Combination dosage form of a mu opioid receptor antagonist and an opioid agent

Abstract

The invention provides a solid composition of the peripheral mu opioid antagonist axelopran and a combination dosage form of the mu opioid antagonist axelopran sulfate in an immediate release form and an opioid analgesic agent which may be in an extended release, sustained release, modified release, or controlled release form and methods of preparing such a combination dosage form.

We claim: 
     
         1 . A solid composition wherein the composition comprises:
 (a) between about 50% and about 95% by weight axelopran sulfate,   (b) between about 5% and about 50% by weight polyvinyl alcohol,   (c) between about 0% and about 45% polyethylene glycol 3350, and   (d) between about 0% and about 10% ascorbic acid.   
     
     
         2 . The solid composition of  claim 1  wherin the axelopran sulfate is in crystalline form. 
     
     
         3 . The solid composition of  claim 2 , wherein the composition comprises
 (a) between about 50% and about 70% by weight axelopran sulfate,   (b) between about 10% and about 50% by weight polyvinyl alcohol,   (c) between about 5% and about 30% polyethylene glycol 3350, and   (d) between about 0.5% and about 10% ascorbic acid.   
     
     
         4 . The solid composition of  claim 2  wherein the composition comprises:
 (a) between about 50% and about 70% by weight axelopran sulfate, 
 (b) between about 12% and about 25% by weight polyvinyl alcohol, 
 (c) between about 12% and about 25% polyethylene glycol 3350, and 
 (d) between about 2% and about 6% ascorbic acid. 
 
     
     
         5 . A combination dosage form comprising:
 a solid dosage form comprising an opioid analgesic agent, and   an immediate release portion comprising axelopran sulfate wherein the immediate release portion is a drug overcoat layer on the solid dosage form.   
     
     
         6 . The combination dosage form of  claim 5  wherein the opioid analgesic agent is in a modified release formulation. 
     
     
         7 . The combination dosage form of  claim 5  wherein the solid dosage form comprising an opioid analgesic agent is a tablet or bead. 
     
     
         8 . The combination dosage form of  claim 5  wherein the solid dosage form comprising an opioid analgesic agent is a tablet. 
     
     
         9 . The combination dosage form of  claim 5  wherein the drug overcoat layer comprises axelopran sulfate in crystalline form and further comprises a film forming polymer and a plasticizer. 
     
     
         10 . The combination dosage form of  claim 9  wherein the drug overcoat layer comprises:
 (a) between about 50% and about 70% by weight axelopran sulfate, 
 (b) between about 10% and about 50% by weight polyvinyl alcohol, 
 (c) between about 5% and about 30% polyethylene glycol 3350, and 
 (d) between about 0.5% and about 10% ascorbic acid. 
 
     
     
         11 . The combination dosage form of  claim 10  wherein the drug overcoat layer comprises:
 (a) between about 50% and about 70% by weight axelopran sulfate, 
 (b) between about 12% and about 25% by weight polyvinyl alcohol, 
 (c) between about 12% and about 25% polyethylene glycol 3350, and 
 (d) between about 2% and about 6% ascorbic acid. 
 
     
     
         12 . The combination dosage form of  claim 9  further comprising a subcoat layer between the drug overcoat layer and the solid dosage form comprising an opioid analgesic agent. 
     
     
         13 . The combination dosage form of  claim 12  wherein the subcoat layer comprises polyvinyl alcohol and polyethylene glycol. 
     
     
         14 . The combination dosage form of  claim 5  wherein the opioid analgesic agent is oxycodone or oxymorphone. 
     
     
         15 . The combination dosage form of  claim 11  further comprising a subcoat layer wherein the subcoat layer comprises polyvinyl alcohol and polyethylene glycol and wherein the opioid analgesic agent is oxycodone or oxymorphone. 
     
     
         16 . The combination dosage form of  claim 15  wherein the dosage form provides an in vitro rate of release of axelopran for less than about one hour and an in vitro rate of release of the opioid analgesic agent for up to about 12 hours. 
     
     
         17 . An aqueous solution wherein the non-aqueous components of the solution comprise:
 (a) between about 50% and about 95% by weight axelopran sulfate,   (b) between about 5% and about 50% by weight polyvinyl alcohol,   (c) between about 0% and about 45% polyethylene glycol 3350, and   (d) between about 0% and about 10% ascorbic acid.   
     
     
         18 . The aqueous solution of  claim 17  wherein the non-aqueous components of the solution comprise:
 (a) between about 50% and about 70% by weight axelopran sulfate, 
 (b) between about 10% and about 50% by weight polyvinyl alcohol, 
 (c) between about 5% and about 30% polyethylene glycol 3350, and 
 (d) between about 0.5% and about 10% ascorbic acid. 
 
     
     
         19 . The aqueous solution of  claim 17  wherein the non-aqueous components of the solution comprise:
 (a) between about 50% and about 70% by weight axelopran sulfate, 
 (b) between about 12% and about 25% by weight polyvinyl alcohol, 
 (c) between about 12% and about 25% polyethylene glycol 3350, and 
 (d) between about 2% and about 6% ascorbic acid. 
 
     
     
         20 . A method of preparing a combination dosage form, the method comprising:
 (a) providing an opioid analgesic agent in a solid dosage form, and   (b) coating the solid dosage form with an aqueous solution wherein the non-aqueous components of the solution comprise:
 (b1) between about 50% and about 70% by weight axelopran sulfate, 
 (b2) between about 10% and about 50% by weight polyvinyl alcohol, 
 (b3) between about 5% and about 30% polyethylene glycol 3350, and 
 (b4) between about 0.5% and about 10% ascorbic acid. 
   
     
     
         21 . The method of  claim 20  wherein step (b) comprises coating the solid dosage form with an aqueous solution wherein the non-aqueous components of the solution comprise:
 (b1) between about 50% and about 70% by weight axelopran sulfate, 
 (b2) between about 12% and about 25% by weight polyvinyl alcohol, 
 (b3) between about 12% and about 25% polyethylene glycol 3350, and 
 (b4) between about 2% and about 6% ascorbic acid. 
 
     
     
         22 . The method of  claim 21  further comprising coating the opioid solid dosage form with a subcoating layer comprising polyvinyl alcohol and polytheylene glycol onto the opioid solid dosage form before applying the drug overcoat layer comprising axelopran. 
     
     
         23 . A method of preparing a combination dosage form comprising axelopran sulfate in crystalline form, the method comprising:
 (a) providing an opioid analgesic agent in a solid dosage form,   (b) coating the solid dosage form with a solution comprising axelopran sulfate, and   (c) exposing the coated solid dosage form to between about 70% and about 86% relative humidity at a temperature between about 20° C. and about 45° C. until axelopran sulfate is converted to crystalline form.   
     
     
         24 . A method of treating pain in a mammal, the method comprising administering to the mammal the combination dosage form of  claim 5 . 
     
     
         25 . A method of ameliorating a gastrointestinal side effect of opioid analgesic therapy, the method comprising administering to the mammal a combination dosage form of  claim 5 .