Pharmaceutical compositions and dosage forms for administration of hydrophobic drugs

Abstract

Pharmaceutical compositions and dosage forms for administration of hydrophobic drugs, particularly fenofibrate, are provided. The compositions comprise a therapeutically effective amount of an active agent and a solubilizer. The solubilizer is selected to effectively solubilize active agent in the composition. The solubilizers employed as part of the invention include: a vitamin E substance; monohydric alcohol esters such as trialkyl citrates, lactones and lower alcohol fatty acid esters; nitrogen-containing solvents; phospholipids; glycerol acetates such as acetin, diacetin and triacetin; glycerol fatty acid esters such as mono-, di- and triglycerides and acetylated mono- and diglycerides; propylene glycol esters; ethylene glycol esters; and combinations thereof. The pharmaceutical dosage forms contain the compositions in a suitable dosage form unit such as a capsule. Methods of treating patients comprising administering the compositions are also provided.

1 - 98 . (canceled)  
     
     
         99 . A pharmaceutical composition for oral administration of fenofibrate, comprising: 
 a therapeutically effective amount of fenofibrate, which is not co-micronized with a solid surfactant; and    a solubilizer admixed with the fenofibrate, said solubilizer comprising tocopherol and a member selected from the group consisting of glycerol fatty acid esters; Vitamin E substances; propylene glycol esters; ethylene glycol esters; lower alcohol fatty acid esters; glycerol acetates and acetylated glycerol fatty acid esters; and mixtures thereof.    
     
     
         100 . The composition of  claim 99 , wherein the ethylene glycol ester is a transesterification product of polyethylene glycol with a triglyceride.  
     
     
         101 . The composition of  claim 99 , wherein the ethylene glycol ester is a transesterification product of polyethylene glycol with a vegetable oil.  
     
     
         102 . The composition of  claim 99 , wherein the Vitamin E substance is alpha-tocopheryl polyethylene glycol 1000 succinate.  
     
     
         103 . The composition of  claim 99 , wherein the glycerol fatty acid ester is a mono-, di-, or triglyceride.  
     
     
         104 . The composition of  claim 103 , wherein the glycerol fatty acid ester is a monoglyceride formed by esterification of glycerol and a fatty acid having about 6-22 carbons.  
     
     
         105 . The composition of  claim 103 , wherein the glycerol fatty acid ester is a diglyceride formed by esterification of glycerol and fatty acids having about 6-22 carbons.  
     
     
         106 . The composition of  claim 103 , wherein the glycerol fatty acid ester is a triglyceride formed by esterification of glycerol and fatty acids having about 6-22 carbons.  
     
     
         107 . The composition of any of  claims 103  to  106 , wherein the fatty acids have about 6-12 carbons.  
     
     
         108 . The composition of  claim 99 , wherein the propylene glycol ester is a propylene glycol monoester with a fatty acid having about 6-22 carbons.  
     
     
         109 . The composition of  claim 99 , wherein the propylene glycol ester is a propylene glycol diester with a fatty acid having about 6-22 carbons.  
     
     
         110 . The composition of  claim 99 , wherein the lower alcohol fatty acid ester is a polyethoxylated sorbitan monooleate.  
     
     
         111 . The composition of  claim 99 , wherein the acetylated glycerol fatty acid ester is an acetylated monoglyceride.  
     
     
         112 . The composition of  claim 99 , wherein the acetylated glycerol fatty acid ester is an acetylated diglyceride.  
     
     
         113 . The composition of  claim 99 , wherein the tocopherol is alpha-tocopherol.  
     
     
         114 . The composition of  claim 99 , wherein the tocopherol is dl-alpha-tocopherol.  
     
     
         115 . The composition of  claim 99 , wherein the fenofibrate is solubilized in the composition.  
     
     
         116 . The composition of  claim 99 , wherein the fenofibrate is about 75% solubilized in the composition.  
     
     
         117 . The composition of  claim 99 , wherein the fenofibrate is about 50% solubilized in the composition.  
     
     
         118 . A pharmaceutical composition for oral administration of fenofibrate, comprising: 
 a therapeutically effective amount of fenofibrate; and    a solubilizer comprising a tocopherol, wherein the composition provides in-vivo absorption of fenofibrate that is substantially independent of lipolysis.    
     
     
         119 . The composition of  claim 118 , wherein the fenofibrate is not co-micronized with a solid surfactant.  
     
     
         120 . The composition of  claim 118 , wherein the solubilizer further comprises at least one member selected from the group consisting of glycerol fatty acid esters; Vitamin E substances; propylene glycol esters; ethylene glycol esters; lower alcohol fatty acid esters; glycerol acetates and acetylated glycerol fatty acid esters; and mixtures thereof.  
     
     
         121 . The composition of  claim 120 , wherein the ethylene glycol ester is a transesterification product of polyethylene glycol with a triglyceride.  
     
     
         122 . The composition of  claim 120 , wherein the ethylene glycol ester is a transesterification product of polyethylene glycol with a vegetable oil.  
     
     
         123 . The composition of  claim 120 , wherein the Vitamin E substance is alpha-tocopheryl polyethylene glycol 1000 succinate.  
     
     
         124 . The composition of  claim 120 , wherein the glycerol fatty acid ester is a mono-, di-, or triglyceride.  
     
     
         125 . The composition of  claim 124 , wherein the glycerol fatty acid ester is a monoglyceride formed by esterification of glycerol and a fatty acid having about 6-22 carbons.  
     
     
         126 . The composition of  claim 124 , wherein the glycerol fatty acid ester is a diglyceride formed by esterification of glycerol and fatty acids having about 6-22 carbons.  
     
     
         127 . The composition of  claim 124 , wherein the glycerol fatty acid ester is a triglyceride formed by esterification of glycerol and fatty acids having about 6-22 carbons.  
     
     
         128 . The composition of any of  claims 124  to  127 , wherein the fatty acids have about 6-12 carbons.  
     
     
         129 . The composition of  claim 120 , wherein the propylene glycol ester is a propylene glycol monoester with a fatty acid having about 6-22 carbons.  
     
     
         130 . The composition of  claim 120 , wherein the propylene glycol ester is a propylene glycol diester with a fatty acid having about 6-22 carbons.  
     
     
         131 . The composition of  claim 120 , wherein the lower alcohol fatty acid ester is a polyethoxylated sorbitan monooleate.  
     
     
         132 . The composition of  claim 120 , wherein the acetylated glycerol fatty acid ester is an acetylated monoglyceride.  
     
     
         133 . The composition of  claim 120 , wherein the acetylated glycerol fatty acid ester is an acetylated diglyceride.  
     
     
         134 . The composition of  claim 118 , wherein the tocopherol increases solubilization of the fenofibrate upon contact with an aqueous medium.  
     
     
         135 . A pharmaceutical composition for oral administration of fenofibrate, comprising: 
 a therapeutically effective amount of fenofibrate; and    a solubilizer comprising a tocopherol which increases solubilization of the fenofibrate upon contact with an aqueous medium.    
     
     
         136 . The composition of  claim 135 , wherein the fenofibrate not co-micronized with a solid surfactant.  
     
     
         137 . The composition of  claim 135 , wherein the solubilizer further comprises at least one member selected from the group consisting of glycerol fatty acid esters; Vitamin E substances; propylene glycol esters; ethylene glycol esters; lower alcohol fatty acid esters; glycerol acetates and acetylated glycerol fatty acid esters; and mixtures thereof.  
     
     
         138 . The composition of  claim 137 , wherein the ethylene glycol ester is a transesterification product of polyethylene glycol with a triglyceride.  
     
     
         139 . The composition of  claim 137 , wherein the ethylene glycol ester is a transesterification product of polyethylene glycol with a vegetable oil.  
     
     
         140 . The composition of  claim 137 , wherein the Vitamin E substance is alpha-tocopheryl polyethylene glycol 1000 succinate.  
     
     
         141 . The composition of  claim 137 , wherein the glycerol fatty acid ester is a mono-, di-, or triglyceride.  
     
     
         142 . The composition of  claim 141 , wherein the glycerol fatty acid ester is a monoglyceride formed by esterification of glycerol and a fatty acid having about 6-22 carbons.  
     
     
         143 . The composition of  claim 141 , wherein the glycerol fatty acid ester is a diglyceride formed by esterification of glycerol and fatty acids having about 6-22 carbons.  
     
     
         144 . The composition of  claim 141 , wherein the glycerol fatty acid ester is a triglyceride formed by esterification of glycerol and fatty acids having about 6-22 carbons.  
     
     
         145 . The composition of any of  claims 141  to  144 , wherein the fatty acids have about 6-12 carbons.  
     
     
         146 . The composition of  claim 137 , wherein the propylene glycol ester is a propylene glycol monoester with a fatty acid having about 6-22 carbons.  
     
     
         147 . The composition of  claim 137 , wherein the propylene glycol ester is a propylene glycol diester with a fatty acid having about 6-22 carbons.  
     
     
         148 . The composition of  claim 137 , wherein the lower alcohol fatty acid ester is a polyethoxylated sorbitan monooleate.  
     
     
         149 . The composition of  claim 137 , wherein the acetylated glycerol fatty acid ester is an acetylated monoglyceride.  
     
     
         150 . The composition of  claim 137 , wherein the acetylated glycerol fatty acid ester is an acetylated diglyceride.  
     
     
         151 . A pharmaceutical composition, comprising a preconcentrate in a capsule having included therein: 
 a therapeutically effective amount of fenofibrate, which is not co-micronized with a solid surfactant; and    a solubilizer admixed with the fenofibrate, said solubilizer comprising tocopherol and a member selected from the group consisting of glycerol fatty acid esters; Vitamin E substances; propylene glycol esters; ethylene glycol esters; lower alcohol fatty acid esters; glycerol acetates and acetylated glycerol fatty acid esters; and mixtures thereof, wherein the solubilizer increases solubilization of the fenofibrate upon contact with an aqueous medium, and the preconcentrate being substantially free of water.    
     
     
         152 . The pharmaceutical composition of  claim 151 , wherein the composition provides in vivo absorption of fenofibrate that is substantially independent of lipolysis.  
     
     
         153 . The pharmaceutical composition of  claim 151 , wherein the capsule is a hard capsule.  
     
     
         154 . The pharmaceutical composition of  claim 151 , wherein the capsule is a soft capsule.  
     
     
         155 . The pharmaceutical composition of  claim 151 , wherein the capsule is comprised of a member selected from the group consisting of a gelatin, a starch, a cellulosic material, or mixtures thereof.