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 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 a immediate release product as a single dose. The controlled release nature of the table 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.

What is claimed is:  
     
         1 . An oral pharmaceutical composition comprising: 
 a controlled release matrix;    an opioid agonist;    an opioid antagonist having greater antagonistic effect when administered parenterally than when administered orally;    wherein said opioid antagonist is present in the composition in an orally effective amount for blocking the opioid effect and/or inducing withdrawal when the controlled release matrix is defeated and the composition improperly administered for immediate release;    wherein said controlled release matrix is selected and incorporated for controlling the release rate of the opioid antagonist such that antagonist levels are not effective for blocking the opioid effect by blocking both the inhibitory and excitatory receptors or for attenuating opioid side effects by selectively blocking the excitatory receptors under proper oral administration regimes.    
     
     
         2 . The pharmaceutical composition 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.  
     
     
         3 . The pharmaceutical composition according to  claim 1  wherein the release rate of the opioid antagonist is approximately 100 percent of the release rate of the opioid agonist.  
     
     
         4 . The pharmaceutical composition according to  claim 1  wherein the release rate of the opioid antagonist is approximately 50 percent of the release rate of the opioid agonist.  
     
     
         5 . The pharmaceutical composition according to  claim 1  wherein the release rate of the opioid antagonist is approximately 25 percent of the release rate of the opioid agonist.  
     
     
         6 . The pharmaceutical composition according to  claim 1  wherein the oral:parenteral potency ratio of the opioid antagonist is at least about 10:1.  
     
     
         7 . The pharmaceutical composition according to  claim 1  wherein the oral:parenteral potency ratio of the opioid antagonist is at least about 25:1.  
     
     
         8 . The pharmaceutical composition according to  claim 1  wherein the oral:parenteral potency ratio of the opioid antagonist is at least about 100:1.  
     
     
         9 . The pharmaceutical composition 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.  
     
     
         10 . The pharmaceutical composition 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-tetrahydrooripavine (or diphenorphine) and the pharmaceutically-acceptable salts thereof.  
     
     
         11 . The pharmaceutical composition according to  claim 1  wherein said opioid antagonist is naloxone.  
     
     
         12 . The pharmaceutical composition according to  claim 1  wherein said opioid agonist is oxycodone.  
     
     
         13 . The pharmaceutical composition according to  claim 1  wherein said opioid agonist is present in concentration pharmaceutically equivalent to oxycodone doses of approximately 10-160 mg.  
     
     
         14 . The pharmaceutical composition according to  claim 1 , wherein the release rate of the antagonist is such that a single dose of the composition does not render available an orally effective amount of antagonist, yet when two or more doses of the composition are combined—with or without crushing—to achieve an abusive dose of the opioid agonist, the opioid antagonist is available at orally effective blocking levels.  
     
     
         15 . A pharmaceutical composition comprising: 
 a controlled release matrix;    an opioid agonist;    an opioid antagonist having greater antagonistic effect when administered parenterally than when administered orally;    wherein said opioid antagonist is present in the composition in an amount proportional to the number of abusive doses of the opioid agonist in the composition such that if the CR matrix is defeated and two or more doses of the composition are combined to yield an abusive dose of the opioid agonist, the amount of opioid antagonist will suffice to block the opioid effect and/or induce withdrawal when taken orally;    wherein said controlled release matrix is selected and incorporated for controlling the release rate of the opioid antagonist such that antagonist levels are not effective for blocking the opioid effect by blocking the inhibitory and excitatory receptors or attenuating opioid side effects by selectively blocking the excitatory receptors under proper oral administration regimes.    
     
     
         16 . The pharmaceutical composition according to  claim 15 , wherein the release rate of the antagonist is such that a single dose of the composition does not render available an orally effective amount of antagonist, yet when two or more doses of the composition are combined—with or without crushing—to achieve an abusive dose of the opioid agonist, the opioid antagonist is available at orally effective blocking levels.  
     
     
         17 . An oral pharmaceutical composition comprising: 
 a controlled release matrix;    approximately 10-160 mg oxycodone;    approximately 2-160 mg naloxone;    wherein the ratio of oxycodone to naloxone is approximately 4-5:1 to 1:1;    wherein said controlled release matrix is selected and incorporated for controlling the release rate of the oxycodone for maintaining pharmaceutical effectiveness for a period up to 12 hours and for controlling the release rate of the naloxone such that naloxone levels are not effective for blocking the opioid effect by blocking both the inhibitory and excitatory receptors or for attenuating opioid side effects by selectively blocking the excitatory receptors under proper oral administration regimes.    
     
     
         18 . An oral pharmaceutical 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 adapted to release the oxycodone at a therapeutically effective rate, and to release said naloxone at a rate ineffective for blocking the opioid effect and/or inducing withdrawal when the controlled release formulation is taken orally in intact form.    
     
     
         19 . The oral pharmaceutical composition according to  claim 18 , 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-tetrahydrooripavine (or salts thereof.  
     
     
         20 . The oral pharmaceutical composition according to  claim 18  wherein said opioid agonist is oxycodone hydrochorlide and said opioid antagonist is naloxone.