Title of Invention

DELAYED RELEASE FORMULATION CONTAINING VENLAFAXINE AND A PROCESS FOR PREPARING THE SAME

Abstract

DELAYED RELEASE FORMULATION CONTAINING VENLAFAXINE AND A PROCESS FOR PREPARING THE SAME A delayed release oral pharmaceutical formulation containing therapeutically effective amount of Venlafaxine or its pharmaceutically acceptable salts, prodrugs, and metabolites thereof to maintain steady state blood level for 24 hours by dispersing the drug in a rate controlled polymeric matrix using pH dependent or pH independent polymers. The invention also relates to a process for the preparation of delayed release formulation containing Venlafaxine Pellets or mini tablets in capsule dosage form for the treatment of depression.

Full Text

FIELD OF INVENTION The present invention relates to a modified release dosage formulation containing a therapeutically effective amount of Venlafaxine or its pharmaceutically acceptable salts, prodrugs and metabolites thereof. The present invention is useful for the treatment of depression. The invention also relates to a process for the preparation of modified release dosage formulation containing a therapeutically effective amount of venlafaxine or its pharmaceutically acceptable salts, prodrugs and metabolites thereof. BACKGROUND AND PRIOR ART OF THE INVENTION: Venlafaxine hydrochloride is a structurally novel antidepressant for oral administration. It is chemically unrelated to tricyclic, tetracyclic, or other available antidepressant agents. It is designated (R/S)-l-[2-(dimethylamino)-I-(4"methoxyphenyI) ethyl] cyclohexanol hydrochloride or (±)-l-[a-[(dimethyl-amino) methyl]-p-methoxybenzyl] cyclohexanol hydrochloride and has the empirical form»'la of C17H27NO2 HC1. ?ls molecf'-ai weight is 313.87. The structural formula is shown below. Venlafaxine and the acid addition salts thereof are disclosed in U.S. Pat. No. 4,535,186. Venlafaxine hydrochloride is presently administered to adults in compressed conventional tablet form in doses ranging from 75 to 350 mg/day (Venlafaxine HCl equivalent to 25mg, 37.5mg, 50mg, 75mg or lOOmg Venlafaxine), in divided doses two or three times a day. In therapeutic dosing with venlafaxine hydrochloride tablets, rapid dissolution results in a rapid increase in blood plasma levels of the active compound shortly after administration followed by a decrease in blood plasma levels over several We Claim: K A solid stable modified release pharmaceutical formulation and its process provide venlafaxine hydrochloride in the form of pellets and / or minitablets in capsules which are resistant to acid media in stomach and dissolves in alkaline media in the distal portion of the small intestine and / or proximal portion of colonic region and useful for the treatment of depression comprises: a) An inert core comprising of a solid carrier: Spherical non-pareil seeds of microcrystalline cellulose (Celpheres) with diameters IO|iim to lOOOjim, more preferably 75fxm to 500|am. b) A coating on the inert core with a drug layer comprising a mixture of Venlafaxine hydrochloride and polymer or a mixture of polymers, an antiadherent agent with a suitable plasticizing agent and forming the resulting mixture into pellets. c) The resulting pellets are coated with modified release layer consisting of copolymers of methacrylic acid, an anti adherent agent with a suitable plasticizing agent. d) The drug loading and modified release coating may be applied on a solid carrier, in fluid bed processor or mechanized perforated coating pan, or using any suitable coating equipment. e) The coated pellets will be filled into hard gelatin capsules or sachets or compressed into mini tablets and filled into hard gelatin capsules. f) Optionally providing an intermediate layer or a barrier containing a mixture of polymers with a diluent, an antiadherent agent with a suitable plasticizing agent. g) Providing 24-hour release mechanism in the distal portion of the small intestine and / or proximal portion of colonic region. 2. A formulation and process as claimed in claim 1, wherein the amount of core may be in the range of preferably about 0.1% to about 50% and more preferably about 1% to about 30% of the total weight of the composition. 3* A formulation and process as claimed in claims 1 to 2, wherein the drug layer on substrate contains a therapeutically effective ingredient, Venlafaxine or its salts, prodrugs and metabolites thereof, preferably in the range of about 5% w/w to about 85% w/w and more preferably in the range of about 7.5% w/w to about 75% w/w of the total weight of the composition. 4. A formulation and process as claimed in claims 1 to 3, wherein the present invention comprises functional coating polymer in drug loading comprising a mixture of Eudragit RSlOO and Eudragit E 100 in the ratio between 100:0 and 10:50. 5. A formulation and process as claimed in claims 1 to 4, wherein the present invention Eudragit RS 100 [poly (ethyl acrylate, methylmethascrylate, trimethylaminoethyl methacrylate chloride) 1:2:0,1], and Eudragit E 100 [poly (butyl methacrylate, (2-dimethy; aminoethyl) methacrylate, methyl mathacrylate) 1:2:1], incorporated as binders in drug loading suspension. The.amount of polymer Eudragit RS 100 employed ranges preferably from about 1% w/w to about 50% w/w, more preferably 2 to 30% w/w and Eudragit El00 employed ranges preferably from about 0.5% w/w to about 30% w/w more preferably 1 to 20% w/w of the total weight of the composition* 6. A formulation and process as claimed in claims I to 5, wherein the present invention functional coating polymer wherein the amount of polymer mixture, Eudragit RSI00 and Eudragit E 100 in drug loading stage is 1 to 90%w/w, 7. A formulation and process as claimed in claims I to 6, wherein the present invention barrier coating / seal coating shall be given optionally as a second layer before modified release coating using a mixture of Eudragit RS 100 and Eudragh E 100. 8. A formulation and process as claimed in claims I to 7, wherein the present invention the amount of polymer mixture, Eudragit RSI00 and Eudragit E 100 in optional barrier coating stage is 2 to 95% of the active ingredient. 9. A formulation and process as claimed in claims I to 8, wherein the present invention Eudragit RLPO [poly (ethylacrylate, methylmethacrylate trimethylammonio ethyl methacrylate chloride) 1:2:0.2], biodegradable polymers such as dUpolylactic acid and polyglycolic acid or their mixture or their copolymers or a mixture thereof, carbopol 71G, carbopol 971P, calcium pectinate, pre-gelatinized starch, hypromellose, hydroxypropylmethylcellulose acetate succinate, ethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, methylcellulose. polyvinylpyrrolidone, sodium carboxymethylcellulose, carboxymethylcellulose, sodium alginate and other salts of alglnic acid, shellac, agar, guar, marine colloids (carrageenan, NF), locust bean, karayaTM, pectin, and tragacanth and the like or a mixture thereof optionally may also be incorporated as binding agents. 10. A formulation and process as claimed in claims 1 to 9, wherein the present invention contains Eudragit FS 30D as colonic functional polymer. The present pharmaceutical compositions comprise the polymer in the range preferably about 0,l%w/w to about 75% w/w, and more preferably about 0.75% w/w to about 55% w/w of the total weight of the composition. 11. A formulation and process as claimed in claims 1 to 10, wherein the present invention Eudragit S 100, Eudragit L 100-55, Eudragit LIOO, Eudragit L 30 D-55^ other polymethacrylates, hydroxypropylmethylcellulose, hydroxypropylcellulose, ethylcellulose, hydroxypropylmethylcellulose phthalate, cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropylmethylcellulose acetate succinate, polyvinylpyrrolidone, sodium carboxy methyl cellulose, carboxy methyl cellulose, pH independent drug permeable polymer such as Eudragit NE 30D, Eudragit NE 40D, Eudragit NE 50D, or a mixture thereof, optionally may be used. 12. A formulation and process as claimed in claims 1 to 11, wherein the present invention uses Lustreclear LC 103, optionally as barrier coating material. 13. A formulation and process as claimed in claims I to 12, wherein the present invention comprises drug layer, optional barrier coating and modified release coating may contain talc as an anti-adherent agent. The amount of the anti-adherent ranges from 5% w/w to about 40% w/w, more preferably about 10% w/w to about 30% w/w of the total weight of the composition. 14. A formulation and process as claimed in claims I to 13, wherein the present invention hag other anti-adherent agents such as aerosil, milled silica (Syloid 244 FP) calcium carbonate, magnesium stearate, calcium stearate, calcium silicate, glyceryl behenate, light mineral oil, polyethylene glycol, sodium stf*aryl fum:)rate, stearic acid, hydrogenated vegetable oil, zinc stearate may be used optionally to prevent agglomeration, 15. A formulation and process as claimed in claims 1 to 14, wherein the present invention contains optionally polyethylene glycol 6000 polyethylene glycol 400, triethyl citrate, acetyltriethyl citrate, acetyltri-n-butyl citrate; glyceryl monostearate, polysorbate 80, dibutyl sebacate, diethyl phthalate, dibutyl phthalate, dioctyl phthalate, hydrogenated castor oil, triacetin cetyl alcohol, steryl alcohol and the like or mixture of phthalate and fatty alcohol may also be incorporated as a plasticizers for a sufficient film formation. The pharmaceutical compositions comprise the plasticizer in the range of about 0,1% w/w to about 30% w/w, preferably about 0.5% w/w to about 20% w/w, and more preferably about 0.75% w/w to about 15% w/w, of the total weight of the composition. 16. A formulation and process as claimed in claims 1 to 15, wherein the present invention isopropyl alcohol and acetone in the ratio from 9:1 to about 1:9 as processing solvents during coating or one or more solvents such as ethyl alcohol, purified water and the like or mixture thereof or other suitable solvents may also be used optionally as processing solvents. 17. A formulation and process as claimed in claims 1 to 16, wherein the present invention, optionally an additional layer may be applied to the modified release coated pellets before drying by wurster coating with Lustreclear LC 103, or hydroxypropylcellulose (Klucel EF / LF) or methyl cellulose (Metolose SM-4) for robust film coating to decrease tackiness of beads for subsequent processing. 18, A formulation and process as claimed in claims I to 17, wherein the present invention optionally, coloring agents such as titanium dioxide, other suitable colors and mixture thereof may also be incorporated. 19, A formulation and process as claimed in claims 1 to 18, wherein the present invention the formulation optionally contains one or more excipients selected from microcrystalline cellulose, starch, pregelatinized starch, mannitol, sorbitol, dextrose, sucrose, gelatin, dextrin, dicalcium phosphate, lactose, carboxyvinyl polymers, thiolated polymers, glycoproteins and poly (methylacrylate) derivatives, hyaluronic acid and chitosans, certain carbohydrates, plant lectins., bacterial adhesions, calcium silicate, carbomers, carrageenan, chitosan colloidal silicon dioxide, gelatin, glyceryl monooleate, polyethylene alkyl ethers, polyethylene glycol, polyethylene oxide, propylene carbonate, sodium ascorbate, polyvinylpyrrolidone, acacia, tragacanth, methylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose and ethylcellulose, alginic acid and salts of alginic acid, magnesium aluminum silicate, guar gum, xanthan gum, polysaccharide acids, bentonites, sucrose-based diluents; calcium sulfate monohydratej calcium sulfate dihydrate, calcium lactate trihydrate granular, kaolin, lactitol, calcium carbonate; glycine; sodium starch glycolate, croscarmellose sodium, clays (such as veegum), vegetable oils, triglycerides, and mixtures thereof. 20. A formulation and process as claimed in claims 1 to 19, wherein the present invention modified release pellets containing Venlafaxine HCL equivalent to 37,5mg, 75mg, 150mg, 225mg, 300mg, 375mg or 450mg Venlafaxine, will be filled into size 5 or 4 or 3 or 2 or 1 or 0 or 0 elongated or 00 hard gelatin capsules.and / or sachets to obtain » * * ' suitable strength. 21. A formulation and process as claimed in claims I to 20, wherein the present invention optionally other processing equipment such as Neo-cota, mechanized perforated coating pan, or any suitable coating equipment may be used* 22. A formulation and process as claimed in claims 1 to 21, wherein the present invention optionally the modified release pellets will be compressed into mini tablets and filled into hard gelatin capsules of suitable size.

Documents:

957-che-2004 abstract.pdf

957-che-2004 claims.pdf

957-che-2004 correspondance others.pdf

957-che-2004 description(complete).pdf

957-che-2004 drawings.pdf

957-che-2004-abstract.pdf

957-che-2004-claims.pdf

957-che-2004-correspondnece-others.pdf

957-che-2004-correspondnece-po.pdf

957-che-2004-description(complete).pdf

957-che-2004-description(provisional).pdf

957-che-2004-form 1.pdf

957-che-2004-form 18.pdf

957-che-2004-form 5.pdf

957-che-2004.tif