Abuse-resistant oral dosage forms and method of use thereof

Abstract

An opioid-antagonist oral dosage form which does not release a therapeutically effective amount of the opioid antagonist when the oral dosage form is orally administered to a human being, but whereby a physical alteration of the oral dosage form results in a release of the therapeutically effective amount of the opioid antagonist. An embodiment of the oral dosage form includes an opioid-antagonist layer coated onto a biologically inert pellet, and a non-releasing membrane coated onto the opioid-antagonist layer. Optionally, the oral dosage form can also include an opioid agonist, such that a method of preventing the abuse of an oral dosage form of an opioid agonist is provided by forming the oral dosage form including an opioid agonist and an opioid antagonist.

1 . An oral dosage form comprising:
 a biologically inert pellet;   an opioid-antagonist layer coated on the biologically inert pellet, wherein the opioid-antagonist layer comprises a therapeutically effective amount of an opioid antagonist; and   a non-releasing membrane coated on the opioid-antagonist layer, wherein the non-releasing membrane comprises a water-retardant polymer which is a non-ionic poly(ethyl acrylate-co-methyl methacrylate) 2:1, wherein 2:1 indicates the molar proportions of the ethyl acrylate and methyl methacrylate monomer units, respectively;   wherein the oral dosage form does not release the therapeutically effective amount of the opioid antagonist when the oral dosage form is orally administered to a human being, and wherein a physical alteration of the oral dosage form results in a release of the therapeutically effective amount of the opioid antagonist.   
     
     
         2 . The oral dosage form of  claim 1 , wherein the release of the opioid antagonist from the oral dosage form in vitro, when measured by the USP Basket method of 100 rpm in 900 ml of water at 37° C., substantially corresponds to the following dissolution rate:
 the therapeutically effective amount of the opioid antagonist is not released from the dosage form after about 14 to 24 hours.   
     
     
         3 . The oral dosage form of  claim 1 , wherein the opioid antagonist comprises naltrexone. 
     
     
         4 . The oral dosage form of  claim 1 , wherein the non-releasing membrane further comprises a lubricant. 
     
     
         5 . The oral dosage form of  claim 4 , wherein the lubricant comprises a member selected from the group consisting of calcium stearate, magnesium stearate, zinc stearate, stearic acid, talc and a combination thereof. 
     
     
         6 . The oral dosage form of  claim 1 , wherein the opioid-antagonist layer further comprises a binder agent. 
     
     
         7 . The oral dosage form of  claim 6 , wherein the binder agent comprises a member selected from the group consisting of hydroxypropylmethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, methyl cellulose and polyvinyl pyrrolidone. 
     
     
         8 . The oral dosage form of  claim 1 , further comprising a sealing layer between the opioid-antagonist layer and the non-releasing membrane. 
     
     
         9 . The oral dosage form of  claim 1 , further comprising at least one of an enteric layer and a sealing layer coated on the non-releasing membrane. 
     
     
         10 . The oral dosage form of  claim 1 , further comprising an opioid-agonist layer coated on the non-releasing membrane, wherein the opioid-agonist layer comprises an opioid agonist. 
     
     
         11 . An oral dosage form including:
 a first pellet comprising:
 a biologically inert pellet; 
 an opioid-antagonist layer coated on the biologically inert pellet, wherein the opioid-antagonist layer comprises a therapeutically effective amount of an opioid antagonist; and 
 a non-releasing membrane coated on the opioid-antagonist layer, wherein the non-releasing membrane comprises a water-retardant polymer which is a non-ionic poly(ethyl acrylate-co-methyl methacrylate) 2:1, wherein 2:1 indicates the molar proportions of the ethyl acrylate and methyl methacrylate monomer units, respectively; 
 wherein the oral dosage form does not release the therapeutically effective amount of the opioid antagonist when the oral dosage form is orally administered to a human being, and wherein a physical alteration of the oral dosage form results in a release of the therapeutically effective amount of the opioid antagonist; and 
   a second pellet comprising an opioid agonist.   
     
     
         12 . The oral dosage form of  claim 11 , wherein the release of the opioid antagonist from the oral dosage form in vitro, when measured by the USP Basket method of 100 rpm in 900 ml of water at 37° C., substantially corresponds to the following dissolution rate:
 the therapeutically effective amount of the opioid antagonist is not released from the dosage form after about 14 to 24 hours.   
     
     
         13 . The oral dosage form of  claim 11 , wherein the opioid agonist comprises oxycodone, and the opioid antagonist comprises naltrexone. 
     
     
         14 . The oral dosage form of  claim 11 , wherein the non-releasing membrane further comprises a lubricant. 
     
     
         15 . The oral dosage form of  claim 14 , wherein the lubricant comprises a member selected from the group consisting of calcium stearate, magnesium stearate, zinc stearate, stearic acid, talc and a combination thereof. 
     
     
         16 . The oral dosage form of  claim 11 , wherein the opioid-antagonist layer further comprises a binder agent. 
     
     
         17 . The oral dosage form of  claim 16 , wherein the binder agent comprises a member selected from the group consisting of hydroxypropylmethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, methyl cellulose and polyvinyl pyrrolidone. 
     
     
         18 . The oral dosage form of  claim 11  in a capsule or a tablet form. 
     
     
         19 . The oral dosage form of  claim 11 , further comprising a sealing layer between the opioid-antagonist layer and the non-releasing membrane. 
     
     
         20 . The oral dosage form of  claim 11 , further comprising at least one of an enteric layer and a sealing layer coated on the non-releasing membrane. 
     
     
         21 . An oral dosage form comprising:
 an opioid-antagonist formulation, wherein the opioid-antagonist formulation comprises a therapeutically effective amount of an opioid antagonist; and   a non-releasing membrane coated on the opioid-antagonist layer, wherein the non-releasing membrane comprises a water-retardant polymer which is a non-ionic poly(ethyl acrylate-co-methyl methacrylate) 2:1, wherein 2:1 indicates the molar proportions of the ethyl acrylate and methyl methacrylate monomer units, respectively;   wherein the oral dosage form does not release the therapeutically effective amount of the opioid antagonist when the oral dosage form is orally administered to a human being, and wherein a physical alteration of the oral dosage form results in a release of the therapeutically effective amount of the opioid antagonist.   
     
     
         22 . The oral dosage form of  claim 21 , wherein the release of the opioid antagonist from the oral dosage form in vitro, when measured by the USP Basket method of 100 rpm in 900 ml of water at 37° C., substantially corresponds to the following dissolution rate:
 the therapeutically effective amount of the opioid antagonist is not released from the dosage form after about 14 to 24 hours.   
     
     
         23 . The oral dosage form of  claim 21 , wherein the opioid antagonist comprises naltrexone. 
     
     
         24 . The oral dosage form of  claim 21 , wherein the non-releasing membrane further comprises a lubricant. 
     
     
         25 . The oral dosage form of  claim 24 , wherein the lubricant comprises a member selected from the group consisting of calcium stearate, magnesium stearate, zinc stearate, stearic acid, talc and a combination thereof. 
     
     
         26 . The oral dosage form of  claim 21 , further comprising a sealing layer between the opioid-antagonist formulation and the non-releasing membrane. 
     
     
         27 . The oral dosage form of  claim 21 , further comprising at least one of an enteric layer and a sealing layer coated on the non-releasing membrane. 
     
     
         28 . The oral dosage form of  claim 21 , further comprising an opioid-agonist layer coated on the non-releasing membrane, wherein the opioid-agonist layer comprises an opioid agonist. 
     
     
         29 . A method of preventing the abuse of an oral dosage form of an opioid agonist, comprising:
 coating a non-releasing membrane onto an opioid-antagonist formulation, and coating an opioid-agonist layer onto the non-releasing membrane to form an oral dosage form; wherein the opioid-antagonist formulation comprises a therapeutically effective amount of an opioid antagonist, wherein the non-releasing membrane comprises a water-retardant polymer which is a non-ionic poly(ethyl acrylate-co-methyl methacrylate) 2:1, wherein 2:1 indicates the molar proportions of the ethyl acrylate and methyl methacrylate monomer units, respectively, and wherein the opioid-agonist layer comprises an opioid agonist;   wherein the oral dosage form does not release the therapeutically effective amount of the opioid antagonist when the oral dosage form is orally administered to a human being, and wherein a physical alteration of the oral dosage form results in a release of the therapeutically effective amount of the opioid antagonist.   
     
     
         30 . The method of  claim 29 , wherein the release of the opioid antagonist from the oral dosage form in vitro, when measured by the USP Basket method of 100 rpm in 900 ml of water at 37° C., substantially corresponds to the following dissolution rate:
 the therapeutically effective amount of the opioid antagonist is not released from the dosage form after about 14 to 24 hours.   
     
     
         31 . The method of  claim 29 , wherein the opioid agonist comprises oxycodone, and the opioid antagonist comprises naltrexone. 
     
     
         32 . The method of  claim 29 , wherein the non-releasing membrane further comprises a lubricant. 
     
     
         33 . The method of  claim 32 , wherein the lubricant comprises a member selected from the group consisting of calcium stearate, magnesium stearate, zinc stearate, stearic acid, talc and a combination thereof. 
     
     
         34 . The method of  claim 29 , further comprising coating a sealing layer onto the opioid-antagonist formulation, such that the non-releasing membrane is coated onto the sealing layer. 
     
     
         35 . The method of  claim 29 , further comprising coating at least one of an enteric layer and a sealing layer onto the non-releasing membrane, such that the opioid-agonist layer is coated onto the at least one of an enteric layer and a sealing layer. 
     
     
         36 . A method of preventing the abuse of an oral dosage form of an opioid agonist, comprising:
 forming an oral dosage form by combining:
 a first pellet comprising an opioid agonist; and 
 a second pellet comprising:
 a biologically inert pellet; 
 an opioid-antagonist layer coated on the biologically inert pellet, wherein the opioid-antagonist layer comprises a therapeutically effective amount of an opioid antagonist; and 
 a non-releasing membrane coated on the opioid-antagonist layer, wherein the non-releasing membrane comprises a water-retardant polymer which is a non-ionic poly(ethyl acrylate-co-methyl methacrylate) 2:1, wherein 2:1 indicates the molar proportions of the ethyl acrylate and methyl methacrylate monomer units, respectively; 
 
 wherein the oral dosage form does not release the therapeutically effective amount of the opioid antagonist when the oral dosage form is orally administered to a human being, and wherein a physical alteration of the oral dosage form results in a release of the therapeutically effective amount of the opioid antagonist. 
   
     
     
         37 . The method of  claim 36 , wherein the release of the opioid antagonist from the oral dosage form in vitro, when measured by the USP Basket method of 100 rpm in 900 ml of water at 37° C., substantially corresponds to the following dissolution rate:
 the therapeutically effective amount of the opioid antagonist is not released from the dosage form after about 14 to 24 hours.   
     
     
         38 . The method of  claim 36 , wherein the opioid agonist comprises oxycodone, and the opioid antagonist comprises naltrexone. 
     
     
         39 . The method of  claim 36 , wherein the non-releasing membrane further comprises a lubricant. 
     
     
         40 . The method of  claim 39 , wherein the lubricant comprises a member selected from the group consisting of calcium stearate, magnesium stearate, zinc stearate, stearic acid, talc and a combination thereof. 
     
     
         41 . The method of  claim 36 , wherein the opioid-antagonist layer further comprises a binder agent. 
     
     
         42 . The method of  claim 41 , wherein the binder agent comprises a member selected from the group consisting of hydroxypropylmethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, methyl cellulose and polyvinyl pyrrolidone. 
     
     
         43 . The method of  claim 36 , wherein the oral dosage form is in a capsule or a tablet form.