Particulates

Abstract

A neutral poly(ethyl acrylate, methyl methacrylate) copolymer is employed as a carrier in the manufacture of pharmaceutical formulations containing an active ingredient. The formulations are preferably made by melt extrusion, and can have rubbery characteristics and can exhibit tamper resistance.

1 - 130 . (canceled) 
     
     
         131 . A process for preparing multiparticulates comprising melt extruding a granulate comprising a neutral poly(ethyl acrylate, methyl methacrylate) copolymer and an active agent. 
     
     
         132 . The process of  claim 131 , further comprising granulating a mix comprising a neutral poly(ethyl acrylate, methyl methacrylate) copolymer and an active agent to produce said granulate. 
     
     
         133 . The process of  claim 132 , wherein said granulating is wet granulating. 
     
     
         134 . The process of  claim 133 , wherein a dispersion of a neutral poly(ethyl acrylate, methyl methacrylate) copolymer is granulated. 
     
     
         135 . The process of  claim 134 , wherein during granulating a dispersion of a neutral poly(ethyl acrylate, methyl methacrylate) copolymer is added by spraying or dropwise to a mixture comprising said active agent. 
     
     
         136 . The process of  claim 135 , wherein said mixture comprising said active agent is a dry mixture. 
     
     
         137 . The process of  claim 132 , wherein said granulating is in a high shear mixer, a fluid bed granulator or a fluid bed granulator with a rotary insert. 
     
     
         138 . The process of  claim 132 , further comprising drying said granulate. 
     
     
         139 . The process of  claim 132 , further comprising extruding said granulate. 
     
     
         140 . The process of  claim 139 , further comprising drying said extruded granulate. 
     
     
         141 . The process of  claim 131 , comprising:
 (a) granulating a mix comprising a neutral poly(ethyl acrylate, methyl methacrylate) copolymer and an active agent to produce a granulate;   (b) optionally extruding said granulate;   (c) drying said granulate or extruded granulate to produce dried granulate;   (d) optionally screening and/or milling said dried granulate or said dried extruded granulate; and   (e) melt extruding the product from step (c) or (d).   
     
     
         142 . The process of  claim 141 , wherein said dried granulate or dried extruded granulate contains less than 5% w/w water. 
     
     
         143 . The process of  claim 141 , wherein the extruded product from step (e) is conveyed to a pelletiser and cut into multiparticulates. 
     
     
         144 . The process of  claim 141 , wherein a cutter cuts the extruded product from step (e) as it emerges from the extruder. 
     
     
         145 . The process of  claim 131 , wherein said extrusion provides a rubbery matrix in said multiparticulates. 
     
     
         146 . The process of  claim 145 , wherein said matrix provides tamper resistance which reduces release of the active agent upon grinding of the formulation and extraction. 
     
     
         147 . The process of  claim 146 , wherein said multiparticulates show at least one of the following characteristics (a) to (e) when tested by a test method comprising admixing a dosage amount of multiparticulates with 10 ml of the liquid in a glass flask and shaking at 500 to 600 oscillations per minute for 15 minutes using a Stuart Scientific Shaker Model SF1:
 (a) 15 minutes shaking in water at room temperature: less than 7.5% release of active agent;   (b) 5 minutes standing in water at 50° C. followed by 15 minutes shaking at the same temperature: less than 15% release of active agent;   (c) 5 minutes standing at 75° C. followed by 15 minutes shaking at the same temperature: less than 20% release of active agent;   (d) 5 minutes standing at 100° C. followed by 15 minutes shaking at the same temperature: less than 25% release of active agent;   (e) 15 minutes shaking in 40% ethanol at room temperature: less than 25% release of active agent.   
     
     
         148 . The process of  claim 131 , wherein the active agent is selected from the group consisting of an opioid, a stimulant, a barbiturate, an anti-depressant, a dissociative anaesthetic, and a combination thereof. 
     
     
         149 . The process of  claim 148 , wherein said active agent is oxycodone, or a pharmaceutically acceptable salt thereof. 
     
     
         150 . The process of  claim 131 , wherein said multiparticulates comprise at least one other polymer to modify release. 
     
     
         151 . The process of  claim 150 , wherein said other polymer is selected from the group consisting of an alkyl cellulose and a water insoluble ammonium methacrylate copolymer. 
     
     
         152 . The process of  claim 151 , wherein said other polymer is ethyl cellulose. 
     
     
         153 . The process of  claim 148 , wherein said multiparticulates comprise an opioid and further comprise an opioid antagonist. 
     
     
         154 . The process of  claim 153 , wherein the opioid is oxycodone, or a pharmaceutically acceptable salt thereof. 
     
     
         155 . The process of  claim 153 , wherein the opioid antagonist is naltrexone, or a pharmaceutically acceptable salt thereof. 
     
     
         156 . The process of  claim 153 , wherein the opioid is oxycodone, or a pharmaceutically acceptable salt thereof, and the opioid antagonist is naltrexone, or a pharmaceutically acceptable salt thereof. 
     
     
         157 . The process of  claim 131 , wherein said multiparticulates further comprise a plasticiser. 
     
     
         158 . the process of  claim 131 , wherein said multiparticulates further comprise a lubricant. 
     
     
         159 . The process of  claim 131 , wherein said multiparticulates comprise 15 to 50%, based on the total weight of ingredients, of a neutral poly(ethyl acrylate, methyl methacrylate) copolymer. 
     
     
         160 . The process of  claim 131 , wherein said multiparticulates comprise 5 to 55%, based on the total weight of ingredients, of active agent. 
     
     
         161 . A process for preparing a controlled release formulation, wherein said formulation comprises a plurality of melt extruded multiparticulates, comprising preparing multiparticulates by the method of  claim 131 .