US 2005O112198A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2005/0112198 A1 Challapalli et al. (43) Pub. Date: May 26, 2005

(54) BUPROPION FORMULATION FOR Related U.S. Application Data SUSTAINED DELIVERY (60) Provisional application No. 60/514,722, filed on Oct. (76) Inventors: Prasad V.N. Challapalli, Lexington, 27, 2003. KY (US); Peddanna Gumudavelli, Lexington, KY (US); Ram B. Murty, Publication Classification Lexington, KY (US) (51) Int. Cl." ...... A61K 9/20 Correspondence Address: (52) U.S. Cl...... 424/464 Dr. Prasad V.N. Challapalli Murty Pharmaceuticals, Inc. 518 Code Drive (57) ABSTRACT Lexington, KY 40509 (US) (21) Appl. No.: 10/975,618 Disclosed is a pharmaceutical formulation for the Stabiliza tion and Sustained delivery of an active pharmaceutical (22) Filed: Oct. 27, 2004 ingredient, Such as the antidepressant, bupropion. Patent Application Publication May 26, 2005 Sheet 1 of 2 US 2005/0112198 A1

120

100

80

60

40 -O-Bup. HC SR Bup.XR(resinate) -A-Zyban 20

Time (hr)

Fig. 1 Patent Application Publication May 26, 2005 Sheet 2 of 2 US 2005/0112198 A1

-0-Bup. HCIXR -O-Weilbutrin XL

25

Fig. 2 US 2005/0112198 A1 May 26, 2005

BUPROPON FORMULATION FOR SUSTAINED to possess certain advantages over the immediate release DELIVERY dosage form in controlling Seizures and in improved patient compliance. Bupropion may also preferable over other RELATED APPLICATIONS agents because of its minimal anticholinergic, cardiovascu lar and antihistaminic effects or in those patients who have 0001 Priority is claimed on the basis of U.S. nonprovi experienced weight gain or Sexual dysfunction with another sional application No. 60/514,722, filed Oct. 27, 2003. antidepressant. Regardless of its available form, the Stability of bupropion hydrochloride is affected by a number of FIELD OF THE INVENTION factors, including formulation microenvironment and Stor 0002 The invention relates to a pharmaceutical formu age conditions. It is recommended that immediate and lation for the Stabilization and Sustained delivery of an active extended release tablets be Stored in a tight container at pharmaceutical ingredient, Such as the antidepressant, 20-25 C. and also protected from light and moisture. bupropion. 0007 One of the requirements for an acceptable pharma ceutical composition is that it must be stable, So as not to BACKGROUND OF THE INVENTION exhibit Substantial decomposition of the active ingredient during the time between manufacture and use by the patient. 0.003 For many therapeutics which are administered A number of drugs are known to undergo hydrolytic decom orally, it is preferred that drug molecules be released into the position, which is one of the most common routes of drug body at a constant, or otherwise controlled rate, over a decomposition. Further, hydrolytic decomposition can be relatively long period of time, Such as, for example, 4-8 hrs influenced by light, oxidation and pH. For example, acid or longer. The primary objectives of a controlled release Stabilization of the related compound diethylpropion hydro System have been to enhance Safety and to provide an chloride has been described by Walters (1980) J. Pharm. extended duration of action. Today, controlled release SyS Sci., 69 (10) 1206-1209. Placing bupropion hydrochloride in tems are designed in order to produce more reliable absorp a relatively low pH environment has also proven to be tion and to improve bioavailability and efficiency of deliv effective in Stabilizing bupropion and its major metabolites ery. in human plasma; see Laisure et al. (1985) Ther. Drug 0004 Bupropion is an antidepressant agent that is chemi Monit. 7(4): 447-450. cally distinct from tricyclic and other commercially avail 0008 Certain of the art concerning bupropion formula able antidepressants, e.g. selective serotonin reuptake inhibi tions is discussed below. tors (SSRIs). Bupropion, described in U.S. Pat. Nos. 3,819, 706 and 3,885,046, is currently available as the 0009. In U.S. Pat. Nos. 5,358,970; 5,541,231; 5,731,000 hydrochloride Salt, i.e. as (t)-1-(3-chlorophenyl)-2-(1,1- and 5,763,493 to Ruffetal is described a stabilized bupro dimethylethyl) amino-1-propanone hydrochloride, and is pion hydrochloride formulation having a Stabilizer Selected used as both an antidepressant (Wellbutrin(R), Wellbutrin(R) from group consisting of L-cysteine hydrochloride, glycine SR and Wellbutrin(R) XL) and a smoking cessation aid hydrochloride, malic acid, Sodium metabisulfite, citric acid, (Zybance). Utility in treating attention deficit hyperactivity tartaric acid, L-cystine dihydrochloride, ascorbic acid, and disorder (ADHD) has also been evaluated. Bupropion isoascorbic(erythorbic) acid. U.S. Pat. No. 6,652,882 to hydrochloride is a water Soluble, crystalline Solid having a Odidiet. al describes stabilization of drug by a saturated melting point of 233-234 C. It is highly hygroscopic and polyglycolised glyceride like Gelucire(R). susceptible to decomposition (Walters, S. M., J. Pharm. Sci., 0010. The other acid stabilization strategies of bupropion 1980, 69(10), 1206-1209 and Laizure, S.C., et al Ther. Drug formulation are achieved by inorganic acids like hydrochlo Monit., 1985, 7,447-458). Because of the drug's instability, ric acid, phosphoric acid, nitric acid and Sulfuric acid (U.S. the shelf life of bupropion formulations has proven to be Pat. No. 5,968,553); dicarboxylic acids like oxalic acid, problematic, and those working in the field have tried a Succinic acid, adipic acid, fumaric acid, benzoic acid and number of different approaches to improving the Storage phthalic acid (U.S. Pat. Nos.: 6,194,002; 6,221,917; 6.242, stability of the drug in formulations. 496; 6,482.987 and 6,652,882); sulfites like potassium met 0005 The typical daily dose of burpropion hydrochloride abisulfite and sodium bisulfite (U.S. Pat. No. 6,238,697); to treat depression is in the range of approximately 50 mg to organic esters like L-ascorbic acid palmitate, tocopherol 450 mg, preferably 200 mg to 300 mg. When used as an aid Solution in alcohol, butylated hydroxy anisole, Vitamin E in Smoking cessation (ZybanE), the typical daily dose is in Succinate, Vitamin E 700 acetate, and L-ascorbic acid G the range of approximately 150 mg to 300 mg, available as palmitate are used in transdermal preparations (U.S. Pat. No. extended release tablets. The preferred daily dosage regimen 6,312,716). The use of acidified granules of microcrystalline for treatment of depression is in the range of 50-300 mg, cellulose (U.S. Pat. No. 6,153,223); salts of organic bases available either as an immediate release (Wellbutrin(R) 75 like creatinine hydrochloride, pyridoxine hydrochloride and and 100 mg tablets) or as an extended release preparation thiamine hydrochloride and inorganic acid like potassium meant for twice daily (Wellbutrin(R) SR, 50 mg-200 mg phosphate monobasic (U.S. Pat. No. 6,333,332) is also tablets) or once daily (Wellbutrin(R) XL, 150 mg and 300 mg reported. tablets) administration. However, the exact dosage regimen 0011. There are also acid-free stabilization strategies will depend on a number of factors, including age, the reported based on film coating, involving coating tablet general condition of the patient, and the particular condition cores with hydroxypropyl cellulose and ethyl cellulose (U.S. or disorder. Pat. No. 6,306.436), or by a two layer coating step with ethyl 0006 The bupropion extended release preparations for cellulose, polyvinylpyrrolidone and eudragit L30D-55 (U.S. twice daily or once daily administration may be considered Pat. Nos. 6,033,686 and 6,143,327) or by giving multiple US 2005/0112198 A1 May 26, 2005 coatings onto drug-coated Sugar pellets (U.S. Pat. No. 6,210, concentration of drug dissolved in the aqueous phase. Drug 716), or a triple layer tablet prepared by melt granulation resin complexes often dissolve more slowly than ordinary technique with carnauba wax, Stearic acid and hypromellose drug formulations. Such complexes are useful in changing mixture (U.S. patent application 2003/0134906) and by dissolution profiles and are frequently used in time-release complexation with cyclodextrins (U.S. Pat. No. 6,462,237). formulations. The release of drug can be extended further A capsule dosage form having a mixture of three Separately either by coating of a drug-resin complex or treating the coated drug pellets to provide both immediate and extended complex with polymeric materials. release is also reported (U.S. Pat. No. 6,589,553). 0012 Ludwig et al (U.S. Pat. No. 5,427,798) reported a 0018. Adsorption of the drug onto the ion exchange resin hypermellose (HPMC)-based controlled released prepara particles to form the drug/resin complex is a well known tion of bupropion hydrochloride containing cysteine hydro technique as reported in U.S. Pat. Nos. 2,990,332 and chloride or glycine hydrochloride as Stabilizer, and the 4.221,778. Akkaramongkolporn et. al (Drug Dev. Ind. release obtained is not less than 80% release in distilled Pharm., 2001, 27(4), 359-364) and Sriwongjanya et. al (Eur: water after 8 hrs. J. Pharm. Biopharm. 1998, 46, 321-327, Chem. Pharm. Bull., 2000, 48(2), 231-234) described studies involving 0013 Sustained release oral formulations of bupropion physical mixture of drug and resin in comparison to con hydrochloride are prepared by mixing Stabilized drug with ventional drug-resin complex, Sriwonganya et. al. also various celluloses, alkyl and hydroxy celluloses, carboxy discussed presenting Such complexes along with Suitable alkyl cellulose, polyalkylene glycols and acrylic acids (U.S. excipients to achieve Sustained action of drug from the Pat. Nos. 6,110,973; 6,120,803; 6,153,223; 6,238,697; compressed matrix. 6,333,332; 6,458,374 and 6,652,882) either individually or by combining with control release agents followed by coat 0019 Liquid pharmaceutical compositions comprising a ing the matrix (U.S. Pat. Nos. 6,210,716 and 6,462,237). It drug bound to an ion exchange resin have been known for is also reported based on osmotic effects (U.S. Pat. Nos.: many years. Currently, the list of Such commercially avail able extended release Suspensions from Celltech Pharma, 4,769,027 and 4,687,660/Re 33,994) and sustained action USA, includes Tussionex(R) (Hydrocodone polistirex/Chlor through a transdermal patch (U.S. Pat. No. 6,312,716). pheniramine polistirex), Delsym(R) (Dextromethorphan 0.014 Ion exchange resin compositions containing phar polistirex), and Codaprex(R) (Codeine polistirex and Chlor macologically active ingredients are known and Such com pheniramine polistirex). Other commercially available prod plexes often reported to have various pharmaceutical appli ucts include nicotine, as nicotine polacrileX in chewing gum cations, primarily for taste masking, as release controlling (Nicorette(R), GSK) and lozenges (Commit(R), GSK), and agents in liquid forms, Such as Suspensions, and in tablet phentermine in capsules (Ionamin(R) Celltech Pharma, formulations, as disintegrants, and to a limited extent act as USA). For instance, British patent 869,149 discloses the a controlled release agent. adsorption of ionizable drugs on ion eXchange resins and the 0.015. An ion exchange resin is an ionic, or charged, dispersion of the resultant Solids in a carrier liquid, and compound which has binding sites that can bind or take up German patent, 2,246,037 discloses drug adsorbed on resin an ionic drug. The most common types of an ion exchange particles, which loaded resin particles are then coated with resins are polymers. The size of the ion-exchange resin a water-insoluble film-forming resin Such as a polyacrylic should preferably fall within the range of about 20 to about acid ester. Sellassie et all in EP249,949 have disclosed solid 200 um; particle sizes substantially below the lower limit are compositions comprising ion eXchange resins. difficult to handle in all Steps of the processing. Particle sizes 0020. Other publications disclose further treatment of Substantially above the upper limit, e.g., commercially drug-ion eXchange resin particles 20 in order to improve available ion-exchange resins having a spherical shape and Sustained release characteristics. For example, U.S. Pat. No. diameters up to about 1000 um, are gritty in liquid dosage 4,221,778 to Raghunathan disclosed ion eXchange resin forms and have greater tendency to fracture when Subjected drug complexes treated with an impregnating agent Such as to drying-hydrating cycles. Moreover, it is believed that the polyethylene glycol or propylene glycol prior to coating increased distance that a displacing ion must travel in its with a water-permeable diffusion barrier such as ethylcel diffusion to displace drug out of these large particles causes lulose, the impregnating treatment is Said to prevent Swell a measurable but not readily controlled prolongation of ing and fracturing of the resin particle in Solutions and to release even when the drug/resin complexes are uncoated. improve coating ability. EP 171,528 and U.S. Pat. No. 0016 Amberlite(R). IRP-69, a cationic exchange resin 4,847,077, to the same inventor, disclose a similar resin (obtained from Rohm and Haas), is a sulfonated polymer treatment using glycerine to improve coating ability. EP composed of polystyrene cross-linked with 8% divinyl ben 254,811 and EP254,822, both to Raghunathan and Chow, Zene, with an ion exchange capacity of about 4.5 to 5.5 disclose similar impregnation of Sulfonic cation exchange med/g of dry resin (H+ form). Amberlite(R). IRP-69 consists resin with agents such as hypromellose (HPMC) and with of irregularly shaped particles with a size range of 47 to 149 high molecular weight polymers, to improve coating ability. um, produced by milling the parent, large sized spheres of U.S. Pat. Nos. 5,071,646 and 6,077.532 reported the use of Amberlite(E) IRP-120. a Sugar Solution as granulating fluid to improve the Strength of the drug-resin particles. EP 139,881 and U.S. Pat. No. 0.017. In general, a drug is mixed with an aqueous Sus 4,762,709 by Shumaker discloses compositions in which all pension of the resin, and the complex is then washed and ionic components having the same charge are present as dried. Adsorption of drug onto the resin may be detected by resin complexes, thereby overcoming variations in the dis measuring a change in the pH of the reaction medium or by Solution profile caused by ionic Substances in the formula other changes in physical properties or by a decrease in tion. US 2005/0112198 A1 May 26, 2005

0021. A dextromethorphan hydrobromide controlled 0028 (i) physical mixing or treating burpropion release Syrup Suspension was achieved by complexing with hydrochloride with a pharmaceutically acceptable Amberlite(RIRP-69 (U.S. Pat. No. 4,788,055), and a similar Stabilizer(s) either alone or in combination of Suit preparation was also reported involving coating drug-com able stabilizers in an effective amount. The method plex particles followed by mixing with uncoated drug/resin utilizes either dry blending or granulation of bupro material (U.S. Pat. No. 6,001,392). Various liquid prepara pion hydrochloride with Suitable pharmaceutical tions based on ion exchange resins have also been reported excipients, Stabilizer and agent(s) for controlled (U.S. Pat. Nos. 4,762,709; 5,368,852 and 6,514,492). release of the drug. 0022. A stable Sustained release wax and polymer-coated 0029 (ii) the addition of an ion exchange resin drug-ion eXchange resin complex useful in preparing oral particles to the aqueous Solution of bupropion hydro suspension has also been reported (U.S. Pat. Nos. 4,999,189 chloride to facilitate the formation of drug-resin and 5,186,930). Drug-resin complexes coated with water complex and dried. The complex achieved is mixed insoluble polymers to achieve Sustained action for oral with Suitable pharmaceutical excipients and a con administration are reported (U.S. Pat. Nos. 4.996,047; 5,288, trolled release agent(s) either by physical mixing or 503; 5,413,782 and U.S. patent application 2003/0099711). by granulation followed compression/filling to A pharmaceutically acceptable preservative and a chelating achieve a stable and Sustained release dosage form. agent have also been added to effect drug-resin complex stabilization (U.S. Pat. Nos.: 4.894,239; 5,368,852; 5,980, 0030 (iii) physical mixing or treatment of ion 882 and 6,001,392). A sustained release opioid preparation eXchange resin particles with other Suitable pharma without any coating has also been reported (U.S. patent ceutical excipients and chosen Stabilizer(s) alone or applications 2002/0164373 and 2003/0118641). Various in combination, optionally included the active drug ophthalmic preparations based on ion exchange resin com also for Such dry mixing or granulation and dried. positions have also been reported (U.S. Pat. Nos. 5,182,102; The treated mixture has been compressed/filled in to 5,296,228; 5,540,918; 5,837,226; 6,022,533 and 6,258,350). tablets/capsules by mixing with Suitable glidants and lubricants to achieve desired release. 0023. In-house studies showed that the salt form of bupropion is stable in normal Storage conditions but can 0031 (iv) coating of the stabilized or un-stabilized degrade easily in the presence of Standard excipients used in dosage form with a film Surrounding the core which commercial formulations. The presence of Such excipients optionally may have added stabilizer(s) to offer can contribute significantly to increase the overall moisture additional control over its release and in maintaining level and hence facilitate forced degradation of the active the Stability of the preparation during its Storage. pharmaceutical agent unless it is protected. An object of the invention is therefore to increase the Stability of active drug 0032. An object of the invention is to provide a release of while controlling its release from the dosage form to obtain bupropion hydrochloride from uncoated/film coated bupro pion HCl SR dosage form, of not less than 25% in 1 hr., not a desired release profile. more than 85% in 4 hr and not less than 80% in 8 hr in a dissolution test conducted at 37 C. in distilled water as per BRIEF DESCRIPTION OF THE DRAWINGS USP27. Bupropion HCl SR and bupropion HCl XR dosage 0024 FIG. 1 shows a comparative dissolution test pro forms when tested in 0.1N HCl buffer, the release after 1 hr files of twice-daily tablet formulations according to the should be not more than 50%, after 4 hr should not be more invention (Bupropion HCl SR and Bupropion XR (resinate), than 85%, and after 8 hr should not be less than 80%. 150 mg each) vs. Zybance (150 mg) in water. Another object of the invention includes providing a release of bupropion hydrochloride from enteric coated bupropion 0.025 FIG.2 shows a comparative dissolution test profile HCl XR dosage form, less than 10% in 2 hr., not more than of a once-daily tablet formulation according to the invention 60% in 4 hr, not less than 60% in 8 hr and not less than 80% (Bupropion HCl XR, 150 mg) vs. Wellbutrin(R) XL (150 mg) in 16 hr in a dissolution test conducted at 37 C. similar to in mixed acid and phosphate buffer medium. the procedure mentioned for enteric coated tablets as per USP 27. SUMMARY OF THE INVENTION 0033. An object of the invention is to provide a release of 0026. An object of the invention is to provide a bupro bupropion from uncoated/film coated bupropion XR resinate pion hydrochloride pharmaceutical composition preferably formulation, of not more than 50% after 1 hr., not more than for controlled or Sustained release that is Stabilized alone or 85% after 4 hr, after 8 hr should not be less than 80% in a in combination of an added Stabilizer(s) or by an cation dissolution test conducted at 37 C. similar to the procedure eXchange resin. Protection may be conferred by an addi mentioned for enteric coated tablets as per USP27. From the tional coat Surrounding the Stabilized/un-Stabilized core bupropion XR resinate dosage form when enteric coated the wherein the film optionally contains Stabilizers to facilitate release of bupropion should be less than 10% in 2 hr., not both enhanced Stability to the preparation and to provide more than 60% in 4 hrs, not less than 60% in 8 hrs and not control over the release of the active ingredient, where it less than 80% in 16 hr in a dissolution test conducted similar contains at least about 80% potency of undegraded burpro to the procedure mentioned for enteric coated tablets as per pion hydrochloride after Storage for three months at about USP 27. 40° C. and 75% RH. 0034. The invention is described below in connection 0.027 Stabilization of the active ingredient, according to with its applicability to bupropion. However, the invention the invention, comprises, for example, any of the following relates additionally to the formulation of other pharmaceu four processes: ticals, Such as any acidic or basic drug, which can be bound US 2005/0112198 A1 May 26, 2005 to an ion exchange resin or can be Stabilized by chosen 0042. The term “sustained release' is used in its conven Stabilizer(s) alone or in combination for the purpose of tional Sense to refer to a drug formulation that provides for Stabilizing the formulation or to mask the taste or any other gradual release of drug over an extended period of time, useful applications known in that art with Such combina which results in substantially constant blood levels of drug tion(s). The invention is particularly well Suited to water over an extended period of time. Soluble drugs, but is useful for Sparingly water-Soluble drugs. 0043 “Enteric coating” or “enterically coated” as used herein relates to the presence of polymeric materials in a 0.035 A formulation according to the invention is also drug formulation that results in an increase in the drug Suitable to achieve desired drug release pattern for any drug resistance to disintegration in the Stomach. which is soluble or slightly soluble by carefully manipulat ing the chosen controlling agents along with other Suitable 0044) The term “resinate” which refers to any drug-resin excipients where Such type of release is recommended for its complex that would have formed by a proceSS in which drug intended pharmacological action or to limit any drug related gets loaded onto any resin preferably in presence of a side effects or any known benefits it offers to the patient. The Solution. Such complex is washed at the end of loading, dosage form is also include a Suitable coating film Surround dried and Stored as needed. ing the core to offer additional assurance either in terms of 0045 According to the invention, an active pharmaceu release or making the preparation more Stable during its tical agent, Such as bupropion hydrochloride, is presented in Storage. a dosage form in any of the following manners: (a) drug is in association of Stabilizer(s) alone or in combination of DETAILED DESCRIPTION OF THE Suitable Stabilizers and/or with excipients treated or granu INVENTION lated with Stabilizers; (b) drug is in association of ion 0.036 The invention provides, for example, a stable for eXchange resin which is complexed to form a resinate mulation of bupropion hydrochloride that releases the medi mixture and further granulated with suitable binder(s) either cament in a controlled manner after oral administration to alone and/or with Suitable excipients; (c) drug is co-mixed provide a desired therapeutic effect to a human patient. Such with ion exchange resin and Suitable excipients followed by a formulation comprises, for example, a core consisting of treating or granulating Such mixture with a Solution of an active drug, a Stabilizer, a controlled release agent, a Stabilizer(s); (d) drug is directly mixed or granulated with pharmaceutically acceptable diluent, a glidant, and a lubri Suitable excipients. Cant. 0046) In-house studies showed that the salt form of bupropion is stable in normal Storage conditions but can 0037 Unless otherwise stated, the following terms have degrade easily in the presence of Standard excipients used in the meaning Set forth below. Notwithstanding the foregoing, commercial formulations. The presence of Such excipients should any of the meanings set forth below conflict with the can contribute significantly to increase the overall moisture meaning of that term as that term is conventionally used in level and hence facilitate forced degradation of the active the pharmaceutical arts, the meaning of that term as that pharmaceutical agent unless it is protected. An object of the term is conventionally used in the pharmaceutical arts shall invention is therefore to increase the Stability of active drug control. while controlling its release from the dosage form to obtain 0038. The term “optional” or “optionally” means that it a desired release profile. may or may not be obvious about its addition to the 0047 Oxidation of organic materials has been widely formulation however it can be added as the situation known in the area of drug research and is usually Studied demands depending on the release pattern aimed from the with help of pure Systems or simple mixtures at extreme dosage form. conditions. It is usually difficult to predict causes of Such 0.039 The term “pharmaceutically acceptable” excipients behavior in a complex pharmaceutical System with vastly means a material may be administered to an individual along different physicochemical properties where drug can exist in with the active agent without causing any undesirable bio crystalline or amorphous form along with excipients of logical effects or interacting in a deleterious manner with different physical nature. This mixture is often subject to any of the other components of the pharmaceutical compo various mixing methods like trituration, blending, compac Sition in which it is contained and these includes, diluents, tion or compression process to induce more physical binders, lubricants, fillers, coloring agents, Stabilizers, ion changes into the overall matrix properties. Oxidation in pure eXchange resins, plasticizers, opacifiers and other Such Solid requires that an oxidizing agent be present in the agents known in the art. System for reaction to occur. Molecular oxygen from the atmosphere has been shown to react with organic materials. 0040. By the term “therapeutically effective amount” of This reactivity depends on the morphology of crystal form, an agent as provided herein are meant a non-toxic but which governs the permeability and Solubility of oxygen in Sufficient amount of the agent to provide the desired thera the crystal matrix. In Some cases, reactivity decreases with peutic effect. The exact amount required will vary from increasing melting point Suggesting that Stronger crystal Subject to Subject depending on age, general condition of the lattice energies inhibit oxygen diffusion. Free radicals are Subject, the Severity of the condition being treated. known to form in crystalline Solids, which can react with 0041. The term “controlled release” is intended to refer to molecular oxygen to form reactive and diffusible oxygen any drug-containing formulation in which release of the Species Such as Superoxide anion or peroxyl radical. These drug is not immediate i.e., with “a controlled release for reactive species can abstract hydrogen atoms at reactive mulation', oral administration does not result in immediate positions on drugs or induce electron transfer from a drug release of the drug into absorption pool. (Waterman K. C., et. al. Pharm. Dev. Technol., 2002, 1-32). US 2005/0112198 A1 May 26, 2005

0.048. In many cases like the bupropion hydrochloride, more readily to Scavenge the oxygen than the drug. This pure drug Substance is quite Stable, while the dosage form Strategy can be especially effective in Systems where the shows Significant drug oxidation. This difference in reactiv amount of oxygen present is limited due to packaging. In ity is generally attributable to amorphous nature of drug or Some cases, this class of antioxidants can be problematic in moisture content of the excipient or due to the impurities the presence of metals since the drug reducing agents can present in the excipient. Firstly, during the processing of Sometimes reduce metals to more reactive forms. Therefore, drug to form a Solid dosage form, it is possible to mechani enough precautions should be taken to handle Such situa cally generate a Small percentage of amorphous drug to tions. cause Stability issues. Amorphous drug regions have both greater mobility and high energy but lack crystal lattice 0050. The environment of pH can play a significant role Stabilization energy, and as a result, oxygen permeability in the Stabilization of drugs to oxidation. It is in general more and solubility will be higher. Any fortuitous radical-pair difficult to remove an electron from a drug when it is initiation is more likely to lead free radicals, which can react positively charged. For this reason, drug Stability against with oxygen in a chain process to make the degradation oxidation is often greater under low pH conditions, which process faster. Secondly, excipeints can potentially Solvate promote protonation of drugs if porotonation is possible. In Some of the drug either directly or by bringing in low levels the converse, higher pH conditions, which deprotonate a of moisture. In a solid solution form, the drug will be drug, generally make the drug more Susceptible to oxidation. amorphous and Such Solvation Step can result in drug With the solid dosage forms, the addition of buffers can be deprotonation to make a drug more reactive and unstable. quite complex. In order them to be more effective it is Thirdly, the excipients can be a Source of oxidants and advisable to add them during wet granulation or by coating metals act often as catalysts rather than consumed even at of particles using fluid bed technology. low levels. Typically, iron and copper are the two metals of 0051. The success of any sustained release or controlled most concern. Alternatively, oxidation is also related to delivery of a drug is achieved by using polymeric excipients highly reactive impurities like peroxides, Superoxides, to control the rate that an active drug is introduced to the hypochlorites and formic acid present in the excipients as targeted delivery Site. The exact mechanism by which a manufacturing related impurities (Hartauer, K. J., et. al. polymer controls the delivery of the drug is dependent on the Pharm. Dev Technol., 2000, 5, 303-310). Mostly, the per rate of polymer hydration and Swelling which is related to its oxides and other oxidants are introduced during the polymer molecular weight. Therefore, any process that significantly manufacturing process including the polymer initiation and reduces the molecular weight of the polymer is likely to purification. Peroxides are used Sometimes as initiators in affect its ability to control the drug delivery. Oxidative polymerization and are difficult to remove completely dur degradation can lead to a loSS in molecular weight for ing the purification processes. For example, it is easily found Several polymers commonly used in controlled release appli in polyethylene glycols, tweens and polyvinylpyrrolidone. cations. In addition to loSS in molecular weight Such deg In Some cellulose based excipeints, a peroxide or hypochlo radation in polymers as mentioned can produce reactive rite bleaching process is used that can allow trace peroxides impurities and end groups to compromise the chemical or hypochlorite to remain in the excipient. In the case of Stability of drugs and also their effectiveness as release polyethylene oxides, high molecular weight material is controlling agents. An example of class of controlled release prepared and then oxidatively degraded to give the desired polymers that can degrade to compromise the drug release molecular weight range. This degradation leads to peroxides rate is the polyoxyethylenes, including poly(ethylene and other low molecular weight Species Such as formate oxides) (PolyoxCF), poly (ethylene glycols), and poly (oxy ions. Aldehyde impurities can also induce drug oxidation in ethylene) alkyl ethers. The polyethylene oxide has been Some cases. In the Solid State, Such chain propagation is treated by manufacturer (Dow chemicals) with 100-1000 hindered by low mobility and such reactions tend to occur ppm of butylated hydroxy toluene (BHT) to reduce such over extremely short distances with fewer chain propagation degradation. This antioxidant is quite effective, however, it StepS. is volatile and can be lost during any heating Steps. In the proposed invention, an additional amount of butylated 0049. The possible strategy to terminate such propaga hydroxyl toluene is used to minimize Such loSS and is also tions includes the addition of chelating agents to the formu combined with butylated hydroxy anisole (BHA) or propyl lation to prevent metal induced oxidation. These include gallate to obtain Synergistic action. citric acid, edetic acid, fumaric acid and malic acid. They can be more effective when added during granulation Step 0052 Appropriate packaging can represent a reasonable than in a physical mix form. In cases, where peroxides are option for Stabilization of the drug against molecular oxygen believed to be the problem it can be overcome by enforcing and light. When drug instability especially caused by atmo Strict quality measures at the time of choosing them or to Spheric oxygen, the amount of headspace available and restrict usage of Such excipients to minimum possible oxygen permeation through the container walls and caps of amounts in the dosage form. Use of antioxidants, which can the packaging System plays a vital role. For most plastic reduce formation of peroxides will be helpful but may be containers, the rate of oxygen permeation can be significant. less effective at elimination of peroxides already present in For example, low density polyethylene (LDPE) and poly a dosage form. Currently, the marketed bupropion hydro Styrene container are more permeable than high density chloride(Zyban(R) and Wellbutrin(R) SR) is stabilized with an polyethylene (HDPE), polypropylene, polyvinyl chloride, antioxidant like L-cysteine hydrochloride. The chain lengths polycarbonate, polyethylene terephthalate (PET), wherein as mentioned are generally shorter in Solid dosage forms the rate of permeation decreases in the order they were than in liquids, the concentration of antioxidant may need to listed. The Oxygen leakage through container top can be be higher to intercept radicals. Sacrificial reductants like countered by heat induction Sealing. The above approaches Sulfites and ascorbic acid are compounds that are oxidized are appropriate for maintaining product Stability until the US 2005/0112198 A1 May 26, 2005 containers are opened for the first time for dispensing, and of forming a complex with a cation eXchange resin for both it is possible for a Sensitive product to lose its characteristics Stabilization and Sustained release. Protection of the drug thereafter. To avoid Such situations, especially in Sensitive with various Stabilizers involves a mechanism of Shielding products like orally or rapidly disintegrating tablets, a blister the drug molecule from degradation through the use of packaging of individual doses is preferred, even though the reductants, chelators, or Substances helpful in maintaining a proceSS is not cost effective but it can offer better product low pH environment recommended for drug stability by Stability. It is Sometimes feasible to blister package under various reported studies (Walters, S. M., J. Pharm. Sci., nitrogen or argon to reduce the head Space oxygen. 1980, 69(10), 1206-1209). 0053. In order to study the compatibility of various 0056 Ion-exchange resins suitable for use in these prepa excipients used in the proposed invention with bupropion rations are water-insoluble and consist of a pharmacologi hydrochloride, various drug-excipient mixtures were pre cally inert organic or inorganic matrix containing covalently pared. The each excipient amount relative to drug varied bound functional groups that are ionic or capable of being from 1:1 to 1:10. Such mixtures were prepared, by mixing ionized under appropriate conditions of pH. them in a pestle and mortar, and transferred to glass Vials and either closed with a rubber Stopper or Studied in an open 0057. A wide range of cationic (for basic drugs) or condition at 50 C/75% RH and 40 C./75% RH. As anionic (for acidic drugs) exchange resin can be used to form predicted with the active drug, it has been observed during a drug-resin complex, with particle sizes normally ranging their analysis at various time intervals by liquid chromatog from about 75 to 1000 um. Illustrative examples employ raphy that most of the excipients Studied are causing deg Amberlite IRP69, which is a milled product of 100-200 radation of the active drug with a result of two distinct mesh size resin particles of Amberlite IR-120, as a model degradation peaks, in which all cellulose based excipients Small particle resin. It is a gel type divinylbenzene Sulfonic considered to be interacting uniquely with the pure drug acid cation exchange resin, which Swells in water with a pH compared to non-cellulose based excipients. In the case of range of 0-14. Ion-exchange resins useful according to the hydroxypropyl cellulose, polyethylene oxide and Sodium invention have eXchange capacities below about 6 med/g carboxymethyl cellulose, rapid degradation was found rela and preferably below about 5.5 med/g. tive to other excipients, with noticeable visual/odor/color 0058 Drug-resin complex was formed by a step-wise changes in the prepared mixtures. The above changes were method, where resin particles, of proportion 0.25 to 2.0 parts more pronounced in Samples Studied under open conditions relative to 1 part of drug, were added at each Step to an compared to closed condition samples. A minimum amount aqueous drug Solution having an initial concentration of or no change was observed with polyvinyl acetate-polyvi about 100-300 mg/ml, and the contents stirred for 2-4 hr nylpyrrolidone coplymers (Kollidon(R) VA64 and Kollidon(R) until equilibrium was attained in the Solution. Samples SR), methylcellulose, colloidal Silicon dioxide, magnesium collected at various intervals were allowed to Settle, filtered, Stearate, enteric coating materials Such as hypromellose and diluted with water for measurement of absorbance by pthalate, hypromellose Succinate and polyvinylacetate UV spectrometry at 298.0 nm. Drug-resin mix solution was phthalate. Such degradation could be due to impurities like allowed to Settle at the end of each Step and decanted into a peroxide, heavy metals and bleaching agents present in Such Separate container. A quantity of fresh resin, in appropriate materials. Even though Such impurities are present within proportion, was added to the decanted Solution to adsorb the acceptable limits, the moisture content carried in them remaining amount of drug; these Steps were repeated until should have acted as Solvent to aggravate Such reactions. In complete adsorption of drug from the Solution onto the resin addition, the proportions according to the invention are had taken place. Usually, complete drug adsorption (>98%) Slightly higher than the required amounts in the actual onto resin was achieved in 3-4 Steps. To achieve that, the dosage form but certainly the above information helps in total added resin quantity varied anywhere from 0.5 to 5.0 minimizing their usage quantities to make the dosage form parts relative to 1 part of drug. The drug loaded resin more Stable. Hence, pure drug is treated with chosen Stabi particles collected at various Stages were combined and lizers and continued the remaining Studies under closed washed in distilled water by stirring for 2-4 hr to remove conditions. The package component Seems to play a vital loosely/Surface bound drug molecules, and Such amounts role for Stabilizing the dosage form: high-density polyeth were estimated by measuring absorbance of the wash Solu ylene (HDPE) containers with additional thickness/weight tion. The washed particles were dried overnight at 50 C. are preferred apart from maintaining Sufficient quantity of and Stored in a tight container; assay was performed by adsorbent added to the packaging System to minimize mois HPLC to confirm the percentage of drug loading onto resin. ture and oxygen/odor levels. It has been observed from applicants’ experience that Step 0.054 Protection of a drug molecule according to the wise loading of drug onto resin particles gave better adsorp invention includes not only minimization of potentially tion yields than adding all the required amount of resin at deleterious drug-excipient interactions, by making drug once to the drug Solution. The dried resinate is useful for molecule more Stable by treating with various Stabilizers, making controlled release formulations according to the but also presentation of drug molecule in a Suitable complex invention. The ratio of drug to resin in Such a complex is or physically mixed form with ion eXchange resin, in addi from about 1:0.5 to 1:5, and preferably from about 1:0.5 to tion to packaging of the final product in a packaging System about 1:3. with desiccants having Sufficient adsorbent capacity to offer 0059. In certain formulations, ion exchange resin is also resistance to permeation of moisture, oxygen, light and by added directly to the free form of a drug, without any any other agents known to degrade the molecule. complex formation, to achieve formulations performing 0.055 An ion-exchange resin is a useful excipient accord Similarly to the resinate under certain circumstances, thus ing to the invention, as bupropion hydrochloride is capable greatly simplifying the manufacturing and regulatory US 2005/0112198 A1 May 26, 2005 aspects, in comparison to resinate-based formulations. For 0062) A stabilized active drug molecule, formed by mix mulations made by Such direct addition may release drug ing active drug either with ion-exchange resin or with other more rapidly, due to weak drug-resin bonding, but release Stabilizers in the form of treated/coated, complexed or characteristics are also manipulated with various controlled physically mixed form, according to a procedure as release agents according to the invention to achieve the described above, is used for making a controlled release desired release from the dosage form. The ratio of drug to formulation of the active drug molecule after mixing with resin in such a physical mix is from about 1:0.01 to about pharmaceutically acceptable excipients. The mass of active 1:0.5, and preferably from about 1:0.03 to about 1:0.4. pharmaceutical agent, whether it be in a pure form, a Salt form or in a complex, ranges from 25 mg to 300 mg. The 0060 Among the ion exchange resins useful in the proportion of active pharmaceutical agent in a final dosage present invention are Styrene-divinyl benzene copolymers form, said final dosage form consisting essentially of active (e.g. IRP69, IRP120, IRP400 and IRP67, Rohm & Haas), pharmaceutical agent, excpients, and any adventitious mate copolymers of methacrylic acid and divinylbenzene (e.g. rials, is from about 10% to about 80% w/w, and preferably IRP 64 and IRP88, Rohm & Haas), phenolic polyamines from about 15% to about 60%. (e.g. IRP58, Rohm & Haas) and styrene-divnylbenzene (e.g., colestyramine resin) and Similarly various type of 0063 A resinate-based formulation of bupropion hydro resins available as DOWEX(R) series (Dow Company). The chloride according to the invention is preferably granulated drug and resin Should be oppositely charged Such that the with a binder to improve the hardness of the formulation. drug will bind to the resin in the dissolved drug solution. Resinate particles are very fine and hence not easily com Since bupropion hydrochloride is a basic drug, it is preferred pressible, especially when the resinate proportion is more that the ion eXchange resin for a buproprion formulation than 60% w/w in the formulation; some segregation of according to the invention be cationic in nature, and more materials may occur, due to different particle sizes of other preferably be strongly acidic in nature. For formulation of excipients added to the final blend. In Some cases, it is another active pharmaceutical ingredient, is possible to use possible to achieve Some minimum hardneSS without granu lation by addition of binders of a certain type, which was other types of ion exchange resins Such as anionic type (e.g. found to contribute significantly to overall hardness of the duolite AP 143, Rohm & Haas) known in the art depending final product. But this makes it difficult to achieve the final on the Specific needs of application and drug nature. A target weight of the product, as they have to be added in preferred ion eXchange resin for a buproprion formulation Sufficiently large quantities to achieve Such desired objec according to the invention is Amberlite IRP 69 or any other tive. Otherwise, they will fail to withstand a coating process equivalent form of resin. for lack of Sufficient hardness. 0061 The invention provides a stabilized bupropion for 0064. The invention also provides a formulation of mulation for oral administration; Said formulation comprises bupropion hydrochloride comprising an ion exchange resin, Stabilizers to inhibit or prevents the degradation of active the formulation manufactured by admixing free buproprion drug. Stabilizers useful in accordance with the present with the ion exchange resin and a Suitable binder, controlled invention maintain at least about 80% of the potency of the release agent, glidant and lubricant. Optionally, Such a drug and preferably over 90% of potency after three months formulation is granulated and a pore forming agent is also storage at 40 C./75% RH. The mechanism of stabilizing the included, depending on the release requirements of the active drug by chosen Stabilizers other than drug-resin designed dosage form. complex form involves Shielding the drug molecule by their anti-oxidative property, chelating action or they are helpful 0065. When the active drug is stabilized with other than in maintaining a low pH environment around the drug ion eXchange resins, the Stabilizier-treated active drug is molecule. The chosen stabilizers were preferably solubilized mixed with a diluent/binder, a controlled agent and either in a Suitable Solvent System Such as water, hydro-alcoholic blended or granulated with an aqueous, hydro-alcoholic or mixtures or in non aqueous Solvents and used to treat the non-aqueous Solvent mixture as demanded by the properties drug particles or excipients. In Some situations, Such as of the chosen materials. Optionally, an ion eXchange resin or when the Stabilizer is hydrophobic in nature, treatment/ a pore former is also included. coating of drug particles with Stabilizer Solutions is found to 0066 Abinding agent according to the invention is water influence the Solubility/release of the drug in dissolution Soluble, and should possess high adhesivity and an appro medium. In those conditions, a Solution of Such Stabilizer is used initially to treat/coat the Suitable excipients of the priate Viscosity, to guarantee good adhesion between the formulation and further granulated/blended with other ingre drug/resinate particles and other added excipients of the dients and active drug as needed. Stabilizers are often formulation. According to the invention, Such a binding directly mixed with active drug and other excipients of the agent also functions as a diluent in that it acts to impart formulation to achieve a controlled release dosage form. cohesive qualities to the material within the formulation and Preferred stabilizers according to the invention are butylated also to increase the bulk weight of the directly compressible hydroxy anisole (BHA), butylated hydroxy toluene (BHT), formulation, to achieve an acceptable formulation weight for toluene Sulfonic acid, disodium edetate, edetic acid, lactic direct compression. In situations where there is a need for acid, maleic acid, propyl gallate, Sodium formaldehyde immediate availability of active drug, a pore-forming agent Sulfoxylate, benzoic acid and aspartic acid. It is possible to is also included in the dosage form. A main function of Such use other Stabilizers known in the art depending on the a pore-forming agent is to create a pore in the matrix Specific needs of the particular application and the nature of predominantly due to the freely Soluble nature of Such an the drug. The proportion of Stabilizer(s) in a formulation agent in aqueous medium or in the gastrointestinal contents. according to the invention is from about 0.001% to about 5% 0067. Therefore, a diluent according to the invention w/w, and preferably from about 0.001% to about 3% w/w. possesses the property of being a binder or a pore-forming US 2005/0112198 A1 May 26, 2005 agent. The following materials commonly known in the art matrix erosion proceSS and thus delaying the overall disso to perform/exhibit Such function include Starch, pregelati lution rate of drug from the dosage form nized Starch, microcrystalline cellulose, Silicified microcryS talline cellulose, dibasic calcium phosphate anhydrous, 0070 A preferred glidant or lubricant according to the powdered cellulose, alginic acid, povidone, chitosan, cara invention is colloidal Silicon dioxide, talc, magnesium Stear geenan, guar gum, Xanthan gum, polyethylene oxide, Sub ate, calcium Stearate, Stearic acid or Sodium Stearyl fumarate. Stituted copolymes of polyvinylacetate-polyvinyl pyrroli The proportion of glidant and lubricant present in the dosage done, Stearic acid, carnauba wax, polacrilin resin, lactose, form is from about 0.5% to about 3% w/w. mannitol, maltitol, maltose, fructose, Xylitol, trehalose, Sor bitol, dextran, dextrins, dextrose, maltodextrin, polyethylene 0071. The manufacturing process for the core is either by glycol, carboxymethylcellulose Sodium, carboxymethylcel wet granulation, dry granulation or direct compression, and lulose calcium, polyvinyl alcohol, hydroxypropyl cellulose, where applicable involves mixing the necessary ingredients hydroxypropyl ethylcellulose, hydroxyethyl cellulose, of the respective formulations according to the Strategies hydroxyethyl methylcellulose, methylcellulose and ethylcel discussed earlier, preferably in a high Shear mixer granulator lulose. The total percentage of their addition to the formu (GMI, India) or planetary mixer (Hobert, USA) to obtain lation as binder either individually or in combination is from homogeneity. If necessary, the drug is mixed with diluents about 1% to about 70% w/w, and preferably from about 5% prior to any granulation Step. In Such case, the premixed to about 55% w/w. The total percentage of optional pore blend is then granulated with water or any Suitable granu former either individually or in combination is from about lation fluid and dried in a fluidized bed dryer (Gansons, 1% to about 30% w/w, and preferably from about 2% to India) or tray dryer (Kothari, India) as required. Alterna about 10% w/w. tively, heat can be applied during granulation to the level 0068 The extended or controlled release of active drug where binder, filler melts and components mixed well to get from a formulation according to the invention is achieved particles coated. The dried granular mass is milled and then using individual or a combination of excipients known in the mixed with any other excipient (Such as any diluent or art to perform as barrier-forming polymer(s), erodable or controlled release agent) not added during granulation. insoluble material(s). Such excipients include hydroxy pro Glidants are blended with the resulting mixture in a pyl cellulose, hydroxypropyl ethyl cellulose, hydroxyethyl V-blender (Patterson-Kelley, USA) or double cone blender cellulose, hydroxyethyl methy cellulose, Sodium carboxym (Gansons, India) or octagonal blender (Gansons, India) ethylcellulose and calcium carboxymethylcellulose, poly which is capable of functioning under preferred low shear ethylene oxides of molecular weight 100,000-7,000,000 conditions followed by addition of lubricants. The lubricated Daltons(Polyox(R), polyvinyl alcohols (MW: 20,000-200, mass is then compressed into tablets using a tablet press 000 Daltons), substituted copolymers of polyvinyl acetate (Cadmach, India) or filled into capsule shells of suitable size and polyvinylpyrrolidone like kollidon(R) VA64 and kolli using a semi-automatic capsule filling machine (Pam, India) donBSR, Sodium alginate, carrageenan, Xanthan gum indi or manual filling machine (Pam, India). The capsule shell vidually or in combination of ceratonia, locust bean gum or preferably comprises gelatin, Starch, chitosan or hypromel Veegum, guar gum, gellan gum, methylcellulose and chito lose. San, ethylcellulose, dextrates, dextrins, eudragitE) (RL and 0072 A dosage form core according to the invention is RS grade), cellulose acetate, cellulose acetate trimelitate, preferably film-coated with a coating material Such as cellulose acetate butyrate, cellulose acetate propionate, ceto hydroxypropyl cellulose, a methacrylate copolymer Such as Stearyl alcohol, cetyl alcohol, glyceryl behenate derivatives eudragit(R) E100 or eudragit(R) EPO, kollicoat(R) IR, opadry(R) like compritol(F) 888 ATO, precirole ATO 5, gelucire(R) II or opadry(E) AMB for identification, taste masking, aes 44/14, gelucire(R) 50/13, glyceryl mono oleate, glyceryl thetic purpose and for Stability. According to the invention, mono Stearates, glyceryl palmito Stearates, lecithin, medium the film coating acts as a moisture barrier. The film coating chain triglycerides, eudragit(R) RSPO, eudragitE) RLPO, does not Substantially affect the release rate of drug from the Stearic acid, Stearyl alcohol, hydrogenated vegatable oil, tablet/capsule, Since the coating is of instant release, which carnauba wax, microcrystalline wax and beeswax. The total rapidly dissolves in the Stomach. Many polymers have been amount of controlled release agent present in the dosage investigated for use in film-coating. Most film coats are form either alone or in combination is from about 5% to prepared by deposition of one or more film-forming poly about 75% w/w, and preferably from about 5% to about 60% merS resulting in coats that usually represent no more than w/w. about 2-5% by weight of the final coated product. A coating 0069 Drug release is controlled by variables such as Solution according to the invention preferably contains, in Surface area and diffusion rate in a dynamic proceSS. Barrier addition to the film-former, a plasticizer, a glidant and an forming polymers form a dynamic hydrophilic matrix Sys opacifying agent or a coloring agent, and a Solvent System tem to allow for slow release of drug in a patient's body. therefor is composed of aqueous, hydro-alcoholic or non Upon exposure to water, these barrier-forming high ViscoS aqueous Solvent mixture with Stabilizer(s), as described ity materials will hydrate and Swell rapidly to form a above, optionally added to Such a coating Solution. Some hydrogel, which expands with time into the interior of the coating materials are readily available in the form of a tablet allowing for diffusion of the drug from the tablet core premix with all the necessary agents required for achieving slowly to facilitate for controlled drug delivery. Further, a Smooth and uniform film with necessary amount of depo Such effects are Supported by insoluble materials of type Sition to protect the core against the moisture. The preferred Swellable or non-Swellable in nature, which can acts as amount of each coating material is as follows: film coating barrier or Shielding the drug molecule under their hydro material, from about 5% to about 20% w/w; plasticizer, from phobic coat to discourage the drug diffusion out of gelled about 0.1% to about 2% w/w; opacifying agent, from about matrix and to an extent it also helps in Slowing down the 0.1% to about 10% w/w; glidant/antitacking agent, from US 2005/0112198 A1 May 26, 2005

about 0.1% to about 10% w/w; optional stabilizer, from mance in dissolution and assay at various intervals during about 0.001% to about 3% w/w. Stability Studies. Stability Studies are conducted as per the 0073. A dosage form core according to the invention is ICH guidelines. The dissolution test is conducted using USP preferably enteric coated to retard release during the initial Type II (Hansons Research, USA) apparatus. The twice period of transit through the gastrointestinal System. Such daily formulations of bupropion are tested using water as enteric coat is applied either directly onto the core of the dissolution medium at 37 C. Once-daily bupropion dosage form or applied over a film coat, which can not only uncoated tablets/capsules are tested at 37 C. in 0.1 NHCl, act as Sub-coat to protect the dosage form against moisture and their coated dosage forms are tested at 37 C. according but also helps in binding of the enteric film firmly and to the procedure recommended by USP27 for enteric-coated uniformly to the dosage form. Examples of Suitable enteric dosage forms. Bupropion resinate based formulations either polymers include hypromellose phthalate, hypromellose for once daily or twice daily administration are tested acetate Succinate, cellulose acetate phthalate, cellulose according to the procedures described for enteric coated acetate trimelliate, polyvinyl acetate phthalate based disper tablets in USP 27. The above procedure with resinate based sions like Opadry(R) enteric and Sureteric(R) either directly or formulations is necessary to Simulate the gastro-intestinal after mixing with Suitable plasticizers, glidants, opacifying conditions as the release from Such dosage form is depen agents or coloring agents wherein the coating Solutions is dent directly on the number of ions available either in prepared in aqueous, hydro-alcoholic or non aqueous Sol dissolution medium or in gastrointestinal fluids. vent mixtures with stabilizer(s) optionally added to such 0078. Any of a wide variety of therapeutically active coating Solutions. agents is formulated into a formulation according to the present invention. A therapeutically active agent according 0.074. In coating solutions other than readily available, to the invention is a water Soluble drugs or a slightly water incorporation of Suitable plasticizers into the polymer matrix Soluble drug. A therapeutically active agent according to the effectively reduces the glass transition temperature, So that invention is, for example, any hydrochloride Salt form of under ambient conditions the films are Softer, more pliable, amoSulalol, aclarubicin, amantadine, amiloride, betazolol, and often Stronger, and thus better able to resist the mechani benazepril, bisoprolol, buSpirone, barnidipine, bifemelane, cal StreSS, which otherwise forms a hard, non-pliable and bepridil, clo?edanol, cetrizine, cevimeline, chloperastine, rather brittle, properties which could be somewhat restric cephalexin, cyclobeZaprine, diltiazem, dobutamine, tive in film coating Since the coated dosage form may be dibucaine, dexamethylphenidate, ethambutol, etafenone, Subjected to a certain amount of external StreSS. Examples of eSmolol, fluoxetine, flurazepam, feXofenadine, granisetron, Suitable plasticizers include dibutyl Sebacate, diethyl phtha hydralazine, indenolol, loperamide, levamisole, lomefloxa late, triethyl citrate, tributyl citrate, castor oil and triacetin. cin, metformin, methylphenidate, metoclopramide, moper 0075) A preferred plasticizer, opacifying agent and one, metixene, mefloquine, nortriptyline, nicardipine, glidant according to the invention are triethyl citrate, tita Ondansetron, oxycodone, oxymorphone, paroxetine, nium dioxide and talc respectively, which are added to a promethazine, propafenone, quinapril, ritoridine, ranitidine, coating Solution prepared freshly by combining them with rimantadine, Sertraline, ticlopidine, tolaZoline teraZosin, necessary film forming materials apart from Suitable color tamsulosin, tramadol, tiapride, tolazoline, terbinafine, ing agents. The preferred amount of each coating material is tirofiban, Verapamil, Valacyclovir, or Venlafaxine or any Salt as follows: enteric coating material, from about 5% to about form of abacavir Sulfate, alendronate Sodium, citalopram 20% w/w; plasticizer, from about 0.1% to about 2% w/w; hydrobromide, clopidogrel bisulfite, cerivastatin Sodium, opacifying agent, from about 0.1% to about 10% w/w; chloroquine phosphate, diclofenac Sodium, diclofenac glidant/antitacking agent, from about 0.1% to about 10% potassium, enalapril maleate, enoxaprin Sodium, fluvastatin w/w; optional stabilizer, from about 0.001% to about 3% Sodium, fosinopril Sodium, indinavir Sulfate, loSartan potas w/w. sium, naproxen Sodium, neostigmine bromide, Oxybutynin 0.076 A dosage form core according to the invention is chloride pravastatin Sodium, primacquine phosphate, piper coated in a pan coater (Ganscoater, India). An aqueous or a acillin Sodium, quetiapine fumarate, risedronate Sodium, mixture of an organic and aqueous Solvent or a mixture of rosiglitaZone maleate, Valporate Sodium, Salbutamol Sulfate, organic Solvent is used for film or enteric coating. Examples Sumatriptan Succinate, warfarin Sodium or Zolpidem tartrate. of Suitable organic Solvents are e.g., ethanol, methanol, 0079 The following materials have been used in prepar methylene chloride, isopropyl alcohol and with or without ing embodiments of the invention but can be replaced with water. The dosage form core is coated until appropriate Similar materials available commercially and known in the weight gain achieved like 1-4% w/w in the case of film art. coating and approximately 5-15% W/w for enteric coated tablets. The tablets are dried or allowed to curing as needed 0080 Bupropion Hydrochloride (Dipharma, Italy) at the end of each coating process. The operational param 0081 Amberlite(R) IRP 69 (Rohm & Hass) eters are maintained according to the manufacturer recom mendations. 0082) Hydroxypropyl cellulose (HPC, Klucel(R), EXF and HXF grade, Hercules) 0.077 Abuproprion hydrochloride formulation according to the invention, for Sustained or controlled release delivery 0083) Polyethylene oxide (Polyox(R 303 WSR grade, of bupropion hydrochloride, is suitable for either twice daily Dow Chemicals) or once daily administration as needed by the therapy or the patient need. Adosage form according to the invention is, for 0084) Hydroxyethyl cellulose (HEC, Natrosol(R), 250 example, a tablet or a capsule containing from about 25 mg HHX grade, Hercules) to about 300 mg of active drug and is evaluated for perfor 0085 Ethylcellulose (ECT 10 grade, Hercules) US 2005/0112198 A1 May 26, 2005 10

0.086 Sodium carboxymethy cellulose (7HXF grade, Hercules) -continued 0087 Polyvinylacetate-polyvinylpyrrolidone copoly Qty (mg/tab) mer (Kollidon(R) SR and Kollidon(R) VA64 from BASF) Butylated hydroxy anisole 5 0088 Cellulose acetate butyrate (CAB, Eastman) Butylated hydroxy toluene 0.4 0089 Compritol(RATO 888 and Glucire(R) 50/13 (Gat Tablet weight 4.09.4 mg tefosse) Pore former (optional) 25 0090 Polyvinyl alcohol (Sigma) Tablet weight 434.4 mg 0.091 Lactose anhydrous, DC grade (DCL 21, JRS Pharma) 0105 Procedure: Stabilizers were dissolved in small quantities of ethyl alcohol and were used to treat the blend 0092 Microcrsyalline cellulose (Avicel PH102, FMC) of microcrystalline cellulose and Xanthan gum by mixing them for 10 min. The granules were dried at 50 C. Dried 0093. Mannitol (Mannogem, SPI Pharma) and milled granules were mixed for about 10 min with sifted 0094) Colloidal Silicon Dioxide (Cab-o-sil, Cabot) bupropion hydrochloride, cab-o-sil and optional pore former. The above granules were lubricated for 2 min and 0.095 Magnesium stearate (Malinkrocdt) compressed into tablets using tablet press. 0.096 Opadry(R II and Opadry(RAMBOboth from Col 0106 Optionally, the treatment of granules is performed orcon) with hydro-alcoholic (1:1) mixture or includes the bupro 0097. Opadry(R) enteric and Sureteric(R) (both from pion hydrochloride part of core granulation. Colorcon) 0107 A formulation similar to the above is manufactured 0098. Hypromellose phthalate and hypromellose suc without BHA or BHT in the core but with a film coating as cinate (Shinetsu) described in example 11 or example 12. 0099 Eudragit(R) RSPO, Eudragit(R) RLPO, Eudragit(E) Example-2 E100, Eudragit(R) EPO (all form Degussa) 0108) 01.00) Kollicoat(R) IR (BASF) 0101 Butylated hydroxy anisole (BHA) and butylated hydroxy toluene (BHT) (Both from Sigma) Qty (mg/tab) Bupropion HCl 150 EXAMPLES Hydroxyethyl cellulose (250 HHX) 8O CR agent # 1 55 0102) The following are examples, specifically with Cab-o-sil 1. respect to a Sustained release dosage form of bupropion Magnesium stearate 3 hydrochloride. The formulation details of bupropion hydro Butylated hydroxy anisole 5 chloride 150 mg tablets are disclosed. Capsule formulations Butylated hydroxy toluene 0.4 are also readily prepared through the use of similar excipient amounts. A tablet or capsule formulation containing between Tablet weight 2.94.4 mg about 25 mg and about 300 mg bupropion or bupropion hydrochloride is manufactured by a method similar to that disclosed in the examples and in a dose-proportional manner 0109 Procedure: Stabilizers were dissolved in small or by using excipients and procedures as disclosed in the quantities of ethyl alcohol and were used to treat the blend examples and adapted as per the release requirements. Such of hydroxyethyl cellulose by mixing them for 10 min and dried at 50° C. The dried granules were milled and blended a formulation eVinces a dissolution profile and a release for 10 min with bupropion hydrochloride and the CR profile Substantially similar to that disclosed herein. agent(s) #1.The agent(s) selected were added either indi 0103) Bupropion HCl SR 150 mg Tablets (Twice Daily) vidually or in combination of one or more chosen from the following like carnauba wax, eudragitE) RSPO, compritol(R) Example-1 ATO 888, gelucire(R) 50/13, cellulose acetate butyrate and 01.04] polyvinyl alcohol. Finally, the mixed granules were blended for 10 min with sifted cab-o-sil followed by lubrication for 2 min and compressed into tablets using tablet press. The treatment of granules can also be done with hydro-alcoholic Qty (mg/tab) (1:1) or non-aqueous Solvent mixture and dried. Optionally Bupropion HCl 150 CR agent #1 and bupropion hydrochloride can be included Microcrystalline cellulose 210 in the core granulation. Xanthan Gum 40 Cab-o-sil 1. 0110. A formulation similar to the above is manufactured Magnesium stearate 3 without BHA or BHT in the core but with a film coating as described in example 11 or example 12. US 2005/0112198 A1 May 26, 2005

Example-3 Example-5 0111 0117)

Qty (mg/tab) Qty (mg/tab) Bupropion HCl 150 Bupropion- resinate Ion exchange resin 25 eq. to active bupropion HCI 150 Polyox (WSR 303) 8O Polyox (R) (WSR 303) 60 CR agent #2 35 Kollidon (R) SR 1OO Cab-o-sil 3 Cab-o-sil 5 Magnesium stearate 3 Magnesium stearate 5 Butylated hydroxy anisole 5 Butylated hydroxy toluene 0.4 Tablet weight 620 mg Tablet weight 301.4 mg 0118 Procedure: Bupropion-resinate mixture, polyoxOR and kollidon(E) SR were sifted, and mixed well for 10 min. 0112 Procedure: The ion exchange resin used was Sifted cab-o-Sil was added to above granules and mixed for Amberlite(E) IRP-69. Stabilizers were dissolved in Small 10 min. The above granules were lubricated for 2 min and quantities of ethyl alcohol and treated the blend of resin for compressed into tablets using a tablet press. 5 min and dried at 50 C. The dried and milled granules were mixed for 10 min with bupropion hydrochloride, polyox and Example-6 CR agent #2. The CR agent(s) selected were added either individually or in combination of one or more chosen from 0119) the following like kollidon(R) SR, kollidon(R) VA 64 and ethylcellulose (ECT10). Finally, the mixed granules were blended for 10 min with sifted cab-o-sil followed by lubri cation for 2 min and compressed into tablets using tablet Qty (mg/tab) preSS. Alternatively, CR agent #2 and bupropion hydrochlo Bupropion- resinate ride can be included in the core granulation. The above eq. to active bupropion HCI 150 Polyox (R) (WSR 303) 50 granulation can also be carried out with purified water and Kollidon (E) VA64 50 dried at 50 C. CR agent # 4 50 Cab-o-sil 6 0113. A formulation similar to the above is manufactured Magnesium stearate 6 without BHA or BHT in the core but with a film coating as Tablet weight 612 mg described in example 11 or example 12. 0114 Bupropion XR(Resinate) 150 mg Tablets (Once/ 0120 Procedure: Bupropion-resinate mixture, kollidon(R) Twice Daily) VA 64 was granulated with purified water by mixing them Example-4 for 10 min and dried at 50° C. The dried and milled granules were mixed with sifted polyox and additional controlled 0115) release agent and mixed well for 10 min. The CR agent(s) #4 selected were added either individually or in combination of kollidon(R) SR and ethylcellulose (ECT10). Further, mixing Qty (mg/tab) was done after the addition of sifted cab-o-sil for 10 min. Bupropion- resinate The above granules were lubricated for 2 min and com eq. to active bupropion HCI 150 pressed into tablets using a tablet preSS. CR agent #3 15 HPC (EXF) 1OO 0121 Bupropion XR(Resinate) 150 mg Capsule (Once/ Cab-o-sil 6 Twice Daily) Magnesium stearate 6 Tablet weight 577 mg Example-7 0122) 0116 Procedure: Bupropion-resinate mixture, binder and controlled release agent were sifted and mixed well for 10 min. The CR agent(s) selected were added either individu ally or in combination of one or more chosen from the Qty (mg/cap) following like HPC (HXF), eudragit(R) RSPO, polyox(R) Bupropion- resinate (WSR 303), sodium carboxymethyl cellulose (7 HXF) and eq. to active bupropion HCI 150 hydroxyethyl cellulose (250 HHX). Further, mixing was Xanthan gum 25 done after the addition of sifted cab-o-sil for 10 min. The HEC(250 HHX) 25 Cab-o-sil 6 above granules were lubricated for 2 min and compressed Magnesium stearate 6 into tablets using a tablet press. Alternatively, the above Tablet weight 512 mg granulation was carried out with purified water and granules were dried at 50° C. US 2005/0112198 A1 May 26, 2005

0123 Procedure: Bupropion-resinate mixture, Xanthan 0129. Procedure: The ion-exchange resin used was gum and HEC were sifted and mixed for 10 min. Further, Amberlite(E) IRP-69. Stabilizers were dissolved in Small mixing was done after the addition of sifted cab-o-sil for 10 quantities of ethyl alcohol and were used to treat the blend min. The above granules were lubricated for 2 min and filled of resin for 5 min and dried at 50° C. The dried granules into a capsule of Suitable size using manual capsule filling were milled and mixed with bupropion hydrochloride, machine. polyox and CR agent #6 for 10 min. The CR agent(s) 0124 Bupropion HCl XR 150 mg Tablets (Once Daily) selected were added either individually or combination of one or more chosen from the following like ethylcellulose Example-8 (ECT10), kollidon(R) SR and kollidon(R) VA64. The blend was mixed for 10 min with sifted cab-o-sil followed by 0125) lubrication for 2 min and compressed into tablets using tablet press. Alternatively, the compositions not in combi nation with kollidon(R) SR can be granulated with ethyl Qty (mg/tab) alcohol and a mixture of water:ethanol (1:1) and dried. A formulation similar to the above is manufactured without Bupropion HCl 150 Ion exchange resin 37.5 BHA or BHT in the core but with a film coating as described HPC (EXF) 62.5 in example 11 or example 12. CR agent #5 62.5 Cab-o-sil 3 Magnesium stearate 3 Example-10 Butylated hydroxy anisole 5 Butylated hydroxy toluene 0.4 0130 Tablet weight 323.9 mg

Qty (mg/tab) 0.126 Procedure: The ion-exchange resin used was Amberlite(E) IRP-69. Stabilizers were dissolved in Small Bupropion HCl 150 quantities of ethyl alcohol and were used to treat the mixed Ion exchange resin 25 blend of resin and HPC (EXF) for 5 min and dried at 50° C. Kollidon (R) SR 12O Dried and milled granules were mixed with burpropion Polyox (303 WSR) 50 hydrochloride and CR agent #5 for 10 min. The CR agent(s) Kollidon (E) VA. 64 50 #5 selected were added either individually or in combination Cab-o-sil 4 of one or more chosen from the following like HPC (HXF), Magnesium stearate polyox(R) (WSR 303), HEC (250 HHX). The above granules Butylated hydroxy anisole 5 were mixed with sifted cab-o-sil for 10 min followed by Butylated hydroxy toluene 0.4 lubrication for 2 min and compressed into tablets using tablet press. Alternatively, they were also granulated with Tablet weight 408.4 mg inclusion of bupropion hydrochloride and CR agent #5 with ethyl alcohol or mixture of water:ethanol (1:1) solution and dried. 0131 Procedure: The ion-exchange resin used was 0127. A formulation similar to the above is manufactured Amberlite(E) IRP-69. Stabilizers were dissolved in Small without BHA or BHT in the core but with a film coating as quantities of ethyl alcohol and were used to treat the mixed described in example 11 or example 12. blend of resin and kollidon(RVA 64 for 5 min. Alternatively, they were also granulated with mixture of water: ethanol Example-9 (1:1) or ethanol solution and dried at 50° C. Dried and milled granules were mixed with bupropion hydrochloride, polyox, 0128 kollidon(R) SR and cab-o-sil for 10 min. The above granules were lubricated for 2 min and compressed into tablets using tablet preSS. Qty (mg/tab) 0132 A formulation similar to the above is manufactured Bupropion HCl 150 Ion exchange resin 25 without BHA or BHT in the core but with a film coating as CR agent # 6 40 described in example 11 or example 12. Polyox (303 WSR) 1OO Cab-o-sil 3 0133) Film Coating Magnesium stearate 3 Butylated hydroxy anisole 5 0134) The examples described in examples #1-9 were Butylated hydroxy toluene 0.4 film coated using in-house prepared coating Solution or Tablet weight 326.4 mg using opadry(R II, opadry(RAMB, Eudragit(R) EPO or kol licoat(R) IR coating dispersion system. The details of the in-house System were mentioned below US 2005/0112198 A1 May 26, 2005 13

Example-11 0140 Procedure: The aqueous/non-aqueous/hydroalco holic enteric coating Solution was prepared and coated by 0135) using convenient coating dispersion Systems like Sureteric(R) or Opadry(E) enteric as per the instructions provided by manufacturer to achieve the required target weight. The Qty (mg/tab) in-house acqueous/non-aqueous coating Solution was pre Core tablets/caps pared by using Suitable enteric coating materials like (examples #1-10) hypromellose phthalate or hypromellose acetate Succinate along with necessary film forming agents mentioned in Film Coating material 10% w/w Plasticizers 0.5% w/w example 12. The core units were coated in a Ganscoater 250 Opacifying agent 0.5% w/w (Bombay, India) with necessary temperature Setting ideal for Glidants/antitacking agent 1.0% w/w respective coating materials and were dried for 30-60 min Solvent(s) mixture after achieving the required weight gain. Alternatively, the Optional 1.0% w/w stabilizers are dissolved in a Suitable solvent and mixed with Stabilizers coating Solution to coat the tablets/capsules. Total weight gain 4.0% w/w 0141) Dissolution Studies 0.136 Procedure: The aqueous/non-aqueous/hydroalco 0142) Dissolution studies were performed at 37 C. holic coating Solution was prepared and coated by using convenient film coating dispersion Systems like kollicoat(R) 0143) Bupropion HCl 150 mg SR Tablets (Twice Daily) IR or opadry(R II/opadry(RAMB or EudragitE) EPO as per 0144. The prepared bupropion hydrochloride 150 mg SR the instructions provided by manufacturer to achieve the required target weight. The in-house acqueous/non-aqueous tablets (examples: 1-3) are tested for dissolution in a USP coating Solution was prepared by using Suitable film coating Type II apparatus at 50 rpm in 900 ml of pure water and the materials like hydroxypropyl cellulose and EudragitE E100 percentage release data is shown in Table 1. along with necessary film forming agents mentioned in example 11. The core units were coated in a Ganscoater 250 TABLE 1. (Bombay, India) with necessary temperature settings ideal Dissolution data for bupropion HCl 150 mg SR Tablets for respective coating materials and were dried for 30-60 min after achieving the required weight gain. Alternatively, Time (hr) Example #1 Example #2 Example #3 the stabilizers are dissolved in a Suitable solvent and mixed 1. 37.2% 31.2% 31.2% with coating Solution to coat the tablets/capsules. 4 72.8% 66.0% 76.1% 0137 Enteric Coating 8 89.7% 89.1% 92.5% 0.138. The examples described from #4-10 were option ally enteric coated over a film coated dosage form described 0145 Bupropion XR(Resinate) 150 mg Tablets (Twice in example 11, using materials like hypromellose phthalate Daily) or hypromellose acetate Succinate or using polyvinyl acetate phthalate (opadry(E) enteric or Sureteric(R) coating dispersion 0146 The prepared bupropion XR(resinate) 150 mg tab System). The coating Solutions were prepared either in lets (examples: 4-6) are tested for dissolution in USPType aqueous or in non-aqueous Solvent System. The readily II apparatus at 75 rpm in 750 ml of 0.1N HCl for 2 hours of dispersible coating Solutions were prepared as per the 250 ml of 0.2M phosphate buffer (pH 6.8) and the percent instructions provided by manufacturer. The details of the age for twice daily tablets is shown in Table 2. in-house System were mentioned below TABLE 2 Example-12 Dissolution data for bupropion XR (resinate) 0139) 150 mg Tablets (Twice daily Time (hr) Example #4 Example #5 Example #6 1. 39.6% 30.9% 25.5% Qty (mg/tab) 4 75.3% 70.2% 73.2% Core tablets/caps 8 86.4% 90.3% 94.3% (examples #4-10) Enteric coating material 10% w/w Plasticizers O.7% w/w 0147 Bupropion XR(Resinate) 150 mg Capsules (Once Opacifying agent 0.3% w/w Daily) Glidants/anti-tacking agent 0.6% w/w Solvent(s) mixture 0148 The prepared bupropion XR(resinate) 150 mg cap Optional 1.0% w/w Sules (example :7) is tested for dissolution in USPType II Stabilizer apparatus at 75 rpm in 750 ml of 0.1N HCl for 2 hours Total weight gain 8.0% w/w followed by addition of 250 ml of 0.2M phosphate buffer (pH 6.8) and the percentage release data obtained for once daily uncoated capsule is shown in Table 3. US 2005/0112198 A1 May 26, 2005 14

0154) Further Embodiments TABLE 3 O155 The invention provides additionally the following Dissolution data for bupropion XR (resinate) 150 mg capsules further embodiments: 0156 1. A pharmaceutical solid tablet dosage form con Time (hr) Example #7 Sisting of bupropion hydrochloride and any acceptable phar 35.4 58.4 maceutical Salts of bupropion base in which the drug and/or 63.7 its formulation is suitably stabilized either alone or in 85.1 combination of an added Stabilizer(s) and/or by an ion 2 89.3 eXchange resin with Suitable excipients in a physically mixed, treated or complexed form and/or by a Suitably coated film Surrounding the core which optionally have 0149 Bupropion HCl XR150 mg Tablets (Once Daily) added Stabilizer in the film and Such preparation intended to 0150. The prepared bupropion XR 150 mg tablets release the drug in a desired manner to provide an controlled (examples: 8-10) are tested for dissolution in USPType II delivery of the drug as needed by the patient or the therapy. apparatus at 75 rpm either in 750 ml of 0.1N HCl for 2 hours O157 2. The solid dosage form mentioned in Further followed by addition of 250 ml of 0.2M phosphate buffer Embodiment 1, (pH 6.8) or tested in 900 ml of 0.1N HCl and the percentage release data is shown in Table 4 and 5. 0158 a... can be a tablet or a capsule dosage form. 0159 b. the pharmaceutically acceptable excipients TABLE 4 Selected from the group consisting of diluents, release controlling agents, glidants and lubricants Dissolution data for bupropion HCl XR 150 mg Tablets in 0.1 N HCl and Phosphate buffer and mixtures thereof. Time (hr) Example #8 Example #9 Example #10 0160 c. the diluent of 2(b) is also a binder and a pore former. 1. O.O O.O O.O 2 O.1 2.0 O.O 0.161 d. the core is surrounded by coating layer with 4 33.3 54.7 44.4 6 51.3 88.8 63.5 stabilizers added optionally to its film. 8 64.6 95.5 75.2 24 86.6 90.6 0162. 3. The dosage form mentioned in Further Embodi ment 2 wherein the active material 0163 a. is in association of stabilizer(s) alone or in 0151) combination of Stabilizers and/or with excipients Suitably treated or granulated with Stabilizers. TABLE 5 0.164 b. is in association of ion exchange resin Dissolution data for bupropion HCl which is complexed to form a drug-resinate mixture XR 150 mg Tablets in 0.1 NHCl and further granulated with suitable binder(s) either Time (hr) Example #8 Example #9 Example #10 alone and/or with Suitable excipients. 1. 24.3 30.4 29.3 0.165 c. is co-mixed with ion exchange resin and 2 39.1 47.5 43.O Suitable excipients followed by treating or granulat 4 67.1 73.1 61.6 6 8O.3 87.4 75.O ing Such mixture with a Solution of Stabilizer(s). 8 89.6 92.8 82.4 0166 d. is directly mixed or granulated with Suitable excipients. 0152 Stability Studies 0.167 4. The dosage form mentioned in Further Embodi 0153. The stability studies are conducted for above illus ment 3 wherein the active materials is treated or granulated trated examples (1-10) of bupropion hydrochloride dosage directly with aqueous/non aqueous Solvents or hydro-alco form meant for once/twice daily administration by Storing holic mixture thereof. them at 40° C./75% RH for 3 months. The samples are 0168 5. The dosage form mentioned in Further Embodi analyzed by an high performance liquid chromatography ment 3 wherein the stabilizer(s) dissolved in aqueous/hydro system (HP 1100, Agilent, USA) with a gradient method alcoholic or non-aqueous Solvent(s) and Such Solution is using C column (Phenomenex, 4.6x100 column, 3.5 um) used to treat granules directly or mixed/diluted with aque having flow rate of 1.5 ml/min at wavelength of 226 nm and ouS/hydro-alcoholic mixture Solutions thereof and granu mobile phase consists of combination of Solvent mixture A lated. (water:acetonitrile:trifluroacetic acid, 900:100:0.4 ml) and mixture B (acetonitrile:Water and trifluorocacetic acid, 0169. 6. The solid dosage form mentioned in Further 950:50:0.3 ml). The assay results have shown that all the Embodiment 2, wherein the dosage form is manufactured by formulation have maintained above 90% potency of the any of the methods like direct compression, direct filling, active drug during Storage. The drug-resinate blend Stored at dry granulation or by wet granulation. 40° C./75% RH for 6 months maintained above 90% of the 0170 7. The solid dosage form mentioned in Further active drug. Embodiment 6, wherein the dosage form is manufactured by US 2005/0112198 A1 May 26, 2005 any method like direct compression or dry granulation using 0183) 19. The solid dosage from mentioned in Further binder(s) to prevent capping of the formulation. Embodiment 17, the ratio proportion between drug and resin 0171 8. The Solid dosage form mentioned in Further complex is ranging from 1:0.5 to 1:5, more appropriately it Embodiment 6, is manufactured by wet granulation using ranges from 1:0.5 to 1:3. binder(s) to offer both enough strength to granules and also 0.184 20. The solid dosage from mentioned in Further to make non-compressible drug-resin complex particles to Embodiment 17, the ratio between the drug and resin in a compress them easily. physical mix is ranging from 1:0.01 to 1:0.5, more prefer 0172 9. The dosage form mentioned in Further Embodi ably from 1:0.03 to 1:0.4. ment 6, wherein the binder(s) used can be aqueous and 0185. 21. The diluent(s) mentioned in Further Embodi non-aqueous Soluble binder(s). ment 2 are used alone or in combination from the following microcrystalline cellulose, Silicified microcrystalline cellu 0173 10. The solid dosage form mentioned in Further lose, dibasic calcium phosphate anhydrous, powdered cel Embodiment 6 wherein binder(s) used can be either poly lulose, alginic acid, poVidone, chitosan, carageenan, guar meric or non-polymeric nature and mixture thereof. gum, Xanthan gum, polyethylene oxide, Substituted copoly 0.174 11. The solid dosage form mentioned in Further mes of polyvinylacetate-polyvinylpyrrollidone, Stearic acid, Embodiment 2 consisting of bupropion hydrochloride or any carnauba wax, polacrilin resin, lactose, mannitol, maltitol, pharmaceutically acceptable Salt thereof, stabilizer(s) alone Xylitol, trehalose, Sorbitol, polyethylene glycol, carboxym or in combination, controlled release agent(s), diluents, ethylcellulose Sodium, polyvinyl alcohol, carboxymethyl glidants and lubricants. cellulose calcium, hydroxypropyl cellulose, hydroxypropyl ethyl cellulose, hydroxyethyl cellulose hydroxyethylmethyl 0175 12. The solid dosage form mentioned in Further Embodiment 2 consisting of bupropion hydrochloride or any cellulose, methylcellulose and ethylcellulose. pharmaceutically acceptable Salt thereof along with ion 0186 22. The diluent(s) mentioned in Further Embodi eXchange resin existing in a complex form along with ment 2, the following perform as binder(s) in any combi necessary controlled release agent(s), diluents, glidants and nation of microcrSyatline cellulose, dibasic calcium phos lubricants. phate anhydrous, Xanthan gum, carnauba wax, povidone, 0176 13. The solid dosage form mentioned in Further polyethylene oxide, Substituted copolymers of polyvinylac Embodiment 2 consisting of bupropion hydrochloride or any etate-polyvinylpyrrolidone, hydroxypropyl cellulose, pharmaceutically acceptable Salt thereof, stabilizer(s) or ion hydroxypropyl ethyl cellulose and hydroxyethyl cellulose, eXchange resin alone or in combination with Suitable con carboxymethylcellulose Sodium, methylcellulose and ethyl trolled release agent(s), diluents, glidants and lubricants. cellulose. 0187. 23. The diluents(s) mentioned in Further Embodi 0177) 13B. The solid dosage form mentioned in Further ment 2, the following added optionally as pore former to the Embodiment 2 consists of bupropion hydrochloride or any dosage form in any combination of lactose, mannitol, poly pharmaceutically acceptable Salt thereof with Suitable con ethylene glycol, polyethylene oxide, microcrystalline cellu trolled release agent(s), diluents, glidants and lubricants. lose, polacrilin potassium and hydroxyethyl cellulose. 0.178 14. The solid dosage form mentioned in Further Embodiment 2, the drug Stabilization is carried out either in 0188 24. The diluent(s) mentioned in Further Embodi a mixed or treated form using Stabilizer(s) Such as butylated ment 2, the total percentage of their addition to the formu hydroxy anisole, butylated hydroxy toluene, toluene Sul lation as binder either individually or in combination is fonic acid, disodium edetate, edetic acid, lactic acid, maleic ranging from 1% to 70%, more specifically in the range of acid, propyl gallate, Sodium formaldehyde Sulfoxylate, ben 5% to 55% w/w. Zoic acid and aspartic acid, and above were used either 0189 25. The solid dosage form mentioned in Further individually or in combination to achieve drug Stability. Embodiment 2, the diluent(s) like hydroxypropyl cellulose, 0179 15. The solid dosage form mentioned in Further hydroxyethyl cellulose, polyvinylacetate-polyvinylpyrroli Embodiment 14, wherein the total Stabilizer(s) percentage done copolymer and polyethylene oxide alone or in combi amount in formulation ranging from 0.001% to 5% w/w, nation added to the formulation maintained in total amounts more precisely the range is in between 0.001% to 3% w/w. of either below 20% w/w or their total amounts maintained above 40% w/w. 0180 16. The solid dosage form mentioned in Further Embodiment 14, the drug stabilization is carried out by 0.190) 26. The diluent(s) mentioned in Further Embodi combination of butylated hydroxy anisole and butylated ment 2, the total percentage of optional pore former either hydroxy toluene wherein any of them is mixed with the other individually or in combination present in the range of 1 to stabilizer in a ratio of 1:0.01 to 1:20, especially the ration is 30% w/w, more preferably from 2% to 10% w/w. between 1:1 to 1:15. 0191 27. The solid dosage form mentioned in Further 0181 17. The solid dosage form mentioned in Further Embodiment 2, the release controlling agent is added either Embodiment 2, the drug is Stabilized with an ion exchange alone or in combination of any of barrier forming poly resin capable of exchanging either anionic or cationic group. mer(s), erodable or insoluble material(s). 0182 18. The solid dosage form mentioned in Further 0.192 28. The controlled releasing agent in Further Embodiment 17, the drug is stabilized with a resin capable Embodiment 27, the total amount of Such agent either alone of exchanging cationic group like amberlite(R) IRP 69 or or in combination ranging from 5% to 75% w/w, more DoweX(R) Series. specifically from 5% to 60% w/w. US 2005/0112198 A1 May 26, 2005

0193 29. The controlled releasing agent in Further 0198 34. The controlled release agent of Further Embodiment 27, consists either individually or in combina Embodiment 27, chosen from a group consist either indi tion of barrier forming polymers of alkyl hydroxy cellulose vidually or in combination of insoluble materials like cel like hydroxy propyl cellulose, hydroxypropyl ethyl cellu lulose acetate, cellulose acetate trimelitate, cellulose acetate lose, hydroxyethyl cellulose, hydroxyethylmethy cellulose, butyrate, cellulose acetate propionate, ethylcellulose, ceto Salts of polycarboxyalkyl cellulose like Sodium carboxym Stearyl alcohol, cetyl alcohol, compritol(R) 888 ATO, pre ethylcellulose and calcium carboxymethylcellulose, poly cirol.8) ATO 5, gelucire(R) 50/13, eudragit(R) RSPO, eudragit(R) ethylene oxide of molecular weight 100,000-7,000,000 Dal RLPO, Stearic acid, carnauba wax and microcrystalline wax. tons(Polyox(R), polyvinyl alcohols (MW: 20,000-200,000 Daltons), Substituted copolymers of polyvinyl acetate and 0199 35. The glidants and lubricants of Further Embodi polyvinylpyrrolidone like kollidon(E) VA64 and kollidon(R) ments 11-13, added are colloidal Silicon dioxide, talc, mag SR, Sodium alginate, carrageenan, Xanthan gum individually nesium Stearate, Stearic acid and Sodium Stearyl fumarate or in combination of ceratonia, locust bean gum or Veegum, wherein glidant and lubricant present in dosage form is guar gum, gellan gum, methyl cellulose and chitosan. ranging from 0.5% to 3% w/w. 0194 30. The controlled release agent of Further 0200 36. The solid dosage form of Further Embodiment Embodiment 27, chosen from a group comprising either 2, the uncoated core or capsule shell consists of active agent individually or in combination of barrier forming polymers in a pure form, Salt form or in complex form ranging from like hydroxy propyl cellulose, hydroxypropyl ethyl cellu 25 mg to 300 mg and the active percentage weight may vary lose, hydroxyethyl cellulose, hydroxyethylmethy cellulose, from 10% to 80% w/w of the dosage form, more specifically Sodium carboxymethylcellulose, polyethylene oxide of in the range of 15% to 60%. molecular weight 100,000-7,000,000 Daltons(Polyox(R), 0201 37. The solid dosage form of Further Embodiment Substituted copolymers of polyvinyl acetate and polyvi 2, wherein the core portion is suitably covered with either by nylpyrrolidone like kollidon(R) VA64 and kollidon(R) SR, a film layer and/or by an enteric layer with stabilizers added Xanthan gum individually or in combination of gellan gum, optionally to its coating Solution to improve the Stability of locust bean gum or Veegum, guar gum and methylcellulose. the dosage form by acting as a barrier to moisture or to 0195 31. The controlled release agent of Further control the drug release in a desired manner. Embodiment 27, consists either individually or in combina 0202) 38. The core dosage form of Further Embodiment tion of erodible materials of alkyl hydroxyl celluloses like 11, is suitably film/sub coated with materials like hydrox hydroxypropylcellulose, hydroxypropyl ethyl cellulose, ypropyl cellulose, methacrylate copolymers like eudragit(R) hydroxyethyl cellulose, methylcellulose, ethylcellulose and E100 or eudragit(R) EPO, kollicoat(R) IR, opadry(R II or hydroxyethyl methyl cellulose; salts of polycarboxyalkyl opadry(RAMB either directly or after mixing with suitable cellulose like Sodium carboxymethylcellulose and calcium plasticizers, glidants and opacifying agents or coloring carboxymethylcellulose, polyethylene oxide of molecular weight 100,000-7,000,000 Daltons,(Polyox(R), high agents, wherein the coating Solutions is prepared in aqueous, molecular weight polyvinyl alcohols (MW: 20,000-200,000 hydro-alcoholic or non aqueous Solvent mixtures with Sta Daltons), Substituted copolymers of polyvinyl acetate and bilizer(s) optionally added to Such coating Solution. polyvinylpyrrolidone like kollidon(E) VA64 and kollidon(R) 0203 39. The core dosage form of Further Embodiment SR grade materials, polyethylene glycols (MW: 1000-35, 11, the enteric coat is applied either directly onto the core or 000), dextrates, dextrins and eudragit(R) (RL and RS grade). applied over a film coat/Subcoat consisting of materials like 0196) 32. The controlled release agent of Further hypromellose phthalate, hypromellose acetate Succinate, Embodiment 27, chosen from a group consists either indi polyvinyl acetate phthalate based dispersions like Opadry(E) vidually or in combination of erodible materials like hydrox enteric and Sureteric(R) either directly or after mixing with ypropylcellulose, hydroxypropyl ethyl cellulose, hydroxy Suitable plasticizers, glidants, opacifying agents or coloring ethyl cellulose, methylcellulose, ethylcellulose, Sodium agents wherein the coating Solutions is prepared in aqueous, carboxymethylcellulose polyethylene oxide of molecular hydro-alcoholic or non aqueous Solvent mixtures with Sta weight 100,000-7,000,000 Daltons, (Polyox(R), high bilizer(s) optionally added to Such coating Solution. molecular weight polyvinyl alcohols (MW: 20,000-200,000 0204 40. The stabilizers added to the coating step of Daltons), Substituted copolymers of polyvinyl acetate and Further Embodiment 37 are present either alone or in polyvinylpyrrolidones are kollidon(R) VA64 and kollidon(R) combination with butylated hydroxy anisole, butylated SR grade materials and polyethylene glycols (MW: 1000 hydroxy toluene, toluene Sulfonic acid, disodium edetate, 35,000). edetic acid, maleic acid, lactic acid, propyl gallate, Sodium 0197) 33. The controlled release agent of Further formaldehyde Sulfoxylate, benzoic acid, and aspartic acid. Embodiment 27, consists either individually or combination 0205) 41. The controlled release solid dosage form men of the insoluble materials like cellulose acetate, cellulose tioned in Further Embodiment 1 is having the following acetate trimellitate, cellulose acetate butyrate, cellulose acetate propionate, ethylcellulose, cetoStearyl alcohol, cetyl dissolution profile for drug from uncoated/film coated alcohol, glyceryl behenate derivatives like compritol(R) 888 bupropion HCl SR dosage form when tested at 37 C. in a ATO, precirole ATO 5, gelucire(R) 44/14, gelucire(R) 50/13, USP type II apparatus, at 50 rpm in 900 mL in distilled glyceryl mono oleate, glyceryl mono Stearates, glyceryl water, after 1 hr the release is not less than 25%, after 4 hr palmito Stearates, lecithin, medium chain triglycerides, is not more than 85%, after 8 hr is more than 80%. eudragit(R) RSPO, eudragitE) RLPO, stearic acid, Stearyl 0206 42. The controlled release solid dosage form men alcohol, hydrogenated vegatable oil, carnauba wax, micro tioned in Further Embodiment 1 exhibits the following crystalline wax and beeswax. dissolution profile for drug from uncoated/film coated US 2005/0112198 A1 May 26, 2005 bupropion HCl SR and bupropion HCl XR dosage forms afine, Verapamil, Valacyclovir, Venlafaxine and other Salt when tested at 37 C. in a USP type II apparatus, at 75 rpm forms of drugs like abacavir Sulfate, alendronate Sodium, in 900 mL in 0.1N HCl buffer, the release after 1 hr is not citalopram hydrobromide, clopidogrel bisulfite, cerivastatin more than 50%, after 4 hours is not more than 85%, after 8 Sodium, enoxaprin Sodium, fluvastatin Sodium, fosinopril hours is not less than 80%. Sodium, indinavir Sulfate, losartan potassium, naproxen Sodium, pravastatin Sodium, piperacillin Sodium, quetiapine 0207 43. The controlled release solid dosage form men fumarate, risedronate Sodium, roSiglitaZone maleate, Valpo tioned in Further Embodiment 1 exhibits the following dissolution profile for drug from enteric coated bupropion rate Sodium, Salbutamol Sulfate, Sumatriptan Succinate, war HCl XR dosage form when tested at 37° C. in a USP type farin Sodium and Zolpidem tartrate. II apparatus, at 75 rpm in 0.1N HCl and phosphate buffer 0213. It is to be understood that the invention is not mixture conducted as per USP 27 for enteric coated dosage limited to the exact details of operation, or to the exact forms, wherein the release is less than 10% in 2 hr., not more compositions, methods, procedures or embodiments shown than 60% in 4 hr, not less than 60% in 8 hr and not less than and described, as obvious modifications and equivalents will 80% in 16 hr. be apparent to one skilled in art, and the invention is therefore to be limited only by the full scope which can 0208. 44. The controlled release solid dosage form in fairly, legally and equitably be accorded to the appended Further Embodiment 1, wherein drug is stabilized by form claims. ing a complex with cation eXchange resin present in the uncoated/film coated bupropion XR resinate dosage form exhibits the following dissolution profile for drug when We claim: tested at 37° C. in a USP type II apparatus, at 75 rpm in 900 1. A pharmaceutical Solid dosage form comprising mL of 0.1N HCl buffer or 0.2M phosphate buffer (pH 6.8), buproprion hydrochloride and at least one member of the after 1 hr the release is not more than 50%, after 4 hours is group consisting of: butylated hydroxyanisole, butylated not more than 85%, after 8 hr is not less than 80%. hydroxytoluene and an ion exchange resin. 2. A pharmaceutical Solid dosage form according to claim 0209 45. The controlled release solid dosage form in 1 and additionally comprising a glidant, a lubricant, a Further Embodiment 1, wherein drug is stabilized by form release-controlling agent, and optionally a pore-forming ing a complex with cation eXchange resin present in the agent. uncoated/film coated bupropion XR resinate dosage form 3. A pharmaceutical Solid dosage form according to claim that exhibits the following dissolution profile for drug when 1 and consisting essentially of buproprion hydrochloride, a tested at 37 C. in a USP type II apparatus, at 75 rpm in 0.1N glidant, a lubricant, a release-controlling agent, a diluent, HCl and phosphate buffer mixture conducted as per USP27 and at least one member of the group consisting of butylated for enteric coated dosage form, wherein the release is leSS hydroxyanisole, butylated hydroxytoluene and an ion than 50% in 1 hr., not more than 85% in 4 hr and not less than eXchange resin. 80% in 8 hr. 4. A pharmaceutical Solid dosage form according to claim 0210 46. The controlled release solid dosage form in 4 and wherein the glidant is Cab-o-sil; the lubricant is Further Embodiment 1, wherein drug is stabilized by form magnesium Stearate; and the release-controlling agent is ing a complex with cation eXchange resin present in the Xanthan gum, hydroxyethyl cellulose, carnauba wax, enteric coated bupropion XR resinate dosage form that Eudragit RSPO, Compritol ATO 888, Gelucire 50/13, cel exhibits the following dissolution profile for drug when lulose acetate butyrate, polyvinyl alcohol, Kollidon VA64, tested at 37 C. in a USP type II apparatus, at 75 rpm in 0.1N ethyl cellulose, Kollidon SR, Polyox WSR 303, or hydrox HCl and phosphate buffer mixture conducted as per USP27 ypropyl cellulose. for enteric coated dosage forms, wherein the release is leSS 5. A pharmaceutical formulation according to claim 1 than 10% in 2 hrs, not more than 60% in 4 hr, not less than comprising only one member of the group and wherein the 60% in 8 hr and not less than 80% in 16 hr. member of the group is an ion eXchange resin. 6. A pharmaceutical Solid dosage form according to claim 02.11 47. The solid dosage form mentioned in Further 5 and wherein the ion exchange resin is Amberlite IRP69. Embodiment 1, wherein the film coated/enteric coated dos 7. A pharmaceutical Solid dosage form according to claim age form stored at 40 C./75% RH for three months period 5 and further comprising at least one member of the group maintains a minimum of 80% of the active drug. consisting of a film coating and an enteric coating. 0212 48. The solid dosage form mentioned in Further 8. A pharmaceutical Solid dosage form comprising a Embodiment 1, wherein the active drug belongs to any of the buproprion-resinate, a glidant, a lubricant, a release-control following mentioned to provide Sustained or controlled ling agent, and a diluent. delivery or taste masking or Stabilization of the drug as 9. A pharmaceutical Solid dosage form according to claim needed, the examples include any hydrochloride Salt form of 8 and wherein the bupropion-resinate complex comprises the drugs like amoSulalol, betazolol, benazepril, bisoprolol, Amberlite IRP69, the glidant is Cab-o-sil, the lubricant is buSpirone, barnidipine, bepridil, clo?edanol, cetrizine, ceph magnesium Stearate, and the release-controlling agent is alexin, cyclobeZaprine, dexamethylphenidate, eSmolol, flu hydroxypropyl cellulose, Eudragit RSPO, Polyox WSR 303, oxetine, flurazepam, feXofenadine, granisetron, hydralazine, Sodium carboxymethyl cellulose, hydroxyethyl cellulose, loperamide, levamisole, lomefloxacin, metformin, meth Xanthan gum, Kollidon VA64, ethyl cellulose, or Kollidon ylphenidate, metoclopramide, mefloquine, nicardipine, SR Ondansetron, Oxycodone, Oxymorphone, paroxetine, pro 10. A pharmaceutical Solid dosage form according to pafenone, quinapril, ritoridine, ranitidine, rimantadine, Ser claim 8 and further comprising at least one member of the traline, ticlopidine, tolaZoline, tamsulosin, tramadol, terbin group consisting of a film coating and an enteric coating. US 2005/0112198 A1 May 26, 2005

11. A pharmaceutical Solid dosage form according to 50% in 1 hr, not more than 85% in 4 hr and not less than 80% claim 1 and wherein the release of bupropion hydrochloride in 8 hr. Challapalli, Gumudavelli & Murty, Buproprion from the formulation occurs according to the limitation: Formulation when tested at 37 C. in a USP type II apparatus, at 50 rpm 18. A pharmaceutical Solid dosage form according to in 900 mL in distilled water, after 1 hr the release of bupropion hydrochloride from the formulation is not less claim 10 and wherein the release of bupropion from the than 25%, after 4 hr is not more than 85%, and after 8 hr is formulation occurs according to the limitation: when tested more than 80%. at 37° C. in a USP type II apparatus, at 75 rpm in 0.1N HCl 12. A pharmaceutical Solid dosage form according to and phosphate buffer mixture conducted as per USP 27 for claim 4 and wherein the release of bupropion hydrochloride enteric coated dosage form, wherein the release is less than from the formulation occurs according to the limitation: 50% in 1 hr, not more than 85% in 4 hr and not less than 80% when tested at 37 C. in a USP type II apparatus, at 50 rpm in 8 hr. in 900 mL in distilled water, after 1 hr the release of 19. A pharmaceutical Solid dosage form according to bupropion hydrochloride from the formulation is not less claim 10 and wherein the release of bupropion from the than 25%, after 4 hr is not more than 85%, and after 8 hr is formulation occurs according to the limitation: when tested more than 80%. at 37° C. in a USP type II apparatus, at 75 rpm in 0.1N HCl 13. A pharmaceutical Solid dosage form according to and phosphate buffer mixture conducted as per USP27 for claim 7 and wherein the release of bupropion hydrochloride enteric coated dosage forms, wherein the release is less than from the formulation occurs according to the limitation: 10% in 2 hrs, not more than 60% in 4 hr, not less than 60% when tested at 37 C. in a USP type II apparatus, at 75 rpm in 8 hr and not less than 80%in 16 hr. in 900mL in 0.1N HCl buffer, the release after 1 hr is not 20. A Stabilized pharmaceutical composition comprising: more than 50%, after 4 hours is not more than 85%, after 8 (a) at least one member of the group of active ingredients hours is not less than 80%. consisting of buproprion and bupropion hydrochloride; and 14. A pharmaceutical Solid dosage form according to (b) at least one member of the group of Stabilizers consisting claim 7 and wherein the release of bupropion hydrochloride of butylated hydroxyanisole, butylated hydroxytoluene, and from the formulation occurs according to the the limitation: an ion-exchange resin; and wherein (c) a tablet or a capsule when tested at 37 C. in a USP type II apparatus, at 75 rpm containing from about 25 mg to about 300 mg of the active in 0.1N HCl and phosphate buffer mixture conducted as per ingredient possesses at least one of the following profiles for USP27 for enteric coated dosage forms, wherein the release the release of active ingredient: (i) when tested at 37° C. in is less than 10% in 2 hr., not more than 60% in 4 hr, not less a USP type II apparatus, at 50 rpm in 900 mL in distilled than 60% in 8 hr and not less than 80% in 16 hr. water, after 1 hr the release is not less than 25%, after 4 hr 15. A pharmaceutical Solid dosage form according to is not more than 85%, after 8 hr is more than 80%; (ii) when claim 8 and wherein the release of bupropion from the tested at 37° C. in a USP type II apparatus, at 75 rpm in 900 formulation occurs according to the limitation: when tested mL in 0.1N HCl buffer, the release after 1 hr is not more than at 37° C. in a USP type II apparatus, at 75 rpm in 900 mL 50%, after 4 hours is not more than 85%, after 8 hours is not of 0.1N HCl buffer or 0.2M phosphate buffer (pH 6.8), after less than 80%; (iii) when tested at 37° C. in a USP type II 1 hr the release is not more than 50%, after 4 hours is not apparatus, at 75 rpm in 0.1N HCl and phosphate buffer more than 85%, after 8 hr is not less than 80%. mixture conducted as per USP27 for enteric coated dosage 16. A pharmaceutical Solid dosage form according to forms, wherein the release is less than 10% in 2 hr., not more claim 10 and wherein the release of bupropion from the than 60% in 4 hr, not less than 60% in 8 hr and not less than formulation occurs according to the limitation: when tested 80% in 16 hr; (iv) when tested at 37° C. in a USP type II at 37° C. in a USP type II apparatus, at 75 rpm in 900 mL apparatus, at 75 rpm in 900 mL of 0.1N HCl buffer or 0.2M of 0.1N HCl buffer or 0.2M phosphate buffer (pH 6.8), after phosphate buffer (pH 6.8), after 1 hr the release is not more 1 hr the release is not more than 50%, after 4 hours is not than 50%, after 4 hours is not more than 85%, after 8 hr is more than 85%, after 8 hr is not less than 80%. not less than 80%; (v) when tested at 37° C. in a USP type 17. A pharmaceutical Solid dosage form according to II apparatus, at 75 rpm in 0.1N HCl and phosphate buffer claim 8 and wherein the release of bupropion from the mixture conducted as per USP27 for enteric coated dosage formulation occurs according to the limitation: when tested form, wherein the release is less than 50% in 1 hr., not more at 37° C. in a USP type II apparatus, at 75 rpm in 0.1N HCl than 85% in 4 hr and not less than 80% in 8 hr. and phosphate buffer mixture conducted as per USP 27 for enteric coated dosage form, wherein the release is less than