Sustained release formulation of naltrexone

Abstract

A sustained-release oral dosage form of naltrexone or a pharmaceutically acceptable salt thereof is provided. The oral dosage form may be administered with another compound. Administration of the oral dosage form may reduce a side effect, which may be a side effect at least partially attributable to a weight-loss treatment. The oral dosage form may be administered to treat a weight-loss condition.

What is claimed is: 
     
         1 . An oral dosage form, comprising a sustained-release naltrexone formulation that is formulated to provide a reduction in at least one adverse effect, wherein the adverse effect is associated with co-administration of an immediate-release naltrexone formulation and a second compound. 
     
     
         2 . The oral dosage form of  claim 1 , wherein the second compound comprises a monoamine reuptake inhibitor. 
     
     
         3 . The oral dosage form of  claim 1 , wherein the second compound comprises bupropion or a pharmaceutically acceptable salt thereof. 
     
     
         4 . The oral dosage form of  claim 1 , wherein the second compound comprises fluoxetine or a pharmaceutically acceptable salt thereof. 
     
     
         5 . The oral dosage form of  claim 1 , wherein the reduction in the at least one adverse effect comprises a reduction in one or more of the severity, the duration, or the probability of experiencing the at least one adverse effect. 
     
     
         6 . The oral dosage form of  claim 1 , wherein the at least one adverse effect comprises nausea. 
     
     
         7 . The oral dosage form of  claim 1 , wherein the sustained-release naltrexone formulation is in a unit dosage form comprising an amount of naltrexone in the range of from about 4 mg to about 50 mg. 
     
     
         8 . The oral dosage form of  claim 1 , wherein the sustained-release naltrexone formulation is in a unit dosage form comprising an amount of naltrexone in the range of from about 10 mg to about 25 mg. 
     
     
         9 . The oral dosage form of  claim 1 , wherein the sustained-release naltrexone formulation is in a unit dosage form comprising about 4 mg, about 8 mg, about 12 mg, about 16 mg, about 32 mg or about 48 mg of naltrexone. 
     
     
         10 . The oral dosage form of  claim 1 , wherein the sustained-release naltrexone formulation is in a unit dosage form suitable for administration one or more times per day. 
     
     
         11 . The oral dosage form of  claim 10 , wherein the unit dosage form is suitable for administration two or more times per day. 
     
     
         12 . The oral dosage form of  claim 1 , wherein the oral dosage form further comprises the second compound. 
     
     
         13 . The oral dosage form of  claim 12 , wherein the second compound comprises bupropion or a pharmaceutically acceptable salt thereof. 
     
     
         14 . The oral dosage form of  claim 13 , wherein the bupropion or a pharmaceutically acceptable salt thereof is a sustained release formulation. 
     
     
         15 . The oral dosage form of  claim 14 , wherein the sustained-release naltrexone formulation is in a unit dosage form; wherein the unit dosage form comprises naltrexone in an amount of about 4 mg, about 8 mg or about 12 mg; and wherein the unit dosage form comprises bupropion or a pharmaceutically acceptable salt thereof in an amount of about 90 mg. 
     
     
         16 . The oral dosage form of  claim 12 , wherein the second compound comprises fluoxetine or a pharmaceutically acceptable salt thereof. 
     
     
         17 . The oral dosage form of  claim 1 , wherein the oral dosage form comprises an amount of a sustained-release carrier composition that is effective to provide, after administration, an in vivo plasma concentration profile comprising at least one selected from:
 (a) a naltrexone C max  that is about 80% or less of the naltrexone C max  of REVIA™ immediate-release naltrexone hydrochloride, and a naltrexone AUC last  that is in the range of about 80% to about 125% of the naltrexone AUC last  of REVIA™ immediate-release naltrexone hydrochloride; and   (b) a 6-beta naltrexol C max  that is about 80% or less of the 6-beta naltrexol C max  of REVIA™ immediate-release naltrexone hydrochloride, and a 6-beta naltrexol AUC last  that is in the range of about 80% to about 125% of the 6-beta naltrexol AUC last  of REVIA™ immediate-release naltrexone hydrochloride.   
     
     
         18 . The oral dosage form of  claim 17 , wherein said sustained-release carrier composition comprises at least one of hydroxypropylmethyl cellulose, polyoxyethylene, polyacrylate, a copolymer of acrylate and methacrylate, a methacrylate polymer, a copolymer of acrylate and methacrylate, a copolymer of acrylate and methacrylate with ammonium group, a copolymer of maleic anhydride and methyl vinyl ether, hydroxy propyl ethyl cellulose, hydroxy propyl cellulose, hydroxy ethyl cellulose, methyl cellulose, hydroxymethyl methacrylate, maltodextrin, natural gum and xanthan gum. 
     
     
         19 . The oral dosage form of  claim 17 , wherein said sustained-release carrier composition comprises at least one of hydroxypropylmethylcellulose and polyoxyethylene. 
     
     
         20 . An oral unit dosage form, comprising a sustained-release naltrexone formulation that is effective to provide, after administration, an in vivo plasma concentration profile comprising at least one selected from:
 (a) a naltrexone C max  that is about 80% or less of the naltrexone C max  of REVIA™ immediate-release naltrexone hydrochloride, and a naltrexone AUC last  that is in the range of about 80% to about 125% of the naltrexone AUC last  of REVIA™ immediate-release naltrexone hydrochloride; and   (b) a 6-beta naltrexol C max  that is about 80% or less of the 6-beta naltrexol C max  of REVIA™ immediate-release naltrexone hydrochloride, and a 6-beta naltrexol AUC last  that is in the range of about 80% to about 125% of the 6-beta naltrexol AUC last  of REVIA™ immediate-release naltrexone hydrochloride.   
     
     
         21 . The oral unit dosage form of  claim 20 , comprising an amount of naltrexone in the range of from about 4 mg to about 50 mg. 
     
     
         22 . The oral unit dosage form of  claim 20 , comprising an amount of naltrexone in the range of from about 10 mg to about 25 mg. 
     
     
         23 . The oral unit dosage form of  claim 20 , comprising about 4 mg, about 8 mg, about 12 mg, about 16 mg, about 32 mg or about 48 mg of naltrexone. 
     
     
         24 . An oral dosage form, comprising naltrexone or a pharmaceutically acceptable salt thereof and a sustained-release carrier composition, wherein said oral dosage form provides an in vitro release rate of the naltrexone or pharmaceutically acceptable salt thereof of less than about 80% in about 1 hour. 
     
     
         25 . The oral dosage form of  claim 24 , wherein said in vitro release rate is less than about 70% in about 1 hour. 
     
     
         26 . The oral dosage form of  claim 24 , wherein said sustained-release carrier composition comprises at least one of hydroxypropylmethyl cellulose, polyoxyethylene, polyacrylate, a copolymer of acrylate and methacrylate, a methacrylate polymer, a copolymer of acrylate and methacrylate, a copolymer of acrylate and methacrylate with ammonium group, a copolymer of maleic anhydride and methyl vinyl ether, hydroxy propyl ethyl cellulose, hydroxy propyl cellulose, hydroxy ethyl cellulose, methyl cellulose, hydroxymethyl methacrylate, maltodextrin, natural gum and xanthan gum. 
     
     
         27 . The oral dosage form of  claim 24 , wherein said sustained-release carrier composition comprises at least one of hydroxypropylmethylcellulose and polyoxyethylene. 
     
     
         28 . The oral dosage form of  claim 24 , wherein the naltrexone salt comprises naltrexone hydrochloride. 
     
     
         29 . A method of administering naltrexone, comprising administering the oral dosage form of  claim 1  to a subject. 
     
     
         30 . The method of  claim 29 , comprising administering the oral dosage form to the subject in a manner that is effective to cause weight loss and/or inhibit weight gain. 
     
     
         31 . The method of  claim 29 , further comprising administering a second compound to the subject. 
     
     
         32 . The method of  claim 31 , wherein the second compound comprises bupropion or a pharmaceutically acceptable salt thereof. 
     
     
         33 . The method of  claim 32 , wherein the sustained-release naltrexone formulation is in a unit dosage form; wherein the unit dosage form comprises naltrexone in an amount of about 4 mg, about 8 mg or about 12 mg; and wherein the unit dosage form comprises bupropion or a pharmaceutically acceptable salt thereof in an amount of about 90 mg. 
     
     
         34 . The method of  claim 31 , wherein the second compound comprises fluoxetine or a pharmaceutically acceptable salt thereof. 
     
     
         35 . A method of administering naltrexone, comprising administering a sustained-release naltrexone formulation to a subject in an amount that is effective to provide an in vivo plasma concentration profile comprising at least one selected from:
 (a) a naltrexone C max  that is about 80% or less of the naltrexone C max  of REVIA™ immediate-release naltrexone hydrochloride, and a naltrexone AUC last  that is in the range of about 80% to about 125% of the naltrexone AUC last  of REVIA™ immediate-release naltrexone hydrochloride; and   (b) a 6-beta naltrexol C max  that is about 80% or less of the 6-beta naltrexol C max  of REVIA™ immediate-release naltrexone hydrochloride, and a 6-beta naltrexol AUC last  that is in the range of about 80% to about 125% of the 6-beta naltrexol AUC last  of REVIA™ immediate-release naltrexone hydrochloride.   
     
     
         36 . The method of  claim 35 , comprising administering the sustained-release naltrexone formulation to the subject in a manner that is effective to cause weight loss and/or inhibit weight gain. 
     
     
         37 . The method of  claim 35 , further comprising administering a second compound to the subject. 
     
     
         38 . The method of  claim 37 , wherein the second compound comprises a monoamine reuptake inhibitor. 
     
     
         39 . The method of  claim 38 , wherein administration of the monoamine reuptake inhibitor in combination with an immediate-release form of naltrexone results in at least one adverse effect that is reduced by the administration of the sustained-release naltrexone formulation. 
     
     
         40 . The method of  claim 38 , wherein the monoamine reuptake inhibitor comprises bupropion or a pharmaceutically acceptable salt thereof. 
     
     
         41 . The method of  claim 40 , wherein the sustained-release naltrexone formulation is in a unit dosage form; wherein the unit dosage form comprises naltrexone in an amount of about 4 mg, about 8 mg or about 12 mg; and wherein the unit dosage form comprises bupropion or a pharmaceutically acceptable salt thereof in an amount of about 90 mg. 
     
     
         42 . The method of  claim 38 , wherein the monoamine reuptake inhibitor comprises fluoxetine or a pharmaceutically acceptable salt thereof.