Extended release formulation

Abstract

This invention relates to a 24 hour extended release dosage formulation and unit dosage form thereof of venlafaxine hydrochloride, an antidepressant, which provides better control of blood plasma levels than conventional tablet formulations which must be administered two or more times a day and further provides a lower incidence of nausea and vomiting than the conventional tablets. More particularly, the invention comprises an extended release formulation of venlafaxine hydrochloride comprising a therapeutically effective amount of venlafaxine hydrochloride in spheroids comprised of venlafaxine hydrochloride, microcrystalline cellulose and, optionally, hydroxypropylmethylcellulose coated with a mixture of ethyl cellulose and hydroxypropylmethylcellulose.

What is claimed is:  
     
         1 . An encapsulated, extended release formulation of venlafaxine hydrochloride comprising a pharmaceutically acceptable capsule containing a therapeutically effective amount of venlafaxine hydrochloride in spheroids comprised of venlafaxine hydrochloride, microcrystalline cellulose and, optionally, hydroxypropylmethylcellulose coated with a mixture of ethyl cellulose and hydroxypropylmethylcellulose.  
     
     
         2 . An extended release formulation according to  claim 1  wherein the spheroids are comprised of from about 6% to about 40% venlafaxine hydrochoride by weight, about 50% to about 94% microcrystalline cellulose, NF, by weight, and, optionally, from about 0.25% to about 1% by weight of hydroxypropylmethylcellulose, USP.  
     
     
         3 . An extended release formulation according to  claim 1  wherein the spheroids are coated with from about 2% to about 12% of total formulation weight of film coating comprised of from about 80% to about 90% by weight of film coating of ethyl cellulose, NF, and from about 10% to about 20% by weight of film coating of hydroxypropylmethylcellulose, USP.  
     
     
         4 . An extended release formulation according to  claim 1  wherein the spheroids are comprised of from about 30% to 40% venlafaxine hydrochloride by weight, about 50% to about 70% microcrystalline cellulose, NF, by weight, and, optionally, from about 0.25% to about 1% by weight of hydroxypropylmethylcellulose, USP.  
     
     
         5 . An extended release formulation according to  claim 4  wherein the spheroids are coated with from about 2% to about 12% of total formulation weight of film coating comprised of from about 80% to about 90% by weight of film coating of ethyl cellulose, NF, and from about 10% to about 20% by weight of film, coating of hydroxypropylmethylcellulose, USP.  
     
     
         6 . An extended release formulation according to  claim 1  wherein the spheroids comprise from about 6% to about 30% venlafaxine hydrochloride by weight, about 70.1% to about 94% microcrystalline cellulose, NF, by weight and, optionally, from about 0.25% to about 1% by weight of hydroxypropylmethylcellulose,  
     
     
         7 . An extended release formulation according to  claim 6  wherein the spheroids are coated with from about 2% to about 12% of total weight of film coating comprised of from about 80% to about 90% by weight of film coating of ethyl cellulose, NF, and from about 10% to about 20% by weight of film coating of hydroxypropylmethylcellulose, USP.  
     
     
         8 . An extended release formulation according to  claim 6  wherein the spheroids comprise from about 5% to about 25% venlafaxine hydrochloride and from about 95% to about 75% microcrystalline cellulose, with an optional amount of from 0.25% to about 1% by weight of hydroxypropyhnethylcellulose  
     
     
         9 . An extended release formulation according to  claim 6  wherein the spheroids comprise from about 6% to about 25% venlafaxine hydrochloride and from about 94% to about 75% microcrystalline cellulose, with an optional amount of from 0.25% to about 1% by weight of hydroxypropylmethylcellulose.  
     
     
         10 . An extended release formulation according to  claim 6  wherein the spheroids comprise from about 6% to about 20% venlafaxine hydrochloride and from about 94% to about 80% microcrystalline cellulose, with an optional amount of from 0.25% to about 1% by weight of hydroxypropylmethylcellulose.  
     
     
         11 . An encapsulated, extended release formulation of venlafaxine hydrochloride according to  claim 1  having the following dissolution profile in USP Apparatus 1 (basket) at 100 rpm in purified water at 37° C.:  
       
         
           
                 
                 
                 
               
                     
                     
                 
                     
                     
                 
                     
                   Time (hours) 
                   Average % Venlafaxine HCl released 
                 
                     
                     
                 
                     
                    2 
                   <30 
                 
                     
                    4 
                   30-55 
                 
                     
                    8 
                   55-80 
                 
                     
                   12 
                   65-90 
                 
                     
                   24 
                   >80 
                 
                     
                     
                 
                     
                     
                 
             
                
                
                
                
               
               
                
                
                
                
                
                
                
               
            
           
         
       
     
     
         12 . An extended release formulation according to  claim 2  wherein the spheroids are composed of about 37% by weight of venlafaxine hydrochloride, about 0.5% by weight of hydroxypropylmethylcellulose 2208, and about 62% by weight of microcrystalline cellulose.  
     
     
         13 . A composition according to  claim 2  wherein the film coating is comprised of ethyl cellulose (4.81% of total weight) and hydroxypropylmethylcellulose (0.85% of total weight).  
     
     
         14 . A composition according to  claim 2  wherein the film coating comprises 6-8% by weight of total weight.  
     
     
         15 . A composition according to  claim 2  wherein the film coating is comprised of ethyl cellulose (2.48% of total weight) and hydroxypropylmethylcellulose (0.437% of total weight).  
     
     
         16 . A composition according to  claim 2  wherein film coating composition is comprised of ethyl cellulose having a 44.0-51.0% content of ethoxy groups and hydroxypropylmethylcellulose having a methoxy content of 28.0-30.0% and a hydroxypropoxy group content of 7.0-12.0%.  
     
     
         17 . A film coating composition according to  claim 2  which is comprised of about 85% by total weight of film coating of ethyl cellulose having a 44.0-51.0% content of ethoxy groups, and about 15% by total weight of film coating of hydroxypropyhnethylcellulose having a methoxy content of 28.0-30.0% and a hydroxypropoxy group content of 7.0-12.0%.  
     
     
         18 . A film coating composition according to  claim 2  which is comprised of 85% by weight of ethyl cellulose type HG 2834 and 15% by weight of hydroxypropylmethylcellulose type 2910.  
     
     
         19 . An extended release formulation of venlafaxine hydrochloride for once daily administration which comprises spheroids containing 31.3% venlafaxine, 62.17% microcrystalline cellulose and 0.5% hydroxypropylmethylcellulose type 2208, coated with a quantity of a mixture comprised of 85% ethyl cellulose type HG 2834 and 15% hydroxypropylmethylcellulose type 2910 sufficient to give coated spheroids having a dissolution profile which gives the desired release rate over a 24 hour period.  
     
     
         20 . An extended release formulation of venlafaxine hydrochloride according to  claim 2  which provides peak serum levels of up to 150 ng/ml and extended therapeutically effective plasma levels over a twenty four hour period.  
     
     
         21 . A method for providing a therapeutic blood plasma concentration of venlafaxine over a twenty four hour period with diminished incidences of nausea and emesis which comprises administering orally to a patient in need thereof, an encapsulated, extended release formulation that provides a peak blood plasma level of venlafaxine in from about four to about eight hours, said formulation containing venlafaxine hydrochloride as the active ingredient.  
     
     
         22 . A method for eliminating the troughs and peaks of drug concentration in a patients blood plasma attending the therapeutic metabolism of plural daily doses of venlafaxine hydrochloride which comprises administering orally to a patient in need thereof, an encapsulated, extended release formulation that provides a peak blood plasma level of venlafaxine in from about four to about eight hours, said formulation containing venlafaxine hydrochloride as the active ingredient.