CA2168364C - Stabilized pharmaceutical composition containing bupropion - Google Patents

Stabilized pharmaceutical composition containing bupropion Download PDF

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CA2168364C
CA2168364C CA002168364A CA2168364A CA2168364C CA 2168364 C CA2168364 C CA 2168364C CA 002168364 A CA002168364 A CA 002168364A CA 2168364 A CA2168364 A CA 2168364A CA 2168364 C CA2168364 C CA 2168364C
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acid
hydrochloride
bupropion hydrochloride
stabiliser
pharmaceutical composition
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CA2168364A1 (en
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Michael David Ruff
Sanyasi Raju Kalidindi
Joel Elmore Sutton, Jr.
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Valeant International Bermuda
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Wellcome Foundation Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/26—Psychostimulants, e.g. nicotine, cocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids

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Abstract

This application discloses a method of inhibiting degradation of the antidep ressant bupropion hydrochloride in a solid pharmaceutica l formulation, so that the pharmaceutical formulation will maintain at least 8 0 % of its initial bupropion potency after one year.

Description

~Yo 95~03791 2 1 6 8 3 6 4 PCT/GB94/01642 STABILIZED PHARMACEUTICAL COMPOSITION CONTAINING BUPROPION

The present invention relates to ph~rm~relltical compositions comprising bupropion hydrochloride and a ph~rm~reutically acceptable stabiliser and methods of stabilising bupropion hydrochloride in a ph~rm~ce~ltical composition.

Bupropion hydrochloride is a known antidepless~lL sold in instant release tablet forrn under the brand narne 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 su~e3sil1g prolactin secretion, in plevel~ g filnctio~ p~;,."~nt and drow~hless seen upon ~lminictration of benzodiazepine, in the tre~tm~nt of minim~l brain dysfunction, tardive dyskin~ci~ il"pahed mental alertness upon ingestion of ethanol and psychosexual dysfunction. While the instant release tablets currently sold are quite suitable for the in~ic~t~l1 use, the method of m~nllf~ctllrin~ these is less than desirable based on cost as well as process co~-lhiorl~.

The object of the present invention is to prevent (inhibit) the ~egr~ tion of bupropion hydrochloride, using stabiliser ingredients, thus allowing the ~ lion of ph~rm~re~ltical compositions such as instant and s--~t~ine(l release tablets and c~psl-les which, from a cost of m~nllf~rtllre and processing standpoint, are much improved over those achievable in the past.

Thus the present invention provides a ph~rm~rel~tical composition in solid form comprising bupropion hydrochloride and a ph~ reutically acceptable stabiliser in an effective stabilising amount, in which the composition contains at least about 80% w/w of undegraded bupropion hydrochloride after storage for 6 weeks at about 40C and 75% relative hllmi-lity and in which an aqueous solution of the stabiliser in a concentration of about 6% w/w has a pH of about 0.9 to about 4, the stabiliser being selected from an organic acid, a carboxylic acid, an acid salt of an arnino acid and sodium metabisulphite.

Alternatively. the present invention also provides a pharrnaceutical composition in solid form comprising bupropion hydrochloride and a pharrnaceutically acceptable stabiliser in an effective stabilisin~ amount, in which the composition contains at least about 80%
2 1 6 8 3 6 4 PCT/GB94/01642~

w/w of undegraded bupropion hydrochloride after storage for 6 weeks at about 50C
and 27% relative hllmi~iity and in which an aqueous solution of the stabiliser in a concentration of about 6% w/w has a pH of about 0.9 to about 4 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.

The plcf~ cd pH of the aqueous solution of the stabiliser is 0.9 to about 2 and most preferably 1.

Preferably the ph~rm~reutical composition according to the present invention con~ills at least about 90% w/w of undegraded bupropion hydrochloride after storage for 6weeks under the above conditions and more preferably 95% or even 98%. In an additional aspect, the amount of lln~çgr~ l 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 hllmi-1ity and tcl~l~eldlLIre conditions usually encountered in ph~ ies and me~licine cabinets i.e. room le~ ,.dLul~ and 35-60% hllrni~ y. Thus, when used in a ph~rm~re~ltic~l plc~dlionfor example, a tablet will still retain at least 80% of its potency and preferably at least 90% after one year of storage at room l~ pe.dLul~, (15-25C (59-77F)) at 35-60%hllmi~lity. For example if the tablet initially contains 100mg bupropion hydrochloride (labelled arnount) at time of ~.~p~ ;on, after one year storage at least 80mg oflm~legr~ 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 ph~ e~1tical formulation (composition) in solid form. For example if a forrnulation contains 100mg of bupropion hydrochloride it would preferably contain about 2.7 to 27g of stabiliser.

Stabilisers 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 ylefell~,d examples of stabilisers according to the present invention include: ascorbic acid, malic acid, isoascorbic acid, citric acid and tartaric ~VO 95/03791 21 h ~3 ~ 4 PCT/GB94/01642 acid. L-cysteine hydrochloride and glycine hydrochloride are the most l~rcr~ d stabilisers.

In the examples the cysteine hydrochloride is in the L form and NF and USP are n~tinrls for standards published in the National Formulary and US Ph~ copeia, ~e;~ecli~rely~

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 ~ l ,i..ed as follows:

The stabiliser is weighed out to provide 3.75 grarns 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 resnltinp: llli~Lule is stirred for approximately 5 minl~tss~ using a stir plate and m~gn~tic stir bar. The resulting solution or dispersion is e~rnine~l using either a Orion Model 701A IonalyzerR, or an Accumet pH Meter Model 915. Solutions are stirred with a m~gnPtic stir bar during analysis. Me&~Luclllents of pH are ~clr~ Led in triplicate and the average thereof is used.

Examples of forms of ~rc~,lcd solid ph~rm~rel~tical composition include a tablet or capsule. Such forms are ~paled using standard procedures known in the art which involve admixing bu~o~l;on 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, m~gn~Cium stearate and colloidal silicon dioxide. Caplets are tablets generally shaped in the form of capsules. C~ps~1es of this invention are generally plcp~d by mixing the stabiliser with bupropion hydrochloride and other excipients and placing same in, e.g., a two-part hard gelatin capsule.

Preferably the veight of the inactive ingredients is greater than about I 1/~ times that of bupropion hydrochloride but less than about 4 times that of bupropion hydrochloride.
The tablets or capsules of this invention generall~ contain 25mg to 500mg of bupropion hvdrochloride and usually contain 50mg, 75mg, 1 00mg or 1 50mg of bupropion hvdrochloride. The arnount of bupropion hydrochloride in solid forrn pharrn~e~tical WO 95/03791 2 1 6 8 3 6 4 PCT/GB94/01642~
compositions e.g. tablets after storage, may be detr rnined using standard procedures such as high p.,.rul.llance liquid chromatography (HPLC).

This invention is also directed to a new and improved method for stabilising theantidepr~ss~lt bupropion hydrochloride to prevent the degradation thereof by s~rlmi~cing the stabiliser with bupropion hydrochloride. In this way a ph~rrnsir,e~tical composition is produced in which the l)u~uio~ion hydrochloride is inhibited from degrading thus f~rilitsiting the storage of the composition over a prolonged period of time at room tenl~e,dlul~ i.e. under hllmi~lity and telllpc;ldLule conditions usually encoullL~l~d in ph~...,~cies and in rne~icinr cabinets.

The compositions according to the present invention include those suitable for oral, rectal, topical (including buccal and sublingual) or tr~nccirrm~ lminictration.

The compositions may conveniently be pre3enL~d in unit dosage form and may be prepared by any of the met_ods well known in the art of pharmacy. All methods include the step of bringing bu~ro~uion hydrochloride and the stabiliser into association with a carrier which conetitl-t~s one or more æce~oly ingre~lirntc. In general, the composistions are prepared by ~ ; ru. ll lly and intimsltely bringing bupropion hydrochloritle and the stabiliser into ~Csoçi~tion with a finely divided solid carrier and then? if n~cecc~ y, sh~ring the product.

Compositions of the present invention suitable for oral ~lminictration may be presented as discrete units such as capsules, cslchPts, tablets or lozenges, each co~ lillr a pre~let~-mined amount of bupropion hyd~uchloride and the stabiliser? as a powder or granules including microenr~rs~ erl or time-release forms.

A tablet may be made by co~ rcssion or molding, optionally with one or more accessory ingredients. Com~ sed tablets may be ple~a~ed by co~llpressillg in a suitable m~ inr, bupropion hydrochloride and the phslrm~r,e~ltic~lly 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 m~rhinr 21 G~3~
~VO 95/037g1 PCT/GB94/01642 Compositions suitable for rectal a-lminictration mav be presented as a suppository with a conventional carrier such as cocoa butter, hydrogenated fats or hydrogenated fatty carboxylic acids.

Compositions suitable for topical ~tlmini~tration 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 lT~g~ç~nth, and p~ctilles compri~ing the active compound in a basis such as gelatin and glycerin or sucrose and acacia.

ln addition to the aforementioned ingredients, the compositions of this invention may further include one or more accessory ingredient(s) selected as ~l~lu~liate fromdiluents, buffers, flavouring agents, binders, disintegrants, surface active agents, thirl~eners, lubricants, preservatives (including antioxidants) and the like.

The following examples are represelllaliv~ of the invention.

In the examples, cysteine hydrochloride means L-cysteine hydrochloride.
FX~lVlP~ F. 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 1 72.6mg 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 hydrochloride, microcystalline cellulose and sodiurn starch glycolate were si~ted through a 30 mesh Russell-Finex sifter.

The sifted ingredients were blended for 15 mimltPs in a 3 cu. ft. slant-cone blender.

The blended ingredients were gr~n~ te-l as follows:

The cysteine hydrochloride was dissolved in 1 .28kg of purified water using a T.ightnin'R
Mixer. This cysteine hydrochloride solution was added to 5.12 kg of SD3A alcohol(anhydrous) and mixed thoroughly using a T.i~htnin'R Mixer. The blended ingredients were placed in a 3 cu. ft. Littleford Lodige ~r~n~ tor and g~n~ t~l using the cysteine hydrochloride solution. Mixing time was 3 to 5 minlltes and chopper time was 3 to 5 minllteS. Wetness was checked and additional 80% w/w SD3A alcohol (aqueous) solution was added to achieve a~ ,pl.ate m~c~in~.

Clurnps 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-TracR, 90C) of granule was between 1 to 2%. Fluid-bed dryer parameters were set as follows:

Inlet air te~.lp~.aLLIre: 60C.
Air volume: 200-800 cu meter/hr Pre-heat te.l.p~,dLu.~: 25C.
Dewpoint: 10C.
By-pass flap: 50%
Shaker interval: 5 seconds everv 2 min~ltes 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 ~WO 95/03791 PCT/GB94/01642 the rem~intler of the granule for 5 mimltps~ 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 m~n~sium stearate/colloidal silicon dioxide blend was then added to the dried granule in the 3 cu. ft. slant-cone blender and blended an additional S minlltes The lubricated granule was coll~lessed on a rotary-type Manesty BeL~icssR in a controlled hl-mi~lity environment of less than 30% relative humidity. Tablets were co~ ssed at a co,n~ies~ion weight of about 230mg for the lOOmg potency and about172.6mg for the 75mg potency. Round, 7.8 mm, concave, plain punches were used for the 100mg potency and round, 7.0 mm, concave, plain punches were used for the 75mg potency.

Tablets were ~ lctecl 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 - CotaR parameters were:

Inlet air temperature: 50-80C.
Inlet air volume: 100-500 cfm Fxh~.lct air temperature: 50-60C.

Tablets were coated to a weight gain of 1-5% based on the core tablet weight to achieve an acceptable color intensity.

FXAl~P~.F. 2 The procedure of Example 1 was repeated except that lubricant levels were changed, resulting in the following formulation:

Ingredient l OOmg potency tablet Weight (mg) per tablet Bupropion hydrochloride 100.0 WO 95/03791 PCTIGB941016n~
Microcrystalline cellulose, NF 91.3 Sodium starch glycolate, NF 9.2 L-Cysteine hydrochloride 5.0 Talc,USP 23.0 ~ s;.... st~r~t~, NF 2.4 Colloidal silicon dioxide, NF 0.6 TOTAL 23 1.5 .

F~l~PT.li 3 The procedure of Example 2 was repeated except;

In order to achieve a 75mg potency, the tablets were conl~lcssed 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 Microcrystalline cellulose, NF68.5 Sodiurn starch glycolate, NF 6.9 L-Cysteine hydrochloride 3.8 Talc, USP ~ 17.3 ~n~sium stearate, NF 1.8 Colloidal silicon dioxide, NF 0.5 TOTAL 173.8 ~MP~ ~. 4 Tablets are m~n~l~rtured according to the following forrnul~tion:

Ingredient 100mg potency tablet Weight (mg) per tablet 21 6836~
~O 95/03791 PCT/GB94/01642 g Bupropion hydrochloride 100.0 Microcrystalline cellulose, NF 91.3 Sodium starch glycolate, NF 9.2 Glycine hydrochloride 5.0 Talc, USP 23.0 Ma~lle~ l stearate, NF 1.2 Colloidal silicon dioxide, NF0.32 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 ~ s in a Patterson-Kelly (PK) v-shellblender.

The blended ingredients were gr~n~ t~l as follows:

A quantity of purified water, USP that equals approximately 25% of the total weight of gr~nnl~ting solvent needed to impart the desired granule wetness was weighed out. The glycine hydrochloride was dissolved in the purified water using a T ightnin'R Mixer.
The glycine hydrochloride solution was added to a quantity of SD3A alcohol, anhydrous, equal to the rem~ining 75% of the total weight of solvent needed to impart the desired granule wetness and mixed thoroughly using a r i~htnin'R Mixer. The blended ingredients were placed in a Hobart planetary mixer and gr~nl-l~tec~ using the glycine hydrochloride solution. Mixing and time was approximately 3 to 5 minlltes Granulation wetness was checked and additional 75% w/w SD3A alcohol (aqueous) solution was added to achieve a~p.opliate m~ing.

Any clumps of wet granule were broken up by hand.

Granule was dried in a Despatch Tray Oven to 50C for approximately 4 hours until loss on drying (by Compu-TracR, 90C) of granule vas 1 to 2%.

WO 95/037gl PCT/GB94/01642 ~

Dried granule was sifted through a 20 mesh Russell-Fine~c 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 rem~in~ler of the granule and blended in a PK v-shell blender for 5 ",i....les. Magnesiurn 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 minlltPs This m~gn~cium stearate/colloidal silicon dioxide blend was then added to the granule/talc blend in the PK v-shell blender and blended an additional S minllt~s, The lubricated granule was co~n~l~àsed on a rotary-type Manesty BetapressR in a controlled hnmi(lity environment of less than 30% relative humidit,v. Tablets were com~essed at a col..~,ession weight of 230mg, using 7.8mm, round, concave, plainpunches.

l~,XAMPTIF, :~

The procedure of Fx~mple 4 is repeated except that the lubricant levels are t h~n~e~l resnltinp: in the following forrnulation:

Ingredient 1 00mg potency tablet Weight (mg) per tablet Bupropion hydrochloride 100.0 Microcrystalline cellulose, NF91.3 Sodium starch glycolate, NF 9.2 Glycine hydrochloride 5.0 Talc, USP ?2.9 Magnesiurn stearate, NF 0.7 Colloidal silicon dioxide, NF 0.2 TOTAL 2?9.3mg Tablets are compressed at appro~imately 229.3mg.

~to Y5/037g1 PCT/GB94/01642 F.XAl\IP~ F 6 The procedure of Exarnple 4 is repeated except that the lubricant levels are changed resulting in the following formulation:

Ingredient 1 00mg 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 1.1 Colloidal silicon dioxide, NF 0.2 TOTAL 217.7mg Tablets are co~ ssed at a~lo~ ately 217.7mg.

F'.XAMP~.F. 7 The procedure of Example 4 was repeated except that the lubricant levels were changed resulting in the following fo~rnulation:

Ingredient 100mg 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 21 7.3mg Tablets are co~ essed at approximately 217.3mg F.X~MPT,F 8 The procedure of Example 4 was repeated except m~gn~cium stearate and colloidal silicon dioxide were replaced with sodium stearyl rulll~dte resulting in the following formulation:

Ingredient 100mg potency tablet Weight (mg) per tablet Bupropion hydrochloride 100.0 Microcrystalline cellulose, NF 91.3 Sodium starch glycolate, NF 9.2 Glycine hydro~hlori(le 5.0 Talc, USP 10.9 SodiD stearyl ru~ll~dlt; 3.3 TOTAL 219.7mg Tablets are colllpl~ssed at approximately 219.7mg F,X~MPT.F. 9 The procedure of Example 4 was repeated except that the formulation is changed as follows:

Ingredient 100mg 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.~

~VO 95103791 2 1 6 8 3 6 4 PcT/GBg4l0l6n Glycine hydrochloride 5.0 Talc, USP 23.0 Magnesium stearate, NF 0.8 Colloidal silicon dioxide, NF 0.2 TOTAL 230.0mg Tablets are co~ essed at a~1uxh11ately 230.0mg.

~l~PT.~ l0 The procedure of Example 4 is repeated except sodium starch glycolate is replaced with crospovidone, resulting in the following formulation:

Ingredient 1 00mg potency tablet Weight (mg) per tablet Bupropion hydrochloride l00.0 Microcrystalline cellulose, NF95.9 Crospovidone 4.6 Glycine hydrochloride 5.0 Talc, USP 23.0 Magnesium s~earate, NF 1.2 Colloidal silicon dioxide, NF 0.3 TOTAL 230.0mg Tablets are compressed at approximately 230.0mg F.XAlV~Pr,~, 11 .
The procedure of Example 4 is repeated except that the formulation is changed asfollows:

Ingredient 1 00mg potency tablet WO 95/03791 2 1 6 g 3 ~ 4 PCT/GB94/01642--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 hydrochlori~e ~.o Talc, USP 23.0 Magnesium stearate, NF 1.2 Colloidal silicon dioxide, NF 0.3 TOTAL 230.5mg Tablets were colllplessed at approximately 230.5mg Fx~ pr~ 12 The procedure of Example 11 is repeated except that L-cysteine hydrochloride is replaced with glycine hydrochloride.

FXAl\~PT.F 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 1 00mg 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 '~
Magnesium stearate. NF 1.1 ~10 95/03791 2 1 6 8 3 6 4 PCTIGB94/01642 TOTAL 221.lmg Tablets were col"p,essed at approximately 221.1mg F.X~MPT,~ 14 The procedure of Example 4 was repeated except that the sodium starch glycolate was removed and the formulation follows:

Ingredient 1 00mg potency tablet Weight (mg) per tablet Bupropion hydrochloride 100.0 Microcrystalline cellulose, NF71.0 Corn starch, NF 22.0 L-Cysteine hydrochloride 5.0 Talc, USP 22.0 Magnesium ste~r~te7 NF 1.1 Colloidal silicon dioxide, NF 0.2 TOTAL 221.3mg Tablets were compressed a~ approximately 221.3mg.
A portion of tablets was film-coated using a Compu-Lab Accela-CotaR film-coater.The aqueous film coat Opadrv Red YS-1-1846 wac used for the 100mg potency. The Acella-CotaR parameters were:
Inlet air lelll~eldl lre: 50-80C.
Inlet air volume: 200-1000 cfm Fxh~llct air tel.lpeldture: 40-60C.
Fxh~llct air volume: 200-1000 cfm Tablets were coated to a weight gain of 1-5% over the core tablet weight to achieve an acceptable color intensity.

1~QMG CAPSUT.F.

wo 95~03791 2 1 6 8 3 6 4 PCT/GB94/01642~

F,X~l~'lP~.F. 15 150mg capsules were prepared according to the following forrnulation and procedure:

Ingredient Weight (mg) per capsule Bupropion hydrochloride 150.0 Microcrystalline cell.ltose, NF 106.5 Corn starch, NF 33.00 Talc, USP 33.00 L-Cystein hydrochloride 7.500 TOTAL 330.0mg A stock blend of bu~ro~uion 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 ~ s The proper amount of cysteine hydrochloride was weighed out and added to 85% w/wSD3A alcohol (aqueous) solution. This mixture was vigorously mixed for approximately 5 minlltes It was then irnmediately added to the proper amount of the above mentioned stock blend and wet-gr~nlll~tecl in a table-top Hobart mixer.

The resnlting wet gr~nnl~tion was screened by hand through a 16 mesh screen.

The wet granule was dried in a tray oven at 50C for 4 hours to obtain a loss on drying (LOD) of below 2% using a CompuTracR moisture analyser 90C. (Upon st~ntling thebatches 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 minutPS.

Finished granule is en~ ~ps~ t~l on a Chemi-Pharm manual capsule-filling m~hine Model No. 201, using size No. 1, white, opaque two part hard gelatin capsules.
J

F.XAMP~.F. 16 .

The procedure of Example lS is repeated except cysteine hydrochloride was replaced with glycine hydrochloride.
li.XAl\lP~.h'. 17 The procedure of Exarnple lS is repeated except cysteine hydrochloride was replaced with L-cystine dihydrochlori~1~
~XAMPr.~. 18 The procedure of Example 15 is repeated except cysteine hydrochloride was replaced with tartaric acid.

F~Al~P~.F. 19 The procedure of Example 15 is repeated except cysteine hydrochloride was replaced with citric acid.

F.XAMP~.F. 20 The procedure of Example 15 is ~ e~L~d except cysteine hydrochloride was replaced with malic acid.

F.~l\IPT.F 21 The procedure of Exarnple l S is repeated e~ccept cysteine hydrochloride is replaced with isoascorbic (erythorbic) acid.

F.XAl~IP~.F. 22 WO 95/03791 2 ~ 6 8 3 6 4 PCT/Gs94/01642--The procedure of Example 15 is repeated except cysteine hydrochloride is replaced with ascorbic acid.

FX~MP~.F 23 The procedure of Example 15 is l~e~ed except cysteine hydrochloride is replaced with sodium metabisulfite.

CAPT.~TS

~.X~l~P~ ~. 24 The caplets were m~nllf~ctured according to the following form~ tion:

Ingredient 1 00mg 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, USP9.00 Talc, USP 12.00 Magnesium stearate, NF 4.00 CORE WEIGHT 414.0MG

(Coating) OpadryR Red, YS-1-1846 12.00 C~rn~llha WaY, NF 0.04 TOTAL WEIGHT 426.0 Sufficient powder ingredients were weighed out to make a batch size of approximately 60.000 caplets.

~o 95~03791 2 1 6 8 3 ~ ~ pcTlGs94lol642 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 ~ es in a 3 cu.ft. slant-cone blender.

The blended ingredients were gr~n~ tçri as follows:

A quantity of purified water, USP that equals approximately no more than 20% of the total weight of gr~n~ ting 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 rem~ining 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 gr~nlll~t~cl using the hydroalcoholic cysteine hydrochloride solution. Mixirlg and chopper time was approximately 5-10 minllt~s Wetness was chçcl~e~ and additional80% w/w SD3A alcohol (aqueous) solution was added to achieve al)propliate m~.cing Any clurnps 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-TracR~ 90C) of granule was 0.8-2.0%. Fluid-bed drying parameters were set as follows:
Inlet air tel~l~elaL~Ire: 60C
Air volume: 200-1~00 cu meter/hr Dried granule was milled using a ComilR and a~pro~liately 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 rem~in~er of the granule and blended in the 3 cu.ft slant-cone blender for 5 minutes.

wo 95,037gl 2 1 6 8 3 6 4 PCTtGB94/01642~

The lubricated granule was co.llplessed on a rotary-type Manesty Bc;l~l~,ssR. Caplets were colnplessed at a con.~lession weight of approximately 414 gm. using 6.5 x 14.5 mm concave, caplet punches co~ a partial score-bar on the upper and lower punches.
-Caplets were ~ tec~ using a Manesty Tablet De.lu~

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
pslr~m~?tlor~ were:
Inlet air tell~ dLul~,: 50-80C.
Inlet air volume: 100-500 cfm F.xh~ t air tel~ dlule; 40-60C.

Caplets were coated to a weight gain of 1-5% over the core tablet weight to achieve an acceptable color hllel,sily.

Caplets were coated with c~m~llb~ wax to assist in p~c~ gin~ C~rn~llb?~ wax was added to the film-coated caplets which were rotated in the coating drum for approximately S l~i....lt?s to distribute the wax.

~X~MPI,F. 25 The procedure of Example 24 is repeated except:
In order to achieve a 75mg potency, the caplets are coll,prejsed at a co~ ,ession weight of apl)ru~illlately 310.5mg, using 5.9 x 13.1mm concave, caplet punches co~ 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 res..ltin~ composition:

Ingredient 75mg potency caplet (Core) Weight (mg) per caplet Bupropion hydrochloride 75.00 I~icrocrystalline cellulose, NF 205.5 ~o 95/03791 2 1 6 8 3 6 4 PCT/GB94/01642 Sodium starch glycolate, NF 11.25 Cysteine hydrochloride, USP 6.750 Talc, USP 9.00 Magnesium stearate, NF 3.00 CORE WEIGHT 310.5mg (Coating) Opadry Yellow, YS--1-2186 9.00 C~rn~--ka WaY, NF 0.03 TOTAL WEIGHT 319.5.0mg ~.X~l~IP~.~ 26 The procedure of Example 24 is repeated except:
In order to achieve a 50mg potency, the caplets are co~ ,essed at a colll~lcs~ion weight of approximately 207mg, using 5.1 x 11.4mm concave, caplet punches co~ a partial scorebar on the upper and lower punches. The aqueous film coat OpadryR White YS-1-7059 is used for the 50mg potency. Caplets have the resllltin~ 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 WO 95/03791 2 t 6 8 3 6 4 PCT/GB94/0164Z ~

TOTAL WEIGHT 213.0mg FXAMP~.F.27 The procedure of Example 24 is repeated except:
The blended powders are gr~n~ t~d with 100% SD3A Alcohol.

l~XAl\~Pr F 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 gr~nnl~ting solution.

The levd of .;y~lei,le hydrochloride is increased giving the caplets the following composltlon:

Ingredient 100mg 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 C~rn~lba Wax, NF 0.040 TOTAL WEIGHT 435.0mg FX~MP~ F 29 ~o gs~o37gl 2 ~ 6 8 3 6 4 PCT/GB94/01642 The procedure of F.x~mple 24 was followed except:
Glycine hydrochloride is used as the Stabiliser, giving the caplets the following composition:

Ingredient 1 00mg potency caplet (Core) Weight (mg) per caplet Bupropion hydrochloride 100.00 Microcrystalline cellulose, NF 274.0 Sodium starch glycolate, NF 15.00 Glycine hydrochloride, USP 9.00 Talc, USP 12.00 Magnesiurn ste~r~t~ NF 4 00 CORE WEIGHT 414.0mg (Coating) Opadry RedR, YS-1-1846 12.00 C~ b~ Wax,NF 0.04 TOT~L WEIGHT 426.0mg ~XAl~lPr.~ 30 The procedure of Example 24 was repeated except:
The blended powders were gr~nl-l~tt~l with 100% Isopropyl alcohol.

Claims (30)

1. A pharmaceutical composition in solid form comprising bupropion hydrochloride and a pharmaceutically acceptable stabiliser or a combination of stabilisers in an effective stabilising amount, in which the composition contains at least about 80% w/w of undegraded bupropion hydrochloride after storage for 6 weeks at about 40°C and 75% relative humidity, an aqueous solution of the stabilisers) in a concentration of about 6% w/w having a pH of about 0.9 to about 4, and the stabilisers) being selected from an organic acid, a carboxylic acid, an acid salt of an amino acid and sodium metabisulphite.
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 or a combination of stabilisers in an effective stabilising amount, in which the composition contains at least about 80% w/w of undegraded bupropion hydrochloride after storage for 6 weeks at about 50°C and 27% relative humidity, an aqueous solution of the stabiliser(s) in a concentration of about 6% w/w having a pH of about 0.9 to about 4, and the stabiliser(s) 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 pharmaceutical composition according to any one of claims 1 to 3, wherein the amount of stabilisers) is about 2.7% to 27% of the weight of bupropion hydrochloride in the composition.
5. A pharmaceutical composition according to claim 4, wherein the amount of stabiliser(s) is about 5% to 16.2% of the weight of bupropion hydrochloride in the composition.
6. A pharmaceutical composition according to any one of claims 1 and 3 to 5, wherein the acid salt of the amino acid is a hydrochloride salt.
7. A pharmaceutical composition according to claim 6, wherein the salt is cysteine hydrochloride, glycine hydrochloride or cystine dihydrochloride.
8. A pharmaceutical composition according to claim 7, wherein the salt is L-cysteine hydrochloride or glycine hydrochloride.
9. A pharmaceutical composition according to any one of claims 1, 3, 4 or 5, wherein the organic acid is tartaric acid, citric acid or malic acid.
10. A pharmaceutical composition according to any one of claims 1, 2, 4 or 5, wherein the stabilizer comprises sodium metabisulphite.
11. A pharmaceutical composition according to any one of claims 1, 2, 4 or 5, wherein the stabilizer comprises sodium bisulphite.
12. A tablet or capsule comprising a composition according to any one of claims 1 to 1 l, wherein the amount of bupropion hydrochloride is 25 to 500mg.
13. A tablet or capsule according to claim 12, wherein the amount of bupropion hydrochloride is 25 to 300mg.
14. A tablet or capsule according to claim 12 or 13, wherein the amount of bupropion hydrochloride is 50, 75, 100 or 150mg.
15. A method of stabilising bupropion hydrochloride in a solid pharmaceutical composition, so that at least about 80% w/w of bupropion hydrochloride is present in the undegraded form after storage for 6 weeks at about 40°C and 75% relative humidity, wherein said method comprises mixing bupropion hydrochloride with a stabiliser or a combination of stabilisers, an aqueous solution of the stabiliser(s) in a concentration of about 6% w/w having a pH of about 0.9 to about 4, and the stabilisers) being selected from an organic acid, a carboxylic acid, an acid salt of an amino acid and sodium metabisulfite.
16. A method as claimed in claim 15, wherein the carboxylic acid is ascorbic or isoascorbic acid.
17. A method of stabilising bupropion hydrochloride in a solid pharmaceutical composition, so that at least about 80% w/w of bupropion hydrochloride is present in the undegraded form after storage for 6 weeks at.
about 50°C and 27% relative humidity, wherein said method comprises mixing bupropion hydrochloride with a stabiliser or a combination of stabilisers, an aqueous solution of the stabiliser(s) in a concentration of about 6% w/w having a pH of about 0.9 to about 4, and the stabiliser(s) being selected from an organic acid, a carboxylic acid other than ascorbic acid or isoascorbic acid, an acid salt of an amino acid and sodium metabisulfite.
18. A method as claimed in claim 15 or 17, wherein the acid salt of an amino acid or the organic acid is as defined in any one of claims 6 to 9.
19. A method as claimed in claim 15 or 17, wherein the stabilizer comprises sodium metabisulphite.
20. A method as claimed in claim 15 or 17, wherein the stabilizer comprises sodium bisulphite.
21. A method as claimed in any one of claims 15 to 20, wherein the amount of stabiliser(s) is as defined in claim 4 or 5.
22. A method as claimed in any one of claims 15 to 21, wherein the amount of bupropion hydrochloride is as defined in any one of claims 12 to 14.
23. The use, either alone or in combination, of compounds selected from an organic acid, a carboxylic acid, an acid salt of an amino acid and sodium metabisulfite, an aqueous solution of the compound in a concentration of about 6% w/w having a pH of about 0.9 to about 4, as a stabiliser in the preparation of a pharmaceutical composition containing bupropion hydrochloride, and the composition containing at least about 80% w/w of undegraded bupropion hydrochloride after storage for 6 weeks at about 40°C
and 75% relative humidity.
24. The use as claimed in claim 23, wherein the carboxylic acid is ascorbic or isoascorbic acid.
25. The use, either alone or in combination, of compounds selected from an organic acid, a carboxylic acid other than ascorbic acid or isoascorbic acid, an acid salt of an amino acid and sodium metabisulfite, an aqueous solution of the compound in a concentration of about 6% w/w having a pH of about 0.9 to about 4, as a stabiliser in the preparation of a pharmaceutical composition containing bupropion hydrochloride, and the composition containing at least about 80% w/w of undegraded bupropion hydrochloride after storage for 6 weeks at about 50°C and 27% relative humidity.
26. The use as claimed in claim 23 or 25, wherein the acid salt of an amino acid or the organic acid is as defined in any one of claims 6 to 9.
27. The use as claimed in claim 23 or 25, wherein the stabilizer comprises sodium metabisulphite.
28. The use as claimed in claim 23 or 25, wherein the stabilizer comprises sodium bisulphite.
29. The use as claimed in any one of claims 23 to 28, in which the amount of stabilisers) in the composition is as defined in claim 4 or 5.
30. The use as claimed in any one of claims 23 to 28, in which the amount of bupropion hydrochloride in the composition is as defined in any one of claims 12 to 14.
CA002168364A 1993-07-30 1994-07-29 Stabilized pharmaceutical composition containing bupropion Expired - Lifetime CA2168364C (en)

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TW419370B (en) 2001-01-21
HU223528B1 (en) 2004-08-30
MY128088A (en) 2007-01-31
JP3721192B2 (en) 2005-11-30
GB9315856D0 (en) 1993-09-15
SI0711154T1 (en) 2003-08-31
US5731000A (en) 1998-03-24
IL127919A0 (en) 1999-11-30
NO960373L (en) 1996-01-29
NZ268951A (en) 1997-03-24
EP0711154A1 (en) 1996-05-15
AU698883B2 (en) 1998-11-12
ES2189804T3 (en) 2003-07-16
JPH09506070A (en) 1997-06-17
DE69432121T2 (en) 2003-10-16
HU9501879D0 (en) 1995-08-28
KR100350940B1 (en) 2002-08-30
IL110513A (en) 1999-06-20
SG49790A1 (en) 1998-06-15
DE69432121D1 (en) 2003-03-20
EP0711154B1 (en) 2003-02-12
IL127919A (en) 2003-03-12
WO1995003791A1 (en) 1995-02-09

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