Pharmaceutical formulations for sustained release of sebacoyl dinalbuphine ester

Abstract

The present invention relates to injectable, extended-release, pharmaceutical formulations comprising a nalbuphine ester prodrug homogenously dissolved in a solution comprising a pharmaceutically acceptable oil and an oil-miscible retaining solvent, as well as manufacturing processes and medical uses of the formulations. The invention further provides methods for adjusting the duration of action of the formulations by varying the ratio of the pharmaceutically acceptable oil and the oil-miscible retaining solvent.

1 - 40 . (canceled) 
     
     
         41 . An extended release pharmaceutical formulation comprising sebacoyl dinalbuphine ester (SDE), benzyl benzoate, and sesame oil, wherein:
 the weight ratio of the benzyl benzoate to the sesame oil is about 1.1:1;   the concentration of the SDE in the formulation is at least about 75 mg/mL; and   the formulation is a homogeneous solution substantially free of solid particles and suitable for administration to a human subject by intramuscular injection of a single dose having a volume of less than about 5 mL.   
     
     
         42 . The extended release pharmaceutical formulation of  claim 41 , wherein the volume is about 1 mL to about 4 mL. 
     
     
         43 . The extended release pharmaceutical formulation of  claim 42 , wherein the volume is about 2 mL to about 4 mL. 
     
     
         44 . The extended release pharmaceutical formulation of  claim 42 , wherein the volume is about 2 mL. 
     
     
         45 . The extended release pharmaceutical formulation of  claim 42 , wherein the volume is about 3 mL. 
     
     
         46 . The extended release pharmaceutical formulation of  claim 42 , wherein the volume is about 4 mL. 
     
     
         47 . The extended release pharmaceutical formulation of  claim 41 , wherein the concentration of the SDE in the formulation is about 75 mg/mL. 
     
     
         48 . The extended release pharmaceutical formulation of  claim 41 , wherein the single dose comprises about 75 mg to about 300 mg of SDE. 
     
     
         49 . The extended release pharmaceutical formulation of  claim 48 , wherein the single dose comprises about 150 mg to about 300 mg of SDE. 
     
     
         50 . The extended release pharmaceutical formulation of  claim 48 , wherein the single dose comprises about 150 mg of SDE. 
     
     
         51 . The extended release pharmaceutical formulation of  claim 48 , wherein the single dose comprises about 225 mg of SDE. 
     
     
         52 . The extended release pharmaceutical formulation of  claim 48 , wherein the single dose comprises about 300 mg of SDE. 
     
     
         53 . The extended release pharmaceutical formulation of  claim 41 , wherein the weight ratio of the benzyl benzoate to the sesame oil is about 1.12:1. 
     
     
         54 . The extended release pharmaceutical formulation of  claim 53 , wherein the concentration of the SDE in the formulation is about 75 mg/mL. 
     
     
         55 . The extended release pharmaceutical formulation of  claim 41 , wherein the formulation is prepared by:
 (1) dissolving the SDE in the benzyl benzoate; and   (2) mixing the resulting solution with the sesame oil to obtain a homogeneous solution.   
     
     
         56 . The extended release pharmaceutical formulation of  claim 55 , wherein the homogeneous solution is sterilized by filtration. 
     
     
         57 . The extended release pharmaceutical formulation of  claim 41 , wherein the formulation does not comprise precipitates or solid particles. 
     
     
         58 . The extended release pharmaceutical formulation of  claim 41 , wherein the formulation remains homogeneous at 2-8° C. for at least 6 months. 
     
     
         59 . The extended release pharmaceutical formulation of  claim 58 , wherein the formulation remains homogenous after one or more freeze-thaw cycles.