Stabilized controlled release substrate having a coating derived from an aqueous dispersion of hydrophobic polymer

Abstract

A stabilized solid controlled release dosage form having a coating derived from an aqueous dispersion of ethylcellulose is obtained by overcoating a substrate including a therapeutically active with an aqueous dispersion of ethylcellulose and then curing the coated substrate at a temperature and relative humidity elevated to a suitable level above ambient conditions until the coated dosage form attains a stabilized dissolution profile substantially unaffected by exposure to storage conditions of elevated temperature and/or elevated relative humidity.

1 . An oral controlled release pharmaceutical formulation comprising 
 a substrate comprising a therapeutically active analgesic agent, said analgesic incorporated into said formulation in an amount sufficient to provide a desired therapeutic effect,    a barrier layer over said substrate, said barrier layer comprising hydroxypropylmethylcellulose,    a controlled release layer over said barrier layer comprising an aqueous dispersion of plasticized ethylcellulose in an amount sufficient to obtain a controlled release of said analgesic when said formulation is exposed to an environmental fluid,    said coated substrate being cured to the temperature greater than the glass transition temperature of the aqueous dispersion of the plasticized ethylcellulose for at least about 24 hours.    
     
     
         2 . The formulation of  claim 1 , wherein said substrate is coated with said controlled release layer to a weight gain from about 2 to about 25%.  
     
     
         3 . The formulation of  claim 1 , wherein said substrate is selected from the group consisting of tablets, spheroids, microspheres, seeds, pellets, and ion-exchange resin beads.  
     
     
         4 . The formulation of  claim 1 , further comprising a second barrier layer over said controlled release layer, said second barrier layer comprising hydroxypropylmethylcellulose.  
     
     
         5 . The formulation of  claim 1 , wherein said controlled release coating further comprises a release-modifying agent in an amount effective to modify the rate of release of said analgesic from said cured, coated substrate.  
     
     
         6 . A method for obtaining an oral controlled release formulation of a therapeutically active analgesic agent, comprising: 
 coating a substrate comprising a therapeutically active analgesic agent with a barrier layer comprising hydroxypropylmethylcellulose;    applying a controlled release layer onto said substrate coated with said barrier layer, said controlled release layer comprising a sufficient amount of a plasticized ethylcellulose to obtain a predetermined controlled release of said analgesic when said coated substrate is exposed to an environmental fluid, said plasticized ethylcellulose being applied to said coated substrate as an aqueous dispersion;    curing said controlled release layered substrate at a temperature greater than the glass transition temperature of the aqueous dispersion of plasticized ethylcellulose for at least 24 hours, and thereafter optionally applying a second barrier coating to said substrate.    
     
     
         7 . The method of  claim 6 , wherein said substrate is selected from the group consisting of tablets, spheroids, microspheres, seeds, pellets, and ion-exchange resin beads.  
     
     
         8 . The method of  claim 6 , wherein said barrier agent comprises hydroxypropylmethylcellulose.  
     
     
         9 . The method of  claim 6 , further comprising applying said controlled release coating onto said substrate to a weight gain from about 2 to about 25%.  
     
     
         10 . The method of  claim 6 , further comprising 
 including a release-modifying agent in said controlled release coating in an amount effective to modify the rate of release of said active agent from said cured, coated substrate.    
     
     
         11 . A solid controlled release formulation, comprising a plurality of substrates comprising a therapeutically active analgesic agent, said formulation comprising an amount of said substrates sufficient to provide a desired effect when said formulation is orally administered to a patient, said substrates being overcoated with a barrier layer comprising hydroxypropylmethylcellulose, said barrier coated substrates being coated with a controlled release layer of plasticized ethylcellulose in an amount sufficient to obtain a controlled release of said analgesic when said formulation is exposed to a gastrointestinal fluid, said ethylcellulose being applied to said substrates as an aqueous dispersion, said coated substrates being cured at a temperature greater than the glass transition temperature of the aqueous dispersion of plasticized ethylcellulose for at least about 24 hours, to cause individual ethylcellulose particles in said coating to coalesce and to gradually slow the release of said analgesic when said formulation is exposed to aqueous fluid, until an endpoint is reached at which said cured coated substrate, when subjected to in-vitro dissolution, releases said analgesic in amounts which do not vary at any time point along the dissolution curve by more than about 20% of the total amount of active agent released, when compared to the in-vitro dissolution of said coated substrate prior to curing.  
     
     
         12 . The formulation of  claim 11 , wherein said cured, coated substrates provide the same rate of release immediately after curing to said endpoint, and after subsequent exposure to accelerated storage conditions of one month at a temperature of 37° C. and at a relative humidity of 80%.  
     
     
         13 . The formulation of  claim 11 , wherein said cured, coated substrates provide the same rate of release immediately after curing to said endpoint, and after subsequent exposure to accelerated storage conditions of one month at a temperature of 40° C. and at a relative humidity of 75%.  
     
     
         14 . The formulation of  claim 11 , wherein said controlled release coating is applied on said barrier coated substrates to a weight gain from about 2% to about 25%.  
     
     
         15 . The formulation of  claim 11 , wherein a plurality of said coated, cured substrates are placed in a capsule in an amount sufficient to provide an effective controlled release dose when contacted by an aqueous solution.  
     
     
         16 . The formulation of  claim 11 , wherein said formulation when administered orally provides effective blood levels of said analgesic for about 24 hours.  
     
     
         17 . The formulation of  claim 11 , which includes a controlled release coating sufficient to obtain a controlled release of said analgesic when measured by the U.S. patent Paddle Method at 100 rpm at 900 ml aqueous buffer (pH between 1.6 and 7.2) at 37° C. from about 12.5% to about 42.5% (by wt) analgesic released after 1 hours, from about 25% to about 55% (by wt) analgesic released after 2 hours, from about 45% to about 75% (by wt) analgesic released after 4 hours and from about 55% to about 85% (by wt) analgesic released after 8 hours.  
     
     
         18 . The formulation of  claim 11 , wherein said controlled release coating further comprises a release-modifying agent in an amount effective to modify the rate of release of said analgesic from said cured, coated substrate.  
     
     
         19 . The formulation of  claim 11 , which provides therapeutically effective blood levels of said analgesic when administered orally for about 12 hours.  
     
     
         20 . The formulation of  claim 11 , further comprising a second barrier layer overcoated on said controlled release coating.  
     
     
         21 . The formulation of  claim 20 , wherein said second barrier layer comprises hydroxypropylmethylcellulose.  
     
     
         22 . The formulation of  claim 1 , wherein said coated substrate is cured for a time from about 24 to about 72 hours.  
     
     
         23 . The formulation of  claim 1 , which includes a controlled release coating sufficient to obtain a controlled release of said analgesic when measured by the U.S. patent Paddle Method at 100 rpm at 900 ml aqueous buffer (pH between 1.6 and 7.2) at 37° C. from about 12.5% to about 42.5% (by wt) analgesic released after 1 hour, from about 25% to about 55% (by wt) analgesic released after 2 hours, from about 45% to about 75% (by wt) analgesic released after 4 hours and from about 55% to about 85% (by wt) analgesic released after 8 hours.  
     
     
         24 . The method of  claim 6 , wherein said curing is conducted for a time from about 24 to about 72 hours.  
     
     
         25 . The formulation of  claim 11 , wherein said coated substrates are cured for a time from about 24 to about 72 hours.  
     
     
         26 . The formulation of  claim 11 , wherein said analgesic is selected from the group consisting of codeine, morphine, dihydromorphinone and oxycodone.  
     
     
         27 . The oral controlled release formulation of  claim 1 , wherein said analgesic is selected from the group consisting of codeine, morphine, dihydromorphinone and oxycodone.  
     
     
         28 . The method of  claim 6 , wherein said analgesic is selected from the group consisting of codeine, morphine, dihydromorphinone and oxycodone.