Modified release formulations for oprozomib

Abstract

This disclosure features modified release pharmaceutical formulations (e.g., extended release pharmaceutical formulations; e.g., solid dosage forms, e.g., tablets) that are useful for the oral administration of oprozomib, or a pharmaceutically acceptable salt thereof, to a human or animal subject as well as methods of making and using the formulations.

1 - 46 . (canceled) 
     
     
         47 . An oral formulation comprising oprozomib or pharmaceutically acceptable salt thereof present in an amount of 15 wt % to 60 wt %; one or more fillers present in an amount of 40 wt % to 70 wt %; one or more surfactants present in an amount of 0.5 wt % to 1.5 wt %; one or more lubricants present in an amount of 0.1 wt % to 1 wt %; and a matrix-forming polymer present in an amount of 3 wt % to 40 wt %. 
     
     
         48 . The formulation of  claim 47 , wherein the oral formulation is a solid dosage form. 
     
     
         49 . The formulation of  claim 48 , wherein the solid dosage form is a tablet. 
     
     
         50 . The formulation of  claim 47 , in which less than 30% of the oprozomib, or pharmaceutically acceptable salt thereof, is released after one hour, as determined by HPLC under the following dissolution conditions. 
       
         
           
                 
                 
                 
               
                     
                     
                 
                     
                   Dissolution medium 
                   pH 5.5 acetate buffer 
                 
                     
                   Media volume 
                   900 mL 
                 
                     
                   Temperature 
                   37 ± 0.5° C. 
                 
                     
                   Apparatus 
                   USP No. 2 (Paddles) 
                 
                     
                   Speed 
                   75 rpm 
                 
                     
                   Sampling Time 
                   up to 24 hours 
                 
                     
                   Infinity Point 
                   30 minutes after the last 
                 
                     
                     
                   sample 
                 
                     
                   Sampling Volume 
                   1 mL 
                 
                     
                     
                 
             
                
               
               
                
                
                
                
                
                
                
                
                
                
               
            
           
         
       
     
     
         51 . The formulation of  claim 47 , in which no more than 80% of the oprozomib, or pharmaceutically acceptable salt thereof, is released after four hours, as determined by HPLC under the following dissolution conditions. 
       
         
           
                 
                 
                 
               
                     
                     
                 
                     
                   Dissolution medium 
                   pH 5.5 acetate buffer 
                 
                     
                   Media volume 
                   900 mL 
                 
                     
                   Temperature 
                   37 ± 0.5° C. 
                 
                     
                   Apparatus 
                   USP No. 2 (Paddles) 
                 
                     
                   Speed 
                   75 rpm 
                 
                     
                   Sampling Time 
                   up to 24 hours 
                 
                     
                   Infinity Point 
                   30 minutes after the last 
                 
                     
                     
                   sample 
                 
                     
                   Sampling Volume 
                   1 mL 
                 
                     
                     
                 
             
                
               
               
                
                
                
                
                
                
                
                
                
                
               
            
           
         
       
     
     
         52 . The formulation of  claim 51 , wherein the oprozomib or pharmaceutically acceptable salt thereof comprises 20 wt % to 30 wt % of the formulation. 
     
     
         53 . The formulation of  claim 52 , wherein the oprozomib or pharmaceutically acceptable salt thereof is a crystalline solid. 
     
     
         54 . The formulation of  claim 51 , wherein the matrix-forming polymer comprises 3 wt % to 11 wt % of the formulation. 
     
     
         55 . The formulation of  claim 51 , wherein the matrix-forming polymer comprises hydroxyl propyl methylcellulose. 
     
     
         56 . The formulation of  claim 51 , wherein the one or more fillers is selected from microcrystalline cellulose, lactose monohydrate, dibasic calcium phosphate (“DCP”), sucrose, glucose, mannitol, and sorbitol. 
     
     
         57 . The formulation of  claim 51 , wherein the one or more fillers comprise microcrystalline cellulose and lactose monohydrate. 
     
     
         58 . The formulation of  claim 51 , wherein the one or more fillers comprise 60 wt % to 70 wt % of the formulation. 
     
     
         59 . The formulation of  claim 51 , wherein the one or more surfactants comprises sodium lauryl sulfate. 
     
     
         60 . The formulation of  claim 51 , wherein the one or more lubricants comprises magnesium stearate. 
     
     
         61 . The formulation of  claim 47 , wherein a single dose of the formulation to a dog produces dose-normalized peak plasma concentration (C max /D) of oprozomib of 15.2±3.3 ng*kg/mg/mL (mean standard error of the mean) for a formulation containing 100 mg of oprozomib. 
     
     
         62 . An oral formulation comprising (a) oprozomib or a pharmaceutically acceptable salt thereof, (b) a matrix-forming polymer, (c) one or more fillers, (d) one or more surfactants, and (e) one or more lubricants, in which less than 30% of the oprozomib, or pharmaceutically acceptable salt thereof, is released after one hour, as determined by HPLC under the following dissolution conditions. 
       
         
           
                 
                 
                 
               
                     
                     
                 
                     
                   Dissolution medium 
                   pH 5.5 acetate buffer 
                 
                     
                   Media volume 
                   900 mL 
                 
                     
                   Temperature 
                   37 ± 0.5° C. 
                 
                     
                   Apparatus 
                   USP No. 2 (Paddles) 
                 
                     
                   Speed 
                   75 rpm 
                 
                     
                   Sampling Time 
                   up to 24 hours 
                 
                     
                   Infinity Point 
                   30 minutes after the last 
                 
                     
                     
                   sample 
                 
                     
                   Sampling Volume 
                   1 mL 
                 
                     
                     
                 
             
                
               
               
                
                
                
                
                
                
                
                
                
                
               
            
           
         
       
     
     
         63 . The formulation of  claim 62 , wherein the oprozomib or pharmaceutically acceptable salt thereof comprises 20 wt % to 30 wt % of the formulation. 
     
     
         64 . The formulation of  claim 62 , wherein the matrix-forming polymer is 3 wt % to 11 wt % of the formulation. 
     
     
         65 . The formulation of  claim 64 , wherein the matrix forming polymer comprises hydroxyl propyl methylcellulose. 
     
     
         66 . The formulation of  claim 62 , wherein the one or more fillers comprise 60 wt % to 70 wt % of the formulation. 
     
     
         67 . The formulation of  claim 66 , wherein the one or more fillers comprise microcrystalline cellulose and lactose monohydrate.