-bed dryer parameters were set as follows:
Inlet air temperature: 60°C.
Air volume: 200-800 cu meter/hr
Pre-heat temperature: 25°C.
Dew point: 10°C.
By-pass flap: 50%
Shaker interval: 5 seconds every 2 minutes
Dried granule was sifted through a 20 mesh Russell-Finex sifter.
Talc (pre-sifted 60 mesh) was added to a small amount of dried granule, sifted through a 20 mesh Russell Finex sifter, added to a 3 cu. ft. slant-cone blender and blended with

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the remainder of the granule for 5 minutes. Magnesium stearate and colloidal silicon dioxide was sifted together through a 30 mesh Russell-Finex sifter and blended in a table-top v-shell blender for 20 minutes. This magnesium stearate/colloidal silicon dioxide blend was then added to the dried granule in the 3 cu. ft. slant-cone blender and blended an additional 5 minutes.
The lubricated granule was compressed on a rotary-type Manesty BetapressR in a controlled humidity environment of less than 30% relative humidity. Tablets were compressed at a compression weight of about 230mg for the lOOmg potency and about 172.6mg for the 75mg potency. Round, 7.8 mm, concave, plain punches were used for the lOOmg potency and round, 7.0 mm, concave, plain punches were used for the 75mg potency.
Tablets were dedusted using a Manesty Tablet Deduster.
A portion of tablets was film-coated using a compu-lab Acella - CotaR film-coater. The aqueous film coat OpadryR Red YS-1-1846 was used for the lOOmg potency and OpadryR Yellow YS-1-2186 for the 75mg potency (supplied by Colocon, Inc. of 415 Moyer Blvd, West Point, PA 19486. The Accela - Cota^- parameters were:
Inlet air temperature: 50-80°C.
Inlet air volume: 100-500 cfm
Exhaust air temperature: 50-60°C.
Tablets were coated to a weight gain of 1-5% based on the core tablet weight to achieve an acceptable color intensity.
EXAMPLE 2
The procedure of Example 1 was repeated except that lubricant levels were changed, resulting in the following formulation:
Ingredient lOOmg potency tablet
Weight (mg) per tablet
Bupropion hydrochloride 100.0

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Microcrystalline cellulose, NF 91.3
Sodium starch glycolate, NF 9.2
L-Cysteine hydrochloride 5.0
TaIc,USP 23.0
Magnesium stearate, NF 2.4
Colloidal silicon dioxide, NF 0.6
TOTAL 231.5
EXAMPLE 3
The procedure of Example 2 was repeated except;
In order to achieve a 75mg potency, the tablets were compressed using 7.0mm, round, concave, plain punches and were not film-coated. Tablets had the resulting formulation:
Ingredient 75mg potency tablet
Weight (mg) per tablet
Bupropion hydrochloride 75.0
Micro crystalline cellulose, NF 68.5
Sodium starch glycolate, NF 6.9
L-Cysteine hydrochloride 3.8
Talc,USP 17.3
Magnesium stearate, NF L8
Colloidal silicon dioxide, NF 0.5
TOTAL 173.8
EXAMPLE 4
Tablets are manufactured according to the following formulation:
Ingredient 1 OOmg potency tablet
Weight (mg) per tablet

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Bupropion hydro chloride 100.0
Microcrystalline cellulose, NF 91.3
Sodium starch glycolate, NF 9.2
Glycine hydrochloride 5.0
Talc,USP 23.0
Magnesium stearate. NF 1.2
Colloidal silicon dioxide, NF 0.32
TOTAL 230.0MG
Sufficient powder ingredients were weighed out to make approximately 24,000 tablets.
The bupropion hydrochloride, microcrystalline cellulose and sodium starch glycolate were sifted through a 30 mesh Russell-Finex sifter.
The sifted ingredients were blended for 15 minutes in a Patterson-Kelly (PK) v-shell blender.
The blended ingredients were granulated as follows:
A quantity of purified water, USP that equals approximately 25% of the total weight of granulating solvent needed to impart the desired granule wetness was weighed out. The glycine hydrochloride was dissolved in the purified water using a Lightnin'^- Mixer. The glycine hydrochioride solution was added to a quantity of SD3A alcohol, anhydrous, equal to the remaining 75% of the total weight of solvent needed to impart the desired granule wetness and mixed thoroughly using a Lightnin'^- Mixer. The blended ingredients were placed in a Hobart planetary mixer and granulated using the glycine hydrochloride solution. Mixing and time was approximately 3 to 5 minutes. Granulation wetness was checked and additional 75% w/w SD3A alcohol (aqueous) solution was added to achieve appropriate massing.
Any clumps of wet granule were broken up by hand.
Granule was dried in a Despatch Tray Oven to 50°C for approximately 4 hours until loss on drying (by Compu-TracR, 90°C) of granule was 1 to 2%.

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Dried granule was sifted through a 20 mesh Russell-Finex sifter.
Talc (pre-sifted 60 mesh) was added to a small amount of dried granule and sifted through a 20 mesh hand screen. This was added to the remainder of the granule and blended in a PK v-shell blender for 5 minutes. Magnesium stearate and colloidal silicon dioxide was sifted together through a 30 mesh hand screen, and blended in a PK v-shell blender for 15-20 minutes. This magnesium stearate/colloidal silicon dioxide blend was then added to the granule/talc blend in the PK v-shell blender and blended an additional 5 minutes.
The lubricated granule was compressed on a rotary-type Manesty BetapressR in a controlled humidity environment of less than 30% relative humidity. Tablets were compressed at a compression weight of 230mg, using 7.8mm, round, concave, plain punches.
EXAMPLE 5
The procedure of Example 4 is repeated except that the lubricant levels are changed resulting in the following formulation:
Ingredient 1 OOmg potency tablet
Weight (mg) per tablet
Bupropion hydrochloride 100.0
Microcrystalline cellulose, NF 91.3
Sodium starch glycolate, NF 9.2
Glycine hydrochloride 5.0
Talc, USP 22.9
Magnesium stearate, NF 0.7
Colloidal silicon dioxide, NF 0.2
TOTAL 229.3mg Tablets are compressed at approximately 229.3mg.

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EXAMPLF, 6
The procedure of Example 4 is repeated except that the lubricant levels are changed resulting in the following formulation:
Ingredient 1 OOmg potency tablet
Weight (mg) per tablet
Bupropion hydrochloride 100.0
Micro crystalline cellulose, NF 91.3
Sodium starch glycolate, NF 9.2
Glycine hydrochloride 5.0
Talc,USP 10.9
Magnesium stearate, NF 1.1
Colloidal silicon dioxide, NF 0.2
TOTAL 217.7mg
Tablets are compressed at approximately 217.7mg.
EXAMPLE 7
The procedure of Example 4 was repeated except that the lubricant levels were changed resulting in the following formulation:
Ingredient lOOmg potency tablet
Weight (mg) per tablet
Bupropion hydrochloride 100.0
Microcrystalline cellulose, NF 91.3
Sodium starch glycolate, NF 9.2
Glycine hydrochloride 5.0
Talc,USP 10.9
Magnesium stearate. NF 0.7
Colloidal silicon dioxide, NF 0.2
TOTAL 217.3mg

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Tablets are compressed at approximately 217.3mg
EXAMPLE 8
The procedure of Example 4 was repeated except magnesium stearate and colloidal silicon dioxide were replaced with sodium stearyl fumarate resulting in the following formulation:
Ingredient lOOmg potency tablet
Weight (mg) per tablet
Bupropion hydrochloride 100.0
Microcrystalline cellulose, NF 91.3
Sodium starch glycolate, NF 9.2
Glycine hydrochloride 5.0
Talc,USP 10.9
Sodium stearyl fumarate 3.3
TOTAL 219.7mg
Tablets are compressed at approximately 219.7mg
EXAMPLE 9
The procedure of Example 4 was repeated except that the formulation is changed as follows:
Ingredient 1 OOmg potency tablet
Weight (mg) per tablet
Bupropion hydrochloride 100.0
Microcrystalline cellulose, NF 68.8
Corn starch, NF 23.0
Sodium starch glycolate, NF 9.2

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Glycine hydrochloride 5.0
TaIc,USP 23.0
Magnesium stearate, NF 0.8
Colloidal silicon dioxide, NF 0.2
TOTAL 230.0mg
Tablets are compressed at approximately 230.0mg.
EXAMPLE 10
The procedure of Example 4 is repeated except sodium starch glycolate is replaced with crospovidone, resulting in the following formulation:
Ingredient lOOmg potency tablet
Weight (mg) per tablet
Bupropion hydrochloride 100.0
Microcrystalline cellulose, NF 95.9
Crospovidone 4.6
Glycine hydrochloride 5.0
Talc,USP 23.0
Magnesium stearate, NF 1.2
Colloidal silicon dioxide, NF 0.3
TOTAL 230.0mg
Tablets are compressed at approximately 230.0mg
EXAMPLE 11
The procedure of Example 4 is repeated except that the formulation is changed as follows:
Ingredient 1 OOmg potency tablet

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Weight (mg) per tablet
Bupropion hydrochloride 100.0
Microcrystalline cellulose, NF 68.8
Corn starch, NF 23.0
Sodium starch glycolate, NF 9.2
L-Cysteine hydrochloride 5.0
Talc,USP 23.0
Magnesium stearate, NF 1.2
Colloidal silicon dioxide, NF 0.3
TOTAL 230.5mg
Tablets were compressed at approximately 230.5mg
EXAMPLE 12
The procedure of Example 11 is repeated except that L-cysteine hydrochloride is replaced with glycine hydrochloride.
EXAMPLE 13
The procedure of Example 4 is repeated except that the sodium starch glycolate and colloidal silicon dioxide are removed and the formulation follows:
Ingredient lOOmg potency tablet
Weight (mg) per tablet
Bupropion hydrochloride 100.0
Microcrystalline cellulose, NF 71.0
Com starch, NF 22.0
L-Cysteine hydrochloride 5.0
Talc, USP 22.0
Magnesium stearate, NF 1.1

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TOTAL 221.1mg
Tablets were compressed at approximately 221. lmg
EXAMPLE 14
The procedure of Example 4 was repeated except that the sodium starch glycolate was removed and the formulation follows:
Ingredient 1 OOmg potency tablet
Weight (mg) per tablet
Bupropion hydrochloride 100.0
Microcrystalline cellulose, NF 71.0
Corn starch, NF 22.0
L-Cysteine hydrochloride 5.0
Talc, USP 22.0
Magnesium stearate, NF 1.1
Colloidal silicon dioxide, NF 0.2
TOTAL 221.3mg
Tablets were compressed at approximately 221.3mg.
A portion of tablets was film-coated using a Compu-Lab Accela-CotaR film-coater.
The aqueous film coat Opadry Red YS-1-1846 was used for the lOOmg potency. The
Acella-CotaR parameters were:
Inlet air temperature: 50-80°C.
Inlet air volume: 200-1000 cfm
Exhaust air temperature: 40-60°C.
Exhaust air volume: 200-1000 cfin
Tablets were coated to a weight gain of 1-5% over the core tablet weight to achieve an
acceptable color intensity.
150MG CAPSULES

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EX AMPLE 15
150mg capsules were prepared according to the following formulation and procedure:
Ingredient Weight (mg) per capsule
Bupropion hydrochloride 150.0
Micro crystalline cellulose, NF 106.5
Corn starch, NF 33.00
Talc,USP 33.00
L-Cystein hydrochloride 7.500
TOTAL 330.0mg
A stock blend of bupropion hydrochloride, corn starch (purity 826) and microcrystalline cellulose (MCC) was prepared as follows:
The above ingredients were sifted by hand through a 30 mesh screen. They were then blended in an Patterson-Kelly (P-K) v- shell blender for 10 minutes.
The proper amount of cysteine hydrochloride was weighed out and added to 85% w/w SD3A alcohol (aqueous) solution. This mixture was vigorously mixed for approximately 5 minutes. It was then immediately added to the proper amount of the above mentioned stock blend and wet-granulated in a table-top Hobart mixer.
The resulting wet granulation was screened by hand through a 16 mesh screen.
The wet granule was dried in a tray oven at 50°C for 4 hours to obtain a loss on drying (LOD) of below 2% using a CompuTracR moisture analyser 90°C. (Upon standing the batches re-equilibrated to 2-3% LOD).
The dried granule was sifted through a 16 or 30 mesh hand screen.
The granule was lubricated with talc (sifted 60 mesh), in a P-K v-shell blender for 5 minutes.

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Finished granule is encapsulated on a Chemi-Pharm manual capsule-filling machine Model No. 201, using size No. 1, white, opaque two part hard gelatin capsules.
EXAMPLE 16
The procedure of Example 15 is repeated except cysteine hydrochloride was replaced with glycine hydrochloride.
EXAMPLE 17
The procedure of Example 15 is repeated except cysteine hydrochloride was replaced with L-cystine dihydrochloride.
EXAMPLE 18
The procedure of Example 15 is repeated except cysteine hydrochloride was replaced with tartaric acid.
EXAMPLE 19
The procedure of Example 15 is repeated except cysteine hydrochloride was replaced with citric acid.
EXAMPLE 20
The procedure of Example 15 is repeated except cysteine hydrochloride was replaced with malic acid.
EXAMPLE 21
The procedure of Example 15 is repeated except cysteine hydrochloride is replaced with isoascorbic (erythorbic) acid.
EXAMPLE 22

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The procedure of Example 15 is repeated except cysteine hydrochloride is replaced with ascorbic acid.
EXAMPLE 23
The procedure of Example 15 is repeated except cysteine hydrochloride is replaced with sodium metabisulfite.
CAPLETS
EXAMPLE 24
The caplets were manufactured according to the following formulation:
Ingredient lOOmg potency caplet
(Core) Weight (mg) per caplet
Bupropion hydrochloride 100.0
Microcrystalline cellulose, NF 274.0
Sodium starch glycolate, NF 15.00
L-Cysteine hydrochloride, USP 9.00
Talc, USP 12.00
Magnesium stearate, NF 4.00
CORE WEIGHT 414.0MG
(Coating)
OpadryRRed, YS-1-1846 12.00
Carnauba Wax, NF 0.04
TOTAL WEIGHT 426.0
Sufficient powder ingredients were weighed out to make a batch size of approximately 60,000 caplets.

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The bupropion hydrochloride, microcrystalline cellulose and sodium starch glycolate were sifted through a 20 or 30 mesh Russell Finex sifter.
The sifted ingredients were blended for 15 minutes in a 3 cu.ft. slant-cone blender. The blended ingredients were granulated as follows:
A quantity of purified water, USP that equals approximately no more than 20% of the total weight of granulating solution needed to impart the desired granule wetness was weighed out. The cysteine hydrochloride was dissolved in the purified water using a mixer. The cysteine hydrochloride solution was added to a quantity of SD3A alcohol, anhydrous, equal to the remaining 80% (no less than) of the total weight of solution needed to impart the desired granule wetness and mixed thoroughly using a mixer. The blended ingredients were placed in a 3 cu.ft. Littleford LodigeR granulator and granulated using the hydroalcoholic cysteine hydrochloride solution. Mixing and chopper time was approximately 5-10 minutes. Wetness was checked and additional 80% w/w SD3A alcohol (aqueous) solution was added to achieve appropriate massing.
Any clumps of wet granule were broken up by hand.
Granule was dried in a WST-30 Glatt fluid-bed dryer until loss on drying (by Corripu-
TracR, 90°C) of granule was 0.8-2.0%. Fluid-bed drying parameters were set as
follows:
Inlet air temperature: 60°C
Air volume: 200-1200 cu meter/hr
Dried granule was milled using a ComilR and appropriately sized screen.
Talc (pre-sifted 60 mesh) was added to small amount of dried granule and mixed by hand. Magnesium stearate (pre-sifted) was added to a small amount of dried granule and mixed by hand. Both mixtures were sifted through a 16 mesh screen in a Russell Finex sifter. This sifted mixture was added to the remainder of the granule and blended in the 3 cu.ft slant-cone blender for 5 minutes.

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The lubricated granule was compressed on a rotary-type Manesty BetapressR. Caplets were compressed at a compression weight of approximately 414 gm. using 6.5 x 14.5 mm concave, caplet punches containing a partial score-bar on the upper and lower punches.
Caplets were dedusted using a Manesty Tablet Deduster.
A portion of tablets was film-coated using a Compu-Lab Accela-CotaR film-coater.
The aqueous film coat Opadry RedR YS-1-1846 was used. The Accela-CotaR
parameters were:
Inlet air temperature: 50-80°C.
Inlet air volume: 100-500 cfm
Exhaust air temperature: 40-60°C.
Caplets were coated to a weight gain of 1-5% over the core tablet weight to achieve an acceptable color intensity.
Caplets were coated with carnauba WELX to assist in packaging. Carnauba wax was added to the film-coated caplets wliich were rotated in the coating drum for approximately 5 minutes to distribute the wax.
EXAMPLE 25
The procedure of Example 24 is repeated except:
In order to achieve a 75mg potency, the caplets are compressed at a compression weight
of approximately 310.5mg, using 5.9 x 13.1mm concave, caplet punches containing a
partial score-bar on the upper and lower punches. The aqueous film coat OpadryR
Yellow-Gold YS-1-2186 is for the 75mg potency.
Caplets have the resulting composition:
Ingredient 75mg potency caplet
(Core) Weight (mg) per caplet
Bupropion hydrochloride 75.00
Microcrystalline cellulose, NF 205.5

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Sodium starch glycolate, NF 11.25
Cysteine hydro chloride, USP 6.750
Talc, USP 9.00
Magnesium stearate, NF 3.00
CORE WEIGHT 310.5mg
(Coating)
Opadry Yellow, YS-1-2186 9.00
Camauba Wax, NF 0.03
TOTAL WEIGHT 319.5.0mg
EXAMPLE 26
The procedure of Example 24 is repeated except:
In order to achieve a 50mg potency, the caplets are compressed at a compression weight of approximately 207mg, using 5.1 x 11.4mm concave, caplet punches containing a partial scorebar on the upper and lower punches. The aqueous film coat Opadry^- White YS-1-7059 is used for the 50mg potency. Caplets have the resulting composition:
Ingredient 50mg potency caplet
(Core) Weight (mg) per caplet
Bupropion hydrochloride 50.00
Microcrystalline cellulose, NF 137.0
Sodium starch glycolate, NF 7.50
Cysteine hydrochloride, USP 4.50
Talc, USP 6.00
Magnesium stearate, NF 2.00
CORE WEIGHT 207.0mg
(Coating)
Opadry WhiteR, YS-1-7059 6.00
Carnauba Wax, NF 0.02

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TOTAL WEIGHT 213.0mg
EXAMPLE 27
The procedure of Example 24 is repeated except:
The blended powders are granulated with 100% SD3A Alcohol.
EXAMPLE 28
The procedure of Example 27 is repeated except:
The cysteine hydrochloride is blended in dry with the other ingredients rather than
adding it to the granulating solution.
The level of cysteine hydrochloride is increased giving the caplets the following composition:
Ingredient 1 OOmg potency caplet
(Core) Weight (mg) per caplet
Bupropion hydrochloride 100.00
Microcrystalline cellulose, NF 274.0
Sodium starch glycolate, NF 15.00
Cysteine hydrochloride, USP 18.00
Talc,USP 12.00
Magnesium stearate, NF 4.00
CORE WEIGHT 423.0mg
(Coating)
Opadry RedR, YS-1-1846 12.00
Camauba Wax, NF 0.040
TOTAL WEIGHT 435.0mg
EXAMPLE 29

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The procedure of Example 24 was followed except:
Glycine hydrochloride is used as the Stabiliser, giving the caplets the following
composition:

TOTAL WEIGHT 426.0mg
EXAMPLE 30
The procedure of Example 24 was repeated except:
The blended powders were granulated with 100% Isopropyl alcohol.

We claim,
1. A pharmaceutical composition in solid form comprising bupropion hydrochloride
and a pharmaceutically acceptable stabiliser in an effective stabilising amount, in
which the composition contains at least 80% w/w of undegraded bupropion
hydrochloride after storage for 6 weeks at 40°C and 75% relative humidity, an
aqueous solution of the stabiliser in a concentration of 6% W/W having a pH of
0.9 to 4, and the stabiliser being selected from an organic acid, a carboxylic acid,
an acid salt of an amino acid and sodium metabisulphite; with the proviso that a
sustained release tablet comprising (i) bupropion hydrochloridE and
hydroxypropyl methylcellulose, the amount of hydroxypropyl methylcellulose to
the amount of bupropion hydrochloride being from 0.19 : 1 to 1.1 : 1, land (ii)
glycine hydrochloride or cysteine hydrochloride, is excluded.
2. A pharmaceutical composition according to claim 1 wherein the carboxylic acid is
ascorbic or isoascorbic acid.
3. A pharmaceutical composition in solid form comprising bupropion hydrochloride
and a pharmaceutically acceptable stabiliser in an effective stabilising amount, in
which the composition contains at least 80% wlw of undegraded bupropion
hydrochloride after storage for 6 weeks at 50°C and 27% relative humidity, an
aqueous solution of the stabiliser in a concentration of 6% wlw having a pH of 0.9
to 4, and the stabiliser being selected from an organic acid, a carboxylic acid other
than ascorbic acid and isoascorbic acid, an acid salt of an amino acid and sodium
metabisulphite.
4. A pharmaceutial composition according to any one of claims 1 to 3 wherein the
aqueous solution of the stabiliser has a pH of 0.9 to 2.
5. A pharmaceutial composition according to claim 4 wherein the aqueous solution of
the stabiliser has a pH of 1.
6. A pharmaceutial composition according to any one of claims 1 to 5 which contains
at least 95% wlw of undegraded bupropion hydrochloride.
7. A pharmaceutical composition according to any one of claims 1 to 6, wherein the
amount of stabiliser is 2.7% to 27% of the weight of bupropion hydrochloride in
the composition.

25
8. A pharmaceutical composition according to claim 7, wherein the amount of
stabiliser is 5% to 16.2% of the weight of bupropion hydrochloridel in the
composition.
9. A pharmaceutical composition according to any one of claims I and 3 to 8,
wherein the acid salt of the amino acid is cysteine hydrochloride, glycine
hydrochloride or cystine dihydrochloride.
10. A pharmaceutical composition according to any one of claims 1 and 3 to 8,
wherein the organic acid is tartaric acid, citric acid or malic acid.
11. A tablet or capsule comprising a composition according to any one of claims 1 to
10, wherein the amount of bupropion hydrochloride is 50, 75, 100 or 150mg.
12. A method of stabilising bupropion hydrochloride in a solid pharmaceutical
composition, so that at least 80% w/w of bupropion hydrochloride is present in
the undegraded form after storage for 6 weeks at 40°C and 75% relative
humidity, wherein said method comprises mixing bupropion hydrochloridk with a
stabilise, an aqueous solution of the stabiliser in a concentration of 6% w/w
having a pH of 0.9 to 4, and the stabiliser being selected from an organic acid, a
carboxylic acid, an acid salt of an amino acid and sodium metabisulfite.
13. A method as claimed in claim 12 wherein the carboxylic acid is ascorbic or
isoascorbic acid.
14. A method of stabilising bupropion hydrochloride in a solid pharmaceutical
composition, so that at least 80% wlw of bupropion hydrochloride is present in
the undegraded form after storage for 6 weeks at 50°C and 27% relative
humidity, wherein said method comprises mixing bupropion hydrochloride with a
stabiliser, an aqueous solution of the stabiliser in a concentration of 6% wlw
having a pH of 0.9 to 4, and the stabiliser being selected from an organjc acid, a
carboxylic acid other than ascorbic acid or isoascorbic acid, an acid salt of an
amino acid and sodium metabisulfite.
15. A method as claimed in any one of claims 12 to 14 wherein the aqueous solution
of the stabiliser has a pH as defined in claim 4 or claim 5.
16. A method as claimed in any one of claims 12 to 15 wherein the composition
contains at least 95% w/w of undegraded bupropion hydrochloride.

26
17. A method as claimed in any one of claims 12 or 14 to 16 wherein the acid salt of
an amino acid or the organic acid is as defined in claim 9 or claim 10.
18. A method as claimed in any one of claims 12 to 17 wherein the amount of
stabiliser is as defined in claim 7 or claim 8.
19. A method as claimed in any one of claims 13 to 18 wherein theftmount of
bupropion hydrochloride is as defined in claim 1I.

Applicants disclose a stabilized pharmaceutical composition in solid form comprising buproprion hydrochloride, an antidepressant and a stabilizer. Degradation of the buproprion hydrochloride in the formulation is inhibited to the extent that the pharmaceutical formulation will maintain at least 80% of its initial buproprion potency after one year.

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Patent Number

209226

Indian Patent Application Number

00080/CAL/1995

PG Journal Number

34/2007

Publication Date

24-Aug-2007

Grant Date

23-Aug-2007

Date of Filing

30-Jan-1995

Name of Patentee

THE WELLCOME FOUNDATION LIMITED

Applicant Address

UNICORN HOUSE, 160 EUSTON ROAD, LONDON, NW1 2BP,

Inventors:

#	Inventor's Name	Inventor's Address
1	MICHAEL DAVID RUFF	215 BENT CREEK DRIVE,GREENVILLE,NORTH CAROLINA 27834,
2	SANYASI RAJU KALIDINDI	8303, HANA ROAD,EDISON,NEW JERSEY 08817,U.S.A.
3	JOEL ELMORE SUTTON	JR. OF 1 DOGWOOD COURT,GREENVILLE,NORTH CAROLINA 27858,U.S.A.

PCT International Classification Number

A 61 K 31/135

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA