Title of Invention	AN INCLUSION COMPLEX OF BUPROPION HYDROCHLORIDE WITH BETA CYCLODEXTRIN
Abstract	1. An inclusion complex of bupropion hydrochloride that is (+)-l-(3-chlorophenyl)-2- [(l,l-dimethylethyl)amino]-l -propane hydrochloride, of the following formula Formula 1 with beta-cyclodextrin, where bupropion hydrochloride and beta cyclodextrin are present in a molar ratio of 1 : (0.25 -4).

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FORM 2 THE PATENTS ACT, 1970 (39 of 1970) As amended by the Patents (Amendment) Act, 2005 & THE PATENTS RULES, 2003 As amended by the Patents (Amendment) Rules, 2005 COMPLETE SPECIFICATION (See section 10 and rule 13) TITLE OF THE INVENTION An inclusion complex of bupropion hydrochloride with beta cyclodextrin INVENTORS Dr Gidwani Suresh Kumar, Singnurkar Purushottam and Tewari Prashant Kumar all Indian Nationals and of USV Limited, BSD Marg, Station Road, Govandi, Mumbai 400 088, Maharashtra, India APPLICANTS USV Limited, BSD Marg, Govandi, Station Road, Mumbai 400 088, Maharashtra, India, an Indian Company PREAMBLE TO THE DESCRIPTION 'The following specification particularly describes the nature of this invention and the manner in which it is to be performed: Field of Invention This invention relates to an inclusion complex of bupropion hydrochloride with beta cyclodextrin. The invention also relates to a stabilized sustained-release pharmaceutical composition of bupropion hydrochloride containing an inclusion complex of bupropion hydrochloride with beta cyclodextrin. The invention also relates to the preparation of a stabilized sustained release pharmaceutical compositions of bupropion hydrochloride containing the inclusion complex of bupropion hydrochloride with beta cyclodextrin. The invention further relates to a method for preventing the degradation of bupropion hydrochloride by making an inclusion complex with beta cyclodextrin, thus allowing the preparation of acceptable pharmaceutical compositions for sustained release tablets and capsules. This application is divisional to patent application No 527/MUM/2002 dated 14th June 2002. Description of Related Art Bupropion hydrochloride is an antidepressant of the aminoketone class. It is designated as (+)-l-(3-chlorophenyl)-2-[(l,l-dimethylethyl)amino]-l-propane hydrochloride. Bupropion 2 hydrochloride has been shown to decompose in variety of pharmaceutical compositions formulated without the use of stabilizer. In the present application the term stabilizer means a composition which prevents the decomposition of bupropion hydrochloride. It has been found that by making an inclusion complex of bupropion hydrochloride with beta cyclodextrin, improved stability of the bupropion hydrochloride results. Accordingly, pharmaceutical compositions of bupropion hydrochloride that contain an inclusion complex of bupropion hydrochloride with beta cyclodextrin will decompose more slowly and maintair their effectiveness for longer periods of time. It is thus desirable to provide an inclusion complex of bupropion hydrochloride with beta cyclodextrin that improves the stability of the bupropion hydrochloride. It is also desirable, to provide a method for preparing an inclusion complex of bupropion hydrochloride with beta cyclodextrin that improves the stability of the bupropion hydrochloride. It is further desirable to provide a stabilized sustained-release pharmaceutical composition of bupropion hydrochloride that contains an inclusion complex of bupropion hydrochloride with beta cyclodextrin. It is still further desirable to provide a method of preparing a stabilized sustained-release pharmaceutical composition of bupropion hydrochloride that contains an inclusion complex of bupropion hydrochloride with beta cyclodextrin. 3 BRIEF SUMMARY OF THE INVENTION One aspect of the invention is to provide a method for prep icing a composition of an inclusion complex of bupropion hydrochloride with beta cyclodextiin that stabilizes bupropion hydrochloride against degradation, is safe for use as a pharmaceutical composition, is efficient, economical and simple, and which is suitable for manufacture on a commercial scale. Another aspect of the invention is to provide a method for preparing a stabilized sustained release pharmaceutical composition containing an inclusion complex of bupropion hydrochloride with beta cyclodextrin, which is safe for use as a pharmaceutical composition and stabilizes bupropion hydrochloride against degradation. DESCRIPTION OF THE DRAWINGS Figure IA shows a DSC Thermogram of Bupropion hydrochloride. Figure IB shows a DSC Thermogram of Beta cyclodextrin . Figure 1C shows a DSC Thermogram of a physical mixture of bupropion hydrochloride with beta cyclodextrin (1:1). 4 Figure ID shows a DSC Thermogram of an inclusion complex of bupropion hydrochloride with beta cyclodextrin. Figure 2A is an HPLC chromatogram showing the decomposition of bupropion hydrochloride in a sustained release tablet (without an inclusion complex of bupropion hydrochloride with beta cyclodextrin) at 50°C after 4 weeks. Assay of bupropion hydrochloride =• 99.998% w/w with respect to standard bupropion hydrochloride. Figure 2B is an HPLC chromatogram showing the decomposition of bupropion hydrochloride in a sustained release tablet containing an inclusion complex of bupropion hydrochloride with beta cyclodextrin at 50°C after 4 weeks. Assay of bupropion hydrochloride = 99.998% w/w with respect to standard bupropion hydrochloride. Figure 2C is an HPLC chromatogram showing the decomposition of bupropion hydrochloride in a sustained release tablet (without an inclusion complex of bupropion hydrochloride with beta cyclodextrin) at 37°C temperature with 75% relative humidity after 4 weeks. Assay of bupropion hydrochloride = 99.998% w/w with respect to standard bupropion hydrochloride. Figure 2D is an HPLC chromatogram showing the decomposition of bupropion hydrochloride in a sustained release tablet containing an inclusion complex of bupropion hydrochloride with beta cyclodextrin at 37°C temperature with 75% relative humidity after 4 weeks. Assay of bupropion hydrochloride = 99.998% w/w with respect to standard bupropion hydrochloride. 5 DETAILED DESCRIPTION OF THE INVENTION The present invention provides a novel inclusion complex of (=j-l-(3-chlorophenyl)-2-[(l .'.-dimethylethyl) amino]-1-propane hydrochloride, commonly known as bupropion hydrochloride, of the following Formula 1 with beta-cyclodextrin. where the molar ratio of bupropion hydrochloride to beta cyclodextrin is 1 : (0.25 - 4). The inclusion complex stabilizes the bupropion hydrochloride against degradation. The present invention further provides a method for preparing a novel inclusion complex of bupropion hydrochloride with beta cyclodextrin, comprising the steps of: 1. wetting an amount of beta cyclodextrin with a pharmaceutical!)' acceptable solvent Such as water, acetone and/or a CI to C4 aliphatic alcohol and mixtures thereof, at room temperature to form a semisolid mixture; 6 2. shear mixing the resulting semisolid mixture with bupropion hydrochloride to form an inclusion complex; and 3. drying the shear mixed inclusion complex at 40 - 80. degrees. C; where the molar ratio of bupropion hydrochloride to beta cyclodextrin is 1 : (0.25 - 4.0), and preferably is 1: (0.5-2.0). In a preferred embodiment, the C1-C4. aliphatic alcohol is selected from the group consisting of isopropyl alcohol, ethanol, and their combinations. The shear mixed inclusion complex ma/ be freeze dried or spray dried or dried by low temperature vacuum evaporation in a fluidized bed dryer or tray dryer. In a preferred embodiment, drying is carried out in a tray dryer at 40 -60. degrees. C. The present invention also provides a novel stabilized sustained release pharmaceutical composition containing the novel inclusion complex of bupropion hydrochloride with beta cyclodextrin, that further contains drug release rate controlling materials selected from a combination of hydroxypropyl methyl cellulose with hydroxypropyl cellulose, sodium carboxymethyl cellulose or stearic acid, the molar ratio of bupropion hydrochloride to beta cyclodextrin being 1 : (0.25 - 4.0). Where a mixture of the release rate controlling materials is employed, the weight ratio of one release rate controlling material to the other is within the range of about 1 : 0.1 to 0.1 : 1 , and preferably is within the range of about 1 : 0.3 to 0.3 : 1. 7 .• In a preferred embodiment, the drug release rate controlling materials include hydroxy-propyl methyl cellulose with average molecular weight of 20000 to 120000, preferably 86000 to 120000, and with a methoxy degree of substitution ranging from 1.36 to 1.90 and hydroxypropyl molar substitution ranging from 0.18 to 0.25. Where hydroxypropyl cellulose is employed as a drug release rate controiling material, it preferably has molecular weight in the range of 370000 to 1150000, preferably from $50000 to 1150000. Where sodium carboxymethylcellulose is so employed, it has a molecular weight in the range of 90000 to 700000. preferably from 250000 to 700000, with degree of substitution ranging from 0.65 to 0.95. The combination of hydroxypropyl methyl cellulose with hydroxypropyl cellulose, sodium carboxymethyl cellulose or stearic acid has been found to effectively control the release rate of bupropion hydrochloride from the pharmaceutical compositions containing the inclusion complex of bupropion hydrochloride with beta cyclodextrin. The novel stabilized sustained release pharmaceutical composition of the present invention may further contain one or more conventional excipients, such as lactose, microcrystalline cellulose, polyvinyl pyrrolidone, hydroxypropyl methyl cellulose, colloidal silicone dioxide, titanium dioxide, propylene glycol, polyethylene glycol-6000, talc, magnesium stearate and other excipients known in the art. 8 The novel pharmaceutical compositions according to the present invention can be used to produce oral dosage forms as compressed tablets of any shape, preferably round, or can be formed into compressed compact slugs filled into capsules using modern capsule filling machines. Dosage forms of the novel pharmaceutical composition of the present invention "generally contain 25 mg to 500 mg of bupropion hydrochloride, and preferably contain 50mg, 75 mg. 100 mg, or 150 mg of active ingredient, bupropion hydrochloride. The present invention also provides a method for preparing a novel stabilized sustained release pharmaceutical composition containing an inclusion complex of bupropion hydrochloride with beta cyclodextrin, and further containing a combination of hydroxypropyl methyl cellulose with hydroxypropyl cellulose, sodium carboxymethyl cellulose or stearic acid, where the molar ratio of bupropion hydrochloride to beta cyclodextrin is 1 : (0.25 - 4.0). The pharmaceutical compositions of the present invention are prepared by following method : a) The novel inclusion complex of bupropion hydrochloride with beta cyclodextrin is admixed with the excipients. b) The mixture is granulated, dried, and milled. Solid dosage forms are prepared such as by compressing the milled granulalion to form tablets or caplets. Alternatively capsules maybe prepared by placing the compact slugs of milled granulation in, for example, a two part hard gelatin capsule. 9 c) Solid dosage forms such as tablets may optionally be film coated with aqueous or organic solvent solution of commonly known film coating maerials such as hydroxy-propyl methyl cellulose, hydroxypropyl cellulose, etc. The method for preparing the pharmaceutical compositions of the present invention is descnbed in greater detail in the examples that follow. The in-vitro release rate of bupropion hydrochloride from the sustained release pharmaceutical compositions disclosed herein (whether or not film coated) in 0.1 X HCI up to the first hour and then continued in Phosphate buffer pH 6.8 USP, is preferably is follows: Time (Hours) % Bupropion HCI release 1st Hour(In 0.1 N HC1) 20 - 40% 2nd Hour(Phosphate Buffer pH 6.8) 40-60% 4,h Hour(Phosphate Buffer pH 6.8) 60 - 80 % 8lh Hour(Phosphate Buffer pH 6.S) NLT 80 % 10 -The stability of the novel sustained release pharmaceutical compositions was tested in accordance with industry standards by storage for four to twelve weeks at various accelerated . conditions such as 40. degrees. C. with about 7.5% relative humidity; and also 50. degrees. C. Sustained release pharmaceutical compositions containing the novel inclusion complex of bupropion hydrochloride with beta cyclodextrin of the present invention stored under these conditions retained at least 98% and at least 95% respectively, of the bupropion hydrochloride in the composition at the time of storage. The amount of bupropion hydrochloride remaining after storage may be determined through HPLC or other standard procedures. A kinetic degradation study of the novel inclusion complex of bupropion hydrochloride with beta cyclodextrin of the present invention also showed excellent stabilization of bupropion hydrochloride when suspended in water and stored at 50 degrees. C for four weeks. Figure 2A shows an HPLC chromatogram obtained for a bupropion hydrochloride sustained release tablet without a beta cyclodextrin inclusion complex, containing the same matrix material for a sustained release dosage form as the one for sustained release tablets of bupropion hydrochloride containing the inclusion complex, illustrated by figure 2B. One can clearly see the difference in degradation products and assay percentage between the two formulations. The sustained release tablet without die inclusion complex showed the degradation as high as 45% as indicated by figure 2A . whereas there is hardly any degradation at 50°C for over a period of 4 weeks with tablets made with the inclusion complex. Figures 2C and 2D further show the HPLC chromatograms illustrating the stability of sustained release tablets not containing the inclusion 11 complex (fig. 2C) versus those containing inclusion complex (fig. 2D) at 37°C with 75% relative humidity. It is clearly again seen that even at low temperature there is sizable degradation. :o the extent of 7% over one month period, with a sustained release tablet containing bupropion hydrochloride without the inclusion complex, while hardly any degradation was found \vi± the sustained release bupropion hydrochloride tablets containing the inclusion complex of the present invention. The preparation of the inclusion complex of the present invention, and of the pharmaceutical compositions of the present invention, is described in greater detail in the following examples. The examples are illustrative, and are not meant to limit the present invention. EXAMPLE 1: Preparation Bupropion hydrochloride-beta cyclodextrin inclusion complex (1 : 0.5 molar ratio): Ingredients Weight per Tablet/Capsule . Total quantity per Batch Bupropion hydrochloride 150 mg 3.000 Kg Beta cyclodextrin 308 mg 6.160 Kg Demineralised Water 1.000 Kg Beta cyclodextrin was wetted in a diasona mixer at a speed of 12 rpm for 15 minutes to get i semisolid mass. To the semisolid mixture, bupropion hydrochloride was added mixed for 1.0 hour. The resulting semisolid mass was dried at 40-60 degrees. C to get solid inclusion complex of bupropion hydrochloride with beta cyclodextrin. 12 Accelerated stability study : Period week % Potency 40°C / 75% RH % Potency50C 0 99.86 99.86 4 99.57 97.94 8 99.21 96.23 12 98.84 95.89 Kinetic degradation study : A 4.0 % w/v solution of bupropion hydrochloride inclusion complex in Demineralised waer was made and kept at 50°C temperature. Period weeks % Potency { 50DC temperature f 0 99.86 f 2 97.54 { 4 95.02 f EXAMPLE 2: Preparation Bupropion hydrochloride-beta cyclodextrin inclusion complex (1 - 0.5 molar ratio): Ingredients Weight per Tablet/Capsule Total quantity per Batch Bupropion hydrochloride 150 mg 3.000 Kg Beta cyclodextrin 308 mg 6.160 Kg Ethanol + Water (1:1) mixture 1.000 Kg ! Beta cyclodextrin was wetted in a diasona mixer at a speed of 12 rpm for 15 minutes to get z semisolid mass. To the semisolid mixture, bupropion hydrochloride was added mixed for 1.0 13 hour. The resulting semisolid mass was dried at 40-60 degrees. C to get a solid inclusion complex of bupropion hydrochloride with beta cyclodextrin. Accelerated stability stud}': Period week % Potency 40°C / 75% RH % Potency SOX 0 100.12 ' 100.12 4 99.97 98.82 8 99.65 97.39 12 99.27 95.94 Kinetic degradation study : A 4.0 % w/w solution of bupropion hydrochloride inclusion complex in Demineralised water was made and kept at 50°C temperature. Period weeks % Potencyj 50°C temperarure f 0 99.86 i 2 97.66 | 4 95.18 | -J>- \k - EXAMPLE 3: Preparation Bupropion hydrochloride-beta cyclodextrin inclusion complex (1 : 0.5 molar ratio): Ingredients Weight per Tablet/Capsule Total quantity per Batch Bupropion hydrochloride 150 mg 3.000 Kg Beta cyclodextrin 308 mg 6.160 Kg Ethanol ■1.000 Kg Beta cyclodextrin was wetted in a diasona mixer at a speed of 12 rpm for 15 minutes to get a semisolid mass. To the semisolid mixture, bucropion hydrochloride was added mixed for 1.0 hour. The resulting semisolid mass was dried at 40-60 degrees.C to get solid inclusion complex of bupropion hydrochloride with beta cyclodextrin. Accelerated stability study: Period week % Potency 40°C / 75% RH % Potency 50°C 0 100.47 100.47 4 100.19 j 98.73 8 99.88 J_97.05 12 99.67 j 95.4 Kinetic degradation study: A 4.0 % w/w solution of bupropion hydrochloride inclusion complex in Demineralised water was made and kept at 50°C temperature. -J#- IS' Period weeks % Potency 50°C temperature 0 100.47 2 98.06 4 95.52 EXAMPLE 4 : Preparation Bupropion hydrochloride-beta cyclodextrin inclusion complex (1:1 molar ratio): Ingredients Weight per Tablet/Capsule Total quantity per Ba:ch j Bupropion hydrochloride 150 mg 3.000 Kg ; Beta cyclodextrin 616 mg 12.320 Kg | Demineralised Water 2.000 Kg j Beta cyclodextrin was wetted in a diasona mixer at a speed of 12 rpm for 15 minutes to ge: a semisolid mass. To the semisolid mixture, bupropion hydrochloride was added mixed for t.O hour. The resulting semisolid mass was dried at 40-60 degrees.C to get solid inclusion complex of bupropion hydrochloride with beta cyclodextrin. Accelerated stability study : Period week % Potency 40°C / 75% RH % Potency 50°C 0 100.05 100.05 4 99.91 98.68 8 99.54 97.05 12 99.33 95.57 -2S Kinetic degradation study : A 4.0 % w/w solution of bupropion hydrochloride inclusion complex in Demineralised water was made and kept at 50°C temperature. Period weeks % Potency50°C temperature 0 100.05 2 97.85 4 95.84 EXAMPLE 5: Preparation Bupropion hydrochJoride-beta cyclodextrin inclusion complex (1:1 molar ratio): Ingredients Weight per Tablet/Capsule i Total quantity per Batch Bupropion hydrochloride 150mg I 3.000 Kg Beta cyclodextrin 616 mg 112.320 Kg Ethanol + Water (1:1) mixture | 2.000 Kg Beta cyclodextrin was wetted in a diasona mixer at a speed of 12 rpm for 15 minutes to get a semisolid mass. To the semisolid mixture, bupropion hydrochloride was added mixed for 1.0 hour in suitable mixers/kneader known in art. The resulting semisolid mass was dried at 40-60 degrees.C to get solid inclusion complex of bupropion hydrochloride with beta cyclodextrin. •Mr- 11 Accelerated stability study : Period : % Potency week 1 40°C / 75% RH % Potency 50°C 0 i 99.91 99.91 4 ; 99.65 98.51 8 ! 99.37 91.16 12 | 99.07 95.64 Kinetic degradation study : A 4.0 % w/w solution of bupropion hydrochloride inclusion complex in Demineralised wifer was made and kept at 50°C temperature. Period weeks % Potency 50°C temperature 0 99.91 2 97.71 4 ■95.56 EXAMPLE 6: Preparation Bupropion hydrochloride-beta cyclodextrin inclusion complex (1 : 2 molar ratio) : - Ingredient's""" Weight per Tablet Capsule Total quantity per Birch Bupropion hydrochloride 150 mg 3.000 Kg Beta cyclodextrin 1232 mg 24.464 Kg Ethanol +Water (1:1) mixture Beta cyclodextrin was wetted in a diasona mixer at a speed of 12 rpm for 15 minutes to get a semisolid mass. To the semisolid mixture, bupropion hydrochloride was added mixed for 1.0 hour. The resulting semisolid mass was dried at 40-60 degrees.C to get solid inclusion ccoiplex of bupropion hydrochloride with beta cyclodextrin. Accelerated stability study : Period week % Potency 40°C / 75% RH % Potency SOX 0 101.02 101.02 4 100.76 99.72 8 100.55 98.22 12 100.32 96.74 Kinetic degradation study : A 4.0 % w/w solution of bupropion hydrochloride inclusion complex in Demineralised witer was made and kept at 50°C temperature. -or-19 Period weeks % Potency 50°C temperature 0 101.02 2 98.82 4 96.39 EXAMPLE 7 : Sustained release tablet: Ingredients Weight per Tablet Total quantiry per Batch Bupropion hydrochloride-beta 458 mg 4580 gir cyclodextrin inclusion complex of (Equivalent to 150mg Example 1. bupropion hydrochloride Hydroxypropyl cellulose : 10 mg 100 gm Hydroxypropyl methyl cellulose ; 40 mg 400 gm Povidone K-30 5 15 mg 150 gm Aerosil® ' 1.5 mg 15 gm Magnesium stearate ; 1.5 mg 15 gm Bupropion hydrochloride-beta cyclodextrin complex, hydroxypropyl cellulose and hydroxypropyl meuhyl cellulose were sifted tfirough #40 mesh screen. The screened ingredients were transferred to a mixer granulator and mixed for 10 minutes. The mixed material was granulated with solution of povidone k-30 in isopropyl alcohol. -M-2tO The granulated material was dried in the tray oven at 40°C and then milled to get required size granules. Aerosil® and magnesium stearate were sifted through #60 mesh screen to milled materials. The screened and milled material was Mended in a double cone blender for 15 minutes- The blend material was compressed into tablets with compression weight of about 526 mg per tablet. The compressed tablet cores ( 5260 gm) were aqueous film coated using 948.8 gm of the following coating formulation. J Ingredients j Weight per Tablet Total quantity per Batch | Hydroxypropyl methyl cellulose 4 mg 40 gm | Titanium dioxide 1.6 mg 16 gm Propylene glycol 0.32 mg 3.2 gm j Polyethylene glycol j 0.32 mg 3.2 gm Talc | 2.4 mg 24 gm | Isopropyl alcohol 21.52 mg 215.2 gm | Demineralised water 64.6 mg 646 gm j Red iron oxide 012 mg 1.2gm The tablet cores were coated using Accela Coata tablet coating machine. Bed Temperature : 38-40°C. Inlet Temperature: 60°C. Pan speed during warming : 1-2 RPM. Pan speed during coating : 4-5 RPM. Spray Rate : 40 - 45 ml per minute. Accelerated stability study : Periodweek % Potency 40°C / 75% RH % Potency 50°C 0 100.56 100.56 4 100.35 99.35 8 100.11 98.02 12 99.92 96.89 The in-vitro release rate of bupropion hydrochloride form the sustained release tablets disclosed (whether or not film coated) herein in 0.1 N HCl up to first hour and then continued in Phosphate buffer pH 6.8 USP, is preferably as follows Time (Hours) % Bupropion HCl release FHour(In 0.1 NHC1) 27 - 29 % 2nd Hour(Phosphate Buffer pH 6.8) 44-47 % 4,h Hour(Phosphate Buffer pH 6.8) 64 - 68 % 8,h Hour(Phosphate Buffer pH 6.8) 89 - 93 % EXAMPLE 8 : Sustained release tablet: - - -2Y-SL9L Ingredients ■ Weight per Tablet Total quantity per Batch Bupropion hydrochloride-beta 458 mg 4580 gm cyclodextrin inclusion complex of "Equivalent to 150mg Example 1. bupropion hydrochloride Carboxymethyl cellulose sodium 10 mg 100 gm Hydroxypropyl methyl cellulose 40 mg 400 gm Povidone K-30 15 mg 150 gm Aerosil® 1.5 mg 15 gm Magnesium stearate 1-5 mg 15 gm Bupropion hydrochloride-beta cyclodextrin complex, carboxymethyl cellulose sodium anc hydroxypropyl methyl cellulose were sifted through =40 mesh screen. The screened ingredients were transferred to a mixer granulator and mixed for 10 minutes. The mixed material was granulated with solution of povidone k-30 in isopropyl alcohol. The granulated material was dried in the tray oven at 40°C and then milled to get required dze granules. Aerosil® and magnesium stearate were sifted through #60 mesh screen to milled materials. The screened and milled material was blended in a double cone blender for 15 minutes. The blepd material was compressed into tablets with compression weight of about 526 mg per tablet. The compressed tablet cores ( 5260 gm) were aqueous film coated using 948.8 gm of the following coating formulation. Ingredients Weight per Tablet Total quantity per Batci Hydroxypropyl methy cellulose 4 mg 40 gm Titanium dioxide 1.6 mg 16gm Propylene glycol 0.32 mg 3.2 gm Polyethylene glycol 0.32 mg 3.2 gm Talc 2.4 mg 24 gm | 215.2 gm j Isopropyl alcohol 21.52 mg Demineralised water 64.6 mg 646 gm Red iron oxide 012mg 1.2gm The tablet cores were coated using Accela Coata tablet coating machine. Bed Temperature : 38-40°C. Inlet Temperature : 60°C. Pan speed during warming : I -2 RPM. Pan speed during coating : 4-5 RPM. Spray Rate : 40- 45 ml per minute. Accelerated stability study: Period week % Potency 40°C / 75% RH % Potency 50°C 0 99.95 99.95 4 99.73 98.69 8 .' 99.52 97.43 12 99.29 96.25 -.23-- $1+ The in-vitro release rate.of bupropion hydrochloride form the sustained release tac."ets disclosed' (whether or not film coated) herein in 0.1 N HCI up to first hour and then continued in Phosphate buffer pH 6.8 USP. is preferably as follows Time (Hours) % Bupropion HCI release 1st Hour(In 0.1 N HCI) 25-27 % 2nd Hour(Phosphate Buffer pH 6.8) i3 - 48 % 4,h Hour(Phosphate Buffer pH 6.8) 63-65% 8,h Hour (Phosphate'BufferpH6.8) 88 - 92 % EXAMPLE 9 : Sustained release tablet: Ingredients Weight per Tablet Toial quantity per Batch Bupropion hydrochloride-beta cyclodextrin inclusion complex of Example 1. 458 mg(Equivalent to 150mgbupropion hydrochloride 45SO gm Stearic acid 10 mg 100 gm Hydroxypropyl methyl cellulose 32 mg | 320 gm Povidone K-30 15 mg 150 gm Aerosil® 1.5 mg 15 gm Magnesium stearate 1.5 mg 15gm -.34-- S-S* Bupropion hydrochloride-beta cyclodextrin complex, stearic acid and hydroxyproDvl me::v[ cellulose were sifted through #40 mesh scree.-. The screened ingredients were transferred to a mixer granulator and mixed for 10 minute.-. The mixed material was granulated with solution of povidone k-30 in isopropyl alcohol. The granulated material was dried in the tray oven at 40°C and then milled to get require:: ;ize granules. AerosiKS and magnesium stearate were sifted through #60 mesh screen to milled material!. The screened and milled material was blended in a double cone blender for 15 minutes. The bisid material was compressed into tablets with compression weight of about 518 mg per tablet. The compressed tablet cores (5180 gm) were iqueous film coated using 948.8 gm of the following coating formulation. Ingredients Weight per Tablet Total quantity per Batch Hydroxypropyl methyl cellulose 4 rrg 40 gm Titanium dioxide 1.6 mg 16 gm Propylene glycol 0.32 mg 3.2 gm Polyethylene glycol 0.32 mg 3.2 gm Talc 2.4 mg 24 gm Isopropyl. alcohol 21.52 mg 21-5:2 gm Demineralised water 64.6 mg 646 gm Red iron oxide 012 mg 1.2gm -J5-- The tablet cores were coated using Acceia Coata tablet coating machine. Bed Temperature: 3 8-40°C. Inlet Temperature : 60°C. -Pan speed during warming : 1-2 RPM. Pan speed during coating : 4-5 RPM. Spray Rate : 40 - 45 ml per minute. Accelerated stability study : Period week % Potency 40°C/75%RH % Potency 50°C 0 100.46 100.46 4 100.23 99.13 8 100.02 97.84 12 99.87 96.5 The in-vitro release rate of bupropion hydrochloride form the sustained release tablets disposed (whether or not film coated) herein in 0.1 N HCl up to first hour and then continued in Phosphate buffer pH 6.8 USP, is preferably as follows -XT- 31 Time (Hours) | % Bupropion HC1 release 1st Hour ' i 28 - 33 % ' i I (In 0.1 NHC1) I 2nd Hour 150-57% (Phosphate Buffer pH 6.8) [ 4lh Hour | 68 - 72 % (Phosphate Buffer pH 6.8) 8,h Hour I 85 - 92 % (Phosphate Buffer pH 6.S) EXAMPLE 10 : Sustained release tablet: Ingredients Weight per Tablet Total quantity per Batch Bupropion hydrochloride-beta cyclodextrin inclusion complex of Example 1. 458 mg(Equivalent to 150mgbupropion hydrochloride 4580 gm Hydroxypropyl cellulose 30 mg 300 gm Hydroxypropyl methyl cellulose 25 mg 250 gm Povidone K-30 15 mg 150gm Aerosil® 1.5 mg 15 gm Magnesium stearate 1.5 mg 15 gm Bupropion hydrochloride-beta cyclodextrin complex, hydroxypropyl cellulose and - ^hydroxypropyl methyl cellulose were sifted tiirough #40 mesh screen. -ar- 38 The screened ingredients were transferred to a mixer granulator and mixed for 10 minute-.. The mixed materia! was granulated with solution of povidone k-30 in isopropyl alcohol. The granulated material was dried in the tray oven at 40°C and 'hen milled to get require:: :"ize granules. Aerosil® and magnesium stearate were sifted through #60 mesh screen to milled materials The screened and milled material was blended in a double cone blender for 15 minutes. The blend material was compressed into tablets with compression weight of about 531 mg per tablei The compressed lablet cores ( 5310 gm) were aqueous film coated using 948.8 gm of the following coating formulation. Ingredients Weight per Tablet Total quantity per Batch Hydroxyproryl methyl cellulose 4 mg 40 gm Titanium dioxide 1.6 mg 16gm Propylene glycol 0.32 mg 3.2 gm Polyethylene glycol 0.32 mg 3.2 gm Talc 2.4 mg 24 gm Isopropyl alcohol 21.52 mg 215.2 gm Demineralisei water 64.6 mg 646 gm Red iron oxide 012 mg 1.2gm The tablet cores were coated using Accela Coata tablet coating machine. Bed Temperature: 38-40"C. Inlet Temperature : 60°C. Pan speed during warming : 1 -2 RPM Pan speed during coating : 4-5 RPM. Spray Rate : 40 - 45 ml per minute. Accelerated stability srudv ; Period week % Po:ency 40°C 75% RH % Potency 50°C 0 101.2 101.2 4 100.9" 99.35 8 100.63 98.49 12 100.36 97.19 The in-vitro release me of bupropion hydrochloride form the sustained release tablets disclosed (whether or not film coated) herein in 0.1 N HCl up to first hour and then continued in Phosphate buffer pH 6.8 USP, is preferably as follows Time (Hours) % Bupropion HCl release lsl Hour(In 0.1 NHC1) 27-28% 2nd Hour(Phosphate Buffer pH 6.8) 44-50% 4,h Hour(Phosphate Buffer pH 6.8) 64-66% 8,h Hour(Phosphate Buffer pH 6.8) 92-94% -2T- 30 EXAMPLE 11 : Sustained release capsule : Ingredients Weight per Tablet Total quantity' per Batch Bupropion hydrochloride-beta cyclodextrin inclusion complex of Example 1. 458 mg(Equivalent to 150mg bupropion hydrochloride 4580 gm Hydroxypropyl cellulose 10 mg 100 gm Hydroxypropyl methyl cellulose 40 mg 400 gm Povidone K-30 15 mg 150 gm Aerosil® 1.5 mg 15 gm Magnesium stearate ( 1.5 mg 15 gm Bupropion hydrochloride-beta cyclodextrin complex, hydroxypropyl cellulose and hydroxypropyl methyl cellulose were sifted through #40 mesh screen. The screened ingredients were transferred to a mixer granulator and mixed for 10 minutes. The mixed material was granulated with solution of povidone k-30 in isopropyl alcohol. The granulated material was dried in the tray oven at 40°C and then milled to get required size granules. -3a--3i Aerosil® andmagnesium stearate were sifted thrcagh =60 mesh screen to milled matemis. The screened and milled material was blended in a double cone blender for 15 minutes. The "Send material was compressed into compact slugs with weight of about 526 mg and filled in ;;ze 0 capsule. . Accelerated stability study: Period week % Potency 40°C / 75% RH % Potency 5(FC 0 99.99 99.99 4 99.74 98.66 8 99.52 97.42 12 99.24 96.105 The in-vitro release rate of bupropion hydrochloride form the sustained release tablets disclosed (whether or not film coated) herein in 6.1 N HCl up to first hour and then continued in Phosphate buffer pH 6.8 USP, is preferably as Mows Time (Hours) c ] Bupropion HCl release ls,Hour(In 0.1 N HCl) " - 29 % 2nd Hour(Phosphate Buffer pH 6.8) 44-47 % 4th Hour(Phosphate Buffer pH 6.8) 6^r - 68 % 8th Hour(Phosphate Buffer pH 6.S) 89-93% ->r- 3SL EXAMPLE 12: Sustained release tablet: Ingredients Weight per Tablet Total quantity per Batch Bupropion hydrochloride-beta cyclodextrin inclusion complex of Example 4. 766 mg(Equivalent to 150mgbupropion hydrochloride 7660 gm Hydroxypropyl cellulose 20 mg 200 gm Hydroxypropyl methyl cellulose 80 mg 800 gm Povidone K-30 20 mg 200 gm Aerosil® 2mg 20 gm Magnesium stearate 2mg 20 gm Bupropion hydrochloride-beta cyclodextrin complex, hydroxypropyl cellulose and hydroxypropyl methyl cellulose were sifted through #40 mesh screen. The screened ingredients were transferred to a mixer granulator and mixed for 10 minutes. The mixed material was granulaied with solution of povidone k-30 in isopropyl alcohol. The granulated material was dried in the tray oven at 40°C and then milled to get required size granules. --32*- 33 Aerosil® and magnesium stearate were sifted through #60 mesh screen to milled materials. The screened and milled material was blended in a double cone blender for 15 minutes. The btend material was compressed into tablets with compression weight of about 890 mg per tablet The compressed tablet cores ( 8900 gm) were aqueous film coated using 1422.9 gm of the following coating formulation. Ingredients Weight per Tablet Total quantity per Batci Hydroxypropvl methyl cellulose 6 mg 60 gm' Titanium dioxide 2.4 mg 24 gm Propylene glycol 0.48 mg 4.8 gm Polyethylene glycol 0.48 mg 4.8 gm Talc 3:6 mg 36 gm Isopropyl alcohol 32.28 mg 322.8 gm Demineralised water 96.9 mg 969 gm Red iron oxide 0.15mg 1.5 gm The tablet cores were coated using Accela Coata tablet coating machine. Bed Temperature: 38-40°C. Inlet Temperature: 60°C. Pan speed during warming : 1-2 RPM Pan speed during coating : 4-5 RPM. Spray Rate : 40 - 45 ml per minute. Accelerated stability study: -xr-3*+ Period week % Potency 40°C / 75% RH % Potency 50°C 0 99.97 99.97 99.71 98.72 8 99.42 97.41 12 99.13 96.09 The in-vitro release rate of bupropion hydrochloride form the sustained release tablets disclosed (whether or not film coated) herein in 0.1 N HCl up to first hour and then continued in Phosphate buffer pH 6.8 USP, is preferably as follows Time (Hours) % Bupropion HCl release PHour(In 0.1 N HCl) 29-31% 2nd Hour(Phosphate Buffer pH 6.8) 46 - 50 % 4* Hour(Phosphate Buffer pH 6.8) 68 - 70 % 8* Hour(Phosphate Buffer pH 6.8) 90 - 93 % The inclusion complex of the present invention is characterized as follows : Thermograms of bupropion hydrochloride, beta cyclodextrin, a physical mixture of bupropion hydrochloride and beta cyclodextrin 1: 1 and the bupropion hydrochloride-beta cyclodextrin inclusion complex of the invention are as shown in figures 1 A, IB, IC, and ID respectively. The • Vr- 3if peak at 224 °C in Fig 1A was due to.the melting of bupropion hydrochloride. Fig !B show's an endothermic peak at 168 °C corresponding to beta cyclodextrin. The physical mixture showed endothermic peaks of both bupropion hydrochloride at 205.9 °C and beta cyclodextrin at 159.5 °C as in Fig 1C. The inclusion complex showed an endothermic peak of cyclodextrin sin-d to 126 °C while endothermic peak of the bupropion hydrochloride remained at 209°C as in rig ID. The weights of the inclusion complex and physical mixture were strictly identical. Normally, when an acidic or basic drug is taken without its salts, it has been observed that the drug's endothermic peak merges with the endothermic peak of beta cyclodextrin. In this case, however, a substantial shift in endothermic peak of beta cyclodextrin in the inclusion complex is seea but not in the case of the physical mixture. This is seen as a proof of inclusion complex fonnHtion. The formation of inclusion complex is further evidenced by 2D NOESY NMR spectra Esirg Bruker 600 Hz FTNMR. While the invention has been described with respect to certain specific embodiments, it will be appreciated that many modifications and changes may be made by those skilled in the an without departing from the invention. It is intended, therefore, by the appended claims to cover all such modifications and changes as may fall within the true spirit and scope of the invention. -W- 3& We claim : 1. An inclusion complex of bupropion hydrochloride that is (+)-l-(3-chlorophenyl)-2-[(l,l-dimethylethyl)amino]-l-propane hydrochloride, of the following formula ■C(CHJ)3 CH3 Formula 1 with beta-cyclodextrin, where bupropion hydrochloride and beta cyclodextrin are present in a molar ratio of 1 : (0.25 --). 2. The inclusion complex of claim 1, wherein the molar ratio of bypropion hydrochloride to beta cyclodextrin is 1 : (0.5 - 2). 3. A stabilized sustained release formulation of an inclusion complex of bupropion hydrochloride with beta-cyclodextrin in combination with pharmaceutically acceptable excipients, wherein buproprion hydrochloride and beta-cyclodextrin are present in a molar ratio of 1 : (0.25 - 1). 4. The stabilized sustained release formulation of claim 3, wherein the pharmaceutically acceptable excipients are drug release rate controlling materials comprising a combination of a first excipient consisting of hydroxypropyl methyl cellulose with a 37 second excipient selected from a group consisting of hydroxypropyl cellulose, sodium carboxymethyl cellulose and stearic acid, where the first excipient and the second excipient are in aweight ratio of about 1 : 01 to 0.1 :1. 5. The stabilized sustained release formulation of claim 3,w herein bupropion hydrochloride and beta-cyclodextrin are present in a molar ratio of 1 : (0.5 - 2). 6. The stabilized sustained release formulation of claim 3, wherein bupropion hydrochloride is present in an amount selected from 50mg, 75mg, lOOmg and 150mg. 7. A method for the preparation of a stabilized sustained release formulation containing a bupropion hydrochloride-beta cyclodextrin inclusion complex, comprising : a) sifting together an amount of bupropion hydrochloride-beta cyclodextrin inclusion complex and an amount of one or more drug release rate controlling materials, through a screen; b) mixing the sifted and screened inclusion complex and drug release rate controlling materials to form a mixed material; c) granulating the mixed material with alcohol; d) drying the granulated material in an oven; e) milling the dried granulated material to obtain granules; f) sifting a first mixture of pharmaceutically acceptable excipients through a mesh screen and adding the sifted excipients to the milled granules; 38 g) blending the sifted excipients and the milled granules to form a blended material; h) compressing the blended material into oral dosage forms, the oral dosage forms having a compression weight of approximately 500-900 mg per form; and i) coating the oral dosage forms with an aqueous second mixture of pharmaceutically acceptable excipients, wherein bupropion hydrochloride and beta cyclodextrin are present in a molar ratio of 1:0.5-1). 8. The method of claim 7, wherein the drug release rate controlling materials comprise a combination of a first substance consisting of hydroxypropyl methyl cellulose with a second substance selected from a group consisting of hydroxypropyl cellulose, sodium caboxymethyl cellulose and stearic acid. 9. The method of claim 7, wherein the first mixture of pharmaceutically acceptable excipients comprises Aerosil® and magnesium stearate. 10. The method of claim 7, wherein the aqueous second mixture of pharmaceutically acceptable excipients consists of an aqueous mixture of hydroxypropylmethyl cellulose, titanium dioxide, propylene glycol, polyethylene glycol, talc, isopropyl alcohol, red 39 iron oxide, and demineralized water, with the hydroxypropylmethyl cellulose, titanium dioxide, propylene glycol, polyethylene glycol, talc, isopropyl alcohol, red iron oxide, and demineralized water being present in the weight ratio of 40:16:3.2:3.2:24:215.2:1.2:646. 11. The method of claim 7, wherein the molar ratio of burpopln hydrochloride to beta cyclodextrin is l:(l-2). Dated this 13th day of January 2004. (Jose M A) '. ofKhaitan&Co Agent for the Applicants 40

Documents:

51-mum-2004-cancelled pages(22-12-2006).pdf

51-mum-2004-claims(granted)-(22-12-2006).doc

51-mum-2004-claims(granted)-(22-12-2006).pdf

51-mum-2004-claims.doc

51-mum-2004-claims.pdf

51-mum-2004-correspondence(22-12-2006).pdf

51-mum-2004-correspondence(ipo)-(28-7-2008).pdf

51-mum-2004-correspondence-received-150104.pdf

51-mum-2004-correspondence-received-170104.pdf

51-mum-2004-correspondence-received-231105.pdf

51-mum-2004-correspondence-received.pdf

51-mum-2004-descripiton (complete).pdf

51-mum-2004-drawing(16-1-2004).pdf

51-mum-2004-drawings.pdf

51-mum-2004-form 1(16-1-2004).pdf

51-mum-2004-form 18(24-11-2005).pdf

51-mum-2004-form 2(granted)-(22-12-2006).doc

51-mum-2004-form 2(granted)-(22-12-2006).pdf

51-mum-2004-form 26(16-1-2004).pdf

51-mum-2004-form 3(16-1-2004).pdf

51-mum-2004-form 5(22-12-2006).pdf

51-mum-2004-form 8(20-1-2004).pdf

51-mum-2004-form-1.pdf

51-mum-2004-form-18.pdf

51-mum-2004-form-2.doc

51-mum-2004-form-2.pdf

51-mum-2004-form-3.pdf

51-mum-2004-form-5.pdf

51-mum-2004-form-8.pdf

51-mum-2004-petition under rule 137(22-12-2006).pdf

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