Solid dispersion formulations and methods of use thereof

Abstract

The present invention relates to formulations and methods for increasing the bioavailability of 1-(4-benzhydrylpiperazin-1-yl)-3,3-diphenylpropan-1-one, 1-(3,3-diphenylpropanoyl)piperazine, or a salt thereof. In particular, the formulation can include one or more pharmaceutically acceptable matrix polymers to form a solid dispersion, e.g., a spray dried dispersion or a hot melt extrusion.

What is claimed is: 
     
         1 . A pharmaceutical composition in unit dosage form for oral administration comprising a solid dispersion of from about 20 mg to about 250 mg of substantially amorphous 1-(4-benzhydrylpiperazin-1-yl)-3,3-diphenylpropan-1-one in a matrix polymer, wherein the percentage loading of said 1-(4-benzhydrylpiperazin-1-yl)-3,3-diphenylpropan-1-one in said solid dispersion is from about 10% to about 80% (w/w). 
     
     
         2 . The pharmaceutical composition of  claim 1 , wherein, following administration of said pharmaceutical composition to subjects, the ratio of the mean bioavailability for fed subjects to the mean bioavailability for fasted subjects is from about 1.0 to about 2.0; or wherein, following administration of said pharmaceutical composition to fasted subjects, the mean bioavailability is greater than about 20%; or wherein, following administration of said pharmaceutical composition to subjects, the ratio of the mean bioavailability for fed subjects to the mean bioavailability for fasted subjects is from about 1.0 to about 2.0; or wherein administration of said pharmaceutical composition to fed and fasted subjects produces a coefficient of variation in C max  of less than about 60%; or wherein administration of said pharmaceutical composition to fasted subjects produces a coefficient of variation in C max  of less than about 65%; or wherein administration of said pharmaceutical composition to fed subjects produces a coefficient of variation in C max  of less than about 65%; or wherein administration of said pharmaceutical composition to fed and fasted subjects produces a coefficient of variation in AUC ∞  of less than about 60%; or wherein administration of said pharmaceutical composition to fasted subjects produces a coefficient of variation in AUC ∞  of less than about 65%; or wherein administration of said pharmaceutical composition to fed subjects produces a coefficient of variation in AUC ∞  of less than about 65%. 
     
     
         3 . The pharmaceutical composition of  claim 1 , wherein the percentage loading of said 1-(4-benzhydrylpiperazin-1-yl)-3,3-diphenylpropan-1-one is of from about 10% to about 80% (w/w). 
     
     
         4 . The pharmaceutical composition of  claim 1 , wherein the weight ratio of said 1-(4-benzhydrylpiperazin-1-yl)-3,3-diphenylpropan-1-one to said pharmaceutically acceptable matrix polymer is from about 1:6 to about 1:1.5. 
     
     
         5 . The pharmaceutical composition of  claim 1 , wherein said pharmaceutically acceptable matrix polymer comprises a polymer selected from the group consisting of a cellulose derivative, a polyacrylate, a polyvinyl pyrrolidone, a polyvinyl acetate, or a copolymer of a polyvinyl pyrrolidone and a polyvinyl acetate. 
     
     
         6 . The pharmaceutical composition of  claim 5 , wherein said matrix polymer is said cellulose derivative selected from the group consisting of a cellulose acetate having from about 10% to about 50% acetyl, an alkyl cellulose, a hydroxyalkyl cellulose, a hydroxyalkylalkyl cellulose, a hydroxyalkylalkyl cellulose ester, a carboxyalkyl cellulose, a carboxyalkylalkyl cellulose, and a carboxyalkyl cellulose ester. 
     
     
         7 . The pharmaceutical composition of  claim 6 , wherein said cellulose acetate is selected from the group consisting of cellulose acetate phthalate (CAP), methylcellulose acetate phthalate, hydroxypropylmethyl cellulose acetate, and hydroxypropylmethyl cellulose acetate succinate (HPMCAS). 
     
     
         8 . The pharmaceutical composition of  claim 5 , wherein said matrix polymer is said polyvinyl acetate selected from the group consisting of a polyvinyl acetate ester and a polyethylene glycol-polyvinylcaprolactam-polyvinylacetate copolymer. 
     
     
         9 . The pharmaceutical composition of  claim 8 , wherein said polyvinyl acetate ester is polyvinylacetate phthalate (PVAP). 
     
     
         10 . The pharmaceutical composition of  claim 1 , further comprising a plasticizer or a surfactant. 
     
     
         11 . The pharmaceutical composition of  claim 1 , wherein the solid dispersion is formed by spray drying a liquid mixture comprising said 1-(4-benzhydrylpiperazin-1-yl)-3,3-diphenylpropan-1-one and said pharmaceutically acceptable matrix polymer. 
     
     
         12 . The pharmaceutical composition of  claim 1 , wherein the solid dispersion is formed by hot melt extrusion of a mixture comprising said 1-(4-benzhydrylpiperazin-1-yl)-3,3-diphenylpropan-1-one and said pharmaceutically acceptable matrix polymer. 
     
     
         13 . The pharmaceutical composition of  claim 1 , wherein said unit dosage form is a tablet, hard gelatin capsule, a hard hydroxypropyl methylcellulose capsule, or a soft gelatin capsule. 
     
     
         14 . The pharmaceutical composition of  claim 1 , wherein said unit dosage form comprises from about 70 mg to about 250 mg of 1-(4-benzhydrylpiperazin-1-yl)-3,3-diphenylpropan-1-one. 
     
     
         15 . A method for reducing the food effect exhibited by 1-(4-benzhydrylpiperazin-1-yl)-3,3-diphenylpropan-1-one following administration to a subject, said method comprising administering a unit dosage form comprising the pharmaceutical composition of  claim 1  to said subject. 
     
     
         16 . A method to treat a disease or condition, said method comprising administering to a subject in need of such treatment an effective amount of the pharmaceutical composition of  claim 1 . 
     
     
         17 . The method of  claim 16 , wherein said subject is a fasted subject or a fed subject. 
     
     
         18 . The method of  claim 16 , wherein said condition is pain. 
     
     
         19 . A method of preparing a pharmaceutical composition of  claim 1 , said method comprising:
 preparing a mixture or a solution comprising 1-(4-benzhydrylpiperazin-1-yl)-3,3-diphenylpropan-1-one and a pharmaceutically acceptable matrix polymer; and   spray drying said mixture or said solution to form a solid dispersion.   
     
     
         20 . A method of preparing a pharmaceutical composition of  claim 1 , said method comprising:
 preparing a mixture or a solution comprising 1-(4-benzhydrylpiperazin-1-yl)-3,3-diphenylpropan-1-one and a pharmaceutically acceptable matrix polymer;   heating said mixture to form a homogenous molten mass;   extruding said molten mass; and   cooling said molten mass to form a solid dispersion.