Abuse-resistant controlled-release opioid dosage form

Abstract

Abuse-resistant, controlled release opioid tablets are a combination containing an opioid antagonist such as naloxone at a level above that needed to suppress the euphoric effect of the opioid, if the combination were crushed to break the controlled release properties causing the opioid and opioid antagonist to be released as an immediate release product as a single dose. The controlled release nature of the tablet prevents the accumulation of orally effective amounts of opioid antagonist when taken normally. The opioid antagonist is contained in a controlled-release matrix and released, over time, with the opioid.

1 . A method of deterring abuse of analgesic compositions comprising: 
 providing an analgesic composition comprising: 
 an opioid agonist; an opioid antagonist present in an amount that blocks an opioid effect and/or induces withdrawal when the entire antagonist dose is released at once; and a controlled release matrix that controls the release rate of the 1) opioid antagonist such that subtherapeutic antagonist levels are maintained and 2) opioid agonist such that therapeutic agonist levels are maintained;  
   maintaining the analgesic composition substantially intact; and    orally administering the substantially intact analgesic composition to a patient.    
     
     
         2 . The method according to  claim 1 , wherein said opioid agonist is selected from the group consisting of morphine, oxycodone, levorphenol, meperdine, hydrocodone, codeine, dihydrocodeine, hydromorphone, propoxyphene, methadone, and oxymorphone.  
     
     
         3 . The method according to  claim 1 , wherein the opioid antagonist is selected from the group consisting of naloxone, naltrexone, N-cyclo propylmethyl-7,8-dihydro-14-hydroxynormorphinone, and 21-cyclopropyl z, -(1-hydroxy-1-methylethyl)-6,14-endo-ethano-tetrahydro-ripavine (or diphenorphine) and the pharmaceutically-acceptable salts thereof.  
     
     
         4 . The method according to  claim 1 , wherein said opioid antagonist is naloxone.  
     
     
         5 . The method according to  claim 1 , wherein said opioid agonist is oxycodone.  
     
     
         6 . The method according to  claim 1 , wherein said opioid agonist is present in concentration pharmaceutically equivalent to oxycodone doses of approximately 10-160 mg.  
     
     
         7 . The method according to  claim 1 , wherein the release rate of the opioid antagonist is approximately 100 to approximately 25 percent of the release rate of the opioid agonist.  
     
     
         8 . A method of treating a patient with an opioid agonist comprising: 
 orally administering the opioid agonist to the patient in a controlled release matrix that is substantially intact such that the controlled release matrix controls the release rate of the opioid agonist to maintain therapeutic agonist levels; and    orally administering an opioid antagonist to the patient in the substantially intact controlled release matrix in an orally effective amount that blocks an opioid effect and/or induces withdrawal when all of the opioid antagonist is released at once such that the substantially intact controlled release matrix controls the release rate of the opioid antagonist to maintain subtherapeutic antagonist levels.    
     
     
         9 . The method according to  claim 8 , wherein said opioid agonist is selected from the group consisting of morphine, oxycodone, levorphenol, meperdine, hydrocodone, codeine, dihydrocodeine, hydromorphone, propoxyphene, methadone, and oxymorphone.  
     
     
         10 . The method according to  claim 8  wherein the opioid antagonist is selected from the group consisting of naloxone, naltrexone, N-cyclo propylmethyl-7,8-dihydro-14-hydroxynormorphinone, and 21-cyclopropyl z, -(1-hydroxy-1-methylethyl)-6,14-endo-ethano-tetrahydro-ripavine (or diphenorphine) and the pharmaceutically-acceptable salts thereof.  
     
     
         11 . The method according to  claim 8 , wherein said opioid antagonist is naloxone.  
     
     
         12 . The method according to  claim 8 , wherein said opioid agonist is oxycodone.  
     
     
         13 . The method according to  claim 8 , wherein said opioid agonist is present in concentration pharmaceutically equivalent to oxycodone doses of approximately 10-160 mg.  
     
     
         14 . The method according to  claim 8 , wherein the release rate of the opioid antagonist is approximately 100 to approximately 25 percent of the release rate of the opioid agonist.  
     
     
         15 . A method of deterring abuse of analgesic compositions comprising: 
 providing an analgesic composition comprising, in % by weight: 
 about 3-35% opioid agonist;  
 about 2-20% opioid antagonist;  
 about 10-50% microcrystalline cellulose, NF;  
 about 30-70% ammonio methacrylate copolymer, NF; and  
 at least one excipient selected from the group consisting of: up to about 5% colloidal silicon dioxide, NF;  
 up to about 5% sodium lauryl sulfate, NF;  
 up to about 2% magnesium hydroxide, USP;  
 up to about 15% povidone, USP;  
 up to about 5% stearic acid, NF; and  
 up to about 5% magnesium stearate, NF;  
 wherein said composition is a controlled release formulation that controls the release rate of the 1) opioid antagonist such that subtherapeutic antagonist levels are maintained and 2) opioid agonist such that therapeutic antagonist levels are maintained;  
   maintaining the analgesic composition substantially intact; and    orally administering the substantially intact composition to a patient.    
     
     
         16 . The method according to  claim 15 , wherein said opioid agonist is selected from the group consisting of morphine, oxycodone, levorphenol, meperdine, hydrocodone, codeine, dihydrocodeine, hydromorphone, propoxyphene, methadone, and oxymorphone and the opioid antagonist is selected from the group consisting of naloxone, naltrexone, N-cyclo propylmethyl-7,8-dihydro-14-hydroxynormorphinone, and 21-cyclopropyl z, -(1-hydroxy-1-methylethyl)-6,14-endo-ethano-tetrayhydrooripavine (or diphenorphine) and the pharmaceutically-acceptable salts thereof.  
     
     
         17 . The method according to  claim 15 , wherein the opioid agonist is oxycodone hydrochloride and said opioid antagonist is naloxone.  
     
     
         18 . The method according to  claim 15 , wherein the opioid antagonist has a greater antagonistic effect when administered parenterally than when administered orally.  
     
     
         19 . The method according to  claim 15 , wherein the opioid antagonist has a greater antagonistic effect when administered parenterally than when administered orally.